Management of cutaneous lupus erythematosus with Janus kinase inhibitor therapy: An evidence-based review

To the Editor: Cutaneous lupus erythematosus (CLE) is a form of lupus erythematosus localized to the skin. CLE results in a wide variety of dermatologic manifestations. Currently, there are no Food and Drug Administration (FDA)-approved treatments for CLE, with initial treatment typically involving topical and systemic corticosteroids.1Petty A.J. Floyd L. Henderson C. Nicholas M.W. Cutaneous lupus erythematosus: progress and challenges.Curr Allergy Asthma Rep. 2020; 20: 12https://doi.org/10.1007/s11882-020-00906-8Crossref PubMed Scopus (18) Google Scholar While there are FDA-approved treatments for systemic lupus erythematosus (SLE), the use of Janus kinase inhibitors (JAKi) for CLE remains novel.2Fetter T. Smith P. Guel T. Braegelmann C. Bieber T. Wenzel J. Selective Janus kinase 1 inhibition is a promising therapeutic approach for lupus erythematosus skin lesions.Front Immunol. 2020; 11: 344https://doi.org/10.3389/fimmu.2020.00344Crossref PubMed Scopus (43) Google Scholar This systematic review examines the literature and summarizes the effectiveness and safety outcomes of JAKi therapies in treating CLE. Following the PRISMA guidelines, MEDLINE and Embase Ovid searches were conducted, using variations of keywords "Lupus" and "JAK" (Supplementary File 1, available via Mendeley at https://data.mendeley.com/datasets/t6gmknc97b/3). Quality of evidence was assessed using Oxford Centre for Evidence-Based Medicine 2011 Levels of Evidence. After the independent screening of 1180 articles by 2 reviewers, 13 studies (publication date: 2016-2022) involving 33 patients were included (Supplementary Fig 1 and File 2, available via Mendeley at https://data.mendeley.com/datasets/t6gmknc97b/3). Mean age was 46.6 years (range: 6-75 years), with 3 males (9.1%) and 30 females (90.9%). Reported sub-types of CLE included subacute (21/33, 63.6%), chilblain (7/33, 21.2%), and discoid (5/33, 15.2%). Concurrent diagnosis of SLE was reported in 11 (33.3%) patients, with no active SLE disease. A total of 33 JAKi use with outcomes were documented, with filgotinib (Tyrosine kinase 2 [TYK2] selectivity) (17/33,51.5%) as the most used JAKi, followed by tofacitinib (JAK1/3 selectivity) (6/33,18.2%), baricitinib (JAK1/2 selectivity) (5/33,15.2%), ruxolitinib (JAK1/2 selectivity) (4/33,12.1%), and upadacitinib (JAK1 selectivity) (1/33,3%) (Supplementary Table I, available via Mendeley at https://data.mendeley.com/datasets/t6gmknc97b/3). Treatment duration was described in 32 patients (mean: 102.6 days; range: 30-360 days). The Cutaneous Lupus Erythematosus Disease Area and Severity Index Activity (CLASI-A) is a validated outcome measure for CLE disease activity (range: 0-70).3Chakka S. Krain R.L. Concha J.S.S. Chong B.F. Merola J.F. Werth V.P. The CLASI, a validated tool for the evaluation of skin disease in lupus erythematosus: a narrative review.Ann Transl Med. 2021; 9: 431https://doi.org/10.21037/atm-20-5048Crossref PubMed Google Scholar Based on existing data, a ≥4-point reduction from baseline represents a clinically significant improvement. CLASI-A scores were measured in 75.8% of cases (25/33), with all patients achieving clinically significant improvement (mean 15.4-point reduction) from baseline. CLE recurrence data with follow-up were available in 97% of patients, with CLE recurrence in one case (6.3%). Concurrent treatment was not noted in cases. Treatment-related adverse events occurred in 11 patients (30.3%), all developing mild infections requiring no intervention. No JAKi treatment discontinuation was reported in any cases (Supplementary File 2, available via Mendeley at https://data.mendeley.com/datasets/t6gmknc97b/3). While specific pathogenesis of CLE remains unknown, studies showing both JAK1 and JAK/signal transducer and activator of transcription (STAT)-associated inflammatory pathways, including TYK2 are strongly expressed in CLE cutaneous lesions.2Fetter T. Smith P. Guel T. Braegelmann C. Bieber T. Wenzel J. Selective Janus kinase 1 inhibition is a promising therapeutic approach for lupus erythematosus skin lesions.Front Immunol. 2020; 11: 344https://doi.org/10.3389/fimmu.2020.00344Crossref PubMed Scopus (43) Google Scholar This down-regulation of inflammatory pathways caused by JAKi may explain the efficacy JAKi has shown for CLE in this study. Only one clinical trial for CLE and JAKi has been completed, involving filgotinib, a TYK2 inhibitor, and showed a mean CLASI-A score reduction from baseline of 8.7 points; this is in line with outcomes found in our study.4Werth V.P. Fleischmann R. Robern M. et al.Filgotinib or lanraplenib in moderate to severe cutaneous lupus erythematosus: a phase 2, randomized, double-blind, placebo-controlled study.Rheumatology (Oxford). 2022; 61: 2413-2423https://doi.org/10.1093/rheumatology/keab685Crossref PubMed Scopus (22) Google Scholar Further clinical trials are being conducted on JAKi for CLE with pending results.5Bristol-Myers Squibb A study to evaluate efficacy and safety of deucravacitinib in participants with active discoid and/or subacute cutaneous lupus erythematosus (DLE/SCLE). ClinicalTrials.gov identifier: NCT04857034.https://clinicaltrials.gov/ct2/show/record/NCT04857034Date: 2022Date accessed: October 30, 2022Google Scholar Despite this, JAKi therapy has shown potential to be both effective and safe for CLE. Further research on JAKi use, including topical JAKi use in CLE should be explored.2Fetter T. Smith P. Guel T. Braegelmann C. Bieber T. Wenzel J. Selective Janus kinase 1 inhibition is a promising therapeutic approach for lupus erythematosus skin lesions.Front Immunol. 2020; 11: 344https://doi.org/10.3389/fimmu.2020.00344Crossref PubMed Scopus (43) Google Scholar Study limitations included a lack of follow-up and recurrence data. Due to limited sample size and heterogeneous outcome data, a meta-analysis could not be performed. Published data found in our review suggest efficacy for JAKi in CLE. More rigorous, larger, and long-term studies are warranted to determine effectiveness and safety outcomes further. Dr Jensen Yeung has been an advisor, consultant, speaker, and/or investigator for AbbVie, Allergan, Amgen, Astellas, Boehringer Ingelheim, Celgene, Centocor, Coherus, Dermira, Eli Lilly, Forward, Galderma, GSK, Janssen, LEO Pharma, Medimmune, Merck, Novartis, Pfizer, Regeneron, Roche, Sanofi Genzyme, Sun Pharma, Takeda, UCB, Valeant, and Xenon. Mr Abrahim Abduelmula, Mr Siddhartha Sood, Dr Asfandyar Mufti, and Dr Anna Hinek have no conflicts of interest to declare.