Ab0573 dupilumab-Induced Enthesitis/Arthritis in Patients With Atopic Dermatitis: A Retrospective Observational Study

Abstract

Background:Atopic dermatitis (AD) is a common skin condition with a prevalence of 2–10% in adults1. IL-4 and IL-13 play a key role in the pathogenesis. Dupilumab, a human IgG4 monoclonal antibody binding the alpha subunit of the IL-4 receptor, blocking IL-4 and IL-13 signaling, has important efficacy in this difficult to treat disease. We first reported a musculoskeletal (MSK) adverse effect of enthesis/arthritis developing in 3 patients in 20192.Objectives:To report the ongoing experience at our centre of this new clinical paradigm, incidence and patient progress including clinical presentation, imaging and management.Methods:Clinical and radiological data was collected from electronic case records of all cases presenting with features of enthesitis/arthritis between October 2018 and January 2021.Results:Since initiation of dupilumab at GSTT, approximately 400 adults with moderate-to-severe AD have received at least one dose. Of these, 23 patients (14 men, 9 women) had the clinical syndrome of inflammatory enthesitis/tenosynovitis/arthritis. Nine patients had both enthesitis and arthritis, 10 enthesitis, 3 enthesitis and tenosynovitis and 1 arthritis only. Four of these also reported new onset inflammatory back pain symptoms. None had a preceding history of arthritis or enthesitis. Median onset of symptoms following initiation of dupilumab was 4 months. However, onset of symptoms ranged between 2 weeks and 48 months. Imaging (US/MRI) was performed in 18 patients, 11 with Doppler US positive enthesitis confirming clinical findings. Most common sites were lateral epicondyles, achilles and patella tendons. Two patients with more disabling symptoms had MRI confirmed gluteus medius and hamstring enthesitis and arthritis. Spine and SI joint MRI in 4 patients was negative. Most patients had normal inflammatory markers except 2; CRP 117, ESR 96 and CRP 13, ESR 10. All patients had very good AD response to dupilumab, average EASI score before and after Dupilumab was 21 and 4.2 respectively. One patient developed skin manifestations of guttate psoriasis, with subsequent disabling arthritis/enthesitis. Due to the life-changing beneficial effect of dupilumab therapy most patients did not want to stop therapy. We used NSAID therapy, etoricoxib/celecoxib/naproxen for symptom relief which was usually partly effective allowing continuation of dupilumab treatment in most. Five patients with severe MSK symptoms stopped Dupilumab completely. Some patients temporarily paused therapy but re-started as their AD became worse, often changing from the usual 2 weekly to 4 weekly dosing. Most patients continuing dupilumab had persistent MSK symptoms. Four patients who stopped dupilumab were treated with baricitinib, which has potential efficacy for both MSK symptoms and AD. Two did not tolerate it and remained on NSAID therapy.Conclusion:These data further characterize a new syndrome of enthesitis and/or arthritis induced by Dupilumab. In those with mild MSK symptoms use of NSAIDs allows continuation of full-dose dupilumab, in moderate cases reducing dupilumab dose frequency plus NSAID therapy maintains function. Most patients had on-going MSK symptoms. In more severe cases JAKi therapy may be an effective strategy. Our initial hypothesis that inhibition of IL-4/13 by dupilumab triggers an IL-17/23/TNF-mediated inflammatory MSK syndrome in some patients is supported by a recent in vitro study3.References:[1]Beck L et al. Dupilumab Treatment in Adults with Moderate-to-Severe Atopic Dermatitis. July 10, 2014. N Engl J Med 2014; 371:130-139[2]Willsmore ZN et al. Development of inflammatory arthritis and enthesitis in patients on dupilumab: a case series. Br J Dermatol 2019; 0. doi:10.1111/bjd.18031.[3]Bridegwood C et al. Regulation of entheseal IL-23 expression by IL-4 and IL-13 as an explanation for arthropathy development under dupilumab therapy. Rheumatology (Oxford). 2020 Nov 30:keaa568. doi: 10.1093/rheumatology/keaa568Disclosure of Interests:Joseph Nathan: None declared., Catherine Hughes Speakers bureau: Presented for Abbvie, Samir Patel: None declared., Libin Mathew: None declared., Catherine Smith Grant/research support from: Grants/research support; Professor Smith is a PI/CoPI on a number of commercially supported studie (Abbvie, Janssen, Leo, Sanofi)., Andrew Pink Paid instructor for: Speaker or advisor to Lilly, Abbvie, Sanofi, Leo, Almirall, Novartis, Janssen, UCB, Galderma, BMS, La-Roche Posay, Richard Woolf: None declared., Bina Menon Speakers bureau: Presented for Abbvie, L Bruce Kirkham Grant/research support from: Professor Kirkham has received honoraria and/or research funding from AbbVie, Eli Lilly, Gilead, Janssen, Novartis, Pfizer and UCB.

Review of dupilumab-associated inflammatory arthritis: An approach to clinical analysis and management

“…Its frequency in patients starting dupilumab for atopic dermatitis is unknown, but in the single retrospective observational study reported, almost 5% of patients treated with dupilumab for atopic dermatitis were at least minimally affected by inflammatory arthritis. 3 , 4 However, based on the small number of case reports in the literature and our own clinical experience, we suspect that either the frequency reported by Nathan et al 3 was spuriously elevated or that the vast majority of cases are mild enough that they go unrecognized and do not require specific therapy or discontinuation of dupilumab. Cessation of dupilumab appears to reliably resolve the arthritis, 3 , 5 although severe cases may take 6 months to a year after discontinuation to resolve.…”

“… 3 , 4 However, based on the small number of case reports in the literature and our own clinical experience, we suspect that either the frequency reported by Nathan et al 3 was spuriously elevated or that the vast majority of cases are mild enough that they go unrecognized and do not require specific therapy or discontinuation of dupilumab. Cessation of dupilumab appears to reliably resolve the arthritis, 3 , 5 although severe cases may take 6 months to a year after discontinuation to resolve.…”

“…Joint pain generally occurred relatively early after the initiation of dupilumab therapy. Although a few cases presented many months after the initiation of therapy, most occurred in 4 months or less 3 , 4 , 8 ; some even began immediately after the first injection. Once the inflammatory arthritis was identified, it appeared that patients could be stratified based on the number of joints and the severity of the pain.…”

“… 2 , 5 The initial severity of pain also differed between the cases, and it appeared that the majority fell into the mild-to-moderate range that minimally affected daily function without complete debilitation. 3 …”

“…The initial severity of the pain appears to be predictive of the overall severity, as patients who originally had mild symptoms were generally able to continue dupilumab without significant worsening. 3 , 9 Meanwhile, those with moderate or severe pain at onset were more likely to discontinue dupilumab. 3 Many cases showed that the joint symptoms in mild and some moderate cases could be managed well with nonsteroidal anti-inflammatory drugs, and the clinical benefit from dupilumab outweighed any lingering inflammatory arthritis, according to the patients.…”