ERS 2024: Rheumatic-Associated Interstitial Lung Disease Rheumatologists and Pulmonologist’s View
Speakers- Michael Kreuter and Anna Maria
Interstitial lung disease (ILD) has a significant impact due to its high prevalence across various rheumatic diseases. For instance, ILD is prevalent in about 50% of systemic sclerosis (SS) patients. In myositis, the prevalence of ILD is even higher. In contrast, rheumatoid arthritis and Sjögren's disease show lower rates of ILD development, but the condition remains a major concern across all subgroups. The importance of ILD is further underscored by its detrimental effect on lung function. Data from Oslo University Hospital, combined with recent findings from the Vancouver Registry, demonstrate that while baseline lung function forced vital capacity (FVC) may appear relatively preserved, many patients already exhibit impaired diffusing capacity of the lungs for carbon monoxide (DLCO). It indicates a significant impact on lung function beyond mere prevalence. Additionally, ILD is associated with reduced survival rates. It is well-established that the severity of ILD correlates with increased mortality. Recent evidence reveals that even patients with mild ILD, characterized by preserved lung function, minimal high-resolution computed tomography (HRCT) findings, experience high risk of mortality. Although respiratory failure is a cause of death for some, most patients with mild ILD succumb to respiratory tract infections despite having preserved lung function.
The significance of ILD screening in patients with rheumatic diseases has been demonstrated. ILD has a major impact on these patients, underscoring the need for systematic screening. While many rheumatologists screen patients, the decision often falls on determining which patients should be referred to pulmonologists for screening. According to the American College of Rheumatology (ACR) guidelines, all patients with systemic autoimmune rheumatic diseases (SARD) at increased risk for ILD should undergo pulmonary function tests (PFT) and HRCT. As per recent analysis that compared patients with SS who had ILD to those without found that, although the identified risk factors correlate with ILD, approximately 25% of patients with SS and ILD did not present any of these risk factors. Consequently, relying solely on these risk factors may lead to missed diagnoses of ILD, reinforcing the recommendation to screen all SS patients. Additionally, a study conducted with a Romanian cohort, where resources for HRCT are limited, showed that patients not screened for ILD experienced similar declines in forced vital capacity (FVC) as those diagnosed with ILD. This finding suggests a significant FVC decline with no alternative explanation indicating ILD. It supports the broader screening approach and emphasizes that screening should not be restricted to patients with identified risk factors alone. In conclusion, the evidence highlights the need for comprehensive screening of all SS patients for ILD rather than relying solely on identified risk factors. The approach ensures that patients with ILD, including those without overt risk factors, are not overlooked.
Respiratory symptoms alone should not be used as a screening tool for ILD. In a retrospective analysis of the SENSCIS trial, which included patients with significant fibrosis on high-resolution computed tomography, found that relying solely on symptoms like cough and dyspnea would miss approximately 20% of patients with substantial fibrosis. Similar results were observed in the Zurich cohort, where normal lung function measurements alone were insufficient for detecting ILD, potentially leading to missed diagnoses in patients needing treatment. When ILD is suspected, accurate diagnosis and monitoring are crucial. Pulmonologists often receive referrals from rheumatologists or general practitioners for further evaluation of suspected ILD in patients with established systemic diseases. Utilizing appropriate biomarkers and autoimmune markers is essential for identifying ILD associated with systemic diseases. Studies indicate that about 20% of patients newly diagnosed with ILD will have an underlying systemic disease initially missed by pulmonologists. Additionally, an initially idiopathic diagnosis of ILD may, over time, reveal signs of a systemic disease. Data show that a significant proportion of patients with idiopathic pulmonary fibrosis or nonspecific interstitial pneumonia may later develop clinical or laboratory evidence of a systemic disease. For instance, approximately 15% of patients initially diagnosed with idiopathic pulmonary fibrosis and 20% with nonspecific interstitial pneumonia may eventually show signs of a systemic disease. Collaboration between pulmonologists and rheumatologists is crucial, as demonstrated by recent experiences where a broader myositis panel revealed a higher prevalence of myositis than previously recognized. It highlights the importance of a coordinated approach in accurately diagnosing and managing ILD and associated systemic diseases.
A critical issue in managing ILD is the distinction between interstitial lung abnormalities and interstitial lung disease itself. ILD is a definitive disease, whereas interstitial lung abnormalities may indicate the potential development of ILD over time. The distinction between these concepts is important for accurate diagnosis and treatment planning. Recent publications, such as those by Sarah Tomasetti and the Fleischner Society, have highlighted that interstitial lung abnormalities should be considered a form of disease that may evolve into ILD. It is particularly relevant for patients with systemic diseases, where early intervention might be crucial. There is also an ongoing debate about handling subclinical or early ILD, where imaging may not reveal significant changes yet. Recent studies show that even early disease can progress significantly, impacting patient outcomes. Hence, it might be more effective to refer to this condition as a limited extent ILD and consider early treatment options. Current guidelines for diagnosing ILD in patients with systemic diseases are not yet fully established. For example, in Germany, protocols for managing ILD are outlined, but specific guidelines for connective tissue disease-related ILD (CTD-ILD) are lacking. There is no clear consensus on whether obtaining histological specimens from these patients is beneficial, although it may be useful in predicting prognosis or tailoring treatment. Similarly, the application of bronchoalveolar lavage (BAL) in assessing inflammation in ILD remains uncertain. While BAL lymphocytosis is often discussed, its utility in guiding treatment decisions lacks strong evidence. As the field evolves, it will be important to stay informed about emerging guidelines and evidence to optimize the management of ILD.
Monitoring ILD requires a comprehensive approach, incorporating various clinical indicators and guidelines. The ACR guidelines suggest frequent monitoring of ILD patients, typically every 6 to 12 months. It aligns with recommendations from other organizations like the Canadian Society of Respiratory Medicine. Regular HRCT scans are essential for monitoring. Effective monitoring also involves utilizing other patient characteristics to predict ILD progression. Collaborations between pulmonologists and rheumatologists can enhance patient management. For instance, in SS patients, an increase in skin fibrosis has been associated with increased lung fibrosis over the following year. Therefore, changes in skin involvement should prompt vigilance for potential ILD progression. Additionally, the six-minute walk test, particularly observing desaturation, is a useful predictor of ILD progression. Combining this with other organ manifestations, such as arthritis, an inflammatory marker, can further aid prognosis. For example, the risk of ILD progression is significantly higher if a patient experiences both desaturation and arthritis, with a likelihood of 86% compared to 36% for either condition alone. Clinical trials have shown that incorporating multiple risk factors for ILD progression can enhance predictive accuracy. For SS, patients with a short disease duration, active skin involvement (Raynaud skin score), and inflammation are particularly likely to experience progression. In trials involving tocilizumab, patients with these characteristics demonstrated rapid disease decline, similar to patterns observed in idiopathic pulmonary fibrosis (IPF). These findings underscore the importance of monitoring various clinical factors to manage and anticipate ILD progression effectively.
In treating ILD associated with systemic diseases, evidence and guidelines are pivotal. While SS is frequently emphasized due to abundant data, similar principles apply to other conditions like Sjögren’s syndrome. The Oslo cohort data for Sjögren’s syndrome highlights that patients with reticular patterns, inflammation, and additional organ manifestations face a higher likelihood of disease progression. The most recent ACR guidelines suggest a tiered approach to treatment, with mycophenolate mofetil (MMF) as the first-line therapy. The recommendation is based on its efficacy in managing SS-related ILD. However, the tiered listing in the guidelines should be interpreted as a preference rather than an absolute order, as treatment should be customized to each patient’s needs. Clinical trial data, such as from the Scleroderma Lung Study 2 (2016), indicate that MMF is as effective as cyclophosphamide for SS ILD. The study showed comparable results in improving lung function and skin involvement with MMF and cyclophosphamide. Despite the study not including a placebo group, the effectiveness of MMF supports its use as a high-priority treatment option. The evidence base for ILD treatment is less extensive for other systemic conditions but follows similar treatment principles. For example, in Sjögren’s syndrome, the choice of therapy should consider the lung involvement pattern and other organ manifestations. Given the complexity of ILD management, collaboration between rheumatologists and pulmonologists is crucial. Rheumatologists generally focus on immunosuppressive therapies, while pulmonologists may prioritize antifibrotic agents for managing lung fibrosis. Combining these approaches can enhance patient outcomes. Overall, while mycophenolate mofetil is highly recommended, treatment decisions should be guided by individual patient profiles and the available evidence. Ongoing study and interdisciplinary collaboration will continue to refine treatment strategies for ILD in systemic diseases.
When evaluating treatment options for ILD, randomized clinical trials (RCTs) are the gold standard for providing robust evidence. However, such trials are often lacking for many therapies, including those for ILD associated with systemic diseases. For instance, there is no RCT data for MMF in this context. While retrospective studies like those by Arey Fisher in 2013 provide some insights, they lack comparators and have small sample sizes, including very few cases of mixed connective tissue disease (MCTD) and Sjögren’s syndrome. These studies suggest that MMF stabilizes lung function, but without a comparator group, the efficacy remains uncertain. Recent data for rheumatoid arthritis (RA) ILD, published in 2023, provides comparative insights into how patients with RA ILD did before and after MMF treatment. Though not from an RCT, the data shows promising results that support MMF's role in managing RA ILD. Cyclophosphamide is another relevant option, particularly in countries where other treatments are unavailable. The Scleroderma Lung Study compared cyclophosphamide to placebo and demonstrated that cyclophosphamide has a significant treatment effect, albeit with noted toxicity and the need for ongoing maintenance treatment. The RECITAL study, which compared cyclophosphamide with rituximab across various rheumatic diseases, showed that both drugs were similarly effective in preventing FVC decline. The study is particularly valuable as it provides evidence for cyclophosphamide's efficacy in a broader context. The American College of Rheumatology (ACR) guidelines suggest a tiered approach to treatment, where MMF is recommended as the first-line therapy based on available data. The guidelines propose a second-line treatment approach for patients who progress despite first-line treatment. However, evidence supporting MMF as a second-line treatment is limited, and other immunosuppressive options need further investigation. In summary, while MMF and cyclophosphamide are valuable treatment options for ILD associated with systemic diseases, the evidence base is not always robust, and treatment decisions should be tailored to individual patient needs and available evidence. Ongoing studies and clinical trials are crucial for refining treatment strategies and improving patient outcomes.
Recent data from Wim Wiet's group in Belgium highlights a significant caution regarding steroid use in fibrosing hypersensitivity pneumonitis (HP). Contrary to initial expectations, steroids are associated with worse outcomes rather than improvements. The finding contrasts with earlier practices for IPF, where steroids were initially thought to be beneficial. Additionally, immunomodulatory treatments, including steroids, may lead to adverse effects such as increased infection risk, which can exacerbate disease progression. Although the risk is less documented in connective tissue disease ILDs, it remains an important consideration. For progressive connective tissue disease ILDs, antifibrotic therapies like Nintedanib have shown promise. Nintedanib, has been evaluated in trials involving progressive connective tissue disease ILDs, demonstrating clinical benefits. Specifically, data from the SENSCIS trial, focusing on SS ILD, indicated that antifibrotic therapy positively impacted disease trajectory when fibrosis exceeded 10% on HRCT. Despite some trials not meeting their primary endpoints, secondary endpoints related to lung function and disease progression revealed positive outcomes. In RA ILD, especially among patients with HRCT patterns resembling IPF, there is emerging evidence supporting the use of antifibrotic therapy. Although the treatment is not officially licensed for rheumatoid arthritis ILD and remains off-label, it has shown benefits in improving disease trajectory. It highlights the potential for tailored medicine, where treatment is adapted based on specific radiological patterns and disease progression characteristics. The future of ILD treatment will likely involve refining approaches based on these individualized patterns and responses.
A comprehensive approach is needed to measure ILD inflammation, particularly with Connective tissue disease-associated interstitial lung disease (CTD ILD). Clinical evaluation is essential, focusing on symptoms like cough, dyspnea, and systemic signs like fever or joint pain. HRCT scans are instrumental in detecting inflammation patterns, such as ground-glass opacities or consolidations. Laboratory tests that assess inflammation markers, like erythrocyte sedimentation rate and C-reactive protein, provide additional information but are less specific. When inflammation is present, treatment strategies vary. For CTD ILD, immune-suppressive therapies such as MMF or corticosteroids are typically used. The management becomes more complex when both inflammation and fibrosis are observed. Evidence from studies like the SENSCIS Trial suggests that combining MMF with an antifibrotic like Nintedanib might improve outcomes, though results are not fully conclusive. The Scleroderma Lung Study III, which looked at MMF combined with Pirfenidone, also had limited results due to a small sample size. In summary, while immune-suppressive therapy addresses inflammation and antifibrotics target fibrosis, the best approach for patients with both conditions remains uncertain. Further study is needed to refine treatment strategies for these challenging cases.
A multidisciplinary team approach is essential to manage ILD effectively`. It includes collaboration between rheumatologists, pulmonologists, and other specialists. Accurate diagnosis involves evaluating the extent of lung involvement and considering external factors. Risk factors must be assessed comprehensively, including the severity of the disease based on HRCT, lung function tests, and patient symptoms. Engagement with radiologists and potentially incorporating artificial intelligence to predict disease progression can enhance diagnostic accuracy. Effective management extends beyond medication; it involves integrating support from ILD nurses, considering clinical trial opportunities, and addressing symptom management and palliative care. In conclusion, ILD prevalence varies among different diseases, with SS having a higher prevalence compared to RA. Screening strategies should be tailored, focusing on high-risk groups. Early diagnosis and appropriate therapy are crucial, as disease progression can occur across all patient groups. Continued study and clinical trials are vital for improving treatment options.
European Respiratory Society Congress 2024, 7–11 September, Vienna, Austria
