High-Dose Vitamin D Supplementation for Immune Recalibration in Autoimmune Diseases

ShiaunTzuen Su^1*Yung Heng Lee²Po Cheng Shih^3*James Cheng-Chung Wei^3,4,5*

• ¹School of Medicine, Chung Shan Medical University Hospital, Chung Shan Medical University, Taichung, Taiwan
• ²Feng Yuan Hospital, Taichung, Taiwan
• ³Chung Shan Medical University, Taichung, Taiwan
• ⁴Chung Shan Medical University Hospital, Taichung, Taiwan
• ⁵China Medical University, Taichung, Taiwan

No potential conflict of interest relevant to this letter was reported. Ref: 23 Vitamin D plays a well-established role in calcium absorption and bone metabolism, and it also exerts important immunomodulatory effects. It exists primarily as vitamin D2 (ergocalciferol) and D3 (cholecalciferol). Endogenous synthesis of vitamin D in the skin upon ultraviolet B (UVB) exposure, together with dietary intake and supplementation, ensures maintenance of adequate serum levels, particularly in populations at risk for deficiency due to geographic latitude, limited sun exposure, or biological factors.Beyond skeletal health, vitamin D modulates both innate and adaptive immune responses, underscoring its potential as an adjunctive immunomodulatory strategy in autoimmune diseases (ADs) such as psoriasis, systemic lupus erythematosus (SLE) and type 1 diabetes mellitus (T1D) 1.2 . Supplementation may decrease disease severity and enhance response to conventional therapies. Hileman et al. reported that ADs arise from a complex interplay of genetic susceptibility and environmental triggers, with viral infections playing a central role. 4 Viruses activate innate immunity by inducing type I interferon (IFN-α/β) production and stimulating neutrophil extracellular trap (NET) release, thereby enhancing dendritic cell maturation and antigen presentation. In genetically predisposed individuals, these events promote adaptive immune activation, leading to B-and Tcell expansion, autoantibody generation, and T-cell dysregulation. autoimmunity through multiple mechanisms: molecular mimicry of human autoantigens, reprogramming of B-cell function, and binding of EBV nuclear antigen 2 (EBNA2) to host super-enhancer regions associated with autoimmune-susceptibility genes. 5 Together, these actions disrupt normal gene regulation and perpetuate chronic immune activation.Taken together, these studies underscore the pivotal role of viral infections in both initiating and exacerbating ADs and highlight potential antiviral or immunomodulatory targets for therapeutic intervention. According to the recent estimation, nearly 15 million Americans live with at least one ADs. Increasing evidence suggests that vitamin D insufficiency is highly prevalent in these patients and correlates with immune dysregulation, higher disease activity, and more frequent flares. 6 Vitamin D supplementation was important to prevent and treat deficiency-related conditions like rickets. However, in vitamin D-replete adults, largescale randomized trials and Mendelian randomization studies consistently showed no significant benefit for preventing cancer, cardiovascular disease, diabetes, or fractures.High-dose supplementation may even pose risks. Thus, routine use in the general population is not supported, except to correct deficiency or in specific at-risk groups. 7 Epidemiological studies have linked low serum 25-hydroxyvitamin D [25(OH)D] levels (<20 ng/mL) to elevated risk for ADs such as psoriasis, T1D, and multiple sclerosis (MS). 8 Vitamin D contributes to immune homeostasis by promoting innate defenses, enhancing macrophage and dendritic cell function, while modulating adaptive responses through suppression of Th1-and Th17-mediated inflammation and upregulation of regulatory T cells. 9 In MS specifically, vitamin D influences lymphocyte activation, T-helper cell polarization, and cytokine production. It decreases pro-inflammatory cytokines (e.g., IFN-γ, IL-17) and increases anti-inflammatory mediators (e.g., IL-10), thereby shifting the immune milieu toward tolerance. 10 Randomized trials of supplementation (e.g., 4,000 IU/day cholecalciferol) have demonstrated significant reductions in relapse rates and Magnetic Resonance Imaging (MRI) lesion burden in relapsingremitting MS, particularly in patients with baseline 25(OH)D <30 ng/mL. 11 Taken together, these findings support a therapeutic role for vitamin D in ADs, especially MS, by rebalancing innate and adaptive immunity and modulating key cytokines such as IL-10 and IL-17. Future large-scale trials are warranted to define optimal dosing, target serum levels, and long-term safety profiles. 已刪除: -exposure, and aging all contribute to impaired vitamin D signaling and elevated autoimmune risk. 14 However, the efficacy of high-dose vitamin D remains debated. 15- 20 Table 1 summarizes clinical trials of high-dose vitamin D in autoimmune diseases. Several studies have revealed high-dose vitamin D₃ supplementation in autoimmune diseases but reported no significant clinical benefits. However, many of these studies have important methodological limitations that may affect the interpretation of their findings. For instance, the study by Cassard SD et al. 15 involved a relatively small sample size, lacked a placebo control, and was conducted only in the United States, limiting its generalizability. Similarly, the trial by Aranow C et al. 16 showed patients with SLE, was also restricted by a small participant pool, a short follow-up period of only 12 weeks, and a predominantly female population with varied baseline disease activity, introducing potential heterogeneity in treatment response. The study by Grove-Laugesen D et al. 17 was also limited to a single country (Denmark), and included mostly female participants, raising concerns about gender representation and external validity. In the trial by Nwosu BU. et al. 18 , the limitations included a small sample size, a narrow age range, a single-country of Denmark.Lastly, the study conducted by Fernandes AL et al. 20 assessed the effects of a single high-dose intervention (200,000 IU) and faced challenges such as a limited sample size for 1 year analysis and reliance on self-reported symptoms, which may compromise the reliability of the outcome assessment. Brustad et al. 21 conducted a systematic review and meta-analysis of 32 randomized trials (n = 8,400 children, doses 1,200-10,000 IU/day; bolus up to 600,000 IU) and found no increase in serious adverse events, including hypercalcemia or nephrolithiasis. In France, Thouvenot et al. 22 treated 316 early MS patients with 100,000 IU cholecalciferol biweekly for 24 months, observing reduced relapse rates and MRI lesion accumulation in clinically isolated syndrome and relapsing-remitting MS. Bendix et al. 23 administered 20,000 IU/day for seven weeks to 40 Crohn's disease patients, reporting a 25% decrease in the need for infliximab dose escalation.These data suggest that high-dose vitamin D can safely modulate immune profiles, decrease disease activity, and potentiate existing therapies in autoimmune disorders. Nonetheless, optimal dosing regimens, especially for individuals with profound deficiency or specific disease phenotypes, require further large randomized trials to balance maximal immunomodulation against potential toxicity. monitoring for hypercalcemia and renal effects will ensure safety, while stratified analyses will reveal which patient subgroups derive the greatest benefit from high dose supplementation. Vitamin D is essential for immune balance, and its deficiency contributes to autoimmunity. High-dose vitamin D can rebalance Th1/Th17 versus Treg activity, lessen disease flares, and boost standard therapies without raising serious safety concerns. Tailoring supplementation to patients' baseline levels and genetics offers a promising adjunct in managing autoimmune diseases.