Lung Disease In Rheumatoid Arthritis Research Articles

Leflunomide Use and Risk of Lung Disease in Rheumatoid Arthritis: A Systematic Literature Review and Metaanalysis of Randomized Controlled Trials.

To evaluate the relative risk (RR) of pulmonary disease among patients with rheumatoid arthritis (RA) treated with leflunomide (LEF). We searched PubMed, Embase, and the Cochrane Central Register of Controlled Trials to April 15, 2014. We included double-blind randomized controlled trials (RCT) of LEF versus placebo or active comparator agents in adults with RA. Studies with fewer than 50 subjects or shorter than 12 weeks were excluded. Two investigators independently searched both databases. All authors reviewed selected studies. We compared RR differences using the Mantel-Haenszel random-effects method to assess total respiratory adverse events, infectious respiratory adverse events, noninfectious respiratory adverse events, interstitial lung disease, and death. Our literature search returned 5673 results. A total of 8 studies, 4 with placebo comparators, met our inclusion criteria. There were 708 respiratory adverse events documented in 4579 participants. Six cases of pneumonitis occurred, all in the comparator group. Four pulmonary deaths were reported, none in the LEF group. LEF was not associated with an increased risk of total adverse respiratory events (RR 0.99, 95% CI 0.56-1.78) or infectious respiratory adverse events (RR 1.02, 95% CI 0.58-1.82). LEF was associated with a decreased risk of noninfectious respiratory adverse events (RR 0.64, 95% CI 0.41-0.97). Our study found no evidence of increased respiratory adverse events in RCT of LEF treatment.

Computed tomography of pulmonary changes in rheumatoid arthritis: carcinoembryonic antigen (CEA) as a marker of airway disease.

Rheumatoid arthritis (RA) classically affects the joints, but can present extra-articular manifestations, including pulmonary disease. The present study aimed to identify possible risk factors or laboratory markers for lung involvement in RA, particularly the presence of rheumatoid factor (RF), anti-citrullinated peptide antibodies (ACPA), and tumor markers, by correlating them with changes observed on chest high-resolution computerized tomography (HRCT). This cross-sectional study involved RA patients who were examined and questioned by a specialist physician and later subjected to chest HRCT and blood collection for measurement of C-reactive protein (CRP), erythrocyte sedimentation rate (ESR), rheumatoid factor (RF), ACPA (anti-vimentin and/or anti-CCP3), and the tumor markers carcinoembryonic antigen (CEA), CA 125, CA 15-3, and CA 19-9. A total of 96 patients underwent chest HRCT. The most frequent findings were bronchial thickening (27/28.1%) and bronchiectasis (25/26%). RF was present in 63.2% of patients (55/87), and ACPA (anti-vimentin or anti-CCP3) was present in 72.7% of patients (64/88). CEA levels were high in 14 non-smokers (37.8%) and 23 smokers (62.2%). CA-19-9 levels were high in 6 of 86 patients (7.0%), CA 15-3 levels were high in 3 of 85 patients (3.5%), and CA 125 levels were high in 4 of 75 patients (5.3%). Multivariate analysis indicated a statistically significant association between high CEA levels and the presence of airway changes in patients with RA (p=0.048). CEA can serve as a predictor of lung disease in RA and can help identify individuals who require more detailed examination for the presence of respiratory disorders.

Factors Associated with Airway Disease and Interstitial Lung Disease in Rheumatoid Arthritis

Objective. This study examined lung involvement in patients with rheumatoid arthritis (RA) and identified factors associated with airway disease (AD) and interstitial lung disease (ILD). Methods. A total of 507 RA patients were enrolled in a cross-sec- tional study. Lung involvement was assessed by high-resolution computed tomography scan. The patient groups were classified according to normal, AD, and ILD. Multinomial logistic regression analysis was performed to identify factors associated with AD and ILD. Results. The most frequent lung involvement was AD (38.3%) followed by ILD (12.6%). Old age (adjust odds ratio (aOR) 2.58, 95% confidence interval (CI) 1.70 to 3.90 for AD; aOR 4.38, 95% CI 2.30 to 8.35 for ILD), male gender (aOR 2.57, 95% CI 1.22 to 5.42 for AD; aOR 5.48, 95% CI 2.20 to 13.65 for ILD) were factors associated with AD and ILD in RA patients. ILD was associated with short disease duration (aOR 0.30, 95% CI 0.14 to 0.62), AD was associated with high titers of anti-cy- clic citrullinated peptides antibodies (anti-CCP; aOR 1.61, 95% CI 1.07 to 2.44). Conclusion. AD was the most frequent lung involvement in patients with RA. Old age and male gender were both associated with AD and ILD. Short disease duration was associated with ILD. High titers of anti-CCP was associated with AD. (J Rheum Dis 2016;23:101-108)

Interstitial lung disease in rheumatoid arthritis treated with methotrexate: A pragmatic approach

Interstitial lung disease in rheumatoid arthritis treated with methotrexate: A pragmatic approach

Clinical and laboratory factors associated with interstitial lung disease in rheumatoid arthritis.

The objective of this study is to examine the clinical, genetic, and environmental factors associated with interstitial lung disease (ILD) in rheumatoid arthritis (RA). We recruited patients with RA from rheumatology practices at the time of a scheduled visit. Each patient participated in a comprehensive assessment that included ascertainment of age, sex, joint tenderness and swelling, subcutaneous nodules, disease severity, use of methotrexate and prednisone, smoking status, rheumatoid factor (RF), antibodies against cyclic citrullinated peptide (anti-CCP),erythrocyte sedimentation rate (ESR), the 28-joint Disease Activity Score (DAS28), and the presence of the HLA-DRB1 shared epitope (SE). As part of a thorough quantification of comorbidity, we identify all comorbid conditions, including ILD. We examined variables associated with ILD using logistic regression. We tested interaction terms between SE and other covariates. We studied 779 RA patients, among whom, ILD was recognized clinically in 69 (8.8 %). Variables significantly associated with ILD in a multivariable analysis included male sex, RA duration, the ESR, the DAS28, anti-CCP, and RF. There was a significant interaction between the HLA-DRB1 SE and smoking, ILD being associated with smoking only in the presence of SE. The association between ILD and anti-CCP, RF, and the ESR displayed a biological gradient, higher titers being more strongly associated with ILD. Anti-CCP antibodies and the RF may be pathogenically related to ILD. The association between ILD and smoking is dependent on the HLA-DRB1 SE, which may reflect gene-environment interaction.

Rheumatoid arthritis and lung - more than a minor aspect of the disease

Although rheumatoid arthritis (RA) mainly manifests as polyarthritis, there is growing evidence that the initiation of the pathological immune reaction against citrullinated peptides takes place in the lung. However, in spite of this important role of the lung in pathophysiology, clinically manifest lung involvement has been demonstrated only in about 2-5 % of the patients with RA, and therefore is relatively rare. In particular the severe interstitial lung involvement with histological pattern of usual interstitial pneumonia has a bad prognosis and an increased mortality. Methotrexate (MTX), as the most important disease modifying drug for treatment of RA is not associated with the appearance or progression of interstitial lung disease in RA. MTX-induced pneumonitis is a rare, although potentially severe complication of this treatment.

100. Are we Screening Appropriately for Interstitial Lung Disease in Rheumatoid Arthritis? A Study into the Use of Lung Function Tests at Predicting ILD

100. Are we Screening Appropriately for Interstitial Lung Disease in Rheumatoid Arthritis? A Study into the Use of Lung Function Tests at Predicting ILD

Interstitial lung disease in rheumatoid arthritis: Current concepts in pathogenesis, diagnosis and therapeutics

Interstitial lung disease in rheumatoid arthritis: Current concepts in pathogenesis, diagnosis and therapeutics

Anti-Cyclic Citrullinated Peptide Antibodies and Severity of Interstitial Lung Disease in Women with Rheumatoid Arthritis.

Objective. To evaluate whether serum titers of second-generation anticyclic citrullinated peptide antibodies (anti-CCP2) are associated with the severity and extent of interstitial lung disease in rheumatoid arthritis (RA-ILD). Methods. In across-sectional study, 39 RA-ILD patients confirmed by high-resolution computed tomography (HRCT) were compared with 42 RA without lung involvement (RA only). Characteristics related to RA-ILD were assessed in all of the patients and serum anti-CCP2 titers quantified. Results. Higher anti-CCP2 titers were found in RA-ILD compared with RA only (medians 77.9 versus 30.2 U/mL, P < 0.001). In the logistic regression analysis after adjustment for age, disease duration (DD), smoke exposure, disease activity, functioning, erythrocyte sedimentation rate, and methotrexate (MTX) treatment duration, the characteristics associated with RA-ILD were higher anti-CCP2 titers (P = 0.003) and + RF (P = 0.002). In multivariate linear regression, the variables associated with severity of ground-glass score were anti-CCP2 titers (P = 0.02) and with fibrosis score DD (P = 0.01), anti-CCP2 titers (P < 0.001), and MTX treatment duration (P < 0.001). Conclusions. Anti-CCP2 antibodies are markers of severity and extent of RA-ILD in HRCT. Further longitudinal studies are required to identify if higher anti-CCP2 titers are associated with worst prognosis in RA-ILD.

The lung may play a role in the pathogenesis of rheumatoid arthritis.

Multiple studies have identified strong associations between the lung and rheumatoid arthritis (RA). Such studies identify a high prevalence of lung disease, both airways and parenchymal disease, in subjects with clinically classifiable RA. It has been suggested that lung disease in RA results from targeting of the lung from circulating autoimmunity or other factors such as medications. However, findings that lung disease, specifically inflammatory airways disease, and lung generation of autoimmunity can be present before the onset of joint symptoms suggest that immune reactions in the lung may be involved in the initial development of RA-related autoimmunity. Herein we review these issues in detail, as well as outline a potential research agenda to understand the natural history of lung involvement in RA and its relation to the overall pathogenesis of RA.

Incidence and Mortality of Obstructive Lung Disease in Rheumatoid Arthritis: A Population‐Based Study

Pulmonary disease represents an important extraarticular manifestation of rheumatoid arthritis (RA). While the association of RA and interstitial lung disease is widely acknowledged, obstructive lung disease (OLD) in RA is less well understood. We therefore aimed to assess the incidence, risk factors, and mortality of OLD in patients with RA. We examined a population-based incident cohort of patients with RA and a comparison cohort of individuals without RA. OLD was defined using a strict composite criterion. Cox proportional hazards models were used to compare OLD incidence between the RA and comparator cohorts to investigate risk factors and to explore the impact of OLD on patient survival. A total of 594 patients with RA and 596 subjects without RA were followed for a mean of 16.3 and 19.4 years, respectively. The lifetime risk of developing OLD was 9.6% for RA patients and 6.2% for subjects without RA (hazard ratio [HR] 1.54, 95% confidence interval [95% CI] 1.01-2.34). The risk of developing OLD was higher among male patients, among current or former smokers, and for individuals with more severe RA. Survival of RA patients diagnosed with OLD was worse compared to those without OLD (HR 2.09, 95% CI 1.47-2.97). Patients with RA are at higher risk of developing OLD, which is significantly associated with premature mortality. Effective diagnostic and therapeutic strategies to detect and manage OLD in patients with RA may help to improve survival in these patients.

AB0217 Relationship between anti-ccp positivity, results of pulmonary function tests and high resolution computed tomography of the lung in patients with rheumatoid arthritis

BackgroundInterstitial lung disease (ILD) represents a severe manifestation in connective tissue diseases, and is it still a challenge for clinicians evaluation and management. ILD is the most common manifestations of...

Prognostic Factors and Radiographic Outcomes of Nontuberculous Mycobacterial Lung Disease in Rheumatoid Arthritis

The aims of our study were to retrospectively review patients with rheumatoid arthritis (RA) with nontuberculous mycobacterial (NTM) lung disease, to assess the prognostic factors, and to analyze the time to disease deterioration according to the antirheumatic drugs received during the NTM lung disease followup period. We retrospectively analyzed medical records of 98 HIV-negative RA patients with NTM lung disease treated at our institution, and investigated potential risk factors of mortality with Cox regression analysis. Time to radiologic deterioration was evaluated if antirheumatic drugs were not changed during observational periods and computed tomography was performed once each year. Mean patient age was 67.6 years, and median followup period was 4.4 years. NTM species included Mycobacterium avium complex (83.7%), M. kansasii (6.1%), M. gordonae (6.1%), and others (4.1%). Radiographic features included nodular/bronchiectatic (NB) disease (57.1%), fibrocavitary (FC) disease (14.3%), FC+NB disease (16.3%), and other types (12.2%). Initial management included observation in 74 (75.5%) patients. Negative prognostic factors of mortality were C-reactive protein (CRP) ≥ 1.0 mg/dl and radiographic features of FC, FC+NB, or other disease types. Median time to radiologic deterioration was 3.6 years. Erythrocyte sedimentation rate (ESR) > 50 mm/h was a negative prognostic factor of radiologic deterioration. The most frequent NTM species was M. avium complex. CRP and radiographic features were prognostic factors for all-cause mortality, and ESR was a prognostic factor of radiologic deterioration. Further studies are warranted focusing on time to disease deterioration according to antirheumatic drug received during NTM followup.

The Multifaceted Aspects of Interstitial Lung Disease in Rheumatoid Arthritis

Interstitial lung disease (ILD) is a relevant extra-articular manifestation of rheumatoid arthritis (RA) that may occur either in early stages or as a complication of long-standing disease. RA related ILD (RA-ILD) significantly influences the quoad vitam prognosis of these patients. Several histopathological patterns of RA-ILD have been described: usual interstitial pneumonia (UIP) is the most frequent one, followed by nonspecific interstitial pneumonia (NSIP); other patterns are less commonly observed. Several factors have been associated with an increased risk of developing RA-ILD. The genetic background plays a fundamental but not sufficient role; smoking is an independent predictor of ILD, and a correlation with the presence of rheumatoid factor and anti-cyclic citrullinated peptide antibodies has also been reported. Moreover, both exnovo occurrence and progression of ILD have been related to drug therapies that are commonly prescribed in RA, such as methotrexate, leflunomide, anti-TNF alpha agents, and rituximab. A greater understanding of the disease process is necessary in order to improve the therapeutic approach to ILD and RA itself and to reduce the burden of this severe extra-articular manifestation.

Interstitial lung disease in rheumatoid arthritis: an update on diagnosis and management

There has been increasing recognition of the importance of respiratory disease in patients with rheumatoid arthritis (RA) over the last 5 years. Interstitial lung disease (ILD) is the only complication of RA increasing in prevalence and accounts for approximately 6% of all RA deaths, with a mean survival of just 3 years following diagnosis in several historic series. Clinically significant ILD is present in approximately 3–5% of all RA patients, making RA-ILD a common and potentially fatal disorder. Although the presence of RA-ILD increasingly influences therapeutic decision-making, our understanding of its pathogenesis remains limited, as is the evidence base to guide therapeutic intervention. Recent data suggests that RA-ILD may relate to smoking and/or the presence of CCP antibodies. High-resolution computed tomography has allowed clarification of the type and extent of pulmonary involvement without recourse to lung biopsy in most cases. Moreover, the use of certain therapeutic agents may be contraindi...

Association of Human Leukocyte Antigen with Interstitial Lung Disease in Rheumatoid Arthritis: A Protective Role for Shared Epitope

IntroductionInterstitial Lung Disease (ILD) is frequently associated with Rheumatoid Arthritis (RA) as one of extra-articular manifestations. Many studies for Human Leukocyte Antigen (HLA) allelic association with RA have been reported, but few have been validated in an RA subpopulation with ILD. In this study, we investigated the association of HLA class II alleles with ILD in RA.MethodsAn association study was conducted on HLA-DRB1, DQB1, and DPB1 in 450 Japanese RA patients that were or were not diagnosed with ILD, based on the findings of computed tomography images of the chest.ResultsUnexpectedly, HLA-DRB1*04 (corrected P [Pc] = 0.0054, odds ratio [OR] 0.57), shared epitope (SE) (P = 0.0055, OR 0.66) and DQB1*04 (Pc = 0.0036, OR 0.57) were associated with significantly decreased risk of ILD. In contrast, DRB1*16 (Pc = 0.0372, OR 15.21), DR2 serological group (DRB1*15 and *16 alleles) (P = 0.0020, OR 1.75) and DQB1*06 (Pc = 0.0333, OR 1.57, respectively) were significantly associated with risk of ILD.Conclusion HLA-DRB1 SE was associated with reduced, while DR2 serological group (DRB1*15 and *16) with increased, risk for ILD in Japanese patients with RA.

Interstitial Lung Disease in Rheumatoid Arthritis in the Era of Biologics

Interstitial lung disease (ILD) represents a severe manifestation in connective tissue diseases (CTD), with an overall incidence of 15%, and it is still a challenge for clinicians evaluation and management. ILD is the most common manifestation of lung involvement in Rheumatoid Arthritis (RA), observed in up to 80% of biopsies, 50% of chest Computed Tomography (CT) and only 5% of chest radiographs. Histopatological patterns of ILD in RA may present with different patterns, such as: usual interstitial pneumonia, non specific interstitial pneumonia, desquamative interstitial pneumonia, organizing pneumonia, and eosinophilic infiltration. The incidence of ILD in RA patients is not only related to the disease itself, many drugs may be in fact associated with the development of pulmonary damage. Some reports suggest a causative role for TNFα inhibitors in RA-ILD development/worsening, anyway, no definitive statement can be drawn thus data are incomplete and affected by several variables. A tight control (pulmonary function tests and/or HRCT) is mandatory in patients with preexisting ILD, but it should be also performed in those presenting risk factors for ILD and mild respiratory symptoms. Biologic therapy should be interrupted, and, after excluding triggering infections, corticosteroids should be administered.

Incidence and mortality of interstitial lung disease in rheumatoid arthritis: A population‐based study

Interstitial lung disease (ILD) has been recognized as an important comorbidity in rheumatoid arthritis (RA). We undertook the current study to assess incidence, predictors, and mortality of RA-associated ILD. We examined a population-based incidence cohort of patients with RA and a matched cohort of individuals without RA. All subjects were followed up longitudinally. The lifetime risk of ILD was estimated. Cox proportional hazards models were used to compare the incidence of ILD between cohorts, to investigate predictors, and to explore the impact of ILD on survival. Patients with RA (n = 582) and subjects without RA (n = 603) were followed up for a mean of 16.4 and 19.3 years, respectively. The lifetime risk of developing ILD was 7.7% for RA patients and 0.9% for non-RA subjects. This difference translated into a hazard ratio (HR) of 8.96 (95% confidence interval [95% CI] 4.02-19.94). The risk of developing ILD was higher in RA patients who were older at the time of disease onset, in male patients, and in individuals with more severe RA. The risk of death for RA patients with ILD was 3 times higher than in RA patients without ILD (HR 2.86 [95% CI 1.98-4.12]). Median survival after ILD diagnosis was only 2.6 years. ILD contributed approximately 13% to the excess mortality of RA patients when compared with the general population. Our results emphasize the increased risk of ILD in patients with RA. The devastating impact of ILD on survival provides evidence that development of better strategies for the treatment of ILD could significantly lower the excess mortality among individuals with RA.

Clinical and high resolution computed tomography characteristics of patients with rheumatoid arthritis lung disease

Rheumatoid arthritis (RA) is a systemic disease of unknown cause. A variety of pulmonary disorders have been described in association with RA. Among the most common are interstitial lung disease (ILD) and bronchiectasis. This study aims to determine the characteristics of RA patients with lung disease in relation to clinical characteristics, pulmonary function test (PFT) and high resolution computed tomography (HRCT) thorax. This is a 6-months cross-sectional study involving 63 consecutive RA patients in an outpatient rheumatology clinic. Patients had a mean disease duration of 5 years and above. Disease activity and severity was assessed by Disease Activity Score 28 (DAS28), Health Assessment Questionnaire (HAQ) and Rheumatoid Arthritis Articular Damage (RAAD) score. Full pulmonary function test (PFT) and HRCT of thorax were performed. The prevalence of RA-ILD is 44% and 67% of patients are asymptomatic. There was significant higher proportion (68%) in patients of Chinese ethnicity who have ILD. Diffusion capacity of carbon monoxide was abnormal in all patients and forced expiratory flow (FEF)(25-75%) was low in 16%. Restrictive pattern was 66.7% by PFT. The most common HRCT findings were reticulation (46%) followed by ground glass opacities (38.1%) and bronchiectasis (28.6%). There was no association between ILD and male gender, duration of the disease, smoking, rheumatoid factor, extra-articular manifestations, disease activity or severity.

Editor's Correspondence

Editor's Correspondence