Seeing red with dupilumab
By Warren R. Heymann, MD, FAAD
March 1, 2023
Vol. 5, No. 9
Since its release in 2017, dupilumab (a fully humanized monoclonal antibody that blocks IL-4 and IL-13) has transformed the therapeutic landscape for managing atopic dermatitis (AD) and other eczematous disorders, bullous pemphigoid, Kimura disease, etc. when used off-label. Increasingly, practitioners have observed erythematous eruptions, usually on the head and neck, attributed to the use of dupilumab.
Such rashes were not observed in over 2,100 patients in phase 3 clinical trials of dupilumab. Dalia and Johnson were the first to report the case of a recalcitrant rash on the face and neck of a 26-year-old woman developing 6 months after the initiation of dupilumab therapy. A skin biopsy demonstrated spongiotic dermatitis, attributed to presumed contact dermatitis. Topical therapies (steroids, calcineurin inhibitors, calcipotriene, ivermectin, antifungal agents) and oral medications (prednisone, fluconazole, doxycycline) offered no relief, although she continued use of dupilumab because of her great improvement in other areas. (1)
Common adverse reactions to dupilumab include dupilumab-induced ocular surface disease (manifesting as conjunctivitis, dry or watery eyes, blepharitis, keratitis, eyelid dermatitis, and palpebral edema), headaches, nasopharyngitis, and injection site reactions. (1,2) Since the initial report of facial dermatitis attributed to dupilumab, this adverse reaction has been reported by several names (dupilumab facial redness, persistent facial dermatitis, paradoxical head and neck erythema, others) — I will use term dupilumab-associated erythema (DAE) in this commentary because it encompasses all presentations. DAE has been reported to occur in up to 10% of patients on dupilumab. (3) In my experience this is an overestimation. In a Portuguese study of 169 patients with AD, 9 (4.7%) demonstrated persistent facial erythema. (4)
Jo et al reviewed a total of 101 patients from 16 studies who were reported to have dupilumab-associated facial or neck erythema. Fifty-two of 101 patients (52%) had baseline atopic dermatitis facial or neck involvement and 45 of 101 (45%) reported different cutaneous symptoms from preexisting atopic dermatitis, possibly suggesting a different etiology. Suggested etiologies included rosacea, allergic contact dermatitis, and head and neck dermatitis. The most commonly used treatments included topical corticosteroids, topical calcineurin inhibitors, and antifungal agents. In the 57 patients with data on the course of the adverse events, improvement was observed in 29, clearance in 4, no response in 16, and worsening in 8. A total of 11 of 101 patients (11%) discontinued dupilumab owing to this adverse event. (3)
This commentary will address practical questions regarding DAE:
Is DAE limited to the head and neck? No. Although most cases have been reported on the face and neck. Kim et al reported 3 cases of acral erythema presenting as eczema of the hands and/or feet. A biopsy from one patient demonstrated eczematous changes (spongiosis and acanthosis). (5)
Can DAE be an allergic contact dermatitis? Yes. Suresh and Murase offer the following 3 principles regarding the assessment of a possible allergic contact dermatitis in patients being treated with dupilumab: 1) Patch testing dupilumab candidates before initiation of therapy helps identify potential underlying ACD, thereby decreasing the chances of falsely identifying treatment as failed. 2) Patients can be patch tested on dupilumab; prior positives in previous testing should act as controls whenever possible. 3) Patients with residual facial dermatitis on dupilumab may benefit from further comprehensive patch testing. (6) According to Jo et al: “The pathogenesis of allergic contact dermatitis is thought to involve allergen-dependent elicitation of Th1, Th2, and Th17. It has been proposed that dupilumab-induced interleukin 4 inhibition, resulting in Th1/Th17 polarization, may therefore worsen more Th1-dependent allergen responses while improving Th2-dominant allergen responses. This hypothesis may explain the conflicting reports of increased incidences of facial or neck erythema in patients with allergic contact dermatitis in one study, whereas other studies show improvement of allergic contact dermatitis with dupilumab treatment.” (3)
Is DAE due to flushing? Rarely. Herz et al reported a 19-year-old woman with atopic dermatitis refractory to topical steroids and topical calcineurin inhibitors, who was subsequently treated with dupilumab. Although her eczema improved rapidly, after 16 weeks she reported the onset of an adverse event — drinking alcohol would always cause a facial flush (with lesser involvement of the neck and décolleté) within 3 to 4 minutes. Symptoms would disappear spontaneously after about 30 min. It was recommended that she continue dupilumab and avoid alcohol. (7) Ingelman et al report the case of a 26-year-old woman on dupilumab would develop periorbital and perioral erythema after drinking alcohol. The symptoms would spontaneously resolve in 20 minutes, regardless of continued alcohol intake. Although the pathophysiology of this reaction with dupilumab is an enigma, the authors speculate that dupilumab could modulate the effect of cytochrome P450 2E1, causing a buildup of acetaldehyde and resulting in facial flush. (8)
Are some cases of DAE rosacea? Yes. Heibel et al detailed the case of a 67-year-old woman who developed rosacea 3 months after initiation of dupilumab therapy, which resolved 12-13 days after injection, but would recur with each subsequent dupilumab administration. (9) I coauthored a manuscript describing 2 adolescent boys who developed Demodex folliculitis in the setting of recent dupilumab administration. The postulate is that dupilumab’s inhibition of IL-4 and IL-13 may permit a proliferation of Demodex mite density in these disorders. (10)
Is Malassezia furfur etiologic in DAE? In some cases, probably yes. It has been demonstrated that Malassezia selectively induces Th17-driven inflammation. Thus, dupilumab may allow a fortified Th17 response induced by inhibition of Th2. This correlates with improvement of facial erythema observed in some patients with the use of antifungal agents and the localized involvement of this adverse event to the face and neck. (3). In their study of “dupilumab facial redness,” Gao et al found that 11/16 patients (69%) treated with itraconazole were clear or almost clear. None of the 4 patients treated with fluconazole responded, suggesting that itraconazole’s benefit may be due to its anti-inflammatory properties such as IL-8 inhibition. (11)
Must dupilumab be discontinued in patients with DAE? For the majority of patients, dupilumab may be continued while treating DAE appropriately for its presumed subtype. (12)
DAE is a complicated affair. Dermatologists must determine if the condition is due to a flare of underlying atopic dermatitis, the unmasking of a contact dermatitis, if Malassezia furfur is contributing to the erythema, rule out the possibility of alcohol-induced flushing, and consider if Demodex is contributory. Much remains to be learned about each subtype of DAE. Fortunately, most patients may continue with dupilumab while this adverse reaction is assessed and treated. To date, there have been no reports of tralokinumab (an IL-13 inhibitor)-associated erythema, but I anticipate seeing them before too long.
Point to Remember: Dupilumab may cause a variety of erythematous rashes, usually distributed on the face and neck (referred to in this commentary as dupilumab-associated erythema). Dermatologists have to consider several clinical scenarios before embarking on the appropriate treatment for this adverse reaction. In most cases, dupilumab therapy may be continued.
Our expert’s viewpoint
David Rosmarin, MD, FAAD
Kampen-Norins Scholar & Chair
Department of Dermatology
Indiana University School of Medicine
As Dr. Heymann notes in his commentary, targeted therapies have revolutionized the treatment of dermatological diseases such as dupilumab for atopic dermatitis. Selectivity of medications has led to high levels of efficacy and safety; however, one lesson learned from the use of biologics is that when one arm of the immune system is suppressed, other arms can get activated. Post FDA approval, there are reports of TNF alpha inhibitors (TNFi) associated with new onset or flared vitiligo, alopecia areata, lichen planus, lupus like reactions, and eczematous eruptions. Additionally, despite TNFi being used to treat psoriasis, hidradenitis suppurativa, and granulomatous disease, “paradoxical” psoriasiform reactions, sarcoidosis-like reactions, and hidradenitis suppurativa have been described. These cutaneous eruptions from TNFi are believed to be due to overproduction of type I interferons, from negative feedback on plasmacytoid dendritic cells.
Analogous to the experience of new inflammatory diseases appearing with biologics used for psoriasis, new inflammatory disorders of the skin are also occurring in patients treated with dupilumab. While dupilumab is approved for treating atopic dermatitis, some patients are experiencing DAE. Additionally, despite off-label use of dupilumab for fibrosing conditions and alopecia areata, there are reports of new onset alopecia areata and morphea.
There are several medications targeting the type 2 inflammatory pathway in development. While blocking both anti-IL4 and IL-13 with dupilumab may offer advantages in treating asthma, efficacy is achieved in atopic dermatitis with biologics that only block IL-13 such as tralokinumab and lebrikizumab. It remains to be seen whether the IL-13 only inhibitors will be associated with similar new inflammatory disorders as seen with dupilumab. Regarding the ocular side effects, dupilumab, lebrikizumab, and tralokinumab all have this risk. Similar to the strategy of switching to a different mechanism of action in patients with psoriasis experiencing immunologic side effects, the same approach will likely be successful for patients with atopic dermatitis. Luckily many of the side effects with dupilumab are uncommon, and it remains an appealing option for many suffering with moderate to severe atopic dermatitis.
Dalia Y, Marchese Johnson S. Case report: first reported case of facial rash after dupilumab therapy. Pract Dermatol; 2018 April, 25-26. http://practicaldermatology.com/2018/04/case- report-first-reported-case-of-facial-rash-after-dupilumab-therapy-call-for-abstracts/.
Fachler T, Shreberk-Hassidim R, Molho-Pessach V. Dupilumab-induced ocular surface disease: A systematic review. J Am Acad Dermatol. 2022 Feb;86(2):486-487. doi: 10.1016/j.jaad.2021.09.029. Epub 2021 Sep 21. PMID: 34560194.
Jo CE, Finstad A, Georgakopoulos JR, Piguet V, Yeung J, Drucker AM. Facial and neck erythema associated with dupilumab treatment: A systematic review. J Am Acad Dermatol. 2021 May;84(5):1339-1347. doi: 10.1016/j.jaad.2021.01.012. Epub 2021 Jan 8. PMID: 33428978.
Torres T, Paiva-Lopes MJ, Gonçalo M, Claro C, Oliveira M, Gomes J, Vieira AP, Amoedo P, Alpalhão M, Nogueira M, Santiago F, Henrique M, Amaro C, Esteves T, Alves J, Cerejeira D, Mendes-Bastos P, Pestana M, Ramos L, Rocha J, Carvalho R, Teixeira L, Selores M, Mota A, Filipe P; Portuguese Group of Atopic Dermatitis. Dupilumab for atopic dermatitis: a real-world Portuguese multicenter retrospective study. J Dermatolog Treat. 2022 Jan 31:1-6. doi: 10.1080/09546634.2022.2035309. Epub ahead of print. PMID: 35083945.
Kim YJ, Lee MY, Won CH. Acral erythema arising in patients with atopic dermatitis after dupilumab therapy: A case report of 3 patients. Asia Pac Allergy. 2022 Jan 10;12(1):e1. doi: 10.5415/apallergy.2022.12.e1. PMID: 35174052; PMCID: PMC8819416.
Suresh R, Murase JE. The role of expanded series patch testing in identifying causality of residual facial dermatitis following initiation of dupilumab therapy. JAAD Case Rep. 2018 Oct 3;4(9):899-904. doi: 10.1016/j.jdcr.2018.08.027. PMID: 30306123; PMCID: PMC6172478.
Herz S, Petri M, Sondermann W. New alcohol flushing in a patient with atopic dermatitis under therapy with dupilumab. Dermatol Ther. 2019 Jan;32(1):e12762. doi: 10.1111/dth.12762. Epub 2018 Oct 21. PMID: 30288874.
Igelman SJ, Na C, Simpson EL. Alcohol-induced facial flushing in a patient with atopic dermatitis treated with dupilumab. JAAD Case Rep. 2020 Jan 25;6(2):139-140. doi: 10.1016/j.jdcr.2019.12.002. PMID: 32021896; PMCID: PMC6994276.
Heibel HD, Hendricks AJ, Foshee JP, Shi VY. Rosacea associated with dupilumab therapy. J Dermatolog Treat. 2021 Feb;32(1):114-116. doi: 10.1080/09546634.2019.1624683. Epub 2019 Jun 9. PMID: 31132923.
Krakowski AC, Senft SC, Heymann WR. Demodex Folliculitis and Recent Dupilumab Administration. Pediatrics. 2021 May;147(5):e2020029520. doi: 10.1542/peds.2020-029520. PMID: 33879520.
Gao DX, Song S, Kahn JS, Cohen SR, Fiumara K, Dumont N, Rosmarin D. Treatment of patients experiencing dupilumab facial redness with itraconazole and fluconazole: A single-institutional, retrospective medical record review. J Am Acad Dermatol. 2022 Apr;86(4):938-940. doi: 10.1016/j.jaad.2021.03.070. Epub 2021 Mar 26. PMID: 33775718.
Narla S, Silverberg JI, Simpson EL. Management of inadequate response and adverse effects to dupilumab in atopic dermatitis. J Am Acad Dermatol. 2022 Mar;86(3):628-636. doi: 10.1016/j.jaad.2021.06.017. Epub 2021 Jun 11. PMID: 34126094.
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