Elsevier

Clinical Immunology

Volume 220, November 2020, 108536
Clinical Immunology

Review Article
Updated therapies for the management of Psoriatic Arthritis

https://doi.org/10.1016/j.clim.2020.108536Get rights and content

Highlights

  • Psoriatic arthritis (PsA) is associated with heterogeneous musculoskeletal involvement and dermatological manifestations.

  • csDMARDs have only a modest benefit in PsA

  • Biologics such as anti-tumor necrosis factor (TNF) agents are highly effective for all clinical domains involved in PsA.

  • Promising new therapies in trials for PsA are anti-IL-23 and its several signaling proteins

  • mTOR, NGF, RORgt and potassium ion channel inhibitors are in development stage for novel therapies of PsA

  • PsA patients need a “Total Care Program”, that is treatment of all comorbidities; and exemplary care of the skin and joint.

Abstract

Psoriatic arthritis (PsA) is a large volume of our clinical practice and its management can be challenging. Traditional DMARDs have been used over last six decades and observational studies have substantiated an effective use of many of these drugs. However, in last two decades use of anti-TNF agents has brought a new dimension in treatment of PsA and in many other autoimmune diseases. Regulatory role of the Th17 cells and its cytokines in the pathogenesis of PsA has successfully paved the foundations of anti-IL antibody based therapies in PsA. Newer therapies targeting the IL-23/IL-17 cytokines and its signaling proteins are now in development and bringing new promises for management of PsA. Herein, we provide an overview of the landscape of drug therapies, including IL-17, IL-12/23, IL-23 inhibitors, and janus kinase (JAK) inhibitors, as well as those in development, such as RORγt inhibitors, anti-NGF agents, mTOR inhibitors and T cell ion-channel blockers.

Introduction

Psoriatic arthritis (PsA) is a chronic inflammatory condition that affects the joints and periarticular structures, as well as the skin and nails. Its prevalence ranges from 0.06% to 0.25% in western countries (e.g. United States) [1]. Although PsA occasionally can precede psoriasis, approximately one third of patients with psoriasis may develop PsA [1].

PsA disease is progressive and closely associated with several comorbidities. Favorable long-term outcomes can be optimized with an early diagnosis, though its heterogeneous presentation can make diagnosis and management challenging for providers. Prompt treatment initiation is essential in improving prognosis and preventing further joint damage. Additionally, diagnosis can be indicative to providers of significant comorbidities requiring screening, including increased cardiovascular disease. Several screening tools have been developed to identify patients at risk for PsA, including the Toronto Psoriatic Arthritis Screening Questionnaire (TOPAS), the Psoriasis Epidemiology Screening Tool (PEST), the Psoriatic Arthritis Screening and Evaluation (PASE), and the Psoriasis and Arthritis Screening Questionnaire (PASQ) [2]. Of these, the TOPAS has the highest specificity, while the PEST has the highest sensitivity.

Outcome measures, such as the American College of Rheumatology Responder Index (ACR20), the Disease Activity Score for 28 joints (DAS28), the Minimal Disease Activity (MDA), the Disease Activity for Psoriatic Arthritis (DAPSA); the Psoriatic Arthritis Joint Activity Index (PsAJAI); the Composite Psoriatic Disease Activity Index (CPDAI), the Psoriasis Area and Severity Index (PASI); and indices for enthesitis and dactylitis currently are now in use to assess disease severity [2]. Using these measures to quantify treatment efficacy, therapy recommendations have been outlined by The Group for Research and Assessment of Psoriatic Arthritis (GRAPPA), the European League Against Rheumatism (EULAR), and more recently, the American Academy of Rheumatology (ACR)/National Psoriasis Foundation (NPF) [1,3].

PsA treatment options are diverse, including the traditional therapies of nonsteroidal anti-inflammatory drugs (NSAIDs) and glucocorticoids, conventional systemic disease-modifying antirheumatic drugs (csDMARDs), and the newest advent of biologics [1]. Despite the variety of drugs available for PsA, the landscape continues to broaden with more targeted and effective medications. Herein, we will review currently available therapies and discuss emerging agents and the mechanisms behind their efficacy.

Section snippets

Overview of treatment guidelines

The GRAPPA, EULAR, and ACR/NPF guidelines provide PsA-specific composite disease measures. Initially established in 2009, the GRAPPA guidelines are based on a review of six clinical domains (arthritis, spondylitis, enthesitis, dactylitis, skin disease, and nail disease) [4]. Recommendations were originally stratified by disease severity (mild, moderate, severe); this was removed in the 2015 updated guidelines, which organized treatment recommendations by available supporting evidence [4]. In

Comorbidities

Psoriasis and PsA are known to be accompanied by numerous comorbidities, including cardiovascular disease, diabetes, obesity, metabolic syndrome, osteoporosis, inflammatory bowel disease, and malignancies, among others [6]. Accordingly, effective management of PsA should incorporate a multidisciplinary approach. Consultations with appropriate subspecialties, including but not limited to endocrinology and cardiology, should be strongly considered in at-risk patients. Addressing management of

Non-steroidal anti-inflammatory drugs

Non-steroidal anti-inflammatory drugs (NSAIDs) are a commonly used initial therapeutic agent for PsA, particularly in those with minor joint involvement. However, previous studies have demonstrated their limited ability to modify or reduce disease progression. A four week clinical trial comparing nimesulide, a COX-2 selective NSAID, versus placebo in 76 patients revealed a significant decrease in tender and swollen joint count with 200 mg and 400 mg daily nimesulide dosing, not seen in the

Anti-TNF agents

Biologics have revolutionized targeted immunotherapy in psoriasis and PsA. The ability to selectively target inflammatory cytokines has improved our understanding of the pathophysiology of the disease. Specifically, TNF inhibitors have drastically improved the management of PsA, as they are effective in inhibiting radiographic disease progression [30]. Used in both psoriasis and PsA, TNF antagonists continue to be the therapy demonstrating the highest efficacy in treating PsA, on par with many

PDE4 inhibitors

Phosphodiesterases (PDEs) are composed of 11 families that serve to degrade cyclic nucleotides, such as cyclic adenosine monophosphate (cAMP), which are second messengers regulating cellular function and metabolism [60]. PDE inhibitors act to increase cAMP levels and therefore modulate inflammatory cellular responses [47]. Patients with inflammatory diseases have been found to have higher quantities of PDE4 than healthy controls. In the skin, PDE4 is expressed in keratinocytes, neutrophils, and

Janus kinase (JAK) inhibitors

The JAK/STAT pathway mediates cytokine signaling in PsA, particularly within the IL-12, IL-23 and IL-17 axis, and may mediate the expansion of Th17 cells [[62], [63], [64]]. Tofacitinib is the first JAK inhibitor to be approved for the treatment of PsA. A phase III trial demonstrated that tofacitinib at doses of 5 mg or 10 mg twice daily in patients with psoriatic arthritis with possible prior DMARD use can improve clinical burden of disease, in several areas such as reduction of arthritis,

Co-stimulatory Blockade (Abatacept)

T cell activation requires interaction between the major histocompatibility complex (MHC) and the T cell receptor (TCR), as well as a second interaction between receptor/ligand pairs. One example of a second interaction is between antigen presenting cells (APCs) and CD28 on T cells [66]. This interaction is blocked by co-stimulatory blockade agents, thereby preventing T cell activation and ensuing damage.

The most well-known co-stimulatory blockade agents are abatacept [67]. Abatacept mimics

Drugs in preclinical development

An array of novel molecules targeting the inflammatory-proliferative mechanisms of psoriatic disease are in progress. A broad discussion is not within the scope of this review. Here, we will briefly discuss a few.

Concept of total care

Treatment for PsA remains incomplete without addressing comorbidities. Psoriatic disease is a multisystem disorder; there is an increased prevalence of metabolic syndrome in PsA (40%–60%), putting PsA patients at high cardiovascular risk [84,85]. Understandably, it is not possible to provide the full spectrum of healthcare during a brief rheumatology office visit. Thus, a multidisciplinary approach involving subspecialists should be employed. These can include dermatologists, cardiologists,

Conclusion

In conclusion, PsA is a chronic inflammatory condition of the skin and joints that is associated with debilitating comorbidities. Clinicians can consider the GRAPPA, EULAR, and ACR/NPF guidelines to create personalized treatment regimens for patients. Early diagnosis can be achieved with the use of screening tools and a multidisciplinary approach can reduce disease-associated morbidity. Successful management should aim to provide a comprehensive program as outlined as a “total care program” for

References (88)

  • S.P. Raychaudhuri et al.

    FR255734, a humanized, fc-silent, anti-CD28 antibody improves psoriasis in the SCID mouse-psoriasis xenograft model

    J Invest Dermatol.

    (2008 Aug)
  • S. Kundu-Raychaudhuri et al.

    IL-9, a local growth factor for synovial T cells in inflammatory arthritis

    Cytokine.

    (2016)
  • A. Mitra et al.

    IL-22 induced cell proliferation is regulated by PI3K/Akt/mTOR signaling cascade

    Cytokine.

    (2012)
  • S. Kundu-Raychaudhuri et al.

    Kv1.3 in psoriatic disease: PAP-1, a small molecule inhibitor of Kv1.3 is effective in the SCIDmouse psoriasis - xenograft model

    J. Autoimmun.

    (2014)
  • C.T. Ritchlin et al.

    Psoriatic arthritis

    N Engl J Med.

    (2017 Mar 9)
  • J.A. Singh et al.

    2018 american college of rheumatology/national psoriasis foundation guideline for the treatment of psoriatic arthritis

    Arthritis Care & Research.

    (2019)
  • L.C. Coates et al.

    Group for research and assessment of psoriasis and psoriatic arthritis 2015 treatment recommendations for psoriatic arthritis

    Arthritis & Rheumatology.

    (2016)
  • L. Gossec et al.

    European league against rheumatism (EULAR) recommendations for the management of psoriatic arthritis with pharmacological therapies: 2015 update

    Ann. Rheum. Dis.

    (2016)
  • S.P. Raychaudhuri

    Comorbidities of psoriatic arthritis -- metabolic syndrome and prevention: a report from the GRAPPA 2010 annual meeting

    J. Rheumatol.

    (2012)
  • P. Sarzi-Puttini et al.

    The role of NSAIDs in psoriatic arthritis: evidence from a controlled study with nimesulide

    Clinical and experimental rheumatology

    (2001)
  • A.J. Kivitz et al.

    A comparison of the efficacy and safety of celecoxib 200 mg and celecoxib 400 mg once daily in treating the signs and symptoms of psoriatic arthritis

  • P. Nash et al.

    Psoriatic arthritis therapy: NSAIDs and traditional DMARDs

    Annals of the rheumatic diseases

    (2005)
  • P. Joshi et al.

    An update on disease modifying antirheumatic drugs

    Inflammation & Allergy-Drug Targets (Formerly Current Drug Targets-Inflammation & Allergy)

    (2014)
  • C.T. Ritchlin et al.

    Treatment recommendations for psoriatic arthritis

    Ann. Rheum. Dis.

    (2009)
  • M.E. Weinblatt

    Methotrexate in rheumatoid arthritis: a quarter century of development

    Trans. Am. Clin. Climatol. Assoc.

    (2013)
  • H. Tian et al.

    Understanding the mechanisms of action of methotrexate: implications for the treatment of rheumatoid arthritis

    Bulletin of the NYU hospital for joint diseases.

    (2007)
  • T.D. Wilsdon et al.

    Methotrexate for psoriatic arthritis

    Cochrane Database Syst. Rev.

    (2019)
  • G.H. Kingsley et al.

    A randomized placebo-controlled trial of methotrexate in psoriatic arthritis

    Rheumatology (Oxford)

    (2012)
  • P.J. Mease et al.

    Etanercept and methotrexate as monotherapy or in combination for psoriatic arthritis: primary results from a randomized, Controlled Phase III Trial

    Arthritis Rheumatol.

    (2019 Jul)
  • F.C. Breedveld et al.

    Leflunomide: mode of action in the treatment of rheumatoid arthritis

    Ann. Rheum. Dis.

    (2000)
  • Q. Dai et al.

    Efficacy and safety of leflunomide in psoriatic arthritis treatment: a single-arm meta-analysis

    Int. J. Rheum. Dis.

    (2019)
  • P.B. Jones et al.

    Reappraisal of the clinical use of leflunomide in rheumatoid arthritis and psoriatic arthritis

    Open Access Rheumatol.

    (2010)
  • D.O. Clegg et al.

    Comparison of sulfasalazine and placebo in the treatment of psoriatic arthritis. A department of veterans affairs cooperative study

    Arthritis & Rheumatism.

    (1996)
  • H. Genc et al.

    The effects of sulfasalazine treatment on enthesal abnormalities of inflammatory rheumatic diseases

    Clin. Rheumatol.

    (2007)
  • A. Soriano et al.

    Cyclosporine in psoriatic arthropathy

    Clin. Exp. Rheumatol.

    (2015)
  • E. Sbidian et al.

    Systemic pharmacological treatments for chronic plaque psoriasis: a network meta-analysis

    The Cochrane database of systematic reviews

    (2017)
  • K. Singh et al.

    CADTH Rapid Response Reports. Cyclosporine for Moderate to Severe Plaque Psoriasis in Adults: A Review of Clinical Effectiveness and Safety. Ottawa (ON): Canadian Agency for Drugs and Technologies in Health Copyright (c) 2018

    (2018)
  • R. Gupta

    Prolonged remission of psoriasis with azathioprine pulse therapy

    Indian J Dermatol.

    (2015)
  • S. D'Angelo et al.

    Review of the treatment of psoriatic arthritis with biological agents: choice of drug for initial therapy and switch therapy for non-responders

    Open Access Rheumatol.

    (2017)
  • A. Mourad et al.

    Treatment of dactylitis and enthesitis in psoriatic arthritis with biologic agents: a systematic review and meta-analysis

    J Rheumatol

    (2020)
  • M. Umeda et al.

    Efficacy of infliximab as a switched biologic in rheumatoid arthritis patients in daily clinical practice

    Immunological Medicine.

    (2018)
  • L. Gibellini et al.

    Anti-TNF-alpha drugs differently affect the TNFalpha-sTNFR system and monocyte subsets in patients with psoriasis

    PLoS One

    (2016)
  • C. Adamopoulos et al.

    Deciphering signaling networks in osteosarcoma pathobiology

    Exp Biol Med (Maywood).

    (2016)
  • J. Roberts et al.

    A review of ustekinumab in the treatment of psoriatic arthritis

    Immunotherapy.

    (2018)
  • Cited by (0)

    View full text