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Longitudinal studies of large cohorts of patients with Raynaud's Phenomenon have addressed the predictors of developing a secondary disease. New insights have been reported into the pathogenesis of Raynaud's phenomenon and the consequences of ischemia. Studies have suggested that more than one defect may cause Raynaud's phenomenon, including increased alpha-2 sympathetic receptor activity on vessels, endothelial dysfunction, deficiency of calcitonin gene related peptide protein--containing nerves or some central thermoregulatory defect. The vasoconstricting and profibrotic cytokine endothelin-1 was found to be elevated in scleroderma but did not correlate with disease subset or with evidence of pulmonary hypertension. Oxidant stress is thought to be increased in scleroderma, causing tissue damage and provoking fibrosis. Treatment with infusion of prostacyclin for primary pulmonary hypertension was approved, paving the way for studies of secondary forms of pulmonary hypertension. Oral prostanoids are being tested for the treatment of Raynaud's phenomenon.

A new awareness of the challenges and pitfalls of clinical research in patients with systemic sclerosis has recently arisen. Several editorials discussed concern about the design of therapeutic trials and the need to use established scientific standards to find better markers of disease activity and better ways to measure improvement or deterioration of organ involvement, including the heart, lung, and gastrointestinal tract. This year, an uncontrolled experience in the use of D-penicillamine in the treatment of patients with rapidly progressive skin involvement was reported. In addition, a multicenter study of photopheresis demonstrated benefit compared with D-penicillamine. Several new prokinetic drugs demonstrated promise for the treatment of gastrointestinal disease in patients with systemic sclerosis. Although studies continue to demonstrate the benefit of intravenous prostaglandins in the treatment of Raynaud's phenomenon and digital ulcers in scleroderma, an initial report of oral prostaglandins was disappointing. Clinical researchers are now working together to design multicenter studies and to define new uniform standards of disease activity so that the appropriate treatment for systemic sclerosis can be determined.