A secosteroid and not just a food for thought


Diet and rheumatism have been traditionally linked across civilisations by mankind, may it be causally or therapeutically. While commercial exploitation of this human weakness is rampant, the science of this subject has been a grey area; but the unfolding has just begun.

The causative role of purine-rich diets in gout and gluten in celiac disease have been well known for some time. Beneficial effects of curcumin, ginger extract, garlic and several other spices, fish oil and several other traditional dietary components are now hot research topics. This issue of IJRD has articles highlighting interaction between diet and medications, relationship between intake of animal protein and back pain and the anti-inflammatory properties of ginger-garlic extract.

One other nutrient that has generated heaps of literature, including many controversies in rheumatology is vitamin D. Emerging evidence and consensus regarding its function have established it as a popular and economic therapeutic agent prescribed by many physicians and rheumatologists for a spectrum of disorders, but not without criticism. Careful and critical appraisal of such confusing and contradicting literature is needed to reach any cautious conclusion.

There are also differing views on the cut-off value of vitamin D to label insufficiency and deficiency, but most agree on a value that keeps parathhormone (PTH) levels in the normal range. Keeping this in mind, 25(OH)D levels more than 30 ng/mL (75 nmol/L) is considered normal, levels between 20 and 30 ng/mL (50–75 nmol/L) is defined as insufficiency and level less than 20 ng/mL (50 nmol/L) is called deficiency.[1]

Vitamin D insufficiency and deficiency are global phenomena and sun exposure alone may not be the sole determinant for this. In spite of good sun exposure, vitamin D deficiency is prevalent from sub-Saharan Africa to south Asia and affects half the population in this region, similar to that in Western countries with temperate climates.[2, 3]

The fascinating molecule of vitamin D belongs to the class of secosteroids. It is different from other steroids by unfolding of two of its four rings. Its role as an anti-inflammatory, immunomodulatory and antineoplastic agent, as well as its role in preventing cardiovascular morbidity and mortality, are well known. It interacts with a large array of molecules, including vitamin D receptor (VDR), and much of it depends on vitamin D binding proteins. The role of VDR polymorphisms in the pathogenesis of autoimmune diseases has also been extensively studied.[4]

Role in Autoimmunity

As expected of a steroid, vitamin D's anti-inflammatory actions are mediated by down regulation of dendritic cells, Th1 cells and B cells, many pro-inflammatory cytokines, and inhibition of micro-RNAs like MiRNA-155, and by inducing apoptosis.[5] Vitamin D is also capable of neutralizing interleukin (IL)-17A and IL-22 which are not achieved even by tumor necrosis factor (TNF) blockade; this action has far-reaching implications in many systemic autoimmune diseases.[6]

There are now studies showing enriched gene expression of vitamin D response elements (VDRE) in non-major histocompatibility loci associated with rheumatoid arthritis (RA) as well as modest association of variants of loci controlling vitamin D levels with RA.[7] These findings strongly support the theory that vitamin D plays an important role in the pathogenesis of RA.

Prevalence of low vitamin D states in RA is reported from most populations,[8] including publications associating low vitamin D state with disease activity.[9, 10] Indeed, a recent meta-analysis of 215 757 participants proves these points beyond doubt.[11] Relatively fewer studies found no correlation between disease activity and low vitamin D state in RA.[12]

Finding of an inverse relationship between vitamin D and chronic periodontal disease, a known risk factor for developing RA, is interesting.[13] Further, vitamin D has been reported to attenuate inflammation in periodontal tissue induced by Porphyromonus gingivalis, again a strong triggering event for development of RA.[14]

Such associations of low vitamin D state with many other systemic autoimmune diseases, including lupus, are also well known and readers will have no difficulty in finding enough, and convincing, publications in this regard.[15, 16]

Cardiovascular Benefit

Apart from its osteoimmunological implications, vitamin D deficiency and the renin angiotensin system (RAS) activity may represent two sides of the same coin which is responsible for metabolic syndrome and high cardiovascular mortality, as hypothesized and reported by some.[17] This is all the more relevant as vitamin D is also reported to have a protective role against metabolic syndrome in RA.[18] An inverse relationship between vitamin D levels and C-reactive protein is yet another factor in imparting cardiovascular protection in RA.[19]

Diffuse Aches and Pains

In contrast, there is a query if vitamin D levels should be tested indiscriminately for every ache and pain in rheumatology and this was addressed in a study from Kuwait published in this issue of IJRD. While the authors report otherwise in this study, there are some elements of truth in the other school of thought too. Most of these studies have methodological flaws, heterogeneous cohort, smaller sample size and are underpowered to address this issue. However, the majority of the reports from different populations have documented lower vitamin D levels in vague aches and pain than reference populations.[20-22] Correlation between low back pain in people with modic changes and vitamin D insufficiency also do exist in the literature.[23] A randomized controlled trial conducted among non-Western immigrants with nonspecific musculoskeletal pain in the Netherlands suggests modest benefit of vitamin D.[24] Low vitamin D state in a cohort of fibromyalgia patients and good response to corrective treatment have been documented both in veiled, conservatively dressed, as well as in non-veiled subsets alike.[25] Even in the elderly, post-menopausal, as well as in mixed cohorts of patients with different rheumatic diseases, vitamin D showed clear improvement in musculoskeletal pain[26-28] and negative studies have been reported only occasionally.[29]

To add further, vitamin D deficiency leading to hypersensitivity to pain in muscles via nerve endings has been described.[30]

And finally, what is non-specific musculoskeletal pain (NSMP)? Is it a harbinger of evolving early inflammatory arthritis at least in a subset of patients, especially in view of its strong association with deficiency of vitamin D in many studies? Can the onset of inflammatory arthritis be delayed by treating a low vitamin D state in this setting? These questions have no answers at this moment.

In conclusion, the global pandemic of vitamin D deficiency is not without any implications and cannot be ignored, especially in patients with rheumatism. Benefits of diagnosing and treating this problem far outweigh the costs and toxicities of this fairly safe agent in the light of a strong biological basis. Whether or not to test for vitamin D in diffuse musculoskeletal pain needs to be weighed against the prevalence of low vitamin D state in the population under study.