Dupilumab’s growing pains

By Warren R. Heymann, MD
January 8, 2020
Vol. 2, No. 1

Dupilumab has been a valuable addition to dermatologists’ therapeutic palette in managing atopic dermatitis (AD). The biologic agent was released in 2017, indicated for moderate to severe AD, and is now approved for patients who are at least 12 years old. I suspect that most clinicians would agree that when AD cannot be adequately controlled with topical agents (steroids, calcineurin inhibitors, or phosphodiesterase inhibitors) or phototherapy, dupilimab is the systemic treatment of choice, supplanting methotrexate, cyclosporine, or mycophenolate mofetil. Other agents, not yet approved or available for AD, include JAK inhibitors, anti-IL13 inhibitors (lebrikizumab, tralokinumab), PDE4 inhibitors (apremilast), and the anti-pruritic anti IL-31 agent (nemolizumab). (1)

Dupilumab is a fully human monoclonal antibody that reduces TH2 inflammation by blocking the shared receptor subunit for interleukin (IL)-4 and IL-13, thereby inhibiting signaling of both cytokines. The diminished quality of life (QoL) in AD, combined with its societal economic burden, drives the impetus for refined therapeutic options. Dupilumab has greatly improved QoL for many afflicted AD patients. In a randomized phase 3 clinical trial including 251 adolescents (mean age 14.5 years) with moderate to severe atopic dermatitis, Simpson et al demonstrated that dupilumab 200 or 300 mg every 2 weeks and 300 mg every 4 weeks resulted in a significant treatment response vs placebo following 16-week treatment, with an acceptable safety profile. (2) This study supports the use of dupilumab in adolescents, just as prior reports confirm its efficacy in adults.

As dupilumab has been such a successful agent for AD, it is no surprise that it has been used effectively for a large number of previously recalcitrant dermatoses. In their systematic review of 33 reports of dupilumab use in non-AD dermatologic conditions, Hendricks et al identified effective use of dupilumab in case reports and case series for the following entities: chronic pruritus, prurigo nodularis, eczematous eruption of aging, allergic contact dermatitis, chronic hand eczema, alopecia areata, urticaria, eosinophilic annular erythema, bullous pemphigoid and papuloerythroderma of Ofuji. The authors report that clinical trials are underway evaluating the efficacy of dupilumab in allergic contact dermatitis, chronic hand eczema, alopecia areata, chronic spontaneous urticaria, and cholinergic urticaria. (3)

One of the realms of active research in AD focuses on its associations and comorbidities. While dermatologists are familiar with the increased risk of asthma, vitiligo, and alopecia areata, recent studies suggest that patients with AD may be at an increased risk of inflammatory bowel disease and rheumatoid arthritis.(4) Severely affected patients with AD may have one or more components of the metabolic syndrome (obesity, diabetes, hypertension, or dyslipidemia). (5)

Dupilumab is remarkably well-tolerated, with injection site reactions, conjunctivitis, or oral herpes infections being among the most frequent adverse reactions. My inspiration for this commentary is a 55-year-old woman with life-long AD, who had failed multiple immunosuppressive agents but responded splendidly to dupilumab. At a recent visit, she stated that multiple joints had become painful, especially her thumbs, for a few months (she had been on dupilumab for about 1.5 years at the onset of her arthritic symptoms). Her questions were direct — “Is this due to dupilumab? Should I stop the medication?” A rheumatological consultation was obtained. There was no serologic evidence for lupus or rheumatoid arthritis; her imaging studies were consistent with osteoarthritis. Dupilumab could not be ruled out as an aggravating factor. For the time being, naproxen will be utilized, followed by methotrexate (should the naproxen prove ineffective), while continuing dupilumab. Should she not improve after those interventions, dupilumab will then be discontinued.

Reports of inflammatory arthritis and enthesitis in patients on dupilumab are starting to appear. deWijs et al detailed a 38- year-old woman who developed severe joint pain and morning stiffness in one ankle, followed by symptoms of her knees, hips, and elbows, starting within days of her first dupilumab injection. Within a month, her skin improved, however the dupilumab was discontinued. Other causes of arthritis were ruled out. The arthritis and arthralgias resolved with prednisolone and celecoxib; a subsequent flare of her AD was controlled with methotrexate. (6) Willsmore et al described 3 cases of inflammatory arthritis and enthesitis:

1) A 40-year-old man developed generalized joint pains and morning stiffness commencing with 16 weeks of dupilumab use, resulting in a progressive decline in mobility. His autoimmune work-up was negative. Dupilumab was discontinued and naproxen administered; four months later, his mobility remained poor.

2) A 48-year-old man developed bilateral Achilles tendinopathy and left thumb tenderness after 6 weeks of dupilumab. Dupilumab was continued, with partial improvement of his rheumatological complaints as of 24 weeks after the onset of symptoms.

3) A 68-year-old woman developed generalized arthralgias 6 weeks after starting dupilumab. At week 12, while still on dupilumab, ultrasound examination demonstrated bilateral lateral epicondylitis. She remained symptomatic 15 weeks following dupilumab discontinuation.

The etiology of dupilumab-induced arthropathy/enthesitis/tendinopathy remains to be defined. The authors 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.” (7)

It is premature to reach any conclusions about dupilumab-induced adverse rheumatologic effects. Inevitably, with escalating growth in the use of dupilumab for AD and other indications, more adverse reactions will be reported. Every effort should be made to learn from them — clinically and biologically.

Point to Remember: Dupilumab may possibly induce various forms of arthropathy/enthesitis/tendinopathy. The pathomechanism(s) of this adverse event and management strategies remain to be determined. Some patients may require discontinuation of dupilumab, or other agents, such as methotrexate or NSAIDs may be utilized simultaneously.

Our Expert’s Viewpoint

Bryan Anderson, MD
Professor of Dermatology
Penn State Health

The development of dupilumab for the treatment of atopic dermatitis has dramatically changed the outlook for individuals suffering from moderate to severe disease. Dupilumab has become my treatment of choice for individuals who have not been adequately controlled with topical agents and/or phototherapy. Its efficacy and safety profile are very palatable (conjunctivitis, herpes simplex, and injection site reactions have been well documented), especially when comparing with other systemic medications such as methotrexate or cyclosporine. The medication works by blocking the receptor subunit for IL-4 and IL-13 thus reducing Th2 inflammation. Reports of inflammatory arthritis in individuals taking dupilumab are popping up, leading physicians to try to determine if the arthritis is induced in some patients by dupilumab. A plausible pathomechanism that has been proposed is that by down regulating IL-4 and IL -13, an enhancement of IL-17 occurs. Enhanced Il-17 has been seen in various inflammatory arthritides. While the jury is still out on its causality, we need to be vigilant and aware of this potential issue.

As with any new medication that comes to market, the side effect that concerns me the most is the one I am not aware of. It will require patients and physicians alike to be on the lookout for rare side effects and report them to the FDA’s MedWatch. This post-marketing surveillance will allow us to better assess these potential side effects and ultimately better take care of our patients. At this point in time stating that there is a link between dupilumab use and inflammatory arthritis is premature. We however need to be vigilant and ask our patients about this possible issue. Ultimately, we owe it to our patients to be on the lookout for them.

1. Hajar T, Gontijo JRV, Hanifin JM. New and developing therapies for atopic dermatitis. An Bras Dermatol 2018; 93: 104-107.

2. Simpson EL. Paller AS, Siegfried EC, Boguniewicz M, et al. Efficacy and safety of dupilumab in adolescents with uncontrolled moderate to severe atopic dermatitis: A phase 3 randomized clinical trial. JAMA Dermatol 2019 Nov 8 [Epub ahead of print].

3. Hendricks AJ, Yosipovitch G, Shi VY. Dupilumab use in dermatologic conditions beyond atopic dermatitis – a systematic review. J Dermatolog Treat 2019; 12: 1-10.

4. Schmitt J, Schwarz K, Baurecht H, Hotze M, et al. Atopic dermatitis is associated with an increased risk for rheumatoid arthritis and inflammatory bowel disease, and a decreased risk for type 1 diabetes. J Allergy Clin Immunol 2016; 137: 130-136.

5. Shalom G, Dreiher J, Kridin K, Horev A, et al. Atopic dermatitis and the metabolic syndrome: A cross-sectional study of 116 816 patients. J Eur Acad Dermatol Venereol 2019; 1762-1767.

6. deWijs LE, der Waa JD, deJong PH, Hijnen DJ. Acute arthritis and arthralgia as an adverse drug reaction to dupilumab. Clin Exp Dermatol 2019 Jul 19 [Epub ahead of print].

7. Willsmore ZN, Woolf RT, Hughes C, Menon B, et al. Development of inflammatory arthritis and enthesitis in patients on dupilumab: A case series. Br J Dermatol 181: 1068-1070.