-
Clinical and Experimental Rheumatology Aug 2023Systemic sclerosis is a rare and chronic connective tissue disease resulting from an intricate pathogenesis and is expressed in very heterogeneous clinical... (Review)
Review
Systemic sclerosis is a rare and chronic connective tissue disease resulting from an intricate pathogenesis and is expressed in very heterogeneous clinical manifestations. Every year many studies try to unravel and shed new insight into the pathogenesis, organ involvement and treatment of this complex and severe disease. We herein provide an overview of the most relevant studies published in the literature in 2022.
Topics: Humans; Scleroderma, Systemic; Connective Tissue Diseases
PubMed: 37199215
DOI: 10.55563/clinexprheumatol/ki76s5 -
RMD Open Aug 2023Through this systematic literature review, we assembled evidence to inform the EULAR recommendations for the non-pharmacological management of systemic lupus... (Review)
Review
Through this systematic literature review, we assembled evidence to inform the EULAR recommendations for the non-pharmacological management of systemic lupus erythematosus (SLE) and systemic sclerosis (SSc). We screened articles published between January 2000 and June 2021. Studies selected for data extraction (118 for SLE and 92 for SSc) were thematically categorised by the character of their intervention. Of 208 articles included, 51 were classified as robust in critical appraisal. Physical activity was the most studied management strategy and was found to be efficacious in both diseases. Patient education and self-management also constituted widely studied topics. Many studies on SLE found psychological interventions to improve quality of life. Studies on SSc found phototherapy and laser treatment to improve cutaneous disease manifestations. In summary, non-pharmacological management of SLE and SSc encompasses a wide range of interventions, which can be combined and provided either with or without adjunct pharmacological treatment but should not aim to substitute the latter when this is deemed required. While some management strategies i.e., physical exercise and patient education, are already established in current clinical practice in several centres, others e.g., phototherapy and laser treatment, show both feasibility and efficacy, yet require testing in more rigorous trials than those hitherto conducted.
Topics: Humans; Quality of Life; Scleroderma, Systemic; Lupus Erythematosus, Systemic
PubMed: 37532469
DOI: 10.1136/rmdopen-2023-003297 -
American Journal of Respiratory and... Jan 2024Interstitial lung disease (ILD) is a significant cause of morbidity and mortality in patients with systemic sclerosis (SSc). To date, clinical practice guidelines...
Interstitial lung disease (ILD) is a significant cause of morbidity and mortality in patients with systemic sclerosis (SSc). To date, clinical practice guidelines regarding treatment for patients with SSc-ILD are primarily consensus based. An international expert guideline committee composed of 24 individuals with expertise in rheumatology, SSc, pulmonology, ILD, or methodology, and with personal experience with SSc-ILD, discussed systematic reviews of the published evidence assessed using the Grading of Recommendations, Assessment, Development, and Evaluation approach. Predetermined conflict-of-interest management strategies were applied, and recommendations were made for or against specific treatment interventions exclusively by the nonconflicted panelists. The confidence in effect estimates, importance of outcomes studied, balance of desirable and undesirable consequences of treatment, cost, feasibility, acceptability of the intervention, and implications for health equity were all considered in making the recommendations. This was in accordance with the American Thoracic Society guideline development process, which is in compliance with the Institute of Medicine standards for trustworthy guidelines. For treatment of patients with SSc-ILD, the committee: ) recommends the use of mycophenolate; ) recommends further research into the safety and efficacy of () pirfenidone and () the combination of pirfenidone plus mycophenolate; and ) suggests the use of () cyclophosphamide, () rituximab, () tocilizumab, () nintedanib, and () the combination of nintedanib plus mycophenolate. The recommendations herein provide an evidence-based clinical practice guideline for the treatment of patients with SSc-ILD and are intended to serve as the basis for informed and shared decision making by clinicians and patients.
Topics: Humans; United States; Immunosuppressive Agents; Lung Diseases, Interstitial; Cyclophosphamide; Rituximab; Scleroderma, Systemic; Lung
PubMed: 37772985
DOI: 10.1164/rccm.202306-1113ST -
Arthritis Research & Therapy Jul 2023Many clinical trial results are available to inform best practices in the treatment of patients with connective tissue disease-associated interstitial lung disease... (Review)
Review
Many clinical trial results are available to inform best practices in the treatment of patients with connective tissue disease-associated interstitial lung disease (CTD-ILD).Herein, we summarize the results of clinical trials, including patient-reported outcome instruments, for the treatment of patients with ILD associated with systemic sclerosis (SSc/scleroderma), rheumatoid arthritis, and idiopathic inflammatory myositis, the diseases with the most available data. For SSc-ILD, the US Food and Drug Administration approved nintedanib (a tyrosine kinase inhibitor) in 2020 and subcutaneous tocilizumab (an IL-6 receptor monoclonal antibody) in 2021. Rituximab was recently shown to have similar efficacy but better tolerability than intravenous cyclophosphamide (CYC) for CTD-ILD therapy. Scleroderma Lung Study II, conducted in patients with SSc-ILD, showed that oral CYC and mycophenolate mofetil (MMF) were comparable in their effects on lung function, but MMF was better tolerated. The increasing treatment armamentarium for patients with CTD-ILD offers physicians new opportunities to improve patient outcomes.
Topics: Humans; Immunosuppressive Agents; Lung Diseases, Interstitial; Connective Tissue Diseases; Cyclophosphamide; Mycophenolic Acid; Scleroderma, Systemic; Scleroderma, Localized; Lung
PubMed: 37422652
DOI: 10.1186/s13075-023-03090-y -
Journal of Inflammation Research 2023Systemic sclerosis (SSc) is a complex autoimmune disease characterized by vascular damage, vasoinstability, and decreased perfusion with ischemia, inflammation, and... (Review)
Review
Systemic sclerosis (SSc) is a complex autoimmune disease characterized by vascular damage, vasoinstability, and decreased perfusion with ischemia, inflammation, and exuberant fibrosis of the skin and internal organs. Biomarkers are analytic indicators of the biological and disease processes within an individual that can be accurately and reproducibly measured. The field of biomarkers in SSc is complex as recent studies have implicated at least 240 pathways and dysregulated proteins in SSc pathogenesis. Anti-nuclear antibodies (ANA) are classical biomarkers with well-described clinical classifications and are present in more than 90% of SSc patients and include anti-centromere, anti-Th/To, anti-RNA polymerase III, and anti-topoisomerase I antibodies. Transforming growth factor-β (TGF-β) is central to the fibrotic process of SSc and is intimately intertwined with other biomarkers. Tyrosine kinases, interferon-1 signaling, IL-6 signaling, endogenous thrombin, peroxisome proliferator-activated receptors (PPARs), lysophosphatidic acid receptors, and amino acid metabolites are new biomarkers with the potential for developing new therapeutic agents. Other biomarkers implicated in SSc-ILD include signal transducer and activator of transcription 4 (STAT4), CD226 (DNAX accessory molecule 1), interferon regulatory factor 5 (IRF5), interleukin-1 receptor-associated kinase-1 (IRAK1), connective tissue growth factor (CTGF), pyrin domain containing 1 (NLRP1), T-cell surface glycoprotein zeta chain (CD3ζ) or CD247, the NLR family, SP-D (surfactant protein), KL-6, leucine-rich α2-glycoprotein-1 (LRG1), CCL19, genetic factors including DRB1 alleles, the interleukins (IL-1, IL-4, IL-6, IL-8, IL-10 IL-13, IL-16, IL-17, IL-18, IL-22, IL-32, and IL-35), the chemokines CCL (2,3,5,13,20,21,23), CXC (8,9,10,11,16), CX3CL1 (fractalkine), and GDF15. Adiponectin (an indicator of PPAR activation) and maresin 1 are reduced in SSc patients. A new trend has been the use of biomarker panels with combined complex multifactor analysis, machine learning, and artificial intelligence to determine disease activity and response to therapy. The present review is an update of the various biomarker molecules, pathways, and receptors involved in the pathology of SSc.
PubMed: 37868834
DOI: 10.2147/JIR.S379815 -
The New England Journal of Medicine Jun 2023Disabling pansclerotic morphea (DPM) is a rare systemic inflammatory disorder, characterized by poor wound healing, fibrosis, cytopenias, hypogammaglobulinemia, and...
BACKGROUND
Disabling pansclerotic morphea (DPM) is a rare systemic inflammatory disorder, characterized by poor wound healing, fibrosis, cytopenias, hypogammaglobulinemia, and squamous-cell carcinoma. The cause is unknown, and mortality is high.
METHODS
We evaluated four patients from three unrelated families with an autosomal dominant pattern of inheritance of DPM. Genomic sequencing independently identified three heterozygous variants in a specific region of the gene that encodes signal transducer and activator of transcription 4 (). Primary skin fibroblast and cell-line assays were used to define the functional nature of the genetic defect. We also assayed gene expression using single-cell RNA sequencing of peripheral-blood mononuclear cells to identify inflammatory pathways that may be affected in DPM and that may respond to therapy.
RESULTS
Genome sequencing revealed three novel heterozygous missense gain-of-function variants in . In vitro, primary skin fibroblasts showed enhanced interleukin-6 secretion, with impaired wound healing, contraction of the collagen matrix, and matrix secretion. Inhibition of Janus kinase (JAK)-STAT signaling with ruxolitinib led to improvement in the hyperinflammatory fibroblast phenotype in vitro and resolution of inflammatory markers and clinical symptoms in treated patients, without adverse effects. Single-cell RNA sequencing revealed expression patterns consistent with an immunodysregulatory phenotype that were appropriately modified through JAK inhibition.
CONCLUSIONS
Gain-of-function variants in caused DPM in the families that we studied. The JAK inhibitor ruxolitinib attenuated the dermatologic and inflammatory phenotype in vitro and in the affected family members. (Funded by the American Academy of Allergy, Asthma, and Immunology Foundation and others.).
Topics: Janus Kinases; Nitriles; Pyrazoles; Pyrimidines; Scleroderma, Systemic; Autoimmune Diseases; Mutation, Missense; Gain of Function Mutation; Dermatologic Agents; Anti-Inflammatory Agents
PubMed: 37256972
DOI: 10.1056/NEJMoa2202318 -
Annals of the Rheumatic Diseases Aug 2023
Topics: Humans; Scleroderma, Systemic; B-Lymphocytes; Adaptor Proteins, Signal Transducing; T-Lymphocytes; Antigens, CD19
PubMed: 37147112
DOI: 10.1136/ard-2023-223952