Bruton’s Tyrosine Kinase Inhibitors in Multiple Sclerosis: A Meta-analysis With Reconstructed Individual Patient Data
Moaz Ezz-Alarab1, Mohamed Ahmed Zanaty1, Mohamed Ahmed Ali1, Mark Messak2, Moaz Nader1, Abdelrahman Shata3, Ismail A. Ibrahim4
1Faculty of medicine, South Valley University, Qena, Egypt, 2Faculty of Medicine, Helwan University, Helwan, Egypt, 3Faculty of Medicine, Horus University-Egypt, New Damietta, Egypt, 4Faculty of Health Sciences, Fenerbahçe University, İstanbul, Turkey
Objective:

To compare the efficacy and safety of Bruton's tyrosine kinase (BTK) inhibitors against placebo and teriflunomide in patients with Multiple Sclerosis (MS).

Background:

BTK inhibitors are emerging oral medications that work by targeting both B-cells and myeloid cells responsible for MS. However, their efficacy and safety remain uncertain.

Design/Methods:

A literature search was conducted through PubMed, Scopus, and WOS to identify RCTs evaluating BTK inhibitors (Tolebrutinib; Evobrutinib) in MS. Quality assessment was performed using RoB-2. Meta-analyses were performed using R, with SMD for continuous outcomes and RRs for binary outcomes, along with 95%CI. A sensitivity analysis was performed to assess the robustness of our results. A Kaplan-Meier curve was reconstructed to assess treatment-confirmed disability progression and improvement sustained for ≥6 months.

Results:

Five studies, comprising seven RCTs, were eligible for meta-analysis. BTK inhibitors had a significant reduction in new or enlarging T2-lesions compared with placebo (SMD=-0.17, 95%CI[-0.28 to -0.06]), but not versus teriflunomide. For gadolinium-enhancing lesions, a non-statistically significant reduction was observed compared with placebo, while comparisons with teriflunomide indicate that BTK inhibitors are less effective (SMD=0.23, 95%CI[0.17 to 0.29]). Reconstructed Kaplan-Meier curves demonstrated a significant difference between arms, with the confirmed disability progression rate at 42 months being 45% for placebo, 15% for BTK inhibitors, and 10% for teriflunomide (P<0.0001). Both active treatments demonstrated a greater sustained improvement in disability (≃15%) compared with placebo (≃5%,p=0.0023). Regarding safety outcomes, BTK inhibitors did not demonstrate an overall increase in adverse or serious adverse events compared with comparators. Event-specific analyses revealed a lower risk of alopecia and gastrointestinal effects compared with teriflunomide (RR=0.49,0.48; respectively), as well as a higher risk of ALT elevation compared with placebo (RR=2.58).

Conclusions:

BTK inhibitors showed potential in reducing MRI lesions and disability progression, improving confirmed disability, and demonstrated acceptable safety profile; however, further studies are needed to confirm these findings.

10.1212/WNL.0000000000217245
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