MICA-129 Val/Val Linked to Poorer IPF Survival on Nintedanib

Key Takeaways

• In a Sardinian IPF cohort, poorer 48-month survival was observed among nintedanib-treated patients with the MICA-129 Val/Val genotype.
• The mortality association in the nintedanib subgroup persisted after adjusted and weighted analyses.
• No significant genotype-associated survival difference was reported among pirfenidone-treated patients.
• MICA-129 genotype frequencies were comparable across treatment groups, and in nintedanib-treated patients, longitudinal lung-function trajectories did not show significant genotype-by-time separation.

Idiopathic pulmonary fibrosis (IPF) remains clinically heterogeneous after antifibrotic therapy begins, with nintedanib and pirfenidone not producing uniform trajectories across patients. Immune-related variation in major histocompatibility complex class I chain-related gene A (MICA) has therefore drawn interest as a possible marker of prognosis or treatment-associated outcome patterns in routine care.

In a single-center observational analysis of a genetically homogeneous Sardinian population recruited from May 2020 through May 2025, Mocci et al. followed 170 patients initially; 7 were excluded for immunosuppressant use and 34 for pulmonary comorbidities, leaving 129 patients with idiopathic pulmonary fibrosis. Treatment groups were 68 receiving nintedanib, 19 pirfenidone, 15 no therapy, and 27 switchers, with movement in both directions between antifibrotic agents in routine care. High-resolution human leukocyte antigen (HLA) and MICA genotyping was performed, and overall survival (OS), forced vital capacity (FVC), and diffusing capacity of the lung for carbon monoxide (DLCO) were assessed, with pulmonary function tracked at baseline and at 12, 24, and 36 months. Kaplan-Meier and Cox models adjusted for age, sex, smoking status, medication burden, comorbidity burden, nintedanib dose, and extended HLA haplotype were used, along with inverse probability of treatment weighting (IPTW) sensitivity analysis.

MICA-129 genotype frequencies did not differ across treatment groups (p = 0.620). Within the nintedanib subgroup, nintedanib subgroup survival by MICA-129 genotype showed lower 48-month OS in Val/Val carriers than in Met/Met-Met/Val patients, 33.8% versus 69.6%, with adjusted Cox p = 0.005 and false discovery rate q = 0.023. In nintedanib-treated patients, Val/Val status remained associated with higher mortality in a multivariable Cox model (HR 7.59; 95% CI, 1.83-31.53; p = 0.01) and in the IPTW-weighted sensitivity analysis (HR 5.22; 95% CI, 1.57-17.39; p = 0.0071). Pirfenidone-treated patients did not show a statistically significant genotype-associated survival difference, the formal treatment-by-genotype interaction was not significant, and adjusted FVC and DLCO trajectories over 36 months did not separate significantly by genotype in nintedanib-treated patients.

Because the analysis was retrospective, observational, and single-center, it cannot establish causality. Treatment-by-genotype strata were small, especially among Val/Val carriers in the nintedanib and pirfenidone groups, and the wide confidence intervals around mortality estimates limited precision. The nonsignificant formal interaction means the data do not prove a treatment-specific predictive effect. Generalizability is limited because this was a genetically homogeneous Sardinian cohort rather than a North American population.

Clinician Questions

Which patients were included in the MICA-129 analysis for idiopathic pulmonary fibrosis, and how were treatment groups defined?

The analysis included adult Sardinian patients with physician-confirmed idiopathic pulmonary fibrosis evaluated through multidisciplinary assessment, high-resolution computed tomography, and pulmonary function testing. The final cohort was divided in routine practice into nintedanib, pirfenidone, no-therapy, and therapy-switcher groups, with individualized treatment allocation rather than randomization. Applicability is therefore bounded by a genetically homogeneous, single-center Sardinian cohort.

What outcome did investigators use to judge prognosis in MICA-129 genotype groups with idiopathic pulmonary fibrosis?

Prognosis was assessed primarily with overall survival defined as time from diagnosis to death or last follow-up, using Kaplan-Meier estimates and Cox modeling. Serial forced vital capacity and diffusing capacity of the lung for carbon monoxide measurements provided a parallel view of lung-function change during follow-up. Together, these endpoints captured both survival and physiologic trajectory.

Does the MICA-129 signal in idiopathic pulmonary fibrosis appear prognostic, predictive, or still unresolved?

The observed association was strongest among nintedanib-treated patients, but the formal treatment-by-genotype interaction was not statistically significant. That means the data do not establish a treatment-specific predictive effect for MICA-129. At this stage, the finding is best read as an exploratory signal that could reflect prognosis, treatment interaction, or both, pending larger validation studies.