A recent study published in British Journal of Dermatology Open found that tirabrutinib, an oral Bruton tyrosine kinase inhibitor, showed tolerability and promising mechanistic effects in patients with systemic sclerosis through B-cell activity suppression.
The randomized double-arm 52-week phase I study enrolled 16 patients with systemic sclerosis who received once-daily tirabrutinib at doses of 40 mg or 80 mg (8 patients per group). All participants experienced grade 1 or 2 treatment-emergent adverse events, with plasma tirabrutinib concentrations maintaining steady-state levels within expected ranges throughout the study period. Clinical efficacy measures showed meaningful improvements in skin involvement. The modified Rodnan skin score decreased by a mean of 4.0 points in the 40-mg group and 4.7 points in the 80-mg group from baseline to week 52. These reductions suggested potential therapeutic benefit across both dosing regimens.
Immunophenotyping analysis revealed consistent B-cell modulation patterns in both treatment groups. The percentage of naïve B cells increased, while nonswitched memory B cells, activated memory CD95+ B cells, and plasmablasts decreased. RNA sequencing data further supported these findings, confirming that B-cell activity suppression represented the primary mechanism of action for tirabrutinib in systemic sclerosis patients. The pharmacokinetic profile remained stable throughout the 52-week treatment period, with both doses achieving therapeutic concentrations without unexpected accumulation or clearance issues. Safety assessments indicated that tirabrutinib was well-tolerated, with no treatment-limiting adverse events reported in either dosing group.
Bruton’s tyrosine kinase (BTK) is a key signaling protein that transmits signals from the B-cell antigen receptor to regulate B-cell activation, proliferation, and survival. With the development of highly specific small-molecule BTK inhibitors, BTK has emerged as an important therapeutic target in autoimmune diseases. Tirabrutinib, a highly potent and selective BTK inhibitor, has been extensively evaluated across multiple B-cell malignancies, including chronic lymphocytic leukemia (CLL), mantle cell lymphoma (MCL), Waldenström macroglobulinemia (WM), and primary central nervous system lymphoma (PCNSL). It received regulatory approval for relapsed or refractory PCNSL in Japan (March 2020), South Korea (November 2021), and Taiwan (February 2022), and in August 2020, was also approved in Japan for the treatment of WM/lymphoplasmacytic lymphoma.
This phase I investigation provided preliminary evidence that tirabrutinib may offer therapeutic potential for systemic sclerosis through targeted B-cell modulation, warranting further evaluation in larger controlled trials to establish definitive efficacy and optimal dosing strategies for this challenging autoimmune connective tissue disease.
References
- Matsuda KM, Harada T, Doi M, Io T, Kitani A, Hasegawa M, Sato S, Yoshizaki A. An open-label randomized parallel-group phase I study of the oral Bruton tyrosine kinase inhibitor tirabrutinib in systemic sclerosis. Br J Dermatol. 2025 Aug 18;193(3):434-441.
- Neys SFH, Rip J, Hendriks RW, Corneth OBJ. Bruton’s Tyrosine Kinase Inhibition as an Emerging Therapy in Systemic Autoimmune Disease. Drugs. 2021 Sep;81(14):1605-1626. doi: 10.1007/s40265-021-01592-0.
- Easaw S, Ezzati S, Coombs CC. SOHO State of the Art Updates and Next Questions: Updates on BTK inhibitors for the treatment of chronic lymphocytic leukemia. Clin Lymphoma Myeloma Leuk. 2023 Oct;23(10):697-704.