Systemic Sclerosis and Sclerodermoid Disorders

Systemic Sclerosis (SSc, Scleroderma)

• An uncommon autoimmune connective tissue disease (AI-CTD) that affects the skin, blood vessels, and various internal organs (e.g. kidney, lung, gastrointestinal tract, heart).

• Etiology is unknown but pathogenesis involves vascular dysfunction, immune activation with autoantibody production, and tissue sclerosis.

• Seen more frequently in women; onset is typically in the 3rd to 4th decades of life; diffuse cutaneous SSc is more frequently seen in African-Americans.

• The criteria for the classification/diagnosis of SSc were updated in 2013 ( Table 35.1 ).

  Table 35.1

  2013 American College of Rheumatology (ACR)/European League Against Rheumatism (EULAR) criteria for the classification of systemic sclerosis (SSc).

  The total score is determined by adding the maximum weight (score) in each category. Patients with a total score of ≥9 are classified as having definite SSc. From Van den Hoogen F, Khanna D, Fransen J, et al. 2013 classification criteria for systemic sclerosis. Arthritis Rheum 2013;65:2737–47.

  Item	Sub-item	Weight/score
  Skin thickening of the fingers of both hands extending proximal to the MCP joints ( sufficient criterion)	–	9
  Skin thickening of the fingers	Puffy fingers - or - sclerodactyly	2 4
  Fingertip lesion	Digital tip ulcers - or - pitting scars	2 3
  Telangiectasias	–	2
  Abnormal nail-fold capillaries	–	2
  Pulmonary arterial hypertension - or - interstitial lung disease		2 2
  Raynaud phenomenon	–	3
  SSc-related autoantibodies	Anti-centromere Anti-topoisomerase I Anti-RNA polymerase III	3

• There are two major clinical subtypes of SSc, based upon the amount of skin sclerosis ( Fig. 35.2 ): limited cutaneous SSc (lcSSc) and diffuse cutaneous SSc (dcSSc).

  

• LcSSc is characterized by skin sclerosis involving the distal extremities and face; whereas in dcSSc, the distal and proximal extremities, trunk, and face are involved; internal organ involvement can be seen in both subtypes.

• LcSSc and dcSSc can also occur in conjunction with other AI-CTDs (called “overlap syndrome”), most notably polymyositis and SLE.

• Raynaud phenomenon is present in almost all SSc patients and is often the earliest presenting feature ( Table 35.2 ; Figs 35.3–35.5 ).

  Table 35.2

  Cutaneous features of systemic sclerosis – possible treatments.

  ILD, interstitial lung disease; SR, slow release.

  Cutaneous feature	Possible treatment options
  Cutaneous sclerosis ( Figs 35.3 and 35.5 )	Topical therapies UV phototherapy D-penicillamine ∗ Minocycline ∗∗ Methotrexate (if no ILD) † Mycophenolate mofetil (when ILD)
  Raynaud phenomenon ( Fig. 35.9 ) ( Tables 35.6 and 35.7 )	First-line Cold avoidance Hand and feet warming packets Discontinue all tobacco products Second-line Calcium channel blockers (e.g. nifedipine SR 30 mg daily–BID, amlodipine 2.5–10 mg daily) Third-line (especially when accompanied by ulceration) Phosphodiesterase type 5 inhibitors (e.g. sildenafil, tadalafil) α-Adrenergic blockers (e.g. prazosin) Angiotensin II receptor blockers (e.g. losartan) Endothelin receptor antagonists (e.g. bosentan) Fourth-line Serotonin reuptake inhibitors (e.g. fluoxetine)
  Cutaneous ulcers ( Figs 35.5B and 35.7 )	Avoid excessive debridement Moist, nonadherent dressings Therapies listed above for Raynaud phenomenon Low-dose aspirin or clopidogrel IV prostanoid (e.g. epoprostenol)
  Calcinosis cutis ( Fig. 35.4 ) (see Ch. 42 )	Low-dose warfarin Calcium channel blockers Sodium thiosulfate
  Mat telangiectasias ( Fig. 35.6 )	Lasers appropriate for vascular lesions

  ∗ Nowadays used infrequently.

  ∗∗ Minimal effect.

  † Methotrexate-induced pneumonitis may complicate SSc-ILD picture.

  
  
  

• Mat telangiectasias ( Fig. 35.6 ), proximal nail-fold capillary abnormalities, and cutaneous ulcerations ( Fig. 35.7 ) are present in both lcSSc and dcSSc subtypes and are important clues to the Dx; additional common cutaneous findings are outlined in Table 35.2 .

  
  

• Patients often have a characteristic facies with microstomia, retraction of the lips, perioral furrows, and a beaked nose; three types of dyspigmentation can also be seen, including diffuse hyperpigmentation and leukoderma of SSc ( Fig. 35.8 ).

  

• Internal organ involvement is seen in both lcSSc and dcSSc ( Table 35.3 ), but patients with dcSSc are at increased risk for more clinically severe extracutaneous disease and overall worse outcomes.

  Table 35.3

  Internal organ involvement in systemic sclerosis – screening and treatment options.

  Items in bold signify those screening tests that are recommended at baseline in all newly diagnosed patients. In addition, autologous hematopoietic stem cell transplantation should be considered for patients with rapidly progressive SSc who are at risk of organ failure. ACE, angiotensin converting enzyme; DLCO, diffusing capacity of the lung for carbon monoxide; N -Tpro-BNP, N -terminal pro b-type natriuretic peptide; PFTs, pulmonary function tests.

  Internal organ	Screening tools ∗	Treatment options
  Lung ∗
  Interstitial lung disease (ILD)	PFTs (DLCO, spirometry, and lung volumes) High-resolution CT Bronchoalveolar lavage and lung biopsy	Immunosuppression (e.g. mycophenolate mofetil, cyclophosphamide, rituximab) Nintedanib ∗∗ , tocilizumab ∗∗ Lung transplantation
  Pulmonary arterial hypertension (PAH)	Transthoracic echocardiography Serum N -Tpro-BNP level Right heart catheterization	Oxygen Anticoagulation Endothelin receptor antagonists (e.g. bosentan) Phosphodiesterase inhibitors (e.g. tadalafil) Prostaglandins (e.g. epoprostenol) Prostacyclin analogues (e.g. treprostinil) Prostacyclin receptor agonists (e.g. selexipag) Soluble guanylate cyclase stimulators (e.g. riociguat) Lung transplantation
  Kidney
  Renal crisis Hypertension	Close monitoring of blood pressure BUN/Cr Urinalysis	ACE inhibitors instituted early for treatment but not helpful for prevention
  Heart
  Fibrosis/restrictive cardiomyopathy Heart failure secondary to PAH	Echocardiography	ACE inhibitors
  Gastrointestinal tract
  Esophageal dysmotility Small bowel involvement	Barium swallow with small bowel follow through Manometry Endoscopy	Proton pump inhibitors Promotility agents (e.g. ondansetron)

  ∗ Patients are typically asymptomatic in the early stages of ILD and PAH, which is when the diagnosis should be made and treatment instituted; cough, dyspnea on exertion, and shortness of breath are typical later-onset symptoms.

  ∗∗ FDA-approved for SSc-ILD.

• Most patients (>95%) with SSc are ANA (+); antinuclear autoantibodies unique to SSc, in particular anti-centromere, anti-topoisomerase I, and anti-RNA polymerase III, are useful for diagnostic and prognostic purposes ( Table 35.4 ).

  Table 35.4

  Systemic sclerosis (SSc) autoantibody profile and the more frequently associated clinical presentations.

  Over 95% of SSc patients will have a (+) ANA. The value of a (+) ANA lies in the subsequent identification of the patient’s SSc-specific autoantibody. More than 90% will have one of ten SSc autoantibodies; rarely (∼2–3%) will a patient have more than one SSc autoantibody. The ten autoantibodies are mostly mutually exclusive and tend not to change with time. These autoantibodies are rarely found in patients with other AI-CTDs, unless features of SSc are also present. ILD, interstitial lung disease or pulmonary fibrosis; MCTD, mixed connective tissue disease; PAH, pulmonary arterial hypertension; ssSSc, systemic sclerosis sine scleroderma.

  SSc autoantibody	Clinical features
  Limited skin sclerosis
  Anti-centromere ∗	Increased risk isolated PAH > ILD Esophageal involvement Small intestinal involvement with malabsorption
  Anti-Th/To	Frequent in patients with ssSSc More severe internal organ involvement (ILD, PAH)
  Anti-U11/U12 RNP ∗∗	Greatest risk for developing ILD, which is often severe and rapidly progressive
  Diffuse skin sclerosis
  Anti-topoisomerase-I ∗ ( formerly Scl-70 )	Increased risk ILD >PAH Poor prognosis
  Anti-RNA polymerase III ∗	Most severe diffuse skin sclerosis; rapidly progressive Greatest risk for renal crisis Gastric antral vascular ectasia (GAVE) Increased risk of internal malignancy (especially breast cancer)
  Anti-U3 RNP	More frequent in African-Americans Non-inflammatory skeletal myopathy Early, often severe internal organ involvement (e.g. PAH, cardiomyopathy, small bowel involvement with malabsorption)
  Overlap syndromes
  Anti-PM/Scl	Polymyositis – SSc overlap Acute-onset inflammatory myositis Less serious internal organ involvement Usually better prognosis because responsive to oral CS
  Anti-U1RNP †	MCTD Increased risk ILD and PAH Usually better prognosis because responsive to oral CS
  Anti-Ku	Myositis and arthritis Increased risk of ILD
  Anti-RuvBL1/2 ∗∗	Combination of diffuse skin sclerosis + myositis

  ∗ The most frequently identified autoantibodies in SSc and currently used as criteria for classification/diagnosis (see Table 35.1 ).

  ∗∗ Testing is currently not commercially available.

  † The U1RNP antibody is specific for MCTD, which is often considered a distinct clinical entity (see Ch. 37 ).

• There are three phases of cutaneous disease:

  • –

    (1) Early edematous phase , featuring puffy hands and pitting edema of the digits (see Fig. 35.5A )

  • –

    (2) Indurated phase , characterized by hardening of the skin with taut and shiny appearance (see Fig. 35.5B )

  • –

    (3) Atrophic phase , with potential/gradual softening of the skin

• The degree of skin sclerosis does not predict the degree of internal organ involvement, and survival is dependent on the type and degree of internal organ involvement.

• Pulmonary disease (interstitial lung disease [ILD] > pulmonary arterial hypertension [PAH]) is the most common cause of mortality.

• All SSc patients should be screened and periodically monitored for internal organ involvement, especially lung and renal disease ( Table 35.3 ).

• DDx includes other sclerodermoid conditions ( Table 35.5 ) and other AI-CTDs (e.g. mixed connective tissue disease; see Ch. 37 ).

  Table 35.5

  Differential diagnosis of sclerodermoid conditions.

  POEMS, polyneuropathy, organomegaly, endocrinopathy, monoclonal gammopathy, and skin changes.

  Mucinoses	Neurologic
  Scleredema Scleromyxedema	Complex regional pain syndrome ∗ Spinal cord injury
  Immunologic	Toxin-mediated
  Chronic scleroderma-like GVHD ∗ Eosinophilic fasciitis Generalized morphea ∗ Fibroblastic rheumatism Overlap syndromes	Nephrogenic systemic fibrosis ∗ Eosinophilia-myalgia syndrome (historic) Toxic oil syndrome ∗ (historic) Silicosis
  Paraneoplastic	Drug- or chemical-induced
  POEMS syndrome Amyloidosis (primary systemic) ∗∗ Carcinoid syndrome Paraneoplastic scleroderma-like syndrome	Bleomycin ∗ Taxanes Vinyl chloride, chlorinated hydrocarbons ∗
  Neoplastic	Venous insufficiency
  Carcinoma en cuirasse ∗	Lipodermatosclerosis ∗
  Metabolic	Other
  Diabetic cheiroarthropathy Porphyria cutanea tarda ∗ , †	Restrictive dermopathy § Stiff skin syndrome ∗

  ∗ Can overlap with morpheaform disorders, which are listed in Table 36.2 .

  ∗∗ Primary cutaneous amyloidosis can also occur in patients with systemic sclerosis and generalized morphea.

  † May also be observed in patients with congenital erythropoietic porphyria and hepatoerythropoietic porphyria.

  § Sclerodermoid changes are typically present at birth.

• Recommendations for the initial evaluation of all patients with suspected SSc are presented in Table 35.3 .

• Rx options for various cutaneous and extracutaneous features of SSc are outlined in Tables 35.2 and 35.3 .