Induction of remission in biologic-naive, severe psoriasis and PsA with dual anti-cytokine combination

• Dual biologic strategies may be needed in order to achieve clinical remission in all domains of psoriatic arthritis. Dear Editor, PsA is a complex and heterogeneous immune-mediated inflammatory arthritis occurring in up to 30% of patients with psoriasis [1]. Despite the significant advances in psoriasis therapeutics, in which targeted biologics often lead to skin clearance (or almost clearance), achieving similar rates of low disease activity in PsA using the same approaches is infrequent. Here we describe, for the first time, the case of a biologic-naïve patient with severe psoriasis and PsA who achieved remission in all clinical domains with a combination of two anti-cytokine drugs. In December 2018, a 27-year-old female with an eight-year history of psoriasis and four-year history of PsA presented to the NYU Psoriatic Arthritis Centre with active skin, joint and enthesial disease. She had previously been treated with topical agents, NSAIDs, and a brief course of SSZ, without any significant improvement in her skin or joints, and had been off any treatment for over a year by the time she first consulted our centre. Physical examination revealed extensive plaque psoriasis involving her arms, legs, trunk, scalp and buttocks area and covering 30% of her body surface area (BSA) (Fig. 1A). Nail psoriasis was present in most of her finger- and toenails. A musculoskeletal examination was significant for six tender joints, four swollen joints, and two areas of enthesitis. Her CRP was 18.3 mg/l (normal <5) and ESR was 45 mm/h (normal <20). Imaging studies showed bilateral sacroiliitis. Adalimumab was initiated in January 2019, and after 3 months of treatment, she had zero tender or swollen joints and no areas of active enthesitis; her inflammatory markers also improved (CRP 9.0 mg/l and ESR 22 mm/h). However, her skin condition remained active (BSA 20%). Both a weekly adalimumab regimen and the addition of MTX were attempted, without further skin response. After an extensive discussion with the patient, the decision was made to add ustekinumab to her baseline adalimumab 40 mg every 2 weeks to address her continued and debilitating skin involvement while maintaining her musculoskeletal remission state. She received one dose of ustekinumab 45 mg in June of 2019 and had improvement in her BSA (10%) by November 2019 (Fig. 1B). She then received a second dose of ustekinumab 45 mg in January 2020, achieving almost full clearance by September 2020 (Fig. 1C). Her joints and entheses remained without any signs or symptoms of inflammation throughout treatment. The patient tolerated the medication well without any adverse effects, even when she had symptoms consistent with Covid-19 during March of 2020, manifested by three days of fever and cough that resolved without any intervention. Left upper arm psoriasis over the course of treatment (A) June 2019 prior to first ustekinumab injection. (B) January 2020 prior to the second ustekinumab injection. (C) September 2020, after two injections of ustekinumab. Extraordinary advances in therapeutics for psoriasis have led to dramatic clinical responses in a significant proportion of patients. These accomplishments, however, are yet to be met in PsA, for which none of these novel targets have demonstrated superiority over established pathway-specific treatments (i.e. TNF blockers). In fact, only about half of the patients with PsA treated with currently available biologics experience a clinically meaningful improvement. Multiple strategies have been attempted to improve PsA outcomes, including earlier aggressive treatment and inhibition of new molecules [2]. However, given the complex and heterogeneous nature of tissue involvement in PsA, it seems biologically implausible that modulating individual pathways will suffice for the induction of deep, enduring clinical responses in all phenotypic domains (i.e. skin, synovium, entheses and axial). In rheumatology, dual therapy with MTX and TNF blockade has been the backbone of treatment in RA [3]. However, recent similar studies in PsA showed no benefit in synovio–entheseal outcomes when adding MTX to etanercept [4] or adalimumab [5]. Dual biologic strategies, and specifically anti-TNF with ustekinumab, have previously been used for the treatment of PsA. Yet, all cases reported in the literature were in patients with long-lasting, recalcitrant disease and following failure of multiple prior regimens [6]. Not unexpectedly, many of them also developed infections. To our knowledge, ours is the first reported case of severe PsA remission in a biologic-naïve patient using a dual anti-cytokine regimen who is yet to report an adverse event. A comparable approach to combination therapy was studied in clinical trials of PsA using bispecific antibodies (e.g. ABT-122, an anti-TNF and anti-IL-17 construct) [7], which showed comparable efficacy (and even higher in some outcomes) with a similar safety profile. In line with the approach used for our patient, there are ongoing efforts to pursue combinatorial strategies early in the disease process so deep remission in PsA can be achieved (an approach already being explored in IBD in the VEGA trial [8]. The timing, sequence and frequency of such strategies are yet to be determined, but potentially include the synchronous use of two different biologics at lower doses; the combination of oral small molecules (i.e. JAKi) with anti-cytokine biologics; or the administration of two different biologics in an asynchronous fashion, perhaps after an initial combination loading strategy. Funding: Funding comes from the Beatrice Snyder Foundation, the Riley Family Foundation, Bloomberg Philanthropies, and the National Psoriasis Foundation. Disclosure statement: R.