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associations between skin pigmentation and lower disability scores in females; congruence of geographical distribution of MS with geographical distribution of low vitamin D levels; associations between seasonal variation in birth and in disease severity with the seasonal variation of low vitamin D levels; associations between remission and pregnancy (when calcitriol levels increase); and variations in risk associated with polymorphisms in the Vdr gene. In addition to the lack of positive evidence, the authors raised concerns about the safety of calcitriol treatment for MS because of the dose-dependent risk for hypercalcemia identified with calcitriol treatment in animal models. No meta-analyses were identified for this indicator.

Additional evidence from randomized controlled trials No RCTs were identified for this indicator.

Observational studies Observational studies in humans have also failed to show a consistent association between serum 25OHD levels and MS. A small longitudinal study of 23 MS patients and 23 controls found no differences in circulating 25OHD levels, no difference in seasonal variation, and comparable rates of vitamin D deficiency or insufficiency based on serum 25OHD levels between MS patients and controls (Soilu-Hanninen et al., 2008). Interestingly, in this study, serum 25OHD levels were significantly lower during relapse episodes, whereas serum levels of intact PTH were significantly higher than in remission periods in MS patients. A prospective nested case–control study in military personnel reported that, for white subjects, serum 25OHD levels were inversely related to the risk of MS and that effect was even greater when serum 25OHD levels were low in individuals under 20 years of age (Munger et al., 2006). Overall, serum 25OHD levels were lower in black and Hispanic compared to white subjects and 25OHD levels were more frequently in the range of 25 to 40 nmol/L in MS patients compared to controls. These findings, however, were unrelated to risk for MS (Munger et al., 2006). In a small population-based case–control study of individuals living at latitudes of 41 to 43°S (similar to New York City and Boston), van der Mei et al. (2007) found that serum 25OHD levels below 25 nmol/L were moderately associated with MS, compared with levels above 40 nmol/L. With more consistent serum 25OHD levels and less seasonal variability, there was an association with less disability.

Taken together, these observational studies show widely variable outcomes for associations between serum 25OHD levels and MS and such associations are not supported by meta-analyses. In addition, the lack of causal evidence further diminishes the likelihood for a relationship between vitamin D and MS.

Rheumatoid arthritis RA is a chronic disease characterized by systemic inflammation that may affect many tissues and organs, but particularly the joints. In RA inflammatory synovitis of the joints can progress to destruction of the articular cartilage and ankylosis. RA can also produce diffuse

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