Tofacitinib for the treatment of psoriasis and psoriatic arthritis

Introduction: 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.     

Unique advantage of Janus kinase 3 as a target for selective and nontoxic immunosupression

Certolizumab pegol (CZP) is a TNF-α inhibitor approved for the treatment of psoriatic arthritis in 38 countries, including many European countries and the USA. It is a pegylated humanized anti-TNF-α antigen-binding fragment, administered subcutaneously. As other TNF-α antibodies, CZP binds to and neutralizes both soluble and membrane TNF-α. In contrast to whole antibodies and etanercept, CZP does not activate antibody-dependent cell-mediated cytotoxicity or complement-dependent cytotoxicity, as it does not have an Fc piece. CZP showed efficacy in improving skin scores and patient reported outcomes in a Phase II study of 176 adults with moderate-to-severe plaque psoriasis. In a Phase III study of CZP in 409 psoriatic arthritis patients, CZP treatment resulted in improvements in peripheral arthritis, as well as dactylitis, enthesitis, nail disease and quality of life. The safety profile of CZP appears to be similar to that of other TNF-α inhibitor.     

Targeted therapies: what they teach us about the pathogenesis of psoriasis and psoriatic arthritis

Introduction: Biologic therapy has revolutionized treatment pathways in psoriatic joint and skin disease. It has also provided a useful tool with which pathological pathways of this condition may be explored.

Areas covered: This review presents data on the clinical and biological effects of targeted therapy in psoriatic arthritis and psoriasis. Therapeutic agents covered include inhibitors of TNFα, inhibitors of the IL-23/IL-17 axis and inhibitors of intracellular small molecules involved in the transduction of the inflammatory signal. Trial data on clinical and imaging efficacy is reviewed in parallel with studies on biological effects at tissue level. Pathological insights gained from the use of these treatments are explored.

Expert commentary: A close relationship exists between specific pathological types and clinical manifestations of psoriatic disease, including responses to treatment. Studying these relationships is likely to improve understanding of disease and enable rational selection of specific treatments for patients with specific pathotypes.     

State of the art of ultrasound in the assessment of psoriasis and psoriatic arthritis

Introduction: Ultrasound (US) is a rapidly evolving technique that is gaining increasing success in the assessment of psoriatic arthritis (PsA). Recently, new research avenues have been opened, and these are focused on the potential of US for the assessment of extra musculoskeletal areas such as skin and nails. This permits work on the concept of ‘holistic US assessment of PsA’.

Areas covered: Here, we analyze the potential role of US in the global assessment of PsA. Additionally, we provide the current evidence supporting its application in routine clinical practice. Literature was obtained from medical databases including PubMed and Embase.

Expert commentary: US can detect not only structural abnormalities but also minimal blood flow changes at the superficial soft tissue level. This makes it a great tool for the global assessment of disease activity in PsA, in which persistently active disease plays a major role in causing anatomical damage and physical functional disability.     

The relationship between smoking,psoriasis and psoriatic arthritis

Introduction: Smoking is the single most important cause of preventable mortality worldwide. Besides being associated with major cardiovascular and bronchopulmonary diseases, and several cancers, it has been linked with a number of immune-related conditions, including psoriasis and psoriatic arthritis (PsA)

We aimed to summarize data on the role of smoking in the development and prognosis of psoriasis and PsA, pointing to the consequences in terms of disease management.

Areas covered: Mechanisms, clinical manifestations, and comorbidities associated with smoking in psoriasis and PsA were reviewed by searching Medline, Embase and Cochrane Library databases for papers published between January 2000 and July 2018 using combination of terms. Articles not written in English were excluded.

Expert commentary: Smoking is a risk factor for psoriasis development. As for PsA, smoking is positively associated with the disease at the population level, but it is negatively associated in patients with psoriasis. This phenomenon is referred to as the ‘smoking paradox’ of PsA. Smoking may cause poor response and reduced adherence to treatment of both psorasis and PsA. Physicians need to be aware of the smoking habits of their patients with psoriasis and PsA; whenever possible, smoking cessation programs should be considered.     

Apremilast for the treatment of psoriatic arthritis

Psoriatic arthritis (PsA) is a chronic inflammatory disease of the joints that occurs in patients with psoriasis. The spectrum of PsA includes arthritis, dactylitis, enthesitis, axial involvement, and skin lesions. Non-biologic disease-modifying anti-rheumatic drugs (DMARDs) such as methotrexate and leflunomide, and biologic DMARDs such as tumor necrosis factor (TNF) antagonists and ustekinumab, have been used to treat PsA. Apremilast is a novel therapy that inhibits phosphodiesterase 4, increases intracellular cAMP levels, and modulates expression of inflammatory mediators in favor of anti-inflammatory activity. It decreases the pro-inflammatory cytokines TNF-α, IFN-γ, IL-17, and IL-23 and increases the anti-inflammatory cytokine IL-10 under certain conditions. One phase II and four phase III clinical trials as well as long-term extension studies showed significant and sustained clinical efficacy and an adequate safety profile for apremilast in patients with active psoriatic arthritis.     

Interleukin‐17A: a unique pathway in immune‐mediated diseases: psoriasis,psoriatic arthritis and rheumatoid arthritis

Experimental evidence points to the importance of the cytokine interleukin‐17A (IL‐17A) in the pathogenesis of several immunoinflammatory diseases including psoriasis, psoriatic arthritis and rheumatoid arthritis. Although a principal effector of T helper type 17 cells, IL‐17A is produced by many other cell types including CD8⁺ T cells and γδ T cells, and is found at high levels associated with mast cells and neutrophils at sites of skin and joint disease in humans. IL‐17A up‐regulates expression of numerous inflammation‐related genes in target cells such as keratinocytes and fibroblasts, leading to increased production of chemokines, cytokines, antimicrobial peptides and other mediators that contribute to clinical disease features. Importantly, IL‐17A must be considered within the context of the local microenvironment, because it acts synergistically or additively with other pro‐inflammatory cytokines, including tumour necrosis factor. Several direct IL‐17A inhibitors have shown promising activity in proof of concept and phase 2 clinical studies, thereby providing confirmation of experimental data supporting IL‐17A in disease pathogenesis, although levels of response are not predicted by pre‐clinical findings. IL‐17A inhibitors produced rapid down‐regulation of the psoriasis gene signature and high clinical response rates in patients with moderate‐to‐severe plaque psoriasis, consistent with an important role for IL‐17A in psoriasis pathogenesis. Clinical response rates with IL‐17A inhibitors in psoriatic arthritis and rheumatoid arthritis, however, were improved to a lesser degree compared with placebo, suggesting that IL‐17A is either important in a subset of patients or plays a relatively minor role in inflammatory joint disease. Ongoing phase 3 clinical trials should provide further information on the role of IL‐17A in these diseases.     

Autoimmunity in psoriatic arthritis: pathophysiological and clinical aspects

Psoriatic arthritis (PsA) is an underdiagnosed entity with a broad impact on the quality of life. Although the pathogenesis is largely unknown, autoimmune footprints of the inflammation in PsA have increasingly been recognized. Most of the genetic variation predisposing to PsA is mapped to the class I major histocompatibility complex (MHC) region and shared by a variety of autoimmune diseases. Polymorphisms in the genes IL12B, IL23R, IL13, TNIP1, TRAF3IP2, TYK2, and many others explain the non-HLA genetic risk with little known functional consequences. Entheseal and synovial cellular infiltrate with oligoclonal CD8⁺ T cells and occasional germinal centers, loss of regulatory T cell function, and specific autoantibodies such as anti-PsA peptide, anti-LL-37, and anti-ADAMTSL5 are the immunopathological findings suggestive of autoimmunity. These were supported by clinical observations of autoimmune multimorbidity and treatment response to calcineurin/mTOR and co-stimulation inhibition.     

Adalimumab for the treatment of psoriatic arthritis

Psoriatic arthritis (PsA) is a chronic inflammatory joint disease occurring in 6–39% of patients with psoriasis. Standard therapy of PsA includes nonsteroidal anti-inflammatory drugs, intra-articular steroids and disease-modifying antirheumatic drugs. Failure of standard therapy is an indication for anti-TNF-α therapy. Adalimumab – a fully human monoclonal antibody against TNF-α – is an effective and generally reasonably well-tolerated drug for treating signs and symptoms of PsA. In placebo-controlled clinical trials, adalimumab showed American College of Rheumatology (ACR)20 response rates of 39–58% and ACR50 response rates of 25–39% in patients with active PsA who had failed previous standard therapy. Significant improvement of psoriatic skin changes and disease-related quality of life were also noted. The response of joints and skin and quality of life improvement was sustained over 2 years of therapy. In addition, adalimumab suppressed structural joint damage and retards radiographic progression of PsA.     

Abatacept for the treatment of psoriatic arthritis

ABSTRACT

Introduction: Psoriatic arthritis (PsA) is a chronic inflammatory disease characterized by the presence of psoriasis, arthritis, and enthesitis, with the association of other musculoskeletal and extra-articular manifestations. Current treatment of PsA is based on the use of conventional, biological and targeted synthetic disease modifying anti-rheumatic drugs; however, patients may not respond or have a loss of response to these agents. Recently, a deeper understanding of the pathogenetic mechanisms has made possible the development of new drugs that actively interact with the activation of immune system, inhibiting the co-stimulation between antigen-presenting cells and lymphocytes.

Areas covered: The aim of this paper is to review the role of the activation of the immune system in the pathogenesis and treatment of PsA, with a discussion on the emerging CTLA4Ig drugs (abatacept) for PsA. A search in PubMed and EMBASE was performed with the keywords: ‘abatacept’, ‘CTLA4,’ and ‘Psoriatic Arthritis.’ We considered preclinical studies, phase I, II and III clinical trials.

Expert commentary: The inhibitors of co-stimulation may represent an effective treatment strategy by acting on the very early phase of the immunological process that brought about the development of inflammation and activation of the immune system, mainly for patients with peripheral joint involvement and mild psoriasis.     

The role of IL-17 in the treatment of psoriatic arthritis

Introduction: Psoriatic arthritis (PsA) is a chronic inflammatory articular disease characterized by psoriasis, synovitis and enthesitis. Current treatment of PsA is mainly based on the use of classical and biological DMARDs; however, 30–40% of patients could not respond to these or have a loss of response.

Areas covered: Recently, the discovery of new pathogenic mechanisms have made possible the development of new drugs that target the IL-17 with the possibility to interfere with the Th17 cells that are considered the cell type mainly involved in the development of the inflammation in PsA. New molecules have shown efficacy and safety over the various components of the disease in randomized clinical trials. These drugs have been recently approved for the treatment of PsA and included in the newest treatment recommendations. Other molecules are currently being tested in phase III clinical trials and are potential new treatment options for PsA.

Expert Commentary: The aim of this paper is to review the role of IL-17 in the pathogenesis and treatment of PsA, with a discussion on the emerging anti-IL-17 drugs for PsA.     

Update in treatment options for psoriatic arthritis

Psoriatic arthritis is a chronic inflammatory joint disease in patients with psoriasis and has a varying disease course. The majority of patients develop important disability and joint destruction within a few years of disease onset, necessitating the initation of disease-modifying therapy. Treatment options for peripheral disease, enthesitis and dactylitis include nonsteroidal anti-inflammatory drugs (NSAIDs), disease-modifying antirheumatic drugs (DMARDs), local steroids and TNF-blocking agents. Axial disease is treated with NSAIDS and TNF blockade. Major clinical response is seen in approximately 30% of patients with methotrexate or leflunomide but no structural effect has yet been documented. Anti-TNF treatment has the best number-needed- to-treat/number-needed-to harm ratio of all DMARDs in psoriatic arthritis and is able to induce clinical remission in at least 30% of patients. TNF-blocking agents have also been demonstrated to slow down or halt radiographic progression.     

New insights into the role of T cells in pathogenesis of psoriasis and psoriatic arthritis

Psoriasis is a chronic, relapsing, autoimmune disorder of the skin affecting 2–3% of general population. Approximately 30% of psoriasis patients are also affected with the psoriatic arthritis, a chronic inflammatory spondyloarthritis. The review aims to present the current knowledge on immunopathogenesis of both diseases to emphasize the involvement of various T helper cell subsets. An extensive literature search in electronic databases was performed on the topic of different Th cell subsets’ involvement in the pathogenesis of psoriasis and psoriatic arthritis. Studies were assessed and selected to present the recent progress in the area. Current data strongly suggest that both PsO and PsA are T cell-mediated diseases, with a key role of various proinflammatory cytokines in their development. The involvement of T cells is highlighted by the superior efficacy of biologic therapies targeting T cell-derived proinflammatory cytokines in both diseases. Initially, PsO and PsA were thought to be Th1-mediated diseases; however, in the last years, several studies have shown the important role of other T cell subsets, including Th17, Th22, Th9 and Treg cells, in the pathogenesis of both diseases, which has led to the development of new therapies.     

RAPID and FAST4WARD trials: certolizumab pegol for rheumatoid arthritis

In the last decade, biological therapies have dramatically changed the treatment for rheumatoid arthritis (RA) in such a way that remission is currently an achievable goal. The armamentarium of therapeutic options for RA has recently been enriched with another approved anti-TNF-α agent, certolizumab pegol (CZP). This article reviews the trials conducted with CZP in RA, the Rheumatoid Arthritis PreventIon of structural Damage (RAPID 1 and 2) and the EFficAcy and Safety of cerTolizumab pegol – 4 Weekly dosAge in RheumatoiD arthritis (FAST4WARD). These trials have demonstrated that this new biological agent significantly improves the clinical signs and symptoms of RA, inhibits progression of structural damage, and improves physical function and quality of life in patients with active RA who have failed treatment with methotrexate. The safety profile of CZP is acceptable and similar to that of other anti-TNF-α agents.     

Periodontitis: a newly identified comorbidity in psoriasis and psoriatic arthritis

ABSTRACT

Introduction: Psoriasis is a chronic autoimmune skin disease with strong genetic background and environmental triggers. Patients with psoriasis and psoriatic arthritis are at greater risk of developing other chronic and potentially severe comorbidities, such as psoriatic arthritis, hyperlipidemia, type 2 diabetes mellitus, obesity, metabolic syndrome, cardiovascular diseases or depression. Recently, accumulating epidemiologic, genetic and pathogenetic evidence indicates that psoriasis is also associated with periodontitis, a chronic progressive inflammatory disease, which may result in tooth loss without early and adequate therapy.

Areas covered: In this review article we summarize and discuss in detail the available epidemiologic, genetic, microbiological and immunological links between psoriasis and periodontitis.

Expert opinion: Periodontitis, via the immunomodulatory effect of the oral microbiota, may play both a direct and indirect role in the development or exacerbation of psoriasis, and may influence the efficacy of antipsoriatic therapy. These new findings indicate a need for increased awareness, early recognition and focus on prevention of periodontitis for patients with psoriasis.     

英夫利昔单抗治疗难治性银屑病关节炎临床观察

目的探讨英夫利昔单抗（INF）治疗难治性银屑病关节炎（PsA）22周的疗效与安全性。方法 18例接受规范的非甾体抗炎药（NSAIDs）和改善病情抗风湿药物（DMARDs）治疗6月以上病情仍活动的PsA患者,0、2、6、14周予INF 3 mg/kg静脉输注。主要疗效评价指标为第2、14、22周达到PsA疗效标准（PsARC）及PASI改善50%（PASI 50）的患者比例,次要疗效指标为第2、14、22周达到PASI 70/90的患者比例及各疗效参数（关节肿胀及压痛数、患者总体评价、健康评估问卷、医师综合评价、PASI评分、CRP）的变化。治疗前及观察期间查血常规、自身抗体、肝肾功、胸片等,记录不良反应。结果治疗2、14、22周时,达到PsARC、PASI 50的患者比例分别为55.6%、55.6%,72.2%、83.3%,88.9%、88.9%;达到PASI 70、PASI 90的患者比例分别为33.3%、22.2%,55.6%、38.9%,77.8%、61.1%;各疗效参数均较基线有改善（P〈0.05）。出现3例感染,对症治疗后痊愈,无严重不良反应发生。结论 INF治疗难治性PsA有较好的疗效和安全性。     

Tumor necrosis factor locus polymorphisms in rheumatoid arthritis

We examined six polymorphic elements in the tumor necrosis factor (TNF) locus and determined their allelic distribution in 98 Caucasian rheumatoid arthritis patients in comparison with 91 ethnically-matched controls. Polymorphic elements at four biallelic sites were distributed similarly between patients and controls, irrespective of the presence or absence of DR4. Differences were observed between the two groups at the TNFa and TNFe loci, but these were consistent with extended MHC haplotypes known to be present in rheumatoid arthritis patients. Therefore, this study suggests that there is little, if any, independent contribution of the TNF locus to the genetic background for rheumatoid arthritis susceptibility.     

Correlation of serum protein biomarkers with disease activity in psoriatic arthritis

ABSTRACT

Objective: To assess the correlation of serum protein biomarkers with disease activity across different domains of psoriatic arthritis (PsA).

Material and methods: A cross-sectional cohort of 45 adult patients with PsA fulfilling the classification for psoriatic arthritis (CASPAR) criteria was recruited from University of California San Diego (UCSD) Arthritis Clinics. Clinical data and serum samples were collected and serum was analyzed for protein biomarkers hypothesized to be relevant to disease activity in PsA. Correlations were evaluated for clinical disease activity measures across disease domains.

Results: Biomarkers with the highest correlation to the composite indices and disease domains were SAA, IL-6, YKL-40, and ICAM-1. In addition, several biomarkers were moderately correlated with individual composite indices and/or disease domains. Low or no correlation was observed with some biomarkers, e.g. MMP-3, MMP-1, EGF, VEGF, and IL-6R. In contrast, the correlation of all biomarkers with certain disease domains was low; specifically, pain, percent body surface area of psoriasis, and patient global assessment. The multi-biomarker disease activity score (MBDA) developed for rheumatoid arthritis (RA) showed high correlations with most composite indices and some disease domains in PsA.

Conclusions: These data suggest biomarker analysis can reflect disease activity across disease domains in PsA. Certain domains would likely benefit from the evaluation of additional biomarkers.     

Quality of life in psoriatic arthritis

Introduction: Psoriatic arthritis (PsA) is a multi-organ chronic inflammatory disease which impacts patients both physically and psychologically. The highest priority for patients goes to pain relief, but also to ability to function and participate in social life, fatigue, and psychological distress.

Areas covered: In the present article, we will review current knowledge on impairments of health-related quality of life related to PsA, as well as patient priorities and patient-reported outcome measures such as the PsA Impact of Disease or the PsA Quality of Life questionnaires. The impact of PsA appears to be very broad, covering all aspects of life, i.e. activities and participation, physical and emotional aspects, but also domains such as fatigue, coping or sleep disturbance. Some of these aspects which are important for PsA patients have been included in the recently updated PsA Core Domain Set to be reported in clinical studies.

Expert commentary: A better understanding of quality of life issues faced by patients with PsA could improve patient-physician communication and ultimately, quality of care. QoL is altered in PsA due both to the physical impact, but also the psychological impact of this disease. Several scores are available to better assess these aspects of PsA.     

Measurement properties of instruments assessing psoriatic arthritis symptoms for psoriasis clinical trials: a systematic literature review

ABSTRACT

Introduction: The International Dermatology Outcome Measures (IDEOM) identified ‘Psoriatic Arthritis (PsA) Symptoms’ as a core domain to be measured in psoriasis clinical trials. This domain includes the measurement of pain, patient global and physical function. Herein, we evaluated the quality (i.e. measurement properties) of five candidate ‘PsA Symptoms’ measures: Patient Global Assessment (PGA) for Joints, PGA for PsA, the Routine Assessment Patient Index 3 (RAPID3), the PsA Impact of Disease 9 (PsAID9) and PsAID12.

Areas covered: We searched MEDLINE and EMBASE (inception-to-March 2018) for studies assessing the measurement properties of candidate instruments. Two reviewers independently assessed the risk of bias of 12 eligible articles using the COSMIN checklist. For each measurement property, we rated the quality of the evidence as ‘high,’ ‘moderate,’ ‘low,’ or ‘very low’ (GRADE approach) and classified the results as ‘sufficient,’ ‘insufficient,’ or ‘inconsistent.’ Finally, we provided recommendations.

Expert opinion: In PsA, RAPID3 had ‘very low’ quality evidence for ‘sufficient’ content validity and no evidence of internal structure. Global assessment instruments had ‘very low’ quality evidence for ‘inconsistent’ content validity. PsAID9 and PsAID12 had ‘low’ evidence for ‘sufficient’ content validity and were recommended to measure ‘PsA Symptoms.’ Further validation studies will improve the level of evidence of this recommendation.