Efficacy of Secukinumab and Adalimumab in Patients With Psoriatic Arthritis and Concomitant Moderate-to-severe Plaque Psoriasis

Results From EXCEED, a Randomized, Double-blind Head-to-head Monotherapy Study

A.B. Gottlieb; J.F. Merola; K. Reich; F. Behrens; P. Nash; C.E.M. Griffiths; W. Bao; P. Pellet; L. Pricop; I.B. McInnes

Disclosures

The British Journal of Dermatology. 2021;185(6):1124-1134. 

In This Article

Discussion

The results of the prespecified analyses in the subset of patients with active PsA and concomitant moderate-to-severe plaque psoriasis are consistent with the primary results of the head-to-head EXCEED monotherapy study.[17]

Psoriasis usually develops long before the symptoms and signs of PsA develop. Thus, it is more likely that patients will visit a dermatologist prior to consulting with a rheumatologist. Furthermore, it is estimated that PsA in approximately 10–15% of patients with psoriasis remains undiagnosed or misdiagnosed.[19] Hence, it is vital to routinely screen patients with psoriasis for the diagnosis of PsA in a dermatology clinic.[20] Delay of PsA diagnosis can lead to irreversible joint damage, even if a significant improvement in psoriasis occurs.[5] Therefore, dermatologists have a pivotal role in early identification of patients with PsA and prevention of irreversible joint damage. This can be achieved by timely screening for PsA in patients with psoriasis and providing therapeutic options that are effective in treating both psoriasis and PsA.[21]

Head-to-head trials could play an important role in clinical decision making, given the increased availability of biologics with distinct modes of action, in the management of patients with active PsA who have concomitant skin disease after csDMARD failure, intolerance or contraindication (including MTX).

The study evaluated an important current gap in our understanding by examining the initiation of biological monotherapy in patients with active PsA. Combination therapy with MTX and biologics has not been shown to be superior to biological treatment alone[22,23] and many patients discontinue MTX as primary or combination therapy because of poor tolerability and/or toxicity, or cannot receive MTX owing to liver abnormalities.[6,15]

EXCEED is the first double-blind, randomized controlled head-to-head monotherapy study to compare secukinumab with adalimumab in patients with active PsA.[17] This study was primarily designed for rheumatologists to address a key question of whether secukinumab was superior to adalimumab for the treatment of patients with PsA as first-line bDMARD treatment after csDMARD failure, intolerance or contraindication.

In the primary analysis of the EXCEED study, secukinumab narrowly missed statistical significance for the primary endpoint of ACR 20 response at week 52; 67·4% with secukinumab vs. 61·5% with adalimumab (P = 0·071).[17]

In this prespecified analysis of patients with PsA who had moderate-to-severe psoriasis, secukinumab showed consistent improvements with respect to efficacy compared with adalimumab for musculoskeletal outcomes (ACR 20/50 responses, resolution of enthesitis and resolution of dactylitis), composite indices targeting remission or LDA, and physical function outcomes at week 52.

Secukinumab demonstrated consistently higher PASI responses vs. adalimumab across skin endpoints (PASI 75/90, P < 0·001; PASI 100, P < 0·05). These results are consistent with previous secukinumab studies (vs. placebo in the FIXTURE study, vs. etanercept and placebo in the ERASURE study, and vs. ustekinumab in the CLARITY study) in patients with PsA and psoriasis.[24–26]

A greater treatment retention rate was observed with secukinumab vs. adalimumab in patients with PsA who had moderate-to-severe plaque psoriasis similar to that of the overall EXCEED study population.[17]

Owing to the diverse clinical manifestations of PsA, improvements in both musculoskeletal and skin outcomes (the combined effect) are considered essential for optimizing overall HRQoL in PsA.[27] Hence, the combination of two stringent endpoints; the musculoskeletal endpoint (ACR 50) and the skin endpoint (PASI 100) represent a treat-to-target endpoint to evaluate the response to active disease in patients with PsA, with both joint and skin components.[28] The combined ACR 50 and PASI 100 response at week 52 with secukinumab vs. adalimumab in the current analysis was 28·2% vs. 17·7% (P = 0·06). This result is consistent with the results in the overall EXCEED study population and the results of the SPIRIT head-to-head study, which compared the IL-17 inhibitor ixekizumab with adalimumab in an open-label, assessor-blind study that recruited patients with PsA who had active plaque psoriasis affecting ≥ 3% of BSA at baseline.[17,28] However, it should be noted that the EXCEED study was a monotherapy study and concomitant csDMARDS were prohibited during the study, whereas in the SPIRIT study approximately 70% of patients were receiving concomitant csDMARDs.[17,28]

The interaction testing between psoriasis status (stratified as 'active PsA with concomitant psoriasis' and 'nonpsoriasis subset of PsA') and the secukinumab treatment effect showed no significant treatment by psoriasis status interaction for any of the four efficacy endpoints, i.e. ACR 20/50, resolution of enthesitis and change from baseline in HAQ-DI. This analysis reflects the lack of treatment heterogeneity in the psoriasis status.

A limitation of this psoriasis subset analysis is that the study was not designed or powered to compare efficacy responses between the two treatments in the mild-to-moderate psoriasis subset. The monotherapy design may also limit the generalization of its findings given that concomitant MTX is widely used in PsA. The lack of nail disease and X-ray assessments are further limitations of this study. It should also be noted that the recommended dose of adalimumab for patients with plaque psoriasis is an initial dose of 80 mg, followed by 40 mg every other week. Therefore, the use of adalimumab 40 mg throughout the study may have impacted skin outcomes during the first few weeks of the study.

In conclusion, the results of this prespecified analysis of the psoriasis subset of the EXCEED study provides further evidence that IL-17 inhibitors offer a comprehensive biological treatment profile to manage the concomitant features of psoriasis and PsA.[17]

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