Systemic Sclerosis

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Thomas A Medsger - One of the best experts on this subject based on the ideXlab platform.

John Varga - One of the best experts on this subject based on the ideXlab platform.

  • scleroderma Systemic Sclerosis
    Clinical Immunology (Fourth Edition), 2013
    Co-Authors: John Varga, Fredrick M. Wigley
    Abstract:

    Abstract Systemic Sclerosis is an orphan disease of unknown cause and complex pathogenesis. Multiple genetic variants that are common to Systemic lupus, and other autoimmune diseases have been identified. Autoimmunity and fibrosis are prominent features of the disease. Systemic Sclerosis predominantly affects women, follows a chronic and unpredictable course with multiple organs affected, and lacks effective disease-modifying therapies. In addition to variable degree of skin involvement and Raynaud phenomenon, interstitial lung disease, widespread microvascular disease, intestinal tract pathology, and cardiovascular complications are common. Late-stage disease is usually accompanied by ischemic digital ulcers, pulmonary artery hypertension, pulmonary fibrosis, and small bowel dysfunction. The diffuse cutaneous form of the disease is associated with increased mortality. Although there are no approved disease-modifying therapies, carefully tailored and individualized management of specific organ-based complications can be highly effective in improving quality of life, reducing complications, and improving outcomes.

  • transforming growth factor beta in Systemic Sclerosis scleroderma
    Frontiers in Bioscience, 2009
    Co-Authors: John Varga, Michael L Whitfield
    Abstract:

    : Deregulated transforming growth factor-beta (TGF-beta) activity and responses play prominent roles in the pathogenesis of Systemic Sclerosis (SSc), a chronic and progressive connective tissue disease characterized by fibrosis of the skin and internal organs. Systemic Sclerosis has highly heterogeneous clinical manifestations, and patients can be classified into multiple subgroups on the basis of distinct molecular signatures defined by transcriptional profiling of gene expression in target organs. Current research to uncover how TGF-beta regulates fibroblast function opens the door for the discovery of targeted therapies. Anti-fibrotic treatments that selectively block TGF-beta expression, biological activity or intracellular signaling in SSc are currently under development.

  • Systemic Sclerosis scleroderma a treatable multisystem disease
    American Family Physician, 2008
    Co-Authors: Monique Hinchcliff, John Varga
    Abstract:

    Systemic Sclerosis (Systemic scleroderma) is a chronic connective tissue disease of unknown etiology that causes widespread microvascular damage and excessive deposition of collagen in the skin and internal organs. Raynaud phenomenon and scleroderma (hardening of the skin) are hallmarks of the disease. The typical patient is a young or middle-age woman with a history of Raynaud phenomenon who presents with skin induration and internal organ dysfunction. Clinical evaluation and laboratory testing, along with pulmonary function testing, Doppler echocardiography, and high-resolution computed tomography of the chest, establish the diagnosis and detect visceral involvement. Patients with Systemic Sclerosis can be classified into two distinct clinical subsets with different patterns of skin and internal organ involvement, autoantibody production, and survival. Prognosis is determined by the degree of internal organ involvement. Although no disease-modifying therapy has been proven effective, complications of Systemic Sclerosis are treatable, and interventions for organ-specific manifestations have improved substantially. Medications (e.g., calcium channel blockers and angiotensin-II receptor blockers for Raynaud phenomenon, appropriate treatments for gastroesophageal reflux disease) and lifestyle modifications can help prevent complications, such as digital ulcers and Barrett esophagus. Endothelin-1 receptor blockers and phosphodiesterase-5 inhibitors improve pulmonary arterial hypertension. The risk of renal damage from scleroderma renal crisis can be lessened by early detection, prompt initiation of angiotensin-converting enzyme inhibitor therapy, and avoidance of high-dose corticosteroids. Optimal patient care includes an integrated, multidisciplinary approach to promptly and effectively recognize, evaluate, and manage complications and limit end-organ dysfunction.

  • Exaggerated Radiation-Induced Fibrosis in Patients With Systemic Sclerosis
    JAMA, 1991
    Co-Authors: John Varga, Richard H. Creech, James P. Dwyer, Uwe-frithjof Haustein, Sergio A Jimenez
    Abstract:

    Four patients with stable Systemic Sclerosis and limited skin involvement received radiation for the treatment of solid malignant neoplasms. Following localized irradiation, each patient developed an exaggerated cutaneous and internal fibrotic reaction in the irradiated areas. The surface area of fibrosis extended beyond the radiation portals employed, and the fibrotic process was poorly responsive to antifibrotic therapy. Three of the patients died of complications caused by fibrous encasement of internal organs. The extent and severity of postradiation fibrosis in these patients was distinctly unusual. These observations suggest that patients with Systemic Sclerosis are particularly susceptible to developing excessive radiation-induced fibrosis. ( JAMA . 1991;265:3292-3295)

Toby M Maher - One of the best experts on this subject based on the ideXlab platform.

  • the identification and management of interstitial lung disease in Systemic Sclerosis evidence based european consensus statements
    The Lancet Rheumatology, 2020
    Co-Authors: Annamaria Hoffmannvold, Toby M Maher, Edward E Philpot, Ali Ashrafzadeh, Rafic Barake, Simone Barsotti, Cosimo Bruni, Paolo Carducci, Patricia Carreira, Ivan Castellvi
    Abstract:

    Summary Background Systemic Sclerosis-associated interstitial lung disease (ILD) carries a high mortality risk; expert guidance is required to aid early recognition and treatment. We aimed to develop the first expert consensus and define an algorithm for the identification and management of the condition through application of well established methods. Methods Evidence-based consensus statements for Systemic Sclerosis-associated ILD management were established for six domains (ie, risk factors, screening, diagnosis and severity assessment, treatment initiation and options, disease progression, and treatment escalation) using a modified Delphi process based on a systematic literature analysis. A panel of 27 Europe-based pulmonologists, rheumatologists, and internists with expertise in Systemic Sclerosis-associated ILD participated in three rounds of online surveys, a face-to-face discussion, and a WebEx meeting, followed by two supplemental Delphi rounds, to establish consensus and define a management algorithm. Consensus was considered achieved if at least 80% of panellists indicated agreement or disagreement. Findings Between July 1, 2018, and Aug 27, 2019, consensus agreement was reached for 52 primary statements and six supplemental statements across six domains of management, and an algorithm was defined for clinical practice use. The agreed statements most important for clinical use included: all patients with Systemic Sclerosis should be screened for Systemic Sclerosis-associated ILD using high-resolution CT; high-resolution CT is the primary tool for diagnosing ILD in Systemic Sclerosis; pulmonary function tests support screening and diagnosis; Systemic Sclerosis-associated ILD severity should be measured with more than one indicator; it is appropriate to treat all severe cases; no pharmacological treatment is an option for some patients; follow-up assessments enable identification of disease progression; progression pace, alongside disease severity, drives decisions to escalate treatment. Interpretation Through a robust modified Delphi process developed by a diverse panel of experts, the first evidence-based consensus statements were established on guidance for the identification and medical management of Systemic Sclerosis-associated ILD. Funding An unrestricted grant from Boehringer Ingelheim International.

  • nintedanib for Systemic Sclerosis associated interstitial lung disease
    The New England Journal of Medicine, 2019
    Co-Authors: Oliver Distler, Martina Gahlemann, Toby M Maher
    Abstract:

    Background Interstitial lung disease (ILD) is a common manifestation of Systemic Sclerosis and a leading cause of Systemic Sclerosis-related death. Nintedanib, a tyrosine kinase inhibitor, has been shown to have antifibrotic and antiinflammatory effects in preclinical models of Systemic Sclerosis and ILD. Methods We conducted a randomized, double-blind, placebo-controlled trial to investigate the efficacy and safety of nintedanib in patients with ILD associated with Systemic Sclerosis. Patients who had Systemic Sclerosis with an onset of the first non-Raynaud's symptom within the past 7 years and a high-resolution computed tomographic scan that showed fibrosis affecting at least 10% of the lungs were randomly assigned, in a 1:1 ratio, to receive 150 mg of nintedanib, administered orally twice daily, or placebo. The primary end point was the annual rate of decline in forced vital capacity (FVC), assessed over a 52-week period. Key secondary end points were absolute changes from baseline in the modified Rodnan skin score and in the total score on the St. George's Respiratory Questionnaire (SGRQ) at week 52. Results A total of 576 patients received at least one dose of nintedanib or placebo; 51.9% had diffuse cutaneous Systemic Sclerosis, and 48.4% were receiving mycophenolate at baseline. In the primary end-point analysis, the adjusted annual rate of change in FVC was -52.4 ml per year in the nintedanib group and -93.3 ml per year in the placebo group (difference, 41.0 ml per year; 95% confidence interval [CI], 2.9 to 79.0; P = 0.04). Sensitivity analyses based on multiple imputation for missing data yielded P values for the primary end point ranging from 0.06 to 0.10. The change from baseline in the modified Rodnan skin score and the total score on the SGRQ at week 52 did not differ significantly between the trial groups, with differences of -0.21 (95% CI, -0.94 to 0.53; P = 0.58) and 1.69 (95% CI, -0.73 to 4.12 [not adjusted for multiple comparisons]), respectively. Diarrhea, the most common adverse event, was reported in 75.7% of the patients in the nintedanib group and in 31.6% of those in the placebo group. Conclusions Among patients with ILD associated with Systemic Sclerosis, the annual rate of decline in FVC was lower with nintedanib than with placebo; no clinical benefit of nintedanib was observed for other manifestations of Systemic Sclerosis. The adverse-event profile of nintedanib observed in this trial was similar to that observed in patients with idiopathic pulmonary fibrosis; gastrointestinal adverse events, including diarrhea, were more common with nintedanib than with placebo. (Funded by Boehringer Ingelheim; SENSCIS ClinicalTrials.gov number, NCT02597933.).

John D Pauling - One of the best experts on this subject based on the ideXlab platform.

  • exploring the patient experience of digital ulcers in Systemic Sclerosis
    Seminars in Arthritis and Rheumatism, 2019
    Co-Authors: Michael Hughes, John D Pauling
    Abstract:

    Abstract Digital ulcers are common in patients with Systemic Sclerosis, affecting over half of patients during the course of their disease. For some patients, digital ulcers occur as isolated phenomena; whereas, for others, digital ulceration is recurrent, and often refractory to intervention. Demonstrating treatment efficacy for digital ulcer disease has typically focussed on clinician opinion of ulcer healing and new ulcer occurrence. Advances in management have improved outcomes which may have had the unfortunate effect of rendering traditional trial endpoints less effective at demonstrating treatment efficacy. Despite recent improvements in management, our work is not complete and digital ulceration remains a major cause of morbidity for many patients with Systemic Sclerosis. This review shall examine the patient experience of digital ulcers in Systemic Sclerosis. We shall consider how a detailed understanding of the severity and burden of digital ulceration, aetiopathogenesis, and their impact on emotional health, function, work and social participation might inform the development of novel clinical trial outcomes that can support future advances in the assessment and management of digital ulceration in Systemic Sclerosis.

Virginia D Steen - One of the best experts on this subject based on the ideXlab platform.

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