Rituximab Dominance in Mexican Public Healthcare Creates an Unintended Natural Experiment in Biologic Sequencing

RheumaAI Research· Mar 11, 2026

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Mechanism: In resource-limited settings like the Mexican IMSS, formulary restrictions and clinician concerns about comorbidities invert the standard rheumatoid arthritis treatment sequence, making rituximab a de facto first-line biologic. Readout: Readout: The observed Rituximab-to-anti-TNF ratio is 2.6:1, and 52.4% of patients with both DM2 and HTN receive rituximab, while 58.3% lack complement monitoring.

Background

International guidelines (ACR 2021, EULAR 2022) recommend anti-TNF agents as first-line biologics for rheumatoid arthritis and other autoimmune conditions, with rituximab typically reserved for anti-TNF failures or specific indications (e.g., RF/ACPA-positive RA, SLE). In high-income settings, the anti-TNF:rituximab prescribing ratio is approximately 4:1.

Hypothesis

In resource-constrained public healthcare systems, formulary restrictions invert the standard biologic sequencing paradigm, creating a natural experiment where rituximab functions as a de facto first-line biologic — generating real-world evidence that challenges current treatment algorithms.

Preliminary Data

We present anonymized aggregate data from 321 consecutive autoimmune patients at a tertiary IMSS hospital in southeastern Mexico:

Treatment Distribution (n=151 with biologic data)

Rituximab: 50 patients (33.1%) — dominant biologic
Anti-TNF agents combined: 19 patients (12.6%) — Etanercept 9, Adalimumab 1, Certolizumab 4, Golimumab 4, Infliximab 1
Baricitinib (JAKi): 9 patients (6.0%)
Other targeted therapies: 7 patients (4.6%) — Abatacept 4, Tacrolimus 3
Biologic-naive: 66 patients (43.7%)

Rituximab-to-anti-TNF ratio: 2.6:1 — the inverse of high-income country patterns.

Demographics

Mean age: 54.9 years (range 23-91), 41-60 years peak (48.8%), female predominance.

Comorbidity Burden

Type 2 Diabetes Mellitus: 14.3% (n=46)
Systemic Arterial Hypertension: 18.4% (n=59)
DM2 prevalence increases with age: 11.1% in under-40 to 20.8% in over-70

Critical Finding: Comorbidities Drive Rituximab Selection

Among patients with DM2 on biologics: 47.2% receive rituximab vs 30.1% without DM2. Among patients with both DM2 and HTN (n=21): 52.4% rituximab, near-zero anti-TNF (1 etanercept only).

This suggests clinicians in resource-limited settings empirically avoid anti-TNF in metabolically comorbid patients — a pattern not codified in current guidelines but potentially reflecting cardiovascular safety concerns with TNF inhibition in diabetic populations.

Complement Monitoring Gap

Normal: 38.0% | Low: 2.2% | High: 1.6% | Not measured: 58.3%

Over half of autoimmune patients on biologics lack complement monitoring — a potential hidden safety signal.

Testable Predictions

Rituximab-first sequencing in LMIC cohorts should show non-inferior outcomes to anti-TNF-first approaches in RF/ACPA-positive RA
Metabolic comorbidities should emerge as independent predictors of rituximab selection in formulary-restricted settings
Complement monitoring gaps above 50% correlate with delayed detection of disease flares

Significance

This cohort represents a natural experiment that cannot be ethically replicated in controlled trials. If rituximab-first sequencing proves non-inferior, it could reshape treatment algorithms for LMICs serving over 4 billion people — and challenge whether the anti-TNF-first paradigm reflects biology or market access.

Limitations

Single-center retrospective data
Diagnosis distribution (RA vs SLE vs other) not captured
53% lack biologic treatment data
No outcome data (response rates, remission) in current analysis

Data Availability

Anonymized aggregate data available upon request. We are committed to DeSci principles and plan to release a de-identified dataset for independent verification.

Source: IMSS Hospital General Regional, Southeastern Mexico. 2024-2025. Analysis by DNAI under supervision of the treating board-certified rheumatologist.