JAK1/2 Inhibitor Baricitinib Improves Skin Fibrosis and Digital Ulcers in Systemic Sclerosis

Abstract

BackgroundSystemic sclerosis (SSc) is a rare disabling connective tissue disease with few available treatment options. Diffuse cutaneous systemic sclerosis (dcSSc) is associated with high mortality. A previous experiment has shown that JAK2 inhibitor can significantly improve skin fibrosis in bleomycin (BLM)-induced murine model, including reducing dermal thickening and collagen accumulation. We aimed to describe the efficacy of oral JAK1/2 inhibitor baricitinib in SSc patients, especially focusing on skin fibrosis and microvascular manifestations.MethodsWe described the different effects of oral selective JAK1, JAK2, or JAK3 inhibitor treatment in a BLM-induced skin fibrosis mouse model. Furthermore, 10 adult patients with dcSSc were treated with baricitinib. We assessed the changes in modified rodman skin score (mRSS) and digital ulcer net burden at week 12 and 24 from baseline. We also compared the absolute changes in scores on the Scleroderma Health Assessment Questionnaire (SHAQ) and a total score on the St. George's Respiratory Questionnaire (SGRQ) over a 24-week period.ResultsIn the experimental mouse model of skin fibrosis, a JAK1 and JAK2 inhibitor ameliorated skin fibrosis, and a JAK2 inhibitor had the most obvious effect. Treatment with the JAK2 inhibitor also blunted the capillary rarefaction. We demonstrated that skin fibrosis and digital ulcers were significantly relieved in 10 SSc patients treated with baricitinib. The mRSS significantly improved at week 12 from baseline, with a mean change in mRSS of −8.3 [95% confidence interval (CI), −12.03 to −4.574; p = 0.0007] and improved greater at week 24 to −11.67 (95% CI, −16.84 to −6.496; p = 0.0008). Among the four patients with digital ulcers (DU), three were completely healed at week 24, the number of ulcers in another patient was significantly reduced, and there was no patient with new ulcers. Only one adverse event (AE) of herpes zoster was observed.ConclusionsOur results indicate that selective JAK1 and JAK2 inhibitor alleviates skin fibrosis, and oral JAK1/2 inhibitor baricitinib is a potentially effective treatment for dcSSc patients with skin fibrosis and DU. Baricitinib was well-tolerated by most patients in this study. Additional large clinical trials are needed to confirm our pilot findings.Chinese Clinical Trial Registry NumberChiCTR2000030995.

Potential Role of JAK Inhibitors in the Treatment of Systemic Sclerosis-Associated Interstitial Lung Disease: A Narrative Review from Pathogenesis to Real-Life Data

“…Our literature search retrieved seven articles that were published between 2018 and 2022. Of these, You et al [21] conducted a single-center, open-label clinical trial, Karalilova et al [22] conducted a pilot study, Hou et al [23] conducted a prospective observational study, and the remaining were case reports [24][25][26][27]. The extracted data were sparse and not complete because treatment with JAKinibs was mainly started for a cutaneous or an articular involvement.…”

“…At both follow ups, no new DU were reported. The mRSS of all nine patients that were evaluated at follow up improved more than 5 points, and 7 (77.78%) cases presented a decrease of more than 25% at week 24 [23].…”

“…Karalilova et al [22] also described 6 cases of gastrointestinal intolerance (nausea, diarrhea), 4 cases of infections (1 urinary tract infection and 3 cases of viral infections), 4 cases of increased levels of transaminases (>1.5 x-<2.5 x), and 2 cases of increased level of cholesterol (>1.5 x). Hou et al [23] reported a single case of herpes zoster infection. No side effects were reported in the case reports.…”

Targeting cytokines and potentiality of JAK–STAT inhibition in systemic sclerosis

“…75 Meanwhile, in a recent pilot study, the JAK1/2 inhibitor, baricitinib, was found to reduce skin fibrosis and digital ulceration in SSc patients. 76 The pharmacological effects of various JAK inhibitors differ depending on which specific cytokines are inhibited. Multiple JAK inhibitors that are currently being investigated in SSc studies, as well as their approved clinical utility for autoimmune diseases, route of administration, dosage, and safety profiles are listed in Table 3.…”

“…Peficitinib, a pan‐JAK inhibitor, reduces lymphocyte activation as well as cytokine and chemokine production in mononuclear cells and skin fibroblasts 75 . Meanwhile, in a recent pilot study, the JAK1/2 inhibitor, baricitinib, was found to reduce skin fibrosis and digital ulceration in SSc patients 76 …”