Portuguese Recommendations for the management of Raynaud's phenomenon and digital ulcers in systemic sclerosis and other connective tissue diseases.

OBJECTIVE: To develop evidence-based recommendations for the non-pharmacological and pharmacological management of Raynaud's phenomenon (RP) and digital ulcers (DUs) in patients with systemic sclerosis and other immune-mediated connective tissue diseases (CTDs). METHODS: A task force comprising 21 rheumatologists, two surgeons (vascular and plastic), two nurses, and one patient representative was established. Following a systematic literature review performed to inform the recommendations, statements were formulated and discussed during two meetings (one online and one in-person). Levels of evidence, grades of recommendation (GoR), and level of agreement (LoA) were determined. RESULTS: Five overarching principles and 13 recommendations were developed. GoR ranged from A to D. The mean ± standard difference (SD) LoA with the overarching principles and recommendations ranged from 7.8±2.1 to 9.8±0.4. Briefly, the management of RP and DUs in patients with CTDs should be coordinated by a multidisciplinary team and based on shared decisions with patients. Nifedipine should be used as first-line therapy for RP and/or DUs. Sildenafil, tadalafil, and/or iloprost IV are second-line options for severe and/or refractory patients with RP and/or DUs. Sildenafil, tadalafil and/or Iloprost IV, should be prescribed for healing and prevention (also including bosentan) of DUs. In patients with RP and/or DUs, non-pharmacological interventions might be considered as add-ons, but there is limited quality and quantity of scientific evidence supporting their use. CONCLUSIONS: These recommendations will inform rheumatologists, specialist nurses, other healthcare professionals, and patients about a comprehensive and personalized management of RP and DUs. A research agenda was developed to address unmet needs, particularly for non-pharmacologic interventions.

Treatment of calcinosis cutis associated with autoimmune connective tissue diseases.

Calcinosis cutis is a condition that is commonly associated with autoimmune connective tissue diseases. It is characterized by the deposition of insoluble calcium salts in the skin and subcutaneous tissue, which can cause pain, impair function, and have significant impacts on quality of life. Calcinosis cutis is difficult to manage because there is no generally accepted treatment: evidence supporting treatments is mostly comprised of case reports and case series, sometimes yielding mixed findings. Both pharmacologic and procedural interventions have been proposed to improve calcinosis cutis, and each may be suited to different clinical scenarios. This review summarizes current treatment options for calcinosis cutis, with discussion of recommendations based on patient-specific factors and disease severity.

Connective tissue disease-associated lung disease in children.

Connective tissue diseases are a heterogeneous group of autoimmune diseases that can affect a variety of organ systems. Lung parenchymal involvement is an important contributor to morbidity and mortality in children with connective tissue disease. Connective tissue disease-associated lung disease in children often manifests as one of several radiologic-pathologic patterns of disease, with certain patterns having a propensity to occur in association with certain connective tissue diseases. In this article, key clinical, histopathologic, and computed tomography (CT) features of typical patterns of connective tissue disease-associated lung disease in children are reviewed, with an emphasis on radiologic-pathologic correlation, to improve recognition of these patterns of lung disease at CT and to empower the pediatric radiologist to more fully contribute to the care of pediatric patients with these conditions.

Imaging of Pulmonary Manifestations of Connective Tissue Disease.

The majority of connective tissue diseases (CTDs) are multisystem disorders that are often heterogeneous in their presentation and do not have a single laboratory, histologic, or radiologic feature that is defined as the gold standard to support a specific diagnosis. Given this challenging situation, the diagnosis of CTD is a process that requires the synthesis of multidisciplinary data which may include patient clinical symptoms, serologic evaluation, laboratory testing, and imaging. Pulmonary manifestations of connective tissue disease include interstitial lung disease as well as multicompartmental manifestations. These CT imaging patterns and features of specific diseases will be discussed in this article.

Connective Tissue Disease Associated Interstitial Lung Disease.

Connective tissue disease associated interstitial lung disease (CTD-ILD) is a heterogenous collection of conditions with a diverse spectrum of interstitial lung disease (ILD) manifestations. Currently, clinical practice of lung-directed immunosuppression in CTD-ILD is supported by several randomized, placebo-controlled trials (RCTs) in patients with scleroderma and several observational, retrospective studies in other autoimmune conditions. However, given the harm of immunosuppression in idiopathic pulmonary fibrosis, there is an urgent need for RCTs of immunosuppression and antifibrotic agents in fibrotic CTD-ILD populations as well as the study of intervention in patients with subclinical CTD-ILD.

Pulmonary Hypertension Associated with Connective Tissue Disease.

Pulmonary hypertension (PH), a syndrome characterized by elevated pulmonary pressures, commonly complicates connective tissue disease (CTD) and is associated with increased morbidity and mortality. The incidence of PH varies widely between CTDs; patients with systemic sclerosis are most likely to develop PH. Several different types of PH can present in CTD, including PH related to left heart disease and respiratory disease. Importantly, CTD patients are at risk for developing pulmonary arterial hypertension, a rare form of PH that is associated with high morbidity and mortality. Future therapies targeting pulmonary vascular remodeling may improve outcomes for patients with this devastating disease.

Clinically Relevant Biomarkers in Connective Tissue Disease-Associated Interstitial Lung Disease.

Interstitial lung disease (ILD) complicates connective tissue disease (CTD) with variable incidence and is a leading cause of death in these patients. To improve CTD-ILD outcomes, early recognition and management of ILD is critical. Blood-based and radiologic biomarkers that assist in the diagnosis CTD-ILD have long been studied. Recent studies, including -omic investigations, have also begun to identify biomarkers that may help prognosticate such patients. This review provides an overview of clinically relevant biomarkers in patients with CTD-ILD, highlighting recent advances to assist in the diagnosis and prognostication of CTD-ILD.

Novel Therapeutic Approaches in Connective Tissue Disease-Associated Interstitial Lung Disease.

Connective tissue diseases (CTD) comprise a group of autoimmune diseases that can affect multiple organs in the body including the lungs. The most common form of pulmonary involvement is interstitial lung disease (ILD). CTD-associated ILD (CTD-ILD) can take one of several courses including nonprogressive, chronically progressive, or rapidly progressive. Chronically and rapidly progressive patterns are associated with increased mortality. Limited randomized controlled trial data are available for treatment of CTD-ILD, with most data coming from systemic sclerosis-related ILD. The current first-line treatment for all CTD-ILD is immunosuppression with consideration of antifibrotics, stem cell transplant, and lung transplant in progressive disease. In this article, we review data for ILD treatment options in systemic sclerosis, rheumatoid arthritis, myositis, and primary Sjögren's syndrome-related ILDs.

Screening value of lung ultrasound and pleural shear wave elastography in connective tissue disease-related interstitial lung disease: a preliminary study.

OBJECTIVE: To explore the diagnostic value of lung ultrasound (LUS) and pleural shear wave elastography (SWE) for connective tissue disease-interstitial lung disease (CTD-ILD). METHODS: We selected 104 patients diagnosed with connective tissue disease (CTD) at our hospital. All patients underwent LUS, SWE, and high-resolution computed tomography (HRCT). With HRCT as the imaging gold standard for diagnosis, patients were categorized into CTD-ILD and CTD-non-ILD groups. We employed paired chi-square tests to compare the diagnostic differences between HRCT and LUS for ILD. Receiver operating characteristic (ROC) curves were used to assess the diagnostic value of pleural SWE for ILD. Correlation analysis was performed between pleural elasticity values and lung ultrasound scores. RESULTS: The sensitivity, specificity, positive likelihood ratio, and negative likelihood ratio of LUS for diagnosing CTD-ILD were 93.3%, 86.2%, 6.761, and 0.078, respectively. There was no statistically significant difference in the results between HRCT and LUS (P = 1.000), with a kappa value of 0.720 (P < 0.001). There was a statistically significant difference in the pleural elasticity in the bilateral lower back region between the case and control groups (P < 0.001). The area under the receiver operating characteristic (ROC) curve (AUC) for pleural SWE in diagnosing CTD-ILD was 0.685. In CTD-ILD patients, there was no significant correlation between pleural elasticity values and LUS scores (P > 0.05). CONCLUSION: The LUS can serve as an important imaging method for screening for CTD-ILD and assessing the severity of the disease. However, pleural SWE has been shown to demonstrate lower diagnostic efficacy for CTD-ILD, and its ability to assess disease severity is limited.

Comparing the safety and efficacy of nintedanib starting dose in patients with connective tissue disease-associated interstitial lung diseases.

OBJECTIVE: This study aimed to analyse whether initiating nintedanib treatment at a reduced dose could improve the treatment continuation rate while maintaining efficacy in patients with connective tissue disease (CTD)-associated interstitial lung disease. METHOD: In total, 51 patients (age 61.6 ± 13.2 years; 38 women, 13 men) were retrospectively analysed. The primary endpoint was the cumulative discontinuation rate due to adverse events. Secondary endpoints included changes in drug dosage, efficacy evaluated based on annual changes in forced vital capacity (FVC), and safety assessed based on the frequency of adverse events. RESULTS: Eighteen patients who started treatment at the standard dose of 300 mg (standard dosage group) were compared with 33 patients who started treatment at a reduced dose (reduced dosage group). Systemic sclerosis was the most common CTD (n = 32), followed by idiopathic inflammatory myopathies and, rarely, rheumatoid arthritis. Both groups exhibited comparable cumulative discontinuation rates due to adverse events and similar frequencies of adverse events. No significant differences were observed in maintenance doses between the two groups; however, patients in the reduced dosage group had a lower cumulative dose for up to 52 weeks than those in the standard dosage group. No significant differences were observed in changes in FVC between the two groups. CONCLUSION: There was no evidence for a difference between the two groups in terms of discontinuation rates, efficacy, and safety. To provide further evidence, future studies using more precise dose-escalation protocols are warranted.

[Interstitial Lung Disease associated with Connective Tissue Diseases]. / Interstitielle Pneumopathien bei Konnektivitiden.

INTRODUCTION: Interstitial Lung Disease associated with Connective Tissue Diseases Abstract: Interstitial lung diseases (ILD) are in up to one-third of cases associated with connective tissue diseases (CTD). In systemic sclerosis, rheumatoid arthritis, polymyositis/dermatomyositis, Sjögren's syndrome, and mixed connective tissue disease, an associated ILD significantly increases morbidity and mortality. The diagnostic workup for suspected CTD-ILD includes a range of functional, radiological, laboratory, and, if necessary, invasive tests. A thorough medical history and physical examination with targeted rheumatological diagnosis is particularly important. Also, patients with unclassified ILDs should be evaluated thoroughly for any underlying CTD. Pharmacological treatment options for CTD-ILD differ significantly from those for other ILDs. In addition to short-term glucocorticoids, antimetabolites and biological agents are often used. Antifibrotic drugs have also been successfully used in CTD-ILDs. The decision on whether and which immunosuppressive and/or antifibrotic therapy is indicated depends on the underlying disease, disease activity, extrapulmonary manifestations, severity of organ involvement, ILD progression, comorbidities, and patient preferences. Complex treatment decisions are ideally made in multidisciplinary expert teams.

The Oral-Lung Microbiome Axis in Connective Tissue Disease-Related Interstitial Lung Disease.

Connective tissue disease-related interstitial lung disease (CTD-ILD) is a frequent and serious complication of CTD, leading to high morbidity and mortality. Unfortunately, its pathogenesis remains poorly understood; however, one intriguing contributing factor may be the microbiome of the mouth and lungs. The oral microbiome, which is a major source of the lung microbiome through recurrent microaspiration, is altered in ILD patients. Moreover, in recent years, several lines of evidence suggest that changes in the oral and lung microbiota modulate the pulmonary immune response and thus may play a role in the pathogenesis of ILDs, including CTD-ILD. Here, we review the existing data demonstrating oral and lung microbiota dysbiosis and possible contributions to the development of CTD-ILD in rheumatoid arthritis, Sjögren's syndrome, systemic sclerosis, and systemic lupus erythematosus. We identify several areas of opportunity for future investigations into the role of the oral and lung microbiota in CTD-ILD.

Diagnostic Approach to Interstitial Lung Diseases Associated with Connective Tissue Diseases.

Interstitial lung disorders are a group of respiratory diseases characterized by interstitial compartment infiltration, varying degrees of infiltration, and fibrosis, with or without small airway involvement. Although some are idiopathic (e.g., idiopathic pulmonary fibrosis, idiopathic interstitial pneumonias, and sarcoidosis), the great majority have an underlying etiology, such as systemic autoimmune rheumatic disease (SARD, also called Connective Tissue Diseases or CTD), inhalational exposure to organic matter, medications, and rarely, genetic disorders. This review focuses on diagnostic approaches in interstitial lung diseases associated with SARDs. To make an accurate diagnosis, a multidisciplinary, personalized approach is required, with input from various specialties, including pulmonary, rheumatology, radiology, and pathology, to reach a consensus. In a minority of patients, a definitive diagnosis cannot be established. Their clinical presentations and prognosis can be variable even within subsets of SARDs.

Interstitial Lung Disease: A Review.

Importance: Interstitial lung disease (ILD) consists of a group of pulmonary disorders characterized by inflammation and/or fibrosis of the lung parenchyma associated with progressive dyspnea that frequently results in end-stage respiratory failure. In the US, ILD affects approximately 650 000 people and causes approximately 25 000 to 30 000 deaths per year. Observations: The most common forms of ILD are idiopathic pulmonary fibrosis (IPF), which accounts for approximately one-third of all cases of ILD, hypersensitivity pneumonitis, accounting for 15% of ILD cases, and connective tissue disease (CTD), accounting for 25% of ILD cases. ILD typically presents with dyspnea on exertion. Approximately 30% of patients with ILD report cough. Thoracic computed tomography is approximately 91% sensitive and 71% specific for diagnosing subtypes of ILDs such as IPF. Physiologic assessment provides important prognostic information. A 5% decline in forced vital capacity (FVC) over 12 months is associated with an approximately 2-fold increase in mortality compared with no change in FVC. Antifibrotic therapy with nintedanib or pirfenidone slows annual FVC decline by approximately 44% to 57% in individuals with IPF, scleroderma associated ILD, and in those with progressive pulmonary fibrosis of any cause. For connective tissue disease-associated ILD, immunomodulatory therapy, such as tocilizumab, rituximab, and mycophenolate mofetil, may slow decline or even improve FVC at 12-month follow-up. Structured exercise therapy reduces symptoms and improves 6-minute walk test distance in individuals with dyspnea. Oxygen reduces symptoms and improves quality of life in individuals with ILD who desaturate below 88% on a 6-minute walk test. Lung transplant may improve symptoms and resolve respiratory failure in patients with end-stage ILD. After lung transplant, patients with ILD have a median survival of 5.2 to 6.7 years compared with a median survival of less than 2 years in patients with advanced ILD who do not undergo lung transplant. Up to 85% of individuals with end-stage fibrotic ILD develop pulmonary hypertension. In these patients, treatment with inhaled treprostinil improves walking distance and respiratory symptoms. Conclusions and Relevance: Interstitial lung disease typically presents with dyspnea on exertion and can progress to respiratory failure. First-line therapy includes nintedanib or pirfenidone for IPF and mycophenolate mofetil for ILD due to connective tissue disease. Lung transplant should be considered for patients with advanced ILD. In patients with ILD, exercise training improves 6-minute walk test distance and quality of life.

Lung adenocarcinoma discovered during the follow-up of lung-dominant connective tissue disease: a case report and literature review.

Interstitial lung disease (ILD) can lead to lung cancer, which brings great challenges to differential diagnosis and comprehensive treatment. However, the clinical features of lung-dominant connective tissue disease (LD-CTD) related ILD combined with lung cancer has not been validated. We report the case of an 80-year-old woman with LD-CTD treated regularly with nintedanib who presented progressive dyspnoea and hypoxemia after recurrent viral infections. Her chest computed tomography (CT) showed aggravated interstitial fibrosis in both lower lungs with moderate right pleural effusion. Clinicians should be alert to lung cancer in patients who are experiencing poor responsiveness to treatment or acute progression of ILD. The available literatures about the differential diagnosis of clinical manifestations, imaging, treatment and prognosis of LD-CTD are reviewed and discussed in this study.

Relationship between idiopathic interstitial pneumonias (IIPs) and connective tissue disease-related interstitial lung disease (CTD-ILD): A narrative review.

While idiopathic interstitial pneumonia (IIP) centering on idiopathic pulmonary fibrosis (IPF) is the most prevalent interstitial lung disease (ILD), especially in the older adult population, connective tissue disease (CTD)-related ILD is the second most prevalent ILD. The pathogenesis of IPF is primarily fibrosis, whereas that of other ILDs, particularly CTD-ILD, is mainly inflammation. Therefore, a precise diagnosis is crucial for selecting appropriate treatments, such as antifibrotic or immunosuppressive agents. In addition, some patients with IIP have CTD-related features, such as arthritis and skin eruption, but do not meet the criteria for any CTD, this is referred to as interstitial pneumonia with autoimmune features (IPAF). IPAF is closely associated with idiopathic nonspecific interstitial pneumonia (iNSIP) and cryptogenic organizing pneumonia (COP). Furthermore, patients with iNSIP or those with NSIP with OP overlap frequently develop polymyositis/dermatomyositis after the diagnosis of IIP. Acute exacerbation of ILD, the most common cause of death, occurs more frequently in patients with IPF than in those with other ILDs. Although acute exacerbation of CTD-ILD occurs at a low rate of incidence, patients with rheumatoid arthritis, microscopic polyangiitis, or systemic sclerosis experience more acute exacerbation of CTD-ILD than those with other CTD. In this review, the features of each IIP, focusing on CTD-related signatures, are summarized, and the pathogenesis and appropriate treatments to improve the prognoses of patients with various ILDs are discussed.

Loeys-Dietz syndrome and Goldenhar syndrome unveiled together.

Haemifacial microsomia is an asymmetrical congenital tissue malformation developed from the first and second branchial arches with or without multi-system involvement. Alternatively recognised as Goldenhar syndrome or oculoauriculovertebral spectrum (OAVS), it is an aetiologically heterogeneous group of disorders showing dominant trends in inheritable form.We present a case of a boy in early childhood with concomitant craniofacial features of craniofacial microsomia with Loeys-Dietz syndrome. He had a unilateral hypoplastic face, asymmetrical ear malformations and multiple preauricular tags with epibulbar dermoid (features suggestive of Goldenhar syndrome). On detailed clinical evaluation, he met Beighton's criteria and was diagnosed with arterial tortuosity. Further molecular testing confirmed the diagnosis of Loeys-Dietz syndrome type II.Loeys-Dietz syndrome is characterised by aortic root enlargement or type A dissection with or without other vascular malformations and facial midline defects. Molecular testing is required to establish the diagnosis because of overlapping features with other connective tissue disorders.

Unusual overlap of systemic sclerosis with Takayasu arteritis.

Overlap syndromes are diseases that meet the criteria of two or more rheumatic diseases. In this case report, a woman in her 20s presented with a constellation of symptoms, including skin thickening, Raynaud's phenomenon, hypertension, absent pulse in both lower limbs with bilateral renal artery bruit. The antinuclear antibody profile revealed Scl-70 positivity. CT thorax identified early interstitial lung disease, and nailfold capillaroscopy showed severe capillary loss. CT angiogram features were suggestive of Takayasu arteritis. Notably, there have been only four documented cases of systemic sclerosis coexisting with Takayasu arteritis, highlighting the rarity of this overlap syndrome. The diagnosis of overlap syndrome was made after a thorough history recording and clinical examination. In the presence of bilateral renal artery stenosis, managing the scleroderma renal crisis may be challenging . This patient received treatment with mycophenolate mofetil and oral corticosteroids, aiming to address both systemic sclerosis and Takayasu arteritis effectively.

Pulmonary Hypertension in Connective Tissue Diseases Other than Systemic Sclerosis.

Pulmonary hypertension (PH) is a known complication of certain connective tissue diseases (CTDs), with systemic sclerosis (SSc) being the most common in the Western world. However, PH in association with non-SSc CTD such as systemic lupus erythematous, mixed connective tissue disease, and primary Sjögren's syndrome constitutes a distinct subset of patients with inherently different epidemiologic profiles, pathophysiologic mechanisms, clinical features, therapeutic options, and prognostic implications. The purpose of this review is to inform a practical approach for clinicians evaluating patients with non-SSc CTD-associated PH.The development of PH in these patients involves a complex interplay between genetic factors, immune-mediated mechanisms, and endothelial cell dysfunction. Furthermore, the broad spectrum of CTD manifestations can contribute to the development of PH through various pathophysiologic mechanisms, including intrinsic pulmonary arteriolar vasculopathy (pulmonary arterial hypertension, Group 1 PH), left-heart disease (Group 2), chronic lung disease (Group 3), chronic pulmonary artery obstruction (Group 4), and unclear and/or multifactorial mechanisms (Group 5). The importance of diagnosing PH early in symptomatic patients with non-SSc CTD is highlighted, with a review of the relevant biomarkers, imaging, and diagnostic procedures required to establish a diagnosis.Therapeutic strategies for non-SSc PH associated with CTD are explored with an in-depth review of the medical, interventional, and surgical options available to these patients, emphasizing the CTD-specific considerations that guide treatment and aid in prognosis. By identifying gaps in the current literature, we offer insights into future research priorities that may prove valuable for patients with PH associated with non-SSc CTD.