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.

Unraveling the genetic collagen connection: clinical and therapeutic insights on genetic connective tissue disorders.

Hereditary connective tissue disorders include more than 200 conditions affecting different organs and tissues, compromising the biological role of the extracellular matrix through interference in the synthesis, development, or secretion of collagen and/or its associated proteins. The clinical phenotype includes multiple signs and symptoms, usually nonspecific but of interest to rheumatologists because of musculoskeletal involvement. The patient´s journey to diagnosis is long, and physicians should include these disorders in their differential diagnoses of diseases with systemic involvement. In this review, insights for the diagnosis and treatment of osteogenesis imperfecta, hypermobility spectrum disorder/Ehlers-Danlos syndrome, Marfan, Loeys-Dietz, and Stickler syndromes are presented.

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.

Conservative management of hand impairment in children and adolescents with heritable disorders of connective tissue: A scoping review.

AIMS: To synthesize and critically appraise available interventions in the conservative management of hand impairment for children and adolescents with heritable disorders of connective tissue (HDCT). METHODS: A search of peer-reviewed literature and online platforms were included with data regarding hand impairment and function, conservative management and outcome measures extracted and appraised. Levels of evidence were applied to published literature. RESULTS: Ten peer-reviewed papers, eleven webpages and YouTube videos met the inclusion criteria. Reported interventions included: strengthening, orthoses, assistive equipment, education and pacing. Evidence of intervention effectiveness and evidence-based guidance on dosage were absent, with no consistency of outcome measures monitoring intervention effectiveness. Online platforms posted by health professionals predominantly provided advice for families without clinical detail of interventions. CONCLUSIONS: There is a consistent suite of interventions identified in both peer-reviewed literature and online platforms used by clinicians and families to manage hand impairment for children and adolescents with HDCT. Clear dosage parameters and outcome measures are needed in future intervention studies to determine the effectiveness of interventions and guide clinicians in how best to treat hand impairment. Increasing accountability and quality of online resources posted by health professionals for families is warranted to ensure dosage details and precautions are provided.

En route towards a personalized medicine approach: Innovative therapeutic modalities for connective tissue disorders.

Connective tissue disorders can be caused by pathogenic variants (mutations) in genes encoding extracellular matrix (ECM) proteins. Such disorders typically manifest during development or postnatal growth and result in significant morbidity and mortality. The development of curative treatments for connective tissue disorders is hampered in part by the inability of many mature connective tissues to efficiently regenerate. To be most effective, therapeutic strategies designed to preserve or restore tissue function will likely need to be initiated during phases of significant endogenous connective tissue remodeling and organ sculpting postnatally and directly target the underlying ECM protein mutations. With recent advances in whole exome sequencing, in-vitro and in-vivo disease modeling, and the development of mutation-specific molecular therapeutic modalities, it is now feasible to directly correct disease-causing mutations underlying connective tissue disorders and ameliorate their pathogenic consequences. These technological advances may lead to potentially curative personalized medicine approaches for connective tissue disorders that have previously been considered incurable. In this review, we highlight innovative therapeutic modalities including gene replacement, exon skipping, DNA/mRNA editing, and pharmacological approaches that were used to preserve or restore tissue function in the context of connective tissue disorders. Inherent to a successful application of these approaches is the need to deepen the understanding of mechanisms that regulate ECM formation and homeostasis, and to decipher how individual mutations in ECM proteins compromise ECM and connective tissue development and function.

Multidisciplinary team discussion: the emerging gold standard for management of cardiopulmonary complications of connective tissue disease.

Cardiopulmonary complications of connective tissue diseases (CTDs), particularly pulmonary arterial hypertension (PAH) and interstitial lung disease (ILD), are major determinants of morbidity and mortality. Multidisciplinary meetings may improve diagnostic accuracy and optimise treatment. We review the literature regarding multidisciplinary meetings in CTD-ILD and PAH and describe our tertiary centre experience of the role of the multidisciplinary meeting in managing CTD-PAH.

Identification and management of connective tissue disease-associated interstitial lung disease: evidence-based Japanese consensus statements.

BACKGROUND: Interstitial lung disease (ILD) is a common complication of connective tissue diseases (CTD), but there are few clinical trials to guide disease management. We aimed to develop expert consensus statements and an algorithm for CTD-ILD management. RESEARCH DESIGN AND METHODS: Based on a targeted literature review, we developed 109 statements on managing CTD-ILD across six domains. We used a modified Delphi process to survey 22 physicians in Japan involved in managing CTD-ILD (specialists in pulmonology, rheumatology, pathology, and radiology). These panelists participated in two rounds of web-based survey to establish consensus statements, which were used to define an algorithm. Consensus was defined as a mean value ≥70 on a scale of 0 (strong disagreement) to 100 (strong agreement). RESULTS: Between May-August 2022, consensus was reached on 93 statements on CTD-ILD management. The most important consensus statements included screening CTD patients for ILD (typically with high-resolution computed tomography), using imaging, pulmonary function testing and serum biomarkers for diagnosis and severity assessment, regularly following up patients, and multidisciplinary management of CTD-ILD. Consensus statements were interpreted into an algorithm for clinical guidance. CONCLUSIONS: Using the Delphi process, we have developed consensus statements and an algorithm to guide clinical decision-making for CTD-ILD.

A systematic review of the incidence, management and prognosis of new-onset autoimmune connective tissue diseases after COVID-19.

A literature review on new-onset autoimmune connective tissue diseases (ACTDs) following COVID-19 is lacking. We evaluated potential associations between COVID-19 and the development of new-onset ACTDs. The "population" was adults with disease terms for ACTDs, including systemic lupus erythematosus (SLE), Sjogren's syndrome, systemic sclerosis (SSc), idiopathic inflammatory myositis (IIM), anti-synthetase syndrome, mixed CTD and undifferentiated CTD, and "intervention" as COVID-19 and related terms. Databases were searched for English-language articles published until September 2022. We identified 2236 articles with 28 ultimately included. Of the 28 included patients, 64.3% were female, with a mean age was 51.1 years. The USA reported the most cases (9/28). ACTD diagnoses comprised: 11 (39.3%) IIM (including four dermatomyositis); 7 (25%) SLE; four (14.3%) anti-synthetase syndrome; four (14.3%) SSc; two (7.1%) other ACTD (one lupus/MCTD overlap). Of eight, four (14.3%) patients (including that with lupus/MCTD) had lupus nephritis. The average time from COVID-19 to ACTD diagnosis was 23.7 days. A third of patients were admitted to critical care, one for treatment of haemophagocytic lymphohistiocytosis in SLE (14 sessions of plasmapheresis, rituximab and intravenous corticosteroids) and nine due to COVID-19. 80% of patients went into remission of ACTD following treatment, while three (10%) patients died-one due to macrophage activation syndrome with anti-synthetase syndrome and two from unreported causes. Our results suggest a potential association between COVID-19 and new-onset ACTDs, notably in young females, reflecting more comprehensive CTD epidemiology. The most common diagnosis in our cohort was IIM. The aetiology and mechanisms by which ACTDs emerge following COVID-19 remain unknown and require further research.

Extent of and Reasons for Discontinuation and Nonpublication of Interventional Trials on Connective Tissue Diseases: An Observational Study.

OBJECTIVE: To assess the proportion, the reasons, and the factors associated with the discontinuation or nonpublication of randomized controlled trials (RCTs) on connective tissue diseases (CTDs). METHODS: We searched all interventional RCTs on CTDs registered in ClinicalTrials.gov since 2000. Two reviewers selected studies according to prespecified eligibility criteria. Completion status, publication status, and reported reasons for discontinuation or nonpublication were retrieved on ClinicalTrials.gov, through literature search, and by contacting investigators. Multivariable logistic regression was used to identify factors associated with study noncompletion and nonpublication. RESULTS: We included 175 studies, mostly phase III, placebo-controlled trials on pharmacologic treatments recruiting patients with systemic lupus erythematosus (51%), systemic sclerosis (20%), Sjögren's syndrome (12%), or other CTDs. Fifty-eight (33%) had been discontinued, mainly for insufficient patient accrual, with no differences in discontinuation rates across the CTDs (P > 0.5). Forty-six (35%) of 130 studies having included at least 1 patient were unpublished, and 86 (65%) were published in a peer-reviewed journal after a median of 24 months (interquartile range 15-41) from completion, with a significantly higher publication rate in completed versus discontinued studies (81% versus 22%; P < 0.001). We were able to obtain reasons for nonpublication in one-third of cases. Small sample size (<100 participants) was the only factor associated with study noncompletion and nonpublication. CONCLUSION: One of 3 registered RCTs on CTDs fails to be completed or published. This represents a waste of resources and raises ethical concerns regarding hidden clinical data and unfruitful participation by patients.

Study protocol for connective tissue disease-associated interstitial lung disease trial (TEL-CTD-ILD): A randomized controlled trial of a home-based telemonitoring of treatment effects.

INTRODUCTION: Interstitial lung disease is one of the most severe pulmonary complications related to connective tissue diseases, resulting in substantial morbidity and mortality. Telepneumology has the potential to improve the long-term management of patients with CTD-ILD. We propose a randomized controlled trial to evaluate the efficacy of home-based telemonitoring of patients with CTD-ILD, in whom treatment was initiated. MATERIALS AND METHODS: We will conduct a randomized controlled trial comparing the standard of care with a telemonitoring program. Telemonitoring will start 10 to 14 days before treatment and will be carried out for three months of therapy. After initial training, patients from the intervention group will perform daily spirometry (FVC), transdermal pulse oximetry, pulse and blood pressure measurements, activity measurement (accelerometry), and assessment of the severity of cough and dyspnea. The results will be reported using a telemetric system designed by Mediguard® for this study. The primary outcome measure will be the health-related quality of life change using EQ-5D-5L questionnaire and St. George's Respiratory Questionnaire, as measured at stationary visits in both study groups. Secondary outcomes will include assessment of lung function, costs of health service utilization, satisfaction from being telemonitored, dyspnea by mMRC, fatigue by FAS, patients' adherence to recommended medications using the ASCD, anxiety and depression symptoms as measured by HADS, PHQ-9, and side effects of treatment. DISCUSSION: This is the first clinical trial protocol to evaluate home-based telemonitoring to optimize connective tissue disease-associated interstitial lung management. The study aims to provide data on the impact of telemonitoring on quality of life, evaluation of health status of patients with CTD-ILD using telemonitoring versus standard care. Additionally, we will evaluate the cost-effectiveness of telemonitoring solutions in patients with CTD-ILD. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT04428957; Registered June 11, 2020; https://clinicaltrials.gov/ct2/show/NCT04428957.

[Recommendations for the diagnosis and treatment of connective tissue disease associated pulmonary arterial hypertension in China].

Pulmonary arterial hypertension (PAH) is a clinicopathological syndrome caused by the increase of pulmonary artery, and it is the most serious complication of connective tissue disease (CTD). In recent years, a lot of progress has been made in the diagnosis, treatment and evaluation of PAH. Chinese Rheumatology Association formulated this recommendation on the basis of current experience and guidelines, in order to promote early screening, early diagnosis and early intervention of CTD-PAH, as well as patient follow-up and management, to improve the prognosis of CTD-PAH patients.

[Recommendations for the diagnosis and treatment of connective tissue disease-associated interstitial lung disease in China].

Interstitial lung disease (ILD) is a frequent complication of patients with connective tissue disease (CTD) and significantly affects morbidity and mortality. Disease course may vary from stable or mildly progressive to more severe, with rapid loss of lung function. At present, there are great challenges and poor prognosis in the diagnosis and treatment of CTD-ILD. Based on the evidence and guidelines from China and other countries, experts from the Chinese Rheumatology Association developed standardization of diagnosis and treatment of CTD-ILD. The aim is to strengthen the early identification of, standardize the diagnosis and treatment of CTD-ILD, and delay the progress of the disease.

[Renal manifestations in connective tissue diseases]. / Nierenbeteiligung bei Kollagenosen.

Connective tissue diseases (CTD) comprise a group of inflammatory systemic diseases that can affect various organs. Kidney involvement is frequently associated with significant irreversible damage and often before patients become symptomatic. Screening tests of blood and urine as well as clinical vigilance are therefore essential for all CTDs with possible renal involvement. A kidney biopsy is the gold standard for the diagnosis, prognosis and treatment decisions. A common and severe organ involvement in systemic lupus erythematosus (SLE) is glomerulonephritis (GN), also collectively referred to as lupus nephritis (LN). If left untreated LN often leads to end-stage renal failure. The treatment depends on the clinical parameters and histopathology of the renal involvement. Mycophenolate mofetil and cyclophosphamide are potent but nonspecific immunosuppressants which have been available for many years. Recently, new substances specific for LN have also been approved for the first time. Kidney involvement in Sjogren's syndrome has been far less studied. In studies the frequency of renal involvement is still unclear and ranges from 5% to 33%. Tubulointerstitial nephritis (IN) is the typical form of renal involvement which clearly differs from GN in its clinical presentation. Recommendations for treatment are based exclusively on retrospective studies. A renal crisis in systemic scleroderma (SSc) is a rare but feared complication with a high mortality. An antiphospholipid syndrome (APS) nephropathy (APSN) can occur during CTD. These entities are vasculopathies and often thrombotic microangiopathies, which clearly differ from GN and IN in terms of pathophysiology, clinical features and treatment. This article provides an overview of the diversity of the most important renal manifestations of CTDs.

[Standardized diagnosis and treatment of undifferentiated connective tissue disease and mixed connective tissue disease].

Undifferentiated connective tissue disease (CTD) usually refers to patients who are presented with certain symptoms and signs related to CTD, and positive serological evidence of autoimmune diseases but don't fulfill any of the classification criteria for a certain CTD. Mixed CTD refers to patients who are presented with one or more clinical manifestations such as hand swelling, synovitis, myositis, Raynaud's phenomenon, and acrosclerosis. Patients with mixed CTD always have high-titer anti-nuclear antibodies (ANA) of speckled pattern and high-titer anti-U1 ribonuclear protein (RNP) antibody in serum, while with negative anti-Sm antibody. The update of diagnosis and treatment of undifferentiated CTD and mixed CTD lags behind other established CTD. There is a lack of evidence from randomized controlled trials or guidelines/recommendations on the treatment of undifferentiated CTD or mixed CTD. At present, the conventional therapy is mainly adopted according to the specific clinical manifestations of the disease. The standardized diagnosis and treatment of undifferentiated CTD and mixed CTD were drafted by the Chinese Rheumatology Association based on the previous guidelines and the progress of available evidence, so as to improve the management of these patients in China.

Sjögren's syndrome and other rare and complex connective tissue diseases: an intriguing liaison.

Sjögren's syndrome (SS) is a systemic autoimmune disease that frequently occurs concomitantly with other systemic connective tissue disorders, including rare and complex diseases such as systemic lupus erythematosus (SLE) and systemic sclerosis (SSc). The presence of SS influences the clinical expression of the other autoimmune diseases, thus offering the unique opportunity to explore the similarities in genetic signatures, as well as common environmental and biologic factors modulating the expression of disease phenotypes. In this review, we will specifically discuss the possibility of defining "SS/SLE" and "SS/SSc" as distinct subsets within the context of connective tissue diseases with different clinical expression and outcomes, thus deserving an individualised assessment and personalised medical interventions.

Emerging therapeutics in the management of connective tissue disease. Part I. Lupus erythematosus and Sjögren syndrome.

The management of connective tissue diseases is dramatically evolving with the advent of biologics and novel oral systemic therapeutics. Despite involvement in the care of these complex patients, there is a knowledge gap in the field of dermatology regarding these emerging agents. The first article in this continuing medical education series discusses new and emerging therapeutics for lupus erythematosus and Sjögren syndrome that target cells, intracellular signaling pathways, and cytokines.

Emerging therapeutics in the management of connective tissue disease. Part II: Dermatomyositis and scleroderma.

The management of connective tissue diseases is dramatically evolving with the advent of biologics and novel oral systemic therapeutics. Despite involvement in the care of these complex patients, there is a knowledge gap in the field of dermatology regarding these emerging agents. The second article in this continuing medical education series discusses new and emerging therapeutics for dermatomyositis and scleroderma that target cells, intracellular signaling pathways, and cytokines.