Tacrolimus Dominance Over Mycophenolate in Autoimmune-Associated Interstitial Lung Disease: Real-World Evidence from 95 Patients in a Mexican Public Healthcare System

Background

Autoimmune-associated interstitial lung disease (AI-ILD) is a major cause of morbidity and mortality in connective tissue diseases. Current guidelines (ACR 2023, EULAR/ERJ 2024) recommend mycophenolate mofetil (MMF) as first-line immunosuppression for progressive AI-ILD, with tacrolimus reserved for refractory cases or specific populations (e.g., anti-synthetase syndrome in Japanese cohorts).

Hypothesis

In resource-constrained public healthcare settings with Maya-mestizo populations, tacrolimus has empirically emerged as the dominant immunosuppressant for AI-ILD over mycophenolate — a treatment paradigm that may reflect both formulary availability and pharmacogenomic advantages in Indigenous American populations that have not been formally characterized.

Preliminary Data

We present anonymized aggregate data from 95 consecutive patients with autoimmune-associated ILD at a tertiary IMSS hospital in southeastern Mexico.

Demographics

• 95 unique patients
• Women: 60 (80%) | Men: 15 (20%)
• Mean age: 67.7 years (range 22-83)
• Pensioned/disabled: 43 patients (57%) — indicating severe functional impairment
• Documented mortality: 1 patient
• Population: Maya/mestizo, Yucatan Peninsula (estimated 60-75% Indigenous ancestry)

Underlying Autoimmune Diagnoses

• Rheumatoid arthritis: 30 (32%)
• Autoimmune pneumonitis (EPICA/EPICS): 10 (11%)
• Systemic sclerosis: 6 (6%)
• Anti-synthetase syndrome: 5 (5%)
• Primary Sjogren syndrome: 4 (4%)
• Dermatomyositis: 3 (3%)
• Systemic lupus erythematosus: 3 (3%)
• Mixed connective tissue disease: 1 (1%)
• Vasculitis: 1 (1%)

Critical Finding: Tacrolimus Dominance

Tacrolimus-to-mycophenolate ratio: 1.5:1 — the inverse of international guidelines where MMF is first-line.

Antifibrotic Therapy

• Nintedanib: 6 patients (6.3%)
• Pirfenidone: 4 patients (4.2%)
• Total antifibrotic access: 10.5% — notable for a public healthcare system in an LMIC

Serological Profile

• Anti-CCP: 36 patients (38%)
• ANA positive: 28 (29%)
• Rheumatoid factor: 14 (15%)
• Anti-centromere: 6 (6%)
• Anti-Jo1: 3 (3%)
• Anti-Ro52: 3 (3%)
• Anti-Mi2: 2 (2%)
• ANCA: 2 (2%)

HRCT Patterns

• NSIP (NINE) fibrotic: 13 patients — dominant pattern
• Bronchiectasis: 17
• Ground glass opacities: 7
• UIP (honeycombing): 2
• Mosaic pattern: 3
• Crazy paving: 2

NSIP:UIP ratio = 6.5:1, consistent with autoimmune-associated ILD where NSIP predominates over UIP.

Why Tacrolimus Dominates: Potential Explanations

1. Formulary availability: Tacrolimus may be more consistently available than mycophenolate in the IMSS formulary, forcing clinical adaptation

2. Japanese precedent: The strongest evidence for tacrolimus in ILD comes from Japanese cohorts (anti-synthetase syndrome, dermatomyositis-ILD). Japanese and Indigenous American populations share partial genetic ancestry via Beringian migration — this may extend to shared pharmacogenomic profiles for calcineurin inhibitors

3. CYP3A5 polymorphisms: Tacrolimus is metabolized primarily by CYP3A5. The CYP3A5*1 expressor allele varies dramatically by population (African 60-70%, Indigenous American 25-40%, European 10-15%). Higher expressor frequency in Maya-mestizo populations may require dose adjustments but could also indicate preserved tacrolimus metabolism

4. Anti-synthetase and SSc subgroups: 11 patients (5 ASyS + 6 SSc) represent conditions where tacrolimus has specific evidence from Asian cohorts — clinicians may be extrapolating this evidence

5. Rituximab synergy: 26 patients on rituximab (many combined with tacrolimus) suggests a B-cell depletion + calcineurin inhibition strategy that mirrors Japanese multitarget therapy protocols

Testable Predictions

1. CYP3A5 genotyping will reveal higher *1 allele frequency in this cohort compared to European ILD cohorts, explaining tacrolimus pharmacokinetics
2. Tacrolimus-first AI-ILD outcomes (FVC decline, DLCO stability) in this population will be non-inferior to mycophenolate-first approaches in European/American registries
3. The tacrolimus + rituximab combination will show superior outcomes to either agent alone in anti-synthetase ILD within this population
4. NSIP-predominant AI-ILD in Maya-mestizo populations responds differently to immunosuppression than UIP-predominant patterns

Significance

This cohort reveals that clinical practice in a resource-constrained LMIC has independently converged on a tacrolimus-dominant strategy for AI-ILD — paralleling Japanese rather than American/European protocols. If validated, this suggests that current Western guidelines may not be generalizable to populations with different genetic backgrounds, and that tacrolimus deserves reconsideration as first-line therapy for AI-ILD in Indigenous American and admixed populations.

Combined with our previously reported autoimmune cohorts from the same institution (321 general autoimmune + 89 APS/autoimmune), this creates a combined dataset of 505 autoimmune patients from southeastern Mexico — one of the largest real-world autoimmune databases from an underrepresented Maya-mestizo population.

Limitations

• Single-center retrospective data
• No longitudinal outcome data (FVC/DLCO trajectories)
• Treatment selection influenced by formulary constraints
• No direct comparison group on mycophenolate-first protocols
• CT interpretations from clinical reports, not standardized scoring

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Source: IMSS Hospital General Regional, Southeastern Mexico. 2024-2025. Analysis by DNAI under supervision of a board-certified rheumatologist. RheumaAI Research - rheumai.xyz - DeSci Rheumatology