Systemic Sclerosis

Chapter: Systemic Sclerosis
McMaster Section Editor(s): Jonathan D. Adachi
Section Editor(s) in Interna Szczeklika: Irena Zimmermann-Górska, Aleksandra Tuchocka-Kaczmarek, Jan Sznajd
McMaster Author(s): Maggie Larché
Author(s) in Interna Szczeklika: Stanisław Sierakowski, Matylda Sierakowska
Additional Information

Definition, Etiology, PathogenesisTop

Systemic sclerosis (SSc) is a connective tissue disease characterized by progressive fibrosis of skin and internal organs (leading to their failure), impairment of the structure and function of blood vessels, and abnormalities of the immune system. The etiology is unknown.

Clinical Features and Natural HistoryTop

Women are affected 3 to 4 times more frequently than men. The incidence peaks between the ages of 30 and 50 years.

Clinical Forms

1. Limited cutaneous SSc (lcSSc) (formerly termed CREST [calcinosis, Raynaud phenomenon, esophageal dysmotility, sclerodactyly, telangiectasia] syndrome): The disease usually has a chronic course and often remains undiagnosed for several months to years after the onset of initial symptoms. Cutaneous involvement includes the face and distal parts of the upper and lower extremities. Thickening of the skin (scleroderma) has a tendency to remain at a constant, usually moderate level for many years; no correlation is observed between the severity of skin thickening and the extent of internal organ involvement. The gastrointestinal (GI) tract (particularly the esophagus) is most commonly affected, followed by interstitial lung disease and relatively rare cardiac involvement. Pulmonary hypertension may occur in lcSSc and should be assessed annually by echocardiography, even in asymptomatic patients. Primary biliary cholangitis is also associated with lcSSc. Patients with long-standing lcSSc may develop progressive dyspnea. This may indicate the development of pulmonary hypertension or pulmonary fibrosis and is associated with an adverse prognosis.

2. Diffuse cutaneous SSc (dcSSc): The course of the skin involvement is much more severe and acute than that in lcSSc; it is symmetric, diffuse, and includes the face, proximal parts of the extremities, and the trunk (occasionally sparing the fingers). Skin thickening usually progresses rapidly and peaks within 3 to 6 years. Organ involvement occurs almost simultaneously with skin thickening, with the lungs being affected most frequently, followed by the GI tract, heart, and kidneys. The rate and extent of internal organ involvement correlates with the severity and extent of skin thickening. Organ lesions developing in early dcSSc (conventionally defined as the first 3 years from the onset) are predictive of the subsequent course of the disease.

3. Systemic sclerosis without skin involvement (SSc sine scleroderma) is manifested by typical systemic features, such as pulmonary fibrosis, pulmonary hypertension, esophageal and other GI involvement, and renal involvement, along with serologic abnormalities, but without skin involvement.

4. Overlap syndromes with clinical features of SSc and other systemic connective tissue diseases, most commonly rheumatoid arthritis, dermatomyositis, systemic lupus erythematosus, or mixed connective tissue disease.

5. Early SSc: Raynaud phenomenon, puffy hands, capillaroscopy findings suggestive of SSc, and positive SSc-specific antinuclear antibodies (ANAs) (anticentromere [ACA], anti–Scl-70 [also known as antitopoisomerase I], antipolymerase III, anti-Th/To) with no or minimal skin thickening or internal organ involvement. This is now recognized as early disease using the new 2013 American College of Rheumatology (ACR)/European League Against Rheumatism (EULAR) criteria.

Organ Involvement

1. Raynaud phenomenon is observed in almost 100% of patients with lcSSc and in >90% of patients with dcSSc. It may precede the development of SSc by many years.

2. Cutaneous manifestations following 3 phases of development: edema, sclerosis, and atrophy; initially swollen digits (limited flexion), followed by flexion contractures; in lcSSc, pain related to damage-prone skin and poorly healing ulcers most commonly affecting fingertips; atrophy of the fingertips and nails, shortening of distal phalanges; a face with taut skin; a pinched, beak-like nose; thin lips surrounded by wrinkles (radial furrowing); reduced oral aperture, making it difficult to protrude the tongue; skin hyperpigmentation or hypopigmentation; telangiectasias, particularly on the face (and sometimes the mucosal surfaces); calcifications (most commonly of the skin of the fingers and extensor surfaces of the elbows and knees); pruritus; digital ulcers or digital pits.

3. Musculoskeletal involvement: Arthralgia or arthritis, usually symmetric, often severe; morning stiffness, usually affecting the fingers, wrists, elbows, and knees; transient episodes of joint swelling; limited joint movement caused by skin thickening; tendon rubs on movement caused by tendon involvement (tenosynovitis, particularly in dcSSc); muscle pain, muscle weakness (especially if there is associated myositis).

4. GI involvement: Sicca symptoms, gingivitis (causing tooth loss); gastroesophageal reflux disease (GERD) (due to impaired peristalsis and reduced function of the lower esophageal sphincter, which leads to gastroesophageal reflux), dysphagia (due to impaired esophageal motility and strictures). Bleeding from upper GI vascular lesions (gastric antral vascular ectasia [GAVE]) is the main cause of anemia in patients with SSc. Bloating and abdominal pain with alternating diarrhea and constipation are often associated with malabsorption (frequently due to bacterial overgrowth syndrome); symptoms of primary biliary cirrhosis may also occur (in <10%). Other GI features commonly found are severe constipation due to colonic hypomotility and fecal incontinence due to involvement of the anal sphincter.

5. Pulmonary involvement: Features of interstitial lung disease: dyspnea (initially on exertion, in advanced disease also at rest), chronic dry cough (patients frequently remain asymptomatic despite severe pulmonary involvement), basal crackles, occasionally pleural pain and pleural rub, tachypnea. Dry cough can be related to severe untreated GERD.

6. Cardiac involvement: Pulmonary arterial hypertension (progressive impairment of exercise tolerance, presyncope or syncope on exertion indicating advanced pulmonary hypertension and right ventricular failure) is the most common cardiac manifestation of SSc. Other features include angina (right ventricular ischemia caused by overload), symptoms of right ventricular failure and pulmonary hypertension (in advanced SSc), symptoms of left ventricular dysfunction (usually systolic), tachyarrhythmias, rarely bradyarrhythmias (palpitations, syncope), ischemic heart disease (most frequently caused by microcirculatory abnormalities), pericardial involvement (acute pericarditis, pericardial effusion, cardiac tamponade, constrictive pericarditis), acute myocarditis (rare).

7. Renal involvement: Symptoms are often mild and nonspecific even in patients with advanced lesions. Scleroderma renal crisis develops in 5% to 10% of patients with dcSSc (in 80% of cases, it occurs within the first 4 years of the disease) and is much less frequent (<2%) in patients with lcSSc. Positive anti-RNA polymerase III antibodies are a risk factor. Renal crisis manifests as rapidly increasing hypertension (this may be accompanied severe headache, visual disturbances, seizures, acute left ventricular failure) and features of renal failure; microangiopathic hemolytic anemia may occur (anemia, schistocytes, increased haptoglobin, reticulocytes, increased unconjugated bilirubin). In ~10% of cases hypertension is absent; these are usually patients already receiving angiotensin-converting enzyme inhibitors (ACEIs) or calcium channel blockers, patients with previous low or low-normal blood pressure, or patients with heart disease. Risk factors for scleroderma renal crisis include dcSSc, male patients, glucocorticoids >15 mgEvidence 1Moderate Quality of Evidence (moderate confidence that we know true effects of the intervention). Quality of Evidence lowered to low due to the observational nature of data but subsequently increased to the moderate level due to the large effect-size estimate and/or presence of a dose-response gradient. Montanelli G, Beretta L, Santaniello A, Scorza R. Effect of dihydropyridine calcium channel blockers and glucocorticoids on the prevention and development of scleroderma renal crisis in an Italian case series. Clin Exp Rheumatol. 2013 Mar-Apr;31(2 Suppl 76):135-9. Epub 2012 Dec 13. PubMed PMID: 23295023. Steen VD, Medsger TA Jr. Case-control study of corticosteroids and other drugs that either precipitate or protect from the development of scleroderma renal crisis. Arthritis Rheum. 1998 Sep;41(9):1613-9. PubMed PMID: 9751093.; the use of calcium channel blockers may be protective.Evidence 2Moderate Quality of Evidence (moderate confidence that we know true effects of the intervention). Quality of Evidence lowered to low due to the observational nature of data but subsequently increased to the moderate level due to the large effect-size estimate and/or presence of a dose-response gradient. Montanelli G, Beretta L, Santaniello A, Scorza R. Effect of dihydropyridine calcium channel blockers and glucocorticoids on the prevention and development of scleroderma renal crisis in an Italian case series. Clin Exp Rheumatol. 2013 Mar-Apr;31(2 Suppl 76):135-9. Epub 2012 Dec 13. PubMed PMID: 23295023. Steen VD, Medsger TA Jr. Case-control study of corticosteroids and other drugs that either precipitate or protect from the development of scleroderma renal crisis. Arthritis Rheum. 1998 Sep;41(9):1613-9. PubMed PMID: 9751093.

DiagnosisTop

Diagnostic Tests

1. Laboratory tests:

1) Blood tests: A normal or mildly elevated erythrocyte sedimentation rate (ESR) (a significantly elevated ESR is usually associated with organ involvement or concomitant infection), anemia (usually mild, worsens in patients with malabsorption and progressive renal involvement), hypergammaglobulinemia (increased IgG and IgM levels), positive serum rheumatoid factor (in 20%-30% of patients), elevated serum B-type natriuretic peptide (BNP) or N-terminal pro–B-type natriuretic peptide (NT-proBNP) levels if heart failure and/or advanced pulmonary hypertension are suspected.

2) Immunologic studies: Positive ANAs (in 90% of patients), antitopoisomerase-I antibodies (Scl-70, typically in dcSSc [in 30% of patients]), ACAs typically in lcSSc (in 70%-80% of patients), antinucleolar antibodies (nucleolar immunofluorescence), for instance, to RNA polymerase I, RNA polymerase III, Th/To, fibrillarin.

2. Radiologic studies: Hand radiographs may reveal osteolysis of the distal phalanges (or total resorption of the distal phalanx in more advanced disease) and calcifications; less frequently, similar lesions are observed on feet radiographs. Contrast-enhanced radiography of the GI tract reveals impaired esophageal motility (in advanced SSc, dilation and pipe-like appearance of the entire esophagus), impaired motor function of the small intestine (alternating segments of strictures and dilations, hypersegmentation) and large intestine (diverticulosis, occasionally significant colonic distention). Chest radiographs and high-resolution computed tomography (HRCT) reveal features of interstitial lung disease, that is, ground-glass linear and reticular opacifications, mainly in the basal peripheral and subpleural areas of the lung, traction bronchiectases, and bronchial (honeycomb) cysts. Magnetic resonance imaging (MRI) and single-photon emission computed tomography (SPECT)-)-CT may be useful in the diagnosis of cardiac involvement.

3. Doppler echocardiography reveals features of pulmonary hypertension (increased right ventricular systolic pressure >35 mm Hg) (see Pulmonary Hypertension), pericardial effusion, as well as systolic and diastolic dysfunction. Even in asymptomatic patients, echocardiography should be performed annually to facilitate early diagnosis and treatment of pulmonary hypertension.

4. Upper GI endoscopy: In the esophagus there are features of gastroesophageal reflux and telangiectasias; in the stomach, diffuse vascular lesions, particularly in the cardia, are observed (solitary or multiple telangiectasias described as a “watermelon stomach” or GAVE).

5. Pulmonary function tests may reveal a low carbon dioxide diffusing capacity of the lungs (DLCO). If there is an isolated reduced DLCO, or if there is a mismatch of DLCO and forced vital capacity (FVC) (FVC%/DLCO% >1.6), consider pulmonary hypertension as the cause and investigate with echocardiography. Even in asymptomatic patients, pulmonary function tests and echocardiography should be performed annually to facilitate early diagnosis and management of pulmonary fibrosis or pulmonary hypertension.

6. Nail-fold capillaroscopy reveals typical (though not pathognomonic) features of so-called megacapillaries or giant loops (more common in lcSSc) and avascular areas, known as “drop-outs” (predominantly in dcSSc).

7. Other studies:

1) Stress tests (6-minute walk test, cardio-respiratory exercise test; these may be used for monitoring the performance status of the patient and progression of SSc).

2) Electrocardiography (ECG) (arrhythmias and conduction disturbances).

3) Cardiac catheterization should be considered in patients with high right ventricular systolic pressure on echocardiography, those with symptoms or signs of right heart failure, and in those with isolated declining DLCO on pulmonary function tests (diagnosis of pulmonary hypertension).

8. Skin biopsy is of limited use in patients with early SSc due to the high rate of false-negative results. In patients with typical clinical manifestations, the diagnosis is straightforward, which makes the skin biopsy unnecessary. Nevertheless, it is indicated in patients suspected of having other diseases characterized by skin thickening, such as eosinophilic fasciitis or scleredema or scleromyxedema.

Diagnostic Criteria

The 2013 ACR//EULAR classification criteria (Table 14.22-1) are useful in both advanced and early SSc.

Differential Diagnosis

1. Early SSc: Raynaud phenomenon of a different etiology; other systemic connective tissue diseases, mainly undifferentiated connective tissue disease, mixed connective tissue disease, other overlap syndromes, dermatomyositis, rheumatoid arthritis.

2. Cutaneous manifestations: Skin thickening in the course of diffuse eosinophilic fasciitis (this is characterized by wood-like skin induration, peripheral blood eosinophilia, hypergammaglobulinemia, and elevated ESR; the etiology is unknown), localized scleroderma (discrete lesions with no symmetric skin changes on the extremities, no internal organ involvement or immunologic abnormalities), Buschke scleredema, scleromyxedema, lichen sclerosus et atrophicus, adipose tissue atrophy, skin thickening caused by other internal diseases (eg, chronic autoimmune hepatitis) or by chemical substances (including drugs that may cause scleroderma-like skin lesions, eg, bleomycin and contrast used in radiology), porphyria cutanea tarda, chronic graft-versus-host disease.

TreatmentTop

General Considerations

1. No treatment can cure, effectively stop, or definitively delay the progression of SSc in the majority of patients; organ-specific therapies (see below) are used to improve the survival of patients with SSc. In highly selected patients with dcSSc and severe, rapidly progressive organ involvement but without significant cardiovascular involvement, autologous hematopoietic stem cell transplantation (HSCT) can be considered by specialized scleroderma teams.Evidence 3Weak recommendation (benefits likely outweigh downsides, but the balance is close or uncertain; an alternative course of action may be better for some patients). Weak recommendation due to the increase in early mortality. Moderate Quality of Evidence (moderate confidence that we know true effects of the intervention). Quality of Evidence lowered due to the relatively low number of patients available for long-term observations. Burt RK, Shah SJ, Dill K, et al. Autologous non-myeloablative haemopoietic stem-cell transplantation compared with pulse cyclophosphamide once per month for systemic sclerosis (ASSIST): an open-label, randomised phase 2 trial. Lancet. 2011 Aug 6;378(9790):498-506. doi: 10.1016/S0140-6736(11)60982-3. Epub 2011 Jul 21. PubMed PMID: 21777972. van Laar JM, Farge D, Sont JK, et al; EBMT/EULAR Scleroderma Study Group. Autologous hematopoietic stem cell transplantation vs intravenous pulse cyclophosphamide in diffuse cutaneous systemic sclerosis: a randomized clinical trial. JAMA. 2014 Jun 25;311(24):2490-8. doi: 10.1001/jama.2014.6368. PubMed PMID: 25058083.

2. Physiotherapy, kinesiotherapy (exercise, commonly preceded by paraffin therapy), and occupational therapy are used to improve or maintain the patient’s physical capacity.

3. Because of the risk of scleroderma renal crisis, do not use glucocorticoids at a dose >15 mg/d (prednisone or prednisolone),Evidence 4Strong recommendation (downsides clearly outweigh benefits; right action for all or almost all patients). Moderate Quality of Evidence (moderate confidence that we know true effects of the intervention). Quality of Evidence lowered to low due to the observational nature of data but increased to moderate due to the large effect-size estimate and/or presence of a dose-response gradient. Montanelli G, Beretta L, Santaniello A, Scorza R. Effect of dihydropyridine calcium channel blockers and glucocorticoids on the prevention and development of scleroderma renal crisis in an Italian case series. Clin Exp Rheumatol. 2013 Mar-Apr;31(2 Suppl 76):135-9. Epub 2012 Dec 13. PubMed PMID: 23295023. Steen VD, Medsger TA Jr. Case-control study of corticosteroids and other drugs that either precipitate or protect from the development of scleroderma renal crisis. Arthritis Rheum. 1998 Sep;41(9):1613-9. PubMed PMID: 9751093. unless the use of glucocorticoids is indispensable because of life-threatening organ involvement. In such situations, a prophylactic calcium channel blocker may be considered along with close monitoring of plasma creatinine levels and blood pressure. Patients with dcSSc are particularly at risk within the first 5 years of disease. Do not use cyclosporine (INN ciclosporin), nonsteroidal anti-inflammatory drugs (NSAIDs), or drugs that may affect vascular tone, such as ephedrine, ergot derivatives, and beta-blockers.

Treatment of Early dSSc

Make attempts to diagnose and treat organ involvement as early as possible. The extent of skin thickening (which may be measured in several areas, including the face, back, chest, arm, forearm, hand, fingers, abdomen, leg, foot) is called the modified Rodnan skin score (mRss). This score correlates with internal organ involvement and may be useful in estimating the severity and dynamics of the disease. In patients with rapidly progressive skin lesions (particularly with mRss >15-20), consider methotrexate at a dose of up to 20 mg/wk, mycophenolate mofetil, or cyclophosphamide (dosage as in interstitial lung disease). In patients with severe rapidly progressive skin involvement, autologous HSCT could be considered by scleroderma specialist teams.Evidence 5Weak recommendation (benefits likely outweigh downsides, but the balance is close or uncertain; an alternative course of action may be better for some patients). Weak recommendation due to the increase in early mortality. Moderate Quality of Evidence (moderate confidence that we know true effects of the intervention). Quality of Evidence lowered due to the relatively low number of patients available for long-term observations. Burt RK, Shah SJ, Dill K, et al. Autologous non-myeloablative haemopoietic stem-cell transplantation compared with pulse cyclophosphamide once per month for systemic sclerosis (ASSIST): an open-label, randomised phase 2 trial. Lancet. 2011 Aug 6;378(9790):498-506. doi: 10.1016/S0140-6736(11)60982-3. Epub 2011 Jul 21. PubMed PMID: 21777972. van Laar JM, Farge D, Sont JK, et al; EBMT/EULAR Scleroderma Study Group. Autologous hematopoietic stem cell transplantation vs intravenous pulse cyclophosphamide in diffuse cutaneous systemic sclerosis: a randomized clinical trial. JAMA. 2014 Jun 25;311(24):2490-8. doi: 10.1001/jama.2014.6368. PubMed PMID: 25058083. Calcium channel blockers may protect against digital ulcers and scleroderma renal crisis.Evidence 6Weak recommendation (benefits likely outweigh downsides, but the balance is close or uncertain; an alternative course of action may be better for some patients). Moderate Quality of Evidence (moderate confidence that we know true effects of the intervention). Quality of Evidence lowered due to the observational nature of data. Montanelli G, Beretta L, Santaniello A, Scorza R. Effect of dihydropyridine calcium channel blockers and glucocorticoids on the prevention and development of scleroderma renal crisis in an Italian case series. Clin Exp Rheumatol. 2013 Mar-Apr;31(2 Suppl 76):135-9. Epub 2012 Dec 13. PubMed PMID: 23295023.

Treatment of Raynaud Phenomenon, Finger Ulcers, and Necrosis

Treatment consists mainly of extended-release formulations of dihydropyridine calcium channel blockers, such as nifedipine; other drugs: see Raynaud Phenomenon. In patients with severe treatment-resistant SSc, and particularly in patients with poorly healing ulcers, intravenous prostacyclins (iloprost, alprostadil) are commonly used. The endothelin-1 receptor antagonist bosentan can prevent the development of new ulcers and could be considered.

Treatment of Interstitial Lung Disease

Also see Selected Other Types of Idiopathic Interstitial Pneumonia.

Treatment of interstitial lung disease in the setting of scleroderma is best conducted by clinicians or teams experienced in both connective tissue and lung diseases. Below are some principles of treatment:

1) Either oral or IV cyclophosphamide can be used for 1 year, or oral mycophenolate for 2 years, with equivalent improvements in lung function. Mycophenolate is often preferred due to fewer adverse reactions and is used also as maintenance therapy after cyclophosphamide.Evidence 7Weak recommendation (benefits likely outweigh downsides, but the balance is close or uncertain; an alternative course of action may be better for some patients). High Quality of Evidence (high confidence that we know true effects of the intervention). Tashkin DP, Roth MD, Clements PJ, et al; Sclerodema Lung Study II Investigators. Mycophenolate mofetil versus oral cyclophosphamide in scleroderma-related interstitial lung disease (SLS II): a randomised controlled, double-blind, parallel group trial. Lancet Respir Med. 2016 Sep;4(9):708-719. doi: 10.1016/S2213-2600(16)30152-7. Epub 2016 Jul 25. PubMed PMID: 27469583; PubMed Central PMCID: PMC5014629. The cumulative dose of cyclophosphamide is lower if given by monthly IV infusion compared with daily oral dosing.

2) Cautious concomitant use of glucocorticoids may be considered (do not exceed doses equivalent to 15 mg/d of prednisone, if possible). Treatment with azathioprine or rituximab may also be considered.

3) Recently nintedanib, a tyrosine kinase inhibitor with antifibrotic effects, has been shown to limit the decline in pulmonary function in patients with systemic sclerosis and pulmonary fibrosis.Evidence 8Weak recommendation (benefits likely outweigh downsides, but the balance is close or uncertain; an alternative course of action may be better for some patients). High Quality of Evidence (high confidence that we know true effects of the intervention).Distler O, Highland KB, Gahlemann M, et al; SENSCIS Trial Investigators. Nintedanib for Systemic Sclerosis-Associated Interstitial Lung Disease. N Engl J Med. 2019 Jun 27;380(26):2518-2528. doi: 10.1056/NEJMoa1903076. Epub 2019 May 20. PubMed PMID: 31112379.

Treatment of Pulmonary Hypertension

See Pulmonary Hypertension.

Treatment of Musculoskeletal Involvement

1. Arthralgia: Acetaminophen (INN paracetamol), tramadol.

2. Progressive polyarthritis or myositis: Methotrexate (doses as in rheumatoid arthritis), initial glucocorticoid treatment (<15 mg/d of prednisone) may be also considered. Biologics could be considered, in particular tumor necrosis factor (TNF) inhibitors, such as etanercept or adalimumab, or interleukin-6 (IL-6) receptor blockers, such as tocilizumab.

3. Myositis:

1) Mild or moderate: Azathioprine 2.5 mg/kg/d (maximum dose, 200 mg/d) orally or methotrexate (as above). Consider adding glucocorticoids at a dose equivalent to <15 mg/d of prednisone.

2) Severe: Methylprednisolone 3 to 4 pulses of 500 to 1000 mg IV (every day or every other day) followed by prednisone (a dose of 1 mg/kg/d may be required; patients should be counselled regarding the possibility of this inducing scleroderma renal crisis) and azathioprine or methotrexate.

Treatment of Gastrointestinal Involvement

Symptomatic treatment, that is, conservative measures, such as raising the head of the bed by 10 to 15 cm, and proton pump inhibitors (PPIs) (high doses are often required) in patients with GERD, prokinetic agents including domperidone 10 mg tid or prucalopride 2 mg once daily in patients with impaired motility, intermittent courses of antibiotics in patients with malabsorption due to bacterial overgrowth syndrome (empiric quinolones, amoxicillin/clavulanic acid, rifaximin).Evidence 9Weak recommendation (benefits likely outweigh downsides, but the balance is close or uncertain; an alternative course of action may be better for some patients). Low Quality of Evidence (low confidence that we know true effects of the intervention). Quality of Evidence lowered due to the observational nature of data and a relatively short observation period. Parodi A, Sessarego M, Greco A, et al. Small intestinal bacterial overgrowth in patients suffering from scleroderma: clinical effectiveness of its eradication. Am J Gastroenterol. 2008 May;103(5):1257-62. doi: 10.1111/j.1572-0241.2007.01758.x. Epub 2008 Apr 16. PubMed PMID: 18422815.

Treatment of Cardiac Involvement

1. Pulmonary hypertension.

2. Arrhythmias, conduction abnormalities, heart failure: Symptomatic treatment.

3. Active myocarditis: Glucocorticoids (doses as in systemic lupus erythematosus); if ineffective, cyclophosphamide (doses as in interstitial lung disease).

Treatment of Scleroderma Renal Crisis

1. Elevated blood pressure >140/90 mm Hg, rise in blood pressure >20 mm Hg (either systolic or diastolic) higher than the patients’ normal blood pressure, ≥2-fold increase in serum creatinine level, or proteinuria: Immediately start an ACEI (hospitalize if blood pressure >160/100 mm Hg). The dose of the ACEI should be titrated up to achieve a decrease in systolic blood pressure of 10 to 20 mm Hg over 24 hours, even if renal function is declining. If normalization of arterial pressure is not being achieved, add another antihypertensive agent, eg, an angiotensin receptor blocker, a calcium channel blocker, or a nitrate (particularly in patients with pulmonary edema).

2. Progressive renal failure: Renal replacement therapy (RRT). In half of the patients requiring RRT, renal function improves over 6 to 24 months to a degree that allows discontinuation of RRT.Evidence 10Moderate Quality of Evidence (moderate confidence that we know true effects of the intervention). Quality of Evidence lowered due to data being limited to 1 center specializing in scleroderma care and relative imprecision. Steen VD, Medsger TA Jr. Long-term outcomes of scleroderma renal crisis. Ann Intern Med. 2000 Oct 17;133(8):600-3. PubMed PMID: 11033587. If kidney transplantation is being considered, it should be postponed for at least 2 years after the episode of scleroderma renal crisis.

3. The use of calcium channel blockers seems to be protective of scleroderma renal crisis and could be considered.Evidence 11Weak recommendation (benefits likely outweigh downsides, but the balance is close or uncertain; an alternative course of action may be better for some patients). Moderate Quality of Evidence (moderate confidence that we know true effects of the intervention). Quality of Evidence lowered to low due to the observational nature of studies but increased to moderate due to the strength of association. Montanelli G, Beretta L, Santaniello A, Scorza R. Effect of dihydropyridine calcium channel blockers and glucocorticoids on the prevention and development of scleroderma renal crisis in an Italian case series. Clin Exp Rheumatol. 2013 Mar-Apr;31(2 Suppl 76):135-9. Epub 2012 Dec 13. PubMed PMID: 23295023. 

Follow-UpTop

Suggested follow-up:

1) It is recommended that the patient is advised to measure blood pressure 3 times a week at home, particularly in the first 5 years of disease. At later stages of the disease, monthly blood pressure monitoring is probably sufficient (or more frequently if blood pressure is rising).

2) Plasma creatinine levels, estimated glomerular filtration rate (eGFR), and urine dipstick test for proteinuria: In early dcSSc these should be measured every 4 to 6 weeks; at later stages of the disease, every 3 to 6 months.

3) ECG and Doppler echocardiography: In early dcSSc these should be performed every 6 to 12 months, and at later stages or in limited SSc every 12 to 24 months (depending on risk factors).

4) Pulmonary function tests (spirometry, DLCO, postexertional pulse oximetry): In early dcSSc these tests should be performed every 6 to 12 months, and at later stages or in limited SSc every 12 months.

5) Other studies depend on symptoms and results of the above investigations and may include, for instance, the 6-minute walk test to monitor performance status. In early dcSSc monitor ESR, complete blood count, and serum creatine kinase, aspartate aminotransferase, and alanine aminotransferase levels every 12 months. Chest HRCT, contrast-enhanced radiographs of the GI, and endoscopy of the upper GI tract could be considered if clinically indicated. If disease progression is observed, the frequency of the follow-up studies could be increased.

PrognosisTop

Prognosis depends on the presence and extent of internal organ involvement. More than half of all deaths in patients with SSc are related to pulmonary fibrosis, pulmonary hypertension, and renal involvement. Other causes of death are mainly infections, malignancy, and cardiovascular complications not directly related to SSc. In patients with cardiac involvement the average survival from the time of diagnosis is 9 years. Ten-year survival in patients with pulmonary involvement but without cardiac or renal involvement is 60%, and ~75% in patients without involvement of any of these organs. In patients with appropriately treated pulmonary hypertension 3-year survival rates are ~65%.

TablesTop

Table 14.22-1. 2013 ACR/EULAR criteria for the classification of systemic sclerosis

Criteria

Score

Comments

Skin thickening of the fingers of both hands extending proximal to the metacarpophalangeal joints

9

Sufficient criterion

Skin thickening of the fingers

 

Puffy fingersa

2

If both are present, only the higher score counts

Sclerodactyly of the fingersb

4

Fingertip lesionsc

 

Digital tip ulcers

2

If both are present, only the higher score counts

Fingertip pitting scars

3

Telangiectasiad

2

Abnormal nail-fold capillariese

2

Pulmonary arterial hypertensionf and/or interstitial lung diseaseg

2

Raynaud phenomenonh

3

SSc-related autoantibodies:

 

– Anticentromere

– Antitopoisomerase I (anti-Scl 70)

– Anti-RNA polymerase III

3

Maximum score: 3

Interpretation: The diagnosis of SSc can be made in patients with a total score ≥9.

a A diffuse, usually nonpitting increase in soft tissue mass of the digits extending beyond the normal confines of the joint capsule, which affects the physiological contour of the fingers (normal digits are tapered distally with the tissues following the contours of the digital bone and joint structures).

b Skin hardening distal to the metacarpophalangeal joints but proximal to the proximal interphalangeal joints.

c Ulcers or scars distal to or at the proximal interphalangeal joint not thought to be due to trauma. Digital pitting scars are depressed areas at digital tips as a result of ischemia, rather than trauma or exogenous causes.

d Telangiectasias are visible, macular, dilated superficial blood vessels, which collapse upon pressure and fill slowly when pressure is released. Telangiectasias in a scleroderma-like pattern are round, well-demarcated, and found on hands, lips, inside of the mouth, and/or are large mat-like telangiectasias. Telangiectasias should be distinguished from rapidly filling spider angiomas with a central arteriole and from dilated superficial vessels.

e Abnormal nail-fold capillary patterns consistent with systemic sclerosis are enlarged capillaries and/or capillary loss with or without pericapillary hemorrhages at the nail fold. They may also be seen on the cuticle.

f Pulmonary arterial hypertension diagnosed by right-sided heart catheterization according to standard definitions.

g Interstitial lung disease: Pulmonary fibrosis seen on high-resolution CT or chest radiography, most pronounced in the basilar portions of the lungs, or occurrence of Velcro crackles on auscultation not due to another cause such as congestive heart failure.

h Raynaud phenomenon: Self-reported or reported by a physician, with at least a 2-phase color change in finger(s) and often toe(s) consisting of pallor, cyanosis, and/or reactive hyperemia in response to cold exposure or emotion; usually one phase is pallor.

The criteria are not applicable to patients with skin thickening sparing the fingers or to patients who have a scleroderma-like disorder that better explains their manifestations (eg, nephrogenic sclerosing fibrosis, generalized morphea, eosinophilic fasciitis, scleredema diabeticorum, scleromyxedema, erythromelalgia, porphyria, lichen sclerosis, graft-versus-host disease, diabetic cheiroarthropathy).

Adapted from Ann Rheum Dis. 2013;72(11):1747-55.

ACR, American College of Rheumatology; CT, computed tomography; EULAR, European League Against Rheumatism.

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