Claim In methotrexate-exposed rheumatoid arthritis and related autoimmune cohorts, a triage model combining baseline DLCO impairment, hypoalbuminemia, and symptom onset within the first 6 months of treatment will discriminate methotrexate pneumonitis better than smoking history alone.

Why this is plausible Methotrexate pneumonitis is typically acute/subacute and diagnostically difficult because infection and RA-ILD overlap clinically. Reviews consistently identify early timing after methotrexate initiation, diffuse interstitial/ground-glass imaging, and host vulnerability factors as relevant signals, while smoking alone is more strongly linked to chronic RA-ILD than to validated methotrexate-pneumonitis diagnosis. Hypoalbuminemia may act as a frailty/inflammation proxy, and reduced baseline DLCO may identify lower pulmonary reserve.

Testable prediction In a prospective multicenter autoimmune registry, a model using baseline DLCO % predicted, serum albumin, and months-since-MTX-start will achieve a higher AUROC for adjudicated methotrexate pneumonitis than a comparator model using smoking history alone. A pre-specified target would be AUROC improvement >=0.10 with preserved calibration slope 0.9-1.1.

Suggested study design

• Population: adults with RA or related autoimmune disease starting methotrexate
• Outcome: blinded adjudication of methotrexate pneumonitis vs infection vs RA-ILD flare
• Predictors: baseline DLCO, albumin, smoking, age, timing from MTX initiation, dyspnea/cough/fever, CT pattern
• Analysis: penalized logistic regression with internal-external cross-validation by site

Falsifiers

• No meaningful AUROC gain over smoking-only model
• Calibration collapse in external sites
• Most signal explained by infection burden rather than MTX-exposure timing

Key references

1. Fragoulis GE, Nikiphorou E, Larsen J, Korsten P, Conway R. Front Med (Lausanne). 2019;6:238. DOI: 10.3389/fmed.2019.00238
2. Conway R, Low C, Coughlan RJ, O'Donnell MJ, Carey JJ. Arthritis Rheumatol. 2014;66(4):803-812. DOI: 10.1002/art.38322
3. Dawson JK, Graham DR, Desmond J, Fewins HE, Lynch MP. Rheumatology (Oxford). 2002;41(3):262-267. DOI: 10.1093/rheumatology/41.3.262

Limitation Methotrexate pneumonitis is uncommon, so event scarcity may require pooled registries or case-cohort enrichment.