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SCLERODERMA (SYSTEMIC SCLEROSIS, CREST)

Introduction

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

Pathophysiology1-10

  • 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 million7,8
  • 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 years1,9

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
ICD-10 Codes

SCLERODERMA (SYSTEMIC SCLEROSIS, CREST)

Diagnostic Guide Name

SCLERODERMA (SYSTEMIC SCLEROSIS, CREST)

ICD 10 Diagnosis, Single Code, Left Code, Right Code and Bilateral Code

DIAGNOSIS SINGLE CODE ONLY LEFT RIGHT BILATERAL (If Available)
SCLERODERMA (SYSTEMIC SCLEROSIS, CREST) M34.1      

ICD-10 Reference

Reproduced from the International statistical classification of diseases and related health problems, 10th revision, Fifth edition, 2016. Geneva, World Health Organization, 2016 https://apps.who.int/iris/handle/10665/246208

Clinical Presentation Photos and Related Diagrams
Scleroderma
  • Chronic scleroderma bilateral hands.
    Chronic scleroderma bilateral hands.
  • Chronic scleroderma left hand
    Chronic scleroderma left hand
  • Chronic scleroderma skin changes and ulcers
    Chronic scleroderma skin changes and ulcers
  • Chronic scleroderma with long finger tip necrosis and privies index amputation
    Chronic scleroderma with long finger tip necrosis and privies index amputation
Symptoms
Arthralgia, joint stiffness (contracture) and atrophy
Calcinosis
Cutaneous and mucosal telangiectasias
Depigmentation or hyperpigmentation and diffuse pruritus
Digital ulcers which can lead to osteomyelitis, gangrene, and amputations
Muscle weakness and myalgia
Vasospastic episodes causing triphasic color changes in the finger, pale (white), cyanotic (blue), and hyperemic flush (red)
Thickening of the skin
Typical History

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. 

Positive Tests, Exams or Signs
Work-up Options
Images (X-Ray, MRI, etc.)
CREST Syndrome
  • CREST Syndrome with painful finger tip calcifications.
    CREST Syndrome with painful finger tip calcifications.
  • CREST Syndrome
    CREST Syndrome
Treatment Options
Treatment Goals
  • Control symptoms like pain
  • Maintain range of motion and overall hand function.
  • Delay or prevent ulcers, chronic infections, and amputations
Conservative

Most treatments for scleroderma are directed at addressing the cutaneous manifestations or the symptoms created by organ involvement.1

Treatment for localized (cutaneous) scleroderma

  • Topical therapy
  • Systemic therapy
  • Corticosteroids
  • Methotrexate
  • Calcitriol
  • Penicillamine
  • Ultraviolet radiation therapy2

Treatment for CREST syndrome

  • Pharmacotherapy
    • Vasodilators
    • Used to treat vascular symptoms of CREST syndrome
    • Calcium channel blockers
    • Prazosin hydrochloride
    • May be used in patients who do not tolerate calcium channel blockers
    • Ketanserin
    • Used to treat digital ischemia
    • NSAIDs
    • Topical nitroglycerin
    • Topical glyceryl trinitrate
    • D-penicillamine
    • Colchicine
    • Sucralfate - Used for heartburn associated with esophageal dysmotility
    • Ranitidine and cimetidine - Used to decrease esophageal irritation from stomach acid
    • Probenecid
    • Warfarin
    • Bisphosphonates
    • Aluminum hydroxide
    • Minocycline
  • Stress reduction
  • Biofeedback
  • Deep breathing exercises for dyspnea
  • Heat conservation and reduced cold exposure
  • Strategies to prevent skin dryness
  • Protection of calcinosis symptoms, including bony prominences with a foam sleeve 
  • Nutritional counseling 
  • Physical and/or occupational therapy including active and passive range of motion (ROM) exercises
  • Psychological intervention for symptoms of depression and anxiety

Treatment for calcinosis

  • Medical treatment options have included:
    • Aspirin
    • Aluminum hydroxide
    • Bisphosphonates
    • Colchicine
    • Corticosteroid intralesional injections
    • Diltiazem
    • Iontophoresis 
    • IVIG
    • Minocycline
    • Probenecid
    • Ultrasound
    • Warfarin
  • Most specific nonsurgical treatment has been found to be reliable but recently intralesional injections of sodium thiosulfate have been found useful in some patients.1,9 REF

Treatment for Raynaud’s phenomenon, digital ulcers and ischemia

  • General measures
    • Gloves and other coverings should be worn to keep hands and feet warm in cold weather
    • Sedation and stress avoidance
    • Avoidance of contraceptives, vasoconstrictive drugs, microtrauma of the hands, and cold
    • Skin care moisturizer use on normal skin and handwashing with antiseptic soap
    • Topical vitamin E ointment to facilitate ulcer healing
  • Pharmacological measures
    • Vasodilating agents are commonly recommended as a first-line treatment, including calcium channel blockers like nifedipine
    • Sildenafil may be added if vasodilating agents fail to elicit a response
    • Iloprost and bosentan are reserved for refractory cases and when critical tissue ischemia and damage occur1
    • Angiotensin-converting enzyme inhibitors (ACEIs) are used to treat hypertension
    • Prednisone and other corticosteroids may be used in the early stages of diffuse disease when hands appear puffy or edematous
    • Penicillamine may be used for patients with early disease who manifest progressive skin changes, pulmonary compromise, or renal disease3
    • Antiplatelet Drugs (aspirin, low-molecular-weight heparin)
    • Vasodilators (cilostazol, type 5 phosphodiesterase inhibitors, calcium channel blockers, bosentan, prostacyclin analogues )
    • Other Drugs (serotonin receptor antagonists and reuptake inhibitors, N-acetylcysteine, statins, botulinum toxin A)1

Treatment for joint contracture

  • Physical therapy
    • Integral part of most multimodal treatment programs for localized scleroderma commonly used in routine clinical practice
    • Especially important in linear localized scleroderma
    • Should be avoided during the acute inflammatory phase
    • One or two treatment sessions for a minimum of three months
    • Connective tissue massage
    • Strengthening exercises2, 9
Operative
  • Localize calcinosis can be treated by surgical excision or curettage of small calcified lesions. Diffuse large calcifications have been treated in the past with excision and flaps but some authorities feel this is unwise due to the poor healing of large flaps in patients with scleroderma.
  • Ischemia and Raynaud's phenomenon that does not respond to chemical sympathectomy by palmer botulinum toxin A injections can be treated by periarterial sympathectomy.  In this procedure the arterial adventitia which contains the sympathetic nerve fibers for these small arteries of the hand is microsurgically excised from a 2 cm segment of the ulnar and radial arteries when it is performed at the wrist. This procedure can also be applied to the superficial palmar arch and to the common digital arteries. This localized sympathectomy was originally described by Flatt in 1980.10Despite a 37% complication rate and 14% amputation rate, these procedures can provide significant number of patients with long-term relief from their ischemic ulcers and pain.
    For ASSH's Hand-e Surgical Video of Sympathectomy by Jones:
  • Amputation is also a necessary surgical procedure in scleroderma patients. Ideally, auto- amputation preserves the most tissue but this can take months; therefore, surgical amputation is often required. However surgical amputations heal very slowly because of the underlying vascular disease.
  • Surgical treatment can also be useful for severe PIP flexion contractures, but arthrodesis with some shortening and functional position not joint release is the optimal surgical procedure in scleroderma patients with PIP contractures. Infection, slow healing and other complications associated with poor vascular supply are again significant risks.
  • Surgical treatment of MP joint extension contractures can also be useful in patients with scleroderma. Indicated procedures are MP arthroplasties, extensor tenolysis and MP joint releases.
  • Cervical thoracic sympathectomy has been used in the past for scleroderma but it is no longer advised because it can be complicated by turning an overreaction of the sympathetic response instead of decreasing the arterial vasospasm causing the ischemia associated with scleroderma.
Treatment Photos and Diagrams
CREST Treatment
  • Painful calcific lesion long finger tip and excised specimen
    Painful calcific lesion long finger tip and excised specimen
Complications
  • 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
  • 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.
Key Educational Points
  • 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 cases1,5
  • Diagnosing CREST syndrome can be challenging during its early stages, because the disease process varies greatly from patient to patien1
References

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