LAUSR

Dear Editor, Tumor necrosis factor-alpha (TNF-α) inhibitors and interleukin-17 (IL17) inhibitors are widely used biologic agents in the treatment of several dermatologic and rheumatologic disorders including psoriasis (PsO), psoriatic arthritis, hidradenitis suppurativa (HS), and ankylosing spondylitis. Even though biologic agents have a good overall safety profile, various immune-mediated cutaneous adverse events with these agents have been reported. Herein, we would like to report two patients who developed leukocytoclastic vasculitis (LCV) under certolizumab pegol and secukinumab treatment, respectively. The first case is a 56-year-old man with a history of chronic heart failure, Type 2 diabetes mellitus, and Hurley Stage 3 HS. He consulted us due to the emergence of violaceous/dark red pustular lesions and palpable purpura on both lower legs within 2 days. For HS, he was started on adalimumab in October 2019 but due to primary inefficiency, it was switched to secukinumab in June 2020. By the time he developed the purpuric rash, he was in the second month of secukinumab. Dermatologic examination revealed palpable purpuric papules and pustules on lower extremities (Figure S1). He did not have any history of recent infection or drug administration other than secukinumab. Skin biopsy revealed findings compatible with LCV (Figure S2). Direct immunofluorescence (DIF) analysis showed only C3 deposition within capillary walls. Laboratory analyses revealed only high C-reactive protein level along with low C4 level. No systemic involvement was revealed. Secukinumab was stopped and regression of the purpuric lesions was noted after topical corticosteroid application. The second case is a 27-year-old woman who had spondyloarthritis (SpA). She was referred to our dermatology unit due to non-blanching, palpable macules and papules on both lower extremities. She was diagnosed with SpA 7 years ago; subcutaneous adalimumab was initiated as the initial biologic agent in November 2017 but it was switched to subcutaneous certolizumab pegol due to secondary inefficiency in July 2019. In the 7 months of certolizumab treatment, she developed purpuric lesions on both extremities. Skin biopsy revealed findings compatible with LCV (Figure S3). DIF analysis showed IgA and C3 deposition within the vessel walls. She was prescribed topical methylprednisolone cream. Blood work-up was normal and urinary analysis showed 15 red blood cells per high-power field (normal count: 0–3), 1+ proteinuria with normal leukocyte count. The patient was diagnosed with certolizumab-induced Henoch– Schonlein purpura. Certolizumab was switched to etanercept and cutaneous lesions resolved without any systemic treatment. Continuous follow-up was recommended for microscopic hematuria and proteinuria by nephrology department. Various inflammatory symptoms and conditions that can be both treated and triggered with the same cytokine-targeted biologic agent are defined as paradoxical reaction. Paradoxical development of PsO, cutaneous vasculitis, lichen planus, and HS with biologics have been reported so far. A French nationwide survey by Saint Marcoux et al. identified 39 cases of vasculitis during TNF-α inhibitor treatment. Even though the exact mechanism is not clear, TNF-α inhibitors might induce Type 3 hypersensitivity reactions within capillaries via formation of immune complexes consisting of anti-TNF-α and TNF-α. There are a few cases of LCV associated with certolizumab or secukinumab in the literature (Table 1). Similar to our patients, LCV cases associated with various biologic agents were reported to have TNF-α inhibitor treatment previously which was switched due to inefficiency. Therefore, we believe that previous administration of TNF-α inhibitors may possibly be considered as a risk factor to develop LCV under subsequent biologic agent administration. The use of TNF-α inhibitors might have resulted in antidrug antibody formation which can contribute to LCV development. Although it is not always straightforward to associate LCV development with TNF-α or IL-17 inhibitor treatment, considerable features that raise the possibility of causal relationship between biologic agents and vasculitis are short time interval between the onset of LCV and drug administration and good response to drug withdrawal. Finally, it should be kept in mind that patients under biologic treatment are prone to develop various cutaneous adverse events; regular dermatologic examination is required for prompt diagnosis and treatment. Informed consent and permission for publication of medical images were taken from the patients.