What makes UpToDate so powerful?

  • over 11000 topics
  • 22 specialties
  • 5,700 physician authors
  • evidence-based recommendations
See more sample topics
Find Print
0 Find synonyms

Find synonyms Find exact match

Overview and classification of scleroderma disorders
UpToDate
Official reprint from UpToDate®
www.uptodate.com ©2017 UpToDate, Inc. and/or its affiliates. All Rights Reserved.
The content on the UpToDate website is not intended nor recommended as a substitute for medical advice, diagnosis, or treatment. Always seek the advice of your own physician or other qualified health care professional regarding any medical questions or conditions. The use of this website is governed by the UpToDate Terms of Use ©2017 UpToDate, Inc.
Overview and classification of scleroderma disorders
View in Chinese
All topics are updated as new evidence becomes available and our peer review process is complete.
Literature review current through: Sep 2017. | This topic last updated: Nov 03, 2016.

INTRODUCTION — The scleroderma disorders comprise a heterogeneous group of conditions linked by the presence of thickened, sclerotic skin lesions [1]. However, the other manifestations of these conditions are quite diverse. These differences have required the development of a classification system that takes into account the different potential complications, prognoses, and management strategies for patients with these disorders.

The simplest division of the scleroderma-related disorders is into localized and systemic forms of the disease (table 1 and table 2). The term systemic sclerosis (SSc) is more appropriate for the latter forms; it emphasizes that frequent involvement of internal organs is generally the most important manifestation of these conditions.

Disorders other than SSc can cause skin thickening. As examples, scleroderma-like skin changes can occur in some endocrine disorders (eg, diabetes mellitus and hypothyroidism), in end-stage renal disease (nephrogenic systemic fibrosis), and in conjunction with inflammatory (eg, eosinophilic fasciitis) and infiltrative (eg, amyloid) disorders. Sclerodermatous skin changes may occur as a result of exposure to certain drugs, toxins, and environmental exposures. These and other causes of sclerodermatous skin changes or non-sclerodermatous skin thickening are discussed separately. (See "Diagnosis and differential diagnosis of systemic sclerosis (scleroderma) in adults", section on 'Differential diagnosis'.)

This topic will provide an overview of the classification schema of scleroderma. Classification systems that have been developed for diagnostic and research purposes are also discussed.

LOCALIZED SCLERODERMA — Localized scleroderma can be divided into linear scleroderma (en coup de sabre) and localized and generalized morpheae (table 1). (See "Localized scleroderma in childhood".)

Linear scleroderma — Linear scleroderma (most commonly occurring in childhood) causes abnormalities of the skin and subcutaneous tissues that often follow a dermatomal distribution and that are found predominantly on one side of the body [2].

En coup de sabre – In this type of linear scleroderma, the phrase “en coup de sabre” was coined to denote the resemblance of the lesions to the consequences of a sabre blow (picture 1A-D) [3]. The face or scalp lesion is accompanied by marked abnormalities of underlying mesenchymally-derived tissues, including the skull.

Morphea — Morpheae can be divided into localized (circumscribed) or generalized disease and are characterized by patches of sclerotic skin that develop on the trunk and limbs at sites of previously normal texture [4].

Localized morphea refers to the presence of one or more circumscribed isolated plaques of sclerotic skin (picture 2).

By comparison, skin changes are much more widespread in generalized morphea (picture 3A-B). These lesions often symmetrically involve the trunk and limbs and can lead to widespread skin sclerosis.

Due to the widespread skin involvement, severe generalized morphea must be distinguished from diffuse systemic sclerosis (SSc) (see 'Limited and diffuse cutaneous SSc' below). As opposed to SSc, generalized morphea typically spares the hands and face and is not associated with major vascular symptoms or with visceral disease. Nevertheless, widespread morphea is not benign and may require the use of the same immunosuppressive and antifibrotic regimens as used in diffuse cutaneous SSc.

Other variants include guttate morphea (picture 4) and morphea profunda. In guttate morphea, the shoulders and chest are frequently involved with multiple, small (2 to 10 mm in diameter), hypopigmented and pigmented papules, with minimal sclerosis. Morphea profunda is a subcutaneous variant with a significant inflammatory component and poorly defined skin borders. Bullous disease is rare [5].

Antibodies to DNA topoisomerase II appear to be very prevalent in localized forms of scleroderma, including generalized morphea. This was illustrated by a study of 46 Japanese patients with linear scleroderma or morphea [6]. Anti-topoisomerase II antibodies were found in 11 of 13 patients (85 percent) with widespread morphea and in 35 of 46 patients (76 percent) with any type of localized scleroderma. A lower prevalence of anti-topoisomerase II antibodies is found in patients with SSc (14 percent), systemic lupus erythematosus (SLE) (8 percent), and dermatomyositis (10 percent), and in healthy persons (7 percent). Unlike testing for antibodies to topoisomerase I (anti-Scl-70), a commercial assay for anti-topoisomerase II is not available.

It has been observed that other autoantibodies associated with SSc and other autoimmune rheumatic diseases also occur in localized scleroderma. However, such antibodies are not predictive of systemic manifestations, and their significance is unclear [7].

SYSTEMIC SCLEROSIS — The extent of skin involvement and the accompanying pattern of internal organ involvement form the basis for the classification of systemic sclerosis (SSc) (table 2) [1]. The skin sclerosis score is a cornerstone for the classification of SSc [8]. The most widely used scoring system grades skin sclerosis at 17 sites, with scores at each site being 0 (normal), 1 (equivocal sclerosis), 2 (definite sclerosis), or 3 (hide-bound) (figure 1A-B). The rate of increase and the maximum skin score can reflect disease severity and mortality, particularly among patients with diffuse disease.

The principal subsets of SSc are [9]:

Diffuse cutaneous SSc (dcSSc)

Limited cutaneous SSc (lcSSc)

SSc sine scleroderma, in which patients have only internal organ involvement

Environmentally-induced scleroderma

Overlap syndromes, in which features of SSc coexist with elements of other rheumatic disorders

Limited and diffuse cutaneous SSc — SSc is generally subdivided into limited and diffuse cutaneous subsets. One-third of patients with SSc have the more severe diffuse form of the disease. (See "Overview of the clinical manifestations of systemic sclerosis (scleroderma) in adults".)

These two subsets are principally distinguished by the extent of skin sclerosis and by the forms of organ involvement.

Limited cutaneous SSc – Patients with lcSSc typically have skin sclerosis restricted to the hands and, to a lesser extent, to the face and neck. They also have prominent vascular manifestations and may be classified as having the CREST syndrome (Calcinosis cutis, Raynaud phenomenon, Esophageal dysmotility, Sclerodactyly, and Telangiectasia). The presence of severe vascular abnormalities on nailfold capillary microscopy may be another sensitive indicator of the presence of lcSSc [10].

Diffuse cutaneous SSc – Patients with dcSSc have extensive skin sclerosis and are at a greater risk for the development of significant renal, lung, and cardiac disease. The central criterion for the diagnosis of dcSSc is the extension of skin sclerosis proximal to the wrists (particularly over the proximal limbs and trunk but commonly sparing the upper back). Since early active dcSSc has a lower survival rate than that of many malignancies, it is usually regarded as the most important disease subset in which to establish an early definitive diagnosis [11].

SSc sine scleroderma — SSc sine scleroderma is a rare form of the illness and is characterized by the typical vascular features and visceral fibrosis of systemic disease without skin sclerosis [12]. Despite visceral involvement, the prognosis of those with this disorder is similar to patients with lcSSc. In one study, five-year survival was approximately 80 percent for both groups [13]. (See "Diagnosis and differential diagnosis of systemic sclerosis (scleroderma) in adults", section on 'Systemic sclerosis sine scleroderma'.)

Environmentally induced scleroderma — Environmentally induced scleroderma is characterized by the generally diffuse distribution of skin sclerosis in combination with a history of exposure to an agent suspected of precipitating scleroderma. Candidate initiating agents include vinyl chloride, epoxy resins, pesticides, and a number of organic solvents used in paints. Chemotherapeutic agents including taxanes have also been linked to development of scleroderma that may resemble that triggered by these other agents [14]. (See "Risk factors for and possible causes of systemic sclerosis (scleroderma)".)

Overlap syndromes — Patients who demonstrate some features of SSc (or uncommonly localized scleroderma) in combination with manifestations of other rheumatic diseases, such as systemic lupus erythematosus (SLE), dermatomyositis, or rheumatoid arthritis, are considered to have an overlap syndrome. This heterogeneous group poses an important management problem and also provides indirect evidence that common etiologic and pathogenetic processes may underlie these various conditions. (See "Undifferentiated systemic rheumatic (connective tissue) diseases and overlap syndromes".)

Some patients with certain clinical features may have an increased risk of developing SSc. As examples:

The accurate diagnosis of patients who present with the Raynaud phenomenon is important since some may develop SSc or another connective tissue disorder (see "Clinical manifestations and diagnosis of the Raynaud phenomenon"). Such patients are sometimes designated as having “autoimmune Raynaud phenomenon” and are characterized by abnormal nailfold capillaroscopic findings and by the presence of positive antinuclear antibodies [15]. Individuals with definite Raynaud phenomenon who also demonstrate one of the hallmark autoantibodies of SSc, such as anticentromere, antitopoisomerase I, or anti RNA polymerase I or III antibodies, may be designated as having pre-scleroderma or early disease. (See "Diagnosis and differential diagnosis of systemic sclerosis (scleroderma) in adults", section on 'Preliminary criteria for early diagnosis'.)

Immunogenetic associations may predict the ultimate clinical phenotype in patients in the early stages of an overlap syndrome. Among 56 patients initially diagnosed with mixed connective tissue disease, for example, 13 eventually developed SSc [16]. An increased likelihood of developing SSc was found with the inheritance of human leukocyte antigen (HLA)-DR5.

Autoantibodies directed against the interferon-inducible gene IFI-16 may also affect the phenotype of SSc. IFI-16 gene expression was greatly increased in the skin of patients with both SLE and SSc. In addition, autoantibodies to this antigen were increased in 50 percent of patients with Sjögren’s syndrome, in 26 percent of patients with SLE, and in 5 percent of healthy controls. Although these autoantibodies were found in only 21 percent of patients with SSc, elevated levels were found predominately in patients with lcSSc [17].

CLASSIFICATION CRITERIA — Classification criteria for systemic sclerosis (SSc) have been developed to identify patients with SSc for inclusion in clinical studies and are discussed separately. (See "Diagnosis and differential diagnosis of systemic sclerosis (scleroderma) in adults", section on 'Systemic sclerosis classification criteria'.)

SUMMARY AND RECOMMENDATIONS

The scleroderma disorders comprise a heterogeneous group of conditions linked by the presence of thickened, sclerotic skin lesions. The simplest division of the scleroderma-related disorders is into localized and systemic forms of the disease (table 1 and table 2). The term systemic sclerosis (SSc) is more appropriate for the latter forms; it emphasizes that frequent involvement of internal organs is generally the most important manifestation of these conditions. (See 'Introduction' above.)

Localized scleroderma can be divided into linear scleroderma (“en coup de sabre”), which most commonly occurs in childhood and follows a dermatomal distribution on one side of the body, and localized and generalized morpheae, which are characterized by patches of sclerotic skin that develop on the trunk and limbs at sites of previously normal texture (table 1). Unlike SSc, generalized morphea typically spares the hands and face and is not associated with major vascular symptoms or with visceral disease. (See 'Localized scleroderma' above.)

The extent of skin involvement and the accompanying pattern of internal organ involvement form the basis for the classification of SSc (table 2). The principal subsets of SSc are (see 'Systemic sclerosis' above):

Diffuse cutaneous SSc (dcSSc) (see 'Limited and diffuse cutaneous SSc' above)

Limited cutaneous SSc (lcSSc) (see 'Limited and diffuse cutaneous SSc' above)

SSc sine scleroderma, in which patients have only internal organ involvement (see 'SSc sine scleroderma' above)

Environmentally-induced scleroderma (see 'Environmentally induced scleroderma' above)

Overlap syndromes, in which features of SSc coexist with elements of other rheumatic disorders (see 'Overlap syndromes' above)

Classification criteria for scleroderma have been developed that are used primarily for research purposes. Although the items generally included in classification criteria reflect those used for the clinical diagnosis, there are other findings used in clinical practice that inform the diagnosis. (See 'Classification criteria' above.)

Use of UpToDate is subject to the  Subscription and License Agreement.

REFERENCES

  1. Black CM. Scleroderma--clinical aspects. J Intern Med 1993; 234:115.
  2. Falanga V, Medsger TA Jr, Reichlin M, Rodnan GP. Linear scleroderma. Clinical spectrum, prognosis, and laboratory abnormalities. Ann Intern Med 1986; 104:849.
  3. Black CM. Scleroderma and fasciitis in children. Curr Opin Rheumatol 1995; 7:442.
  4. Falanga V. Localized scleroderma. Med Clin North Am 1989; 73:1143.
  5. Rencic A, Goyal S, Mofid M, et al. Bullous lesions in scleroderma. Int J Dermatol 2002; 41:335.
  6. Hayakawa I, Hasegawa M, Takehara K, Sato S. Anti-DNA topoisomerase IIalpha autoantibodies in localized scleroderma. Arthritis Rheum 2004; 50:227.
  7. Laxer RM, Zulian F. Localized scleroderma. Curr Opin Rheumatol 2006; 18:606.
  8. Black CM. Measurement of skin involvement in scleroderma. J Rheumatol 1995; 22:1217.
  9. LeRoy EC, Black C, Fleischmajer R, et al. Scleroderma (systemic sclerosis): classification, subsets and pathogenesis. J Rheumatol 1988; 15:202.
  10. Lonzetti LS, Joyal F, Raynauld JP, et al. Updating the American College of Rheumatology preliminary classification criteria for systemic sclerosis: addition of severe nailfold capillaroscopy abnormalities markedly increases the sensitivity for limited scleroderma. Arthritis Rheum 2001; 44:735.
  11. Silman AJ. Scleroderma. Baillieres Clin Rheumatol 1995; 9:471.
  12. Molina JF, Anaya JM, Cabrera GE, et al. Systemic sclerosis sine scleroderma: an unusual presentation in scleroderma renal crisis. J Rheumatol 1995; 22:557.
  13. Poormoghim H, Lucas M, Fertig N, Medsger TA Jr. Systemic sclerosis sine scleroderma: demographic, clinical, and serologic features and survival in forty-eight patients. Arthritis Rheum 2000; 43:444.
  14. Itoh M, Yanaba K, Kobayashi T, Nakagawa H. Taxane-induced scleroderma. Br J Dermatol 2007; 156:363.
  15. Kallenberg CG, Wouda AA, Hoet MH, van Venrooij WJ. Development of connective tissue disease in patients presenting with Raynaud's phenomenon: a six year follow up with emphasis on the predictive value of antinuclear antibodies as detected by immunoblotting. Ann Rheum Dis 1988; 47:634.
  16. Gendi NS, Welsh KI, Van Venrooij WJ, et al. HLA type as a predictor of mixed connective tissue disease differentiation. Ten-year clinical and immunogenetic followup of 46 patients. Arthritis Rheum 1995; 38:259.
  17. Mondini M, Vidali M, De Andrea M, et al. A novel autoantigen to differentiate limited cutaneous systemic sclerosis from diffuse cutaneous systemic sclerosis: the interferon-inducible gene IFI16. Arthritis Rheum 2006; 54:3939.
Topic 7545 Version 14.0

All topics are updated as new information becomes available. Our peer review process typically takes one to six weeks depending on the issue.