Smoking-associated IgG4-positive cell infiltration in rheumatoid arthritis lung: an exploratory cross-sectional study
Introduction Smoking is the first recognized modifiable risk factor for IgG4-related disease (IgG4-RD) and a driver of rheumatoid arthritis (RA)-associated interstitial lung disease, yet whether it is associated with IgG4-positive cell infiltration in RA lung tissue remains unclear. Methods We analyzed 28 RA patients with abnormal chest CT findings undergoing bronchoalveolar lavage (BAL) and transbronchial lung biopsy; tissue IgG and IgG4 were quantified immunohistochemically. An exploratory IgG4/IgG ratio ≥10% defined IgG4-rich infiltration (only one patient met the conventional ≥40% pathology threshold). BAL and peripheral blood were phenotyped by flow cytometry. Comparisons used non-parametric tests, exploratory Firth penalized logistic regression to address quasi-complete separation, and exploratory subgroup and sensitivity analyses. Results Six patients (21%) had IgG4/IgG ratio ≥10%; all were male ever-smokers with higher ACPA (343.1 vs 96.2 U/mL, p=0.015), although serum IgG4 did not differ (p=0.194). BAL fluid showed lower CD4/CD8 ratio, higher CD8, higher CD22+ B cells, and a trend toward higher Treg; peripheral blood T-helper subsets did not differ. IgG4-rich patients had more interstitial lung disease, more frequent reported probable UIP, higher emphysema scores, and lower baseline %FEV1.0. Tissue IgG4/IgG ratio correlated with ACPA and inversely with %FEV1.0. In an exploratory Firth analysis, male sex and log(ACPA) were associated with tissue IgG4 positivity; because all IgG4-rich cases were male ever-smokers, smoking and male sex could not be disentangled. Discussion In this exploratory cohort, tissue IgG4-positive cell infiltration was observed only among male ever-smokers and was accompanied by a distinct BAL immune-cell profile without parallel peripheral-blood changes. Given the small sample size, the exploratory cutoff, and the unresolved confounding between sex and smoking, these findings should be regarded as hypothesis-generating and require validation in larger prospective studies.