piperidines and apremilast

Granuloma annulare (GA) is an inflammatory granulomatous skin disease that can be localized (localized GA) or disseminated (generalized GA), with patch, perforating, and subcutaneous subtypes being less common variants of this benign condition. Recently, new research has emerged that further elucidates GA epidemiology and etiopathogenesis; importantly, new therapeutic options for GA have also been described, although there remains a paucity of randomized controlled studies. In this review, we summarize recent updates on GA epidemiology and etiopathogenesis and offer an updated review of the therapeutic options for GA currently reported in the literature. We hope that the current review galvanizes randomized controlled studies that will in turn help lead to the recommendation of evidence-based treatments for GA.

Topics: Anti-Infective Agents; Antimalarials; Biological Therapy; Comorbidity; Dermatologic Agents; Diabetes Complications; Diagnosis, Differential; Glucocorticoids; Granuloma Annulare; Humans; Iatrogenic Disease; Infections; Methotrexate; Neoplasms; Pentoxifylline; Phosphodiesterase 4 Inhibitors; Phototherapy; Piperidines; Pyrimidines; Thalidomide

In recent years, different studies regarding psoriatic arthritis (PsA) have shown the pathogenetic role of dysfunction of signaling pathways involving the phosphodiesterase-4 enzyme and transcription factors or enzymes belonging to the kinase (JAK)-signal family pathway. These also represent the target of several drugs known as targeted synthetic disease-modifying antirheumatic drugs (tsDMARDs).. The authors performed a systematic literature search using the PubMed database, as well as through retrieving data from randomized controlled trials, their. In PsA, the PDE4i, apremilast, and the JAKi, tofacitinib, are effective across multiple clinical domains and have an acceptable tolerability profile, thus expanding the treatment options available for PsA patients. Apremilast and tofacitinib show several advantages mainly represented by their oral administration, a fast onset of action, and a short half-life. Data on tsDMARDs in PsA are still limited, and randomized trials and real-life studies are advocated.

Topics: Administration, Oral; Antirheumatic Agents; Arthritis, Psoriatic; Azetidines; Humans; Janus Kinases; Molecular Targeted Therapy; Phosphodiesterase 4 Inhibitors; Piperidines; Purines; Pyrazoles; Pyrimidines; Pyrroles; Randomized Controlled Trials as Topic; Sulfonamides; Thalidomide; Treatment Outcome

Psoriatic arthritis (PsA) is associated with progressive joint destruction and reduced quality of life. The time until a drug treatment starts to show an effect (TOA) is important for preventing joint destruction. The objective was to assess the time until onset of action of drugs when treating PsA. A systematic review of PsA drug trials was performed. Outcomes were: time until 25% of patients (TOA) reached (1) ≥ 20%, (2) ≥ 50% improvement in modified American College of Rheumatology response criteria (ACR), (3) ≥ 75% reduction in Psoriasis Area and Severity Index (PASI75). 95% confidence intervals were calculated extracting data from graphs using a novel method. Meta-analysis was conducted. Two head-to-head trials show no difference between ixekizumab and adalimumab or adalimumab and tofacitinib for TOA-ACR outcomes. For PASI75, ixekizumab had a faster onset than adalimumab. Infliximab plus MTX was faster than MTX alone. Pooled results from 32 study arms for TOA-ACR20 (week [95% CI]) are: < 2 weeks: infliximab (1.18 [0.72-1.65]), ixekizumab (1.04 [0.80-1.28]), tofacitinib (10 mg 1.56 [1.14-1.98]); ≤ 4 weeks: adalimumab (1.95 [1.35-2.55]), secukinumab (75 mg 1.89 [0.16-3.62], 150 mg 2.13 [1.34-2.91], 300 mg 2.26 [1.75-2.76]), tofacitinib (5 mg 2.20 [1.41-2.99]); 4 + weeks: apremilast, ustekinumab. For TOA-ACR50, all pooled point estimates are > 4 weeks. For TOA-PASI75, the range is between 2.24 [1.65-2.84] for ixekizumab and 6.03 [3.76-8.29] for adalimumab. Indirect, mixed comparison suggest a faster onset of infliximab, ixekizumab and tofacitinib compared to apremilast, methotrexate and ustekinumab for ACR20, not ACR50. For PASI75, ixekizumab is faster than adalimumab.

Topics: Adalimumab; Antibodies, Monoclonal, Humanized; Antirheumatic Agents; Arthritis, Psoriatic; Confidence Intervals; Humans; Infliximab; Methotrexate; Piperidines; Pyrimidines; Pyrroles; Thalidomide; Time Factors; Treatment Outcome; Tumor Necrosis Factor Inhibitors; Ustekinumab

Tofacitinib and apremilast have shown considerable efficacy in placebo-controlled trials of active psoriatic arthritis, but the relative efficacy and safety remain unclear because of a lack of head-to-head comparisons.. The aim of this study was to assess the relative efficacy and safety of tofacitinib and apremilast at different doses in patients with active psoriatic arthritis.. We performed a Bayesian network meta-analysis to combine evidence from randomized controlled trials for examination of the efficacy and safety of tofacitinib 10 mg, tofacitinib 5 mg, apremilast 30 mg, and apremilast 20 mg in psoriatic arthritis.. Eight randomized controlled trials including 3086 patients met the inclusion criteria. There were ten pairwise comparisons including six direct comparisons of five interventions. All the interventions achieved a significant American College of Rheumatology 20 response compared with placebo. Tofacitinib 10 mg and apremilast 30 mg were among the most effective treatments for active psoriatic arthritis, followed by tofacitinib 5 mg, and apremilast 20 mg. The ranking probability based on the surface under the cumulative ranking curve (SUCRA) indicated that tofacitinib 10 mg had the highest probability of being the best treatment in terms of the American College of Rheumatology 20 response rate (SUCRA = 0.785). This was followed by apremilast 30 mg (SUCRA = 0.670), tofacitinib 5 mg (SUCRA = 0.596), apremilast 20 mg (SUCRA = 0.448), and placebo (SUCRA = 0.001). We observed no significant differences in the incidence of serious adverse events after treatment with tofacitinib 10 mg, apremilast 30 mg, tofacitinib 5 mg, apremilast 20 mg, or placebo.. In patients with active psoriatic arthritis, tofacitinib 10 mg and apremilast 30 mg were the most efficacious interventions and were not associated with a significant risk of serious adverse events.

Topics: Anti-Inflammatory Agents, Non-Steroidal; Arthritis, Psoriatic; Bayes Theorem; Humans; Network Meta-Analysis; Piperidines; Protein Kinase Inhibitors; Pyrimidines; Pyrroles; Randomized Controlled Trials as Topic; Thalidomide; Treatment Outcome

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

Dermatologists are on the front line to identify psoriatic arthritis (PsA) in their patients with psoriasis. PsA is a prevalent and underdiagnosed disease with potential long-term complications and sequelae for patients. Targeted biologics have transformed the landscape of psoriasis and PsA therapy. These medications variably treat clinical manifestations of psoriatic disease: skin psoriasis, peripheral and axial arthritis, enthesitis, and nail disease. With many new medications either on the market or currently being evaluated by the Food and Drug Administration, the purpose of this article is to review PsA for the dermatologist, to identify the current therapies that are available, and to help select which patients may benefit from these medications. Overall, it is important to decide therapy for patients based on the active domains of their disease, their comorbidities, and the safety profiles of these medications, as well as patient preference for route of administration, frequency, and tolerability.

Topics: Antibodies, Monoclonal; Antirheumatic Agents; Arthritis, Psoriatic; Dermatologic Agents; Dermatology; Humans; Interleukin-17; Interleukin-23; Janus Kinase Inhibitors; Molecular Targeted Therapy; Phosphodiesterase 4 Inhibitors; Piperidines; Pyrimidines; Pyrroles; Severity of Illness Index; Thalidomide; Tumor Necrosis Factor-alpha

The majority of psoriatic arthritis (PsA) patients experience a good clinical response to conventional synthetic disease-modifying antirheumatic drugs (csDMARDs) and biologic therapies (bDMARDs). However, treatment failure with these drugs can represent a relevant clinical problem. Moreover, in daily clinical practice, the appropriate identification of patients eligible for these agents can be conditioned by numerous aspects, mainly represented by comorbidities, such as history of malignancies, chronic and recurrent infectious diseases. Areas covered: We searched in the PUBMED database and review published data on the efficacy and safety profile of the small molecules, inhibitor of phosphodiesterase 4, apremilast, and of JAK/STAT pathways, tofacitinib, in PsA. Moreover, we report data on the other JAK inhibitor, baricitinib, and the A(3) adenosine receptors agonist, CF101, emerging by studies conducted in psoriasis patients. Expert opinion: In Psoriatic Arthritis, apremilast appears promising for PsA and recent studies have shown a good efficacy and an acceptable safety profile. Data on tofacitinib in PsA are limited. Studies on the small molecules, baricitinib and CF101 are still incomplete and limited to trials conducted in Rheumatoid Arthritis and in psoriasis. Further studies on small molecules and on their underlining mechanisms are advocated in PsA.

Topics: Antirheumatic Agents; Arthritis, Psoriatic; Humans; Piperidines; Pyrimidines; Pyrroles; Randomized Controlled Trials as Topic; Severity of Illness Index; Small Molecule Libraries; Thalidomide; Treatment Outcome

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

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

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

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

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

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

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

During the last years there has been an increasing availability of drugs (biologics and small molecules) with different mechanisms of action (MoA) in psoriatic arthritis (PsA). New issues about treatment strategies have arisen. The main aim of this study is to verify if there is a difference in terms of clinical efficacy (i.e. retention rate) between cycling (i.e. treating patients with the same MoA after the failure of the previous one) or swap (i.e choosing drugs with a MoA different from the failed previous one) strategies in PsA.In this mono-centric medical records review study, PsA patients treated with biologics, apremilast or tofacitinib were enrolled. Every prescription was clustered in three groups: cycling (CG), swap (SG) or first line group (1LG). Kaplan-Meier analysis and Cox test estimated and compared drugs' retention rate in CG, SG and 1LG. P < .05 was considered statistically significant.One hundred eighty-three PsA patients were enrolled (9967 patient-months). In CG and 1LG the more prescribed drugs were tumor necrosis factor inhibitor (respectively 99% and 89%), in SG interleukin 17 inhibitor (60%). There were no differences in terms of sex, age, disease duration, and retention rate between CG and SG. The 18-months retention rate of 1LG, SG and CG was 77%, 60%, and 51% respectively. The CG retention rate was lower than in 1LG (P = .03).The findings of this study suggest that in PsA the swap strategy gives no remarkable advantage compared to cycling. However, patients undergoing swap strategy may experience the same failure rate observed in naives.

Topics: Antirheumatic Agents; Arthritis, Psoriatic; Biological Products; Cluster Analysis; Drug Substitution; Female; Humans; Kaplan-Meier Estimate; Male; Middle Aged; Piperidines; Proportional Hazards Models; Pyrimidines; Thalidomide; Treatment Outcome; Tumor Necrosis Factor Inhibitors

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

Topics: Alopecia Areata; Animals; Mice; Piperidines; Pyrimidines; Pyrroles; Thalidomide

The treatment of atopic dermatitis in adults is based on the use of topical steroids and emollients. When AD is resistant to a well-conducted topical treatment, phototherapy or systemic treatments can be used: ciclosporin, methotrexate, azathioprine or mycophenolate mofetil. The therapeutic landscape of adult AD is about to change and even be revolutionized by the imminent arrival of new treatments: topical phosphodiesterase 4 inhibitors, topical or systemic JAK inhibitors, anti-IL-4 and/or antiIL-13 biotherapies (dupilumab, tralokinumab, lebrikizumab), anti-IL-31 (nemolizumab), anti-TSLP.

Topics: Adult; Antibodies, Monoclonal; Antibodies, Monoclonal, Humanized; Azathioprine; Boron Compounds; Bridged Bicyclo Compounds, Heterocyclic; Cyclosporine; Dermatitis, Atopic; Dermatologic Agents; Glucocorticoids; Humans; Methotrexate; Mycophenolic Acid; Piperidines; Pyrimidines; Pyrroles; Thalidomide; Ustekinumab

Topics: Antifungal Agents; Attention Deficit Disorder with Hyperactivity; Boron Compounds; Botulinum Toxins, Type A; Bridged Bicyclo Compounds, Heterocyclic; Brimonidine Tartrate; Depression; Dermatitis, Atopic; Food Hypersensitivity; Humans; Immunologic Factors; Ivermectin; Phosphodiesterase Inhibitors; Phototherapy; Piperidines; Protein Kinase Inhibitors; Pyrimidines; Pyrroles; Quinoxalines; Skin Diseases; Societies, Medical; Thalidomide; Triazoles; United States

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