Are You Sure the Patient Has Scleroderma?

Scleroderma is a generalized connective tissue disorder affecting the skin and internal organs and is characterized by fibrotic arteriosclerosis of peripheral and visceral vasculature. Accumulation of extracellular matrix (mostly collagen) occurs in both skin and viscera. Scleroderma patients are classified into subsets of disease by the degree of clinically-involved skin.

Diffuse scleroderma has the following features:

  • Onset of Raynaud’s within 1 year of onset of skin changes (puffy or hidebound skin)

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  • Truncal and acral skin involvement

  • Presence of tendon friction rubs

  • Early and significant incidence of interstitial lung disease, oliguric renal failure, diffuse gastrointestinal disease, and myocardial involvement

  • Nailfold capillary dilation and capillary destruction

  • Antitopoisomerase antibodies (30% of patients)

In limited scleroderma the following features are characteristic:

  • Raynaud’s phenomenon for years (occasionally decades)

  • Skin involvement limited to hands, face, feet, and forearms

  • A significant late incidence of pulmonary hypertension, with or without interstitial lung disease, trigeminal neuralgia, skin calcifications, telangiectasias

  • A high incidence of anticentromere antibodies (70%-80%)

  • Dilated nailfold capillary loops, usually without capillary dropout

What Else Could the Patient Have?

Morphea, or localized scleroderma, usually begins between the ages of 20 to 50 years as patches of yellowish or ivory-colored rigid, dry skin. These are followed by the appearance of firm, hard, oval-shaped plaques with ivory centers that are encircled by a violet ring. These spots generally appear on the trunk, face, and/or extremities. Many patients with localized morphea improve without treatment. Generalized morphea is more rare and serious, and involves the skin but not the internal organs.

Linear scleroderma appears as a band-like thickening of skin on the arms or legs. This type of scleroderma is most likely to be on one side of the body but may be on both sides. Linear scleroderma generally appears in young children and is characterized by the failure of one limb (i.e., arm or leg) to grow as rapidly as its counterpart.

Diffuse fasciitis with eosinophilia (Shulman’s syndrome) is a rare condition that mimics scleroderma with swelling, stiffness, and decreased flexibility of the limbs associated with skin thickening. Although the symptoms can be widespread and involve the trunk and limbs, in contrast to scleroderma, the fingers, hands, and face are usually not affected. In addition, there is no occurrence of Raynaud’s or gastrointestinal involvement (GI). Eosinophilia-myalgia syndrome (EMS) and toxic oil syndrome (TOS) are toxin-induced disorders that mimic scleroderma. Both conditions result in skin fibrosis and can become chronic.

Scleroderma-like skin changes have also been associated with insulin-dependent diabetes, carcinoid syndrome, myeloma, scleromyxedema, chronic graft-versus-host disease, porphyria cutanea tarda, Werner’s syndrome, progeria, phenylketonuria, bleomycin exposure, local lipodystrophies, and POEMS syndrome (Polyneuropathy , Organomegaly, Endocrinopathy or Edema, M-protein and Skin abnormalities (including hyperpigmentation and hypertrichosis).

Inflammatory involvement in scleroderma most commonly manifests in the lungs and joints. The most popular approach to controlling the inflammatory phase of scleroderma is the use of immunosuppressive therapy. The rationale is that an autoimmune process is causing the inflammation and the downstream result is tissue damage and fibrosis. There are several drugs that are being used: methotrexate, cyclosporine, mycophenolate mofetil and cyclophosphamide. Mycophenolate is often better tolerated and can be used longer-term than cyclophosphamide.

Key Laboratory and Imaging Tests

The presence of anti-centromere (ACA) antibodies is very highly correlated with a diagnosis of CREST (limited scleroderma). However, only about 57% of patients who are diagnosed with CREST by symptoms alone have detectable ACA antibodies. Similarly, the presence of anti-topoisomerase I (anti-SCL-70) antibodies is highly correlated with diffuse scleroderma, while only about 40% of patients diagnosed with diffuse scleroderma by symptoms alone have detectable anti-SCL-70 antibodies. It is very rare for an individual to have both antibodies.

Overall, only about 60% of patients diagnosed with scleroderma have positive specific antibody tests; this means that the lack of specific antibodies does not rule out the diagnosis of scleroderma. Measurement of these antibodies should be considered secondary to the clinical features when making a diagnosis of scleroderma.

Other Tests That May Prove Helpful Diagnostically

  • Esophagram which may show characteristic esophageal dysfunction with lower esophageal sphincter incompetence and impairment of esophageal peristalsis.

  • Pulmonary function tests and high-resolution computed axial tomography (CAT) scan of the lungs indicating interstitial fibrosis.

  • Cardiac and pulmonary findings of pulmonary hypertension.

Management and Treatment of the Disease

Patients with Raynaud’s phenomenon are advised to stop smoking, avoid cold exposure, wear warm clothing and gloves, and avoid vasoconstrictive substances (clonidine, sympathomimetics, cocaine, ergot alkaloids). Various pharmacologic agents are aimed at reversing digital vasospasm. The calcium channel blockers are first-line agents for the treatment of scleroderma-associated Raynaud’s phenomenon. Sustained-release preparations are preferred, and the dose should be adjusted to reduce the severity and frequency of attacks.

For patients who do not respond to calcium channel blockers, other drugs such as topical nitrates, and α-adrenergic blockers may be tried. The role of antiplatelet and anticoagulant therapy is unclear, although in the absence of contraindications, most experts would recommend low dose aspirin to patients with Raynaud’s phenomenon. Phosphodiesterase-5 inhibitors like sildenafil, tadalafil or vardenafil, have been found to be particularly useful in ameliorating refractory digital ischemia and ulceration, presumably because of their vasodilative properties.

Endothelin receptor antagonists (such as bosentan) are proved effective for the prevention of ischemic digital ulcers. Intravenous prostanoids (e.g., epoprostenol, alprostadil, or iloprost) have also been shown to ameliorate severe digital ischemia and improve digital ulceration. When medical therapy fails, digital sympathectomy may be tried to inhibit sympathetic-mediated vasoconstriction. Organ involvement beyond Raynaud’s has proven much more difficult to treat and is beyond the scope of this text.

Regarding bone mineral density (BMD), some researchers have proposed that scleroderma could be an independent risk factor for osteoporosis, especially for patients with prolonged disease duration, severe joint involvement with secondary immobility, malabsorption syndrome, and renal insufficiency. Also, scleroderma patients often have very low levels of 25-hydroxyvitamin D3 compared to controls and a higher incidence of thyroid disease, both of which affect metabolic bone disease.

Treatment options with oral bisphosphonates may be limited secondary to esophageal disease; treatment with hormone therapy and raloxifene may be limited secondary to potential thrombotic complications. Intravenous zoledronate, teriparatide, and denosumab are better options for treatment of osteoporosis in these patients as they avoid the gastrointestinal tract.

What’s the Evidence?/References

LeRoy, EC. “Scleroderma (systemic sclerosis): Classification, subsets and pathogenesis”. J Rheumatol. vol. 15. 1988. pp. 202-5. (Three feasible, reliable and valid preliminary indices to define disease activity in SSc are proposed.)

Kallenberg, CG. “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. vol. 47. 1988. pp. 634-41. (A study in patients initially with primary Raynaud's phenomenon or possible connective tissue disease (CTD) and the antibody specificities of anti-nuclear antibodies (ANA) as determined by immunoblotting and its prognostic value for the development of certain disease entities.)

Nadashkevich, O. “A proposal of criteria for the classification of systemic sclerosis”. Med. Sci. Monit. vol. 10. (2004) Nov. pp. CR615-21. (A review of criteria for diagnosis of systemic sclerosis: skin involvement, Raynaud's, organ involvement, nail fold findings, ANA.)

Ibn Yacoub, Y. “Assessment of bone density in women with systemic scleroderma and its relationships with disease parameters and vitamin D status. EULAR 2011 SAT0451”. Ann Rheum Dis. vol. 70. 2011. pp. 669(A study documenting the importance of bone loss in Moroccan women with SSc comparing to healthy controls. Decreased BMD seems to be associated with prolonged disease duration, severe joint involvement, malabsorption syndrome and immunological status. Also, SSc patients had very low levels of25-hydroxyvitamin D3.)

Loucks, J. “Osteoporosis in scleroderma”. Semin Arthritis Rheum. vol. 34. 2005. pp. 678-82. (A review documenting the lack of strong evidence in the literature for consistently lower BMD scores in SSc, or for altered biomarkers of bone resorption. Earlier menopause, corticosteroid use in some patients, and other factors secondary to SSc may be the causal factors.)

Hummers, LK, Wigley, FM. “Management of Raynaud's phenomenon and digital ischemic lesions in scleroderma”. Rheum Dis Clin North Am. vol. 29. 2003. pp. 293-313. (Vasodilator therapy remains the main method to treat Raynaud's phenomenon, but new understanding of the pathophysiology of scleroderma vascular disease is reviewed with potential new treatment options.)

Levien, TL. “Phosphodiesterase inhibitors in Raynaud's phenomenon”. Ann Pharmacother. vol. 40. 2006. pp. 1388-93.

Tashkin, D, Roth, M. “Efficacy and Safety of mycophenolate vs oral cyclophophosphamide for treatment of scleroderma interstitial lung disease”. 2015. pp. 148(Improved blood flow and clinical improvements have been observed in some patients with primary Raynaud's phenomenon treated with PDE5 inhibitors; however, studies have yielded conflicting results.)

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