Rheumatoid Arthritis-related Interstitial Lung Disease Research Articles

Rituximab for rheumatoid arthritis-related interstitial lung disease: A systematic review and meta-analysis.

This systematic review and meta-analysis aimed at summarizing the evidence of efficacy and safety of rituximab in rheumatoid arthritis-related interstitial lung disease (RA-ILD). PubMed and Embase databases were searched until June 22, 2022, to identify studies on RA-ILD treated with rituximab, confined to predefined inclusion and exclusion criteria. A systematic review and meta-analysis were performed on the included studies to assess the overall stabilization or improvement in ILD, changes in percent-predicted (%-predicted) forced vital capacity (FVC), and %-predicted diffusion capacity of lungs for carbon monoxide (DLCO) following rituximab therapy. A total of 15 studies (4 prospective and 11 retrospective studies) were included, with a total of 314 patients. There were 105 (60.7%) females out of 173 subjects for whom sex details were available from seven studies. The overall pooled proportion of patients with stabilization or improvement in ILD was 0.88 [95% confidence interval (CI): 0.76-0.96, p=0.02]. Rituximab improved FVC from baseline by 7.50% (95% CI: 1.35-13.65; p=0.02, fixed effect). Similarly, rituximab improved DLCO by 6.39% (95% CI: 1.366-14.43; p=0.12, random-effect). Two retrospective studies reported reduced mortality with rituximab therapy compared to tumor necrosis factor-alpha inhibitors. Treatment with rituximab in RA-ILD was associated with a significant improvement in %-predicted FVC, as well as stabilization or improvement in ILD after one year of treatment.

Reliability and responsiveness of the D12 and validity of its scores as a measure of dyspnoea severity in patients with rheumatoid arthritis-related interstitial lung disease

BackgroundInterstitial lung disease due to rheumatoid arthritis (RA-ILD) affects a substantial minority of patients with RA, inducing life-altering symptoms, impairing quality of life (QOL) and forcing patients to confront the...

Rituximab for rheumatoid arthritis-related interstitial lung disease: A systematic review and meta-analysis

Objectives: This systematic review and meta-analysis aimed at summarizing the evidence of efficacy and safety of rituximab in rheumatoid arthritis- related interstitial lung disease (RA-ILD). Materials and methods: PubMed and Embase databases were searched until June 22, 2022, to identify studies on RA-ILD treated with rituximab, confined to predefined inclusion and exclusion criteria. A systematic review and meta-analysis were performed on the included studies to assess the overall stabilization or improvement in ILD, changes in percent-predicted (%-predicted) forced vital capacity (FVC), and %-predicted diffusion capacity of lungs for carbon monoxide (DLCO) following rituximab therapy. Results: A total of 15 studies (4 prospective and 11 retrospective studies) were included, with a total of 314 patients. There were 105 (60.7%) females out of 173 subjects for whom sex details were available from seven studies. The overall pooled proportion of patients with stabilization or improvement in ILD was 0.88 [95% confidence interval (CI): 0.76-0.96, p=0.02]. Rituximab improved FVC from baseline by 7.50% (95% CI: 1.35-13.65; p=0.02, fixed effect). Similarly, rituximab improved DLCO by 6.39% (95% CI: 1.366-14.43; p=0.12, random-effect). Two retrospective studies reported reduced mortality with rituximab therapy compared to tumor necrosis factor-alpha inhibitors. Conclusion: Treatment with rituximab in RA-ILD was associated with a significant improvement in %-predicted FVC, as well as stabilization or improvement in ILD after one year of treatment.

Factors associated with interstitial lung disease in patients with rheumatoid arthritis: A systematic review and meta-analysis.

Interstitial lung disease (ILD) is frequent in patients with rheumatoid arthritis (RA) and is a potentially life-threatening complication with significant morbidity and mortality. This meta-analysis aims to systematically determine the factors associated with the development of rheumatoid arthritis-related interstitial lung disease (RA-ILD). All primary studies which reported the factors associated with of RA-ILD were eligible for the review except case reports. The Cochrane Library, PubMed, Embase, Web of Science, Chinese Biological Medicine Database (CBM), China National Knowledge Infrastructure (CNKI), and WANFANG electronic databases were searched through to December 30, 2022, for studies investigating the factors associated with RA-ILD. The methodological quality assessment of the eligible studies was performed using the Newcastle-Ottawa Scale (NOS). 2 reviewers extracted relevant data independently. Then, weighed mean differences (WMDs) or pooled odds ratios (ORs) and corresponding 95% confidence intervals (CIs) were obtained for the relationships between the factors and RA-ILD. The statistical meta-analysis, subgroup and sensitivity analyses were performed using the Review Manager 5.3, and publication bias with Egger's test were performed using the Stata12.0 software. A total of 22 articles were screened for a meta-analysis which involved 1887 RA-ILD patients and 8066 RA without ILD patients. Some identified factors that were associated with an increased risk of RA-ILD included male sex (OR = 1.92, 95% CI: 1.54-2.39; P < 0.00001), older age (WMD = 5.77 years, 95% CI: 3.50-8.04; P < 0.00001), longer duration of RA (WMD = 0.80 years, 95% CI 0.12-1.47; P = 0.02), older age at onset of RA (WMD = 6.41 years, 95% CI: 3.17-9.64; P = 0.0001), smoking (OR = 1.69, 95% CI: 1.30-2.18; P < 0.0001). Five factors of laboratory items associated with the development of RA-ILD were evaluated in the meta-analysis. Compared with RA without ILD patients, positive rheumatoid factor (RF) (OR = 1.72, 95% CI: 1.47-2.01; P < 0.00001) and positive anti-citrullinated protein antibodies (ACPA) (OR = 1.58, 95% CI: 1.31-1.90; P < 0.00001) increased the risk of RA-ILD. Meanwhile, RF titer (WMD = 183.62 (IU/mL), 95% CI: 66.94-300.30; P = 0.002) and ACPA titer (WMD = 194.18 (IU/mL), 95% CI: 115.89-272.47; P < 0.00001) were significantly associated with increased risk of RA-ILD. Elevated erythrocyte sedimentation rate (ESR) (WMD = 7.41 (mm/h), 95% CI: 2.21-12.61; P = 0.005) and C-reactive protein (CRP) (WMD = 4.98 (mg/L), 95% CI: 0.76-9.20; P = 0.02) were also significantly associated with the development of the RA-ILD, whereas antinuclear antibody (ANA) positive status was not significantly associated with increased risk of RA-ILD (OR = 1.27, 95% CI: 1.00-1.60; P = 0.05). This meta-analysis showed that male gender, older age, longer duration of RA, older age at onset of RA, smoking, positive RF, positive ACPA, elevated RF titer, elevated ACPA titer, higher ESR and higher CRP were associated with RA-ILD.

Rheumatoid arthritis associated interstitial lung disease: Trends in epidemiology and mortality in Ontario from 2000 to 2018

BackgroundThe epidemiology and mortality of rheumatoid arthritis related interstitial lung disease (RA-ILD) have not been described in Canada. Our aim was to describe recent trends in RA-ILD prevalence, incidence, and mortality in Ontario, Canada. MethodsThis was a retrospective population-based study using repeated cross-sections from 2000 to 2018. We estimated annual age- and sex-standardized rates for RA-ILD prevalence, incidence and mortality. ResultsAmong 184,400 RA patients identified between 2000 and 2018, 5722 (3.1%) were diagnosed with RA-ILD. Most RA-ILD patients were women (63.9%) and ≥60 years old (76.9%) at the time of RA-ILD diagnosis. RA-ILD incidence rose from 1.6 (95% confidence interval (CI) 1.3–2.0) to 3.3 (95% CI 3.0–3.6) per 1000 RA patients (204% relative increase, p < 0.0001) during this time. RA-ILD incidence increased in both sexes and all age groups over time. The cumulative prevalence of RA-ILD increased from 8.4 (95% CI 7.6–9.2) to 21.1 (95% CI 20.3–21.8) per 1000 RA patients (250% relative increase, p < 0.0001), increasing in both sexes and all age groups. All-cause and RA-ILD related mortality declined in patients with RA-ILD over time [55.1% relative reduction, (p < 0.0001) and 70.9% relative reduction, (p < 0.0001), respectively]. In RA-ILD patients, RA-ILD contributed to the cause of death in approximately 29% of cases. Men and older patients had higher all-cause and RA-ILD related mortality. ConclusionIn a large, diverse Canadian population, the incidence and prevalence of RA-ILD are increasing. RA-ILD related mortality is declining, but remains an important cause of death in this population.

Factors associated with interstitial lung disease and the progressive fibrosing phenotype in rheumatoid arthritis–related interstitial lung disease

BackgroundThe risk factors for interstitial lung disease (ILD) in rheumatoid arthritis (RA) are inconsistent among previous studies. Furthermore, the factors associated with the emergence of the recently defined progressive fibrosing (PF) phenotype are unknown. Herein, we analyze the risk factors for ILD in RA. We also analyze the factors associated with a PF phenotype. MethodsWe collected the clinical and laboratory details of subjects with RA with (cases) or without (controls) ILD. Scoring of high-resolution computed tomography (HRCT) features of ILD was performed. We identified the subgroup that developed the PF phenotype during follow-up. We analyzed the factors associated with ILD using logistic regression (primary objective). We also compared the characteristics of ILD subjects with or without the PF phenotype (secondary objective). ResultsWe included 60 subjects (30 cases, 30 controls). Subjects with ILD had higher age, lower body mass index, longer duration of RA, and poorer lung function than the controls. Age (p = 0.007) and the duration of RA (p = 0.049) were the only significant predictors of ILD on univariate and multivariate analysis, respectively. Six (20%) subjects with RA-ILD developed a PF phenotype. These subjects were older, had greater frequency of honeycombing, and higher HRCT scores for honeycombing and aggregate fibrosis than those without the PF phenotype. Among subjects with honeycombing, 41.7% developed the PF phenotype. ConclusionsRA-ILD was associated with the duration of RA and age. Subjects with the PF phenotype were older and had higher honeycombing and fibrosis scores on HRCT chest.

SER-SEPAR recommendations for the management of rheumatoid arthritis-related interstitial lung disease. Part 1: Epidemiology, risk factors and prognosis

ObjectiveTo develop multidisciplinary recommendations to improve the management of rheumatoid arthritis-related interstitial lung disease (RA-ILD). MethodsClinical research questions relevant to the objective of the document were identified by a panel of rheumatologists and pneumologists selected based on their experience in the field. Systematic reviews of the available evidence were conducted, and evidence was graded according to the Scottish Intercollegiate Guidelines Network (SIGN) criteria. Specific recommendations were made. ResultsSix PICO questions were selected, three of which analysed the incidence and prevalence of RA-ILD, associated risk factors, and predictors of progression and mortality. A total of 6 specific recommendations on these topics, structured by question, were formulated based on the evidence found and/or expert consensus. ConclusionsWe present the first official SER-SEPAR document with specific recommendations for RA-ILD management developed to resolve some common clinical questions and facilitate decision-making for patients.

SER-SEPAR recommendations for the management of rheumatoid arthritis-related interstitial lung disease. Part 2: Treatment

ObjectiveTo develop multidisciplinary recommendations to improve the management of rheumatoid arthritis-related interstitial lung disease (RA-ILD). MethodsClinical research questions relevant to the objective of the document were identified by a panel of rheumatologists and pneumologists selected based on their experience in the field. Systematic reviews of the available evidence were conducted, and evidence was graded according to the Scottish Intercollegiate Guidelines Network (SIGN) criteria. Specific recommendations were made. ResultsSix PICO questions were selected, three of which analysed the safety and effectiveness of glucocorticoids, classical synthetic disease-modifying anti-rheumatic drugs (DMARDs) and other immunosuppressants, biological agents, targeted synthetic DMARDs, and antifibrotic therapies in the treatment of this complication. A total of 12 recommendations were formulated based on the evidence found and/or expert consensus. ConclusionsWe present the first official SER-SEPAR document with specific recommendations for RA-ILD management developed to resolve some common clinical questions, reduce clinical healthcare variability, and facilitate decision-making for patients.

Predictors of long-term prognosis in rheumatoid arthritis-related interstitial lung disease.

The aim of the study was to identify specific clinical and serum protein biomarkers that are associated with longitudinal outcome of RA-associated interstitial lung disease (RA-ILD). 60 RA patients with clinical and serological profiles were assessed by HRCT and pulmonary function tests (PFTs) at baseline (Year 0) and 5 years post enrollment (Year 5). Progression versus non-progression was defined based on changes in Quantitative Modified HRCT scores and PFTs over time. Specific serum protein biomarkers were assessed in serum samples at baseline and Year 5 by Multiplex enzyme-linked immunosorbent assays (ELISAs). At Year 5, 32% of patients demonstrated progressive RA-ILD, 35% were stable, and 33% improved. Baseline age and rheumatoid factor (RF) were significantly different between RA-ILD outcomes of progression vs. no-progression (p < 0.05). Changes in levels of CXCL11/I-TAC and MMP13 over 5 years also distinguished pulmonary outcomes (p < 0.05). A final binary logistic regression model revealed that baseline age and changes in serum MMP13 as well as CXCL11/I-TAC were associated with RA-ILD progression at Year 5 (p < 0.01), with an AUC of 0.7772. Collectively, these analyses demonstrated that baseline clinical variables (age, RF) and shifts in levels of selected serum proteins (CXCL11/I-TAC, MMP13) were strongly linked to RA-ILD outcome over time.

Risk factors for the progression of rheumatoid arthritis-related interstitial lung disease: Clinical features, biomarkers, and treatment options

ObjectivesThe clinical heterogeneity of the progression of rheumatoid arthritis-associated interstitial lung disease (RA-ILD) is high, and there is a lack of consensus on the clinical relevance and medical protocols. The purpose of this study is to explore the impact of clinical characteristics, new biomarkers and treatment options on the prognosis of RA-ILD patients and to explore whether these factors can predict the progression and death of these patients. MethodsWe retrospectively collected case data on RA-ILD patients who visited or were admitted to Changhai Hospital between October 2010 and September 2021. We followed up and finally included 75 patients. The main outcome indicator of disease progression was pulmonary functional impairment, which was assessed by changes of high-resolution computed tomography (HRCT) score or pulmonary function test before and after treatment. The demographics, clinical characteristics, laboratory tests, and treatment plans of RA-ILD patients in the progressive and stable groups were compared and analyzed. Clinically relevant variables were identified, and the incidence of pulmonary dysfunction and adverse events was recorded. Cox regression analysis was used to determine factors related to the progression of ILD. ResultsThe mean age of RA-ILD onset was 64.0 years (SD 10.3), and 53 (70.7%) patients were female. Thirty-two (42.7%) patients had lung dysfunction, who were classified as the progressive group, and 13 (40.6%) of them died. In univariate analyses, male, smoking, high HRCT scores at baseline, RF-IgA>200 RU/ml, diffusing capacity of the lungs for carbon monoxide (DLCO), and usual interstitial pneumonia (UIP) pattern were significant risk factors for disease progression; while use of Leflunomide (LEF) was associated with better prognosis. The multivariate analysis revealed that RF-IgA>200 RU/ml (hazard ratio [HR] 3.17 [95% confidence interval (CI) 1.29, 7.81], P = 0.012), UIP pattern (HR 3.94 [95% CI 1.68, 9.26], P = 0.002), and male (HR 2.52 [95% CI 1.16, 5.46], P = 0.019) were significantly correlated with unfavorable outcomes in patients with RA-ILD. LEF (HR 0.25 [95% CI 0.10, 0.61], P = 0.002) was related to a better prognosis. However, it might be related to investigating medications changes after baseline. ConclusionOur data suggests that male, UIP pattern, and increased RF-IgA may be potential predicting factors for poor prognosis of RA-ILD patients. We report a significant association between high titer of RF-IgA at baseline and RA-ILD progression for the first time, which might be a potentially important biomarker for the prognosis of RA-ILD.

Rheumatoid arthritis-related interstitial lung disease (RA-ILD): a possible association between disease activity and prognosis.

We hypothesized that RA disease activity might be associated with the survival of RA-ILD patients. To evaluate this possibility, we analyzed data on disease activity during follow-up in an RA-ILD cohort and compared disease activity between surviving patients and those who died during follow-up. RA-ILD patients referred for medical evaluation and treatment at a single center, with CDAI scores during all follow up were included. We estimated the HR of the mean of the CDAI score during follow-up with survival. Also, we compared the survival function of patients with high disease activity (CDAI scores ≥ 22) during all follow-up with those with moderate and low disease activity. Thirty-seven patients were included. The mean of the CDAI score during follow-up was higher in death patients (median 30.8 ± 18.5 Vs. 16.8 ± 11.3), and a single unit increase in the mean of the CDAI score was associated with non-survival, HR:1.07 (95% CI: 1.02 -1.12). Patients with high disease activity during all follow-up (CDAI scores > 22) had lower survival function in comparison with moderate and low disease activity (P = 0.042). The results of the study suggest that higher RA disease activity is associated with a worse prognosis of RA-ILD patients. The hypothesis that high disease activity is associated with worse survival in RA-ILD patients must be evaluated in more extensive cohort studies and clinical trials. • RA-ILD patients with high disease activity during follow-up had a worse prognosis than those with moderate or low disease activity. • The study results suggest the hypothesis that patients with RA-ILD must be treated with a treat to target strategy, with the aim of remission or low RA disease activity.

Rituximab experience from a single centre for patients with rheumatoid arthritis-related interstitial lung disease.

To demonstrate the effects of rituximab (RTX) in patients with rheumatoid arthritis-related interstitial lung disease (RA-ILD). A total of 165 patients who used RTX for the management of rheumatoid arthritis were retrospectively scrutinised. Among these, 26 patients diagnosed with RA-ILD were analysed (61.5% male, mean age at RTX infusion 61.4 ± 6.5 years). To evaluate the efficacy of RTX on lung response, patients with pulmonary function test results and/or thorax computed tomography (chest-CT) of pre- and post-RTX were compared. Disease progression was defined as either a decline of ≥10% in forced vital capacity (FVC) and/or a decline of ≥15% in diffusion capacity of carbon monoxide (DLCO), or an increase of parenchymal involvement on chest-CT images according to the radiologists' assessment. Among 26 patients, the most common radiologic pattern was usual interstitial pneumonia (42.3%), followed by non-specific interstitial pneumonia (38.5%). Data for lung response was available in 20 patients. Median pre- and post- RTX DLCO values were 71.0% (60.0-77.0) and 63.0% (47.0-74.0), respectively (p= 0.06). Median pre- and post-RTX FVC values were 74.0% (61.0-99.0) and 84.0% (63.0-100.0), respectively (p= 0.28). Overall, stabilization or regression of RA-ILD was provided in 13 (65.0%) patients, whereas 7 patients had progressive RA-ILD. Post-RTX, 5 patients were diagnosed with RA-ILD. Our results suggest that RTX is effective in achieving stabilization or even improvement of RA-ILD. However, considering that it does not cause regression in every patient and some develop RA-ILD under RTX, we still need more effective treatment options.

Protective effect of methotrexate on lung function and mortality in rheumatoid arthritis-related interstitial lung disease: a retrospective cohort study.

Studies on the risk and protective factors for lung function decline and mortality in rheumatoid arthritis-related interstitial lung disease (RA-ILD) are limited. We aimed to investigate clinical factors and medication uses associated with lung function decline and mortality in RA-ILD. This retrospective cohort study examined the medical records of patients with RA-ILD who visited Severance Hospital between January 2006 and December 2019. We selected 170 patients with RA-ILD who had undergone at least one spirometry test and chest computed tomography scan. An absolute decline of ⩾10% in the functional vital capacity (FVC) was defined as significant decline in pulmonary function. Data for analysis were retrieved from electronic medical records. Ninety patients (52.9%) were female; the mean age was 64.0 ± 10.2 years. Multivariate logistic regression showed that a high erythrocyte sediment rate level at baseline [odds ratio (OR) = 3.056; 95% confidence interval (CI) = 1.183-7.890] and methotrexate (MTX) use (OR = 0.269; 95% CI = 0.094-0.769) were risk and protective factors for lung function decline, respectively. Multivariate Cox regression analysis indicated that age ⩾65 years (OR = 2.723; 95% CI = 1.142-6.491), radiologic pattern of usual interstitial pneumonia (UIP) or probable UIP (OR = 3.948; 95% CI = 1.522-10.242), baseline functional vital capacity (FVC) % predicted (OR = 0.971; 95% CI = 0.948-0.994), and MTX use (OR = 0.284; 95% CI = 0.091-0.880) were predictive of mortality. We identified risk and protective factors for lung function decline and mortality in patients with RA-ILD. MTX use was associated with favorable outcome in terms of both lung function and mortality in our cohort.

Bibliometric Analysis of the Scientific Literature on Rheumatoid Arthritis-Associated Interstitial Lung Disease.

Background In recent years, the number of studies on rheumatoid arthritis-related interstitial lung disease (RA-ILD) has been increasing, which has led to many publications on this topic. Our purpose is to identify research trends in RA-ILD and analyze the most-cited RA-ILD-related high-quality scientific publications. Methods All publications on RA-ILD in the Core Collection database of Web of Science were searched. The publication year, country, institution, total citations, and journal were extracted and analyzed. We used VOSviewer software or an online bibliometric analysis platform for cooccurrence analysis of the keywords, institutions, and countries involved. The 100 most frequently cited RA-ILD publications were analyzed. Results In total, 596 publications related to RA-ILD were obtained. Over time, the frequency of RA-ILD publications has increased. Globally, the United States provides the most publications on RA-ILD (n = 195). The institution with the highest publication output was the Mayo Clinic (n = 43). The journal “Annals of the Rheumatic Diseases” published most with 93 articles and received 338 citations. A clinical description was the most common research topic in RA-ILD-related publications. Conclusions In recent years, there has been an increasing number of studies on RA-ILD, and related publications have increased rapidly. This study is the first bibliometric study of RA-ILD-related publications. It can be used as a guide for clinicians and can help researchers choose research directions of interest in this field.

High-titer rheumatoid factor seropositivity predicts mediastinal lymphadenopathy and mortality in rheumatoid arthritis-related interstitial lung disease

Rheumatoid arthritis-related interstitial lung disease (RA-ILD) is a common connective tissue disease-related ILD (CTD-ILD) associated with high morbidity and mortality. Although rheumatoid factor (RF) seropositivity is a risk factor for developing RA-ILD, the relationship between RF seropositivity, mediastinal lymph node (MLN) features, and disease progression is unknown. We aimed to determine if high-titer RF seropositivity predicted MLN features, lung function impairment, and mortality in RA-ILD. In this retrospective cohort study, we identified patients in the University of Chicago ILD registry with RA-ILD. We compared demographic characteristics, serologic data, MLN size, count and location, and pulmonary function over 36 months among patients who had high-titer RF seropositivity (≥ 60 IU/ml) and those who did not. Survival analysis was performed using Cox regression modeling. Amongst 294 patients with CTD-ILD, available chest computed tomography (CT) imaging and serologic data, we identified 70 patients with RA-ILD. Compared to RA-ILD patients with low-titer RF, RA-ILD patients with high-titer RF had lower baseline forced vital capacity (71% vs. 63%; P = 0.045), elevated anti-cyclic citrullinated peptide titer (122 vs. 201; P = 0.001), CT honeycombing (50% vs. 80%; P = 0.008), and higher number of MLN ≥ 10 mm (36% vs. 76%; P = 0.005). Lung function decline over 36 months did not differ between groups. Primary outcomes of death or lung transplant occurred more frequently in the high-titer RF group (HR 2.8; 95% CI 1.1–6.8; P = 0.028). High-titer RF seropositivity was associated with MLN enlargement, CT honeycombing, and decreased transplant-free survival. RF titer may be a useful prognostic marker for stratifying patients by pulmonary disease activity and mortality risk.

Abstract 17047: Nintedanib And Cardiomyopathy: A Vascular Failure?

Description of the Case: Patient 1 is a 61-year-old woman with a history of rheumatoid arthritis-related interstitial lung disease (ILD). Six months after initiation of nintedanib, she was diagnosed with new-onset heart failure. Cardiac magnetic resonance imaging (CMR) was consistent with nonischemic cardiomyopathy (NICM) with ejection fraction (EF) of 15-25%. EKG showed new bifascicular block (right bundle branch block and left anterior fascicular block). Nintedanib was discontinued, and four months later, echocardiogram showed recovered EF (50-54%). EKG abnormalities resolved with biventricular pacing. Patient 2 is a 57-year-old-man with a history of scleroderma-related ILD and stable diastolic heart failure (EF = 55-60%). Six months after initiation of nintedanib, he was admitted for heart failure exacerbation. CMR showed NICM with EF = 35%, and EKG showed prolonged QRS (130 ms). Given the rapid progression of cardiomyopathy, nintedanib was discontinued. Discussion: We report two patients with underlying connective tissue disease who developed significant nonischemic cardiomyopathy in temporal association with initiation of nintedanib. Nintedanib is a tyrosine kinase inhibitor, antagonizing three angiogenic signaling pathways mediated by vascular endothelial growth factor receptor (VEGFR), fibroblast growth factor receptor (FGFR), and platelet derived growth factor receptor (PDGFR). The nintedanib-treated cohorts of the TOMORROW and INPULSIS trials for idiopathic pulmonary fibrosis showed a high incidence of myocardial infarction (MI). With the recent SCENSIS trial, nintedanib was approved in 2019 for ILD associated with systemic sclerosis. There are likely multifactorial effects of this triple angiokinase inhibitor, seeing that it inhibits multiple growth factors essential for vascular homeostasis, the balance between mesenchymal and endothelial cell fates. Thus, there may be multiple pathways for cardiomyopathy due to “vascular failure,” including MI and importantly, cardiac fibrosis. Based on our observations, we urge other clinicians to report their experience with nintedanib use in patients with underlying connective tissue disease and to carefully monitor these patients for adverse cardiovascular effects.

Soluble programmed death molecule 1 (sPD-1) as a predictor of interstitial lung disease in rheumatoid arthritis

BackgroundPrevious studies have indicated that the programmed death molecule 1 (PD-1) signaling pathway may play a key role in rheumatoid arthritis (RA). However, the pathogenesis of rheumatoid arthritis-related interstitial lung disease (RA-ILD) is not clear. We examined the serum levels of soluble PD-1 in patients with RA and its relationship with RA-ILD.MethodsBlood samples were obtained from 87 patients with RA (58 with ILD and 29 without ILD) and 45 healthy controls. Serum sPD-1 was measured by Enzyme-Linked Immunosorbent Assay. The pulmonary interstitial disease score was completed by a pulmonary physician and a radiologist through chest high-resolution computed tomography. Patients with RA-ILD were tested for lung function [e.g., forced vital capacity (FVC%), diffusing capacity of lungs for carbon monoxide (DLCO%)]. Associations between ILD and various markers, including sPD-1 and confounding factors, were investigated by logistic regression analysis. Diagnostic values of sPD-1 for the presence of ILD were investigated using receiver operating characteristic curve analysis.ResultsSerum sPD-1 levels were higher in RA patients with ILD than in RA patients without ILD and healthy controls (185.1 ± 109.0 pg/ml vs. 119.1 ± 77.5 pg/ml vs. 52.1 ± 21.7 pg/ml, P < 0.05). Serum sPD-1 levels were positively correlated with RF titer (P = 0.02, r = 0.249), anti-cyclic citrullinated peptide antibody status (P = 0.02, r = 0.243), and serum IgG levels (P < 0.001, r = 0.368), negatively associated with FVC% (P = 0.02, r = − 0.344), forced expiratory volume (FEV1%) (P = 0.01, r = − 0.354), total lung capacity (TLC%) (P = 0.046, r = − 0.302), and was independently associated with the presence of ILD in RA patients by multivariate logistic regression analysis. The sensitivity and specificity of sPD-1 levels for the detection of ILD in RA patients were 58.6% and 75.9%, respectively. The area under the curve was 0.689.ConclusionSerum sPD-1 levels were increased in RA patients with ILD. Increased sPD-1 may be a valuable biomarker to predict the presence of ILD in patients with RA.

DESPITE THEIR UTILITY IN IDIOPATHIC PULMONARY FIBROSIS, SERUM IGA AND MONOCYTE COUNT ARE NOT PREDICTIVE OF BASELINE PULMONARY FUNCTION, MORTALITY, OR INTERSTITIAL LUNG DISEASE PATTERN IN RHEUMATOID ARTHRITIS-ASSOCIATED INTERSTITIAL LUNG DISEASE

TOPIC: Diffuse Lung Disease TYPE: Original Investigations PURPOSE: Idiopathic pulmonary fibrosis (IPF) is a chronic, progressive lung disease that confers a poor prognosis. Previously, immunoglobulin A (IgA) level has been used as a surrogate marker of transforming growth factor (TGF)-beta, an important mediator of pulmonary fibrosis, and increased IgA level was associated with worse outcomes in IPF [1]. Recent studies have also described associations between serum monocyte count and clinical outcomes in IPF [2]. Rheumatoid arthritis related interstitial lung disease (RA-ILD) has many similarities with IPF, including similar genetic risk, survival, and ILD pattern. We hypothesized that elevated IgA and monocyte count would correlate with clinical outcomes and ILD patterns in RA-ILD. METHODS: We performed a single-center, retrospective chart review of patients diagnosed with RA-ILD between 2010 and 2021 using an ICD9 and ICD10 based search. Of 256 patients who met our search criteria, 77 were included in the final analysis. Patients were included if they had serum IgA and monocyte count in the chart, a confirmed diagnosis of RA based on ACR/EULAR criteria, and ILD based on chart diagnosis and confirmatory imaging. Patients were excluded if they received rituximab prior to their blood draw. High resolution computed tomography images closest to the date of the blood draw were analyzed by consensus reads by two blinded thoracic radiologists using the 2018 ATS/ERS/JRS/ALAT guidelines. IgA level and monocyte count were compared to pulmonary function at time of blood draw, time to death or lung transplant, UIP pattern as well as sex, ethnicity and age. RESULTS: The mean and median IgA levels were 342.8 mg/dl and 329.0 mg/dl, respectively. There was no statistically significant association between IgA level and the UIP pattern (p = 0.689). IgA level was not associated with baseline FVC% predicted or baseline DLCO% predicted (p = 0.218 and p = 0.639). The effect of IgA level on overall survival is not significant in the simple Cox regression model [hazard ratio (HR) = 1.002, 95% confidence interval (CI) 0.999-1.004, p = 0.203].The mean and median absolute monocyte counts were 6.5×108 cells/liter and 6.0×108 cells/liter, respectively. There was no association between monocyte count and the UIP pattern (p = 0.762). Monocyte count was not associated baseline with FVC% predicted (p = 0.963) or baseline DLCO% predicted (p = 0.882). The effect of monocyte count on overall survival is not significant in the simple Cox regression model (HR = 1.099, 95% CI 0.449-2.690, p = 0.836). CONCLUSIONS: Serum IgA and monocyte concentration were not associated with important clinical outcomes in this RA-ILD cohort. This was a retrospective analysis, it may be that prospective, longitudinal analysis of IgA and monocyte count in RA-ILD could yield different results. CLINICAL IMPLICATIONS: N/A DISCLOSURES: No relevant relationships by Joe Johnstone, source=Web Response Consultant relationship with Boehringer Ingelheim Please note: $1001 - $5000 by Joyce Lee, source=Web Response, value=Consulting fee Consultant relationship with Genentech Please note: $1001 - $5000 by Joyce Lee, source=Web Response, value=Consulting fee Consultant relationship with Celgene Please note: $1001 - $5000 by Joyce Lee, source=Web Response, value=Consulting fee Consultant relationship with Galapagos Please note: $1001 - $5000 by Joyce Lee, source=Web Response, value=Consulting fee Consultant relationship with Eleven P15 Please note: $1001 - $5000 by Joyce Lee, source=Web Response, value=Consulting fee No relevant relationships by Scott Matson, source=Web Response No relevant relationships by Sahil Pandya, source=Web Response No relevant relationships by Kristen Pope, source=Web Response No relevant relationships by Xiaosong Shi, source=Web Response No relevant relationships by Christopher Walker, source=Web Response

Intravenous cyclophosphamide in acute exacerbation of rheumatoid arthritis-related interstitial lung disease: A propensity-matched analysis using a nationwide inpatient database

ObjectivesWe aimed to investigate the effect of intravenous cyclophosphamide (CYC) as the initial therapy in patients with acute exacerbation of rheumatoid arthritis-related interstitial lung disease. MethodsThis was a retrospective observational study. Using the Japanese Diagnosis Procedure Combination inpatient database from July 2010 to March 2018, we identified patients with acute exacerbation of rheumatoid arthritis-related interstitial lung disease (RA-ILD) who received high-dose methylprednisolone within 3 days after admission. RA-ILD was defined as having either the diagnosis of RA-ILD or the diagnoses of both RA and ILD, based on the ICD-10 codes recorded by attending physicians. Patients were divided into two groups: those receiving intravenous CYC within 3 days after admission (CYC group) and those who did not (control group). One-to-four propensity-score matching analyses were performed. ResultsA total of 6130 eligible patients were included. After propensity score matching, 129 patients in the CYC group and 516 patients in the control group were further analyzed. 90-day in-hospital mortality, defined as all-cause mortality during hospitalization within 90 days after admission, was not significantly different between the CYC and control groups (50.4% versus 42.2%, hazard ratio 1.20, 95% confidence interval 0.91–1.58). A larger proportion of patients in the CYC group received platelet transfusion than that in the control group (7.0% versus 2.3%, odds ratio 3.05, 95% confidence interval 1.20–7.73). ConclusionIn this retrospective database study, the initial therapy with CYC did not show a survival benefit in patients with acute exacerbation of RA-ILD. CYC was associated with a larger proportion of platelet transfusion.

Mortality rate in rheumatoid arthritis-related interstitial lung disease: the role of radiographic patterns

BackgroundTo assess mortality rate (MR) and standardized mortality rate (SMR) of rheumatoid arthritis-related interstitial lung disease (RA-ILD) patients and to evaluate the role of radiographic patterns in mortality.MethodsA longitudinal multicentric study was conducted in RA-ILD patients from 2005 to 2015 and followed-up until October 2018 in Madrid. Patients were included in the Neumologia-Reumatología y Enfermedades Autoinmunes Registry, from diagnosis of ILD. The main outcome was all-cause mortality. The radiographic pattern at baseline [usual interstitial pneumonia (UIP), nonspecific interstitial pneumonia (NSIP), or others] was the independent variable. Covariables included sociodemographic and clinical data. Survival techniques were used to estimate MR, expressed per 1000 persons-year with their 95% confidence intervals [CI]. Cox multiple regression model was run to examine the influence of radiographic patterns on survival. SMR [CI] was calculated comparing MR obtained with MR expected in the general population of Madrid by indirect age-gender standardization.Results47 patients were included with a follow-up 242 patients-year. There were 16 (34%) deaths, and most frequent causes were acute ILD exacerbation and pneumonia. MR was 64.3 [39.4–104.9], and 50% of the patients died at 8.3 years from ILD diagnosis. After adjusting for confounders, (UIP compared to NSIP was associated with higher mortality risk. The overall SMR was 2.57 [1.4–4.17]. Women of 60–75 years of age were the group with the highest SMR.ConclusionsRA-ILD is associated with an excess of mortality compared to general population. Our results support that UIP increases the risk of mortality in RA-ILD, regardless other factors.