Vitamin D and Raynaud's Disease

What is raynaud's disease?

Vasoconstriction of cutaneous arterioles due to cold is a normal biological mechanism that causes blood flow from the surface circulation to internal organs. This is performed to guard the body from loss of excess heat. This constriction of blood vessels is facilitated by release of norepinephrine through the reflex sympathetic nervous system¹ as well as by increased sensitivity of the vasculature.² When this vasoconstriction which is induced by cold is overstated, it leads to a scientific condition identified as Raynaud’s phenomenon (RP). This was discovered by Maurice Raynaud in 1862. He described this disease as part of his doctoral thesis. He observed this in a female patient who had transient digital ischemia.^2,3 The patient felt no senses in her fingers, and on exposure to cold, she attained a whitish-yellowish hue. These vascular events usually were accompanied with pain, eventually returning to normal after some time.^2,4

Epidemiology

According to latest statistics, it is extensively observed that RP is present in 3-5% of the general population, even though prevalence shows a great degree of variation.⁵ How a doctor defines RP majorly accounts for this variation. Epidemiology of RP is also dependent on climatic and geographical aspects.^5,6 The colder areas have been observed to have a higher rate of prevalence.⁷ In RP, a gender bias has also been observed as it affects more women compared to men.⁸ Additionally, 95% of patients having systemic sclerosis (SSc) or scleroderma have RP.⁹

Pathophysiology

In human skin, blood vessels are distinctive in that they are innervated both by sympathetic nor adrenergic and cholinergic nerves. This brings about cutaneous vasoconstriction and vasodilation, respectively.¹⁰ In the areas of skin of the finger or toes (glabrous skin), there are numerous thick-walled, low resistance arteriovenous anastomoses (AVA). These permit an increased flow of blood from arterioles to veins. Norepinephrine causes vasoconstriction of arterioles through alpha receptors that are commonly present on vascular smooth muscle. These AVAs are associated with cutaneous capillaries that present nutritional blood to the skin. In patients with RP there is decreased flow through AVA as well in reducing nutritional flow to skin.¹¹ In RP, the vasoconstriction can be so extreme that the affected area receives almost no blood for a short period of time. The most distinguishing feature of Raynaud's phenomenon is a triphasic color change in the affected digits. First white, due to lack of blood flow; then ‘blue’ or purple, because of desaturation of residual blood volume in the area that is affected. This is followed by red as the episode diminishes and blood flow is reinstated.⁵

Classification

Many approaches have been presented to classify RP. The most recent approach is to categorize it into primary RP or idiopathic RP (also called Raynaud's disease (RD)), and secondary RP (also called Raynaud's syndrome (RS)). Secondary RP is mainly a clinical indication of a primary disease. In contrast, if there is no underlying or primary illness, then it is defined as primary RP.¹² Thus, the essential point for management of RP patients is to establish if  a secondary cause is present or not. This method helps not only to treat the abnormal vascular reactivity,but essentially to also manage any specific underlying cause.

The difference between primary and secondary RP is made purely on clinical grounds. Symmetry observed in RP was formerly used as a criterion for primary RP. Primary RP patients typically do not develop problems like digital ulcers, tissue necrosis, or gangrene. It has been observed that at the nailfold, capillaries run parallel to the skin surface. Therefore, nailfold capillaries can be envisaged for structural modifications. Nailfold capillaroscopy is a non-invasive method to observe any kind of abnormalities in capillary number, morphology, orientation and distribution. As primary RP is contemplated as a functional disorder, its nailfold capillaroscopic examination is quite normal. However, in case of secondary RP, changes in capillary morphology and other structural abnormalities have been observed.¹³ In secondary RP, the occurrence of painful vasospastic episodes are very common. Clinical characteristics that point towards the presence of either hematopoietic or connective tissue disease further suggest the presence of secondary RP. Presence of autoreactive antibodies, specifically anti-centromere, ANA, and anti-RNA polymerase, specifies secondary RP. Presence of cutaneous lesions including calcinosis, fibrosis, and ulcerations basically indicate secondary RP.¹⁴ Moreover, an increased risk of an underlying illness or systemic disease or risk of digital loss are commonly observed in secondary RP.

Treatment

The first and foremost treatment for RP is lifestyle changes and self-management by avoiding exposure to cold and keeping oneself warm. Vasodilator therapies come into light when these lifestyle changes are considered ineffective. The first line of treatment is by using calcium channel blockers (CCBs). In a Cochrane meta-analysis, it was observed that CCBs reduced the number of RP attacks by around one third in RP patients. Increased doses of CCBs were observed to be more effective. Furthermore, the response of CCBs in primary RP was better than secondary RP patients.¹⁵

Another strongly proposed drug targets the renin-angiotensin system for the treatment of RP associated with connective tissue diseases. However, the proof for the use of ACE inhibitors for RP is inadequate and contradictory, with very small evidence to propose any positive effect.¹⁶ Different forms of nitrate therapy have also been investigated for the treatment of RP (e.g., topical ointments and sustained-release patches).¹⁷ However, these have been observed to be associated with unbearable effects related to systemic vasodilation. Hence, their clinical applicability is limited. Another class of drugs that have gained importance in RP treatment include Phosphodiesterase-5(PDE-5) inhibitors such as sildenafil, tadalafil, vardenafil and udenafil.^18,19 Even though contradictory results are present, some studies do suggest an improvement in RP with PDE-5 inhibitors.^20,21 However, more long- term clinical trials are still needed to confirm these findings.

Many patients also prefer the use of alternative therapies like acupuncture, ginkgo biloba gamolenic acid, biofeedback, and vitamins C or E. However, presently there is very little proof to support these therapies for the treatment of RP.

Role of vitamin D in the body

Vitamin D is universally described as the “sunshine vitamin”. Even though vitamin D is a multi purpose hormone, its leading role is to maintain mineral metabolism, calcium homeostasis, and skeletal health. Vitamin D helps in binding calcitriol, which is an activated metabolite of vitamin D to its receptor (vitamin D receptor (VDR)).²² Vitamin D was discovered with the identification of a disease called rickets, which mainly affects childrens’ bones. Francis Glisson in 1650 was the first person to formally describe rickets as a disease found in the rich. The prevalence of rickets increased in the 1800s during the Industrial Revolution. More than 50% of children were observed to have rickets in polluted and crowded urban areas. It was in 1822 that another scientist Sniadecki reported the connection between rickets and lack of exposure to sunlight.²³ 

The three main sources of vitamin D in humans are from food, local synthesis in the skin, and supplementation. It exists in two main forms: cholecalciferol (vitamin D3) and ergocalciferol (vitamin D2). These forms differ in their side chain structure, but their biological activity is the same.

Synthesis of vitamin D in the skin stimulated by exposure to sun is the most distinguished source of vitamin D. On exposure to sun, the precursor of vitamin D, 7-dehydrocholesterol that is present in the epidermal basal, suprabasal keratinocytes and dermal fibroblasts is transformed into its pre-vitamin D3 form. This cutaneously formed vitamin D3 is released into the systemic circulation after it is bound to vitamin D-binding protein (DBP).²⁴ After its release into the circulation, it is converted into 25-hydroxyvitamin D (25(OH)D; calcidiol) by a hepatic hydroxylase. This circulating 25(OH)D level is basically an indicator of the vitamin D status. As and when needed, under a tightly controlled process by the help of parathyroid hormone, this 25(OH)D is converted into its active form 1,25-dihydroxyvitamin D (1,25(OH)2D; calcitriol) in the kidney.²⁵

Seasonal changes

he main source of vitamin D in the body is through cutaneous synthesis as explained previously  (80%–100%).²⁶ So, the levels of vitamin D are vastly affected by the amount of sun exposure and hence seasons. The length of the day generally varies with the time of the year and.latitude. Therefore, people living at the equator approximately experience daytime of 12 hours throughout the year. However, people residing at the Polar Circle latitudes (north or south), experience sun for 24 hours at least one day per year, and at least one day per year there is no sunlight for 24 hours. During winter, the exposure to natural sunlight decreases with increasing latitude.²⁷ 

Benefits of vitamin D

The most characterized and established function of vitamin D is to maintain bone mineralization by controlling the homeostasis of calcium. However, the benefits of vitamin D are not limited to this. It may benefit us in many ways such as? 

Immunomodulatory agent

Vitamin D receptor (VDR) is commonly expressed on several types of immune cells like lymphocytes, macrophages, monocytes, and dendritic cells. It has been observed to be involved in the management of innate immunity by enhancing the body defense system against microbes and other pathogenic organisms. Also, as it affects T cell activation and the function of antigen presenting cells, especially dendritic cells, it has a crucial role in adaptive immunity.²⁸

Depression

The role of Vitamin D in depression is the talk of the town in the scientific world. At present, there are mainly three lines of suggestion that support this connection. Firstly, with identification of increased number of VDRs in the areas of the brain that control mood.²⁹ Secondly, as explained above, because of its immunomodulatory function, there may be a possible role that  vitamin D carries out between depression and inflammation.³⁰ Thirdly, because of its neuroprotective characteristics.³¹ 

Cancer

The antitumor characteristics of active vitamin D and its analogs are mainly facilitated by binding of vitamin D-vitamin D receptor (VDR) complex to DNA and consequent genomic regulation of its target genes and related pathways. Some of these effects are induction of differentiation and apoptosis, inhibition of malignant cell proliferation, inhibition of angiogenesis, metastasis and invasion, and inhibition of cancer-related inflammation.³² 

Cardiovascular diseases

Cardiovascular disease has been observed to be associated with increased activity of the renin-angiotensin system (RAS). This RAS is expressed in the kidney and it helps to maintain the homeostatic balance between electrolytes and water. Hence, it plays an important role in blood volume and blood pressure regulation. Vitamin D acts as a suppressor of the RAS by inhibiting the cyclic AMP response element activity in the renin gene promoter vitamin D.³³

Vitamin D deficiency and its consequences

A minimum circulating level of 25-(OH) D of >75 nmol/L is essential to maximize vitamin D's beneficial effects for health in humans. However, in the absence of adequate sun exposure, at least 800–1000 IU vitamin D3/day may be required to achieve these benefits in children and adults.³⁴ As vitamin D is involved in multiple molecular pathways, its deficiency paves way for many diseases such as rickets in children, osteopenia or osteoporosis in adults, type 2 diabetes, cancer, cardiovascular problems, depression, obesity, and autoimmune diseases to name a few.

 Vitamin D3 and raynaud’s disease

Very few studies linking vitamin D with Raynaud’s phenomenon have been reported.^35,36 As discussed above, in Raynaud’s disease, the most important issue is mainly the imbalance of vasoconstriction and vasodilation due to variations in neural control of vascular tone and circulating mediators.³⁷ One of the interesting facts is that angiotensin II which is a vasoconstriction is a part of RAS which is tightly regulated by Vitamin D. Hence, there may be a possible connection between these two as vitamin D deficiency can lead to increased vasodilation and hence more severe RP.

Summary 

To sum up, Raynaud’s phenomenon (RP) is used to describe a symptom complex relating to digital vascular compromise, typically aggravated by the vasoconstrictive effects of cold exposure and other sympathomimetic drivers. The clinician must implement a thorough clinical assessment with targeted investigations to differentiate between primary and secondary RP, as both the prognosis and treatment of the disease may differ considerably. First-line or initial treatment for RP is a calcium channel blocker. Other pharmaceutical agents that can be used include selective serotonin receptor antagonists and angiotensin-II receptor antagonists.

Sufficient vitamin D levels are essential for maintaining normal calcium homeostasis. Its main source of synthesis is exposure to sunlight. However, due to change in lifestyle and working conditions, the exposure to sun is limited. Hence, it has led to identification of a connection between vitamin D deficiency and various diseases. This is mainly due to the fact that vitamin D plays a very significant role in various molecular pathways in our body.

However, studies establishing the link between vitamin D and Raynaud’s phenomenon are very limited. Though some connection is there because it has been observed that there is improvement in RP symptoms on supplementation of vitamin D in patients with RP. Therefore, more large scale clinical trials are needed to further confirm this observation.