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Vitamin D levels in Jamaican patients with systemic lupus erythematosus TK McGhie, K DeCeulaer, CA Walters, A Soyibo and MG Lee Lupus published online 18 March 2014 DOI: 10.1177/0961203314528556 The online version of this article can be found at: http://lup.sagepub.com/content/early/2014/03/18/0961203314528556
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Vitamin D levels in Jamaican patients with systemic lupus erythematosus TK McGhie1, K DeCeulaer1, CA Walters2, A Soyibo1 and MG Lee1 1
Department of Medicine; and 2Faculty of Medical Sciences, The University of the West Indies, Kingston, Jamaica
Vitamin D has important effects on the immune system as it has been shown to exert antiproliferative and relative immunosuppressant effects. Low levels of this hormone may contribute to the immune activation in systemic lupus erythematosus (SLE) and other autoimmune diseases. Serum levels of 25-OH vitamin D were measured in 75 patients with SLE in Jamaica, using an enzyme-linked immunoassay. Correlations with clinical data and disease activity as determined by the BILAG index were determined. Of a total of 75 patients, 33 (44%) had vitamin D sufficiency with mean vitamin D level of 39.45 ng/ml (range, 30.35–58.16). Forty-two (56%) patients had either vitamin D deficiency or insufficiency, 30 (40%) had vitamin D insufficiency, mean 26.36 ng/ml (range, 20.26–29.88), and 12 (16%) had vitamin D deficiency, mean 16.07 ng/ ml (range, 7.78–19.90). There was an overall negative relationship between the total disease activity score using the BILAG index and vitamin D levels, and this was influenced primarily by the relationship seen among the vitamin D-deficient subgroup. This was also impacted on by a patient population that was significantly skewed toward low disease activity. The negative association trended toward statistical significance. Vitamin D deficiency is prevalent among patients with SLE in Jamaica. A relationship between low serum levels of vitamin D and SLE activity may occur. Lupus (2014) 0, 1–5. Key words: Vitamin D; enzyme-linked immunoassay; systemic lupus erythematosus; disease activity score
Introduction Apart from its critical role in regulation of calcium homeostasis, bone mineralization and remodeling, and neuromuscular function, vitamin D, a secosteroid hormone, also has important effects on the immune system. It has been shown to exert antiproliferative and relative immunosuppressant effects.1 Previous studies have suggested a relationship between low serum levels of vitamin D and systemic lupus erythematosus (SLE).2,3 Vitamin D receptor ligands can mediate immunosuppressive effects, and low levels of this hormone have been proposed as contributing to immune activation in SLE and other autoimmune diseases.4 Many studies, but not all, have documented an association between higher disease activity and a low level of vitamin D. Correspondence to: Michael G. Lee, Department of Medicine, The University of the West Indies, Kingston, Jamaica. Email: [email protected] Received 23 December 2013; accepted 26 February 2014
A significant negative correlation between 25hydroxy (25-OH) vitamin D and Systemic Lupus Erythematosus Disease Activity Index (SLEDAI) and European Consensus Lupus Activity Measurement (ECLAM) scores was noted in European patients.4 Another study using data from three centers documented a significant difference in SLEDAI scores between patients with severe deficiency and those who were less deficient.5 Vitamin D deficiency is more prevalent in patients with darker skin pigmentation because of a reduced ability of ultraviolet B light (UVB, sunlight) to convert 7-dehydrocholesterol to vitamin D cutaneously.6,7 In recent years, vitamin D status has been evaluated in non-Caucasian SLE populations and has confirmed this.8 However, there are no such studies involving the Caribbean population of SLE patients, which is relatively large. These patients are predominantly of dark skin pigmentation but are also exposed to year-long sunlight. This cross-sectional study was conducted to determine the vitamin D levels of patients with SLE and to assess whether low serum vitamin D
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Vitamin D levels in Jamaican patients with SLE TK McGhie et al.
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concentrations are related to disease activity of patients with SLE as measured by the BILAG index at the University Hospital of the West Indies, Jamaica.
This study received ethics approval from the University Hospital of the West Indies/University of the West Indies/Faculty of Medical Sciences Ethics Committee. Written informed consent was obtained from all patients.
Materials and methods Results Patients with SLE attending the rheumatology clinic and inpatients at the University Hospital of the West Indies, Jamaica, during a six-month (January to June 2011) period were reviewed. All patients met the 1997 revised American College of Rheumatology criteria for the classification of SLE. Pregnant patients were excluded. The patient charts were reviewed and data recorded including demographic details of age, gender and ethnic group. Additional data recorded included the duration of disease, drug history with particular reference to the use of Hydroxychloroquine (HCQS) and vitamin D supplementation. The clinical features and laboratory investigations covered by the British Isles Lupus Assessment Group (BILAG) index of systemic lupus disease activity were recorded in a standardized way on data forms devised specifically for this purpose. The data were subsequently entered in the BILAG-2004 index using the BLIPS software program and the BILAG score was calculated using version 3 of the BILAG index. BILAG-2004 measures disease activity (scored from A to E) in nine systems: constitutional, mucocutaneous, neuropsychiatric, musculoskeletal, cardiorespiratory, gastrointestinal, ophthalmic, renal and hematologic. An ‘A’ flare was recorded when a patient recorded an A score in any of the eight organs/systems. At the time of evaluation, a single serum sample was obtained and the level of 25-OH vitamin D was measured using an enzyme-linked immunoassay (IDS OCTEIA kit). The sample size was calculated using raosoft. com/sample size.html: Given a 5% margin of error, 95% confidence interval, 92 patients-population size (as determined by the Lupus Registry) and 50% response distribution, a sample size of 75 patients was deemed sufficient. Univariate summaries including frequency tables, histograms, means and standard deviations (SDs) were generated as appropriate for the various variables. In addition, bivariate tests of association (Fisher’s exact and Pearson’s chi-squared) as well as t tests, analysis of variance (or its nonparametric analogue Kruskal-Wallis) for the comparison of means were employed.
Seventy-five patients were studied. There were 69 females (92%) and six males. Of these, 61 (81%) were outpatients and 14 (19%) were inpatients. The ages ranged from 12 to 71 years, with a mean age of 41.5 (SD, 14.3) years. The age range was similar for females, with a mean age of 41.8 (SD, 14.5) years. Ages ranged from 20 to 52 years among the males, with a mean age of 38.5 (SD, 12.8) years. The duration of disease for 73 patients was a mean of 9.0 (SD, 8.6) years, and ranged from one to 35 years. However, given the skewed distribution, the median was six years and an interquartile range (IQR) of three to 11 years would more accurately reflect the central tendency and spread of the distribution. Of the 74 patients for whom data were obtained on HCQS use, 25 (33.8%) were on HCQS, 49 (66.2%) patients were not. Serum vitamin D values were available for all 75 patients and the mean (SD) was 30.5 ng/ml (10.3) and ranged from 7.78 to 58.16. Thirty-three (44%) had vitamin D sufficiency with a mean level of 39.45 ng/ml (range, 30.35–58.16). Forty-two (56%) patients had either vitamin D deficiency or insufficiency; 30 (40%) had vitamin D insufficiency with a mean of 26.36 ng/ml (range, 20.26–29.88), and 12 (16%) had vitamin D deficiency with a mean 16.07 ng/ml (range, 7.78–19.90). An analysis of variance used to compare average ages across the three vitamin D subgroups revealed no significant differences (F ¼ 0.66, p ¼ 0.5196). There was also no significant association between vitamin D subgroups and whether patients were taking vitamin D supplements (p value based on Chi-squared test of association ¼ 0.306). Given the significant departures from normality for the duration of disease, in order to compare average duration in years across the three vitamin D subgroups, we used the nonparametric KruskalWallis test, which revealed no significant differences in average duration of disease (p ¼ 0.3521). There was no significant association between vitamin D subgroups and HCQS (p ¼ 0.996, Pearson’s chi-squared test). Looking at the values for the vitamin D levels; among individuals not on
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HCQS, vitamin D levels for the 49 patients was a mean (SD) of 29.73 ng/ml (10.12), range 7.78 to 58.16; among those on HCQS, mean vitamin D levels for the 25 patients was 30.92 ng/ml (9.85) with a range from 18.01 to 49.62. Based on the t test for comparison of means, there was no significant difference in mean vitamin D levels between the two HCQS groups (p ¼ 0.632). Creatinine clearance values were available for 71 patients with a mean of 105.9 ml/min/1.73 m2 (SD, 43.5), and range from 10.81 to 201.07. There was no significant association between creatinine clearance and vitamin D subgroups (p ¼ 0.109 based on Fisher’s exact test). For the disease activity, scores were available for 72 of the 75 patients with a mean (SD) of 13.69 (15.57) and ranged from 0 to 69. The distribution of scores was significantly right-skewed (p ¼ 0.0001). Median (IQR) score was 8 (range, 1 to 24.5). Scatter plots were generated to assess the relationship of disease activity for all patients as well as within subgroups of vitamin D levels. The correlation coefficient for all patients combined was 0.198 (p ¼ 0.095), indicating a somewhat weak negative relationship between the two variables. Among the vitamin D-deficient subgroup, the correlation coefficient was 0.525 (p ¼ 0.079), indicating a moderate negative relationship between the two variables. Among the vitamin D-insufficient subgroup, the correlation coefficient was 0.127 (p ¼ 0.512), indicating a fairly weak negative relationship between the two variables. Among the vitamin D-sufficient subgroup, the correlation coefficient was 0.210 (p ¼ 0.257), indicating a somewhat weak positive relationship between the two variables. Based on these results, the overall negative relationship between the total disease activity score and vitamin D levels is influenced primarily by the relationship seen among the vitamin D-deficient subgroup.
Discussion This is the first Caribbean-based study to evaluate vitamin D in SLE and is of significance because SLE is associated with a worse prognosis in patients of African descent. Also, such patients are at higher risk of vitamin D deficiency because of reduced efficacy of conversion of 7-dehydrocholesterol to vitamin D by UVB light cutaneously in darker pigmented skin. Greater amounts of the pigment melanin in the epidermal layer result in darker
skin and reduce the skin’s ability to produce vitamin D from sunlight. Reports consistently show lower serum 25(OH) vitamin D levels in people identified as black compared with those identified as white.9 Vitamin D insufficiency is emerging as a clinical problem of global proportions and epidemiology has linked vitamin D status with autoimmune disease susceptibility and severity.7 SLE is a prototypic, systemic, autoimmune disease characterized by the production of immunoglobulin (Ig)G autoantibodies that are specific for self-antigens, such as DNA, nuclear proteins and certain cytoplasmic components, in association with a diverse array of clinical manifestations. The primary pathological findings in patients with SLE are those of inflammation, vasculitis, immune complex deposition, and vasculopathy. The first observation linking vitamin D to the innate immune system was the ability of immune cells such as macrophages to synthesize calcitriol (1,25(OH)2D) from calcidiol (25(OH)D). Vitamin D promotes immune stability in the innate and adoptive immune systems, preventing lapses toward autoimmunity.10–14 The identiEcation of vitamin D receptors on the membranes of immune cells as well as the existence of 1a-hydroxylase in these cells clearly underline the importance of vitamin D for immune regulation.11,13 A number of recent studies have highlighted the association between SLE and vitamin D deficiency.10,15–17 Vitamin D deficiency skews the immunological response toward loss of tolerance. Adding vitamin D in vitro reverses immunological abnormalities characteristic of SLE. Low serum 25-OH vitamin D (25-hydroxycholecalciferol) was highly prevalent in patients with SLE originating from different regions of Europe.16 In another study, SLE patients, especially those with leukopenia or renal involvement, were at high risk of vitamin D deficiency even during the warm season and vitamin D supplementation was recommended.18 In a smaller study in Texas, in 37 patients with SLE, 20% had levels of 25-OH vitamin D that were lower than the normal range for the assay.15 The group of patients with the lowest levels showed disease activity measures, including global assessment scores, that were higher than in those with levels considered normal in the assay (p 0.003). In a cohort from Europe and Israel a signiEcant negative correlation was found between the serum concentration of vitamin D and the standardized values (z scores) of disease activity scores as measured by the SLEDAI-2000 (2K) and Lupus
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ECLAM scales.17 However, previous studies have failed to demonstrate this association.19,20 Although vitamin D is consumed in food, dietary intake alone is often insufficient, supplying only 20% of the body’s requirements. Patients with SLE have multiple risk factors for vitamin D deficiency with the chief one being avoidance of UV exposure. Also, drugs such as glucocorticoids enhance vitamin D metabolism and decrease its absorption. Other factors include HCQS therapy, chronic kidney disease, higher prevalence of obesity and possibly anti-vitamin D antibodies that may clear vitamin D from the serum.19,21,22 HCQS may lower the conversion of 25(OH)-vitamin D to 1,25(OH)2-vitamin D.19 The Jamaican population is at significant risk because of the predominantly darker skin pigmentation.23 In this study, less than half of the patients had vitamin D sufficiency (44%), with 56% patients having either vitamin D deficiency or insufficiency: Forty percent had vitamin D insufficiency and 16% had vitamin D deficiency. No overall significant associations were obtained between important clinical parameters such as renal function. There was no association with HCQS use as suggested by an earlier study.19 The skewness of the disease activity could possibly be explained by the method of sampling, as 81% of the patients were routine follow-ups in the outpatient clinic and had stable or quiescent disease confirmed by their low BILAG scores. Inpatients were evaluated at the time of their hospitalization (19%), and the numbers obtained represent the disparity between those stable and those requiring in-hospital care and thus more active disease. Overall the results of this study are consistent with the widely held hypothesis that low vitamin D levels are associated with higher disease activity. The clinical relevance of this study is its potential to direct further management of patients with SLE with respect to the need for routine evaluation of vitamin D sufficiency and supplementation. Further interventional studies focusing on vitamin D supplementation are warranted in order to determine whether vitamin D has therapeutic value as well. The most important limitation of this study is the fact that vitamin D levels of healthy controls in our population are unknown and the reference ranges used to determine the participants’ status were derived from the latest Endocrine Society Clinical Practice Guideline based on a nonCaribbean population.23 Another limitation of this study is the cross-sectional design, whereby only the disease activity at the time of assessment
is considered. No allowance was made for other factors linked to treatment decisions, such as prior disease activity, current therapy, previous therapy and presence of comorbidities. In conclusion, this study demonstrates that vitamin D deficiency is prevalent among patients with SLE managed at the University Hospital of the West Indies and underlines the observational association between low serum vitamin D levels and disease activity in SLE.
Funding This work was supported by the Lupus Foundation of Jamaica.
Conflict of interest statement The authors have no conflicts of interest to declare.
Acknowledgments The authors are grateful to Gordon Hamilton of Limathon for his benevolence in providing access and assistance with the use of the BILAG BLIPS software. Thanks to the residents and research nurses who helped to identify patients for participation in this study.
References 1 Chan OT, Madaio MP, Shlomchik M. The central and multiple roles of B cells in lupus pathogenesis. Immunol Rev 1999; 69: 107–121. 2 Munoz LE, van Bavel C, Franz S, Berden J, Herrmann M, van der Vlag J. Apoptosis in the pathogenesis of SLE. Lupus 2008; 17: 371–375. 3 Pascual V, Banchereau J, Palucka AK. The central role of dendritic cells and interferon-alpha in SLE. Curr Opin Rheumato 2003; 15: 548–556. 4 Cooper GS, Dooley MA, Treadwell EL, St Clair EW, Parks CG, Gilkeson GS. Hormonal, environmental, and infectious risk factors for developing systemic lupus erythematosus. Arthritis Rheum 1998; 41: 1714–1724. 5 Holick MF. Vitamin D: Important for prevention of osteoporosis, cardiovascular heart disease, type 1 diabetes, autoimmune diseases, and some cancers. South Med J 2005; 98: 1024–1027. 6 Adams JS, Sharma OP, Gacad MA, Singer FR. Metabolism of 25hydroxyvitamin D3 by cultured pulmonary alveolar macrophages in sarcoidosis. J Clin Invest 1983; 72: 1856–1860. 7 Adams JS, Hewison M. Unexpected actions of vitamin D: New perspectives on the regulation of innate and adaptive immunity. Nat Clin Pract Endocrinol Metab 2008; 4: 80–90. 8 Adams JS, Sharma OP, Gacad MA, Singer FR. Metabolism of 25hydroxyvitamin D3 by cultured pulmonary alveolar macrophages in sarcoidosis. J Clin Invest 1983; 72: 1856–1860.
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5 9 Kamen DL, Cooper GS, Bouali H, Shaftman SR, Hollis BW, Gilkeson GS. Vitamin D deficiency in systemic lupus erythematosus. Autoimmun Rev 2006; 5: 114–117. 10 Adorini L, Penna G. Control of autoimmune diseases by the vitamin D endocrine system. Nat Clin Pract Rheumatol 2008; 4: 404–412. 11 Arnson Y, Amital H, Shoenfeld Y. Vitamin D and autoimmunity: New aetiological and therapeutic considerations. Ann Rheum Dis 2007; 66: 1137–1142. 12 Cantorna MT. Vitamin D and its role in immunology: Multiple sclerosis, and inFammatory bowel disease. Prog Biophys Mol Biol 2006; 92: 60–64. 13 Cutolo M, Otsa K. Review: Vitamin D, immunity and lupus. Lupus 2008; 17: 6–10. 14 Shimada A, Kanazawa Y, Motohashi Y, et al. Evidence for association between vitamin D receptor BsmI polymorphism and type 1 diabetes in Japanese. J Autoimmun 2008; 30: 207–211. 15 Thudi A, Yin S, Wandstrat AE, Li QZ, Olsen NJ. Vitamin D levels and disease status in Texas patients with SLE. Am J Med Sci 2008; 335: 99–104. 16 Cutolo M, Otsa K, Paolino S, Yprus M, Veldi T, Seriolo B. Vitamin D involvement in arthritis and SLE. Ann Rheum Dis 2009; 68: 446–447. 17 Amital H, Szekanecz Z, Szu¨cs G, et al. Serum concentrations of 25OH vitamin D in patients with SLE are inversely related to disease
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activity: Is it time to routinely supplement patients with SLE with vitamin D? Ann Rheum Dis 2010; 69: 1155–1157. Bogaczewicz J, Sysa-Jedrzejowska A, Arkuszewska C, et al. Vitamin D status in systemic lupus erythematosus patients and its association with selected clinical and laboratory parameters. Lupus 2012; 21: 477–484. Huisman AM, White KP, Algra A, et al. Vitamin D levels in women with SLE and fibromyalgia. J Rheumatol 2001; 28: 2535–2539. Ruiz-Irastorza G, Egurbide MV, Olivares N, Martinez-Berriotxoa A, Aguirre C. Vitamin D deEciency in SLE: Prevalence, predictors and clinical consequences. Rheumatology (Oxford) 2008; 47: 920–923. Carvalho JF, Blank M, Kiss E, Tarr T, Amital H, Shoenfeld Y. Anti-vitamin D, vitamin D in SLE: Preliminary results. Ann N Y Acad Sci 2007; 1109: 550–557. dos Santos Fde M, Borges MC, Correia MI, Telles RW, Lanna CC. Assessment of nutritional status and physical activity in systemic lupus erythematosus patients [article in English, Portuguese]. Rev Bras Reumatol 2010; 50: 631–638. Holick MF, Binkley NC, Bischoff-Ferrari HA, et al. Evaluation, treatment, and prevention of vitamin D deficiency: An Endocrine Society clinical practice guideline. J Clin Endocrinol Metab 2011; 96: 1911–1930.
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Vitamin D levels in Jamaican patients with systemic lupus erythematosus TK McGhie, K DeCeulaer, CA Walters, A Soyibo and MG Lee Lupus published online 18 March 2014 DOI: 10.1177/0961203314528556 The online version of this article can be found at: http://lup.sagepub.com/content/early/2014/03/18/0961203314528556
Published by: http://www.sagepublications.com
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Vitamin D levels in Jamaican patients with systemic lupus erythematosus TK McGhie1, K DeCeulaer1, CA Walters2, A Soyibo1 and MG Lee1 1
Department of Medicine; and 2Faculty of Medical Sciences, The University of the West Indies, Kingston, Jamaica
Vitamin D has important effects on the immune system as it has been shown to exert antiproliferative and relative immunosuppressant effects. Low levels of this hormone may contribute to the immune activation in systemic lupus erythematosus (SLE) and other autoimmune diseases. Serum levels of 25-OH vitamin D were measured in 75 patients with SLE in Jamaica, using an enzyme-linked immunoassay. Correlations with clinical data and disease activity as determined by the BILAG index were determined. Of a total of 75 patients, 33 (44%) had vitamin D sufficiency with mean vitamin D level of 39.45 ng/ml (range, 30.35–58.16). Forty-two (56%) patients had either vitamin D deficiency or insufficiency, 30 (40%) had vitamin D insufficiency, mean 26.36 ng/ml (range, 20.26–29.88), and 12 (16%) had vitamin D deficiency, mean 16.07 ng/ ml (range, 7.78–19.90). There was an overall negative relationship between the total disease activity score using the BILAG index and vitamin D levels, and this was influenced primarily by the relationship seen among the vitamin D-deficient subgroup. This was also impacted on by a patient population that was significantly skewed toward low disease activity. The negative association trended toward statistical significance. Vitamin D deficiency is prevalent among patients with SLE in Jamaica. A relationship between low serum levels of vitamin D and SLE activity may occur. Lupus (2014) 0, 1–5. Key words: Vitamin D; enzyme-linked immunoassay; systemic lupus erythematosus; disease activity score
Introduction Apart from its critical role in regulation of calcium homeostasis, bone mineralization and remodeling, and neuromuscular function, vitamin D, a secosteroid hormone, also has important effects on the immune system. It has been shown to exert antiproliferative and relative immunosuppressant effects.1 Previous studies have suggested a relationship between low serum levels of vitamin D and systemic lupus erythematosus (SLE).2,3 Vitamin D receptor ligands can mediate immunosuppressive effects, and low levels of this hormone have been proposed as contributing to immune activation in SLE and other autoimmune diseases.4 Many studies, but not all, have documented an association between higher disease activity and a low level of vitamin D. Correspondence to: Michael G. Lee, Department of Medicine, The University of the West Indies, Kingston, Jamaica. Email: [email protected] Received 23 December 2013; accepted 26 February 2014
A significant negative correlation between 25hydroxy (25-OH) vitamin D and Systemic Lupus Erythematosus Disease Activity Index (SLEDAI) and European Consensus Lupus Activity Measurement (ECLAM) scores was noted in European patients.4 Another study using data from three centers documented a significant difference in SLEDAI scores between patients with severe deficiency and those who were less deficient.5 Vitamin D deficiency is more prevalent in patients with darker skin pigmentation because of a reduced ability of ultraviolet B light (UVB, sunlight) to convert 7-dehydrocholesterol to vitamin D cutaneously.6,7 In recent years, vitamin D status has been evaluated in non-Caucasian SLE populations and has confirmed this.8 However, there are no such studies involving the Caribbean population of SLE patients, which is relatively large. These patients are predominantly of dark skin pigmentation but are also exposed to year-long sunlight. This cross-sectional study was conducted to determine the vitamin D levels of patients with SLE and to assess whether low serum vitamin D
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(LUP)
[1–5] [PREPRINTER stage]
Vitamin D levels in Jamaican patients with SLE TK McGhie et al.
2
concentrations are related to disease activity of patients with SLE as measured by the BILAG index at the University Hospital of the West Indies, Jamaica.
This study received ethics approval from the University Hospital of the West Indies/University of the West Indies/Faculty of Medical Sciences Ethics Committee. Written informed consent was obtained from all patients.
Materials and methods Results Patients with SLE attending the rheumatology clinic and inpatients at the University Hospital of the West Indies, Jamaica, during a six-month (January to June 2011) period were reviewed. All patients met the 1997 revised American College of Rheumatology criteria for the classification of SLE. Pregnant patients were excluded. The patient charts were reviewed and data recorded including demographic details of age, gender and ethnic group. Additional data recorded included the duration of disease, drug history with particular reference to the use of Hydroxychloroquine (HCQS) and vitamin D supplementation. The clinical features and laboratory investigations covered by the British Isles Lupus Assessment Group (BILAG) index of systemic lupus disease activity were recorded in a standardized way on data forms devised specifically for this purpose. The data were subsequently entered in the BILAG-2004 index using the BLIPS software program and the BILAG score was calculated using version 3 of the BILAG index. BILAG-2004 measures disease activity (scored from A to E) in nine systems: constitutional, mucocutaneous, neuropsychiatric, musculoskeletal, cardiorespiratory, gastrointestinal, ophthalmic, renal and hematologic. An ‘A’ flare was recorded when a patient recorded an A score in any of the eight organs/systems. At the time of evaluation, a single serum sample was obtained and the level of 25-OH vitamin D was measured using an enzyme-linked immunoassay (IDS OCTEIA kit). The sample size was calculated using raosoft. com/sample size.html: Given a 5% margin of error, 95% confidence interval, 92 patients-population size (as determined by the Lupus Registry) and 50% response distribution, a sample size of 75 patients was deemed sufficient. Univariate summaries including frequency tables, histograms, means and standard deviations (SDs) were generated as appropriate for the various variables. In addition, bivariate tests of association (Fisher’s exact and Pearson’s chi-squared) as well as t tests, analysis of variance (or its nonparametric analogue Kruskal-Wallis) for the comparison of means were employed.
Seventy-five patients were studied. There were 69 females (92%) and six males. Of these, 61 (81%) were outpatients and 14 (19%) were inpatients. The ages ranged from 12 to 71 years, with a mean age of 41.5 (SD, 14.3) years. The age range was similar for females, with a mean age of 41.8 (SD, 14.5) years. Ages ranged from 20 to 52 years among the males, with a mean age of 38.5 (SD, 12.8) years. The duration of disease for 73 patients was a mean of 9.0 (SD, 8.6) years, and ranged from one to 35 years. However, given the skewed distribution, the median was six years and an interquartile range (IQR) of three to 11 years would more accurately reflect the central tendency and spread of the distribution. Of the 74 patients for whom data were obtained on HCQS use, 25 (33.8%) were on HCQS, 49 (66.2%) patients were not. Serum vitamin D values were available for all 75 patients and the mean (SD) was 30.5 ng/ml (10.3) and ranged from 7.78 to 58.16. Thirty-three (44%) had vitamin D sufficiency with a mean level of 39.45 ng/ml (range, 30.35–58.16). Forty-two (56%) patients had either vitamin D deficiency or insufficiency; 30 (40%) had vitamin D insufficiency with a mean of 26.36 ng/ml (range, 20.26–29.88), and 12 (16%) had vitamin D deficiency with a mean 16.07 ng/ml (range, 7.78–19.90). An analysis of variance used to compare average ages across the three vitamin D subgroups revealed no significant differences (F ¼ 0.66, p ¼ 0.5196). There was also no significant association between vitamin D subgroups and whether patients were taking vitamin D supplements (p value based on Chi-squared test of association ¼ 0.306). Given the significant departures from normality for the duration of disease, in order to compare average duration in years across the three vitamin D subgroups, we used the nonparametric KruskalWallis test, which revealed no significant differences in average duration of disease (p ¼ 0.3521). There was no significant association between vitamin D subgroups and HCQS (p ¼ 0.996, Pearson’s chi-squared test). Looking at the values for the vitamin D levels; among individuals not on
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HCQS, vitamin D levels for the 49 patients was a mean (SD) of 29.73 ng/ml (10.12), range 7.78 to 58.16; among those on HCQS, mean vitamin D levels for the 25 patients was 30.92 ng/ml (9.85) with a range from 18.01 to 49.62. Based on the t test for comparison of means, there was no significant difference in mean vitamin D levels between the two HCQS groups (p ¼ 0.632). Creatinine clearance values were available for 71 patients with a mean of 105.9 ml/min/1.73 m2 (SD, 43.5), and range from 10.81 to 201.07. There was no significant association between creatinine clearance and vitamin D subgroups (p ¼ 0.109 based on Fisher’s exact test). For the disease activity, scores were available for 72 of the 75 patients with a mean (SD) of 13.69 (15.57) and ranged from 0 to 69. The distribution of scores was significantly right-skewed (p ¼ 0.0001). Median (IQR) score was 8 (range, 1 to 24.5). Scatter plots were generated to assess the relationship of disease activity for all patients as well as within subgroups of vitamin D levels. The correlation coefficient for all patients combined was 0.198 (p ¼ 0.095), indicating a somewhat weak negative relationship between the two variables. Among the vitamin D-deficient subgroup, the correlation coefficient was 0.525 (p ¼ 0.079), indicating a moderate negative relationship between the two variables. Among the vitamin D-insufficient subgroup, the correlation coefficient was 0.127 (p ¼ 0.512), indicating a fairly weak negative relationship between the two variables. Among the vitamin D-sufficient subgroup, the correlation coefficient was 0.210 (p ¼ 0.257), indicating a somewhat weak positive relationship between the two variables. Based on these results, the overall negative relationship between the total disease activity score and vitamin D levels is influenced primarily by the relationship seen among the vitamin D-deficient subgroup.
Discussion This is the first Caribbean-based study to evaluate vitamin D in SLE and is of significance because SLE is associated with a worse prognosis in patients of African descent. Also, such patients are at higher risk of vitamin D deficiency because of reduced efficacy of conversion of 7-dehydrocholesterol to vitamin D by UVB light cutaneously in darker pigmented skin. Greater amounts of the pigment melanin in the epidermal layer result in darker
skin and reduce the skin’s ability to produce vitamin D from sunlight. Reports consistently show lower serum 25(OH) vitamin D levels in people identified as black compared with those identified as white.9 Vitamin D insufficiency is emerging as a clinical problem of global proportions and epidemiology has linked vitamin D status with autoimmune disease susceptibility and severity.7 SLE is a prototypic, systemic, autoimmune disease characterized by the production of immunoglobulin (Ig)G autoantibodies that are specific for self-antigens, such as DNA, nuclear proteins and certain cytoplasmic components, in association with a diverse array of clinical manifestations. The primary pathological findings in patients with SLE are those of inflammation, vasculitis, immune complex deposition, and vasculopathy. The first observation linking vitamin D to the innate immune system was the ability of immune cells such as macrophages to synthesize calcitriol (1,25(OH)2D) from calcidiol (25(OH)D). Vitamin D promotes immune stability in the innate and adoptive immune systems, preventing lapses toward autoimmunity.10–14 The identiEcation of vitamin D receptors on the membranes of immune cells as well as the existence of 1a-hydroxylase in these cells clearly underline the importance of vitamin D for immune regulation.11,13 A number of recent studies have highlighted the association between SLE and vitamin D deficiency.10,15–17 Vitamin D deficiency skews the immunological response toward loss of tolerance. Adding vitamin D in vitro reverses immunological abnormalities characteristic of SLE. Low serum 25-OH vitamin D (25-hydroxycholecalciferol) was highly prevalent in patients with SLE originating from different regions of Europe.16 In another study, SLE patients, especially those with leukopenia or renal involvement, were at high risk of vitamin D deficiency even during the warm season and vitamin D supplementation was recommended.18 In a smaller study in Texas, in 37 patients with SLE, 20% had levels of 25-OH vitamin D that were lower than the normal range for the assay.15 The group of patients with the lowest levels showed disease activity measures, including global assessment scores, that were higher than in those with levels considered normal in the assay (p 0.003). In a cohort from Europe and Israel a signiEcant negative correlation was found between the serum concentration of vitamin D and the standardized values (z scores) of disease activity scores as measured by the SLEDAI-2000 (2K) and Lupus
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ECLAM scales.17 However, previous studies have failed to demonstrate this association.19,20 Although vitamin D is consumed in food, dietary intake alone is often insufficient, supplying only 20% of the body’s requirements. Patients with SLE have multiple risk factors for vitamin D deficiency with the chief one being avoidance of UV exposure. Also, drugs such as glucocorticoids enhance vitamin D metabolism and decrease its absorption. Other factors include HCQS therapy, chronic kidney disease, higher prevalence of obesity and possibly anti-vitamin D antibodies that may clear vitamin D from the serum.19,21,22 HCQS may lower the conversion of 25(OH)-vitamin D to 1,25(OH)2-vitamin D.19 The Jamaican population is at significant risk because of the predominantly darker skin pigmentation.23 In this study, less than half of the patients had vitamin D sufficiency (44%), with 56% patients having either vitamin D deficiency or insufficiency: Forty percent had vitamin D insufficiency and 16% had vitamin D deficiency. No overall significant associations were obtained between important clinical parameters such as renal function. There was no association with HCQS use as suggested by an earlier study.19 The skewness of the disease activity could possibly be explained by the method of sampling, as 81% of the patients were routine follow-ups in the outpatient clinic and had stable or quiescent disease confirmed by their low BILAG scores. Inpatients were evaluated at the time of their hospitalization (19%), and the numbers obtained represent the disparity between those stable and those requiring in-hospital care and thus more active disease. Overall the results of this study are consistent with the widely held hypothesis that low vitamin D levels are associated with higher disease activity. The clinical relevance of this study is its potential to direct further management of patients with SLE with respect to the need for routine evaluation of vitamin D sufficiency and supplementation. Further interventional studies focusing on vitamin D supplementation are warranted in order to determine whether vitamin D has therapeutic value as well. The most important limitation of this study is the fact that vitamin D levels of healthy controls in our population are unknown and the reference ranges used to determine the participants’ status were derived from the latest Endocrine Society Clinical Practice Guideline based on a nonCaribbean population.23 Another limitation of this study is the cross-sectional design, whereby only the disease activity at the time of assessment
is considered. No allowance was made for other factors linked to treatment decisions, such as prior disease activity, current therapy, previous therapy and presence of comorbidities. In conclusion, this study demonstrates that vitamin D deficiency is prevalent among patients with SLE managed at the University Hospital of the West Indies and underlines the observational association between low serum vitamin D levels and disease activity in SLE.
Funding This work was supported by the Lupus Foundation of Jamaica.
Conflict of interest statement The authors have no conflicts of interest to declare.
Acknowledgments The authors are grateful to Gordon Hamilton of Limathon for his benevolence in providing access and assistance with the use of the BILAG BLIPS software. Thanks to the residents and research nurses who helped to identify patients for participation in this study.
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