Comment on: Alopecia in Multiple Sclerosis Patients Treated with Disease Modifying Therapies

With great interest we read the publication by Porwal MH et al. ¹ With 117 registered cases, a high number of unreported cases can be postulated. If younger patients with multiple sclerosis (PwMS) tend to be affected more frequently, preventive oral vitamin D (VitD) supplementation should be discussed. This adjuvant VitD administration during the entire 48-month therapy with alemtuzumab (ALEM) has a double benefit. There is increasing evidence that the serum level of VitD influences the severity and duration of alopecia areata (AA). VitD deficiency plays a major role in pathogenesis and therapy. Several studies revealed that serum VitD levels significantly and inversely correlate with the duration and severity of AA.^2-4 Patient affected by various autoimmune diseases showed low serum levels of VitD (25(OH)D). VitD plays a role in the pathogenesis of AA. Lin et al ² are currently showing the connections between vitD and AA. VitD plays a role in the pathogenesis of AA-related

a) Loss of immune privilege in hair follicle

b) Autoreactive effector-T-cells and mast cells

c) nature-killer-group 2 member d-positive cytotoxic T cells

d) Janus kinase/signal transducer and activators of the transcriptional signaling pathway

e) Regulatory T cells

f) Immune checkpoints,

g) Oxidative stress

Genetic VitD-receptor (VDR) mutations may result in an alteration of the effects produced by the binding of the receptor with 1,25(OH)₂D₃ in the promoter regions of genes that respond to VitD. Low VitD-status and VDR polymorphism have been thought to be important environmental risk factors in the development of autoimmune disease. ⁵ AA is an autoimmune disease.^6,7 Porwal et al point to the occurrence of polyautoimmunity (2 or more autoimmune diseases). Polyautoimmunity may increase morbidity due to inflammation. Interdisciplinary assessment is beneficial for PwMS. ⁸

VitD plays a different role in women and men. VitD insufficiency has been linked to autoimmune disorders that commonly display significant differences between females and males due to genetic, epigenetic, hormonal, and environmental factors. Notably, estrogen has been demonstrated to enhance VitD function favoring its accumulation, and increasing the expression of VDR, thus resulting in a more potent anti-inflammatory response in females than males. ⁹ A higher protective effect of VitD-based therapeutic approaches in women, at least in fertile age, than in men, can be assume. ⁹

VitD can only unfold its complex immunmodulatory effects if the dose-response relationship is observed. Both for PwMS and adjuvant VitD supplementation as well as against ALEM-induced autoimmune diseases (ALEM-iAD), pharmacological doses are necessary to achieve long-term success. The benefit of VitD supplementation can only be achieved with a dose of 5000-10.000IU/day and a serum target from above 40-60 ng/mL 25(OH)D influence MS as well as autoimmune disease. The daily VitD dose is determined by the inter-individual differences in response to the VitD supplement. One of many causes may be 4 single nucleotide polymorphisms (SNPs) associated with 25(OH)D eg CYP27B1 variants with loss of function or a CAYP24A1 gene variant resulting in a low 1,25dihydroxyvitamin D-level.

A sufficient VitD supplementation. would not only have prophylactic goals to influence ALEM-iAD rather the vitD status also has an influence on the MS Risk and course. Serum 25(OH) D levels correlated inversely with risk of relapse, inversely with CNS lesions, and inversely with disability progression. ¹⁰

The association between autoimmune diseases and VitD deficiency is know and the immunological mechanisms have been documented. With the beginning of the ALEM therapy and the obligatory 48-month monitoring, a VitD supplementation could be started in parallel with the aim of achieving a double therapeutic effect. Influencing the course of MS and preventing or attenuating ALEM-induced secondary autoimmune diseases must become a goal to strive for. Daily VitD supplementation with up to 14.000 IU may be necessary individually in order to achieve serum target values of 40-60 ng/mL 25(OH) D values. These serum levels are necessary to achieve the complex immunomodulatory effects. The VitD status can be influenced by genetic factors and indicates an individual VitD requirement through the year.