番茄社区

Following the pivotal manuscript that outlined unique disease features half a century ago, investigators in the field of psoriatic arthritis (PsA) have extrapolated clinical trial data and molecular insights from the more expansive experience in rheumatoid arthritis (RA). As a result, many of the diagnostic approaches, imaging modalities, therapeutics and outcome measures paralleled (and at times became identical to) those developed for RA. This paradigm was reinforced twenty years ago when TNF inhibitors (TNFi) significantly improved signs and symptoms of not only RA but also PsA and psoriasis. However, and as practitioners familiarized themselves with its diagnosis and management, it became apparent that PsA was highly varied in presentation and clinical course. This heterogeneity and complexity are largely due to the interaction of multiple different tissue pathologies, orchestrated by an array of immune cells and molecular mediators (beyond TNF) not directly involved in RA pathogenesis.

The revelation that psoriatic disease pathogenesis is orchestrated by the IL-23/IL-17 axis, coupled with the domain approach to diagnostics and therapeutics, established PsA as markedly distinct from RA1. Nonetheless, the therapeutic landscape and management strategies for both diseases remain remarkably analogous to this date.

The arrival of monoclonal antibodies targeting IL-23 and IL-17 marked a transformative era characterized by extraordinary improvement in outcomes for cutaneous psoriasis. Musculoskeletal responses in PsA to these same biologic therapies, however, did not significantly advance when compared to the ACR composite outcomes reported in the first PsA TNFi trial in 2001. Indeed, 12 agents (TNFi: etanercept, adalimumab, infliximab, golimumab, certolizumab; IL-17i: secukinumab, ixekizumab; IL12/23i: ustekinumab; IL-23i: guselkumab; PDE4i: apremilast; CTLA4-Ig: abatacept; JAKi: tofacitinib) with remarkably similar levels of efficacy are currently approved by the FDA for treatment of PsA. Importantly, and although still the benchmark for regulatory approval, ACR20 as primary endpoint is known to be clinically inadequate for most PsA patients. Moreover, measures that resemble a state of low disease activity or remission, such as minimal disease activity (MDA), are achieved by a relatively small proportion of PsA patients, irrespective of the therapeutic agent.

Taken together, these findings underscore the concept that multiple diverse pathways, cell types and cytokines promote and sustain synovio-enthesial disease that demand new and fundamentally different treatment methodologies to achieve the depth of responses observed in psoriasis.

Read an interview with the first study author here and expert commentary on the clinical implications here.