Clinical effectiveness of Biqi capsule combined with methotrexate in rheumatoid arthritis: an integrated retrospective, meta-analytic, and machine learning study

Introduction Methotrexate (MTX) monotherapy provides inadequate disease control in many patients with rheumatoid arthritis (RA). Biqi Capsule (BQC), a proprietary traditional Chinese medicine formulation, is used as an adjunct to MTX, but its clinical benefits remain uncertain. Methods We evaluated Biqi Capsule plus MTX by integrating a retrospective cohort study, exploratory machine-learning analysis, and a systematic review and meta-analysis. The cohort comprised 100 patients who received either MTX monotherapy (n = 50) or Biqi Capsule plus MTX (n = 50). Results After adjustment for the corresponding baseline values, anti-cyclic citrullinated peptide antibody (anti-CCP) levels at week 24 were lower in the combination-therapy group than in the MTX monotherapy group ( P = 0.002), whereas other inflammatory markers and liver and kidney function indices showed no significant between-group differences. Among patients receiving combination therapy, 24 (48.0%) met the prespecified serological response criterion, defined as a ≥25% reduction in anti-CCP levels from baseline. Among the eight algorithms evaluated, the bagged trees model achieved the highest area under the receiver operating characteristic curve (AUC, 0.601; 95% confidence interval [CI], 0.445 to 0.752), with blood urea nitrogen (BUN), erythrocyte sedimentation rate (ESR), and C-reactive protein (CRP) exhibiting the greatest permutation importance. This meta-analysis included nine studies involving 952 participants. Compared with the controls, BQC-based regimens were associated with significantly lower rheumatoid factor (RF), ESR, and CRP levels, shorter duration of morning stiffness, lower tender and swollen joint counts, and higher overall clinical response rates. The pooled analysis showed no significant between-group difference in the odds of adverse events. Subgroup analyses by treatment regimen showed significant pooled effects favoring BQC plus MTX over the controls for RF, ESR, CRP, morning stiffness duration, swollen joint count, and overall clinical response. Relative to their respective controls, the BQC plus MTX subgroup showed greater pooled reductions in RF and ESR than the BQC monotherapy subgroup, with significant between-subgroup differences. Discussion Overall, Biqi Capsule may offer additional benefits alongside MTX. However, residual confounding, modest model discrimination, and between-study heterogeneity limit firm conclusions. Larger prospective multicenter studies and independent external validation are warranted to confirm these findings.