- Indian Rheumatology association
Ashish Jacob Mathew DNB, DM
Professor, Department of Rheumatology, Christian Medical College, Vellore
Psoriatic disease is a multifaceted condition with varying degrees of activity, responding differentially to medications across clinical domains. The last two decades have witnessed a plethora of novel targeted therapies being effectively studied for this disease. The choice of a therapeutic agent depends on multiple factors, including comorbidities, extra-musculoskeletal manifestations, and concomitant chronic diseases.
Conventional disease-modifying anti-rheumatic drugs (cDMARDs) have a role in the treatment of clinical domains like peripheral arthritis, enthesitis, and dactylitis. Nevertheless, they fall short in comparison to targeted therapies in achieving minimal disease activity states in a significant proportion of patients. Tumour necrosis factor inhibitors (TNFi) have stood the test of time for the treatment of Psoriatic arthritis (PsA) across domains, with outstanding cardiovascular outcomes. The advent of newer molecules targeting the IL-23/Th17 axis has aided excellent outcomes in extra-articular domains. Two head-to-head trials of TNFi and IL-17i (ixekizumab and secukinumab) have demonstrated comparable efficacy of both molecules in joint disease, with significantly superior effects of IL-17i for the skin.
Bimekizumab (dual blockage of IL-17A and IL-17F) was recently approved by the EMA for use in PsA. IL-23 inhibitors (guselkumab, risankizumab, and tildrakizumab) seem to signal a differential outcome in the axial disease domain in patients with PsA and axial spondyloarthritis. Janus kinase inhibitors (JAKi) and TYK-2i have transformed the therapeutic space in PsA, with many newer molecules on the anvil. They seem to be comparable to TNFi in their efficacy, though plagued with the black box warning of major adverse cardiovascular events and thrombosis. The TYK2 inhibitor, deucravacitinib is currently undergoing phase III clinical trials.
Considering the differential effects on domains, combination targeted therapies are undergoing phase II and III trials currently. Brepocitinib, a JAK1 and TYK2 inhibitor, has shown good efficacy in phase IIb trials across the domains. The phase IIa AFFINITY trial [a combination of guselkumab (IL23i) and golimumab (TNFi)] is underway. Nanobody cytokine blockers are the latest molecules being studied in PsA. These molecules presumably have better tissue penetration, which may yield better outcomes in enthesitis and dactylitis. A trivalent nanobody molecule specific to IL-17A and IL-17F, sonelokimab, is currently undergoing phase IIb development in PsA. Izokibep, an IL-17Ai nanobody molecule, demonstrated resolution of enthesitis, as determined by the Leeds enthesitis index, in 88% of patients with PsA at week 16. Inhibition of other targets like GM-CSF is in the pipeline for PsA.
Even with all these developments, about 30–40% of patients remain non-responders to multiple treatments. The choice of an appropriate therapeutic agent and the ability to predict response to treatment remain the two key unmet needs in PsA. Multidisciplinary models of care, including rheumatologists, dermatologists, gastroenterologists, and allied health staff, will allow early referrals, better comorbidity management, and escalation of therapy. Personalized medicine directed by deep phenotyping of disease, multi-omics biomarkers, and imaging will enable stratification of the choice of targeted therapies based on the domains affected and comorbidities.
