eMedicine Specialties > Rheumatology > Systemic Rheumatic Disease

Scleroderma

Author: Sergio A Jimenez, MD, Director, The Scleroderma Center; Co-Director, Jefferson Institute of Molecular Medicine; Director, Division of Connective Tissue Diseases; Professor of Medicine, Department of Dermatology and Cutaneous Biology, Thomas Jefferson University
Coauthor(s): Patrick M Cronin, DO, FACR, Clinical Associate Professor of Medicine, Department of Medicine, Division of Rheumatology, University of Pennsylvania Health System, Pennsylvania Hospital; Andrew Koenig, ; Marie Spevak O'Brien, DO, Assistant Clinical Professor of Medicine, Arthritis and Rheumatology, Lehigh Valley Physician Group
Contributor Information and Disclosures

Updated: Oct 14, 2008

Introduction

Background

Scleroderma is derived from the Greek words skleros (hard or indurated) and derma (skin). Hippocrates first described this condition as thickened skin.1 Carlo Curzio (1752) offered the first detailed description of scleroderma in a patient with hard skin, which he described as woodlike or as containing a dry hide. In 1836, Giovambattista Fantonetti applied the term scleroderma to a patient's condition.2 He applied the term to describe a patient with dark leatherlike skin who exhibited a loss of range of joint motion due to skin tightening. Robert H. Goetz first described in detail the concept of scleroderma as a systemic disease in 1945; he introduced the term progressive systemic sclerosis to emphasize the systemic and often progressive nature of the disease.

Definition

The term systemic sclerosis is used to describe a systemic disease characterized by skin induration and thickening accompanied by various degrees of tissue fibrosis and chronic inflammatory infiltration in numerous visceral organs, prominent fibroproliferative vasculopathy, and humoral and cellular immune alterations.

The American College of Rheumatology (ACR) criteria for the classification of systemic sclerosis require one major criterion or two minor criteria, as follows:

  • Major criterion: Proximal scleroderma is characterized by symmetric thickening, tightening, and induration of the skin of the fingers and the skin that is proximal to the metacarpophalangeal or metatarsophalangeal joints. These changes may affect the entire extremity, face, neck, and trunk (thorax and abdomen; see Images 1-2).
  • Minor criteria
    • Sclerodactyly is characterized by thickening, induration, and tightening of the skin, limited to only the fingers.
    • Digital pitting scars or a loss of substance from the finger pad: As a result of ischemia, depressed areas of the fingertips or a loss of digital pad tissue occurs.
    • Bibasilar pulmonary fibrosis includes a bilateral reticular pattern of linear or lineonodular densities most pronounced in basilar portions of the lungs on standard chest roentgenography. These densities may assume the appearance of diffuse mottling or a honeycomb lung and are not attributable to primary lung disease.

Pathophysiology

Systemic sclerosis is a systemic disease that affects many organ systems. It is most obvious in the skin; however, the GI tract; the respiratory, renal, cardiovascular, and genitourinary systems; and numerous vascular structures are frequently involved. The symptoms result from inflammation and progressive tissue fibrosis and occlusion of the microvasculature by excessive production and deposition of types I and III collagens. The levels of other macromolecules (eg, glycosaminoglycans, tenascin, fibronectin) found in the connective tissue are also increased.

The vascular alterations show a predilection for the small arteries and arterioles. Vascular dysfunction is one of the earliest alterations of systemic sclerosis and may represent the initiating event in its pathogenesis. Severe alterations in small blood vessels of skin and internal organs, including fibrosis and perivascular cellular infiltration with activated T cells, are almost always present in systemic sclerosis.

Frequency

United States

The estimated incidence of systemic sclerosis is 19 cases per million population, and the prevalence of systemic sclerosis has been estimated at 240 cases per million population, although the reported prevalence has ranged from 138 to 286 cases per million population. The prevalence has increased because of earlier detection through better diagnosis and an increased survival rate. Obtaining an exact estimate of prevalence is difficult because systemic sclerosis is frequently misdiagnosed. Juvenile-onset systemic sclerosis is uncommon and usually presents as an overlap syndrome with myositis. In the United States, the prevalence of systemic sclerosis has been reported to be as high as 400 cases per million women aged 35-65 years.

International

Systemic sclerosis is found worldwide.

Mortality/Morbidity

Pulmonary hypertension and scleroderma renal crisis are the most frequent causes of mortality. Survival averages 12 years from diagnosis and correlates best with the clinical disease subtype (diffuse cutaneous vs limited cutaneous) and extent of organ involvement.

  • The limited cutaneous subset carries a 10-year survival rate of 71%.
  • The diffuse cutaneous subset carries a 10-year survival rate of 21%.
  • Pulmonary hypertension is a major prognostic factor for survival.

Race

Systemic sclerosis affects individuals of all races.

  • The risk of systemic sclerosis in blacks is slightly higher than in whites; in young black women, the risk is 10 times higher.
  • Incidence rates among ethnically related groups who are geographically separate show some discrepancy. The incidence of systemic sclerosis is lower in native Nigerians than in African Americans. Oklahoma Choctaw Indians have an incidence of 472 cases per million population, which is higher than that of the Missouri Choctaw Indians. These differences may be due to environmental exposures or differences in genetic predisposition.

Sex

The risk of systemic sclerosis is 3-9 times higher in women than in men.

Age

The peak onset occurs in individuals aged 30-50 years.

Clinical

History

  • Skin (see Images 1-3)
    • Diffuse pruritus
    • Skin tightness and induration (see Images 1-2)
    • Skin pigmentary changes (hyperpigmentation or hypopigmentation; see Image 3)
  • Vascular system
    • Raynaud phenomenon (70% of patients with systemic sclerosis initially present with this symptom; 95% eventually develop it during the course of their disease)
    • Healed pitting ulcers in fingertips
    • Cutaneous and mucosal telangiectasis
  • Gastrointestinal system
    • Gastroesophageal reflux caused by lower esophageal sphincter (LES) incompetence and decreased or absent peristalsis in the lower two thirds of the esophagus (may lead to hoarseness, aspiration pneumonia, and dysphagia)
    • Dyspepsia, bloating, and early satiety
    • Constipation alternating with diarrhea (may lead to malabsorption)
  • Respiratory system
  • Musculoskeletal system3
    • Arthralgia
    • Myalgia
    • Loss in joint range of motion
    • Symptoms of carpal tunnel syndrome
    • Muscle weakness
  • Cardiovascular system
  • Genitourinary system
  • Ears, nose, and throat
    • Sicca syndrome
    • Poor dentition due to sicca syndrome
    • Loosening of dentition due to alteration in the tooth suspensory ligament and thickening of the periodontal membrane
    • Hoarseness due to acid reflux or vocal cord fibrosis
  • Endocrine system -Hypothyroidism
  • Renal system
  • Neurologic
    • Facial pain and hand paresthesias due to sensory peripheral entrapment neuropathy
    • Headache and stroke during hypertensive renal crisis
  • Constitutional
    • Fatigue
    • Weight loss

Physical

  • Skin
    • Skin pigmentary changes include a salt-and-pepper appearance, with areas of hyperpigmentation alternating with hypopigmentation, or an overall appearance of tanned skin that persists long after sun exposure (see Image 3).
    • Telangiectasias are dilated vessels located just beneath the dermis on any skin area, but they are most obvious in the face (perioral area), hands, and anterior chest.
    • The skin of the hands may be edematous or swollen early in the disease, and the patient may initially report this as puffy changes. This edematous stage precedes the indurated sclerotic stage; longer time to progression to the sclerotic phase indicates a better prognosis. A rapid progression of sclerosis is associated with a worse prognosis and, often, more extensive and aggressive visceral organ involvement with an increased risk of renal crisis development.
    • In the sclerotic phase, the skin may appear tight and shiny, with a characteristic loss of hair, decreased sweating, and loss of the ability to make a skin fold. This process of thickening generally begins distally on the fingers. Structures such as skin creases and dorsal veins begin to fade. The skin induration usually progresses proximally in a continuous symmetrical fashion.
    • Calcinosis may develop on the fingers and extremities, usually the extensor side of the forearms and the prepatellar areas; however, any area can be affected (see Image 4).
    • Limited cutaneous systemic sclerosis involves areas distal to the elbow and knee but may involve the face and neck. CREST (calcinosis, Raynaud phenomenon, esophageal dysmotility, sclerodactyly, and telangiectasias [not all are needed to be called CREST]) syndrome is an older term used to describe this subset of limited cutaneous systemic sclerosis.
    • Diffuse cutaneous systemic sclerosis refers to skin thickening on the trunk and proximal aspects of the extremities in addition to the face.
    • Reduced oral aperture (microstomia) due to perioral involvement (measure incisor-to-incisor distance) may develop.
    • Edema may be the result of hydrophilic glycosaminoglycan deposits in the dermis. These changes (edema) may also reflect vascular changes, inflammation, and hydrostatic changes. The mechanism by which the edema resolves is not clear. Possibly, the edema becomes less apparent owing to a reduction of the hydrophilic glycosaminoglycan deposits as they are replaced by the less hydrophilic fibrous collagens. Alternatively, the edema does not resolve but becomes clinically less apparent because of dermal thickening. The edema usually does not improve with the use of diuretic therapy.
  • Eyes, ears, nose, and throat
    • Salivary production may be decreased and spontaneous sublingual pooling of saliva may be absent.
    • Xerostomia and xerophthalmia may be part of the examination findings. A confirmatory minor salivary gland biopsy may show fibrosis without the pronounced lymphocytic aggregates that would be expected with primary Sjögren syndrome. In addition, patients with systemic sclerosis typically do not harbor anti-Ro and anti-La antibodies.
    • Oropharyngeal and esophageal cancers are more common in persons with diffuse systemic sclerosis.4,5,6
  • Vascular changes
    • Raynaud phenomenon results in characteristic color changes of pallor, cyanosis, and then redness (white, blue, red), which are accompanied by numbness, tingling, or pain. These events may be triggered by cold, smoking, or emotional stress. Subintimal hyperplasia, typically present in systemic sclerosis vessels, can reduce the luminal diameter by more than 75%, limiting blood flow. This baseline reduction, in addition to the natural response to cold, accounts for the exaggerated response.
    • Raynaud phenomenon occurs in 5-15% of the general population. The female-to-male ratio is 4:1, with onset occurring during the teenaged years.
    • Raynaud phenomenon may precede obvious systemic sclerosis features by months or even years. Symptoms may last longer than 2 years. If this occurs without the development of characteristic connective-tissue diseases, a benign primary Raynaud phenomenon is generally indicated, with an excellent prognosis. However, 5-10% of this population may eventually develop systemic sclerosis.
    • Infarction and dry gangrene may be due to severe vasospasm or to structural vascular occlusion. This process usually involves the digits but can also involve the lips, nose, and ears.
    • Nail-fold capillary microscopy demonstrates fewer capillaries than normal (ie, capillary loop drop [see Image 5]) and numerous dilated capillary loops.
  • Musculoskeletal system3
    • Patients may present with generalized arthralgias and morning stiffness that may mimic other systemic autoimmune diseases. Clinically apparent synovitis is uncommon. Hand and joint function may decline over time because of skin tightening rather than arthropathy. Tendon friction rubs are found almost exclusively in diffuse systemic sclerosis and may be detected as the tendon is moved actively or passively.
    • The following palpable tendon friction rubs may be found:
      • Shoulder - Scapula
      • Elbow - Olecranon
      • Knee - Patella
      • Wrists - Flexor or extensor
      • Fingers - Flexor or extensor (rare)
      • Ankle - Anterior tibia, posterior tibia, peroneal, Achilles
    • Myositis may cause weakness and muscle wasting. Levels of serum creatine kinase (CK) and aldolase are elevated.
    • Acroosteolysis (ie, resorption or dissolution of the distal end of the phalanx) may occur.
    • Flexion contractures of any affected joint may occur.
  • Respiratory system
    • Dry rales may be the only physical examination finding that suggests pulmonary involvement in systemic sclerosis.
    • An accentuated pulmonic secondary heart sound (P2) or right ventricular heave may indicate the presence of pulmonary artery hypertension.
    • Transthoracic echocardiography is a noninvasive study for assessing pulmonary artery pressure. A systolic pulmonary artery pressure of greater than 35 mm Hg is considered to represent pulmonary artery hypertension. However, right-sided heart catheterization provides the most accurate pulmonary artery pressure (see Imaging Studies).7
    • Pulmonary function testing is important in all patients with systemic sclerosis, although lung volumes can correlate poorly with extent of interstitial lung disease. Results of pulmonary function testing are ultimately abnormal in 80% of the patients. Carbon monoxide diffusion capacity (DLCO) is very sensitive and helps establish organ involvement at an earlier stage. Pulmonary function tests may demonstrate a decreased forced vital capacity and total lung capacity and a low DLCO. These changes reflect fibrotic infiltration in the lung (see Images 6-7). An isolated or disproportionate reduction of DLCO with a ratio of forced vital capacity (FVC) or total lung capacity (TLC) to DLCO of greater than 1.6 indicates pulmonary vascular fibrosis and vascular obliteration that leads to pulmonary hypertension.
    • A high-resolution CT scan (HRCT) is highly sensitive for revealing pulmonary involvement (see Imaging Studies). It may demonstrate a ground-glass appearance in areas of active alveolitis or septal fibrosis and honeycombing in areas of interstitial fibrosis. Patients with normal initial HRCT findings have a good long-term prognosis.8
    • Patients are at risk for aspiration pneumonia due to lower esophageal sphincter incompetence.
  • Gastrointestinal system
    • Reflux due to decreased lower esophageal sphincter pressure
    • Severe esophagitis
    • Barrett metaplasia (can lead to cancer)
    • Candida esophagitis
    • Esophageal strictures
    • Gastric vascular antral ectasia (dilated submucosal capillaries), also known as watermelon stomach
    • Primary biliary cirrhosis (PBC) associated with antimitochondrial antibodies (Studies have shown that liver dysfunction in patients with PBC and systemic sclerosis may progress more slowly than in patients with PBC alone.9 )
    • Wide-mouth colonic diverticula
    • Malabsorption
    • Atrophy of smooth muscle and fibrotic changes leading to decreased peristalsis throughout the GI tract (gastroesophageal reflux disease [GERD], gastroparesis, constipation, pseudo-obstruction; see Image 8)
    • Anal sphincter incompetence
  • Renal system
    • Patients with diffuse, rapid skin involvement have the highest risk (approximately 20-25%) of developing scleroderma renal crisis. Renal crisis occurs in about 10% of all patients with systemic sclerosis.
    • Renal crisis presents as accelerated hypertension, oliguria, headache, dyspnea, edema, and rapidly rising serum creatinine levels.
    • Approximately 10% of renal crisis cases occur in the absence of an elevated blood pressure.
    • Renal crisis is observed within 4 years of diagnosis in about 75% of patients but may develop as late as 20 years after diagnosis. Renal crises are slightly more common in black than in whites, and men have a greater risk than women.
    • Scleroderma renal crisis that is not treated aggressively invariably leads to renal failure, requiring dialysis or renal transplantation, or even death.
    • Preventing renal crisis is critical. Check blood pressure, monitor serum creatinine, and start angiotensin-converting enzyme (ACE) inhibitors early in at-risk patients.
    • Avoid high doses of corticosteroids since this is a significant risk factor for renal crisis.
  • Cardiovascular system
    • Cardiac involvement indicates a worse prognosis. Pericardial effusion is usually asymptomatic and may develop in up to one third of patients with systemic sclerosis. Clinically significant pericarditis is rare.
    • Cor pulmonale may develop secondary to long-standing pulmonary fibrosis or pulmonary artery hypertension.
    • Conduction abnormalities, including complete A-V block, may be revealed with routine ECG or, more frequently, with 24-hour Holter monitor or echocardiography.
    • Infiltrative cardiomyopathy with replacement of cardiac muscle by fibrous tissue can lead to arrhythmias, heart failure, or both.
    • Contraction band necrosis results from global ischemia and reperfusion. Patients may have recurrent episodes of vasospasm that are caused by the same mechanism involved in Raynaud phenomenon. This process can lead to cardiomyopathy and heart failure.
  • Neurologic system: Trigeminal neuralgia (uncommon) and carpal tunnel symptoms may result from peripheral entrapment neuropathies. Although rare, sensory neuropathies unrelated to entrapment may be present.
  • Obstetrics and gynecology
    • Women may experience vaginal dryness, dyspareunia, and menstrual irregularities.
    • Pregnancy in women with systemic sclerosis is considered a high risk because of a higher risk of pregnancy loss and higher complication rates, but a diagnosis of systemic sclerosis is not an absolute contraindication for pregnancy. A study of 50 patients (67 pregnancies) showed that 18% miscarried, 26% delivered preterm, and 55% delivered at full term. Pregnancy risk is greatest in those who have had the disease for less than 4 years and who also have diffuse cutaneous involvement.
    • Some symptoms may increase during pregnancy (eg, edema, arthralgias, GERD). Skin manifestations are not reported to worsen, but the data on this matter are incomplete. Raynaud symptoms may improve during pregnancy, only to worsen after delivery.
    • Certain medications, such as D-penicillamine, cytotoxic agents, and ACE inhibitors, should be discontinued prior to pregnancy.
  • Genitourinary system
    • Erectile dysfunction is common in males and is the presenting symptom in some cases.
    • Urinary bladder infiltration may cause microhematuria.

Causes

  • The exact etiology of systemic sclerosis is unclear; however, the following pathogenic mechanisms are always present:
    • Endothelial cell injury
    • Fibroblast activation
    • Cellular and humoral immunologic derangement
  • Environmental factors (eg, triggers or accelerators) for the development of systemic sclerosis include the following:
    • Silica exposure
    • Solvent exposure (vinyl chloride, trichloroethylene, epoxy resins, benzene, carbon tetrachloride)10
    • Radiation exposure or radiotherapy
  • Cytomegalovirus, human herpesvirus 5, and parvovirus B19 have been proposed as viral accelerating factors, but evidence of their involvement is inconclusive.
  • Drugs: Bleomycin and pentazocine may be involved in the development of systemic sclerosis.

More on Scleroderma

Overview: Scleroderma
Differential Diagnoses & Workup: Scleroderma
Treatment & Medication: Scleroderma
Follow-up: Scleroderma
Multimedia: Scleroderma
References
[ CLOSE WINDOW ]

References

  1. David M. A case of scleroderma mentioned by Hippocrates in his aphorisms. Korot. 1981;8(1-2):61-3. [Medline].

  2. Fantonetti G. Case of general induration of the skin. Dublin J Med Sci. 1838;13:158-9.

  3. Pope JE. Musculoskeletal involvement in scleroderma. Rheum Dis Clin North Am. May 2003;29(2):391-408. [Medline].

  4. Derk CT, Rasheed M, Spiegel JR, et al. Increased incidence of carcinoma of the tongue in patients with systemic sclerosis. J Rheumatol. Apr 2005;32(4):637-41. [Medline].

  5. Derk CT, Rasheed M, Artlett CM, et al. A cohort study of cancer incidence in systemic sclerosis. J Rheumatol. Jun 2006;33(6):1113-6. [Medline].

  6. Wooten M. Systemic sclerosis and malignancy: a review of the literature. South Med J. Jan 2008;101(1):59-62. [Medline].

  7. Hsu VM, Moreyra AE, Wilson AC, et al. Assessment of pulmonary arterial hypertension in patients with systemic sclerosis: comparison of noninvasive tests with results of right-heart catheterization. J Rheumatol. Mar 2008;35(3):458-65. [Medline].

  8. Launay D, Remy-Jardin M, Michon-Pasturel U, et al. High resolution computed tomography in fibrosing alveolitis associated with systemic sclerosis. J Rheumatol. Sep 2006;33(9):1789-801. [Medline].

  9. Rigamonti C, Shand LM, Feudjo M, et al. Clinical features and prognosis of primary biliary cirrhosis associated with systemic sclerosis. Gut. Mar 2006;55(3):388-94. [Medline].

  10. Nietert PJ, Sutherland SE, Silver RM, et al. Is occupational organic solvent exposure a risk factor for scleroderma?. Arthritis Rheum. Jun 1998;41(6):1111-8. [Medline].

  11. Perera A, Fertig N, Lucas M, et al. Clinical subsets, skin thickness progression rate, and serum antibody levels in systemic sclerosis patients with anti-topoisomerase I antibody. Arthritis Rheum. Aug 2007;56(8):2740-6. [Medline].

  12. Arnett FC. Is scleroderma an autoantibody mediated disease?. Curr Opin Rheumatol. Nov 2006;18(6):579-81. [Medline].

  13. Baroni SS, Santillo M, Bevilacqua F, et al. Stimulatory autoantibodies to the PDGF receptor in systemic sclerosis. N Engl J Med. Jun 22 2006;354(25):2667-76. [Medline].

  14. Allanore Y, Borderie D, Meune C, et al. N-terminal pro-brain natriuretic peptide as a diagnostic marker of early pulmonary artery hypertension in patients with systemic sclerosis and effects of calcium-channel blockers. Arthritis Rheum. Dec 2003;48(12):3503-8. [Medline].

  15. Strange C, Bolster MB, Roth MD, et al. Bronchoalveolar lavage and response to cyclophosphamide in scleroderma interstitial lung disease. Am J Respir Crit Care Med. Jan 1 2008;177(1):91-8. [Medline].

  16. Nash RA, McSweeney PA, Nelson JL, et al. Allogeneic marrow transplantation in patients with severe systemic sclerosis: resolution of dermal fibrosis. Arthritis Rheum. Jun 2006;54(6):1982-6. [Medline].

  17. [Best Evidence] Fries R, Shariat K, von Wilmowsky et al. Sildenafil in the treatment of Raynaud's phenomenon resistant to vasodilatory therapy. Circulation. Nov 8 2005;112(19):2980-5. [Medline].

  18. Badesch DB, Hill NS, Burgess G, et al. Sildenafil for pulmonary arterial hypertension associated with connective tissue disease. J Rheumatol. Dec 2007;34(12):2417-22. [Medline].

  19. Tashkin DP, Elashoff R, Clements PJ, et al. Cyclophosphamide versus placebo in scleroderma lung disease. N Engl J Med. Jun 22 2006;354(25):2655-66. [Medline].

  20. Liossis SN, Bounas A, Andonopoulos AP. Mycophenolate mofetil as first-line treatment improves clinically evident early scleroderma lung disease. Rheumatology (Oxford). Aug 2006;45(8):1005-8. [Medline].

  21. Oldfield V, Lyseng-Williamson KA. Bosentan: a review of its use in pulmonary arterial hypertension and systemic sclerosis. Am J Cardiovasc Drugs. 2006;6(3):189-208. [Medline].

  22. Swigris JJ, Olson AL, Fischer A, et al. Mycophenolate mofetil is safe, well tolerated, and preserves lung function in patients with connective tissue disease-related interstitial lung disease. Chest. Jul 2006;130(1):30-6. [Medline].

  23. Gerbino AJ, Goss CH, Molitor JA. Effect of mycophenolate mofetil on pulmonary function in scleroderma-associated interstitial lung disease. Chest. Feb 2008;133(2):455-60. [Medline].

  24. Sitbon O, Badesch DB, Channick RN, et al. Effects of the dual endothelin receptor antagonist bosentan in patients with pulmonary arterial hypertension: a 1-year follow-up study. Chest. Jul 2003;124(1):247-54. [Medline].

  25. 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. Sep 1998;41(9):1613-9. [Medline].

  26. Schachna L, Medsger TA Jr, Dauber JH, et al. Lung transplantation in scleroderma compared with idiopathic pulmonary fibrosis and idiopathic pulmonary arterial hypertension. Arthritis Rheum. Dec 2006;54(12):3954-61. [Medline].

  27. Vonk MC, Marjanovic Z, van den Hoogen FH, et al. Long-term follow-up results after autologous haematopoietic stem cell transplantation for severe systemic sclerosis. Ann Rheum Dis. Jan 2008;67(1):98-104. [Medline].

  28. Passweg J, Tyndall A. Autologous stem cell transplantation in autoimmune diseases. Semin Hematol. Oct 2007;44(4):278-85. [Medline].

  29. Kissin EY, Schiller AM, Gelbard RB, et al. Durometry for the assessment of skin disease in systemic sclerosis. Arthritis Rheum. Aug 15 2006;55(4):603-9. [Medline].

  30. American Rheumatism Association Diagnostic and Therapeutic Criteria Committee. Preliminary criteria for the classification of systemic sclerosis (scleroderma). Subcommittee for scleroderma criteria of the American Rheumatism Association Diagnostic and Therapeutic Criteria Committee. Arthritis Rheum. May 1980;23(5):581-90. [Medline].

  31. Barnett AJ, Miller MH, Littlejohn GO. A survival study of patients with scleroderma diagnosed over 30 years (1953-1983): the value of a simple cutaneous classification in the early stages of the disease. J Rheumatol. Feb 1988;15(2):276-83. [Medline].

  32. Bogoch ER, Gross DK. Surgery of the hand in patients with systemic sclerosis: outcomes and considerations. J Rheumatol. Apr 2005;32(4):642-8. [Medline].

  33. Boin F, Hummers LK. Scleroderma-like fibrosing disorders. Rheum Dis Clin North Am. Feb 2008;34(1):199-220; ix. [Medline].

  34. Cepeda EJ, Reveille JD. Autoantibodies in systemic sclerosis and fibrosing syndromes: clinical indications and relevance. Curr Opin Rheumatol. Nov 2004;16(6):723-32. [Medline].

  35. Champion HC. The heart in scleroderma. Rheum Dis Clin North Am. Feb 2008;34(1):181-90; viii. [Medline].

  36. Chifflot H, Fautrel B, Sordet C, et al. Incidence and prevalence of systemic sclerosis: a systematic literature review. Semin Arthritis Rheum. Feb 2008;37(4):223-35. [Medline].

  37. Czirjak L, Kumanovics G, Varju C, et al. Survival and causes of death in 366 Hungarian patients with systemic sclerosis. Ann Rheum Dis. Jan 2008;67(1):59-63. [Medline].

  38. Denton CP, Black CM. Pulmonary hypertension in systemic sclerosis. Rheum Dis Clin North Am. May 2003;29(2):335-49, vii. [Medline].

  39. Derk CT, Huaman G, Jimenez SA. A retrospective randomly selected cohort study of D-penicillamine treatment in rapidly progressive diffuse cutaneous systemic sclerosis of recent onset. Br J Dermatol. May 2008;158(5):1063-8. [Medline].

  40. Derk CT, Jimenez SA. Systemic sclerosis: current views of its pathogenesis. Autoimmun Rev. Jun 2003;2(4):181-91. [Medline].

  41. Deswal A, Follansbee WP. Cardiac involvement in scleroderma. Rheum Dis Clin North Am. Nov 1996;22(4):841-60. [Medline].

  42. Di Ciaula A, Covelli M, Berardino M, et al. Gastrointestinal symptoms and motility disorders in patients with systemic scleroderma. BMC Gastroenterol. Feb 27 2008;8:7. [Medline].

  43. Distler J, Distler O. Novel treatment approaches to fibrosis in scleroderma. Rheum Dis Clin North Am. Feb 2008;34(1):145-59; vii. [Medline].

  44. Distler JH, Hoeper MM, Distler O. Diagnosis of pulmonary arterial hypertension in a patient with systemic sclerosis. Nat Clin Pract Rheumatol. Mar 2008;4(3):160-4. [Medline].

  45. Distler O, Behrens F, Huscher D, et al. Need for improved outcome measures in pulmonary arterial hypertension related to systemic sclerosis. Rheumatology (Oxford). Dec 2006;45(12):1455-7. [Medline].

  46. Domsic R, Fasanella K, Bielefeldt K. Gastrointestinal manifestations of systemic sclerosis. Dig Dis Sci. May 2008;53(5):1163-74. [Medline].

  47. Ebert EC. Gastric and enteric involvement in progressive systemic sclerosis. J Clin Gastroenterol. Jan 2008;42(1):5-12. [Medline].

  48. Gerbracht DD, Steen VD, Ziegler GL, et al. Evolution of primary Raynaud's phenomenon (Raynaud's disease) to connective tissue disease. Arthritis Rheum. Jan 1985;28(1):87-92. [Medline].

  49. Goh NS, Desai SR, Veeraraghavan S, et al. Interstitial lung disease in systemic sclerosis: a simple staging system. Am J Respir Crit Care Med. Jun 1 2008;177(11):1248-54. [Medline].

  50. Guiducci S, Giacomelli R, Cerinic MM. Vascular complications of scleroderma. Autoimmun Rev. Sep 2007;6(8):520-3. [Medline].

  51. Hachulla E, Coghlan JG. A new era in the management of pulmonary arterial hypertension related to scleroderma: endothelin receptor antagonism. Ann Rheum Dis. Sep 2004;63(9):1009-14. [Medline].

  52. Herrick AL. Pathogenesis of Raynaud's phenomenon. Rheumatology (Oxford). May 2005;44(5):587-96. [Medline].

  53. Hettema ME, Bootsma H, Kallenberg CG. Macrovascular disease and atherosclerosis in SSc. Rheumatology (Oxford). May 2008;47(5):578-83. [Medline].

  54. Highland KB, Garin MC, Brown KK. The spectrum of scleroderma lung disease. Semin Respir Crit Care Med. Aug 2007;28(4):418-29. [Medline].

  55. Hoyles RK, Ellis RW, Wellsbury J, et al. 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. Arthritis Rheum. Dec 2006;54(12):3962-70. [Medline].

  56. Janiak P, Thumshirn M, Menne D, et al. Clinical trial: the effects of adding ranitidine at night to twice daily omeprazole therapy on nocturnal acid breakthrough and acid reflux in patients with systemic sclerosis--a randomized controlled, cross-over trial. Aliment Pharmacol Ther. Nov 1 2007;26(9):1259-65. [Medline].

  57. Jaovisidha K, Csuka ME, Almagro UA, et al. Severe gastrointestinal involvement in systemic sclerosis: report of five cases and review of the literature. Semin Arthritis Rheum. Feb 2005;34(4):689-702. [Medline].

  58. Jimenez SA, Derk CT. Following the molecular pathways toward an understanding of the pathogenesis of systemic sclerosis. Ann Intern Med. Jan 6 2004;140(1):37-50. [Medline].

  59. Johnson SR, Feldman BM, Hawker GA. Classification criteria for systemic sclerosis subsets. J Rheumatol. Sep 2007;34(9):1855-63. [Medline].

  60. Khurma V, Meyer C, Park GS, et al. A pilot study of subclinical coronary atherosclerosis in systemic sclerosis: coronary artery calcification in cases and controls. Arthritis Rheum. Apr 15 2008;59(4):591-7. [Medline].

  61. Knockaert DC. Cardiac involvement in systemic inflammatory diseases. Eur Heart J. Aug 2007;28(15):1797-804. [Medline].

  62. Lawrence RC, Helmick CG, Arnett FC, et al. Estimates of the prevalence of arthritis and selected musculoskeletal disorders in the United States. Arthritis Rheum. May 1998;41(5):778-99. [Medline].

  63. Manetti M, Neumann E, Milia AF, et al. Severe fibrosis and increased expression of fibrogenic cytokines in the gastric wall of systemic sclerosis patients. Arthritis Rheum. Oct 2007;56(10):3442-7. [Medline].

  64. Mayes MD. Scleroderma epidemiology. Rheum Dis Clin North Am. May 2003;29(2):239-54. [Medline].

  65. Medsger TA Jr. Natural history of systemic sclerosis and the assessment of disease activity, severity, functional status, and psychologic well-being. Rheum Dis Clin North Am. May 2003;29(2):255-73, vi. [Medline].

  66. Medsger TA Jr, Masi AT. Survival with scleroderma. II. A life-table analysis of clinical and demographic factors in 358 male U.S. veteran patients. J Chronic Dis. Oct 1973;26(10):647-60. [Medline].

  67. Nihtyanova SI, Denton CP. Current approaches to the management of early active diffuse scleroderma skin disease. Rheum Dis Clin North Am. Feb 2008;34(1):161-79; viii. [Medline].

  68. 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. May 2008;103(5):1257-62. [Medline].

  69. Penn H, Howie AJ, Kingdon EJ, et al. Scleroderma renal crisis: patient characteristics and long-term outcomes. QJM. Aug 2007;100(8):485-94. [Medline].

  70. Poncelet AN, Connolly MK. Peripheral neuropathy in scleroderma. Muscle Nerve. Sep 2003;28(3):330-5. [Medline].

  71. Rodnan GP, Benedek TG. An historical account of the study of progressive systemic sclerosis (diffuse scleroderma). Ann Intern Med. Aug 1962;57:305-19. [Medline].

  72. Rose RF, Goodfield MJ. Combining PUVA therapy with systemic immunosuppression to treat progressive diffuse morphoea. Clin Exp Dermatol. May 2005;30(3):226-8. [Medline].

  73. Rubin LJ. Treatment of pulmonary arterial hypertension due to scleroderma: challenges for the future. Rheum Dis Clin North Am. Feb 2008;34(1):191-7; viii. [Medline].

  74. Scalapino K, Arkachaisri T, Lucas M, et al. Childhood onset systemic sclerosis: classification, clinical and serologic features, and survival in comparison with adult onset disease. J Rheumatol. May 2006;33(5):1004-13. [Medline].

  75. Schwarzer AC, Derby R, Aprill CN, et al. The value of the provocation response in lumbar zygapophyseal joint injections. Clin J Pain. Dec 1994;10(4):309-13. [Medline].

  76. Shah AA, Wigley FM. Often forgotten manifestations of systemic sclerosis. Rheum Dis Clin North Am. Feb 2008;34(1):221-38; ix. [Medline].

  77. Steen V. Predictors of end stage lung disease in systemic sclerosis. Ann Rheum Dis. Feb 2003;62(2):97-9. [Medline].

  78. Steen VD. Scleroderma and pregnancy. Rheum Dis Clin North Am. Feb 1997;23(1):133-47. [Medline].

  79. Steen VD. Scleroderma renal crisis. Rheum Dis Clin North Am. May 2003;29(2):315-33. [Medline].

  80. Steen VD, Brodeur M, Conte C. Prospective pregnancy (PG) study in women with systemic sclerosis (SSc). Arthr Rheum. 1996;39:5151.

  81. Steen VD, Syzd A, Johnson JP, et al. Kidney disease other than renal crisis in patients with diffuse scleroderma. J Rheumatol. Apr 2005;32(4):649-55. [Medline].

  82. Strange C, Highland KB. Interstitial lung disease in the patient who has connective tissue disease. Clin Chest Med. Sep 2004;25(3):549-59, vii. [Medline].

  83. Thombs BD, Hudson M, Taillefer SS, et al. Prevalence and clinical correlates of symptoms of depression in patients with systemic sclerosis. Arthritis Rheum. Apr 15 2008;59(4):504-9. [Medline].

  84. [Best Evidence] Trad S, Amoura Z, Beigelman C, et al. Pulmonary arterial hypertension is a major mortality factor in diffuse systemic sclerosis, independent of interstitial lung disease. Arthritis Rheum. Jan 2006;54(1):184-91. [Medline].

  85. Tuchinda C, Kerr HA, Taylor CR, et al. UVA1 phototherapy for cutaneous diseases: an experience of 92 cases in the United States. Photodermatol Photoimmunol Photomed. Oct 2006;22(5):247-53. [Medline].

  86. van Wijk RM, Geurts JW, Wynne HJ, et al. Radiofrequency denervation of lumbar facet joints in the treatment of chronic low back pain: a randomized, double-blind, sham lesion-controlled trial. Clin J Pain. Jul-Aug 2005;21(4):335-44. [Medline].

  87. Varga JA, Trojanowska M. Fibrosis in systemic sclerosis. Rheum Dis Clin North Am. Feb 2008;34(1):115-43; vii. [Medline].

  88. Walker JG, Fritzler MJ. Update on autoantibodies in systemic sclerosis. Curr Opin Rheumatol. Nov 2007;19(6):580-91. [Medline].

  89. White B. Interstitial lung disease in scleroderma. Rheum Dis Clin North Am. May 2003;29(2):371-90. [Medline].

  90. Zulian F. Systemic sclerosis and localized scleroderma in childhood. Rheum Dis Clin North Am. Feb 2008;34(1):239-55; ix. [Medline].

[ CLOSE WINDOW ]

Further Reading

[ CLOSE WINDOW ]

Keywords

scleroderma, systemic sclerosis, proximal scleroderma, diffuse cutaneous scleroderma, limited cutaneous scleroderma, diffuse systemic scleroderma, progressive systemic sclerosis, hard skin, skin tightening, skin tightness, sclerodactyly, bibasilar pulmonary fibrosis, Raynaud phenomenon, Raynaud's phenomenon, pulmonary hypertension, calcinosis, esophageal dysmotility, telangiectasias, CREST, juvenile-onset systemic sclerosis

[ CLOSE WINDOW ]

Contributor Information and Disclosures

Author

Sergio A Jimenez, MD, Director, The Scleroderma Center; Co-Director, Jefferson Institute of Molecular Medicine; Director, Division of Connective Tissue Diseases; Professor of Medicine, Department of Dermatology and Cutaneous Biology, Thomas Jefferson University
Sergio A Jimenez, MD is a member of the following medical societies: American College of Physicians, American College of Rheumatology, American Society for Biochemistry and Molecular Biology, and Society for Investigative Dermatology
Disclosure: Nothing to disclose.

Coauthor(s)

Patrick M Cronin, DO, FACR, Clinical Associate Professor of Medicine, Department of Medicine, Division of Rheumatology, University of Pennsylvania Health System, Pennsylvania Hospital
Patrick M Cronin, DO, FACR is a member of the following medical societies: American College of Rheumatology, American Osteopathic Association, and Pennsylvania Medical Society
Disclosure: Nothing to disclose.

Andrew Koenig, 
Andrew Koenig is a member of the following medical societies: American College of Physicians-American Society of Internal Medicine, American College of Rheumatology, and American Osteopathic Association
Disclosure: Nothing to disclose.

Marie Spevak O'Brien, DO, Assistant Clinical Professor of Medicine, Arthritis and Rheumatology, Lehigh Valley Physician Group
Marie Spevak O'Brien, DO is a member of the following medical societies: American College of Physicians, American College of Rheumatology, American Medical Association, American Osteopathic Association, International Society for Clinical Densitometry, and Pennsylvania Medical Society
Disclosure: Nothing to disclose.

Medical Editor

John Varga, MD, Professor, Department of Internal Medicine, Division of Rheumatology, Northwestern University
John Varga, MD is a member of the following medical societies: American College of Physicians, American College of Rheumatology, Central Society for Clinical Research, and Society for Investigative Dermatology
Disclosure: Nothing to disclose.

Pharmacy Editor

Francisco Talavera, PharmD, PhD, Senior Pharmacy Editor, eMedicine
Disclosure: Nothing to disclose.

Managing Editor

Elliot Goldberg, MD, Dean of the Western Pennsylvania Clinical Campus, Professor, Department of Medicine, Temple University School of Medicine
Elliot Goldberg, MD is a member of the following medical societies: Alpha Omega Alpha, American College of Physicians, and American College of Rheumatology
Disclosure: Nothing to disclose.

CME Editor

Alex J Mechaber, MD, FACP, Associate Dean for Undergraduate Medical Education, Associate Professor of Medicine, University of Miami Miller School of Medicine
Alex J Mechaber, MD, FACP is a member of the following medical societies: Alpha Omega Alpha, American College of Physicians-American Society of Internal Medicine, and Society of General Internal Medicine
Disclosure: Nothing to disclose.

Chief Editor

Herbert S Diamond, MD, Professor of Medicine, Temple University School of Medicine; Chairman Emeritus, Department of Internal Medicine, Western Pennsylvania Hospital
Herbert S Diamond, MD is a member of the following medical societies: Alpha Omega Alpha, American College of Physicians, American College of Rheumatology, American Medical Association, and Phi Beta Kappa
Disclosure: medifocus Honoraria Review panel membership; health dialogs Honoraria Consulting; Merck, Amgen, Biogen, Zimmer, Wyeth, Johnson&Johnson, Stryker, Medtronic, Zimmer.Abbott,  Ownership interest Other; West Penn Allegheny Health System Consulting fee Consulting; Alpharma Honoraria Consulting; Proctor&Gamble Grant/research funds Independent contractor

 
 
HONcode

We subscribe to the
HONcode principles of the
Health On the Net Foundation

All material on this website is protected by copyright, Copyright© 1994- by Medscape.
This website also contains material copyrighted by 3rd parties.

DISCLAIMER: The content of this Website is not influenced by sponsors. The site is designed primarily for use by qualified physicians and other medical professionals. The information contained herein should NOT be used as a substitute for the advice of an appropriately qualified and licensed physician or other health care provider. The information provided here is for educational and informational purposes only. In no way should it be considered as offering medical advice. Please check with a physician if you suspect you are ill.