Nestled within the British Virgin Island archipelago is an isle known as Jost Van Dyke. Swimming up to its shoreline, it is easy to be lulled into the relaxing tides. But the benefits of blood pressure reduction are not the only advantage of visiting paradise — it turns out soaking up a little bit of sunshine may also benefit those with antiphospholipid syndrome (APS).
It is well known that vitamin D is linked to calcium regulation and bone health. More recently, it has been recognized as a central component of immunologic function; with deficiency being linked to autoimmunity, chronic inflammation, thrombosis, and even malignancy.1,2 In this Mini Review, we will examine vitamin D metabolism, present evidence of its role in autoimmunity with a focus on APS, and discuss current guidelines.
Vitamin D Metabolism: A Brief Review
The primary mechanism for vitamin D synthesis is the nonenzymatic conversion and isomerization of its precursor, 7-dehydrocholesterol, to vitamin D3 (cholecalciferol) in the skin when exposed to ultraviolet (UV) B light. An alternative method of vitamin D absorption is dietary supplementation, primarily from fatty fish or foods fortified with vitamin D2, ergocalciferol.1,3,4 This fat-soluble vitamin is then incorporated into chylomicrons.3
The inert forms of vitamin D2 and D3 require activation, which occurs in a three-step process: 25-hydroxylation, 1α-hydroxylation, and 24-hydroxylation. 25-hydroxylation occurs within the liver, where 25-hydroxyvitamin D (25-OH) is formed and released into systemic circulation bound to vitamin D–binding protein. It is delivered to the kidneys and undergoes receptor-mediated endocytosis into renal tubular cells. Here, 25-OH encounters two important enzymes, 1-alpha-hydroxylase, and 24-alpha-hydroxylase, ultimately resulting in the production of the active vitamin D or 1,25-dihydroxyvitamin D.1,3 1-alpha-hydroxylase activity occurs in extrarenal sites including the vasculature and the immune system. T cells, B cells, macrophages, and dendritic cells can induce 1-alpha-hydroxylase activity for vitamin D production, indicating the critical role it plays in immunologic function.5
The daily recommended nutritional intake for vitamin D in adults younger than 50 years is 600 IU/day. Recommended dosages increase to 600 to 800 IU/day in older individuals and are even higher in pregnant or breastfeeding women.3 Deficiency in vitamin D can occur by three mechanisms: inadequate availability due to limited UV exposure and dietary consumption, hepatic dysfunction, or impaired renal function. Due to its role in intestinal calcium and phosphate absorption, vitamin D deficiency often initially manifests dysregulation of these electrolytes. Over time, persistent hypocalcemia triggers secondary hyperparathyroidism and ultimately bone demineralization.
Vitamin D and Autoimmune Disease
In the 2000s, a multitude of studies emerged describing vitamin D as an important immunomodulator of both the innate and adaptive immune systems. As a general construct, vitamin D promotes innate immune function, while lessening the adaptive immune response.6,7 Vitamin D affects the adaptative immune system through downregulatory effects on B and T lymphocyte proliferation. It inhibits the production of proinflammatory cytokines by suppressing Th1 cell proliferation and augmenting Th2, and impedes ongoing proliferation of activated B cells, inducing their apoptosis.5,7-9 It is through these mechanisms that vitamin D is postulated to promote a tolerogenic immune response and reduce the risk for autoimmune dysfunction.5-7,10
Response to vitamin D is largely facilitated by nuclear receptors known as vitamin D receptors (VDRs).1,2,10,11 There is growing interest in VDR polymorphisms and their possible role in the predisposition of patients to autoimmune disease. For example, in systemic lupus erythematosus (SLE), four VDR polymorphisms have been linked to SLE susceptibility, though further investigations are needed to fully understand this connection.11 Meanwhile, vitamin D deficiency in those with established autoimmune disease has been associated with increased severity of clinical manifestations.2,12,13
Vitamin D and APS
APS is a systemic autoimmune disease linked to antiphospholipid antibodies (APLAs): anti-B2 glycoprotein 1 (anti-B2 GP1), anti-cardiolipin, lupus anticoagulant, and most recently, anti-phosphatidylserine.14,15 APS is characterized by recurrent arterial or venous thromboembolic events and/or obstetric complications and presents with a variety of other clinical findings. Examples of other manifestations of APS include hemolytic anemia, thrombocytopenia, livedo reticularis, and nonbacterial thrombotic endocarditis.15,16 APS can occur in isolation (primary APS) or in the setting of other autoimmune diseases such as systemic lupus erythematosus (secondary APS).
The simple presence of APLAs does not necessarily destine a patient to thrombotic events and clinical APS. To explain this, a “two hit” hypothesis for thrombosis has been adopted. The “first hit” is the presence of APLAs that are known to promote thrombosis through multiple mechanisms. Inhibition of protein C and its ability to inactivate factor V and factor VIII, antithrombin activation, and dysregulation of the complement system are a few previously described mechanisms.15-17
The “second hit” is an additional factor promoting hypercoagulability, such as inflammation due to infection, surgery, etc.16 Vitamin D deficiency could represent another “second hit.” An in vitro study in 2010 by Dr. Nancy Agmon-Levin and colleagues demonstrated anti-B2 GP1 antibody activation of endothelial cells and monocytes, leading to tissue factor expression. The group described vitamin D as a powerful inhibitor of anti-B2 GP1-mediated tissue factor expression in the endothelium and reported a significant association between vitamin D deficiency with thrombotic events.2,15 Interestingly, vitamin D levels in APS patients with thrombotic manifestations were found to be significantly lower than APS patients experiencing isolated obstetrical morbidity.18,19
Vitamin D deficiency as a “second hit” theory is further supported by data gathered during the COVID-19 pandemic. Initial studies noted the presence of APLAs in patients with COVID-19, with subsequent studies demonstrating an increased frequency of APLAs in patients with COVID-19 who were experiencing thrombosis when compared to those without.20 Vitamin D deficiency also occurred more frequently in those with thrombosis. Authors speculated this to be due to the previously established ability of vitamin D to suppress anti-B2GP1 activity, decrease expression of toll-like receptor 4, and adhesion molecules involved in the inflammatory process.21
Vitamin D Deficiency: Diagnosis and Treatment
The 2011 Endocrine Society Consensus Guidelines recommend screening for patients at risk for vitamin D deficiency. This includes patients with malabsorption syndromes, chronic kidney disease, or hepatic dysfunction. It also includes patients with high suspicion for osteoporosis, long-term use of glucocorticoids or antiseizure medications, and obese patients. Serologic evaluation is recommended with 25-hydroxyvitamin D (25-OH) levels. Vitamin D insufficiency is defined as 25-OH levels below 30 ng/mL, with vitamin D deficiency at levels below 20 ng/mL, though these cut-offs are controversial.1,3
Given the increasing evidence for vitamin D deficiency as a likely contributor to thrombotic events in APS, the 16th International Congress on Antiphospholipid Syndrome supports vitamin D supplementation as adjunctive therapy in APS management in patients with concomitant APS and vitamin D deficiency. The task force recommends a goal 25,OH level of greater than 30 ng/mL with supplementation guidelines as outlined for the general population. One study evaluated the antithrombotic effect of high-dose vitamin D; however, this strategy did not conclusively demonstrate additional benefits over standard dosing.18,22
When vitamin D deficiency is identified, doses exceeding the standard daily intake requirement are initially needed. Current society guidelines support the use of 50,000 IU of vitamin D2 or D3 once weekly for eight weeks, with a goal serum 25-OH D level of 30 ng/mL or greater. Once achieved, a daily maintenance dose of 1,500 to 2,000 IU/day is recommended.3
Conclusions: A Radiant Remedy
Though insurance companies will likely never reimburse a Caribbean-dosed vitamin D supplementation strategy, that trip to paradise may be more important to wellness than previously thought. In the revised words of a well-known Jost Van Dyke patron, country music artist Kenny Chesney, “no shoes, no shirt” (in the sun) may help contribute to “no thrombus” in patients with APS. Vitamin D can no longer be construed as solely a mechanism for calcium regulation or bone health in patients with autoimmune disease; it is much more integral. For patients with APS, vitamin D deficiency represents a potentially reversible contributor to thrombogenesis.
Clinicians should remain vigilant when evaluating patients with APS to consider vitamin D deficiency as a potential mediating factor. When deficiency (defined as serum 25 OH levels <30 ng/mL) is identified, supplementation should be pursued. Further studies are needed to better understand optimal vitamin D levels and supplementation strategies in those with APS.
Dr. Brunton, Dr. Casanegra, and Dr. Houghton indicated no relevant conflicts of interest.