( PDF ) Rev Osteoporos Metab Miner. 2017; 9 (1) Supplement: 31-39
DOI: http://dx.doi.org/10.4321/S1889-836X2017000200007

Castro Domínguez F, Salman Monte TC, Blanch Rubió J
Servicio de Reumatología – Hospital Universitario del Mar – Parc de Salut-Mar – Barcelona (España)

 

Introduction
In the field of rheumatic diseases there is growing evidence that vitamin D plays a relevant role in the pathophysiological mechanisms of autoimmunity. To this must be added that vitamin D deficiency in patients with rheumatic diseases is high. In contrast, there are few clinical trials demonstrating that vitamin D supplementation may contribute to the severity of the activity or the risk of systemic autoimmune diseases.
It seems that with the current schemes of vitamin D3 supplements, autoimmunity is not affected in the expected way1,2, postulating that for the regulation of immunological homeostasis it is necessary to administer doses of vitamin D much higher than those used in standard clinical practice3,4. There is no general consensus on what dose of vitamin D3 should be used, nor as to what levels of 25(OH) vitamin D (25HCC) –the metabolite that best reflects the vitamin D status of the organism– would be optimal to modulate favorably immunity or pain pathways.
As mentioned, most quality studies demonstrate a higher prevalence of 25HCC insufficiency in autoimmune rheumatic diseases5. The causes of this insufficiency could be –in addition to the classic factors for the failure of 25HCC in the general population– others that are characteristic of rheumatologic autoimmune processes such as the use of corticosteroids, photosensitivity, cutaneous fibrosis and intestinal malabsorption, among others have not yet been fully elucidated6,7.
Vitamin D3 could be one of the key factors that would act as an immunomodulator in the control of self-tolerance8.
In Nordic regions, which are less exposed to ultraviolet radiation and consequently with lower levels of 25HCC, a higher prevalence of autoimmune diseases such as multiple sclerosis and inflammatory bowel disease has been described9,10. However, in southern countries, where there is a high exposure to sunlight and one could expect sufficient levels of 25HCC, the high prevalence of vitamin D deficiency persists11,12, despite the current supplementation guidelines which apply to many patients. Consequently, the existence of a possible malabsorption associated with the autoimmune disorder could be postulated13,14. Finally, in relation to greater or lesser sun exposure, the seasonal factor in the development of some autoimmune diseases is a well-known fact15.
Our objective is to review the main evidence on the role of vitamin D in autoimmune rheumatic diseases, osteoarthritis, and fibromyalgia.

 

Systemic lupus erythematosus
Systemic lupus erythematosus (SLE) is one of the most prevalent systemic autoimmune diseases. It is a chronic process and clinically courses with multiorgan involvement and periods of exacerbation and remission.
Age and sex matched studies revealed a higher prevalence of 25HCC insufficiency in patients with SLE in relation to the controls. Kamen et al.16, in the Carolina Lupus Inception cohort, compared 240 healthy controls versus 124 SLE patients, determining a higher prevalence of 25HCC insufficiency in these patients. It reached up to 67%, a figure consistent with that published in other cohorts of patients with this same disease17 even in studies conducted in southern latitudes17,18.
To date, the factors that have been associated with low levels of 25HCC in patients with SLE are: daily use of sun protection, elevated body mass index17, use of glucocorticoids, seasonal change, serum creatinine19, nephritis20, altered protein/creatinine21, low bone mineral density, fragility fractures22, shorter telomere length in African American patients23, lack of sun exposure and no treatment with hydroxychloroquine24, a drug known to raise 25HCC levels at the expense of reduced levels of the active metabolite 1.25-DHCC.
Recently, the presence of low levels of 25HCC has been associated with a higher prevalence of classic cardiovascular risk factors such as hypertension and hyperlipidemia25, as well as with sleep disorders26 and fatigue27.
Many studies27-34, though not all16,17,27,35-39, have shown an association between 25HCC deficiency and increased SLE activity. It is important to emphasize that 4 of the 7 studies that did not find an association between 25HCC insufficiency and an increased SLE activity were performed in Spanish population groups17,36,37,39, so that certain sociodemographic, geographic and ethnic factors could influence this type of association.
On the other hand, low levels of 25HCC have been associated with fatigue and sleep disorders26,27. Fatigue is a symptom and therefore a subjective variable, difficult to quantify, but present in up to 90% of patients with SLE, with the consequent impact on their quality of life40. Fatigue has also been associated with low levels of 25HCC in Iranian nurses 41, and these same findings have also been observed in other Spanish series of patients with SLE27,39. It is not known if the 25HCC insufficiency influences the level of fatigue in patients with SLE or vice versa. In 2016, Lima et al. carried out a placebo-controlled clinical trial in a young lupus population in which patients receiving vitamin D3 supplements improved the KSFS (Kids severity fatigue scale) scores when compared to the placebo group42.
Glucocorticoids are known to activate the destruction of 25HCC and 1.25DHCC in inactive calcitriol acid. In 2010, Toloza et al. identified seasonal change, cumulative glucocorticoid dose and serum creatinine as factors associated with reduced levels of 25 HCC19. Recently, a significant correlation between failure of 25HCC and use of oral corticosteroids in women with SLE has been described in our country39. In fact, there was a positive correlation between the use of oral corticosteroids and the failure of 25HCC in patients who did not receive pharmacological vitamin D3 supplements, a fact that was not observed in the supplementation group39. At the European Rheumatology Congress (EULAR 2016), Lomarat W et al.43 presented a randomized, placebo-controlled trial where it was found that high-dose supplementation of ergocalciferol could serve as a safe adjuvant therapy generating a saving effect of corticosteroids in SLE patients (supplemented patients had used less oral prednisolone).
Therefore, patients with SLE are a high-risk group for vitamin D3 insufficiency. Thus, it is imperative to study, monitor, prevent and treat alterations of bone metabolism in them. In addition, pending the full results of the study by Lomarat W et al.29, it appears that vitamin D3 supplementation may reduce the use of corticosteroids. Given the benefit/risk profile, the possibility of supplementation with vitamin D3 as an adjuvant treatment in SLE should be considered.

 

Systemic sclerosis
Systemic sclerosis (SSc) is a connective tissue disease characterized by vascular obliteration, immune dysfunction, excessive deposition of the extracellular matrix and fibrosis of the connective tissue of the skin, lungs, gastrointestinal tract, heart and kidneys.
The prevalence of 25HCC insufficiency in SSc is high. According to Vacca et al., the figure was around 84% and the deficiency was 32%. 28% of patients had levels lower than 10 ng/mL44. These levels of insufficiency were associated with higher levels of disease activity and a higher negative correlation with ESR values, pulmonary fibrosis, and the value of the estimated pulmonary artery systolic pressure measured by echocardiography44, a poor prognostic factor. Arson et al. found lower 25-HCC levels in patients than in controls. They did not find statistically significant differences when comparing the SSc subgroup limited with diffuse SSc and between genders.
Additionally, Vacca A et al. found that supplementation with standard doses of vitamin D3 did not fully protect against the deficiency. There were also no differences in levels according to the types of SSc, limited or diffuse44.
In a multicenter study with 327 patients and 141 healthy controls, Arnson et al. found a negative correlation between 25HCC insufficiency and disease severity, skin thickness and age45.
Caramaschi P et al. reported that patients with 25HCC deficiency had a significantly longer duration of illness from the first non-Raynaud symptom and that it was associated with a lower DLCO, an increased systolic pressure estimated in the pulmonary artery compared to the group in the range of failure46. They found no correlation with sex, age, antibody profile, cutaneous involvement assessed by the Rodnan score or presence or absence of digital ischemic ulcers46.
Humbert P et al. found that increased fibrosis of cutaneous tissue was correlated with low levels of 25HCC47.
Oral calcitriol supplementation in SSc showed positive cutaneous results in small open studies two decades ago48,49. Conversely, in a prospective, randomized, double-blind study, the effect of oral supplementation with calcitriol was no more effective than with placebo50.
Recently the expression of the vitamin D receptor (VDR) in fibroblasts of SSc patients and in murine SSc models was analyzed, appearing diminished. It was observed that VDR is a negative regulator of the TGF-β/Smad pathway such that poor signaling through poor cell expression and low levels of its specific ligand could contribute to hyperactivation of GFR leading to the aberrant activation of the fibroblasts51.
Cutaneous fibrosis plays a key role in the low levels of 25HCC both by inhibition of cutaneous synthesis and by malabsorption at the intestinal level. However, whether vitamin D3 deficiency in humans could perpetuate the mechanisms of fibrosis via the GFR-β/Smad pathway is insufficient in humans because of the impossibility of vitamin D3 deficiency for the down-regulation of this pathway and whether, in this case, high dose supplementation may have the expected effects.
Therefore, it seems that patients with SSc are at a high risk of vitamin D3 insufficiency. In an orphan disease of a therapy that modifies its clinical course, by the benefit/risk profile and cost/effectiveness, it would be prudent to recommend maintaining levels of sufficiency of 25HCC. It is unclear what supplement dosages would be adequate to achieve this goal, as well as the delimitation of optimal levels to be reached in blood to obtain the greatest clinical benefit. Higher quality clinical trials should be conducted to decide which doses are appropriate.

 

Sjögren’s syndrome
Sjögren’s syndrome (SS) is a systemic autoimmune disease characterized by a chronic inflammation of the exocrine glands mainly salivary and lacrimal glands. Xerostomia and keratoconjunctivitis sicca are the key clinical elements.
A recent study reported that 25HCC levels were significantly lower in patients with primary Sjögren’s syndrome than in the general population. This difference was significant in women but not in men52.
Baldini et al. assessed the prevalence of the 25HCC deficiency, concluding that it is associated with an early stage of the disease, not being related to the activity of the process or to glandular or extra-glandular clinical manifestations53.
Agmon-Levin et al. replicated the study with a greater number of cases and controls, and demonstrated that 25 HCC levels were comparable between patients with primary SSc and healthy controls. Importantly, their research also revealed that low levels of 25HCC correlated with the presence of peripheral neuropathy and lymphoma54, an association that has been studied by other authors. Thus, for example, 125DHCC has been reported to have an antiproliferative effect resulting in tumor regression in low grade non-Hodgkin follicular lymphomas of malignancy55.
Lee SJ et al. investigated the association between disease activity and serum levels of 25HCC. Included in this study were 69 patients with primary SS and 22 controls. These investigators concluded that serum levels of 25HCC were significantly lower in patients with SS syndrome compared to controls matched for age and sex. When assessing the activity with EULAR Sjögren’s syndrome disease activity index (ESSDAI) found a negative association with 25HCC levels56.
With the data available to date, patients with primary SS are those with an increased risk of vitamin D3 deficiency. Therefore, alterations of bone metabolism in these patients should be studied, monitored, prevented and treated without being possible to venture with the available evidence what role supplementation might play in disease activity.

 

Mixed connective tissue disease
Mixed connective tissue disease (MCTD) is an uncommon connective tissue disease in which the clinical signs of systemic lupus erythematosus, scleroderma, polymyositis and/or rheumatoid arthritis are combined.
As in the rest of autoimmune entities, the prevalence of vitamin D insufficiency is higher than in the general population. Zold E et al. reported that 25HCC levels were significantly lower in patients with MCTD than in healthy controls. Dermatological manifestations (photosensitivity, erythema and discoid rash) and pleuritis were associated with levels of 25HCC insufficiency 57.
The same group postulated that those patients who ended up differentiating themselves from a specific connective disease had lower levels of 25HCC (in the range of deficiency) than those who remained as MCTDs, so that the failure of 25HCC could be a modifiable factor to prevent the progression of an MCTD to definite connective tissue disease57.
Hajas et al. determined that patients with MCTD had levels lower than 25HCC than the control group. These low levels of 25HCC correlated inversely and significantly with intima-media thickness of the carotid artery, high levels of fibrinogen, total cholesterol, endothelin, and ApoA1. They also reported that 25HCC levels were inversely correlated with IL-6, IL-23 and IL-10 serum cytokines and that these patients were at increased risk for cardiovascular disease58.
With the data available today, we can state that there is insufficient vitamin D3 in MCTD. There are no clinical trials that have investigated the role of supplementation over the clinical course and disease activity, so it would be prudent to conduct quality clinical trials to discern their role in this pathology. As practical clinical advice, we believe it judicious to keep patients at sufficient 25HCC levels.

 

Spondyloarthropathies
Spondyloarthropathies are chronic inflammatory arthritis, autoimmune rachis, spinal, and especially sacroiliac joints, which are characterized by sharing the same symptoms and therapeutic responses. In some cases, they are associated with HLA B27. These include: ankylosing spondylitis, psoriatic arthropathy, arthritis associated with inflammatory bowel diseases, reactive arthritis and undifferentiated spondyloarthropathies.
Cross-sectional studies show that 25HCC insufficiency is more frequent in patients with spondyloarthropathies compared to the general population59-61. Recently published data from the DESIR cohort was 11.7%, compared to 5% in the control population62. In addition, they suggest an inverse correlation between 25HCC levels, activity, radiological progression, and increase of acute phase reactants. They describe a higher percentage of patients with severe 25HCC deficiency in early axial spondyloarthritis, associating the 25HCC deficiency with an increased activity and severity of the disease as well as the presence of metabolic syndrome61,62.
Erten et al. describe an increased 25HCC deficiency in male patients with ankylosing spondylitis as well as an inverse correlation with acute phase reactants61.
In spondyloarthropathies, two opposing effects on bone metabolism have been described: on the one hand, an increase in osteoporosis and the prevalence of vertebral fracture related to trabecular bone resorption induced by the RANK-ligand positive regulation pathway63,64. On the other hand, an increase of bone formation in the entheses through morphogenic bone proteins 65, TFG-β66 and positive regulation of the Wnt pathway67-71.
In vitro studies demonstrate that vitamin D3 interferes with the molecular pathways of inflammation and ossification at the level of entheses, mainly at the level of IL-23 and increasing sclerostin (Wnt inhibitor). Saad et al. reported that serum levels of sclerostin (Wnt inhibitor) increased significantly after one year of treatment with anti-TNF, also improving bone mineral density of the lumbar spine70.
In their study, Appel H et al. determined that serum levels of sclerostin were significantly lower in patients with ankylosing spondylitis (AS) than in healthy controls. Thus, low levels of sclerostin were associated with the formation of syndesmophytes, emphasizing the role of sclerostin in the suppression of bone formation at this level in spondyloarthropathies67.
In addition, vitamin D3 insufficiency may also be related to intestinal inflammation and malabsorption in spondyloarthropathies61.
Therefore, insufficient 25HCC levels have been reported in spondyloarthropathies that appear to correlate with increased disease activity. Supplementation with vitamin D3 could represent a therapeutic adjuvant pathway in this pathology. But quality clinical trials with vitamin D3 supplementation that take into account all the variables that may influence are necessary to discern the complex relationships between 25HCC insufficiency and spondyloarthropathies.

 

Rheumatoid arthritis
Rheumatoid arthritis (RA) is an autoimmune systemic inflammatory disease, characterized by persistent inflammation of the joints, which typically affects the small joints of the hands and feet, causing their progressive destruction and generating different degrees of deformity and functional disability. Autoimmunity plays a major role in its origin, its chronicity and the progression of the disease. The disease is associated with the presence of autoantibodies (rheumatoid factor and citrullinated cyclic antibodies). Sometimes, it also manifests with extra-articular manifestations.
As in the rest of the systemic autoimmune diseases, the 25HCC insufficiency in patients with rheumatoid arthritis is higher than in the general population. Kerr GS et al. estimated the prevalence of 25HCC insufficiency in 84% of their series, while the prevalence of 25HCC deficiency was estimated in 45% of their patients72. According to Gopinath et al., the prevalence of the 25 HCC deficiency was 68.1%73.
The onset, severity and outbreaks of rheumatoid arthritis have been described as seasonally dependent74. For example, Mouterde et al. suggested that patients who experienced the first symptoms of rheumatoid arthritis in winter or spring had a more severe progression of joint damage at 6 months than patients who experienced the first symptoms in the summer74.
Merlino LA et al. linked 25HCC insufficiency in Caucasian patients, with an increased risk of disease development and increased disease activity75. In their series with 76% of Caucasian patients, Kerr GS et al. found a significant link between deficiency and failure of 25HCC for the anti-CCP positivity in non-Caucasian patients72. The deficiency, but not 25HCC insufficiency, was associated with a greater number of painful joints and higher values of high C-reactive protein72. In contrast to European cohorts, Craig SM et al. did not find associations with the disease activity in African-American patients76. Significant clinical improvement was correlated with the immunomodulatory potential of 1.25-DHCC77.
To date, there are only three clinical trials that assess the efficacy of vitamin D3 supplements and disease activity.
In the open-label trial by Salesi and Farajzadegan, comparing patients on triple immunosuppressive therapy and supplementation with 1.25DHCC versus triple therapy alone, patients showed greater pain relief without any effect on disease activity78. In another randomized double-blind trial with methotrexate at steady-dose and supplementation with 25HCC 50,000 IU weekly versus methotrexate at steady-dose and placebo, there were no improvements in efficacy results79. Nor did supplements have the expected effect in a double-blind controlled trial in which supplements were given with 25 HCC 50,000 IU 3 times per week for 4 weeks and then 50,000 IU twice monthly for 11 months, with no improvement in disease activity or in measurements of bone mineral density and increasing levels of TNF-alpha in the supplemented group79. In the same line, Dehghan et al. concluded that 25HCC insufficiency is not a risk factor for increased disease activity, nor does it have an impact on the number of outbreaks80.
With these results, patients with rheumatoid arthritis could be considered a high risk group for vitamin D3 insufficiency, so it is necessary to study, monitor, prevent and treat alterations of bone metabolism in patients who already present an independent risk factor for osteoporosis. There is insufficient evidence to recommend treatment at high doses of vitamin D3 in search of a potential immunosuppressive effect.

 

Arthrosis
Osteoarthritis or arthrosis is a chronic non-inflammatory disease caused by progressive wear of cartilage and joints. The affected joints cause pain, lose mobility and become deformed. It is the most frequent rheumatic disease, especially among the elderly. Observational data have suggested an association between low levels of 25HCC, pain and radiographic changes in osteoarthritis81,82. A cross-sectional analysis of data from the Hertfordshire cohort suggested that 25HCC may be associated more to pain than to radiographic change83. The prospective study of the Framingham cohort concluded that low serum levels of 25HCC may be associated with an increased risk of osteoarthritis of the knee84. A recent prospective observational study demonstrated that vitamin D3 deficiency independently predicts the onset or worsening of knee pain in the next 5 years, and of hip in the following 2.4 years. Based on this association, it has been suggested that correction of 25HCC deficiency may reduce the worsening of knee or hip pain in the elderly, but supplementing those without non-deficiency would probably be ineffective85.
However, two randomized clinical trials of vitamin D3 supplementation have found no benefit in this approach86,87, although another trial reported a small degree of symptomatic improvement88.
In the largest and most recent of these randomized controlled trials86, 413 patients with symptomatic knee osteoarthritis and low levels of 25HCC participated. Supplementation with cholecalciferol (50,000 IU administered orally monthly) showed no significant difference compared to placebo in both knee pain and volume of the tibial cartilage measured by magnetic resonance at two years86. On the other hand, McAlindon et al. had obtained similar results in a previous study recruiting 146 patients who randomized cholecalciferol supplementation to 2,000 IU/day (with dose escalation if 25HCC levels remained below 36 ng/ml) or placebo. After 2 years of supplementation, when comparing the two groups, there was no difference either in pain or in the volume of cartilage lost87.
Sanghi D et al. recruited 106 randomized patients to receive 60,000 IU per month of 25HCC or placebo and found a small but statistically significant improvement in pain and function. However, the differences in this study were 1 mm in the visual analogue scale and 2 in the WOMAC questionnaire88.
Therefore, although vitamin D levels appear to be lower in the arthritic population than in the general population, the possible role of vitamin D3 in treating osteoarthritis is not entirely clear. Future studies are required with larger sample sizes, longer follow-up and probably higher doses of supplementation. Based on current evidence, it cannot be concluded that there is benefit for the arthrosic population when treated with high doses of vitamin D3.

 

Fibromyalgia
Fibromyalgia is part of central sensitization syndromes. Its main symptom is chronic, generalized musculoskeletal pain with a wide variety of accompanying symptoms, mainly cognitive (difficulty concentrating, sleep disturbances, anxiety, depression), fatigue, irritable bowel, sleep disturbances and bruxism.
Current therapeutic approaches for patients with fibromyalgia have a multidimensional nature, which includes patient education, behavioral therapy, exercise, pain management and relief of chronic symptoms, rather than mechanisms based pharmacological therapies Pathophysiology of the disease89.
Vitamin D is assumed to play a role in regulating the processing of chronic, widespread pain in fibromyalgia through complex central and peripheral interactions, so its deficiency could result in an amplification of pain signals. The presence of the vitamin D receptor (VDR) and the 1-alpha hydroxylase and the vitamin D binding protein (VDBP) in the hypothalamus is suggested as a mechanism.
Some, but not all, observational studies report that 25HCC insufficiency is more common in fibromyalgia patients than in the general population. However, this association may be due to the existence of concomitant confounding factors, such as physical inactivity, obesity or depression89-91.
To date there is only one randomized placebo-controlled clinical trial in patients with fibromyalgia92. Wepner F et al. included 37 women and 3 men whose serum levels of 25HCC were less than 32 ng/ml. Patients were randomly assigned to receive 25HCC or placebo for 20 weeks. The supplemented group received 2,400 IU/day if they presented deficiency levels and 1,200 IU/day if they were in levels of insufficiency, with the objective of reaching serum levels of 25HCC between 32 and 48 ng/ml92 . In post hoc sub-analysis, significant results were found regarding pain improvement and functionality in patients who normalized the levels of 25HCC92.
However, we have two randomized, placebo-controlled clinical trials in patients with non-specific generalized chronic pain 93,94, and several uncontrolled trials with multiple bias95-99, both in patients with non-specific generalized chronic pain95,96,99 and with Diagnosis of fibromyalgia97-99. From their analysis, most of the potential benefits of treatment with vitamin D3 on the pain and severity of the disease seem to be concluded.
Warner et al. contradict this possibility in their research94. Although methodologically they had a placebo control group, as in the rest of the studies, there are biases to consider. Patients included had a mean age of 60 years. Patients with levels below 9 ng/ml were excluded and supplementation was performed with ergocalciferol. In addition, the study was performed in summer, which would justify an improvement in the placebo group94. On the other hand, in the most recent uncontrolled trials [99], which included patients with non-specific generalized chronic pain (50% met fibromyalgia criteria), patients with 50,000 IU/week of oral 25HCC were supplemented for 3 months, with no control group. The authors reported improvements in musculoskeletal symptoms, depression level, and quality of life99.
In the results of the European Male Ageing Study cohort, male patients included with non-specific generalized chronic pain had lower levels of 25HCC than those without pain. It was concluded that the 25HCC deficiency increased the risk of suffering generalized non-specific chronic pain by 50%100. After a follow-up period, those patients who had levels below 15.6 ng/dl had a significantly increased risk of developing non-specific generalized chronic pain91. On the other hand, a cross-sectional study with 75 patients demonstrated a relationship between 25HCC deficiency and anxiety or depression101. Therefore, patients with fibromyalgia are a high-risk group for vitamin D3 deficiency, particularly those with smoking and/or drinking and obesity and/or depression91, so it would be prudent to keep these patients at levels of 25HCC sufficiency to minimize the risk of osteoporosis and maximize muscle strength. Given the current evidence, it is not possible to say whether vitamin D3 supplements may improve pain and function in these patients, and therefore more randomized, double-blind, and minimal-bias clinical trials are needed to provide high-quality evidence on this hypothesis .

Conflict of interest: The authors declare they have no conflict of interest regarding this work.

 

 

Bibliografía

1. Marques CD, Dantas AT, Fragoso TS, Rocha Junior LF, Melo JH, Costa AJ, et al. The importance of vitamin D levels in autoimmune diseases. Rev Bras Rheumatol. 2010;50:60-5.
2. Hewison M. An update on vitamin D and human immunity. Clin Endocrinol. (Oxf) 2012;76:315-25.
3. Sainaghi PP, Bellan M, Nerviani A, et al. Superiority of a high loading dose of cholecalciferol to correct hypovitaminosis D in patients with inflammatory/autoimmune rheumatic diseases. J Rheumatol. 2013;40:166-72.
4. van Groningen L, Opdenoordt S, van Sorge A, Telting D, Giesen A, de Boer H. Cholecalciferol loading dose guideline for vitamin D-deficient adults. Eur J Endocrinol. 2010;162:805-11.
5. Orbach H, Zandman-Goddard G, Amital H, Barak V, Szekanecz Z, Szucs G, et al. Novel biomarkers in autoimmune diseases: prolactin, ferritin, vitamin D, and TPA levels in autoimmune diseases. Ann N Y Acad Sci. 2007;1109:385-400.
6. Kamen DL, Cooper GS, Bouali H, Shaftman SR, Hollis BW, Gilkeson GS. Vitamin D deficiency in systemic lupus erythematosus. Autoimmun Rev. 2006;5:114-7.
7. Amital H, Szekanecz Z, Szucs G, Danko K, Nagy E, Csepany T, et al. Serum concentrations of 25-OH vitamin D in patients with systemic lupus erythematosus (SLE) are inversely related to disease activity: is it time to routinely supplement patients with SLE with vitamin D? Ann Rheum Dis. 2010;69:1155-7.
8. Ritterhouse LL, Crowe SR, Niewold TB, Kamen DL, Macwana SR, Roberts VC, et al. Vitamin D deficiency is associated with an increased autoimmune response in healthy individuals and in patients with systemic lupus erythematosus. Ann Rheum Dis. 2011;70:1569-74.
9. Cantorna MT, Mahon BD. Mounting evidence for vitamin D as an environmental factor affecting autoimmune disease prevalence. Exp Biol Med. (Maywood) 2004;229:1136-42.
10. Ponsonby AL, McMichael A, van der Mei I. Ultraviolet radiation and autoimmune disease: insights from epidemiological research. Toxicology. 2002;82:718-9.
11. Eyal O, Aharon M, Safadi R, Elhalel MD. Serum vitamin D levels in kidney transplant recipients: the importance of an immunosuppression regimen and sun exposure. Isr Med Assoc J. 2013;15:628-33.
12. Oren Y, Shapira Y, Agmon-Levin N, Kivity S, Zafrir Y, Altman A, et al. Vitamin D insufficiency in a sunny environment: a demographic and seasonal analysis. Isr Med Assoc J. 2010;12:751-6
13. Goff JP, Koszewski NJ, Haynes JS, Horst RL. Targeted delivery of vitamin D to the colon using β-glucuronides of vitamin D: therapeutic effects in a murine model of inflammatory bowel disease. Am J Physiol Gastrointest Liver Physiol. 2012;302:G460-9.
14. Binkley N, Novotny R, Krueger D, Kawahara T, Daida YG, Lensmeyer G, et al. Low vitamin D status despite abundant sun exposure. J Clin Endocrinol Metab. 2007;92: 2130-5.
15. Disanto G, Chaplin G, Morahan JM, Giovannoni G, Hypponen E, Ebers GC, et al. Month of birth, vitamin D and risk of immune mediated disease: a case control study. BMC Med. 2012 Jul 6;10:69. doi: 10.1186/1741-7015-10-69.
16. Kamen DL, Cooper GS, Bouali H, Shaftman SR, Hollis BW, Gilkeson GS. Vitamin D deficiency in systemic lupus erythematosus. Autoimmun Rev. 2006;5:114-7.
17. Muñoz-Ortego J, Torrente-Segarra V, Prieto-Alhambra D, Salman-Monte TC, Carbonell-Abello J. Prevalence and predictors of vitamin D deficiency in nonsupplemented women with systemic lupus erythematosus in the Mediterranean region: a cohort study. Scand J Rheumatol. 2012;41:472-5.
18. Souto M, Coelho A, Guo C, Mendonça L, Argolo S, Papi J, et al. Vitamin D insufficiency in Brazilian patients with SLE: prevalence, associated factors, and relationship with activity. Lupus. 2011;20:1019-26.
19. Toloza SM, Cole DE, Gladman DD, Ibañez D, Urowitz MB. Vitamin D insufficiency in a large female SLE cohort. Lupus. 2010;19:13-9.
20. Sumethkul K, Boonyaratavej S, Kitumnuaypong T, Angthararuk S, Cheewasat P, Manadee N, et al. The predictive factors of low serum 25-hydroxyvitamin D and vitamin D deficiency in patients with systemic lupus erythematosus. Rheumatol Int. 2013;33:1461-7.
21. Petri M, Bello KJ, Fang H, Maqder LS. Vitamin D in SLE: Modest Association with Disease Activity and Urine Protein/Creatinine Ratio. Arthritis Rheum. 2013;65:1865-71.
22. Kamen DL, Alele JD. Skeletal manifestations os systemic autoimmune disease. Curr Opin Endocrinol Diabetes Obes. 2010;17:540-5.
23. Brett M. Hoffecker, Laura M. Raffield, Diane L. Kame, Nowling TK. Systemic Lupus and Vitamin D deficiency are associated with shorter Telomere Length among African Americans: A Case-Control Study. PLoS One. 2013 May 20;8(5):e63725. doi: 10.1371/journal.pone.0063725.
24. Ruiz-Irastorza G, Egurbide MV, Olivares N, Martínez-Berriotxoa A, Aguirre C. Vitamin D deficiency in systemic lupus erythematosus: prevalence, predictors and clinical consequences. Rheumatology. 2008;47:920-3.
25. Lertratankul A, Wu P, Dyer A, Urowitz M, Gladman D, Fortin P. 25-Hydroxyvitamin D and cardiovascular disease in patients with systemic lupus erythematosus: data from a large international inception cohort. Arthritis Care Res. (Hoboken) 2014;66:1167-76.
26. Gholamrezaei A, Bonakdar ZS, Mirbagher L, Hosseini N. Sleep disorders in systemic lupus erythematosus. Does vitamin D play a role? Lupus. 2014;23:1054-8.
27. Ruiz-Irastorza G, Gordo S, Olivares N, Egurbide MV, Aguirre C. (2010) Changes in vitamin D levels in patients with systemic lupus erythematosus: effects on fatigue, disease activity, and damage. Arthritis Care Res. (Hoboken) 62:1160-5.
28. Mok CC, Birmingham DJ, Ho LY, Hebert LA, Song H, Rovin BH. (2012) Vitamin D deficiency as marker for disease activity and damage in systemic lupus erythematosus: a comparison with anti-dsDNA and anti-C1q. Lupus. 21:36-42.
29. Borba VZ, Vieira JG, Kasamatsu T, Radominski SC, Sato EI, Lazaretti-Castro M. Vitamin D deficiency in patients with active systemic lupus erythematosus. Osteoporos Int. 2009;20:427-33.
30. Hamza RT, Awwad KS, Ali MK, Hamed AI. Reduced serum concentrations of 25-hydroxy vitamin D in Egyptian patients with systemic lupus erythematosus: relation to disease activity. Med Sci Monit. 2011;17:CR711-8.
31. Bonakdar ZS, Jahanshahifar L, Jahanshahifar F, Gholamrezaei A. Vitamin D deficiency and its association with disease activity in new cases of systemic lupus erythematosus. Lupus. 2011;20:1155-60.
32. Szodoray P, Tarr T, Bazso A, Poor G, Szegedi G, Kiss E. The immunopathological role of vitamin D in patients with SLE: data from a single centre registry in Hungary. Scand J Rheumatol. 2011;40:122-6.
33. Mok CC, Birmingham DJ, Leung HW, Hebert LA, Song H, Rovin BH. Vitamin D levels in Chinese patients with systemic lupus erythematosus: relationship with disease activity, vascular risk factors and atherosclerosis. Rheumatology. 2012;51:644-52.
34. Yeap SS, Othman AZ, Zain AA, Chan SP. Vitamin D levels: its relationship to bone mineral density response and disease activity in premenopausal Malaysian systemic lupus erythematosus patients on corticosteroids. Int J Rheum Dis. 2012;15:17-24.
35. Reynolds JA, Haque S, Berry JL, Pemberton P, Teh LS, Ho P, et al. 25-Hydroxyvitamin D deficiency is associated with increased aortic stiffness in patients with systemic lupus erythematosus. Rheumatology. 2012;51:544-51.
36. Ruiz-Irastorza G, Egurbide MV, Olivares N, Martinez-Berriotxoa A, Aguirre C. Vitamin D deficiency in systemic lupus erythematosus: prevalence, predictors and clinical consequences. Rheumatology. 2008;47:920-3.
37. Kim HA, Sung JM, Jeon JY, Yoon JM, Suh CH. Vitamin D may not be a good marker of disease activity in Korean patients with systemic lupus erythematosus. Rheumatol Int. 2011;31:1189-94.
38. Fragoso TS, Dantas AT, Marques CD, Junior LFR, Melo JH, Costa AJ, et al. 25-Hydroxyivitamin D3 levels in patients with systemic lupus erythematosus and its association with clinical parameters and laboratory tests. Rev Bras Reumatol. 2012;52:60-5.
39. Salman-Monte TC, Torrente-Segarra V, Almirall M, Corzo P, Mojal S, Carbonell-Abelló J. Prevalence and predictors of vitamin D insufficiency in supplemented and non- supplemented women with systemic lupus erythematosus in the Mediterranean region. Rheumatol Int. 2016;36:975-85.
40. Ad Hoc Committee on Systemic Lupus Erythematosus Response Criteria for Fatigue. Measurement of fatigue in systemic lupus erythematosus: a systematic review. Arthritis Rheum. 2007;57:1348-57.
41. Masoudi Alavi N, Madani M, Sadat Z, Haddad Kashani H, Reza Sharif M. Fatigue and Vitamin D Status in Iranian Female Nurses.Glob J Health Sci. 2015;8:430-43.
42. Lima GL, Paupitz J, Takayama L, Bonfa, Pereira RM. A Randomized Double-Blind Placebo-Controlled Trial of Vitamin D Supplementation in Juvenile-Onset Systemic Lupus Erythematosus: Improvement in Disease Activity and Fatigue Scores. Arthritis Care Res. 2016;68:91-8.
43. W. Lomarat, R. Rattapol Pakchotanon, S. Chaiamnuay, P. Narongroeknawin, P. Asavatanabodee (2016). Ann Rheum Dis. 2016;75(Suppl2):165.
44. Vacca A, Cormier C, Piras M, Mathieu A, Kahan A, Allanore Y, et al. Vitamin D deficiency and insufficiency in 2 independent cohorts of patients with systemic sclerosis. J Rheumatol. 2009;36:1924-9.
45. Arnson Y, Amital H, Agmon-Levin N, Alon D, Sánchez-Castañon M, López-Hoyos M, et al. Serum 25-OH vitamin D concentrations are linked with various clinical aspects in patients with systemic sclerosis: a retrospective cohort study and review of the literature. Autoimmun Rev. 2011;10:490-4.
46. Caramaschi P, Dalla Gassa A, Ruzzenente O, Volpe A, Ravagnani V, Tinazzi I, et al. Very low levels of vitamin D in systemic sclerosis patients. Clin Rheumatol. 2010;29:1419-25.
47. Gatenby P, Lucas R, Swaminathan A. Vitamin D deficiency and risk for rheumatic diseases: an update. Curr Opin Rheumatol. 2013;25:184-91.
48. Humbert P, Dupond JL, Agache P, Laurent R, Rochefort A, Drobacheff C, et al. Treatment of scleroderma with oral 1,25-dihydroxyvitamin D3: evaluation of skin involvement using noninvasive techniques. Results of an open prospective trial. Acta Derm Venereol. 1993;73:449-51.
49. Elst EF, Van Suijlekom-Smit LW, Oranje AP. Treatment of linear scleroderma with oral 1,25- dihydroxyvitamin D3 (calcitriol) in seven children. Pediatr Dermatol. 1999;16:53-8.
50. Hulshof MM, Bouwes-Bavinck JN, Bergman W, Maclee AA, Heickedorff L, Breedveld FC, et al. Double-blind, placebo controlled study of oral calcitriol for the treatment of localized and systemic scleroderma. J Am Acad Dermatol. 2000;43:1017-23.
51. Zerr P, Vollath S, Palumbo-Zerr K, Tomcik M, Huang J, Distler A, et al. Vitamin D receptor regulates TGF-β signalling in systemic sclerosis. Ann Rheum Dis. 2015;74:e20.
52. Erten ş, şahin A, Altunoğlu A, Gemcioğlu E, Koca C. Comparison of plasma vitamin D levels in patients with Sjogren’s syndrome and healthy subjects. Int J Rheum Dis. 2015;18:70-5.
53. Baldini C, Delle Sedie A, Luciano N, Pepe P, Ferro F, Talarico R, Tani C, Mosca M. Vitamin D in “early” primary Sjogren’s syndrome: does it play a role in influencing disease phenotypes? Rheumatol Int. 2014;34:1159-64.
54. Agmon-Levin N, Kivity S, Tzioufas AG, López Hoyos M, Rozman B, Efes I, et al. Low levels of vitamin-D are associated with neuropathy and lymphoma among patients with Sjogren’s syndrome. J Autoimmun. 2012;39:234-9.
55. Hickish T, Cunningham D, Colston K, Millar BC, Sandle J, Mackay AG, et al. The effect of 1,25- dihydroxyvitamin D3 on lymphoma cell lines and expression of vitamin D receptor in ly mphoma. Br J Cancer. 1993;68:668-72.
56. Lee SJ, Oh HJ, Choi BY, Jang YJ, Lee JY, Park JK, et al. Serum 25-Hydroxyvitamin D3 and BAFF Levels Are Associated with Disease Activity in Primary Sjogren’s Syndrome. J Immunol Res. 2016;2016:5781070. doi: 10.1155/2016/5781070.
57. Zold E, Szdoray P, Gaal J, Kappelmayer J, Csathy L, Gyimesi E, et al. Vitamin D deficiency in undifferentiated connective tissue disease. Arthritis Research & Therapy. 200810:R123.
58. Hajas A, Sandor J, Csathy L, Csipo I, Barath S, Paragh G, et al. Vitamin D insufficiency in a large MCTD population. Autoimmun Rev. 2011;10:317-24.
59. Memerci Baskan B, Pekin Doğan Y, Sivas F, Bodur H, Ozoran K. The relation between osteoporosis and vitamin D levels and disease activity in ankylosing spondylitis. Rheumatol Int. 2010;30:375-81
60. Muntean LM, Simon SP, Font P. Vitamin D deficiency in men with ankylosing spondylitis. Ann Rheum Dis. 2011;70(Suppl 3):33.
61. Erten S, Kucuksahin O, Sahin A, Altunoglu A, Akyol M, Koca C. Decreased plasma vitamin D levels in patients with undifferentiated spondyloarthritis and ankylosing spondylitis. Intern Med. 2013;52:33-44.
62. Hmamouchi I, Paternotte S, Molto A, Etcheto A, Borderie D, Combe B, et al. Vitamin D, disease activity and comorbidities in early spondyloarthritis Clin Exp Rheumatol. 2016;34:396-403.
63. Lukic IK, Grčević D, Kovačić N, Katavić V, Ivčević S, Kalajzić I, et al. Alteration of newly induced enchondral bone formation in adult mice without tumour necrosis factor receptor 1. Clin Exp Immunol. 2005;139:236-44.
64. Kim HR, Kim HY, Lee SH. Elevated serum levels of soluble receptor activator of nuclear factor-κB ligand (sRANKL) and reduced bone mineral density in patients with ankylosing spondylitis (AS). Rheumatology. 2006;45:1197-200.
65. Lories RJ, Luyten FP. Bone morphogenetic proteins in destructive and remodeling arthritis. Arthritis Res Ther. 2007;9:207.
66. Lories RJ, Derese I, De Bari C, Luyten FP. Evidence for uncoupling of inflammation and joint remodeling in a mouse model of spondylarthritis. Arthritis Rheum. 2007;56:489-97.
67. Appel H, Ruiz-Heiland G, Listing J, Zwerina J, Herrmann M, Mueller R, et al. Altered Skeletal Expression of Sclerostin and Its Link to Radiographic Progression in Ankylosing Spondylitis. Arthritis Rheum. 2009;60:3257-62.
68. Heiland GR, Appel H, Poddubnyy D, Zwerina J, Hueber A, Haibel H, et al. High level of functional dickkopf-1 predicts protection from syndesmophyte formation in patients with ankylosing spondylitis. Ann Rheum Dis. 2012;71:572-4.
69. Haynes KR, Pettit AR, Duan R, Tseng H-W, Glant TT, Brown MA, et al. Excessive bone formation in a mouse model of ankylosing spondylitis is associated with decreases in Wnt pathway inhibitors. Arthritis Res Ther. 2012;14:R253.
70. Saad CG, Ribeiro AC, Moraes JC, Takayama L, Goncalves CR, Rodrigues MB, et al. Low sclerostin levels: a predictive marker of persistent inflammation in ankylosing spondylitis during anti-tumor necrosis factor therapy? Arthritis Res Ther. 2012;14:R216.
71. Haynes KR, Pettit AR, Duan R, Tseng H-W, Glant TT, Brown MA, et al. Dickkopf-1 is a master regulator of joint remodeling. Nat Med. 2007;13:156-63.
72. Kerr GS, Sabahi I, Richards JS, Caplan L, Cannon GW, Reimold A, et al. Prevalence of vitamin D insufficiency/deficiency in rheumatoid arthritis and associations with disease severity and activity. J Rheumatol. 2011;38:53-9.
73. Gopinath K, Danda D. Supplementation of 1,25 dihydroxy vitamin D3 in patients with treatment naive early rheumatoid arthritis: a randomised controlled trial. Int J Rheum Dis. 2011;14:332-9.
74. Mouterde G, Lukas C, Logeart I, Flipo RM, Rincheval N, Daures JP, et al. Predictors of radi graphic progression in the ESPOIR cohort: the season of first symptoms may influence the short-term outcome in early arthritis. Ann Rheum Dis. 2011;70:1251-6.
75. Merlino LA, Curtis J, Mikuls TR, Cerhan JR, Criswell LA, Saag KG. Vitamin D intake is inversely associated with rheumatoid arthritis: results from the Iowa Women’s Health Study. Arthritis Rheum. 2004;50:72-7.
76. Craig SM, Yu F, Curtis JR, Alarcon GS, Conn DL, Jonas B, et al. Vitamin D status and its associations with disease activity and severity in African Americans with recent onset rheumatoid arthritis. J Rheumatol. 2010;37:275-81.
77. Andjelkovic Z, Vojinovic J, Pejnovic N, Popovic M, Dujic A, Mitrovic D, et al. Disease modifying and immunomodulatory effects of high dose 1 alpha (OH) D3 in rheumatoid arthritis patients. Clin Exp Rheumatol. 1999;17:453-6.
78. Salesi M, Farajzadegan Z. Efficacy of vitamin D in patients with active rheumatoid arthritis receiving methotrexate therapy. Rheumatol Int. 2012;32:2129-33.
79. Hansen KE, Bartels CM, Gangnon RE, Jones AN, Gogineni J. An evaluation of high-dose vitamin D for rheumatoid arthritis. J Clin Rheumatol. 2014;20:112-4.
80. Dehghan A, Rahimpour S, Soleymani-Salehabadi H, Owlia MB. Role of vitamin D in flare ups of rheumatoid arthritis. Z Rheumatol. 2014;73:461-4.
81. Ding C, Cicuttini F, Parameswaran V, Burgess J, Quinn S, Jones G. Serum levels of vitamin D, sunlight exposure, and knee cartilage loss in older adults: the Tasmanian older adult cohort study. Arthritis Rheum. 2009;60:1381-9.
82. Bergink AP, Uitterlinden AG, Van Leeuwen JP, Buurman CJ, Hofman A, Verhaar JA, et al. Vitamin D status, bone mineral density, and the development of radiographic osteoarthritis of the knee: The Rotterdam Study. J Clin Rheumatol. 2009;15:230-7.
83. M Raki S, Dennison E, Jameson K, Boucher BJ, Akune T, Yoshimura N, et al. Association of vitamin D status with knee pain and radiographic knee osteoarthritis. Osteoarthritis Cartilage. 2011;19:1301-6.
84. McAlindon TE, Felson DT, Zhang Y, Hannan MT, Aliabadi P, Weissman B, et al. Relation of dietary intake and serum levels of vitamin D to progression of osteoarthritis of the knee among participants in the Framingham Study. Ann Intern Med. 1996;125:353.
85. Laslett LL, Quinn S, Burgess JR, Parameswaran V, Winzenberg TM, Jones G, et al. Moderate vitamin D deficiency is associated with changes in knee and hip pain in older adults: a 5-year longitudinal study. Ann Rheum Dis. 2014;73:697-703.
86. Jin X, Jones G, Cicuttini F, Wluka A, Zhu Z, Han W, et al. Effect of Vitamin D Supplementation on Tibial Cartilage Volume and Knee Pain Among Patients With Symptomatic Knee Osteoarthritis: A Randomized Clinical Trial. JAMA. 2016;315:1005.
87. McAlindon T, LaValley M, Schneider E, Nuite M, Lee JY, Price LL, et al. Effect of vitamin D supplementation on progression of knee pain and cartilage volume loss in patients with symptomatic osteoarthritis: a randomized controlled trial. AU JAMA. 2013;309:155-62.
88. Sanghi D, Mishra A, Sharma AC, Singh A, Natu SM, Agarwal S, et al. Does vitamin D improve osteoarthritis of the knee: a randomized controlled pilot trial. Clin Orthop Relat Res. 2013;471:3556-62.
89. Karras S, Rapti E, Matsoukas S, Kotsa K. Vitamin D in Fibromyalgia: A Causative or Confounding Biological Interplay? Nutrients. 2016;8(6). E343.
90. Maafi AA, Ghavidel-Parsa B, Haghdoost A, Aarabi Y, Hajiabbasi A, Shenavar Masooleh I, et al. Serum Vitamin D Status in Iranian Fibromyalgia Patients: according to the Symptom Severity and Illness Invalidation. Korean J Pain. 2016;29:172-8.
91. McCabe PS, Pye SR, Mc Beth J, Lee DM, Tajar A, Bartfai G, et al. Low vitamin D and the risk of developing chronic widespread pain: results from the European male ageing study. BMC Musculoskelet Disord. 2016;17:32.
92. Wepner F, Scheuer R, Schuetz-Wieser B, Machacek P, Pieler-Bruha E, Cross HS, et al. Effects of vitamin D on patients with fibromyalgia syndrome: a randomized placebo controlled trial. MSO Pain. 2014;155:261-8.
93. Schreuder F, Bernsen RM, van der Wouden JC. Vitamin D supplementation for nonspecific musculoskeletal pain in non-Western immigrants: a randomized controlled trial. Ann Fam Med. 2012;10:547-55.
94. Warner AE, Arnspiger SA. Diffuse musculoskeletal pain is not associated with low vitamin D levels or improved by treatment with vitamin D. J Clin Rheumatol. 2008;14:12-6
95. Badsha H, Daher M, Ooi Kong K. Myalgias or non-specific muscle pain in Arab or Indo-Pakistani patients may indicate vitamin D deficiency. Clin Rheumatol. 2009;28:971-3.
96. Harari M, Dramsdahl E, Shany S, Baumfeld Y, Ingber A, Novack V, Sukenik S. Increased vitamin D serum levels correlate with clinical improvement of rheumatic diseases after Dead Sea climatotherapy. IsrHYPERLINK “https://www.ncbi.nlm.nih.gov/pubmed/21598808” Med HYPERLINK “https://www.ncbi.nlm.nih.gov/pubmed/ 21598808″AssocHYPERLINK “https://www.ncbi.nlm.nih. gov/pubmed/21598808” J. 2011;13:212-5.
97. Matthana MH. The relation between vitamin D deficiency and fibromyalgia syndrome in women. Saudi Med J. 2011;32:925-9.
98. Abokrysha NT. Vitamin D deficiency in women with fibromyalgia in Saudi Arabia. Pain Med. 2012;13:452-8.
99. Yilmaz R, Salli A, Cingoz HT, Kucuksen S, Ugurlu H. Efficacy of vitamin D replacement therapy on patients with chronic nonspecific widespread musculoskeletal pain with vitamin D deficiency. Int J Rheum Dis. 2016;19:1255-62.
100. McBeth J, Pye SR, O’Neill TW, Macfarlane GJ, Tajar A, Bartfai G, et al. Musculoskeletal pain is associated with very low levels of vitamin D in men: results from the European Male Ageing Study. Ann Rheum Dis. 2010;69:1448-52.
101. Armstrong DJ, Meenagh GK, Bickle I, Lee AS, Curran ES, Finch MB. Vitamin D deficiency is associated with anxiety and depression in fibromyalgia. Clin Rheumatol. 2007;26:551-4.