Scleroderma pathophysiology
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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: M. Khurram Afzal, MD [2]
Overview
Pathophysiology
Pathogenesis
- Scleroderma, also known as systemic sclerosis (SSc) is an autoimmune connective tissue disease.[1][2]
- Important features of scleroderma include:[3]
- Production of autoantibodies against various cellular antigens
- Small vessel vasculopathy
- Fibrosis of the skin and internal organs
- Excess of collagen deposition in the skin and internal organs
- Features of Scleroderma include:
- Sclerodactyly (thickened skin of the fingers) is common
- Extensive skin fibrosis may be present
- Raynaud phenomenon
- Esophageal dysmotility
- Pulmonary arterial hypertension
- Cardiac involvement
- Interstitial lung disease
- Inflamatory arthritis
- Digital ulcers
- There is an association between diagnosis of cancer and onset of scleroderma:[4]
- Patients with RNA polymerase III autoantibodies are at high risk for cancer associated scleroderma
- Patients with an older age of onset are also at risk for cancer associated scleroderma
- Screening for malignancy is recommended in these patients at risk for malignancy.
- An increase in alpha2-adrenergic activity in vascular smooth muscle is responsible for vasospasm in scleroderma[5]
- Circulating autoantibodies found in patients with scleroderma include:
- Anti-topoisomerase I (Scl-70) antibody[6][7][8]
- Specific for Scleroderma
- Presence is associated with higher risk of interstitial lung disease
- Increased disease activity
- Anti-centromere antibody
- Present in limited cutaneous scleroderma (CREST syndrome)
- Anti-RNA polymerase III antibody[9]
- Associated with higher prevalence of malignancy in scleroderma patients
- Anti-nucleolar antibody (ANA)
- Anti-topoisomerase I (Scl-70) antibody[6][7][8]
- Growth factors and cytokines play a role in the underlying mechanism of disease:[1]
Genetics
Genetics associated with the development of scleroderma include:[14]
- Scleroderma occurs in a sporadic pattern in the general population.
- Variations in human leukocyte antigen (HLA) genes can predispose an individual to developing scleroderma.
- Other genes that increase the risk of developing scleroderma include:
- IRF5
- STAT4
- Genetic variation in the IRF5 gene predisposes an individual to developing diffuse cutaneous systemic scleroderma.
- Genetic variation in the STAT4 gene predisposes an individual to developing limited cutaneous systemic scleroderma.
Associated Conditions
Conditions that are associated with scleroderma include:[2]
- Nephrogenic sclerosing fibrosis
- Scleroderma diabeticorum
- Scleromyxedema
- Erythromyalgia
- Porphyria
- Lichen sclerosis
- Diabetic cheiroarthropathy
- Primary biliary cirrhosis[15]
- Systemic lupus erythematosus (SLE)
- Rheumatoid arthritis
- Polymyositis
- Sjögren's syndrome
- Graft-versus-host disease[16]
- Mixed connective tissue disease
- Malignancy[17][4]
Gross Pathology
- On gross pathology, [feature1], [feature2], and [feature3] are characteristic findings of [disease name].
Microscopic Pathology
- On microscopic histopathological analysis, [feature1], [feature2], and [feature3] are characteristic findings of [disease name].
References
- ↑ 1.0 1.1 Gabrielli A, Avvedimento EV, Krieg T (May 2009). "Scleroderma". N. Engl. J. Med. 360 (19): 1989–2003. doi:10.1056/NEJMra0806188. PMID 19420368.
- ↑ 2.0 2.1 Pope JE, Johnson SR (August 2015). "New Classification Criteria for Systemic Sclerosis (Scleroderma)". Rheum. Dis. Clin. North Am. 41 (3): 383–98. doi:10.1016/j.rdc.2015.04.003. PMID 26210125.
- ↑ Barnes J, Mayes MD (March 2012). "Epidemiology of systemic sclerosis: incidence, prevalence, survival, risk factors, malignancy, and environmental triggers". Curr Opin Rheumatol. 24 (2): 165–70. doi:10.1097/BOR.0b013e32834ff2e8. PMID 22269658.
- ↑ 4.0 4.1 Shah AA, Casciola-Rosen L (November 2015). "Cancer and scleroderma: a paraneoplastic disease with implications for malignancy screening". Curr Opin Rheumatol. 27 (6): 563–70. doi:10.1097/BOR.0000000000000222. PMC 4643720. PMID 26352736.
- ↑ Flavahan NA, Flavahan S, Liu Q, Wu S, Tidmore W, Wiener CM, Spence RJ, Wigley FM (August 2000). "Increased alpha2-adrenergic constriction of isolated arterioles in diffuse scleroderma". Arthritis Rheum. 43 (8): 1886–90. doi:10.1002/1529-0131(200008)43:8<1886::AID-ANR27>3.0.CO;2-S. PMID 10943881.
- ↑ Reveille JD, Solomon DH (June 2003). "Evidence-based guidelines for the use of immunologic tests: anticentromere, Scl-70, and nucleolar antibodies". Arthritis Rheum. 49 (3): 399–412. doi:10.1002/art.11113. PMID 12794797.
- ↑ Hu PQ, Fertig N, Medsger TA, Wright TM (May 2003). "Correlation of serum anti-DNA topoisomerase I antibody levels with disease severity and activity in systemic sclerosis". Arthritis Rheum. 48 (5): 1363–73. doi:10.1002/art.10977. PMID 12746909.
- ↑ Black CM (1995). "The aetiopathogenesis of systemic sclerosis: thick skin--thin hypotheses. The Parkes Weber Lecture 1994". J R Coll Physicians Lond. 29 (2): 119–30. PMID 7595885.
- ↑ Shah AA, Rosen A, Hummers L, Wigley F, Casciola-Rosen L (September 2010). "Close temporal relationship between onset of cancer and scleroderma in patients with RNA polymerase I/III antibodies". Arthritis Rheum. 62 (9): 2787–95. doi:10.1002/art.27549. PMC 2946521. PMID 20506513.
- ↑ Kawakami T, Ihn H, Xu W, Smith E, LeRoy C, Trojanowska M (January 1998). "Increased expression of TGF-beta receptors by scleroderma fibroblasts: evidence for contribution of autocrine TGF-beta signaling to scleroderma phenotype". J. Invest. Dermatol. 110 (1): 47–51. doi:10.1046/j.1523-1747.1998.00073.x. PMID 9424086.
- ↑ Rajkumar VS, Sundberg C, Abraham DJ, Rubin K, Black CM (May 1999). "Activation of microvascular pericytes in autoimmune Raynaud's phenomenon and systemic sclerosis". Arthritis Rheum. 42 (5): 930–41. doi:10.1002/1529-0131(199905)42:5<930::AID-ANR11>3.0.CO;2-1. PMID 10323448.
- ↑ Needleman BW, Wigley FM, Stair RW (January 1992). "Interleukin-1, interleukin-2, interleukin-4, interleukin-6, tumor necrosis factor alpha, and interferon-gamma levels in sera from patients with scleroderma". Arthritis Rheum. 35 (1): 67–72. PMID 1731816.
- ↑ Bashkin P, Doctrow S, Klagsbrun M, Svahn CM, Folkman J, Vlodavsky I (February 1989). "Basic fibroblast growth factor binds to subendothelial extracellular matrix and is released by heparitinase and heparin-like molecules". Biochemistry. 28 (4): 1737–43. PMID 2541764.
- ↑ "Systemic scleroderma - Genetics Home Reference".
- ↑ Powell FC, Winkelmann RK, Venencie-Lemarchand F, Spurbeck JL, Schroeter AL (October 1984). "The anticentromere antibody: disease specificity and clinical significance". Mayo Clin. Proc. 59 (10): 700–6. PMID 6384675.
- ↑ Artlett CM, Smith JB, Jimenez SA (April 1998). "Identification of fetal DNA and cells in skin lesions from women with systemic sclerosis". N. Engl. J. Med. 338 (17): 1186–91. doi:10.1056/NEJM199804233381704. PMID 9554859.
- ↑ Shah AA, Casciola-Rosen L (2017). "Mechanistic and clinical insights at the scleroderma-cancer interface". J Scleroderma Relat Disord. 2 (3): 153–159. doi:10.5301/jsrd.5000250. PMC 5734659. PMID 29264402.