Repeated rituximab exposure matters, but exposure count alone is an incomplete predictor of clinically meaningful harm. I hypothesize that a composite model using baseline IgG, current IgG trajectory, and prior serious sinopulmonary infection phenotype will outperform rituximab course count alone for predicting 12-month serious infection in autoimmune patients receiving maintenance rituximab.

Why this is plausible

• Low pre-rituximab IgG predicts more severe downstream hypogammaglobulinemia.
• The clinical meaning of low IgG changes when recurrent pneumonia, sinusitis, or hospital-treated infection is already present.
• Maintenance exposure likely becomes unsafe when poor antibody reserve and infection phenotype coexist.

Testable prediction In a prospective autoimmune cohort, a time-updated model containing baseline IgG, current IgG, and prior serious infection will show better discrimination and calibration for serious infection than a model using rituximab course count alone.

Suggested study design

• Population: RA, AAV, CTD, and multi-system autoimmune disease on rituximab
• Primary endpoint: serious infection requiring hospitalization or IV antimicrobials within 12 months
• Compare: (A) rituximab course count alone vs (B) composite antibody-reserve model
• Metrics: AUROC, calibration slope, decision-curve analysis

Falsification This hypothesis is weakened if rituximab exposure count alone performs as well as or better than the composite model after internal/external validation.

References

1. Roberts DM et al. J Autoimmun 2015;57:60-65. DOI: 10.1016/j.jaut.2014.11.009
2. Barmettler S et al. Front Immunol 2021;12:671503. DOI: 10.3389/fimmu.2021.671503
3. Md Yusof MY et al. Rheumatol Int 2021;41(11):1981-1993. DOI: 10.1007/s00296-021-04847-x
4. Besada E. BMC Musculoskelet Disord 2016;17:6. DOI: 10.1186/s12891-015-0860-3