Background/Purpose: Seropositivity for anti-citrullinated protein antibodies (ACPA) has been shown to increase risk for RA-associated interstitial lung disease (RA-ILD). However, RA-related autoantibodies used in clinical care are unable to accurately predict future RA-ILD. Previous investigations of specific ACPA and RA-ILD were cross-sectional and had inconsistent results. Therefore, we aimed to investigate fine specificity ACPA and subsequent risk of RA-ILD.

Methods: We performed a nested case-control study among patients with RA in a single center prospective registry. Three radiologists/pulmonologists confirmed RA-ILD through research review of the images of chest computed tomography imaging (index date). We matched each incident RA-ILD case to three RA controls (without patient/physician report or billing codes for ILD) on age, sex, RA duration, rheumatoid factor (RF) status, and time from blood draw to index date. Reactivities to three isotypes of 26 different fine specificity ACPA were measured from serum using a previously developed multiplex bead-based platform. The primary analysis investigated log-transformed levels of IgG ACPA. Secondary analyses considered IgA1 and IgA2 isotypes. Covariates at time of blood draw included smoking pack-years, BMI, and RA clinical factors. Conditional logistic regression estimated ORs for RA-ILD, adjusting for matching factors and covariates. We accounted for multiple comparisons using a 10% false discovery rate.

Results: We identified 84 incident RA-ILD cases and 243 RA controls without ILD. Mean age was 65.8 years, 79.2% were female, 89.0% were seropositive for ACPA/RF, and median RA duration was 19 years. Blood was drawn a median of 1.7 years prior to the index date of RA-ILD. After accounting for multiple comparisons, four IgG ACPA biomarkers were significantly associated with subsequent risk of RA-ILD (Table 1). Filaggrin_48_65_cit2_cyclic was strongly associated with increased risk for incident RA-ILD (multivariable OR 3.08 per each log-transformed unit, 95%CI 1.63-5.84) adjusted for matching factors, smoking pack-years, and BMI. Clusterin_231_250_cit_cyclic (OR 1.24, 95%CI 1.04-1.48), fibronectin_cit_1035_1036 (OR 1.20, 95%CI 1.02-1.42), and H4_33_48_cit39_40 (OR 1.23, 95%CI 1.04-1.46) were also associated with incident RA-ILD. The association of filaggrin_48_65_cit2_cyclic with RA-ILD was also observed in the IgA1 (OR 1.83, 95%CI 1.03-3.26) and IgA2 (OR 4.36, 95%CI 1.13-16.90) isotype analyses.

Conclusion: We identified several fine specificity ACPA associated with subsequent risk of RA-ILD that may inform pathogenesis. In particular, autoimmunity to a specific citrullinated epitope of filaggrin was associated with RA-ILD across all isotypes investigated and is potentially a novel predictive biomarker for RA-ILD. External replication is in process, but these results suggest that fine specificity ACPA biomarkers may have utility in RA-ILD prediction.

Table 1. Associations of log-transformed IgG fine specificity ACPA with incident RA-ILD in 84 RA-ILD cases and 243 RA controls without ILD.

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ACR Meeting Abstracts - https://acrabstracts.org/abstract/fine-specificity-anti-citrullinated-protein-antibodies-as-biomarkers-for-prediction-of-incident-rheumatoid-arthritis-associated-interstitial-lung-disease/