Progress Continues in Systemic Sclerosis

Baron et al investigated 586 patients from the Canadian Scleroderma Research Group Registry and used a validated instrument to assess malnutrition: the malnutrition universal screening tool.²² These investigators showed that 18% of their cohort were at high risk for malnutrition and that malnutrition was associated with increased disease severity, shorter disease duration, and more frequent GIT involvement. Large randomized controlled trials have not been conducted in individuals with GIT involvement, partly due to lack of a validated instrument. Khanna is leading a team of researchers at three large scleroderma centers to develop a fully validated GI instrument, the University of California, Los Angeles (UCLA) Scleroderma Clinical Trial Consortium (SCTC) GIT 2.0. This instrument includes 34 items with seven scales: reflux, distention/bloating, diarrhea, fecal soilage, constipation, emotional well-being, and social functioning.²³ Table 1 (below) depicts symptom severity and disease correlations supporting the reliability and validity of the method. This instrument is currently being used as a secondary outcome measure in several ongoing randomized clinical trials in the treatment of SSc.

Therapy

In double-blind trials, treatment with methotrexate was shown to be effective for the skin involvement but with moderate effect; it may potentially have an effect on the lungs, although this is not proven statistically. A large randomized, placebo-controlled trial of cyclophosphamide suggested a small effect in reducing loss for forced vital capacity (FVC) while improving measures of quality of life and dyspnea.²⁴ Subsequent exploratory analysis suggested that the magnitude of the effect was strongly related to disease severity at treatment outset, includingthe level of FVC and extent of fibrosis by high-resolution computerized tomography (HRCT) of the lung. “Traditional” measures of activity (inflammation) including cellularity on bronchoalveolar lavage and “ground glass” on HRCT predicted neither the clinical course nor the response to therapy. Other prospective data sets offered complementary information.²⁵ The implications are important for bedside decision making and for design of future trials.

click for large version

Figure 3: Improvements in serial modified Rodnan Skin Scores (A), Health Assessment Questionnaires (B), Forced Vital Capacity (FVC) (C), and Diffusion Capacity (DLCO) (D) following immunoablation and autologous hematopoietic cell transplantation. Gray solid lines depict individual patient parameters, solid black lines are mean values, and dashed lines represent the generalized estimating equation for repeated measures. Improvements in skin score over time were significant (P<.001), as were the health assessment scores (P<.001). The mean FVC values improved over time (P=.01), whereas the DLCO did not change significantly (P=.5).³⁶

Conventional treatments are directed nonspecifically as macrophage/lymphocyte activity therapy (methotrexate) or as nonspecific alkylating therapy (cyclophosphamide). On the other hand, with increasing understanding of the pathogenesis of SSc, the possibility of more targeted therapy is beginning to evolve. As shown in Figure 1 (above), a number of cytokines and proteins have potential roles in the pathogenesis of this disease. Anti–TGF-beta was tested in a pilot study of SSc, but was not effective, although the pilot nature of this trial makes it very underpowered.²⁶ This substance or congeners may still find a place in the therapy of SSc. Suppression of PDGF through combined c-Abl/PDGF TK receptor binders such as imatinib, nilotinib, or dasatinib has undergone a few open label studies and possible encouraging results will be tested in well-controlled trials.²⁷ Because endothelin receptor antagonists have an antifibrotic effect in animals, they have also been tested in patients with SSc. The results of these studies, however, have not been fully published, although data regarding use of endothelin receptor antagonists in PAH and bosentan in digital ulcers indicates the possibility that this class of drugs has a vascular effect.²⁸