Study of the Immune Infiltration and Sonic Hedgehog Expression Mechanism in Synovial Tissue of Rheumatoid Arthritis-Related Interstitial Lung Disease under Machine Learning CIBERSORT Algorithm.

Rheumatoid arthritis-related interstitial lung disease (RA-ILD) is one of the common complications in patients with RA, which affects their quality of life. The CIBERSORT algorithm is widely employed to determine the proportion of immune cells (ICs) in diseased tissues, while the Sonic Hedgehog (Shh) signaling pathway, as an imperative regulatory factor, has also attracted attention in the pathology of RA-ILD. This work was to explore the mechanisms of RA-ILD immune infiltration and synovial tissue (ST) Shh expression based on the CIBERSORT algorithm. The differential genes of RA-ILD were subjected to pathway enrichment analysis using R language. The content and proportion of 22 types of ICs in RA-ILD lung tissues were analyzed using machine learning-based CIBERSORT algorithm. Meanwhile, immunoblotting was employed to detect and analyze the expression of Shh, Smoothened (Smo), and bone morphogenetic proteins (BMPs) proteins in ST samples from RA-ILD and Ctrl groups (RA patients without ILD). The hub target genes in the protein network associated with RA-ILD include BSG, CCL2, CTLA4, FGFBP1, GLI1, HHIP, HLA-DRB1, IFNAR1, IL17A, IL23A, IL-6, INPP4A, LILRB1, MUC5B, PADI4, PPM1A, PTCH1, PTPN22, RSPO4, Shh, SMO, STAT4, SUFU, TAOK2, TIMP2, and TWSG1, which are involved in multiple pathways, such as B cell regulation, transcription factors of the Shh pathway, and ST immune tolerance-related pathways. In the immunological analysis of RA-ILD using the CIBERSORT algorithm, HLA (r = - 0.26), PTPN22 (r = - 0.36), STAT4 (r = - 0.18), IL-6 (r = - 0.17), CTLA4 (r = - 0.27), and PADI4 (r = - 0.21) were all found to exhibit negative correlations with CD4+T cells (P < 0.05). Monocytes were found to be more abundant in RA-ILD patients' serum versus the Ctrl group. Shh, Smo, and BMP expressions were drastically lower in the RA-ILD group versus Ctrl group (P < 0.05). Significant immune cell infiltration was observed in the lung tissues of RA-ILD patients. Further analysis utilizing the CIBERSORT algorithm revealed alterations in the proportions of different IC subtypes, indicating their association with disease severity and prognosis. Moreover, there was a significant decrease in the expression levels of Shh, Smo, and BMP. These findings underscore the importance of immune cells in the pathophysiology of RA-ILD and suggest a potential involvement of the Shh signaling pathway in the pathogenesis of RA-ILD.

Analyzing how SiMiao Wan regulates ferroptosis to prevent RA-ILD using metabolomics and cyberpharmacology.

BACKGROUND: Interstitial lung disease (ILD) is a common complication of rheumatoid arthritis (RA) that plays a significant role in the morbidity and mortality of individuals with this condition. In clinical settings, Si Miao Wan (SMW), a traditional Chinese medicine, is often utilized for the management of RA, as it is believed to possess properties that aid in reducing inflammation, eliminating excess moisture, and alleviating joint pain. PURPOSE: The primary objective of this investigation was to elucidate the potential mechanism of RA-ILD prevention from the perspective of ferroptosis mediated by SMW. METHODS: UPLC-Q-TOF/MS and network pharmacology were employed to forecast the potential targets of SMW for the early prevention of RA-ILD. Following this, HE staining, metabolomics, and RT-PCR were utilized to investigate the mechanism by which SMW prevents RA-ILD at an early stage. RESULTS: Following six weeks of continuous administration of SMW extract at a dosage of 2.16 g/kg/day, it was observed that SMW exhibited early preventive effects against RA-ILD. Metabolomics analysis revealed seven potential biomarkers linked to the pharmacological efficacy of SMW in the early prevention of RA-ILD. Additionally, network pharmacology analysis suggested that SMW may exert its therapeutic effects on RA-ILD by modulating signaling pathways associated with lipid metabolism, atherosclerosis, TNF, and IL-17. Ultimately, through the integration of metabolomics and network pharmacology analysis, along with subsequent verification, it was determined that the early prevention of rheumatoid arthritis-associated interstitial lung disease (RA-ILD) by Shenmai injection (SMW) is associated with the ferroptosis pathway. CONCLUSION: This research offers preliminary insights into the potential mechanism by which traditional Chinese medicine Shen Mai Wan (SMW) may mitigate the early onset of Rheumatoid Arthritis-Interstitial Lung Disease (RA-ILD) via the process of ferroptosis. Furthermore, it establishes a theoretical framework for the development of innovative SMW-based pharmaceuticals for the management of RA-ILD. The signal proteins implicated in this process are anticipated to emerge as crucial targets for the prevention of RA-ILD.

The Lung in Rheumatoid Arthritis-Friend or Enemy?

Rheumatoid arthritis (RA) is a chronic autoimmune condition frequently found in rheumatological patients that sometimes raises diagnosis and management problems. The pathogenesis of the disease is complex and involves the activation of many cells and intracellular signaling pathways, ultimately leading to the activation of the innate and acquired immune system and producing extensive tissue damage. Along with joint involvement, RA can have numerous extra-articular manifestations (EAMs), among which lung damage, especially interstitial lung disease (ILD), negatively influences the evolution and survival of these patients. Although there are more and more RA-ILD cases, the pathogenesis is incompletely understood. In terms of genetic predisposition, external environmental factors act and subsequently determine the activation of immune system cells such as macrophages, neutrophils, B and T lymphocytes, fibroblasts, and dendritic cells. These, in turn, show the ability to secrete molecules with a proinflammatory role (cytokines, chemokines, growth factors) that will produce important visceral injuries, including pulmonary changes. Currently, there is new evidence that supports the initiation of the systemic immune response at the level of pulmonary mucosa where the citrullination process occurs, whereby the autoantibodies subsequently migrate from the lung to the synovial membrane. The aim of this paper is to provide current data regarding the pathogenesis of RA-associated ILD, starting from environmental triggers and reaching the cellular, humoral, and molecular changes involved in the onset of the disease.

Resveratrol attenuates inflammation and fibrosis in rheumatoid arthritis-associated interstitial lung disease via the AKT/TMEM175 pathway.

BACKGROUND AND PURPOSE: Interstitial lung disease (ILD) represents a significant complication of rheumatoid arthritis (RA) that lacks effective treatment options. This study aimed to investigate the intrinsic mechanism by which resveratrol attenuates rheumatoid arthritis complicated with interstitial lung disease through the AKT/TMEM175 pathway. METHODS: We established an arthritis model by combining chicken type II collagen and complete Freund's adjuvant. Resveratrol treatment was administered via tube feeding for 10 days. Pathological changes in both the joints and lungs were evaluated using HE and Masson staining techniques. Protein expression of TGF-ß1, AKT, and TMEM175 was examined in lung tissue. MRC-5 cells were stimulated using IL-1ß in combination with TGF-ß1 as an in vitro model of RA-ILD, and agonists of AKT, metabolic inhibitors, and SiRNA of TMEM175 were used to explore the regulation and mechanism of action of resveratrol RA-ILD. RESULTS: Resveratrol mitigates fibrosis in rheumatoid arthritis-associated interstitial lung disease and reduces oxidative stress and inflammation in RA-ILD. Furthermore, resveratrol restored cellular autophagy. When combined with the in vitro model, it was further demonstrated that resveratrol could suppress TGF-ß1 expression, and reduce AKT metamorphic activation, consequently inhibiting the opening of AKT/MEM175 ion channels. This, in turn, lowers lysosomal pH and enhances the fusion of autophagosomes with lysosomes, ultimately ameliorating the progression of RA-ILD. CONCLUSION: In this study, we demonstrated that resveratrol restores autophagic flux through the AKT/MEM175 pathway to attenuate inflammation as well as fibrosis in RA-ILD by combining in vivo and in vitro experiments. It further provides a theoretical basis for the selection of therapeutic targets for RA-ILD.

Potential Rheumatoid Arthritis-Associated Interstitial Lung Disease Treatment and Computational Approach for Future Drug Development.

Rheumatoid arthritis (RA) is a systemic autoimmune disease characterized by swelling in at least one joint. Owing to an overactive immune response, extra-articular manifestations are observed in certain cases, with interstitial lung disease (ILD) being the most common. Rheumatoid arthritis-associated interstitial lung disease (RA-ILD) is characterized by chronic inflammation of the interstitial space, which causes fibrosis and the scarring of lung tissue. Controlling inflammation and pulmonary fibrosis in RA-ILD is important because they are associated with high morbidity and mortality. Pirfenidone and nintedanib are specific drugs against idiopathic pulmonary fibrosis and showed efficacy against RA-ILD in several clinical trials. Immunosuppressants and disease-modifying antirheumatic drugs (DMARDs) with anti-fibrotic effects have also been used to treat RA-ILD. Immunosuppressants moderate the overexpression of cytokines and immune cells to reduce pulmonary damage and slow the progression of fibrosis. DMARDs with mild anti-fibrotic effects target specific fibrotic pathways to regulate fibrogenic cellular activity, extracellular matrix homeostasis, and oxidative stress levels. Therefore, specific medications are required to effectively treat RA-ILD. In this review, the commonly used RA-ILD treatments are discussed based on their molecular mechanisms and clinical trial results. In addition, a computational approach is proposed to develop specific drugs for RA-ILD.

Serum C-reactive protein is associated with earlier mortality across different interstitial lung diseases.

BACKGROUND AND OBJECTIVE: The acute-phase protein C-reactive protein (CRP) is known to be associated with poor outcomes in cancer and cardiovascular disease, but there is limited evidence of its prognostic implications in interstitial lung diseases (ILDs). We therefore set out to test whether baseline serum CRP levels are associated with mortality in four different ILDs. METHODS: In this retrospective study, clinically measured CRP levels, as well as baseline demographics and lung function measures, were collected for ILD patients first presenting to the Royal Brompton Hospital between January 2010 and December 2019. Cox regression analysis was used to determine the relationship with 5-year mortality. RESULTS: Patients included in the study were: idiopathic pulmonary fibrosis (IPF) n = 422, fibrotic hypersensitivity pneumonitis (fHP) n = 233, rheumatoid arthritis associated ILD (RA-ILD) n = 111 and Systemic Sclerosis associated ILD (SSc-ILD) n = 86. Patients with a recent history of infection were excluded. Higher CRP levels were associated with shorter 5-year survival in all four disease groups on both univariable analyses, and after adjusting for age, gender, smoking history, immunosuppressive therapy and baseline disease severity (IPF: HR (95% CI): 1.3 (1.1-1.5), p = 0.003, fHP: 1.5 (1.2-1.9), p = 0.001, RA-ILD: 1.4 (1.1-1.84), p = 0.01 and SSc-ILD: 2.7 (1.6-4.5), p < 0.001). CONCLUSION: Higher CRP levels are independently associated with reduced 5-year survival in IPF, fHP, RA-ILD and SSc-ILD.

Survival differences in rheumatoid arthritis interstitial lung disease and idiopathic pulmonary fibrosis may be explained by delays in presentation: results from multivariate analysis in a monocentric UK study.

Rheumatoid arthritis-associated interstitial lung disease (RA-ILD) has a better prognosis compared to idiopathic pulmonary fibrosis (IPF). Recent data suggest that antifibrotics are effective in slowing progression across both groups. Hence, we designed this study to investigate the similarities and differences between these groups of patients. This is a retrospective cohort study examining baseline data, progression and outcomes in patients with RA-ILD and IPF prior to antifibrotic use in the Coventry ILD database. Ethics approval was obtained from the University Hospital Coventry and Warwickshire NHS Trust. Statistical analysis was performed using R software and Cox's proportional hazards technique was used for survival analysis. We identified 131 cases, including 49 patients with IPF, 34 patients with RA-ILD and 48 patients with other forms of idiopathic interstitial pneumonia. At baseline, there were significant differences in the groups with RA-ILD patients being significantly younger (65.7 vs 72.4 years), had preserved lung volumes (FVC 95% vs 84.7%) and higher gas transfer (61.5% vs 48.2%) compared to IPF patients. 5-year survival was better for RA-ILD compared to IPF (87.5% vs 40.4%, p = 0.0042). Univariate analysis revealed gas transfer, FVC, age, sex and phenotype (IPF or RA-ILD) were all significant predictors, but multivariate analysis revealed that gas transfer and age were both significantly associated with prognosis, whereas sex, FVC or phenotype were not significant. This study suggests that the difference between RA-ILD and IPF prognosis may be due to demographics and early diagnosis rather than the diseases behaving differently. This has important management implications.

Associations of frailty with RA-ILD and poor control of disease activity in patients with rheumatoid arthritis: A multi-center retrospective observational study.

BACKGROUND: This study aimed to investigate factors associated with frailty in rheumatoid arthritis (RA) patients. METHODS: A total of 656 RA patients were evaluated using data from an observational study in 2022. Among these patients, 152 with frailty were assigned to the frailty group, and 504 without frailty were assigned to the non-frailty group. Patient characteristics were compared between the two groups by univariate analysis, and factors associated with frailty were assessed by logistic regression analysis. Patient characteristics were also compared between patients with RA-associated interstitial lung disease (RA-ILD) (n = 102) and those without RA-ILD (n = 554). RESULTS: The frailty group was older (mean: 73.6 vs. 66.8 years) and had a higher DAS28-ESR (3.67 vs. 2.66), a higher HAQ-DI (1.13 vs. 0.32), and a higher rate of RA-ILD (25.0 vs. 12.7 %) than the non-frailty group. Age (OR: 1.03, 95 % CI: 1.01-1.05), HAQ-DI (3.22, 2.28-4.56), DAS28-ESR (1.44, 1.19-1.75), and RA-ILD (2.21, 1.24-3.94) were associated with frailty. RA patients with RA-ILD were older (73.3 vs. 67.5 years) and had a higher DAS28-ESR (3.30 vs. 2.80), a higher HAQ-DI (1.19 vs. 0.32), a higher proportion of frail patients (37.3 vs. 20.6 %), lower MTX use (26.5 vs. 62.9 %), and higher steroid use (44.1 vs. 26.8 %) than those without RA-ILD. CONCLUSIONS: Maintaining reasonable control of disease activity is necessary for RA patients, including those with RA-ILD, to recover from frailty.

Plasma Wnt7b protein in rheumatoid arthritis: Detection of interstitial lung disease.

OBJECTIVE: To determine the plasma level of Wingless-related integration site 7b (Wnt7b) protein in rheumatoid arthritis (RA) patients (with and without interstitial lung disease (ILD)) and in idiopathic pulmonary fibrosis (IPF) patients and its relationship with RA disease activity and/or severity of pulmonary fibrosis. To assess the validity of plasma Wnt7b for the detection of ILD among RA patients. METHOD: This case-control study included 128 subjects (32 RA-ILD, 32 RA, 32 IPF, and 32 healthy controls). RA and RA-ILD Patients were evaluated for disease activity by DAS28 and disease activity grades were recorded according to DAS28 grades. Laboratory parameters as Erythrocyte sedimentation rate (ESR), C-reactive protein (CRP), Rheumatoid Factor (RF), Anti-citrullinated peptide (Anti-CCP) were recorded. Plasma Wnt7b levels were measured by ELISA. Diagnosis of pulmonary fibrosis (for RA-ILD and IPF patients) was done by high resolution computed tomography (HRCT) and its severity was assessed mainly by pulmonary function test using forced vital capacity (FVC) grading. RESULTS: Comparison of Wnt7b plasma levels showed a significant difference between the studied groups with the P-value < 0.018 (RA-ILD had the highest levels). Post hoc analysis revealed a significant difference in Wnt7b plasma levels between RA-ILD and IPF groups (P = 0.008). Also, RA-ILD and control groups had a significant difference (P = 0.039). However, there was a non-significant relationship between Wnt7b plasma levels and RA disease activity as well as the severity of pulmonary fibrosis. ROC curve analysis for the plasma Wnt7b levels revealed that a level  ≥285.1 pg/ml had a sensitivity of 87.5% and a specificity of 43.8% for the detection of ILD in RA patients with positive likelihood ratio of 1.56 and negative likelihood ratio of 0.29. CONCLUSION: RA-ILD patients had significantly higher plasma Wnt7b levels than the controls and IPF patients. These data suggest that the Wnt7b secretion is augmented by the concomitant presence of RA with pulmonary fibrosis. In addition, plasma Wnt7b may be used as a highly sensitive test for the detection of immunologically induced fibrotic changes in lung tissue among RA patients.

Activation of angiotensin II type 2 receptor attenuates lung injury of collagen-induced arthritis by alleviating endothelial cell injury and promoting Ly6Clo monocyte transition.

As one of the most frequent extra-articular manifestations of rheumatoid arthritis (RA), interstitial lung disease (ILD) is still challenging due to unrevealed pathophysiological mechanism. To address this question, in the present study, we used the classical collagen-induced arthritis (CIA) mouse model to determine the related-immune mechanism of lung injury and possible pharmacological treatment for RA-ILD. At the peak of arthritis, we found CIA mice developed apparent lung injury, characterized by interstitial thickening, inflammatory cell infiltration, and lymphocyte follicle formation. Additionally, the endothelial injury occurred as the number of endothelial cells (ECs) and their CD31 expression decreased. Along with those, monocytes, predominantly Ly6Chi monocytes with pro-inflammatory phenotype, were also increased. While in the remission period of arthritis, ECs gradually increased with retrieved CD31 expression, leading to decreased infiltrating monocytes, but boosted Ly6Clo population. Ly6Clo monocytes were prone to locate around damaged ECs, promoted ECs proliferation and vascular tube formation, and lessened the expression of adhesion molecules. In addition, we evaluated angiotensin II type 2 receptor (Agtr2), which has been demonstrated to be protective against lung injury, could be beneficial in RA-ILD. We found elevated Agtr2 in CIA lung tissue, and activation of Agtr2, within its specific agonist C21, alleviated the pulmonary inflammation in vivo, reduced ECs injury, and promoted monocytes conversion from Ly6Chi to Ly6Clo monocytes in vitro. Our data reveal a potential pathological mechanism of RA-ILD that involves ECs damage and inflammatory monocytes infiltration and provide a potential drug target, Agtr2, for RA-ILD treatment.

Resveratrol Ameliorates Fibrosis in Rheumatoid Arthritis-Associated Interstitial Lung Disease via the Autophagy-Lysosome Pathway.

Interstitial lung disease associated with rheumatoid arthritis (RA-ILD) can lead to interstitial fibrosis and even lung failure as a complication of rheumatoid arthritis (RA), and there is currently no effective treatment and related basic research. Studies have found that resveratrol (Res) can improve the progression of RA by regulating autophagy, and increasing evidence supports the connection between autophagy and common interstitial lung disease (ILD). We explored changes in autophagy levels in fibrotic lungs in RA-ILD and found that the level of autophagy is enhanced in the early stage but inhibited in the late stage. However, resveratrol treatment improved the level of autophagy and reversed the inhibition of autophagy, and attenuated fibrosis. We created corresponding cell models that exhibited the same phenotypic changes as animal models; under the effect of resveratrol, the level of fibrosis changed accordingly, and the fusion process of lysosomes and autophagosomes in autophagy was liberated from the inhibition state. Resveratrol effects were reversed by the addition of the late autophagy inhibitor chloroquine. These results suggest that resveratrol attenuates pulmonary fibrosis, increases autophagic flux, and modulates the autophagy-lysosome pathway, and particularly it may work by improving the formation of autophagic lysosomes, which may be an effective treatment for induced RA-ILD.

Pulmonary fibrosis associated with rheumatoid arthritis: from pathophysiology to treatment strategies.

INTRODUCTION: Rheumatoid arthritis (RA) is the most common inflammatory autoimmune disease, characterized by symmetric destructive arthritis and synovitis. Lung involvement is frequent, including in the form of interstitial lung disease (ILD). RA-ILD often presents with a radiologic and pathologic pattern of usual interstitial pneumonia, similar to idiopathic pulmonary fibrosis, highlighting the similarities between the two diseases, but other patterns and pathological associations are described. AREAS COVERED: This article reviews the pathogenesis of pulmonary fibrosis in the setting of rheumatoid arthritis as well as the current and future therapeutic options. EXPERT OPINION: Pulmonary fibrosis in the setting of RA-ILD is an example of genotype-environment interaction and involves multiple mechanisms including autoimmunity, inflammation, and fibrogenesis. Although ILD conveys most of the exceeding mortality in RA patients, there are no official guidelines for the management of RA-ILD. Attention should be paid to potential lung toxicity of RA treatment even though some of them might help stabilize the ILD. Current standard of care is often composed of glucocorticoids that may be associated with immunosuppressive therapy. Following the approval of antifibrotic therapy for ILDs with a progressive fibrosing phenotype, current works are evaluating the benefit of such treatment in RA-ILD.

Collagen 1a1 Expression by Airway Macrophages Increases In Fibrotic ILDs and Is Associated With FVC Decline and Increased Mortality.

Within the Interstitial Lung Diseases (ILD), patients with idiopathic pulmonary fibrosis (IPF) and a subset of those with non-IPF fibrotic ILD have a distinct clinical phenotype of progression despite management. This group of patients has been collectively termed the progressive fibrotic phenotype (PFP). Their early recognition may facilitate access to antifibrotic therapies to prevent or slow progression. Macrophages/monocytes within the lung orchestrate the progression and maintenance of fibrosis. A novel role for monocyte-derived macrophages during tissue damage and wound healing is the expression of collagens. We examined Collagen 1a1 expression in airway macrophages from ILD patients at diagnosis. COL1A1 mRNA levels from BAL cells were elevated in IPF and Non-IPF patients. The presence of a UIP pattern and a subsequent progressive phenotype were significantly associated with the higher BAL COL1A1 levels. In Non-IPF patients, higher COL1A1 levels were associated with a more than twofold increase in mortality. The intracellular localisation of COL1A1 in airway macrophages was demonstrated by confocal microscopy in CD45 and CD163 co-staining assays. Additionally, airway macrophages co-expressed COL1A1 with the profibrotic SPP1 gene product osteopontin. The levels of SPP1 mRNA and OPN in the BAL were significantly higher in IPF and Non-IPF patients relative to healthy. Our results suggest that profibrotic airway macrophages are increased in the BAL of patients with IPF and other ILDs and co-express COL1A1 and OPN. Importantly, COL1A1 expression by pro-fibrotic airway macrophages could be a marker of disease progression and poor survival in ILDs.

IL-23 amplifies the epithelial-mesenchymal transition of mechanically conditioned alveolar epithelial cells in rheumatoid arthritis-associated interstitial lung disease through mTOR/S6 signaling.

Epithelial-mesenchymal transition (EMT) creates an environment facilitating fibrosis following alveolar epithelial cell injury. IL-23 has important roles in chronic autoimmune conditions like rheumatoid arthritis (RA), but its role in the interstitial lung disease that affects patients with RA is unclear. This study aimed to determine the profibrogenic role of IL-23 on somatic alveolar type I (ATI) epithelial cells. Primary ATI cells were isolated from rats and cultured on plastic dishes for 1-3 wk. After prolonged culture (≥14 days) on rigid culture dishes, primary ATI cells gradually acquired a mesenchymal phenotype, identified by decreased expression of caveolin-1, and reorganization of F-actin cytoskeleton, indicating the initiation of EMT by matrix stiffness. To determine how IL-23 promotes EMT in vitro, transitioning ATI cells, cultured on a stiff substrate for ≥14 days were stimulated with IL-23. The EMT phenotype was significantly enhanced by IL-23, which upregulated α-smooth muscle actin (α-SMA), collagen I/III protein, and decreased caveolin-1. Furthermore, IL-23 significantly promoted cell invasion, as well as apoptotic resistance on transitioning ATI cells. Mechanistically, IL-23-induced EMT was mammalian target of rapamycin/ribosomal protein S6 (mTOR/S6) signaling dependent and reversible by rapamycin. Transcriptional sequencing analysis of human lung fibrosis biopsy tissue revealed key roles for IL-23 in rheumatoid arthritis-associated interstitial lung disease (RA-ILD). This result was further validated by significantly upregulated IL-23 expression at the mRNA level in RA-ILD lung sections. Notably, transitioning ATI epithelial cells were abundantly detected in RA-ILD tissue. Taken together, these data support a role for IL-23 in the pathogenesis of RA lung fibrosis by promoting EMT in alveolar epithelial cells through mTOR/S6 signaling.

A Closer Look at the Role of Anti-CCP Antibodies in the Pathogenesis of Rheumatoid Arthritis-Associated Interstitial Lung Disease and Bronchiectasis.

Rheumatoid arthritis (RA) is an articular disease with extra-articular manifestations. Pulmonary manifestations are not uncommon and can involve all compartments of the lungs with airway disease in the form of bronchiectasis or bronchiolitis, interstitial lung disease (ILD), pleural effusions and parenchymal lung nodules. The pulmonary features may present synchronously or after the articular disease, but, importantly, it may be the first presentation in 10% of patients in the absence of articular symptoms. Here we discuss the pathogenesis of RA lung involvement, particularly interstitial lung disease and bronchiectasis, focusing on the role anti-CCP antibodies (ACPAs). We highlight the complex interplay among genetic, environmental and immune factors. Furthermore, we explore the relationship of citrullination and smoking as well as the concept of interstitial pneumonia with autoimmune features (IPAF), where patients do not have evidence of another known cause of interstitial pneumonia and have incomplete features of connective tissue disease (CTD). We surmise that the frequency and titers of rheumatoid factor (RF) and ACPAs are increased in bronchiectasis and RA-bronchiectasis compared to RA patients without lung disease. ACPA is associated with more severe disease in both RA-ILD and RA-bronchiectasis even in the absence of articular symptoms. There is no clear prediction of development of articular RA with high ACPA levels in the context of positive ACPA and ILD; however, in RA-bronchiectasis, patients with positive antibodies can develop RA within a year after diagnosis of bronchiectasis. Though the primary focus of this narrative is to highlight the role of ACPA in pathogenesis and clinical practice, we also discuss the current treatment options and trials in RA-ILD and RA-bronchiectasis. Currently, there are no clear treatment guidelines. The treatments are now focusing on using a combination of immunosuppression and antifibrotic agents. Combination treatment targets both the fibrotic and inflammatory components of the disease process. Further studies are needed to identify the use of ACPA as a biomarker to tailor the treatment in RA-ILD and RA-bronchiectasis.

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.

Reinterpreting Evidence of Rheumatoid Arthritis-Associated Interstitial Lung Disease to Understand Etiology.

Interstitial Lung Disease (ILD) is a well-known complication of rheumatoid arthritis (RA) which often results in significant morbidity and mortality. It is often diagnosed late in the disease process via descriptive criteria. Multiple subtypes of RA-ILD exist as defined by chest CT and histopathology. In the absence of formal natural history studies and definitive diagnostics, a conventional dogma has emerged that there are two major subtypes of RA-ILD (nonspecific interstitial pneumonia (NSIP) and Usual Interstitial Pneumonia (UIP)). These subtypes are based on clinical experience and correlation studies. However, recent animal model data are incongruous with established paradigms of RA-ILD and beg reassessment of the clinical evidence in order to better understand etiology, pathogenesis, prognosis, and response to therapy. To this end, here we: 1) review the literature on epidemiology, radiology, histopathology and clinical outcomes of the various RAILD subtypes, existing animal models, and current theories on RA-ILD pathogenesis; 2) highlight the major gaps in our knowledge; and 3) propose future research to test an emerging theory of RAILD that posits initial rheumatic lung inflammation in the form of NSIP-like pathology transforms mesenchymal cells to derive chimeric disease, and subsequently develops into frank UIP-like fibrosis in some RA patients. Elucidation of the pathogenesis of RA-ILD is critical for the development of effective interventions for RA-ILD.

Biologics-induced interstitial lung diseases in rheumatic patients: facts and controversies.

INTRODUCTION: Interstitial lung disease (ILD) is a common, devastating pulmonary complication. An increased number of reports suggesting that biological disease modifying antirheumatic drugs (DMARDs) induced or exacerbated ILDs in rheumatoid arthritis (RA) patients has garnered increased attention. Areas covered: This article discusses ILDs induced by or exacerbated during biological therapy in RA patients. The article summarizes the efficacy and safety of a variety of licensed and off-label biologics clinically used for rheumatic diseases, focusing on the onset or exacerbation of RA-associated ILDs (RA-ILDs) in RA patients treated with biologics targeting tumor necrosis factor, CD20, interleukin 1 (IL-1) and IL-6 receptors. Additionally, the pathogenesis of RA-ILDs is discussed. Expert opinion: To some extent, the possibility of biologic-induced RA-ILDs increases the difficulty in choosing an optimal regimen for RA treatment with biological agents, as the relationship between biological therapy safety and the induction or exacerbation of RA-ILDs has not been established. A framework to assess baseline disease severity, particularly standardizing the evaluation of the pulmonary condition stage in RA patients and monitoring the outcome during the biological therapy treatment, is highly needed and may substantially help guide treatment decisions and predict the treatment benefits.

Are risk predicting models useful for estimating survival of patients with rheumatoid arthritis-associated interstitial lung disease?

BACKGROUND: Risk predicting models have been applied in idiopathic pulmonary fibrosis (IPF), but still not validated in patients with rheumatoid arthritis-associated interstitial lung disease (RA-ILD). The purpose of this study was to test the suitability of three prediction models as well as individual lung function and demographic factors for evaluating the prognosis of RA-ILD patients. METHODS: Clinical and radiological data of 59 RA-ILD patients was re-assessed. GAP (gender, age, physiologic variables) and the modified interstitial lung disease (ILD)-GAP as well as the composite physiologic indexes (CPI) were tested for predicting mortality using the goodness-of-fit test and Cox model. Potential predictors of mortality were also sought from single lung function parameters and clinical characteristics. RESULTS: The median survival was 152 and 61 months in GAP / ILD-GAP stages I and II (p = 0.017). Both GAP and ILD-GAP models accurately estimated 1-year, 2-year and 3-year mortality. CPI (p = 0.025), GAP (p = 0.008) and ILD-GAP (p = 0.028) scores, age (p = 0.002), baseline diffusion capacity to carbon monoxide (DLCO) (p = 0.014) and hospitalization due to respiratory reasons (p = 0.039), were significant predictors of mortality in the univariate analysis, whereas forced vital capacity (FVC) was not predictive. CPI score (HR 1.03, p = 0.018) and baseline DLCO (HR 0.97, p = 0.011) remained significant predictors of mortality after adjusting for age. CONCLUSIONS: GAP and ILD-GAP are applicable for evaluating the risk of death of patients with RA-ILD in a similar manner as in those with IPF. Baseline DLCO and CPI score also predicted survival.