Janus kinase (JAK) inhibitors have enriched our armamentarium to treat autoimmune rheumatic diseases, with their approval in inflammatory arthritides (rheumatoid arthritis, spondyloarthritides). The rationale supporting a role for inhibition of the JAK/STAT pathway in the management of systemic lupus erythematosus (SLE) was provided by two fundamental facts: first, interferons (IFN) type I (α/β) and II (γ) are well-established and important players in SLE pathophysiology; second, the JAK/STAT signalling pathway has been identified as the cascade responsible for the signal transduction from the activated IFN receptor to the nucleus. Subsequently, evidence from in vitro studies and animal models supported a role for JAK inhibitors targeted against different JAKs in the treatment of cutaneous and systemic lupus erythematosus, including amelioration of lupus nephritis.¹

Contrary to these encouraging preclinical data, clinical trials of JAK inhibitors in SLE were recently marked by the recent discontinuation of the development program of baricitinib (a selective JAK1/JAK2 inhibitor) for SLE, after the discordant results of the two identical SLE-BRAVE phase 3 trials, and following a very successful phase 2 trial.^{2 3} Post-hoc analyses of the two studies are eagerly awaited to clarify the reasons behind these results. Regarding other JAK inhibitors, only a phase 1 study of tofacitinib has been published with reassuring safety results, and more data are needed.⁴

Notwithstanding these setbacks, evidence from case series and case reports still support a role for JAK inhibitors in SLE, particularly in patients with skin and joint disease. This is further supported by the fact that baricitinib and upadacitinib are also indicated for autoimmune dermatologic diseases, like alopecia areata (baricitinib) and atopic dermatitis (baricitinib and upadacitinib).

References

1. Alunno A, et al. Pathogenic and therapeutic relevance of JAK/STAT signaling in systemic lupus erythematosus: integration of distinct inflammatory pathways and the prospect of their inhibition with an oral agent. Cells. 2019 Aug 15;8(8):898. doi: 10.3390/cells8080898.

2. Morand EF, et al. Baricitinib for systemic lupus erythematosus: a double-blind, randomised, placebo-controlled, phase 3 trial (SLE-BRAVE-I). Lancet. 2023 Mar 25;401(10381):1001–1010. doi: 10.1016/S0140-6736(22)02607-1.

3. Petri M, et al. Baricitinib for systemic lupus erythematosus: a double-blind, randomised, placebo-controlled, phase 3 trial (SLE-BRAVE-II). Lancet. 2023 Mar 25;401(10381):1011–1019. doi: 10.1016/S0140-6736(22)02546-6.

4. Hasni SA, et al. Phase 1 double-blind randomized safety trial of the Janus kinase inhibitor tofacitinib in systemic lupus erythematosus. Nat Commun. 2021 Jun 7;12(1):3391. doi: 10.1038/s41467-021-23361-z.

Learning Objectives

• Explain the scientific rationale for testing JAK inhibitors in SLE

• Discuss preclinical data that provided proof-of-concept for clinical trials of JAK inhibitors in SLE

• Discuss the main results and conclusion from clinical trials of JAK inhibitors in SLE, with a focus on baricitinib

• Provide potential insight into the future of JAK-STAT inhibition of SLE following the failure of baricitinib and halting of its clinical programme in SLE