Lung Disease In Rheumatoid Arthritis Research Articles

Prevalence and clinical characteristics of symptomatic diffuse interstitial lung disease in rheumatoid arthritis in a Spanish population

Background and objectivesIn Spain, epidemiological studies of the prevalence of diffuse interstitial lung disease (ILD) in rheumatoid arthritis (RA) are limited. Our objective was to estimate the prevalence of symptomatic ILD in RA and its characteristics in our area. Materials and methodsIn our hospital’s interdisciplinary rheumatology and pulmonology clinic, a prospective longitudinal observational study was designed in which we included RA with respiratory symptoms and ILD confirmed by high resolution computed tomography. ResultsOf the 2729 people with RA in our area, 47 had symptomatic ILD, estimating a prevalence of symptomatic ILD in RA of 1.72% (95% CI 1.26–2.29) with an age at diagnosis of RA of 57.3 ± 13.3 years. It was more frequent in men, 60.6% had a history of smoking, and 84.3% and 84.7% had rheumatoid factor (RF) and anti-cyclic citrullinated peptide (Anti-CCP) antibodies, respectively. The most frequent pattern was usual interstitial pneumonitis (UIP), appearing in 28 (31.1%). Nonspecific interstitial pneumonia (NSIP) was more frequent in women, while the combined pulmonary fibrosis-emphysema (CPFE) syndrome presented exclusively in men. ConclusionsWe have analysed the prevalence of symptomatic RA-ILD in our area, which is lower than expected, probably in relation to the definitions used. We have also described that the UIP pattern is the most frequent in RA in our environment, followed by the NSIP. Lastly, we have analysed the prevalence of CPFE in RA, which reaches 13%, for the first time.

Abatacept in rheumatoid arthritis-associated interstitial lung disease: short-term outcomes and predictors of progression

IntroductionInterstitial lung disease in rheumatoid arthritis (RA-ILD) is an extra-articular involvement that impairs the prognosis and for which there is still no well-coded treatment. The aim of this study was to evaluate abatacept (ABA) effectiveness and safety in patients with RA-ILD.MethodsRA-ILD patients who started ABA treatment were consecutively enrolled. Chest high-resolution computed tomography (HRCT), clinical, laboratory and respiratory function variables were collected at baseline and after 18 months of ABA treatment. HRCT abnormalities were evaluated using a computer-aided method (CaM). ABA response was established based on the change in the percentage of fibrosis evaluated at HRCT-CaM, dividing patients into “worsened” (progression ≥ 15%), “improved” (reduction ≥ 15%), and “stable” (changes within the 15% range). The multivariate regression model was used to assess the associations between RA characteristics and ABA response.ResultsForty-four patients (81% women, mean age 59.1 ± 8.0, mean disease duration of 7.5 ± 3.1 years) were studied. Five patients (11.4%) showed RA-ILD progression, 32 patients (72.6%) were considered stable, and 7 patients (16.0%) showed an RA-ILD improvement. The proportion of current smokers was significantly different between “worsened” patients, respect to those defined as "improved/stable” (p = 0.01). Current smoking habit (p = 0.005) and concomitant methotrexate treatment (p = 0.0078) were the two variables related to RA-ILD progression in multivariate regression analysis.ConclusionTreatment with ABA is associated with a RA-ILD stability or improvement in the 88.6% of patients. Current smoking habit and concomitant treatment with methotrexate are the modifiable factors associated with RA-ILD worsening.Key Points• Abatacept plays a favourable role in the control of RA-ILD, with a significant worsening in only 11.4% of patients during a 18-month follow-up period.• The predictive variables related to RA-ILD progression during abatacept therapy are the concomitant treatment with methotrexate and current smoking habit.

Lung involvement in rheumatic diseases

Lung involvement is one of the most frequent organ manifestation in rheumatic diseases (CTD-ILD). Especially patients with rheumatoid arthritis, systemic sclerosis, and idiopathic inflammatory myopathies are affected. Interstitial lung diseases (ILD) are still associated with significant morbidity and mortality. The last years have brought advances in management and treatment of ILDs. Methotrexate is probably not a significant cause of lung disease in rheumatoid arthritis but might even delay the presentation of interstitial lung disease (ILD). Tocilizumab could be a treatment option in SSc-ILD, despite the limitations of the current studies. For Systemic Sclerosis-ILD (SSc-ILD) and progressive fibrosing ILD, antifibrotic therapy with nintedanib is now approved.

Interstitial Lung Disease and its Associations in Rheumatoid Arthritis: Data from a District General Hospital in Sri Lanka.

Context:Interstitial lung disease (ILD) is a frequent pulmonary manifestation of rheumatoid arthritis (RA). No Sri Lankan studies have determined the prevalence of lung disease in RA and its associations.Aims:To find the prevalence of ILD in RA and its association with rheumatoid factor (RF), erosions, Disease activity score in 28 joints (DAS 28), disease duration, Body mass index(BMI), erythrocyte sedimentation rate (ESR), smoking, and also to determine the prevalence of lung disease with demographic factors like age, sex, and income.Settings and Design:Questionnaire based retrospective study at a District General Hospital in Sri Lanka.Materials and Methods:Diagnosed RA patients included through convenient sampling as it was a simple method that could facilitate data collection in a short duration. Since all patients with a diagnosis of RA were eligible, all consecutive patients with a diagnosis of RA at the rheumatology clinics were included in the study. To reduce the bias a large sample of patients were used as well as patients attending different rheumatology clinics were included and also patients who were referred to the hospital from peripheries were included in the study. The calculated sample size was 384 and according to patient numbers attending clinics, a period of 6 months was decided to select the study sample.Statistical Analysis Used:Chi-Square calculation and logistic regression analysis using Minitab 17 software.Results:From 384 patients, the prevalence of ILD was 14.58%, been 5.4% in early RA (<2 years disease duration). Mean age of ILD group was 52.94 years (95% CI 64.66-41.22). Mean RA duration was 7.69 years (95% CI, 2.38-12.99). Male to female sex ratio of RA was 1:7, and that of ILD was 2:9. DAS 28 was 4.58 (95% CI, 3.48-5.68). Statistically significant associations were noted with ILD and DAS 28 (P = .0006), ESR (P = .005), RF (P = .03), erosions (P < .00001), and smoking (P < .05). Mean BMI was 22.67 kg and 75.78% had low income (<50 000 rupees/month = 327 US $).Conclusions:ILD significantly associates RA severity indices like DAS 28, ESR, erosions, RF, and also with smoking. No significant association was found with BMI or gender difference. Therefore, disease severity indices could be used to predict progression to ILD in RA.

Biomarkers for interstitial lung disease and acute-onset diffuse interstitial lung disease in rheumatoid arthritis.

Interstitial lung disease (ILD) is frequently a complication of rheumatoid arthritis (RA) as an extra-articular manifestation which has a poor prognosis. Acute-onset diffuse ILD (AoDILD) occasionally occurs in RA and includes acute exacerbation of ILD, drug-induced ILD, and Pneumocystis pneumonia. AoDILD also confers a poor prognosis in RA. Previously-established biomarkers for ILD include Krebs von den lungen-6 and surfactant protein-D originally defined in patients with idiopathic pulmonary fibrosis; the sensitivity of these markers for RA-associated ILD (RA-ILD) is low. Although many studies on ILD markers have been performed in idiopathic pulmonary fibrosis, only a few validation studies in RA-ILD or AoDILD have been reported. Biomarkers for RA-ILD and AoDILD are thus still required. Recently, genomic, cytokine, antibody, and metabolomic profiles of RA-ILD or AoDILD have been investigated with the aim of improving biomarkers. In this review, we summarize current preliminary data on these potential biomarkers for RA-ILD or AoDILD. The development of biomarkers on RA-ILD has only just begun. When validated, such candidate biomarkers will provide valuable information on pathogenesis, prognosis, and drug responses in RA-ILD in future.

Rheumatoid arthritis related interstitial lung disease - improving outcomes over 25 years: a large multicentre UK study.

This study explores whether the prognosis of interstitial lung disease in rheumatoid arthritis (RA-ILD) has improved over time and assesses the potential influence of drug therapy in a large multicentre UK network. We analysed data from 18 UK centres on patients meeting criteria for both RA and ILD diagnosed over a 25-year period. Data included age, disease duration, outcome and cause of death. We compared all cause and respiratory mortality between RA controls and RA-ILD patients, assessing the influence of specific drugs on mortality in four quartiles based on year of diagnosis. A total of 290 RA-ILD patients were identified. All cause (respiratory) mortality was increased at 30% (18%) compared with controls 21% (7%) (P=0.02). Overall, prognosis improved over quartiles with median age at death rising from 63 years to 78 years (P=0.01). No effect on mortality was detected as a result of DMARD use in RA-ILD. Relative risk (RR) of death from any cause was increased among patients who had received anti-TNF therapy [2.09 (1.1-4.0)] P=0.03, while RR was lower in those treated with rituximab [0.52(0.1-2.1)] or mycophenolate [0.65 (0.2-2.0)]. Patients receiving rituximab as their first biologic had longer three (92%), five (82%) and seven year (80%) survival than those whose first biologic was an anti-TNF agent (82%, 76% and 64%, respectively) (P=0.037). This large retrospective multicentre study demonstrates survival of patients with RA-ILD has improved. This may relate to the increasing use of specific immunosuppressive and biologic agents.

Performance of Administrative Algorithms to Identify Interstitial Lung Disease in Rheumatoid Arthritis.

To determine the performance of administrative-based algorithms for classifying interstitial lung disease (ILD) complicating rheumatoid arthritis (RA). Participants in a large, multicenter RA registry were screened for ILD using codes from the International Classification of Diseases, Ninth Revision (ICD-9) and the ICD-10. Medical record review confirmed ILD among participants screening positive and a random sample of those screening negative. ICD and procedure codes, provider specialty, and dates were extracted from Veterans Affairs administrative data to construct ILD algorithms. Performance of these algorithms against medical record review was assessed by sensitivity, specificity, positive predictive value (PPV), negative predictive value, and kappa using inverse probability weighting to account for sampling methods. Medical records of 536 RA patients were reviewed, confirming 182 (stringent definition) and 203 (relaxed definition) cases of ILD. Initially, we identified ≥2 ICD codes from inpatient or outpatient encounters as optimal discriminating factors (specificity 96.0%, PPV 65.5%; κ = 0.70). Subsequently, we constructed a set of ICD-9 and ICD-10 codes that improved algorithm specificity (specificity 96.8%, PPV 69.5%; κ = 0.72). Algorithms that included a pulmonologist diagnosis or chest computed tomography plus pulmonary function testing or lung biopsy had improved performance (specificity 98.0%, PPV 77.4%; κ = 0.75). PPV increased with exclusion of other ILD causes (78.5%) in comparison with the relaxed ILD definition (82.4%) and in sensitivity analyses (83.4-86.3%). Gains in specificity and PPV with greater algorithm requirements were accompanied by declines in sensitivity. Administrative algorithms with optimal combinations of ICD codes, provider specialty, diagnostic testing, and exclusion of other ILD causes accurately classify ILD in RA.

Increased serum soluble programmed death ligand 1(sPD-L1) is associated with the presence of interstitial lung disease in rheumatoid arthritis: A monocentric cross-sectional study.

This paper is to examine the relationship between serum soluble programmed death ligand 1(sPD-L1) levels and the development of interstitial lung disease (ILD) in patients with rheumatoid arthritis (RA). Serum sPD-L1 were measured by enzyme-linked immunosorbent assay. sPD-L1 levels in RA with ILD, RA without ILD and healthy controls were compared. Associations between ILD and various markers including sPD-L1 and confounding factors were investigated by logistic regression analysis. Diagnostic values of sPD-L1 for the presence of ILD were investigated using receiver operating characteristics curve analysis. Serum sPD-L1 levels were higher in RA patients with ILD than RA patients without ILD and healthy controls (23.7±9.8 vs. 18.0±7.7pg/mL, P=0.01 and 23.7±9.8 vs. 2.9±1.5pg/mL, P<0.0001). sPD-L1 levels were positively correlated with RF titer (r=0.245, P=0.03), CRP (r=0.265,P=0.01), HRCT score (r=0.265, P=0.04) and Ferritin (r=0.442, P=0.01), but negatively associated with FVC% (r=-0.359, P=0.01) and DLCO% (r=-0.399, P=0.008). sPD-L1 and anti-CCP antibody status were independently associated with the presence of ILD during multivariate logistic regression analysis. Sensitivity and specificity of sPD-L1 levels for the detection of ILD in RA patients were 51.7% and 79.3%, respectively (area under the curve=0.661). Serum sPD-L1 levels were increased in RA patients with ILD. Increased sPD-L1 levels were associated with the presence of ILD.

Decreased peripheral blood memory B cells are associated with the presence of interstitial lung disease in rheumatoid arthritis: a case-control study

Objectives Interstitial lung disease sometimes occurs in rheumatoid arthritis patients. Although the underlying immunological mechanisms responsible for interstitial lung disease associated with rheumatoid arthritis have not yet been clarified, some reports have suggested possible roles of B cells. To examine the role of B-cell subsets in interstitial lung disease in rheumatoid arthritis patients, we analyzed peripheral blood B-cell subsets. Methods We analyzed the frequencies of the peripheral blood B-cell subsets by flow cytometry in rheumatoid arthritis patients with and without interstitial lung disease (n = 16 and 81, respectively) and in healthy donors (n = 110) by high-resolution computed tomography. Results Compared with healthy donors, rheumatoid arthritis patients showed statistically higher frequencies of naive B cells and lower frequencies of memory B cells. Moreover, the frequencies of memory B cells were lower in rheumatoid arthritis patients with interstitial lung disease than in those without. Multivariate analysis showed that the frequency of memory B cells, particularly switched memory B cells, was significantly decreased in rheumatoid arthritis patients with interstitial lung disease, even after adjusting for prednisolone dose. Conclusions We suspect memory B cells play important roles in interstitial lung disease associated with rheumatoid arthritis.

Assessment of Interstitial Lung Disease in Rheumatoid Arthritis by Lung Ultrasound

Assessment of Interstitial Lung Disease in Rheumatoid Arthritis by Lung Ultrasound

Interstitial Lung Disease in Rheumatoid Arthritis Remains a Challenge for Clinicians.

Interstitial lung disease (ILD) is a serious complication of rheumatoid arthritis (RA) contributing to significantly increased morbidity and mortality. Other respiratory complications, such as chronic obstructive pulmonary disease and bronchiectasis, are frequent in RA. Infections and drug toxicity are important differential diagnoses and should be considered in the diagnostic work-up of patients with RA presenting with respiratory symptoms. This review provides an overview of the epidemiology and pathogenesis of RA-ILD, the radiological and histopathological characteristics of the disease as well as the current and future treatment options. Currently, there is no available evidence-based therapy for RA-ILD, and immunosuppressants are the mainstay of therapy. Ongoing studies are exploring the role of antifibrotic therapy in patients with progressive fibrotic ILD, which may lead to a new treatment approach for subgroups of patients with RA-ILD.

Effect of tumor necrosis factor inhibitors on interstitial lung disease in rheumatoid arthritis: angel or demon?

Objectives: This study evaluated the correlation between tumor necrosis factor alpha inhibitor (TNF-I) and interstitial lung disease (ILD) in rheumatoid arthritis (RA). We aimed to raise awareness and consummate therapy by summarizing the characteristics of the adverse events of ILD.Methods: A comprehensive search of the PubMed, Embase, Ovid, Cochrane, China National Knowledge Infrastructure, and Wanfang databases was performed from inception to November 2018. Statistical analysis of demographic characteristics, clinical features, and relative risks was performed using Microsoft Excel 2007 and SPSS version 20.0.Results: A total of 7 eligible articles and another 28 case reports were enrolled. The 7 cohort studies demonstrated the tendency that ILD cases might not benefit from TNF-I therapy. TNF-I might be associated with ILD adverse events. The case reports further confirmed these findings, as most (87.5%) of the cases showed that TNF-1 was harmful to patients with ILD and even resulted in a 35% mortality rate. Further investigation revealed that ILD adverse events tended to appear in female patients with a long RA history (p<0.05). The subgroup analysis suggested that early detection and precise treatment are key factors in determining survival or death when an ILD adverse event occurs. A large proportion of ILD adverse events (48.6%) appeared at 2.38±1.03 weeks after the infusion of infliximab.Conclusion: A fresh look at the evidence highlights that TNF-I might be associated with ILD adverse events in RA, which can induce more severe pulmonary symptoms and even result in death. Therefore, more attention should be paid to effective prevention, early diagnosis, and precise management. Notably, further prospective cohort studies are warranted to better interpret the association or causality between TNF-I and ILD.

Combined Collagen-Induced Arthritis and Organic Dust-Induced Airway Inflammation to Model Inflammatory Lung Disease in Rheumatoid Arthritis.

Rheumatoid arthritis (RA) is characterized by extra-articular involvement including lung disease, yet the mechanisms linking the two conditions are poorly understood. The collagen-induced arthritis (CIA) model was combined with the organic dust extract (ODE) airway inflammatory model to assess bone/joint-lung inflammatory outcomes. DBA/1J mice were intranasally treated with saline or ODE daily for 5 weeks. CIA was induced on days 1 and 21. Treatment groups included sham (saline injection/saline inhalation), CIA (CIA/saline), ODE (saline/ODE), and CIA + ODE (CIA/ODE). Arthritis inflammatory scores, bones, bronchoalveolar lavage fluid, lung tissues, and serum were assessed. In DBA/1J male mice, arthritis was increased in CIA + ODE > CIA > ODE versus sham. Micro-computed tomography (µCT) demonstrated that loss of BMD and volume and deterioration of bone microarchitecture was greatest in CIA + ODE. However, ODE-induced airway neutrophil influx and inflammatory cytokine/chemokine levels in lavage fluids were increased in ODE > CIA + ODE versus sham. Activated lung CD11c+ CD11b+ macrophages were increased in ODE > CIA + ODE > CIA pattern, whereas lung hyaluronan, fibronectin, and amphiregulin levels were greatest in CIA + ODE. Serum autoantibody and inflammatory marker concentrations varied among experimental groups. Compared with male mice, female mice showed less articular and pulmonary disease. The interaction of inhalation-induced airway inflammation and arthritis induction resulted in compartmentalized responses with the greatest degree of arthritis and bone loss in male mice with combined exposures. Data also support suppression of the lung inflammatory response, but increases in extracellular matrix protein deposition/interstitial disease in the setting of arthritis. This coexposure model could be exploited to better understand and treat RA-lung disease. © 2019 American Society for Bone and Mineral Research.

Clinicoradiological profile of interstitial lung disease in rheumatoid arthritis

Background: The burden of interstitial lung disease (ILD) in rheumatoid arthritis (RA) patients in resource limited countries like India is often under-reported. This study was conducted to find out the clinicoradiological profile of ILD in patients with RA in India.&#x0D; Aims and Objectives: (1)To find out the frequency of Interstitial Lung Disease (ILD) in Rheumatoid Arthritis (RA) (2) To correlate the clinical findings with those of radiological(Chest x-ray &amp; HRCT Thorax) and pulmonary function tests including Spirometry, TLCO (Diffusing capacity of the Lung for Carbon monoxide/DLCO Corrected for alveolar volume i.e., DLCO/V) Estimation.&#x0D; Materials and Methods: Thirty consecutive patients of RA (with or without pulmonary symptoms or signs) who fulfill the American Classification of Rheumatology criteria1987 were selected from the patients attending the General Medicine OPD (Rheumatology Division) of B.R. Singh Hospital during the study period regardless of being on any medications for RA. This was a cross-sectional, descriptive study. Results were tabulated in Microsoft office excel worksheet and descriptive statistics were expressed as means, standard deviations (SD) mean for continuous normally distributed data and as percentages. Statistical software SPSS version 19.0 was used for data analysis. Unpaired t test (for continuous data)/Chi square test (for proportion) was used for comparing cases and controls.&#x0D; Results: The frequency of ILD in RA was 60%. Female patients with a positive rheumatoid factor had a greater chance of development of ILD.The frequency was found to be increased after the age of 40 years. Though in this study 60% of patients had restrictive pattern, 31% had obstructive and 3 % had mixed pattern on Spirometry. The patients with deforming RA had greater frequency of restrictive or mixed pattern on Spirometry. 22.22% patients had a decreased TLCO despite having normal CXR. Despite being asymptomatic12 patients had restrictive lung disease and reduced TLCO with HRCT evidence of ILD. Overall, Spirometry &amp; TLCO are the most appropriate tests to detect restrictive lung disease in patients with RA. In fact, HRCT can show evidence of ILD even when clinical parameters and Chest X-ray are normal.On HRCT of thorax reticular pattern and sub-pleural fibrosis (UIP-Usual interstitial pneumonia) are the predominant pattern.&#x0D; Conclusion: The frequency of ILD in RA is quite high. It may be recommended to use Spirometry &amp; TLCO as screening test for detection of restrictive lung disease in patients with RA who should undergo HRCT of chest to confirm presence of ILD in a resource limited setting.

A CASE OF NEWLY DIAGNOSED RHEUMATOID ARTHRITIS IN AN OCTOGENARIAN PRECEDED BY A 10-YEAR HISTORY OF BRONCHIECTASIS AND MULTIPLE DVTS

SESSION TITLE: Lung Pathology 1 SESSION TYPE: Fellow Case Report Posters PRESENTED ON: 10/09/2018 01:15 PM - 02:15 PM INTRODUCTION: Bronchiectasis is a disease increasing in prevalence in the United States with an estimated 100,000 patients affected. Common etiologies include cystic fibrosis, sequala of prior pulmonary infection, immune dysregulation and rheumatologic disorders. We present a case of rheumatoid arthritis diagnosed in an octogenarian, preceded by a 10-year history of progressive bronchiectasis and multiple DVTs. CASE PRESENTATION: A 79 year old male with history of upper and lower extremity DVTs, seborrheic dermatitis and pancytopenia was seen in clinic for evaluation of progressive bronchiectasis, first documented 10 years prior. Serial imaging revealed previously stable, mild, basal predominant disease (Fig. 1) with evidence of more rapid progression over the last 2 years (Fig. 2.) The patient remained essentially asymptomatic except for a dry cough. He was scheduled for diagnostic bronchoscopy, but before he could undergo the procedure, he presented to the ED with bilateral hand swelling and pain. Repeat ultrasound revealed increased propagation of his known upper extremity DVT while on Apixaban. There was increased concern at that time for underlying hypercoagulable state. Rheumatologic workup was undertaken, remarkable for elevated SS-A antibody, positive RF and ANA, negative CCP. The patient was treated with prednisone 15 mg daily which resulted in rapid symptom improvement. He then underwent bronchoscopy, which revealed normal cytology and cell differential and no growth on cultures. The patient was rapidly titrated down to 7.5 mg prednisone with continued resolution of his bilateral hand swelling. Repeat serologic testing showed him to have a persistent markedly elevated RF. At that time he was diagnosed with rheumatoid arthritis by 2010 ACR criteria. DISCUSSION: Extra-articular manifestations of rheumatoid arthritis are many, including VTE (2X increased risk) and pulmonary disease (up to 39-60% of patients.) Bronchiectasis is a less common pulmonary manifestation of the disease (2-3.1% prevalence in RA population.) In our patient, an evaluation for other causes of bronchiectasis was extensive and unrevealing. Bronchiectasis is much more commonly seen after the development of arthritis in RA, and is thought to result from activation of a common inflammatory pathway. In our patient, the reverse appears to be the case. He had a period of more rapid progression of bronchiectasis preceding the development of a new DVT and arthritis and finally leading to a diagnosis of RA. This pathophysiologic sequence may help explain the unusually advanced age at RA diagnosis (median age is 58.) CONCLUSIONS: Bronchiectasis is commonly associated with immune dysfunction. Rheumatoid arthritis is commonly associated with bronchiectasis, and the presence of bronchiectasis may act as a harbinger of RA, even many years before symptoms sufficient for diagnosis develop. Reference #1: Wilczynska M, Condliffe A, McKeon D. Coexistence of bronchiectasis and rheumatoid arthritis: revisited. Respir Care. 2013 Apr;58(4):694-701. Reference #2: Yunt Z, Solomon J. Lung disease in rheumatoid arthritis. Rheum Dis Clin North Am. 2015 May;41(2):225-36. Reference #3: Innala L et al. Age at onset determines severity and choice of treatment in early rheumatoid arthritis: a prospective study. Arthritis Res Ther. 2014 Apr 14;16(2):R94. DISCLOSURES: No relevant relationships by Andrew Hersh, source=Web Response No relevant relationships by Ian McInnis, source=Web Response Speaker/Speaker's Bureau relationship with Janssen Pharmaceuticals Please note: $1001 - $5000 Added 11/27/2017 by Michael Morris, source=Web Response, value=Consulting fee Speaker/Speaker's Bureau relationship with Vyaire Medical Please note: $1001 - $5000 Added 11/27/2017 by Michael Morris, source=Web Response, value=Consulting fee

Interleukin-18 is associated with the presence of interstitial lung disease in rheumatoid arthritis: a cross-sectional study

Objective: Serum interleukin-18 (IL-18) levels are increased in patients with interstitial lung disease (ILD). In addition, IL-18 levels are increased in patients with rheumatoid arthritis (RA) and are associated with arthritis activity. We determined whether increased IL-18 levels are associated with ILD in RA.Method: RA patients were enrolled using an RA cohort database. Plasma IL-18 levels were measured by enzyme-linked immunosorbent assay. ILD was determined by a pulmonologist and a radiologist based on chest radiography and computed tomography findings. IL-18 levels for RA with ILD and RA without ILD were compared. Associations between ILD and various markers including IL-18 and confounding factors (e.g. smoking history) were investigated by logistic regression analysis. Diagnostic values of IL-18 for the presence of ILD were investigated using receiver operating characteristics curve analysis.Results: ILD was complicated in 8.2% (n = 26) of the study population (N = 312). Plasma IL-18 levels were higher for RA patients with ILD than for RA patients without ILD (721.0 ± 481.4 vs 436.8 ± 438.9 pg/mL, p < 0.001). IL-18, Krebs von den Lungen-6, and anti-cyclic citrullinated peptide antibody titre and glucocorticoid doses were independently associated with the presence of ILD during multivariate logistic regression analysis. Sensitivity and specificity of IL-18 levels for the detection of ILD in RA patients were 65.3% and 76.3%, respectively (area under the curve = 0.73).Conclusion: Plasma IL-18 levels were higher for RA patients with ILD than for those without ILD. Increased IL-18 levels were associated with the presence of ILD.

Autoreactive T cells to citrullinated HSP90 are associated with interstitial lung disease in rheumatoid arthritis.

Previous analysis of comparative anti-citrullinated heat shock protein 90 (citHSP90) antibody profiles between bronchoalveolar lavage fluid and serum indicates that the lung plays a direct role in shaping the immune repertoire of rheumatoid arthritis-associated interstitial lung disease (RA-ILD). To address the contribution of citHSP90β-specific T cells in this process, we evaluated invitro cytokine responses to citHSP90β in RA patients with different stages of ILD as well as in controls with non-RA connective tissue disease-associated ILD (CTD-ILD). Cultures derived from whole blood were individually stimulated with HSP90β, citHSP90β, citrullinated BSA, or no antigen. The concentrations of 13 cytokines and chemokines in the plasma supernatant were then measured using Luminex xMAP technology. CitHSP90β induced significantly higher levels of interferon-γ (IFN-γ) levels in RA-ILD (interstitial lung abnormalities=2+3) groups compared to the RA-no ILD group (P=0.01), but did not stimulate the production of other cytokines (P>0.05). Furthermore, citHSP90β did not stimulate the production of IFN-γ or other cytokines in those individuals with non-RA CTD-ILD. Overall, the production of IFN-γ by T cells stimulated with citHSP90β demonstrates a bias toward TH1 immune responses that are likely involved in the pathogenesis of RA-ILD.

Fibrocyte measurement in peripheral blood correlates with number of cultured mature fibrocytes in vitro and is a potential biomarker for interstitial lung disease in Rheumatoid Arthritis

BackgroundInterstitial lung disease (ILD) can be a severe extra-articular disease manifestation in Rheumatoid Arthritis (RA). A potential role of fibrocytes in RA associated ILD (RA-ILD) has not previously been described. We present a modified faster method for measuring circulating fibrocytes, without intracellular staining. The results are compared to the traditional culture method, where the number of monocytes that differentiate into mature fibrocytes in vitro are counted. The results are following compared to disease activity in patients with severe asthma, ILD, RA (without diagnosed ILD) and RA with verified ILD (RA-ILD).MethodCD45+ CD34+ CD11b+ (7-AAD− CD3− CD19− CD294−) cells were isolated by cell sorting and stained for pro-collagen type 1. Thirty-nine patients (10 RA, 9 ILD and 10 with severe asthma, 10 with RA-ILD) and 10 healthy controls (HC) were included. Current medication, disease activity, pulmonary function test and radiographic data were collected. Circulating fibrocytes were quantified by flow cytometry. Peripheral blood mononuclear cells were isolated and cultured for 5 days and the numbers of mature fibrocytes were counted.Results90.2% (mean, SD = 1.5%) of the sorted cells were pro-collagen type 1 positive and thereby fulfilled the criteria for being circulating fibrocytes. The ILD and RA-ILD groups had increased levels of circulating fibrocytes compared to HC (p < 0.05). Levels of circulating fibrocytes correlated overall to number of monocytes that subsequently in vitro differentiated to mature fibrocytes (r = 0.81, p < 0.001). RA patients with pathologically reduced diffusion capacity for carbon monoxide adjusted for hemoglobin (DLCOc) in both the RA and in the combined RA + RA-ILD group, had significantly higher levels of both circulating and number of cultured mature fibrocytes (both p < 0.05). In both groups, the level of circulating fibrocytes and number of mature fibrocytes in culture also correlated to a reduction in DLCOc (r = −0.61 an r = −0.58 both p < 0.05).ConclusionsWe presented a fast and valid method for measuring circulating fibrocytes using flow cytometry on lysed peripheral blood. Further, we showed for the first time, that the level of circulating fibrocytes correlated with the number of peripheral blood mononuclear cells, that differentiated into mature fibrocytes in vitro. Reduced DLCOc was correlated with high levels of circulating and mature fibrocytes in RA, which have not been reported previously. In such, this study suggests that fibrocytes may exhibit an important role in the pathogenesis of RA-ILD, which requires further clarification in future studies.Trial registrationClinicalTrials.gov:NCT02711657, registered 13/3–2016, retrospectively registered.

Clinical characteristics associated with occurrence and poor prognosis of interstitial lung disease in rheumatoid arthritis.

Background/AimsTo analyze clinical characteristics of interstitial lung disease (ILD) associated with rheumatoid arthritis (RA), especially in patients with poor prognosis. MethodsSeventy-seven RA patients with ILD and 231 age, sex, and disease duration-matched RA patients without ILD were enrolled in this retrospective study. Epidemiologic, clinical, and laboratory information were obtained through a medical chart review. Logistic regression analysis was used to estimate the risk of mortality in RA patients with ILD. ResultsCompared to the RA without ILD group, the RA with ILD group had significantly higher titers of rheumatoid factor and the anti-cyclic citrullinated peptide (p = 0.001 for both), higher levels of C-reactive protein (CRP) at the time of RA diagnosis (p = 0.014), and a higher erythrocyte sedimentation rate (p = 0.022) and CRP levels (p < 0.001) throughout the 10-year follow-up period. These patients also received a higher mean daily dose of corticosteroids (p < 0.001). In the subgroup analysis of RA patients with ILD, 28 patients (36.4%) died during follow-up. Multivariate analysis revealed that older age at the time of ILD diagnosis was significantly associated with mortality. Usual interstitial pneumonia (UIP) subtype on high-resolution computed tomography (HRCT) was also suggested as a poor prognostic factor. ConclusionsThe survival of RA patients with ILD is adversely affected by age at the time of ILD diagnosis. RA-ILD patients diagnosed after age 65 or with a UIP subtype on HRCT may have a poor prognosis.

Methotrexate and lung disease in rheumatoid arthritis.

Rheumatoid arthritis (RA) is a common chronic inflammatory disease affecting many tissues and resulting in substantial morbidity and increased mortality. Arthritis is the most notable clinical feature, but extra-articular features can have devastating consequences. Pulmonary manifestations are common in RA, with high rates of disease related lung disease and a propensity to pulmonary infections. Respiratory illness remains a leading cause of death among RA populations. Modern medicine greatly reduces the illness burden among patients with RA, particularly through the use of disease-modifying medications. Methotrexate is recommended as the first-line treatment of RA as it effectively reduces disease activity, morbidity and mortality. However, it has long been implicated as a causative agent in lung disease. The evidence for a cause and effect relationship in modern populations is contentious, but critically important. Increasing recognition of the importance and prevalence of interstitial lung disease in RA, and recent studies on the incidence of lung disease among RA and non-RA populations have cast doubt on the role of methotrexate as a causative agent. A correct understanding of the complex pulmonary disease processes in RA is crucial if we are to improve outcomes in this patient group. In this article we will discuss the epidemiology and characteristics of lung disease in rheumatoid arthritis and its possible relationship to methotrexate use.