SCLERODERMA (SYSTEMIC SCLEROSIS, CREST)

Scleroderma is a rare and complex autoimmune connective tissue disease that can potentially affect all organ systems. Technically, scleroderma is an aspect of systemic sclerosis, a systemic connective tissue disease that involves subcutaneous tissue, muscles, and internal organs. The cause of scleroderma is not known, so it is typically diagnosed by its clinical manifestations: skin thickening, vascular abnormalities, and other systemic effects most commonly affecting the lungs and kidneys.  The limited cutaneous type of scleroderma affects the hands.  Scleroderma is also associated with Raynaud’s phenomenon—which may precede the occurrence of scleroderma by months or even years.  CREST syndrome is a limited cutaneous type of scleroderma that has a more indolent course and less visceral involvement than the diffuse type. CREST syndrome involves calcinosis, Raynaud's phenomenon, esophageal problems, sclerodactyly, and telangiectasias.  Treatment may include vasodilating agents, corticosteroids, topical therapies, antiplatelet drugs, physical therapy, or covering the hands and feet if Raynaud’s phenomenon is present. Surgical intervention has specific limited, but sometimes very helpful, uses in scleroderma.^1-6,9

Pathophysiology^1-10

• Scleroderma symptoms result from non-inflammatory and progressive tissue fibrosis and occlusion of the microvasculature by excessive production and deposition of types I and III collagen³
• The pathophysiology involves several cell lines, including the endothelium, fibroblasts, lymphocytes, and their soluble mediators, which account for the early vascular phase with an inflammatory infiltrate that eventually leads to fibrosis
  • The vascular phase begins in the endothelium of small vessels throughout the body, but the primary event that triggers endothelial damage is unknown¹
  • In the endothelial phase, baseline hypoxia activates the overproduction of endothelin, which disturbs the balance of endothelin with nitric oxide and prostacyclins, and generates a potent vasoconstrictor action that is not countered; this starts a vicious cycle in which unresolved tissue ischemia leads to increased vasoconstriction, release of proinflammatory cytokines, and platelet aggregation, as well as stimulation of fibroblast activity¹
  • CREST syndrome is named after the 5 clinical features that may be present (Calcinosis cutis, Raynaud’s phenomenon, Esophageal dysmotility, Sclerodactyly, and Telangiectasias), although not all patients display every symptom and the disease process varies greatly.  CREST syndrome is thought to be an autoimmune disorder that results from abnormal fibroblast activity and increased collagen deposition, although the primary triggering mechanism is not known⁵  Silicone breast implants, toxic oil ingestion, exposure to silica dust and vinyl chloride, and administration of antineoplastic drugs are all environmental factors that have been linked to the development of scleroderma, CREST syndrome, and other connective tissue diseases⁵

Related Anatomy

• The two major forms of scleroderma are localized and systemic:
  • Systemic scleroderma is further divided two subsets: limited (cutaneous) or diffuse²
• Localized scleroderma can be further divided into four basic types: limited, generalized, linear, and deep²
• CREST syndrome is one representation of the limited type of systemic scleroderma⁵

Incidence and Related Conditions

• Scleroderma is a rare disease, with an incidence of ~27 cases per million^7,8
• The incidence of scleroderma is 4-9 times higher in women than men³
  • CREST syndrome is relatively rare, but it affects women 3-4 times more often than men⁴
  • Scleroderma has a higher incidence in African Americans than whites, and African Americans generally tend to have more severe symptoms and poorer outcomes³
  • Calcinosis will occur in 22% of the patients with scleroderma in the first 10-15 years.  Calcinosis seems to be triggered by microtrauma and it occurs in localized and diffuse patterns.⁹
  • Raynaud’s phenomenon
    • A transient reversible, vasospastic phenomenon induced by cold or stress occurring in the fingers, toes, and less frequently, the nose, ears, and nipples
    • ~70% of individuals have Raynaud’s phenomenon when they initially present with scleroderma, and ~95% will eventually develop it at some point in the course of the disease
    • Raynaud’s phenomenon may precede the clinical manifestations of scleroderma by months up to as long as 10 years^1,9

Differential Diagnosis

• Amyloidosis
• Buschke’s disease
• Diabetic cheiroarthropathy
• Diabetic scleredema
• Eosinophilia-myalgia syndrome
• Eosinophilic fasciitis
• Generalized morphea
• Graft-versus-host disease
• Lupus
• Lyme disease
• Mixed connective tissue disease
• Morphea
• Nephrogenic systemic fibrosis
• Polymyositis
• Porphyria cutanea tarda
• Pseudoscleroderma
• Raynaud’s disease
• Reflex sympathetic dystrophy
• Rheumatoid arthritis
• Scleromyxedema
• Shulman’s syndrome
• Toxic oil syndrome

A 44-year-old woman reports occasionally experiencing cold and numbness in her fingers and toes when exposed to cold, which has been occurring for the past 2 years. Her affected digits turn white and then blue when this occurs, and upon exposure to warmth, the color usually changes to red and her affected digits start to throb with pain, tingle, or swell. More recently, she started noticing more lasting changes in her skin, including hyperpigmentation and depigmentation and progressive skin tightening in the face and skin thickening of the fingers. 

• Digital ulcers
• Digital gangrene and subsequent amputations
• Joint contractures especially involving the PIP and M P joints
• Arterial stenosis and occlusion
• Upper extremity digital malalignment
• Infections including osteomyelitis
• Intrinsic muscle weakness after a Botulinum toxin A injection

• Outcomes for scleroderma are largely based on the extent of significant organ involvement, especially the lungs and kidneys
• In one study, the 5-year survival rate was >90% in patients without organ involvement, 70% in patients with pulmonary involvement, and 50% in patients with renal involvement
• Patients with diffuse skin involvement generally experience shorter survival times and are at risk of early progressive end-organ damage, while those with limited involvement are at a small but significant risk of developing pulmonary hypertension or small bowel malabsorption³
  • Disease resolution has been reported to occur in a mean of 2.5 years in ~50% of patients with limited involvement, compared to an average duration of 5.5 years for those with generalized, linear, and deep types²
• Ultraviolet radiation therapy has been found to be one of the most effective therapies for sclerotic skin disorders²
• CREST syndrome has a better prognosis than the diffuse form of the disease;^5,6 patients with the serum anticentromere antibody have a more favorable prognosis and are more likely to have telangiectasia and calcinosis and less restrictive lung disease⁵
• No pharmacologic intervention has been found to be consistently effective for preventing or eliminating calcinosis⁶
• In one level 1 evidence study of Botulinum toxin A,s usefulness in scleroderma, only slightly better subjective outcomes were seen in those patients treated with Botulinum toxin A.
• Skin incision and calcium drainage has been found to produce immediate pain reduction and improve digital movement⁶
• Periarterial sympathectomy helps patients with scleroderma but there is a 37% complication rate and a 14% amputation rate associated with these procedures are performed.

• Hand involvement and scleroderma occurs most commonly and those with the limited cutaneous type of scleroderma.
• The triphasic color changes of Raynaud’s phenomenon or disease; pale (white), cyanotic (blue) and reperfusion hyperemia (red) are a key characteristic of Raynaud's disease and Raynaud's phenomenon.
• It is not advisable to repeat periarterial sympathectomies is on same vessels in the same hand.
• Raynaud’s phenomenon, calcinosis, and digital ulcers produce varying degrees of disability in scleroderma patients, and it is important to exhaust all therapeutic options to prevent the occurrence of new ulcers and achieve rapid healing to prevent permanent loss of tissue¹
• Surgery should only be performed once scleroderma becomes inactive—preferably for several years—to minimize the risk of flare-ups²
• The beneficial effects of sympathectomy as an emergency procedure to achieve rapid vasodilation observed in some patients may be transient²
• Scleroderma patients must be monitored for their response to treatment and the progression of Raynaud’s phenomenon; if Raynaud’s phenomenon and hence tissue ischemia is prolonged, or underlying calcinosis is not resolved, ulcers are difficult to cure and, once installed, tend to become chronic¹
• Although many patients with CREST syndrome will have a relatively positive outcome, a multidisciplinary team approach and long-term treatment with appropriate psychological support will be needed for success in most cases^1,5
• Diagnosing CREST syndrome can be challenging during its early stages, because the disease process varies greatly from patient to patien¹

Cited

1. Nitsche A. Raynaud, digital ulcers and calcinosis in scleroderma. Reumatol Clin 2012;8(5):270-7. PMID: 22835924
2. Kreuter A, Krieg T, Worm M, et al. German guidelines for the diagnosis and therapy of localized scleroderma. J Dtsch Dermatol Ges 2016;14(2):199-216. PMID: 26819124
3. Adnan ZA. Diagnosis and treatment of scleroderma. Acta Med Indones 2008;40(2):109-12. PMID: 18560030
4. Chaffee NR. CREST syndrome: clinical manifestations and dental management. J Prosthodont 1998;7(3):155-60. PMID: 9807098
5. Bertsch C. CREST syndrome: a variant of systemic sclerosis. Orthop Nurs 1995;14(2):53-60. PMID: 7761133
6. Merlino G, Germano S, Carlucci S. Surgical management of digital calcinosis in CREST syndrome. Aesthetic Plast Surg 2013;37(6):1214-9. PMID: 24142114
7. Silman A, Jannini S, Symmons D, et al. An epidemiological study of scleroderma in the West Midlands. Br J Rheumatol 1988;27:286–90. PMID: 3261609
8. Peterson LS, Nelson AM, Su WP, et al. The epidemiology of morphea (localized scleroderma) in Olmstedt county 1960–1993. J Rheumatol 1997;24:73–80. PMID: 9002014
9. Williams AA, Carl HM, Lifchez SD. The scleroderma hand: manifestations of disease and approach to management. J Hand Surg AM. 2018; 43: 550-557.
10. Flatt AE. Digital artery sympathectomy. J Hand Surg AM. 1980; 5(6): 550-556.

New Articles

1. Young A, Namas R, Dodge C, Khanna D. Hand Impairment in Systemic Sclerosis: Various Manifestations and Currently Available Treatment. Curr Treatm Opt Rheumatol 2016;2(3):252-269. PMID: 28018840
2. Fernández-Codina A, Walker KM, Pope JE; Scleroderma Algorithm Group. Treatment algorithms for systemic sclerosis according to experts. Arthritis Rheumatol 2018. [Epub] PMID: 29781586

Reviews

1. Vona R, Giovannetti A, Gambardella L, et al. Oxidative stress in the pathogenesis of systemic scleroderma: An overview. J Cell Mol Med 2018. [Epub] PMID: 29664231
2. Paxton D, Pauling JD. Does nailfold capillaroscopy help predict future outcomes in systemic sclerosis? A systematic literature review. Semin Arthritis Rheum 2018. [Epub] PMID: 29602558

Classics

1. Wigley JE. Scleroderma. Proc R Soc Med 1929;23(2):159-60. PMID: 19987250
2. Sympson T. Case of Scleroderma Affecting the Left Lower Extremity. Br Med J 1884;1(1223):1089. PMID: 20750925