piperidines and Psoriasis

Psoriasis is a chronic immune-mediated skin disease with a significant impact on patients' quality of life. Mild-to-moderate forms of the disease usually require long-term topical treatment, but prolonged use of corticosteroids and vitamin D analogues is limited by adverse effects. With further understanding of psoriasis pathogenesis, new molecules are emerging aiming to fulfil these clinical needs. Tapinarof, an aryl hydrocarbon receptor modulator, has completed a phase III study and demonstrated good efficacy results, even in long treatment courses, with a favourable safety profile. It additionally appears to have a promising remitting effect as patients presented with an average relapsing time of over 3 months. Roflumilast, a phosphodiesterase type 4 inhibitor, also underwent a phase III study with significant lesion improvement and notable pruritus management, and with no reported side effects. Roflumilast was evaluated as an option for intertriginous areas with good outcomes in a small sample, but larger trials are required. The Janus kinase-signal transducer and activator of transcription pathway has been targeted in recent clinical investigations with promising options, currently with brepocitinib pending phase IIb results. Ongoing preclinical studies involving interleukin-2 inhibition, RNA modulators and amygdalin analogues may lead to forthcoming clinical trials. New topical drugs are successfully emerging and future research comparing them to classical options will dictate their clinical role in the treatment of psoriasis.

Topics: Administration, Topical; Aminopyridines; Amygdalin; Benzamides; Boron Compounds; Bridged Bicyclo Compounds, Heterocyclic; Cyclopropanes; Dermatologic Agents; Humans; Interleukin-2; MicroRNAs; Nitriles; Phosphodiesterase 4 Inhibitors; Piperidines; Psoriasis; Pyrazoles; Pyrimidines; Resorcinols; Stilbenes

Psoriasis is a systemic inflammatory disease that is associated with increased risk of several diseases, such as psoriatic arthritis (PsA), inflammatory bowel disease, and cardiovascular diseases. About 20 to 30% patients with psoriasis subsequently develop PsA. IgA nephropathy is the most common primary glomerular disease world-wide. Psoriasis and IgA nephropathy appear to be associated, but the mechanism underlying this connection is unclear. Tofacitinib and leflunomide are common treatments for psoriatic arthritis. We administered tofacitinib combined with leflunomide to a 38-year-old female patient who presented with PsA and IgA nephropathy. After treatment, she experienced significant reductions in the psoriatic lesions, pain in the right knee joint, and proteinuria. Administration of tofacitinib combined with leflunomide for treatment of a patient who had PsA complicated with IgA nephropathy led to significant resolution of the symptoms of both conditions. These results suggest similarities in the pathogenesis of PsA and IgA nephropathy and a possible new treatment for IgA nephropathy.

Topics: Adult; Arthritis, Psoriatic; Female; Glomerulonephritis, IGA; Humans; Leflunomide; Piperidines; Psoriasis; Pyrimidines

Janus kinase (JAK) inhibitors are novel treatment approaches for psoriasis. However, there is no direct comparison of JAK inhibitors in plaque psoriasis. In order to compare the efficacy and safety of JAK inhibitors in psoriasis, we conducted a network meta-analysis using eligible randomized clinical trials (RCTs). The efficacy of JAK inhibitors was evaluated using a 75% improvement in Psoriasis Area and Severity Index (PASI75) from baseline, and the proportion of patients achieving the Physician's Global Assessment (PGA) response. The incidence of treatment-related adverse events (AEs) was also assessed. A total of eight RCTs with tofacitinib, peficitinib, solcitinib, baricitinib, abrocitinib and deucravacitinib were included. A total of 3612 participants who were diagnosed with moderate-to-severe plaque psoriasis were analysed. Overall, JAK inhibitors showed superior PASI75 response over placebo at both 8 and 12 weeks. Among all included JAK inhibitors, tofacitinib 15 mg twice a day (BID) had the highest probability of achieving PASI75 at both 8 and 12 weeks (SUCRA = 0.938 and 0.937, separately), followed by tofacitinib 10 mg BID (SUCRA = 0.905 and 0.908, separately) and deucravacitinib 12 mg once daily (QD) (SUCRA = 0.874 and 0.837, separately). A similar finding was observed for PGA response. Safety assessment showed that all JAK inhibitors had non-inferior safety compared with placebo, except for deucravacitinib 6 mg BID and 12 mg QD. Tofacitinib 2 mg BID was the first-ranked drug for safety profile followed by deucravacitinib 3 mg QD, and tofacitinib 5 mg BID. When comprehensively evaluated the efficacy and safety, tofacitinib (2 mg, 5 mg, 10 mg, 15 mg BID) was superior to other included JAK inhibitors with satisfying PASI75 and PGA response, as well as relatively low incidence of AEs. Our study confirmed that JAK inhibitors had promising treatment efficacy for moderate-to-severe plaque psoriasis. Tofacitinib showed superior efficacy and safety over peficitinib, solcitinib, baricitinib, abrocitinib and deucravacitinib.

Topics: Adamantane; Azetidines; Heterocyclic Compounds; Humans; Immunosuppressive Agents; Janus Kinase Inhibitors; Janus Kinases; Network Meta-Analysis; Niacinamide; Piperidines; Protein Kinase Inhibitors; Psoriasis; Purines; Pyrazoles; Pyrimidines; Sulfonamides; Treatment Outcome

Tofacitinib citrate is an oral Janus kinase 1/3 inhibitor approved for rheumatoid arthritis, ulcerative colitis, and active psoriatic arthritis. Tofacitinib is being increasingly used off-label for dermatological conditions, with varying efficacy across recent studies. A review of these studies will be a helpful resource for dermatologists considering the use of tofacitinib for conditions refractory to first-line therapies.. MEDLINE, Embase, CINAHL Plus, Cochrane Library, Scopus, Web of Science, Clinicaltrials.gov, and the WHO International Clinical Trials Registry Platform were all searched for articles and trials mentioning the term 'tofacitinib', then manually reviewed to identify published data on off-label uses of tofacitinib. The article was structured according to the quality of the evidence available.. Tofacitinib appears to show strong efficacy for numerous dermatologic conditions. Randomized controlled trial data is available for atopic dermatitis, alopecia areata, and plaque psoriasis. Case report and case series data is available for numerous other dermatologic conditions.. While tofacitinib has a wide array of immunoregulatory properties, making it a possible candidate for treating many dermatologic conditions refractory to other treatments, further testing is needed to better characterize its efficacy and utility moving forward, as well as its safety and adverse effect profile.

Topics: Alopecia Areata; Arthritis, Psoriatic; Colitis, Ulcerative; Dermatitis, Atopic; Dermatology; Humans; Off-Label Use; Piperidines; Protein Kinase Inhibitors; Psoriasis; Pyrimidines; Randomized Controlled Trials as Topic

Janus kinase inhibitors (JAKi) have been approved for use in various immune-mediated inflammatory diseases. With five agents licensed, it was timely to summarise the current understanding of JAKi use based on a systematic literature review (SLR) on efficacy and safety.. Existing data were evaluated by a steering committee and subsequently reviewed by a 29 person expert committee leading to the formulation of a consensus statement that may assist the clinicians, patients and other stakeholders once the decision is made to commence a JAKi. The committee included patients, rheumatologists, a gastroenterologist, a haematologist, a dermatologist, an infectious disease specialist and a health professional. The SLR informed the Task Force on controlled and open clinical trials, registry data, phase 4 trials and meta-analyses. In addition, approval of new compounds by, and warnings from regulators that were issued after the end of the SLR search date were taken into consideration.. The Task Force agreed on and developed four general principles and a total of 26 points for consideration which were grouped into six areas addressing indications, treatment dose and comedication, contraindications, pretreatment screening and risks, laboratory and clinical follow-up examinations, and adverse events. Levels of evidence and strengths of recommendations were determined based on the SLR and levels of agreement were voted on for every point, reaching a range between 8.8 and 9.9 on a 10-point scale.. The consensus provides an assessment of evidence for efficacy and safety of an important therapeutic class with guidance on issues of practical management.

Topics: Adamantane; Advisory Committees; Antirheumatic Agents; Arthritis, Psoriatic; Arthritis, Rheumatoid; Azetidines; Cytokines; Drug Therapy, Combination; Europe; Heterocyclic Compounds, 3-Ring; Humans; Inflammatory Bowel Diseases; Janus Kinase Inhibitors; Niacinamide; Piperidines; Psoriasis; Purines; Pyrazoles; Pyridines; Pyrimidines; Rheumatology; Spondylarthropathies; Spondylitis, Ankylosing; Sulfonamides; Triazoles

JAK inhibitor therapies are effective treatment options for immune-mediated inflammatory diseases (IMIDs), but their use has been limited by venous thromboembolism (VTE) risk warnings from licensing authorities. We undertook this study to evaluate the VTE risk of JAK inhibitors in patients with IMIDs.. Systematic searches of Medline and Embase databases from inception to September 30, 2020 were conducted. Phase II and phase III double-blind, randomized controlled trials (RCTs) of JAK inhibitors at licensed doses were included in our analyses. RCTs with no placebo arm, long-term extension studies, post hoc analyses, and pooled analyses were excluded. Three researchers independently extracted data on exposure to JAK inhibitors or placebo and VTE events (e.g., pulmonary embolism [PE] and deep vein thrombosis [DVT]) and assessed study quality.. A total of 42 studies were included, from an initial search that yielded 619. There were 6,542 JAK inhibitor patient exposure years (PEYs) compared to 1,578 placebo PEYs. There were 15 VTE events in the JAK inhibitor group and 4 in the placebo group. The pooled incidence rate ratios (IRRs) of VTE, PE, and DVT in patients receiving JAK inhibitors were 0.68 (95% confidence interval [95% CI] 0.36-1.29), 0.44 (95% CI 0.28-0.70), and 0.59 (95% CI 0.31-1.15), respectively.. This meta-analysis of RCT data defines the VTE risk with JAK inhibitors as a class in IMID patients. The pooled IRRs do not provide evidence that support the current warnings of VTE risk for JAK inhibitors. These findings will aid continued development of clinical guidelines for the use of JAK inhibitors in IMIDs.

Topics: Arthritis, Psoriatic; Arthritis, Rheumatoid; Azetidines; Clinical Trials, Phase II as Topic; Clinical Trials, Phase III as Topic; Heterocyclic Compounds, 3-Ring; Humans; Inflammatory Bowel Diseases; Janus Kinase Inhibitors; Piperidines; Psoriasis; Pulmonary Embolism; Purines; Pyrazoles; Pyridines; Pyrimidines; Randomized Controlled Trials as Topic; Risk; Spondylarthropathies; Spondylitis, Ankylosing; Sulfonamides; Triazoles; Venous Thromboembolism; Venous Thrombosis

To assess the relative efficacy and safety of tofacitinib administration (5 and 10 mg) twice daily in psoriasis patients.. Randomized controlled trials (RCTs) examining the efficacy and safety of tofacitinib in psoriasis patients were included in this network meta-analysis. A Bayesian network meta-analysis was performed to combine the direct and indirect evidence from the RCTs.. Five RCTs, including 3,265 patients, met the inclusion criteria. The 75% or more reduction in Psoriasis Area and Severity Index (PASI75) response rate was significantly higher in the 10-mg tofacitinib group than in the placebo group (OR, 20.53; 95% credible interval (CrI), 13.98 - 32.69). Similarly, the PASI75 response rate was significantly higher in the 50-mg etanercept and 5-mg tofacitinib groups than in the placebo group (OR, 18.39; 95% CrI, 10.19 - 36.97 and OR, 8.87; 95% CrI, 6.02 - 13.55, respectively). However, 10 mg tofacitinib tended to be more efficacious than 50 mg etanercept and 5 mg tofacitinib. Ranking probability based on Surface under the cumulative ranking curve (SUCRA) indicated that 10 mg tofacitinib had the highest probability of being the best treatment for achieving the PASI75 response rate, followed by 50 mg etanercept, 5 mg tofacitinib, and placebo. The Physician's Global Assessment (PGA) and PASI75 response rates showed similar distribution patterns. In contrast, the number of patients with serious adverse events (SAEs) or withdrawals due to AEs did not differ significantly among the 4 treatment options.. Tofacitinib (10 mg) showed the highest efficacy for the intervention for psoriasis, followed by 50 mg etanercept and 5 mg tofacitinib, and was not associated with a significant risk for SAEs or AE-induced withdrawals.

Topics: Humans; Network Meta-Analysis; Piperidines; Psoriasis; Pyrimidines; Pyrroles; Randomized Controlled Trials as Topic; Treatment Outcome

Tofacitinib is an oral JAK inhibitor for the treatment of rheumatoid arthritis (RA), psoriatic arthritis, and ulcerative colitis, and has been previously investigated for psoriasis (PsO). This meta-analysis of genome-wide association studies (GWAS) was performed to identify genetic factors associated with increased risk/faster onset of herpes zoster (HZ) in subjects with RA or PsO receiving tofacitinib treatment, and to determine potential mechanisms that could be attributed to the varying rates of HZ across ethnicities.. In an ethnicity/indication-specific, trans-ethnic, trans-population meta-analysis of GWAS in subjects with RA or PsO from phase II, phase III, and long-term extension studies of tofacitinib, 8 million genetic variants were evaluated for their potential association with time to an HZ event and incidence of an HZ event (case versus control) with tofacitinib treatment, using Cox proportional hazard and logistic regression analyses, respectively.. In total, 5,246 subjects were included (3,168 with RA and 2,078 with PsO). After adjustment for age, baseline absolute lymphocyte count, genetically defined ethnicity, and concomitant methotrexate use (in RA subjects only), 4 loci were significantly associated with faster onset of HZ in European subjects (P < 5 × 10. Genetic analysis of tofacitinib-treated subjects with RA or PsO identified multiple loci associated with increased HZ risk. Prevalent variants near the immune-relevant genes CD83 and IL17RB in European and East Asian populations, respectively, may contribute to risk of HZ in tofacitinib-treated subjects.

Topics: Antigens, CD; Arthritis, Rheumatoid; Asian People; CD83 Antigen; Genome-Wide Association Study; Herpes Zoster; Humans; Immunoglobulins; Janus Kinase Inhibitors; Logistic Models; Membrane Glycoproteins; Piperidines; Polymorphism, Single Nucleotide; Proportional Hazards Models; Psoriasis; Pyrimidines; Receptors, Interleukin-17; White People

Various systemic immunomodulating therapies have been investigated to treat nail psoriasis, but the efficacy remains unclear.. To perform a systematic review and network meta-analysis to evaluate the efficacy of small molecule inhibitors and biologics in treating nail psoriasis.. Eligible studies in online databases were identified until March 10, 2020. To assess the efficacy of small molecule inhibitors and biologics, network meta-analyses with surface under the cumulative ranking curve of improvement in nail score at 10 to 16 and at 24 to 26 weeks, as well as 100% improvement of Nail Psoriasis Severity Index (NAPSI), were performed.. Thirty-nine studies with a total of 13 treatment arms involving 15,673 patients with nail psoriasis were included. An network meta-analysis showed that tofacitinib (weighted mean difference, 56.67; 95% confidence interval [CI], 35.87-77.48) and ixekizumab (weighted mean difference, 59.40; 95% CI, 45.87-72.93) presented the most improvement of nail score at 10 to 16 weeks and 24 to 26 weeks, respectively. For 100% improvement of the Nail Psoriasis Severity Index, ixekizumab showed the best efficacy among all treatments (odds ratio, 2.98; 95% CI, 1.74-5.10).. Insufficiency of eligible data and no long-term follow-up data.. Tofacitinib and ixekizumab presented the best efficacy for treating nail psoriasis in 10 to 16 weeks and 24 to 26 weeks, respectively.

Topics: Adalimumab; Antibodies, Monoclonal, Humanized; Dermatologic Agents; Etanercept; Humans; Infliximab; Nail Diseases; Network Meta-Analysis; Piperidines; Protein Kinase Inhibitors; Psoriasis; Pyrimidines; Severity of Illness Index

Inhibitors of Janus kinases (JAKs) are being developed for treatment of inflammatory bowel diseases and other immune-mediated diseases. Tofacitinib is effective in treatment of ulcerative colitis, but there are safety concerns. We performed a systematic review and meta-analysis to investigate the safety profile of tofacitinib, upadacitinib, filgotinib, and baricitinib in patients with rheumatoid arthritis, inflammatory bowel diseases, psoriasis, or ankylosing spondylitis.. We searched the MEDLINE, EMBASE, and Cochrane Central Register of Controlled Trials from January 1, 1990, through July 1, 2019. We performed a manual review of conference databases from 2012 through 2018. The primary outcome was incidence rates of adverse events (AEs) and serious AEs. We also estimated incidence rates of serious infections, herpes zoster infection, non-melanoma skin cancer, other malignancies, major cardiovascular events, venous thromboembolism, and mortality. We performed a meta-analysis, which included controlled studies, to assess the relative risk of these events.. We identified 973 studies; of these, 82 were included in the final analysis, comprising 66,159 patients with immune-mediated diseases who were exposed to a JAK inhibitor. Two-thirds of the included studies were randomized controlled trials. The incidence rate of AEs was 42.65 per 100 person-years and of serious AEs was 9.88 per 100 person-years. Incidence rates of serious infections, herpes zoster infection, malignancy, and major cardiovascular events were 2.81 per 100 person-years, 2.67 per 100 person-years, 0.89 per 100 person-years, and 0.48 per 100 person-years, respectively. Mortality was not increased in patients treated with JAK inhibitors compared with patients given placebo or active comparator (relative risk 0.72; 95% confidence interval 0.40-1.28). The meta-analysis showed a significant increase in risk of herpes zoster infection among patients who received JAK inhibitors (relative risk 1.57; 95% confidence interval 1.04-2.37).. In a systematic review and meta-analysis, we found an increased risk of herpes zoster infection among patients with immune-mediated diseases treated with JAK inhibitors. All other AEs were not increased among patients treated with JAK inhibitors.

Topics: Arthritis, Rheumatoid; Azetidines; Herpes Zoster; Heterocyclic Compounds, 3-Ring; Humans; Incidence; Inflammatory Bowel Diseases; Janus Kinase Inhibitors; Janus Kinases; Piperidines; Placebos; Psoriasis; Purines; Pyrazoles; Pyridines; Pyrimidines; Pyrroles; Randomized Controlled Trials as Topic; Spondylitis, Ankylosing; Sulfonamides; Survival Analysis; Treatment Outcome; Triazoles

Janus kinase (JAK) inhibitors are novel small molecules with a mechanism of action in multiple signaling pathways that allows their application in a broad spectrum of autoimmune and autoinflammatory diseases. As far as the field of dermatology is concerned, chronic plaque psoriasis is currently one of the most studied indications regarding the potential use of JAK inhibitors. The purpose of this review is to provide a summarized overview of the existing information on the efficacy and safety of JAK inhibitors in plaque psoriasis, with a focus on tofacitinib, ruxolitinib, baricitinib, peficitinib and filgotinib. Although the published data on the therapeutic benefit of these agents in the therapy of this chronic condition are promising, further prospective studies and real-life data are necessary in order to sufficiently evaluate their role as an adequate treatment option for psoriatic patients.

Topics: Adamantane; Azetidines; Humans; Janus Kinase Inhibitors; Janus Kinases; Niacinamide; Nitriles; Piperidines; Prospective Studies; Psoriasis; Purines; Pyrazoles; Pyridines; Pyrimidines; Pyrroles; Sulfonamides; Triazoles

Tofacitinib is a novel oral janus kinase (JAK) inhibitor approved for the treatment of psoriatic arthritis. It was also investigated for the treatment of plaque psoriasis, although it is not approved by the Food and Drug Administration for this indication. This article aimed to summarize the efficacy and safety data of tofacitinib for treatment of psoriatic disease.. A comprehensive review of literature was conducted on the PubMed database using the search terms: "((tofacitinib) AND (psoriasis)) OR ((tofacitinib) AND (psoriatic arthritis))". Data from the pivotal clinical trials evaluating tofacitinib in the treatment of psoriatic disease were summarized.. The Oral-treatment Psoriasis Trial (OPT) study series demonstrated that tofacitinib is efficacious in the treatment of plaque psoriasis with an acceptable safety profile. The OPT studies also demonstrated the non-inferiority of tofacitinib 10 mg twice daily compared to etanercept. The Oral Psoriatic Arthritis Trial (OPAL) study series demonstrated that tofacitinib significantly improved psoriatic arthritis outcomes compared to placebo and had an acceptable safety profile. Its efficacy is comparable to adalimumab in psoriatic arthritis.. Patients treated with tofacitinib should be monitored for herpes zoster, malignancies, blood clots, and changes in laboratory values. Overall, tofacitinib is a useful new systemic agent in the treatment of psoriatic disease. Its oral route of administration, novel JAK pathway target, short half-life, and strong recapture rates after treatment interruption make it a unique new tool for psoriatic disease management. Further long-term studies will help determine its role in the treatment algorithm for psoriatic arthritis and its indication for plaque psoriasis.

Topics: Adalimumab; Administration, Oral; Arthritis, Psoriatic; Etanercept; Humans; Janus Kinase Inhibitors; Piperidines; Psoriasis; Pyrimidines

With recent advancements in the understanding of vitiligo pathogenesis, Janus kinase (JAK) inhibitors have emerged as a promising new treatment modality, but their effects remain incompletely elucidated. Tofacitinib, an oral JAK 1/3 inhibitor approved for the treatment of rheumatoid arthritis, has previously been shown to induce significant re-pigmentation in vitiligo. However, as with other novel targeted therapies, cutaneous adverse effects have been observed. We report a 36-year-old woman with a history of rheumatoid arthritis, refractory to multiple pharmacotherapies, who was initiated on tofacitinib and subsequently developed progressive depigmented patches consistent with new-onset vitiligo. Although definitive causation cannot be established in this case without additional studies, it is important to note that many targeted therapies have the potential to induce paradoxical effects, that is, the occurrence or exacerbation of pathologic conditions that have been shown to respond to these medications. Paradoxical findings with other targeted therapies include the occurrence of melanoma during treatment with BRAF inhibitors, keratoacanthomas with PD-1 inhibitors, vitiligo and psoriasis with TNF-alpha inhibitors, and hidradenitis suppurativa with various biologic agents. Although JAK inhibitors hold therapeutic promise in the treatment of inflammatory skin disorders, further research is warranted to more fully comprehend their effects.

Topics: Adult; Arthritis, Rheumatoid; Female; Hidradenitis Suppurativa; Humans; Janus Kinase Inhibitors; Keratoacanthoma; Melanoma; Piperidines; Programmed Cell Death 1 Receptor; Protein Kinase Inhibitors; Proto-Oncogene Proteins B-raf; Psoriasis; Pyrimidines; Pyrroles; Tumor Necrosis Factor-alpha; Vitiligo

The Dermatology Life Quality Index (DLQI) is commonly used to assess the quality of life of patients with skin diseases. Clinical trials confirm the positive effect of the use of biologics and new molecules on the quality of life of patients with plaque psoriasis.. Investigation of the effect of infliximab, adalimumab, ixekizumab, secukinumab and tofacitinib on Health-Related Quality of Life (HRQOL) measured by the DLQI in adult plaque psoriatic patients with respect to the patients' race, type of used agent/placebo, agent's dosage and treatment duration as well as the DLQI score prior to and after commencement of treatment.. Systematic literature searching for referential papers written in English using four databases: PubMed, EMBASE, Scopus, ClinicalTrials.gov as well as and manual searching (Google) Cochran's (Q) and I2 tests were used for evaluation of heterogeneity or the degree of variation in the true effect size estimates between the analysed studies. The standardized mean difference (the SMD; Hedge's g score) was applied to measure the differences between the two means (i.e. two groups: treated vs non-treated or treated vs placebo). The data coding and Hedge's g values were calculated according to the guidance of MetaXL software version 5.3.. 43 studies, in total 25,898 individuals, were evaluated by the DLQI and weighted mean scores were derived for the analysis. The mean DLQI scores ranged from 6.83 to 17.8 with the overall DLQI score of 12.12 (95%CI: 11.24 to 13.06). A random-effects model demonstrated significant considerable heterogeneity of the study results (I2 = 98%; p<0.001).. Infliximab, adalimumab, ixekizumab, secukinumab and tofacitinib in adult plaque psoriatic patients improved HRQOL measured by the DLQI. The patients with lower quality of life before treatment obtained better results.

Topics: Adalimumab; Adolescent; Adult; Aged; Aged, 80 and over; Antibodies, Monoclonal; Antibodies, Monoclonal, Humanized; Female; Humans; Infliximab; Male; Middle Aged; Piperidines; Psoriasis; Pyrimidines; Quality of Life; Severity of Illness Index; Young Adult

Psoriasis is a chronic, inflammatory multisystem disease that affects up to 3.2% of the US population. This guideline addresses important clinical questions that arise in psoriasis management and care, providing recommendations based on the available evidence. The treatment of psoriasis with biologic agents will be reviewed, emphasizing treatment recommendations and the role of the dermatologist in monitoring and educating patients regarding benefits as well as associated risks.

Topics: Adalimumab; Antibodies, Monoclonal; Antibodies, Monoclonal, Humanized; Biological Products; Biosimilar Pharmaceuticals; Certolizumab Pegol; Dermatologic Agents; Drug Therapy, Combination; Etanercept; Evidence-Based Medicine; Humans; Infliximab; Piperidines; Psoriasis; Pyrimidines; Pyrroles; Ustekinumab

Tofacitinib is an oral Janus kinase (JAK) inhibitor that targets JAK1 and JAK3, and thus regulates immune response. Therefore, tofacitinib is used to treat immune-mediated inflammatory diseases such as chronic plaque psoriasis. The objective of this study was to systematically assess the efficacy and safety of tofacitinib in treating chronic plaque psoriasis.. To systematically review the efficacy and safety of tofacitinib in the treatment of chronic plaque psoriasis, we performed a meta-analysis to evaluate the efficacy and safety of tofacitinib in patients with chronic plaque psoriasis.. Databases including PubMed, Embase, and The Cochrane Library were searched for randomized controlled trials about the efficacy and safety of tofacitinib in treating chronic plaque psoriasis from inception to August 2017 (PROSPERO Code No: CRD42017076587).. Six articles (seven randomized controlled trial studies) involving 3743 patients were included. The meta-analysis results showed that for efficacy, tofacitinib (5 mg or 10 mg) compared with placebo can significantly improve the Physician's Global Assessment response, PASI75, and PASI90 after treatment. For safety, the incidence of adverse reactions was statistically significantly higher for tofacitinib compared with placebo.. Treatment of chronic plaque psoriasis with tofacitinib is effective, but there may be more adverse reactions.

Topics: Chronic Disease; Humans; Piperidines; Protein Kinase Inhibitors; Psoriasis; Pyrimidines; Pyrroles; Treatment Outcome

Psoriasis is a common, chronic, immune-mediated disease associated with several comorbidities. Biologic therapy revolutionized the treatment of moderate-to-severe psoriasis, improving physical and emotional burden of the disease. Still, there are unmet needs in the treatment of psoriasis regarding long-term efficacy, tolerability, safety, route of administration, and cost. The increased knowledge of the pathogenesis of the intracellular metabolic pathways allowed the development of new compounds that inhibit certain intracellular proteins involved in the immune response. Tofacitinib is an oral small molecule that inhibits JAK/STAT pathway, which is then unable to upregulate the pro-inflammatory genes implicated in psoriasis. Data from phase II and III trials reveal that tofacitinib is a well-tolerated treatment for moderate-to-severe chronic plaque psoriasis with sustained efficacy for up to 2 years. With a convenient oral administration in the absence of organ toxicity associated with conventional oral treatments, tofacitinib may represent an important therapeutic to be included in the treatment algorithms of psoriasis.

Topics: Administration, Oral; Clinical Trials as Topic; Humans; Janus Kinases; Piperidines; Protein Kinase Inhibitors; Psoriasis; Pyrimidines; Pyrroles

The effects of tofacitinib in treating moderate-to-severe plaque psoriasis were unclear. We aimed to assess the effects of tofacitinib in treating moderate-to-severe plaque psoriasis. We searched PubMed, Cochrane Central Register of Controlled Trials and EMBASE for relevant randomized controlled trials (RCTs) and conducted a systematic review and meta-analysis. Four RCTs with 2724 participants were included. Compared to placebo, tofacitinib significantly improved psoriasis {≥75% reduction in the Psoriasis Area and Severity Index score: 5 mg BID: risk difference (RD) 0.32 [95% confidence interval (CI) 0.28-0.35], 10 mg BID: RD 0.51 (95% CI 0.43-0.58); ≥90% reduction in the Psoriasis Area and Severity Index score: 5 mg BID: RD 0.19 (95% CI 0.17-0.22), 10 mg BID: RD 0.36 (95% CI 0.31-0.42); Physician's Global Assessment 0/1: 5 mg BID: RD 0.31 (95% CI 0.27-0.35), 10 mg BID: RD 0.48 (95% CI 0.44-0.53)} and participants' life quality [Dermatology Life Quality Index 0/1: 5 mg BID: RD 0.24 (95% CI 0.20-0.2), 10 mg BID: RD 0.36 (95% CI 0.33-0.40)]. Tofacitinib was associated with an increase in minor adverse events [upper respiratory tract infection: 5 mg BID: RD 0.02 (95% CI 0.00-0.03), 10 mg BID: RD 0.02 (95% CI 0.00-0.04); hypercholesterolaemia: 5 mg BID: RD 0.02 (95% CI 0.01-0.04), 10 mg BID: RD 0.02 (95% CI 0.01-0.04)]. In conclusion, tofacitinib may be a treatment option for moderate-to-severe plaque psoriasis that is unresponsive to other therapies and patients who are intolerable to other therapies or prefer oral medications.

Topics: Dermatologic Agents; Humans; Janus Kinase Inhibitors; Piperidines; Placebos; Psoriasis; Pyrimidines; Pyrroles; Quality of Life; Randomized Controlled Trials as Topic; Severity of Illness Index; Treatment Outcome

Psoriasis and psoriatic arthritis (PsA) are inflammatory immune-mediated conditions which can cause considerable disability and reduced quality of life. Management can be complex as clinical heterogeneity may lead to different treatment pathways. Tofacitinib is a novel, oral Janus Kinase (JAK) inhibitor with proven efficacy in rheumatoid arthritis. Areas covered: This review analyzes recent studies of tofacitinib in psoriatic disease treatment. The relevant literature was identified using clinicaltrials.gov, PubMed, and Google Scholar. Tofacitinib efficacy was demonstrated in PsA by the OPAL Broaden and OPAL Beyond phase-III studies, and received FDA and EMA approval. Tofacitinib was superior to placebo for the treatment of moderate-to-severe plaque psoriasis in the OPT Pivotal 1 and 2, OPT Retreatment studies, but FDA approval was declined for this indication based on issues of clinical efficacy and long-term safety. Expert commentary: Tofacitinib is an important oral drug for the treatment of PsA. However, the long-term safety data require further evaluation. Tofacitinib and other JAK inhibitors show potential to broaden the treatment options in PsA and other inflammatory conditions.

Topics: Antirheumatic Agents; Arthritis, Psoriatic; Clinical Trials as Topic; Drug Approval; Humans; Janus Kinases; Nasopharyngitis; Piperidines; Protein Kinase Inhibitors; Psoriasis; Pyrimidines; Pyrroles

Psoriasis is chronic inflammatory skin condition that imposes a significant physical and psychosocial burden on patients. Moderate to severe psoriasis often requires systemic treatments, including oral systemic therapies and biologics. An addition to the treatment repository for psoriasis is oral small molecules, which include apremilast, tofacitinib, and ponesimod. Of these 3 medications, only apremilast is currently approved for the treatment of psoriasis. Long-term safety data for apremilast suggest that it has a tolerable safety profile and leads to significant improvement in patients with psoriasis; however, there are few head-to-head comparisons with other oral systemic medications. Tofacitinib and ponesimod have demonstrated clinical efficacy in treating psoriasis; however, further studies are required to understand the benefit-risk profile of these medications in psoriasis patients.

Topics: Administration, Oral; Anti-Inflammatory Agents, Non-Steroidal; Humans; Patient Selection; Piperidines; Protein Kinase Inhibitors; Psoriasis; Pyrimidines; Pyrroles; Thalidomide; Thiazoles

Tofacitinib is an oral immunosuppressant approved for the treatment of rheumatoid arthritis (RA) and is currently undergoing investigation (Phase III trials) for treating chronic plaque psoriasis. Tofacitinib inhibits Janus kinases (JAKs), which are essential for the signaling of multiple inflammatory pathways and have been implicated in the pathogenesis of RA and psoriasis. The efficacy and safety of tofacitinib in the treatment of RA and psoriasis have been demonstrated in Phase III trials. Across all studies, the efficacy of tofacitinib in alleviating symptoms of RA and psoriasis were superior to placebo. Moreover, treatment was generally well-tolerated, with the most frequently reported adverse events, for both RA and psoriasis, being nasopharyngitis and upper respiratory tract infection. As such, tofacitinib proves to be an effective therapeutic option for RA and a promising new therapy for psoriasis.

Topics: Arthritis, Rheumatoid; Clinical Trials, Phase III as Topic; Humans; Janus Kinase 3; Piperidines; Protein Kinase Inhibitors; Psoriasis; Pyrimidines; Pyrroles; Treatment Outcome

Aggregate data model-based meta-analysis is a regression approach to compare the dose-response and/or time-course across different treatments using summary level data from the literature. Literature search and systematic review following the Cochrane approach yielded 912 sources for investigational and approved treatments for psoriasis. In addition, data for tofacitinib were obtained from an internal database. Tofacitinib is an oral Janus kinase inhibitor. Two mathematical models were developed for Psoriasis Area and Severity Index (PASI) response in moderate to severe psoriasis patients to quantify the time to maximum effect for PASI75 and to evaluate the dose-response relationship for PASI responders (PASI50, PASI75, PASI90, PASI100) at Week 12. Body weight exhibited an inverse effect on the placebo component of both models, suggesting that body weight affects the overall PASI response regardless of drug. This analysis provides a quantitative framework for efficacy comparisons across psoriasis treatments.

Topics: Dose-Response Relationship, Drug; Humans; Models, Statistical; Piperidines; Protein Kinase Inhibitors; Psoriasis; Pyrimidines; Pyrroles; Severity of Illness Index; Time Factors; Treatment Outcome

Psoriatic arthritis is a heterogeneous disease that has been difficult to manage until the recent advent of biologics. However, there are still unmet medical needs for newer agents. Tofacitinib is a Janus family of kinases inhibitor approved for treating rheumatoid arthritis in many countries and psoriasis in Russia. We reviewed the evidences of tofacitinib in psoriatic arthritis treatment. The efficacy and safety profiles result from Phase III clinical trials (OPAL BROADEN and OPAL BEYOND) and one open-label extension study (OPAL BALANCE). Both tofacitinib 5 or 10 mg twice a day were superior to placebo for American College of Rheumatology 20% improvement criteria response at 3 months and showed significant improvement of skin, enthesitis and dactylitis. Tofacitinib is a promising treatment option for psoriatic arthritis.

Topics: Animals; Arthritis, Psoriatic; Clinical Trials as Topic; Humans; Janus Kinases; Piperidines; Protein Kinase Inhibitors; Psoriasis; Pyrimidines; Pyrroles

Due to the chronic nature of psoriasis, the population of elderly psoriasis patients is increasing. However, many elderly psoriatic patients are not adequately treated because management is challenging as a result of comorbidities, polypharmacy, and progressive impairment of organ systems. Physicians may hesitate to use systemic or biologic agents in elderly psoriasis patients because of an increased risk of adverse events in this patient population. Small molecule medications are emerging as promising options for elderly patients with psoriasis and other inflammatory conditions. Areas covered: Here we review the efficacy, safety and tolerability of small molecule inhibitors apremilast, tofacitinib, ruxolitinib, baricitinib, and peficitinib in the treatment of psoriasis, with focus on their use in the elderly population. Expert opinion: Although small molecule inhibitors demonstrate efficacy in elderly patients with psoriasis, they will require larger head-to-head studies and post-marketing registries to evaluate their effectiveness and safety in specific patient populations. Apremilast, ruxolitinib, and peficitinib are effective agents with favorable side effect profiles; however, physicians should exercise caution when prescribing tofacitinib or baricitinib in elderly populations due to adverse events. The high cost of these drugs in the U.S. is likely to limit their use.

Topics: Adamantane; Azetidines; Clinical Trials as Topic; Humans; Niacinamide; Nitriles; Phosphodiesterase 4 Inhibitors; Piperidines; Psoriasis; Purines; Pyrazoles; Pyrimidines; Pyrroles; Severity of Illness Index; Small Molecule Libraries; Sulfonamides; Thalidomide

Janus kinase inhibitors are emerging treatment alternatives in various immune-mediated diseases including alopecia universalis. Herein, we report a patient with psoriasis and alopecia universalis in whom treatment with tofacitinib led to remission of psoriasis without improvement in alopecia universalis. Despite the promising potential in alopecia areata treatment, research evaluating the efficacy of different Janus kinase inhibitors and possible prognostic factors related with a more favorable response are warranted.

Topics: Alopecia Areata; Humans; Janus Kinase Inhibitors; Male; Piperidines; Psoriasis; Pyrimidines; Pyrroles; Treatment Failure; Young Adult

Janus kinase family (JAKs) has recently attracted the attention of many researchers, and several JAK inhibitor drugs have been developed targeting different members of the JAK family. Tofacitinib and ruxolitinib are US FDA approved drugs in this family for rheumatoid arthritis and myeloproliferative diseases, respectively. Dysregulation of JAK/STAT pathway is also involved in many skin diseases, specifically inflammatory disorders. The JAK/STAT signaling pathway and its involvement in skin diseases are overviewed in this study. We also review clinical studies of JAK inhibitors in field of dermatology, including psoriasis, atopic dermatitis, alopecia areata and vitiligo. Although the available evidence shows promising results, it is still too early to draw a firm conclusion about the place of these drugs in dermatological treatment.

Topics: Alopecia Areata; Azetidines; Dermatitis, Atopic; Humans; Janus Kinase Inhibitors; Janus Kinases; Nitriles; Piperidines; Psoriasis; Purines; Pyrazoles; Pyrimidines; Pyrroles; Skin Diseases; Sulfonamides; Vitiligo

Tofacitinib (formerly known as CP-690,550, CP690550, tasocitinib), a novel selective immunosuppressant, is a small molecule classified as Janus kinase inhibitor. The aim of this review article is to present updated data summary on the tofacitinib in the field of dermatology.. We undertook a structured search of bibliographic databases for peer-reviewed scientific articles, including review articles, original research articles as well as case report articles based on inclusion/exclusion criteria. Technical reports on tofacitinib from U.S. Food and Drug Administration and European Medical Agency were also included.. Forty-three papers were included in this review. We report current data on tofacitinib chemical properties, pharmacology, non-clinical toxicity, as well as efficacy and safety in potential new indications in dermatology: psoriasis, alopecia areata, vitiligo, atopic dermatitis and nail dystrophy associated with alopecia areata.. JAK/STAT pathway has an important role in the pathogenesis of psoriasis, alopecia areata, atopic dermatitis, and vitiligo. Despite encouraging efficacy, due to concerns about the overall safety profile of tofacitinib, additional studies will have to determine the adequate risk-to-benefit ratio.

Topics: Administration, Oral; Alopecia Areata; Dermatitis, Atopic; Humans; Janus Kinases; Piperidines; Protein Kinase Inhibitors; Psoriasis; Pyrimidines; Pyrroles; Signal Transduction; Skin Diseases; Vitiligo

New molecularly targeted therapeutics are changing dermatologic therapy. Janus kinase-signal transducer and activator of transcription (JAK-STAT) is an intracellular signaling pathway upon which many different proinflammatory signaling pathways converge. Numerous inflammatory dermatoses are driven by soluble inflammatory mediators, which rely on JAK-STAT signaling, and inhibition of this pathway using JAK inhibitors might be a useful therapeutic strategy for these diseases. Growing evidence suggests that JAK inhibitors are efficacious in atopic dermatitis, alopecia areata, psoriasis, and vitiligo. Additional evidence suggests that JAK inhibition might be broadly useful in dermatology, with early reports of efficacy in several other conditions. JAK inhibitors can be administered orally or used topically and represent a promising new class of medications. The use of JAK inhibitors in dermatology is reviewed here.

Topics: Alopecia Areata; Anti-Inflammatory Agents; Azetidines; Clinical Trials as Topic; Dermatitis, Atopic; Dermatologic Agents; Humans; Janus Kinases; Molecular Targeted Therapy; Nitriles; Piperidines; Protein Kinase Inhibitors; Psoriasis; Purines; Pyrazoles; Pyrimidines; Pyrroles; Signal Transduction; Skin Diseases; Sulfonamides; Vitiligo

Janus kinase (JAK) inhibitors are emerging as a promising new treatment modality for many inflammatory conditions.. Our aim was to systematically review the available data on the use of JAK inhibitors in cutaneous diseases.. This is a systematic review of PubMed and ClinicalTrials.gov.. One hundred thirty-four articles matched our search terms, of which 78 were original articles and 12 reports on adverse events. Eighteen clinical trials were found. JAK inhibitors have been extensively studied for psoriasis, showing beneficial results that were comparable to the effects achieved by etanercept. Favorable results were also observed for alopecia areata. Promising preliminary results were reported for vitiligo, dermatitis, graft versus host disease, cutaneous T cell lymphoma, and lupus erythematosus. The most common adverse events reported were infections, mostly nasopharyngitis and upper respiratory tract infections.. It was not possible to perform a meta-analysis of the results.. This systematic review shows that while JAK inhibitors hold promise for many skin disorders, there are still gaps regarding the correct dosing and safety profile of these medications for dermatologic indications. Additional trials are necessary to address these gaps.

Topics: Alopecia Areata; Anti-Inflammatory Agents; Antineoplastic Agents; Azetidines; Dermatologic Agents; Drug Eruptions; Humans; Janus Kinases; Molecular Targeted Therapy; Nitriles; Piperidines; Protein Kinase Inhibitors; Psoriasis; Purines; Pyrazoles; Pyrimidines; Pyrroles; Randomized Controlled Trials as Topic; Signal Transduction; Skin Diseases; Sulfonamides

The outlook for patients with psoriasis has improved significantly over the last 10 years with the introduction of targeted therapies. Cytokines exert their effects by activating intracellular signaling and transcription pathways, among which there are Janus kinases (JAKs) and signal transducers and activators of transcription (STAT) pathways. JAKs are intracellular second messengers that are crucial for transmitting extracellular cytokine signals to the cell. JAK inhibition interrupts intracellular signaling and can suppress immune cell activation and inflammation in T-cell-mediated disorders, such as psoriasis. Consequently, JAKs are the subject of intensive research activity, since they represent possible therapeutic targets. Tofacitinib is an orally available compound belonging to a novel category of nonbiologic drugs, the "JAK inhibitors", which target JAKs. Recently, oral and topical formulations of tofacitinib have been demonstrated to be safe and effective for the treatment of plaque psoriasis in randomized clinical trials. In particular, a 10 mg bid dose of tofacitinib was shown to be noninferior to etanercept 50 mg subcutaneously twice weekly. Questions remain unresolved regarding the safety risk beyond the 5 mg bid dose. This review, assessing the available scientific literature, focuses on the profile of tofacitinib, as investigational compound in the treatment of plaque psoriasis. An overview of the efficacy and safety data from randomized clinical trials is provided. In addition, the authors highlight future potential applications of tofacitinib in other skin diseases, in particular alopecia areata and vitiligo.

Topics: Chronic Disease; Clinical Trials as Topic; Humans; Janus Kinase 3; Piperidines; Protein Kinase Inhibitors; Psoriasis; Pyrimidines; Pyrroles

Several classes of new oral therapy are in use or in development for the treatment of psoriasis. Despite the high efficacy of biologics, new oral therapies remain important as patients generally prefer this mode of administration and they offer an alternative risk-benefit profile. In this review, we discuss the novel modes of action of these drugs, including modulation of cellular pathways involving diverse targets such as Janus kinase, phosphodiesterase 4, sphingosine 1-phosphate, A3 adenosine receptor and rho-associated kinase 2. We review the available evidence around licensed drugs (apremilast) and drugs that are advanced (tofacitinib) or early (ponesimod, baricitinib, peficitinib, INCB039110, CF101, KD025) in the development pipeline. The key limitations of these oral therapies are their modest efficacy profile (apremilast, ponesimod) and the limitations of their safety profile (tofacitinib, ponesimod), while the evidence for the early pipeline drugs are at phase II level only. Potential niches of current unmet needs include apremilast for patients with concomitant psoriatic arthritis, as combination treatments with biologic therapies, and/or for patients in whom multiple biologic therapies have failed due to immunogenicity and secondary inefficacy. The present knowledge gap regarding these novel drugs includes the need for longer clinical trials or observational studies to evaluate safety, and randomised phase III trials for the early pipeline drugs. We conclude that further research and data are necessary to conclusively establish the role of these agents in the current psoriasis treatment paradigm.

Topics: Adamantane; Adenosine; Adenosine A3 Receptor Antagonists; Administration, Oral; Arthritis, Psoriatic; Azetidines; Biological Factors; Biological Therapy; Clinical Trials as Topic; Humans; Isonicotinic Acids; Janus Kinases; Niacinamide; Phosphodiesterase 4 Inhibitors; Piperidines; Protein Kinase Inhibitors; Psoriasis; Purines; Pyrazoles; Pyrimidines; Pyrroles; Receptors, Lysosphingolipid; rho-Associated Kinases; Sulfonamides; Thalidomide; Thiazoles

The identification of a number of psoriasis-susceptibility genes and a better understanding of the pathogenesis of the intracellular metabolic pathways, have generated new perspectives on psoriasis treatment, in particular new compounds that inhibit certain intracellular proteins involved in the immune response. In contrast to biologic agents, these compounds block intracellular targets such as transcriptional factors or enzymes.. Tofacitinib is a small molecule that acts as a reversible, competitive inhibitor of ATP in the ATP binding site of JAK proteins, determining their inactivation, thus prevents the downstream activation of the STAT proteins, which are then unable to up-regulate the pro-inflammatory genes implicated in psoriasis. The authors present an overview of Phases I - III clinical trials of tofacitinib for psoriasis based on peer-reviewed literature.. In clinical practice, it is important to assess the response of psoriasis to tofacitinib and identify possible clinical, genetic, and immune biomarkers to predict the response. Comorbidities associated with psoriasis, in particular metabolic syndrome and obesity, are also an important aspect of using tofacitinib in clinical practice. There are some evidences that a drug such as tofacitinib could be used to improve not only psoriasis, but also some of its important comorbidities.

Topics: Biomarkers; Drug Administration Schedule; Humans; Piperidines; Protein Kinase Inhibitors; Psoriasis; Pyrimidines; Pyrroles

PsA is an immune-mediated chronic inflammatory disease that affects both skin and joints; it is a heterogeneous disease characterized by synovitis, enthesitis, dactylitis and spondylitis. The impact on patients and the burden of disease are substantial. For assessment of the disease, patient-reported outcomes are increasingly important. Conventional therapy consists of NSAIDs, local and systemic CSs, and synthetic and biological DMARDs. While MTX, LEF, SSZ and CYC are the synthetic drugs mainly used, TNF-α blocking agents have represented the majority of biologics used in the last decade (infliximab, etanercept, adalimumab, certolizumab and golimumab). Treat-to-target strategies have been used successfully in PsA. This review concentrates on new developments, mainly covering biologic agents with an IL-17 inhibitor (secukinumab) and an anti-IL-23 agent (ustekinumab), but also synthetic drugs, including a novel phosphodiesterase-4 inhibitor (apremilast) and a Janus kinase inhibitor (tofacitinib) that blocks mainly Jak3 and Jak1 and, to a lesser extent, Jak2. The efficacy of some of these new agents may be even better for the skin than for the joints.

Topics: Adalimumab; Antibodies, Monoclonal; Antibodies, Monoclonal, Humanized; Antirheumatic Agents; Arthritis, Psoriatic; Cyclophosphamide; Etanercept; Humans; Infliximab; Methotrexate; Molecular Targeted Therapy; Phosphodiesterase 4 Inhibitors; Piperidines; Psoriasis; Pyrimidines; Pyrroles; Sulfasalazine; Thalidomide; 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

Because of the increased knowledge about the underlying cytokine network in psoriasis, selective systemic agents for the treatment of moderate-to-severe psoriasis have been developed during the past decade. The marked upregulation of JAK/STAT pathways in psoriasis and the identification of multiple key mediators in psoriasis pathogenesis that signal through JAK/STAT pathways led to investigation of JAK proteins as potential therapeutic targets for psoriasis treatment. A novel JAK-STAT inhibitor, tofacitinib, has been tested in preclinical studies for the treatment of psoriasis. Considering the satisfactory safety profile and the encouraging efficacy observed in the Phase II and Phase III trials, tofacitinib may represent an important therapeutic to be included into the psoriasis paradigm.

Topics: Animals; Clinical Trials as Topic; Disease Progression; Humans; Janus Kinases; Molecular Targeted Therapy; Piperidines; Protein Kinase Inhibitors; Psoriasis; Pyrimidines; Pyrroles; STAT Transcription Factors

Over the last decade, expanded understanding of psoriasis pathogenesis has led to the development of new systemic agents such as biological drugs that have revolutionized the treatment of psoriasis. Small molecule inhibitors also have been studied and offer patients options for oral administration. This article reviews recently approved and in-the-pipeline biologics (IL-17 inhibitors and IL-23 blockers) as well as small molecule inhibitors (phosphodiesterase 4 [PDE4] and Janus kinase [Jak] inhibitors).

Topics: Anti-Inflammatory Agents, Non-Steroidal; Antibodies, Monoclonal; Antibodies, Monoclonal, Humanized; Biological Factors; Humans; Piperidines; Protein Kinase Inhibitors; Psoriasis; Pyrimidines; Pyrroles; Thalidomide

During the past several years, targeted therapies have significantly improved outcomes in advanced basal cell carcinoma, psoriasis, and metastatic melanoma. This article reviews how advances in our understanding of the molecular pathogenesis of these diseases led to the development of targeted therapies and how these therapies are improving outcomes. Research is ongoing to address continuing challenges of drug resistance, adverse effects, and how best to use the new medications.

Topics: Adult; Anilides; Antibodies, Monoclonal; Antibodies, Monoclonal, Humanized; Antineoplastic Agents; Azetidines; Brain Neoplasms; Carcinoma, Basal Cell; Dermatologic Agents; Dermatology; Etanercept; Female; Humans; Imidazoles; Indoles; Interleukin-17; Male; Melanoma; Middle Aged; Molecular Targeted Therapy; Oximes; Piperidines; Proto-Oncogene Proteins B-raf; Psoriasis; Pyridines; Pyridones; Pyrimidinones; Skin Neoplasms; Sulfonamides; Tumor Necrosis Factor-alpha; Ustekinumab; Vemurafenib

Increased knowledge of the molecular regulatory mechanisms that contribute to the pathogenesis of psoriasis and other inflammatory diseases has created new opportunities for the development of targeted drug therapy for inflammatory conditions. Two new oral medications, apremilast and tofacitinib, have been developed for their immunomodulatory properties, and their potential efficacy in treating psoriasis is being evaluated.. We reviewed phase III randomized, placebo-controlled clinical trial results for apremilast and tofacitinib for efficacy and safety in psoriasis.. Psoriasis Area and Severity Index (PASI) 75 after 16 weeks for apremilast was between 28.8% and 33.1%. PASI 75 was 39.5% after 12 weeks on tofacitinib 5 mg, and 63.6% after 12 weeks on tofacitinib 10 mg. Common side effects for both drugs included nasopharyngitis and upper respiratory tract infections. Gastrointestinal disturbance was common for apremilast. Dyslipidemia and infections were more common with tofacitinib than placebo.. Both new oral medications, apremilast and tofacitinib, appear to be effective in treating psoriasis

Topics: Administration, Oral; Clinical Trials, Phase III as Topic; Humans; Immunologic Factors; Phosphodiesterase 4 Inhibitors; Piperidines; Protein Kinase Inhibitors; Psoriasis; Pyrimidines; Pyrroles; Randomized Controlled Trials as Topic; Severity of Illness Index; Thalidomide

Cytokines are key mediators of the development and homeostasis of haematopoietic cells, critical for host defense, but also for the development of autoimmune and inflammatory diseases such as psoriasis or rheumatoid arthritis (RA). Blocking cytokines activity by interfering with the ligand-receptor association has been successfully employed to treat several immune disorders. A subgroup of cytokines signals through receptors requiring the association with a family of cytoplasmic protein tyrosine kinases known as Janus kinases (Jaks). Jaks have recently gained significant attention as therapeutic targets in inflammation and autoimmunity, and several Jak inhibitory small molecules have been developed. The first two Jak inhibitors, tofacitinib and ruxolitinib, have been approved for the treatment of RA and primary myelofibrosis, respectively. Efficacy and safety data suggest that some of these oral Jak inhibitors as well as their topical formulations may soon enter the daily clinical practice for treating patients with psoriasis, lupus erythematosus or other inflammatory skin diseases. While biologics typically target one single cytokine, these new immunomodulators can inhibit signals from multiple cytokines intra-cellularly and therefore could be useful when other therapies are ineffective. Thus, Jak inhibitors may replace some traditional immunosuppressive agents and help patients not responding to previous therapies.

Topics: Animals; Autoimmune Diseases; Cytokines; Humans; Immunosuppressive Agents; Inflammation; Janus Kinases; Mice; Nitriles; Piperidines; Protein Kinase Inhibitors; Psoriasis; Pyrazoles; Pyrimidines; Pyrroles; Signal Transduction

Psoriasis is a chronic debilitating disease in which dermatologists take a frontline role in improving the quality of life of affected patients. Although recent years have seen the advent of numerous new medications for the treatment of psoriasis, there still is considerable room for improvement in our treatment of this condition. Novel insights into the underlying mechanisms of psoriasis have yielded exciting new potential medications, many with promising preliminary efficacy data. The upcoming systemic agents for the treatment of psoriasis are presented in this article, encompassing novel biologics and small-molecule medicines (eg, IL-17 receptor blockers, Janus kinase [Jak] inhibitors). The underlying mechanisms and currently available data for each drug will be discussed to impart a working knowledge of these new treatment options to dermatology residents, as these drugs may soon be added to our armamentarium for treating psoriasis.

Topics: Adalimumab; Antibodies, Monoclonal; Antibodies, Monoclonal, Humanized; Arthritis, Psoriatic; Certolizumab Pegol; Etanercept; Humans; Immunoglobulin Fab Fragments; Immunoglobulin G; Immunosuppressive Agents; Infliximab; Interleukin-12 Subunit p40; Janus Kinases; Nitriles; Piperidines; Polyethylene Glycols; Protein Kinase Inhibitors; Psoriasis; Pyrazoles; Pyrimidines; Pyrroles; Receptors, Interleukin-17; Receptors, Tumor Necrosis Factor; Tumor Necrosis Factor-alpha; Ustekinumab

Janus kinase (JAK) pathways are key mediators in the immunopathogenesis of psoriasis. Psoriasis treatment has evolved with the advent of targeted therapies, which inhibit specific components of the psoriasis proinflammatory cascade. JAK inhibitors have been studied in early phase trials for psoriasis patients, and the data are promising for these agents as potential treatment options. Tofacitinib, an oral or topically administered JAK1 and JAK3 inhibitor, and ruxolitinib, a topical JAK1 and JAK2 inhibitor, have been most extensively studied in psoriasis, and both improved clinical symptoms of psoriasis. Additional JAK1 or JAK3 inhibitors are being studied in clinical trials. In phase III trials for rheumatoid arthritis, tofacitinib was efficacious in patients with inadequate responses to tumor necrosis factor inhibitors, methotrexate monotherapy, or disease-modifying antirheumatic drugs. The results of phase III trials are pending for these therapies in psoriasis, and these agents may represent important alternatives for patients with inadequate responses to currently available agents. Further investigations with long-term clinical trials are necessary to verify their utility in psoriasis treatment and assess their safety in this patient population.

Topics: Clinical Trials as Topic; Gene Expression Regulation; Humans; Janus Kinase 1; Janus Kinase 2; Janus Kinase 3; Molecular Targeted Therapy; Nitriles; Piperidines; Protein Kinase Inhibitors; Psoriasis; Pyrazoles; Pyrimidines; Pyrroles; Signal Transduction; Treatment Outcome

Advances in molecular biology have provided the basis for development of new therapeutic approaches to psoriasis. New, more effective therapies target specific molecules in the inflammatory cascade involved in the pathogenesis of psoriasis.The biologic era of psoriasis therapy began with inhibitors of T-cell activation, tumor necrosis factor-α, and interleukin (IL)-12/23. Continued investigation has led to therapies and therapeutic candidates that target IL-17, IL-23, phosphodiesterase-4, and isomers of Janus kinase.

Topics: Antibodies, Monoclonal; Antibodies, Monoclonal, Humanized; Clinical Trials as Topic; Humans; Immunologic Factors; Interleukin-23; Phosphodiesterase Inhibitors; Piperidines; Protein Kinase Inhibitors; Psoriasis; Pyrimidines; Pyrroles; Thalidomide; Treatment Outcome

Inflammatory cytokines play a crucial role in the pathophysiology of psoriasis. New therapies are targeting Janus kinases (JAKs), enzymes involved with transduction of cytokine receptor signaling.. Review the utility of JAK inhibitors in the treatment of psoriasis.. A review was performed using PubMed and Google to identify research relevant to the treatment of psoriasis using JAK inhibitors.. In a CD18 mutant PL/J mouse model with T-cell dependent psoriasiform skin disease, the JAK inhibitor R348 reduced skin inflammation, with reductions in CD4+, CD8+, and CD25+ T-cell infiltration and systemic decreases of IL-17, IL-19, IL-22, IL-23 and TNF-α. Two JAK inhibitors, CP-690,550 (tasocitinib) and INCB018424 (ruxolitinib), were effective in psoriasis clinical trials. In a phase 1, randomized, double-blind, dose escalation trial for plaque psoriasis, CP-690,050 led to improvements in Psoriatic Lesion Severity Sum score at doses greater than 5 mg. A phase 2 trial showed CP-690,050 administered at 2, 5, and 15 mg twice daily resulted in a 75% reduction in Psoriasis Area and Severity Index (PASI) in 25%, 40.8%, and 66.7% of patients, respectively, for moderate to severe psoriasis. A phase 3 study of CP-690,550 for plaque psoriasis was begun in September 2010 (NCT01163253). INCB018424, another JAK inhibitor, was used topically at 3 doses (0.5%, 1%, 1.5%) in a phase 2B, double-blind, placebo-controlled trial, resulting in improved total lesion score, global assessment, and PASI for all doses.. Janus Kinase inhibitors are promising potential therapeutic options for psoriasis.

Topics: Animals; Cytokines; Humans; Janus Kinases; Nitriles; Piperidines; Psoriasis; Pyrazoles; Pyrimidines; Pyrroles; Severity of Illness Index

Pfizer Inc is developing the novel JAK3 inhibitor CP-690550 for the potential prevention of transplant rejection and treatment of autoimmune diseases, such as rheumatoid arthritis (RA) and psoriasis. The benefits of currently available immunosuppressive drugs are countered by numerous side effects, caused mainly by the ubiquitous distribution of the target molecules of these treatments. CP-690550 is expected to overcome these limitations by selectively targeting JAK3, which is expressed generally only in immune cells and is only bound by gamma-chain-bearing cytokine receptors involved in the JAK/STAT signaling pathway. CP-690550 exhibited potent immunosuppressive activity in preclinical models of RA and organ transplant rejection. Phase I and II clinical trials demonstrated the efficacy and safety of CP-690550 in preventing transplant rejection and alleviating the symptoms of RA and psoriasis. At the time of publication, CP-690550 was in phase II/III trials in patients with RA, phase II trials in patients with psoriasis, ulcerative colitis and Crohn's disease, and transplant recipients, and a phase I/II trial for dry eye disease (xerophthalmia). Thus, the preclinical and clinical data strongly support the use of CP-690550 to produce sufficient immunosuppression to prevent organ transplant rejection and to treat autoimmune diseases; CP-690550 could herald the beginning of a new generation of safe and effective immunosuppressive therapies.

Topics: Animals; Arthritis, Rheumatoid; Clinical Trials as Topic; Drug Evaluation, Preclinical; Graft Rejection; Humans; Immunosuppressive Agents; Janus Kinase 3; Piperidines; Protein Kinase Inhibitors; Psoriasis; Pyrimidines; Pyrroles

Chemokines belong to a large family of chemoattractant molecules involved in the directed migration of immune cells. They achieve their cellular effects by direct interaction with cell surface receptors. The chemokine receptor CCR1 appears to be involved in a variety of proinflammatory and autoimmune diseases and this makes it a very attractive therapeutic target. This review discusses the identification, chemistry, biology and therapeutic potential of BX 471 a potent CCR1 antagonist that is currently in the clinic for a variety of indications.

Topics: Animals; Anti-Inflammatory Agents; Arthritis, Rheumatoid; Humans; Multiple Sclerosis; Phenylurea Compounds; Piperidines; Protein Serine-Threonine Kinases; Psoriasis

Tofacitinib is an oral, small-molecule JAK inhibitor for the treatment of ulcerative colitis (UC). Creatine kinase (CK) levels and CK-related adverse events (AEs) in tofacitinib-treated patients with UC were evaluated.. Data were analyzed for three UC cohorts: Induction (phase 2 and 3 induction studies); Maintenance (phase 3 maintenance study); Overall [patients who received tofacitinib 5 or 10 mg twice daily (b.d.) in phase 2, phase 3, or open-label, long-term extension studies; data at November 2017]. Clinical trial data for tofacitinib-treated patients with rheumatoid arthritis, psoriasis, and psoriatic arthritis are presented for contextualization.. Week 8 mean change from baseline CK with tofacitinib 10 mg b.d. induction therapy was 91.1 U/L (95% CI, 48.1-134.1) versus 19.2 U/L (8.5-29.9) with placebo. Among patients completing induction with 10 mg b.d. and re-randomized to 52 weeks of maintenance therapy, mean increases from induction baseline to the end of maintenance were 35.9 (8.1-63.7), 90.3 (51.9-128.7), and 115.6 U/L (91.6-139.7), with placebo, 5 and 10 mg b.d., respectively. The incidence rate (unique patients with events per 100 patient-years) for AEs of CK elevation in the tofacitinib-treated UC Overall cohort was 6.6 versus 2.2, 6.5, and 3.7 for tofacitinib-treated patients with rheumatoid arthritis, psoriasis, and psoriatic arthritis, respectively. No serious AEs of CK elevation or AEs of myopathy occurred in UC studies.. In patients with UC, CK elevations with tofacitinib appeared reversible and not associated with clinically significant AEs. UC findings were consistent with tofacitinib use in other inflammatory diseases.. NCT00787202; NCT01465763; NCT01458951; NCT01458574; NCT01470612; NCT01262118; NCT01484561; NCT00147498; NCT00413660; NCT00550446; NCT00603512; NCT00687193; NCT01059864; NCT01164579; NCT00976599; NCT01359150; NCT02147587; NCT00960440; NCT00847613; NCT00814307; NCT00856544; NCT00853385; NCT01039688; NCT02187055; NCT00413699; NCT00661661; NCT01710046; NCT00678210; NCT01276639; NCT01309737; NCT01241591; NCT01186744; NCT01163253; NCT01877668; NCT01882439; NCT01976364.

Topics: Adult; Arthritis, Psoriatic; Arthritis, Rheumatoid; Cohort Studies; Colitis, Ulcerative; Creatine Kinase; Dose-Response Relationship, Drug; Female; Humans; Male; Middle Aged; Piperidines; Protein Kinase Inhibitors; Psoriasis; Pyrimidines; Risk Factors

In patients with moderate-to-severe and severe psoriasis and high efficacy of therapy (PASI≥75) with signaling pathway inhibitors (apremilast, tofacitinib), cytokine spectra in the skin and blood plasma were studied using xMAP technology at baseline and on weeks 14 and 26 of treatment. Comparison of cytokine levels in psoriatic lesional skin and plasma samples of patients treated with apremilast or tofacitinib revealed statistical difference only for IFNγ level (р<0.05) at week 26.

Topics: Adult; Cohort Studies; Cytokines; Female; Humans; Janus Kinase Inhibitors; Male; Middle Aged; Phosphodiesterase 4 Inhibitors; Piperidines; Psoriasis; Pyrimidines; Severity of Illness Index; Skin; Thalidomide; Treatment Outcome; Young Adult

The application of machine learning to longitudinal gene-expression profiles has demonstrated potential to decrease the assessment gap, between biochemical determination and clinical manifestation, of a patient's response to treatment. Although psoriasis is a proven testing ground for treatment-response prediction using transcriptomic data from clinically accessible skin biopsies, these biopsies are expensive, invasive, and challenging to obtain from certain body areas. Response prediction from blood biochemical measurements could be a cheaper, less invasive predictive platform. Longitudinal profiles for 92 inflammatory and 65 cardiovascular disease proteins were measured from the blood of psoriasis patients at baseline, and 4-weeks, following tofacitinib (janus kinase-signal transducer and activator of transcription-inhibitor) or etanercept (tumor necrosis factor-inhibitor) treatment, and predictive models were developed by applying machine-learning techniques such as bagging and ensembles. This data driven approach developed predictive models able to accurately predict the 12-week clinical endpoint for psoriasis following tofacitinib (area under the receiver operating characteristic curve [auROC] = 78%), or etanercept (auROC = 71%) treatment in a validation dataset, revealing a robust predictive protein signature including well-established psoriasis markers such as IL-17A and IL-17C, highlighting potential for biologically meaningful and clinically useful response predictions using blood protein data. Although most blood classifiers were outperformed by simple models trained using Psoriasis Area Severity Index scores, performance might be enhanced in future studies by measuring a wider variety of proteins.

Topics: Adult; Aged; Anti-Inflammatory Agents; Biomarkers, Pharmacological; Cohort Studies; Computer Simulation; Double-Blind Method; Etanercept; Female; Humans; Inflammation Mediators; Interleukin-17; Machine Learning; Male; Middle Aged; Piperidines; Placebos; Predictive Value of Tests; Prognosis; Psoriasis; Pyrimidines; Time Factors; Treatment Outcome; Young Adult

Patients with psoriasis have an increased risk of myocardial infarction, and psoriasis is now recognized as an independent risk factor for coronary heart disease and cardiovascular mortality. To understand the effects of psoriasis medications on systemic inflammation associated with cardiovascular risks, we studied blood proteins related to inflammation and cardiovascular disease archived from a phase 3 clinical trial of tofacitinib and etanercept in adults with moderate-to-severe psoriasis. A total of 157 blood proteins were quantified by a proximity extension assay from 266 patients at baseline and week 4. Protein changes in the blood after 1 month of treatment were compared between tofacitinib (10 mg two times a day) and etanercept (50 mg biweekly), and by response status at week 12. Tofacitinib and etanercept commonly reduced IL-6, CCL20, and CXCL10, but IL-17A was significantly reduced only in responders of either treatment. Compared with etanercept, tofacitinib showed a wider spectrum of cardiovascular blood protein reduction, but the protein reduction effects of tofacitinib were strictly confined to treatment responders. Tumor necrosis factor receptor 1, E-selectin, hK11, tumor necrosis factor-related activation-induced cytokine, CHI3L1, IL-16, and matrix metalloproteinase-12 were cardiovascular proteins significantly reduced only in tofacitinib responders. Our data suggest that a short-term systemic psoriasis treatment can cause reductions in circulating inflammatory and other proteins associated with cardiovascular risks.

Topics: Adult; Aged; Cardiovascular Diseases; Cytokines; Etanercept; Female; Humans; Inflammation; Male; Middle Aged; Piperidines; Protein Kinase Inhibitors; Proteomics; Psoriasis; Pyrimidines; Pyrroles; Risk Factors; Treatment Outcome; Young Adult

Psoriasis is a systemic inflammatory disease with a pathophysiology involving interleukin (IL)-17. Tofacitinib is an oral Janus kinase inhibitor. Etanercept is a tumour necrosis factor-α inhibitor used in the treatment of psoriasis. Neither agent inhibits IL-17 directly.. To evaluate correlations between circulating IL-17A and clinical efficacy in patients with psoriasis treated with tofacitinib or etanercept.. Serum concentrations of IL-17A homodimer and IL-17A/F heterodimer were determined by immunoassays at weeks 0, 4 and 12 in patients with moderate to severe psoriasis treated with placebo (n = 60), tofacitinib 5 mg twice daily (n = 184), tofacitinib 10 mg twice daily (n = 190), or etanercept 50 mg subcutaneously twice weekly (n = 190). Disease severity was assessed using the Psoriasis Area and Severity Index (PASI) and clinical response was defined as patients achieving ≥ 75% improvement from baseline PASI (PASI75).. Serum levels of IL-17A homodimer at week 0 showed moderate correlation with PASI, with a Spearman correlation coefficient of 0.43. Furthermore, serum levels of IL-17A homodimer showed a clear correlation with clinical response, with a decrease of 57.1% in patients achieving PASI75 at week 12, but only 15.9% decrease in nonresponders. PASI75 responders had lower median concentrations of IL-17A (range across treatments: 0.24-0.27 pg/mL) at week 12 vs. nonresponders (0.37-0.62 pg/mL), regardless of the treatment. Serum IL-17A/F heterodimer showed similar decreases at week 12 in responders and nonresponders.. Baseline serum IL-17A correlates moderately with psoriasis severity. Reduction in circulating IL-17A is required for disease remission regardless of therapeutic agent.

Topics: Double-Blind Method; Etanercept; Female; Humans; Immunosuppressive Agents; Interleukin-17; Linear Models; Male; Piperidines; Protein Kinase Inhibitors; Psoriasis; Pyrimidines; Pyrroles; Remission Induction; Severity of Illness Index; Tumor Necrosis Factor-alpha

Tofacitinib is an oral Janus kinase inhibitor. Final safety and efficacy data from an open-label extension study of tofacitinib in psoriasis are reported.. To evaluate the long-term safety and durability of efficacy of tofacitinib in adults with moderate-to-severe chronic plaque psoriasis.. Eligible patients who completed qualifying phase II/III tofacitinib studies received tofacitinib 10 mg twice daily (q12h) until month 3; subsequently, the dose could be adjusted by investigators to either 5 or 10 mg q12h. Adverse events (AEs) are reported up to month 66 and laboratory data up to month 54. Efficacy end points up to month 54 included Physician's Global Assessment of 'clear' or 'almost clear' (PGA response) and 75% improvement in Psoriasis Area and Severity Index (PASI 75).. Overall, 2867 patients received tofacitinib, with a median treatment duration of 35·6 months. Adverse events (AEs) and serious AEs were reported in 82·5% and 13·7% of patients, respectively; 13·9% of patients discontinued owing to AEs; and 29 patients died. Incidence rates (patients with event/100 patient-years) were 1·16 for serious infections, 0·67 for malignancies and 0·26 for major adverse cardiovascular events. After initial changes in qualifying studies, most laboratory parameters were generally stable over 54 months. PGA response was achieved by 52-62% of patients and PASI 75 by 56-74% of patients at each study visit through month 54.. In patients with psoriasis, the safety profile of tofacitinib over 66 months was similar to previous reports in phase III studies and efficacy was sustained through 54 months (NCT01163253).

Topics: Administration, Oral; Adult; Drug Administration Schedule; Drug-Related Side Effects and Adverse Reactions; Female; Follow-Up Studies; Humans; Janus Kinase 3; Male; Middle Aged; Piperidines; Protein Kinase Inhibitors; Psoriasis; Pyrimidines; Pyrroles; Severity of Illness Index; Time Factors; Treatment Outcome

Tofacitinib is an oral Janus kinase inhibitor. An integrated analysis was conducted to evaluate dosage optimality for tofacitinib in patients with moderate-to-severe plaque psoriasis and the impact of body weight on optimality in this patient population. Data were pooled from one phase IIb trial (2, 5, and 15 mg twice daily (b.i.d.)) and four phase III trials (5 and 10 mg b.i.d.). A longitudinal exposure-response model for Psoriasis Area and Severity Index (PASI) improvement (percent change from baseline) was established. Body weight influenced potency; heavier subjects require higher doses to achieve comparable benefit to lighter subjects. Disease severity, sex, and prior biologic usage were also predictive of response. The 10 and 5 mg doses were predicted to achieve 81% and 65%, respectively, of the maximum effect based on a 75% improvement in PASI. The greater efficacy of 10 mg over 5 mg was clinically meaningful.

Topics: Administration, Oral; Body Weight; Dose-Response Relationship, Drug; Double-Blind Method; Female; Humans; Janus Kinase Inhibitors; Male; Middle Aged; Models, Biological; Piperidines; Psoriasis; Pyrimidines; Pyrroles; Treatment Outcome

Tofacitinib is an oral Janus kinase inhibitor. Efficacy and safety of tofacitinib in patients with moderate-to-severe plaque psoriasis have been demonstrated.. We sought to assess the efficacy of tofacitinib for the treatment of nail psoriasis over a period of 52 weeks.. In 2 identical phase 3 studies (OPT Pivotal 1 and 2), patients were randomized 2:2:1 to receive tofacitinib 5 mg, tofacitinib 10 mg, or placebo, twice daily. At week 16, placebo-treated patients were re-randomized to tofacitinib. This post hoc analysis of patients with existing nail psoriasis assessed the Nail Psoriasis Severity Index (NAPSI) score and proportions of patients achieving ≥50% reduction in NAPSI from baseline (NAPSI50), NAPSI75, or NAPSI100.. Baseline mean NAPSI scores for patients treated with tofacitinib 5 mg (N = 487), tofacitinib 10 mg (N = 476), and placebo (N = 233) twice daily were 27.0, 27.3, and 26.9, respectively. At week 16, significantly (all P < .05) more patients receiving tofacitinib 5 mg and tofacitinib 10 mg versus placebo twice daily achieved NAPSI50 (32.8%, 44.2% vs 12.0%), NAPSI75 (16.9%, 28.1% vs 6.8%), and NAPSI100 (10.3%, 18.2% vs 5.1%), respectively. Improvements were sustained to week 52.. Limitations include discontinuation of clinical nonresponders at week 28.. Tofacitinib treatment resulted in improvements in nail psoriasis versus placebo at week 16; improvements were maintained over 52 weeks [NCT01276639; NCT01309737].

Topics: Adolescent; Adult; Aged; Aged, 80 and over; Double-Blind Method; Female; Humans; Male; Middle Aged; Nail Diseases; Piperidines; Protein Kinase Inhibitors; Psoriasis; Pyrimidines; Pyrroles; Time Factors; Treatment Outcome; Young Adult

Tofacitinib is an oral Janus kinase inhibitor.. This study assessed tofacitinib efficacy and safety vs placebo in Asian patients with moderate to severe chronic plaque psoriasis.. Patients from China mainland, Taiwan, and Korea were randomized 2:2:1:1 to tofacitinib 5mg (N=88), tofacitinib 10mg (N=90), placebo→5mg (N=44), or placebo→10mg (N=44), twice daily (BID) for 52 weeks. Placebo-treated patients advanced to tofacitinib at Week 16. Co-primary efficacy endpoints: proportions of patients achieving Physician's Global Assessment (PGA) response ('clear' or 'almost clear') and proportion achieving ≥75% reduction from baseline Psoriasis Area and Severity Index (PASI75) at Week 16.. At Week 16, more patients achieved PGA and PASI75 responses with tofacitinib 5mg (52.3%; 54.6%) and 10mg (75.6%; 81.1%) BID vs placebo (19.3%; 12.5%; all p<0.0001). Of patients with a Week 16 response, 73.6% and 75.0% maintained PGA response, and 76.8% and 84.9% maintained PASI75 to Week 52 with tofacitinib 5mg and 10mg BID, respectively. Over 52 weeks, 2.2-4.5% of patients across treatment groups experienced serious adverse events, and 1.1-6.8% discontinued due to adverse events.. Tofacitinib demonstrated efficacy vs placebo at Week 16 in Asian patients with moderate to severe plaque psoriasis; efficacy was maintained through Week 52. No unexpected safety findings were observed. [NCT01815424].

Topics: Administration, Oral; Adult; Asian People; China; Double-Blind Method; Female; Humans; Janus Kinases; Male; Middle Aged; Piperidines; Protein Kinase Inhibitors; Psoriasis; Pyrimidines; Pyrroles; Republic of Korea; Severity of Illness Index; Taiwan; Treatment Outcome

To analyse the correlation between serum human beta-defensin-2 (hBD-2) levels and response to JAK inhibitor in psoriasis.. We evaluated the psoriasis area and severity index (PASI) and serum hBD-2 levels of 18 psoriasis patients randomized to receive placebo or tofacitinib 5 or 10 mg b.i.d. at baseline, week 8, and week 16. Serum hBD-2 levels were measured by enzyme-linked immunosorbent assay (ELISA).. The PASI achieved a dramatic reduction after tofacitinib 5 or 10 mg b.i.d. treatment for 16 weeks (p < 0.05). Serum hBD-2 levels significantly decreased in patients treated with tofacitinib 10 mg b.i.d. compared with baseline and the placebo-treated patients (p < 0.05). A significant correlation was found between hBD-2 levels and PASI (r = 0.52, p < 0.01). A serum hBD-2 level of 1,255.45 pg/mL was a cut-off between mild and moderate-to-severe psoriasis in ROC analysis.. Serum hBD-2 level might be a possible biomarker for monitoring psoriasis treatment response and differentiating mild from moderate-to-severe psoriasis.

Topics: Adult; Aged; beta-Defensins; Biomarkers; Female; Humans; Janus Kinases; Male; Middle Aged; Piperidines; Protein Kinase Inhibitors; Psoriasis; Pyrimidines; Pyrroles; ROC Curve; Severity of Illness Index

Tofacitinib is an oral Janus kinase inhibitor. These post-hoc analyses assessed tofacitinib efficacy and safety in Japanese patients with psoriasis enrolled in a 52-week global phase 3 study. Patients received tofacitinib 5 mg, tofacitinib 10 mg or placebo twice daily (b.i.d.); placebo-treated patients advanced to tofacitinib at week 16. Primary efficacy end-points were the proportions of patients with 75% or more reduction from baseline Psoriasis Area and Severity Index (PASI-75) and Physician's Global Assessment (PGA) of "clear" or "almost clear" (PGA response) at week 16. Other end-points included: Itch Severity Item (ISI), Dermatology Life Quality Index (DLQI) score and Nail Psoriasis Severity Index (NAPSI). Adverse events (AEs) were recorded throughout the study. Overall, 58 Japanese patients were included in this analysis (tofacitinib 5 mg b.i.d., n = 22; 10 mg b.i.d., n = 24; placebo, n = 12); 29 completed the study. At week 16, significantly more patients receiving tofacitinib 5 and 10 mg b.i.d. versus placebo achieved PASI-75 (50% and 75% vs 0%, P < 0.01) and PGA response (59% and 75% vs 0%, P < 0.001). Substantial improvements in ISI, DLQI and NAPSI score were observed with both tofacitinib doses. Over 52 weeks, similar rates of AEs were reported across treatment groups; one serious AE occurred with tofacitinib 10 mg b.i.d. Herpes zoster occurred in three patients receiving tofacitinib 10 mg b.i.d. No deaths, serious infections, malignancies or gastrointestinal perforations were reported. Results were generally consistent with global analysis, suggesting sustained efficacy and a manageable safety profile, with increased herpes zoster incidence, of tofacitinib in Japanese patients with psoriasis.

Topics: Adult; Female; Humans; Male; Middle Aged; Piperidines; Protein Kinase Inhibitors; Psoriasis; Pyrimidines; Pyrroles

The ability to predict response to psoriasis treatments has important implications. Tofacitinib is an oral JAK inhibitor being investigated for psoriasis.. The objective of this study is to identify and validate the clinical predictors of responses in psoriasis patients treated with tofacitinib.. Selected baseline characteristics or early improvement in Psoriasis Area and Severity Index (PASI) in the phase 3 tofacitinib study OPT 1 (NCT01276639) were evaluated as predictors for a clinical response (75% improvement in PASI [PASI75]) at week 16. Predictive ability was assessed by the area-under-the-receiver operating characteristic curve (AUC-ROC). The predictive ability of the identified variables was validated with study OPT 2 (NCT01309737).. PASI improvement at weeks 8 and 12 demonstrated good discriminatory abilities to predict PASI75 response at week 16 (AUC-ROC ≥86% and 94%, respectively) in OPT 1. Validation with PASI50 response at week 8 in OPT 2 to predict PASI75 response at week 16 showed that the sensitivity, specificity, PPV, and NPV were 88%, 69%, 80%, and 81%, respectively, in tofacitinib-treated subjects.. Achieving a PASI50 response after 8 weeks of treatment with tofacitinib in psoriasis patients appears to be a reliable predictor of achieving a PASI75 response at week 16.. clinicaltrials.gov: NCT01276639 and NCT01309737.

Topics: Administration, Oral; Double-Blind Method; Female; Humans; Male; Middle Aged; Piperidines; Psoriasis; Pyrimidines; Pyrroles; ROC Curve; Severity of Illness Index; Treatment Outcome

Tofacitinib is an oral Janus kinase inhibitor being investigated for psoriasis. A Phase 3 withdrawal/re-treatment study (NCT01186744; OPT Retreatment) showed tofacitinib re-treatment was effective in patients with chronic plaque psoriasis.. To describe the effects of tofacitinib withdrawal/re-treatment on health-related quality of life (HRQoL) and disease symptoms measured by patient-reported outcomes (PROs).. The study was divided into initial treatment, treatment withdrawal, and re-treatment periods. Initial treatment: patients were randomized to receive tofacitinib 5 (n = 331) or 10 mg (n = 335) BID for 24 weeks. Treatment withdrawal: patients who achieved both ≥ 75% reduction in Psoriasis Area and Severity Index (PASI) score from baseline and Physician's Global Assessment of 'clear'/'almost clear' at Week (W)24 received placebo (withdrawal) or the previous dose (continuous treatment). Re-treatment: at relapse (> 50% loss of W24 PASI response) or at W40, patients received their initial tofacitinib dose. PROs included: Dermatology Life Quality Index (DLQI), Itch Severity Item (ISI), Short Form-36 (SF-36) and Patient's Global Assessment (PtGA).. After initial treatment with tofacitinib 5 and 10 mg BID, substantial and significant improvements were reported for mean DLQI (baseline: 12.6 and 12.6; W24: 5.1 and 2.6) and ISI (baseline: 6.7 and 6.9; W24: 2.9 and 1.6). Patients continuously treated with tofacitinib 5 and 10 mg BID maintained those improvements through Week 56 (DLQI: 3.0 and 2.1; ISI: 2.3 and 1.4). By W40, patients withdrawn from tofacitinib 5 and 10 mg BID showed worsening in DLQI (5.0 and 6.2) and ISI (3.7 and 4.0) scores; improvements were regained upon re-treatment (W56, DLQI: 3.4 and 2.4; ISI: 2.2 and 1.6). Similar results were reported for PtGA and SF-36.. Continuous tofacitinib treatment provided sustained improvement in HRQoL and disease symptoms. Patients randomized to treatment withdrawal lost initial improvements. Upon re-treatment, improvements were recaptured to levels comparable to those seen with continuous treatment.

Topics: Chronic Disease; Dermatologic Agents; Double-Blind Method; Humans; Piperidines; Psoriasis; Pyrimidines; Pyrroles; Quality of Life; Severity of Illness Index

Topics: Administration, Cutaneous; Dermatologic Agents; Humans; Janus Kinase Inhibitors; Piperidines; Psoriasis; Pyrimidines; Pyrroles; Treatment Outcome

Tofacitinib is an oral Janus kinase inhibitor that is being investigated for psoriasis and psoriatic arthritis. Japanese patients aged 20 years or more with moderate to severe plaque psoriasis and/or psoriatic arthritis were double-blindly randomized 1:1 to tofacitinib 5 or 10 mg b.i.d. for 16 weeks, open-label 10 mg b.i.d. for 4 weeks, then variable 5 or 10 mg b.i.d. to Week 52. Primary end-points at Week 16 were the proportion of patients achieving at least a 75% reduction in Psoriasis Area and Severity Index (PASI75) and Physician's Global Assessment of "clear" or "almost clear" (PGA response) for psoriasis, and 20% or more improvement in American College of Rheumatology criteria (ACR20) for patients with psoriatic arthritis. Safety was assessed throughout. Eighty-seven patients met eligibility criteria for moderate to severe plaque psoriasis (5 mg b.i.d., n = 43; 10 mg b.i.d., n = 44), 12 met eligibility criteria for psoriatic arthritis (5 mg b.i.d., n = 4; 10 mg b.i.d., n = 8) including five who met both criteria (10 mg b.i.d.). At Week 16, 62.8% and 72.7% of patients achieved PASI75 with tofacitinib 5 and 10 mg b.i.d., respectively; 67.4% and 68.2% achieved PGA responses; all patients with psoriatic arthritis achieved ACR20. Responses were maintained through Week 52. Adverse events occurred in 83% of patients through Week 52, including four (4.3%) serious adverse events and three (3.2%) serious infections (all herpes zoster). No malignancies, cardiovascular events or deaths occurred. Tofacitinib (both doses) demonstrated efficacy in patients with moderate to severe plaque psoriasis and/or psoriatic arthritis through 52 weeks; safety findings were generally consistent with prior studies.

Topics: Administration, Oral; Adult; Aged; Arthritis, Psoriatic; Double-Blind Method; Female; Herpes Zoster; Humans; Japan; Male; Middle Aged; Piperidines; Protein Kinase Inhibitors; Psoriasis; Pyrimidines; Pyrroles; Treatment Outcome

Tofacitinib is an oral Janus kinase inhibitor being investigated for psoriasis.. We sought to elucidate the molecular mechanisms underlying the clinical efficacy of tofacitinib in patients with psoriasis.. Twelve patients with plaque psoriasis were randomized (3:1) to receive 10 mg of tofacitinib or placebo twice daily for 12 weeks. Biopsy specimens were taken from nonlesional (baseline) and lesional (baseline, days 1 and 3, and weeks 1, 2, 4, and 12) skin. Biopsy specimens were examined for psoriatic epidermal features (thickness, Ki67(+) keratinocytes and keratin 16 [KRT16] mRNA expression, and phosphorylated signal transducer and activator of transcription [pSTAT](+) nuclei) and T-cell and dendritic cell (DC) subsets by using immunohistochemistry, and mRNA transcripts were quantified by using a microarray.. In lesional skin keratinocyte pSTAT1 and pSTAT3 staining was increased at baseline but reduced after 1 day of tofacitinib (baseline, median of 1290 pSTAT1(+) cells/μm(2); day 1, median of 332 pSTAT1(+) cells/μm(2); and nonlesional, median of 155 pSTAT1(+) cells/μm(2)). Epidermal thickness and KRT16 mRNA expression were significantly and progressively reduced after days 1 and 3 of tofacitinib administration, respectively (eg, KRT16 decreased 2.74-fold, day 3 vs baseline, P = .016). Decreases in DC and T-cell numbers were observed after weeks 1 and 2, respectively. At week 4, significant decreases in IL-23/TH17 pathways were observed that persisted through week 12. Improvements in clinical and histologic features were strongly associated with changes in expression of psoriasis-related genes and reduction in IL-17 gene expression.. Tofacitinib has a multitiered response in patients with psoriasis: (1) rapid attenuation of keratinocyte Janus kinase/STAT signaling; (2) removal of keratinocyte-induced cytokine signaling, leading to reductions in pathologic DC and T-cell numbers to nonlesional levels; and (3) inhibition of the IL-23/TH17 pathway.

Topics: Adolescent; Adult; Aged; Aged, 80 and over; Biomarkers; Biopsy; Double-Blind Method; Drug Administration Schedule; Female; Humans; Keratinocytes; Male; Middle Aged; Piperidines; Protein Kinase Inhibitors; Psoriasis; Pyrimidines; Pyrroles; Signal Transduction; Skin; Treatment Outcome; Young Adult

Tofacitinib is a Janus kinase inhibitor being investigated for the treatment of moderate-to-severe plaque psoriasis. We report efficacy of tofacitinib in patient subgroups based on pooled data from two Phase 3 trials (NCT01276639, NCT01309737).
. To assess consistency of treatment effects of tofacitinib versus placebo in subgroups defined by baseline characteristics, and to ascertain whether baseline characteristics are of value in optimizing tofacitinib use.
. Pooled data from the two trials were used to evaluate ≥75% reduction in PASI from baseline (PASI75 response) in subgroups defined by age, age at psoriasis onset, gender, race, geographical region, weight, body mass index, diabetes, metabolic syndrome, tobacco/alcohol use, psoriatic arthritis, disease activity, and prior therapy.
. Week 16 PASI75 response rates (N=1843) were 43%, 59% and 9% with tofacitinib 5 and 10mg twice daily (BID) and placebo, respectively (each P<0.0001 versus placebo). Tofacitinib 5 and 10mg BID were effective regardless of baseline characteristics. Across subgroups, tofacitinib generally produced greater response rates with the 10 versus 5mg BID dosage. Lower absolute response rates were seen in heavier patients and patients with prior biologic experience.
. Both tofacitinib dosages demonstrated consistent efficacy versus placebo across subgroups. Lower response rates were seen in heavier patients and those with prior biologic experience. Tofacitinib 10mg BID resulted in a substantial proportion of responders regardless of baseline characteristics.

J Drugs Dermatol. 2016;15(5):568-580.

Topics: Aged; Drug Administration Schedule; Female; Humans; Male; Middle Aged; Piperidines; Protein Kinase Inhibitors; Psoriasis; Pyrimidines; Pyrroles; Severity of Illness Index; Treatment Outcome

Tofacitinib is an oral Janus kinase inhibitor that is being investigated for psoriasis. Psoriasis impacts on physical and psychological well-being; improvements in health-related quality of life (HRQoL) with etanercept in psoriasis are well documented.. To evaluate HRQoL with tofacitinib, vs. placebo or etanercept, in the Phase 3, randomized, placebo-controlled, non-inferiority, Oral-treatment Psoriasis Trial (OPT) Compare Study (NCT01241591).. Adults with moderate to severe chronic plaque psoriasis were randomized 3:3:3:1 to tofacitinib 10 or 5 mg twice daily (BID), etanercept 50 mg twice weekly or placebo, for 12 weeks. Patient-reported outcomes (PROs) included Dermatology Life Quality Index (DLQI), Itch Severity Item and Patient Global Assessment of psoriasis.. At baseline, 83.4% (911/1092) of patients had a DLQI score ranging between 6 and 30, indicating a substantial burden of disease. By Week 12, 47.3%, 43.6% and 30.9% of patients in the tofacitinib 10 mg BID, etanercept and tofacitinib 5 mg BID groups, respectively, had a DLQI score of 0 or 1 (no effect of psoriasis on QoL) vs. 7.8% for placebo (all P < 0.0001). Tofacitinib significantly reduced itch vs. placebo (P < 0.05 both doses) and etanercept (P < 0.0001 both doses) within 1 day of starting treatment. Furthermore, reductions in itch were greater with tofacitinib 10 mg BID, vs. etanercept, at Weeks 2-12 (all time points P < 0.05). At Week 2, an Itch Severity Item score of 'little or no itch' was more frequent with tofacitinib 10 mg (68.6%) vs. etanercept (57.4%) and placebo (12.2%), and the PtGA response rate was significantly greater with tofacitinib 10 mg vs. placebo (P < 0.05).. Oral tofacitinib provided significant improvements across multiple PROs by Week 12. Improvements with tofacitinib 10 mg BID were comparable to etanercept, and improvements in itch were greater and more rapid with tofacitinib 10 mg BID.

Topics: Chronic Disease; Dermatologic Agents; Etanercept; Humans; Patient Satisfaction; Piperidines; Placebos; Psoriasis; Pyrimidines; Pyrroles; Treatment Outcome

Tofacitinib is an oral Janus kinase inhibitor that improves clinical measures of psoriasis.. We sought to assess patient-reported outcomes in tofacitinib-treated patients with moderate to severe plaque psoriasis over 52 weeks.. In 2 identical, phase III studies (Oral treatment for Psoriasis Trial Pivotal 1 [NCT01276639], n = 901, and Pivotal 2 [NCT01309737], n = 960), patients were randomized 2:2:1 to receive 5 or 10 mg of tofacitinib or placebo, twice daily. At week 16, placebo-treated patients were re-randomized to tofacitinib. Dermatology Life Quality Index score, Itch Severity Item score, Patient Global Assessment score, and patient satisfaction were assessed.. Baseline Dermatology Life Quality Index score indicated substantial health-related quality of life impairment. At week 16, a greater proportion of patients achieved Dermatology Life Quality Index score of 1 or less (no effect of psoriasis on health-related quality of life) with tofacitinib 5 and 10 mg twice daily versus placebo (Oral treatment for Psoriasis Trial Pivotal 1/2: 26.7%/28.6% and 40.2%/48.2% vs 4.6%/6.0%, respectively; P < .0001); improvements were maintained through week 52. Similar patterns were observed with Patient Global Assessment. Improvements in itch were particularly rapid, observed 1 day after treatment initiation for both tofacitinib doses versus placebo (P < .05). At week 16, more patients were satisfied with tofacitinib versus placebo (P < .0001).. Clinical nonresponders discontinued at week 28.. Tofacitinib demonstrated improvement in health-related quality of life and patient-reported symptoms that persisted over 52 weeks.

Topics: Adult; Female; Humans; Male; Middle Aged; Pain; Patient Satisfaction; Piperidines; Protein Kinase Inhibitors; Pruritus; Psoriasis; Pyrimidines; Pyrroles; Quality of Life; Severity of Illness Index

Most psoriasis patients have mild to moderate disease, commonly treated topically. Current topical agents have limited efficacy and undesirable side effects associated with long-term use. Tofacitinib is a small molecule Janus kinase inhibitor investigated for the topical treatment of psoriasis.. This was a 12-week, randomized, double-blind, parallel-group, vehicle-controlled Phase 2b study of tofacitinib ointment (2 % and 1 %) applied once (QD) or twice (BID) daily in adults with mild to moderate plaque psoriasis. Primary endpoint: proportion of patients with Calculated Physician's Global Assessment (PGA-C) clear or almost clear and ≥2 grade improvement from baseline at Weeks 8 and 12. Secondary endpoints: proportion of patients with PGA-C clear or almost clear; proportion achieving Psoriasis Area and Severity Index 75 (PASI75) response; percent change from baseline in PASI and body surface area; change from baseline in Itch Severity Item (ISI). Adverse events (AEs) were monitored and clinical laboratory parameters measured.. Overall, 435 patients were randomized and 430 patients received treatment. The proportion of patients with PGA-C clear or almost clear and ≥2 grade improvement from baseline at Week 8 was 18.6 % for 2 % tofacitinib QD (80 % confidence interval [CI] for difference from vehicle: 3.8, 18.2 %) and 22.5 % for 2 % tofacitinib BID (80 % CI: 3.1, 18.5 %); this was significantly higher vs vehicle for both dosage regimens. No significant difference vs vehicle was seen at Week 12. Significantly more patients achieved PGA-C clear or almost clear with 2 % tofacitinib QD and BID and 1 % tofacitinib QD (not BID) at Week 8, and with 2 % tofacitinib BID at Week 12. Pruritus was significantly reduced vs vehicle with 2 % and 1 % tofacitinib BID (starting Day 2), and 2 % tofacitinib QD (starting Day 3). Overall, 44.2 % of patients experienced AEs, 8.1 % experienced application site AEs, and 2.3 % experienced serious AEs. The highest incidence of AEs (including application site AEs) was in the vehicle QD group.. In adults with mild to moderate plaque psoriasis, 2 % tofacitinib ointment QD and BID showed greater efficacy than vehicle at Week 8, but not Week 12, with an acceptable safety and local tolerability profile.. NCT01831466 registered March 28, 2013.

Topics: Adult; Aged; Dose-Response Relationship, Drug; Double-Blind Method; Female; Humans; Janus Kinases; Male; Middle Aged; Ointments; Piperidines; Protein Kinase Inhibitors; Psoriasis; Pyrimidines; Pyrroles; Young Adult

Tofacitinib is a novel, oral Janus kinase inhibitor being investigated for psoriasis. This study assessed the relationship between pruritus and clinical signs of psoriasis (assessed by Physician's Global Assessment [PGA]) in patients with moderate-to-severe chronic plaque psoriasis receiving tofacitinib.. In this 16-week (12-week treatment period, 4-week observation period), double-blind, placebo-controlled, phase IIb study (NCT00678210), 197 patients were randomized to tofacitinib 2, 5 or 15 mg BID, or placebo. Pruritus was patient assessed using the Itch Severity Score (ISS), a 0-10 (10=worst itching) rating scale recorded daily from baseline to week 2 and at study visits. Mediation modeling was used to determine relationships between ISS (average score weeks 2-12), PGA (average score weeks 2-12) and treatment groups.. Mediation analysis showed that 70.2-80.5% (p<0.001 versus placebo) of tofacitinib's effect on pruritus was direct, and mostly independent of improvements in erythema, induration and scaling. ISS measurements had acceptable test-retest reliability. Correlation analyses with clinical outcomes supported the validity of the ISS as a pruritus measure.. Tofacitinib has a direct, beneficial effect on patient-reported pruritus independent from improvements in clinician-reported psoriasis severity signs. The ISS demonstrated favorable psychometric characteristics, supporting its use as a pruritus assessment tool.

Topics: Adult; Double-Blind Method; Female; Humans; Male; Middle Aged; Piperidines; Protein Kinase Inhibitors; Pruritus; Psoriasis; Psychometrics; Pyrimidines; Pyrroles; Reproducibility of Results; Treatment Outcome

The Itch Severity Score (ISS), a 0-10 numeric rating scale, was used to assess pruritus due to psoriasis in a Phase 2 b trial of tofacitinib, a novel oral Janus kinase inhibitor. 197 patients with moderate-to-severe plaque psoriasis were randomized to tofacitinib 2, 5 or 15 mg twice daily, or placebo. The ISS was recorded daily from baseline to week 2 and at study visits. Following good and recommended research practice, we performed analyses to examine the clinically important differences (CID) (between-group difference or within-group difference) and clinically important responders (CIR) (within-patient change) for the ISS. The CID and CIR were defined using Patient Global Assessment of psoriasis as an anchor and were estimated with a longitudinal model. A CID on the ISS was 1.64 and, by day 10, the mean changes from baseline in ISS values for the tofacitinib doses (placebo-adjusted) exceeded CID. A CIR on the ISS was a 30% improvement from baseline and, at week 12, 87.2% to 100% of patients receiving tofacitinib reached ≥30% improvement versus 29.4% of patients receiving placebo (p < 0.0001). Overall, the CID and CIR analyses play vital roles in the interpretation of the treatment effects measured by ISS.

Topics: Double-Blind Method; Humans; Piperidines; Pruritus; Psoriasis; Pyrimidines; Pyrroles; Treatment Outcome

Tofacitinib is an oral Janus kinase inhibitor being investigated for the treatment of moderate-to-severe plaque psoriasis.. To compare outcomes following tofacitinib withdrawal with outcomes of continuation.. In this phase 3 study (NCT01186744), patients received tofacitinib 5 mg (n = 331) or 10 mg (n = 335) twice daily for 24 weeks. The patients who achieved both ≥ 75% reduction in Psoriasis Area and Severity Index (PASI 75) score from baseline and Physician's Global Assessment (PGA) of 'clear' or 'almost clear' (PGA response) received a placebo (withdrawal) or the previous dose. At relapse (> 50% reduction in the PASI improvement during initial treatment) or week 40, the patients received the initial dose.. Initial treatment: 33·5% and 55·2% achieved both PASI 75 and PGA responses with tofacitinib 5 and 10 mg twice daily, respectively, making them eligible for the treatment-withdrawal period. Withdrawal: 56·2%, 62·3%, 23·3% and 26·1% maintained PASI 75 responses with tofacitinib 5, 10 mg, placebo (5 mg) and placebo (10 mg) twice daily, respectively; 49·9%, 63·9%, 22·9% and 18·0% maintained PGA responses; and 92·3%, 93·0%, 32·8% and 42·9% did not relapse. Elevations in low-density lipoprotein-cholesterol levels following initial treatment (mean increase: 8·71 mg dL(-1) with 5 mg twice daily, 10·26 mg dL(-1) with 10 mg twice daily) were reversed upon withdrawal. Retreatment: 36·8% and 61·0% of patients who relapsed achieved PASI 75 responses with tofacitinib 5 or 10 mg after 16 weeks; 44·8% and 57·1% regained PGA responses.. Patients who received continuous treatment maintained a response more effectively when compared with placebo recipients. Safety profiles were comparable in both the continuous treatment group and retreatment group. Of those patients who relapsed, up to 60% recaptured a response with tofacitinib.

Topics: Adolescent; Adult; Aged; Chronic Disease; Dermatologic Agents; Double-Blind Method; Drug Administration Schedule; Female; Humans; Male; Middle Aged; Patient Outcome Assessment; Piperidines; Protein Kinase Inhibitors; Psoriasis; Pyrimidines; Pyrroles; Quality of Life; Retreatment; Treatment Outcome; Young Adult

Plaque psoriasis is a debilitating skin condition that affects approximately 2% of the adult population and for which there is currently no cure. Tofacitinib is an oral Janus kinase inhibitor that is being investigated for psoriasis.. The design of this study has been reported previously (NCT00678210). Patients with moderate to severe chronic plaque psoriasis received tofacitinib (2 mg, 5 mg, or 15 mg) or placebo, twice daily, for 12 weeks. Lymphocyte sub-populations, cytomegalovirus (CMV) and Epstein-Barr virus (EBV) DNA were measured at baseline and up to Week 12.. Tofacitinib was associated with modest, dose-dependent percentage increases from baseline in median B cell count at Week 4 (24-68%) and Week 12 (18-43%) and percentage reductions from baseline in median natural killer cell count at Week 4 (11-40%). The proportion of patients with detectable CMV and EBV DNA (defined as >0 copies/500 ng total DNA) increased post-baseline in tofacitinib-treated patients. However, multivariate analyses found no relationship between changes in CMV or EBV viral load and changes in lymphocyte sub-populations or tofacitinib treatment.. Twelve weeks of treatment with tofacitinib had no clinically significant effects on CMV or EBV viral load, suggesting that lymphocyte sub-populations critical to the response to chronic viral infections and viral reactivation were not significantly affected. Replication of these findings during long-term use of tofacitinib will allow confirmation of this observation.

Topics: Adult; C-Reactive Protein; Cytomegalovirus; DNA, Viral; Dose-Response Relationship, Drug; Female; Herpesvirus 4, Human; Humans; Lymphocyte Count; Lymphocyte Subsets; Male; Middle Aged; Piperidines; Protein Kinase Inhibitors; Psoriasis; Pyrimidines; Pyrroles; Viral Load

New therapeutic options are needed for patients with psoriasis. Tofacitinib, an oral Janus kinase inhibitor, is being investigated as a treatment for moderate-to-severe chronic plaque psoriasis. In this study, we aimed to compare two tofacitinib doses with high-dose etanercept or placebo in this patient population.. In this phase 3, randomised, multicentre, double-dummy, placebo-controlled, 12-week, non-inferiority trial, adult patients with chronic stable plaque psoriasis (for ≥12 months) who were candidates for systemic or phototherapy and had a Psoriasis Area and Severity Index (PASI) score of 12 or higher and a Physician's Global Assessment (PGA) of moderate or severe, and had failed to respond to, had a contraindication to, or were intolerant to at least one conventional systemic therapy, were enrolled from 122 investigational dermatology centres worldwide. Eligible patients were randomly assigned in a 3:3:3:1 ratio to receive tofacitinib 5 mg or 10 mg twice daily at about 12 h intervals, etanercept 50 mg subcutaneously twice weekly at about 3-4 day intervals, or placebo. Randomisation was done by a computer-generated randomisation schedule, and all patients and study personnel were masked to treatment assignment. The co-primary endpoints were the proportion of patients at week 12 with at least a 75% reduction in the PASI score from baseline (PASI75 response) and the proportion of patients achieving a PGA score of "clear" or "almost clear" (PGA response), analysed in the full analysis set (all patients who were randomised and received at least one dose of study drug). This study is registered with ClinicalTrials.gov, number NCT01241591.. Between Nov 29, 2010, and Sept 13, 2012, we enrolled 1106 eligible adult patients with chronic plaque psoriasis and randomly assigned them to the four treatment groups (330 to tofacitinib 5 mg twice daily, 332 to tofacitinib 10 mg twice daily, 336 to etanercept 50 mg twice weekly, and 108 to placebo). Of these patients, 1101 actually received their assigned study medication (329 in the tofactinib 5 mg group, 330 in the tofacitinib 10 mg group, 335 in the etanercept group, and 107 in the placebo group). At week 12, PASI75 responses were recorded in 130 (39·5%) of 329 patients in the tofacitinib 5 mg group, 210 (63·6%) of 330 in the tofacitinib 10 mg group, 197 (58·8%) of 335 in the etanercept group, and six (5·6%) of 107 in the placebo group. A PGA response was achieved by 155 (47·1%) of 329 patients in the tofacitinib 5 mg group, 225 (68·2%) of 330 in the tofacitinib 10 mg group, 222 (66·3%) of 335 in the etanercept group, and 16 (15·0%) of 107 in the placebo group. The rate of adverse events was similar across the four groups, with serious adverse events occurring in seven (2%) of 329 patients in the tofacitinib 5 mg group, five (2%) of 330 in the tofacitinib 10 mg group, seven (2%) of 335 in the etanercept group, and two (2%) of 107 in the placebo group. Three (1%) of 329 patients in the tofacitinib 5 mg group, ten (3%) of 330 in the tofacitinib 10 mg group, 11 (3%) of 335 in the etanercept group, and four (4%) of 107 patients in the placebo group discontinued their assigned treatment because of adverse events.. In patients with moderate-to-severe plaque psoriasis, the 10 mg twice daily dose of tofacitinib was non-inferior to etanercept 50 mg twice weekly and was superior to placebo, but the 5 mg twice daily dose did not show non-inferiority to etanercept 50 mg twice weekly. The adverse event rates over 12 weeks were similar for tofacitinib and etanercept. This study indicates that in the future tofacitinib could provide a convenient and well-tolerated therapeutic option for patients with moderate-to-severe plaque psoriasis.. Pfizer Inc.

Topics: Adult; Anti-Inflammatory Agents, Non-Steroidal; Chronic Disease; Dose-Response Relationship, Drug; Double-Blind Method; Drug Administration Schedule; Etanercept; Female; Humans; Immunoglobulin G; Male; Middle Aged; Piperidines; Protein Kinase Inhibitors; Psoriasis; Pyrimidines; Pyrroles; Receptors, Tumor Necrosis Factor; Treatment Outcome

Tofacitinib is an oral Janus kinase inhibitor being investigated for psoriasis.. To determine the 16-week efficacy and safety of two oral tofacitinib doses vs. placebo in patients with moderate-to-severe chronic plaque psoriasis.. Patients in two similarly designed phase III studies (OPT Pivotal 1, NCT01276639, n = 901; OPT Pivotal 2, NCT01309737, n = 960) were initially randomized 2 : 2 : 1 to tofacitinib 10 or 5 mg or placebo, twice daily. Coprimary efficacy end points (week 16) included the proportion of patients achieving Physician's Global Assessment (PGA) of 'clear' or 'almost clear' (PGA response) and the proportion achieving ≥ 75% reduction in Psoriasis Area and Severity Index (PASI 75).. Across OPT Pivotal 1 and OPT Pivotal 2, 745 patients received tofacitinib 5 mg, 741 received tofacitinib 10 mg and 373 received placebo. At week 16, a greater proportion of patients achieved PGA responses with tofacitinib 5 and 10 mg twice daily vs. placebo (OPT Pivotal 1, 41·9% and 59·2% vs. 9·0%; OPT Pivotal 2, 46·0% and 59·1% vs. 10·9%; all P < 0·001). Higher PASI 75 rates were observed with tofacitinib vs. placebo (OPT Pivotal 1, 39·9%, 59·2% and 6·2%, respectively, for tofacitinib 5 and 10 mg twice daily and placebo; OPT Pivotal 2, 46·0%, 59·6% and 11·4%; all P < 0·001 vs. placebo). Adverse event (AE) rates appeared generally similar across groups; rates of serious AEs, infections, malignancies and discontinuations due to AEs were low. Twelve patients reported herpes zoster across the tofacitinib treatment groups in both studies vs. none in the respective placebo groups. The most common AE across groups was nasopharyngitis.. Oral tofacitinib demonstrated significant efficacy vs. placebo during the initial 16 weeks of treatment in patients with moderate-to-severe psoriasis. Safety findings were consistent with prior studies.

Topics: Administration, Oral; Adolescent; Adult; Aged; Chronic Disease; Dose-Response Relationship, Drug; Drug Administration Schedule; Female; Humans; Male; Middle Aged; Piperidines; Protein Kinase Inhibitors; Psoriasis; Pyrimidines; Pyrroles; Treatment Outcome; Young Adult

Intra-subject, left-right, randomized, controlled study designs are often used for proof-of-concept studies in dermatology. This design was used to evaluate the safety and efficacy of a topical solution of tofacitinib (NCT00678561), a small-molecule Janus kinase inhibitor under investigation for the topical and oral treatment of patients with chronic plaque psoriasis. Eighty-one patients, each with matched left and right target plaques, were randomized to 2%, 0.2%, or 0.02% tofacitinib or vehicle solution once or twice daily. Patients treated one plaque as per their randomization group (2%, 0.2%, 0.02% tofacitinib, or vehicle solution), and used vehicle to treat the contralateral plaque for 4 weeks. Except during clinic visits, study drug applications were performed unsupervised outside the clinical trial site. Intra-subject, vehicle-adjusted mean percent change from baseline in Target Plaque Severity Score at week 4 (primary efficacy endpoint) was not significantly different from baseline for any treatment group (P values of 0.28-0.68). However, skin biopsy analyses detected tofacitinib in both tofacitinib- and vehicle-treated plaques of some patients, suggesting cross-contamination or solution misapplication. Lack of efficacy with tofacitinib relative to vehicle may be due to the intra-subject study design with unsupervised applications. These findings have potential implications for future intra-subject studies of topical treatments.

Topics: Adult; Aged; Female; Humans; Male; Medication Adherence; Middle Aged; Pilot Projects; Piperidines; Protein Kinase Inhibitors; Psoriasis; Pyrimidines; Pyrroles; Research Design; Self Care; Severity of Illness Index

Tofacitinib is a novel, oral Janus kinase inhibitor currently under investigation for plaque psoriasis.. This exploratory analysis of a Phase IIb, 12-week, dose-ranging study (clinicaltrials.gov identifier: NCT00678210) evaluated tofacitinib efficacy in four body regions of patients with moderate-to-severe chronic plaque psoriasis. Patients (n=197) were randomized to tofacitinib 2, 5, or 15 mg, or placebo, twice daily (BID). Psoriasis Area and Severity Index (PASI) score, body surface area values and change from baseline to week 12 were measured according to body region (head/neck, upper limbs, trunk and lower limbs). Change in Target Plaque Severity Score (TPSS) from baseline to week 12 was measured according to typically responsive as well as non-responsive treatment areas.. At week 12, mean improvements in PASI and body surface area values were significantly greater with tofacitinib doses vs placebo across all four body regions measured (P<0.0001). TPSS in responsive areas decreased (improved) with tofacitinib 2, 5, and 15 mg BID vs placebo: -4.35, -4.79 and -6.32, vs -2.06, respectively (P<0.0001). In non-responsive areas, TPSS decreased with tofacitinib 2, 5, and 15 mg BID vs placebo: -3.74, -4.60 and -6.15, vs -2.23, respectively (P<0.01).. Short-term (12-week) treatment with oral tofacitinib produced clinical improvement across all body regions assessed in patients with moderate-to-severe plaque psoriasis, including areas typically non-responsive to treatment.

Topics: Administration, Oral; Dose-Response Relationship, Drug; Double-Blind Method; Humans; Janus Kinases; Piperidines; Protein Kinase Inhibitors; Psoriasis; Pyrimidines; Pyrroles; Severity of Illness Index; Treatment Outcome

Psoriasis is a chronic, inflammatory skin disease with a significant impact on health-related quality of life (HRQoL). Tofacitinib (CP-690,550) is a novel, oral Janus kinase inhibitor that is being investigated as a targeted immunomodulator.. This Phase 2b study assessed three tofacitinib dosage regimens vs. placebo to characterize the efficacy and safety of tofacitinib in patients with moderate-to-severe chronic plaque psoriasis. We report the patient-reported outcome (PRO) data.. A total of 197 patients were randomized to tofacitinib 2, 5, 15 mg twice daily or placebo for 12 weeks. Six PRO questionnaires were completed during the study: Dermatology Life Quality Index, Itch Severity Score (ISS), Short Form-36 questionnaire, version 2 (SF-36), Pain/Discomfort Assessment (PDA), Patient Satisfaction with Study Medication (PSSM) item and Patient Global Assessment of psoriasis.. Treatment with tofacitinib resulted in significant, dose-dependent improvements in several PROs vs. placebo from week 2 onwards. At week 12, least squares mean changes from baseline for Dermatology life quality index, ISS and SF-36 mental component scores were significantly greater for all active drug arms vs. placebo (P < 0.05), and significantly greater for tofacitinib 5 and 15 mg for SF-36 physical component scores vs. placebo (P < 0.05). At week 12, all dose groups had significantly greater numbers of patients reporting 'Clear' or 'Almost clear' on the PtGA vs. placebo.. In patients with moderate-to-severe chronic plaque psoriasis, short-term (12-week) treatment with oral twice-daily tofacitinib improves HRQoL outcomes and patient assessment of disease severity and symptoms, with an early onset noted.

Topics: Adult; Double-Blind Method; Female; Humans; Janus Kinase 3; Male; Middle Aged; Patient Outcome Assessment; Patient Satisfaction; Piperidines; Protein Kinase Inhibitors; Psoriasis; Pyrimidines; Pyrroles; Quality of Life; Severity of Illness Index; Surveys and Questionnaires

The Physician Global Assessment (PGA) is a key measure of psoriasis frequently used in clinical trials. A psychometric validation of a three-item (erythema, induration, and scaling) PGA scale was performed using Phase 2 data.. Confirmatory factor analysis (CFA) tested the PGA measurement model and appropriateness of equal weighting of the items. PGA test-retest reliability was assessed by estimating the intraclass correlation coefficient (ICC). Internal consistency reliability was gauged by calculating Cronbach's coefficient α (CCα). Clinically important difference (CID) was defined using the repeated measures model to estimate the relationship between PGA and Patient Global Assessment (PtGA). Known-group, convergent, and divergent validity for the PGA were also assessed.. 197 patients with psoriasis were randomized to tofacitinib 2, 5, 15 mg twice daily, or placebo. CFA demonstrated that the PGA measurement model fitted the data using equal weighting of the PGA items. The PGA scale demonstrated good test-retest reliability (ICC > 0.7) and internal consistency reliability (CCα > 0.8). The CID for PGA was estimated at 0.52 (95 % confidence interval: 0.47, 0.56). A robust monotonic relationship between PGA and Psoriasis Area and Severity Index (PASI) data substantiated known-group validity. Relatively high correlations of PGA with PASI and PtGA data (all correlations >0.5 except at baseline) supported convergent validity; relatively low correlations of PGA with the Pain/Discomfort Assessment and the Ocular Comfort Index supported divergent validity.. The three-item PGA scale has sound psychometric properties with respect to reliability and validity, with equal weighting of the items being appropriate.

Topics: Double-Blind Method; Factor Analysis, Statistical; Humans; Pain Measurement; Physicians; Piperidines; Protein Kinase Inhibitors; Psoriasis; Psychometrics; Pyrimidines; Pyrroles; Quality of Life; Reproducibility of Results; Severity of Illness Index

The Janus kinase (JAK) inhibitor, tofacitinib, has shown efficacy for the treatment of psoriasis in a phase IIb trial (A3921047; NCT00678210).. To report haematology data from the phase IIb trial, given the importance of JAK-dependent signalling in haematopoiesis.. Patients with moderate-to-severe chronic plaque psoriasis were randomized to receive tofacitinib 2, 5 or 15 mg, or placebo, twice daily over 12 weeks. Blood samples were collected at screening, baseline, weeks 2, 4, 8 and 12 during treatment, and weeks 14 and 16 during off-treatment follow-up.. Baseline haematology was similar across patients receiving tofacitinib 2 mg (n = 49), 5 mg (n = 49) or 15 mg (n = 49), or placebo (n = 50). Tofacitinib conferred dose-dependent decreases in haemoglobin, haematocrit and red blood cell counts, while reticulocyte counts initially declined, before recovering by week 8, and exceeding baseline levels after treatment cessation. With regard to white blood cells, tofacitinib had no clear dose-dependent effects on basophils or monocytes, but appeared to be associated with transient or reversible dose-dependent decreases in neutrophil and eosinophil counts and transient increases in lymphocyte counts, which were primarily attributable to increases in B-cell counts. Natural killer cell counts declined with tofacitinib.. Tofacitinib conferred tolerable, dose-dependent changes in haematological parameters during short-term administration in patients with psoriasis. The effects did not appear to be progressive, and were often transient or reversible.

Topics: Adolescent; Adult; Aged; Basophils; Blood Cell Count; Chronic Disease; Dermatologic Agents; Dose-Response Relationship, Drug; Female; Hematocrit; Hemoglobins; Humans; Killer Cells, Natural; Leukocytes; Male; Middle Aged; Monocytes; Piperidines; Protein Kinase Inhibitors; Psoriasis; Pyrimidines; Pyrroles; Young Adult

Tofacitinib (CP-690,550) is a novel Janus kinase inhibitor in development as an oral formulation for the treatment of several inflammatory diseases including psoriasis.. This phase 2a study aimed to assess the efficacy, systemic safety, local tolerability and systemic pharmacokinetics of topical tofacitinib in mild-to-moderate plaque psoriasis.. Two tofacitinib ointment formulations were evaluated in this multicentre, double-blind, vehicle-controlled trial (NCT01246583). Seventy-one patients were randomized 2 : 1 : 2 : 1 to 2% tofacitinib ointment 1, vehicle 1, 2% tofacitinib ointment 2 and vehicle 2, each administered twice daily for 4 weeks to a single fixed 300 cm(2) treatment area containing a target plaque with or without one or more nontarget plaques and normal skin.. The primary endpoint of percentage change from baseline in the Target Plaque Severity Score at week 4 demonstrated statistically significant improvement for ointment 1 [least squares mean (LSM) -54.4%] vs. vehicle 1 (LSM -41.5%), but not ointment 2 (LSM -24.2%) vs. vehicle 2 (LSM -17.2%). Secondary endpoints (target plaque area and Itch Severity Item) improved similarly for tofacitinib ointment vs. corresponding vehicle. Adverse event (AE) occurrence was similar across treatment groups. All AEs were mild or moderate and none were serious or led to subject discontinuation. One application-site AE (erythema) was reported. Tofacitinib mean systemic exposure was minimal and was greater for ointment 1 than for ointment 2.. Tofacitinib ointment 1 was well tolerated and efficacious compared with vehicle for the treatment of plaque psoriasis. Further study of topical tofacitinib for psoriasis treatment is warranted.

Topics: Administration, Cutaneous; Adult; Aged; Chronic Disease; Dermatologic Agents; Double-Blind Method; Drug Administration Schedule; Female; Humans; Male; Middle Aged; Ointments; Piperidines; Protein Kinase Inhibitors; Psoriasis; Pyrimidines; Pyrroles; Treatment Outcome; Young Adult

Tofacitinib is a novel, oral Janus kinase inhibitor under investigation as a potential treatment for plaque psoriasis.. This Phase 2b, 12-week, dose-ranging study (A3921047, NCT00678210) aimed to characterize the exposure-response, efficacy and safety of tofacitinib vs. placebo in patients with moderate-to-severe chronic plaque psoriasis.. One hundred and ninety-seven patients were randomized. The primary endpoint was the proportion of patients achieving a ≥ 75% reduction in the Psoriasis Area and Severity Index (PASI 75) score at week 12.. At week 12, PASI 75 response rates were significantly higher for all tofacitinib twice-daily groups: 25·0% (2 mg; P < 0·001), 40·8% (5 mg; P < 0·0001) and 66·7% (15 mg; P < 0·0001), compared with placebo (2·0%). Significant increases in the proportion of PASI 75 responses were seen by week 4 and were maintained at week 12. Exposure-response over the 0-15 mg tofacitinib twice-daily dose range was successfully characterized. PASI 50, PASI 90 and Physician's Global Assessment response rates were also higher for tofacitinib vs. placebo. The most frequently reported adverse events (AEs) were infections and infestations: 22·4% (2 mg twice daily), 20·4% (5 mg twice daily), 36·7% (15 mg twice daily) and 32·0% (placebo). Discontinuations due to AEs were 6·0%, 2·0%, 4·1% and 6·1% of patients in the placebo, and 2, 5 and 15 mg twice-daily tofacitinib groups, respectively. Dose-dependent increases from baseline in mean serum high-density lipoprotein, low-density lipoprotein and total cholesterol, and decreases in haemoglobin and neutrophils were observed.. Short-term treatment with oral tofacitinib results in significant clinical improvement in patients with moderate-to-severe plaque psoriasis and is generally well tolerated.

Topics: Administration, Oral; Adult; Chronic Disease; Dermatologic Agents; Dose-Response Relationship, Drug; Double-Blind Method; Female; Humans; Janus Kinase 3; Male; Piperidines; Psoriasis; Pyrimidines; Pyrroles; Treatment Outcome

Topics: Adult; Biopsy; Dose-Response Relationship, Drug; Double-Blind Method; Humans; Middle Aged; Piperidines; Psoriasis; Pyrimidines; Pyrroles

Several reports have indicated that the chemokine receptor CCR5 and its ligands, especially CCL5 (formerly known as RANTES), may play a role in the pathogenesis of psoriasis. The purpose of this investigation was to examine the expression of CCR5 and its ligands in chronic plaque psoriasis and to evaluate the clinical and immunohistochemical effect of a CCR5 receptor inhibitor. Immunohistochemical analysis showed low but significant increased total numbers of CCR5 positive cells in epidermis and dermis of lesional skin in comparison to non-lesional skin. However, relative expression of CCR5 proportional to the cells observed revealed that the difference between lesional and non-lesional skin was only statistically significant in the epidermis for CD3 positive cells and in the dermis for CD68 positive cells. Quantification of mRNA by reverse transcriptase-polymerase chain reaction only showed an increased expression of CCL5 (RANTES) in lesional skin. A randomized placebo-controlled clinical trial in 32 psoriasis patients revealed no significant clinical effect and no changes at the immunohistochemical level comparing patients treated with placebo or a CCR5 inhibitor SCH351125. We conclude that although CCR5 expression is increased in psoriatic lesions, this receptor does not play a crucial role in the pathogenesis of psoriasis.

Topics: Adult; Aged; CCR5 Receptor Antagonists; Cyclic N-Oxides; Double-Blind Method; Female; Humans; Immunohistochemistry; Male; Middle Aged; Oximes; Piperidines; Psoriasis; Pyridines; Receptors, CCR5; Reverse Transcriptase Polymerase Chain Reaction; Skin

Interleukin (IL)-12 and IL-23 are pro-inflammatory cytokines produced by dendritic cells (DCs) and associated with Psoriasis (Pso) and Psoriatic Arthritis (PsA) pathogenesis. Tofacitinib, a Janus kinase inhibitor, effectively suppresses inflammatory cascades downstream the IL-12/IL-23 axis in Pso and PsA patients. Here, we investigated whether Tofacitinib directly regulates IL-12/IL-23 production in DCs, and how this regulation reflects responses to Tofacitinib in Pso patients. We treated monocyte-derived dendritic cells and myeloid dendritic cells with Tofacitinib and stimulated cells with either lipopolysaccharide (LPS) or a combination of LPS and IFN-γ. We assessed gene expression by qPCR, obtained skin microarray and blood Olink data and clinical parameters of Pso patients treated with Tofacitinib from public data sets. Our results indicate that in DCs co-stimulated with LPS and IFN-γ, but not with LPS alone, Tofacitinib leads to the decreased expression of IL-23/IL-12 shared subunit IL12B (p40). In Tofacitinib-treated Pso patients, IL-12 expression and psoriasis area and severity index (PASI) are significantly reduced in patients with higher IFN-γ at baseline. These findings demonstrate for the first time that Tofacitinib suppresses IL-23/IL-12 shared subunit IL12B in DCs upon active IFN-γ signaling, and that Pso patients with higher IFN-γ baseline levels display improved clinical response after Tofacitinib treatment.

Topics: Arthritis, Psoriatic; Dendritic Cells; Humans; Interferon-gamma; Interleukin-12 Subunit p40; Janus Kinase Inhibitors; Lipopolysaccharides; Piperidines; Psoriasis; Pyrimidines; Skin

Focal resistant plaques are still common despite the use of biologics for psoriasis. significant impact on quality of life.. We compared the relative efficacy of different biologics and tofacitinib in different body areas in 177 Asian patients with moderate-to-severe psoriasis in 10 biologics or tofacitinib trials conducted between 2004 and 2019. Pooled data were analyzed at weeks 12-16 and weeks 44-52, respectively, for total and four regional PASI 75, 90, and 100 responses.. The result showed that secukinumab, ixekizumab, guselkumab, and risankizumab had more favorable efficacy, followed by adalimumab, ustekinumab, and tofacitinib, while etanercept showed the least efficacy. The regional PASI response peaked early in the head area with subsequent decline, while the lower extremities improved slowly. At week 52, the head and neck and lower extremities were less likely to achieve PASI responses compared to the trunk and upper extremities.. The treatment responses of different body regions of biologics and tofacitinib were in line with the overall response. However, the head region responds fast, but total clearance at 52 weeks was similarly lower as the leg region. More subjects and prospective studies may be required to compare the efficacy of different biologics in different body regions.

Topics: Biological Products; Humans; Piperidines; Prospective Studies; Psoriasis; Pyrimidines; Quality of Life; Randomized Controlled Trials as Topic; Severity of Illness Index; Treatment Outcome

Patients with ulcerative colitis (UC) are at elevated risk of cardiovascular disease vs the general population, despite a lower prevalence of traditional risk factors, including hyperlipidemia. Mechanistic studies in patients with rheumatoid arthritis and psoriasis suggest that tofacitinib restores serum lipids to preinflammation levels by reversing inflammation-induced cholesterol metabolism changes. We reviewed data on lipid levels and cardiovascular events, alongside recommendations for managing lipid levels during tofacitinib treatment in patients with UC, based on up-to-date expert guidelines.. Data were identified from a phase 3/open-label, long-term extension (OLE) tofacitinib UC clinical program (cutoff May 27, 2019). Literature was identified from PubMed (search terms "lipid," "cholesterol," "lipoprotein," "cardiovascular," "inflammation," "atherosclerosis," "tofacitinib," "rheumatoid arthritis," "psoriasis," "inflammatory bowel disease," "ulcerative colitis," "hyperlipidemia," and "guidelines") and author knowledge. Data were available from 4 phase 3 clinical trials of 1124 patients with moderately to severely active UC who received ≥1 dose of tofacitinib 5 or 10 mg twice daily in induction (two identical trials), maintenance, and OLE studies (treatment duration ≤6.8 years; 2576.4 patient-years of drug exposure).. In the OLE study, tofacitinib treatment was not associated with major changes from baseline in total cholesterol, high-density lipoprotein cholesterol, low-density lipoprotein cholesterol, triglycerides, total cholesterol/high-density lipoprotein cholesterol, and low-density lipoprotein cholesterol/high-density lipoprotein cholesterol, with lipid levels and ratios generally remaining stable over time. The major adverse cardiovascular events incidence rate was 0.26/100 patient-years (95% confidence interval, 0.11-0.54).. Lipid levels and ratios remained generally unchanged from baseline in the OLE study after tofacitinib treatment, and major adverse cardiovascular events were infrequent. Long-term studies are ongoing.. NCT01465763, NCT01458951, NCT01458574, NCT01470612.

Topics: Arthritis, Rheumatoid; Cardiovascular Diseases; Cholesterol; Clinical Trials, Phase III as Topic; Colitis, Ulcerative; Heart Disease Risk Factors; Humans; Inflammation; Lipids; Lipoproteins, HDL; Lipoproteins, LDL; Piperidines; Protein Kinase Inhibitors; Psoriasis; Pyrimidines; Pyrroles; Risk Factors; Treatment Outcome

Nail involvement is common in synovitis, acne, pustulosis, hyperostosis, and osteitis (SAPHO) syndrome, which has a strong association with quality of life in patients with SAPHO. Tofacitinib is an oral Janus kinase inhibitor that has been previously shown to be effective for nail psoriasis.. To assess the efficacy and safety of tofacitinib for the treatment of nail involvement in SAPHO syndrome.. Participants received tofacitinib, 5 mg, twice daily, for 12 weeks.. This open-label, single-arm, prospective pilot study included 13 patients with SAPHO syndrome accompanied by nail lesions and active palmoplantar pustulosis who were recruited from Peking Union Medical College Hospital from September 2019 to December 2019. Follow-up was completed in March 2020. Analysis began March 2020.. The primary end point was the percentage of the change from baseline in Nail Psoriasis Severity Index scores at week 12. Secondary end points included the percentage of the change from baseline in Palmoplantar Psoriasis Area and Severity Index scores, change from baseline in Visual Analogue Scale scores in global osteoarticular pain, Dermatology Life Quality Index scores, and inflammatory markers. Adverse events were recorded throughout the study.. Thirteen female Asian patients (means [SD] age, 39.7 [12.3] years) were included, all of whom completed the study. At week 12, significant improvements were observed in Nail Psoriasis Severity Index scores (median, -67% [interquartile range (IQR), -56% to -77%]; P < .001) and Palmoplantar Psoriasis Area and Severity Index scores (median, -71% [IQR, -58% to -78%]; P < .001). Significant improvement was also noted in Dermatology Life Quality Index scores (median, -12 [IQR, -8.5 to -15]; P < .001) at week 12. A significant decrease in Visual Analogue Scale scores in global osteoarticular pain was observed at week 8 (median, -4 [IQR, 0 to -5]; P = .02) but was not significant at week 12. Inflammatory marker levels were decreased, as indicated by erythrocyte sedimentation rate (median, -8 mm/h [IQR, -4 mm/h to -11 mm/h]; P < .001) and high-sensitivity C-reactive protein levels (median, -1.6 [IQR, -0.3 to -4.1]; P = .01). No severe adverse events were observed.. In this pilot study, tofacitinib yielded significant remission of nail lesions and palmoplantar psoriasis accompanied by an improvement in quality of life in patients with SAPHO syndrome. Additional follow-up studies to evaluate the long-term efficacy and safety of tofacitinib for nail involvement in SAPHO syndrome are warranted.. Chinese Clinical Trial Registry number: ChiCTR1900025941.

Topics: Acquired Hyperostosis Syndrome; Adult; Arthralgia; Child; Female; Humans; Middle Aged; Nail Diseases; Pain Measurement; Pilot Projects; Piperidines; Prospective Studies; Psoriasis; Pyrimidines; Quality of Life; Severity of Illness Index; Treatment Outcome; Young Adult

Mutations in DDX58 (DExD/H-box helicase 58), which encodes the cytoplasmic RNA sensor retinoic acid-inducible gene I (RIG-I), were recently identified in the rare autoimmune disease Singleton-Merten syndrome (SMS). We report the spontaneous development of psoriasis-like skin lesions as an SMS-like symptom in transgenic mice harboring one of the RIG-I SMS variants, E373A. Histological analysis revealed typical characteristics of psoriasis, including the abnormal proliferation and differentiation of keratinocytes leading to epidermal hyperplasia, and infiltrates consisting of neutrophils, dendritic cells and T cells. Levels of the IL-23/IL-17 immune axis cytokines were high in the skin lesions. Rag2-/- transgenic mice showed partial amelioration of the phenotype, with down-regulation of inflammatory cytokines, including IL-17A, suggesting the importance of lymphocytes for the pathogenesis similar to that of human psoriasis. Of note, IL-17A deficiency abolished the skin phenotype, and treatment using the JAK inhibitor tofacitinib not only prevented onset, but also improved the skin manifestations even after onset. Our study provides further evidence for the involvement of RIG-I activation in the onset and progression of psoriasis via type I interferon signaling and the IL-23/IL-17 axis.

Topics: Animals; Aortic Diseases; DEAD Box Protein 58; Dendritic Cells; Dental Enamel Hypoplasia; DNA-Binding Proteins; Epidermis; Hyperplasia; Interferon Type I; Interleukin-17; Interleukin-23 Subunit p19; Janus Kinase Inhibitors; Janus Kinases; Keratinocytes; Metacarpus; Mice; Mice, Inbred C57BL; Mice, Knockout; Muscular Diseases; Neutrophils; Odontodysplasia; Osteoporosis; Piperidines; Psoriasis; Pyrimidines; T-Lymphocytes; Vascular Calcification

To analyse adverse events (AEs) of special interest across tofacitinib clinical programmes in rheumatoid arthritis (RA), psoriatic arthritis (PsA), ulcerative colitis (UC) and psoriasis (PsO), and to determine whether the incidence rates (IRs; unique patients with events per 100 patient-years) of these events are consistent across diseases.. The analysis included data from patients exposed to ≥1 dose of tofacitinib in phase 1, 2, 3 or 3b/4 clinical trials and long-term extension (LTE) studies (38 trials) in RA (23 trials), PsA (3 trials), UC (5 trials) and PsO (7 trials). All studies were completed by or before July 2019, except for one ongoing UC LTE study (data cut-off May 2019). IRs were obtained for AEs of special interest.. 13 567 patients were included in the analysis (RA: n=7964; PsA: n=783; UC: n=1157; PsO: n=3663), representing 37 066 patient-years of exposure. Maximum duration of exposure was 10.5 years (RA). AEs within the 'infections and infestations' System Organ Class were the most common in all diseases. Among AEs of special interest, IRs were highest for herpes zoster (non-serious and serious; 3.6, 1.8, 3.5 and 2.4 for RA, PsA, UC and PsO, respectively) and serious infections (2.5, 1.2, 1.7 and 1.3 for RA, PsA, UC and PsO, respectively). Age-adjusted and sex-adjusted mortality ratios (weighted for country) were ≤0.2 across cohorts.. The tofacitinib safety profile in this analysis was generally consistent across diseases and with longer term follow-up compared with previous analyses.

Topics: Arthritis, Psoriatic; Arthritis, Rheumatoid; Colitis, Ulcerative; Humans; Piperidines; Psoriasis; Pyrimidines; Treatment Outcome

Psoriasis is a chronic, multifactorial, inflammatory disorder, with an estimated prevalence of 0.71% in children. The commonly used therapeutic agents target the underlying inflammation. Tofacitinib has demonstrated efficacy in adult psoriasis.. To study the efficacy, safety, and tolerability of tofacitinib in pediatric patients with moderate to severe chronic plaque psoriasis.. The study included children aged between 8 and 17 years, with moderate to severe psoriasis, given tofacitinib 5 mg orally twice daily for at least 36 weeks. The clinical response was estimated using the Psoriasis Area and Severity Index (PASI) score, Physician's Global Assessment (PGA), and the Children's Dermatology Life Quality Index (CDLQI). The incidence and severity of adverse events (AEs) were meticulously recorded in each case.. A total of 47 patients, with a median age of 12.3 years, completed the study. At week 12, 55.32% achieved PASI 75, and 70.21% at week 36. PGA of clear or almost clear responses at week 12 were 59.57 and 65.96%, -respectfully, at week 36. Relatively few and mostly minor -adverse effects were noted. No severe AEs were reported. -Conclusion: The treatment with tofacitinib was safe and well tolerated, and led to significant improvement of their disease and quality of life as reflected in CDLQI scores. However, the results need to be validated in larger multicenter trials.

Topics: Adolescent; Child; Female; Humans; Male; Piperidines; Protein Kinase Inhibitors; Psoriasis; Pyrimidines; Pyrroles; Treatment Outcome

Psoriasis is an unchecked chronic inflammation characterized by thick, erythematous, and scaly plaques on the skin. The role of innate immune cells in the pathogenesis of psoriasis is well documented. Bruton's tyrosine kinase (BTK) has been reported to execute important signaling functions in innate immune cells such as dendritic cells (DCs) and gamma delta T cells. However, whether inhibition of BTK would lead to modulation of innate immune function in the context of psoriatic inflammation remains largely unexplored. In the present study, we investigated the effect of selective BTK inhibitor, PCI-32765 on inflammatory signaling in CD11c + DCs and gamma delta T cells in imiquimod (IMQ)-induced mouse model of psoriasis-like inflammation. Our results show that IMQ treatment led to induction of p-BTK expression along with concomitant increase in inflammatory cytokines (IL-23, TNF-α) in CD11c + DCs in the skin. Preventive treatment with BTK inhibitor led to significant reversal in IMQ-induced inflammatory changes in CD11c + DCs of skin. Further, there was a significant decrease in dermal IL-17A levels and IL-17A + γδ + T cells after treatment with BTK inhibitor. Furthermore, short treatment of back skin with IMQ led to upregulated expression of p-BTK along with inflammatory cytokines in CD11c + DCs (IL-23, TNF-α) and IL-17A in γδ + T cells which were reversed by BTK inhibitor. Overall, our study proposes that BTK signaling serves a crucial signaling function in innate immune cells in the context of psoriatic inflammation in mice. Therefore, BTK might be a promising therapeutic target to treat psoriatic inflammation.

Topics: Adenine; Agammaglobulinaemia Tyrosine Kinase; Animals; Dendritic Cells; Disease Models, Animal; Humans; Imiquimod; Immunity, Innate; Interleukin-17; Interleukin-23; Intraepithelial Lymphocytes; Male; Mice; Piperidines; Protein Kinase Inhibitors; Psoriasis; Pyrazoles; Pyrimidines; Signal Transduction; Skin

Psoriasis is a chronic inflammatory disease involving multiple organ systems and affecting approximately 2% of the world's population. In this guideline, we focus the discussion on systemic, nonbiologic medications for the treatment of this disease. We provide detailed discussion of efficacy and safety for the most commonly used medications, including methotrexate, cyclosporine, and acitretin, and provide recommendations to assist prescribers in initiating and managing patients on these treatments. Additionally, we discuss newer therapies, including tofacitinib and apremilast, and briefly touch on a number of other medications, including fumaric acid esters (used outside the United States) and therapies that are no longer widely used for the treatment of psoriasis (ie, hydroxyurea, leflunomide, mycophenolate mofetil, thioguanine, and tacrolimus).

Topics: Acitretin; Cyclosporine; Drug Monitoring; Humans; Methotrexate; Piperidines; Psoriasis; Pyrimidines; Thalidomide

Psoriasis is clinically characterized by well-demarcated silvery plaques which may appear on the extremities, scalp, and sacral area. The multidimensional interactions among innate immune cells [neutrophils and dendritic cells (DCs)], adaptive immune cells and skin resident cells result in characteristic features of psoriatic inflammation such as acanthosis, hyperkeratosis, and parakeratosis. Tec family kinases are involved in the pathogenesis of several inflammatory diseases. One of them is Bruton's tyrosine kinase (BTK) which is reported to carry out inflammatory and oxidative signaling in neutrophils and DCs. Effect of BTK inhibitor with regard to psoriatic inflammation has not been explored previously especially in a therapeutic setting. In the current investigation, effect of BTK inhibitor, Ibrutinib on oxidative/inflammatory signaling in dermal/splenic neutrophils [phosphorylated BTK (p-BTK), inducible nitric oxide synthase (iNOS), nitrotyrosine], CD11c + DCs (p-BTK, iNOS, nitrotyrosine, MCP-1, TNF-α) and enzymatic antioxidants [superoxide dismutase (SOD), glutathione peroxidase (GPx), glutathione reductase (GR)] in imiquimod (IMQ)-induced psoriatic inflammation was evaluated using therapeutic mode. Our results show that IMQ treatment led to induction of p-BTK expression along with concomitant increase in oxidative stress in neutrophils, and CD11c + DCs in skin/periphery. Therapeutic treatment with Ibrutinib caused attenuation of IMQ-induced oxidative stress in CD11c + DCs and neutrophils. Further there were dysregulations in antioxidants enzymes (SOD/GPx/GR) in the skin of IMQ-treated mice, which were corrected by Ibrutinib. In short, our study reveals that BTK signaling in neutrophils and CD11c + DCs upregulates oxidative stress which is concomitant with psoriatic inflammation in mice. Ibrutinib attenuates psoriasis inflammation through downregulation of oxidative stress in these innate immune cells.

Topics: Adenine; Animals; BALB 3T3 Cells; Dendritic Cells; Down-Regulation; Imiquimod; Inflammation Mediators; Male; Mice; Neutrophils; Oxidation-Reduction; Oxidative Stress; Peroxidase; Piperidines; Psoriasis; Signal Transduction; Skin

Psoriatic arthritis (PsA) is a chronic, systemic immune-mediated inflammatory musculoskeletal disease. The onset of dermatologic symptoms often precedes rheumatic manifestations. Tofacitinib is an oral Janus kinase inhibitor for the treatment of PsA that has been shown to improve dermatologic symptoms in patients with PsA.. To investigate the efficacy of tofacitinib in improving dermatologic endpoints in adult patients with active PsA.. This analysis included data from two placebo-controlled, double-blind, phase 3 studies in patients with active PsA and an inadequate response (IR) to ≥1 conventional synthetic disease-modifying antirheumatic drug (csDMARD) who were tumor necrosis factor inhibitor (TNFi)-naïve (OPAL Broaden; NCT01877668) or an IR to ≥1 TNFi (OPAL Beyond; NCT01882439). Patients had active plaque psoriasis at screening and received a stable dose of one csDMARD during the study. Patients were randomized to tofacitinib 5 mg twice daily (BID), 10 mg BID, adalimumab 40 mg subcutaneous injection once every 2 weeks (OPAL Broaden only) or placebo (to Month 3). Dermatologic endpoints: Psoriasis Area and Severity Index (PASI) total score; PASI90 overall; PASI75 and PASI90 by baseline PASI severity; Physician's Global Assessment of Psoriasis; Nail Psoriasis Severity Index; Dermatology Life Quality Index total and sub-dimension scores; Itch Severity Item; and Patient's Global Joint and Skin Assessment-Visual Analog Scale-Psoriasis question.. In patients with active PsA, including those stratified by mild or moderate/severe dermatologic symptoms, greater improvements from baseline and percentage of responders were observed in tofacitinib-treated patients vs. placebo for the majority of analyzed dermatologic endpoints at Months 1 and 3, and improvements were maintained to Month 12 in OPAL Broaden and Month 6 in OPAL Beyond. Similar effects were observed in adalimumab-treated patients vs. placebo in OPAL Broaden across dermatologic endpoints.. Tofacitinib provides a treatment option for patients with active PsA, including the burdensome dermatologic symptoms of PsA.

Topics: Adult; Arthritis, Psoriatic; Double-Blind Method; Humans; Piperidines; Psoriasis; Pyrimidines; Pyrroles; Quality of Life; Treatment Outcome

Topics: Humans; Piperidines; Psoriasis; Pyrimidines; Pyrroles

The ability to predict the efficacy of systemic psoriasis therapy based on immune profiles in skin biopsies could reduce the use of inappropriate treatment and its associated costs and adverse events. It could considerably decrease drug development trial costs as well.. To develop a bioinformatic gene signature score derived from skin mRNA to predict psoriasis treatment outcomes for a variety of therapies.. In this decision analytical model using 1145 skin samples from different cohorts of 12 retrospective psoriasis studies, samples were analyzed using the CIBERSORT algorithm to define the immune landscape of psoriasis lesions and controls. Random forest classification and principal component analysis algorithms were used to estimate psoriatic microenvironment (PME) signature genes and construct a PME score. Overall, 85 and 421 psoriasis lesions from 1 and 4 independent cohorts were used as discovery and validation studies, respectively. Among them, 157, 71, 89, and 90 psoriasis lesions were treated with etanercept, tofacitinib, adalimumab, and methotrexate, respectively.. Number of weeks after treatment initiation when responders and nonresponders could be predicted.. Overall, 22 immune cell subtypes formed infiltration patterns that differentiated psoriasis lesions from healthy skin. In psoriasis lesions, the expression of 33 PME signature genes defined 2 immune phenotypes and in aggregate could be simplified to a numerical PME score. A high PME score, characterized by keratinocyte differentiation, correlated with a better treatment response (Psoriasis Area and Severity Index [PASI] reduction, 75.8%; 95% CI, 69.4% to 82.2%; P = .03), whereas a low PME score exhibited an immune activation signature and was associated with a worse response (PASI reduction, 53.5%; 95% CI, 45.3% to 61.7%; P = .03). The PME score at week 4 after treatment initiation correlated with future responder vs nonresponder to treatment status 8 to 12 weeks earlier than PASI reduction for etanercept, methotrexate plus adalimumab, and tofacitinib.. The PME score is a biometric score that may predict clinical efficacy of systemic psoriasis therapy in advance of clinical responses. As an application of personalized medicine, it may reduce the exposure of patients with psoriasis to ineffective and expensive therapies.

Topics: Adalimumab; Biological Factors; Biopsy; Clinical Decision-Making; Datasets as Topic; Etanercept; Gene Expression Profiling; Humans; Methotrexate; Piperidines; Precision Medicine; Prognosis; Psoriasis; Pyrimidines; Retrospective Studies; RNA, Messenger; Severity of Illness Index; Skin; Transcriptome; Treatment Outcome; Whole Genome Sequencing

Topics: Arthritis, Psoriatic; Arthritis, Rheumatoid; Humans; Incidence; Piperidines; Psoriasis; Pulmonary Embolism; Pyrimidines; Pyrroles

Topics: Female; Humans; Middle Aged; Piperidines; Protein Kinase Inhibitors; Psoriasis; Pyrimidines; Pyrroles

Although existing psoriasis treatments are effective and well tolerated in many patients, there is still a need for new effective targeted treatment options. Tofacitinib is an oral Janus kinase inhibitor that has been investigated in patients with moderate-to-severe chronic plaque psoriasis.. To consider the benefits and risks of tofacitinib in patients with moderate-to-severe psoriasis.. Data were pooled from one phase II, four phase III and one long-term extension study comprising 5204 patient-years of tofacitinib treatment. Efficacy end points included patients achieving Physician's Global Assessments of 'clear' or 'almost clear', ≥ 75% and ≥ 90% reduction in Psoriasis Area and Severity Index (coprimary end points) and improvements in Dermatology Life Quality Index score, Hospital Anxiety and Depression Scale depression score and Itch Severity Item score, at weeks 16 and 52. Safety data were summarized for 3 years of tofacitinib exposure.. Tofacitinib 5 and 10 mg twice daily (BID) showed superiority over placebo for all efficacy end points at week 16, with response maintained for 52 weeks of continued treatment. Tofacitinib improved patients' quality of life and was well tolerated. Rates of safety events of interest (except herpes zoster) were similar to those in the published literature and healthcare databases for other systemic psoriasis therapies. Tofacitinib 10 mg BID demonstrated greater efficacy than 5 mg BID.. Tofacitinib has a benefit-risk profile in moderate-to-severe psoriasis consistent with that of other systemic treatments.

Topics: Administration, Oral; Adolescent; Adult; Aged; Aged, 80 and over; Chronic Disease; Dose-Response Relationship, Drug; Female; Humans; Male; Middle Aged; Piperidines; Protein Kinase Inhibitors; Psoriasis; Pyrimidines; Pyrroles; Quality of Life; Randomized Controlled Trials as Topic; Risk Assessment; Severity of Illness Index; Young Adult

Janus kinase (JAK) inhibition may be a promising new treatment modality for inflammatory (skin) diseases. However, little is known about direct effects of kinase inhibitors on keratinocyte differentiation and function as well as skin barrier formation.. Our aim was to address the direct impact of kinase inhibition of the JAK1/3 pathways by tofacitinib on keratinocyte immune function and barrier formation in atopic dermatitis (AD) and psoriasis.. 3D skin equivalents of both diseases were developed and concurrently pretreated with tofacitinib. To induce AD, 3D skin equivalents were stimulated with recombinant human IL-4 and IL-13. Psoriasis-like conditions were induced by incubation with IL-17A, IL-22 and tumour necrosis factor α (TNFα). The activation of signal transducer and activator of transcription (STAT)1, STAT3 and STAT6 was assessed by Western blot analysis. Microarray analysis and quantitative real-time PCR were used for gene expression analysis.. Tofacitinib pretreatment preserved epidermal morphology and reduced STAT3 and STAT6 phosphorylation of AD-like and STAT3 phosphorylation of psoriasis-like culture conditions in 3D skin models compared to sham-controls. Filaggrin expression was fully maintained in the AD-like models, but only partially in psoriasis-like conditions after pretreatment with tofacitinib. In addition, tofacitinib upregulated DSC1, FLG and KRT1. Using gene expression analysis, downregulation of POSTN and IL24 was observed in AD-like conditions, whereas downregulation of IL20 and IL1B was observed in psoriasis-like conditions.. JAK1/3 inhibition counteracted cytokine-induced AD- and psoriasis-like epidermal morphology and enhanced keratinocyte differentiation in 3D skin models. This effect was more pronounced in the AD-like models compared to the psoriasis-like 3D skin models.

Topics: Cell Proliferation; Computer Simulation; Dermatitis, Atopic; Filaggrin Proteins; Humans; Imaging, Three-Dimensional; Intermediate Filament Proteins; Janus Kinase 1; Keratinocytes; Piperidines; Psoriasis; Pyrimidines; Pyrroles; Sensitivity and Specificity; STAT6 Transcription Factor

The Janus kinase 1/3 inhibitor tofacitinib has demonstrated an antipruritic effect in two phase III studies in psoriasis. However, the mechanisms behind this antipruritic effect are still unknown. We presently investigated whether tofacitinib affects spontaneous itch as well as expression of itch-related cytokines and epidermal nerve fiber density (ENFD) in the imiquimod-induced mouse model of psoriasis. Psoriasis-like skin lesions were produced by daily topical application of imiquimod to the back skin. Imiquimod treatment resulted in spontaneous scratching, which was significantly inhibited by tofacitinib treatment. Imiquimod treatment significantly increased mRNA expression of Il22, Il23, and Il31, reduced peptidergic ENFD, and increased nonpeptidergic ENFD compared to naive mice. Tofacitinib significantly decreased the expression of those cytokines and increased peptidergic ENFD without a significant effect on nonpeptidergic ENFD. Tofacitinib may inhibit psoriatic itch through inhibition of cytokine expression as well as modulation of epidermal innervation.

Topics: Animals; Antipruritics; Behavior, Animal; Disease Models, Animal; Imiquimod; Interleukin-22; Interleukin-23; Interleukins; Janus Kinase Inhibitors; Male; Mice, Inbred C57BL; Nerve Fibers; Piperidines; Pruritus; Psoriasis; Pyrimidines; Pyrroles; Skin

Topics: Humans; Janus Kinase Inhibitors; Piperidines; Psoriasis; Pyrimidines; Pyrroles

Several different Physician Global Assessment (PGA) versions have been used in clinical studies as a co-primary end point to evaluate psoriasis severity. Tofacitinib is an oral Janus kinase inhibitor. We performed an analysis of the PGA using data from studies of tofacitinib in moderate to severe chronic plaque psoriasis.. Data from 3641 patients with moderate to severe chronic plaque psoriasis, enrolled in one of four phase III tofacitinib studies (OPT Pivotal 1 and 2, OPT Compare and OPT Retreatment), were used to evaluate a three-item PGA scale.. Confirmatory Factor Analyses showed that equal weighting of the three items (erythema, induration and scaling) was appropriate. The PGA demonstrated acceptable test-retest reliability (Intraclass Correlation Coefficient, 0.7) and internal consistency (Cronbach's Coefficient Alpha ≥ 0.9 at primary time points). The Clinically Important Difference was estimated as 0.55 (95% confidence interval: 0.546-0.563). Known-group validity was shown by demonstrating that PGA scores could discriminate between different degrees of disease severity. The PGA was significantly correlated with other clinical end points in the studies (Psoriasis Area and Severity Index, r = 0.75-0.79; Dermatology Life Quality Index, r = 0.44-0.57; Patient Global Assessment, r = 0.66-0.72).. Consistent with previous findings from a phase II study, these results indicate that this PGA is a valid, reliable instrument for evaluating disease severity in clinical studies of psoriasis.

Topics: Administration, Oral; Adolescent; Adult; Aged; Aged, 80 and over; Clinical Trials, Phase III as Topic; Female; Humans; Janus Kinase Inhibitors; Male; Middle Aged; Piperidines; Psoriasis; Pyrimidines; Pyrroles; Quality of Life; Reproducibility of Results; Severity of Illness Index; Skin; Treatment Outcome; Young Adult

Psoriasis is often treated with immunomodulatory therapies that can affect the immune response to common antigens. Tofacitinib is an oral Janus kinase inhibitor.. To characterize the effect of long-term exposure to tofacitinib 10 mg twice daily on T-cell function in psoriasis patients.. Patients completing at least 3 months' continuous treatment with tofacitinib 10 mg twice daily were vaccinated with T-cell-dependent vaccines (monovalent tetanus toxoid and 13-valent pneumococcal conjugate [PCV-13]). Patients were assessed at baseline (before vaccination) and then again 4 weeks after vaccination. For PCV-13, we evaluated serotype-specific, opsonophagocytic antibody responses, and for tetanus toxoid, we evaluated humoral responses.. Among 60 patients who completed the study, the geometric mean fold rise from baseline for the 13 PCV serotypes at 4 weeks postvaccination varied from 8.3 (serotype 3) to 101.9 (serotype 6A). Similar results were observed for patients with and without lymphopenia at baseline. For tetanus toxoid, 51 (88%) patients had ≥2-fold and 35 (60%) patients had ≥4-fold rise in antibody concentration.. There was no placebo control.. Most psoriasis patients who receive tofacitinib can mount satisfactory T-cell-dependent responses to PCV-13 and tetanus vaccines.

Topics: Adult; Aged; Cohort Studies; Dose-Response Relationship, Drug; Drug Administration Schedule; Female; Humans; Immunity, Cellular; Male; Middle Aged; Piperidines; Pneumococcal Vaccines; Prospective Studies; Protein Kinase Inhibitors; Psoriasis; Pyrimidines; Pyrroles; Sensitivity and Specificity; Severity of Illness Index; T-Lymphocytes; Tetanus Toxoid; Vaccination; Vaccines, Conjugate; Young Adult

Tofacitinib is an oral Janus kinase inhibitor. This post-hoc analysis aimed to investigate the psychometric properties of the Itch Severity Item (ISI), a numeric rating scale from 0 (no itching) to 10 (worst possible itching) for pruritus in psoriasis, and review the effect of tofacitinib on pruritus in patients with psoriasis participating in Phase 3 studies (N = 3,641). The ISI showed high test-retest reliability (intra-class correlation coefficient: 0.84). The clinically important difference was defined as a 1.48-point change, using Patient Global Assessment as an anchor. Mean changes from baseline in ISI scores with tofacitinib were significantly greater than placebo by Day 2 and exceeded the clinically important difference by Week 4 and Week 2 for tofacitinib 5 and 10 mg twice daily, respectively. The sound psychometric properties of the ISI as an assessment tool for pruritus in psoriasis were confirmed. Tofacitinib provided clinically meaningful improvements in psoriatic pruritus versus placebo.

Topics: Antipruritics; Clinical Trials, Phase III as Topic; Humans; Piperidines; Predictive Value of Tests; Pruritus; Psoriasis; Psychometrics; Pyrimidines; Pyrroles; Randomized Controlled Trials as Topic; Remission Induction; Reproducibility of Results; Severity of Illness Index; Surveys and Questionnaires; Time Factors; Treatment Outcome

Tofacitinib is a Janus kinase (JAK) inhibitor, which has shown efficacy in treating psoriasis. The mode of action of tofacitinib is not completely understood but it has been thought to be mediated by the inhibition of CD4+ T-cell activation. Here, we investigated whether the molecular targets of tofacitinib are expressed in keratinocytes, and whether tofacitinib can modulate the activity of the JAK/Signal Transducer and Activators of Transcription (STAT)-pathway in keratinocytes. Transcriptomic profiling of human keratinocytes treated with IL-22 in combination with tofacitinib revealed that tofacitinib could prevent the majority of IL-22-mediated gene expression changes. Pathway analysis of tofacitinib-regulated genes in keratinocytes revealed enrichment of genes involved in the JAK/STAT signalling pathway. Quantitative real-time-PCR confirmed the upregulation of S100A7 and downregulation of EGR1 expression by IL-22, which was prevented by tofacitinib pre-treatment. These results indicate a direct effect of tofacinitib on keratinocytes, which can have relevance for systemic as well as for topical treatment of psoriasis with tofacitinib.

Topics: Case-Control Studies; Cells, Cultured; Down-Regulation; Early Growth Response Protein 1; Humans; Interleukin-22; Interleukins; Janus Kinases; Keratinocytes; Piperidines; Protein Kinase Inhibitors; Psoriasis; Pyrimidines; Pyrroles; S100 Calcium Binding Protein A7; Signal Transduction; STAT Transcription Factors

Tofacitinib is an oral Janus kinase (JAK) inhibitor. This study characterized the pharmacokinetics of tofacitinib in patients with psoriasis and evaluated the impact of patient factors on disposition. Pooled phase 2/3 data (2981 patients: 9735 concentrations, dose range: 2-15 mg twice daily) up to 56 weeks were used for modeling. A one-compartment model parameterized in terms of apparent oral clearance (CL/F), apparent volume of distribution, zero-order absorption (duration, D), with interindividual variability and inter-occasion variability terms, described tofacitinib pharmacokinetics. A full covariate model incorporated effects for age, sex, race, ethnicity, and baseline variables (body weight, Psoriasis Area Severity Index [PASI], C-reactive protein [CRP], creatinine clearance [CrCl]). The parameter estimates (95%CI) for CL/F, Vd/F, and D in a typical individual (white, male, 86 kg, 46 years, CrCl 121 mL/min, PASI 19.8, and CRP 0.267 mg/dL) were 26.7 (25.9, 27.5) L/h, 125 (120.8, 128.3) liters, and 0.69 (0.646, 0.735) hours, respectively. Only CrCl led to clinically relevant changes in exposure. The analysis suggested no dosing modifications for age, body weight, sex, race, ethnicity, baseline PASI, or CRP based on the magnitude of exposure change. Dosing adjustments for renal impairment were derived from a separate phase 1 study.

Topics: Adult; Clinical Trials, Phase II as Topic; Clinical Trials, Phase III as Topic; Dose-Response Relationship, Drug; Female; Humans; Inactivation, Metabolic; Janus Kinase Inhibitors; Male; Models, Biological; Piperidines; Psoriasis; Pyrimidines; Pyrroles; Severity of Illness Index; Tissue Distribution

Topics: Humans; Janus Kinase Inhibitors; Piperidines; Psoriasis; Pyrimidines; Pyrroles

Tofacitinib is an oral Janus kinase (JAK) inhibitor. Immunomodulatory therapies can increase the risk for herpes zoster (HZ) in patients with psoriasis.. To evaluate the relationship between tofacitinib use and HZ risk.. We used phases 2 and 3 and long-term extension (LTE) data from the tofacitinib development program in psoriasis to calculate HZ incidence rates (IR; events per 100 patient-years); potential HZ risk factors were evaluated using Cox-proportional hazard models.. One hundred thirty (3.6%) patients on tofacitinib (IR 2.55), no patients on placebo, and 2 using etanercept (IR 2.68) developed HZ. Nine patients (7%) were hospitalized, and 8 (6%) had multidermatomal HZ; no encephalitis, visceral involvement, or deaths occurred. In total, 121 (93%) patients on tofacitinib continued or resumed use after HZ. HZ risk factors included Asian descent (hazard ratio [HR] 2.92), using tofacitinib 10 mg twice daily (vs 5 mg twice daily; HR 1.72), prior use of biologics (HR 1.72), and older age (HR 1.30).. Generalizability to other psoriasis populations might be limited. The effect of HZ vaccination was not studied.. Tofacitinib is associated with increased HZ risk relative to placebo. Asian race, increasing age, higher dose, and prior biologic exposure are associated with heightened risk.

Topics: Adolescent; Adult; Age Factors; Aged; Aged, 80 and over; Asian People; Biological Products; Etanercept; Female; Herpes Zoster; Hospitalization; Humans; Immunosuppressive Agents; Incidence; Male; Middle Aged; Piperidines; Proportional Hazards Models; Psoriasis; Pyrimidines; Pyrroles; Risk Factors; Young Adult

Topics: Adult; Humans; Male; Piperidines; Psoriasis; Pyrimidines; Pyrroles

Tofacitinib is an oral Janus kinase inhibitor being investigated for psoriasis.. We sought to report longer-term tofacitinib efficacy and safety in patients with moderate to severe psoriasis.. Data from 2 identical phase-III studies, Oral-treatment Psoriasis Trial Pivotal 1 and 2, were pooled with data from these patients in an ongoing open-label long-term extension study. Patients (n = 1861) were randomized 2:2:1 to tofacitinib 5 mg, 10 mg, or placebo twice daily (BID). At week 16, placebo patients were rerandomized to tofacitinib. Pivotal study participants could enroll into the long-term extension where they received tofacitinib at 10 mg BID for 3 months, after which dosing could be 5 or 10 mg BID.. At week 28, the proportions of patients randomized to tofacitinib 5 and 10 mg BID achieving 75% or greater reduction in Psoriasis Area and Severity Index score from baseline were 55.6% and 68.8%, and achieving Physician Global Assessment of clear or almost clear were 54.7% and 65.9%. Efficacy was maintained in most patients through 24 months. Serious adverse events and discontinuations because of adverse events were reported in less than 11% of patients over 33 months of tofacitinib exposure.. There was no dose comparison beyond week 52.. Oral tofacitinib demonstrated sustained efficacy in patients with psoriasis through 2 years, with 10 mg BID providing greater efficacy than 5 mg BID. No unexpected safety findings were observed.

Topics: Administration, Oral; Adult; Aged; Chronic Disease; Clinical Trials, Phase III as Topic; Dose-Response Relationship, Drug; Drug Administration Schedule; Female; Follow-Up Studies; Humans; Janus Kinases; Male; Middle Aged; Patient Safety; Piperidines; Protein Kinase Inhibitors; Psoriasis; Pyrimidines; Pyrroles; Quality of Life; Randomized Controlled Trials as Topic; Severity of Illness Index; Time Factors; Treatment Outcome; Young Adult

Tofacitinib is an oral Janus kinase inhibitor for the treatment of rheumatoid arthritis (RA), and is being investigated for the treatment of psoriasis. Both conditions can present in women of child-bearing potential, but pregnancy was an exclusion and discontinuation criterion in tofacitinib randomized controlled trials (RCTs) because of the unknown effects of tofacitinib on mother and child. Tofacitinib is a small molecule that has the potential to cross the placenta.. The objective was to report outcomes of pregnancy cases identified through April 2014 from tofacitinib RA/psoriasis RCTs, RA post-approval non-interventional studies, and spontaneous adverse-event reporting.. Pregnancy outcomes were categorized as follows: healthy newborn, medical termination, fetal death, congenital malformation, spontaneous abortion, or pending/lost to follow-up.. Out of 9815 patients, 1821 female patients of child-bearing age were enrolled in the RA/psoriasis RCTs; 47 women became pregnant, including 33 who received tofacitinib monotherapy, 13 who received combination therapy with methotrexate (RA patients only), and one patient whose therapy was still blinded. No fetal deaths were reported. One congenital pulmonary valve stenosis (monotherapy, n = 1), seven spontaneous abortions (monotherapy, n = 4; combination therapy, n = 3), and eight medical terminations (monotherapy, n = 4; combination therapy, n = 3; blinded therapy, n = 1) were identified. Remaining cases reported healthy newborns (n = 25) or were pending/lost to follow-up (n = 6). Forty-four cases of paternal exposure to tofacitinib were reported (monotherapy, n = 43; combination therapy, n = 1), including five spontaneous abortions (monotherapy, n = 4; combination therapy, n = 1), 23 healthy newborns, and 16 pending/lost to follow-up.. The pregnancy outcomes reported in this small number of RA/psoriasis patients appear similar to those observed in the general population and in patients treated with biologic therapies for inflammatory diseases. However, definitive conclusions cannot be drawn, and pregnancy outcomes in patients receiving tofacitinib will continue to be monitored.

Topics: Adult; Antirheumatic Agents; Arthritis, Rheumatoid; Databases, Factual; Drug Therapy, Combination; Female; Follow-Up Studies; Humans; Infant, Newborn; Methotrexate; Piperidines; Pregnancy; Pregnancy Outcome; Protein Kinase Inhibitors; Psoriasis; Pyrimidines; Pyrroles; Randomized Controlled Trials as Topic; Young Adult

Phototherapy with UV light is a standard treatment for psoriasis, yet the mechanisms underlying the therapeutic effects are not well understood. Studies in human and mouse keratinocytes and in the skin tissues from human patients and mice showed that UV treatment triggers ubiquitination and downregulation of the type I IFN receptor chain IFNAR1, leading to suppression of IFN signaling and an ensuing decrease in the expression of inflammatory cytokines and chemokines. The severity of imiquimod-induced psoriasiform inflammation was greatly exacerbated in skin of mice deficient in IFNAR1 ubiquitination (Ifnar1(SA)). Furthermore, these mice did not benefit from UV phototherapy. Pharmacologic induction of IFNAR1 ubiquitination and degradation by an antiprotozoal agent halofuginone also relieved psoriasiform inflammation in wild-type but not in Ifnar1(SA) mice. These data identify downregulation of IFNAR1 by UV as a major mechanism of the UV therapeutic effects against the psoriatic inflammation and provide a proof of principle for future development of agents capable of inducing IFNAR1 ubiquitination and downregulation for the treatment of psoriasis.

Topics: Animals; Cell Line; Chemokines; Cytokines; Disease Models, Animal; Down-Regulation; Humans; Inflammation; Keratinocytes; Male; Mice; Mice, Inbred C57BL; Mice, Knockout; Piperidines; Psoriasis; Quinazolinones; Receptor, Interferon alpha-beta; Signal Transduction; Skin; Ubiquitination; Ultraviolet Therapy

Psoriasis is a systemic inflammatory condition that is associated with a higher risk of cardiovascular (CV) disease. Tofacitinib is being investigated as a treatment for psoriasis.. We sought to evaluate the effects of tofacitinib on CV risk factors and major adverse CV events (MACEs) in patients with plaque psoriasis.. Changes in select CV risk factors and the incidence rate (IR) of MACEs were evaluated in patients who were treated with tofacitinib.. Tofacitinib treatment was associated with small, dose-dependent increases in total cholesterol, low-density lipoprotein (LDL), and high-density lipoprotein (HDL) cholesterol, while the total/HDL cholesterol ratio was unchanged. There were no changes in blood pressure and glycated hemoglobin levels; C-reactive protein levels decreased. The IRs of a MACE were low and similar for both tofacitinib doses. Among 3623 subjects treated with tofacitinib, the total patient-years of exposure was 5204, with a median follow-up of 527 days, and the IR of MACEs was 0.37 (95% confidence interval, 0.22-0.57) patients with events per 100 patient-years.. There was relatively short follow-up time for patients who had MACEs.. While treatment with tofacitinib is associated with a small increase in cholesterol levels, the total/HDL cholesterol ratio does not change, there are no unfavorable changes in several CV risk factors, and the incidence of MACEs is low.

Topics: Adult; Blood Pressure; C-Reactive Protein; Cardiovascular Diseases; Cholesterol; Clinical Trials, Phase II as Topic; Clinical Trials, Phase III as Topic; Comorbidity; Dyslipidemias; Female; Glycated Hemoglobin; Humans; Male; Metabolic Syndrome; Middle Aged; Piperidines; Protein Kinase Inhibitors; Psoriasis; Pyrimidines; Pyrroles; Risk Factors; Treatment Outcome; Triglycerides

Acitretin is an older, oral, non-immunosuppressive medication for the treatment of psoriasis. Tofacitinib is an oral Janus kinase inhibitor that has been studied for use in psoriasis. Each offers efficacy in certain settings and patient types but carries substantial safety risks.

Topics: Acitretin; Administration, Oral; Dermatologic Agents; Evidence-Based Medicine; Humans; Piperidines; Psoriasis; PUVA Therapy; Pyrimidines; Pyrroles; Treatment Outcome

The introduction of tumor necrosis factor (TNF)-α inhibitors dramatically improved the management of psoriasis. Some newer or investigational biologics with different mechanisms of action have demonstrated noninferiority or superiority to etanercept, the first self-injectable anti-TNF-α agent to become available in the United States. Nonetheless, TNF-α inhibitors are likely to remain a mainstay of therapy for many years.

Topics: Adalimumab; Antibodies, Monoclonal; Antibodies, Monoclonal, Humanized; Arthritis, Psoriatic; Cardiovascular Diseases; Certolizumab Pegol; Clinical Trials as Topic; Clinical Trials, Phase III as Topic; Dermatologic Agents; Etanercept; Humans; Infliximab; Piperidines; Psoriasis; Pyrimidines; Pyrroles; Treatment Outcome; Tumor Necrosis Factor-alpha; Ustekinumab

Topics: Antirheumatic Agents; Arthritis, Rheumatoid; Female; Humans; Janus Kinase Inhibitors; Middle Aged; Piperidines; Psoriasis; Pyrimidines; Pyrroles; Treatment Outcome

Medications in dermatology are used in a variety of different methods and dosages and for numerous different diseases entities that are not approved by the US Food and Drug Administration (FDA); however, there are medications that have only recently hit the market that require our attention, as they are either FDA approved for the intended dermatologic use or could be effective in treating conditions that previously have been poorly managed.

Topics: Aminolevulinic Acid; Antibodies, Monoclonal; Antibodies, Monoclonal, Humanized; Antineoplastic Agents; Arthritis, Psoriatic; Azetidines; Biphenyl Compounds; Carcinoma, Basal Cell; Cosmetic Techniques; Deoxycholic Acid; Dermatologic Agents; Drug Approval; Facial Dermatoses; Humans; Keratosis, Actinic; Melanoma; Oncolytic Virotherapy; Piperidines; Psoriasis; Pyridines; Scalp Dermatoses; Skin Neoplasms; United States; United States Food and Drug Administration

Topics: Alopecia; Humans; Male; Piperidines; Psoriasis; Pyrimidines; Pyrroles

Topics: Dermatologic Agents; Female; Humans; Male; Piperidines; Protein Kinase Inhibitors; Psoriasis; Pyrimidines; Pyrroles

Topics: Anti-Inflammatory Agents, Non-Steroidal; Female; Humans; Immunoglobulin G; Male; Piperidines; Protein Kinase Inhibitors; Psoriasis; Pyrimidines; Pyrroles; Receptors, Tumor Necrosis Factor

Tofacitinib is a novel drug that inhibits the JAK-STAT signaling pathway. It has been approved for the treatment of psoriatic arthritis and it is under investigation for the treatment of psoriasis and other inflammatory disorders. We report a case of pulmonary cryptococcosis in an otherwise immunocompetent patient taking tofacitinib for psoriasis. We hypothesized that tofacitinib contributed to this infection through inhibition of cytokines required for differentiation of T cells and suppression of macrophage activation. As dermatologists begin to use this drug they should be aware of the potential for cryptococcocal infection, because delay of diagnosis may increase the risk of a life-threatening outcome.

Topics: Aged; Cryptococcosis; Humans; Lung Diseases; Male; Piperidines; Protein Kinase Inhibitors; Psoriasis; Pyrimidines; Pyrroles

Topics: Adult; Alopecia; Dose-Response Relationship, Drug; Humans; Male; Piperidines; Protein Kinase Inhibitors; Psoriasis; Pyrimidines; Pyrroles; Treatment Outcome

Protein kinases play a crucial role in the intracellular signaling pathways involved in inflammation and cell proliferation. Advances in our understanding of these metabolic pathways and of the role played by intracellular signaling in the pathogenesis of psoriasis have led to research in this area and the development of a new class of drugs for the treatment of psoriasis and other inflammatory processes. Since kinase inhibitors are small molecules, oral and topical treatments are possible. The future role of these molecules in the therapeutic arsenal used to treat psoriasis is as yet unknown because in most cases they are still in the early stages of research. The fact that these drugs may cost much less than biologic therapies could favor their approval in coming years. Tofacitinib, a Janus kinase inhibitor, is the drug that has reached the most advanced stage of research and has shown the most promising results.

Topics: Humans; Piperidines; Protein Kinase Inhibitors; Psoriasis; Pyrimidines; Pyrroles

Topics: Dermatologic Agents; Female; Humans; Male; Piperidines; Protein Kinase Inhibitors; Psoriasis; Pyrimidines; Pyrroles

Topics: Alefacept; Antibodies, Monoclonal; Antibodies, Monoclonal, Humanized; Clinical Trials as Topic; Dermatologic Agents; Humans; Interleukin-17; Piperidines; Psoriasis; Pyrimidines; Pyrroles; Recombinant Fusion Proteins; Thalidomide; Ustekinumab

Topics: Carcinoma; Chemotherapy, Adjuvant; Drug Eruptions; Histamine H2 Antagonists; Humans; Lymph Node Excision; Lymphatic Metastasis; Male; Middle Aged; Piperidines; Psoriasis; Radiodermatitis; Radiotherapy, Adjuvant; Tongue Neoplasms

The peptide substance P (SP) has been implicated in inflammatory conditions, such as psoriasis, where mast cells and VEGF are increased. A relationship between SP and VEGF has not been well studied, nor has any interaction with the proinflammatory cytokines, especially IL-33. Here we report that SP (0.1-10 microM) induces gene expression and secretion of VEGF from human LAD2 mast cells and human umbilical core blood-derived cultured mast cells (hCBMCs). This effect is significantly increased by coadministration of IL-33 (5-100 ng/mL) in both cell types. The effect of SP on VEGF release is inhibited by treatment with the NK-1 receptor antagonist 733,060. SP rapidly increases cytosolic calcium, and so does IL-33 to a smaller extent; the addition of IL-33 augments the calcium increase. SP-induced VEGF production involves calcium-dependent PKC isoforms, as well as the ERK and JNK MAPKs. Gene expression of IL-33 and histidine decarboxylase (HDC), an indicator of mast cell presence/activation, is significantly increased in affected and unaffected (at least 15 cm away from the lesion) psoriatic skin, as compared with normal control skin. Immunohistochemistry indicates that IL-33 is associated with endothelial cells in both the unaffected and affected sites, but is stronger and also associated with immune cells in the affected site. These results imply that functional interactions among SP, IL-33, and mast cells leading to VEGF release contribute to inflammatory conditions, such as the psoriasis, a nonallergic hyperproliferative skin inflammatory disorder with a neurogenic component.

Topics: Calcium; Cytosol; Humans; Immunohistochemistry; Interleukin-33; Interleukins; Mast Cells; Neurokinin-1 Receptor Antagonists; Piperidines; Psoriasis; RNA, Messenger; Skin; Substance P; Vascular Endothelial Growth Factor A