Sun Exposure, Vitamin D, and MRI Measures in MS
Sun Exposure, Vitamin D, and MRI Measures in MS
The purpose of this study was to systematically assess the relative contributions of different environmental factors to vitamin D metabolite levels in MS patients and to determine whether sunlight exposure was associated with MRI measures of brain injury. Our results indicate that BMI, multivitamin supplementation, summer sun exposure and eye colour had strong associations with vitamin D metabolite levels. Increased sun exposure was associated with increased WBV and GMV after adjusting for disability and 25-hydroxy vitamin D3 levels. Our results are consistent with the possibility that immunomodulation resulting directly from sun exposure may be a contributing factor to MRI outcomes in MS.
The main limitation of this study is that it is a cross sectional study, which limits the ability to obtain cause–effect assessments from associations. Our findings are consistent with an effect of sun exposure on WBV and GMV but they could potentially also be caused by lifestyle changes consequent to disability. Although we undertook several precautions to address the potential adverse effects of reverse causation by obtaining blood biomarker assessments and using MRI measures, only prospective longitudinal studies can fully eliminate the confounding effects of reverse causation. Both longitudinal MR measures and longitudinal measures of environmental factors are needed, with careful repeated measurements of both summer and winter sun exposure and 25-hydroxy vitamin D levels.
We found that multivitamin supplementation results in greater changes in 25-hydroxy vitamin D3 levels in individuals with lower levels of sunlight exposures. Our results are consistent with the possibility that the active metabolite levels are regulated. Steffensen et al also found similar results for supplementation in a randomised clinical trial of vitamin D effects on bone mineral density that involved 60 MS patients. Recent data suggest that interferon beta treatment is more effective against relapses if vitamin D levels are sufficient. We also assessed but did not find evidence that present treatment with interferon β increased levels of either 25 hydroxy vitamin D3 or 1, 25 dihydroxy vitamin D3. However, a prospective vitamin D add-on study would be appropriate for directly addressing this issue. Analogously, we also assessed whether the presence or absence of disease modifying treatments (including glatiramer acetate or natalizumab) were associated with vitamin D metabolites but did not find evidence for significant associations (data not shown). One potential criticism of our methodology is that we did not collect information on the precise multivitamin brands used by our subjects, which might have enabled more systematic dose estimation for vitamin D and a better understanding of the role of other vitamins and minerals. Many currently available multivitamin supplements are taken once daily and contain vitamins and minerals at levels close to the required daily allowance.
Our study complements longitudinal studies that have investigated the seasonal dependence of relapses, contrast enhancing lesions (CEL) and new T2 lesions. However, there are studies that did not find evidence to support seasonal dependence of CEL or of relapses. A study of 28 patients by Killestein et al did not find seasonality in the number of active lesions but reported seasonal variation in interferon γ secretion, which was weakly associated with MRI variations. Seasonality in interferon γ secretion was also found in a Tasmanian study of untreated MS and in a study of progressive MS. In our study, we obtained long term self-reported sun exposure measures rather than month of measurement to assess the impact on MRI measures of lesion burden and neurodegeneration. We did not assess CEL because these are transient compared with the period over which the sun exposure measures were obtained. We conducted the analyses (data not shown) but did not find evidence for seasonality for CEL. However, longitudinal serial MRI scanning is necessary to effectively answer this question. Also, the majority of our patients were on disease modifying therapies, which are known to suppress CEL activity.
A critical challenge in assessing environmental factors such as sun exposure is that these measurements are difficult to make and are subject to recall errors. Latitude and meteorological exposure data have frequently been used as objective surrogate measures of incident sunlight exposure in epidemiological studies but these cannot be used for studies such as ours that span a geographically small area. The biological exposure at a given level of sun exposure can further be modulated by skin pigmentation, level of outdoor activity, clothing and sunscreen use. Because our sample contained patients of Caucasian and non-Caucasian racial ancestry who differ in skin pigmentation, we conducted subanalyses of the results shown in Table 2 and Table 3 for the subset of patients of Caucasian race. The conclusions were not substantively changed (data not shown). Clothing and sunscreen use are more difficult to meaningfully measure although surveys to collect these data have been developed. Silicone skin casts have been used to image skin damage induced by UVR and can serve as a surrogate marker for long term sun exposure to skin. We did not obtain silicone skin casts. However, to address these concerns, we included multiple vitamin D metabolites as biomarkers, which are dependent in part on sun exposure, but can be objectively measured. We also focused on obtaining information on sun exposure in the preceding 2 years given the potential recall problems associated with obtaining past sun exposure of longer duration. Systematic studies of sun exposure have shown good test–retest reproducibility in MS. Sun exposure and vitamin D were reported to be independent risk factors for CNS demyelination in an Australian multicentre case control study of MS incidence. Greater UV induced skin damage and higher vitamin D levels were associated with a decreased risk of the initial demyelinating event.
The doses of oral vitamin D necessary for achieving therapeutic outcomes in clinical trials and MS prevention remains unclear, given the lack of large randomised placebo controlled studies. In a small 48 week study of 15 patients, 1, 25 (OH)2 vitamin D (calcitriol 2.5 μg/day) treatment reduced the relapse rate compared with the period preceding study entry; treatment discontinuation was associated with an increase in EDSS. Two patients experienced hypercalcaemia. An open label randomised 52 week trial of high dose vitamin D escalation (up to 40 000 IU/day) followed by de-escalation, found a trend towards lower relapse rates compared with the control group, which received 4000 IU/day vitamin D supplementation (4000 IU/day). A 6 month, placebo controlled, double blind clinical trial of vitamin D2 in MS patients failed to find improvements on MRI and clinical outcomes despite increasing vitamin D levels in serum. A randomised trial of the vitamin D3–interferon β-1b combination therapy (20 000 IU or 500 μg of vitamin D3, once weekly) did not meet its primary MRI endpoint of T2 disease burden; however, CEL burden was significantly reduced. Additional preplanned analysis of this study showed a smaller T2-LV growth and less new/enlarging T2 brain MRI lesions in the vitamin D3 treated compared with the placebo treated subgroup. A 96 week trial of vitamin D3 supplementation did not find evidence for a vitamin D effect. The Institute of Medicine report, which was based on a systematic review of an extensive body of clinical literature, found that there was evidence to support calcium and vitamin D use in bone health but did not find evidence to support its use in other conditions, such as MS. The therapeutic potential of vitamin D in MS should therefore be viewed with equipoise until the outcomes of larger randomised clinical trials are available.
In conclusion, the results from our cross sectional study suggest that sun exposure could have an effect on brain volume in MS. These effects appear to be dissociated from the increased vitamin D levels that result from increased sun exposure. However, it is necessary to overcome the limitations of the cross sectional study design before definitive conclusions can be established. Further prospective longitudinal studies of the effects of sun exposure on brain volume reserve in controls and on neurodegeneration in MS patients are therefore needed.
Discussion
The purpose of this study was to systematically assess the relative contributions of different environmental factors to vitamin D metabolite levels in MS patients and to determine whether sunlight exposure was associated with MRI measures of brain injury. Our results indicate that BMI, multivitamin supplementation, summer sun exposure and eye colour had strong associations with vitamin D metabolite levels. Increased sun exposure was associated with increased WBV and GMV after adjusting for disability and 25-hydroxy vitamin D3 levels. Our results are consistent with the possibility that immunomodulation resulting directly from sun exposure may be a contributing factor to MRI outcomes in MS.
The main limitation of this study is that it is a cross sectional study, which limits the ability to obtain cause–effect assessments from associations. Our findings are consistent with an effect of sun exposure on WBV and GMV but they could potentially also be caused by lifestyle changes consequent to disability. Although we undertook several precautions to address the potential adverse effects of reverse causation by obtaining blood biomarker assessments and using MRI measures, only prospective longitudinal studies can fully eliminate the confounding effects of reverse causation. Both longitudinal MR measures and longitudinal measures of environmental factors are needed, with careful repeated measurements of both summer and winter sun exposure and 25-hydroxy vitamin D levels.
We found that multivitamin supplementation results in greater changes in 25-hydroxy vitamin D3 levels in individuals with lower levels of sunlight exposures. Our results are consistent with the possibility that the active metabolite levels are regulated. Steffensen et al also found similar results for supplementation in a randomised clinical trial of vitamin D effects on bone mineral density that involved 60 MS patients. Recent data suggest that interferon beta treatment is more effective against relapses if vitamin D levels are sufficient. We also assessed but did not find evidence that present treatment with interferon β increased levels of either 25 hydroxy vitamin D3 or 1, 25 dihydroxy vitamin D3. However, a prospective vitamin D add-on study would be appropriate for directly addressing this issue. Analogously, we also assessed whether the presence or absence of disease modifying treatments (including glatiramer acetate or natalizumab) were associated with vitamin D metabolites but did not find evidence for significant associations (data not shown). One potential criticism of our methodology is that we did not collect information on the precise multivitamin brands used by our subjects, which might have enabled more systematic dose estimation for vitamin D and a better understanding of the role of other vitamins and minerals. Many currently available multivitamin supplements are taken once daily and contain vitamins and minerals at levels close to the required daily allowance.
Our study complements longitudinal studies that have investigated the seasonal dependence of relapses, contrast enhancing lesions (CEL) and new T2 lesions. However, there are studies that did not find evidence to support seasonal dependence of CEL or of relapses. A study of 28 patients by Killestein et al did not find seasonality in the number of active lesions but reported seasonal variation in interferon γ secretion, which was weakly associated with MRI variations. Seasonality in interferon γ secretion was also found in a Tasmanian study of untreated MS and in a study of progressive MS. In our study, we obtained long term self-reported sun exposure measures rather than month of measurement to assess the impact on MRI measures of lesion burden and neurodegeneration. We did not assess CEL because these are transient compared with the period over which the sun exposure measures were obtained. We conducted the analyses (data not shown) but did not find evidence for seasonality for CEL. However, longitudinal serial MRI scanning is necessary to effectively answer this question. Also, the majority of our patients were on disease modifying therapies, which are known to suppress CEL activity.
A critical challenge in assessing environmental factors such as sun exposure is that these measurements are difficult to make and are subject to recall errors. Latitude and meteorological exposure data have frequently been used as objective surrogate measures of incident sunlight exposure in epidemiological studies but these cannot be used for studies such as ours that span a geographically small area. The biological exposure at a given level of sun exposure can further be modulated by skin pigmentation, level of outdoor activity, clothing and sunscreen use. Because our sample contained patients of Caucasian and non-Caucasian racial ancestry who differ in skin pigmentation, we conducted subanalyses of the results shown in Table 2 and Table 3 for the subset of patients of Caucasian race. The conclusions were not substantively changed (data not shown). Clothing and sunscreen use are more difficult to meaningfully measure although surveys to collect these data have been developed. Silicone skin casts have been used to image skin damage induced by UVR and can serve as a surrogate marker for long term sun exposure to skin. We did not obtain silicone skin casts. However, to address these concerns, we included multiple vitamin D metabolites as biomarkers, which are dependent in part on sun exposure, but can be objectively measured. We also focused on obtaining information on sun exposure in the preceding 2 years given the potential recall problems associated with obtaining past sun exposure of longer duration. Systematic studies of sun exposure have shown good test–retest reproducibility in MS. Sun exposure and vitamin D were reported to be independent risk factors for CNS demyelination in an Australian multicentre case control study of MS incidence. Greater UV induced skin damage and higher vitamin D levels were associated with a decreased risk of the initial demyelinating event.
The doses of oral vitamin D necessary for achieving therapeutic outcomes in clinical trials and MS prevention remains unclear, given the lack of large randomised placebo controlled studies. In a small 48 week study of 15 patients, 1, 25 (OH)2 vitamin D (calcitriol 2.5 μg/day) treatment reduced the relapse rate compared with the period preceding study entry; treatment discontinuation was associated with an increase in EDSS. Two patients experienced hypercalcaemia. An open label randomised 52 week trial of high dose vitamin D escalation (up to 40 000 IU/day) followed by de-escalation, found a trend towards lower relapse rates compared with the control group, which received 4000 IU/day vitamin D supplementation (4000 IU/day). A 6 month, placebo controlled, double blind clinical trial of vitamin D2 in MS patients failed to find improvements on MRI and clinical outcomes despite increasing vitamin D levels in serum. A randomised trial of the vitamin D3–interferon β-1b combination therapy (20 000 IU or 500 μg of vitamin D3, once weekly) did not meet its primary MRI endpoint of T2 disease burden; however, CEL burden was significantly reduced. Additional preplanned analysis of this study showed a smaller T2-LV growth and less new/enlarging T2 brain MRI lesions in the vitamin D3 treated compared with the placebo treated subgroup. A 96 week trial of vitamin D3 supplementation did not find evidence for a vitamin D effect. The Institute of Medicine report, which was based on a systematic review of an extensive body of clinical literature, found that there was evidence to support calcium and vitamin D use in bone health but did not find evidence to support its use in other conditions, such as MS. The therapeutic potential of vitamin D in MS should therefore be viewed with equipoise until the outcomes of larger randomised clinical trials are available.
In conclusion, the results from our cross sectional study suggest that sun exposure could have an effect on brain volume in MS. These effects appear to be dissociated from the increased vitamin D levels that result from increased sun exposure. However, it is necessary to overcome the limitations of the cross sectional study design before definitive conclusions can be established. Further prospective longitudinal studies of the effects of sun exposure on brain volume reserve in controls and on neurodegeneration in MS patients are therefore needed.
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