Table 3 Application of BTK inhibitors in inflammatory diseases

SLE

1. Reduced accumulation of T cells, B cells, macrophages; 2. Reduced production of autoantibodies and inflammatory cytokines; 3. Improved cognitive function in brain disease of lupus [295,296,297]; 4. Reduced proteinuria, improved glomerular pathology scores and survival in lupus nephritis [295, 296]

Fenebrutinib monotherapy (Phase 2):

1. Reduced anti-dsDNA autoantibodies, total IgG, and IgM levels;

2. Acceptable safety profile;

3. Limited benefits in SRI- 4 response rates: 52% for fenebrutinib vs. 44% for placebo [21]

RA

1. Inhibit B cell proliferation and the production of autoantibodies [22]; 2. Inhibit FcγRIII-dependent production of cytokines (e.g., TNF-α, IL-1β, and IL-6) from macrophages [22]; 3. Reduced paw swelling, histological improvement without body weight loss in CIA [88, 298]

Spebrutinib monotherapy (Phase 2a): Over 20% improvement in ACR response criteria in active RA patients with good tolerability [101]

Fenebrutinib monotherapy (phase 2): Showed equivalent efficacy (36%) with adalimumab when fenebrutinib was administered at a dose of 200 mg twice daily [299]

MS

Ex vivo BTK inhibition helped abolish the aberrant activation and expression of costimulatory molecules on B cells from untreated MS patients [300]

Tolebrutinib (phase 2b): reduced the number of new gadolinium-enhancing lesions in a dose-dependent manner in RMS patients [73]

Evobrutinib (phase 2): 1. Reduced the number of enhancing MRI lesions in RMS patients at 75 mg once daily; 2. Showed no benefits on the annualized relapse rates or disability deterioration; 3. Elevated liver aminotransferase levels [23]

Pemphigus

1. Reduced anti-desmoglein IgG antibody titers; 2. Rapid reduction in lesions and Pemphigus Disease Activity Index score in the first 2 weeks; 3. Complete or sustained disease control by 20 weeks in canine models [107, 301]

Rilzabrutinib (phase 2 BELIEVE study): .1. CR: 15% by week 12 and 22% by week 24; 2. A reduction in mean prednisone-equivalent corticosteroid: 20.0 to 11.8 mg/d for naive patients; 10.3 to 7.8 mg/d for relapsing patients; 3. Mostly mild treatment-related AEs [302]

Tirabrutinib (phase 2): 1. CR: 18.8% by week 24 and 50.0% by week 52; 2. A reduction in mean prednisone-equivalent corticosteroid: 17.03 to 7.65 mg/day [303]

CSU

–

Fenebrutinib (phase 2): dose-dependent improvements in UAS7 in week 8 in antihistamine-refractory patients [304]

ITP

–

Rilzabrutinib (phase 1/2): 1. An overall response in 40% patients after a median of 167.5 days; 2. Only low-level toxicities [91]

Severe COVID-19

1. Ibrutinib and zanubrutinib may interfere with viral entry and replication [305]; 2. Prevent thromboinflammation via direct or indirect interactions with platelets [306]

Acalabrutinib: 1. Normalized inflammation C-reactive protein, IL-6, and lymphopenia; 2. Improved oxygenation within 1–3 days; 3. No discernable toxicity [307]