Scleroderma

Scleroderma is an autoimmune disease now called systemic sclerosis. Sclerosis means scarring so scarring of skin is the prototypical feature. There are 2 types of SSc: 

• Limited (CREST)
• Diffuse

Diagnosis

Classification criteria were Developed in 1980 and revised in 2013  by the American College of Rheumatology and European league against rheumatism. If skin thickening is found only distal to the MCP joints, then a point system is applied based on the presence of seven other specific manifestations. These manifestations include

• skin thickening of the fingers
• fingertip lesions
• Telangiectasias
• abnormal nail-fold capillaries
• PAH and/or ILD
• RP
• scleroderma-related autoantibodies

Patients with a combined score of 9 or more points are classified as having scleroderma. The new criteria have a specificity of 0.91 and a sensitivity of 0.92^[1]. Most experts would accept the finding of three of the five features of the CREST syndrome (calcinosis, Raynaud’s phenomenon, esophageal dysfunction, sclerodactyly, and telangiectasias) to make a clinical diagnosis of scleroderma.

Nailfold capillaroscopy

One way to diagnose scleroderma is looking at small blood vessels with magnification. This is done with nailfold capillaroscopy using a dermatology light.^[2] 

Natural History

Late age at onset increases the risks for PAH and poor survival. Males may have a more aggressive disease course than do females. African-American or Native-American background predicts a worse disease course and worse multisystem disease.^[3]

Lab

Autoantibodies

The 3 most common antibodies associated with scleroderma are

• centromere
• anti-topoisomerase-1
• RNA polymerase 3.

Anti-CCP antibodies and rheumatoid factor are not uncommon in patients with systemic sclerosis. In a study published in Adv Clin Exp Med. 2018;27(9):1253–1257, prevalence of CCP antibody was 10 in 100 (10%) and RF was 71 of 100 (71%). 6 of the 100 were considered to have an overlap of RA and scleroderma, 34% had arthritis. Higher CCP, ESR and CRP levels were observed in the SSc group with arthritis. 90% had arthralgia and correlation was found between the arthralgia group and presence of IgM RF.^[4]

Nucleolar ANA

Antinuclear antibody testing is a screening test for lupus. It detects antibodies that bond with human antigen such as DNA (i.e. anti-DNA antibody). Antigens on the nucleus are a substrate for antinuclear antibody (ANA). This can be tested by sampling a person’s blood serum and seeing if ANA binds to it. A microscope equipped to detect a glow in the dark (fluorescence) is used and the appearance of a positive ANA is described as a pattern. The most common patterns are homogenous and speckled but one that is strongly associated with scleroderma is a nucleolar pattern.

Treatment

Raynaud’s Phenomenon and digital ischemia

• Avoid cold temperatures.
• Minimize emotional distress
• Avoid aggravating:

• Smoking
• Sympathomimetic drugs
• Migraine medicine
• Nonselective beta blockers

• Behavioral therapies

• Biofeedback
• Autogenic training
• Classical conditioning

• Pharmacotherapy for Raynaud’s at risk for digital ischemia

• Calcium channel blocker long-active
• PDE-5 inhibitor
• Low dose ASA

Do beta blockers need to be stopped in SSc?

Initial studies with nonselective beta blockers (eg, propranolol) in patients with severe peripheral artery disease described a variety of complications including worsening claudication, cold extremities, absent pulses, and, in some cases, cyanosis and impending gangrene. Raynaud's phenomenon can also be a manifestation of nonselective beta blockade. It was thought that both the reduction in cardiac output and blockade of beta-2-receptor-mediated vasodilation of vessels within skeletal muscle contribute to the vascular insufficiency. Beta blockers with beta-1 selectivity (metoprolol, atenolol) or ISA (pindolol) do not affect the peripheral vessels to the same degree as the nonselective drugs. A meta-analysis of published studies in patients with mild to moderate peripheral artery disease found no exacerbation of symptoms with beta blockers. Thus, the concern may be overstated, particularly in patients with mild to moderate disease treated with a beta-1 selective agent. Although selective agents can also be used in patients with severe disease, they should be used cautiously. [4.5]

Skin disease Treatment

The efficacy of MTX for the treatment of skin disease in patients with diffuse and progressive skin disease has been evaluated in two randomized, placebo-controlled, double blind trials. Both trials demonstrated an improvement in clinician-assessed skin thickening (the modified Rodnan skin score [mRSS]), although neither result was statistically significant. Consistent with an earlier study, another large observational cohort study including 326 patients with early dcSSc (within three years of onset) compared the efficacy of four treatment protocols (methotrexate, MMF, cyclophosphamide, and no immunosuppression) and found a modest improvement in the mRSS across all groups. While there was no significant difference between protocols, there was a trend in favor of the protocols with immunosuppression. Based upon these trials as well as observational data, The European League Against Rheumatism (EULAR) endorses the use of MTX for progressive skin involvement in the early stages of disease. However, there is no evidence that MTX is effective for visceral organ involvement.^[5]

The benefits of mycophenolate for the improvement of skin sclerosis are based upon small observational studies. A prospective study including 15 patients with dcSSc found that those who were administered mycophenolate for at least three months demonstrated significant improvement in the mRSS. Another small prospective study with 25 previously untreated patients with dcSSc of recent onset (less than 24 months) also demonstrated improvement of skin involvement after an average of 18 months of therapy with MMF. Skin biopsies from three of the patients demonstrated histopathological improvement. A larger retrospective analysis of 98 patients with dcSSc treated with mycophenolate found improved mRSS compared with baseline within three months of starting treatment. The improved skin score in dcSSc patients treated with mycophenolate persisted during the 12 months of follow-up when compared with historical controls. A subsequent analysis of two major scleroderma lung fibrosis trials, Scleroderma Lung Study (SLS)-1 and SLS-II, further support benefit of MMF and cyclophosphamide for skin in dcSSc.

Other cutaneous manifestations Treatment

Pruritus —

Intense pruritus can occur in the earliest stages of dcSSc, and excessive scratching and excoriation may be a major problem. There is little immediate effective therapy; however, pruritus usually decreases as the disease plateaus.^[6]

Antihistamines are generally used as first-line treatment but can cause drowsiness. Maintaining adequate lubrication of the skin is essential, and patients should use lubricating creams, especially those that are lanolin-based. Counter-irritants such as capsaicin or menthol may also be used for symptomatic relief. Simple measures such as avoiding repeated exposure to environmental factors associated with itch such as heat or excessive drying after water exposure can also be helpful. Low-dose oral glucocorticoids (less than 10 mg daily dose of prednisone or equivalent) can be effective for severe pruritus, but topical corticosteroids are rarely helpful.

There are anecdotal reports that montelukast or ondansetron may be effective, as they have been in refractory itching in other diseases such as cholestasis or opiate-induced pruritus, although formal trials have not been performed with these agents. In addition, one case series found that low-dose naltrexone may also be helpful.

Gastrointestinal Manifestations

Oropharynx^[7]

• Perioral tight skin
• Decreased oral aperture
• Periodontitis, gum disease
• Dry mouth

Esophagus^[8]

• Lifestyle modifications
• Proton pump inhibitors
• Prokinetics

PROGNOSIS

Mortality

There is a substantial increase in the risk of death in patients with systemic sclerosis (SSc). This was illustrated in a meta-analysis that included 2691 SSc patients followed within a 40-year period; the standardized mortality ratio (SMR) was almost fourfold higher than that of age- and sex-matched controls in the general population (SMR 3.5, 95% CI 3.03-4.11). Among 732 deaths from known causes, 389 (53 percent) were considered to be related to SSc, whereas 223 (30 percent) deaths were defined as not related to SSc, and 120 deaths (16 percent) were due to unknown causes.^[9]

Most deaths among patients with SSc are related to pulmonary fibrosis, pulmonary arterial hypertension, or cardiac causes. Other significant causes of death include renal disease, malignancy, gastrointestinal, and infectious causes].

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