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Immunotherapy of systemic sclerosis.

ABSTRACT: Scleroderma is a multisystem autoimmune disease characterized by an abnormal immune activation associated with the development of underlying vascular and fibrotic disease manifestations. This article highlights the current use of drugs targeting the immune system in scleroderma. Nonselective immunosuppression, and in particular cyclophosphamide, remains the main treatment for progressing skin involvement and active interstitial lung disease. Mycophenolate mofetil is a promising alternative to cyclophosphamide. The use of cyclosporine has been limited by modest efficacy and serious renal toxicity. Newer T-cell (sirolimus and alefacept) and B-cell (rituximab)-targeted therapies have provided some encouraging results in small pilot studies. Hematopoietic stem cell transplantation can be effective for severe fibrotic skin disease, but toxicity remains a concern. Clinical efficacy and safety of antifibrotic treatments (e.g., imatinib) await confirmation. Newer biological agents targeting key molecular or cellular effectors in scleroderma pathogenesis are now available for clinical testing.

SUBMITTER: Manno R

PROVIDER: S-EPMC3059511 | biostudies-literature | 2010 Nov

REPOSITORIES: biostudies-literature

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Immunotherapy of systemic sclerosis.

Manno Rebecca R Boin Francesco F

Immunotherapy 20101101 6

Scleroderma is a multisystem autoimmune disease characterized by an abnormal immune activation associated with the development of underlying vascular and fibrotic disease manifestations. This article highlights the current use of drugs targeting the immune system in scleroderma. Nonselective immunosuppression, and in particular cyclophosphamide, remains the main treatment for progressing skin involvement and active interstitial lung disease. Mycophenolate mofetil is a promising alternative to cy ...[more]

PMID: 21091117

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New Autoantibody Specificities in Systemic Sclerosis and Very Early Systemic Sclerosis.

Project description:Chemokine (C-X-C motif) ligand 4 (CXCL4) is a biomarker of unfavorable prognosis in Systemic Sclerosis (SSc), a potentially severe autoimmune condition, characterized by vasculitis, fibrosis and interferon (IFN)-I-signature. We recently reported that autoantibodies to CXCL4 circulate in SSc patients and correlate with IFN-α. Here, we used shorter versions of CXCL4 and CXCL4-L1, the CXCL4 non-allelic variant, to search for autoantibodies exclusively reacting to one or the other CXCL4 form. Moreover, to address whether anti-CXCL4/CXCL4-L1 antibodies were present before SSc onset and predicted SSc-progression, we longitudinally studied two VEDOSS (Very Early Diagnosis of Systemic Sclerosis) patient cohorts, separating SSc-progressors from SSc-non-progressors. We found that anti-CXCL4-specific autoantibodies were present in both SSc and VEDOSS patients (both SSc-progressors and SSc-non-progressors). Anti-CXCL4-L1-specific autoantibodies were especially detected in long-standing SSc (lsSSc). Anti-CXCL4/CXCL4-L1 antibodies correlated with IFN-α and with specific SSc-skin features but only in lsSSc and not in early SSc (eaSSc) or VEDOSS. Thus, a broader antibody response, with reactivity spreading to CXCL4-L1, is characteristic of lsSSc. The early anti-CXCL4 autoantibody response seems qualitatively different from, and likely less pathogenic than, that observed in advanced SSc. Lastly, we confirm that anti-CXCL4 autoantibodies are SSc-biomarkers and uncover that also CXCL4-L1 becomes an autoantigen in lsSSc.

| S-EPMC8103273 | biostudies-literature

Genetic factors in systemic sclerosis.

Project description:A number of genetic loci have been identified that appear to be associated with systemic sclerosis (SSc; scleroderma). There is mounting evidence suggesting that these genetic associations may in fact be associated with distinct phenotypes in SSc based on autoantibody pattern rather than with SSc as a single disease entity. This may ultimately have implications for approaches to therapy as well as responses to therapy. The most promising candidate genes are those involved in pathways that lead to the vascular damage and fibrosis that are the hallmarks of this disease. There is uncertainty, however, regarding the nature of the key pathological mechanisms that link these two disease processes. Recent studies have focused on Fli1 (friend leukaemia integration 1), a transcription factor that is found in immune cells, fibroblasts, and endothelial cells that regulates collagen gene function and angiogenesis. Fli1 is dysregulated in SSc skin and dermal blood vessels, and appears to play a pathological role in SSc skin fibrosis and vessel degeneration. Whether this dysregulation is due to genetic polymorphisms in the Fli1 pathway or to epigenetic mechanisms is not clear.

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Mycophenolate Treatment in Systemic Sclerosis

Project description:Skin gene expression signatures, including intrinsic subset, are associated with improvement during Mycophenolate mofetil (MMF) treatment. Longitudinal SSc patient biopsies and controls were integrated into 83 sample dataset totaling 165 arrays for gene expression and analysis

2014-07-25 | E-GEOD-59785 | biostudies-arrayexpress

Biomarkers in systemic sclerosis.

Project description:PURPOSE OF REVIEW:To discuss recent advances in identification of biomarkers in systemic sclerosis for disease severity, prognosis, and treatment response. RECENT FINDINGS:Recent reports describe novel circulating markers of disease severity, autoantibody associations with specific manifestations including cancer, and skin gene expression-based predictors of modified Rodnan skin score progression and treatment response. Moreover, there is converging evidence that C-reactive protein and pneumoproteins such as Krebs von den Lungen-6 and chemokine ligand 18 could serve as prognostic biomarkers in systemic sclerosis-associated interstitial lung disease. SUMMARY:Several novel biomarkers show promise in improving the assessment of systemic sclerosis (SSc) disease severity, prognosis, and treatment response. Their potential utility in prospective selection of patients for clinical trials and in individual patient management require additional research.

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Pharmacotherapy of systemic sclerosis.

Project description:Systemic sclerosis (SSc) is an uncommon autoimmune disease with variable degrees of fibroproliferation in blood vessels and certain organs of the body. There is currently no cure. The purpose of this article is to review the current literature regarding pathogenesis and treatment of complications of SSc.All available articles regarding research related to SSc pathogenesis and treatment listed in the PubMed database were searched; relevant articles were then reviewed and used as sources of information for this review.This review attempts to highlight for the reader some current thought regarding mechanisms of SSc pathogenesis and how autoimmunity relates to vascular changes and fibrogenesis of the disease, as well as providing a review of results of completed clinical trials and current ongoing clinical trials that address organ-specific or global therapies for this disease. This can aid physicians who provide medical care for patients with SSc.SSc is a complex autoimmune disease, the pathogenesis of which, although not completely understood, is under active study; new insights into pathogenesis are continually being discovered. Although there is no effective disease-modifying treatment for patients with SSc, quality of life, morbidity and mortality can be improved by using targeted therapy directed at affecting the consequences of damage to lungs, blood vessels, kidneys and the gastrointestinal tract. Innovative approaches to treating SSc are under intense investigation.

| S-EPMC2837533 | biostudies-literature

Pathogenesis of Systemic Sclerosis.

Project description:Systemic scleroderma (SSc) is one of the most complex systemic autoimmune diseases. It targets the vasculature, connective tissue-producing cells (namely fibroblasts/myofibroblasts), and components of the innate and adaptive immune systems. Clinical and pathologic manifestations of SSc are the result of: (1) innate/adaptive immune system abnormalities leading to production of autoantibodies and cell-mediated autoimmunity, (2) microvascular endothelial cell/small vessel fibroproliferative vasculopathy, and (3) fibroblast dysfunction generating excessive accumulation of collagen and other matrix components in skin and internal organs. All three of these processes interact and affect each other. The disease is heterogeneous in its clinical presentation that likely reflects different genetic or triggering factor (i.e., infection or environmental toxin) influences on the immune system, vasculature, and connective tissue cells. The roles played by other ubiquitous molecular entities (such as lysophospholipids, endocannabinoids, and their diverse receptors and vitamin D) in influencing the immune system, vasculature, and connective tissue cells are just beginning to be realized and studied and may provide insights into new therapeutic approaches to treat SSc.

| S-EPMC4459100 | biostudies-literature

Mycophenolate Treatment in Systemic Sclerosis

Project description:Skin gene expression signatures, including intrinsic subset, are associated with improvement during Mycophenolate mofetil (MMF) treatment.

2014-07-25 | GSE59785 | GEO

Systemic sclerosis-associated pulmonary arterial hypertension.

Project description:Pulmonary arterial hypertension (PAH) is the leading cause of death in systemic sclerosis (SSc) and affects up to 12% of all patients with SSc, with a 50% mortality rate within 3 years of PAH diagnosis. Compared with the idiopathic form of PAH (IPAH), patients with SSc-associated PAH (SSc-PAH) have a threefold increased risk of death and may receive a diagnosis late in the course of disease because of insidious onset and the high prevalence of cardiac, musculoskeletal, and pulmonary parenchymal comorbidities. Treatment with conventional forms of PAH therapy often yield poor results compared with IPAH cohorts; unfortunately, the exact reasons behind this remain poorly understood but likely include variations in the pathologic mechanisms, differences in cardiovascular response to increasing afterload, and inadequate strategies to detect and treat SSc-PAH early in its course. Current methods for screening and longitudinal evaluation of SSc-PAH, such as the 6-min walk test, transthoracic echocardiography, and MRI, each have notable advantages and disadvantages. We provide an up-to-date, focused review of SSc-PAH and how it differs from IPAH, including pathogenesis, appropriate screening for disease onset, and new approaches to treatment and longitudinal assessment of this disease.

| S-EPMC3787920 | biostudies-other

Update on immunopathogenesis and immunotherapy in multiple sclerosis.

Project description:Multiple sclerosis is a chronic inflammatory demyelinating disease of the central nervous system. Both genetic and environmental factors are believed to contribute to the pathogenesis of the disease. Histopathological findings suggest that multiple sclerosis is an immune-mediated disease, involving both the cellular and humoral immune systems. Within the last 20 years, several disease-modifying therapies for the treatment of multiple sclerosis were established. Moreover, promising new substances are currently being tested in clinical trials and will likely broaden the therapeutic opportunities available within the upcoming years.

| S-EPMC4928362 | biostudies-other

Disease progression in systemic sclerosis-overlap syndrome is significantly different from limited and diffuse cutaneous systemic sclerosis.

Project description:BACKGROUND: Systemic sclerosis (SSc)-overlap syndromes are a very heterogeneous and remarkable subgroup of SSc-patients, who present at least two connective tissue diseases (CTD) at the same time, usually with a specific autoantibody status. OBJECTIVES: To determine whether patients, classified as overlap syndromes, show a disease course different from patients with limited SSc (lcSSc) or diffuse cutaneous SSc (dcSSc). METHODS: The data of 3240 prospectively included patients, registered in the database of the German Network for Systemic Scleroderma and followed between 2003 and 2013, were analysed. RESULTS: Among 3240 registered patients, 10% were diagnosed as SSc-overlap syndrome. Of these, 82.5% were female. SSc-overlap patients had a mean age of 48±1.2?years and carried significantly more often 'other antibodies' (68.0%; p<0.0001), including anti-U1RNP, -PmScl, -Ro, -La, as well as anti-Jo-1 and -Ku antibodies. These patients developed musculoskeletal involvement earlier and more frequently (62.5%) than patients diagnosed as lcSSc (32.2%) or dcSSc (43.3%) (p<0.0001). The onset of lung fibrosis and heart involvement in SSc-overlap patients was significantly earlier than in patients with lcSSc and occurred later than in patients with dcSSc. Oesophagus, kidney and PH progression was similar to lcSSc patients, whereas dcSSc patients had a significantly earlier onset. CONCLUSIONS: These data support the concept that SSc-overlap syndromes should be regarded as a separate SSc subset, distinct from lcSSc and dcSSc, due to a different progression of the disease, different proportional distribution of specific autoantibodies, and of different organ involvement.

| S-EPMC4392314 | biostudies-literature

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