The use of Dupilumab and the Development of Drug-induced Sarcoidosis-like Reactions

Dear Editor, Dupilumab is a monoclonal antibody targeting the interleukin-4 receptor (IL-4Rα), inhibiting both IL-4 and IL-13, and is widely used in the treatment of T-helper type 2 (Th2)- driven inflammatory diseases.[1] Approved by the Food and Drug Administration (FDA) for atopic dermatitis, asthma, chronic rhinosinusitis with nasal polyps, eosinophilic esophagitis, and prurigo nodularis, its most common adverse effects include ocular symptoms and injection site reactions. Rare adverse effects have been infrequently reported, such as erythema nodosum and systemic granulomatous syndromes.[1] Drug-induced sarcoidosis-like reactions (DISRs) are systemic granulomatous syndromes that are clinically indistinguishable from sarcoidosis, and are typically associated with the introduction of a new medication.[1] The development of sarcoidosis requires a genetic predisposition and the presence of specific risk factors.[2] The exact immunopathogenesis of sarcoidosis remains unknown, and its diagnosis is based on subjective clinical criteria.[3] DISRs and sarcoidosis share several features, including bilateral hilar adenopathy, cutaneous lesions, uveitis, scar infiltration, non-caseating granulomas, hypercalcemia, and elevated serum angiotensin-converting enzyme levels.[1-3] Symptoms typically manifest within one to three months of drug exposure.[1] A temporal correlation between initiation of a drug known to be associated with DISRs and symptom onset, along with symptom resolution following drug discontinuation, is a key diagnostic criterion.[2] Other drugs implicated in the development of DISRs include etanercept, adalimumab, ipilimumab, nivolumab, and antiretroviral therapy.[3] It is hypothesized that the immunomodulatory effect of dupilumab causes a Th1–Th2 imbalance, promoting granuloma formation and inducing this syndrome.[1,2,5] Treatment for DISRs is not always required, as symptoms may resolve with drug discontinuation. However, in severe cases, corticosteroids or medications commonly used for sarcoidosis are recommended.[2] There are also reports of successful resolution of DISRs without immunosuppressants, as described by Saito et al.[4] This report presents a case of rapid development of an uncommon systemic granulomatous syndrome that occurred twice in the same patient. The events were, temporally associated with dupilumab use. Symptom improvement following drug discontinuation strongly supports the diagnosis of DISRs. This case involves a 48-year-old woman with a diagnosis of severe atopic dermatitis, for which dupilumab (300 mg every 14 days) was prescribed. The medication was initiated in 2022, after which the patient developed pulmonary symptoms, asthenia, and bilateral hilar adenopathy. Following evaluation by a pulmonologist, sarcoidosis was diagnosed. Dupilumab was subsequently discontinued, resulting in symptom improvement and omalizumab was initiated. The patient experienced limited clinical improvement with omalizumab, and in January 2024, she opted to restart dupilumab (300 mg every 14 days) due to the poor response to other available treatments for atopic dermatitis. Three months after the reintroduction of dupilumab, in April 2024, the patient reported dyspnea along with other respiratory symptoms, localized eczemas, and erythema nodosum on the lower limbs, accompanied by fatigue and myalgia [Figures 1 and 2]. She was again referred to a pulmonologist, and a chest computed tomograpgy [Figure 3] scan revealed findings consistent with granulomatous disease, along with elevated inflammatory markers (C-reactive protein: 16.6 mg/L; erythrocyte sedimentation rate: 36 mm/h). Dupilumab was discontinued once more, and methotrexate was initiated. After three months, the patient reported a complete resolution of symptoms related to DISRs [Figure 4].Figure 1: Erythema nodosum on the lower limbsFigure 2: Erythema nodosum on the left footFigure 3: Oval-shaped lesions with faint irregularities of the adjacent parenchyma scattered throughout the lungsFigure 4: Timeline of the case. NRS - Numeric Rating ScaleProving a causal relationship between sarcoidosis and dupilumab remains challenging. However, with increasing use, more cases are emerging, supporting this hypothesis. Therefore, further investigations and validation of the relationship between dupilumab and DISRs are warranted.[5] Declaration of patient consent The authors certify that they have obtained all appropriate patient consent forms. In the form the patient has given her consent for her images and other clinical information to be reported in the journal. The patient understands that her name and initials will not be published and due efforts will be made to conceal her identity, but anonymity cannot be guaranteed. Financial support and sponsorship Nil. Conflicts of interest There are no conflicts of interest. Use of artificial intelligence (AI) The preparation of this manuscript was carried out entirely by the authors without the use of artificial intelligence technologies.