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BACKGROUND: A usual interstitial pneumonia (UIP) pattern of lung injury is a key feature of idiopathic pulmonary fibrosis (IPF) and is also observed in up to 40% of individuals with rheumatoid arthritis (RA)-associated interstitial lung disease (RA-ILD). The RA-UIP phenotype could result from either a causal relationship of RA on UIP or vice versa, or from a simple co-occurrence of RA and IPF due to shared demographic, genetic or environmental risk factors. METHODS: We used two-sample bidirectional Mendelian randomisation (MR) to test the hypothesis of a causal effect of RA on UIP and of UIP on RA, using variants from genome-wide association studies (GWAS) of RA (separately for seropositive (18 019 cases and 991 604 controls) and seronegative (8515 cases and 1 015 471 controls) RA) and of IPF (4125 cases and 20 464 controls) as genetic instruments. Sensitivity analyses were conducted to assess the robustness of the results to violations of the MR assumptions. FINDINGS: IPF showed a significant causal effect on seropositive RA, with developing IPF increasing the risk of seropositive RA (OR=1.06, 95% CI: 1.04 to 1.08, p<0.001) which was robust under all models. For the MR in the other direction, seropositive RA showed a significant protective effect on IPF (OR=0.93; 95% CI: 0.87 to 0.99; p=0.032), but the effect was not significant when sensitivity analyses were applied. This was likely because of bias due to exclusion of patients with RA from among the cases in the IPF GWAS, or possibly because our genetic instruments did not fully capture the effect of the complex human leucocyte antigen region, the strongest RA genetic risk factor. INTERPRETATION: Our findings support the hypothesis that RA-UIP may be due to a cause-effect relationship between UIP and RA, rather than due to a coincidental occurrence of IPF in patients with RA. The significant causal effect of IPF on seropositive RA suggests that pathomechanisms involved in the development of UIP may promote RA, and this may help inform future guidelines on screening for ILD in patients with RA.
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Artritis Reumatoide , Estudio de Asociación del Genoma Completo , Fibrosis Pulmonar Idiopática , Análisis de la Aleatorización Mendeliana , Humanos , Artritis Reumatoide/genética , Artritis Reumatoide/complicaciones , Fibrosis Pulmonar Idiopática/genética , Factores de Riesgo , Masculino , Femenino , Predisposición Genética a la EnfermedadRESUMEN
With the COVID-19 pandemic having lasted more than 3 years, concerns are growing about prolonged symptoms and respiratory complications in COVID-19 survivors, collectively termed post-COVID-19 condition (PCC). Up to 50% of patients have residual symptoms and physiologic impairment, particularly dyspnea and reduced diffusion capacity. Studies have also shown that 24%-54% of patients hospitalized during the 1st year of the pandemic exhibit radiologic abnormalities, such as ground-glass opacity, reticular opacity, bronchial dilatation, and air trapping, when imaged more than 1 year after infection. In patients with persistent respiratory symptoms but normal results at chest CT, dual-energy contrast-enhanced CT, xenon 129 MRI, and low-field-strength MRI were reported to show abnormal ventilation and/or perfusion, suggesting that some lung injury may not be detectable with standard CT. Histologic patterns in post-COVID-19 lung disease include fibrosis, organizing pneumonia, and vascular abnormality, indicating that different pathologic mechanisms may contribute to PCC. Therefore, a comprehensive imaging approach is necessary to evaluate and diagnose patients with persistent post-COVID-19 symptoms. This review will focus on the long-term findings of clinical and radiologic abnormalities and describe histopathologic perspectives. It also addresses advanced imaging techniques and deep learning approaches that can be applied to COVID-19 survivors. This field remains an active area of research, and further follow-up studies are warranted for a better understanding of the chronic stage of the disease and developing a multidisciplinary approach for patient management.
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COVID-19 , Lesión Pulmonar , Humanos , Lesión Pulmonar/diagnóstico por imagen , Lesión Pulmonar/etiología , COVID-19/complicaciones , COVID-19/diagnóstico por imagen , Pandemias , Síndrome Post Agudo de COVID-19 , BronquiosRESUMEN
BACKGROUND: Fibrotic hypersensitivity pneumonitis (FHP) is an irreversible lung disease with high morbidity and mortality. We sought to evaluate the safety and effect of pirfenidone on disease progression in such patients. METHODS: We conducted a single-centre, randomised, double-blinded, placebo-controlled trial in adults with FHP and disease progression. Patients were assigned in a 2:1 ratio to receive either oral pirfenidone (2403 mg/day) or placebo for 52 weeks. The primary end point was the mean absolute change in the per cent predicted forced vital capacity (FVC%). Secondary end points included progression-free survival (PFS, time to a relative decline ≥10% in FVC and/or diffusing capacity of the lung for carbon monoxide (DLCO), acute respiratory exacerbation, a decrease of ≥50 m in the 6 min walk distance, increase or introduction of immunosuppressive drugs or death), change in FVC slope and mean DLCO%, hospitalisations, radiological progression of lung fibrosis and safety. RESULTS: After randomising 40 patients, enrolment was interrupted by the COVID-19 pandemic. There was no significant between-group difference in FVC% at week 52 (mean difference -0.76%, 95% CI -6.34 to 4.82). Pirfenidone resulted in a lower rate of decline in the adjusted FVC% at week 26 and improved PFS (HR 0.26, 95% CI 0.12 to 0.60). Results for other secondary end points showed no significant difference between groups. No deaths occurred in the pirfenidone group and one death (respiratory) occurred in the placebo group. There were no treatment-emergent serious adverse events. CONCLUSIONS: The trial was underpowered to detect a difference in the primary end point. Pirfenidone was found to be safe and improved PFS in patients with FHP. TRIAL REGISTRATION MUMBER: NCT02958917.
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Alveolitis Alérgica Extrínseca , COVID-19 , Fibrosis Pulmonar Idiopática , Adulto , Humanos , Fibrosis Pulmonar Idiopática/diagnóstico , Resultado del Tratamiento , Pandemias , Capacidad Vital , Piridonas/efectos adversos , Método Doble Ciego , Progresión de la Enfermedad , Alveolitis Alérgica Extrínseca/tratamiento farmacológicoRESUMEN
BACKGROUND: A genomic classifier for usual interstitial pneumonia (gUIP) has been shown to predict histological UIP with high specificity, increasing diagnostic confidence for idiopathic pulmonary fibrosis (IPF). Whether those with positive gUIP classification exhibit a progressive, IPF-like phenotype remains unknown. METHODS: A pooled, retrospective analysis of patients who underwent clinically indicated diagnostic bronchoscopy with gUIP testing at seven academic medical centres across the USA was performed. We assessed the association between gUIP classification and 18-month progression-free survival (PFS) using Cox proportional hazards regression. PFS was defined as the time from gUIP testing to death from any cause, lung transplant, ≥10% relative decline in forced vital capacity (FVC) or censoring at the time of last available FVC measure. Longitudinal change in FVC was then compared between gUIP classification groups using a joint regression model. RESULTS: Of 238 consecutive patients who underwent gUIP testing, 192 had available follow-up data and were included in the analysis, including 104 with positive gUIP classification and 88 with negative classification. In multivariable analysis, positive gUIP classification was associated with reduced PFS (hazard ratio 1.58, 95% CI 0.86-2.92; p=0.14), but this did not reach statistical significance. Mean annual change in FVC was -101.8â mL (95% CI -142.7- -60.9â mL; p<0.001) for those with positive gUIP classification and -73.2â mL (95% CI -115.2- -31.1â mL; p<0.001) for those with negative classification (difference 28.7â mL, 95% CI -83.2-25.9â mL; p=0.30). CONCLUSIONS: gUIP classification was not associated with differential rates of PFS or longitudinal FVC decline in a multicentre interstitial lung disease cohort undergoing bronchoscopy as part of the diagnostic evaluation.
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Fibrosis Pulmonar Idiopática , Enfermedades Pulmonares Intersticiales , Humanos , Pulmón/patología , Estudios Retrospectivos , Fibrosis Pulmonar Idiopática/diagnóstico , Fibrosis Pulmonar Idiopática/genética , Enfermedades Pulmonares Intersticiales/diagnóstico , Enfermedades Pulmonares Intersticiales/genética , Capacidad Vital , Genómica , Progresión de la EnfermedadRESUMEN
PURPOSE OF REVIEW: In idiopathic inflammatory myopathies (IIMs), interstitial lung disease (ILD) is common and the autoantibody profile, made up of myositis-specific and myositis-associated (MSA and MAA) antibodies, can predict the clinical phenotype and progression over time. This review will focus on the characteristics and management of antisynthetase syndrome related ILD and anti-MDA5 positive ILD, which are the most clinically relevant subtypes. RECENT FINDINGS: The prevalence of ILD in IIM has been estimated in Asia, North America and Europe at 50, 23 and 26%, respectively, and is increasing. In antisynthetase syndrome related ILD, the clinical presentation, progression and prognosis varies among anti-ARS antibodies. ILD is more common and severe in patients with anti-PL-7/anti-PL-12 antibodies when compared with anti Jo-1 patients. The prevalence of anti-MDA5 antibodies is higher in Asians (11-60%) than in whites (7-16%). Sixty-six percent of antisynthetase syndrome patients had 'chronic ILD' compared with the more rapidly progressive ILD (RP-ILD) seen in 69% of patients with anti-MDA5 antibodies. SUMMARY: ILD is most common in the antisynthetase subtype of IIM and can be a chronic indolent or RP- ILD. The MSA and MAAs are associated with different clinical phenotypes of ILD. Treatments typically involve combinations of corticosteroids and other immunosuppressants.
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Enfermedades Pulmonares Intersticiales , Miositis , Humanos , Miositis/complicaciones , Miositis/tratamiento farmacológico , Autoanticuerpos , Enfermedades Pulmonares Intersticiales/etiología , Enfermedades Pulmonares Intersticiales/complicaciones , InmunosupresoresRESUMEN
OBJECTIVES: This study sought to determine the level of understanding and opinion among rheumatologist and pulmonologists regarding risk factors, diagnostic approach and treatment of RA-associated interstitial lung disease (RA-ILD). METHODS: We conducted an international electronic survey of rheumatologists and pulmonologists utilizing two separate Redcap-based surveys with questions on the epidemiology, workup and management of RA-ILD as well as ILD screening questions using case-based scenarios directed at rheumatologists. The survey also collected demographic data on participants including their practice setting, years in practice and country of practice. RESULTS: We received a total of 616 responses (354 rheumatologists and 262 pulmonologists) from six continents. There were significant differences in responses between pulmonologists and rheumatologists in estimated prevalence and mortality, risk factors for the development of ILD in RA and medications that are effective or should be avoided. Rheumatologists were much less likely to consider assessment for ILD in high risk, asymptomatic patients compared with high-risk patients with either symptoms or exam findings suggestive of ILD. CONCLUSION: Our study brought to light the variability in disease assessment and clinical practice among providers caring for patients with RA-ILD and indicate that greater education is needed to optimize clinical decision making in the risk assessment, screening and treatment of RA-ILD. Research questions that address appropriate screening and treatment strategies for RA-ILD will be valuable for rheumatologists given their central role in the overall health and lung health of patients with RA.
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Artritis Reumatoide , Enfermedades Pulmonares Intersticiales , Artritis Reumatoide/tratamiento farmacológico , Actitud , Humanos , Enfermedades Pulmonares Intersticiales/diagnóstico , Enfermedades Pulmonares Intersticiales/etiología , Enfermedades Pulmonares Intersticiales/terapia , Atención al Paciente , ReumatólogosRESUMEN
The acute course of COVID-19 is variable and ranges from asymptomatic infection to fulminant respiratory failure. Patients recovering from COVID-19 can have persistent symptoms and CT abnormalities of variable severity. At 3 months after acute infection, a subset of patients will have CT abnormalities that include ground-glass opacity (GGO) and subpleural bands with concomitant pulmonary function abnormalities. At 6 months after acute infection, some patients have persistent CT changes to include the resolution of GGOs seen in the early recovery phase and the persistence or development of changes suggestive of fibrosis, such as reticulation with or without parenchymal distortion. The etiology of lung disease after COVID-19 may be a sequela of prolonged mechanical ventilation, COVID-19-induced acute respiratory distress syndrome (ARDS), or direct injury from the virus. Predictors of lung disease after COVID-19 include need for intensive care unit admission, mechanical ventilation, higher inflammatory markers, longer hospital stay, and a diagnosis of ARDS. Treatments of lung disease after COVID-19 are being investigated, including the potential of antifibrotic agents for prevention of lung fibrosis after COVID-19. Future research is needed to determine the long-term persistence of lung disease after COVID-19, its impact on patients, and methods to either prevent or treat it. © RSNA, 2021.
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COVID-19/complicaciones , Enfermedades Pulmonares/diagnóstico por imagen , Enfermedades Pulmonares/etiología , Tomografía Computarizada por Rayos X/métodos , Enfermedad Aguda , Humanos , Pulmón/diagnóstico por imagen , SARS-CoV-2RESUMEN
QUESTION ADDRESSED BY THE STUDY: Methotrexate (MTX) is a key anchor drug for rheumatoid arthritis (RA) management. Fibrotic interstitial lung disease (ILD) is a common complication of RA. Whether MTX exposure increases the risk of ILD in patients with RA is disputed. We aimed to evaluate the association of prior MTX use with development of RA-ILD. METHODS: Through a case-control study design with discovery and international replication samples, we examined the association of MTX exposure with ILD in 410 patients with chronic fibrotic ILD associated with RA (RA-ILD) and 673 patients with RA without ILD. Estimates were pooled over the different samples using meta-analysis techniques. RESULTS: Analysis of the discovery sample revealed an inverse relationship between MTX exposure and RA-ILD (adjusted OR 0.46, 95% CI 0.24-0.90; p=0.022), which was confirmed in the replication samples (pooled adjusted OR 0.39, 95% CI 0.19-0.79; p=0.009). The combined estimate using both the derivation and validation samples revealed an adjusted OR of 0.43 (95% CI 0.26-0.69; p=0.0006). MTX ever-users were less frequent among patients with RA-ILD compared to those without ILD, irrespective of chest high-resolution computed tomography pattern. In patients with RA-ILD, ILD detection was significantly delayed in MTX ever-users compared to never-users (11.4±10.4â years and 4.0±7.4â years, respectively; p<0.001). ANSWER TO THE QUESTION: Our results suggest that MTX use is not associated with an increased risk of RA-ILD in patients with RA, and that ILD was detected later in MTX-treated patients.
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Antirreumáticos , Artritis Reumatoide , Enfermedades Pulmonares Intersticiales , Antirreumáticos/efectos adversos , Artritis Reumatoide/complicaciones , Artritis Reumatoide/tratamiento farmacológico , Estudios de Casos y Controles , Humanos , Enfermedades Pulmonares Intersticiales/inducido químicamente , Enfermedades Pulmonares Intersticiales/tratamiento farmacológico , Metotrexato/efectos adversosRESUMEN
Interstitial lung disease (ILD) is a common pulmonary manifestation of rheumatoid arthritis. There is lack of clarity around predictors of mortality and disease behaviour over time in these patients.We identified rheumatoid arthritis-related interstitial lung disease (RA-ILD) patients evaluated at National Jewish Health (Denver, CO, USA) from 1995 to 2013 whose baseline high-resolution computed tomography (HRCT) scans showed either a nonspecific interstitial pneumonia (NSIP) or a "definite" or "possible" usual interstitial pneumonia (UIP) pattern. We used univariate, multivariate and longitudinal analytical methods to identify clinical predictors of mortality and to model disease behaviour over time.The cohort included 137 subjects; 108 had UIP on HRCT (RA-UIP) and 29 had NSIP on HRCT (RA-NSIP). Those with RA-UIP had a shorter survival time than those with RA-NSIP (log rank p=0.02). In a model controlling for age, sex, smoking and HRCT pattern, a lower baseline % predicted forced vital capacity (FVC % pred) (HR 1.46; p<0.0001) and a 10% decline in FVC % pred from baseline to any time during follow up (HR 2.57; p<0.0001) were independently associated with an increased risk of death.Data from this study suggest that in RA-ILD, disease progression and survival differ between subgroups defined by HRCT pattern; however, when controlling for potentially influential variables, pulmonary physiology, but not HRCT pattern, independently predicts mortality.
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Artritis Reumatoide/complicaciones , Fibrosis Pulmonar Idiopática/mortalidad , Anciano , Estudios de Cohortes , Progresión de la Enfermedad , Femenino , Volumen Espiratorio Forzado , Humanos , Fibrosis Pulmonar Idiopática/diagnóstico por imagen , Fibrosis Pulmonar Idiopática/etiología , Fibrosis Pulmonar Idiopática/fisiopatología , Estimación de Kaplan-Meier , Enfermedades Pulmonares Intersticiales/diagnóstico por imagen , Enfermedades Pulmonares Intersticiales/etiología , Enfermedades Pulmonares Intersticiales/mortalidad , Enfermedades Pulmonares Intersticiales/fisiopatología , Masculino , Persona de Mediana Edad , Análisis Multivariante , Modelos de Riesgos Proporcionales , Capacidad de Difusión Pulmonar , Tasa de Supervivencia , Tomografía Computarizada por Rayos X , Capacidad VitalRESUMEN
The connective tissue diseases (CTDs) are a group of systemic disorders characterized by autoimmunity and autoimmune-mediated organ damage. The lung is a frequent target and all components of the respiratory system are at risk. Interstitial lung disease (ILD) represents a broad group of diffuse parenchymal lung injury patterns characterized by varying degrees of inflammation and fibrosis, is a common manifestation of CTD particularly common in systemic sclerosis, polymyositis/dermatomyositis, and rheumatoid arthritis, and is a leading cause of significant morbidity and mortality. The lung injury patterns of CTD-associated ILD (CTD-ILD) mirror those of idiopathic interstitial pneumonia and may arise at any time during the course of the CTD or may be the first manifestation of CTD. Patients with CTD that present with respiratory failure often present significant diagnostic dilemmas. Thorough and comprehensive assessments to exclude respiratory *infection, acute interstitial pneumonia, medication toxicity, pulmonary embolism, cardiac dysfunction, and diffuse alveolar hemorrhage are the fundamental components for the evaluation of such patients. Furthermore, patients with CTD are also at risk of acute exacerbations of underlying ILD. Acute exacerbations are manifested by subacute respiratory deterioration with worsening hypoxemia in the setting of new radiographic abnormalities. The prognosis of patients with CTD having respiratory failure is often quite poor, highlighting the need for prompt and thorough clinical assessments to determine the underlying etiology and implementation of appropriate therapeutic strategies.
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Enfermedades del Tejido Conjuntivo/complicaciones , Enfermedades Pulmonares Intersticiales/complicaciones , Humanos , Pronóstico , Insuficiencia Respiratoria/etiologíaRESUMEN
PURPOSE OF REVIEW: To review current approaches to the complex intersection of interstitial lung disease (ILD) with the spectrum of connective tissue disease (CTD). RECENT FINDINGS: There is a growing appreciation that the approach to CTD-associated ILD (CTD-ILD) can be enhanced by a multidisciplinary evaluation that often incorporates the rheumatologist. Determining that ILD is associated with an established CTD requires the exclusion of alternative causes and thorough assessments of the clinical features of both the CTD and ILD. The detection of occult CTD in patients with presumed 'idiopathic' disease requires careful attention to the demographic profile, historical clues, subtle physical examination findings, specific autoantibody positivity, radiologic, and histopathologic features. A comprehensive treatment program for CTD-ILD should address comorbid conditions and consider implementation of adjunctive therapeutic strategies. Pharmacologic intervention for CTD-ILD is reserved for those with progressive, clinically significant disease and typically involves use of immunosuppressive therapies. SUMMARY: A multidisciplinary approach can be helpful for CTD-ILD. Further research and controlled trials are needed to determine how to best manage the diverse spectrum of CTD-ILD.
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Enfermedades del Tejido Conjuntivo/etiología , Enfermedades Pulmonares Intersticiales/complicaciones , Autoanticuerpos/inmunología , Enfermedades del Tejido Conjuntivo/tratamiento farmacológico , Diagnóstico Diferencial , HumanosRESUMEN
RATIONALE: In interstitial lung disease (ILD), symptoms drive impairments in health-related quality of life (HRQL). Patient-reported outcome measures (PROs) can assess whether interventions change symptom severity. The meaningfulness of change in a PRO's score is estimated by anchoring it to a related variable for which meaningful change has been previously established. Patient global impressions of severity (PGIS) are single item PROs that may make trustworthy anchors, but for ILD, the meaningfulness of change in PGIS items for shortness of breath, cough, and fatigue/low energy are unknown. OBJECTIVES: To improve understanding of how patients with ILD rate and categorize symptoms; how differing levels of symptom severity affect lived experiences; and how patients derive and apply meaningfulness to change in symptoms. METHODS: We used one-on-one interviews and an electronic survey to collect data from patients with various forms of ILD. Interviews were conducted to provide richness and context to survey responses. We conducted certain analyses with respondents stratified by oxygen use. RESULTS: Interviewees (N=18) confirmed shortness of breath (SOB), cough and fatigue/low energy are the most bothersome symptoms of ILD. Among 298 survey respondents, on a PGIS for SOB with a 0 to 4 numeric rating scale, on average, those who used O2 had more severe SOB than non-users, and most respondents considered a 2-point change meaningful for worsening (45.5%) or improvement (47.2%). On a PGIS with a 5-option ordinal response scale, for SOB, most considered a 1-category change meaningful for worsening (49.8%) and a 2-category change meaningful for improvement (42.3); for cough frequency, most respondents considered a 1-category change on the 5-option ordinal response scale meaningful for worsening (48.2%) or improvement (45.0%). Survey responses for how SOB is now compared to 3 months ago (patient global impressions of change or PGIC) were biased toward the present state. CONCLUSIONS: PGIS's can be used as anchors for meaningful change analyses of PRO's that assess SOB or cough in patients with ILD. PGIC's demonstrate present state bias and should not be used. Patients' descriptions paint a vivid picture of lived experience with varying levels of symptom severity and can help contextualize change scores.
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Background: Idiopathic pulmonary fibrosis (IPF) leads to progressive loss of lung function and mortality. Understanding mechanisms and markers of lung injury in IPF is paramount to improving outcomes for these patients. Despite the lack of systemic involvement in IPF, many analyses focus on identifying circulating prognostic markers. Using a proteomic discovery method followed by ELISA validation in multiple IPF lung compartments and cohorts we explored novel markers of IPF survival. Methods: In our discovery analysis, agnostic label-free quantitative proteomics differentiated lung tissue protein expression based on survival trajectory (n=10). Following selection of the candidate pathway (neutrophil extracellular trap (NET) formation), we subsequently validated the presence of NETs in the IPF lung microenvironment using fully quantitative assays of known NET remnants in separate IPF cohorts (n=156 and n=52) with bronchoalveolar lavage fluid. We then assessed the correlation of these markers with baseline pulmonary function and survival. Results: Discovery lung tissue proteomics identified NET formation as significantly associated with poor IPF survival. Using fully quantitative confirmatory tests for reproducibility we confirmed the presence of NET markers in IPF BALF and found significant correlations with worse pulmonary function in both cohorts (p<0.03 and p = 0.04 respectively). In the survival cohort, higher levels of NET markers predicted worse survival after adjusting for gender, age, and baseline physiologic severity (hazard ratio range: 1.79-2.19). Conclusions: NET markers were associated with disease severity and worse survival in IPF. These findings suggest NET formation contributes to lung injury and decreased survival in IPF and may represent a potential therapeutic target.
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Background: Idiopathic interstitial pneumonias (IIPs) such as idiopathic pulmonary fibrosis (IPF) and interstitial pneumonia with autoimmune features (IPAF), present diagnostic and therapeutic challenges due to their heterogeneous nature. This study aimed to identify intrinsic molecular signatures within the lung microenvironment of these IIPs through proteomic analysis of bronchoalveolar lavage fluid (BALF). Methods: Patients with IIP (n=23) underwent comprehensive clinical evaluation including pre-treatment bronchoscopy and were compared to controls without lung disease (n=5). Proteomic profiling of BALF was conducted using label-free quantitative methods. Unsupervised cluster analyses identified protein expression profiles which were then analyzed to predict survival outcomes and investigate associated pathways. Results: Proteomic profiling successfully differentiated IIP from controls. k-means clustering, based on protein expression revealed three distinct IIP clusters, which were not associated with age, smoking history, or baseline pulmonary function. These clusters had unique survival trajectories and provided more accurate survival predictions than the Gender Age Physiology (GAP) index (C-index 0.794 vs. 0.709). The cluster with the worst prognosis featured decreased inflammatory signaling and complement activation, with pathway analysis highlighting altered immune response pathways related to immunoglobulin production and B cell-mediated immunity. Conclusions: The unsupervised clustering of BALF proteomics provided a novel stratification of IIP patients, with potential implications for prognostic and therapeutic targeting. The identified molecular phenotypes underscore the diversity within the IIP classification and the potential importance of personalized treatments for these conditions. Future validation in larger, multi-ethnic cohorts is essential to confirm these findings and to explore their utility in clinical decision-making for patients with IIP.
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Interstitial lung disease (ILD) is a frequent complication of rheumatoid arthritis (RA) that is associated with a significant increase in mortality. Several risk factors for the development of ILD in patients with RA have been identified, but ILD can still develop in the absence of these risk factors. Screening tools for RA-ILD are required to facilitate early detection of RA-ILD. Close monitoring of patients with RA-ILD for progression is crucial to enable timely implementation of treatment strategies to improve outcomes. Patients with RA are commonly treated with immunomodulatory therapies, although their efficacy in slowing the progression of RA-ILD remains the subject of debate. Clinical trials have shown that antifibrotic therapies slow decline in lung function in patients with progressive fibrosing ILDs, including patients with RA-ILD. The management of patients with RA-ILD should be based on multidisciplinary evaluation of the severity and progression of their ILD and the activity of their articular disease. Close collaboration between rheumatologists and pulmonologists is essential to optimize patient care.
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Artritis Reumatoide , Enfermedades Pulmonares Intersticiales , Humanos , Artritis Reumatoide/complicaciones , Artritis Reumatoide/tratamiento farmacológico , Enfermedades Pulmonares Intersticiales/diagnóstico , Enfermedades Pulmonares Intersticiales/etiología , Enfermedades Pulmonares Intersticiales/terapia , Factores de Riesgo , Fibrosis , InmunomodulaciónRESUMEN
BACKGROUND: Interstitial lung disease due to rheumatoid arthritis (RA-ILD) affects a substantial minority of patients with RA, inducing life-altering symptoms, impairing quality of life (QOL) and forcing patients to confront the potential for shortened survival. Dyspnoea is the predominant respiratory symptom of RA-ILD and a strong driver of QOL impairment in patients with it. The D12 is a 12-item questionnaire that assesses the physical and affective components of dyspnoea. It was one of a battery of patient-reported outcomes used in the double-blind, placebo-controlled TRAIL 1 trial of pirfenidone for RA-ILD. There is little information on the reliability, validity or responsiveness of the D12 in RA-ILD. METHODS: In accordance with COSMIN (COnsensus-based Standards for the selection of health Measurement INstruments) methodology, we conducted analyses on data from the TRAIL 1 trial to assess the measurement properties of the D12. RESULTS: Internal consistency (α=0.95, 0.95, 0.95, 0.95 and 0.96 at baseline, 13, 26, 39 and 52 weeks) and test-retest reliability 0.85 (0.71 to 0.92) exceeded acceptability criteria. Well over the 75% benchmark of hypotheses (43/46=93%) around D12 measurement properties were confirmed. Known-groups validity was supported by significant differences between subgroups of patients with differing levels of dyspnoea (eg, St. George's Respiratory Questionnaire (SGRQ) Activity score ≥50 vs <50, 9.36 (1.27) points, p<0.0001, with a large effect size=1.7) and physiological impairment at baseline. Longitudinal validity was supported by significant associations between D12 and anchor scores over time (eg, at 52 weeks, correlation between D12 change and SGRQ Activity change was 0.54, p<0.0001; between D12 change and Routine Assessment of Patient Index Data (RAPID) Functioning Component was 0.41, p<0.0001). A battery of analyses confirmed the responsiveness of D12 scores for capturing change in dyspnoea over time. We estimated the minimal within-patient change threshold for worsening as 3 points. CONCLUSIONS: D12 scores possess acceptable measurement properties in RA-ILD, such that it can be used with confidence in this population to assess dyspnoea severity defined by its physical and affective components. As validation is an ongoing process, and never accomplished in a single study, additional research on the psychometric properties of the D12 in RA-ILD is encouraged.
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Artritis Reumatoide , Enfermedades Pulmonares Intersticiales , Humanos , Calidad de Vida , Reproducibilidad de los Resultados , Artritis Reumatoide/complicaciones , Disnea/diagnóstico , Disnea/tratamiento farmacológico , Disnea/etiología , Enfermedades Pulmonares Intersticiales/complicaciones , Enfermedades Pulmonares Intersticiales/diagnóstico , Enfermedades Pulmonares Intersticiales/tratamiento farmacológicoRESUMEN
OBJECTIVE: Interstitial lung disease (ILD) is a leading cause of mortality in rheumatoid arthritis (RA), particularly in those with the usual interstitial pneumonia subtype (RA-UIP). Serum antibodies to peptidylarginine deiminase type 4 (anti-PAD4), particularly a subset that cross-react with PAD3 (PAD3/4XR), have been associated with imaging evidence of ILD. We aimed to determine the specificity of anti-PAD4 antibodies in RA-ILD and to examine associations with markers of ILD severity. METHODS: 48 RA-ILD and 31 idiopathic pulmonary fibrosis (IPF) patients were identified from the National Jewish Health Biobank. RA-ILD subtype was defined by imaging pattern on high-resolution chest computed tomography (CT), and serum was tested for anti-PAD4 and anti-PAD3/4XR antibodies. Antibody prevalence, measures of ILD severity (% predicted forced vital capacity, FVC; % predicted diffusion capacity carbon monoxide, DLCO; quantitative CT fibrosis) and mortality were compared between groups. RESULTS: Anti-PAD4 antibodies were present in 9/48 (19%) subjects with RA-ILD and no subjects with IPF. Within RA-ILD, anti-PAD4 antibodies were found almost exclusively in RA-UIP (89%). Within RA-UIP subjects, % predicted FVC was higher in anti-PAD4+ subjects, and this finding was most strongly associated with anti-PAD3/4XR antibodies. In addition, quantitative CT fibrosis score was lower in anti-PAD4+ RA-UIP subjects, including those with mono-reactive anti-PAD4 antibodies and anti-PAD3/4XR antibodies. Anti-PAD4+ RA-UIP subjects also exhibited decreased mortality. CONCLUSIONS: We demonstrate the presence of serum anti-PAD4 antibodies in a subset of patients with RA-UIP that were notably associated with better lung function, less fibrosis and decreased mortality.
Asunto(s)
Artritis Reumatoide , Fibrosis Pulmonar Idiopática , Enfermedades Pulmonares Intersticiales , Humanos , Enfermedades Pulmonares Intersticiales/complicaciones , Artritis Reumatoide/complicaciones , Arginina Deiminasa Proteína-Tipo 4 , AutoanticuerposRESUMEN
OBJECTIVE: Mitochondria are found in the extracellular space in rheumatoid arthritis (RA). However, whether mitochondria are a source of autoantigens in RA has not been carefully addressed. Thus, we undertook this study to investigate the presence and significance of antimitochondrial antibodies (AMAs) in patients with RA. METHODS: AMAs were measured in serum samples from 3 cross-sectional cohorts of RA patients (n = 95, n = 192, and n = 117) and healthy individuals (n = 38, n = 72, and n = 50) using a flow cytometry-based assay. Further, AMAs were detected using an anti-mitofusin-1 (anti-MFN-1) IgG enzyme-linked immunosorbent assay and Western blot analysis. A longitudinal inception cohort, followed up for a median of 8 years, was used to study disease progression. RESULTS: AMA levels were elevated in RA patients from all 3 cohorts as compared to healthy individuals (P < 0.001, P < 0.05, and P < 0.01), with a range of 14-26% positivity. Levels of anti-MFN-1 antibodies correlated with AMA levels (r = 0.31, P = 0.006) and were elevated in RA patients as compared to healthy individuals (P < 0.001). The presence of AMAs was associated with erosive disease (P < 0.05) and interstitial lung disease (P < 0.01). Further, AMA levels were found to predict erosive disease (odds ratio [OR] 4.59, P = 0.006) and joint space narrowing (OR 3.08, P = 0.02) independent of anti-citrullinated protein antibodies. Finally, anti-MFN-1 antibodies identified seronegative patients developing erosive disease (OR 9.33; P = 0.02). CONCLUSION: Our findings demonstrate the presence of novel autoantibodies targeting mitochondria in the setting of RA. AMAs were used to stratify patients based on disease phenotype and to predict development of erosive disease, including in patients with seronegative disease. Our results highlight the essential role of mitochondria in the pathogenesis of RA and suggest a possible benefit of therapies targeting mitochondrial-mediated inflammation and clearance in these patients.