The role of interleukin-17 inhibition in systemic lupus erythematosus—paradoxical hindrance or new therapeutic potential? Results from a systematic literature review and mendelian randomization

Introduction Systemic lupus erythematosus (SLE) is a disease with few licensed drugs when compared to rheumatoid arthritis, axial spondyloarthropathies, and psoriatic arthritis. We report on results of a systematic literature review of IL-17i in SLE with appraisal of published cases of both efficacy of treatment and the risk of developing new SLE following treatment with IL-17i through investigation of adverse events in the setting of clinical trials of IL-17i in non-SLE indications. Methods We performed a PubMed, EMBASE, and MEDLINE search from inception till 30 June 2025 for case reports of IL-17i–induced SLE. The four EMA-licensed IL-17 inhibitors secukinumab, bimekizumab, brodalumab, and ixekizumab were included for analysis. All four monoclonal antibodies block IL-17A, with bimekizumab having the dual functionality of blocking IL-17A/F. Furthermore, the clinical trial data for secukinumab in psoriasis, psoriatic arthritis, and axial spondylarthritis from inception till 2024 was reviewed for adverse event reporting of new cases of SLE. Both systemic and cutaneous SLE were reported on. We also reported on secukinumab case reports for treating SLE. Results Clinical efficacy of IL-17i in case reports of active SLE: in the case of patients treated with secukinumab for known active SLE outside of the clinical trial setting ( n = 4), the commonest indications for the use of secukinumab were active cutaneous disease and inflammatory arthritis (75%, n = 3), with 25% [ n = 1] having lupus nephritis. All four patients had positive serology for ANA and dsDNA. New-onset SLE following IL-17i in the literature: amongst 56 clinical trials for secukinumab, there have been no reports of drug-induced or paradoxical/new-onset SLE following treatment in the reporting periods for each respective trial ( n = 13,000). To date, there are no case reports of bimekizumab- or ixekizumab-induced SLE, although there are two case reports for ixekizumab-induced lupus tumidus, which were excluded from the analysis. One case report exists for new-onset SLE in a patient undergoing treatment with brodalumab for psoriasis, and six cases of SLE following initiation of secukinumab were identified. We identified four of the uses of secukinumab in the treatment of SLE. Conclusion Despite a handful of case reports for paradoxical reactions with IL-17i, they remain a potential therapeutic option in SLE. All patients recovered upon cessation of the offending IL-17i, and generally patients with drug-induced lupus only require symptomatic management and withdrawal of the offending agent. The efficacy of IL-17i for use in SLE remains unclear due to the limited data from case reports. Among the case reports there was heterogeneity in the reporting of disease activity with no standardization or the use of classic disease metrics such as the SLEDAI or DORIS, which can provide its own challenge in appreciating the results and validating the findings. In conclusion, this is an area that deserves further investigation. Translational research is needed to better understand the role of IL-17 in the pathogenesis of SLE. Dedicated studies and trials of clinical efficacy are needed. Systematic Review Registration https://www.crd.york.ac.uk/prospero/ , identifier 1338317.