Systemic Sclerosis
GENERAL PRINCIPLES
Definition
Systemic sclerosis (scleroderma) is a systemic illness characterized by progressive fibrosis of the skin and visceral organs. The etiology is unknown, but immune dysregulation, vasculopathy, and fibrosis are implicated in disease pathogenesis.
Classification
• Scleroderma can be subdivided based on anatomic skin distribution into localized scleroderma (morphea and linear scleroderma) and systemic sclerosis (diffuse cutaneous, limited cutaneous, and systemic sclerosis sine scleroderma). The limited cutaneous form involves the extremities distal to the knees and elbows as well as the face. Diffuse cutaneous scleroderma involves the skin of the proximal extremities and the trunk. Systemic sclerosis sine scleroderma affects the internal organs without skin involvement. The CREST syndrome is calcinosis, Raynaud phenomenon, e sophageal dysmotility, sclerodactyly, and telangiectasias.
• Overlap syndrome is the term used to describe patients who have overlapping clinical or serologic features of two or more CTDs. Arguably, the most well-defined of these overlap syndromes is MCTD which encompasses features of SLE, systemic sclerosis, and inflammatory myopathies. Therefore, it is important to recognize that the features of systemic sclerosis that will be reviewed here can be present along with features of other CTDs.
DIAGNOSIS
Clinical Presentation
• Nearly all patients with systemic sclerosis have RP. It is typically the presenting feature. Nail fold capillary changes are also common. Digital ischemia can result in digital pitting or ulcers and in some cases digital resorption. Ulcerations can also occur over DIP and PIP joint contractures.
• Diffuse scleroderma is associated with scleroderma “renal crisis,” and multiple internal organs are affected. Long-term survival is poor.
î Skin involvement: presents initially with edematous skin, erythema may be present reflecting active inflammation.
Pruritus is often present in early stages. Pigment changes with the classic “salt and pepper” appearance can be seen. Eventually the skin tightens and becomes hide bound. Some patients may experience loosening of skin over time either spontaneously or with treatment. Calcium deposition can also occur in the skin often in areas subject to pressure.î GI involvement: Decreased gut motility can occur, leading to bacterial overgrowth, malabsorption, diarrhea, and weight loss. Occasionally, severe constipation and intestinal pseudo-obstruction occur. Classic endoscopic findings include colonic wide-mouth diverticula, patulous esophagus, esophageal strictures, and gastric antral vascular ectasia (GAVE), also known as watermelon stomach.
î Renal involvement: The appearance of sudden hypertension and renal insufficiency indicates potential scleroderma renal crisis. It is associated with a microangiopathic hemolytic anemia and carries a poor prognosis.
î Cardiac involvement: Patchy myocardial fibrosis can result in heart failure or arrhythmias.
î Pulmonary involvement includes pleural effusions and ILD. Predominantly nonspecific interstitial pneumonia pattern although one-third develop usual interstitial pneumonia pattern.
î Musculoskeletal involvement: manifestations range from arthralgias to arthritis with joint contractures because of the regional skin involvement. Myositis can be seen especially in patients with overlap syndrome. Tendon friction rubs are very typical of this diagnosis, often heard over the tendons of the hands.
• Limited scleroderma is more often associated with primary pulmonary hypertension in the absence of ILD, telangiectasias, and calcinosis. There is a strong association with primary biliary cirrhosis.
Diagnostic Testing
• More than 95% of scleroderma patients are ANA positive.18 Well-known antibodies associated with scleroderma are anticentromere antibodies (ACA) and anti-DNA topoisomerase I (Scl-70), but many others have been described.
These tend to correlate with the scleroderma subtype and specific manifestations.19• Antibodies associated with limited scleroderma:
î ACA: pulmonary arterial hypertension (PAH), ILD, digital ulcerations, and calcinosis
î Th/To: ILD and PAH
o U11/U12 RNP: severe ILD
• Antibodies associated with diffuse scleroderma:
î Scl-70: ILD, digital ulcerations and myopathy
î RNA polymerase III: renal crisis, severe skin involvement, and GAVE
o U3-RNP: PAH, myositis, cardiomyopathy, severe GI involvement
• Antibodies associated with overlap syndromes:
o U1-RNP (MCTD): ILD, myositis, and arthritis
î PmScl: ILD and myositis
î Ku: myositis
• Common disease-antibody scenarios include
î Limited scleroderma + ACA: highest risk PAH. Lower risk ILD or renal crisis
î Limited scleroderma + Scl-70: higher risk ILD. Lower risk renal crisis
î Diffuse scleroderma + RNA III: highest of renal crisis and higher risk of malignancy
TREATMENT
• Therapeutic options for scleroderma are limited. Treatment focuses on organ involvement and symptoms. In general, the indications for immunosuppressive therapy include progressive skin thickening, ILD, inflammatory myopathy, and inflammatory arthritis. Other manifestations require symptomatic treatment but not immunosuppression.
• Skin: Methotrexate and mycophenolate mofetil (MMF) are commonly used and can prevent progression. Physical therapy is important to retard and reduce joint contractures.
• GI involvement
î Reflux esophagitis generally responds to standard therapy (e.g., H2-receptor antagonists, proton pump inhibitors, and promotility agents).
î For dysmotility, short courses of prokinetic drugs like domperidone, metoclopramide, or erythromycin can be considered. Injectable octreotide has been used in severe or refractory cases.
î For symptomatic small intestine bacterial overgrowth, intermittent or rotating antibiotics like rifaximin, ciprofloxacin, amoxicllin-clavulanic acid, or metronidazole can be used.
î Occasionally, esophageal strictures require mechanical esophageal dilation.
• Renal involvement: Aggressive blood pressure control with ACE inhibitors is indicated in scleroderma renal crisis. ARBs do not appear to be as effective. Blood pressure and renal function should be carefully monitored if the patient is receiving glucocorticoids since it is known that use of glucocorticoids can precipitate scleroderma renal crisis.
• Cardiac involvement: Coronary artery vasospasm can cause angina pectoris and may respond to calcium channel antagonists.
• Pulmonary involvement, such as pulmonary hypertension, is treated with standard therapies for these conditions. For patients with ILD, MMF is considered first-line treatment. Cyclophosphamide is viewed as a second-line agent due to the increased risk of adverse effects when compared to MMF.20 Refractory cases may benefit from the addition of nintedanib, an antifibrotic agent.21