Gregory C. McDermott

Objective: Rheumatoid factor (RF), anti-cyclic citrullinated peptide (CCP), and novel autoantibodies including anti-malondialdehyde-acetaldehyde (MAA), anti-carbamylated protein (CarP), and anti-peptidylarginine deiminase (PAD) have been associated with clinical RA-associated interstitial lung disease (RA-ILD), but comprehensive autoantibody profiling across clinical and subclinical RA-ILD is lacking. Methods: We retrospectively identified patients with clinically-indicated chest computed tomography (CT) imaging (discovery dataset) and prospectively enrolled RA patients across 5 US sites for research chest CT screening (validation dataset). Clinical ILD (≥10% extent, symptomatic and diagnosed) and subclinical ILD (≥5% extent, undiagnosed with/without symptoms) were adjudicated by thoracic radiologists and analyzed by deep-learning quantitative computed tomography (QCT). Thirty-one biomarkers were measured and log-standardized. We used multivariable logistic regression with 10% false discovery rate (FDR) in the discovery dataset and considered replication if p<0.05 in the validation dataset. Results: We analyzed 1,005 participants: the discovery dataset comprised 149 clinical RA-ILD, 378 RA-noILD, 50 IPF, and 99 healthy controls; the validation dataset comprised 38 subclinical RA-ILD and 291 RA without subclinical ILD. Five autoantibodies replicated across both datasets for RA-ILD risk had higher QCT interstitial abnormalities: RF IgA, RF IgM, CCP3 IgA, CarP IgG, and PAD3 IgG. A composite panel of these autoantibodies had negative predictive values for RA-ILD of 0.81 (discovery) and 0.94 (validation). Conclusion: RF IgA/IgM, CCP3 IgA, CarP IgG, and PAD3 IgG were associated with clinical and subclinical RA-ILD. These biomarkers implicate carbamylation and citrullination in RA-ILD pathogenesis and may be clinically useful for risk stratification.

Sung Hae Chang, M.D., Ph.D., M.P.H., Gregory C. McDermott, M.D., M.P.H., Yeon-Ah Lee, M.D., Ph.D., Eun Ha Kang, M.D., Ph.D., M.P.H., Yong-Beom Park, M.D., Ph.D., Jung-Yoon Choe, M.D., Ph.D., Eun Young Lee, M.D., Ph.D., Jeffrey A. Sparks, M.D., M.M.S.c.. J Rheum Dis -0001;0:. https://doi.org/10.4078/jrd.2025.0161

Objective: The HLA-B27 allele is strongly associated with spondyloarthritis (SpA). HLA-B27 is included in SpA classification criteria and referral strategies for axial SpA. Investigations of HLA-B27 testing in usual clinical practice are limited. Methods: We identified all adult patients tested for HLA-B27 from January 1, 2022, to December 31, 2022, in the Mass General Brigham healthcare system. We examined patient demographics; ordering provider specialty; testing indication; concurrent testing with antinuclear antibodies (ANA), rheumatoid factor, and/or anticyclic citrullinated peptide autoantibodies; and rheumatology referral. We compared the rate of rheumatology referral between HLA-B27–positive and HLA-B27–negative patients. Results: HLA-B27 tests were ordered for 1960 patients (62.4% female; average age: 47.4 yrs). The most common specialties testing HLA-B27 were rheumatology (39.7%) and ophthalmology (21.4%). The most common indications for HLA-B27 testing were peripheral arthritis (33%), uveitis (22%), and back pain (16.7%). The majority of HLA-B27 tests (69.3%) were ordered concurrently with other autoantibody tests. A total of 11% of tested patients were HLA-B27 positive. Ophthalmology had the highest positive rate (15.4%), whereas reactive arthritis was the indication with the highest positive test rate (50%). A greater proportion of HLA-B27–positive patients were referred to rheumatology (53% vs 32%; P = 0.002). Conclusion: HLA-B27 testing was frequently performed by rheumatologists and nonrheumatologists for a broad spectrum of indications. Cotesting HLA-B27 with ANA and rheumatoid arthritis autoantibodies was common. Nearly half of HLA-B27–positive patients were not referred to rheumatology. Further efforts are needed to promote judicious use of HLA-B27 testing and optimize referral pathways to rheumatology.

Background Risk factors and screening strategies for rheumatoid arthritis-associated interstitial lung disease (RA-ILD) have received limited evaluation in patients with early RA. We investigated RA-ILD prevalence, risk factors, and the performance of proposed RA-ILD screening methodologies in a multicenter, prospective study of patients with early RA. Methods Participants with early RA, defined as being within two years of RA diagnosis, were enrolled at five US sites and assessed with high-resolution computed tomography (HRCT) chest imaging, pulmonary function tests, and autoantibodies. RA-ILD presence was determined through independent HRCT review by thoracic radiologists. We investigated RA-ILD risk factors using multivariable logistic regression and reported the predictive performance of RA-ILD screening strategies (ANCHOR-RA, 2023 ACR/CHEST, Four Factor Score, and ESPOIR). Results Among 172 participants (74% female, 82% seropositive, median RA duration 0.79 years, mean age 55.3 years), 19 (11%) had ILD on HRCT. Moderate/high RA disease activity by DAS28-ESR (OR 7.00 [1.95, 25.1]) and age ≥60 years (OR 3.87 [1.33, 11.3]) were associated with RA-ILD. Sensitivity and specificity of screening strategies ranged from 0.32-0.95 and 0.32-0.81, respectively. The number of early RA patients needing screening to detect one ILD case ranged from 3.6 to 6.4. Discussion In this prospective, multicenter study, ILD prevalence in early RA was 11%. Disease activity and older age were strongly associated with ILD in early RA, and several proposed ILD screening strategies performed showed promise for enabling ILD screening in early RA. Several risk factors for rheumatoid arthritis-associated interstitial lung disease have been identified. However, most prior studies have focused on patients with established RA. Several approaches to RA-ILD screening have been proposed, including the recent 2023 ACR/CHEST guidelines. However, none have been specifically evaluated in patients with early RA. In a multicenter, prospective cohort of patients with early RA (diagnosed within 2 years of enrollment), moderate or high RA disease activity and older age were significantly associated with evidence of interstitial lung disease on high resolution CT chest imaging. Several proposed RA-ILD screening criteria performed well in the early RA period. The simplest screening strategy included older age, male sex, and moderate/high RA disease activity and had a number needed to screen of 3.6 patients to detect one RA-ILD case. Simple screening strategies using demographic and clinical data may enable selection of early RA patients for RA-ILD screening.

Objective: To investigate baseline and change of pulmonary damage biomarkers (serum Krebs von den Lungen 6 [KL-6], human surfactant protein D [hSP-D], and matrix metalloproteinase 7 [MMP-7]) with rheumatoid arthritis–associated interstitial lung disease (RA-ILD) progression.Methods: In the Korean Rheumatoid Arthritis Interstitial Lung Disease (KORAIL) cohort, a prospective cohort, we enrolled patients with RA and ILD confirmed by chest computed tomography imaging and followed annually. ILD progression was defined as worsening in physiological and radiological domains of the 2022 American Thoracic Society, European Respiratory Society, Japanese Respiratory Society, and Latin American Thoracic Society guideline for progressive pulmonary fibrosis (PPF). Associations between biomarkers and RA-ILD progression were analyzed using multivariable Cox regression, adjusting for potential confounders.Results: We analyzed 136 patients with RA-ILD (mean age 66.5 yrs, 30% male, 60.3% with usual interstitial pneumonia pattern). During a median 3.0 years of follow-up, 47 patients (34.6%) experienced progression. Higher baseline KL-6 and hSP-D levels were associated with higher risk of ILD progression (multivariable hazard ratios [HRs] 1.37 [95% CI 1.03-1.82] and 1.51 [95% CI 1.09-2.08], respectively), whereas only the highest quartile of MMP-7 showed an increased risk (multivariable HR 2.60 [95% CI 1.07-6.33]). Increasing levels of serum KL-6 at 1 year showed the strongest association with progression (ΔKL-6: multivariable HR 2.00 [95% CI 1.29-3.11]), additionally adjusting for baseline biomarker levels.Conclusion: In this first prospective study to apply PPF criteria to RA-ILD, 34.6% progressed over 3 years. Higher baseline KL-6 and hSP-D were associated with progression. In follow-up, greater change in KL-6 was associated with progression. Serial measurement of pulmonary damage biomarkers may predict RA-ILD progression and may be helpful in monitoring patients and treatment decisions.

Objective: Rheumatoid arthritis–associated interstitial lung disease (RA‐ILD) includes multiple subtypes with varying histopathology, prognosis, and potential treatments. Limited research has investigated risk factors for different RA‐ILD subtypes. Therefore, we examined demographic, serologic, and lifestyle associations with RA‐ILD subtypes. Methods: We systematically identified RA‐ILD cases and RA controls without ILD (RA‐noILD) in the Brigham RA Sequential Study and Mass General Brigham Biobank RA cohort. We determined RA‐ILD subtype (usual interstitial pneumonia [UIP], nonspecific interstitial pneumonia [NSIP], and other/indeterminate) through chest high‐resolution computed tomography imaging pattern. We investigated associations of demographic, lifestyle, and serologic factors with major RA‐ILD subtypes using multivariable logistic regression. Results: Among 3,328 patients with RA, we identified 208 RA‐ILD cases and 547 RA‐noILD controls. RA‐UIP was associated with older age (odds ratio [OR] 1.03 per year, 95% confidence interval [95% CI] 1.01–1.05), male sex (OR 2.15, 95% CI 1.33–3.48), and seropositivity (OR 2.08, 95% CI 1.24–3.48), whereas RA‐NSIP was significantly associated only with seropositive status (OR 3.21, 95% CI 1.36–7.56). Nonfibrotic ILDs were significantly associated with smoking (OR 2.81, 95% CI 1.52–5.21). Having three RA‐ILD risk factors (male, seropositive, smoking) had an OR of 6.89 (95% CI 2.41–19.7) for RA‐UIP compared with having no RA‐ILD risk factors. Conclusion: Older age, seropositivity, and male sex were strongly associated with RA‐UIP, whereas RA‐related autoantibodies were associated with RA‐NSIP. These findings suggest RA‐ILD sex differences may be driven by RA‐UIP and emphasize the importance of further studies to clarify RA‐ILD heterogeneity and optimize screening and treatment approaches.