BAricitinib in patients with SystemIC Sclerosis (BASICS): a prospective, open-label, randomised trial.

Background and aims: Despite advances in approaches to treatment for patients with systemic sclerosis (SSc), the effects have been modest at best. This investigator-initiated study aimed to evaluate the therapeutic benefit, safety and the genetic characteristics related to effect of baricitinib in SSc.

Methods: In this 24-week study, eligible SSc patients were randomised to baricitinib 4 mg, 2 mg or control group. The primary outcome was the change in modified Rodnan skin score (mRSS) from baseline to week 12. Secondary outcomes included changes in the American College of Rheumatology Combined Response Index in Systemic Sclerosis (ACR-CRISS) score, forced vital capacity (FVC), Systemic Sclerosis Score, tender and swollen joint counts, digital ulcers, EQ5D (EuroQol five-dimensions) and safety at week 12 and 24. Transcriptome differences in blood samples from patients before and after baricitinib treatment were compared. Gene Ontology enrichment analysis was performed to identify potential biological functions and canonical pathways.

Results: Between April 2021 to January 2022, 48 patients were randomly assigned to three groups. Mean change in mRSS score from baseline to week 12 was - 8.9 in 4 mg group, - 3.8 in 2 mg group, and - 3.6 in control group (P = 0.019). At week 12, the ACR-CRISS scores were 0.5 and 0.3 in baricitinib 4 mg and 2 mg group, as compared with 0.2 among those in control group (P = 0.171). FVC (%), digital ulcers and EQ5D in 4 mg baricitinib group showed favorable responses over 24 weeks. There were no significant differences in adverse events among groups. The differentially expressed genes (DEGs) identified in our analysis were significantly enriched in gene ontology (GO) terms related to the positive regulation of cytokine production, immune response-activating signaling pathway, and activation of immune response pathway. Interleukin- 1 Receptor Like 1 (IL- 1RL1 or ST2) and synaptotagmin- 17 (SYT17) were downregulated and upregulated respectively, after baricitinib treatment.

Conclusions: The therapy with baricitinib 4 mg appeared to improve mRSS of SSc patients, probably by influencing mechanisms of immune inflammation, and had an acceptable safety profile. This study paves the way for further investigations into Janus kinase (JAK) 1/2 inhibition with baricitinib as a prospective treatment for SSc. Key Points • The baricitinib 4 mg seems to improve clinical outcomes of SSc patients with safety profiles. • The mechanism of JAK inhibitors has been confirmed to be related to anti-inflammatory pathways and molecules in clinical samples.