Paul F. Dellaripa

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.

Interstitial lung disease (ILD) is a major cause of morbidity and mortality in systemic sclerosis (SSc); however, the immunopathologic mechanisms driving lung disease in SSc are unclear. T cells have been implicated as a likely driver of lung injury in SSc. Here, we evaluated T cells in the blood of patients with SSc-ILD and identified a specific population of cytotoxic CD8 ⁺ T cells that was expanded in patients with SSc-ILD. Cytotoxic effector memory CD8 ⁺ T cells marked by CD57 expression were preferentially expanded in patients with SSc-ILD compared with patients with SSc but no ILD and control individuals and showed prominent clonal expansion. These CD57 ⁺ T effector memory (Tem) cells differed from T effector memory cells reexpressing CD45RA (Temra) transcriptomically and functionally, with cytotoxic function that was enhanced by CD155 engagement of the costimulatory receptor CD226. We performed immunostaining of lung tissue samples obtained from independent patients with SSc-ILD (biopsy or explant) and confirmed the presence of CD57 ⁺ Tem cells. In parallel, we analyzed publicly available lung scRNA-seq datasets from multiple ILD cohorts and identified endothelial cells as a likely source of CD155 for the activation of CD57 ⁺ cytotoxic T cells. Together, the results implicate a CD57 ⁺ cytotoxic CD8 ⁺ T cell population as a potential mediator of lung injury in SSc-ILD.

Objective: Mycophenolate mofetil (MMF) can stabilize or improve lung function in systemic sclerosis–related interstitial lung disease (SSc‐ILD). We hypothesized that combining MMF with pirfenidone (PFD) would produce a significantly more rapid and/or greater improvement in lung function. Methods: A randomized (1:1), double‐blind, placebo (PLA)‐controlled phase 2 trial was conducted in SSc‐ILD in which patients received PFD or PLA (801 mg three times daily) along with MMF (1,500 mg twice daily) for 18 months. The primary outcome was change in percent predicted forced vital capacity (FVC‐%). Linear mixed‐effects models assessed treatment differences in a modified intention‐to‐treat population. Results: Only fifty‐one of 150 intended subjects (34%) were randomized (MMF+PLA, n = 24; MMF+PFD, n = 27). The FVC‐% improved from baseline to 18 months by 2.24 ± 1.35 (least‐squares mean [LSM] ± SEM) in the MMF+PLA group and 2.09 ± 1.28 in the MMF+PFD group (LSM treatment difference −0.14; P = 0.93). Median time to achieve a ≥3% improvement in FVC‐% was numerically faster in the MMF+PFD versus MMF+PLA group (12.3 vs 17.8 months, respectively), but the difference was not significant ( P = 0.33). For secondary outcomes, only the change over 18 months in the Patient‐Reported Outcomes Measurement Information System 29‐item physical function score, favoring MMF+PFD, reached statistical significance ( P = 0.04). Although other related patient‐reported outcomes (PROs) numerically favored the MMF+PFD group, as did quantitative high‐resolution computed tomography measures of ILD, the differences between groups did not reach statistical significance. Early withdrawals from study medication and adverse events of special interest were numerically greater with MMF+PFD (n = 8 vs 2 and n = 20 vs 7, respectively). Conclusion: In this underpowered study, there was no statistically significant treatment difference in overall change in FVC‐% between groups. MMF+PFD was not as well tolerated as MMF+PLA.

Objectives: This randomized, placebo-controlled pilot trial evaluated the efficacy and safety of abatacept in patients with anti-synthetase syndrome-associated interstitial lung disease (ASyS-ILD). Methods: Participants with active ASyS-ILD were randomized to receive abatacept (n = 9) or placebo (n = 11) for 24 weeks, followed by a 24-week open-label extension with abatacept for all participants. The primary endpoint was a change in % predicted forced vital capacity (%FVC) from baseline to week 24. Secondary endpoints included changes in the FVC (ml), % predicted diffusing capacity of the lung for carbon monoxide (%DLCO), shortness of breath questionnaire (SOBQ) and pulmonary disease activity on a visual analogue scale (VAS) at weeks 24 and 48. Pre-post baseline analysis of FVC and quantitative image analysis (QIA) of high-resolution computed tomographic scans were performed. Data were analysed using a generalized linear mixed model. The study was not powered for primary or secondary endpoints. Results: At week 24, there was no significant difference in the primary endpoint of %FVC change between abatacept and placebo (between treatment difference of −0.35, 95%CI −6.91 to 6.21, P = 0.914) and in all secondary endpoints. However, by week 48, trends favouring abatacept in %FVC, FVC (ml), %DLCO and SOBQ were observed without statistical significance. There was a significant improvement in pulmonary disease activity VAS and pre-post baseline slopes of %FVC and QIA scores in the abatacept arm. Abatacept was generally well tolerated. Conclusion: Abatacept did not significantly improve %FVC at 24 weeks. However, trends at 48 weeks suggest potential benefits, supporting the need for a larger, long-term randomized controlled trial. Clinical trial registration: clinicaltrials.gov; NCT03215927

Sjögren’s disease (SjD) is characterized by immune-mediated glandular dysfunction and can occur in isolation or accompany other autoimmune rheumatic disorders. Although sicca symptoms are the principal manifestation of SjD, it is the extraglandular manifestations, particularly in the respiratory system, that may be the more significant contributor to morbidity and mortality. Almost all compartments of the respiratory system have been described in association with SjD, including (1) the airways, with xerotrachea that may lead to chronic cough, bronchiolitis, and bronchiectasis; (2) the lung parenchyma, with both fibrotic and cystic lung diseases; (3) the pulmonary vasculature, with pulmonary hypertension; and (4) lymphoproliferative complications such as amyloidosis, light-chain deposition disease, and mucosa-associated lymphoid tissue (MALT) lymphomas. Depending upon the modalities used for screening, these abnormalities can be present in the majority of patients with SjD, some of whom are asymptomatic. Thus, awareness from both rheumatology and pulmonary specialists is essential to facilitate early detection, using available consensus guidelines to direct appropriate screening and monitoring strategies. Although specific clinical trials for patients with pulmonary manifestations of SjD are lacking, the extrapolation of the literature from similar pulmonary complications of other rheumatic diseases is available to guide the clinician when intervention is needed.

Objectives: To explore the association between the extent of CT abnormalities by quantitative imaging analysis (QIA) and clinical/physiological disease parameters in patients with antisynthetase syndrome associated interstitial lung disease (ARS-ILD). Methods: We analysed 20 patients with antisynthetase antibodies and active ILD enrolled in the Abatacept in Myositis-Associated Interstitial Lung Disease study. High-resolution chest CT was obtained at weeks 0, 24 and 48 and QIA scored the extent of ground glass (quantitative score for ground glass), fibrosis (quantitative score for lung fibrosis, QLF) and total ILD (quantitative ILD, QILD). Mixed-effects models estimated longitudinal QIA scores over time. Associations between QIA scores with clinical/physiological parameters were analysed longitudinally using repeated-measures mixed-effects models. Results: Patients were median age 57 years, 55% males and 85% white. Higher (worse) baseline QIA scores correlated with lower baseline forced vital capacity (FVC) and diffusing capacity adjusted for haemoglobin (DLCO). Longitudinal QIA trajectories trended towards improving scores during the trial, and patients on O₂ at baseline had worsening QIA trajectories which were different from patients who were not on O₂. Longitudinal QIA scores demonstrated strong associations with both FVC and DLCO over time. Higher QILD scores over time were also associated with worse dyspnoea scores, pulmonary visual analogue scale, physician and patient global disease activity, health status in 6/8 domains of the Short Form-36 and higher oxygen requirements. Patients with significant radiographic improvement at 48 weeks had higher baseline QLF, QILD and worse DLCO. Conclusions: Longitudinal QIA scores associate with lung physiology, patient perception of respiratory status, overall disease activity and quality of life over time in ARS-ILD. QIA may allow reproducible monitoring of disease progression and response to therapy over time. Trial registration number: NCT03215927.

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.

Objective: Environmental hazards and heightened neighborhood social vulnerability coexist and disproportionately affect minoritized populations. We investigated associations between exposure to adverse environmental burden concentrated in areas with high social vulnerability and care fragmentation (missed appointments, emergency department visits, and hospitalizations) and social needs (eg, food and housing insecurity) among individuals with rheumatic conditions.Methods: We identified adults receiving care in a Massachusetts multihospital system with at least two rheumatic disease codes and complete street addresses. Geocoded addresses were linked to the Centers for Disease Control and Prevention/Agency for Toxic Substances and Disease Registry Social–Environmental Ranking (SER), which combines census‐tract social vulnerability variables (eg, socioeconomic status) with environmental hazards (eg, air and water pollution). Social needs were obtained from self‐reported surveys. Multilevel, multinomial regression models estimated associations between SER quartiles and care fragmentation and social need burden, accounting for demographics and comorbidities.Results: Among 16,856 individuals with rheumatic conditions, 70% were female, 6% were Black, 82% were White, and 7% resided in the highest combined social vulnerability and environmental burden (SER quartile 4) areas. Among 7,083 with social needs data, 19% experienced more than one challenge. Individuals in SER quartile 4 areas (vs quartile 1) had 2.02 (95% confidence interval [CI] 1.67–2.46) times greater odds of at least four care fragmentation occurrences (vs 0) and 2.37 (95% CI 1.73–3.25) times greater odds of at least two social needs (vs 0).Conclusion: Residence in areas of high combined adverse environmental burden and social vulnerability was associated with significantly greater odds of care fragmentation and social needs. Addressing structural factors and emerging environmental threats contributing to these adverse exposures is essential to reduce rheumatic disease care inequities.