The Burden of Interstitial Lung Involvement in Rheumatoid Arthritis: Could Lung Ultrasound Have a Role in Its Detection? A Literature Review.

Lung involvement represents a fearful complication in rheumatoid arthritis (RA), potentially involving all compartments of the pulmonary system. Regarding interstitial lung disease (ILD), the HRCT represents the gold standard technique for its diagnosis; however, the examination is burdened by radiation exposure and high costs. In addition, although some risk factors for ILD are known, no algorithms exist to know which patients to submit to HRCT and when. In this context, lung ultrasound (LUS) showed promising results for at least 10 years, demonstrating correlation with high resolution computed tomography (HRCT) findings in other rheumatic diseases. Here, LUS may represent a screening test providing additional information to clinical examination and pulmonary function tests. The data deriving from LUS experience in other rheumatic diseases could steer the future towards the use of this technique also in RA patients, and in this review, we report the most relevant literature regarding LUS in RA-ILD.

Use of Mycophenolate mofetil for the treatment of fibrotic hypersensitivity pneumonitis.

INTRODUCTION: The optimal treatment of fibrosing hypersensitivity pneumonitis (fHP) is not well understood. The aim of the study was to obtain information about the usefulness of mycophenolate mofetil (MMF) in its treatment. MATERIAL AND METHODS: Quasi-experimental analysis of patients diagnosed with fHP and treated with MMF for one year, in a single centre. From the start of treatment, data collection was prospective. RESULTS: Seventy-three patients were included and 58 completed the study. FVC% and DLCO% decreased until starting MMF (year -1 to year 0). After completion of treatment (year 1), FVC% stabilised (p=0.336) and DLCO% improved significantly (p=0.004) compared to year 0. Dyspnoea, number of patients without corticosteroids and mean corticosteroid dose also improved significantly (p<0.001 in all cases). Being male and having a history of tuberculosis were predictors of poor drug response [AUC = 0.89 (95%CI: 0.80-0.98)]. Forty-five adverse effects were observed in 34 patients (46.6%). In 4 cases (5.5%), the adverse effect was severe and required discontinuation of treatment. CONCLUSIONS: In patients with fHP, MMF improves lung function and dyspnoea and reduces both the number of patients requiring oral corticosteroids and their mean dose in those who completed 1 year of treatment. The model constructed predicts which patients will respond poorly to treatment, with good discriminative ability and only a small percentage of patients will not tolerate treatment. Further prospective, randomised clinical trials are needed to define the role of this treatment in fHP.

Time trends in the incidence of interstitial lung disease across Brazil, Russia, India, China and South Africa (BRICS) from 1990 to 2019: An age-period-cohort analysis.

BACKGROUND AND OBJECTIVE: The global incidence of interstitial lung disease (ILD) has risen over the past few decades. However, few studies have evaluated the status and incidence trends of ILD in Brazil, Russia, India, China and South Africa (BRICS). This study assesses the trends of ILD incidence across the BRICS with an emphasis on ILD changes from 1990 to 2019. METHODS: Incidence rates were estimated by the data obtained from the Global Burden of Disease Study 2019 (GBD 2019). Age-period-cohort modelling was used to estimate the effects on ILD from 1990 to 2019, and the net drift and local drift were calculated. RESULTS: In 2019, a total of 11.4 million cases of ILD were reported in the BRICS countries. From 1990 to 2019, the incidence rate of ILD in BRICS showed an upward trend. India consistently reported the highest incidence rate, while China showed the fastest growth rate (107.6%). Russia reported a similar incidence rates for men and women, with a lower age of peak incidence compared to the other four countries. We found the time effect was unfavourable for BRICS in the first decade, especially for Brazil; in China and Brazil, the risk of people born after 1960 has rapidly decreased. CONCLUSION: ILD shows a rising incidence in BRICS. with the trends varying based on age and other environmental factors. BRICS should strengthen specific public health approaches and policies for different stages and populations.

Challenges in the management of idiopathic pulmonary fibrosis from a low- and middle-income country.

Idiopathic pulmonary fibrosis (IPF) is the most common progressive form of interstitial lung disease (ILD) that leads to gradual deterioration of lung function and ultimately death. Data from low- and middle-income countries (LMIC) on IPF is scarce. In this communication, we report the challenges encountered in managing IPF from Pakistan's largest tertiary care centre. A total of 108 patients with IPF were evaluated at the Aga Khan University Hospital in Karachi, Pakistan from January 2017 to March 2020. A significant concern was that most patients with IPF presented late during their disease. A bigger challenge encountered in clinical practice was the cost and nonavailability of antifibrotic therapy in the country until mid-2020. Successfully addressing these limitations, it is anticipated that better care will be available for the patients suffering from IPF in this part of the world.

Use of Mendelian randomization to assess the causal status of modifiable exposures for rheumatic diseases.

The explosion in Mendelian randomization (MR) publications is hard to ignore and shows no signs of slowing. Clinician readers, who may not be familiar with jargon-ridden methods, are expected to discern the good from the many low-quality studies that make overconfident claims of causality or stretch the plausibility of what MR can investigate. We aim to equip readers with foundational concepts, contextualized using examples in rheumatology, to appraise the many MR papers that are or will appear in their journals. We highlight the importance of assessing whether exposures are under plausibly specific genetic influence, whether the hypothesized causal pathways make biological sense, and whether results stand up to replication and use of control outcomes. Quality of research can vary substantially using MR as with any design, and all methods have inherent limitations. MR studies have provided and can still contribute valuable insights in the context of evidence triangulation.

Prognostic impact of cytokines and chemokines in bronchoalveolar lavage fluid on acute exacerbation of fibrosing interstitial lung disease.

BACKGROUND AND OBJECTIVE: Acute exacerbation of fibrosing interstitial lung disease (AE-FILD) is a serious condition with a high mortality rate. We aimed to comprehensively analyze cytokines in bronchoalveolar lavage fluid and their association with the clinical course of AE-FILD. METHODS: We retrospectively enrolled 60 patients with AE-FILD who underwent bronchoalveolar lavage. We comprehensively measured 44 cytokines and chemokines in the obtained bronchoalveolar lavage fluid using a Luminex analyzer. Patients were grouped into those who died within 90 days (non-survival group) and survived beyond 90 days (survival group) to investigate the association of the levels of cytokines and chemokines with mortality. RESULTS: The levels of matrix metalloproteinase 1 (p = 0.003), granulocyte-macrophage colony-stimulating factor (p = 0.040), interleukin 6 (p = 0.047), interleukin 8 (p = 0.050), monocyte chemoattractant protein-1 (p = 0.043), and eotaxin (p = 0.044) were significantly higher in the non-survival group than in the survival group. In the receiver operating characteristic analysis, their areas under the curve were 0.80, 0.68, 0.71, 0.70, 0.70, and 0.72, respectively. Using machine learning with these six cytokines and chemokines, the predictive accuracy for the survival group was 0.94. CONCLUSIONS: Our study demonstrated that several cytokines and chemokines in bronchoalveolar lavage fluid could be prognostic predictors in patients with AE-FILD.

Melanoma Differentiation-associated Gene 5-Positive Rapidly Progressive Interstitial Lung Disease Successfully Treated with Tofacitinib.

Anti-melanoma differentiation-associated gene 5 (MDA-5) antibody-positive dermatomyositis is associated with rapidly progressive interstitial lung disease (RP-ILD). We encountered a man in his 40s who presented with a history of a fever and dry cough. Based on laboratory tests and computed tomography scans of his chest, he was diagnosed with anti-MDA5 antibody-positive dermatomyositis with RP-ILD refractory to antimicrobial agents. Although the patient was treated with glucocorticoids, calcineurin inhibitors, intravenous cyclophosphamide, and plasma exchange, ventilatory management was still required. The patient survived additional therapy with tofacitinib; however, he developed a catheter-related pulmonary embolism as a complication.

2023 Brazilian Society of Rheumatology guidelines for the treatment of systemic sclerosis.

BACKGROUND: Systemic sclerosis (SSc) is a rare chronic autoimmune disease with heterogeneous manifestations. In the last decade, several clinical trials have been conducted to evaluate new treatment options for SSc. The purpose of this work is to update the recommendations of the Brazilian Society of Rheumatology in light of the new evidence available for the pharmacological management of SSc. METHODS: A systematic review including randomized clinical trials (RCTs) for predefined questions that were elaborated according to the Patient/Population, Intervention, Comparison, and Outcomes (PICO) strategy was conducted. The rating of the available evidence was performed according to the Grading of Recommendations Assessment, Development and Evaluation (GRADE) methodology. To become a recommendation, at least 75% agreement of the voting panel was needed. RESULTS: Six recommendations were elaborated regarding the pharmacological treatment of Raynaud's phenomenon, the treatment (healing) and prevention of digital ulcers, skin involvement, interstitial lung disease (ILD) and gastrointestinal involvement in SSc patients based on results available from RCTs. New drugs, such as rituximab, were included as therapeutic options for skin involvement, and rituximab, tocilizumab and nintedanib were included as therapeutic options for ILD. Recommendations for the pharmacological treatment of scleroderma renal crisis and musculoskeletal involvement were elaborated based on the expert opinion of the voting panel, as no placebo-controlled RCTs were found. CONCLUSION: These guidelines updated and incorporated new treatment options for the management of SSc based on evidence from the literature and expert opinion regarding SSc, providing support for decision-making in clinical practice.

Size-matching in lung transplantation by computed tomography for end-stage interstitial disease: a retrospective analysis.

Background: Size matching between donors and recipients is a major issue in lung transplantation (LTx), especially in patients with restrictive lung disease (RLD). This study aims to evaluate computed tomography (CT) as an additional method for defining the total lung capacity (TLC) in patients with end-stage interstitial disease awaiting LTx. Methods: Clinical data and CT scans from patients who underwent a first LTx from January 2014 to July 2018 in Bichat Hospital, Paris, were prospectively included in a database. CT TLC (ctTLC) was retrospectively calculated after semi-automatic contouring of the parenchyma and compared with measured TLC (mTLC) and predicted TLC (pTLC) values. Results: The study group included 89 patients (male:female =68:21; mean age, 59.5±10.0 years). The time between pulmonary function tests (PFTs) and CT scan was 162±270 days [median, 67 days; interquartile range (IQR), 0-233 days]. ctTLC was inferior to mTLC and pTLC (respectively 2,979±1,001 mL, 3,530±1,077 and 6,381±955 mL, P<0.001). The relative difference between CT lung volume (ctLV) and measured lung volume (mLV) was higher on the left than on the right side (25.4% vs. 16.3%, respectively, P=0.11). After exclusion of two outliers, we found a significant correlation between ctTLC and mTLC (r=0.762, P<0.001). Conclusions: CT volume is a feasible method to assess TLC in patients with end-stage interstitial disease awaiting LTx. This study highlights potential size-mismatch for graft selection before LTx and opens the perspective of a prospective trial evaluating impact of size-matching by donor-recipient (D-R) ctTLC ratio on postoperative outcomes.

Systemic Sclerosis With a Normotensive Scleroderma Renal Crisis: A Diagnostic Dilemma.

Systemic sclerosis (SSc), also called scleroderma, is an auto-immune rheumatic disease that is characterized by fibrosis of the skin and internal organs and vasculopathy. Three of the severe manifestations of the disease include a scleroderma renal crisis (SRC), pulmonary arterial hypertension, and digital ulceration. Vascular manifestations like Raynaud's phenomenon are an almost universal symptom in patients with SSc and are often the earliest manifestation of the disease. An SRC occurs in approximately 10% of all patients with scleroderma. It is characterized by malignant hypertension and progressive renal failure. However, about 10% of SRC cases present with normal blood pressure or a normotensive renal crisis. A 65-year-old man with a history of peripheral vascular disease and newly diagnosed heart failure presented to the emergency department on account of progressive discoloration of the left big toe and intermittent confusion. Initially, he was noted to be hemodynamically stable, with bluish discoloration of his left lower extremity and left big toe, which was tender to palpation with palpable distal pulses. His left toe progressively became dusky and gangrenous, necessitating ray amputation by vascular surgery. His hospital course was further complicated by worsening acute kidney injury, requiring initiation of hemodialysis, and progressive hypoxia with the transition from room air to high-flow oxygen. As part of his workup for acute kidney injury (AKI), his antinuclear antibody (ANA) was found to be positive, with high titers, as well as elevated SCl-70 IgG. Despite the initiation of hemodialysis, and post-surgical revision, he continued to deteriorate. His family opted for comfort care measures, and he died a few days later. Although SSc is a rare disease, it is associated with significant morbidity and has one of the highest mortality rates among connective tissue diseases. SSc can present with heterogeneous manifestations, mimicking several isolated organ-specific conditions. This makes the diagnosis challenging, especially early in the course of the disease. A high index of suspicion, especially in the setting of rapidly progressing multi-organ involvement without a clear cause, should prompt further evaluation of systemic sclerosis.

Hypersensitivity Pneumonitis on Thin-Section Chest CT Scans: Diagnostic Performance of the ATS/JRS/ALAT versus ACCP Imaging Guidelines.

Purpose To compare the diagnostic performance of the American Thoracic Society, Japanese Respiratory Society, and Asociación Latinoamericana del Tórax (ATS/JRS/ALAT) versus the American College of Chest Physicians (ACCP) imaging classifications for hypersensitivity pneumonitis (HP). Materials and Methods Patients in the institutional review board-approved Interstitial Lung Disease (ILD) registry referred for multidisciplinary discussion (MDD) at the authors' institution (January 1, 2006-April 1, 2021) were included in this retrospective study when ILD was diagnosed at MDD. MDD diagnoses included HP, connective tissue disease-ILD, and idiopathic pulmonary fibrosis. Retrospective review of thin-section CT images was performed in consensus by two cardiothoracic radiologists blinded to the diagnosis. Diagnostic patterns were determined for thin-section CT images using both classifications. Discordance rates were determined. Sensitivity, specificity, positive predictive value, negative predictive value, and accuracy were assessed using MDD diagnosis as the reference standard. Results A total of 297 patients were included in the study: 200 (67%) with HP, 49 (16%) with connective tissue disease-ILD, and 48 (16%) with idiopathic pulmonary fibrosis at MDD. The discordance rate between the two classifications was 21%. Assuming low HP prevalence (10%), ATS/JRS/ALAT classification outperformed ACCP classification, with greater accuracy (92.3% vs 87.6%) and greater positive predictive value (60.7% vs 42.9%). Assuming high prevalence (50%), accuracy and negative predictive value were superior using ACCP classification (81.7% vs 79.7% and 77.7% vs 72.6%, respectively), and positive predictive value was superior using ATS/JRS/ALAT classification (93.3% vs 87.1%). Conclusion Accuracy of the ATS/JRS/ALAT and ACCP HP classifications was greater in settings with low and high HP prevalence, respectively. Diagnostic performance of both classifications was discordant in a minority of cases. Keywords: CT, Thorax, Hypersensitivity Pneumonitis, Interstitial Lung Disease Supplemental material is available for this article. © RSNA, 2024.

Case Report: Common variable immunodeficiency phenotype and granulomatous-lymphocytic interstitial lung disease with a novel SOCS1 variant.

Common variable immunodeficiency is a heterogeneous symptomatic group of inborn errors of immunity that mainly affects antibodies production and/or function, predisposing patients to recurrent and severe infections. More than half of them usually develop autoimmunity, lymphoproliferation, enteropathy, and malignancies. Among these conditions, chronic lung disease such as granulomatous-lymphocytic interstitial lung disease is one of the leading causes of death in these patients. Recently, many genes that play a key role in B and T cells' development, maintenance, and/or cytokines signaling pathways have been implicated in the pathogenesis of the disease. Here, we describe the first Argentinian patient presenting with common variable immunodeficiency and granulomatous-lymphocytic interstitial lung disease, harboring two in cis heterozygous variants in the SOCS1 gene.

Childhood interstitial lung diseases: current understanding of the classification and imaging findings.

Childhood interstitial lung diseases (chILDs) encompass a diverse group of disorders with a high mortality rate and severe respiratory morbidities. Recent investigations have revealed that the classification of adult ILDs is not valid for chILDs, particularly for ILDs of early onset. Therefore, Children's Interstitial Lung Disease Research Cooperative of North America proposed a new classification of chILDs for affected children under 2 years of age, and later another classification for affected individuals between 2 and 18 years of age. In this review, we provide an overview of the imaging findings of chILDs by classification. Most infantile ILDs have unique clinical, radiological, and molecular findings, while the manifestation of pediatric ILDs overlaps with that of adult ILDs.

Proposed Clinical Algorithm for Pleuroparenchymal Fibroelastosis (PPFE).

Pleuroparenchymal fibroelastosis (PPFE) is characterized by fibrosis involving the pleura and subpleural lung parenchyma, predominantly in the upper lobes. As PPFE appears to occur in patients with heterogeneous etiologies, the disease course is thus also heterogenous, with some patients showing rapid progression while others have slow progression. Therefore, it is very difficult to predict prognosis with PPFE. Needless to say, this problematic matter has influenced the treatment strategy of PPFE patients. In fact, until now no evidence has been shown for use in creating an appropriate management algorithm for PPFE. We speculate that "uncoordinated breathing" is the most important reason for dyspnea in PPFE patients. Because monitoring of physique and not just pulmonary function and radiological evaluation is also very important, particularly in PPFE patients, this review focused on the characteristics of PPFE through an overview of previous studies in this field, and we proposed an algorithm as precision medicine based on the current evidence. Multiple views by the pulmonologist are needed to standardize a clinical algorithm that is necessary to correctly assess PPFE patients under the premise of maintenance of physique by providing appropriate nutritional care and pulmonary rehabilitation.

Initial Respiratory System Involvement in Juvenile Idiopathic Arthritis with Systemic Onset Is a Marker of Interstitial Lung Disease: The Results of Retrospective Cohort Study Analysis.

Background: Pulmonary involvement in systemic juvenile idiopathic arthritis (SJIA) is a rare but dangerous complication. The main risk factors are already known, such as macrophage activation syndrome, a refractory course of systemic juvenile arthritis, infusion reaction to interleukin 1 and/or interleukin 6 blockers, trisomy 21, and eosinophilia. However, information about respiratory system involvement (RSI) at the onset of SJIA is scarce. Our study aimed to evaluate the specific features of children with SJIA with RSI and their outcomes. Methods: In a single-center retrospective cohort study, we compared the information from the medical records of 200 children with SJIA according to ILAR criteria or SJIA-like disease (probable/possible SJIA) with and without signs of RSI (dyspnea, shortness of breath, pleurisy, acute respiratory distress syndrome, and interstitial lung disease (ILD)) at the disease onset and evaluated their outcomes (remission, development of chronic ILD, clubbing, and pulmonary arterial hypertension). Results: A quarter (25%) of the SJIA patients had signs of the RSI at onset and they more often had rash; hepato- and splenomegaly; heart (pericarditis, myocarditis), central nervous system, and kidney involvement; hemorrhagic syndrome; macrophage activation syndrome (MAS, 44.4% vs. 9.0%, p = 0.0000001); and, rarely, arthritis with fewer active joints, compared to patients without RSI. Five patients (10% from the group having RSI at the onset of SJIA and 2.5% from the whole SJIA cohort) developed fibrosing ILD. All of them had a severe relapsed/chronic course of MAS; 80% of them had a tocilizumab infusion reaction and further switched to canakinumab. Unfortunately, one patient with Down's syndrome had gone. Conclusion: Patients with any signs of RSI at the onset of the SJIA are required to be closely monitored due to the high risk of the following fibrosing ILD development. They required prompt control of MAS, monitoring eosinophilia, and routine checks of night oxygen saturation for the prevention/early detection of chronic ILD.

Cross-Cancer Type Evaluation of Potential Interstitial Lung Disease Complications of Immune Checkpoint Inhibitors Using JADER.

Interstitial lung disease (ILD) is a serious adverse event caused by the administration of immune checkpoint inhibitors (ICIs). However, only few large-scale studies have explored the association among ICI use, underlying cancer type, and ILD complications. This study aimed to analyze the association between the primary cancer type and ICI-induced ILD in a cross-sectional manner using the Japanese Adverse Drug Event Report (JADER) database. Nivolumab and pembrolizumab (anti-programmed cell death 1 (PD-1) antibodies) and durvalumab, avelumab, and atezolizumab (anti-programmed cell death ligand 1 (PD-L1) antibodies) were included as ICIs in this study. Adverse events were identified based on the preferred terms of Medical Dictionary for Regulatory Activities (MedDRA) version 27.0/J listed in the Standardized MedDRA Queries (SMQ) "interstitial lung disease." The reporting odds ratio was calculated to detect the association between ICI use and ILD complications, and a signal was detected if the lower limit of the 95% confidence interval exceeded 1. In the analysis of all cancer types, a signal was detected for all ICIs except avelumab. An association between ICI and ILD was detected for all cancer types with nivolumab. However, pembrolizumab exhibited a signal only in colorectal cancer. In contrast, anti-PD-L1 antibodies displayed signals in five cancer types, excluding head and neck cancer, which was not reported in JADER. Among these cancer types, atezolizumab exhibited a signal only in breast cancer. The results of this study will help guide the safe use of ICIs based on the underlying cancer type in terms of ILD complications.

Epidemiology of childhood interstitial lung disease in France: the RespiRare cohort.

INTRODUCTION: Interstitial lung disease in children (chILD) are rare and mostly severe lung diseases. Very few epidemiological data are available in limited series of patients. The aim of this study was to assess the prevalence and incidence of chILD in France. METHODS: We performed within the RespiRare network a multicentre retrospective observational study in patients with chILD from 2000 to 2022 and a prospective evaluation of chILD's incidence between February 2022 and 2023. RESULTS: chILD was reported in 790 patients in 42 centres. The estimated 2022 prevalence in France was 44 /million children (95% CI 40.76 to 47.46) and the computed incidence was 4.4 /million children (95% CI 3.44 to 5.56). The median age at diagnosis was 3 months with 16.9% of familial forms. Lung biopsy and genetic analyses were performed in 23.4% and 76.9%, respectively. The most frequent chILD aetiologies in the <2 years group were surfactant metabolism disorders (16.3%) and neuroendocrine cell hyperplasia of infancy (11.8%), and in the 2-18 years group diffuse alveolar haemorrhage (12.2%), connective tissue diseases (11.4%), hypersensitivity pneumonitis (8.8%) and sarcoidosis (8.8%). The management included mainly oxygen therapy (52%), corticosteroid pulses (56%), oral corticosteroids (44%), azithromycin (27.2%), enteral nutrition (26.9%), immunosuppressants (20.3%) and hydroxychloroquine (15.9%). The 5-year survival rate was 57.3% for the patients diagnosed before 2 years and 86% between 2 and 18 years. CONCLUSION: This large and systematic epidemiological study confirms a higher incidence and prevalence of chILD than previously described. In order to develop international studies, efforts are still needed to optimise the case collection and to harmonise diagnostic and management practices.

Rheumatoid arthritis extra-articular lung disease: new insights on pathogenesis and experimental drugs.

INTRODUCTION: Pulmonary involvement is one of the most common extra-articular manifestations of rheumatoid arthritis (RA), a systemic inflammatory disease characterized by joint swelling and tenderness. All lung compartments can be interested in the course of RA, including parenchyma, airways, and, more rarely, pleura and vasculature. AREAS COVERED: The aim of this paper is to review the main RA lung manifestations, focusing on pathogenesis, clinical and therapeutic issues of RA-related interstitial lung disease (ILD). Despite an increasing number of studies in the last years, pathogenesis of RA-ILD remains largely debated and the treatment of RA patients with lung involvement is still challenging in these patients. EXPERT OPINION: Management of RA-ILD is largely based on expert-opinion. Due to the broad clinical manifestations, including both joints and pulmonary involvement, multidisciplinary discussion, including rheumatologist and pulmonologist, is essential, not only for diagnosis, but also to evaluate the best therapeutic approach and follow-up. In fact, the coexistence of different lung manifestations may influence the treatment response and safety. The identification of biomarkers and risk-factors for an early identification of RA patients at risk of developing ILD remains a need that still needs to be fulfilled, and that will require further investigation in the next years.