Rheumatoid Arthritis-associated Interstitial Lung Disease Research Articles

Related factors, increased mortality and causes of death in patients with rheumatoid arthritis-associated interstitial lung disease

Objectives: Interstitial lung disease (ILD) is a life-threatening extra-articular manifestation of rheumatoid arthritis (RA). We aimed to clarify the relationship between chronic ILD with a pattern of usual interstitial pneumonia (UIP) or non-UIP and mortality in RA patients.Methods: We retrospectively surveyed information of consecutive RA patients who visited our hospital from 2009 to 2014. The relationship between their mortality and chronic ILD (UIP or non-UIP) detected by high-resolution computed tomography was examined.Results: Of 2702 patients enrolled, 261 (9.7%) had chronic ILD and among these 120 had a UIP pattern. At the onset of RA, the prevalence of chronic ILD was 6%. Patients with chronic ILD had a higher mortality than those without. The most frequent cause of death was pneumonia including acute exacerbation (AE) of chronic ILD. Lung cancer death was frequently identified in deceased patients with chronic ILD with a UIP pattern compared with the other decedents (p=.062). The estimated mortality of lung cancer in patients with chronic ILD with a UIP pattern was five times higher than the general population.Conclusion: RA patients with ILD with a UIP pattern have a high mortality rate and are prone to die of AE or lung cancer.

Increased circulating Wnt5a protein in patients with rheumatoid arthritis-associated interstitial pneumonia (RA-ILD)

An early diagnosis of interstitial lung disease (ILD) is important for guiding treatments of rheumatoid arthritis (RA)-associated ILD (RA-ILD) in clinical settings. The non-canonical Wnt signaling representative ligand Wnt5a was recently found to involve in idiopathic pulmonary fibrosis (IPF) and pathogenesis of RA. The goal of this study was to examine the clinical relevance of Wnt5a in RA-ILD. In this report, the clinical relevance of plasma Wnt5a protein was evaluated in 40 RA-ILD patients and 41 non-ILD RA cohorts. The results showed an elevated Wnt5a protein in plasmas of RA-ILD patients compared with non-ILD RA patients (p < 0.01), which was positively correlated with the plasma level of rheumatoid factor (RF). Of note, more abundant Wnt5a was also found in patients with usual interstitial pneumonia (UIP) than those with nonspecific interstitial pneumonia (NSIP) and other ILD patterns. More importantly, the disease severity was correlated with the circulating Wnt5a as ascertained by high-resolution computed tomography (HRCT)-UIP scores. The multiple-factor non-conditional logistic regression analysis further revealed that the age, RA duration, smoking and plasma Wnt5a were risk factors with clinical significance for RA-ILD. Interestingly, more Wnt5a-positive patients were identified in RA-ILD smokers relative to RA-ILD never-smokers, and longer smoking duration was strongly correlated with Wnt5a in RA-ILD patients. In consistence, ROC curve also suggested that the Wnt5a was a potential candidate biomarker for identifying patients with RA-UIP. These results demonstrate that the circulating Wnt5a may be a risk factor and potential biomarker for identifying UIP and accessing the severity and progression of ILD in RA patients.

Profibrotic effect of IL-17A and elevated IL-17RA in idiopathic pulmonary fibrosis and rheumatoid arthritis-associated lung disease support a direct role for IL-17A/IL-17RA in human fibrotic interstitial lung disease.

Interleukin (IL)-17 is a T helper 17 cytokine implicated in the pathogenesis of many autoimmune diseases, including rheumatoid arthritis (RA). Although IL-17A has a well-established role in murine pulmonary fibrosis models, its role in the tissue remodeling and fibrosis occurring in idiopathic pulmonary fibrosis (IPF) and RA-associated interstitial lung disease (RA-ILD) is not very well defined. To address this question, we utilized complimentary studies to determine responsiveness of human normal and pathogenic lung fibroblasts to IL-17A and used lung biopsies acquired from patients with IPF and RA-ILD to determine IL-17A receptor (IL-17RA) expression. Both normal and pathogenic IPF lung fibroblasts express functional IL-17RA and respond to IL-17A stimulation with cell proliferation, generation of extracellular matrix (ECM) proteins, and induction of myofibroblast transdifferentiation. Small interfering RNA (siRNA) silencing of IL-17RA attenuated this fibroblast response to IL-17A on ECM production. These fibroblast responses to IL-17A are dependent on NF-κB-mediated signaling. In addition, inhibiting Janus activated kinase (JAK) 2 by either siRNA or a selective pharmacological inhibitor, AZD1480-but not a JAK1/JAK3 selective inhibitor, tofacitinib-also significantly reduced this IL-17A-induced fibrogenic response. Lung biopsies of RA-ILD patients demonstrate significantly higher IL-17RA expression in areas of fibroblast accumulation and fibrosis, compared with either IPF or normal lung tissue. These observations support a direct role for IL-17A in lung fibrosis that may be particularly relevant in the context of RA-ILD.

Vitamin D deficiency and pulmonary affection in rheumatoid arthritis

Background Vitamin D appears to play a key role both in the innate and in the adaptive immune system, and the presence of its receptors in different cell types seems to play a role in the pathogenesis of rheumatoid arthritis (RA). Vitamin D deficiency is common and seems to be correlated with the course of RA and outcome of pulmonary disease, which is a major contributor to morbidity and mortality in RA patients. Aim This study aimed to evaluate the prevalence of vitamin D deficiency and its relationship with pulmonary affection in a cohort of Egyptian RA patients. Patients and methods A total of 100 RA patients were enrolled in this study, who underwent a clinical examination, with a focus on articular and extra-articular manifestations including pulmonary manifestations. Assessment of RA disease activity was performed using the disease activity score (DAS)-28 score and serum vitamin D level was measured. Spirometry and diffusion lung capacity for carbon monoxide were performed. Radiographic evaluation, Plain x-ray on hands, chest x-ray and high-resolution computed tomography (HRCT) chest were done. Results Our study included 100 RA patients (40 patients with pulmonary affection and 60 patients without pulmonary affection). DAS-28 and rheumatoid factor titer were increased in RA patients with pulmonary affection. Moreover, vitamin D serum levels were decreased in RA patients with pulmonary affection. Multiple regression analysis showed that older age, disease activity parameters, and decreased vitamin D levels had an independent effect on increasing the HRCT chest total score. Logistic regression analysis showed that the increase in the DAS-28 score and the rheumatoid factor titer and the decrease in the vitamin D levels had an independent effect on increasing the probability of pulmonary affection occurrence. Conclusion Patients with RA-associated interstitial lung disease ‘proved by HRCT and/or diffusion lung capacity for carbon monoxide’ tend to have a high prevalence of vitamin D deficiency and high disease activity; also, lower levels of vitamin D play a significant role in the pathogenesis of RA-interstitial lung disease.

Risk factors for progression and prognosis of rheumatoid arthritis-associated interstitial lung disease: single center study with a large sample of Chinese population.

Factors associated with progression and survivals in rheumatoid arthritis-associated interstitial lung disease (RA-ILD) have not been described in a large center China cohort. Seven-hundred and ninety-one consecutive RA patients who completed lung HRCT were considered as potential participants in this retrospective cohort study. Determinants of ILD progression were identified through multivariable logistic analysis. Cox hazards analysis was used to determine significant variables associated with survival. Of 307 patients diagnosed with RA-ILD, 266 were finally included. The 3-year survival rate of RA-ILD patients was 81.24%, and the 5-year survival rate was 69.71%. A total of 82 deaths occurred during follow-up, of which 56 died of respiratory failure due to ILD progression and/or pneumonia while 14 with malignancies (8 with lung cancer). Logistic regression analysis showed that anti-CCP antibody high titer positive (OR: 4.03, 95% CI: 1.04-15.69) and DLCO% < 45% (OR: 8.31, 95% CI: 2.17-31.75) were independent risk factors for the ILD progression. Cox hazards analysis revealed that advanced age (> 60years old) of RA-ILD diagnosis (HR: 2.32, 95% CI: 1.27-4.25) and extensive lung involvement on HRCT (HR: 2.19, 95% CI: 1.24-3.87) were associated with worse survival. Treatment with cyclophosphamide (HR: 0.43, 95% CI: 0.26-0.69) was associated with better survival. In RA-ILD patients, anti-CCP antibody high titer positive and DLCO% < 45% are risk factors for ILD progression. Advanced age and extensive lung involvement on HRCT, rather than the baseline UIP pattern, independently predict mortality after controlling for potentially influential variables. Furthermore, cyclophosphamide treatment helps to improve the prognosis in real-world experience.

AMBIGUOUS PRESENTATION OF A COMMON DISEASE ASSOCIATED WITH INTERSTITIAL LUNG DISEASE

SESSION TITLE: Pulmonary Manifestations of Systemic Diesase SESSION TYPE: Fellow Case Report Posters PRESENTED ON: 10/09/2018 01:15 PM - 02:15 PM INTRODUCTION: Ambiguous presentation of connective tissue disease may delay decision making in diagnosis and treatment of interstitial lung disease. CASE PRESENTATION: 60-year-old African-American woman presents with dry non-resolving cough following upper respiratory tract infection. She has no environment exposure and 15 pack-year smoking. Medical history is remarkable for hypertension, knee and shoulder osteoarthritis. She had tightening of skin around mouth, Raynaud’s phenomenon, diffuse non-specific large and small joint occasional polyarthralgias and stiffness, but no swelling or deformities (other than osteoarthritic changes). Key negative points of history include absence of fever, night sweats, orthopnea and PND. Vital signs are normal, SpO2 93%, RR 20 and BMI 39. She is alert, oriented, clubbing of digits noted and “Velcro” crackles auscultated at lung bases, normal heart sounds heard and no pedal edema noted. Chest X-ray shows interstitial thickening and atelectasis; HRCT reveals “possible UIP” pattern (no honey combing). Lung function tests showed normal ratio with FVC 47% TLC60% DLCO 50%, air trapping. Dyspnea precluded a 6’ walk study. Laboratory studies: Anti-RNP and speckled ANA were positive; ANCA negative; RF and CCP negative. Hand X-rays were non-diagnostic for rheumatoid arthritis. Four months later, lung biopsy reveals areas of fibrosing NSIP, UIP, pleural inflammation and extensive onion skin proliferation within medium size pulmonary vasculature. DISCUSSION: Following the biopsy, she required 2 liters to maintain 91% saturation. An echocardiogram showed pulmonary hypertension PASP 90 mm Hg and increased LVEDP with diastolic dysfunction. Right heart catheterization showed mean PAP 50 mmHg with high PVR 800 dynes-sec/cm5 and wedge, 14 mmHg. Over 4 months, treatment with ambrisentan, tadalafil, and diuresis failed to improve PA pressures and she was hospitalized with cor pulmonale. At this point, 14 months from the initial evaluation, mycophenolate and steroids are given based on a diagnosis of mixed connective tissue disease (ILD). Milrinone is added to her inpatient regimen and her 6’ walk improves to 0 to 140 ft. 20 months from the initial evaluation, hand X-rays reveal classical changes of rheumatoid arthritis and rituximab infusion given and mycophenolate continues. Echocardiographic PA pressures improve significantly. Improvements in pulmonary function testing and 6’ walk are shown (Graph). CONCLUSIONS: Non-specific systemic symptoms with “possible” UIP on HRCT, may incline physicians to obtain lung biopsy, however a lack of clinical factors may lead to misinterpretation of the findings. In the biopsy, pleural inflammation was a significant factor suggesting the presence of a systemic inflammatory connective tissue disease. This case demonstrates nonspecific disease presentation which was definable by tissue biopsy which dictated earlier therapeutic intervention. Reference #1: Kim EJ, Collard HR, King TE. Rheumatoid Arthritis-Associated Interstitial Lung Disease: The Relevance of Histopathologic and Radiographic Pattern. Chest. 2009;136(5):1397-1405. Reference #2: Egerer K, Feist E, Burmester G-R. The Serological Diagnosis of Rheumatoid Arthritis: Antibodies to Citrullinated Antigens. Deutsches Ärzteblatt International. 2009;106(10):159-163. Reference #3: Jee AS, Adelstein S, Bleasel J, et al. Role of Autoantibodies in the Diagnosis of Connective-Tissue Disease ILD (CTD-ILD) and Interstitial Pneumonia with Autoimmune Features (IPAF). Huang P, ed. Journal of Clinical Medicine. 2017;6(5):51. DISCLOSURES: No relevant relationships by Kunal Patel, source=Web Response No relevant relationships by Edward Sivak, source=Web Response No relevant relationships by Prashanth Thalanayar Muthukrishnan, source=Web Response no disclosure on file for Joseph Tomashefski

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.

Editorial introductions

Current Opinion in Rheumatology was launched in 1989. It is one of a successful series of review journals whose unique format is designed to provide a systematic and critical assessment of the literature as presented in the many primary journals. The field of Rheumatology is divided into 15 sections that are reviewed once a year. Each section is assigned a Section Editor, a leading authority in the area, who identifies the most important topics at that time. Here we are pleased to introduce the Journal's Section Editors for this issue. SECTION EDITORS William J. McCuneWilliam J. McCuneDr McCune is a graduate of Harvard College and the University of Cincinnati Medical School, USA. Following residency at the University of Michigan and fellowship at Brigham and Women's Hospital, USA, he joined the faculty of the University of Michigan, USA, where he is the Michael and Marcia Klein Professor of Rheumatic Diseases and Director of the Lupus Program. Dr McCune has devoted much of his research career to systemic lupus. He reported the clinical and immunologic effects of monthly bolus cyclophosphamide for severe lupus using methods that were subsequently adopted as standard treatment for lupus nephritis. He has since focused on improving the efficacy and safety of immunosuppressive therapy, including the use of leuprolide for ovarian protection in women receiving cyclophosphamide. His work in medical imaging helped establish the importance of MRI in neurological complications of lupus and rheumatoid arthritis, and he was the first to describe ultrasound imaging of articular cartilage. His current interests include the pathogenesis of cardiovascular disease in SLE, advanced MRI in SLE, and detailed population-based epidemiologic studies of the SLE in southeastern Michigan. Jon T. GilesJon T. GilesDr Giles's research interests are centered primarily within the inflammatory arthritides. His current projects center around understanding the inflammatory and non-inflammatory determinants of body composition abnormalities in rheumatoid arthritis and psoriatic arthritis, and their subsequent effects on health outcomes. Other current and past research involves the investigation of accelerated atherosclerosis and myocardial dysfunction in rheumatoid arthritis patients, understanding the determinants of rheumatoid arthritis-associated interstitial lung disease, and exploring the musculoskeletal side-effects of a class of medications used to suppress estrogen in women with certain forms of breast cancer. He is the recipient of grant support from the National Institutes of Health, the Arthritis Foundation, the Rheumatology Research Foundation, the Marianne Legato Foundation, and the Arthritis National Research Foundation.

Nintedanib reduces pulmonary fibrosis in a model of rheumatoid arthritis-associated interstitial lung disease.

Rheumatoid arthritis (RA)-associated interstitial lung disease (RA-ILD) develops in ~20% of patients with RA. SKG mice, which are genetically prone to development of autoimmune arthritis, develop a pulmonary interstitial pneumonia that resembles human cellular and fibrotic nonspecific interstitial pneumonia. Nintedanib, a tyrosine kinase inhibitor approved for treatment of idiopathic pulmonary fibrosis, has been shown to reduce the decline in lung function. Therefore, we investigated the effect of nintedanib on development of pulmonary fibrosis and joint disease in female SKG mice with arthritis induced by intraperitoneal injection of zymosan (5 mg). Nintedanib (60 mg·kg-1·day-1 via oral gavage) was started 5 or 10 wk after injection of zymosan. Arthritis and lung fibrosis outcome measures were assessed after 6 wk of treatment with nintedanib. A significant reduction in lung collagen levels, determined by measuring hydroxyproline levels and staining for collagen, was observed after 6 wk in nintedanib-treated mice with established arthritis and lung disease. Early intervention with nintedanib significantly reduced development of arthritis based on joint assessment and high-resolution μ-CT. This study impacts the RA and ILD fields by facilitating identification of a therapeutic treatment that may improve both diseases. As this model replicates the characteristics of RA-ILD, the results may be translatable to the human disease.

Anti-citrullinated alpha enolase antibodies, interstitial lung disease and bone erosion in rheumatoid arthritis.

RA is an articular chronic inflammatory disease that in a subgroup of patients can also present with extra-articular manifestations (EAMs). Despite intense investigation on this topic, reliable biomarkers for EAMs are lacking. In recent years several ACPAs, including those targeting anti-citrullinated alpha enolase peptide-1 (anti-CEP-1), have been identified in patients with RA. Data about the ability of anti-CEP-1 to predict the development of erosive disease are confliciting and no evidence concerning their possible association with EAMs in RA is currently available. The aim of this study was to investigate the prevalence and significance of anti-CEP-1 with regard to the association with erosive disease and EAMs in a large cohort of patients with RA. Anti-CCP and anti-CEP-1 antibodies have been assessed on serum samples of RA patients, healthy donors and patients with SpA using commercially available ELISA kits. Anti-CEP-1 antibodies are detectable in over 40% of RA patients and are associated with erosive RA and with RA-associated interstitial lung disease (ILD). Anti-CEP-1 antibodies may represent a useful biomarker for RA-associated ILD and erosive disease to be employed in clinical practice.

Abatacept in patients with rheumatoid arthritis and interstitial lung disease: A national multicenter study of 63 patients.

Interstitial lung disease (ILD) is one of the most serious complications of rheumatoid arthritis (RA). In the present study, we aimed to assess the efficacy of abatacept (ABA) in patients with ILD associated to RA. National multicenter, non-controlled, open-label registry study of RA patients with ILD treated with ABA. 63 patients (36 women) with RA-associated ILD undergoing ABA therapy were studied. The mean ± standard deviation age at the time of the study was 63.2 ± 9.8 years. The median duration of RA and ILD from diagnosis were 6.8 and 1 year, respectively. RA was seropositive in 55 patients (87.3%). In 15 (23.8%) of 63 patients the development of ILD was closely related to the administration of synthetic or biologic disease modifying anti-rheumatic drugs. After a follow-up of 9.4 ± 3.2 months, two-thirds of patients remained stable whereas one-quarter experienced improvement in the Modified Medical Research Council scale. At that time forced vital capacity remained stable in almost two-thirds of patents and improved in one out of five patients assessed. Also, diffusing capacity of the lung for carbon monoxide remained stable in almost two-thirds and showed improvement in a quarter of the patients assessed. At 12 months, 50% of the 22 patients in whom chest HRCT scan was performed due persistence of respiratory symptoms showed stabilization, 8 (36.4%) improvement and 3 worsening of the HRCT scan pattern. Eleven of 63 patients had to discontinue ABA, mainly due to adverse events. ABA appears to be an effective in RA-associated ILD.

Upregulation of citrullination pathway: From Autoimmune to Idiopathic Lung Fibrosis

BackgroundIncreased protein citrullination and peptidylarginine deiminases (PADIs), which catalyze the citrullination process, are central in Rheumatoid arthritis pathogenesis and probably involved in the initial steps towards autoimmunity. Approximately, 10% of RA patients develop clinically significantly ILD. A possible shared role of protein citrullination in rheumatoid arthritis associated interstitial lung disease (RA-ILD), and idiopathic pulmonary fibrosis (IPF) pathogenesis remains unclear.MethodsWe evaluated PADI2 and PADI4 mRNA expression in bronchoalveolar lavage fluid (BALF) cells of 59 patients with IPF, 27 patients RA-ILD and 10 healthy controls. PADI 2 and 4 expression was analyzed by western blot and immunohistochemistry. Citrullinated protein levels were also quantified.ResultsPADI4 mRNA and protein levels were higher in RA-ILD and IPF than controls. Furthermore, PADI4 mRNA levels showed an increase among smokers in RA-ILD. PADI4 expression was detected in granulocytes and macrophages in all groups, with the strongest cytoplasmic expression observed in granulocytes in RA-ILD and IPF. PADI2 mRNA and immunostaining of BAL cells, were similar in all groups among smokers. Overall, stronger staining was observed in current smokers. Citrullinated peptides were significantly increased in IPF compared to RA-ILD and controls. In RA-ILD, protein citrullination strongly correlated with PADI4 expression and anti-citrullinated protein antibodies (ACPAs).ConclusionsThese results suggest that the citrullination pathway is upregulated in IPF and in RA-ILD.

Several high-resolution computed tomography findings associate with survival and clinical features in rheumatoid arthritis-associated interstitial lung disease.

To compare the presence and extent of several high-resolution computed tomography (HRCT) observations in different subtypes of rheumatoid arthritis-related interstitial lung disease (RA-ILD) and to examine associations between radiological findings, hospitalization, age, RA duration, pulmonary function tests (PFT) and survival. HRCTs from 60 RA-ILD patients were independently evaluated and re-categorized into usual interstitial pneumonia (UIP), nonspecific interstitial pneumonia (NSIP), organizing pneumonia (OP), diffuse alveolar damage (DAD) and unclassified subtypes by two radiologists. The presence and extent, which was reported using a semi-quantitative scoring system, of e.g. reticulation, ground-glass opacity, honeycombing, emphysema, traction bronchiectasis and architectural distortion were further evaluated and compared between the subtypes. Associations between radiological findings and survival were identified with the Kaplan-Meier method and Cox's univariate model. The correlations between radiological findings, hospitalization, age, pack years, RA duration and PFT were calculated using Spearman's correlation coefficient. The extents of reticulation (HR 1.144, p=0.041), traction bronchiectasis (HR 1.184, p=0.030), architectural distortion (HR 1.094, p=0.044) and the presence of pleural fluid (HR 14.969, p<0.001) were associated with decreased survival. A negative correlation was observed between ground-glass opacity (GGO) and the duration of RA (r=-0.308, p=0.023). The extents of honeycombing (r=0.266, p=0.046), traction bronchiectasis (r=0.333, p=0.012) and architectural distortion (r=0.353, p=0.007) correlated with hospitalizations due to respiratory reasons. Many radiological findings associate with the course of the disease of RA-ILD and could potentially be useful when planning the RA treatment or evaluating the risk of death in these patients.

Rheumatoid Arthritis-Associated Interstitial Lung Disease: Current Concepts.

Among the many extra-articular complications of rheumatoid arthritis (RA), interstitial lung disease (ILD) contributes significantly to morbidity and mortality. Prevalence estimates for RA-ILD vary widely depending on the specific clinical, radiographic, and functional criteria used to establish the diagnosis. A key unresolved issue is whether early, subclinical forms of RA-ILD represent a precursor to end stage, fibrotic lung disease. Based on uncertainties surrounding the natural history of RA-ILD, incomplete understanding of underlying disease pathogenesis, and lack of controlled clinical trials, evidence-based therapeutic strategies remain largely undefined. Correlative clinico-epidemiological studies have identified key risk factors for disease progression. Complementing these findings, the identification of specific molecular and serological markers of RA-ILD has improved our understanding of disease pathogenesis and established the foundation for predictive biomarker profiling. Experience from case series and cohort studies suggests that newer biological agents such as rituximab may be viable treatment options. RA-ILD continues to have a major impact on "disease intrinsic" morbidity and mortality. Increased understanding of disease pathogenesis and the natural history of subclinical RA-ILD will promote the development of more refined therapeutic strategies.

CD11b+Gr-1dim Tolerogenic Dendritic Cell-Like Cells Are Expanded in Interstitial Lung Disease in SKG Mice.

SKG mice develop interstitial lung disease (ILD) resembling rheumatoid arthritis-associated ILD in humans. The aim of this study was to clarify the mechanism underlying the lung pathology by analyzing lung-infiltrating cells in SKG mice with ILD. We assessed the severity of zymosan A (ZyA)-induced ILD in SKG mice histologically, and we examined lung-infiltrating cells by flow cytometry. Total lung cells and isolated monocytic myeloid-derived suppressor cells (MDSCs) were cultured invitro with granulocyte-macrophage colony-stimulating factor (GM-CSF) and interleukin-4. The proliferation of 5,6-carboxyfluorescein diacetate N-succinimidyl ester-labeled naive T cells cocultured with isolated CD11b+Gr-1dim cells and MDSCs was evaluated by flow cytometry. CD11b+Gr-1dim cells were adoptively transferred to ZyA-treated SKG mice. MDSCs, Th17 cells, and group 1 and 3 innate lymphoid cells (ILC1s and ILC3s) were increased in the lungs; the proportion of these cells varied with ILD severity. In this process, we found that a unique cell population, CD11b+Gr-1dim cells, was expanded in the severely inflamed lungs. Approximately half of the CD11b+Gr-1dim cells expressed CD11c. CD11b+Gr-1dim cells were induced from monocytic MDSCs with GM-CSF invitro and were considered tolerogenic because they suppressed T cell proliferation. These CD11b+Gr-1dim cells have never been described previously, and we termed them CD11b+Gr-1dim tolerogenic dendritic cell (DC)-like cells. Th17 cells, ILC1s, and ILC3s in the inflamed lung produced GM-CSF, which may have expanded CD11b+Gr-1dim tolerogenic DC-like cells invivo. Furthermore, adoptive transfer of CD11b+Gr-1dim tolerogenic DC-like cells significantly suppressed progression of ILD in SKG mice. We identified unique suppressive myeloid cells that were differentiated from monocytic MDSCs in SKG mice with ILD, and we termed them CD11b+Gr-1dim tolerogenic DC-like cells.

The serum level and significance of lysyl oxidase-like 2 in patients with rheumatoid arthritis-associated interstitial lung disease.

Our previous experiments found that lysyl oxidase-like 2 (LOXL2) may be a useful preclinical serological marker for pulmonary fibrosis in the mouse model. The role of LOXL2 in rheumatoid arthritis-associated interstitial lung disease (RA-ILD) is still unclear. We investigated whether serum LOXL2 levels are associated with RA-ILD patients. The levels of serum LOXL2 were measured by enzyme-linked immunosorbent assay in 49 RA-ILD patients (21 patients with ILD disease duration < 3months; 28 patients with ILD disease duration > 3months), 43 RA patients without ILD and 20 normal healthy controls. We assessed the correlations between the serum LOXL2 levels and clinical variables. Serum LOXL2 levels were significantly higher in RA patients than in normal healthy controls (326.79±192.56 vs. 53.27±35.86pg/ml, P<0.01). No significant difference was present between the RA-ILD group and RA without ILD group (298.87±219.85 vs. 358.60±152.16pg/ml, P=0.13). Notably, the serum LOXL2 levels were significantly higher in patients with ILD disease duration < 3months than in those with ILD disease duration > 3months (462.71±208.97 vs. 175.99±130.55pg/ml, P<0.01) or without ILD (462.71±208.97 vs. 358.60±152.16pg/ml, P=0.03). The serum LOXL2 levels in RA-ILD patients significantly correlated with DAS28 (rs=0.31, P=0.034), C-reactive protein (rs=0.41, P=0.004), rheumatoid factor (rs=0.41, P=0.003), forced vital capacity (rs=- 0.39, P=0.02), and diffusion capacity of the lung for carbon monoxide (rs=- 0.44, P=0.009). LOXL2 may be involved in the pathogenesis of rheumatoid arthritis-associated interstitial lung disease and might be helpful in early diagnosis of RA-ILD.

Pneumopathies interstitielles diffuses au cours de la polyarthrite rhumatoïde

Despite its severity, rheumatoid arthritis-associated interstitial lung disease is still underdiagnosed. The prevalence of this extra-articular complication has been recently reassessed by the use of high-performance imaging tools such as high-resolution thoracic CT scan. Rheumatoid associated interstitial lung disease is not similar to the other autoimmune diseases related lung involvement. The high frequency of the fibrotic pattern, the poor response to treatment and the poor prognosis are some of its characteristics. Because of a high morbidity and mortality rate, rheumatologists should especially focus on this complication. While an early detection could lead to a better follow-up and care by the pulmonologist, first pulmonary functional signs are often delayed compared to the extension of the lung damage. Finally, current studies on the impact of the rheumatoid arthritis treatments on the interstitial lung disease are still contradictory. Thus, this review will present actual data about the characteristics of rheumatoid arthritis associated interstitial lung disease but will also try to sum up the different studies about rheumatoid arthritis treatments influence on this complication.

Practical Management of Respiratory Comorbidities in Patients with Rheumatoid Arthritis.

Lung disease is one of the most common causes of extra-articular morbidity and mortality in patients with rheumatoid arthritis (RA). Development of pulmonary manifestations may be due to the systemic disease itself; to serious respiratory adverse events such as pneumonitis and infections secondary to therapy; or to lifestyle habits such as smoking. Rheumatologists often need to make important treatment decisions and plan future care in RA patients with respiratory comorbidities, despite the absence of clear evidence or consensus. In this review we evaluate the clinical assessment and management of RA-associated interstitial lung disease, bronchiectasis, serious (including opportunistic) infection, and smoking-related diseases. We summarize the international recommendations for the management of such conditions where available, refer to published best practice on the basis of scientific literature, and propose practical management suggestions to aid informed decision-making.

A population-based cohort study of rheumatoid arthritis-associated interstitial lung disease: comorbidity and mortality

ObjectivesTo compare mortality risks in patients with rheumatoid arthritis-associated interstitial lung disease (RA-ILD) and patients with RA without ILD.DesignMatched cohort study.SettingThe study was conducted in Denmark, using nationwide, prospectively collected...

Shared genetic predisposition in rheumatoid arthritis-interstitial lung disease and familial pulmonary fibrosis.

Despite its high prevalence and mortality, little is known about the pathogenesis of rheumatoid arthritis-associated interstitial lung disease (RA-ILD). Given that familial pulmonary fibrosis (FPF) and RA-ILD frequently share the usual pattern of interstitial pneumonia and common environmental risk factors, we hypothesised that the two diseases might share additional risk factors, including FPF-linked genes. Our aim was to identify coding mutations of FPF-risk genes associated with RA-ILD.We used whole exome sequencing (WES), followed by restricted analysis of a discrete number of FPF-linked genes and performed a burden test to assess the excess number of mutations in RA-ILD patients compared to controls.Among the 101 RA-ILD patients included, 12 (11.9%) had 13 WES-identified heterozygous mutations in the TERT, RTEL1, PARN or SFTPC coding regions. The burden test, based on 81 RA-ILD patients and 1010 controls of European ancestry, revealed an excess of TERT, RTEL1, PARN or SFTPC mutations in RA-ILD patients (OR 3.17, 95% CI 1.53-6.12; p=9.45×10-4). Telomeres were shorter in RA-ILD patients with a TERT, RTEL1 or PARN mutation than in controls (p=2.87×10-2).Our results support the contribution of FPF-linked genes to RA-ILD susceptibility.