fumarates and Psoriasis

The persistence and effectiveness of systemic therapies for moderate-to-severe psoriasis in current clinical practice are poorly characterized.. To systematically review observational studies investigating the persistence and effectiveness of acitretin, ciclosporin, fumaric acid esters (FAE) and methotrexate, involving at least 100 adult patients with moderate-to-severe psoriasis, exposed to therapy for ≥ 3 months.. MEDLINE, Embase, the Cochrane Library and PubMed were searched from 1 January 2007 to 1 November 2017 for observational studies reporting on persistence (therapy duration or the proportion of patients discontinuing therapy during follow-up) or effectiveness [improvements in Psoriasis Area and Severity Index (PASI) or Physician's Global Assessment (PGA)]. This review was registered with PROSPERO, number CRD42018099771.. Of 411 identified studies, eight involving 4624 patients with psoriasis were included. Variations in the definitions and analyses of persistence and effectiveness outcomes prevented a meta-analysis from being conducted. One prospective multicentre study reported drug survival probabilities of 23% (ciclosporin), 42% (acitretin) and 50% (methotrexate) at 1 year. Effectiveness outcomes were not reported for either acitretin or ciclosporin. The persistence and effectiveness of FAE and methotrexate were better characterized, but mean discontinuation times ranged from 28 to 50 months for FAE and 7·7 to 22·3 months for methotrexate. At 12 months of follow-up, three studies reported that 76% (FAE), 53% (methotrexate) and 59% (methotrexate) of patients achieved ≥ 75% reduction in PASI, and one reported that 76% of FAE-exposed patients achieved a markedly improved or clear PGA.. The comparative persistence and effectiveness of acitretin, ciclosporin, FAE and methotrexate in real-world clinical practice in the past decade cannot be well described due to the inconsistency of the methods used.

Topics: Acitretin; Adult; Cyclosporine; Dermatologic Agents; Drug Therapy, Combination; Fumarates; Humans; Methotrexate; Multicenter Studies as Topic; Observational Studies as Topic; Psoriasis; Severity of Illness Index; Treatment Outcome

Fumarates (fumaric acid esters, FAEs) are orally administered systemic agents used for the treatment of psoriasis and multiple sclerosis. In 1994, a proprietary combination of FAEs was licensed for psoriasis by the German Drug Administration for use within Germany. Since then, fumarates have been established as one of the most commonly used treatments for moderate-to-severe psoriasis in Germany and other countries. The licensed FAE formulation contains dimethyl fumarate (DMF), as well as calcium, zinc, and magnesium salts of monoethyl fumarate (MEF). While the clinical efficacy of this FAE mixture is well established, the combination of esters on which it is based, and its dosing regimen, was determined empirically. Since the mid-1990s, the modes of action and contribution of the different FAEs to their overall therapeutic effect in psoriasis, as well as their adverse event profile, have been investigated in more detail. In this article, the available clinical data for DMF are reviewed and compared with data for the other FAEs. The current evidence substantiates that DMF is the main active compound, via its metabolic transformation to monomethyl fumarate (MMF). A recent phase III randomized and placebo-controlled trial including more than 700 patients demonstrated therapeutic equivalence when comparing the licensed FAE combination with DMF alone, in terms of psoriasis clearance according to the Psoriasis Area and Severity Index (PASI) and Physician's Global Assessment (PGA). Thus, DMF as monotherapy for the treatment of psoriasis is as efficacious as in combination with MEF, making the addition of such fumarate derivatives unnecessary.

Topics: Dermatologic Agents; Dimethyl Fumarate; Drug Therapy, Combination; Fumarates; Germany; Humans; Psoriasis; Randomized Controlled Trials as Topic; Severity of Illness Index; Treatment Outcome

Psoriasis is a chronic skin disease associated with increased morbidity and mortality. Effective and safe long term treatment options are required to manage the illness successfully. A number of systemic agents are available, however, each of them has potentially significant side effects. Fumaric acid esters (FAE) are used first line in Germany for the management of moderate to severe psoriasis, however, their use in Ireland is on an unlicensed basis (Clinical and Experimental Dermatology 37:786-801, 2012).. The purpose of this literature review is to evaluate the efficacy and safety of FAEs in the management of moderate to severe psoriasis in adult patients. The reviewer intends to systematically review all available literature on the efficacy and/or safety of fumaric acid esters in the management of moderate to severe psoriasis in adult patients.. A systematic review of the literature was performed by one reviewer. The PubMed, TRIP, Embase, and Cochrane Collaboration databases were systematically interrogated to include randomised controlled trials, cohort studies and case studies evaluating the efficacy and/or safety of FAEs in the management of moderate to severe psoriasis in adult patients. Inclusion criteria were studies which included adults over 18 years of age, with a diagnosis of moderate to severe chronic plaque psoriasis, who were treated with FAEs and no other systemic anti-psoriatic agents concurrently. Exclusion criteria were studies involving children, mild psoriasis, studies which did not include patients with chronic plaque psoriasis, the use of FAE for the management of illnesses other than psoriasis, and patients treated with more than one systemic anti-psoriatic agent concurrently.. In total 19 articles were selected for review including 2 randomised placebo controlled trials, 1 non-randomised comparative study, 7 retrospective cohort studies, 2 prospective cohort studies and 7 case studies. The findings suggest that FAEs are a safe and effective treatment option for the management of moderate to severe psoriasis in adult patients. Gastrointestinal side effects may occur on treatment initiation and may be minimised by slow dose titration. Lymphocytopenia and eosinophilia are common, however, they are rarely of significance and there is no high level of evidence available to suggest a resultant increased risk of infection or malignancy. Rarely alterations of renal and hepatic function may occur, however, these are largely reversible on treatment withdrawal.. In conclusion, the use of FAE in the management of moderate to severe psoriasis is a promising treatment option, especially for those patients intolerant of, or unresponsive to other agents. If blood parameters are closely monitored during treatment as per the European Medicine Agencies guidelines (European Medicines Agency, 'Updated recommendations to minimise the risk of the rare brain infection PML with Tecfidera', http://www.ema.europa.eu/docs/en_GB/document_library/Press_release/2015/10/WC500196017.pdf , 2015) they may be safely used in practice. The licensing of FAEs in Ireland for the treatment of moderate to severe psoriasis would be desirable, increasing available treatment options.

Topics: Adult; Chronic Disease; Dermatologic Agents; Fumarates; Germany; Humans; Ireland; Psoriasis; Treatment Outcome

Fumaric acid esters (FAEs) are increasingly used as a systemic treatment for psoriasis, but there are still uncertainties regarding their suitability. The objective of this systematic review was to assess the evidence for the efficacy and safety of FAEs in psoriasis treatment. A systematic literature search was performed in seven databases up to 17 August 2015. Inclusion criteria were studies that reported clinical effects of FAEs in patients with psoriasis without restrictions in study design, language or publication date. Methodological quality of randomized controlled trials (RCTs) and overall level of quality were assessed using the Cochrane risk of bias tool and the Grading of Recommendation, Assessment, Development and Evaluation approach, respectively. A total of 68 articles were included. There were seven RCTs (total 449 patients) that had an unclear risk of bias and were too clinically heterogeneous to allow a meta-analysis. Overall, mean Psoriasis Area and Severity Index decreased by 42-65% following 12-16 weeks of treatment. There were 37 observational studies (a total of 3457 patients) that supported the RCT findings, but most were uncontrolled with a high risk of bias. Commonly reported adverse events included gastrointestinal complaints and flushing, leading to treatment withdrawal in 6-40% of patients. Several case-reports described rare adverse events, such as renal Fanconi syndrome and progressive multifocal leukoencephalopathy. There was a lack of studies focusing on long-term use and comparisons with other treatments. This review concluded that there is low-quality evidence to recommend the use of oral FAEs to treat plaque psoriasis in adult patients. Studies focusing on long-term safety and comparison with systemic psoriasis treatments could lead to a better understanding of the role of FAEs as a treatment for psoriasis.

Topics: Dermatologic Agents; Fumarates; Humans; Observational Studies as Topic; Patient Safety; Psoriasis; Randomized Controlled Trials as Topic; Treatment Outcome

Several lines of evidence have demonstrated the potential biomedical applications of fumaric acid (FA) and its ester derivatives against many human disease conditions. Fumaric acid esters (FAEs) have been licensed for the systemic treatment of the immune-mediated disease psoriasis. Biogen Idec Inc. announced about the safety and efficacy of the formulation FAE (BG-12) for treating RRMS (relapsing-remitting multiple sclerosis). Another FAE formulation DMF (dimethyl fumarate) was found to be capable of reduction in inflammatory cardiac conditions, such as autoimmune myocarditis and ischemia and reperfusion. DMF has also been reported to be effective as a potential neuroprotectant against the HIV-associated neurocognitive disorders (HAND). Many in vivo studies carried out on rat and mice models indicated inhibitory effects of fumaric acid on carcinogenesis of different origins. Moreover, FAEs has emerged as an important matrix ingredient in the fabrication of biodegradable scaffolds for tissue engineering applications. Drug delivery vehicles composed of FAEs have shown promising results in delivering some leading drug molecules. Apart from these specific applications and findings, many more studies on FAEs have revealed new therapeutic potentials with the scope of clinical applications. However, until now, this scattered vital information has not been written into a collective account and analyzed for minute details. The aim of this paper is to review the advancement made in the biomedical application of FA and FAEs and to focus on the clinical investigation and molecular interpretation of the beneficial effects of FA and FAEs.

Topics: Animals; Dimethyl Fumarate; Esters; Fumarates; Humans; Multiple Sclerosis, Relapsing-Remitting; Neuroprotective Agents; Psoriasis

Fumaric acid esters (FAEs) are licensed for the treatment of moderate-to-severe psoriasis in Germany but are also used off-label in many other countries. We conducted this systematic review to synthesize the highest-quality evidence for the benefits and risks of FAEs for psoriasis. Our primary outcomes were change in Psoriasis Area and Severity Index score and dropout rates due to adverse effects. Randomized controlled trials (RCTs) of FAEs or dimethylfumarate were included, with no restriction on age or psoriasis subtype. We searched the Cochrane Skin Group Specialised Register, CENTRAL in the Cochrane Library, Medline, Embase, LILACS and five trials registers, and hand searched six conference proceedings. Six RCTs with a total of 544 participants were included, four of which were published only as abstracts or brief reports, limiting study reporting. Five RCTs compared FAEs with placebo, and all demonstrated benefit in favour of FAEs. However, meta-analysis was possible only for PASI 50 response after 12-16 weeks, which was achieved by 64% of participants on FAEs compared with 14% on placebo: risk ratio (RR) 4·55, 95% confidence interval (CI) 2·80-7·40; two studies; 247 participants; low-quality evidence). There was no difference in dropout rates due to adverse effects (RR 5·36, 95% CI 0·28-102·12; one study; 27 participants; very low-quality evidence and wide CI). More participants experienced nuisance adverse effects with FAEs (76%) than with placebo (16%) (RR 4·72, 95% CI 2·45-9·08; one study; 99 participants; moderate-quality evidence), mainly abdominal pain, diarrhoea and flushing. One head-to-head study of very low-quality evidence comparing FAEs with methotrexate reported comparable efficacy and dropout rates, although FAEs caused more flushing. The evidence in this review was limited and must be interpreted with caution; studies with better design and outcome reporting are needed.

Topics: Administration, Oral; Dermatologic Agents; Fumarates; Humans; Methotrexate; Placebos; Psoriasis; Quality of Life; Randomized Controlled Trials as Topic; Treatment Outcome

There is evidence that patients with moderate to severe psoriasis have an increased risk of conditions such as cardiovascular disease, obesity, diabetes mellitus, and metabolic syndrome. The precise mechanisms underlying the observed increase in cardiovascular disease in psoriasis remain to be defined but inflammatory pathways mutual to both conditions are probably involved. Suppression of systemic inflammation in psoriasis could help reduce cardiovascular inflammation but robust evidence is still lacking evidence is lacking. This article summarizes the current literature on cardiovascular and metabolic comorbidities in psoriasis, identifies research gaps, and suggests management strategies to reduce cardiovascular risk in patients with moderate to severe psoriasis.

Topics: Acitretin; Adipokines; Alcoholism; Antibodies, Monoclonal, Humanized; Cardiovascular Diseases; Comorbidity; Cyclosporine; Dermatologic Agents; Diabetes Mellitus; Fumarates; Humans; Immunosuppressive Agents; Inflammation; Metabolic Syndrome; Methotrexate; Obesity; Psoriasis; Risk Factors; Smoking; Tumor Necrosis Factor-alpha; Ustekinumab

For patients with moderate to severe psoriasis, there is a large range of variably effective and safe oral, systemic medications. With appropriate monitoring, these therapies may be used as either monotherapy or in combination with other therapies. Newer drugs in the research pipeline hold significant promise.

Topics: Acitretin; Anti-Inflammatory Agents, Non-Steroidal; Antimetabolites; Cyclosporine; Fumarates; Humans; Hydroxyurea; Immunosuppressive Agents; Isoxazoles; Keratolytic Agents; Leflunomide; Methotrexate; Mycophenolic Acid; Piperidines; Protein Kinase Inhibitors; Psoriasis; Pyrimidines; Pyrroles; Sulfasalazine; Thalidomide; Thioguanine

Psoriasis is a chronic inflammatory skin condition that can markedly reduce life quality. Several systemic therapies exist for moderate to severe psoriasis, including oral fumaric acid esters (FAE). These contain dimethyl fumarate (DMF), the main active ingredient, and monoethyl fumarate. FAE are licensed for psoriasis in Germany but used off-licence in many countries.. To assess the effects and safety of oral fumaric acid esters for psoriasis.. We searched the following databases up to 7 May 2015: the Cochrane Skin Group Specialised Register, CENTRAL in the Cochrane Library (Issue 4, 2015), MEDLINE (from 1946), EMBASE (from 1974), and LILACS (from 1982). We searched five trials registers and checked the reference lists of included and excluded studies for further references to relevant randomised controlled trials. We handsearched six conference proceedings that were not already included in the Cochrane Skin Group Specialised Register.. Randomised controlled trials (RCTs) of FAE, including DMF monotherapy, in individuals of any age and sex with a clinical diagnosis of psoriasis.. Two review authors independently assessed trial quality and extracted data. Primary outcomes were improvement in Psoriasis Area and Severity Index (PASI) score and the proportion of participants discontinuing treatment due to adverse effects.. We included 6 studies (2 full reports, 2 abstracts, 1 brief communication, and 1 letter), with a total of 544 participants. Risk of bias was unclear in several studies because of insufficient reporting. Five studies compared FAE with placebo, and one study compared FAE with methotrexate. All studies reported data at 12 to 16 weeks, and we identified no longer-term studies. When FAE were compared with placebo, we could not perform meta-analysis for the primary outcome of PASI score because the three studies that assessed this outcome reported the data differently, although all studies reported a significant reduction in PASI scores with FAE. Only 1 small study designed for psoriatic arthritis reported on the other primary outcome of participants discontinuing treatment due to adverse effects (2 of 13 participants on FAE compared with none of the 14 participants on placebo; risk ratio (RR) 5.36, 95% confidence interval (CI) 0.28 to 102.1; 27 participants; very low-quality evidence). However, these findings are uncertain due to indirectness and a very wide confidence interval. Two studies, containing 247 participants and both only reported as abstracts, allowed meta-analysis for PASI 50, which showed superiority of FAE over placebo (RR 4.55, 95% CI 2.80 to 7.40; low-quality evidence), with a combined PASI 50 of 64% in those given FAE compared with a PASI 50 of 14% for those on placebo, representing a number needed to treat to benefit of 2. The same studies reported more participants achieving PASI 75 with FAE, but we did not pool the data because of significant heterogeneity; none of the studies measured PASI 90. One study reported significant improvement in participants' quality of life (QoL) with FAE, measured with Skindex-29. However, we could not compute the mean difference because of insufficient reporting in the abstract. More participants experienced adverse effects, mainly gastrointestinal disturbance and flushing, on FAE (RR 4.72, 95% CI 2.45 to 9.08; 1 study, 99 participants; moderate-quality evidence), affecting 76% of participants given FAE and 16% of the placebo group (representing a number needed to treat to harm of 2). The other studies reported similar findings or did not report adverse effects fully.One study of 54 participants compared methotrexate (MTX) with FAE. PASI score at follow-up showed superiority of MTX (mean Difference (MD) 3.80, 95% CI 0.68 to 6.92; 51 participants; very low-quality evidence), but the difference was not signific. Evidence suggests that FAE are superior to placebo and possibly similar in efficacy to MTX for psoriasis; however, the evidence provided in this review was limited, and it must be noted that four out of six included studies were abstracts or brief reports, restricting study reporting. FAE are associated with nuisance adverse effects, including flushing and gastrointestinal disturbance, but short-term studies reported no serious adverse effects.

Topics: Administration, Oral; Arthritis, Psoriatic; Dermatologic Agents; Fumarates; Humans; Methotrexate; Psoriasis; Randomized Controlled Trials as Topic; Severity of Illness Index

Dermatologists may choose from various conventional and biological systemic agents to treat patients with moderate-to-severe psoriasis. We set out to analyse systematically the efficacy and tolerability of approved treatments for moderate-to-severe psoriasis. We undertook a systematic review and meta-analysis of randomized controlled trials (RCTs) investigating the efficacy of systemic treatment approved for moderate-to-severe psoriasis. Efficacy was assessed as the proportion of participants with 75% improvement in Psoriasis Area and Severity Index at primary efficacy measurement (week 8-16). Safety was summarized as rates of adverse events and withdrawals. Direct and indirect comparative efficacy was assessed by random effects meta-analysis of risk differences (RDs). In total, 48 eligible RCTs totalling 16 696 patients (11 178 randomized to biologics, 1888 to conventional treatments) were identified. In placebo-controlled trials, infliximab was the most efficacious [RD 76%, 95% confidence interval (CI) 73-79%]. Adalimumab (RD 61%, 95% CI 56-67%), and ustekinumab 45 mg (RD 63%, 95% CI 59-66%) and 90 mg (RD 67%, 95% CI 60-74%) each had similar efficacy. These biologics are more effective than etanercept and all conventional treatments. Head-to-head trials indicate the superiority of adalimumab and infliximab over methotrexate (MTX), the superiority of ustekinumab over etanercept, the nonsignificant superiority of ciclosporin over MTX, and the dose-dependent efficacy of etanercept and ustekinumab. Fumaric acid is as efficacious as MTX. Safety of treatments could not be pooled due to a lack of standardization in reporting across trials. In conclusion, the qualitative and quantitative evidence is much stronger for biological interventions than for conventional treatments.

Topics: Biological Factors; Cyclosporine; Dermatologic Agents; Fumarates; Humans; Methotrexate; Psoriasis; Randomized Controlled Trials as Topic; Retinoids; Risk Factors; Treatment Outcome

Topics: Administration, Oral; Adult; Dose-Response Relationship, Drug; Drug Administration Schedule; Female; Follow-Up Studies; Fumarates; Humans; Multiple Sclerosis; Psoriasis; Severity of Illness Index; Treatment Outcome

Topics: Adult; Antibodies, Monoclonal; Calcitriol; Dermatologic Agents; Dihydroxycholecalciferols; Fumarates; Humans; Psoriasis; Ultraviolet Therapy; Vitamins

Dimethyl fumarate (DMF) has been used as fungicide, but oral DMF activates anti-inflammatory and anti-oxidative pathways that are beneficial in the treatment of psoriasis. BG-12, a specific formulation of DMF, has been approved very recently for the treatment of relapsing-remitting multiple sclerosis (RRMS), which is characterized by both autoimmune lymphocytes leading to inflammation and mitochondrial alterations associated with oxidative stress.. This review describes the pharmacokinetics and the mode of action of DMF, with a focus on molecular and cellular pathways, and discusses clinical results of DMF in RRMS treatment. To identify relevant publications, the author searched the PubMed database by using appropriate keywords and by searching for references cited within the obtained articles.. DMF demonstrated efficacy in several RRMS outcome measures related to disease activity and severity, but results on disability progression have been inconsistent. The overall safety profile might qualify DMF for long-term use, the frequency of side effects such as gastrointestinal complaints and flushing might hamper treatment adherence of MS patients. Since DMF covalently binds to intracellular proteins, the fate of this molecule in the body might need thorough long-term observation during clinical use.

Topics: Animals; Antioxidants; Dimethyl Fumarate; Fumarates; Humans; Immunosuppressive Agents; Multiple Sclerosis; Psoriasis; Treatment Outcome

Nicotinic acid (NA) and fumaric acid esters (FAE) such as monomethyl fumarate or dimethyl fumarate are drugs that elicit a cutaneous reaction called flushing as a side effect. NA is used to reduce progression of atherosclerosis through its anti-dyslipidemic activity and lipid-independent mechanisms involving immune cells, whereas FAE are used to treat psoriasis via largely unknown mechanisms. Both, NA and FAE, induce flushing by the activation of the G-protein-coupled receptor (GPCR) Hydroxy-carboxylic acid receptor 2 (HCA₂, GPR109A) in cells of the epidermis. While the wanted effects of NA are at least in part also mediated by HCA₂, it is currently not clear whether this receptor is also involved in the anti-psoriatic effects of FAE. The HCA₂-mediated flushing response to these drugs involves the formation of prostaglandins D₂ and E₂ by Langerhans cells and keratinocytes via COX-1 in Langerhans cells and COX-2 in keratinocytes. This review summarizes recent progress in the understanding of the mechanisms underlying HCA₂-mediated flushing, describes strategies to mitigate it and discusses the potential link between flushing, HCA₂ and the anti-psoriatic effects of FAE.

Topics: Animals; Flushing; Fumarates; Humans; Niacin; Prostaglandin-Endoperoxide Synthases; Prostaglandins; Psoriasis; Receptors, G-Protein-Coupled; Receptors, Nicotinic; Skin

Topics: Dermatologic Agents; Fumarates; Humans; Psoriasis

Psoriasis, a chronic common immune-mediated disease with frequent remitting/relapsing courses, has a high negative impact on the quality of life, especially in patients moderately or severely affected by the disease. It is also associated with various co-morbidities resulting in a decreased life expectancy and remarkable socioeconomic costs. At least one third of the patients who suffer from it has moderate or severe psoriasis and require continuous treatment to control disease activity. The therapeutic approach in daily practice is usually determined by the severity of the disease. Whether the definition of disease severity is not always clear, there is a considerable number of patients requiring systemic treatment to control the symptoms of psoriasis. The treatment options available for the management of moderate-severe psoriasis have dramatically increased over the past decade, and now range from phototherapy to traditional systemic treatments to biologics. Available data from clinical trials and growing number of patients treated with biologics shows that this new agent are effective and relatively safe to control psoriasis, and are coupled with improved tolerability, convenience and improvement in quality of life. This review shortly presents the characteristics, safety and efficacy profile of the conventional and newer systemic drugs used in moderate-to-severe psoriasis.

Topics: Abnormalities, Drug-Induced; Alefacept; Antibodies, Monoclonal; Clinical Trials as Topic; Contraindications; Cyclosporine; Etanercept; Female; Fumarates; Hematologic Diseases; Humans; Hypertension; Immunoglobulin G; Immunosuppressive Agents; Kidney Diseases; Male; Methotrexate; Photochemotherapy; Pregnancy; Pregnancy Complications; Psoriasis; Receptors, Tumor Necrosis Factor; Recombinant Fusion Proteins; Retinoids; Severity of Illness Index; Tumor Necrosis Factor-alpha

Psoriasis is a systemic chronic inflammatory disorder. One of the major characteristics is an excess of infiltration of inflammatory cells, mainly lymphocytes, into the skin. Because the adhesion family of selectins is suggested to play a relevant role in this process, selectins have emerged as an interesting target for drug discovery and development in psoriasis. Different strategies targeting selectins have been described. This review discusses these approaches and summarises the current development of selectin antagonists for the treatment of psoriasis. An expert opinion will give the authors' personal opinion about selectin antagonism in psoriasis and which approach might be preferable.

Topics: Acetylcysteine; Animals; Dermatologic Agents; Dimethyl Fumarate; Fumarates; Gene Expression Regulation; Glycoproteins; Glycosphingolipids; Glycosylation; Humans; Leukocyte Rolling; Leukocytes; Ligands; Models, Animal; Protease Inhibitors; Proteasome Endopeptidase Complex; Proteasome Inhibitors; Protein Processing, Post-Translational; Psoriasis; Randomized Controlled Trials as Topic; Selectins

Fumaric acid esters (FAEs) have been used for the oral treatment of psoriasis since 1959 and have been registered for this indication in Germany since 1994. Dimethylfumarate (DMF) and its metabolite methylhydrogenfumarate (MHF) are the pharmacologically active compounds, with DMF being the main component of the marketed FAE-mixture. However, the mechanism of action of FAE is yet to be fully understood. It has been shown that DMF inhibits NFkappaB translocation, which leads to (i) the inhibition of pro-inflammatory cytokine production and adhesion molecule expression, (ii) the inhibition of dendritic cell differentiation and, at higher concentrations, (iii) the induction of apoptosis. Recent evidence also shows that these effects are mediated through the interference of the intracellular redox system by DMF. Here, the mode of action of FAE and its clinical use for psoriasis will be discussed.

Topics: Apoptosis; Cell Adhesion Molecules; Cell Differentiation; Cytokines; Dendritic Cells; Dermatologic Agents; Dimethyl Fumarate; Fumarates; Humans; NF-kappa B; Oxidation-Reduction; Protein Transport; Psoriasis

Psoriasis is a chronic, recurrent disease that affects between 1% and 3% of the population. Patients with moderate to severe disease generally require phototherapy (e.g. narrowband ultraviolet B radiation), photochemotherapy (oral psoralen plus ultraviolet A radiation) or systemic agents (e.g. ciclosporin, methotrexate, oral retinoids, fumaric acid esters) to control their disease adequately. In general, these therapeutic modalities have proven to be highly effective in the treatment of psoriasis. However, potentially serious toxicities can limit their long-term use. Given that there is no standard therapeutic approach for patients with moderate to severe psoriasis, the benefits and risks of phototherapy, photochemotherapy and systemic therapy must be weighed carefully for each patient, and treatment individualized accordingly. This review summarizes the benefits and risks of traditional, nonbiological therapies for moderate to severe chronic plaque psoriasis.

Topics: Administration, Oral; Chronic Disease; Cyclosporine; Dermatologic Agents; Ficusin; Fumarates; Humans; Immunosuppressive Agents; Methotrexate; Photosensitizing Agents; Psoriasis; PUVA Therapy; Retinoids; Risk Assessment; Ultraviolet Therapy

Topics: Adalimumab; Antibodies, Monoclonal; Antibodies, Monoclonal, Humanized; Biological Products; Cyclosporine; Dermatologic Agents; Forecasting; Fumarates; Humans; Infliximab; Nicotinic Acids; Psoriasis; Receptors, Tumor Necrosis Factor; Receptors, Tumor Necrosis Factor, Type I; Tacrolimus; Tumor Necrosis Factor Decoy Receptors; Ustekinumab

Fumapharm AG has developed a second-generation fumarate (fumaric acid) derivative, BG 12 [BG 00012, FAG-201, BG 12/Oral Fumarate], for the oral treatment of psoriasis. Biogen Idec is currently evaluating the product in clinical trials as an oral treatment for multiple sclerosis (phase II) and psoriasis (phase III) trials.BG 12 has an immunomodulatory mechanism of action. It seems that this product has been developed to reduce the adverse effects associated with a first-generation product containing fumaric acid esters (mixed dimethylfumarate and monoethylfumarate salts), Fumaderm. Fumaderm was approved in Germany in August 1994 and is currently the leading oral systemic therapy for moderate-to-severe psoriasis in Germany. One of the problems associated with Fumaderm capsules has been its gastrointestinal adverse effects (including diarrhoea and nausea). In September 2003, Biogen (now Biogen Idec) licensed exclusive worldwide rights (excluding Germany) from Fumapharm to develop and market BG 12. Biogen plans to collaborate with Fumapharm to accelerate phase III development for psoriasis and the registration programme worldwide. Financial terms of the agreement were not disclosed. Development plans for BG 12 include other autoimmune and inflammatory disorders, such as multiple sclerosis. In November 2003, Biogen and IDEC Pharmaceuticals merged to form Biogen Idec. Fumapharm completed phase II trials of this second-generation fumarate derivative for psoriasis prior to licensing of the product to Biogen, also with positive results.

Topics: Clinical Trials as Topic; Dimethyl Fumarate; Drugs, Investigational; Fumarates; Humans; Immunologic Factors; Multiple Sclerosis; Psoriasis

Topics: Dermatologic Agents; Dimethyl Fumarate; Esters; Fumarates; Humans; Psoriasis; T-Lymphocytes

Psoriasis is an autoimmune disease affecting 2-4% of the Caucasian population. Inflammatory processes induce the migration of interferon (IFN) gamma producing Th1 lymphocytes into the skin. These play a key role in the pathogenesis of psoriasis. These Th1 lymphocytes are responsible for the pathological reactions in psoriatic skin leading to keratinocyte hyperproliferation, small vessel proliferation and neutrophilic infiltration. Antigen-presenting cells activate dermal CD4+ T lymphocytes, and various signals can support the polarization of Th1 responses. The main signal for Th1 development is interleukin (IL) 12. After binding to their receptors both IL-12 and IFN-gamma promote intracellular IFN-gamma production by activating signal transducer and activator of transcription (STAT) 4 or 1. STAT1 activation by IFN-gamma is followed by T-bet activation, a master transcription factor for Th1 lymphocytes. In experimental models of Th1-mediated autoimmune diseases immune deviation of polarized autoreactive Th1 into anti-inflammatory Th2 responses generally improves the disease. Therefore new therapeutic approaches based on immunomodulating molecules have been developed for psoriasis, a prototypical Th1-mediated autoimmune disorder. Recently IL-4, the most effective Th2-inducing cytokine, has been shown to be safe and efficient for treating psoriasis. Improvement was associated with the induction of a Th2 phenotype of skin infiltrating lymphocytes. This review summarizes the IL-4 inducing potential of various conventional and newer systemic therapies for psoriasis. Many of these were thought to be primarily immunosuppressive. A review of the literature reveals that most of them can induce IL-4 and Th2, and that Th2 induction may be an underestimated mode of action in the therapy of Th1-mediated autoimmune disease. Further studies are needed to determine the central role of IL-4 in the control of Th1-induced autoimmune disease, namely psoriasis.

Topics: Cholecalciferol; Cyclosporine; Cytokines; Fumarates; Humans; Inflammation Mediators; Interleukin-4; Methotrexate; Phototherapy; Psoriasis; Th1 Cells; Th2 Cells; Vitamin A

There is a high medical need for better therapies for psoriasis. Based on new insight into the pathophysiology of this frequent immune disease, a number of novel systemic immunomodulatory therapies are currently in clinical development. These include approaches targeting antigen presentation and costimulation, T cell activation and leukocyte adhesion, action of proinflammatory mediators, and modulating the cytokine balance. Although mainly only preliminary data are available so far, these trials contribute to a further understanding of the disease and will eventually lead to new therapeutic options for psoriasis. Moreover, since psoriasis can be considered as a visible model disease for T cell-mediated disorders characterized by a type 1 cytokine pattern in general, such approaches may have impact for other immune disorders as well. Here we review the rationale and the initial clinical data of these important recent experimental therapies.

Topics: Antibodies, Monoclonal; Calcitriol; Cytokines; Dimethyl Fumarate; Fumarates; Humans; Immunotherapy; Mycophenolic Acid; Psoriasis; Receptors, Leukotriene B4; T-Lymphocytes

Long-term management of psoriasis requires an individualized approach. Some treatments such as calcipotriol, methotrexate and acitretin may be used as maintenance treatment for many months. However, most anti-psoriasis treatments should be prescribed for restricted periods of time. Rotational treatment is a practical approach to reduce the cumulative toxicity of anti-psoriasis treatments. The selection of a treatment is based on the clinical presentation of psoriasis and whether contraindications might exist. Combination treatment is another approach, which is used by the majority of patients. Useful combinations are calcipotriol-acitretin, calcipotriol-cyclosporin, calcipotriol-PUVA, calcipotriol-topical corticosteroids, dithranol-UVB, dithranol-tar, coaltar-UVB, acitretin-UVB and acitretin-PUVA. Combinations which are contraindicated are coaltar-PUVA, UVB-cyclosporin, PUVA-cyclosporin and methotrexate-acitretin. Combined use of UVB-methotrexate, UVB-PUVA; PUVA-methotrexate; methotrexate-cyclosporin and cyclosporin-acitretin require careful monitoring and might be helpful in patients with severe and recalcitrant psoriasis. Depending on the individual presentation of psoriasis, previous anti-psoriatic treatments and side-effects, treatment adjustments are made.

Topics: Acitretin; Administration, Topical; Anti-Inflammatory Agents; Autoimmune Diseases; Calcitriol; Dermatologic Agents; Drug Administration Schedule; Drug Therapy, Combination; Fumarates; Glucocorticoids; Humans; Immunosuppressive Agents; Keratolytic Agents; Methotrexate; Phototherapy; Psoriasis; PUVA Therapy

Severe cases of psoriasis and psoriasis arthritis require systemic treatment. Although a number of established drugs are in clinical use, there is a need for new compounds with an improved risk-benefit ratio with a major emphasis on long-term safety. Furthermore, patients with moderate psoriasis ask for systemic drugs to make therapy easier and to avoid excessive local treatments. This article aims to give a brief overview about new drugs or groups of compounds together with an evaluation of their present status in the treatment of psoriasis and their future role with particular respect to efficacy, tolerability, safety and usability.

Topics: Antibodies, Monoclonal; Anticarcinogenic Agents; Antigen-Presenting Cells; Arthritis, Psoriatic; Autoimmune Diseases; Dermatologic Agents; Fumarates; Humans; Immunosuppressive Agents; Immunotherapy; Keratolytic Agents; Platelet Aggregation Inhibitors; Psoriasis; Receptors, Cytoplasmic and Nuclear; Transcription Factors

The treatment of psoriasis vulgaris with fumaric acid esters has been controversial for more than 30 years. Recently the fumaric acid derivatives are marketed antipsoriatics in many European countries. In this paper the clinical efficacy, the side effects as well as the mode of action of these highly potent substances are summarized.

Topics: Dermatologic Agents; Esters; Fumarates; Humans; Immunotherapy; Psoriasis

Topics: Antineoplastic Agents; Antirheumatic Agents; Fumarates; Humans; Hydroxyurea; Photochemotherapy; Phototherapy; Psoriasis; Retinoids

Topics: Acitretin; Cyclosporine; Dermatologic Agents; Fumarates; Glucocorticoids; Humans; Immunosuppressive Agents; Keratolytic Agents; Methotrexate; Photochemotherapy; Phototherapy; Psoriasis

For the past two decades fumaric acid (FA) therapy has become an increasingly popular treatment in Western Europe for psoriasis. FA therapy originally was developed by Schweckendiek and subsequently standardized by Schäfer. Schäfer's fumaric acid compound therapy (FACT) consists of the oral intake of dimethylfumaric acid ester (DMFAE) and several salts of monoethylfumaric acid ester (MEFAE) in combination with topical fumaric acid therapy (1% to 3% MEFAE in an ointment or FA in bathing oils) and a diet. Schäfer claimed excellent results in a large number of patients. Preliminary studies by German dermatologists, however, revealed contradictory therapeutic results and serious side effects, and FA treatment was soon abandoned by dermatologists. To assess the value of FA therapy we conducted an open pilot study of 36 patients in which FACT therapy appeared to be rather effective. Thereafter, several controlled studies with MEFAE sodium in two different dosages versus placebo, and DMFAE versus placebo, were done. The results indicated that MEFAE sodium in dosages up to 240 mg daily was ineffective, whereas daily dosages of 720 mg resulted in a significant decrease in scaling and itching but did not affect extension of the eruption. DMFAE, 240 mg daily, produced a significant amelioration and prevented extension. Side effects of FA treatment were nausea, diarrhea, general malaise, and severe stomachache. Mild disturbances of liver and kidney function during treatment were observed with the 720 mg dosage of MEFAE and with the 240 mg dosage of DMFAE. Moreover, a relative lymphopenia with a selective decrease of suppressor T lymphocytes occurred in about 50% of the patients treated with DMFAE.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Administration, Oral; Clinical Trials as Topic; Double-Blind Method; Female; Fumarates; Humans; Male; Pilot Projects; Psoriasis; Random Allocation

Fumaric acid esters (FAEs; Fumaderm. To compare risankizumab treatment to FAEs in patients with psoriasis.. This phase III randomized, active-controlled, open-label study with blinded assessment of efficacy was conducted in Germany. Patients were randomized (1 : 1) to subcutaneous risankizumab 150 mg (weeks 0, 4 and 16) or oral FAEs at increasing doses from 30 mg daily (week 0) up to 720 mg daily (weeks 8-24). Enrolled patients were adults naïve to and candidates for systemic therapy, with chronic moderate-to-severe plaque psoriasis. Phototherapy was not allowed within 14 days before or during the study.. Key efficacy endpoints were met at week 24 for risankizumab (n = 60) vs. FAEs (n = 60) (P < 0·001): achievement of a ≥ 90% improvement in Psoriasis Area and Severity Index (PASI; primary endpoint 83·3% vs. 10·0%), ≥ 100% improvement in PASI (50·0% vs. 5·0%), ≥ 75% improvement in PASI (98·3% vs. 33·3%), ≥ 50% improvement in PASI (100% vs. 53·3%) and a Static Physician's Global Assessment of clear/almost clear (93·3% vs. 38·3%). The rates of gastrointestinal disorders, flushing, lymphopenia and headache were higher in the FAE group. One patient receiving risankizumab reported a serious infection (influenza, which required hospitalization). There were no malignancies, tuberculosis or opportunistic infections in either treatment arm.. Risankizumab was found to be superior to FAEs, providing earlier and greater improvement in psoriasis outcomes that persisted with continued treatment, and more favourable safety results, which is consistent with the known safety profile. No new safety signals for risankizumab or FAEs were observed.

Topics: Adult; Antibodies, Monoclonal; Double-Blind Method; Fumarates; Humans; Psoriasis; Severity of Illness Index; Treatment Outcome

The effect of adalimumab and fumaric acid esters (FAE) on the cardiovascular risk associated with psoriasis has only been investigated scarcely in randomized controlled studies.. The aim of this prospective, randomized controlled head-to-head trial was to compare the influence of adalimumab and FAE on cardiovascular disease markers in psoriasis patients.. Sixty-five patients with moderate to severe plaque psoriasis were randomly assigned to adalimumab or FAE treatment for 6 months. Cardiovascular haemodynamic parameters [flow-mediated dilation (FMD), nitro-glycerine mediated dilation (NMD) and carotid intima-media thickness (CIMT), blood pressure] were assessed at baseline (v0) and after 6 months (v6). Cutaneous disease severity, inflammatory and lipid cardiovascular risk markers were analysed at baseline(v0), after 3 (v3) and 6 months (v6).. After 6 months of treatment FMD in the adalimumab group increased significantly [v0 5.9% (6.4% SD), v6 8.0% (4.8% SD), P = 0.048) but not in the FAE group. (v0 7.0% (4.1% SD), v6 8.4% (6.1% SD), P = 0.753]. This was paralleled by a significant decrease of high sensitive C-reactive protein (hsCRP) in the adalimumab group in comparison to the FAE group (v0: 0.39 mg/dL (0.38 SD), v6: 0.39 mg/dL (0.48 SD), P = 0.043). No significant changes were observed in any other haemodynamic parameters. FAE, however, additionally decreased total cholesterol (P = 0.046) and apolipoprotein B (P = 0.041) levels compared to adalimumab. Mean Psoriasis Area and Severity Index (psoriasis area severity score) reduction was greater but not significant (P = 0.116) under adalimumab treatment compared to FAE treatment [-71.1% (29.9 SD) vs. -54.6% (45.7%)].. In our study, both treatments were documented to exert effects on the cardiovascular system. While adalimumab showed anti-inflammatory effects and improved FMD, FAE interacted favourably with the cholesterol metabolism.

Topics: Adalimumab; Cardiovascular Diseases; Carotid Intima-Media Thickness; Dermatologic Agents; Fumarates; Heart Disease Risk Factors; Humans; Prospective Studies; Psoriasis; Risk Factors; Severity of Illness Index; Treatment Outcome

Topics: Acitretin; Fumarates; Humans; Prospective Studies; Psoriasis; PUVA Therapy; Treatment Outcome

Brodalumab is a fully human monoclonal immunoglobulin IgG2 antibody that binds to the human IL-17 receptor subunit A and by that inhibits the biologic action of IL-17A, IL-17F, IL-17C and IL-17E. Therapy with fumaric acid esters (FAE) is a well established and widely used first-line systemic treatment for subjects with moderate-to-severe plaque psoriasis.. To compare brodalumab to FAE in terms of clinical efficacy, patient-reported outcomes and safety in subjects with moderate-to-severe plaque psoriasis who were naïve to systemic treatment.. Eligible subjects were randomized 1 : 1 to 210 mg brodalumab injections or oral FAE according to product label in this 24-week, open-label, assessor-blinded, multi-centre, head-to-head phase 4 trial. The primary endpoints were having PASI75 and having sPGA score of 0 or 1 (sPGA 0/1). Subjects with missing values for the primary endpoints were considered non-responders.. A total of 210 subjects were randomized. 91/105 subjects completed brodalumab treatment and 58/105 subjects completed FAE treatment. At Week 24, significantly more subjects in the brodalumab group compared to the FAE group had PASI75 (81.0% vs. 38.1%, P < 0.001) and sPGA 0/1 (64.8% vs. 20.0%, P < 0.001). In the brodalumab group, the median time to both PASI75 and to PASI90 was significantly shorter than in the FAE group (4.1 weeks vs. 16.4 weeks, and 7.4 weeks vs. 24.4 weeks, respectively, P < 0.0001 for both). The rate of adverse events was lower in subjects treated with brodalumab compared to subjects treated with FAE (616.4 vs. 1195.8 events per 100 exposure years). No new safety signals were detected for brodalumab.. Brodalumab was associated with rapid and significant improvements in signs and symptoms of moderate-to-severe plaque psoriasis, with a superior efficacy profile to what was observed with FAE in systemic-naïve subjects over 24 weeks.

Topics: Administration, Oral; Adult; Antibodies, Monoclonal, Humanized; Fumarates; Humans; Injections, Subcutaneous; Psoriasis; Severity of Illness Index; Treatment Outcome

Apart from biologics, no systemic drugs are approved in Europe for children with moderate-to-severe psoriasis. Retrospective observational studies have shown promising results for fumaric acid esters (FAE) in this setting.. To show superiority of FAE over placebo in terms of treatment response after 20 weeks in children and adolescents aged 10-17 years.. In a multicentre, randomized, double-blind, placebo-controlled phase IIIb study, patients aged 10-17 years with moderate-to-severe plaque psoriasis requiring systemic therapy were randomized 2 : 1 to receive FAE (n = 91) or placebo (n = 43) over 20 weeks, followed by an open-label FAE treatment phase. The coprimary endpoints were ≥ 75% improvement in Psoriasis Area and Severity Index (PASI 75) and Physician's Global Assessment (PGA) score of 0 or 1 (clear or almost clear) at week 20. The study was registered with EudraCT number 2012-000035-82.. At week 20, 55% [95% confidence interval (CI) 0·44-0·65] of FAE-treated patients achieved a PASI 75 response vs. 19% (95% CI 0·08-0·33) in the placebo group (absolute difference 36%, 95% CI 0·20-0·53; P < 0·001). In total, 42% (95% CI 0·32-0·53) in the FAE group vs. 7% (95% CI 0·01-0·19) in the placebo group achieved a PGA score of 0 or 1 at week 20 (absolute difference 35%, 95% CI 0·21-0·49; P < 0·001). During the double-blind period, drug-related adverse events occurred more frequently in patients receiving FAE compared with placebo (76% vs. 47%). Gastrointestinal disorders were the most common adverse events.. FAE administered over a period of 20 weeks demonstrated a better response than placebo; the difference was statistically significant and clinically meaningful. Application up to 40 weeks was generally well tolerated. However, further studies are required.

Topics: Adolescent; Child; Double-Blind Method; Europe; Fumarates; Humans; Psoriasis; Retrospective Studies; Severity of Illness Index; Treatment Outcome

In a phase 3 clinical study, patients from Germany with moderate to severe psoriasis who were naïve to systemic treatment and received risankizumab had greater and more rapid disease improvements compared with those who received fumaric acid esters (FAEs).. To evaluate patient-reported outcomes (PROs) in patients treated with risankizumab compared with FAEs.. Adult patients were randomized 1:1 to receive either risankizumab 150 mg subcutaneous injections at weeks 0, 4 and 16 or FAEs (Fumaderm. Sixty patients each were randomized to receive risankizumab or FAEs. A significant PSS improvement was observed with risankizumab vs. FAEs at weeks 16 and 24 for total and psoriasis-associated redness, itching and burning scores (P < 0.001). DLQI scores were significantly lower (reflecting better health-related quality of life) with risankizumab vs. FAEs, with least squares (LS) mean differences of -7.4 and -7.6 at weeks 16 and 24, respectively (both P < 0.001). Patients randomized to risankizumab also had larger improvements in SF-36 Physical and Mental Component Summary scores, HADS anxiety and depression scores, PtGA, and EQ-5D-5L index and visual analogue scale scores (all P ≤ 0.002) at weeks 16 and 24 compared with FAEs. PBI was significantly higher, indicating greater benefit, with risankizumab vs. FAEs, with an LS mean difference of 1.1 and 1.3 at weeks 16 and 24, respectively (both P < 0.001).. Risankizumab provides significant benefits over FAEs in improving PROs across several dimensions in patients with moderate to severe psoriasis.

Topics: Adult; Antibodies, Monoclonal; Double-Blind Method; Fumarates; Germany; Humans; Patient Reported Outcome Measures; Psoriasis; Quality of Life; Severity of Illness Index; Treatment Outcome

Guselkumab, a fully human interleukin-23 antibody, is approved for systemic treatment of patients with moderate-to-severe plaque psoriasis.. To compare the efficacy and safety of guselkumab with those of fumaric acid esters (FAE) in patients with moderate-to-severe plaque psoriasis who are naive to systemic treatment.. Eligible patients were randomized to this multicentre, randomized, open-label, assessor-blinded, active-comparator-controlled phase IIIb study to receive guselkumab 100 mg by subcutaneous injection or oral FAE according to local label guidelines.. Through week 24, 56 of 60 patients completed guselkumab treatment and 36 of 59 completed FAE treatment. The primary endpoint (proportion of patients with ≥ 90% improvement from their baseline Psoriasis Area and Severity Index; PASI 90 response) was achieved by significantly more patients receiving guselkumab than FAE at week 24 (82% vs. 14%, P < 0·001). Analysis of the major secondary endpoints confirmed a statistically significant difference between the treatments with regards to PASI 75 response (90% vs. 27%, P < 0·001) and Dermatology Life Quality Index score of 0 or 1 (no effect at all on the patient's quality of life; 62% vs. 17%, P < 0·001). More patients in the guselkumab group achieved completely clear skin (PASI 100 response) than in the FAE group (32% vs. 3%, P < 0·001). The incidence of adverse events was lower with guselkumab than with FAE (73% vs. 98%). Overall, 28% of patients on FAE discontinued due to an adverse event, compared with none receiving guselkumab. No new safety findings were observed for guselkumab.. Guselkumab demonstrated superiority over FAE in systemic-treatment-naive patients with moderate-to-severe plaque psoriasis through 24 weeks.

Topics: Antibodies, Monoclonal; Antibodies, Monoclonal, Humanized; Fumarates; Humans; Psoriasis; Quality of Life; Severity of Illness Index; Treatment Outcome

Interleukin-17 antagonists have received a first-line label for moderate-to-severe plaque psoriasis.. We conducted the first head-to-head trial between the two most commonly used first-line therapies in Germany, fumaric acid esters (FAEs) and methotrexate, and the interleukin-17A antagonist, ixekizumab.. Systemic-naive patients were randomized in this parallel-group, active-comparator, open-label, rater-blinded trial (each group n = 54). The primary outcome was the proportion of patients achieving ≥ 75% improvement in Psoriasis Area and Severity Index (PASI 75) at 24 weeks. Key secondary outcomes included 24-week PASI 90 and 100, static Physician's Global Assessment (sPGA) score of 0 or 1, and Dermatology Life Quality Index (DLQI) score of 0 or 1. Safety events at week 24 were analysed using Fisher's exact test. Missing data were imputed using nonresponder imputation. The trial was registered at ClinicalTrials.gov (NCT02634801) and EudraCT (2015-002649-69).. At week 24, more ixekizumab-treated patients achieved PASI 75 [91% vs. 22% FAEs (P < 0·001) and 70% methotrexate (P = 0·014)], PASI 90 [80% vs. 9% FAEs (P < 0·001) and 39% methotrexate (P < 0·001)] and PASI 100 [41% vs. 4% FAEs (P < 0·001) and 13% methotrexate (P = 0·0041)], as well as sPGA (0,1) and DLQI (0,1).. Ixekizumab was superior in inducing PASI 75/90/100, sPGA (0,1) and DLQI (0,1) responses at week 24 compared with methotrexate and FAEs. Safety profiles for all treatments were consistent with prior studies.

Topics: Antibodies, Monoclonal, Humanized; Double-Blind Method; Fumarates; Germany; Humans; Methotrexate; Psoriasis; Severity of Illness Index; Treatment Outcome

Fumaric acid esters (FAE) are safe and effective in patients with moderate-to-severe psoriasis but have a slow onset of action. A short-term combination with narrowband ultraviolet B (NB-UVB) may substantially accelerate the therapeutic response in the induction phase of treatment.. To assess the synergistic effect of a 6-week course of NB-UVB phototherapy in addition to FAE in adults with moderate-to-severe plaque psoriasis.. In this randomized, assessor-masked trial, patients with a Psoriasis Area and Severity Index (PASI) of ≥ 10 and a body surface area affected of ≥ 10 were randomized either to monotherapy with FAE (n = 16) or a combination of FAE with NB-UVB (n = 14). The primary outcome parameter of the study was the mean PASI reduction after 6 weeks of treatment. In addition, the PASI 75 response (≥ 75% improvement from baseline PASI), the Psoriasis Log-based Area and Severity Index (PLASI) and the Dermatology Life Quality Index (DLQI) were assessed as secondary outcome measures.. In total, 30 patients (19 men, 11 women; median age 52 years, interquartile range 36-56) were analysed. The mean reduction in PASI after 6 weeks was significantly greater with the combination treatment than with FAE monotherapy (P = 0·016). This was paralleled by a much faster improvement in the DLQI in the combination group than in the FAE-monotherapy group.. Adding a 6-week course of NB-UVB to FAE both accelerates and augments the therapeutic response during the early phase of treatment and increases quality of life in patients with moderate-to-severe plaque psoriasis.

Topics: Adolescent; Adult; Aged; Aged, 80 and over; Combined Modality Therapy; Dermatologic Agents; Esters; Female; Fumarates; Humans; Male; Middle Aged; Prospective Studies; Psoriasis; Quality of Life; Severity of Illness Index; Treatment Outcome; Ultraviolet Therapy; Young Adult

Secukinumab is a fully human antibody that neutralizes interleukin-17A. It has significant efficacy and a favourable safety profile in moderate-to-severe plaque psoriasis and psoriatic arthritis.. To compare secukinumab with fumaric acid esters (FAEs) in a randomized controlled trial.. In this 24-week, randomized, open-label, multicentre study with blinded assessment, patients with moderate-to-severe plaque psoriasis, naive to systemic treatments, were randomized to receive secukinumab 300 mg subcutaneously or oral FAEs. The primary end point was ≥ 75% improvement from baseline Psoriasis Area and Severity Index score (PASI 75 response) at week 24, and missing patients were considered responders if they were responders at the time of dropout.. In total 202 patients were randomized and 200 were treated with at least one dose. Outcomes at week 24 were available for 147 and imputed for 53 patients. Discontinuations were mostly due to adverse events, and occurred more frequently in the FAE group (1·9% vs. 40·0%). At week 24, significantly more patients receiving secukinumab compared with FAEs achieved PASI 75 response (89·5% vs. 33·7%, P < 0·001), PASI 90 response (75·2% vs. 18·9%, P < 0·001) and Dermatology Life Quality Index 0 or 1 response (71·4% vs. 25·3%, P < 0·001).. Secukinumab demonstrated superior efficacy to FAEs in patients with psoriasis over a 24-week period.

Topics: Administration, Oral; Adult; Antibodies, Monoclonal; Antibodies, Monoclonal, Humanized; Double-Blind Method; Drug Substitution; Female; Fumarates; Humans; Injections, Subcutaneous; Male; Psoriasis; Treatment Outcome

Biologics are a safe and efficacious therapy for psoriasis. The drug survival of biologics may be disappointing, primarily due to loss of efficacy. Therefore, safe combination treatments are sought to improve their clinical response.. To assess the efficacy, safety and tolerability of the combination therapy of etanercept with fumarates versus etanercept monotherapy.. Thirty-three patients with psoriasis were randomized 1:1 to receive etanercept combined with fumarates or etanercept monotherapy. The primary outcome measure was the difference in PASI-75 response after 24 weeks; additionally, a longitudinal analysis was performed. An important secondary outcome measure was the proportion of patients with a Physician Global Assessment (PGA) of clear or almost clear. Adverse events were collected throughout the study.. In the combination therapy group, 78% (14 out of 18 patients) reached PASI-75 at week 24 versus 57% (8 out of 14 patients) in the monotherapy group (p = 0.27). The longitudinal analysis showed a PASI reduction of 5.97% per week for the combination therapy group and of 4.76% for the monotherapy group (p = 0.11). In the combination therapy group, 94% (17 out of 18 patients) of patients had a PGA of clear/almost clear versus 64% (9 out of 14 patients) in the monotherapy group (p = 0.064). The incidence of mild gastrointestinal complaints was higher in the combination group than in the monotherapy group.. Using the PGA, combination therapy showed a trend towards faster improvement in the first 24 weeks. The difference in the PASI score between the two groups was not statistically significant. Addition of fumarates to etanercept for 48 weeks appeared safe with an acceptable tolerability.

Topics: Adult; Biopsy; Dose-Response Relationship, Drug; Drug Therapy, Combination; Etanercept; Female; Follow-Up Studies; Fumarates; Humans; Immunosuppressive Agents; Male; Middle Aged; Psoriasis; Severity of Illness Index; Skin; Time Factors; Treatment Outcome

Fumaric acid esters (FAEs) are considered an effective and safe long-term treatment for psoriasis. However, 30-40% of patients need to discontinue FAE treatment due to intolerable adverse events.. To assess whether the addition of cetirizine, an oral histamine-1 receptor antagonist, to FAEs would reduce the incidence of adverse events.. In a randomized, double-blind, placebo-controlled trial, patients with psoriasis with a Psoriasis Area and Severity Index ≥ 10 starting an FAE up to a dose of dimethylfumarate 720 mg per day were randomized 1 : 1 to receive either additional cetirizine 10 mg once daily (n = 25) or placebo (n = 25) for 12 weeks. Randomization and treatment allocation were done at our hospital trial pharmacy. Primary outcomes were the incidence of adverse events and the proportion of patients discontinuing treatment.. Fifty patients (33 male, 17 female; median age 44 years) were enrolled. Addition of cetirizine did not reduce the incidence of adverse events compared with placebo (84% vs. 84%, P = 1·00). The types of adverse events were not different between the cetirizine and placebo groups, the most common being gastrointestinal complaints (68% vs. 64%) and flushes (60% vs. 48%). The proportion of patients discontinuing treatment was not statistically different between the cetirizine and placebo groups (24% vs. 32%, P = 0·53).. Addition of oral cetirizine 10 mg once daily to FAE treatment did not reduce adverse events in patients with psoriasis during the first 12 weeks of treatment. The mechanisms underlying FAE-induced gastrointestinal and flushing symptoms likely involve mediators other than histamine.

Topics: Administration, Oral; Adult; Cetirizine; Dermatologic Agents; Double-Blind Method; Drug Therapy, Combination; Female; Fumarates; Histamine Antagonists; Humans; Male; Middle Aged; Psoriasis; Treatment Outcome

Severe psoriasis is associated with significant cardiovascular mortality. We therefore investigated the effects of systemic therapy on the cardiovascular risk of psoriasis patients. Thirteen consecutive patients receiving fumaric acid esters were included and followed for 24 weeks both clinically and by means of laboratory monitoring, 10 completed the study. Eight of ten patients showed a PASI-50 response. Two of three patients with clinical insulin resistance (Homeostasis Model Assessment of insulin resistance >2.5) showed normal insulin responsiveness at the end of the study. Clinical improvement was paralleled by a reduction of high-sensitive CRP serum levels (median -25%). There was a trend toward reduced serum levels for the vascular endothelial growth factor (median -10%) and resistin (median -4%), while the potentially cardio-protective adiponectin showed a trend toward increased serum levels under therapy (median +19%). Systemic endothelial function assessed by venous occlusion plethysmography revealed an improvement of endothelial vasodilator function after 24 weeks of treatment (p < 0.02). This is the first prospective study documenting an amelioration of endothelial cell function in patients with moderate-to-severe plaque-type psoriasis under effective continuous systemic therapy. Future studies need to compare the cardioprotective effects of different treatment modalities, based on hard end points such as the rate of myocardial infarction.

Topics: Adult; Aged; Biomarkers; C-Reactive Protein; Cardiovascular Diseases; Disease Progression; Endothelium, Vascular; Female; Follow-Up Studies; Fumarates; Humans; Inflammation; Male; Middle Aged; Pilot Projects; Prospective Studies; Psoriasis; Risk; Vascular Endothelial Growth Factor A

Methotrexate and fumarates are effective systemic therapies for moderate to severe psoriasis according to the European S3 guidelines.. We conducted a randomized controlled trial comparing the effectiveness and the adverse events of methotrexate and fumarates.. Sixty patients with moderate to severe psoriasis vulgaris were randomly assigned to treatment for 16 weeks with either methotrexate (30 patients; 15 mg per week) or fumarates (30 patients; 30 mg, followed by 120 mg according to a standard progressive dosage regimen) and were followed up for 4 weeks. The primary endpoint with respect to the efficacy was the difference in mean change from baseline in Psoriasis Area and Severity Index (PASI) after 12 weeks of treatment. The study was powered to detect a difference of five points. Analyses were by intention to treat.. Six patients were excluded because five were not eligible and one withdrew consent. Two patients in the methotrexate group and one in the fumarate group dropped out during the 12 weeks of treatment because of nonappearance at the outpatient clinic. In total, 25 patients in the methotrexate group and 26 in the fumarate group were evaluated in the primary analysis. After 12 weeks of treatment, the mean ± SD PASI decreased from 14·5 ± 3·0 at baseline to 6·7 ± 4·5 in the 25 patients treated with methotrexate, whereas it decreased from 18·1 ± 7·0 to 10·5 ± 6·7 in the 26 patients treated with fumarates. After adjustment for baseline values, the absolute difference (fumarates minus methotrexate) in the mean values at 12 weeks was 1·4 (95% confidence interval -2·0 to 4·7; P = 0·417).. In this randomized trial methotrexate and fumarates were found to be equally effective in the treatment of patients with moderate to severe psoriasis. No serious or irreversible adverse events were observed in any of the patients.

Topics: Adult; Female; Fumarates; Humans; Immunosuppressive Agents; Male; Methotrexate; Middle Aged; Prospective Studies; Psoriasis; Severity of Illness Index

Psoriasis is a common, chronic, cell-mediated, inflammatory skin disease. Treatment limitations and a developing understanding of its pathogenesis on a molecular level have encouraged much interest in the field of immunomodulatory therapy.. To evaluate the efficacy and safety of fumaric acid esters, in particular dimethylfumarate (DMF), in the treatment of moderate to severe plaque psoriasis intolerant and/or resistant to other conventional systemic therapies.. A total of 40 patients were enrolled in this study. DMF was orally administered at the daily dose of 30 mg up to 360 mg for a minimum of 6 months treatment. Patients were followed-up with psoriasis area and severity index (PASI) score assessment, and clinical and photographic documentation.. A total of 33 (82.5%) patients achieved complete clinical remission with DMF treatment: eight after 3 months and 25 after 6 months. Adverse events, such as intolerable abdominal cramps and incoercible diarrhoea, occurred in four patients who, for this reason, interrupted therapy.. The findings suggest that DMF is a safe, effective and well-tolerated long-term oral treatment worthy of consideration for selective patients.

Topics: Adolescent; Adult; Aged; Dermatologic Agents; Dimethyl Fumarate; Female; Fumarates; Humans; Italy; Male; Middle Aged; Psoriasis

Topics: Adult; Aged; Dermatologic Agents; Dimethyl Fumarate; Female; Fumarates; Humans; Male; Middle Aged; Prospective Studies; Psoriasis; Treatment Outcome

Calcipotriol is an established topical therapy for psoriasis vulgaris.. This study aimed to investigate whether the addition of calcipotriol to fumaric acid ester (FAE) monotherapy had an additive efficacy and an FAE-sparing effect in patients with severe plaque psoriasis.. This multicentre, randomised, double-blind, vehicle-controlled study included 143 patients for up to 13 weeks treatment. Group A received FAE tablets (Fumaderm) with an increasing daily dosage from 105 to 1,075 mg + ointment vehicle. Group B received FAE tablets + calcipotriol ointment (50 microg/g). Ointments were applied twice daily. Clinical response was assessed using percentage changes in the Psoriasis Area and Severity Index (PASI), from baseline to treatment end.. The mean percentage change in the PASI was -76.1% in group B and -51.9% in group A, the difference between treatments was -24.2% (95% CI from -34.2 to -14.2%; p < 0.001). Group B responded more rapidly to treatment. Investigators' and patients' overall efficacy assessments were significantly more favourable for group B (p < or = 0.001). Group B was prescribed less FAE than group A. This difference was greatest at the last visit (mean daily dose 529 and 685 mg, respectively; p = 0.006). Overall adverse events in the two groups were similar.. This study shows that the combination of calcipotriol and FAEs is significantly more effective and faster acting than FAE monotherapy in the treatment of severe plaque psoriasis. The combination has a slight FEA-sparing effect and therefore a superior benefit/risk ratio.

Topics: Administration, Oral; Administration, Topical; Adult; Calcitriol; Chronic Disease; Dermatologic Agents; Dimethyl Fumarate; Double-Blind Method; Drug Therapy, Combination; Female; Fumarates; Humans; Male; Prospective Studies; Psoriasis

For severe forms of psoriasis vulgaris, the antipsoriatic fumaric acid esters (FAE) therapy has recently gained increasing acceptance and importance. Until today, there is little knowledge about the mode of action of FAE. However, some evidence exists indicating immunosuppressive effects.. The aim of this study was to examine the systemic, particularly the immunological changes in patients suffering from psoriasis treated with FAE over a long period of time, since we expect to see pharmacological effects of FAE at this point.. This study is based on continuously recorded clinical data and laboratory parameters of 10 patients, who were treated over a period of 12 months with FAE. A quantitative analysis of lymphocytes and their subtypes was carried out by means of flowcytometric methods.. 3 months after starting treatment with FAE, a clinical effect with a remission index > 95% was achieved in all 10 patients examined. This remained constant until the end of this study. Focusing on leukopenia, and particularly on lymphopenia as important parameters, these effects were found in all patients. The lymphocyte subpopulations data demonstrated extensive proportionate reductions. Within the T cell fraction a stronger suppression of CD8+ lymphocytes was observed.. Our investigations of systemic effects of fumaric acid esters demonstrate the suppressive character of this medication. Effects of cell count reduction in leukocyte and lymphocyte numbers over the entire period of 12 months could be observed. The lymphocytic cell count number is obviously linked to the clinical effect.

Topics: Administration, Oral; Adult; Aged; Alanine Transaminase; Aspartate Aminotransferases; B-Lymphocytes; Blood Cell Count; CD4-CD8 Ratio; CD4-Positive T-Lymphocytes; CD8-Positive T-Lymphocytes; Creatinine; Dose-Response Relationship, Drug; Eosinophils; Female; Fumarates; gamma-Glutamyltransferase; HLA-DR Antigens; Humans; Leukocyte Count; Lymphocyte Count; Male; Middle Aged; Monocytes; Psoriasis; Receptors, Interleukin-2; Time Factors; Treatment Outcome; Urea

Systemic treatment of psoriasis with fumaric acid esters (FAE) has been found effective by empirical means. In recent years clinical studies have confirmed the antipsoriatic activity of a defined mixture of different FAE. The aim of the present prospective multicentre study was to investigate further the efficacy and safety of FAE therapy in a large number of patients with severe psoriasis vulgaris. From 101 patients included in the study 70 completed the treatment period of 4 months. Discontinuation was due to adverse events in seven, lack of efficacy in two, and other reasons, such as non-attendance for scheduled visits, in 22 patients. Evaluation of overall efficacy showed a decrease in psoriasis area and severity index of 80% after 4 months of FAE therapy. Laboratory investigations revealed a slight overall decrease of lymphocytes during the treatment period which was more than 50% below baseline in 10 patients. During weeks 4 and 8 mean eosinophil counts were above the normal range. At the end of FAE therapy elevated eosinophil counts had returned to normal values. None of the patients showed changes in renal function parameters throughout the study. Adverse events were reported in 69% of the patients mainly consisting of gastrointestinal complaints (56%) and flushing (31%). In five patients gastrointestinal complaints and in two patients flushing led to withdrawal from the study. Taken together the results of this multicentre study showed in a large number of patients that systemic FAE treatment is effective in severe psoriasis vulgaris. Transient eosinophilia seems to be a characteristic feature of FAE therapy, while lymphocytopenia is usually mild. Adverse effects are dose-related and consist mainly of gastrointestinal complaints and flushing.

Topics: Adult; Aged; Dermatologic Agents; Dimethyl Fumarate; Drug Administration Schedule; Female; Fumarates; Gastrointestinal Diseases; Humans; Male; Middle Aged; Prospective Studies; Psoriasis; Treatment Outcome

The therapeutic effect and the side of effects fumaric acid derivatives used in treatment of psoriasis vulgaris have been subjects of controversy for more than 30 years. A total of 83 patients with severe psoriasis vulgaris were investigated in a single-centre, long-term open (12 months) clinical trial to evaluate the efficacy and safety profile of the fumaric acid ester preparations Fumaderm initial and Fumaderm. The antipsoriatic effect of the fumaric acid derivatives was clear, with a mean reduction of 76% in PASI. Adverse events in were noted in 62% of the patients (mainly flushing and gastrointestinal complaints). These were dose-dependent and decreased in frequency in the course of the study. No severe adverse events occurred. We believe that of fumaric acid derivatives are indicated in cases of severe therapy-resistant psoriasis to and can be used even for long-term application.

Topics: Administration, Oral; Adolescent; Adult; Aged; Dimethyl Fumarate; Dose-Response Relationship, Drug; Drug Administration Schedule; Drug Combinations; Female; Fumarates; Humans; Keratolytic Agents; Long-Term Care; Male; Middle Aged; Psoriasis; Treatment Outcome

Psoriasis vulgaris may benefit from treatment with fumaric acid and/or its derivatives; however, because different preparations have been used, results have been contradictory and difficult to interpret.. The purpose of this clinical trial was to evaluate the therapeutic value of fumaric acid derivatives.. A randomized double-blind study was carried out in patients with psoriasis, comparing a well-characterized formulation of fumaric acid derivatives with placebo.. The results indicated statistically significant superiority of the fumaric acid derivatives over placebo. Adverse events (flush, gastrointestinal disturbances) were initially relatively frequent, but decreased thereafter.. Fumaric acid derivatives were found to be effective and safe in the treatment of psoriasis.

Topics: Abdominal Pain; Adult; Aged; Diarrhea; Dimethyl Fumarate; Double-Blind Method; Drug Combinations; Female; Flushing; Fumarates; Humans; Joints; Male; Middle Aged; Pain; Placebos; Psoriasis; Remission Induction

Thirty-nine patients with psoriasis (12 females, 27 males) entered a randomised, double-blind, placebo-controlled study on the efficacy of fumaric acid therapy in an outpatient setting. During 16 weeks the patients were treated with tablets containing a combination of dimethylfumarate and different salts of monoethylfumarate, with octylhydrogen fumarate or with placebo tablets. All patients were treated with identical indifferent topical therapy and followed an elimination diet (avoidance of spices, wine and nuts). Thirty-four patients completed the study. Five patients dropped out because of side effects or aggravation of the skin lesions. The patients treated with the combination of monoethyl- and dimethylfumarate showed a significantly better therapeutic response compared with those who were treated with placebo or octylhydrogen fumarate. Side effects of the fumarate containing tablets were flushing, diarrhoea, a reversible elevation of transaminases, lymphocytopenia and eosinophilia. One patient developed a disturbance of the kidney function which normalised after discontinuation of the therapy.

Topics: Adult; Aged; Double-Blind Method; Female; Fumarates; Humans; Male; Middle Aged; Psoriasis

Topics: Administration, Oral; Adult; Aged; Double-Blind Method; Drug Administration Schedule; Female; Fumarates; Humans; Male; Middle Aged; Psoriasis; Random Allocation

In a 4-month double-blind study the effects of dimethylfumaric acid esters (DMFAE-EC) and DMFAE plus salts of monoethylfumaric acid esters (fumaric acid combination, FAC-EC) in enteric-coated tablets were compared in 22 respectively 23 patients with psoriasis. In both groups about 50% showed a considerable improvement, i.e. the initial score was more than halved. The therapeutic effects showed no significant differences in both groups with respect to the total psoriasis score or the different parameters. In the FAC-EC group the effects were obtained more rapidly. Most frequently observed side effects in both groups were flushings, stomachache and diarrhea. Due to these complaints 3 respectively 8 patients discontinued therapy. Eosinophilia, leukopenia and lymphopenia were the most frequently observed differences in lab tests. It was concluded that FAC-EC had no significantly better effect than monotherapy with DMFAE-EC. Moreover, enteric coating of the tablets did not prevent stomach complaints. Until more information has been obtained about the pharmacokinetics, the toxicity and optimal composition of the drug, the fumaric acid therapy in psoriasis should be seen as experimental.

Topics: Adolescent; Adult; Aged; Dimethyl Fumarate; Double-Blind Method; Drug Therapy, Combination; Esters; Female; Fumarates; Humans; Male; Middle Aged; Psoriasis; Random Allocation

For the past two decades fumaric acid (FA) therapy has become an increasingly popular treatment in Western Europe for psoriasis. FA therapy originally was developed by Schweckendiek and subsequently standardized by Schäfer. Schäfer's fumaric acid compound therapy (FACT) consists of the oral intake of dimethylfumaric acid ester (DMFAE) and several salts of monoethylfumaric acid ester (MEFAE) in combination with topical fumaric acid therapy (1% to 3% MEFAE in an ointment or FA in bathing oils) and a diet. Schäfer claimed excellent results in a large number of patients. Preliminary studies by German dermatologists, however, revealed contradictory therapeutic results and serious side effects, and FA treatment was soon abandoned by dermatologists. To assess the value of FA therapy we conducted an open pilot study of 36 patients in which FACT therapy appeared to be rather effective. Thereafter, several controlled studies with MEFAE sodium in two different dosages versus placebo, and DMFAE versus placebo, were done. The results indicated that MEFAE sodium in dosages up to 240 mg daily was ineffective, whereas daily dosages of 720 mg resulted in a significant decrease in scaling and itching but did not affect extension of the eruption. DMFAE, 240 mg daily, produced a significant amelioration and prevented extension. Side effects of FA treatment were nausea, diarrhea, general malaise, and severe stomachache. Mild disturbances of liver and kidney function during treatment were observed with the 720 mg dosage of MEFAE and with the 240 mg dosage of DMFAE. Moreover, a relative lymphopenia with a selective decrease of suppressor T lymphocytes occurred in about 50% of the patients treated with DMFAE.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Administration, Oral; Clinical Trials as Topic; Double-Blind Method; Female; Fumarates; Humans; Male; Pilot Projects; Psoriasis; Random Allocation

Oral treatment of psoriasis on an outpatient basis, using a preparation containing fumaric acid derivatives, was evaluated as initial monotherapy (3 months) and as long-term basic therapy (12-14 months) in 13 and 11 patients, respectively. The course of the disease was analysed in each individual case. After completion of both parts of the trial, half of the patients that had only responded poorly to conventional antipsoriatic therapy showed a significant improvement which occurred after several weeks of treatment. In 4 patients the medication had to be stopped because of abdominal pain. No severe side effects, particularly of a renal, hepatic or haematological nature, could be established. Studies in mice and rats disclosed only a low acute toxicity of the fumaric acid derivatives used. In additional analyses, hypotheses were dealt with concerning the mechanism of action of fumaric acid in psoriasis. To establish fumaric acid derivatives in the treatment of psoriasis, studies on chronic toxicity and pharmacokinetics will have to be conducted. Further clinical trials should evaluate a single fumaric acid derivative instead of mixtures.

Topics: Animals; Clinical Trials as Topic; Combined Modality Therapy; Dose-Response Relationship, Drug; Female; Fumarates; Humans; Long-Term Care; Male; Mice; Mice, Inbred Strains; Psoriasis

Topics: Administration, Oral; Adult; Blood Urea Nitrogen; Clinical Trials as Topic; Creatinine; Drug Eruptions; Esters; Fever; Fumarates; Glycosuria; Humans; Kidney Diseases; Leukocytes; Male; Middle Aged; Nausea; Psoriasis; Uric Acid; Urobilinogen; Vomiting

Topics: Acitretin; Cohort Studies; Cyclosporine; Fumarates; Humans; Methotrexate; Psoriasis

Real-world data evaluating effectiveness and persistence of systemic therapies for patients with psoriasis are limited. Objectives To determine the effectiveness and persistence of acitretin, ciclosporin, fumaric acid esters (FAEs) and methotrexate in patients with moderate-to-severe psoriasis.. Data from the British Association of Dermatologists Biologics and Immunomodulators Register (BADBIR), a prospective, multicentre pharmacovigilance register of patients with moderate-to-severe psoriasis receiving biologic and/or conventional systemic therapies, were analysed. Eligible patients were ≥ 16 years of age receiving a first course of acitretin, ciclosporin, FAEs or methotrexate between 2007 and 2021 with ≥ 6 months' follow-up. Effectiveness was defined as achieving absolute Psoriasis Area and Severity Index (aPASI) ≤ 2 reported ≥ 4 weeks after treatment start date until date of cessation. To identify baseline clinical variables associated with treatment effectiveness, we used multivariable logistic regression models estimating the adjusted odds ratio (aOR) of achieving aPASI ≤ 2. To describe drug persistence associated with ineffectiveness, occurrence of adverse events or other reasons for discontinuation, survival estimates with 95% confidence intervals (CIs) were obtained using a flexible parametric model. Results were obtained using multiple imputed data.. In total, 5430 patients were included in the analysis. Overall, 1023 (19%) patients were receiving acitretin, 1401 (26%) patients were on ciclosporin, 347 (6%) patients were on FAEs, and 2659 (49%) patients were receiving methotrexate at registration. The proportion of patients who achieved aPASI ≤ 2 was lower for those treated with acitretin [n = 118 (21%)] compared with those receiving ciclosporin [n = 233 (34%)], FAEs [n = 43 (29%)] and methotrexate [n = 372 (32%)]. Factors associated with ineffectiveness included prior experience to previous nonbiologic systemic therapies (acitretin) (aOR 0.64, 95% CI 0.42-0.96), male sex (methotrexate) (aOR 0.58, 95% CI 0.46-0.74), comorbidities (aOR 0.70, 95% CI 0.51-0.97) and alcohol consumption (≤ 14 units per week) (ciclosporin) (aOR 0.70, 95% CI 0.50-0.98). Persistence associated with all reasons for discontinuation showed better survival for methotrexate compared with acitretin, ciclosporin and FAEs cohorts at 12 months [survival estimate 46.1 (95% CI 44.0-48.3), 31.9 (95% CI 29.4-34.7), 30.0 (95% CI 27.5-32.4) and 35.0 (95% CI 29.9-40.9), respectively].. The real-world effectiveness and persistence of acitretin, ciclosporin, FAEs and methotrexate were generally low. Previous nonbiologic systemic therapies, male sex, comorbidities and alcohol consumption were risk factors associated with treatment ineffectiveness.

Topics: Acitretin; Adjuvants, Immunologic; Biological Factors; Cohort Studies; Cyclosporine; Dermatologic Agents; Fumarates; Humans; Immunologic Factors; Male; Methotrexate; Prospective Studies; Psoriasis; Treatment Outcome

Topics: Acitretin; Cohort Studies; Cyclosporine; Fumarates; Humans; Methotrexate; Psoriasis

Topics: Antibodies, Monoclonal; Fumarates; Humans; Psoriasis

Topics: Dimethyl Fumarate; Fumarates; Humans; Immunosuppressive Agents; Italy; Psoriasis

Topics: Adenine; Alanine; Antibodies, Monoclonal, Humanized; Antiviral Agents; Fumarates; Hepatitis B; Hepatitis B virus; Humans; Psoriasis; Tenofovir; Tumor Necrosis Factor Inhibitors

Fumaric acid esters (FAEs) are a well-established treatment option for long-term therapy of moderate to severe plaque psoriasis. This study examines effectiveness of FAEs for the treatment of plaque psoriasis in real-world practice at 12 months and if patient characteristics affect the odds of clinical response.. A descriptive, multivariable logistic regression analysis was conducted in a cohort drawn from the German registry PsoBest. Baseline patient characteristics were assessed as potential treatment effect modifiers.. 444 patients (mean age 47.0 years, 39.0% female) were eligible for response analysis using nonresponder imputation at month 12. Of these, 39.6% achieved clinical response, i.e. Psoriasis Area and Severity Index (PASI) ≤ 3 or skin clearance. In logistic regression analysis (. FAEs showed a favorable response at 12 months, largely independent of patient characteristics.

Topics: Female; Fumarates; Humans; Male; Middle Aged; Psoriasis; Registries; Treatment Outcome

Fumaric acid ester (FAE) is the most commonly prescribed first-line systemic therapy for the treatment of psoriasis in Germany. Although developed in the 1990s, only limited long-term data are available.. Data of 200 adult psoriatic patients from 10 study centers were collected in a noninterventional, multicenter, retrospective analysis. The inclusion criteria was treatment with FAE in 2015.. Eighty-two percent of the patients were naive to systemic treatment. Ten percent of all patients had FAE-treatment for 10 years or longer with an average drug survival of 4.32 years. The maintenance dose was ranging from 1-4 120 mg tablets for 87.5% of the patients. In our population, 14% of the patients stopped therapy during the first six month mainly due to gastro-intestinal side effects. No serious side effects were reported. Seventy-eight percent of the patients responded to FAE therapy with improvement of their psoriasis to mild (61%) or clear (17%). The PASI 75 response was achieved in 44% of the patient during long-term treatment without remarkable differences between moderate or severe plaque psoriasis.. Our study confirms FAE therapy as a long-term, first-line treatment for moderate-to-severe plaque psoriasis.

Topics: Adult; Fumarates; Humans; Psoriasis; Retrospective Studies; Severity of Illness Index; Treatment Outcome

Topics: Antibodies, Monoclonal, Humanized; Dermatologic Agents; Fumarates; Humans; Methotrexate; Psoriasis; Severity of Illness Index; Treatment Outcome

Fumaric acid esters (FAEs) have been used for fifty years to treat moderate-to-severe psoriasis. However, recent case reports of progressive multifocal leukoencephalopathy, associated with FAE-induced lymphopaenia, have been a cause for concern (J Dtsch Dermatol Ges. 2009;7:603).. We report six cases of persistent lymphopaenia following cessation of treatment with FAEs, with a mean duration of lymphopaenia of 33 months.. Given the lack of evidence regarding expected recovery of lymphocyte counts, further research is required to guide physicians in the risk stratification of patients prior to considering treatment with FAEs.

Topics: Aged; Female; Fumarates; Humans; Lymphocyte Count; Lymphopenia; Male; Middle Aged; Psoriasis

Topics: Child; Dimethyl Fumarate; Fumarates; Humans; Psoriasis

Dimethyl fumarate (DMF) is a fumaric acid esters derivate approved for plaque psoriasis as first-line systemic therapy. It has been available in Italy since 2017 and an increasing number of patients are treated with this drug. To evaluate DMF effectiveness, side effects and drug survival in a dermatological real-life setting. We performed a retrospective multi-center study in five dermatologic clinics in Emilia-Romagna, Northern Italy, which included all consecutive patients affected by moderate-severe psoriasis treated with DMF. We assessed effectiveness (in terms of PASI50 and PASI75 in an intention to treat observation) and safety (occurrence of side effects) of DMF and their association with demographic and disease characteristics, mean daily dose taken and treatment discontinuation. We included 103 patients, 78 (75.72%) had at least one comorbidity including 19 (18.44%) with a history of cancer; the mean treatment duration was 23.61 ± 17.99 weeks (min 4, max 130) and the mean daily dose was 262.13 ± 190.94 mg. Twenty-four patients (23.30%) reached PASI75 at week 12, while a further 18 patients (17.47%) reached it at week 26. Side effects occurred in 63 patients (61.16%), the most frequent were diarrhea, epigastric discomfort, nausea, and flushing. Sixteen patients (15.53%) showed an alteration of laboratory tests. In some cases side effects were transitory, while in 53 patients (51.45%) they led to cessation of therapy. The median daily dose showed a direct association with PASI50 achievement and an indirect association with treatment discontinuation. Our study shows the peculiarities of DMF in a real-world setting: effectiveness is often reached after 12 weeks of treatment and side effects could limit the continuation of the therapy but, at the same time, DMF has no major contraindications and, due to the wide range of dosage, it can allow both to manage side effects and to personalize the prescription for each patient.

Topics: Dermatologic Agents; Dimethyl Fumarate; Fumarates; Humans; Psoriasis; Retrospective Studies; Treatment Outcome

Several therapies are available for psoriasis, including in some countries oral fumaric acid derivatives (FADs). Even if FADs are not available in the Italian market, they can be prescribed and reimbursed by the National Health Service, on request from the treating physician, when considered as a valuable option in selected patient.. We performed a retrospective analysis of the PsoReal registry data, restricted to adult psoriatic patients enrolled between 2009 and 2017. Demographic and clinical data were collected together with information on systemic therapies prescribed for psoriasis, drug shifts and adverse effects. We focused our analysis on FADs compared with other systemic drugs.. From the registry data, a total of 17,064 patients were extracted, and 11,592 patients (67.9%), fulfilled inclusion criteria. The majority of them had chronic plaque psoriasis, the mean disease duration was 17.1±12.6 years, and the mean PASI was 17.8±10.9, with 51.5% presenting a moderate Ps (PASI between 10 and 20). A total of 36 patients (0.3%) were treated by FADs. The average treatment duration of conventional (9.0±10.0 months) and biological agents (13.7±11.6 months) was lower compared to the duration of FADs (28.1±20.1, P value<0.001). FADs were used at an average dosage of 361.0±146.3 mg/day and FADs treated patients displayed an overall lower healthcare cost compared with other drugs.. The current study confirms previous European data about efficacy and safety of FADs and suggests a decrease of healthcare costs for FADs treated patients as compared to other treatments.

Topics: Adult; Fumarates; Humans; Italy; Psoriasis; Retrospective Studies; State Medicine

Topics: Antibodies, Monoclonal; Antibodies, Monoclonal, Humanized; Dermatologic Agents; Fumarates; Humans; Psoriasis

Fumaric acid esters (FAE) represent the most widely-used oral systemic treatment for moderate-to-severe psoriasis in Germany. Not licensed outside Germany, little is known about the demographics of patients receiving FAE. PsoBest is a large national patient registry documenting long-term treatment of psoriasis in Germany.. To evaluate FAE relative to methotrexate (MTX) in patients from the PsoBest registry.. Patient demographics, disease severity at baseline and dosing regimen were reported for patients who initiated treatment with either FAE or MTX between 2007 and 2015.. Overall, 1,409 patients treated with FAE and 877 with MTX were analysed. At baseline, compared with the MTX cohort, patients receiving FAE were younger (45.4 vs. 50.2 years; p≤0.001) and had a lower BMI (28.0 vs. 28.3 kg/m. This study contributes to a better understanding of the usual practices of long-term FAE use, which may also lead to improved treatment strategies not only in Germany, but in other countries where FAE may become available in the near future.

Topics: Adolescent; Adult; Aged; Aged, 80 and over; Comorbidity; Dermatologic Agents; Female; Fumarates; Germany; Humans; Hypertension; Male; Methotrexate; Middle Aged; Prevalence; Psoriasis; Quality of Life; Registries; Severity of Illness Index; Time Factors; Young Adult

Plaque psoriasis has significant impact on patients' quality of life. Topical therapy is considered the treatment mainstay for mild-to-moderate disease according to guidelines. Calcipotriol/betamethasone dipropionate (Cal/BD) [0.005%/0.05%] aerosol foam is indicated for psoriasis vulgaris treatment in adults. Cal/BD foam trials demonstrated improved efficacy and similar safety in this population. Psoriasis treatment is complicated by the broad range of disease presentation, variability and therapeutic options; particularly decisions on transition from topical to non-biologic systemic treatment are difficult. Assessing comparative effectiveness of treatment options provides meaningful value to treatment decisions.. To compare efficacy of Cal/BD foam individual patient data from pooled trials with efficacy of non-biologic systemic treatments based on aggregated patient characteristics and treatment outcomes.. Individual data from four Cal/BD foam trials in 749 psoriasis patients were pooled to conduct matching-adjusted indirect comparisons. Literature review identified non-biologic systemic treatment trials where methods, populations and outcomes align with Cal/BD foam trials. Of 3090 screened publications, four studies of apremilast, methotrexate, acitretin or fumaric acid esters (FAE) were included.. After baseline matching, patients treated with 4 weeks of Cal/BD foam had greater Physician's Global Assessment 0/1 response compared to those treated with 16 weeks of apremilast (52.7% vs. 30.4%; P < 0.001). Patients treated with Cal/BD foam had significantly greater Psoriasis Area and Severity Index (PASI) 75 response at Week 4 compared to 16 weeks of apremilast treatment (51.1% vs. 21.6%; P < 0.001). Cal/BD foam patients demonstrated significantly greater PASI 75 response improvements at Week 4 vs. 12 weeks of methotrexate (50.8% vs. 33.5%; P < 0.001) or acitretin (50.9% vs. 31.7%; P = 0.009), and comparable response to FAE (42.4% vs. 47.0%; P = 0.451).. Despite recent treatment advances, unmet needs for psoriasis patients remain. Cal/BD foam offers improved efficacy in baseline matched psoriasis patients compared to apremilast, methotrexate or acitretin, and comparable efficacy to FAE.

Topics: Acitretin; Administration, Cutaneous; Aerosols; Betamethasone; Calcitriol; Dermatologic Agents; Drug Therapy, Combination; Esters; Female; Fumarates; Humans; Male; Methotrexate; Middle Aged; Psoriasis; Thalidomide; Treatment Outcome

Fumaric acid esters (FAEs) are used for systemic therapy of moderate to severe psoriasis. Until recently, only a mixture of dimethyl fumarate (DMF) and three salts of ethyl hydrogen fumarate was available. However, a drug containing DMF as the sole ingredient was registered for the same indication in 2017. This prospective study aimed to investigate the switch from the currently used FAE mixture to DMF alone.. Forty patients were consecutively recruited, for whom the FAE mixture was switched to DMF alone on the basis of the last DMF-equivalent dose without interrupting treatment. At the first check-up after switching, the efficacy and tolerability of the DMF drug was compared with that of the previous treatment.. The data show that the efficacy remained unchanged in the majority of patients. Tolerability (e.g. gastrointestinal complaints and flushing) of the DMF drug was rated equal or better in most patients than with the previous treatment.. The results show that it is possible to switch psoriasis patients under stable therapy with the FAE mixture to the DMF drug directly and without interruption.

Topics: Administration, Oral; Adolescent; Adult; Aged; Dermatologic Agents; Dimethyl Fumarate; Drug Administration Schedule; Drug Substitution; Female; Fumarates; Humans; Male; Middle Aged; Prospective Studies; Psoriasis; Treatment Outcome; Young Adult

Fumaric acid esters (FAEs) are used to treat psoriasis and are known to cause lymphopenia in roughly 60% of the patients. Much remains to be elucidated about the biological effects of FAEs on lymphocytes.. To evaluate the influence of long-term FAE (Fumaderm. In this single-centre retrospective observational subcohort study, we obtained leucocyte and lymphocyte subset counts before initiating FAE therapy in 371 psoriasis patients (mean age, 47.8 years; 63.3% males) and monitored them during treatment (mean treatment duration, 2.9 years). Multiparametric flow cytometry was used for immunophenotyping.. FAEs significantly reduced the numbers of CD4. Monitoring distinct T-cell subsets rather than just absolute lymphocyte counts may provide more meaningful insights into both the FAE treatment safety and efficacy. We therefore suggest optimizing pharmacovigilance by additionally monitoring CD4

Topics: Adolescent; Adult; Aged; Aged, 80 and over; Child; Dermatologic Agents; Esters; Female; Fumarates; Humans; Immunophenotyping; Lymphopenia; Male; Middle Aged; Psoriasis; Retrospective Studies; T-Lymphocytes; Young Adult

Topics: Dermatologic Agents; Dimethyl Fumarate; Esters; Fumarates; Humans; Psoriasis

Neutrophil (polymorphonuclear) granulocytes (PMN) have been shown to contribute to the pathogenesis of psoriasis by releasing interleukin-17 and LL37-DNA complexes via neutrophil extracellular traps (NETs), webs of chromatin strands decorated with antimicrobial peptides, in psoriatic skin. Fumaderm. To elucidate the effect of FAE treatment on human psoriasis and healthy donor NET formation.. Among the compounds present in the FAE formulation, dimethyl fumarate (DMF) pretreatment of human psoriasis and healthy donor PMN resulted in a consistent inhibitory effect on NET formation in response to phorbol 12-myristate 13-acetate but not to platelet activating factor and ionomycin. This effect was l-glutathione (GSH) dependent and involved a decrease in reactive oxygen species (ROS) production, a key event in NET formation. In contrast, G-protein-coupled signalling and protein synthesis were not involved. Monomethyl fumarate (MMF) was found to slightly reduce ROS production without affecting NET formation.. We report DMF as a potent, stimulus-specific, GSH- and ROS-dependent modulator of NET formation. Our results support the notion that modulation of NET formation contributes to the beneficial effects of FAEs in a variety of inflammatory conditions.

Topics: Analysis of Variance; Antioxidants; Caspases; Cells, Cultured; Dermatologic Agents; Dimethyl Fumarate; Dose-Response Relationship, Drug; Extracellular Traps; Fumarates; Glutathione; GTP-Binding Proteins; Humans; Ionomycin; Platelet Activating Factor; Psoriasis; Reactive Oxygen Species; Superoxides; Tetradecanoylphorbol Acetate

Topics: Adalimumab; Adolescent; Adult; Age Factors; Aged; Aged, 80 and over; Biological Products; Dermatologic Agents; Etanercept; Female; Fumarates; Humans; Male; Medication Adherence; Methotrexate; Middle Aged; Psoriasis; Sex Factors; Ustekinumab; Young Adult

Biologics have greatly improved psoriasis management. However, primary and secondary non-response to treatment requires innovative strategies to optimize outcomes.. To describe the use of combined treatment of biologics with conventional systemic agents or phototherapy in daily clinical practice.. We collected data on frequency of use, demographics, treatment characteristics and drug survival of biologics combined with conventional systemic agents or phototherapy in five PSONET registries.. Of 9922 biologic treatment cycles, 982 (9.9%) were identified as combination treatment. 72.9% of treatment cycles concerned concomitant use of methotrexate, 25.3% concerned concomitant UVB therapy, acitretin or cyclosporin and 1.8% concerned combined treatment with PUVA, fumaric acids or a second biologic. Substantial variation was detected in type and frequency of combination treatments prescribed across registries. Patients initiated on combined treatment had generally severe disease and were affected with psoriasis for many years. The extent to which patients had been priory treated with biologic monotherapy and the proportion of patients affected with psoriatic arthritis differed between registries. Survival rates for etanercept, adalimumab, infliximab and ustekinumab with methotrexate ranged between 43 and 92%, 28 and 83%, 65 and 87% and 53 and 77%, respectively, across registries after one year with no consistent superior survival for a particular biologic. Longest survival on a biologic combined with methotrexate, acitretin or cyclosporin was 103, 78 and 34 months, respectively.. Methotrexate was the most commonly used concomitant treatment for patients on a biologic. Wide geographical variations in treatment selection and persistence of combination treatment exist. Data derived from ongoing studies may help to determine whether combined treatment is superior to biologic monotherapy.

Topics: Acitretin; Adalimumab; Austria; Biological Products; Combined Modality Therapy; Cyclosporine; Czech Republic; Dermatologic Agents; Drug Therapy, Combination; Etanercept; Female; Fumarates; Humans; Infliximab; Israel; Italy; Kaplan-Meier Estimate; Male; Methotrexate; Middle Aged; Netherlands; Psoriasis; PUVA Therapy; Registries; Severity of Illness Index; Ustekinumab

Topics: Adolescent; Adult; Aged; Aged, 80 and over; Female; Fumarates; Humans; Lymphocyte Count; Lymphopenia; Male; Middle Aged; Pharmacovigilance; Psoriasis; Retrospective Studies; Risk Assessment; Young Adult

Fumaric acid has an important role in the citric acid cycle. Its esters were first used by a German chemist to treat his own psoriasis, hypothesizing that the disease may be related to disturbances in this very cycle. Meanwhile, the mechanisms underlying its anti-inflammatory efficacy are much better understood. A monosubstance derived from the mix of esters used originally is now being authorized for treating multiple sclerosis, and in 2017 dimethylfumaric acid ester became a globally available option to treat psoriasis. This very practical therapeutic will most likely become quite popular amongst patients. Therefore, general practitioners might need to familiarize themselves with the profile of this drug, including its potential risks and some very rare but potentially important adverse effects.. L’acide fumarique joue un rôle important dans le cycle de Krebs. Ses esters ont été utilisés pour la première fois par un chimiste allemand pour traiter son propre psoriasis dans l’hypothèse d’une implication du cycle de Krebs. Depuis, les mécanismes anti-inflammatoires des esters d’acide fumarique ont été mieux décrits. Une mono-substance dérivée du mélange d’esters original est désormais autorisée pour traiter la sclérose en plaques. En 2017, le diméthylfumarate a été ainsi reconnu globalement comme une option thérapeutique pour le psoriasis. Très pratique, ce médicament deviendra probablement très populaire chez les patients. Pour cette raison, les médecins généralistes devraient se familiariser avec son profil pharmacologique, y compris ses risques potentiels et certains effets indésirables rares mais potentiellement dangereux.

Topics: Dietary Supplements; Esters; Fumarates; Humans; Multiple Sclerosis; Psoriasis

Topics: Dimethyl Fumarate; Fumarates; Humans; Prospective Studies; Psoriasis

Fumaric acid esters (FAEs) are an established systemic treatment for moderate-to-severe psoriasis. However, the long-term clinical safety and effectiveness of continuous FAE monotherapy and combination therapy have not been established.. To examine the long-term safety and effectiveness of FAEs as monotherapy and in combination with phototherapy or methotrexate in patients with psoriasis treated at a single centre in Germany.. This monocentric, retrospective observational study, with a follow-up period of up to 32.5 years, included 859 patients: 626 received FAE monotherapy, 123 received FAEs with concomitant phototherapy and 110 received FAEs with methotrexate.. Approximately half of patients (49.0%) reported adverse events (566 total events), most of which involved the gastrointestinal tract. Serious adverse events were reported in 2.3% of patients, but none were deemed to have a causal relationship with any of the treatment regimens. Adverse events leading to treatment discontinuation were observed in 12.9% of patients. A median duration of 1 year was observed in all three treatment subcohorts (P = 0.70) from initiation of FAE treatment to a 50% response rate, where response was defined as achieving a cumulative static Physician's Global Assessment (PGA) score of 'light' and at least a 2-point reduction in baseline PGA. A 50% response rate for the cumulative Psoriasis Area and Severity Index 75 was achieved in the FAE monotherapy subcohort after a median of 3 years of treatment, in the FAEs + phototherapy subcohort after 6.7 years and in the FAEs + methotrexate subcohort after 8.1 years (P = 0.001).. According to our data, FAEs as monotherapy or in combination with phototherapy or methotrexate are safe and beneficial for long-term clinical use. However, multicentre, randomized controlled trials are required to establish the clinical value of monotherapy versus combination therapy and the optimal treatment duration.

Topics: Adolescent; Adult; Aged; Aged, 80 and over; Child; Dermatologic Agents; Drug Therapy, Combination; Esters; Female; Fumarates; Humans; Longitudinal Studies; Male; Methotrexate; Middle Aged; Psoriasis; PUVA Therapy; Retrospective Studies; Severity of Illness Index; Young Adult

Psoriasis is a complex inflammatory and hyperproliferative skin disease. The pathogenesis and mechanisms involved are not completely understood, which makes treatment a difficult issue. Angiotensin II, the most active peptide of the renin-angiotensin system, seems to be involved in processes related to psoriasis pathogenesis, such as inflammation and cell proliferation. The aim of this study was to investigate the influence of renin inhibition on inflammation parameters and keratinocyte proliferation in a mouse model of chronic skin inflammation induced by croton oil. Aliskiren had anti-inflammatory effects by reducing levels of tumor necrosis factor-α and interleukin -6, and by inhibiting myeloperoxidase activity. Aliskiren also showed antiproliferative activity by reducing epidermal hyperplasia and proliferating cell nuclear antigen levels. Aliskiren treatment did not induce alterations in the cardiovascular system, normal skin thickness, and organ weight. These results suggest that aliskiren could be a valuable tool to be incorporated in the treatment of hyperproliferative and inflammatory skin disorders such as psoriasis.

Topics: Amides; Angiotensin II; Animals; Anti-Inflammatory Agents; Antihypertensive Agents; Cardiovascular System; Disease Models, Animal; Female; Fumarates; Inflammation; Keratinocytes; Mice; Psoriasis; Renin; Renin-Angiotensin System; Skin Diseases

Fumaric acid esters (FAEs) are a systemic treatment for psoriasis considered to have a favourable long-term safety profile without an increased risk for immunosuppression. However, progressive multifocal leukoencephalopathy (PML), a rare, opportunistic viral infection of the central nervous system, has been linked anecdotally to FAE treatment.. To assess clinical features and outcomes of FAE-associated PML cases.. Systematic literature search in multiple databases up to 25th February 2016 for reports of PML in psoriasis patients treated with FAEs.. Eight cases (four male, four female) of FAE-associated PML were identified. Median age was 64 years (range 42-74 years); median FAE treatment duration was 3 years (range 1.5-5 years). Six patients were treated with a formulation containing dimethyl fumarate (DMF) and monoethyl fumarates, and two patients with a DMF formulation. Patients exhibited neurological symptoms, such as aphasia, hemiparesis and dysarthria. PML diagnosis was based on MRI findings and presence of JC virus in cerebrospinal fluid and/or brain tissue. All cases were linked to moderate-to-severe reductions in absolute lymphocyte counts, with nadirs ranging from 200 to 792 cells per mm. Progressive multifocal leukoencephalopathy is infrequently linked to FAE treatment, but underreporting cannot be excluded. Physicians treating patients with FAEs should be vigilant for the occurrence of PML, and both clinicians and patients should be alert for onset of new neurological symptoms. Periodic monitoring of lymphocyte counts and FAE discontinuation in case of moderate-to-severe lymphocytopenia is recommended to minimize the risk for PML.

Topics: Adult; Aged; Female; Fumarates; Humans; Leukoencephalopathy, Progressive Multifocal; Lymphocyte Count; Male; Middle Aged; Psoriasis; Risk Factors; Treatment Outcome

Oxidative stress contributes to inflammatory skin diseases, including psoriasis. Monomethylfumarate (MMF) is an antipsoriatic agent with a poorly understood mechanism of action. In other cell types MMF increases the expression of nuclear factor erythroid-derived 2-like 2 (Nrf2), a transcription factor that regulates cellular antioxidant responses, to reduce oxidative stress like that observed in inflammatory disorders such as multiple sclerosis. We tested the hypothesis that MMF enhances Nrf2 activity in keratinocytes, thereby improving their capacity to counteract environmental stresses. We used Western analysis, immunofluorescence, and real-time quantitative reverse-transcription polymerase chain reaction to examine the effect of MMF on the expression of Nrf2 and its targets. We also measured intracellular reactive oxygen species (ROS) levels following MMF treatment. Our data show that MMF increased total and nuclear Nrf2 levels in primary mouse keratinocytes and enhanced mRNA expression of several Nrf2-downstream effectors, including heme oxygenase-1 and peroxiredoxin-6. Moreover, MMF treatment attenuated the generation of ROS following hydrogen peroxide treatment. On the other hand, the expression and membranous localization of aquaporin-3 (AQP3), a glycerol channel implicated in keratinocyte differentiation, was stimulated by MMF, which also enhanced keratinocyte glycerol uptake. The Nrf2 activator sulforaphane also increased AQP3 levels, suggesting that AQP3 expression may be regulated by Nrf2. We show for the first time that MMF stimulates Nrf2 and AQP3 expression and function/activity in keratinocytes. This effect may account, in part, for the previously observed ability of MMF to inhibit proliferation and inflammatory mediator production and promote differentiation in keratinocytes and to treat psoriasis.

Topics: Animals; Animals, Newborn; Aquaporin 3; Base Sequence; Cells, Cultured; Fumarates; Gene Expression; Keratinocytes; Maleates; Mice; NF-E2-Related Factor 2; Psoriasis; RNA, Messenger

Is there any influence of a therapy with TNF-alpha inhibitors or fumaric acid esters and of disease activity status on male fertility and sperm quality in patients with psoriasis?. In this monocentric, open-label, prospective study, semen samples were collected from patients receiving either TNF-alpha inhibitors or fumaric acid esters for moderate-to-severe plaque psoriasis. Semen was analysed at baseline before onset of the systemic therapy and monitored every 3 months under therapy. Sperm parameters were assessed according to the current WHO definitions.. In total, 101 semen specimens from 27 patients were obtained. Mean Psoriasis Area and Severity Index (PASI) score at baseline was 11.05. Only 14.8% of patients showed a normozoospermia without any other abnormal seminal values. 85.2% of patients had at least one sperm/seminal abnormality, including two patients showing an azoospermia. Interestingly, 48.1% showed sperm parameters indicative of genital tract inflammation. Therapy with TNF-alpha inhibitors or fumaric acid esters did not have any negative effects on relevant sperm parameters such as mean total sperm number, sperm concentration, total and progressive motility. No major gonadal dysfunction was observed in any patient.. At baseline, many patients with psoriasis showed abnormal semen/sperm parameters and remarkably elevated leukocytes and values of seminal polymorphonuclear elastase, indicating a genital tract inflammation. Thus, genital tract inflammation may represent an important comorbidity of psoriasis, little attention paid to so far. Regarding treatment with TNF-alpha inhibitors or fumaric acid esters, no major negative (side-) effects on sperm quality were observed.

Topics: Fertility; Fumarates; Humans; Male; Prospective Studies; Psoriasis; Spermatozoa; Tumor Necrosis Factor-alpha

Psoriasis vulgaris often leads to a significant impaired quality of life and dissatisfaction with the existing therapeutic approaches. However, patients' quality of life and treatment satisfaction are of utmost importance, since it is positively related to therapy adherence and encourages patient's compliance. The study described herein evaluates the quality of life, treatment satisfaction and efficacy during the initial 6 months of treatment with a non-biological systemic agent in a real-life clinical setting.. This observational study compares quality of life, treatment satisfaction and the efficacy of non-biological systemic therapy between 60 patients suffering from plaque psoriasis receiving the non-biological systemic therapies with apremilast, methotrexate and fumaric acid esters.. Ethics approval was provided by the ethics committee of the medical faculty of the University of Heidelberg. Ethics approval number is S-298/2015. The design and the final results of the study will be published and made available to the public.. German Clinical Trial Register (DRKS): DRKS00008721 (https://www.germanctr.de/).

Topics: Adult; Anti-Inflammatory Agents, Non-Steroidal; Dermatologic Agents; Fumarates; Humans; Methotrexate; Patient Compliance; Patient Satisfaction; Personal Satisfaction; Pilot Projects; Prospective Studies; Psoriasis; Quality of Life; Thalidomide

Fumaric acid esters (FAEs) are a well-established efficacious systemic treatment for psoriasis. Recent recommendations from the European Medicines Agency suggest monitoring of full blood count every 4 weeks for the duration of therapy for psoriasis. The aim of our study was to assess the incidence of lymphopenia in patients taking FAEs and the impact of recent recommendations for our practice.. We reviewed 151 patients treated with FAEs for psoriasis between December 2013 and 2015.. Lymphopenia <700 × 109/L was detected within the last 12 months in 36/151 (24%) and lymphopenia <500 × 109/L in 10/151 (7%). Of 39 patients no longer on treatment, 7 (18%) stopped because of persistent lymphopenia.. The implementation of these recommendations would have significant resource implications and also likely influence the acceptability of FAEs to patients. Cessation of FAEs necessitates the need for alternative therapy, commonly biologic therapy.

Topics: Blood Cell Count; Drug Monitoring; Esters; Fumarates; Humans; Lymphopenia; Practice Guidelines as Topic; Psoriasis

Fumaric acid esters (FAEs) are a broadly used therapy option for patients suffering from moderate-to-severe plaque psoriasis. Various studies in psoriasis have already shown peripheral blood lymphopenia during oral FAE therapy. Smaller studies also documented a reduction of CD4+ and CD8+ cell counts. Up to now, there are few case reports on opportunistic infections under FAE therapy - all of them associated with lymphopenia.. To examine the influence of FAEs on white blood cells with special regard to leukocytes, lymphocytes, and CD4+ and CD8+ cells during psoriasis therapy.. A cohort of 105 patients with diagnosed moderate-to-severe chronic plaque psoriasis was enrolled in this single-centre observational trial. For a cohort of 36 patients, T-cell subset analyses were performed.. Of the total, 65 patients were male (61.9%) and 40 (38.1%) female; the mean age was 43.3 years (range 16-73 years). The median lymphocyte count was significantly reduced by about 35.8% after the first 6 months of therapy. When assessing the lymphocyte count nadir over the whole period observed, 46.7% of the patients developed lymphopenia. Severe lymphopenia (<500/µL) was documented in 11.4% of the patients. The CD4+ and CD8+ cell counts were significantly reduced by about 30.2 and 45.3%, respectively.. To the best of our knowledge this is the largest clinical investigation analysing prospectively CD4+ and CD8+ cell counts in psoriasis patients receiving FAEs. We suggest periodic monitoring of absolute lymphocyte counts as well as the establishment of the determination of T-cell subsets prior to and during therapy.

Topics: Adolescent; Adult; Aged; CD4-Positive T-Lymphocytes; CD8-Positive T-Lymphocytes; Female; Follow-Up Studies; Fumarates; Humans; Lymphocyte Count; Lymphopenia; Male; Middle Aged; Prospective Studies; Psoriasis; Young Adult

Topics: Dimethyl Fumarate; Fumarates; Healthy Volunteers; Humans; Hydrolases; Indoleamine-Pyrrole 2,3,-Dioxygenase; Kynurenine; Leukocytes, Mononuclear; Maleates; Primary Cell Culture; Psoriasis

Fumaric acid esters (FAE) have been used for over 30 years in the management of psoriasis. There have been a number of case reports linking the use of FAE with nephrotoxicity, including acute renal injury and Fanconi syndrome. However, one large multicentre retrospective trial showed no evidence of renal dysfunction with FAE.. The aim of this study was to determine the number of patients in our institution being treated with FAE who developed significant proteinuria or renal dysfunction.. This was a single-centre retrospective study assessing all patients on FAE who attended for follow-up during an 18-week period between February and June 2015. Demographics, comorbidities, duration and dose of treatment with FAE, proteinuria, renal function and other biochemical serum abnormalities were recorded.. One hundred and twenty-seven patients were included in the study. Eighty-two patients had proteinuria detected at some stage during treatment with FAE, and 18 of these had persistent proteinuria (positive in at least three consecutive specimens, 12 weeks apart). Six patients (five female) developed proximal tubular dysfunction (PTD). The risk factors for the development of PTD appear to be lower bodyweight (P = 0.03), higher dose per weight (P = 0.03) and longer duration of treatment (P = 0.03). Renal dysfunction improved on discontinuation or dose reduction in FAE.. Fumaric acid esters are frequently associated with transient or persistent proteinuria. Significant renal dysfunction is rare and usually reversible on dose reduction or discontinuation of FAE. This study highlights the importance of screening for proteinuria. Higher doses per weight of treatment and longer duration of FAE therapy are likely risk factors for PTD.

Topics: Adult; Aged; Aged, 80 and over; Body Weight; Creatinine; Cross-Sectional Studies; Dermatologic Agents; Fanconi Syndrome; Female; Fumarates; Glomerular Filtration Rate; Humans; Male; Middle Aged; Proteinuria; Psoriasis; Retrospective Studies; Risk Factors; Time Factors; Young Adult

Fumarates or fumaric acid esters derivates (FAED) have appeared to be effective and less toxic than other systemic treatments for psoriasis. Due to its safe adverse event profile, FAED can be used as a long-term maintenance therapy. One of the greatest reasons why FAED are not preferred as a first-line treatment is that according to the recommended dosing schedule, clinically meaningful improvement is seen just after 6 to 8 weeks of therapy. In this manuscript, we suppose an alternative induction scheme with a combination therapy of fumarates and cyclosporine for a more rapid improvement and better compliance.

Topics: Cyclosporine; Drug Therapy, Combination; Fumarates; Humans; Patient Compliance; Psoriasis

Given that there is no standard systemic treatment for children and adolescents with plaque psoriasis, this non-interventional, multicenter, retrospective study collected data on the efficacy and safety of long-term treatment with fumaric acid esters (FAEs) in this particular patient group.. In patients younger than 18 years of age at the start of FAE treatment, data on efficacy and safety was retrospectively collected for at least 36 months.. Data from 127 patients (aged 6-17 years) was collected for treatment durations of up to 60 months. Physician's Global Assessment, Psoriasis Area and Severity Index, and Body Surface Area showed marked improvement in the first six months. After 36 months, these parameters had, on average, improved by up to two-thirds of baseline values. Thirty-seven patients experienced at least one adverse event (AE), which was FAE-related in 36 individuals. Three AEs (proteinuria (one case), flushing (two cases)) persisted during the observation period while on treatment. Fifteen AEs led to the discontinuation of therapy; nearly all of these cases were related to gastrointestinal disorders.. The KIDS FUTURE study - for the first time - included a larger population of children and adolescents with psoriasis who were treated with FAEs. The data obtained suggests that long-term FAE therapy in this patient group may be effective and safe. The results are currently being verified in an ongoing clinical study.

Topics: Adolescent; Age Distribution; Child; Dermatologic Agents; Female; Fumarates; Germany; Humans; Longitudinal Studies; Male; Prevalence; Psoriasis; Retrospective Studies; Risk Factors; Sex Distribution; Treatment Outcome

Fumaric acid esters (FAE) are beneficial in the treatment of psoriasis. However, about a third of psoriasis patients do not respond to FAE. We aimed to determine whether glutathione-S-transferase (GST) M1 and GSTP1 polymorphisms are associated with treatment outcome in psoriasis patients treated with FAE. We studied 84 psoriasis patients who were treated with FAE for 3 months. FAE nonresponders were defined as having psoriasis area and severity improvement index less than 50% after 3-month therapy. GSTM1 genotyping for gene deletion and GSTP1 exon 5 105 Ile→Val polymorphisms were assessed using a high-resolution melting analysis. A dropout rate of 23.8% (20/84) was found; 25% (16/64) were FAE nonresponders. We observed 42 (84/50%) patients with G 9STM1*0 homozygous alleles and 42 (84/50%) patients with one or two active GSTM1 alleles. The Ile/Ile GSTP1 genotype was observed in 37 (84/44%), the Ile/Val GSTP1 genotype in 38 (84/45.2%) patients and the Val/Val GSTP1 genotype in nine (84/10.7%) patients. There was no significant (P>0.05) association between the GST genotypes assessed and the frequency FAE responder status, except for the Val/Val GSTP1 polymorphism, which was a significant (overall model fit; P=0.0012) predictor for nonresponders with an odds ratio of 43.4 (95% confidence interval: 4.2-511.1). The coefficient of regression was 3.9, with a SE of 1.2 as assessed by logistic regression analysis (P=0.0017). The Val/Val GSTP1 polymorphism predicts nonresponders in FAE treatment of psoriasis patients and may therefore serve as a biomarker that enables a laboratory-based pretreatment selection of patients.

Topics: Adult; Aged; Female; Fumarates; Glutathione S-Transferase pi; Humans; Male; Middle Aged; Pharmacogenomic Variants; Psoriasis; Severity of Illness Index; Treatment Outcome; Valine

Psoriasis vulgaris is a common, chronic inflammatory skin disease with a prevalence of 1.5-2% in Western industrialized countries. A relevant percentage of patients suffer from moderate-to-severe psoriasis and experience a significant reduction in quality of life. The choice of an adequate therapy could help to prevent disease and exacerbation of comorbidity, which could increase quality of life, avoid hospitalization and avoid reduction of working days. The present guidelines are focused on the initiation and management of systemic therapies in cases of moderate-to-severe plaque-type psoriasis in adults to optimize treatment response, adherence and quality of life. This first version of the Swiss S1 guidelines presents therapeutic recommendations which are based on a systematic literature search as well as an informal expert consensus of dermatologists in Switzerland.

Topics: Acitretin; Biological Factors; Cyclosporine; Dermatology; Fumarates; Glucocorticoids; Humans; Immunosuppressive Agents; Psoriasis; Societies, Medical; Switzerland; Thalidomide

Topics: Fumarates; Humans; Psoriasis; Severity of Illness Index

Monomethylfumarate (MMF) is thought to be the bioactive ingredient of the drug Fumaderm (Biogen Idec, Cambridge, MA), licensed in Germany since 1994 for the treatment of moderate-to-severe psoriasis. Psoriasis is a common inflammatory hyperproliferative skin disorder that involves cross-talk between different cell types, including immune cells and keratinocytes. Psoriatic lesions are characterized by hyperproliferation, aberrant differentiation, and inflammation, with the psoriatic cytokine network maintained by communication between immune cells and keratinocytes. Recently, there is increasing evidence regarding the pivotal role of keratinocytes in mediating the disease process, and these cells can be regarded as safe therapeutic targets. From the data available on human subjects treated with Fumaderm, MMF is an effective antipsoriatic agent with known effects on immune cells. However, little is known about its direct effects on keratinocytes. We hypothesized that MMF has direct antiproliferative, prodifferentiative, and anti-inflammatory effects on keratinocytes. Indeed, MMF dose-dependently inhibited [(3)H]thymidine incorporation into DNA, indicating a direct antiproliferative action on keratinocytes. MMF significantly increased the protein level of keratin 10, the early keratinocyte differentiation marker, and the activity of transglutaminase, a late differentiation marker. These results are consistent with an ability of MMF to promote keratinocyte differentiation and inhibit proliferation, thereby improving psoriatic lesions. In 12-O-tetradecanoylphorbol-13-acetate (TPA)-induced keratinocytes, MMF significantly inhibited the expression of the proinflammatory cytokines, tumor necrosis factor-α (TNFα), interleukin-6, and interleukin-1α as well as the production of TNFα. Our results support the notion that MMF has direct antiproliferative, prodifferentiative, and anti-inflammatory effects on keratinocytes, highlighting its potential use as a multifactorial antipsoriatic agent.

Topics: Animals; Anti-Inflammatory Agents; Cell Differentiation; Cell Proliferation; Dose-Response Relationship, Drug; Endothelial Cells; Female; Fumarates; Gene Expression Regulation; Keratinocytes; Male; Maleates; Mice; Psoriasis; RNA, Messenger; Tumor Necrosis Factor-alpha

Topics: Acitretin; Adolescent; Child; Child, Preschool; Cyclosporine; Dapsone; Dermatologic Agents; Fumarates; Humans; Immunosuppressive Agents; Methotrexate; Practice Patterns, Physicians'; Psoriasis; United Kingdom

Patients with psoriasis have an increased risk of cardiovascular disease that is partly attributable to chronic systemic inflammation. The aim of our prospective pilot study was to investigate the impact of fumaric acid esters (FAE), a first-line systemic antipsoriatic treatment in Germany, on cardiovascular risk parameters. Participants with moderate-to-severe psoriasis from the University Medical Center Mannheim and the University Hospital Würzburg were treated with FAE for 16 weeks according to standard dosage recommendations. Disease severity, life quality and depression scores as well as biomarkers of inflammation, lipid and glucose metabolism were assessed prior to initiation of FAE and after 16 weeks. Out of 39 participants recruited, 27 completed the study. 44% of all participants and 63% of those completing the 16-week treatment achieved PASI 50 response and 27 or 37% PASI 75 response. Clinical improvement was paralleled by significant improvement in quality of life, high treatment satisfaction and significant reduction of depressive symptoms. Adverse events, most frequently mild gastrointestinal complaints, flush and lymphocytopenia occurred in 89%. FAE did not modify glucose metabolism or inflammatory parameters substantially. However, a highly significant increase in serum levels of the atheroprotective cytokine adiponectin was noted after 16 weeks (median 4.7 vs. 8.9 µg/ml; p = 0.0002). Our study demonstrates a significant beneficial impact of FAE on adiponectin, indicating a potential cardioprotective effect. It will be interesting to verify this finding in larger cohorts and to assess the long-term influence of FAE on cardiovascular risk and disease.

Topics: Adiponectin; Adult; Biomarkers; Blood Glucose; Cardiovascular Diseases; Depressive Disorder; Esters; Female; Fumarates; Humans; Inflammation; Lipid Metabolism; Male; Middle Aged; Pilot Projects; Prospective Studies; Psoriasis; Risk Factors

In the literature as well as in existing psoriasis guidelines, only little evidence is available on combination regimens with systemic antipsoriatic agents. However, if systemic monotherapy is not efficacious enough to control the disease, a combination therapy might be necessary.. To evaluate the use of fumaric acid esters (FAEs) in combination with other antipsoriatic agents in 6 specialized dermatological departments in Germany.. A systematic retrospective chart review of patients receiving FAEs was performed.. A total of 17 cases of patients receiving FAEs combined with at least one other systemic therapy (methotrexate, acitretin, etanercept, cyclosporine, leflunomide and infliximab) to treat psoriasis or psoriatic arthritis were identified.. FAEs can be combined in an off-label setting with conventional as well as biological agents to treat recalcitrant psoriasis or psoriatic arthritis. Safety monitoring should be taken seriously as no controlled data for these combination regimens exist.

Topics: Acitretin; Adult; Aged; Anti-Inflammatory Agents; Cyclosporine; Dermatologic Agents; Drug Therapy, Combination; Etanercept; Female; Fumarates; Germany; Humans; Infliximab; Isoxazoles; Keratolytic Agents; Leflunomide; Male; Methotrexate; Middle Aged; Prednisolone; Psoriasis; Retrospective Studies

Topics: Dimethyl Fumarate; Fatal Outcome; Female; Fumarates; Humans; Immunosuppressive Agents; Leukocyte Count; Leukoencephalopathy, Progressive Multifocal; Lymphocyte Count; Lymphopenia; Middle Aged; Opportunistic Infections; Psoriasis

Topics: Acitretin; Adalimumab; Anti-Inflammatory Agents, Non-Steroidal; Cyclosporine; Drug Therapy, Combination; Etanercept; Fumarates; Humans; Immunosuppressive Agents; Keratolytic Agents; Methotrexate; Psoriasis; Ustekinumab

Glutathione S-transferases (GSTs) are involved in detoxification of xenobiotics such as fumaric acid esters (FAE).. To perform GSTT1 geno- and phenotyping in psoriasis patients treated with FAE to find out whether the responder status and/or occurrence of side-effects are associated with allelic variants and enzymatic activity of GSTT1.. We treated 106 psoriasis patients with FAE. GSTT1 genotyping was performed using PCR, phenotyping was carried out by means of a validated high performance liquid chromatography assay at baseline and under treatment.. The distribution of GSTT1 genotypes was as follows: 31% *A/*A; 49% *A/*0; 20% *0/*0. GSTT1 phenotypes as expressed in enzyme activity significantly differed between conjugators classes. (P < 0.001). GSTT1 activity under treatment was significantly (P = 0.0001) increased when compared with baseline. There were no significant associations between the aforementioned GSTT1 pheno- and genotypes and clinical parameters such as psoriasis area and severity index (PASI)50, adverse effects and FAE dosage (P > 0.05), except for the frequent occurrence of reduction (>50%) of circulating lymphocytes in patients with *0/*0 GSTT1 status (P = 0.036; odds ratio: 6, 95% CI: 1.1-32).. GSTT1 geno- and phenotypes significantly correlate in psoriasis patients and do not substantially differ from healthy controls. Response to FAE does likely not depend on GSTT1. However, *0/*0 GSTT1 status is a predictor for the occurrence of marked reduction of lymphocyte counts under FAE therapy. Notably, FAE seem to enhance GSTT1 enzyme activity in high and low conjugators.

Topics: Administration, Oral; Adult; Aged; Chromatography, High Pressure Liquid; Esters; Female; Fumarates; Genotype; Glutathione Transferase; Humans; Male; Middle Aged; Molecular Sequence Data; Phenotype; Psoriasis

Psoriasis vulgaris is a T-cell mediated disease that affects 2-3% of the worldwide white-skinned population. Fumaric acid esters are mentioned as an effective therapy for moderate-to-severe psoriasis vulgaris in adult patients in the new guidelines for psoriasis treatment.. To obtain an insight into the use of fumaric acid esters by Dutch dermatologists in the Netherlands.. This was a cross-sectional postal survey. An anonymous survey was posted to all Dutch dermatologists. In this survey, data were collected on the extent of fumaric acid esters use, the reasons for use, the reasons for non- or limited use of fumaric acid esters, the perception of fumaric acid esters as a mono-therapy with regards to the effectiveness, the safety, the adverse events and the overall satisfaction of fumaric acid esters as a mono-therapy.. Sixty-three per cent of the 300 responders indicated to prescribe fumaric acid esters for the treatment of psoriasis. About 37% of the dermatologists indicated (almost) never to prescribe it. Biologicals were considered as the most effective therapy. Fumaric acid esters were regarded as the safest therapy. They were generally well-tolerated by the patients similar to that for methotrexate according to the respondents.. A large proportion of the dermatologists in our survey indicated to prescribe fumaric acid esters. It is considered to be effective, safe and without adverse events profile that is favourable in the practice, also as compared with other systemic therapies such as methotrexate and biologicals.

Topics: Biological Products; Cross-Sectional Studies; Dermatology; Fumarates; Health Surveys; Humans; Methotrexate; Netherlands; Practice Patterns, Physicians'; Psoriasis; Severity of Illness Index; Treatment Outcome

Fumaric acid esters (FAEs) have been used for over 30 years in the management of psoriasis.. To determine drug survival of FAEs in patients with psoriasis, treatment-limiting adverse drug events and the range of effective drug doses.. A retrospective, single-centre study assessing all patients commenced on FAEs between October 2003 and July 2012. Demographic data, length of treatment, reasons for discontinuation of FAEs, side-effects and range of doses were recorded.. Two hundred and forty-nine patients [160 (64%) male] were included. The mean age at which FAEs were commenced was 44·5 years (range 17-82 years). The mean length of treatment was 28 months (range 1 week to 106 months). In patients who were commenced on FAEs ≥ 4 years before inclusion in this study, the 4-year drug survival was 60% (64/107). FAEs were discontinued in 146/249 patients (59%); this was due to lack of efficacy in 59/146 (40%) and gastrointestinal upset in 39/146 (27%). A very low dose of FAEs (< 240 mg daily) was successful in maintaining control of psoriasis in 26 (10%) patients. The mean treatment duration of these patients was 64 months (range 32-106 months).. Fumaric acid esters have a 4-year drug survival rate of 60%, which compares favourably with reported 4-year survival rates of 40% for etanercept and adalimumab and 70% for infliximab. Longer drug survival is more likely in the significant subgroup of patients in whom a very low dose of FAEs is sufficient to control disease. The reasons for this are unclear.

Topics: Adolescent; Adult; Aged; Dermatologic Agents; Drug Administration Schedule; Drug Substitution; Female; Fumarates; Humans; Long-Term Care; Male; Medication Adherence; Middle Aged; Psoriasis; Retrospective Studies; Young Adult

Topics: Antibodies, Monoclonal; Antibodies, Monoclonal, Humanized; Cerebellum; Dimethyl Fumarate; Fumarates; Humans; Leukoencephalopathy, Progressive Multifocal; Male; Psoriasis; Treatment Outcome

Fumaric acid esters (FAEs) are effective in patients with moderate to severe psoriasis. Recent studies also report the efficacy of one FAE component, dimethylfumarate, in relapsing forms of multiple sclerosis (MS). We describe the case of a patient with MS who developed severe plaque psoriasis during interferon-β-1a treatment for MS. The psoriasis was unresponsive to usual topical treatments and phototherapy. The patient was started on FAE 720 mg daily, with complete remission of the psoriatic lesions and neurological stabilization at follow-up at 24 months. Our case suggests that FAEs could represent a therapeutic option for patients with MS who develop plaque psoriasis following exposure to immune-modulating agents.

Topics: Adjuvants, Immunologic; Drug Eruptions; Esters; Fumarates; Humans; Immunosuppressive Agents; Interferon beta-1a; Interferon-beta; Male; Middle Aged; Multiple Sclerosis, Relapsing-Remitting; Psoriasis; Treatment Outcome

Patients with psoriasis suffer from chronic skin disease and impaired quality of life. With a prevalence of 1-3% of the population, psoriasis is one of the most common chronic inflammatory autoimmune diseases. Fumaric acid esters (Fumaderm(®)) are approved for the treatment of psoriasis in Germany, but regular Fumaderm therapy with six tablets per day is often limited due to adverse events.. This observational study recorded data on quality of life, treatment efficacy and drug dosing in patients suffering from psoriasis treated with Fumaderm under conditions of daily practice in 78 dermatological centres.. In this prospective, multicentre, noninterventional trial we included adult patients with severe plaque psoriasis under outpatient conditions receiving Fumaderm according to the current summary of product characteristics for systemic treatment of psoriasis. At baseline and after 3, 6 and 12 months the dosing regimen under daily conditions, Dermatology Life Quality Index (DLQI) and clinical efficacy with the Psoriasis Area and Severity Index (PASI) were documented.. A total of 249 patients were included. The mean DLQI score at study entry was 9·95; the mean PASI was 16·8. The average treatment dose of Fumaderm was 2·8 tablets daily. More than 70% of patients were treated with one to three tablets daily and < 30% were treated with a dose ranging from four to six tablets daily. DLQI and PASI improved in the entire study population by 67·2% and 66·6%, respectively. Specifically, when analysing patients who started Fumaderm within 4 weeks before baseline the mean DLQI score decreased from 11·8 to 2·9 (75% reduction) and the mean PASI score from 19·84 to 7·35 after 12 months (63% improvement).. This is the first field study analysing the use of Fumaderm and the improvement of quality of life in patients with psoriasis under daily outpatient conditions. The improvement of DLQI obtained with Fumaderm was comparable with the improvement observed in patients with psoriasis treated with modern biologics. Importantly, in most patients with good clinical response, the treatment dose was one to three tablets daily.

Topics: Adolescent; Adult; Aged; Aged, 80 and over; Dermatologic Agents; Dimethyl Fumarate; Dose-Response Relationship, Drug; Drug Substitution; Female; Fumarates; Humans; Male; Middle Aged; Prospective Studies; Psoriasis; Quality of Life; Tablets; Treatment Outcome; Young Adult

Fumaric acid esters (FAEs) are widely used in Europe for the treatment of psoriasis because of their clinical efficacy and favourable safety profile. However, the mechanisms of action by which FAEs improve psoriasis remain largely unknown.. To identify pathways and mechanisms affected by FAE treatment and to compare these with pathways affected by treatment with the antitumour necrosis factor (anti-TNF)-α biologic etanercept.. In a prospective cohort study, 50 patients with plaque psoriasis were treated with FAEs for 20 weeks. Nine patients were randomly selected for gene expression profiling of plaque biopsies from week 0 and week 12. The groups consisted of FAE responders [> Psoriasis Area and Severity Index (PASI)-75 improvement] and nonresponders (< PASI-50 improvement). Changes in gene expression profiles were analysed using Ingenuity Pathway Analysis (IPA) and the outcome was compared with gene expression affected by etanercept.. Response to FAE treatment was associated with a ≥ 2-fold change (P < 0.05) in the expression of 458 genes. In FAE responders the role of interleukin-17A in the psoriasis pathway was most significantly activated. Glutathione and Nrf2 pathway molecules were specifically induced by FAE treatment and not by etanercept treatment, representing an FAE-specific effect in psoriatic skin. In addition, FAE treatment specifically induced the transcription factors PTTG1, NR3C1, GATA3 and NFκBIZ in responding patients.. FAE treatment induces glutathione and Nrf2 pathway genes in lesional skin of patients with psoriasis. In responders, FAEs specifically regulate the transcription factors PTTG1, NR3C1, GATA3 and NFκBIZ, which are important in normal cutaneous development, and the T-helper (Th)2 and Th17 pathways, respectively.

Topics: Administration, Oral; Adult; Aged; Biological Factors; Dermatologic Agents; Etanercept; Female; Fumarates; Gene Expression; Gene Expression Profiling; Genes, Regulator; Humans; Immunoglobulin G; Male; Middle Aged; Prospective Studies; Psoriasis; Receptors, Tumor Necrosis Factor; Signal Transduction; Tablets; Transcription Factors; Young Adult

Topics: Adult; Antiviral Agents; Demyelinating Diseases; Dimethyl Fumarate; Fumarates; Humans; Immunosuppressive Agents; Interferons; Magnetic Resonance Imaging; Male; Psoriasis

Psoriasis is one of the most common inflammatory skin disorders. There are only limited data on systemic treatment in children.. To assess the safety and clinical efficacy of the treatment of six paediatric patients with fumaric acid esters (FAE, Fumaderm) for psoriasis.. Six patients aged 6-17 years were treated with FAE. Patients underwent regular assessment. Treatment efficacy was evaluated using the Psoriasis Area and Severity Index (PASI) and body surface area (BSA).. The mean duration of treatment was 17.8 months. PASI and BSA were determined after 12 weeks. All patients showed improvement in their skin condition, two achieving PASI75, one PASI90 and three PASI100 response. Proteinuria was encountered in one patient and two patients suffered from gastrointestinal discomfort. Treatment was discontinued due to remission in two patients.. Treatment with FAE in paediatric patients is a valuable alternative option when systemic treatment is needed.

Topics: Academic Medical Centers; Administration, Oral; Adolescent; Child; Dermatologic Agents; Dimethyl Fumarate; Dose-Response Relationship, Drug; Drug Administration Schedule; Female; Follow-Up Studies; Fumarates; Germany; Humans; Male; Maximum Tolerated Dose; Psoriasis; Retrospective Studies; Sampling Studies; Severity of Illness Index; Time Factors; Treatment Outcome

Topics: Dermatologic Agents; Female; Fumarates; Genes, Regulator; Humans; Male; Psoriasis

Topics: Aged; Colitis, Collagenous; Dermatologic Agents; Dimethyl Fumarate; Dose-Response Relationship, Drug; Female; Fumarates; Humans; Psoriasis; Treatment Outcome

Topics: Aspirin; Flushing; Fumarates; Germany; Guideline Adherence; Humans; Psoriasis

Safety and efficacy of fumaric acid esters (FAE) in patients with psoriasis requiring treated comorbidit condition were investigated.. Data collected from 7 dermatology centers were used for a retrospective analysis of patients treated continuously with FAE for at least 6 weeks who required at least one medication for a comorbid condition. The records were analyzed at baseline and after 1, 3, 6, 12 and 24 months of therapy. Safety parameters were monitored and the severity of skin symptoms was assessed by 'Physician's Global Assessment' (PGA).. A total of 69 patients with moderate to severe psoriasis and a mean duration of 27.4 months of continuous treatment were included in the study. In less than 5% were interactions between FAE and co-medications observed. Changes of hepatic, renal or hematological laboratory parameters were usually insignificant and required a modification of FAE treatment in less than 12% of the cases. The percentage of patients documented as markedly improved or clear was 61% after 6 months, 77% after 12 months, and 75% after 24 months of therapy.. In patients with moderate to severe psoriasis on co-medications, FAE were effective and safe without any noteworthy drug interactions.

Topics: Cardiovascular Diseases; Comorbidity; Dermatologic Agents; Drug-Related Side Effects and Adverse Reactions; Female; Fumarates; Germany; Humans; Male; Metabolic Diseases; Middle Aged; Prevalence; Psoriasis; Retrospective Studies; Risk Assessment; Treatment Outcome

Topics: Aged; Brain; Dermatologic Agents; Fumarates; Humans; Immune Reconstitution Inflammatory Syndrome; Immunologic Deficiency Syndromes; Leukoencephalopathy, Progressive Multifocal; Male; Psoriasis

Topics: Adult; Dermatologic Agents; Dimethyl Fumarate; Drug Compounding; Female; Fumarates; Humans; Leukoencephalopathy, Progressive Multifocal; Magnetic Resonance Imaging; Paresis; Pharmacies; Psoriasis

Fumaric acid esters (FAE) are used as an effective and safe oral treatment for plaque psoriasis in adult patients, but little is known about their efficacy and safety in children with psoriasis.. To assess the effectiveness and safety of FAE in the treatment of paediatric psoriasis.. This is a retrospective analysis of 14 paediatric patients with psoriasis (age <18 years) treated with FAE between 2004 and 2012 at several Dutch university and regional clinics. Patients were identified through databases or registries.. The median age at the start of FAE treatment was 15 years (range 8-17 years). The median duration of FAE treatment was 10 months (range 1-80 months), and the median maintenance dosage per day was 360 mg dimethylfumarate (range 240-600 mg). Five patients (36%) achieved a complete clearance of their psoriasis, one patient (7%) had a good improvement, three patients (21%) had a partial response and five patients (36%) were nonresponders. FAE treatment was well tolerated, but two patients (14%) discontinued FAE, one with severe diarrhoea and one with flushes. Five patients (36%) had transient, slightly abnormal laboratory values of liver-function tests or leucocytes that did not necessitate FAE dosage reduction or treatment discontinuation. No serious adverse events occurred.. In this retrospective case series FAE seemed to be an effective and safe treatment for children with psoriasis. FAE may be an attractive therapeutic alternative to the currently used systemic immunosuppressive agents for paediatric patients with psoriasis. Further studies are needed to evaluate the suitability of FAE in paediatric psoriasis.

Topics: Adolescent; Child; Dimethyl Fumarate; Female; Fumarates; Humans; Immunosuppressive Agents; Male; Netherlands; Psoriasis; Retrospective Studies; Severity of Illness Index; Time Factors; Treatment Outcome

Mast cells modulate autoimmune diseases such as psoriasis and multiple sclerosis. Fumaric acid esters (FAEs) are widely used for the treatment of psoriasis, and dimethylfumarate (DMF) has recently been approved for multiple sclerosis. In this study, we analysed the cytotoxic effect of FAEs on human mast cells. Specifically, cell death was analysed in the human mast cell line HMC-1 and in primary cord blood-derived mast cells (CBMCs) after incubation with fumaric acid (FA), monomethylfumarate (MMF), DMF and calcium bis(monomethylfumarate) (Ca-MF). Our data show that only DMF potently induces apoptotic cell death in HMC-1 cells and CBMCs. DMF-mediated apoptosis was associated with increased expression of Bax and Bak and activation of caspase-9 and caspase-6. Interestingly, DMF also enhanced the sensitivity of CBMCs towards TRAIL- and dexamethasone-induced apoptosis. These findings demonstrate for the first time that DMF induces apoptosis of human mast cells, primarily via the mitochondrial apoptotic pathway. Our study contributes to the understanding of the beneficial effects of FAEs in autoimmune diseases and provides a rationale for exploiting FAEs for other diseases associated with mast cells.

Topics: Apoptosis; bcl-2 Homologous Antagonist-Killer Protein; bcl-2-Associated X Protein; Calcium; Caspase 6; Caspase 9; Cell Death; Cell Line; Dermatologic Agents; Dexamethasone; Dimethyl Fumarate; Etoposide; Fumarates; Humans; Interleukin-8; Maleates; Mast Cells; Methotrexate; Psoriasis; TNF-Related Apoptosis-Inducing Ligand

To compare the clinical efficacy of methotrexate (MTX) vs. fumaric acid esters (FAE) in psoriasis treated under daily life conditions.. Data were extracted from a registry (http://www.psoriasisregistry.at) of 272 adult patients with moderate-to-severe chronic plaque psoriasis treated primarily with MTX (n = 72) or FAE (n = 200) between 2004 and 2011. Data from all patients, including those who did not complete at least 3 months of monotherapy, were included in an intention-to-treat (ITT) worst-case analysis.. Thirty of 72 (41.7%) patients treated with MTX and 85 of 200 (42.5%) patients treated with FAE discontinued early, mainly due to side-effects or lack of response. Among patients who completed at least 3 months of treatment, the response to primary treatment with MTX vs. FAE did not differ significantly at any time point. In the ITT worst-case analysis at month 3, complete remission rate, PASI90, PASI75 and PASI50 rates were 6%, 7%, 24% and 39% in MTX-treated patients vs. 1%, 5%, 27% and 44% in FAE-treated patients. Overall mean PASI reduction score improved significantly in response to primary MTX and FAE treatment (by 10.6% and 12.6%, respectively) between 3 and 6 months (P = 0.0005; exact Wilcoxon test), but not between 6 and 12 months (P = 0.16). A subset of 32 patients who did not respond satisfactorily to primary treatment with FAE responded better to subsequent MTX therapy (P < 0.0001; paired Wilcoxon test).. As shown by retrospective analysis, the primary efficacy of FAE was similar to that of MTX under daily life conditions.

Topics: Adult; Chronic Disease; Fumarates; Humans; Immunosuppressive Agents; Methotrexate; Middle Aged; Psoriasis; Registries; Retrospective Studies; Severity of Illness Index

Density functional theory (DFT) calculations at B3LYP/6-31 G (d,p) and B3LYP/6-311+G(d,p) levels for the substituted pyridine-catalyzed isomerization of monomethyl maleate revealed that isomerization proceeds via four steps, with the rate-limiting step being proton transfer from the substituted pyridinium ion to the C=C double bond in INT1. In addition, it was found that the isomerization rate (maleate to fumarate) is solvent dependent. Polar solvents, such as water, tend to accelerate the isomerization rate, whereas apolar solvents, such as chloroform, act to slow down the reaction. A linear correlation was obtained between the isomerization activation energy and the dielectric constant of the solvent. Furthermore, linearity was achieved when the activation energy was plotted against the pKa value of the catalyst. Substituted-pyridine derivatives with high pKa values were able to catalyze isomerization more efficiently than those with low pKa values. The calculated relative rates for prodrugs 1-6 were: 1 (406.7), 2 (7.6×10(6)), 3 (1.0), 4 (20.7), 5 (13.5) and 6 (2.2×10(3)). This result indicates that isomerizations of prodrugs 1 and 3-5 are expected to be slow and that of prodrugs 2 and 6 are expected to be relatively fast. Hence, prodrugs 2 and 3-5 have the potential to be utilized as prodrugs for the slow release of monomethylfumarate in the treatment of psoriasis and multiple sclerosis.

Topics: Catalysis; Computer Simulation; Fumarates; Humans; Isomerism; Kinetics; Maleates; Models, Molecular; Multiple Sclerosis; Prodrugs; Psoriasis; Pyridines; Quantum Theory; Solvents; Thermodynamics

Fumarates are approved for the systemic treatment of moderate and severe psoriasis vulgaris in Germany. However, a number of studies and case reports indicate their efficacy in the treatment of further inflammatory skin disorders or granulomatous skin diseases.. To examine the efficacy and safety of fumarates for the treatment of granulomatous and inflammatory skin diseases other than psoriasis vulgaris.. The therapeutic efficacy and side-effects of fumarate therapy were analysed retrospectively in patients with granuloma annulare (GA, n = 4), cutaneous sarcoidosis (SA, n = 1), lichen planus (LP, n = 3), pityriasis rubra pilaris (PRP, n = 1) or chronic discoid lupus erythematosus (CDLE, n = 1).. Six patients (GA: 3/4; LP: 2/3; PRP: 1/1) showed complete clearance and two patients (GA: 1/3; SA: 1/1) had a partial response, and the CDLE patient showed stable disease under a combination therapy with hydroxychloroquine. Side-effects associated with fumarate therapy were seen in seven of ten patients and resolved spontaneously upon dose reduction or discontinuation of the therapy.. According to this data, fumarates may represent a new approach in the treatment of granulomatous and inflammatory skin diseases other than psoriasis vulgaris. For the first time, the successful treatment of LP and CDLE with fumarates is reported. Side-effects are not limiting in most cases, but can hamper a dose escalation.

Topics: Adolescent; Adult; Aged; Dermatitis; Female; Fumarates; Granuloma; Humans; Male; Middle Aged; Off-Label Use; Psoriasis; Retrospective Studies; Treatment Outcome

Topics: Adenosine Triphosphate; Adult; Aged; Biomarkers; CD4-Positive T-Lymphocytes; Female; Flow Cytometry; Fumarates; Germany; Humans; Immunosuppressive Agents; Male; Middle Aged; Pilot Projects; Psoriasis; Time Factors; Treatment Outcome

Overexpression of antimicrobial peptides and proteins (AMPs) such as human β-defensin-2 (hBD2), LL37, and psoriasin has frequently been observed in lesional skin of psoriasis patients. We aimed to evaluate whether circulating AMP levels correlate with disease severity, and change under therapy with fumaric acid esters (FAE). We studied psoriasis patients who underwent systemic therapy using oral FAE (Fumaderm(®)). An enzyme-linked immunosorbent assay for the detection of serum protein expression of hBD2, LL37, and psoriasin was performed at baseline and after 12-week therapy. After 12-week FAE treatment of 28 patients, the median PASI significantly (P < 0.0001) decreased from 27.1 to 12.5. In psoriasis patients, mean ± SD serum hBD2, psoriasin, and LL37 levels at baseline were 295.6 ± 93.5 pg/ml, 79.4 ± 32.7 ng/ml, and 106.3 ± 90 ng/ml, respectively, which were significantly increased when compared to healthy controls (110 ± 53.7 pg/ml, P ≤ 0.0001; 3.1 ± 0.7 ng/ml, P ≤ 0.0001; 3.8 ± 0.9 ng/ml, P = 0.0004, respectively). After 12-week FAE treatment, a significant increase of serum hBD2 (339.7 ± 74.3 pg/ml; P = 0.0046), psoriasin (106 ± 58.9 ng/ml; P = 0.0014), and LL37 (136.6 ± 115.1 ng/ml; P = 0.0035) was observed. Correlation studies did not reveal significant relationships between serum AMP levels and PASI (r < 0.1; P > 0.05). In contrast to AMP expression in psoriatic skin serum, AMP levels seem not to correlate with disease severity. Increased serum AMP protein levels in psoriasis resolution are an unexpected observation that needs to be investigated more in detail in future studies.

Topics: Adult; Antimicrobial Cationic Peptides; beta-Defensins; Cathelicidins; Female; Fumarates; Humans; Male; Middle Aged; Psoriasis; S100 Calcium Binding Protein A7; S100 Proteins; Severity of Illness Index

Response pathways of the metabolic and the immune system have been evolutionary conserved, resulting in a high degree of integrated regulation. Insulin is a central player in the metabolic system and potentially also in the homeostasis of the skin. Psoriasis is a frequent and often severe autoimmune skin disease, clinically characterized by altered epidermal homeostasis, of which the molecular pathomechanisms are only little understood. In this study, we have examined a potential role for insulin signaling in the pathogenesis of this disease. We show that IL-1β is present in high quantities in tissue fluid collected via microdialysis from patients with psoriasis; these levels are reduced under successful anti-psoriatic therapy. Our results suggest that IL-1β contributes to the disease by dual effects. First, it induces insulin resistance through p38MAPK (mitogen-activated protein kinase), which blocks insulin-dependent differentiation of keratinocytes, and at the same time IL-1β drives proliferation of keratinocytes, both being hallmarks of psoriasis. Taken together, our findings point toward insulin resistance as a contributing mechanism to the development of psoriasis; this not only drives cardiovascular comorbidities, but also its cutaneous phenotype. Key cytokines inducing insulin resistance in keratinocytes and kinases mediating their effects may represent attractive targets for novel anti-psoriatic therapies.

Topics: Cell Proliferation; Cells, Cultured; Epidermis; Female; Fumarates; Homeostasis; Humans; Insulin Resistance; Interleukin-1beta; Keratinocytes; Male; p38 Mitogen-Activated Protein Kinases; Psoriasis

Topics: Adult; Aged; Dermatologic Agents; Esters; Female; Fumarates; Humans; Ireland; Male; Middle Aged; Psoriasis; Retrospective Studies; Young Adult

Topics: Drug Eruptions; Flushing; Fumarates; Humans; Male; Middle Aged; Pigmentation Disorders; Psoriasis

Fumaric acid esters are considered efficacious and safe drugs for the treatment of psoriasis. Renal damage, caused either by acute renal injury or Fanconi syndrome, is a recognized side-effect of this therapy.. To investigate whether the measurement of urinary excretion of β2-microglobulin, a marker of renal proximal tubular dysfunction, allows early detection of kidney damage before an increase in serum creatinine or significant proteinuria occurs.. Urinary β2-microglobulin excretion was measured regularly in 23 patients undergoing fumaric acid ester therapy.. Urinary β2-microglobulin remained normal in all 10 male patients. Three (23%) out of 13 female patients experienced an increase in urinary β2-microglobulin excretion. In two of these patients a sharp increase was observed in association with high doses. One further patient had moderately elevated levels on rather low doses of fumaric acid esters. After discontinuing treatment, urinary β2-microglobulin levels returned to normal within a few weeks.. Determination of urinary β2-microglobulin possibly allows early detection of renal damage by fumaric acid esters. Female patients seem to be prone to this side-effect, especially when taking high doses.

Topics: Acute Kidney Injury; Adult; beta 2-Microglobulin; Biomarkers; Early Diagnosis; Female; Fumarates; Humans; Kidney Function Tests; Male; Middle Aged; Psoriasis

Severe psoriasis is associated with significant cardiovascular mortality.. We investigated the effects of continuous systemic therapy on the cardiovascular risk of patients with severe plaque-type psoriasis.. A total of 42 consecutive patients receiving systemic treatment for their severe plaque-type psoriasis were included. The clinical course was monitored over 24 weeks. Initially as well as after 12 and 24 weeks, oral glucose tolerance tests were performed along with comprehensive laboratory monitoring.. Responding patients, defined as a Psoriasis Area and Severity Index (PASI)-50 response, showed correlations between the PASI and high-sensitive C-reactive protein (r = 0.45, P = 0.03) as well as with vascular endothelial growth factor (r = 0.76, P = 0.007). The adipokine resistin was positively and the potentially cardio-protective adiponectin was negatively correlated with the PASI (r = 0.50, P = 0.02 and r = -0.56, P = 0.007, respectively). Oral glucose tolerance tests yielded a correlation between the PASI and plasma levels for C-peptide (r = 0.73, P = 0.02) at t = 120 min in patients with a pathological Homeostasis Model Assessment (>2.5), indicating that the state of peripheral insulin resistance is driven at least in part by the severity of the psoriatic inflammation. Correlations between the change of adipokine levels and change in PASI were more pronounced among patients with better clinical improvement (PASI-75 vs. PASI-50).. We document an amelioration of biomarkers of cardiovascular risk in patients with severe plaque-type psoriasis responding to continuous systemic therapy. The impact on the patients'metabolic state was found to be better if the psoriatic inflammation was controlled for longer. Future studies need to compare the cardioprotective effects of different treatment modalities, based on hard clinical endpoints.

Topics: Adalimumab; Adipokines; Adult; Aged; Antibodies, Monoclonal, Humanized; Biomarkers; C-Reactive Protein; Cardiovascular Diseases; Cyclosporine; Etanercept; Female; Fumarates; Humans; Immunoglobulin G; Longitudinal Studies; Male; Methotrexate; Middle Aged; Prospective Studies; Psoriasis; Receptors, Tumor Necrosis Factor; Resistin; Risk Factors; Severity of Illness Index; Treatment Outcome; Vascular Endothelial Growth Factor A

Microdialysis is a novel technique suitable to analyse soluble mediators in the skin compartment. We applied this methodical approach to monitor changes in the micromilieu of psoriatic plaques under therapy. Tissue fluid was collected from lesional and non-lesional skin of three patients with severe plaque-type psoriasis prior to as well as after 12 weeks of continuous oral therapy with fumaric acid esters. Concentrations of a spectrum of cytokines and adipokines were measured using a commercial fluorescent bead immunoassay. The procedure was well tolerated even without local anaesthesia. Prior to initiation of therapy, we found elevated levels for IL-2, IL-6, IL-18, IL-23, and resistin in lesional versus non-lesional skin, whereas adiponectin levels were higher in non-lesional skin. All patients showed significant clinical improvement under treatment, paralleled by reduced concentrations of IL-6, IL-18, IL-23, and resistin, but not IL-2 and adiponectin in lesional skin. Thus, we were able to demonstrate through microdialysis a shift in the micromilieu of psoriatic plaques, characterized by reduced levels of pro-inflammatory mediators in three patients under effective systemic anti-inflammatory therapy with fumaric acid esters. Our observations need to be confirmed by larger studies. This approach is limited by practical aspects as it is very time-consuming, but suitable to directly explore pathomechanisms causing the psoriatic phenotype in general and insulin resistance in the skin compartment in particular.

Topics: Adiponectin; Administration, Oral; Adult; Epidermis; Female; Fumarates; Humans; Interleukin-18; Interleukin-2; Interleukin-23; Interleukin-6; Longitudinal Studies; Male; Microdialysis; Middle Aged; Prospective Studies; Psoriasis; Resistin

The fumaric acid esters (FAEs) have been used for the oral treatment of psoriasis for some 50 years. Given that a persistent and maintained angiogenesis is associated with several cutaneous diseases, including psoriasis, we sought in our study to gain further insight into their mechanism of action by investigating whether FAEs are able to interfere with angiogenesis mechanisms. Our results demonstrate that dimethylfumarate (DMF) inhibits certain functions of endothelial cells, namely, differentiation, proliferation, and migration. This activity was not exhibited by similar concentrations of monomethylfumarate or fumaric acid. Our data indicate that DMF inhibits the growth of transformed and nontransformed cells in a dose-dependent manner. The growth-inhibitory effect exerted by this compound on proliferating endothelial cells could be due, at least in part, to an induction of apoptosis. Inhibition by DMF of the mentioned essential steps of in vitro angiogenesis is consistent with the observed inhibition of in vivo angiogenesis, substantiated using chick chorioallantoic membrane and live fluorescent zebrafish embryo neovascularization assays. The antiangiogenic activity of DMF may contribute to the antipsoriatic, antitumoral, and antimetastatic activities of this compound and suggests its potential in the treatment of angiogenesis-related malignancies.

Topics: Angiogenesis Inhibitors; Animals; Apoptosis; Cattle; Cell Movement; Cell Proliferation; Cells, Cultured; Chick Embryo; Dimethyl Fumarate; Endothelial Cells; Fumarates; Humans; Mice; Psoriasis; Vascular Endothelial Growth Factor Receptor-2; Zebrafish

Dimethylfumarate (DMF) is used in the treatment of psoriasis. Macrophage migration inhibitory factor (MIF) is elevated in patients with severe psoriasis. We studied the effect of DMF on the MIF-induced activation of the mitogen- and stress-activated kinase 1 (MSK1) and p90 kDa ribosomal S6 kinase (RSK1) signaling pathways which regulate the proliferation of human keratinocytes via transcription factors.. The effects of DMF on the MIF-induced activation of MSK1, RSK1, cAMP-responsive element-binding protein (CREB), Cox-2 and c-Jun, JunB and p53 were studied by Western blotting using phospho-specific antibodies.. DMF inhibited the MIF-induced phosphorylation of MSK1, RSK1, CREB and JunB, and reduced Cox-2 expression and the proliferation of cultured human keratinocytes. The expression of p-p53 (S15) was induced simultaneously with the inhibition of Cox-2. Addition of DMF before MIF induced nuclear expression of p-c-Jun (S63) and c-Jun. Transfection with small interfering MSK1 and RSK1 RNA before MIF incubation stimulated p-p53 (S15) and nuclear p-c-Jun (S63) similarly to DMF.. Our results indicate that the specific inhibitory effects of DMF on RSK1 and MSK1 activation together with the induction of p-c-Jun (S63) and p-p53 (S15) lead to the inhibition of keratinocyte proliferation, partly explaining the anti-psoriatic effect of DMF.

Topics: Cell Proliferation; Cells, Cultured; Cyclic AMP Response Element-Binding Protein; Dermatologic Agents; Dimethyl Fumarate; Flavonoids; Fumarates; Humans; JNK Mitogen-Activated Protein Kinases; Keratinocytes; Macrophage Migration-Inhibitory Factors; Psoriasis; Ribosomal Protein S6 Kinases, 90-kDa; Signal Transduction; Tumor Suppressor Protein p53

Topics: Biological Therapy; Dermatologic Agents; Fumarates; Humans; Immunosuppressive Agents; Methotrexate; Psoriasis

Moderate to severe psoriasis is common in childhood and adolescence and is often a challenge for the treating dermatologist. In most cases, systemic therapies in children are only available 'off-label'. Fumaric acid esters (FAEs) have been used successfully in the treatment of moderate to severe psoriasis in adults and are recommended for long-term treatment in the German S3 guideline. In childhood psoriasis, FAEs may be a treatment alternative if a systemic therapy is indicated. Here, we report about the successful long-term treatment with FAEs in a male child with severe psoriasis.

Topics: Adrenal Cortex Hormones; Child; Drug Therapy, Combination; Fumarates; Humans; Long-Term Care; Lymphocyte Count; Male; Psoriasis; Severity of Illness Index; Vitamin D

Topics: Angiogenesis Inhibitors; Dimethyl Fumarate; Fumarates; Humans; Male; Middle Aged; Neoplasms; Psoriasis

Fumarate esters--an oral therapy for psoriasis--are used primarily in Europe, but not at all in the United States. Given that biological therapies are exceedingly expensive and pose an increased risk for infections and malignancy, the need for safer and less expensive therapies for psoriasis is compelling. Nonbiological therapies for psoriasis, including methotrexate and systemic retinoids, carry potentially severe side effects and relatively high cost. Fumarate, a natural product that is generated internally in humans during the Krebs cycle, is an attractive alternative to these therapies. However, the mechanism for fumarate's activity in psoriasis remains unknown.

Topics: Angiogenesis Inhibitors; Citric Acid Cycle; Dimethyl Fumarate; Fumarates; Humans; Hypoxia-Inducible Factor 1, alpha Subunit; Isocitrate Dehydrogenase; Psoriasis

The basis of induction therapy for psoriasis in Germany is the S3-guideline which for moderate to severe psoriasis recommends the systemic agents fumaric acid esters, methotrexate, cyclosporine and the biologicals infliximab, etanercept, adalimumab and ustekinumab. Systemic glucocorticosteroids (GCS) are not proposed.. To what extend are systemic glucocorticosteroids prescribed in psoriasis therapy?. The database of a German nationwide statutory health insurance 2007 was analyzed. Prescriptions of systemic glucocorticosteroids were identified by ATC-encoding. Psoriasis patients with comorbidities requiring systemic glucocorticosteroid medication were analyzed separately.. Among 1,423,308 continuously insured patients in 2007 n = 34,728 (2.4 %) were patients with psoriasis. The most prescribed systemic agents were corticosteroids (2774 patients), followed by methotrexate (853), fumaric acid esters (342), retinoids (110) and cyclosporine A (105). Even after excluding patients with psoriatic arthritis, systemic corticosteroids were still the most often prescribed systemic drugs. The average number of DDD (Defined Daily Doses) per insured patient was 120 (general practitioners), 141 (internists) and 68 (dermatologists). These results were confirmed by a control analysis with IMS data.. In Germany, psoriasis is often treated with systemic corticosteroids though these are not recommended by the S3-guideline. General practitioners and internists are the main prescribers.

Topics: Administration, Oral; Adrenal Cortex Hormones; Anti-Inflammatory Agents; Cyclosporine; Drug Utilization; Female; Fumarates; General Practice; Germany; Guideline Adherence; Humans; Internal Medicine; Male; Methotrexate; Off-Label Use; Psoriasis; Retinoids

Fumaric acid esters (FAE) have been used in the treatment of psoriasis for many years. In general, they are regarded as relatively safe compared with other antipsoriatic systemic treatments, with the most notable adverse effects being gastrointestinal upset, lymphopenia and transient flushing. Renal toxicity has only rarely been reported, and was not found in two independent prospective trials nor in a large retrospective evaluation of almost 1000 patients treated for a median of 44 months. We report three patients developing reversible proteinuria during FAE treatment. One of these displayed the same pattern upon repeated drug administration, thereby clearly indicating FAE treatment to be the causal trigger. The presented cases highlight proteinuria as a clinical concern in FAE treatment. Furthermore, as the novel FAE agent dimethylfumaric (DMF) ester (contained in BG00012/Panaclar) has previously been shown to be effective in psoriasis in a phase III trial and not shown renal toxicity in a large trial for multiple sclerosis, the current report suggests that market introduction of DMF for psoriasis should be pursued.

Topics: Adolescent; Dermatologic Agents; Female; Fumarates; Humans; Male; Middle Aged; Proteinuria; Psoriasis

Topics: Administration, Oral; Alopecia Areata; Autoimmune Diseases; Biological Availability; Clinical Trials as Topic; Comorbidity; Dermatologic Agents; Dimethyl Fumarate; Dose-Response Relationship, Drug; Drug Administration Schedule; Education; Etanercept; Follow-Up Studies; Fumarates; Humans; Immunoglobulin G; Metabolic Clearance Rate; Pilot Projects; Prospective Studies; Psoriasis; PUVA Therapy; Quality of Life; Receptors, Tumor Necrosis Factor; Registries; Sick Role

Fumarates improve multiple sclerosis (MS) and psoriasis, two diseases in which both IL-12 and IL-23 promote pathogenic T helper (Th) cell differentiation. However, both diseases show opposing responses to most established therapies. First, we show in humans that fumarate treatment induces IL-4-producing Th2 cells in vivo and generates type II dendritic cells (DCs) that produce IL-10 instead of IL-12 and IL-23. In mice, fumarates also generate type II DCs that induce IL-4-producing Th2 cells in vitro and in vivo and protect mice from experimental autoimmune encephalomyelitis. Type II DCs result from fumarate-induced glutathione (GSH) depletion, followed by increased hemoxygenase-1 (HO-1) expression and impaired STAT1 phosphorylation. Induced HO-1 is cleaved, whereupon the N-terminal fragment of HO-1 translocates into the nucleus and interacts with AP-1 and NF-κB sites of the IL-23p19 promoter. This interaction prevents IL-23p19 transcription without affecting IL-12p35, whereas STAT1 inactivation prevents IL-12p35 transcription without affecting IL-23p19. As a consequence, GSH depletion by small molecules such as fumarates induces type II DCs in mice and in humans that ameliorate inflammatory autoimmune diseases. This therapeutic approach improves Th1- and Th17-mediated autoimmune diseases such as psoriasis and MS by interfering with IL-12 and IL-23 production.

Topics: Animals; Cell Differentiation; Dendritic Cells; Encephalomyelitis, Autoimmune, Experimental; Female; Fumarates; Heme Oxygenase-1; Humans; Interleukin-12; Interleukin-23; Macrophages; Mice; Multiple Sclerosis; NIH 3T3 Cells; Promoter Regions, Genetic; Psoriasis; Reactive Oxygen Species; Signal Transduction; T-Lymphocytes; Transcription Factor RelA

Fumaric acid esters (FAE) are used in Germany as a first-line systemic treatment for chronic plaque psoriasis, with proven efficacy and low toxicity. Their use in the U.K. is variable, and they remain unlicensed. Consequently, efficacy and safety data from U.K. patients is limited and their place in the psoriasis treatment armamentarium is unclear.. To examine the efficacy and safety of FAE in a prospective cohort of U.K. patients with severe, treatment-recalcitrant, chronic plaque psoriasis.. A single-centre, open, nonrandomized, prospective study was performed in a regional referral centre for patients with severe psoriasis. Outcomes were measured by the Psoriasis Area and Severity Index (PASI), Dermatology Life Quality Index (DLQI), blood investigations and adverse events monitoring.. Eighty patients were recruited. Fifty-nine per cent were taking a concomitant oral antipsoriatic agent; 20% achieved a PASI-50, 8% a PASI-75 and 4% a PASI-90 on intention-to-treat analysis at 3 months with an overall, statistically significant, reduction in PASI from 13.9 + or - 9.0 to 11.3 + or - 9.2 (P < 0.0001). At 3 months, lymphopenia was seen in 33% of the cohort with significantly lower counts in patients responsive to FAE (P = 0.008). In addition, by 3 months, 36% of concomitant antipsoriatic medication had been stopped and 25% of doses had been reduced without loss of disease control. Side-effects (most commonly diarrhoea, abdominal pain and flushing) were reported by 74% of patients resulting in cessation of FAE in 36%.. FAE is a useful alternative treatment option in patients with severe, treatment-resistant, chronic plaque psoriasis and can allow dose reduction, and subsequent cessation, of other, potentially more toxic agents.

Topics: Adult; Aged; Chronic Disease; Cohort Studies; Dermatologic Agents; Dimethyl Fumarate; Female; Fumarates; Humans; Male; Middle Aged; Prospective Studies; Psoriasis; Severity of Illness Index; Treatment Outcome; Young Adult

Topics: Dermatologic Agents; Esters; Fumarates; Humans; Psoriasis; United Kingdom

T-cell infiltration, epidermal hyperproliferation, and disturbed keratinization are pathologic hallmarks of plaque psoriasis. Oral fumaric acid esters are an effective therapy for psoriasis and are believed to exert their effects mainly through their anti-inflammatory properties.. To investigate the differential effects of dimethylfumarate (BG-12; FAG-201) for psoriasis on lesional T-cell subsets, natural killer (NK) T cells, and keratinocyte hyperproliferation and differentiation.. A before-and-after clinical and immunohistochemical study as part of a larger clinical trial.. Single outpatient clinic.. Six patients with moderate-to-severe psoriasis.. Dimethylfumarate 720 mg daily for 16 weeks.. Biopsies were taken from the lesional skin of six psoriatic patients, at baseline and after 16 weeks of treatment with dimethylfumarate. Clinical severity scores were obtained (Psoriasis Area Severity Index [PASI] and psoriasis severity SUM scores). T-cell subsets (CD4+, CD8+, CD45RO+, CD45RA+, CD2+, CD25+), cells expressing NK receptors (CD94, CD161), an epidermal proliferation marker (Ki67), and a keratinization marker (K10) were immunohistochemically stained and, together with 'epidermal thickness,' quantified using image analysis.. At week 16, the mean PASI and SUM scores were reduced by 55% (p < 0.01) and 49% (p < 0.01), respectively. In line with these results, epidermal hyperproliferation, keratinocyte differentiation, and epidermal thickness significantly improved. In the dermis and the epidermis, the relevant T-cell subsets significantly declined. However, in both the lesional psoriatic dermis and epidermis, cells expressing NK receptors (CD94 and CD161) persisted after 16 weeks of treatment.. Dimethylfumarate is an effective therapy for moderate-to-severe plaque psoriasis. The drug may act by reducing lesional T-cell subsets and normalizing epidermal hyperproliferation and keratinization, but does not reduce NKT cells.

Topics: Adult; Cell Differentiation; Cell Proliferation; Dermatologic Agents; Dermis; Dimethyl Fumarate; Epidermis; Female; Fumarates; Humans; Immunohistochemistry; Immunosuppressive Agents; Male; Middle Aged; Natural Killer T-Cells; Psoriasis; Severity of Illness Index; T-Lymphocyte Subsets

The aim of this study was to evaluate pharmacokinetic parameters of fumaric acid esters (FAE) in psoriasis patients for the first time. For this prupose new HPLC assays were developed. Additionally, physicochemical parameters of FAE were determined, allowing a better interpretation of the in vivo data. In vivo, monomethylfumarate (MMF) and monoethylfumarate (MEF) were detected after t (lag) = 120 min. T (max) and c (max) of MMF were 210 min and 11.2 microM, respectively, 210 min and 5.2 microM for MEF. The half-life of MMF was 38.7 min, and 25.4 min of MEF. The AUC(0-infinity) of MMF was 172 min microg ml(-1) and 63.6 min microg ml(-1) of MEF. Data display median of three subjects. No plasma levels of dimethylfumarate (DMF) or fumaric acid (FA) were detected. The evaluation of physicochemical parameters of FAE showed that only DMF fulfils the criteria of Lipinski's rule of five. The pKa of MMF was determined as 3.63. The data of this study provide evidence that DMF is most likely absorbed out of the duodenum into the presystemic circulation and is not completely hydrolysed to MMF before uptake as assumed by others.

Topics: Adult; Duodenum; Fumarates; Half-Life; Humans; Hydrolysis; Male; Maleates; Middle Aged; Psoriasis

Topics: CD4-Positive T-Lymphocytes; Cytokines; Fumarates; Humans; Immunosuppressive Agents; Interleukin-4; Methotrexate; Psoriasis

  We present the case of a 49-year old male who presented with dyspnoea, cough, weight loss, night sweats and general malaise. He had been on treatment with oral fumaric acid esters (FAE, Fumaderm®; Biogen Idec GmbH, Ismaning, Germany) for 6 months..   Report of a case..   His chest X-ray showed patchy infiltrates in the left upper lobe which failed to resolve under empiric antibiotic therapy. A computed tomography of thorax revealed bilateral, mostly peripheral foci of consolidation with air bronchograms. Transbronchial biopsies showed a pattern of organising pneumonia (OP)..   Therapy with oral prednisolone (40 mg/day) resulted in a rapid clinical and radiological improvement. An association of FAE and OP has not previously been reported. Please cite this paper as: Deegan AP, Kirby B, Rogers S, Crotty TB and McDonnell TJ. Organising pneumonia associated with fumaric acid ester treatment for psoriasis.

Topics: Administration, Oral; Biopsy; Cryptogenic Organizing Pneumonia; Fumarates; Glucocorticoids; Humans; Lung Diseases; Male; Middle Aged; Prednisolone; Psoriasis; Tomography, X-Ray Computed

Topics: Animals; Chemistry, Pharmaceutical; Dermatology; Dimethyl Fumarate; Fumarates; Gene Amplification; Glutathione; Humans; Mice; Models, Chemical; Psoriasis; Urinalysis

This study collected data on the safety and efficacy of fumaric acid esters (FAE; Fumaderm) in the long-term treatment of psoriasis.. Patients were included at 163 dermatological centers if they either had been treated continuously with FAE for at least 24 months, or for 36 months with interruptions of no longer than 6 months. Data were reported from baseline, after 3, 6, 12, 24, and 36 or more months of therapy. Safety parameters were monitored and the severity of skin symptoms was assessed by "Physician's Global Assessment" (PGA) and "Psoriasis Area and Severity Index" (PASI).. 984 patients were included with a mean duration of 44 months of continuous treatment. The percentage of patients documented as markedly improved or clear was 67 % after six months, 78 % after 24 months, and 82 % after 36 months of therapy. Improvement was similar in patients with moderate and severe disease. Changes of laboratory parameters were usually insignificant and did not require a modification of FAE treatment in more than 90 % of the cases.. In the long-term treatment of patients with moderate and severe psoriasis FAE show a good and sustained clinical efficacy combined with a favorable safety profile.

Topics: Adolescent; Adult; Aged; Aged, 80 and over; Dermatologic Agents; Dimethyl Fumarate; Drug Eruptions; Female; Fumarates; Germany; Humans; Longitudinal Studies; Male; Middle Aged; Prevalence; Psoriasis; Retrospective Studies; Risk Assessment; Treatment Outcome; Young Adult

Topics: Carcinoma, Squamous Cell; Fumarates; Humans; Male; Middle Aged; Psoriasis; Skin Neoplasms

The use of fumaric acid esters in the treatment of psoriasis was first proposed in 1959. In the 1980s, more standardized oral preparations of fumaric acid esters were developed, containing dimethylfumarate and monoethylfumarate as the main compounds. In 1994, the drug was approved for the treatment of psoriasis in Germany, and since then it has become the most commonly used systemic therapy in this country. In the last few years, an oral integrator containing dimethylfumarate and monoethylfumarate (Psocaps, Dermatika s.r.l., Padua) has also been available in Italy for the treatment of psoriasis. In this paper we report on the history of treatment using fumaric acid esters and we describe our own experience during and following the treatment with such drugs in 41 patients affected by mild vulgar psoriasis. In our trial, an improvement in cutaneous psoriasis was observed in 46% of treated patients, while side effects were noticed in 52% of patients; only three patients dropped out due to gastrointestinal problems. Our results are comparable to literature data in terms of efficacy, safety and side effects.

Topics: Administration, Oral; Adult; Aged; Aged, 80 and over; Esters; Female; Fumarates; Humans; Male; Middle Aged; Psoriasis; Treatment Outcome

Nicotinic acid has been used for several decades to treat dyslipidemia. In mice, the lipid-lowing effect of nicotinic acid is mediated by the Gi coupled receptor PUMA-G. In humans, high (GPR109A) and low (GPR109B) affinity nicotinic acid receptors have been characterized. Here we identify monomethylfumarate as a GPR109A agonist. Monomethylfumarate is the active metabolite of the psoriasis drug Fumaderm. We show that monomethylfumarate activates GPR109A in a calcium based aequorin assay, cAMP assay and demonstrate competitive binding with nicotinic acid. We show that GPR109A is highly expressed in neutrophils and epidermal keratinocytes, and that its expression is increased in human psoriatic lesions. Our findings provide evidence that GPR109A is a target for the drug Fumaderm and suggest that niacin should be investigated to treat psoriasis in addition to its role in treating lipid disorders.

Topics: Cell Line; Dermatologic Agents; Dimethyl Fumarate; Fumarates; Humans; Hypolipidemic Agents; Maleates; Niacin; Psoriasis; Receptors, G-Protein-Coupled; Receptors, Nicotinic

Evidence-based guidelines can make a substantial contribution to improving medical care. However, it is important to ensure that guidelines are: (1) developed in areas in which they are needed the most; and (2) translated effectively into everyday clinical practice.. To evaluate the need for guidelines in the treatment of psoriasis vulgaris, the success of the dissemination activities undertaken to date, and the potential benefits of educational interventions in encouraging guideline compliance.. All dermatologists working in the Berlin-Brandenburg region of Germany were invited to attend a workshop on the psoriasis treatment guidelines. Participants could take part in a survey examining the general need for psoriasis guidelines and the success of previous dissemination activities.. A total of 42% of survey participants had not received a copy of the guidelines prior to the workshop. Of those who had received a copy, only 15% had studied the guidelines in detail. In total, 76% of survey participants felt that physicians' low levels of confidence in administering systemic treatments had resulted in these treatment options being used less frequently than they should. Seventy-nine per cent of survey participants believed that the guidelines would be helpful in improving physicians' confidence and ultimately lead to an increased use of systemic treatments.. The results of the present study indicate that there is a great need for guidelines on the treatment of psoriasis vulgaris in Germany, especially in light of dermatologists' low levels of confidence administering systemic treatments. Strategies for broad dissemination are essential for proper guideline implementation.

Topics: Anti-Inflammatory Agents; Attitude of Health Personnel; Berlin; Clinical Competence; Dermatologic Agents; Dermatology; Diffusion of Innovation; Education, Medical, Continuing; Evidence-Based Medicine; Fumarates; Health Knowledge, Attitudes, Practice; Humans; Immunosuppressive Agents; Information Dissemination; Needs Assessment; Practice Guidelines as Topic; Psoriasis; Remission Induction; Self Efficacy; Severity of Illness Index; Treatment Outcome; Tumor Necrosis Factor-alpha

Persistent Nuclear Factor-kappaB (NF-kappaB) activation is hypothesized to contribute to myocardial injuries following ischemia-reperfusion. Because inhibition or control of NF-kappaB signaling in the heart probably confers cardioprotection, we determined the potency of the NF-kappaB inhibitor dimethyl fumarate (DMF) in cardiovascular cells, and determined whether administration of DMF translates into beneficial effects in an animal model of myocardial infarction. In rat heart endothelial cells (RHEC), we analysed inhibitory effects of DMF on NF-kappaB using shift assay and immunohistofluorescence. In in vivo experiments, male Sprague Dawley rats undergoing left coronary artery occlusion for 45 min received either DMF (10 mg/kg body weight) or vehicle 90 min before ischemia as well as immediately before ischemia. After 120 min of reperfusion, the hearts were stained with phthalocyanine blue dye and triphenyltetrazolium chloride. Additionally, acute hemodynamic and electrophysiologic effects of DMF were determined in dose-response experiments in isolated perfused rat hearts. DMF inhibited TNF-alpha-induced nuclear entry of NF-kappaB in RHEC. In in vivo experiments, myocardial infarct size was significantly smaller in rats that had received DMF (20.7%+/-9.7% in % of risk area; n=17) than in control rats (28.2%+/-6.2%; n=15). Dose-response experiments in isolated perfused rat hearts excluded acute hemodynamic or electrophysiologic effects as mechanisms for the effects of DMF. DMF inhibits nuclear entry of NF-kappaB in RHEC and reduces myocardial infarct size after ischemia and reperfusion in rats in vivo. There was no indication that the beneficial effects of DMF were due to acute hemodynamic or electrophysiologic influences.

Topics: Animals; Dermatologic Agents; Dimethyl Fumarate; Electrocardiography; Electrophoretic Mobility Shift Assay; Electrophysiology; Endothelial Cells; Fluorescent Antibody Technique; Fumarates; Heart Rate; In Vitro Techniques; Male; Myocardial Infarction; Myocardial Reperfusion Injury; Myocardium; NF-kappa B; Nuclear Proteins; Psoriasis; Rats; Rats, Sprague-Dawley

Fumaric acid esters (FAEs) offer an effective alternative to patients with psoriasis in whom other systemic agents are contraindicated or have failed.. We assessed the efficacy and side effect profile of FAEs in a group of patients with psoriasis.. A retrospective study was carried out on patients treated with FAEs over 21 months. Information was gathered from patients' notes. Dosage, response and side effects were recorded.. In total, 31 patients were included. The mean age was 46.8 years. All patients had been treated with other modalities and 61.5% had received previous systemic treatment. There was good to excellent response in 58.6% of patients. Subjective side-effects were common (87.1%), and lymphopenia occurred in 61.3%. The drug was not tolerated by one-fifth of patients.. The relatively low toxicity and absence of hepatotoxicity makes FAEs a reasonable first-line systemic treatment in selected patients with difficult psoriasis.

Topics: Adult; Aged; Dermatologic Agents; Esters; Female; Fumarates; Humans; Male; Middle Aged; Psoriasis; Retrospective Studies

Topics: Adult; Anti-Inflammatory Agents, Non-Steroidal; Disease Susceptibility; Drug Combinations; Etanercept; Fumarates; Humans; Immunoglobulin G; Male; Psoriasis; Receptors, Tumor Necrosis Factor; Treatment Outcome; Tuberculin Test; Tuberculosis, Lymph Node

The p38 mitogen-activated protein kinase (MAPK) signaling pathway, which regulates the activity of different transcriptions factors including NF-kappaB, is activated in lesional psoriatic skin. The purpose of this study was to investigate the effect of fumaric acid esters (FAEs) on the p38 MAPK and the downstream kinases mitogen- and stress-activated protein kinase (MSK)1 and 2 in cultured human keratinocytes. Cell cultures were incubated with dimethylfumarate (DMF), methylhydrogenfumarate (MHF), or fumaric acid (FA) and then stimulated with IL-1beta before kinase activation was determined by Western blotting. A significant inhibition of both MSK1 and 2 activations was seen after preincubation with DMF and stimulation with IL-1beta, whereas MHF and FA had no effect. In addition, DMF decreased phosphorylation of NF-kappaB/p65 (Ser276), which is known to be transactivated by MSK1. Furthermore, incubation with DMF before stimulation with IL-1beta resulted in a significant decrease in NF-kappaB binding to the IL-8 kappaB and the IL-20 kappaB-binding sites as well as a subsequent decrease in IL-8 and IL-20 mRNA expression. Our results suggest that DMF specifically inhibits MSK1 and 2 activations and subsequently inhibits NF-kappaB-induced gene-transcriptions, which are believed to be important in the pathogenesis of psoriasis. These effects of DMF explain the anti-psoriatic effect of FAEs.

Topics: Binding Sites; Cells, Cultured; Dimethyl Fumarate; Enzyme Inhibitors; Fumarates; Humans; Immunosuppressive Agents; Interleukin-1beta; Interleukins; Keratinocytes; NF-kappa B; Oxidation-Reduction; Phosphorylation; Psoriasis; Ribosomal Protein S6 Kinases, 90-kDa

Nail psoriasis is common in adult psoriatic patients and it causes serious psychological and physical distress. Topical treatments such as corticosteroids, calcipotriol, retinoids, and 5-fluorouracil have limited efficacy and are not without side effects. Relative effective systemic treatments are ciclosporin, methotrexate and acitretin, all of which have a serious toxicity potential. Biologics in the treatment of nail psoriasis have been the subject of recent research, but their cost-effectiveness is questionable. We present a case of psoriatic nail disease which improved greatly on treatment with fumaric acid esters (FAE).

Topics: Adult; Dermatologic Agents; Fumarates; Humans; Male; Nail Diseases; Psoriasis

Topics: Dermatologic Agents; Dimethyl Fumarate; Fumarates; Germany; Humans; Practice Guidelines as Topic; Psoriasis

Topics: Dermatologic Agents; Diagnosis, Differential; Dimethyl Fumarate; Fumarates; Gastrointestinal Diseases; Humans; Intestinal Neoplasms; Intestinal Obstruction; Male; Psoriasis

Topics: Adrenal Cortex Hormones; Anthralin; Arthritis, Psoriatic; Biological Products; Cyclosporine; Dermatologic Agents; Female; Fumarates; Humans; Male; Methotrexate; Phototherapy; Psoriasis; PUVA Therapy; Retinoids; Sex Factors

Topics: Adult; Dermatologic Agents; Female; Fumarates; Humans; Male; Middle Aged; Psoriasis; Retrospective Studies

Topics: Adult; Dermatologic Agents; Female; Fumarates; Humans; Male; Middle Aged; Patient Satisfaction; Psoriasis; Retrospective Studies; Treatment Outcome

Fumaric acid esters (FAE) have been used to treat severe psoriasis in northern Europe for over 20 years. A recent systematic review has shown FAE to be an effective systemic treatment for severe psoriasis. However, FAE remain unlicensed in the U.K.. To present data relating to the efficacy and tolerability of FAE in severe psoriasis and report our experiences of FAE therapy at one U.K. centre.. Patients who had received FAE for severe psoriasis at one U.K. regional referral centre between June 1999 and October 2003 were identified from pharmacy records. Their records were analysed retrospectively.. Fifty-eight patients (25 women, 33 men) were identified. Fifty-five (95%) of the 58 patients had previously used other systemic antipsoriatic therapies with over 70% previously using two or more agents. Thirty-two patients (55%) showed improvement in their psoriasis with 10 (17%) being rated as 'clear' or 'virtually clear' by the attending physician. No improvement was seen in 28% patients and 16% showed worsening of their disease. Adverse events were common and were reported in 66% patients. These mainly consisted of abdominal pain (61%), diarrhoea (55%), flushing (45%), nausea (21%) and malaise (15%). They led to discontinuation of treatment in 15 patients after a mean period of 4.7 months. Lymphocytopenia developed during treatment in 57% of patients, all of whom had had a baseline value within the normal range. In only one patient was this considered severe enough to warrant withdrawal of treatment.. Our study has shown that FAE are an effective therapy in selected patients with severe psoriasis, even in those who have previously been intolerant of systemic therapy or where it has failed.

Topics: Adolescent; Adult; Aged; Chemical and Drug Induced Liver Injury; Chi-Square Distribution; Dimethyl Fumarate; Eosinophilia; Female; Fumarates; Humans; Immunosuppressive Agents; Liver; Liver Diseases; Lymphopenia; Male; Middle Aged; Psoriasis; Retrospective Studies; Treatment Outcome

Psoriasis vulgaris, a type-1 cytokine-mediated chronic skin disease, can be treated successfully with fumaric acid esters (FAE). Beneficial effects of this medication coincided with decreased production of IFN-gamma. Since dendritic cells (DC) regulate the differentiation of T helper (Th) cells, this study focussed on effects of monomethylfumarate (MMF, bioactive metabolite of FAE) on polarization of monocyte-derived DC. MMF-incubated, lipo-polysaccharide-stimulated DC (MMF-DC) produced dramatically (p<0.05) reduced levels of IL-12p70 and IL-10 (8+/-4% and 20+/-4%, respectively) compared to control DC. MMF-DC were mature. MMF affected polarization of DC irrespective of polarization factor(s) and ligands for the various Toll-like receptors used. Coculture of MMF-DC with naive and primed allogenous Th cells resulted in lymphocytes producing less IFN-gamma, i.e. 59% and 54% of that by the respective Th cells cocultured with control DC. IL-4 production by primed, but not naive Th cells cocultured with MMF-DC was decreased as compared to cocultures with control DC. IL-10 production by naive and primed Th cells cocultured with MMF-DC and control DC did not differ. In addition, MMF inhibited LPS-induced NF-kappaB activation in DC. Together, beneficial effects of FAE in psoriasis involve modulation of DC polarization by MMF such that these cells down-regulate IFN-gamma production by Th cells.

Topics: Antigens, CD; Cell Differentiation; Cell Polarity; Coculture Techniques; Dendritic Cells; Down-Regulation; Enzyme-Linked Immunosorbent Assay; Flow Cytometry; Fumarates; Humans; Interleukin-10; Interleukin-12; Interleukin-8; Lymphocyte Activation; Maleates; Monocytes; Protein Subunits; Psoriasis; Th1 Cells; Tumor Necrosis Factor-alpha

Fumaric acid esters (FAE) are used as a systemic treatment for severe psoriasis in Germany but there has been only very little published experience from the U.K. The potential for use in combination with other systemic drugs has not been explored.. To present data relating to the efficacy of FAE in severe psoriasis and to examine the potential dose-sparing effect and safety issues when FAE are combined with other systemic agents.. We retrospectively analysed the records of patients who had received FAE for severe psoriasis either alone (in two cases) or along with other systemic medications (in 10 cases). We reviewed the efficacy of FAE and assessed whether dose reductions were achieved for other systemic drugs. Patients were monitored carefully for possible adverse effects.. Of 12 patients treated with FAE one discontinued the drug very early, due to flushing, while on a very low dose. The other 11 patients all demonstrated an improvement in psoriasis after starting FAE. Nine patients received FAE in combination with other systemic therapies including ciclosporin, acitretin, hydroxyurea and methotrexate. Seven achieved useful overall reductions in the dose of the other drugs. In two patients severe psoriasis was controlled using FAE alone. The side-effect profile of FAE was similar to that previously reported. There was no evidence of drug interactions.. FAE appear effective and less toxic than other systemic treatments for psoriasis. FAE were used successfully in combination with other systemic agents and generally enabled the doses of the more hazardous drugs to be reduced. Extremely careful monitoring is required when using FAE in such combined regimens as experience is currently very limited.

Topics: Adult; Aged; Cyclosporine; Dermatologic Agents; Drug Interactions; Drug Therapy, Combination; Esters; Female; Flushing; Fumarates; Humans; Male; Middle Aged; Psoriasis; Retrospective Studies; Time Factors; Treatment Outcome

Psoriasis is a chronic inflammatory skin disease that can be successfully treated with a mixture of fumaric acid esters (FAE) formulated as enteric-coated tablets for oral use. These tablets consist of dimethylfumarate (DMF) and salts of monoethylfumarate (MEF) and its main bioactive metabolite is monomethylfumarate (MMF). Little is known about the pharmacokinetics of these FAE. The aim of the present study was to investigate the hydrolysis of DMF to MMF and the stability of MMF, DMF and MEF at in vitro conditions representing different body compartments.. DMF is hydrolyzed to MMF in an alkaline environment (pH 8), but not in an acidic environment (pH 1). In these conditions MMF and MEF remained intact during the period of analysis (6 h). Interestingly, DMF was hardly hydrolyzed to MMF in a buffer of pH 7.4, but was rapidly hydrolyzed in human serum having the same pH. Moreover, in whole blood the half-life of DMF was dramatically reduced as compared to serum. The concentrations of MMF and MEF in serum and whole blood decreased with increasing time. These data indicate that the majority of the FAE in the circulation are metabolized by one or more types of blood cells. Additional experiments with purified blood cell fractions resuspended in phosphate buffered saline (pH 7.4) revealed that at concentrations present in whole blood monocytes/lymphocytes, but not granulocytes and erythrocytes, effectively hydrolyzed DMF to MMF. Furthermore, in agreement with the data obtained with the pure components of the tablet, the enteric-coated tablet remained intact at pH 1, but rapidly dissolved at pH 8.. Together, these in vitro data indicate that hydrolysis of DMF to MMF rapidly occurs at pH 8, resembling that within the small intestines, but not at pH 1 resembling the pH in the stomach. At both pHs MMF and MEF remained intact. These data explain the observation that after oral FAE intake MMF and MEF, but not DMF, can be readily detected in the circulation of human healthy volunteers and psoriasis patients.

Topics: Blood Cells; Buffers; Dermatologic Agents; Dimethyl Fumarate; Drug Stability; Esters; Fumarates; Half-Life; Humans; Hydrogen-Ion Concentration; Hydrolysis; In Vitro Techniques; Intestine, Small; Maleates; Psoriasis; Serum; Stomach

Fumarates have been shown to be effective in psoriasis vulgaris.. To find out whether successful therapy is associated with modulation of cytokines.. We determined interferon (IFN)-gamma, interleukin (IL)-4 and IL-10 secretion capacities of peripheral blood mononuclear cells (PBMC) after phytohaemagglutinin stimulation, and IL-12p70 and IL-10 secretion capacities of PBMC after endotoxin stimulation in psoriasis vulgaris patients during treatment with fumarates. In a cohort study, 12 patients (five men, median age 50 years; seven women, median age 46 years) with psoriasis vulgaris were followed during 24 months of fumarate treatment. In addition, we followed 14 healthy controls (six men, median age 31 years; eight women, median age 29 years) without skin diseases during 12 months to investigate possible changes in the cytokine secretion capacity of PBMC as a result of seasonal changes. Disease activity in patients was determined by Psoriasis Area and Severity Index (PASI) score. Blood was collected for measurement by enzyme-linked immunosorbent assay of cytokine levels after stimulation of PBMC.. Within 6 months of fumarate treatment, the mean +/- SD PASI score had decreased to 22 +/- 9% of its initial value. These beneficial effects coincided with lymphocytopenia and a significant (P < 0.05) downregulation of IFN-gamma expression by circulating blood cells, followed by a significant downregulation of IL-4 expression. Notably, production of the cytokine synthesis inhibitor IL-10 by PBMC was unchanged.. The beneficial effects of fumarates may be attributed to their downregulatory action on type 1 cytokines.

Topics: Cohort Studies; Down-Regulation; Enzyme-Linked Immunosorbent Assay; Female; Fumarates; Humans; Interferon-gamma; Interleukin-10; Interleukin-12; Interleukin-4; Interleukins; Leukocyte Count; Leukocytes, Mononuclear; Male; Middle Aged; Phenotype; Prospective Studies; Psoriasis; Severity of Illness Index

Topics: Adult; Cataract; Dimethyl Fumarate; Fumarates; Humans; Immunosuppressive Agents; Long-Term Care; Male; Psoriasis; Risk Assessment; Vision Disorders

Therapy with fumaric acid esters (FAE) has been shown to be safe and effective in patients with severe psoriasis in several clinical studies with limited follow-up periods. In view of the chronic character of psoriasis, long-term safety aspects are of major importance in determining the suitability of a drug during prolonged periods of treatment.. To investigate adverse events of therapy with systemic FAE with follow-up periods of up to 14 years, in order to determine safety aspects of their long-term use in patients with severe psoriasis.. Current and/or past therapeutic use of FAE was reviewed in 66 patients with severe psoriasis.. Forty-one of 66 patients had received FAE for at least 1 year, and 12 of these 41 patients had received FAE for between 10 and 14 years. Adverse events were reported in 73% of the patients. These were usually mild and mainly consisting of flushing (55%), diarrhoea (42%), nausea (14%), tiredness (14%) and stomach complaints (12%). A relative lymphocytopenia was observed in 76% of patients during therapy with FAE, resulting in a permanent discontinuation of therapy with FAE in four patients. A transient eosinophilia and moderate liver enzyme elevations were observed in 14% and 25% of patients, respectively.. The present study indicates that FAE can be considered as a safe long-term treatment in patients with severe psoriasis.

Topics: Adult; Aged; Aged, 80 and over; Creatinine; Dermatologic Agents; Drug Administration Schedule; Female; Fumarates; Humans; Liver; Lymphopenia; Male; Middle Aged; Psoriasis

Psoriasis is a chronic inflammatory skin disease. Its treatment is based on the inhibition of proliferation of epidermal cells and interference in the inflammatory process. A new systemic antipsoriasis drug, which consists of dimethylfumarate and ethylhydrogenfumarate in the form of their calcium, magnesium and zinc salts has been introduced in Europe with successful results. In the present study, a homologous series of mono- and diesters of fumaric acid has been studied with respect to the sites and kinetics of presystemic ester degradation using pancreas extract, intestinal perfusate, intestinal homogenate and liver S9 fraction. In addition, intestinal permeability has been determined using isolated intestinal mucosa as well as Caco-2 cell monolayers, in order to obtain estimates of the fraction of the dose absorbed for these compounds. Relationships between the physicochemical properties of the fumaric acid esters and their biological responses were investigated. The uncharged diester dimethylfumarate displayed a high presystemic metabolic lability in all metabolism models. It also showed the highest permeability in the Caco-2 cell model. However, in permeation experiments with intestinal mucosa in Ussing-type chambers, no undegraded DMF was found on the receiver side, indicating complete metabolism in the intestinal tissue. The intestinal permeability of the monoesters methyl hydrogen fumarate, ethyl hydrogen fumarate, n-propylhydrogen fumarate and n-pentyl hydrogen fumarate increased with an increase in their lipophilicity, however, their presystemic metabolism rates likewise increased with increasing ester chain length. It is concluded that for fumarates, an increase in intestinal permeability of the more lipophilic derivatives is counterbalanced by an increase in first-pass extraction.

Topics: Animals; Atenolol; Biological Availability; Caco-2 Cells; Cell Membrane Permeability; Cells, Cultured; Dimethyl Fumarate; Enzyme Inhibitors; Fumarates; Humans; Intestinal Absorption; Intestinal Mucosa; Intestines; Liver Extracts; Microvilli; Pancreatic Extracts; Propranolol; Psoriasis; Swine

Fumaric acid esters have proved to be effective for the systemic treatment of severe psoriasis vulgaris. These compounds have been shown to induce a Th2-like cytokine secretion pattern in T cells and to reduce keratinocyte proliferation in vitro. Dendritic cells seem to be of major importance as regulatory cells driving the psoriatic tissue reaction. Monocytes or CD34-positive myeloid progenitor cells are precursors of dendritic cells that can be generated in vitro by culture with granulocyte-macrophage colony-stimulating factor and interleukin-4. Using this model the effect of fumaric acid esters on granulocyte-macrophage colony-stimulating factor/interleukin-4-induced differentiation of monocyte-derived dendritic cells was investigated. The results of this study show that dimethylfumarate as well as methylhydrogenfumarate-calcium-salt (0.01-100 microg per ml) concentration-dependently inhibit monocyte-derived dendritic cell differentiation. This was reflected by an inhibition of CD1a, CD40, CD80, CD86, and HLA-DR expression as well as by a reduced capacity of dimethylfumarate-treated monocyte-derived dendritic cells to stimulate lymphocytes in the allogeneic mixed lymphocyte reaction. Other fumaric acid esters showed no effect on monocyte-derived dendritic cell-differentiation. At higher concentrations (30-100 microg per ml) dimethylfumarate, but not methylhydrogenfumarate calcium-salt induced apoptosis in monocyte-derived dendritic cells as measured by expression of Apo 2.7 and DNA fragmentation (TUNEL assay). These data point to a high susceptibility of the monocyte/dendritic cell system to dimethylfumarate and its main metabolite methylhydrogenfumarate. Other fumaric acid esters investigated were without effect. As the effects of fumarates on monocyte-derived dendritic cells observed occur at concentrations 20-fold lower compared with lymphocytes, our data seem to be of relevance in explaining the possible mode of action of these compounds in psoriasis.

Topics: Adjuvants, Immunologic; Antibody Formation; Antigen Presentation; Apoptosis; Cell Differentiation; Cell Survival; Dendritic Cells; Dose-Response Relationship, Drug; Fumarates; Humans; In Situ Nick-End Labeling; Monocytes; Psoriasis

We report about a rare case of a pathological fracture of the shank following earlier pathological fractures at other locations in a comparatively young female patient with no history of trauma. There were no known diseases other than psoriasis. The shank fracture was treated surgically by osteosynthesis. Osteoporosis, myeloma, or malignancy as causative factors of this fracture could be excluded. Scintigraphy showed an enhancement, especially at the extremities. Other than reactive bone growth, histological examination revealed no further aspects. Laboratory analysis indicated a massive lack of vitamin D3. After transferring the patient to the internal department of our hospital, long-term medication with fumaric acid was determined to be the reason for the osteomalacia of a Fanconi's syndrome. Three months after cessation of these medicaments and treatment with active vitamin D3 metabolites, the patient was free of complaints. The radiographs showed an essential improvement of the demineralization.

Topics: Adult; Ankle Injuries; Diagnosis, Differential; Fanconi Syndrome; Female; Femoral Neck Fractures; Fracture Fixation, Internal; Fractures, Spontaneous; Fumarates; Humans; Psoriasis; Radiography; Reoperation; Tibial Fractures

The effectiveness of systemic treatment of psoriasis with fumaric acid esters has been proven, but their mode of action at the cellular and molecular level has not yet been fully elucidated.. To study the effect of dimethylfumarate (DMF) on the production of the chemokines CXCL1, CXCL8, CXCL9, CXCL10 and CXCL11, formerly known as GROalpha, interleukin-8, Mig, IP-10 and IP-9/I-TAC, respectively, in human keratinocytes and peripheral blood mononuclear cells (PBMC).. Cultured keratinocytes were stimulated with interferon (IFN) -gamma to produce CXCL9, CXCL10 and CXCL11 and with phorbol myristate acetate to produce CXCL1 and CXCL8 in the absence and presence of DMF (5, 15 and 45 micromol L(-1)). PBMC were stimulated with either IFN-gamma to produce CXCL9 and CXCL10 or lipopolysaccharide to produce CXCL8, in the absence and presence of DMF (5, 15 and 45 micromol L(-1)). RNA preparations from isolated keratinocytes were analysed by Northern blotting; protein production by keratinocytes and PBMC was monitored by an enzyme-linked immunosorbent assay.. Northern blot analysis on isolated keratinocyte RNA preparations showed a dose-dependent inhibition of CXCL1, CXCL8, CXCL9, CXCL10 and CXCL11 transcription by DMF. At 45 micromol L(-1) the inhibition was almost complete. In addition, keratinocytes and PBMC showed in the presence of DMF a dose-dependent inhibition of CXCL8, CXCL9 and CXCL10 protein production.. These results show the ability of DMF to inhibit the production of chemokines that may be critically involved in the development and perpetuation of psoriatic lesions. This might explain, at least in part, the beneficial effects of treatment with fumaric acid esters in psoriasis patients.

Topics: Blotting, Northern; Cell Culture Techniques; Chemokines, CXC; Dermatologic Agents; Dimethyl Fumarate; Dose-Response Relationship, Drug; Down-Regulation; Fumarates; Humans; Immunosuppressive Agents; Keratinocytes; Leukocytes, Mononuclear; Psoriasis; RNA, Messenger

Topics: Antibodies, Monoclonal; Cholecalciferol; Clinical Trials as Topic; Combined Modality Therapy; Fumarates; Humans; Prognosis; Psoriasis; PUVA Therapy; Tumor Necrosis Factor-alpha

Fumaric acid esters are thought to improve psoriasis by altering leukocyte, keratinocyte, and/or endothelial functions. To determine specificity, kinetics, and molecular mechanisms of different fumaric acid esters in their ability to inhibit endothelial cell activation, we analyzed CD62E and CD54 expression in endothelial cells in vivo and in vitro. In lesional skin of psoriatic patients, oral fumaric acid ester treatment resulted in a marked reduction of CD62E but not CD54 expression on dermal microvessels. Using human umbilical vein endothelial cells, dimethylfumarate almost completely inhibited tumor-necrosis-factor-induced CD62E, but not CD54 expression at concentrations < or = 70 microM, mimicking the situation in vivo. A 60 min dimethylfumarate preincubation was sufficient to block tumor-necrosis-factor-induced CD62E expression for up to 24 h. In contrast, equimolar concentrations of methylhydrogenfumarate, the hydrolysis product of dimethylfumarate, did not suppress tumor-necrosis-factor-induced CD62E expression. Likewise, all fumaric acid esters other than dimethylfumarate were ineffective. Using CD62E, NF-kappa B, or AP-1-responsive promoter constructs, dimethylfumarate inhibited tumor-necrosis-factor-induced activation of the CD62E and the NF-kappa B but not the AP-1 promoter construct. In summary, at a dose range < or = 70 microM, dimethylfumarate appeared to be a specific inhibitor of CD62E expression in an NF-kappa B-dependent manner.

Topics: Capillaries; Cells, Cultured; Dermatologic Agents; Dimethyl Fumarate; E-Selectin; Endothelium, Vascular; Fumarates; Gene Expression; Humans; Intercellular Adhesion Molecule-1; NF-kappa B; Psoriasis; RNA, Messenger; Skin; Tumor Necrosis Factor-alpha; Umbilical Veins

Topics: Anticarcinogenic Agents; Clinical Trials as Topic; Dermatologic Agents; Fumarates; Humans; Kidney; Kidney Function Tests; Kidney Tubules; Prospective Studies; Psoriasis; Time Factors

Newest studies have shown that psoriasis is not primarily a skin disorder but an immunological disturbance under the skin. The skin manifestations are a result of overstimulation of superficial skin cells (Langerhans cells) due to increased production of interleukin 2, 6 and 8 as well as transforming growth-factor-alpha. Interleucin-10 production is diminished. In a recent study (11 German University Skin Clinics) fumaric acid was shown to improve the skin leasons in 80% of treated patients.. Our own studies on 54 patients which where treated in addition with intravenous thymus extract (Thymoject) and selenium (Selenase) showed a faster healing rate with fumaric acid alone. From these results one can postulate that the above treatments (fumaric acid, thymus and selenium) have a synergystic effect.. Internal immunmodulating treatments should therefore have preference over external symptomatic treatments like UV-light, ointments, salt water bath, etc.

Topics: Administration, Oral; Adult; Anticarcinogenic Agents; Drug Synergism; Drug Therapy, Combination; Female; Fumarates; Humans; Infusions, Intravenous; Male; Middle Aged; Psoriasis; Selenium; Thymus Extracts

We report the successful clearance of severe chronic plaque psoriasis following treatment with fumaric acid esters (FAE) in two patients who had failed previous systemic therapy. FAE is gaining increasing acceptance for the treatment of psoriasis in countries such as Germany and the Netherlands, but at present remains unlicensed in Britain.

Topics: Fumarates; Humans; Male; Middle Aged; Psoriasis

Fumaric acid ester (FAE) therapy has proved to be safe and effective in patients with severe psoriasis vulgaris. This treatment was introduced nearly 30 years ago, but is only now gaining renewed interest among dermatologists. FAE therapy is licensed in Germany and registration is pending in many European countries. Multicentre trials have confirmed the beneficial effect of FAE in psoriasis and have defined the spectrum of its adverse effects. Although the mode of action of FAEs in the treatment of psoriasis is not fully understood, recent experimental data point towards a skewing of the Th1-dominated T-cell response in psoriasis to a Th2-like pattern, and inhibition of proliferation of keratinocytes. This article reviews the experimental and clinical information on FAEs in psoriasis and provides guidelines for the clinical use of FAEs derived from a consensus meeting of leading experts.

Topics: Cytokines; Drug Administration Schedule; Flushing; Fumarates; Humans; Keratinocytes; Liver; Lymphocyte Count; Practice Guidelines as Topic; Psoriasis; T-Lymphocytes

Fumaric acid preparations are used as longterm and effective treatment of psoriasis. Apart from gastrointestinal, dermatological and hematological side-effects, transient renal damage was observed during treatment with fumaric acid. The case of a 38 year old woman who was treated with fumaric acid (420 mg bid) for 5 years before she complained of fatigue and weakness. According to clinical laboratory she had developed severe proximal tubular damage. Hypophosphatemia, glycosuria and proteinuria persisted although medication was stopped immediately.

Topics: Adult; Fanconi Syndrome; Female; Fumarates; Glycosuria; Humans; Hypophosphatemia; Proteinuria; Psoriasis; Time

Interactions between infiltrating T cells and keratinocytes via the secretion of the TH1 cytokines interleukin (IL) 2 and interferon gamma (INF-gamma), the keratinocyte growth factor transforming growth factor alpha (TGF-alpha) and the cytokines IL-6 and IL-8 are thought to be the predominant mechanisms inducing skin lesions in psoriatic patients. Systemic treatment of psoriasis with fumaric acid derivatives (FAEs) has been reported to be effective in the treatment of psoriasis, but the mode of action is still unknown. To clarify this phenomenon, keratinocytes from psoriatic patients as well as from healthy volunteers were mono- and cocultured with HUT 78 T cells with/without the addition of FAEs; the cytokine concentrations were then measured in the culture supernatants. Furthermore, mRNA expression was determined in epidermal growth factor (EGF) -activated keratinocytes as well as in phytohaemagglutinin (PHA)-activated HUT 78 T cells. Only dimethylfumarate (DMF) diminished IL-6 and TGF-alpha secretion in the psoriatic cocultures. However, it did not have this effect on cocultures from control subjects or on monocultures. DMF suppresses EGF-induced TGF-alpha mRNA induction in psoriatic keratinocytes. DMF inhibited INF-gamma secretion in all cultures but stimulated the IL-10 secretion. This immunomodulation away from the TH1 cytokine IFN-gamma to the TH2 cytokine IL-10 was confirmed in HUT 78 T cells by Northern blot analysis. An increased number of eosinophils is a known side-effect in patients treated with this drug, suggesting a clinical relevance of this immunomodulation in vivo. This immunomodulation and the suppression of cytokines from the psoriatic cytokine network could be responsible for the beneficial effect of DMF in the treatment of a hyperproliferative and TH1 cytokine-mediated skin disease.

Topics: Adult; Aged; Blotting, Northern; Cell Communication; Cell Culture Techniques; Cytokines; Dimethyl Fumarate; Female; Fumarates; Gene Expression; Humans; Immunosuppressive Agents; Male; Middle Aged; Psoriasis; RNA, Messenger; T-Lymphocytes

Most studies on the antipsoriatic mode of action of dimethylfumarate focused on its antiproliferative effects in keratinocytes. Because inflammatory skin diseases are associated with an upregulation of endothelial cell adhesion molecules and because the presence of inflammatory cells in dermis and epidermis is considered an important feature in psoriasis, we tested the effect of DMF on cytokine-induced adhesion molecule expression in HUVEC, using in situ ELISA and Northern blotting. Dimethylfumarate inhibited ICAM-1, VCAM-1, and E-selectin expression and reduced adhesion of U937 cells to stimulated HUVEC. Monoethylfumarate and fumaric acid had no effect. Similar inhibitory effects for DMF on VCAM-1 expression were observed after stimulation of HUVEC with LPS, PMA, IL-4, and IL-1 alpha or in combinations with TNF alpha. These data are in agreement with previously reported effects of DMF on intracellular thiol levels and inhibition of NF-kappa B activation. The inhibitory effect on cytokine-induced endothelial adhesion molecule expression may represent another target of dimethylfumarate in psoriasis.

Topics: Blotting, Northern; Cell Adhesion; Cell Adhesion Molecules; Cytokines; Dimethyl Fumarate; E-Selectin; Endothelium, Vascular; Enzyme-Linked Immunosorbent Assay; Fumarates; Gene Expression Regulation; Humans; Intercellular Adhesion Molecule-1; Interleukins; Lipopolysaccharides; Psoriasis; Tetradecanoylphorbol Acetate; Tumor Necrosis Factor-alpha; Umbilical Cord; Vascular Cell Adhesion Molecule-1

Monomethylfumarate (MMF), the most active metabolite of the new antipsoriasis drug Fumaderm, stimulates an anti-inflammatory mediator profile in human leucocytes and inhibits the proliferation of keratinocytes. These effects of MMF on cells in vitro may in part explain the beneficial action of Fumaderm in patients. In addition, we have reported that MMF stimulates an increase in the intracellular free Ca2+ concentration ([Ca2+]i) and the cyclic adenosine monophosphate (cAMP) concentration in granulocytes and keratinocytes. Because Ca2+ and cAMP control many physiological cellular responses, including cell proliferation and inflammatory mediator production, the present study focused on the intracellular signal transduction pathway which links interaction between MMF and granulocytes with increases in [Ca2+]i and the cAMP concentration. The increase in [Ca2+]i in granulocytes after MMF depended both on extracellular Ca2+ and Ca2+ from intracellular stores. Ca2+ is essential for the increase in the cAMP concentration after stimulation with MMF. The results found for pharmacological inhibitors of various protein kinases suggest that a staurosporine-sensitive protein kinase different from protein kinase C (PKC) and protein kinase A is involved in the MMF-induced increase in [Ca2+]i in granulocytes. As MMF activated protein tyrosine kinase (PTK), and inhibition of this protein kinase partially reduced the increase in [Ca2+]i in granulocytes, PTK activity most likely is involved. In addition, activation of protein kinase histone 4 (PKH4) probably plays a part in the MMF-stimulated increase in [Ca2+]i in granulocytes as well. As MMF stimulated an increase in the GTP-ase activity of membranes and pertussis toxin (PTX) inhibited the increase in the [Ca2+]i and PKH4 activity of granulocytes stimulated by this compound, it is concluded that MMF activates PTX-sensitive G proteins. Competition binding studies with radiolabelled dimethylfumarate (DMF) and unlabelled DMF and MMF revealed the presence of specific binding sites for methylated fumarates on granulocytes. In summary, MMF binds to specific sites on the plasma membrane of cells. This interaction activates pertussis toxin-sensitive G proteins which then stimulate an increase in PTK and PKH4 activity. These protein kinases may regulate the rise in [Ca2+]i and the intracellular cAMP concentration. Elevated [Ca2+]i and intracellular cAMP concentration stimulate protein kinases that regulate transcription factors. A

Topics: Binding Sites; Binding, Competitive; Calcium; Cell Membrane; Cells, Cultured; Cyclic AMP; Dimethyl Fumarate; Fumarates; Furocoumarins; Genistein; Granulocytes; GTP Phosphohydrolases; GTP-Binding Proteins; Humans; Inositol 1,4,5-Trisphosphate; Intracellular Fluid; Isoflavones; Maleates; Protein Kinase C; Protein-Tyrosine Kinases; Psoriasis; Signal Transduction; Staurosporine

Although the effectiveness of systemic antipsoriatic treatment with fumaric acid esters has been proven, their mode of action is still not understood. Recent results indicate their potency in inducing cytokine production in stimulated T cells. Since monocytes and their cytokines are also considered to be of pathogenic importance in psoriasis, we investigated the effect of monomethylfumarate (MMF) on proinflammatory (TNF-alpha, IL-12) and antiinflammatory (IL-10, IL-1RA) cytokine production by peripheral blood mononuclear cells (PBMC) and separated monocytes. In 24-h PBMC cultures from both psoriatic patients (n = 6-13) and healthy volunteers (n = 7-9), MMF at 100 microM induced secretion of TNF-alpha, IL-10, and IL-1RA. Kinetics of IL-10 protein and mRNA expression indicated de novo production. Moreover, MMF significantly augmented endotoxin-induced synthesis of TNF-alpha, IL-10 and IL-1RA. In contrast, no influence on IL-12 secretion was found. Similar effects of MMF in purified monocytes indicated these cells to be responsible for aberrant cytokine formation. Furthermore, enhanced expression of costimulatory molecules after MMF stimulation confirmed monocyte activation. Multiple restimulation with fumaric acid esters in vitro, however, and immunomonitoring in a patient during Fumaderm initial therapy suggested that initial monocyte activation is followed by subsequent deactivation associated with an antiinflammatory response. Our results may explain the well-known effects of therapy with fumaric acid esters. Thus, initial treatment is often accompanied by adverse effects which may be caused by MMF-induced TNF-alpha formation. The change in the IL-10/IL-12 balance as a result of elective induction of IL-10, however, may have antipsoriatic activity by diminishing type-1/proinflammatory cytokine over-expression and the antigen-presenting capacity of monocytes/macrophages, and by upregulation of IL-1RA.

Topics: Cells, Cultured; Cytokines; Fumarates; Humans; Maleates; Monocytes; Psoriasis; RNA, Messenger

Topics: Administration, Oral; Dermatologic Agents; Follow-Up Studies; Fumarates; Humans; Psoriasis; Tablets

Fumaric acid, fumaric acid dimethylester, and the dithranol derivative C4-lactone were studied in the mouse tail test to evaluate their effects on epidermal cell differentiation compared with other topical antipsoriatic drugs, such as betamethasone, calcipotriol, and dithranol. Mouse tails were treated for 2 weeks and longitudinal histological sections prepared of the tail skin. The length of the orthokeratotic regions (stratum granulosum) was measured on 10 sequential scales per tail and expressed as percentage of the full length of the scale. In addition, epidermal thickness was measured and the efficacy of the various compounds evaluated. In comparison to 2% salicylic acid ointment, all tested compounds except fumaric acid significantly (p < or = 0.05) increased the proportion of the orthokeratotic region. C4-lactone and calcipotriol were less effective than dithranol, fumaric acid dimethylester only moderately influenced cell differentiation, and betamethasone showed the least potent effect. Dithranol was the most potent substance inducing orthokeratosis without increasing epidermal thickness.

Topics: Administration, Topical; Animals; Anti-Inflammatory Agents; Anticarcinogenic Agents; Cell Differentiation; Epidermal Cells; Epidermis; Fumarates; Keratosis; Male; Mice; Psoriasis; Tail

In this study we investigated the histological changes, regression of acanthosis and rate of proliferation, that accompany the healing of psoriatic lesions after fumaric acid esters and dithranol treatment. Biopsies were taken before and during therapy as well as from neighbouring untreated, clinically uninvolved skin and healthy, non-psoriatic volunteers. Specimens were assessed using computer-supported image analysis and immunohistology. The parameters primarily examined were the height of the rete pegs and of the epithelium above the papillary body, the rate of proliferation, the actual number of cells in the two epidermal compartments and the cellular density in the epidermis. Both fumaric acid esters and dithranol reduce the degree of acanthosis; however, the mechanism and the rate of the reduction differ. While under fumaric acid esters the reduction is more rapid at first but subsequently slows down, dithranol leads to a slow but steady decrease of epidermal thickness, so that at the end of our study the degree of acanthosis was less under dithranol. As an underlying mechanism of action, we found that fumaric acid esters reduce the rate of proliferation and thereby decrease the number of cells per rete peg as well as the size of the individual keratinocytes. Dithranol in contrast does not reduce cell renewal. The decrease of the number of cells in the rete pegs might be caused by an increased differentiation time.

Topics: Administration, Topical; Anthralin; Anti-Inflammatory Agents; Cell Count; Cell Division; Cell Size; Dimethyl Fumarate; Fumarates; Humans; Keratinocytes; Psoriasis; Skin

Type 2 cytokines are thought to have a protective role in psoriasis vulgaris by dampening the activity of T helper 1 (Th1) lymphocytes. The aim of the present study was to determine the effect of monomethylfumarate (MMF), the most active metabolite of the new anti-psoriatic drug Fumaderm, on the production of cytokines and the development of Th subsets. MMF was found to enhance interleukin (IL)-4 and IL-5 production by CD2/CD8 monoclonal antibody-stimulated peripheral blood mononuclear cells (PBMC) in a dose-dependent manner. Maximal effects of MMF were found at a concentration of 200 microM and resulted in tenfold enhanced levels of IL-4 and IL-5 production. MMF did not affect the levels of IL-2 production, interferon (IFN)-gamma production or proliferative T cell responses in these cultures. Similar effects of MMF were observed in cultures of purified peripheral blood T cells indicating that this compound can act directly on T cells. MMF did not influence cytokine production by purified CD4+CD45RA+ (unprimed) T cells, but greatly enhanced IL-4 and IL-5 production without affecting IFN-gamma production by purified CD4+CD45RO+ (primed) T cells. Furthermore, MMF also augmented IL-4 and IL-5 production in established Th1/Th0 clones that were stimulated with CD2/CD28 monoclonal antibody. Finally, when PBMC were challenged with Mycobacterium tuberculosis that typically induces Th1 recall responses with strong IFN-gamma secretion, MMF again appeared to induce high levels of IL-4 and IL-5 secretion while IFN-gamma production was unaffected. These results may be relevant for the development of therapeutic regimens designed to correct inappropriate Th1 subset development in immunopathologic conditions.

Topics: Animals; Fumarates; Humans; Immunologic Memory; Interleukin-4; Interleukin-5; Leukocyte Common Antigens; Lymphocyte Activation; Maleates; Psoriasis; Sheep; Th2 Cells

Topics: Anticarcinogenic Agents; Fumarates; Humans; Psoriasis; Treatment Outcome

Topics: Administration, Cutaneous; Administration, Oral; Dimethyl Fumarate; Fumarates; Humans; Psoriasis

Topics: Dimethyl Fumarate; Dose-Response Relationship, Drug; Drug Administration Schedule; Fumarates; Humans; Psoriasis; Treatment Outcome

In the psoriatic plaque both IL-1 dysregulation and ICAM-1 expression on keratinocytes have been previously described. Furthermore systemic administration of fumarates has been reported to be effective in psoriasis. We, therefore, studied the effect of dimethyl-fumarate ester (DMF) on the putative IL-1-induced ICAM-1 expression.. Hyperproliferative human keratinocytes (HaCaT cell line) were incubated in 10 to 100 U/mL IL-1 alpha for 24 h with and without preincubation with 0.4-12.0 microM DMF: Expression of ICAM-1 was measured by a special ELISA-APAAP technique.. The exposure to IL-1 led to a significant dose-dependent induction of ICAM-1 expression of from 124 +/- 17 to 194 +/- 22% (control 100 +/- 12%), while proliferation remained unaltered. Pretreatment with > or = 4 microM DMF resulted in a distinct suppression of ICAM-1 expression and a slight decrease in proliferation.. The present results show that ICAM-1 expression on hyperproliferative keratinocytes may be triggered by IL-1 alpha and serve as a molecular target for antipsoriatic DMF.

Topics: Cell Adhesion Molecules; Cells, Cultured; Dimethyl Fumarate; Dose-Response Relationship, Drug; Fumarates; Humans; Intercellular Adhesion Molecule-1; Interleukin-1; Keratinocytes; Psoriasis

A histological-immunohistological study was conducted to investigate the effect of systemically administered fumaric acid esters (FAEs) on epidermal thickness and composition of the inflammatory infiltrate in psoriatic plaques. The very first effect of systemic therapy with FAEs is the disappearance of CD 15-positive cells in the beneath the epidermis, accompanied by a significant reduction in T-helper cells beneath the epidermis, pointing to an immunosuppressive effect. This is followed after some delay by a reduction in acanthosis and hyperkeratosis. The reduction in infiltrating T-lymphocytes corresponds to that seen after systemic or intralesional therapy with cyclosporin. However, the normalization of the psoriatic plaques takes longer under the influence of FAEs than under cyclosporin.

Topics: Adult; Aged; Antigens, CD; Antigens, Differentiation, Myelomonocytic; Esters; Female; Fumarates; Humans; Lewis X Antigen; Lymphocyte Subsets; Male; Middle Aged; Psoriasis; Skin

Oral administration with complex mixtures of fumaric acid derivatives is known to have antipsoriatic efficacy. The present studies aimed to clarify the mode of action and toxicity of the individual compounds. Hyperproliferative HaCaT keratinocytes in monolayer cultures were exposed to fumaric acid, dimethylfumarate, zinc monoethylfumarate, calcium monoethylfumarate and magnesium monoethylfumarate at concentrations between 0.4 microM and 960 microM for 48 h. Cell proliferation was studied by [3H]thymidine incorporation. In addition 14C-labelled amino acid uptake and total protein content were measured. Direct cytotoxicity was determined by the release of cytoplasmic lactate dehydrogenase (LDH) into the culture medium. The corresponding 50% inhibition concentrations (IC50) were calculated for DNA/protein synthesis: 2.3/2.5 microM (dimethylfumarate), 133/145 microM (zinc monoethylfumarate), 215/230 microM (calcium monoethylfumarate), 275/270 microM (magnesium monoethylfumarate), > 960/> 960 microM (fumaric acid). The total protein content was less sensitive. Antiproliferative activity was found for dimethylfumarate and to a lesser degree for calcium monoethylfumarate already at the subtoxic concentrations of 1.3 and 4 microM, respectively. In the case of magnesium monoethylfumarate, zinc monoethylfumarate and fumaric acid there was no such dissociation between their cytotoxic and antiproliferative potential. These data indicate that most of the antipsoriatic potential of fumaric therapies is due to the dimethylfumarate compound.

Topics: Cell Death; Cell Division; Cells, Cultured; Dimethyl Fumarate; DNA; Fumarates; Humans; Keratinocytes; L-Lactate Dehydrogenase; Protein Biosynthesis; Psoriasis

Purine nucleotide concentrations in skin- and blood-cells of psoriatic patients are abnormal: The increase in the steady state level of cGMP and the decrease in the cAMP concentrations are associated with an enhanced rate of cellular proliferation. Concomitantly we found in the present study decreased ADP and ATP concentrations in blood cells (p less than 0.0001). The change in nucleotide concentrations suggests a defective purine nucleotide synthesis pathway. Stimulation of the Krebs cycle with fumaric acid raises ATP (p less than 0.0001) and most probably cAMP levels and at the same time slows down the purine nucleotide synthesis through end-product inhibition. Both effects can inhibit DNA and protein synthesis activity, which results in inhibition of cellular proliferation. Fumaric acid seems therefore a useful treatment for psoriatic lesions if liver and kidney functions (purine nucleotide and urea cycle) are controlled during treatment.

Topics: Adenosine Diphosphate; Adenosine Monophosphate; Adenosine Triphosphate; Adult; Cell Division; Fumarates; Humans; Middle Aged; Psoriasis; Purine Nucleotides

A case of fully reversible tubular toxicity with consecutive metabolic osteopathy following systemic fumaric acid therapy is reported. This secondary effect of oral fumaric acid therapy obviously occurs very rarely, never having been described before. A 46-year-old female patient with a long history of recurrent palmoplantar psoriasis underwent oral treatment with fumaric acid and its esters in accordance with the Schäfer method, preceding attempts at curative treatment with conventional antipsoriatic agents having proved unsatisfactory. Two months later, the patient started to experience arthralgia, back pain in the early hours of the morning and myalgia with increasing frequency, progressing to disablement in moving and walking and, finally, to total immobility. Not until 9 months later was the reason for these severe disabilities found: they stemmed from hypophosphataemic osteomalacia as a result of a complex disturbance of the renal tubular system. The clinical symptoms and the results of laboratory chemistry tests returned to normal as soon as fumaric acid medication was discontinued. Two attempts at reexposure confirmed the causal relationship. Oral fumaric acid medication should never be administered without clinical and chemical controls.

Topics: Administration, Oral; Biopsy; Bone and Bones; Fanconi Syndrome; Female; Fumarates; Humans; Kidney Function Tests; Middle Aged; Osteomalacia; Psoriasis

Topics: Adult; Dimethyl Fumarate; Drug Therapy, Combination; Follow-Up Studies; Fumarates; Humans; Psoriasis

We report on two cases of adverse reactions to topical treatment with monoethyl fumarate. One patient suffering from atopic dermatitis reacted with contact dermatitis; the other, suffering from psoriasis, developed a generalized, partly pustulous exanthema as well as signs of systemic involvement, such as tachycardia and dyspnea. As the causative mechanism we suggest non-immunological contact urticaria syndrome.

Topics: Administration, Topical; Adult; Anaphylaxis; Drug Eruptions; Eczema; Female; Fumarates; Humans; Male; Psoriasis

Two sisters, aged 25 and 29 years, with generalized psoriasis guttata since childhood, developed nausea, upper-abdominal pain, loss of appetite, palpitations and flushes in the course of local and oral administration of fumaric acid esters. Because of these side effects the treatment was discontinued after about two weeks, and the symptoms disappeared. But proteinuria and haematuria were subsequently noted, creatinine concentration rose to 2.2 and 2.5 mg/dl, respectively, while creatinine clearance fell to 44 and 27 ml/min, respectively. Examination of urinary sediments and analysis of urinary proteins gave results compatible with tubular-interstitial renal damage. The abnormal renal functions and urinary findings proved reversible within three weeks.

Topics: Administration, Oral; Adult; Baths; Combined Modality Therapy; Digestive System; Drug Therapy, Combination; Female; Fumarates; Humans; Kidney; Kidney Diseases; Ointments; Psoriasis; Time Factors

Topics: Dermatologic Agents; Fumarates; Humans; Psoriasis

24 days after starting treatment of psoriasis with fumaric acid derivatives (0.8-1.0 g orally, plus unknown quantities locally) a 21-year-old woman developed acute oliguric renal failure with a rise of serum creatinine levels to 1094 mumol/l (12.4 mg/dl). Deterioration of renal function had been preceded by severe abdominal symptoms with nausea, vomiting and colicky pain. On admission to hospital she was dehydrated with hyponatraemia and hypokalaemia. There was glomerular microhaematuria, increased excretion of renal epithelia, and tubular proteinuria. Renal biopsy demonstrated acute tubular damage with vacuolization of proximal epithelia, dilated tubules and scattered necroses. After intermittent haemodialysis (13 courses over two weeks) renal function gradually recovered, as demonstrated at a follow-up examination four months after discharge.

Topics: Acute Kidney Injury; Adult; Biopsy; Chronic Disease; Drug Combinations; Drug Therapy, Combination; Female; Fumarates; Humans; Kidney; Powders; Psoriasis

We describe four female patients with psoriasis treated with fumaric acid esters. In two patients acute renal failure developed during this therapy. Histological investigation of renal biopsy in one patient was compatible with the diagnosis of acute tubular necrosis; her renal function was reversible after cessation of the medication. The histological diagnosis of the other patient was tubulo-interstitial nephritis, possibly as a reaction to acute tubular necrosis. The recovery of her renal function was incomplete after 9 months.

Topics: Acute Kidney Injury; Adult; Female; Fumarates; Humans; Kidney Cortex; Psoriasis

We describe two patients who developed acute renal failure during therapy with fumaric acid-esters. Histologic findings after renal biopsy in one patient were compatible with the diagnosis of acute tubular necrosis (ATN), and renal function was restored after cessation of the medication. The histologic diagnosis in the other patient was tubulo-interstitial nephritis (TIN), possibly reactive to ATN. The recovery of renal function was incomplete after 9 months. Two other patients had deterioration of renal function and proteinuria during therapy with fumaric acid-esters. The symptoms were completely reversible in one patient after discontinuation of the medication, and incompletely reversible in the other. The literature is reviewed and a comparison is drawn with the maleic acid model in the rat.

Topics: Acute Kidney Injury; Adult; Female; Fumarates; Humans; Psoriasis; Renal Dialysis

Topics: Adult; Aged; Drug Evaluation; Female; Fumarates; Humans; Male; Middle Aged; Psoriasis

Fumaric acid may not be regarded as an antipsoriatic drug. Beneficial effects on psoriatic lesions may be explained by secondary changes such as the acidification of gastric juice in cases of anacidity or hypacidity . Monoethylfumarate exerts true antipsoriatic activities but is by far too toxic for clinical use. Experimental investigations have confirmed an inhibitory action of the above-mentioned fumarate on nucleic acid synthesis and protein synthesis of PHA-stimulated human lymphocytes.

Topics: DNA; Fumarates; Gastric Acidity Determination; Humans; Proteins; Psoriasis

Topics: Female; Fumarates; Humans; Methotrexate; Middle Aged; Psoriasis; Vitamin A

Topics: Folic Acid Antagonists; Fumarates; Humans; Psoriasis

Topics: Fumarates; Humans; Psoriasis

Topics: Fumarates; Humans; Psoriasis