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Systemic sclerosis (SSc) is a multisystem autoimmune disease in which there is increased fibroblast activity resulting in abnormal growth of connective tissue. This causes vascular damage and fibrosis. Fibrosis occurs in skin, the gastrointestinal (GI) tract and other internal organs.
The name scleroderma is derived from the Greek for 'hard skin' and emphasises the dermatological component of the disease. It was described by Hippocrates. There is a localised form of scleroderma, also known as morphoea. See the separate article Morphoea.
Types of systemic sclerosis
SSc is classified into two main types, according to the extent of skin involvement.
Limited cutaneous systemic sclerosis (lcSSc), or limited scleroderma
- 70% of SSc cases.
- Affects only the face, forearms and lower legs up to the knee.
- The older term for limited scleroderma is CREST syndrome (= Calcinosis, Raynaud's disease, (O)Esophageal dysmotility, Sclerodactyly, Telangiectasia).
Diffuse cutaneous systemic sclerosis (dcSSc), or diffuse scleroderma
- 30% of SSc cases.
- Involves also the upper arms, thighs or trunk.
There are rarer types, including systemic sclerosis sine scleroderma, in which there is internal organ involvement without the skin changes.
SSc is present throughout the world and is represented in all ethnic groups. Incidence and prevalence figures vary widely, and there appears to be a large geographical variation. Reported prevalence in the USA is 276 per million adults compared to 88 per million in the UK. Women are affected more often than men with a reported ratio of 4-5:1. The usual age of onset is 30-50 years, but it can affect any age group. It is rare in children.
The cardinal features of SSc are excessive collagen production and deposition, vascular damage, and inflammation or autoimmunity.
The cause is unknown, although there is probably a genetic predisposition. Environmental factors may play a role in triggering the disease. These may include viruses (such as cytomegalovirus), chemicals (such as vinyl chloride, some pesticides, benzene derivatives and silica), and drugs (such as cocaine, appetite suppressants, penicillamine and vitamin K).
Common presenting symptoms are Raynaud's phenomenon (which may precede other symptoms by some years), skin hardening in hands or face, and oesophageal symptoms. Early symptoms can also be nonspecific - eg, fatigue, musculoskeletal pains and hand swelling. Both limited and diffuse scleroderma can involve internal organs, and the severity of skin changes does not necessarily reflect the severity of internal organ involvement.
- Generally a milder disease, with less skin involvement, slow onset and slow progression.
- The slow onset may mean that symptoms are relatively unnoticed until internal complications occur.
- Usually a more rapid onset, with skin thickening and Raynaud's phenomenon occurring together or within a short interval. The skin changes may spread rapidly, within a few months of disease onset.
- Skin changes can remit after several years, with softening of the skin and significant improvement in mobility.
- Symptoms tend to be worst in the first 3 to 5 years of the disease, after which there is a stable phase and further deterioration is unlikely. The disease may then reverse to some extent, with softening of the skin and improved mobility.
- Internal organ involvement is more common.
- Weight loss.
- Signs in the hand:
- Swelling (non-pitting oedema) of fingers and toes - a common early sign; digits may look sausage-like; hand movement may be limited.
- Skin becomes hard and thickened - this may limit joint movement or cause joint contractures; in the fingers, this is known as sclerodactyly.
- Swelling and sclerosis reduce hand movements, so patients may be unable to make a fist, or to place the palmar surfaces together - the 'prayer sign'.
- Fingertips may have pitting, ulcers or loss of bulk from finger pads.
- Raynaud's phenomenon. This is the most common symptom and is present at some point in 90% of cases. Raynaud's phenomenon with puffy fingers is thought to be a cardinal sign of likely SSc.
- Calcinosis - nodules or lumps of chalky material which may break through the skin.
- Face and mouth:
- Tightening of facial skin.
- Tight lips (microstomia) - can make dental hygiene difficult.
- 'Salt and pepper' appearance of skin, due to areas of hypopigmentation and hyperpigmentation.
- Dry or itchy skin; reduced hair over affected skin areas.
- Joint pain and swelling.
- Myalgia (due to inflammatory myopathy).
- Restriction of joint movement, contractures and muscle atrophy due to skin sclerosis.
- Tendon friction rubs - palpable/audible over the flexor/extensor tendons of the hands, knees and ankles.
- Heartburn and reflux oesophagitis.
- Oesophageal scarring and dysphagia.
- Delayed gastric emptying - eg, fullness after meals.
- Reduced small bowel motility - can cause bacterial overgrowth, with bloating, malabsorption, diarrhoea and malnutrition.
- Constipation due to reduced colonic motility.
- Pulmonary fibrosis (interstitial lung disease):
- Occurs in as many as 75% of scleroderma patients, but only a few develop end-stage disease.
- Causes restrictive lung disease.
- Symptoms and signs: exertional dyspnoea, cough, coarse basal crackles.
- Pulmonary arterial hypertension (PAH):
- Occurs in about 10-15% of patients with scleroderma.
- A leading cause of death in SSc. The presence of PAH drastically reduces survival rate.
- Symptoms and signs: exertional dyspnoea, syncope, right ventricular strain features.
- Recent research has attempted to define predictive screening tools. These include monitoring lung function, ECG, urate levels, and N-terminal prohormone of brain natriuretic peptide (NT-proBNP); and by taking into account anti-centromere antibody (ACA) presence and history or presence of telangiectasia.
- ESR and CRP.
- Baseline biochemistry and renal function.
- Antinuclear antibody - positive in 90-95% but not specific to SSc.
- Other autoantibodies in SSc:
- Anti-topoisomerase 1 (Scl 70) antibody - strongly associated with lung fibrosis and with renal disease.
- Anti-centromere antibody (ACA) - seen almost only in patients with lcSSc, and is associated with increased risk of pulmonary hypertension but relative protection from lung fibrosis and kidney involvement.
- Anti-RNA polymerase III antibody - associated with dcSSc and especially with kidney involvement. There is a strong association between presence of anti-RNA polymerase III antibodies and the development of scleroderma renal crisis which helps to identify at-risk patients.
- Anti-fibrillarin (anti-U3RNP) antibody - associated with heart involvement, pulmonary hypertension, kidney involvement and myositis.
- Anti-PM-Scl antibody - strongly associated with the combination of myositis and scleroderma.
- Anti-U1RNP (anti-nRNP) antibody - associated with joint involvement and overlap syndromes.
- Urine protein - as baseline or if there are renal complications.
- Skin biopsy - may aid diagnosis.
- Nailfold capillaroscopy - helps to assess the likelihood of scleroderma in patients with Raynaud's phenomenon or swollen fingers. This is also useful in predicting risk of developing ulcers.
- Hand X-ray may show calcinosis.
- Thermography with cold challenge helps to assess the severity of Raynaud's phenomenon.
- Endoscopy and/or barium studies, depending on GI symptoms.
Regular monitoring for complications includes:
- Renal function.
- Lung function tests and chest CT scan.
- ECG and echocardiography.
Diagnosis may be difficult, particularly in the early stages, as symptoms overlap with other connective tissue diseases. Diagnosis depends on the overall clinical picture rather than a specific test.
Diagnostic criteria for SSc
Diagnostic and classification criteria are in the process of revision in the interests of including and picking up early disease. Since 1980, diagnostic criteria have been proximal scleroderma (proximal to the metacarpophalangeal (MCP) joints, sclerodactyly, digital pitting scars or pulp loss, and bilateral basilar pulmonary fibrosis. However in 2013, the collaboration of the American college of rheumatology and the European league against rheumatism (ACR/EULAR) proposed a new set of criteria. Further items are given a weighted score, and a score of 9 or more is diagnostic of SSc. The traditional 'major' criterion of skin thickening extending proximal to the MCP joints is given a score of 9, and therefore is sufficient on its own to make a diagnosis. The following features are included in the new system:
- Skin thickening extending proximal to the MCP joints (Score 9).
- Skin thickening of the fingers (Score 2 for puffy fingers, 4 for sclerodactyly).
- Fingertip lesions (Score 2 for ulcers, 3 for fingertip pitting scars).
- Telangiectasia (Score 2).
- Abnormal nailfold capillaries (Score 2).
- Pulmonary arterial hypertension and/or interstitial lung disease (Score 2).
- Raynaud's phenomenon (Score 3).
- SSc-related autoantibodies (Score 3).
Early diagnosis - the VEDOSS initiative
The VEDOSS (= Very Early Diagnosis Of Systemic Sclerosis) initiative in Europe identified the following features as being key to diagnosing SSc in the very early stage:
- Antinuclear antibodies.
- Scleroderma-specific antibodies.
- SSc pattern on nailfold capillaroscopy.
- Puffy fingers in Raynaud's syndrome patients.
Several other diseases can present in a similar way to SSc, including:
- Raynaud's phenomenon from other causes.
- Vibration injury.
- Other connective tissue disease or mixed connective tissue disease, eg with features of rheumatoid arthritis (RA) or systemic lupus erythematosus (SLE).
- Undifferentiated connective tissue disease.
- Chronic graft-versus-host disease.
- Paraneoplastic syndromes.
There is no cure for SSc, and management consists of controlling symptoms and preventing complications.
Regular monitoring and reviews are aimed at early detection and treatment of complications. Monitoring includes:
- Regular review of symptoms.
- Blood pressure monitoring.
- Renal function monitoring.
- Lung function tests and chest CT scan.
- ECG and echocardiography.
- Patient involvement and education:
- 'Expert patient' programmes and the Scleroderma Society.
- Awareness of urgent problems such as renal crisis or intestinal obstruction symptoms.
- Physiotherapy to promote joint mobility and muscle strength.
- Home exercises to maintain range of motion (such as gentle mouth, face and hand stretches).
- Avoid tobacco and maintain healthy weight.
- Nutritional advice, and supplements if needed.
- For Raynaud's phenomenon:
- Prevention - avoid cold and trauma; use warm clothing or heated clothing.
- For an attack - warm the body, hands and feet gently (the skin may be numb and unable to feel if the heat source is too hot); use gentle arm movements or gentle massage to help restore circulation.
- Occupational therapists - for adaptations to assist in daily living.
- Camouflage products - for cosmetic help with skin changes.
- Non-selective immunosuppressives - cyclophosphamide is the most commonly used and has been associated with improvements in both pulmonary function and skin involvement but efficacy may reduce beyond two years. Mycophenolate mofetil has also been used with improvements in lung function. Azathioprine and methotrexate alone may not be as beneficial but have been shown to be effective for skin involvement.
- T-cell targeted immunotherapy - T cells play a central role in much of the pathology of scleroderma, which probably explains why ciclosporin is effective. Other T-cell targeted therapy which is being tested includes sirolimus, antithymocyte globulin, and basiliximab.
- Oral corticosteroids.
- Other medical treatments - rituximab, intravenous immunoglobulins and anti-tumour necrosis factor alpha (anti-TNF-alpha) are also being investigated for the treatment of scleroderma.
Management of skin problems
Raynaud's phenomenon symptoms and ulcers:
- Nifedipine is currently the only drug licensed for Raynaud's phenomenon in the UK.
- Other treatments for Raynaud's phenomenon which may be effective but are not yet licensed in the UK include:
- Nitroglycerin (ointment).
- Phosphodiesterase type 5 inhibitors as they are well tolerated vasodilators.
- Prostaglandins - iloprost is recommended intravenously for severe symptoms in Europe.
- Losartan may be more effective than nifedipine.
- For ischaemic ulcers:
- Simple protective dressings.
- Antibiotics if infected.
- Vasodilators may help in some situations - eg, bosentan may reduce the occurrence of new ulcers, and is recommended by EULAR when nifedipine and prostaglandins are ineffective.
Skin dryness or itching:
- Topical steroids (short course) or antihistamines.
- For patients with rapidly progressing diffuse scleroderma, consider a trial of immunosuppressant treatment - eg, mycophenolate or cyclophosphamide.
Management of musculoskeletal symptoms
Surgical procedures for specific indications such as:
- Release of contractures.
- Removal of troublesome calcinosis.
Myalgia, arthralgia and painful oedema:
- Non-steroidal anti-inflammatory drugs (NSAIDs), if tolerated.
- Simple analgesics.
Management of GI symptoms
For upper GI symptoms:
- Maintain upright posture after meals; raise the head of the bed; limit alcohol.
- Proton pump inhibitors.
- May also need H2-receptor antagonists and pro-motility agents (metoclopramide or domperidone).
- Dilatation of oesophageal strictures if required.
For intestinal bacterial overgrowth and malabsorption:
- Cyclical antibiotics.
- Nutritional advice and nutritional supplements; rarely, parenteral nutrition is required.
- Dietary fibre and good fluid intake.
- Softening laxatives (such as lactulose) and/or soluble fibre (such as ispaghula).
Management of pulmonary disease
Pulmonary fibrosis (interstitial lung disease)
- Benefits of cyclophosphamide seem clear, but must be weighed against side-effects.
- Supportive treatment: prompt treatment of chest infections - oxygen if needed.
Pulmonary arterial hypertension (PAH)
- Drug treatment of PAH has improved recently and includes:
- Endothelin receptor antagonists - eg, bosentan or sitaxsentan.
- Vasodilators - eg, sildenafil.
- Prostaglandin derivatives - eg, iloprost (nebulised or intravenous) or epoprostenol (infusion).
- Supportive treatment - eg, oxygen.
See also specific GI sections under 'Clinical features' and 'Management' headings.
- Malnutrition due to swallowing problems and other digestive issues.
- 'Watermelon stomach' (gastric antral vascular ectasia):
- May cause anaemia and GI bleeding.
- May need endoscopic laser coagulation to prevent bleeding.
- Obstruction and pseudo-obstruction:
- Can occur due to reduced motility and bacterial overgrowth.
- Can be complicated by perforation and peritonitis.
- Pseudo-obstruction is treated initially by bowel rest and antibiotics.
- Laparotomy may be needed.
- Anorectal dysfunction:
- In some cases, the rectum and anus are involved, causing faecal incontinence.
- This may require surgery.
Scleroderma renal crisis
- A serious complication with features of accelerated hypertension.
- Can lead to renal failure if not treated promptly.
- Occurs in 5-10% of patients with scleroderma and is more common in those with diffuse or rapidly progressive disease.
- Usually presents as accelerated hypertension with oliguria, headache, fatigue, oedema, rapidly rising serum creatinine levels, proteinuria and microscopic haematuria.
- Scleroderma renal crises can occur with apparently normal blood pressure, but the blood pressure is higher than baseline values - hence the importance of regular blood pressure monitoring.
- Treatment is with angiotensin-converting enzyme (ACE) inhibitors, plus dialysis if necessary.
- Testing patients with scleroderma for anti-RNA polymerase III antibodies may help identify at-risk patients.
- Aspiration pneumonia from severe reflux.
- Respiratory muscle weakness if there is severe myositis or extensive skin disease involving the chest.
- Many different cardiac abnormalities can be associated with SSc. These include:
- Microvascular coronary artery disease (with resultant myocardial ischemia).
- Myocardial fibrosis.
- Left ventricular (LV) systolic dysfunction, LV diastolic dysfunction.
- Pericarditis or pericardial effusion; these may cause cardiac impairment or congestive cardiac failure.
- Arrhythmias and conduction defects (including bradyarrhythmias and tachyarrhythmias).
- The wide variety of abnormalities makes it difficult to assess prevalence. It is likely that the subclinical cardiac involvement rates are very high.
- Treatment is according to the clinical features.
- Erectile dysfunction.
- Osteoporosis - due to reduced blood flow.
- Hypothyroidism may be associated.
- This may occur in patients with an 'overlap syndrome', where there are both scleroderma and Sjögren's syndrome features.
- Common symptoms are dry eyes and mouth; other mucous membranes (eg, vagina) may be symptomatic.
- Can cause eye irritation, dysphagia, dysphonia and increased dental decay.
- Treat with lubricants (eg, artificial tears and saliva), and dental care.
Successful pregnancy is possible. It should be planned when the disease is stable to avoid complications. Close monitoring, multidisciplinary care and individually tailored treatment are needed. Reflux is the most common problem. The most dangerous complication is scleroderma renal crisis. Outcomes on the whole are good although there is a risk of prematurity.
The disease course varies with each individual. The prognosis depends on the extent of complications. Therefore, mortality figures vary enormously. Broadly, 10-year survival is 60-70%. Deaths from kidney disease have dropped over recent years, and most mortality is caused by severe cardiac or pulmonary complications.
Further reading & references
- Raynaud's and Scleroderma Association
- Scleroderma Society
- Zulian F, Martini G; Childhood systemic sclerosis. Curr Opin Rheumatol. 2007 Nov;19(6):592-7.
- Understanding and managing scleroderma; Scleroderma Society, Revised October 2008
- Chifflot H, Fautrel B, Sordet C, et al; Incidence and prevalence of systemic sclerosis: a systematic literature review. Semin Arthritis Rheum. 2008 Feb;37(4):223-35. Epub 2007 Aug 9.
- Systemic Sclerosis; DermNet NZ
- Hinchcliff M, Varga J; Systemic sclerosis/scleroderma: a treatable multisystem disease. Am Fam Physician. 2008 Oct 15;78(8):961-8.
- Minier T, Guiducci S, Bellando-Randone S, et al; Preliminary analysis of the Very Early Diagnosis of Systemic Sclerosis (VEDOSS) EUSTAR multicentre study: evidence for puffy fingers as a pivotal sign for suspicion of systemic sclerosis. Ann Rheum Dis. 2013 Aug 12. doi: 10.1136/annrheumdis-2013-203716.
- Bussone G, Mouthon L; Interstitial lung disease in systemic sclerosis. Autoimmun Rev. 2011 Mar;10(5):248-55. doi: 10.1016/j.autrev.2010.09.012. Epub 2010 Sep 21.
- Coghlan JG, Denton CP, Grunig E, et al; Evidence-based detection of pulmonary arterial hypertension in systemic sclerosis: the DETECT study. Ann Rheum Dis. 2013 May 18.
- Shanmugam VK, Steen VD; Renal disease in scleroderma: an update on evaluation, risk stratification, pathogenesis and management. Curr Opin Rheumatol. 2012 Nov;24(6):669-76.
- Jung P, Trautinger F; Capillaroscopy. J Dtsch Dermatol Ges. 2013 Aug;11(8):731-6. doi: 10.1111/ddg.12137. Epub 2013 Jun 5.
- van den Hoogen F, Khanna D, Fransen J, et al; 2013 classification criteria for systemic sclerosis: an American college of rheumatology/European league against rheumatism collaborative initiative. Ann Rheum Dis. 2013 Nov 1;72(11):1747-55. doi: 10.1136/annrheumdis-2013-204424.
- Muller-Ladner U, Tyndall A, Czirjak L, et al; Ten years EULAR Scleroderma Research and Trials (EUSTAR): what has been achieved? Ann Rheum Dis. 2013 Oct 11. doi: 10.1136/annrheumdis-2013-203997.
- Manno R, Boin F; Immunotherapy of systemic sclerosis. Immunotherapy. 2010 Nov;2(6):863-78.
- Goundry B, Bell L, Langtree M, et al; Diagnosis and management of Raynaud's phenomenon. BMJ. 2012 Feb 7;344:e289. doi: 10.1136/bmj.e289.
- Kowal-Bielecka O, Landewe R, Avouac J, et al; EULAR recommendations for the treatment of systemic sclerosis: a report from the EULAR Scleroderma Trials and Research group (EUSTAR). Ann Rheum Dis. 2009 May;68(5):620-8. doi: 10.1136/ard.2008.096677. Epub 2009 Jan 15.
- Denton CP, Lapadula G, Mouthon L, et al; Renal complications and scleroderma renal crisis. Rheumatology (Oxford). 2009 Jun;48 Suppl 3:iii32-5. doi: 10.1093/rheumatology/ken483.
- Desai CS, Lee DC, Shah SJ; Systemic sclerosis and the heart: current diagnosis and management. Curr Opin Rheumatol. 2011 Nov;23(6):545-54. doi: 10.1097/BOR.0b013e32834b8975.
- Seftel AD; Re: Erectile dysfunction is frequent in systemic sclerosis and associated with severe disease: a study of the EULAR Scleroderma Trial and Research group. J Urol. 2012 Aug;188(2):549-50. doi: 10.1016/j.juro.2012.04.091. Epub 2012 Jun 15.
- Josselin-Mahr L, Carbonne B, Cabane J; [Systemic sclerosis and pregnancy]. Rev Med Interne. 2011 Jun;32(6):363-8. doi: 10.1016/j.revmed.2010.02.004. Epub 2010 Jul 14.
- Miniati I, Guiducci S, Mecacci F, et al; Pregnancy in systemic sclerosis. Rheumatology (Oxford). 2008 Jun;47 Suppl 3:iii16-8.
- Scleroderma; University of Maryland Medical Center
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|Original Author: Dr Naomi Hartree||Current Version: Dr Mary Harding||Peer Reviewer: Prof Cathy Jackson|
|Last Checked: 10/12/2013||Document ID: 2831 Version: 24||© EMIS|