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{{Scleroderma}}
{{Scleroderma}}


{{CMG}}
{{CMG}}; {{AE}} {{MKA}}
 
==Overview==
==Overview==
Scleroderma is an [[autoimmune]] [[connective tissue disease]]. The hallmark of the underlying pathophysiology is production of [[autoantibodies]] against various [[cellular]] [[antigens]], small [[vessel]] [[vasculopathy]], [[fibrosis]] of [[skin]] and internal organs, and excess [[collagen]] deposition in the [[skin]] and internal organs. Circulating [[autoantibodies]] found in patients with scleroderma are anti-[[topoisomerase I]] (Scl-70) [[antibody]], [[Anti-centromere antibodies|anti-centromere]] [[antibody]], anti-[[RNA polymerase III]] [[antibody]], anti-nucleolar [[antibody]]. [[Growth factors]] and [[cytokines]] play an important role in the underlying pathogenesis of scleroderma. Increased [[fibroblast]] activity leads to the excessive [[collagen]] deposition in scleroderma. Although the hallmark of this disease is [[skin]] [[fibrosis]], internal organ involvement is a fatal complication and includes, [[esophageal dysmotility]], [[interstitial lung disease]], [[pulmonary arterial hypertension]], scleroderma [[renal]] crisis, [[myocardial]] [[fibrosis]], [[pericardial]] [[fibrosis]] and [[pericardial effusion]]. Although scleroderma occurs in a sporadic pattern in the general population, variations in the [[Human leukocyte antigen|human leukocyte antigen (HLA)]] genes can predispose an individual to developing scleroderma. On gross pathology, [[sclerodactyly]], [[skin]] [[fibrosis]], [[edema]] and [[calcinosis]] are characteristic findings of scleroderma. On [[microscopic]] [[histopathological]] analysis, characteristic findings of scleroderma include microvascular damage, [[Perivascular cell|perivascular]] infiltrates of [[immune]] [[cells]], loss of [[microvasculature]], [[Perivascular cell|perivascular]] [[edema]], [[fibrosis]], densely packed [[collagen]] in the lower [[dermis]] and upper [[subcutaneous]] layer, [[atrophy]], and loss of [[cells]] in the later stages of the disease.


==Pathophysiology==
==Pathophysiology==


The overproduction of collagen is thought to result from an [[autoimmune disorder|autoimmune dysfunction]], in which the immune system would start to attack the [[kinetochore]] of the chromosomes. This would lead to genetic malfunction of nearby genes. [[T cell]]s accumulate in the skin; these are thought to secrete [[cytokine]]s and other proteins that stimulate collagen deposition. Stimulation of the [[fibroblast]], in particular, seems to be crucial to the disease process, and studies have converged on the potential factors that produce this effect.<ref name=JimenezDerk/>
===Pathogenesis===
 
*Scleroderma, also known as [[Systemic sclerosis|systemic sclerosis (SSc)]] is an [[autoimmune]] [[connective tissue disease]].<ref name="pmid19420368">{{cite journal |vauthors=Gabrielli A, Avvedimento EV, Krieg T |title=Scleroderma |journal=N. Engl. J. Med. |volume=360 |issue=19 |pages=1989–2003 |date=May 2009 |pmid=19420368 |doi=10.1056/NEJMra0806188 |url=}}</ref><ref name="pmid26210125">{{cite journal |vauthors=Pope JE, Johnson SR |title=New Classification Criteria for Systemic Sclerosis (Scleroderma) |journal=Rheum. Dis. Clin. North Am. |volume=41 |issue=3 |pages=383–98 |date=August 2015 |pmid=26210125 |doi=10.1016/j.rdc.2015.04.003 |url=}}</ref>
*Important features of scleroderma include:<ref name="pmid22269658">{{cite journal |vauthors=Barnes J, Mayes MD |title=Epidemiology of systemic sclerosis: incidence, prevalence, survival, risk factors, malignancy, and environmental triggers |journal=Curr Opin Rheumatol |volume=24 |issue=2 |pages=165–70 |date=March 2012 |pmid=22269658 |doi=10.1097/BOR.0b013e32834ff2e8 |url=}}</ref>
**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
*Other 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]]
**[[Inflamation|Inflamatory]] [[arthritis]]
**Digital [[ulcers]]
*There is an association between scleroderma and malignancy:<ref name="pmid26352736">{{cite journal |vauthors=Shah AA, Casciola-Rosen L |title=Cancer and scleroderma: a paraneoplastic disease with implications for malignancy screening |journal=Curr Opin Rheumatol |volume=27 |issue=6 |pages=563–70 |date=November 2015 |pmid=26352736 |pmc=4643720 |doi=10.1097/BOR.0000000000000222 |url=}}</ref>
**Patients with [[RNA polymerase III]] [[autoantibodies]] are at high risk for scleroderma associated malignancy
**Patients with an older age of onset of scleroderma are at higher risk for [[cancer]]
**Screening for [[malignancy]] is recommended in these patients at risk
*An increase in [[Alpha2-adrenergic receptor|alpha2-adrenergic]] activity in [[vascular]] [[smooth muscle]] is responsible for [[vasospasm]] in scleroderma.<ref name="pmid10943881">{{cite journal |vauthors=Flavahan NA, Flavahan S, Liu Q, Wu S, Tidmore W, Wiener CM, Spence RJ, Wigley FM |title=Increased alpha2-adrenergic constriction of isolated arterioles in diffuse scleroderma |journal=Arthritis Rheum. |volume=43 |issue=8 |pages=1886–90 |date=August 2000 |pmid=10943881 |doi=10.1002/1529-0131(200008)43:8<1886::AID-ANR27>3.0.CO;2-S |url=}}</ref>
*Circulating [[autoantibodies]] found in patients with scleroderma include:
**Anti-topoisomerase I (Scl-70) [[antibody]]<ref name="pmid12794797">{{cite journal |vauthors=Reveille JD, Solomon DH |title=Evidence-based guidelines for the use of immunologic tests: anticentromere, Scl-70, and nucleolar antibodies |journal=Arthritis Rheum. |volume=49 |issue=3 |pages=399–412 |date=June 2003 |pmid=12794797 |doi=10.1002/art.11113 |url=}}</ref><ref name="pmid12746909">{{cite journal |vauthors=Hu PQ, Fertig N, Medsger TA, Wright TM |title=Correlation of serum anti-DNA topoisomerase I antibody levels with disease severity and activity in systemic sclerosis |journal=Arthritis Rheum. |volume=48 |issue=5 |pages=1363–73 |date=May 2003 |pmid=12746909 |doi=10.1002/art.10977 |url=}}</ref><ref name="pmid7595885">{{cite journal |vauthors=Black CM |title=The aetiopathogenesis of systemic sclerosis: thick skin--thin hypotheses. The Parkes Weber Lecture 1994 |journal=J R Coll Physicians Lond |volume=29 |issue=2 |pages=119–30 |date=1995 |pmid=7595885 |doi= |url=}}</ref>
***Associated with higher risk of [[interstitial lung disease]]
***Increased disease activity
**[[Anti-centromere antibodies|Anti-centromere antibody]]
***Present in limited cutaneous scleroderma ([[CREST syndrome]])
**Anti-[[RNA polymerase III]] [[antibody]]<ref name="pmid20506513">{{cite journal |vauthors=Shah AA, Rosen A, Hummers L, Wigley F, Casciola-Rosen L |title=Close temporal relationship between onset of cancer and scleroderma in patients with RNA polymerase I/III antibodies |journal=Arthritis Rheum. |volume=62 |issue=9 |pages=2787–95 |date=September 2010 |pmid=20506513 |pmc=2946521 |doi=10.1002/art.27549 |url=}}</ref>
***Associated with higher [[prevalence]] of [[malignancy]] in scleroderma patients
**Anti-nuclear [[antibody]] ([[ANA]])
*[[Growth factors]] and [[Cytokine|cytokines]] play a role in the underlying mechanism of disease:<ref name="pmid19420368">{{cite journal |vauthors=Gabrielli A, Avvedimento EV, Krieg T |title=Scleroderma |journal=N. Engl. J. Med. |volume=360 |issue=19 |pages=1989–2003 |date=May 2009 |pmid=19420368 |doi=10.1056/NEJMra0806188 |url=}}</ref>
**[[TGF-beta|Transforming growth factor-beta (TGF-beta)]]<ref name="pmid9424086">{{cite journal |vauthors=Kawakami T, Ihn H, Xu W, Smith E, LeRoy C, Trojanowska M |title=Increased expression of TGF-beta receptors by scleroderma fibroblasts: evidence for contribution of autocrine TGF-beta signaling to scleroderma phenotype |journal=J. Invest. Dermatol. |volume=110 |issue=1 |pages=47–51 |date=January 1998 |pmid=9424086 |doi=10.1046/j.1523-1747.1998.00073.x |url=}}</ref>
**[[Platelet-derived growth factor]]<ref name="pmid10323448">{{cite journal |vauthors=Rajkumar VS, Sundberg C, Abraham DJ, Rubin K, Black CM |title=Activation of microvascular pericytes in autoimmune Raynaud's phenomenon and systemic sclerosis |journal=Arthritis Rheum. |volume=42 |issue=5 |pages=930–41 |date=May 1999 |pmid=10323448 |doi=10.1002/1529-0131(199905)42:5<930::AID-ANR11>3.0.CO;2-1 |url=}}</ref>
**[[Interleukins]]<ref name="pmid1731816">{{cite journal |vauthors=Needleman BW, Wigley FM, Stair RW |title=Interleukin-1, interleukin-2, interleukin-4, interleukin-6, tumor necrosis factor alpha, and interferon-gamma levels in sera from patients with scleroderma |journal=Arthritis Rheum. |volume=35 |issue=1 |pages=67–72 |date=January 1992 |pmid=1731816 |doi= |url=}}</ref>
***[[IL-1]], [[Interleukin 6|IL-6]], [[IL-8]], IL-17
**[[BFGF|Basic fibroblast growth factor (bFGF)]]<ref name="pmid2541764">{{cite journal |vauthors=Bashkin P, Doctrow S, Klagsbrun M, Svahn CM, Folkman J, Vlodavsky I |title=Basic fibroblast growth factor binds to subendothelial extracellular matrix and is released by heparitinase and heparin-like molecules |journal=Biochemistry |volume=28 |issue=4 |pages=1737–43 |date=February 1989 |pmid=2541764 |doi= |url=}}</ref>
**[[Interferon-gamma]]
**[[Tumor necrosis factor alpha|Tumor necrosis factor (TNF) alpha]]
*Increased [[fibroblast]] activity leads to excess [[collagen]] deposition<ref name="pmid4430718">{{cite journal |vauthors=LeRoy EC |title=Increased collagen synthesis by scleroderma skin fibroblasts in vitro: a possible defect in the regulation or activation of the scleroderma fibroblast |journal=J. Clin. Invest. |volume=54 |issue=4 |pages=880–9 |date=October 1974 |pmid=4430718 |pmc=301627 |doi=10.1172/JCI107827 |url=}}</ref>
**The mechanism responsible is thought to be increased [[transcription]] of [[collagen]] specific [[mRNA]]<ref name="pmid8615828">{{cite journal |vauthors=Eckes B, Mauch C, Hüppe G, Krieg T |title=Differential regulation of transcription and transcript stability of pro-alpha 1(I) collagen and fibronectin in activated fibroblasts derived from patients with systemic scleroderma |journal=Biochem. J. |volume=315 ( Pt 2) |issue= |pages=549–54 |date=April 1996 |pmid=8615828 |pmc=1217231 |doi= |url=}}</ref>
**The [[transformation]] of [[fibroblasts]] to [[myofibroblasts]] leads to the over expression of [[cytokines]] and [[growth factors]]<ref name="pmid16207328">{{cite journal |vauthors=Rajkumar VS, Howell K, Csiszar K, Denton CP, Black CM, Abraham DJ |title=Shared expression of phenotypic markers in systemic sclerosis indicates a convergence of pericytes and fibroblasts to a myofibroblast lineage in fibrosis |journal=Arthritis Res. Ther. |volume=7 |issue=5 |pages=R1113–23 |date=2005 |pmid=16207328 |pmc=1257439 |doi=10.1186/ar1790 |url=}}</ref><ref name="pmid9424086">{{cite journal |vauthors=Kawakami T, Ihn H, Xu W, Smith E, LeRoy C, Trojanowska M |title=Increased expression of TGF-beta receptors by scleroderma fibroblasts: evidence for contribution of autocrine TGF-beta signaling to scleroderma phenotype |journal=J. Invest. Dermatol. |volume=110 |issue=1 |pages=47–51 |date=January 1998 |pmid=9424086 |doi=10.1046/j.1523-1747.1998.00073.x |url=}}</ref>
**[[Reactive oxygen species]] also play a role in the [[differentiation]] of [[fibroblasts]]<ref name="pmid17607298">{{cite journal |vauthors=Bellini A, Mattoli S |title=The role of the fibrocyte, a bone marrow-derived mesenchymal progenitor, in reactive and reparative fibroses |journal=Lab. Invest. |volume=87 |issue=9 |pages=858–70 |date=September 2007 |pmid=17607298 |doi=10.1038/labinvest.3700654 |url=}}</ref>
*Internal organ involvement:
**[[Gastrointestinal system]]<ref name="pmid4701683">{{cite journal |vauthors=Turner R, Lipshutz W, Miller W, Rittenberg G, Schumacher HR, Cohen S |title=Esophageal dysfunction in collagen disease |journal=Am. J. Med. Sci. |volume=265 |issue=3 |pages=191–9 |date=March 1973 |pmid=4701683 |doi= |url=}}</ref><ref name="pmid11501722">{{cite journal |vauthors=Marie I, Dominique S, Levesque H, Ducrotté P, Denis P, Hellot MF, Courtois H |title=Esophageal involvement and pulmonary manifestations in systemic sclerosis |journal=Arthritis Rheum. |volume=45 |issue=4 |pages=346–54 |date=August 2001 |pmid=11501722 |doi=10.1002/1529-0131(200108)45:4<346::AID-ART347>3.0.CO;2-L |url=}}</ref><ref name="pmid14449181">{{cite journal |vauthors=HOSKINS LC, NORRIS HT, GOTTLIEB LS, ZAMCHECK N |title=Functional and morphologic alterations of the gastrointestinal tract in progressive systemic sclerosis (scleroderma) |journal=Am. J. Med. |volume=33 |issue= |pages=459–70 |date=September 1962 |pmid=14449181 |doi= |url=}}</ref>
***[[Esophageal dysmotility]]
***[[Lower esophageal sphincter]] incompetence
**[[Pulmonary]] system
***[[Interstitial lung disease]] ([[pulmonary fibrosis]])<ref name="pmid1892314">{{cite journal |vauthors=Harrison NK, Myers AR, Corrin B, Soosay G, Dewar A, Black CM, Du Bois RM, Turner-Warwick M |title=Structural features of interstitial lung disease in systemic sclerosis |journal=Am. Rev. Respir. Dis. |volume=144 |issue=3 Pt 1 |pages=706–13 |date=September 1991 |pmid=1892314 |doi=10.1164/ajrccm/144.3_Pt_1.706 |url=}}</ref>
***[[Pulmonary arterial hypertension]]
**[[Renal system]]
***Scleroderma [[renal]] crisis<ref name="pmid6355755">{{cite journal |vauthors=Traub YM, Shapiro AP, Rodnan GP, Medsger TA, McDonald RH, Steen VD, Osial TA, Tolchin SF |title=Hypertension and renal failure (scleroderma renal crisis) in progressive systemic sclerosis. Review of a 25-year experience with 68 cases |journal=Medicine (Baltimore) |volume=62 |issue=6 |pages=335–52 |date=November 1983 |pmid=6355755 |doi= |url=}}</ref><ref name="pmid22189167">{{cite journal |vauthors=Nikpour M, Hissaria P, Byron J, Sahhar J, Micallef M, Paspaliaris W, Roddy J, Nash P, Sturgess A, Proudman S, Stevens W |title=Prevalence, correlates and clinical usefulness of antibodies to RNA polymerase III in systemic sclerosis: a cross-sectional analysis of data from an Australian cohort |journal=Arthritis Res. Ther. |volume=13 |issue=6 |pages=R211 |date=2011 |pmid=22189167 |pmc=3334664 |doi=10.1186/ar3544 |url=}}</ref>
****[[Microalbuminuria]]
****Elevated plasma [[creatinine]]
****[[Hypertension]]
**[[Cardiovascular system]]<ref name="pmid2690346">{{cite journal |vauthors=Janosik DL, Osborn TG, Moore TL, Shah DG, Kenney RG, Zuckner J |title=Heart disease in systemic sclerosis |journal=Semin. Arthritis Rheum. |volume=19 |issue=3 |pages=191–200 |date=December 1989 |pmid=2690346 |doi= |url=}}</ref>
***[[Pericarditis]]<ref name="pmid9227172">{{cite journal |vauthors=Byers RJ, Marshall DA, Freemont AJ |title=Pericardial involvement in systemic sclerosis |journal=Ann. Rheum. Dis. |volume=56 |issue=6 |pages=393–4 |date=June 1997 |pmid=9227172 |pmc=1752384 |doi= |url=}}</ref>
***[[Pericardial effusion]]
***[[Myocardial]] [[fibrosis]]<ref name="pmid17968945">{{cite journal |vauthors=Tzelepis GE, Kelekis NL, Plastiras SC, Mitseas P, Economopoulos N, Kampolis C, Gialafos EJ, Moyssakis I, Moutsopoulos HM |title=Pattern and distribution of myocardial fibrosis in systemic sclerosis: a delayed enhanced magnetic resonance imaging study |journal=Arthritis Rheum. |volume=56 |issue=11 |pages=3827–36 |date=November 2007 |pmid=17968945 |doi=10.1002/art.22971 |url=}}</ref>
***[[Myocardial ischemia]] leading to [[myocardial infarction]]<ref name="pmid23945149">{{cite journal |vauthors=Nordin A, Jensen-Urstad K, Björnådal L, Pettersson S, Larsson A, Svenungsson E |title=Ischemic arterial events and atherosclerosis in patients with systemic sclerosis: a population-based case-control study |journal=Arthritis Res. Ther. |volume=15 |issue=4 |pages=R87 |date=August 2013 |pmid=23945149 |pmc=3979018 |doi=10.1186/ar4267 |url=}}</ref><ref name="pmid24157289">{{cite journal |vauthors=Chu SY, Chen YJ, Liu CJ, Tseng WC, Lin MW, Hwang CY, Chen CC, Lee DD, Chen TJ, Chang YT, Wang WJ, Liu HN |title=Increased risk of acute myocardial infarction in systemic sclerosis: a nationwide population-based study |journal=Am. J. Med. |volume=126 |issue=11 |pages=982–8 |date=November 2013 |pmid=24157289 |doi=10.1016/j.amjmed.2013.06.025 |url=}}</ref>
***[[Arrhythmia]]
****[[Ventricular arrhythmias]]
****Due to [[fibrosis]] of the [[myocardium]] and [[Conduction system disease|conduction system]]
 
==Genetics==
[[Genetics]] associated with the development of scleroderma include:<ref name="urlSystemic scleroderma - Genetics Home Reference,US national library of medicine">{{cite web |url=https://ghr.nlm.nih.gov/condition/systemic-scleroderma#sourcesforpage |title=Systemic scleroderma - Genetics Home Reference |format= |work= |accessdate=}}</ref>
*Scleroderma occurs in a sporadic pattern in the general population.
*Variations in [[Human leukocyte antigen|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:<ref name="pmid26210125">{{cite journal |vauthors=Pope JE, Johnson SR |title=New Classification Criteria for Systemic Sclerosis (Scleroderma) |journal=Rheum. Dis. Clin. North Am. |volume=41 |issue=3 |pages=383–98 |date=August 2015 |pmid=26210125 |doi=10.1016/j.rdc.2015.04.003 |url=}}</ref>
*Nephrogenic sclerosing fibrosis
*Scleroderma diabeticorum
*[[Scleromyxedema]]
*Erythromyalgia
*[[Porphyria]]
*Lichen sclerosis
*Diabetic cheiroarthropathy
*[[Primary biliary cirrhosis]]<ref name="pmid6384675">{{cite journal |vauthors=Powell FC, Winkelmann RK, Venencie-Lemarchand F, Spurbeck JL, Schroeter AL |title=The anticentromere antibody: disease specificity and clinical significance |journal=Mayo Clin. Proc. |volume=59 |issue=10 |pages=700–6 |date=October 1984 |pmid=6384675 |doi= |url=}}</ref>


A significant player in the process is [[transforming growth factor]] (TGFβ). This protein appears to be overproduced, and the fibroblast (possibly in response to other stimuli) also overexpresses the receptor for this mediator. An intracellular pathway (consisting of ''SMAD2/SMAD3'', ''SMAD4'' and the inhibitor ''SMAD7'') is responsible for the secondary messenger system that induces [[transcription (genetics)|transcription]] of the proteins and enzymes responsible for collagen deposition. ''Sp1'' is a [[transcription factor]] most closely studied in this context. Apart from TGFβ, connective tissue growth factor (CTGF) has a possible role.<ref name=JimenezDerk/>
*[[Systemic lupus erythematosus|Systemic lupus erythematosus (SLE)]]
*[[Rheumatoid arthritis]]
*[[Polymyositis]]
*[[Sjögren's syndrome]]
*[[Graft-versus-host disease]]<ref name="pmid9554859">{{cite journal |vauthors=Artlett CM, Smith JB, Jimenez SA |title=Identification of fetal DNA and cells in skin lesions from women with systemic sclerosis |journal=N. Engl. J. Med. |volume=338 |issue=17 |pages=1186–91 |date=April 1998 |pmid=9554859 |doi=10.1056/NEJM199804233381704 |url=}}</ref>
*[[Mixed connective tissue disease]]
*[[Malignancy]]<ref name="pmid29264402">{{cite journal |vauthors=Shah AA, Casciola-Rosen L |title=Mechanistic and clinical insights at the scleroderma-cancer interface |journal=J Scleroderma Relat Disord |volume=2 |issue=3 |pages=153–159 |date=2017 |pmid=29264402 |pmc=5734659 |doi=10.5301/jsrd.5000250 |url=}}</ref><ref name="pmid26352736">{{cite journal |vauthors=Shah AA, Casciola-Rosen L |title=Cancer and scleroderma: a paraneoplastic disease with implications for malignancy screening |journal=Curr Opin Rheumatol |volume=27 |issue=6 |pages=563–70 |date=November 2015 |pmid=26352736 |pmc=4643720 |doi=10.1097/BOR.0000000000000222 |url=}}</ref>


Damage to [[endothelium]] is an early abnormality in the development of scleroderma, and this too seems to be due to collagen accumulation by fibroblasts, although direct alterations by cytokines, [[platelet]] adhesion and a type II hypersensitivity reaction have similarly been implicated. Increased [[endothelin]] and decreased [[vasodilation]] has been documented.<ref name=JimenezDerk/>
==Gross Pathology==
*On gross pathology, [[sclerodactyly]], [[skin]] [[fibrosis]], [[edema]] and [[calcinosis]] are characteristic findings of scleroderma.<ref name="pmid23541012">{{cite journal |vauthors=Shah AA, Wigley FM |title=My approach to the treatment of scleroderma |journal=Mayo Clin. Proc. |volume=88 |issue=4 |pages=377–93 |date=April 2013 |pmid=23541012 |pmc=3666163 |doi=10.1016/j.mayocp.2013.01.018 |url=}}</ref><ref name="pmid6607734">{{cite journal |vauthors=Steen VD, Ziegler GL, Rodnan GP, Medsger TA |title=Clinical and laboratory associations of anticentromere antibody in patients with progressive systemic sclerosis |journal=Arthritis Rheum. |volume=27 |issue=2 |pages=125–31 |date=February 1984 |pmid=6607734 |doi= |url=}}</ref><ref name="pmid26210125">{{cite journal |vauthors=Pope JE, Johnson SR |title=New Classification Criteria for Systemic Sclerosis (Scleroderma) |journal=Rheum. Dis. Clin. North Am. |volume=41 |issue=3 |pages=383–98 |date=August 2015 |pmid=26210125 |doi=10.1016/j.rdc.2015.04.003 |url=}}</ref>


Jimenez & Derk<ref name=JimenezDerk/> describe three theories about the development of scleroderma:
==Microscopic Pathology==
* The abnormalities are primarily due to a physical agent, and all other changes are secondary or reactive to this direct insult.
*On microscopic [[Histopathology|histopathological]] analysis characteristic findings of scleroderma include:
* The initial event is fetomaternal cell transfer causing microchimerism, with a second summative cause (e.g. environmental) leading to the actual development of the disease.
**Microvascular damage<ref name="pmid1517881">{{cite journal |vauthors=Prescott RJ, Freemont AJ, Jones CJ, Hoyland J, Fielding P |title=Sequential dermal microvascular and perivascular changes in the development of scleroderma |journal=J. Pathol. |volume=166 |issue=3 |pages=255–63 |date=March 1992 |pmid=1517881 |doi=10.1002/path.1711660307 |url=}}</ref>
* Physical causes lead to phenotypic alterations in susceptible cells (e.g. due to genetic makeup), which then effectuate DNA changes which alter the cell's behavior.
***[[Arterioles]] are primarily affected
***[[Perivascular cell|Perivascular]] [[edema]]
***Large gaps between [[endothelial cells]]
***Loss of integrity of the [[endothelial]] lining
***[[Platelet aggregation]] in the [[vessels]]
***[[Vacuolization]] of the [[cytoplasm]] of [[endothelial cells]]
***[[Perivascular cell|Perivascular]] infiltrates of [[Mononuclear cell|mononuclear]] [[immune]] cells in the walls of [[arterioles]]<ref name="pmid7364973">{{cite journal |vauthors=Fleischmajer R, Perlish JS |title=Capillary alterations in scleroderma |journal=J. Am. Acad. Dermatol. |volume=2 |issue=2 |pages=161–70 |date=February 1980 |pmid=7364973 |doi= |url=}}</ref>
***Obliterative microvascular lesions
***[[Rarefaction]] of [[capillaries]]
***Small [[vessel]] [[effacement]]<ref name="pmid18197262">{{cite journal |vauthors=Fleming JN, Nash RA, McLeod DO, Fiorentino DF, Shulman HM, Connolly MK, Molitor JA, Henstorf G, Lafyatis R, Pritchard DK, Adams LD, Furst DE, Schwartz SM |title=Capillary regeneration in scleroderma: stem cell therapy reverses phenotype? |journal=PLoS ONE |volume=3 |issue=1 |pages=e1452 |date=January 2008 |pmid=18197262 |pmc=2175530 |doi=10.1371/journal.pone.0001452 |url=}}</ref>
**[[Fibrosis]]<ref name="pmid202203">{{cite journal |vauthors=Fleischmajer R, Perlish JS, West WP |title=Ultrastructure of cutaneous cellular infiltrates in scleroderma |journal=Arch Dermatol |volume=113 |issue=12 |pages=1661–6 |date=December 1977 |pmid=202203 |doi= |url=}}</ref>
***Densely packed [[collagen]] in the lower [[dermis]]
***Upper [[subcutaneous]] layer also affected
***Loss of [[reticular]] structure
***Accumulation of [[proteoglycans]], [[Fibrillarin|fibrillar]] and [[elastic fibers]]<ref name="pmid2046331">{{cite journal |vauthors=Fleischmajer R, Jacobs L, Schwartz E, Sakai LY |title=Extracellular microfibrils are increased in localized and systemic scleroderma skin |journal=Lab. Invest. |volume=64 |issue=6 |pages=791–8 |date=June 1991 |pmid=2046331 |doi= |url=}}</ref>
***Accumulation of [[type I collagen]]<ref name="pmid3335789">{{cite journal |vauthors=Perlish JS, Lemlich G, Fleischmajer R |title=Identification of collagen fibrils in scleroderma skin |journal=J. Invest. Dermatol. |volume=90 |issue=1 |pages=48–54 |date=January 1988 |pmid=3335789 |doi= |url=}}</ref>
**[[Atrophy]] and loss of [[cells]] in later stages


==References==
==References==
{{Reflist|2}}
{{Reflist|2}}
{{WH}}
{{WS}}
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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

Scleroderma is an autoimmune connective tissue disease. The hallmark of the underlying pathophysiology is production of autoantibodies against various cellular antigens, small vessel vasculopathy, fibrosis of skin and internal organs, and excess collagen deposition in the skin and internal organs. Circulating autoantibodies found in patients with scleroderma are anti-topoisomerase I (Scl-70) antibody, anti-centromere antibody, anti-RNA polymerase III antibody, anti-nucleolar antibody. Growth factors and cytokines play an important role in the underlying pathogenesis of scleroderma. Increased fibroblast activity leads to the excessive collagen deposition in scleroderma. Although the hallmark of this disease is skin fibrosis, internal organ involvement is a fatal complication and includes, esophageal dysmotility, interstitial lung disease, pulmonary arterial hypertension, scleroderma renal crisis, myocardial fibrosis, pericardial fibrosis and pericardial effusion. Although scleroderma occurs in a sporadic pattern in the general population, variations in the human leukocyte antigen (HLA) genes can predispose an individual to developing scleroderma. On gross pathology, sclerodactyly, skin fibrosis, edema and calcinosis are characteristic findings of scleroderma. On microscopic histopathological analysis, characteristic findings of scleroderma include microvascular damage, perivascular infiltrates of immune cells, loss of microvasculature, perivascular edema, fibrosis, densely packed collagen in the lower dermis and upper subcutaneous layer, atrophy, and loss of cells in the later stages of the disease.

Pathophysiology

Pathogenesis

Genetics

Genetics associated with the development of scleroderma include:[29]

Associated Conditions

Conditions that are associated with scleroderma include:[2]

Gross Pathology

Microscopic Pathology

References

  1. ↑ 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. ↑ 2.0 2.1 2.2 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.
  3. ↑ 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. ↑ 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.
  5. ↑ 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.
  6. ↑ 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.
  7. ↑ 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.
  8. ↑ 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.
  9. ↑ 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.
  10. ↑ 10.0 10.1 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.
  11. ↑ 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.
  12. ↑ 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.
  13. ↑ 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.
  14. ↑ LeRoy EC (October 1974). "Increased collagen synthesis by scleroderma skin fibroblasts in vitro: a possible defect in the regulation or activation of the scleroderma fibroblast". J. Clin. Invest. 54 (4): 880–9. doi:10.1172/JCI107827. PMC 301627. PMID 4430718.
  15. ↑ Eckes B, Mauch C, Hüppe G, Krieg T (April 1996). "Differential regulation of transcription and transcript stability of pro-alpha 1(I) collagen and fibronectin in activated fibroblasts derived from patients with systemic scleroderma". Biochem. J. 315 ( Pt 2): 549–54. PMC 1217231. PMID 8615828.
  16. ↑ Rajkumar VS, Howell K, Csiszar K, Denton CP, Black CM, Abraham DJ (2005). "Shared expression of phenotypic markers in systemic sclerosis indicates a convergence of pericytes and fibroblasts to a myofibroblast lineage in fibrosis". Arthritis Res. Ther. 7 (5): R1113–23. doi:10.1186/ar1790. PMC 1257439. PMID 16207328.
  17. ↑ Bellini A, Mattoli S (September 2007). "The role of the fibrocyte, a bone marrow-derived mesenchymal progenitor, in reactive and reparative fibroses". Lab. Invest. 87 (9): 858–70. doi:10.1038/labinvest.3700654. PMID 17607298.
  18. ↑ Turner R, Lipshutz W, Miller W, Rittenberg G, Schumacher HR, Cohen S (March 1973). "Esophageal dysfunction in collagen disease". Am. J. Med. Sci. 265 (3): 191–9. PMID 4701683.
  19. ↑ Marie I, Dominique S, Levesque H, Ducrotté P, Denis P, Hellot MF, Courtois H (August 2001). "Esophageal involvement and pulmonary manifestations in systemic sclerosis". Arthritis Rheum. 45 (4): 346–54. doi:10.1002/1529-0131(200108)45:4<346::AID-ART347>3.0.CO;2-L. PMID 11501722.
  20. ↑ HOSKINS LC, NORRIS HT, GOTTLIEB LS, ZAMCHECK N (September 1962). "Functional and morphologic alterations of the gastrointestinal tract in progressive systemic sclerosis (scleroderma)". Am. J. Med. 33: 459–70. PMID 14449181.
  21. ↑ Harrison NK, Myers AR, Corrin B, Soosay G, Dewar A, Black CM, Du Bois RM, Turner-Warwick M (September 1991). "Structural features of interstitial lung disease in systemic sclerosis". Am. Rev. Respir. Dis. 144 (3 Pt 1): 706–13. doi:10.1164/ajrccm/144.3_Pt_1.706. PMID 1892314.
  22. ↑ Traub YM, Shapiro AP, Rodnan GP, Medsger TA, McDonald RH, Steen VD, Osial TA, Tolchin SF (November 1983). "Hypertension and renal failure (scleroderma renal crisis) in progressive systemic sclerosis. Review of a 25-year experience with 68 cases". Medicine (Baltimore). 62 (6): 335–52. PMID 6355755.
  23. ↑ Nikpour M, Hissaria P, Byron J, Sahhar J, Micallef M, Paspaliaris W, Roddy J, Nash P, Sturgess A, Proudman S, Stevens W (2011). "Prevalence, correlates and clinical usefulness of antibodies to RNA polymerase III in systemic sclerosis: a cross-sectional analysis of data from an Australian cohort". Arthritis Res. Ther. 13 (6): R211. doi:10.1186/ar3544. PMC 3334664. PMID 22189167.
  24. ↑ Janosik DL, Osborn TG, Moore TL, Shah DG, Kenney RG, Zuckner J (December 1989). "Heart disease in systemic sclerosis". Semin. Arthritis Rheum. 19 (3): 191–200. PMID 2690346.
  25. ↑ Byers RJ, Marshall DA, Freemont AJ (June 1997). "Pericardial involvement in systemic sclerosis". Ann. Rheum. Dis. 56 (6): 393–4. PMC 1752384. PMID 9227172.
  26. ↑ Tzelepis GE, Kelekis NL, Plastiras SC, Mitseas P, Economopoulos N, Kampolis C, Gialafos EJ, Moyssakis I, Moutsopoulos HM (November 2007). "Pattern and distribution of myocardial fibrosis in systemic sclerosis: a delayed enhanced magnetic resonance imaging study". Arthritis Rheum. 56 (11): 3827–36. doi:10.1002/art.22971. PMID 17968945.
  27. ↑ Nordin A, Jensen-Urstad K, Björnådal L, Pettersson S, Larsson A, Svenungsson E (August 2013). "Ischemic arterial events and atherosclerosis in patients with systemic sclerosis: a population-based case-control study". Arthritis Res. Ther. 15 (4): R87. doi:10.1186/ar4267. PMC 3979018. PMID 23945149.
  28. ↑ Chu SY, Chen YJ, Liu CJ, Tseng WC, Lin MW, Hwang CY, Chen CC, Lee DD, Chen TJ, Chang YT, Wang WJ, Liu HN (November 2013). "Increased risk of acute myocardial infarction in systemic sclerosis: a nationwide population-based study". Am. J. Med. 126 (11): 982–8. doi:10.1016/j.amjmed.2013.06.025. PMID 24157289.
  29. ↑ "Systemic scleroderma - Genetics Home Reference".
  30. ↑ 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.
  31. ↑ 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.
  32. ↑ 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.
  33. ↑ Shah AA, Wigley FM (April 2013). "My approach to the treatment of scleroderma". Mayo Clin. Proc. 88 (4): 377–93. doi:10.1016/j.mayocp.2013.01.018. PMC 3666163. PMID 23541012.
  34. ↑ Steen VD, Ziegler GL, Rodnan GP, Medsger TA (February 1984). "Clinical and laboratory associations of anticentromere antibody in patients with progressive systemic sclerosis". Arthritis Rheum. 27 (2): 125–31. PMID 6607734.
  35. ↑ Prescott RJ, Freemont AJ, Jones CJ, Hoyland J, Fielding P (March 1992). "Sequential dermal microvascular and perivascular changes in the development of scleroderma". J. Pathol. 166 (3): 255–63. doi:10.1002/path.1711660307. PMID 1517881.
  36. ↑ Fleischmajer R, Perlish JS (February 1980). "Capillary alterations in scleroderma". J. Am. Acad. Dermatol. 2 (2): 161–70. PMID 7364973.
  37. ↑ Fleming JN, Nash RA, McLeod DO, Fiorentino DF, Shulman HM, Connolly MK, Molitor JA, Henstorf G, Lafyatis R, Pritchard DK, Adams LD, Furst DE, Schwartz SM (January 2008). "Capillary regeneration in scleroderma: stem cell therapy reverses phenotype?". PLoS ONE. 3 (1): e1452. doi:10.1371/journal.pone.0001452. PMC 2175530. PMID 18197262.
  38. ↑ Fleischmajer R, Perlish JS, West WP (December 1977). "Ultrastructure of cutaneous cellular infiltrates in scleroderma". Arch Dermatol. 113 (12): 1661–6. PMID 202203.
  39. ↑ Fleischmajer R, Jacobs L, Schwartz E, Sakai LY (June 1991). "Extracellular microfibrils are increased in localized and systemic scleroderma skin". Lab. Invest. 64 (6): 791–8. PMID 2046331.
  40. ↑ Perlish JS, Lemlich G, Fleischmajer R (January 1988). "Identification of collagen fibrils in scleroderma skin". J. Invest. Dermatol. 90 (1): 48–54. PMID 3335789.

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