Association of Cross-Reactive Antibodies Targeting Peptidyl-Arginine Deiminase 3 and 4 with Rheumatoid Arthritis-Associated Interstitial Lung Disease

Background: A subset of rheumatoid arthritis (RA) patients have detectable antibodies directed against the peptidyl-arginine deiminase (PAD) enzyme isoforms 3 and 4. Anti-PAD3/4 cross-reactive antibodies (anti-PAD3/4XR) have been shown to lower the calcium threshold required for PAD4 activation, an effect potentially relevant to the pathogenesis of RA-associated interstitial lung disease (ILD). Methods: RA patients underwent multi-detector computed tomography (MDCT) of the chest with interpretation by a pulmonary radiologist for ILD features. A semi-quantitative ILD Score (range 0–32) was calculated. Concurrent serum samples were assessed for antibodies against PAD by immunoprecipitation with radiolabeled PAD3 and PAD4. Results: Among the 176 RA patients studied, any ILD was observed in 58 (33%) and anti-PAD3/4XR was detected in 19 (11%). The frequency of any ILD among those with anti-PAD3/4XR was 68% vs. 29% among those with no anti-PAD (crude OR = 5.39; p = 0.002) and vs. 27% among those with anti-PAD4 that was not cross-reactive with PAD3 (crude OR = 5.74; p = 0.001). Both associations were stronger after adjustment for relevant confounders (adjusted ORs = 7.22 and 6.61, respectively; both p-values<0.01). Among ever smokers with anti-PAD3/4XR, the adjusted frequency of any ILD was 93% vs. 17% for never smokers without the antibody (adjusted OR = 61.4; p = 0.001, p-value for the interaction of smoking with anti-PAD3/4XR<0.05). Conclusions: The prevalence and extent of ILD was markedly higher among RA patients with anti-PAD3/4 cross-reactive antibodies, even after accounting for relevant confounders, particularly among ever smokers. These findings may suggest etiopathologic mechanisms of RA-ILD, and their clinical utility for predicting ILD warrants additional study

Smoking and Subclinical ILD in RA versus the Multi-Ethnic Study of Atherosclerosis

A population-based cohort showed an association between cigarette smoking and subclinical parenchymal lung disease defined as regions of increased computed tomography (CT) lung densitometry. This technique has not been applied to the rheumatoid arthritis (RA) population where associated ILD is highly prevalent. The association between cumulative cigarette smoking and volume of areas of high attenuation (HAA: >-600 and <-250 Hounsfield Units) on full inspiratory CT was compared in 172 RA participants and 3,969 controls in a general population sample. Multivariable regression models were used to adjust for demography, anthropometrics, percent emphysema, and CT parameters. The mean cumulative cigarette smoking exposure was 25 (IQR 10–42) and 15(IQR 5–31) pack-years for the RA and non-RA cohorts, respectively. Mean HAA was 153(±57) cm3 and 129(±50) cm3 in the RA and non-RA cohorts, respectively. Each 10 cigarette pack-year increment was associated with a higher HAA by 0.03% (95% CI, 0.007–0.05%) in RA patients and by 0.008% (95% CI, 0.003–0.01%) in those without RA (interaction p = 0.001). Cigarette smoking was associated with higher lung attenuation; with a magnitude of association more pronounced in those with RA than in the general population. These data suggest that cigarette smoking may be a more potent ILD risk factor for RA patients than in the general population

The MUC5B Promoter Variant and Autoimmune Associated Interstitial Lung Disease

Learning Objectives: 1. Understand the epidemiology of myositis-Interstitial Lung Disease. 2. Appreciate the importance of myositis specific autoantibodies. 3. Review known genetic risk factors for myositis-Interstitial Lung Disease. Presentation: 30 minutes (turn up volume for audio

Identification and prognosis of patients with interstitial pneumonia with autoimmune features

Background/Objective Patients classified as interstitial pneumonia with autoimmune features (IPAF) have interstitial lung disease (ILD) and features of autoimmunity but do not fulfill criteria for connective tissue diseases (CTDs). Our goal was to identify patients classifiable as IPAF, CTD-ILD, and idiopathic pulmonary fibrosis (IPF) from a preexisting pulmonary cohort and evaluate the prognosis of patients with IPAF. Methods We reviewed the medical records of 456 patients from a single-center pulmonary ILD cohort whose diagnoses were previously established by a multidisciplinary panel that did not include rheumatologists. We reclassified patients as IPAF, CTD-ILD, or IPF. We compared transplant-free survival using Kaplan-Meier methods and identified prognostic factors using Cox models. Results We identified 60 patients with IPAF, 113 with CTD-ILD, and 126 with IPF. Transplant-free survival of IPAF was not statistically significantly different from that of CTD-ILD or IPF. Among IPAF patients, male sex (hazard ratio, 4.58 [1.77–11.87]) was independently associated with worse transplant-free survival. During follow-up, only 10% of IPAF patients were diagnosed with CTD-ILD, most commonly antisynthetase syndrome. Conclusion Despite similar clinical characteristics, most patients with IPAF did not progress to CTD-ILD; those who did often developed antisynthetase syndrome, highlighting the critical importance of comprehensive myositis autoantibody testing in this population. As in other types of ILD, male sex may portend a worse prognosis in IPAF. The routine engagement of rheumatologists in the multidisciplinary evaluation of ILD will help ensure the accurate classification of these patients and help clarify prognostic factors

Pulmonary Outcomes According to PAD3/4 Cross-Reactive Antibody Status.

<p>Values are median (interquartile range) unless otherwise noted.</p><p>*p-values are for the comparison of the no anti-PAD vs. anti-PAD3/4XR groups.</p><p>PAD = peptidyl-arginine deiminase; anti-PAD3/4XR = anti-PAD3/4 Cross-Reactive antibodies; RA = rheumatoid arthritis; ILD = interstitial lung disease; GGO = ground glass opacification; R/TB/HC = reticulation/traction bronchiectasis/honeycombing; PFT = pulmonary function testing; Impaired Diff = impaired diffusion.</p

Crude and Adjusted Associations of PAD3/4 Cross-Reactive Antibodies with Pulmonary Outcomes in RA.

<p>*Adjusted for age, RA duration, RF, CCP2, IL-6, SHS.</p><p>**Adjusted for age, gender, RF, CCP2, RA duration, DAS28, prednisone use, biologic DMARD use, current and past smoking, and SHS.</p>†<p>β coefficients are Odds Ratios.</p><p>ILD = interstitial lung disease; GGO = ground glass opacification; R/TB/HC = reticulation/traction bronchiectasis/honeycombing; PFT = pulmonary function testing; Impaired Diff = impaired diffusion; RA = rheumatoid arthritis; RF = rheumatoid factor; CCP2 = 2^nd generation anti-cyclic citrullinated peptide antibody; DAS = disease activity score; CRP = C-reactive protein; IL = interleukin; SHS = Total modified Sharp-van der Heijde Score; DMARD = disease modifying anti-rheumatic drug.</p

Patient Characteristics According to the Presence of CT-ILD Features.

<p>Values are mean ± standard deviation or median (interquartile range) unless otherwise noted.</p><p>RA = rheumatoid arthritis; RF = rheumatoid factor; CCP2 = 2^nd generation anti-cyclic citrullinated peptide antibody; DAS = disease activity score; CRP = C-reactive protein; IL = interleukin; SHS = Total modified Sharp-van der Heijde Score; HAQ = Health Assessment Questionnaire Disability Index; TNF = tumor necrosis factor; DMARD = disease modifying anti-rheumatic drug; ILD = interstitial lung disease; PFT = pulmonary function testing; Impaired Diff = impaired diffusion.</p

CT Densitometry by Smoking History, Controlled for Emphysema%.

<p>CT Densitometry by Smoking History, Controlled for Emphysema%.</p

Association between Cigarette Pack-Years and Log High Attenuation Volume.

<p>Association between Cigarette Pack-Years and Log High Attenuation Volume.</p

The Combined Effects of anti-PAD3/4 Cross-reactive Antibodies and Smoking Were Robust Indicators of Radiographic RA-ILD.

<p>The cohort was grouped based on the presence of anti-PAD3/4XR (closed markers) and history of ever smoking (i.e. current or former smokers). The association of anti-PAD3/4XR with ILD was stronger among ever smokers compared to never smokers in both crude (Panel A) and adjusted (Panel B) analyses. Average probabilities and 95% confidence intervals are depicted. Panel B associations adjusted for age, gender, rheumatoid factor and CCP2 seropositivity, DAS28, current use of methotrexate and prednisone, RA duration, and total Sharp-van der Heijde Score.</p