Targeted therapies against type I interferon and TNF-alpha in cutaneous lupus erythematosus: A systematic review of randomized trials.
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BACKGROUND: Cutaneous lupus erythematosus (CLE) is associated with high symptomatic burden and sustained activation of immune pathways, notably type I interferon (IFN-I) and tumor necrosis factor-alpha (TNF-α). In patients refractory to standard treatments, such as photoprotection, corticosteroids, antimalarials, and immunomodulators, targeted therapies have emerged as potential alternatives. OBJECTIVE: To assess the efficacy and safety of targeted therapies against IFN-I or TNF-α compared to standard treatments in patients with CLE. METHODS: A systematic review was conducted of randomized controlled trials (RCTs) involving adults or adolescents with CLE (with or without systemic lupus erythematosus), reporting cutaneous outcomes (CLASI-A, CLASI-50, responder rates) and safety. Literature searches were performed in MEDLINE, Embase, and LILACS without language restrictions. Risk of bias was evaluated using the Cochrane RoB 2 tool. Owing to clinical heterogeneity, results were synthesized narratively. RESULTS: Eight RCTs met inclusion criteria, predominantly evaluating IFN-I pathway inhibitors. Anifrolumab showed significant benefit in TULIP-2 (CLASI-50: 49% vs 25%; P = .001) and MUSE (63% vs 30.8%). Sifalimumab achieved CLASI-50 responses up to 73%. Deucravacitinib (TYK2 inhibitor) and BIIB059 (anti-BDCA2) also showed clinical improvements. RSLV-132 and epratuzumab did not demonstrate efficacy. IFN-I blockade was associated with increased viral infections, particularly herpes zoster. Two studies were rated as high risk of bias; the remainder presented some concerns. CONCLUSION: Targeted inhibition of IFN-I and TYK2 pathways appears effective in reducing cutaneous activity in CLE, with acceptable safety profiles. Evidence for anti-TNF therapies remains insufficient. Further trials stratified by CLE subtype and patient-reported outcomes are warranted to inform clinical guidelines.