Core Dermatology Diagnoses / CategoriesInflammatory

Scleroderma

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Publish date: Posted on
Last updated: October 22, 2023

Keywords #

morphea
systemic sclerosis
scleroderma
CREST syndrome

Diagnosis #

Scleroderma is an autoimmune connective tissue disease. The term scleroderma is derived from the Greek words scleros and derma, together referring to thickened, hardened skin. The etiology of scleroderma is not fully understood, but it is thought to result from a multifactorial process involving the immune system and genetic and epigenetic factors. Scleroderma can either present in a localized form only involving the skin, known as morphea, or with sclerosis and fibrosis of the internal organs, referred to as systemic sclerosis (SSc).[1]

Morphea presents as fibrosis and scarring of the dermis and subcutis, creating patches of hard skin. It does not present with any internal organ involvement and the risk of transforming to the systemic form is very low. Morphea therefore has an excellent prognosis. Subtypes of morphea are commonly classified as plaque (circumscribed), linear (known as “en coup de sabre” when present unilaterally on the scalp and forehead ), generalized, or profundas if the sclerosis extends to involve underlying fascia or muscle.[2,3]

Unlike morphea, the fibrosis of systemic sclerosis can affect the connective tissue of any organ, not just the skin. This includes the lungs, gastrointestinal tract, muscles, and heart. Lung involvement is the most common cause of death in patients with systemic sclerosis, typically presenting as interstitial lung disease or pulmonary arterial hypertension.[4] Kidney involvement can precipitate a life-threatening condition known as scleroderma renal crisis, wherein patients abruptly develop severe hypertension and experience rapid, progressive kidney failure.[5]

Systemic sclerosis can be further classified as diffuse cutaneous systemic sclerosis (dcSSc) or limited cutaneous systemic sclerosis (lcSSc). In dcSSc skin thickening involves the proximal limbs or trunk. If skin thickening is restricted to the limbs distal to the elbows or knees and does not involve the face and neck it is considered lcSSc. In some cases, patients can present with internal organ sclerosis without skin thickening. This is referred to as systemic sclerosis sine scleroderma. If dcSSc, lcSSc, or systemic sclerosis sine scleroderma present together with features of another autoimmune disease, this is known as systemic sclerosis overlap syndrome. Notably, many patients with lcSSc exhibit scleroderma as a manifestation of CREST syndrome (calcinosis cutis, Raynaud phenomenon, esophageal dysmotility, sclerodactyly, telangiectasia) which is further described below in ‘clinical features.’[6]

Key Concepts #
  • Autoimmune sclerosis is known as morphea if limited to just the skin, or systemic sclerosis if there is visceral organ involvement.
  • Autoimmune cutaneous sclerosis may be a manifestation of CREST syndrome, an autoimmune condition that involves calcinosis cutis, Raynaud phenomenon, esophageal dysmotility, sclerodactyly, and telangiectasia.
  • First line treatment for the early active inflammatory phase of morphea with minimal body surface area involvement are topical or intralesional corticosteroids and aminoquinoline antimalarial drugs such as hydroxychloroquine. The goal of treatment is not to return to normal skin, but to soften skin and minimize further spread.
  • Treatment for systemic sclerosis is determined by visceral organ involvement.
Epidemiology #

Morphea and systemic sclerosis are relatively uncommon disorders that affect both adults and children. There is a wide spectrum of reported incidence rates for systemic sclerosis, with recent reports suggesting a global incidence from 8 to 56 new cases per million persons per year.[7] Women tend to be affected more commonly than men, with patients of African descent affected at nearly twice the rate of white patients.[7] African American patients also present earlier, at age 35 to 44, compared to age 45 to 55 for other races. Additionally, they have been shown to have a more severe disease course and increased mortality even after controlling for potential confounding variables.[8]

The incidence of morphea has been reported as slightly lower than that of systemic sclerosis, ranging from 3.4 to 27 new cases per million per year. Morphea has a bimodal distribution, with most cases presenting in patients in their mid-40s, and pediatric cases between ages 2 and 14.[9,10]

Clinical Features #
  • Both morphea and the cutaneous involvement of systemic sclerosis appear as sclerotic, sharply demarcated, indurated plaques.
  • The inflammatory activity of early plaque-type morphea lesions presents with a lilac border and white center, with mature lesions characterized by post-inflammatory hyperpigmentation.[11]
  • The lesions may itch, but most are asymptomatic.

Morphea that crosses joint lines may lead to decreased mobility, craniofacial morphea may lead to ocular complications, and morphea at the wrist may predispose patients to carpal tunnel.[12,13]

  • A majority of patients with systemic sclerosis present with digit involvement where the thickened skin produces ‘sausage-like’ fingers and toes, referred to as sclerodactyly.
  • Patients with severe disease can also develop ulcerations on the fingertips that heal into pitted scars.
  • Systemic sclerosis often presents concurrently with Raynaud’s phenomenon, a reversible vasospasm that leads to white, red and/or blue discoloration of the digits.
  • Sclerodactyly and Raynaud’s phenomenon are part of the classic CREST syndrome, which includes hard bumps in the skin from calcium deposits (calcinosis cutis), difficulty swallowing (esophageal dysmotility), and web-like red microvascular patterns on the skin (telangiectasias).[11]
Differential Diagnoses #
  • Acute graft-versus-host disease (in the correct clinical context)
  • Lichen sclerosis
  • Necrobiosis lipoidica
  • Scleredema
  • Scleromyxedema
  • Generalized myxedema
  • Eosinophilic fasciitis
  • Stiff-skin syndrome
  • Nephrogenic systemic fibrosis
  • Reflex sympathetic dystrophy
  • Porphyria cutanea tarda
Diagnostic Workup #

The diagnosis of scleroderma is based on clinical findings. Ninety-five percent of patients with systemic sclerosis have a positive antinuclear antibody (ANA) test, commonly with a speckled or nucleolar pattern. Systemic sclerosis additionally can be diagnosed with disease specific antibodies: limited systemic sclerosis with anti-centromere antibodies, and diffuse systemic sclerosis with anti-topoisomerase I (also known as Scl-70) antibodies and RNA polymerases.[11] Although studies have reported that 5.9-68% of patients with morphea may have a positive ANA test, morphea, unlike systemic sclerosis, is not associated with specific antibodies.[10]

Biopsy of inflammatory lesions reveals a lymphocytic infiltrate and characteristic collagen bundles that increase in thickness and number as the sclerosis progresses. These changes are most apparent in the lower two thirds of the dermis and may extend into the subcutaneous fat. As the sclerosis advances, dermal appendages are obliterated and only a few hyalinized blood vessels remain.[3,11]

If presentation and diagnostic workup are suggestive of systemic sclerosis, laboratory work should be expanded to evaluate for systemic involvement for which there is reasonable suspicion. This includes pulmonary function testing and high-resolution CT imaging for lung involvement, barium swallow for esophageal involvement, and creatinine monitoring for kidney involvement.[11]

Treatment #

Although there are several options available for the treatment of scleroderma, the evidence behind the efficacy of these modalities is limited. For most patients, the goal of treatment is not to expect return of completely normal skin, but to have improvement in erythema, softening of the lesion, and to limit the spread of new lesions in those with progressive disease. Active lesions (present < 3 months) are the most likely to respond to therapy, with little to no change seen in mature, atrophic lesions.[14]

Initial treatments for those with morphea include topical and intralesional corticosteroids, topical vitamin D, topical macrolides, and topical calcipotriene.[11] Phototherapy can also be used as a first line therapy, though it has limited efficacy in deep morphea given the poor penetration of UV light into deep tissues.[15]  UVA 1 phototherapy has proven to be of greater clinical value than other forms of phototherapy.  Oral hydroxychloroquine can be of value during the active inflammatory phase of morphea. [16]  However, it is less effective in later, fully-established morphea lesions.  For more severe or widespread disease, immunosuppressive therapy via methotrexate, mycophenolate mofetil, or systemic steroids in combination with phototherapy is often preferred.[14] Additionally, physical therapy that is specifically focused on daily range of motion exercises can be helpful in slowing the development of sclerotic contractures.[11]

Therapeutic options in systemic sclerosis should be guided by visceral organ involvement. The cutaneous fibrosis of systemic sclerosis can be treated in the same fashion as morphea, and patients with concurrent Raynaud’s could additionally benefit from protection from the cold exposure, oral vasodilators and intralesional Botox.  [17] Notably, high-dose systemic steroids should be avoided in patients with systemic sclerosis since they could precipitate scleroderma renal crisis, which, if it does occur, is treated with ACE inhibitors.[5,18]

Slide Viewer #
https://utahderm.med.utah.edu/image-viewer/
References #
  1. Pearson DR, Werth VP, Pappas-Taffer L. Systemic sclerosis: Current concepts of skin and systemic manifestations. Clinics in Dermatology. 2018;36(4):459-474.
  2. Li SC. Scleroderma in Children and Adolescents: Localized Scleroderma and Systemic Sclerosis. Pediatric Clinics of North America. 2018;65(4):757-781.
  3. Jacobe H. Pathogenesis, clinical manifestations, and diagnosis of morphea (localized scleroderma) in adults. 2019; https://www.uptodate.com/contents/pathogenesis-clinical-manifestations-and-diagnosis-of-morphea-localized-scleroderma-in-adults.
  4. Denton CP, Wells AU, Coghlan JG. Major lung complications of systemic sclerosis. Nat Rev Rheumatolo. 2018;14(11):511-527.
  5. Bose N, Chiesa-Vottero A, Chatterjee S. Scleroderma renal crisis. Semin Arthritis Rheum. 2015;44(6):687-694.
  6. Varga J. Clinical manifestations and diagnosis of systemic sclerosis (scleroderma) in adults. 2020; https://www.uptodate.com/contents/clinical-manifestations-and-diagnosis-of-systemic-sclerosis-scleroderma-in-adults.
  7. Ingegnoli F, Ughi N, Mihai C. Update on the epidemiology, risk factors, and disease outcomes of systemic sclerosis. Best Practice & Research Clinical Rheumatology. 2018;32(2):223-240.
  8. Gelber AC, Manno R, Shah AA, et al. Race and association with disease manifestations and mortality in scleroderma: a 20-year experience at the Johns Hopkins Scleroderma Center and review of the literature. Medicine (Baltimore). 2013;92(4):191-205.
  9. Browning JC. Pediatric morphea. Dermatologic Clinics. 2013;31(2):229-237.
  10. Mertens JS, Seyger MMB, Thurlings RM, Radstake T, de Jong E. Morphea and Eosinophilic Fasciitis: An Update. American Journal of Clinical Dermatology. 2017;18(4):491-512.
  11. Marks JG, JJM. Scleroderma/Morphea. In: Lookingbill and Marks’ Principles of Dermatology. 6 ed.: Elsevier; 2019:251-255.
  12. Zannin ME, Martini G, Athreya BH, et al. Ocular involvement in children with localised scleroderma: a multi-centre study. British Journal of Ophthalmology. 2007;91(10):1311-1314.
  13. Winkelmann R, Connolly SM, Doyle JA. Carpal tunnel syndrome in cutaneous connective tissue disease: generalized morphea, lichen sclerosus, fasciitis, discoid lupus erythematosus, and lupus panniculitis. Journal of the American Academy of Dermatology. 1982;7(1):94-99.
  14. Jacobe H. Treatment of morphea (localized scleroderma) in adults. 2018; https://www.uptodate.com/contents/treatment-of-morphea-localized-scleroderma-in-adults. .
  15. Hassani J, Feldman SR. Phototherapy in Scleroderma. Dermatology and Therapy (Heidelb). 2016;6(4):519-533.
  16. Kumar AB, Blixt EK, Drage LA, El-Azhary RA, Wetter DA. Treatment of morphea with hydroxychloroquine: A retrospective review of 84 patients at Mayo Clinic, 1996-2013. J Am Acad Dermatol. 2019 Jun;80(6):1658-1663. doi: 10.1016/j.jaad.2019.01.040. Epub 2019 Jan 29. PMID: 30703458; PMCID: PMC6526062
  17. Pattanaik D, Brown M, Postlethwaite AE. Vascular involvement in systemic sclerosis (scleroderma). J Inflamm Res. 2011;4:105-125.
  18. Trang G, Steele R, Baron M, Hudson M. Corticosteroids and the risk of scleroderma renal crisis: a systematic review. Rheumatol Int. 2012;32(3):645-653.
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