Editing Systemic scleroderma

{{Short description|Accumulation of collagen in the skin and internal organs}}
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| name            = Systemic scleroderma
| synonyms        = Diffuse scleroderma, systemic sclerosis, Curzio's Syndrome
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| caption         = Patient with systemic scleroderma
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'''Systemic [[scleroderma]],''' or '''systemic sclerosis''', is an [[systemic autoimmune disease|autoimmune]] [[Rheumatology|rheumatic disease]] characterised by excessive production and accumulation of [[collagen]], called [[fibrosis]], in the skin and internal organs  and by injuries to small [[Artery|arteries]]. There are two major subgroups of  systemic sclerosis based on the extent of skin involvement: limited and diffuse. The limited form affects areas below, but not above, the elbows and knees with or without involvement of the face. The diffuse form also affects the skin above the elbows and knees and can also spread to the [[torso]]. [[Organ (anatomy)|Visceral organs]], including the [[kidney]]s, [[heart]], [[lung]]s, and [[Human gastrointestinal tract|gastrointestinal tract]] can also be affected by the fibrotic process.
Prognosis is determined by the form of the disease and the extent of visceral involvement. Patients with limited systemic sclerosis have a better prognosis than those with the diffuse form. Death is most often caused by lung, heart, and kidney involvement. The risk of [[cancer]] is increased slightly.<ref>{{cite journal|date=July 2013|title=Cancer incidence in systemic sclerosis: meta-analysis of population-based cohort studies|journal=Arthritis Rheum.|volume=65|issue=7|pages=1913–21|doi=10.1002/art.37969|pmid=23576072|vauthors=Onishi A, Sugiyama D, Kumagai S, Morinobu A|doi-access=free}}</ref>

Survival rates have greatly increased with effective treatment for [[kidney failure]]. Therapies include [[immunosuppressive drug]]s, and in some cases, [[glucocorticoid]]s.<ref name="Harrison's">{{cite book|editor1=Longo, Dan L. |editor2=Kasper, Dennis L |editor3=Fauci, Anthony |editor4=Hauser, Stephen L.|title=Harrison's Principles of Internal Medicine |edition=16th |publisher=McGraw-Hill|location=New York|date=July 2011 |orig-date=2005|isbn=978-0-07-174889-6|display-editors=etal}}</ref>

==Signs and symptoms==
[[Calcinosis|'''C'''alcinosis]], [[Raynaud's phenomenon|'''R'''aynaud's phenomenon]], [[Esophagus|'''E'''sophageal dysfunction]], [[Sclerodactyly|'''S'''clerodactyly]], and [[Telangiectasia|'''T'''elangiectasia]] ([[CREST syndrome]]) are associated with limited scleroderma. Other symptoms include:

===Skin symptoms===
[[File:Systemic sclerosis finger.jpg|thumb|Clinical appearance of acrosclerotic piece-meal [[necrosis]] of the thumb in a patient with systemic sclerosis.]]
[[File:Riehl Zumbusch Tafel LXVIII (1).jpg|thumb|Systemic scleroderma in the limbs, showing [[carcinoma]] subsequent to ulceration]]
In the skin, systemic sclerosis causes hardening and scarring. The skin may appear tight, reddish, or scaly. Blood vessels may also be more visible. Where large areas are affected, fat and muscle wastage may weaken limbs and affect appearance. Patients report severe and recurrent [[itch]]ing of large skin areas. The severity of these symptoms varies greatly among patients: Some having scleroderma of only a limited area of the skin (such as the fingers) and little involvement of the underlying tissue, while others have progressive skin involvement.<ref>{{cite journal |vauthors=Hinchcliff M, Varga J |title=Systemic sclerosis/scleroderma: a treatable multisystem disease |journal=Am Fam Physician |volume=78 |issue=8 |pages=961–8 |date=October 2008 |pmid=18953973 }}</ref>  Digital ulcers—open wounds especially on fingertips and less commonly the knuckles—are not uncommon.<ref>{{cite journal|last1=Abraham|first1=S|last2=Steen|first2=V|title=Optimal management of digital ulcers in systemic sclerosis|journal=Therapeutics and Clinical Risk Management|date=2015|volume=11|pages=939–47|doi=10.2147/TCRM.S82561|pmid=26109864|pmc=4474386|doi-access=free}}</ref>

===Other organs===
Diffuse scleroderma can cause [[musculoskeletal system|musculoskeletal]], pulmonary, gastrointestinal, renal, and other complications.<ref name=Primer>{{cite book |author=Klippel, John H. |title=Primer On the Rheumatic Diseases 11ED |year=2020 |publisher=Arthritis Foundation |location=Atlanta, GA |isbn=978-1-912423-16-3}}</ref> Patients with greater cutaneous involvement are more likely to have involvement of the internal tissues and organs. Most patients (over 80%) have vascular symptoms and Raynaud's phenomenon, which leads to attacks of discoloration of the hands and feet in response to cold. Raynaud's normally affects the fingers and toes. Systemic scleroderma and Raynaud's can cause painful ulcers on the fingers or toes, which are known as digital ulcers. Calcinosis (deposition of calcium in lumps under the skin) is also common in systemic scleroderma, and is often seen near the elbows, knees, or other [[joints]].<ref>{{cite web |title=Limited Scleroderma |url=https://www.mayoclinic.org/diseases-conditions/crest-syndrome/symptoms-causes/syc-20355535 |website=www.mayoclinic.org |publisher=Mayo Clinic |access-date=6 June 2019}}</ref>

;Musculoskeletal
The first joint symptoms that patients with scleroderma have are typically nonspecific [[arthralgia|joint pains]], which can lead to [[arthritis]], or cause discomfort in [[tenosynovitis|tendons]] or [[myalgia|muscles]].<ref name=Primer/>  Joint mobility, especially of the small joints of the hand, may be restricted by calcinosis or skin thickening.<ref>{{cite journal |vauthors=Valentini G, Black C |title=Systemic sclerosis |journal=Best Practice & Research. Clinical Rheumatology |volume=16 |issue=5 |pages=807–16 |year=2002 |pmid=12473275| doi = 10.1053/berh.2002.0258}}</ref>  Patients may develop muscle weakness, or [[myopathy]], either from the disease or its treatments.<ref>{{cite journal |vauthors=Olsen NJ, King LE, Park JH |title=Muscle abnormalities in scleroderma |journal=Rheum. Dis. Clin. North Am. |volume=22 |issue=4 |pages=783–96 |year=1996 |pmid=8923596| doi = 10.1016/S0889-857X(05)70301-X}}</ref>

;Lungs
Some impairment in lung function is almost universally seen in patients with diffuse scleroderma on [[pulmonary function test]]ing,<ref>{{cite journal |author=Steen VD |title=The lung in systemic sclerosis |journal=Journal of Clinical Rheumatology |volume=11 |issue=1 |pages=40–6 |year=2005 |pmid=16357695 |doi=10.1097/01.rhu.0000152147.38706.db}}</ref> but it does not necessarily cause symptoms, such as shortness of breath.  Some patients can develop [[pulmonary hypertension]], or elevation in the pressures of the [[pulmonary arteries]]. This can be progressive, and can lead to right-sided [[heart failure]]. The earliest manifestation of this may be a decreased [[diffusion capacity]] on pulmonary function testing.{{citation needed|date=October 2020}} Other pulmonary complications in more advanced disease include [[aspiration pneumonia]], [[pulmonary hemorrhage]] and [[pneumothorax]].<ref name=Primer/>

;Digestive tract
[[Image:Peptic stricture.png|right|thumb|200px|[[Gastroscopy|Endoscopic]] image of peptic stricture, or narrowing of the [[esophagus]] near the junction with the [[stomach]] due to chronic [[gastroesophageal reflux]]: This is the most common cause of [[dysphagia]], or difficulty swallowing, in scleroderma.]]
Diffuse scleroderma can affect any part of the gastrointestinal tract.<ref name=Sallam>{{cite journal |vauthors=Sallam H, McNearney TA, Chen JD |title=Systematic review: pathophysiology and management of gastrointestinal dysmotility in systemic sclerosis (scleroderma) |journal=Aliment. Pharmacol. Ther. |volume=23 |issue=6 |pages=691–712 |year=2006 |pmid=16556171 |doi=10.1111/j.1365-2036.2006.02804.x|s2cid=46188776 |doi-access=free }}</ref>  The most common manifestation in the esophagus is reflux [[esophagitis]], which may be complicated by [[esophageal stricture]]s or benign narrowing of the esophagus.<ref name=Rose>{{cite journal |vauthors=Rose S, Young MA, Reynolds JC |title=Gastrointestinal manifestations of scleroderma |journal=Gastroenterol. Clin. North Am. |volume=27 |issue=3 |pages=563–94 |year=1998 |pmid=9891698 | doi = 10.1016/S0889-8553(05)70021-2}}</ref>  This is best initially treated with [[proton pump inhibitor]]s for acid suppression,<ref>{{cite journal |vauthors=Hendel L, Hage E, Hendel J, Stentoft P |title=Omeprazole in the long-term treatment of severe gastro-oesophageal reflux disease in patients with systemic sclerosis |journal=Aliment. Pharmacol. Ther. |volume=6 |issue=5 |pages=565–77 |year=1992 |pmid=1420748 |doi=10.1111/j.1365-2036.1992.tb00571.x|s2cid=31418099 }}</ref> but may require [[esophageal dilatation|bougie dilatation]] in the case of stricture.<ref name=Sallam/>

Scleroderma can decrease [[motility]] anywhere in the gastrointestinal tract.<ref name=Sallam/> The most common source of decreased motility is the esophagus and the lower esophageal sphincter, leading to dysphagia and chest pain. As scleroderma progresses, esophageal involvement from abnormalities in decreased motility may worsen due to progressive fibrosis (scarring). If this is left untreated, acid from the stomach can back up into the esophagus, causing esophagitis and [[gastroesophageal reflux disease]]. Further scarring from acid damage to the lower esophagus many times leads to the development of fibrotic narrowing, also known as strictures, which can be treated by dilatation{{citation needed|date=December 2020}}.

In patients with neuromuscular disorders, particularly progressive systemic sclerosis and visceral myopathy, the [[duodenum]] is frequently involved.<ref>{{Cite journal |last=Tandaipan |first=Jose Luis |last2=Castellví |first2=Ivan |date=April 2020 |title=Systemic sclerosis and gastrointestinal involvement |url=https://linkinghub.elsevier.com/retrieve/pii/S2444440520300017 |journal=Revista Colombiana de Reumatología (English Edition) |language=en |volume=27 |pages=44–54 |doi=10.1016/j.rcreue.2019.12.003|url-access=subscription }}</ref> Dilatation may occur, which is often more pronounced in the second, third, and fourth parts. The dilated duodenum may be slow to empty, and the grossly dilated, atonic organ may produce a sump effect.{{citation needed|date=December 2020}}

The [[small intestine]] can also become involved, leading to [[bacterial overgrowth]] and [[malabsorption]] of [[bile salts]], [[fat]]s, [[carbohydrate]]s, [[protein]]s, and [[vitamin]]s. The [[colon (anatomy)|colon]] can be involved, and can cause [[Ogilvie's syndrome|pseudo-obstruction]] or [[ischemic colitis]].<ref name=Primer/>

Rarer complications include [[pneumatosis cystoides intestinalis]], or gas pockets in the bowel wall, [[diverticulosis|wide-mouthed diverticula]] in the colon and esophagus, and [[cirrhosis|liver fibrosis]].  Patients with severe gastrointestinal involvement can become profoundly [[malnutrition|malnourished]].<ref name=Rose/>

Scleroderma may also be associated with [[gastric antral vascular ectasia]], also known as "watermelon stomach". This is a condition in which atypical blood vessels proliferate, usually in a radially symmetric pattern around the [[pylorus]] of the stomach. It can be a cause of [[upper gastrointestinal bleeding]] or [[iron deficiency anemia|iron-deficiency anemia]] in patients with scleroderma.<ref name=Rose/>

;Kidneys
[[Image:Thrombotic microangiopathy - very high mag.jpg|thumb|[[Micrograph]] showing [[thrombotic microangiopathy]], the [[histomorphology|histomorphologic]] finding seen in scleroderma renal crisis, [[kidney biopsy]], [[PAS stain]]]]
Kidney involvement, in scleroderma, is considered a poor prognostic factor and frequently a cause of death.<ref>{{cite journal |vauthors=Ruangjutipopan S, Kasitanon N, Louthrenoo W, Sukitawut W, Wichainun R |title=Causes of death and poor survival prognostic factors in thai patients with systemic sclerosis |journal=Journal of the Medical Association of Thailand |volume=85 |issue=11 |pages=1204–9 |year=2002 |pmid=12546318 }}</ref>

The most important clinical complication of scleroderma involving the kidney is scleroderma renal crisis (SRC), the  symptoms of which are [[malignant hypertension]] (high blood pressure with evidence of acute organ damage), [[Renin|hyperreninemia]] (high renin levels), [[azotemia]] (kidney failure with accumulation of waste products in the blood), and [[microangiopathic hemolytic anemia]] (destruction of red blood cells).<ref>{{cite journal |vauthors=Steen VD, Mayes MD, Merkel PA |title=Assessment of kidney involvement |journal=Clin. Exp. Rheumatol. |volume=21 |issue=3 Suppl 29 |pages=S29–31 |year=2003 |pmid=12889219 }}</ref> Apart from the high blood pressure, [[hematuria]] (blood in the urine) and [[proteinuria]] (protein loss in the urine) may be indicative of SRC.<ref>{{cite journal |author=Steen VD |title=Renal involvement in systemic sclerosis |journal=Clin. Dermatol. |volume=12 |issue=2 |pages=253–8 |year=1994 |pmid=8076263 | doi = 10.1016/S0738-081X(94)90329-8|s2cid=906790 }}</ref>

In the past, SRC was almost uniformly fatal.<ref name=steen>{{cite journal |author=Steen VD |title=Scleroderma renal crisis |journal=Rheum. Dis. Clin. North Am. |volume=29 |issue=2 |pages=315–33 |year=2003 |pmid=12841297| doi = 10.1016/S0889-857X(03)00016-4}}</ref> While outcomes have improved significantly with the use of [[ACE inhibitors]],<ref>{{cite journal |vauthors=Rhew EY, Barr WG |title=Scleroderma renal crisis: new insights and developments |journal=Current Rheumatology Reports |volume=6 |issue=2 |pages=129–36 |year=2004 |pmid=15016343| doi = 10.1007/s11926-004-0057-5|s2cid=37453739 }}</ref><ref name="steen11033587">{{cite journal|year=2000|title=Long-term outcomes of scleroderma renal crisis|url=http://aramis.stanford.edu/downloads/2000SteenAIM600.pdf|journal=Ann. Intern. Med.|volume=133|issue=8|pages=600–3|doi=10.7326/0003-4819-133-8-200010170-00010|pmid=11033587|archive-url=https://web.archive.org/web/20150619184802/http://aramis.stanford.edu/downloads/2000SteenAIM600.pdf|archive-date=19 June 2015|vauthors=Steen VD, Medsger TA|citeseerx=10.1.1.494.6389|s2cid=29564540}}</ref> the prognosis is often guarded, as a significant number of patients are refractory to treatment and develop [[kidney failure]]. About 7–9% of all diffuse cutaneous scleroderma patients develop renal crisis at some point in the course of their disease.<ref>{{Cite journal|last1=Turk|first1=Matthew|last2=Pope|first2=Janet E.|date=July 2016|title=The Frequency of Scleroderma Renal Crisis over Time: A Metaanalysis|journal=The Journal of Rheumatology|volume=43|issue=7|pages=1350–1355|doi=10.3899/jrheum.151353|issn=0315-162X|pmid=27134252|s2cid=23093684}}</ref><ref name="Denton">{{cite journal |vauthors=Denton C, Lapadula G, Mouthon L, Müller-Ladner U | year = 2009 | title = Renal complications and scleroderma renal crisis | journal = Rheumatology | volume = 48 | pages = 32–35 | doi = 10.1093/rheumatology/ken483 | pmid = 19487221 | doi-access = free }}</ref> Patients who have rapid skin involvement have the highest risk of renal complications.<ref name=jimenez>Jimenez S, Koenig AS. [http://www.emedicine.com/MED/topic2076.htm Scleroderma]. eMedicine.com. Accessed: May 22, 2006.</ref> It is most common in diffuse cutaneous scleroderma, and is often associated with antibodies against [[RNA polymerase]] (in 59% of cases). Many proceed to dialysis, although this can be stopped within three years in about a third of cases. Higher age and (paradoxically) a lower blood pressure at presentation make  dialysis more likely to be needed.<ref>{{cite journal  |vauthors=Penn H, Howie AJ, Kingdon EJ, etal |title=Scleroderma renal crisis: patient characteristics and long-term outcomes |journal=QJM |volume=100 |issue=8 |pages=485–94 |date=August 2007 |pmid=17601770 |doi=10.1093/qjmed/hcm052 |url=http://qjmed.oxfordjournals.org/cgi/content/full/100/8/485|doi-access=free }}</ref>

Treatments for SRC include ACE inhibitors. Prophylactic use of ACE inhibitors is currently not recommended, as recent data suggest a poorer prognosis in patient treated with these drugs prior to the development of renal crisis.<ref>{{cite journal|last1=Hudson|first1=M|last2=Baron|first2=M|last3=Tatibouet|first3=S|last4=Furst|first4=DE|last5=Khanna|first5=D|last6=International Scleroderma Renal Crisis Study|first6=Investigators|title=Exposure to ACE inhibitors prior to the onset of scleroderma renal crisis-results from the International Scleroderma Renal Crisis Survey|journal=Seminars in Arthritis and Rheumatism|date=April 2014|volume=43|issue=5|pages=666–72|doi=10.1016/j.semarthrit.2013.09.008|pmid=24176729}}</ref>{{MEDRS|date=November 2014}} Transplanted kidneys are known to be affected by scleroderma, and patients with early-onset renal disease (within one year of the scleroderma diagnosis) are thought to have the highest risk for recurrence.<ref>{{cite journal  |vauthors=Pham PT, Pham PC, Danovitch GM, etal |title=Predictors and risk factors for recurrent scleroderma renal crisis in the kidney allograft: case report and review of the literature |journal=Am. J. Transplant. |volume=5 |issue=10 |pages=2565–9 |date=October 2005 |pmid=16162209 |doi=10.1111/j.1600-6143.2005.01035.x |s2cid=36783555 |doi-access=free }}</ref>

==Causes==
No clear cause for scleroderma and systemic sclerosis has been identified. Genetic predisposition appears to be limited, as genetic concordance is small; still, a familial predisposition for autoimmune disease is often seen. Polymorphisms in ''[[COL1A2]]'' and ''[[TGF beta 1|TGF-β1]]'' may influence severity and development of the disease. Evidence implicating [[cytomegalovirus]] (CMV) as the original epitope of the immune reaction is limited, as is parvovirus B19.<ref>{{cite journal |pmid=10609071 | volume=17 | issue=6 | title=Parvovirus B19 infection of bone marrow in systemic sclerosis patients | year=1999 | journal=Clin. Exp. Rheumatol. | pages=718–20 |vauthors=Ferri C, Zakrzewska K, Longombardo G, Giuggioli D, Storino FA, Pasero G, Azzi A }}</ref> [[Organic solvent]]s and other chemical agents have been linked with scleroderma.<ref name=JimenezDerk/>

One of the suspected mechanisms behind the autoimmune phenomenon is the existence of [[microchimerism]], i.e. fetal cells circulating in maternal blood, triggering an immune reaction to what is perceived as foreign material.<ref name=JimenezDerk/><ref name=Bianchi>{{cite journal |author=Bianchi DW |title=Fetomaternal cell trafficking: a new cause of disease? |journal=Am. J. Med. Genet. |volume=91 |issue=1 |pages=22–8 |year=2000 |pmid=10751084| doi = 10.1002/(SICI)1096-8628(20000306)91:1<22::AID-AJMG4>3.0.CO;2-3|citeseerx=10.1.1.605.5548 }}</ref>

A distinct form of scleroderma and systemic sclerosis may develop in patients with [[chronic kidney failure]]. This form, [[nephrogenic fibrosing dermopathy]] or nephrogenic systemic fibrosis,<ref name="pmid20299369">{{cite journal |vauthors=Abdel-Kader K, Patel PR, Kallen AJ, Sinkowitz-Cochran RL, Bolton WK, Unruh ML |title=Nephrogenic Systemic Fibrosis: A Survey of Nephrologists' Perceptions and Practices |journal=Clin J Am Soc Nephrol |volume= 5|issue= 6|pages= 964–71|date=March 2010 |pmid=20299369 |pmc=2879309 |doi=10.2215/CJN.00140110 |url=http://cjasn.asnjournals.org/cgi/pmidlookup?view=long&pmid=20299369}}</ref><ref name="pmid20120045">{{cite journal |title=[Nephrogenic systemic fibrosis or kidney failure--how great is the risk?] |language=de |journal=Rofo |volume=182 |issue=2 |pages=114–5 |date=February 2010 |pmid=20120045 }}</ref><ref name="pmid20118047">{{cite journal |vauthors=Panos A, Milas F, Kalakonas S, Myers PO |title=Cardiac autotransplantation for aortic and mitral valve replacement in a patient with nephrogenic systemic fibrosis |journal=Hellenic J Cardiol |volume=51 |issue=1 |pages=64–6 |year=2010 |pmid=20118047 |url=http://www.hellenicjcardiol.org/archive/full_text/2010/1/2010_1_64.pdf}}</ref><ref name="pmid20063400">{{cite journal |vauthors=Fine DM, Perazella MA |title=Nephrogenic systemic fibrosis: what the hospitalist needs to know |journal=J Hosp Med |volume=5 |issue=1 |pages=46–50 |date=January 2010 |pmid=20063400 |doi=10.1002/jhm.493}}</ref> has been linked to exposure to [[gadolinium]]-containing [[radiocontrast]].<ref>{{cite journal |vauthors=Boyd AS, Zic JA, Abraham JL |title=Gadolinium deposition in nephrogenic fibrosing dermopathy |journal=J. Am. Acad. Dermatol. |volume=56 |issue=1 |pages=27–30 |year=2007 |pmid=17109993 |doi=10.1016/j.jaad.2006.10.048}}</ref>

[[Bleomycin]]<ref>{{cite journal  |vauthors=Sharma SK, Handa R, Sood R, etal |title=Bleomycin-induced scleroderma |journal=The Journal of the Association of Physicians of India |volume=52 |pages=76–7 |year=2004 |pmid=15633728 }}</ref> (a chemotherapeutic agent) and possibly [[taxane]] chemotherapy<ref>{{cite journal |vauthors=Farrant PB, Mortimer PS, Gore M |title=Scleroderma and the taxanes. Is there really a link? |journal=Clin. Exp. Dermatol. |volume=29 |issue=4 |pages=360–2 |year=2004 |pmid=15245529 |doi=10.1111/j.1365-2230.2004.01519.x|s2cid=11105198 }}</ref> may cause scleroderma, and occupational exposure to [[solvent]]s has been linked to an increased risk of systemic sclerosis.<ref>{{cite journal  |vauthors=Kettaneh A, Al Moufti O, Tiev KP, etal |title=Occupational exposure to solvents and gender-related risk of systemic sclerosis: a metaanalysis of case-control studies |journal=J. Rheumatol. |volume=34 |issue=1 |pages=97–103 |year=2007 |pmid=17117485 }}</ref>

==Pathophysiology==
Overproduction of collagen is thought to result from an autoimmune dysfunction, in which the immune system starts 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/>
[[File:NIH 3T3.jpg|thumb|Fibroblasts]]
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/> Indeed, a common ''CTGF'' gene polymorphism is present at an increased level in systemic sclerosis.<ref>{{cite journal  |vauthors=Fonseca C, Lindahl GE, Ponticos M, etal |title=A polymorphism in the CTGF promoter region associated with systemic sclerosis |journal=N. Engl. J. Med. |volume=357 |issue=12 |pages=1210–20 |date=September 2007 |pmid=17881752 |doi=10.1056/NEJMoa067655 |s2cid=7042371 |doi-access=free }}</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  similarly have been implicated. Increased [[endothelin]] and decreased [[vasodilation]] have been documented.<ref name=JimenezDerk/>

Jimenez and Derk<ref name=JimenezDerk/> describe three theories about the development of scleroderma:
* The abnormalities are primarily due to a physical agent, and all other changes are secondary or reactive to this direct insult.
* 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.
* Physical causes lead to phenotypic alterations in susceptible cells (e.g. due to genetic makeup), which then effectuate DNA changes that alter the cells' behavior.

==Diagnosis==
In 1980, the [[American College of Rheumatology]] agreed on diagnostic criteria for scleroderma.<ref>{{cite journal|year=1980|title=Preliminary criteria for the classification of systemic sclerosis (scleroderma). Subcommittee for scleroderma criteria of the American Rheumatism Association Diagnostic and Therapeutic Criteria Committee|journal=Arthritis Rheum.|volume=23|issue=5|pages=581–90|doi=10.1002/art.1780230510|pmid=7378088|author=Masi AT }} Available online at {{cite web|url=http://www.rheumatology.org/publications/classification/systsclr.asp|title=1980 Criteria for the Classification of Systemic Sclerosis|access-date=2007-08-05|archive-date=2007-10-15|archive-url=https://web.archive.org/web/20071015132731/http://rheumatology.org/publications/classification/systsclr.asp}}</ref>

Diagnosis is by clinical suspicion, presence of autoantibodies (specifically [[anti-centromere antibodies|anticentromere]] and anti-scl70/[[antitopoisomerase antibodies]]), and occasionally by biopsy. Of the antibodies, 90% have a detectable [[antinuclear antibody]]. Anticentromere antibody is more common in the limited form (80–90%) than in the diffuse form (10%), and anti-scl70 is more common in the diffuse form (30–40%) and in African-American patients (who are more susceptible to the systemic form).<ref name="JimenezDerk">{{cite journal |vauthors=Jimenez SA, Derk CT |title=Following the molecular pathways toward an understanding of the pathogenesis of systemic sclerosis |journal=Ann. Intern. Med. |volume=140 |issue=1 |pages=37–50 |year=2004 |pmid=14706971 |doi=10.7326/0003-4819-140-2-200401200-00013}}</ref>

Other conditions may mimic systemic sclerosis by causing hardening of the skin. Diagnostic hints that another disorder is responsible include the absence of Raynaud's phenomenon, a lack of abnormalities in the skin on the hands, a lack of internal organ involvement, and a normal antinuclear antibodies test result.<ref>{{cite journal |vauthors=Moenning R, Grau RG |title=Skin hardening, but is it systemic sclerosis? |journal=The Journal of Musculoskeletal Medicine |date=March 30, 2009 |url=http://jmm.consultantlive.com/display/article/1145622/1391088 |access-date=August 27, 2009 |archive-date=May 5, 2009 |archive-url=https://web.archive.org/web/20090505132903/http://jmm.consultantlive.com/display/article/1145622/1391088 }}</ref>

== Treatment ==
No cure for scleroderma is known, though treatments exist for some of the symptoms, including drugs that soften the skin and reduce inflammation. Some patients may benefit from exposure to heat.<ref>{{cite journal |vauthors=Oliver GF, Winkelmann RK |title=The current treatment of scleroderma |journal=Drugs |volume=37 |issue=1 |pages=87–96 |year=1989 |pmid=2651089 |doi=10.2165/00003495-198937010-00006|s2cid=25010323 }}</ref>  Holistic care of patients comprising patient education tailored to patients' education level is useful in view of the complex nature of the disease symptoms and progress.<ref>{{cite book |author1=Philip J. Clements |author2=Daniel E. Furst |title=Systemic Sclerosis, 2nd ed., Chapt. 23 |url=http://www.hopkinsscleroderma.org/downloads/SystemicSclerosis_Chapter23.pdf}}</ref>

===Topical/symptomatic===
Topical treatment for the skin changes of scleroderma do not alter the disease course, but may improve pain and ulceration. A range of [[NSAID|nonsteroidal anti-inflammatory drugs]], such as [[naproxen]], can be used to ease painful symptoms.{{Citation needed|date=May 2008}} The benefit from [[glucocorticoid|steroids]] such as prednisone is limited.{{Citation needed|date=May 2008}} Episodes of Raynaud's phenomenon sometimes respond to [[nifedipine]] or other calcium channel blockers; severe digital ulceration may respond to [[prostacyclin]] analogue [[iloprost]], and the dual endothelin-receptor antagonist [[bosentan]] may be beneficial for Raynaud's phenomenon.<ref name=Zandberg>{{cite journal |vauthors=Zandman-Goddard G, Tweezer-Zaks N, Shoenfeld Y |title=New therapeutic strategies for systemic sclerosis--a critical analysis of the literature |journal=Clin. Dev. Immunol. |volume=12 |issue=3 |pages=165–73 |year=2005 |pmid=16295521 |doi=10.1080/17402520500233437 |pmc=2275417}}</ref> Skin tightness may be treated systemically with [[methotrexate]] and [[ciclosporin]].<ref name=Zandberg/> and the skin  thickness can be treated with penicillamine.

===Kidney disease===
Scleroderma renal crisis (SRC) is a life-threatening complication of systemic sclerosis that may be the initial manifestation of the disease.  Renal vascular injury (due in part to collagen deposition) leads to renal ischemia, which results in activation of the renin-angiotensin-aldosterone system (RAAS).  This raises blood pressure and further damages the renal vasculature, causing a vicious cycle of worsening hypertension and renal dysfunction (e.g., elevated creatinine, edema).  Hypertensive emergency with end-organ dysfunction (e.g., encephalopathy, retinal hemorrhage) is common.  Thrombocytopenia and microangiopathic hemolytic anemia can be seen.  Urinalysis is usually normal but may show mild proteinuria, as in this patient; casts are unexpected.{{citation needed|date=September 2021}}

The mainstay of therapy for SRC includes ACE inhibitors, which reduce RAAS activity and improve renal function and blood pressure.  Short-acting ACE inhibitors (typically captopril) are used because they can be rapidly uptitrated.  An elevated serum creatinine level is not a contraindication for ACE inhibitors in this population, and slight elevations in creatinine are common during drug initiation.

Scleroderma renal crisis, the occurrence of [[acute kidney injury]], and [[malignant hypertension]] (very high blood pressure with evidence of organ damage) in people with scleroderma are effectively treated with drugs from the class of the ACE inhibitors. The benefit of ACE inhibitors extends even to those who have to commence [[hemodialysis|dialysis]] to treat their kidney disease, and may give sufficient benefit to allow the discontinuation of renal replacement therapy.<ref name=Zandberg/>

===Lung disease===
Active alveolitis is often treated with pulses of [[cyclophosphamide]], often together with a small dose of steroids. The benefit of this intervention is modest.<ref>{{cite journal  |vauthors=Tashkin DP, Elashoff R, Clements PJ, etal |title=Cyclophosphamide versus placebo in scleroderma lung disease |journal=N. Engl. J. Med. |volume=354 |issue=25 |pages=2655–66 |date=June 2006 |pmid=16790698 |doi=10.1056/NEJMoa055120 |doi-access=free }}</ref><ref>{{cite journal  |vauthors=Hoyles RK, Ellis RW, Wellsbury J, etal |title=A multicenter, prospective, randomized, double-blind, placebo-controlled trial of corticosteroids and intravenous cyclophosphamide followed by oral azathioprine for the treatment of pulmonary fibrosis in scleroderma |journal=Arthritis Rheum. |volume=54 |issue=12 |pages=3962–70 |date=December 2006 |pmid=17133610 |doi=10.1002/art.22204 |doi-access=free }}</ref>

Pulmonary hypertension may be treated with [[epoprostenol]], [[treprostinil]], [[bosentan]], and possibly aerolized iloprost.<ref name=Zandberg/> [[Nintedanib]] was approved for use in the United States [[Food and Drug Administration]] on September 6, 2019, to slow the rate of decline in pulmonary function in patients with systemic sclerosis-associated [[interstitial lung disease]] (SSc-ILD).<ref>{{Cite web|url=http://www.fda.gov/news-events/press-announcements/fda-approves-first-treatment-patients-rare-type-lung-disease|archive-url=https://web.archive.org/web/20190906201437/https://www.fda.gov/news-events/press-announcements/fda-approves-first-treatment-patients-rare-type-lung-disease|url-status=dead|archive-date=September 6, 2019|title=FDA approves first treatment for patients with rare type of lung disease|last=Commissioner|first=Office of the|date=2020-02-20|website=FDA|language=en|access-date=2020-02-25}}</ref><ref>{{Cite web |title=FDA approves Ofev® as the first and only therapy in the U.S. to slow the rate of decline in pulmonary function in patients with systemic sclerosis-associated ILD |url=https://www.boehringer-ingelheim.com/press-release/fda-approves-nintedanib-ssc-ild |access-date=2022-11-30 |website=www.boehringer-ingelheim.com}}</ref>

===Other===
Some evidence indicates that [[plasmapheresis]] (therapeutic plasma exchange) can be used to treat the systemic form of scleroderma. In Italy, it is a government-approved treatment option. This is done by replacing [[blood plasma]] with a fluid consisting of [[albumin]], and is thought to keep the disease at bay by reducing the circulation of scleroderma autoantibodies.<ref>{{cite journal|title=Therapeutic plasma exchange for the treatment of systemic sclerosis: A comprehensive review and analysis|doi=10.1177/2397198318758606|year=2018|last1=Harris|last2=Meiselman|last3=Moriarty|last4=Metzger|last5=Malkovsky|first1=Edward|first2=Herbert|first3=Patrick|first4=Allan|first5=Miroslav|journal=Journal of Scleroderma and Related Disorders|volume=3|issue=2|pages=132–152|pmid=35382237 |pmc=8892860 |s2cid=79950781|doi-access=free}}</ref>

== Epidemiology ==
Systemic scleroderma is a [[rare disease]], with an annual incidence that varies in different populations. Estimates of incidence (new cases per million people) range from 3.7 to 43 in the United Kingdom and Europe, 7.2 in Japan, 10.9 in Taiwan, 12.0 to 22.8 in Australia, 13.9 to 21.0 in the United States, and 21.2 in Buenos Aires.<ref name=Barnes>{{cite journal |last1=Barnes |first1=Jammie |last2=Mayes |first2=Maureen D. |title=Epidemiology of systemic sclerosis |journal=Current Opinion in Rheumatology |date=March 2012 |volume=24 |issue=2 |pages=165–170 |doi=10.1097/BOR.0b013e32834ff2e8|pmid=22269658 |s2cid=24050211 }}</ref> The interval of peak onset starts at age 30<ref name=uptodate>[https://www.uptodate.com/contents/systemic-sclerosis-scleroderma-and-pregnancy Systemic sclerosis (scleroderma) and pregnancy] By Bonnie L Bermas, MD. Retrieved on Dec 13, 2009</ref> and ends at age 50.<ref name=uptodate/>

Globally, estimates of prevalence vary from 31.0 to 658.6 affected people per million.<ref name=Barnes/> Systemic sclerosis has a female:male ratio of 3:1 (8:1 in mid- to late childbearing years). Incidence is twice as high among African Americans. Full-blooded [[Choctaw|Choctaw Native Americans]] in Oklahoma have the highest prevalence in the world (469 per 100,000).<ref>{{Cite journal |last1=Arnett |first1=F. C. |last2=Howard |first2=R. F. |last3=Tan |first3=F. |last4=Moulds |first4=J. M. |last5=Bias |first5=W. B. |last6=Durban |first6=E. |last7=Cameron |first7=H. D. |last8=Paxton |first8=G. |last9=Hodge |first9=T. J. |last10=Weathers |first10=P. E. |last11=Reveille |first11=J. D. |date=August 1996 |title=Increased prevalence of systemic sclerosis in a Native American tribe in Oklahoma. Association with an Amerindian HLA haplotype |journal=Arthritis and Rheumatism |volume=39 |issue=8 |pages=1362–1370 |doi=10.1002/art.1780390814 |issn=0004-3591 |pmid=8702445|doi-access=free }}</ref>

The disease has some hereditary association. It may also be caused by an immune reaction to a virus ([[molecular mimicry]]) or by toxins.<ref name="Harrison's" />

== Society and culture ==

===Support groups===
The Juvenile Scleroderma Network is an organization dedicated to providing emotional support and educational information to parents and their children living with juvenile scleroderma, supporting pediatric research to identify the cause of and the cure for juvenile scleroderma, and enhancing public awareness.<ref>{{cite web| url=http://www.jsdn.org/ | title=Juvenile Scleroderma Network | access-date=2008-05-11}}</ref>

In the US, the Scleroderma Foundation is dedicated to raise awareness of the disease and assist those who are affected.<ref>{{cite web |url=http://www.scleroderma.org/ | title=Scleroderma Foundation | access-date=2008-05-11}}</ref>

The [[Scleroderma Research Foundation]] sponsors research into the condition.<ref>{{cite web | url=http://www.srfcure.org | title=Scleroderma Research Foundation | access-date=2008-05-11}}.</ref> Comedian and television presenter [[Bob Saget]], a board member of the SRF, directed the 1996 ABC TV movie ''[[For Hope]]'', starring [[Dana Delany]], which depicts a young woman fatally affected by scleroderma; the film was based on the experiences of Saget's sister Gay.<ref>{{IMDb title|qid=Q2870219|id=tt0116335|title=For Hope}}</ref>

Scleroderma and Raynaud's UK is a British charity formed by the merger of two smaller organisations in 2016 to provide support for people with scleroderma and fund research into the condition.<ref>{{Cite web|url=https://www.sruk.co.uk/|title=SRUK – Scleroderma & Raynaud's UK &#124; SRUK|website=www.sruk.co.uk}}</ref><ref>{{cite web|title=NHS Choices Scleroderma|url=http://www.nhs.uk/conditions/scleroderma/pages/introduction.aspx|access-date=26 September 2015}}</ref>

==Prognosis==
A 2018 study placed 10-year survival rates at 88%, without differentiation based on subtype. Diffuse systemic sclerosis, internal organ complications, and older age at diagnosis are associated with worse prognoses.<ref>{{cite journal |author=Hu, Shasha|title=Prognostic profile of systemic sclerosis: analysis of the clinical EUSTAR cohort in China |journal=Arthritis Research & Therapy |year=2018 |volume=20 |issue=1 |pages=235 |doi = 10.1186/s13075-018-1735-4|pmid=30348207 |pmc=6235213 |display-editors=etal |doi-access=free }}</ref>

==Research==
Given the difficulty in treating scleroderma, treatments with a smaller [[evidence based medicine|evidence base]] are often tried to control the disease. These include [[antithymocyte globulin]] and [[mycophenolate mofetil]]; some reports have shown improvements in the skin symptoms, as well as delaying the progress of systemic disease, but neither has been subjected to large clinical trials.<ref name=Zandberg/>

Autologous [[hematopoietic stem cell transplantation]] (HSCT) is based on the assumption that autoimmune diseases such as systemic sclerosis occur when the white blood cells of the immune system attack the body. In this treatment, stem cells from the patient's blood are extracted and stored to preserve them. The patient's white blood cells are destroyed with cyclophosphamide and rabbit antibodies against the white blood cells. Then, the stored blood is returned to the patient's bloodstream to reconstitute a healthy blood and immune system that will not attack the body. The results of a phase-III trial, the Autologous Stem Cell Transplantation International Scleroderma (ASTIS) trial, with 156 patients, were published in 2014. HSCT itself has a high treatment mortality, so in the first year, the survival of patients in the treatment group was lower than the placebo group, but at the end of 10 years, the survival in the treatment group was significantly higher. The authors concluded that HSCT could be effective, if limited to patients who were healthy enough to survive HSCT itself. Therefore, HSCT should be given early in the progression of the disease, before it does damage. Patients with heart disease, and patients who smoked cigarettes, were less likely to survive.<ref name="JAMA2014-editorial">{{cite journal| title =Autologous Hematopoietic Stem Cell Therapy in Severe Systemic Sclerosis: Ready for Clinical Practice?| journal =JAMA | date =June 25, 2014 |vauthors=Dinesh Khanna D, Georges GE, Couriel DR | volume =311| issue =24| pages =2485–2487 | doi =10.1001/jama.2014.6369| pmid =25058081| pmc =4926767}}</ref><ref name="JAMA2014">{{cite journal |title=Autologous Hematopoietic Stem Cell Transplantation vs Intravenous Pulse Cyclophosphamide in Diffuse Cutaneous Systemic Sclerosis: A Randomized Clinical Trial |journal=JAMA |date=June 25, 2014 |vauthors=van Laar JM, Farge Sont JK, etal |volume=311 |issue=24 |pages=2490–2498 |doi=10.1001/jama.2014.6368 |pmid=25058083 |hdl=2066/136804 |s2cid=205060178 |url=https://eprints.whiterose.ac.uk/134696/1/P909.pdf |hdl-access=free}}</ref> Another trial, the Stem Cell Transplant vs. Cyclophosphamide (SCOT) trial, is ongoing.<ref>Stem Cell Transplant vs. Cyclophosphamide (SCOT), NCT00114530</ref>

[[Asengeprast]] is an experimental systemic scleroderma drug candidate. It is a small molecule inhibitor of the G-protein coupled receptor GPR68 with antifibrotic activity.

==References==
{{Reflist}}

{{Medical resources
|  ICD11          = {{ICD11|4A42}}
|  ICD10          = {{ICD10|M34}}
|  ICD9           = {{ICD9|710.1}}
|  ICDO           =
|  OMIM           = 181750
|  MedlinePlus    = 000429
|  eMedicineSubj  = derm
|  eMedicineTopic = 677
|  eMedicine_mult = {{eMedicine2|ped|2197}}
|  DiseasesDB     = 12845
|  MeshID         = D012595
}}
{{Systemic connective tissue disorders}}
{{Medicine}}

{{DEFAULTSORT:Systemic Scleroderma}}
[[Category:Ailments of unknown cause]]
[[Category:Mucinoses]]
[[Category:Connective tissue diseases]]
[[Category:Autoimmune diseases]]
[[Category:Disorders of fascia]]
[[Category:Systemic connective tissue disorders]]