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| | __NOTOC__ |
| | {{Scleroderma}} |
| | {{CMG}}; '''Associate Editor-In-Chief:''' {{MKA}} {{CZ}} |
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| '''For patient information click [[{{PAGENAME}} (patient information)|here]]''' | | '''For patient information click [[{{PAGENAME}} (patient information)|here]]''' |
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| {{DiseaseDisorder infobox | | | {{SK}} Systemic sclerosis; CREST syndrome; limited scleroderma; progressive systemic sclerosis; localized scleroderma; mixed connective disease; morphea - linear; sclerosis, systemic; systemic scleroderma |
| Name = Systemic sclerosis |
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| ICD10 = {{ICD10|M|34||m|30}} |
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| ICD9 = {{ICD9|710.1}} |
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| ICDO = |
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| Image = Scleroderma-301.jpg|
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| Caption = MCP, PIP and DIP joints destructions in patient with Scleroderma. <br> [http://www.radswiki.net Image courtesy of RadsWiki]|
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| OMIM = 181750 |
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| MedlinePlus = 000429 |
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| DiseasesDB = 12845 |
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| MeshID = D012595 |
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| }}
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| {{SI}}
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| {{CMG}}
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| '''Associate Editor-In-Chief:''' {{CZ}}
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| ===Click [[The Heart in Progressive Systemic Sclerosis (Scleroderma)|here]] for The heart in Scleroderma===
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| ==Overview==
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| '''Scleroderma''' is a [[rare disease|rare]], [[chronic disease]] characterized by excessive deposits of [[collagen]] in the [[skin]] or other organs. The localized type of the disease, while disabling, tends not to be fatal. '''Diffuse scleroderma''' or '''systemic sclerosis''', the generalized type of the disease, can be fatal as a result of heart, kidney, lung or intestinal damage.<ref name=Primer>Klippel J (ed). Systemic sclerosis and related syndromes. ''Primer on the rheumatic diseases, 11th edition''. The Arthritis Society. 1997;269. ISBN 1-91242-316-2.</ref>
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| == Epidemiology ==
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| * Scleroderma affects approximately 300.000 people in the United States.
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| * It is four times as common in women than in men.
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| * Incidence rates are estimated at 2-20 per million per year in the United States.
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| * Juvenile scleroderma affects approximately 7,000 children in the United States.
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| * The most common form of Juvenile Scleroderma is Localized Scleroderma - Morphea and/or Linear.
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| ==Pathophysiology==
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| 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/>
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| 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/>
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| 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/>
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| Jimenez & Derk<ref name=JimenezDerk/> describe three theories about the development of scleroderma:
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| * The abnormalities are primarily due to a physical agent, and all other changes are secondary or reactive to this direct insult.
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| * 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.
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| * 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.
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| ==Etiology==
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| There is no clear obvious cause for scleroderma and systemic sclerosis. Genetic predisposition appears to be limited: genetic concordance is small; still, there often is a familial predisposition for autoimmune disease. Polymorphisms in ''COL1A2'' and ''[[TGF beta 1|TGF-β1]]'' may influence severity and development of the disease. There is limited evidence implicating [[cytomegalovirus]] (CMV) as the original epitope of the immune reaction, and [[organic solvent]]s and other chemical agents have been linked with scleroderma.<ref name=JimenezDerk/>
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| 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=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=}}</ref><ref name=JimenezDerk/>
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| A distinct form of scleroderma and systemic sclerosis may develop in patients with [[chronic renal failure]]. This entity, [[nephrogenic fibrosing dermopathy]] or nephrogenic systemic fibrosis,<ref>{{cite journal |author=Galan A, Cowper SE, Bucala R |title=Nephrogenic systemic fibrosis (nephrogenic fibrosing dermopathy) |journal=Current opinion in rheumatology |volume=18 |issue=6 |pages=614-7 |year=2006 |pmid=17053507 |doi=10.1097/01.bor.0000245725.94887.8d}}</ref> has been linked to the exposure to [[gadolinium]]-containing [[radiocontrast]].<ref>{{cite journal |author=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>
| | ===Click [[The Heart in Progressive Systemic Sclerosis (Scleroderma)|here]] for The Heart in Scleroderma=== |
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| [[Bleomycin]]<ref>{{cite journal |author=Sharma SK, Handa R, Sood R, ''et al'' |title=Bleomycin-induced scleroderma |journal=The Journal of the Association of Physicians of India |volume=52 |issue= |pages=76-7 |year=2004 |pmid=15633728 |doi=}}</ref> (a chemotherapeutic agent) and possibly [[taxane]] chemotherapy<ref>{{cite journal |author=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}}</ref> may cause scleroderma, and occupational exposure to [[solvent]]s has been linked with an increased risk of systemic sclerosis.<ref>{{cite journal |author=Kettaneh A, Al Moufti O, Tiev KP, ''et al'' |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 |doi=}}</ref>
| | ==[[Scleroderma overview|Overview]]== |
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| ==Types of Scleroderma== | | ==[[Scleroderma historical perspective|Historical Perspective]]== |
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| There are three major forms of scleroderma: diffuse, limited (''CREST syndrome'') and morphea/linear. Diffuse and limited scleroderma are both a systemic disease, whereas the linear/morphea form is localized to the skin. (Some physicians consider CREST and limited scleroderma one and the same, others treat them as two separate forms of scleroderma.) There is also a subset of the systemic form known as "systemic scleroderma sine scleroderma", meaning the usual skin involvement is not present.
| | ==[[Scleroderma classification|Classification]]== |
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| ===Diffuse scleroderma=== | | ==[[Scleroderma pathophysiology|Pathophysiology]]== |
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| Diffuse scleroderma (progressive systemic sclerosis) is the most severe form - it has a rapid onset, involves more widespread skin hardening, will generally cause much internal organ damage (specifically the [[lung]]s and [[gastrointestinal tract]]), and is generally more life threatening.
| | ==[[Scleroderma causes|Causes]]== |
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| ===Limited scleroderma/CREST syndrome=== | | ==[[Differentiating Scleroderma from other diseases|Differentiating Scleroderma from other Diseases]]== |
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| The limited form is much milder: it has a slow onset and progression, skin hardening is usually confined to the hands and face, internal organ involvement is less severe, and a much better prognosis is expected.
| | ==[[Scleroderma epidemiology and demographics|Epidemiology and Demographics]]== |
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| In typical cases of limited scleroderma, Raynaud's phenomenon may precede scleroderma by several years. Raynaud's phenomenon is due to vasoconstriction of the small arteries of exposed peripheries - particularly the hands and feet - in the cold. It is classically characterised by a triphasic colour change - first white, then blue and finally red on rewarming. The scleroderma may be limited to the fingers - known as sclerodactyly.
| | ==[[Scleroderma risk factors|Risk Factors]]== |
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| The limited form is often referred to as CREST [[syndrome]].<ref>{{cite journal |author=Winterbauer RH |title=Multiple telangiectasia, Raynaud'S phenomenon, sclerodactyly, and subcutanious calcinosis: a syndrome mimicking hereditary hemorrhagic telangiectasia |journal=Bulletin of the Johns Hopkins Hospital |volume=114 |issue= |pages=361-83 |year=1964 |pmid=14171636 |doi=}}</ref> "CREST" is an acronym for the five main features:
| | ==[[Scleroderma screening|Screening]]== |
| * [[Calcinosis|'''C'''alcinosis]]
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| * [[Raynaud's phenomenon|'''R'''aynaud's syndrome]]
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| * [[Esophagus|'''E'''sophageal]] dysmotility
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| * [[Sclerodactyly|'''S'''clerodactyly]]
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| * [[Telangiectasia|'''T'''elangiectasia]]
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| ===Morphea/linear scleroderma=== | | ==[[Scleroderma natural history, complications and prognosis|Natural History, Complications and Prognosis]]== |
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| [[Morphea]]/linear scleroderma involves isolated patches of hardened skin - there generally is no internal organ involvement.<ref>[http://premium.edition.cnn.com/HEALTH/library/DS/00718.html Morpea] CNN.com, (May 05, 2006).</ref> | |
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| ==Diagnosis== | | ==Diagnosis== |
| | [[Scleroderma diagnostic study of choice|Diagnostic Study of Choice]] | [[Scleroderma history and symptoms|History and Symptoms]] | [[Scleroderma physical examination|Physical Examination]] | [[Scleroderma laboratory findings|Laboratory Findings]] | [[Scleroderma electrocardiogram|Electrocardiogram]] | [[Scleroderma x ray|X Ray]] | [[Scleroderma CT|CT]] | [[Scleroderma MRI|MRI]] | [[Scleroderma echocardiography or ultrasound|Echocardiography or Ultrasound]] | [[Scleroderma other imaging findings|Other Imaging Findings]] | [[Scleroderma other diagnostic studies|Other Diagnostic Studies]] |
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| Diagnosis is by clinical suspicion, presence of autoantibodies (specifically [[anti-centromere antibodies|anti-centromere]] and anti-scl70/[[anti-topoisomerase antibodies]]) and occasionally by biopsy. Of the antibodies, 90% have a detectable [[anti-nuclear antibody]]. Anti-centromere antibody is more common in the limited form (80-90%) than in the systemic 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 |author=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=}}</ref>
| | ==Treatment== |
| | | [[Scleroderma medical therapy|Medical Therapy]] | [[Scleroderma surgery|Surgery]] | [[Scleroderma primary prevention|Primary Prevention]] | [[Scleroderma secondary prevention|Secondary Prevention]] | [[Scleroderma cost-effectiveness of therapy|Cost-Effectiveness of Therapy]] | [[Scleroderma future or investigational therapies|Future or Investigational Therapies]] |
| In 1980 the American College of Rheumatology agreed upon diagnostic criteria for scleroderma.<ref>{{cite journal |author= |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 |year:1980 |pmid=7378088 |doi=}} Available online at {{cite web | title=Criteria for the Classification of Systemic Sclerosis 1980| work= | url=http://www.rheumatology.org/publications/classification/systsclr.asp | accessdate:5 August 2007}}</ref>
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| Diffuse scleroderma can cause [[musculoskeletal system|musculoskeletal]], [[lung|pulmonary]], [[gastrointestinal tract|gastrointestinal]], [[kidney|renal]] and other complications.<ref name=Primer/>Patients with larger amounts of cutaneous involvement are more likely to have involvement of the internal tissues and organs.
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| ===[[The heart in progressive systemic sclerosis (scleroderma)|Cardiovascular Symptoms]]===
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| [http://www.peir.net Images courtesy of Professor Peter Anderson DVM PhD and published with permission © PEIR, University of Alabama at Birmingham, Department of Pathology]
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| <gallery>
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| Image:Scleroderma heart 1.jpg|This is a gross photograph of the heart from this case. There is thickening of the left ventricular wall and some thickening of the right ventricle as well.
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| Image:Scleroderma heart 2.jpg|Scleroderma: Right ventricular hypertrophy due to pulmonary fibrosis in Scleroderma
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| Image:Scleroderma heart 3.jpg|Scleroderma: Right ventricular hypertrophy due to pulmonary fibrosis in Scleroderma
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| Image:Scleroderma heart 4.jpg|Scleroderma: Right ventricular hypertrophy due to pulmonary fibrosis in Scleroderma
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| </gallery>
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| ===Skin Symptoms===
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| * Scleroderma affects the [[skin]], and in more serious cases it can affect the [[blood vessel]]s and internal organs. The most evident symptom is the hardening of the skin and associated scarring. Typically, the skin appears reddish or scaly. Blood vessels may also be more visible. Where large areas are affected, fat and muscle wastage will weaken limbs and affect appearance.
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| * The seriousness of the disease varies hugely between cases. The two most important factors to consider are the level of internal involvement (beneath the skin) and the total area covered by the disease. For example, there have been cases where the patient has no more than one or two [[lesions]], perhaps covering a few inches. Less serious cases tend not to involve the internal bodily functions.
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| * There is discoloration of the hands and feet in response to cold. Most patients (over 80%) have [[Raynaud's phenomenon]], a vascular symptom that can affect the [[finger]]s and toes.
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| * Systemic scleroderma and [[Raynaud's phenomenon]] can cause painful ulcers on the fingers or toes which are known as digital ulcers.
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| * [[Calcinosis]] is also common in systemic scleroderma, and is often seen near the elbows, knees or other [[joint|joints]].
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| [http://www.peir.net Image courtesy of Professor Peter Anderson DVM PhD and published with permission © PEIR, University of Alabama at Birmingham, Department of Pathology]
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| <gallery perRow="3">
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| Image:Progressive systemic sclerosis 001.jpg|Panniculitis and fascitis, streptococcus A septicemia in a patient with Scleroderma who was on high dose steroids
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| Image:Progressive systemic sclerosis 002.jpg|Necrosis of distal finger in a patient with panniculitis and fascitis, streptococcus A septicemia in a patient with Scleroderma who was on high dose steroids
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| Image:Progressive systemic sclerosis 003.jpg|Panniculitis and fascitis, streptococcus A septicemia in a patient with Scleroderma who was on high dose steroids
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| Image:Progressive systemic sclerosis 004.jpg|Skin: Scleroderma; shoulders & back
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| Image:Progressive systemic sclerosis 005.jpg|Skin: Scleroderma in crest syndrome; calcinosis at elbow
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| Image:Progressive systemic sclerosis 006.jpg|Hands: Scleroderma,
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| Image:Progressive systemic sclerosis 007.jpg|Hand: Scleroderma, finger, posterior nail fold
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| Image:Progressive systemic sclerosis 008.jpg|Skin: Scleroderma, chest, salt and pepper pigmentation
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| Image:Progressive systemic sclerosis 009.jpg|Leg: Morphea, circumscribed scleroderma; age 19
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| Image:Progressive systemic sclerosis 010.jpg|Face: Morphea, circumscribed scleroderma
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| Image:Systemic sclerosis finger.jpg|Clinical appearance of acrosclerotic piece-meal [[necrosis]] of the thumb in a patient with systemic sclerosis.
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| Image:Left Arm Scleroderma Patient .jpg|Left arm of Scleroderma patient, showing skin lesions
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| Image:MercMorphea.JPG|Morphea
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| </gallery>
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| ===Musculoskeletal System Related Symptoms===
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| The first joint symptoms that patients with scleroderma have are typically non specific [[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 |author=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=}}</ref> Patients who have progressed later in their disease may develop muscle weakness, or [[myopathy]], either from the disease, or its treatments.<ref>{{cite journal |author=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=}}</ref>
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| [http://www.radswiki.net Image courtesy of RadsWiki]
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| <div align="left">
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| <gallery heights="200" widths="200">
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| Image:Scleroderma-301.jpg|MCP, PIP and DIP joints destructions in patient with Scleroderma.
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| </gallery>
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| </div>
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| ===Respiratory System Symptoms===
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| 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=}}</ref> however, 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 lead to right sided [[heart failure]]. The earliest manifestation of this may be a decreased [[diffusion capacity]] on pulmonary function testing.
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| Other pulmonary complications in more advanced disease include [[aspiration pneumonia]], [[pulmonary hemorrhage]] and [[pneumothorax]].<ref name=Primer/>
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| [http://www.radswiki.net Images courtesy of RadsWiki]
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| <gallery perRow="3">
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| Image:Scleroderma-001.jpg|CT: Lung involvement in Scleroderma
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| Image:Scleroderma-002.jpg|CT: Lung involvement in Scleroderma
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| Image:Scleroderma-003.jpg|CT: Lung involvement in Scleroderma
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| Image:Scleroderma-004.jpg|CT: Lung involvement in Scleroderma
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| Image:Scleroderma-005.jpg|CT: Lung involvement in Scleroderma
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| Image:Scleroderma-006.jpg|CT: Lung involvement in Scleroderma
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| Image:Scleroderma-007.jpg|CT: Lung involvement in Scleroderma
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| Image:Scleroderma-008.jpg|CT: Lung involvement in Scleroderma
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| </gallery>
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| ===Gastrointestinal System Related Symptoms===
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| Diffuse scleroderma can affect any part of the gastrointestinal tract.<ref name=Sallam>{{cite journal |author=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}}</ref> The most common manifestation in the [[esophagus]] is [[esophagitis|reflux esophagitis]], which may be complicated by peptic stricturing, or benign narrowing of the esophagus.<ref name=Rose>{{cite journal |author=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=}}</ref> This is best initially treated with [[proton pump inhibitor]]s for acid suppression,<ref>{{cite journal |author=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=}}</ref> but may require [[esophageal dilatation|bougie dilatation]] in the case of stricture.<ref name=Sallam/>
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| Scleroderma can decrease [[motility]] anywhere in the gastrointestinal tract.<ref name=Sallam/> The most common source of decreased motility involvement 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|GERD]]. 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, and [[Barrett's esophagus]]. The [[small intestine]] can also become involved, leading to bacterial overgrowth and [[malabsorption]], of [[bile salts]], [[fats]], [[carbohydrates]], [[proteins]], and [[vitamins]]. The [[colon (anatomy)|colon]] can be involved, and can cause [[Ogilvie's syndrome|pseudo-obstruction]] or [[ischemic colitis]].<ref name=Primer/> | |
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| 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/>
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| Scleroderma may also be associated with [[gastric antral vascular ectasia]] (GAVE), also known as ''watermelon stomach''. This is a condition where atypical blood vessels proliferate usually in a radially symmetric pattern around the [[pylorus]] of the stomach. GAVE can be a cause of [[upper gastrointestinal bleeding]] or [[iron deficiency anemia]] in patients with scleroderma.<ref name=Rose/> | |
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| <div align="left">
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| <gallery heights="150" widths="150">
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| Image:Peptic stricture.png|[[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.
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| Image:Scleroderma-302.jpg|Barium graphy: Lower esophageal sphincter involvement. [http://www.radswiki.net Image courtesy of RadsWiki]
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| Image:Scleroderma-303.jpg|Barium graphy: Small intestine and colon involvements. [http://www.radswiki.net Image courtesy of RadsWiki]
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| </gallery>
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| </div>
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| ===Renal Symptoms===
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| Renal involvement, in scleroderma, is considered a poor prognostic factor and not infrequently a cause of death in patients with scleroderma.<ref>{{cite journal |author=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 |doi=}}</ref>
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| The most important clinical complication of scleroderma involving the kidney is ''scleroderma renal crisis''. Symptoms of scleroderma renal crisis 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 |author=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 |doi=}}</ref> Apart from the high blood pressure, [[hematuria]] (blood in the urine) and [[proteinuria]] (protein loss in the urine) may be indicative.<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=}}</ref>
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| In the past scleroderma renal crisis was almost uniformily 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=}}</ref> While outcomes have improved significantly with the use of [[ACE inhibitors]]<ref>{{cite journal |author=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=}}</ref><ref name=steen11033587>{{cite journal |author=Steen VD, Medsger TA |title=Long-term outcomes of scleroderma renal crisis |journal=Ann. Intern. Med. |volume=133 |issue=8 |pages=600-3 |year=2000 |pmid=11033587 |doi=}}</ref> the prognosis is often guarded, as a significant number of patients are refractory to treatment and develop [[renal failure]]. Approximately 10% of all scleroderma patients develop renal crisis at some point in the course of their disease.<ref name=jimenez>Jimenez S, Koenig AS. [http://www.emedicine.com/MED/topic2076.htm Scleroderma]. eMedicine.com. Accessed: May 22, 2006.</ref> Patients that have rapid skin involvement have the highest risk of renal complications.<ref name=jimenez/>
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| == Therapy ==
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| There is no cure for every patient with scleroderma, though there is treatment 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 |author=Oliver GF, Winkelmann RK |title=The current treatment of scleroderma |journal=Drugs |volume=37 |issue=1 |pages=87-96 |year=1989 |pmid=2651089 |doi=}}</ref>
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| Digital ulcerations and pulmonary hypertension can be helped by [[prostacyclin]] (iloprost) infusion. Iloprost being a drug which increases blood flow by relaxing the arterial wall.<ref>{{cite journal |author=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=}}</ref>
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| ===Topical/symptomatic===
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| Topical treatment for the skin changes of scleroderma do not alter the disease course, but may improve pain and ulceration. A range of [[NSAID]]s (nonsteroidal anti-inflammatory drugs) can be used to ease painful symptoms, such as [[naproxen]]. There is limited benefit from [[glucocorticoid|steroids]] such as prednisone. 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 |author=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=}} {{PMC|2275417}}</ref> The skin tightness may be treated systemically with [[methotrexate]] and [[cyclosporin]].<ref name=Zandberg/> If there is esophageal dysmotility (in CREST or systemic sclerosis), care must be taken with NSAIDs as they are gastric irritants, and so a [[proton pump inhibitor]] (PPI) such as [[omeprazole]] can be given in conjunction.
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| ===Kidney disease===
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| Scleroderma renal crisis, the occurrence of [[acute renal failure]] and [[malignant hypertension]] (very high blood pressure with evidence of organ damage) in people with scleroderma, is effectively treated with drugs from the class of the [[ACE inhibitor]]s. 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/> [[ACE inhibitors]] are also used for [[prophylaxis]],<ref name=jimenez/><ref name=steen11033587/> and [[renal transplantation]]. 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>Pham PT, Pham PC, Danovitch GM, Gritsch HA, Singer J, Wallace WD, Hayashi R, Wilkinson AH. Predictors and risk factors for recurrent scleroderma renal crisis in the kidney allograft: case report and review of the literature. Am J Transplant. 2005 Oct;5(10):2565-9. PMID 16162209.</ref>
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| ===Lung disease and pulmonary hypertension===
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| 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 |author=Tashkin DP, Elashoff R, Clements PJ, ''et al'' |title=Cyclophosphamide versus placebo in scleroderma lung disease |journal=N. Engl. J. Med. |volume=354 |issue=25 |pages=2655–66 |year=2006 |month=June |pmid=16790698 |doi=10.1056/NEJMoa055120 |url=http://content.nejm.org/cgi/content/full/354/25/2655}}</ref><ref>{{cite journal |author=Hoyles RK, Ellis RW, Wellsbury J, ''et al'' |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 |year=2006 |month=December |pmid=17133610 |doi=10.1002/art.22204 | url=http://www3.interscience.wiley.com/cgi-bin/fulltext/113490260/HTMLSTART}}</ref>
| | ==Case Studies== |
| | [[Scleroderma case study one|Case #1]] |
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| Pulmonary hypertension may be treated with [[epoprostenol]], [[bosentan]] and possibly aerolized iloprost.<ref name=Zandberg/>
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| ===Experimental treatments===
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| 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 reported improvements in the skin symptoms as well as delaying the progress of systemic disease, but neither of them have been subjected to large clinical trials.<ref name=Zandberg/>
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| While still experimental (given its high rate of complications), [[hematopoietic stem cell transplantation]] is being studied in patients with severe systemic sclerosis; improvement in life expectancy and severity of skin changes has been noted.<ref>{{cite journal |author=Nash RA, McSweeney PA, Crofford LJ, ''et al'' |title=High-dose immunosuppressive therapy and autologous hematopoietic cell transplantation for severe systemic sclerosis: long-term follow-up of the U.S. multicenter pilot study |journal=Blood |volume=110 |issue=4 |pages= 1388–96|year=2007 |pmid=17452515 |doi=10.1182/blood-2007-02-072389}}</ref>
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| ==Case Examples==
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| ===Case #1===
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| ====Clinical Summary====
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| A 29-year-old black female had a history of scleroderma involving the lung, kidney, heart, and skin. Her main clinical problems centered on her [[restrictive lung disease]]. She was able to live at home with supplemental oxygen but recently she had developed [[edema]], [[chest pain]], [[weakness]], [[lightheadedness]], and a loss of appetite. The patient was admitted to the hospital with a working diagnosis of [[congestive heart failure]] brought on by her lung disease.
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| Echocardiographic evaluation revealed a [[pericardial effusion]] that was tapped. Soon after this procedure her respiratory status degenerated and she required [[intubation]]. Despite aggressive supportive treatment for her cardiac and pulmonary problems, she could not be weaned from the ventilator. Two weeks after admission she became febrile and Gram positive cocci were isolated from sputum culture. She was placed on antibiotics but her condition deteriorated and she developed bradycardia followed by [[electromechanical dissociation]] (EMD).
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| ====Autopsy Findings====
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| Upon opening the thorax there was 600 cc of cloudy serous fluid in each hemithorax and 100 cc of similar fluid in the pericardial sac. The heart weighed 530 grams and there was thickening of both the left and right ventricular walls. The liver weighed 1880 grams and was congested. The spleen weighed 200 grams and was also congested. The combined lung weight was 1875 grams; the lungs were markedly fibrotic with severe emphysema. In addition, dermal thickening was evident throughout the body and the wall of the esophagus was thickened and firm.
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| ====Histopathological Findings====
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| [http://www.peir.net Images courtesy of Professor Peter Anderson DVM PhD and published with permission © PEIR, University of Alabama at Birmingham, Department of Pathology]
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| [[Image:Scleroderma lung 1.jpg|left|thumb|400px|This is a gross photograph of cut section of the lungs from this patient. Note the extensive fibrosis of the lung parenchyma. ]]
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| <br clear="left"/>
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| [[Image:Scleroderma lung 2.jpg|left|thumb|400px|This is a gross photograph of a cut section of one lung from this patient. Note the extensive fibrosis lower lobe (arrows).]]
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| <br clear="left"/>
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| [[Image:Scleroderma lung 3.jpg|left|thumb|400px|This is a closer view of the cut section of lung from this patient. Note the extensive fibrosis and the severe emphysematous changes. ]]
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| <br clear="left"/>
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| [[Image:Scleroderma lung 4.jpg|left|thumb|400px|This is a closer view of the cut section of lung from this patient showing the extensive fibrosis and the severe emphysematous change. ]]
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| <br clear="left"/>
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| [[Image:Scleroderma heart 1.jpg|left|thumb|400px|This is a gross photograph of the heart from this case. There is thickening of the left ventricular wall and some thickening of the right ventricle as well. ]]
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| <br clear="left"/>
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| ==References==
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| {{Reflist|2}}
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| ==External links==
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| * [http://goldminer.arrs.org/search.php?query=scleroderma Goldminer: Scleroderma]
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| * [http://dermnetnz.org/immune/systemic-sclerosis.html DermnetNZ: Systemic sclerosis]
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| * [http://www.jsdn.org/ Juvenile Scleroderma Network]
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| * [http://www.juvenile-scleroderma.com/ Juvenile Systemic Sclerosis]
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| * [http://www.scleroderma.org/ Scleroderma Foundation]
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| * [http://www.sclerodermaontario.ca/ Scleroderma Society of Ontario]
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| * [http://www.sclero.org/index.html International Scleroderma Network]
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| * [http://www.sclerodermaresearch.org/ The Scleroderma Research Foundation]
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| * [http://www.sclerodermasociety.co.uk/ UK Scleroderma Society]
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| * [http://scleroderma.jhmi.edu/ Scleroderma Information from Johns Hopkins University]
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| {{Diseases of the musculoskeletal system and connective tissue}} | | {{Diseases of the musculoskeletal system and connective tissue}} |
| {{SIB}}
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| [[Category:Autoimmune diseases]]
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| [[Category:Diseases involving the fasciae]]
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| [[Category:Rheumatology]]
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