Updating Treatment Strategies for PsA: Aiming for Minimal Disease Activity

Psoriatic arthritis (PsA) is a chronic inflammatory disease presenting with various combinations of primary clinical manifestations including sacroiliitis, spondylitis, enthesitis, psoriasis, and uveitis, some of which may appear years before diagnosis.

In the absence of substantial research in PsA, the original guidelines for treatment were general and loosely based on treatment for rheumatoid arthritis.^1,2 In recent years, however, a number of disease-modifying antirheumatic drugs (DMARDs) were developed specifically for PsA, and the treatment armamentarium has been expanded to include a number of biologic DMARDs, tumor necrosis factor (TNF) inhibitor therapies, and potential interleukin (IL)-based treatments.

This rapid expansion of effective therapies for PsA has driven new, ambitious treatment targets of minimal disease activity (MDA) and disease remission. Since the establishment of these goals in 2015, with the release of both the Group for Research and Assessment of Psoriasis and Psoriatic Arthritis (GRAPPA)³ and European League Against Rheumatism (EULAR)² updated guidelines, measures of MDA have increasingly been used as clinical trial outcomes.

The GRAPPA guidelines³ provided updated recommendations for the treatment of primary manifestations of PsA across the affected clinical domains of peripheral arthritis, axial disease, enthesitis, dactylitis, skin disease, and nail disease. They identified 6 overarching principles:

1. The goals of therapy are to achieve MDA, optimize functional status, and minimize complications.
2. Clinical assessment of PsA should include evaluation of all 6 major domains.
3. A complete examination, including history and patient-reported measures, should be considered along with the most widely accepted metrics validated in PsA.
4. Treatment should include evaluation of all comorbid conditions.
5. Therapeutic decisions need to be individualized.
6. Prompt, regular evaluations and follow-up should be performed and should be designed to adjust therapies as needed.

The EULAR guidelines⁴ presented 5 similar general principles, along with 10 specific guidelines aimed at treatment strategies for PsA:

1. Treatment aims at remission of disease or, alternatively, minimal/low disease activity, through regular monitoring and adjustment of therapy as needed.
2. Nonsteroidal anti-inflammatory drugs (NSAIDs) can be used to relieve musculoskeletal signs and symptoms.
3. Conventional synthetic (cs) DMARDs should be considered at an early stage for peripheral arthritis, particularly when manifested by many swollen joints, structural damage in the presence of inflammation, high erythrocyte sedimentation rate (ESR)/C-reactive protein (CRP), and/or clinically relevant extra-articular manifestations, with methotrexate preferred in patients with relevant skin involvement.
4. Use of glucocorticoids at the lowest effective dose injected locally should be considered as adjunctive therapy.

In patients with peripheral arthritis and an inadequate response to at least one csDMARD:

1. Biologic (b) DMARDs should be initiated (usually a TNF inhibitor).
2. When TNF inhibitors are not appropriate, bDMARDs targeting IL12/23 or IL17 pathways may be considered.
3. When bDMARDs are not appropriate, a targeted synthetic DMARD such as a phosphodiesterase 4 inhibitor may be considered.
4. In patients with active enthesitis and/or dactylitis and insufficient response to NSAIDs or local glucocorticoid injections, bDMARD therapy with a TNF inhibitor should be considered.
5. In patients with predominantly axial disease that is active and has insufficient response to NSAIDs, bDMARD therapy with a TNF inhibitor should be considered.
6. In patients who fail to respond adequately to a bDMARD, switching to another bDMARD should be considered, including switching between TNF inhibitors.

Defining Minimal Disease Activity

A major challenge to the implementation of the new guidelines is the continued discrepancy in designating standards for MDA. In 2010, Coates and colleagues⁵ proposed that MDA should be defined as fulfilling 5 of the following 7 criteria, including:

• Tender joint count ≤1
• Swollen joint count ≤1
• Psoriasis Area and Severity Index ≤1 or body surface area ≤3
• Patient pain visual analog scale (VAS) score ≤15 mm
• Patient global disease activity VAS score ≤20 mm
• Health Assessment Questionnaire score ≤0.5
• Tender entheseal points ≤1

In 2016, the investigators suggested updating their classic definition using new indices — the Psoriatic Arthritis Disease Activity Score (PASDAS) and the Composite Psoriatic Disease Activity Index (CPDAI) — to require meeting 5 of the 7 criteria and requiring the inclusion of tender and swollen joints.⁶ They also proposed an additional category of very low disease activity, measured by meeting all 7 criteria. No specific guidelines have been developed to define remission.

Application of the New Guidelines

An estimated 20% to 30% of patients with psoriasis already have PsA, and skin manifestations in up to 80% of patients may precede the disease by many years.⁷ Patients who present with signs of enthesitis, dactylitis, anterior uveitis or iritis, and gastrointestinal involvement may also meet the criteria for PsA, allowing for early treatment with DMARD therapies that target MDA and remission.^7,8

A number of therapies currently available have the potential to achieve MDA in specific patients, including established csDMARDs (methotrexate, leflunomide, and cyclosporine) and newer bDMARDs under investigation (TNF inhibitors, T-cell modulators, and anti-interleukin agents). A prospective study by Perrotta and colleagues⁹ showed that 61.3% of patients treated with TNF-α blockers achieved the criteria for MDA, “identifying this as an achievable target for patients with PsA.” New developments with synthetic agents are also expected to yield therapies that have a place in PsA treatment.

References

1. Gossec L, McGonagle D, Korotaeva T, et al. Minimal disease activity as a treatment target in psoriatic arthritis: a review of the literature. J Rheumatol. 2017;44(12):jrheum.170449.  
2. Gossec L, Smolen JS, Ramiro S, et al. European League Against Rheumatism (EULAR) recommendations for the management of psoriatic arthritis with pharmacological therapies: 2015 update. Ann Rheum Dis. 2016;75(3):499-510.
3. Coates LC, Kavanaugh A, Mease PJ, et al. Group for Research and Assessment of Psoriasis and Psoriatic Arthritis 2015 treatment recommendations for psoriatic arthritis. Arthritis Rheumatol. 2016;68(5):1060-1071.
4. Ramiro S, Smolen JS, Landewé R, et al. Pharmacological treatment of psoriatic arthritis: a systematic literature review for the 2015 update of the EULAR recommendations for the management of psoriatic arthritis. Ann Rheum Dis. 2016;75:490-498.
5. Coates LC, Fransen J, Helliwell PS. Defining minimal disease activity in psoriatic arthritis: a proposed objective target for treatment. Ann Rheum Dis. 2010;69:48-53.
6. Coates LC, Helliwell PS. Defining low disease activity states in psoriatic arthritis using novel composite disease instruments. J Rheumatol. 2016;43:371-375.
7. Huynh D, Kavanaugh A. Psoriatic arthritis: current therapy and future approaches. Rheumatology. 2015:54:20-25.
8. Gladman DD. Toward treating to target in psoriatic arthritis. J Rheumatol Suppl. 2015;93:14-16.
9. Perrotta FM, Marchesoni A, Lubrano E. Minimal disease activity and remission in psoriatic arthritis patients treated with anti-TNF-a drugs.  2016;43(20;350-355.