Development of inflammatory arthritis and enthesitis in patients on dupilumab: a case series

Dear Editor, Dupilumab (Dupixent®; Sanofi Biotechnology, Paris, France), a fully human monoclonal antibody that blocks interleukin (IL)‐4 and IL‐13 signalling, is the first biologic approved in the U.K. for adult patients with moderate‐to‐severe atopic dermatitis (AD). In phase III studies, dupilumab was an effective treatment with 44–51% of patients achieving at least 75% improvement in Eczema Area and Severity Index (EASI).1 2 To date, dupilumab has been well tolerated; common adverse reactions reported from phase III data include injection‐site reactions (8–19%), allergic conjunctivitis (3–19%) and oral herpes (2–5%).1 2 We report three cases of new‐onset seronegative arthropathy and enthesitis that developed within 16 weeks of starting dupilumab. Patient 1, our index case was a 40‐year‐old man with severe AD who presented with generalized joint pain and morning stiffness 16 weeks after commencing dupilumab. This resulted in a progressive decline in mobility, requiring him to use crutches whereas he had been mobilizing independently prior to treatment. He had no history of joint disease, but his mother had rheumatoid arthritis. He had previously failed multiple systemic therapies (methotrexate, azathioprine, ciclosporin and mycophenolate mofetil). On dupilumab his AD had cleared (baseline EASI 36, week 12 EASI 0) with associated improvement of itch and Dermatology Life Quality Index (reduced from 26/30 to 2/30). Rheumatology examination revealed a reduced range of movement of knees, ankles and right shoulder, swelling of the small joints of the hands and wrists, and enthesitis affecting the knees and Achilles tendons, consistent with an inflammatory arthropathy and enthesitis. Blood parameters were normal, including inflammatory markers (erythrocyte sedimentation rate, C‐reactive protein), creatine kinase (CK) and negative autoimmune serology. Ultrasound (US) confirmed synovitis of both wrists and a right wrist effusion. Magnetic resonance imaging of the knees, ankles and feet did not demonstrate inflammation. Sixteen weeks after discontinuation of dupilumab and initiation of naproxen, symptoms had only mildly improved and mobility remained poor. We present two further cases with striking clinical similarities (Table 1). Summary of patient characteristics EASI, Eczema Area and Severity Index; MRI, magnetic resonance imaging; N, normal; N/A, not applicable; US, ultrasound. Summary of patient characteristics EASI, Eczema Area and Severity Index; MRI, magnetic resonance imaging; N, normal; N/A, not applicable; US, ultrasound. Patient 2, a 48‐year‐old man, developed bilateral Achilles and left thumb tenderness at week 6 of dupilumab treatment, progressing to pain and stiffness affecting the ankles, knees, left wrist and metacarpophalangeal (MCP) joints by week 8. Rheumatology examination revealed bilateral Achilles tendon, wrist and MCP joint tenderness. US scan showed low‐grade mid‐portion left Achilles peritendonitis, with magnetic resonance imaging showing mid‐portion Achilles tendinopathy. He continues to take dupilumab with partial improvement of rheumatological symptoms on celecoxib 24 weeks after onset. Patient 3, a 68‐year‐old woman, developed generalized arthralgia 6 weeks after starting dupilumab. Rheumatological examination after 12 weeks of treatment revealed multiple. symmetrical tender entheseal points throughout her body. US scan showed bilateral lateral epicondylitis. She remained symptomatic 15 weeks following discontinuation of dupilumab. Patients 3 and 3 both had severe AD that responded to dupilumab with almost complete skin clearance (Table 1). Inflammatory markers and CK were normal, with negative autoimmune serology in both cases. We present an unreported potential association between dupilumab and new‐onset seronegative arthropathy and enthesitis/tendinopathy, occurring within 16 weeks of dupilumab initiation with associated radiological changes (Table 1). To date, dupilumab has been well tolerated with low rates of either serious adverse events (AEs) or treatment discontinuation due to AEs. The Summary of Product Characteristics for dupilumab makes no reference to arthritis or joint pain in the undesirable effects.3 Arthralgia was reported in phase III studies (0·8–4·5%) but the incidence was equivalent to placebo groups.1 2 A meta‐analysis of AEs reported back pain as lower with dupilumab vs. placebo, while musculoskeletal pain was numerically lower in the dupilumab group but did not achieve significance (P = 0·27).4 Despite this, the Dupixent® patient information leaflet includes arthralgia as a potential AE. The aetiology of the arthropathy/enthesitis/tendinopathy seen in our patients is uncertain. Dupilumab blocks IL‐4 and IL‐13 signalling by binding the alpha subunit of the IL‐4 receptor. These cytokines are predominantly produced by type 2 helper T (Th2) lymphocytes and are central to the pathogenesis of AD. IL‐4 and IL‐13 have also been reported to inhibit cartilage damage and bone destruction in animal models of inflammatory arthritis.5 6 The counter‐regulation between Th2 and Th1 (defined by interferon production) immune responses is well described. Recently IL‐4 and IL‐13 were reported to selectively suppress IL‐23 production with reduced Th17 function.7 Although not a consistent finding, IL‐4 and IL‐13 have been found in synovial fluid in early seropositive arthritis.8 We hypothesize that in certain highly atopic individuals dupilumab, by inhibiting IL‐4 and IL‐13, may enhance an IL‐17‐mediated peripheral spondyloarthritis/psoriatic arthritis pattern of inflammatory arthritis/enthesitis. Further evaluation is needed to establish a causal link and to understand the pathogenesis. Post‐marketing pharmacovigilance remains of crucial importance with newly approved medications such as dupilumab. The development of eczema registries, such as the U.K.–Irish Atopic Eczema Systemic Therapy Register (A‐STAR), will facilitate the reporting of rare adverse drug reactions and should include arthritis/enthesitis as an event of special interest. Funding sources: none. Conflicts of interest: none to declare. Z.N.W. and R.T.W contributed equally to this paper.