Clinical Briefs

With Comments from Russell H. Greenfield, MD, Dr. Greenfield is Clinical Assistant Professor, School of Medicine, University of North Carolina, Chapel Hill, NC; and Visiting Assistant Professor, University of Arizona, College of Medicine, Tucson, AZ.

D Answer? Vitamin D Levels and MS

Source: Munger KL, et al. Serum 25-hydroxyvitamin D levels and risk of multiple sclerosis. JAMA 2006;296:2832-2838.

Goal: To determine whether serum levels of 25-hydroxyvitamin D (25-OHD) are associated with risk of multiple sclerosis (MS).

Design: Prospective, nested case control study.

Subjects: Medical records of active duty military personnel who had received a diagnosis of MS and had at least one serum sample drawn prior to symptom onset (n = 237 with definite MS, n = 78 with probable MS). Data were drawn from that of more than 7 million personnel with serum samples stored in the Department of Defense Serum Repository (DoDSR).

Methods: Medical records of possible cases of MS were reviewed by trained study personnel to determine the degree of confidence in the diagnosis of MS. Controls were randomly selected from the DoDSR population and two controls were matched to each case according to, among other things, race and branch of military service. Data were also collected regarding latitude of place of residence at time of entry into the military. Up to four serum samples were obtained, three prior to symptom onset (including the earliest and latest available) and one after symptom onset (earliest available). The main outcome measure was the odds ratio of MS associated with 25-OHD levels within each racial group.

Results: Most people with MS received a diagnosis of relapsing-remitting MS (73%), while for 20% the type of MS was uncertain. The average time between collection of first and last serum samples before symptom onset was 4.4 years, and between first serum sample and MS symptom onset was 5.3 years. Mean levels of 25-OHD were consistent with those previously found within the general U.S. popu-lation, with Caucasians having markedly higher levels than African Americans. Among whites, for every 50 nmol/L increase in 25-OHD there was a 41% decrease in risk of MS. MS risk was highest in those subjects in the lowest quintile of 25-OHD level, and lowest among those in the highest quintile, with an overall inverse trend across all quintiles that was significant. The inverse relationship between 25-OHD levels and risk of MS was strongest in those younger than 20 years of age.

Conclusion: High serum vitamin D levels are associated with a lower risk for development of MS in Caucasians.

Study strengths: Prospective nature; sample size; analyses restricted to those subjects with MS (n = 257) and matched controls (n = 514) who had at least two 25-OHD levels on record prior to symptom onset; adjustments made for seasonal variation and time of collection of serum sample; analysis stratified by race and adjustments made based on latitude of residence; appropriate controls could not be identified for 10 cases, and data from these 10 subjects were excluded from the final analysis; additional analysis done to exclude possibility that results were due to MS having an effect on 25-OHD levels rather than 25-OHD levels having an effect on MS risk; thorough consideration of other potential reasons for the identified inverse relationship.

Study weaknesses: Observational nature; due to small numbers, data from Hispanic subjects or those who fell into another classification were combined together into one group; inability to assess whether high 25-OHD levels in African Americans are associated with reduced risk of MS (small sample size and significantly lower 25-OHD levels).

Of note: MS affects more than 350,000 Americans and more than 2 million people worldwide, most commonly occurring in young adulthood; African Americans have a lower incidence of MS than Caucasians, likely due to genetic factors (African Americans also have lower 25-OHD levels than Caucasians); there is an increasing incidence of MS with increasing latitude both north and south of the equator; the hormonal form of vitamin D has been shown to prevent an animal model of MS (autoimmune encephalomyelitis, or EAE); military personnel typically provide a blood sample upon enlistment and, on average, every two years thereafter; the DoDSR holds more than 30 million serum samples from routine HIV and deployment-related blood tests obtained since 1985; in a prior study, Epstein-Barr virus antibody titers were strongly associated with risk of MS in a subset analysis of subjects from the DoDSR database; much higher vitamin D levels than those previously acknowledged to be "normal" may be required to optimize bone health, and perhaps to help prevent MS; adverse effects associated with vitamin D intake have only been reported with doses significantly higher than 2,000 IU/d (the Institute of Medicine currently lists the adequate intake of vitamin D as 200 IU/d for those younger than 50 years of age).

We knew that: Some debate the conclusiveness of existing data, but significant evidence points to a protective effect of sun exposure and use of vitamin D supplementation for prevention of MS, especially during adolescence; prior data showed that women taking vitamin D supplements have a lower risk of MS; while the latitude gradient and associated vitamin D levels may offer evidence of the protective effect of vitamin D against MS, latitudes at birth or early childhood also reflect socioeconomic status, as well as age at infection with common viruses, both of which have been deemed potential risk factors for MS; experts feel that MS is likely an autoimmune disorder mediated by T-cells that ultimately results in central nervous system tissue demyelinization; the major source of vitamin D is sun exposure, however at latitudes of 42° or more (approximately that of Boston) the majority of UV-B radiation is absorbed by the atmosphere during winter months, so that even prolonged sun exposure does not generate needed vitamin D (thus, seasonal vitamin D deficiency is common); there appears to be a genetic predisposition towards MS, but data on MS risk and migration strongly support a role for environmental factors; vitamin D supplementation during infancy appears to confer a protective effect against Type 1 diabetes.

Clinical import: This is an extremely well-done article limited only by the fact that it is observational in nature. In recent months, Alternative Medicine Alert has devoted a significant number of pages to the proposed therapeutic benefits of achieving optimal 25-OHD levels. While the definition of an optimal 25-OHD level is yet to be determined, a compelling array of data suggest that, at least in this instance, more actually is better, additionally that vitamin D supplementation is safe up to at least 2,000 IU/d. In certain locales, 15 minutes of sunshine daily may suffice, but in many others the call for widespread vitamin D supplementation is gaining support, and rapidly. This trial's results can be added to others touting the potential benefit of vitamin D for bone health, as a cancer chemopreventive agent, and to enhance mood and lessen musculoskeletal pain in select populations. It is striking that the final line of this paper reads "…use of vitamin D supplements for MS prevention should not be undertaken until efficacy is proven." The data provided in this article are not definitive, that is true, but in the face of growing evidence of potential benefits associated with a good safety profile, perhaps this is one of those rare instances where a broad recommendation for supplementation can be made. To this reviewer, to do so at this time seems less bold than pragmatic.

What to do with this article: Make copies to hand out to your peers.

Which Itch to Scratch? Stress and Skin Disorders

Source: Choi E-H, et al. Glucocorticoid blockade reverses psychological stress-induced abnormalities in epidermal structure and function. Am J Physiol Regul Integr Comp Physiol 2006;291:R1657-R1662. Epub 2006 Jul 20.

Goal: To determine whether increased endogenous production of glucocorticoids (GC) mediates the adverse cutaneous effects seen with psychological stress (PS).

Subjects: Animal (murine) model using 8- to 10-week-old female hairless mice.

Methods: Prior to starting the experiment, small cohorts of four animals each were kept in separate cages for at least two weeks. Groups of six animals were then transferred to a 12.5-cm diameter, 12.5-cm high clear glass jar for two days in which they experienced continuous light exposure and radio noise. Mice in the control group were maintained in ordinary cages without continuous stimulation with sound and light. Mice in the intervention groups were selected to receive intraperitoneal injections of either 1) RU-486 or 2) antalarmin (see Of note below), or 3) simply a liquid vehicle, all administered one hour before stress and 24 hours after stress. Both groups were permitted to eat and drink freely. Following 48 hours of stress, blood samples were obtained, measures of transepidermal water loss were determined, and skin biopsy samples were assessed for proliferation cell nuclear antigen (a measure of epidermal proliferation) and also taken for electron microscopic studies.

Results: GC receptor blockade by co-administration of RU-486 with PS reversed PS-induced decreases in keratinocyte proliferation and epidermal differentiation, reversed PS-induced abnormalities in permeability barrier homeostasis, and normalized stratum corneum integrity in the face of PS. Inhibition of GC production by co-administration of antalarmin created similar results.

Conclusion: PS induces abnormalities in epidermal structure and function that are mediated through increased and excessive endogenous GC production.

Study strengths: Use of two different approaches for addressing potential influence of excess GC production; exacting methodology; attention paid to diurnal peak of GC in methodology.

Study weaknesses: Attendant limitations noted with an animal model.

Of note: RU-486 (often referred to as the morning after pill) inhibits GC action at the cellular level; antalarmin is a corticotropin-releasing hormone (CRH) receptor antagonist that prevents the increase in GC production due to increased CRH levels; GC levels increase rapidly after stress, which explains why the researchers chose to administer the active agents one hour prior to stress.

We knew that: PS increases endogenous GC production by increasing hypothalamic CRH, which leads to increased pituitary adrenocorticotropic hormone secretion and subsequent GC production by the adrenal glands, and has been shown to exacerbate, if not actually initiate, various dermatologic conditions, including psoriasis and atopic dermatitis, mainly by impacting basal permeability barrier function (retention of moisture); additionally, PS decreases epidermal lipid synthesis, negatively impacts keratinocyte proliferation, diminishes the integrity of the stratum corneum, and impairs epidermal differentiation; topical and systemic GC treatment produce similar skin abnormalities as those listed above in association with PS; topical application of barrier lipids largely corrects the skin abnormalities identified with both PS and GC administration.

Clinical import: This trial employs an animal model and the researchers reasonably try to extrapolate their findings to human beings. In and of itself this is not an affront, but it is nonetheless remarkable to note that the authors' recommendations focus wholly on identifying means of lessening GC production or action (i.e., pharmaceutical means), all without a single mention of the importance of helping people learn to manage stress effectively. It is often stated that everyone experiences stress, but it is the rare individual who possesses adequate means to manage stress. A number of dermatologists have taken notice, and either employ or work closely with therapists who help patients identify appropriate ways to manage stress that uniquely work for them. While the findings of this article shed further light on the pathophysiology behind the association of PS with exacerbations of skin disorders such as psoriasis and atopic dermatitis, the authors missed an opportunity to emphasize prevention. Certainly, one hopes that additional pharmaceutical tools to help modulate GC levels and thereby minimize symptoms safely and effectively will be forthcoming as a result of published data like these, especially in light of the fact that PS is not the only reason for excessive endogenous or exogenous GC (consider Cushing's syndrome or pituitary adenomas, as well as the therapeutic administration of GC); however, one would also hope that the hard science presented in this paper would lend added credibility to the need for widespread popular training in appropriate methods of management of an entity that is essentially universal—psychological stress. Frankly, after reading how the animals in this trial were treated, I need to go do my breathing exercises…

What to do with this article: Keep a copy on your computer.