International Journal of Rheumatic Diseases 2016; 19: 355–361
ORIGINAL ARTICLE
The association between serum vitamin D Level and disease activity in Thai rheumatoid arthritis patients Rattapol PAKCHOTANON, Sumapa CHAIAMNUAY, Pongthorn NARONGROEKNAWIN, and Paijit ASAVATANABODEE Rheumatic Disease Unit, Department of Medicine, Phramongkutklao Hospital, Bangkok, Thailand
Abstract Background: Serum vitamin D level was inversely associated with the risk of developing new onset rheumatoid arthritis (RA) and disease activity, but some conflicting results have been reported. Objective: To examine the serum vitamin D status in Thai RA patients and possible independent factors affecting serum 25 hydroxyvitamin vitamin D (25(OH)D) and the associations of serum 25(OH)D level and the disease activity and functional status in Thai RA patients. Methods: A cross-sectional study was performed in 239 Thai RA patients. The blood levels of 25(OH)D2 and D3 were measured by chemiluminescent immunoassay. Disease activity was assessed according to tender and swollen joint counts, erythrocyte sedimentation rate (ESR), visual analog scale for global patient assessment, Disease Activity Score-28 (DAS-28) and Thai Health Assessment Questionnaire (Thai HAQ). Result: The mean vitamin D level was 28.79 ng/mL. There were no associations between 25(OH)D levels and number of tender and swollen joint counts, DAS-28 score, HAQ score or rheumatoid factor (RF) and/or anticyclic citrulinated peptide (CCP) positivity. After multivariated analysis, Bangkok residents, non-farmer, obesity and non-vitamin D supplementation were the predictors for vitamin D insufficiency in Thai patients with RA. Conclusion: There are no associations of serum 25(OH)D levels with disease activity or functional status in Thai RA patients. The factors associated with vitamin D insufficiency are Bangkok resident, non-farmer, obesity and not taking vitamin D supplementation. Key words: disease activity, obesity, rheumatoid arthritis, Thai, vitamin D.
INTRODUCTION Nowadays vitamin D deficiency and vitamin D insufficiency constitute common problems in many populations worldwide and approximately 10 million people are affected. In Thailand, the prevalence of vitamin D levels below 30 ng/mL affects premenopausal and postmenopausal women to the level of at least 77.8% and 60.2%, respectively.1 Preliminary studies suggest that
Correspondence: Dr Rattapol Pakchotanon, Phramongkutklao Hospital, 4th floor, Rheumatic Disease Unit, 315 Ratchavithi Road, Phayathai, Ratchathevee, Bangkok 10400, Thailand. Email: [email protected]
the prevalence of vitamin D below 20 ng/mL and below 30 ng/mL in rheumatoid arthritis (RA) are approximately 43–52%2,3 and 84%, respectively. The discovery of vitamin D receptors (VDRs) on several immune cells and local vitamin D metabolism within the immune cells are evidence that vitamin D plays an important role in immune regulation which suppresses T cell and B cell proliferation and inhibits the expression of pro-inflammatory cytokines.4 Moreover, vitamin D deficiency may be a risk factor for development and severity of autoimmune rheumatic diseases.5,6 Most studies in many European countries and the United States found that serum vitamin D level was inversely associated with the risk of developing new
© 2013 Asia Pacific League of Associations for Rheumatology and Wiley Publishing Asia Pty Ltd
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onset RA and disease activity, but some conflicting results have been reported.2,3,7–12Therefore, this study aimed to investigate the association between serum 25OH vitamin D (25(OH)D) levels and disease activity and functional status in Thai RA patients and to estimate the prevalence and determinants of vitamin D deficiency and vitamin D insufficiency in Thai RA patients.
MATERIALS AND METHODS Study design This was a cross-sectional study.
Study population The subjects were enrolled from the rheumatic clinic in Phramongkutklao Hospital, Bangkok, Thailand between August 2011 and January 2012. All study subjects had to be over 18 years, provide informed written consent and meet the American College of Rheumatology RA classification criteria 1987. The exclusions were the patients who had overlapping syndrome except secondary Sjogren’s syndrome. We also excluded patients with fibromyalgia, neuropathic pain, polyneuropathy, end-stage renal disease (ESRD) and taking active forms of vitamin D.
Vitamin D status The serum was collected at the time of study enrollment. The serum 25(OH)D was measured using a commercial chemiluminescent immunoassay kit (The LIAISONâ 25 OH Vitamin D 2 and 3 assay, Venus Co., Italy; unit: ng/mL). The definition of vitamin D deficiency, vitamin D insufficiency and normal vitamin D levels are defined as the serum 25(OH)D concentration ≤ 20 ng/mL, between 20–30 ng/mL and ≥ 30 ng/mL, respectively. Serum intact parathyroid hormone (iPTH) was measured using a commercial electrochemiluminescent immunoassay (Roche Co., Basel, Switzerland; unit: pg/mL). The sera were collected into ethylenediaminetetraacetic acid (EDTA) tubes and kept at 20°C until their measurement.
Clinical evaluation Baseline patient characteristics were collected, including age, sex, occupation, workplace, body mass index (BMI), current smoking, current alcoholic drinking, comorbidities and disease duration from the diagnosis of RA. RA-specific treatments were collected, including the current glucocorticoids and disease-modifying antirheumatic drugs (DMARDs). The patients were
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interviewed regarding current use of calcium and vitamin D (calciferol) supplements.
Measures of RA disease activity, severity and functional status The evaluation included subcutaneous nodules (present or absent) and tender and swollen joint counts (0–28). Rheumatoid factor (RF immunoglobulin G [IgG], IU/ mL) was determined by the immunoturbidimetric method and RF > 14 IU/mL was defined as positive. Anti-cyclic citrulinated peptide (anti-CCP IgG, IU/mL) was determined by the enzyme-linked immunosorbent assay (ELISA) method and anti-CCP > 5 IU/mL was defined as positive. Erythrocyte sedimentation rate (ESR, mm/h) was assessed with the Westergren method. Visual analog scale (VAS; 0–10) for global patient assessment (GPA) and Disease Activity Score-28 (DAS28) were collected for measuring the disease activity. Thai Health Assessment Questionnaire (Thai HAQ) was also collected for measuring functional status.
Statistical analysis The data were analyzed statistically using a computer statistical program (SPSS for Windows version 13.0; SPSS Inc., Chicago, IL, USA). Associations between the serum 25(OH)D levels and disease activity and functional status were examined by univariate and multivariate linear regression analysis. The determinant factors affecting serum 25(OH)D levels below 20 and 30 ng/ mL were examined by univariate logistic regression analysis. The significant variables from univariate analysis were further examined by multivariate logistic regression analysis for odds ratios. Chi-square tests were used for categorical data. Differences were considered significant at P < 0.05.
RESULTS Patient characteristics The study included 239 Thai RA patients. These were mostly female (87.4%) with a mean (SD) age of 58.85 (12.56) years and median disease duration of 84 (range 48–132) months. Baseline demographic, health and disease-specific characteristics of study participants are shown in Table 1. The average BMI (SD) was 22.90 (4.15).
RA disease characteristics, disease activity and severity Subcutaneous nodules were infrequently present (28.1%). The positivity of RF and anti-CCP antibodies
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Serum vitamin D and Thai RA patients
Table 1 Baseline demographic, health and disease-specific characteristics of Thai RA patients Number (%) Sociodemographic data Female Age (years) Disease duration (months) Occupation Housewife, retired Officer Self-employed Farmer Income (THB/month) Resident Bangkok Urban Rural Current smoking Current alcohol use RA disease characteristics Subcutaneous nodules RF-positive Anti-CCP-positive RF level (IU/mL) Anti-CCP level (IU/mL) < 4 DMARDS use Biological agents use Prednisolone (mg/week) Tender joints Swollen joints ESR (mm/h) GPA (0–100) HAQ (0–3) DAS-28
Mean (SD)
Median
Percentile 25th
Percentile 75th
209 (87.4) 58.85 (12.56) 112.79 (203.03)
60.00 84.00
51.00 48.00
68.00 132.00
8000.00
0.00
20000.00
136.44 (105.45) 116.22 (137.62)
64.00 74.30
25.70 8.00
209.70 181.00
10.75 (18.78) 3.76 (5.81) 3.03 (4.25) 49.11 (30.15) 28.63 (23.71) 0.8 (0.85) 4.07 (1.48)
0.00 1.00 2.00 45.00 24.00 0.50 3.90
0.00 0.00 0.00 24.00 10.00 0.13 2.83
17.50 5.00 4.00 67.00 44.00 1.31 5.08
110 (49.8) 72 (32.6) 25 (11.3) 14 (6.3) 12567.32 (15659.86) 98 (41.4) 60 (25.3) 79 (33.3) 9 (3.8) 5 (2.1) 66 (28.1) 137 (74.1) 62 (71.3)
212 (88.7) 14 (5.9)
Anti-CCP, anti-cyclic citrulinated peptide; DAS-28, Disease Activity Score-28; ESR, erythrocyte sedimentation rate; GPA, Global Health Assessment; HAQ, Health Assessment Questionnaire; RF, rheumatoid factor; SD, standard deviation.
was 74.1% and 71.3% respectively. Both anti-CCP antibodies and RF were positive in 57.1% of patients and only 26.2% of patient had negative results in both serologies. Eighty-eight percent of patients were taking less than four DMARDs regularly and 5.9% of patients were on biological DMARDs. The average dose of prednisolone was 10.75 mg per week. The mean (SD) tender joint and swollen joint counts were 3.76 (5.81) and 3.03 (4.25), respectively. The mean (SD) plasma level of ESR was 49.11 (30.15). Most patients (41.7%) had moderate disease activity and the mean (SD) DAS-28 score was 4.07 (1.48). The mean (SD) HAQ score was 0.80 (0.85).
Prevalence of vitamin D deficiency, insufficiency and adequacy The mean (SD) vitamin D levels was 28.79 (11.3) ng/ mL. The proportion of these patients with vitamin D
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deficiency (≤ 20 ng/mL), vitamin D insufficiency (20– 30 ng/mL) and normal vitamin D levels (≥ 30 ng/mL) were 13.4%, 51% and 35.6%, respectively. The prevalence of vitamin D levels below 30 ng/mL in Bangkok residents, urban and rural residents were 74.5%, 66.7% and 50.6%, respectively (data not shown). The median dose of vitamin D (calciferol) intake was 5600 IU (range 2800–5600) per week (data not shown). The average weekly vitamin D (calciferol) intake in patients with vitamin D deficiency, vitamin D insufficiency and normal vitamin D levels were 4675, 5269.6 and 9285.7 IU per week, respectively. Twenty-five percent of patients were not using any vitamin D supplement. Most patients (46.8%) used 5600 IU of vitamin D (calciferol) supplement per week. Only 15.6% of patients use over 20 000 IU of vitamin D (calciferol) supplement per week (Table 2). Most patients took elemental
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Number (%)
Mean (SD)
Vitamin D level (ng/mL) 28.79 (11.13) ≤ 20 32 (13.4) 20–30 122 (51.0) ≥ 30 85 (35.6) Vitamin D supplementation (IUs/week) No 58 (24.5) 2800 25 (10.5) 5600 111 (46.8) 8400 6 (2.5) 20 000 27 (11.4) 22 800 5 (2.1) 25 600 2 (0.8) 40 000 3 (1.3)
Vitamin D supplementation (%)
Weekly vitamin D supplementation (IU/week)
62.5 72.9 84.7
4675.00 5269.42 9285.71
Table 2 Vitamin D status (vitamin D deficiency, insufficiency and normal level) and vitamin D (calciferol) supplementation in Thai RA patients
SD, standard deviation.
calcium supplements of 600 mg per day. There were 6% of patients who had clinical osteoporotic fractures. Serum 25(OH)D levels and parathyroid hormone (PTH) levels were inversely correlated (b = 0.147, P = 0.024). In contrast, the study did not show the cutoff values of serum 25(OH)D levels to predict the significant change of serum PTH by using the area under the receiver operating curve (AUROC) approach. The AUROC was estimated to be 0.54 (95% CI: 0.42–0.62).
The associations between the serum 25(OH)D levels and disease activity and functional status in patients with RA There was no association between serum 25(OH)D levels with DAS-28. There were no associations between the serum 25(OH)D levels and number of tender joint counts and swollen joint counts, GPA, Thai HAQ, RF levels, anti-CCP levels or positivity of RF and/or antiCCP (Table 3).
The determinant factors affecting serum 25 (OH)D levels in patients with RA In univariate analyses, the study found that female, non-farmer, Bangkok residents, obesity (BMI ≥ 25 Kg/ mm2) and non-vitamin D supplementation were associated with serum 25(OH)D levels below 30 ng/mL (P = 0.33, 0.007, 0.008, 0.013 and 0.019, respectively) (Table 4). After multivariate adjustments for sex, occupation, residents, BMI and vitamin D supplementation, the Bangkok residents, non-farmer, obesity and non-vitamin D supplementation were the determinant
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Table 3 Univariate associations of serum 25-OH vitamin D level with measures of disease activity or severity and functional status of patients with RA Measures of disease Subcutaneous nodules RF-positive Anti-CCP-positive RF level Anti-CCP level Tender joints Swollen joints GPA (0–100) HAQ (0–3) DAS-28
b 0.014 0.033 0.037 0.208 0.310 0.018 0.057 0.140 0.003 0.003
t 0.841 2.396 1.711 0.055 0.308 0.414 1.785 0.974 0.628 0.345
P 0.359 0.122 0.191 0.956 0.759 0.680 0.076 0.331 0.534 0.731
Anti-CCP, anti-cyclic citrulinated peptide; b, coefficient of the regression model; DAS-28, Disease Activity Score-28; ESR, erythrocyte sedimentation rate; GPA, Global Health Assessment; HAQ, Health Assessment Questionnaire; RF, rheumatoid factor.
factors (OR 2.03; 95% CI: 1.07–3.84, OR 4.54; 95% CI: 1.12–18.48, OR 2.09; 95% CI: 1.04–4.17, OR 2.54; 95% CI: 1.17–5.70, respectively) for serum 25 (OH)D levels below 30 ng/mL in patients with RA (Table 5). The study found no determinant factors of vitamin D levels below 20 ng/mL due to the small number of patients (data not shown). More than 60% of patients taking vitamin D (calciferol) at least 20 000 IU per week had serum vitamin D levels ≥ 30 ng/mL, while only 20% of patients not taking vitamin D (calciferol) had serum vitamin D levels ≥ 30 ng/mL (Table 6).
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Serum vitamin D and Thai RA patients
Table 4 The determinant factors affecting serum 25-OH vitamin D levels below 30 ng/mL in patients with RA by univariate logistic regression analysis
Table 6 Vitamin D (calciferol) supplementation and vitamin D status (vitamin D deficiency, insufficiency and normal levels) in Thai RA patients.
The determinant factors
Weekly vitamin D supplementation (IU/week)
Vitamin D deficiency (≤ 20 ng/ mL) n = 32 (%)
Vitamin D insufficiency (20–30 ng/ mL) n = 122 (%)
Normal vitamin D level (≥ 30 ng/ mL) n = 85 (%)
No supplementation 2800 5600 8400 20 000 22 800 25 600 40 000
12 (20.7)
33 (56.9)
13 (22.4)
4 (16.0) 14 (12.6) 0 (0) 1 (3.7) 0 (0) 0 (0) 1 (33.3)
16 (64) 58 (52.3) 3 (50) 9 (33.3) 1 (20.0) 0 (0) 1 (33.3)
5 (20) 39 (35.1) 3 (50) 17 (63)* 4 (80)* 2 (100) 1 (33.3)
Female Age (years) Duration of disease (months) Non-farmers Income ≥ 12.993 THB/month (Thai GDP) Bangkok residents Obesity (BMI ≥ 25 kg/m2) Weekly cumulative dose of prednisolone (mg) Non-vitamin D (calciferol) supplementation
P
OR
95% CI
0.033 0.281 0.506
2.39 1.00 1.01
1.07–5.02 0.97–1.01 1.0–1.01
0.007 0.094
5.22 1.73
1.58–17.27 0.91–3.28
0.008 0.013
2.15 2.24
1.22–3.79 1.19–4.23
0.831
1.0
0.98–1.01
0.019
2.28
1.15–4.52
BMI, body mass index, CI, confidence interval; OR, odds ratio; THB, Thai Baht; Thai GDP, Thai gross domestic product (GDP) in year 2011 (reference: Office of the National Economic and Social Development Board).
Table 5 The independent determinant factors affecting serum 25-OH vitamin D levels below 30 ng/ml in patients with RA by multivariate logistic regression analysis Independent determinant factors Bangkok residents Non-farmers Obesity (BMI ≥ 25 Kg/m2) Non-vitamin D (calciferol) supplementation
P
Adjusted OR
95% CI
0.030 0.034 0.038 0.019
2.03 4.54 2.09 2.54
1.04–4.17 1.12–18.48 1.04–4.17 1.17–5.70
Sex, occupation, residents, BMI and vitamin D supplementation were adjusted for the multivariate analysis. BMI, body mass index; CI, confidence interval; OR, odds ratio.
DISCUSSION Although Thai RA patients have a higher year-round exposure to sunlight, the current study shows that vitamin D deficiency and insufficiency are still common in Thai RA patients. In order to compare the current study result with previous research, the definition of vitamin D levels from previous research is then required in the current study. This study demonstrated lower rates of vitamin D deficiency and vitamin D insufficiency in Thai RA patients than the results of RA patients in the United States and European countries. These studies found the prevalence of vitamin D deficiency and vitamin D insufficiency were 43–52% and 84%, respec-
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*P ≤ 0.001 Fisher exact test compared with no vitamin D supplementation.
tively.2,3 The important factor that may account for the difference is the latitude which influences the zenith angle of the sun. Thailand is closer to the equator than these countries. Cutaneous vitamin D syntheses can occur all year round. Conversely, cutaneous vitamin D synthesis is markedly reduced during November through February in countries located above 37° latitude because of the decreasing number of UVB photons reaching the earth’s surface.13 Soontrapa and colleagues found the prevalence of vitamin D levels below 35 ng/mL in normal Thai postmenopausal women was 60.2% and in elderly women who live in urban or rural areas were 65.1% and 17.4%, respectively.1,14,15 In contrast, most participants in the current study were middle-aged or elderly women who demonstrate higher prevalence of vitamin D levels below 30 ng/mL in urban or rural areas. There are some factors that may account for the differences observed between the two populations. First, Thai RA patients mostly had moderate disease activity and might spend less time outdoors. Second, most of the RA patients took prednisolone, and anti-malarial agents (chloroquine or hydroxychloroquine) which increases the metabolism of vitamin D and anti-malarial agents’ effects on cutaneous vitamin D synthesis.16,17 Finally, poor nutritional status of RA patients may affect vitamin D intake and absorption. This study did not find an association between disease activity and serum vitamin D level. Previous studies in the United States and European countries found an inverse relationship between serum vitamin D levels
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and disease activity and functional status in RA patients.2,3,8,9 In contrast to the current study population who were exclusively Thai, this may be caused by the difference in genetic predisposition factors. Previous studies found the association between vitamin D receptor gene (VDR) polymorphisms and risk of RA susceptibility and severity, especially in RA patients in the United States and European countries.11 Although this study did not show the determinant factors of vitamin D deficiency in Thai RA patients, it found independent factors which were associated with vitamin D insufficiency were Bangkok residents, nonfarmer, obesity and not taking vitamin D (calciferol) supplementation. The effect of Bangkok residents and being a non-farmer may be indirectly explained by less sun exposure in comparison with the residents in rural areas and farmers.1,14,15 In addition, the current study also found an association between obesity and vitamin D insufficiency. This association has also been reported by Rossini et al.3 This can be explained by obesity decreasing bioavailability of vitamin D from any sources because of its deposition in body fat compartments.18 In addition, this study found most patients taking vitamin D (calciferol) supplementation at least 20 000 IU per week have normal serum vitamin D levels. Alternatively, some patients had vitamin D inadequacy although they were taking vitamin D supplementation at least 20 000 IU per week. According to US recommendations for vitamin D (calciferol) supplementation, this should be at higher dosages (at least 3000–6000 IUs per day) for patients at risk or taking prednisolone to maintain normal levels of vitamin D.19 Because Thai RA patients have lower incidences of vitamin D deficiency and more adequate sun exposure, which is a better source of vitamin D, Thai patients may need the lower limited amount of vitamin D supplementation than Europeans or Americans to maintain normal vitamin D levels.20 There are many limitations to the current study that may affect the different results between this study and previous research. First, this study did not have normal healthy controls so the differences in prevalence of vitamin D levels below 20 or 30 ng/mL between RA patients and a Thai normal population cannot be demonstrated. Second, the lack of an association between serum vitamin D levels with disease activity or functional status in this study may be caused by a lower number of patients and the lower rates of vitamin D deficiency compared with previous studies.2,3 In addition, RA disease activity in this study was influenced by several confounding factors, such as current DMARDs
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and steroid use and longer disease duration. These confounders might obscure the effects of vitamin D. In contrast, a previous study by Patel et al.21 in which DMARDs therapy was controlled, their study showed the association between vitamin D levels with early RA disease activity. Furthermore, in the current study, the patients who took vitamin D supplements were not separated from those who did not take vitamin D supplements. This may confound the association between RA activity and serum vitamin D levels. Finally, the study design was a cross-sectional study which may not be suitable for demonstrating the effects of vitamin D in controlling disease activity. Case control or prospective studies may be suitable for answering this question, as well as the study by Andjelkovic et al. which organized an open label trial on active RA patients. Their result showed a positive effect of vitamin D adjunctive therapy with DMARDs in controlling disease activity in RA.9 Further investigations are needed to reveal more information about vitamin D deficiency or insufficiency in RA patients.
CONCLUSION Vitamin D deficiency and vitamin D insufficiency are common in Thai RA patients. There is no association between serum 25(OH)D levels with disease activity or functional status in Thai RA patients. The factors associated with vitamin D insufficiency are Bangkok residency, non-farmer, obesity and not taking vitamin D supplementation. In Thai RA patients, adequate vitamin D (calciferol) supplementation is crucial to maintain normal serum vitamin D levels in addition to sun exposure and a vitamin D-rich diet intake.
ACKNOWLEDGEMENTS The authors would like to thank Ms Dollapas Punpanich for her help with statistical analysis. This study was supported by the grant from Thai rheumatism association.
DISCLOSURE None.
REFERENCES 1 Soontrapa S, Soontrapa S, Chailurkit LO (2009) Hypovitaminosis D in Thailand. J Med Assoc Thai 92 (Suppl 5), S26–9.
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2 Kerr GS, Sabahi I, Richards JS et al. (2011) Prevalence of vitamin D insufficiency/deficiency in rheumatoid arthritis and associations with disease severity and activity. J Rheumatol 38 (1), 53–9. 3 Rossini M, Maddali Bongi S, La Montagna G et al. (2010) Vitamin D deficiency in rheumatoid arthritis: prevalence, determinants and associations with disease activity and disability. Arthritis Res Ther 12 (6), R216. 4 Baeke F, Takiishi T, Korf H, Gysemans C, Mathieu C (2010) Vitamin D: modulator of the immune system. Curr Opin Pharmacol 10 (4), 482–96. 5 Schwalfenberg GK (2011) A review of the critical role of vitamin D in the functioning of the immune system and the clinical implications of vitamin D deficiency. Mol Nutr Food Res 55 (1), 96–108. 6 Adorini L, Penna G (2008) Control of autoimmune diseases by the vitamin D endocrine system. Nat Clin Pract Rheumatol 4 (8), 404–12. 7 Sokka T (2005) Rheumatoid arthritis databases in Finland. Clin Exp Rheumatol 23 (5 Suppl 39), S201–4. 8 Cutolo M, Otsa K, Laas K et al. (2006) Circannual vitamin D serum levels and disease activity in rheumatoid arthritis: Northern versus Southern Europe. Clin Exp Rheumatol 24 (6), 702–4. 9 Andjelkovic Z, Vojinovic J, Pejnovic N et al. (1999) Disease modifying and immunomodulatory effects of high dose 1 alpha (OH) D3 in rheumatoid arthritis patients. Clin Exp Rheumatol 17 (4), 453–6. 10 Craig SM, Yu F, Curtis JR et al. (2010) Vitamin D status and its associations with disease activity and severity in African Americans with recent-onset rheumatoid arthritis. J Rheumatol 37 (2), 275–81. 11 Lee YH, Bae SC, Choi SJ, Ji JD, Song GG (2011) Associations between vitamin D receptor polymorphisms and susceptibility to rheumatoid arthritis and systemic lupus erythematosus: a meta-analysis. Mol Biol Rep 38 (6), 3643–51.
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12 Baker JF, Baker DG, Toedter G, Shults J, Von Feldt JM, Leonard MB (2012) Associations between vitamin D, disease activity, and clinical response to therapy in rheumatoid arthritis. Clin Exp Rheumatol 30 (5), 658–64. 13 Holick MF (2003) Vitamin D: a millenium perspective. J Cell Biochem 88 (2), 296–307. 14 Soontrapa S, Pongchaiyakul C, Somboonporn C, Somboonporn W, Chailurkit LO. (2001) Prevalence of hypovitaminosis D in elderly women living in urban area of Khon Kaen province, Thailand. J Med Assoc Thai 84 (Suppl 2), S534–41. 15 Soontrapa S, Boonsiri P, Khampitak T (2009) The prevalence of hypovitaminosis D in the elderly women living in the rural area of Khon Kaen Province, Thailand. J Med Assoc Thai 92 (Suppl 5), S21–5. 16 Need AG, O’Loughlin PD, Morris HA, Coates PS, Horowitz M, Nordin BE (2008) Vitamin D metabolites and calcium absorption in severe vitamin D deficiency. J Bone Miner Res 23 (11), 1859–63. 17 Zhou C, Assem M, Tay JC et al. (2006) Steroid and xenobiotic receptor and vitamin D receptor crosstalk mediates CYP24 expression and drug-induced osteomalacia. J Clin Invest 116 (6), 1703–12. 18 Wortsman J, Matsuoka LY, Chen TC, Lu Z, Holick MF (2000) Decreased bioavailability of vitamin D in obesity. Am J Clin Nutr 72 (3), 690–3. 19 Holick MF, Binkley NC, Bischoff-Ferrari HA et al. (2011) Evaluation, treatment, and prevention of vitamin D deficiency: an Endocrine Society clinical practice guideline. J Clin Endocrinol Metab 96 (7), 1911–30. 20 Holick MF (2004) Sunlight and vitamin D for bone health and prevention of autoimmune diseases, cancers, and cardiovascular disease. Am J Clin Nutr 80 (Suppl 6), 1678S–88S. 21 Patel S, Farragher T, Berry J, Bunn D, Silman A, Symmons D (2007) Association between serum vitamin D metabolite levels and disease activity in patients with early inflammatory polyarthritis. Arthritis Rheum 56 (7), 2143–9.
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ORIGINAL ARTICLE
The association between serum vitamin D Level and disease activity in Thai rheumatoid arthritis patients Rattapol PAKCHOTANON, Sumapa CHAIAMNUAY, Pongthorn NARONGROEKNAWIN, and Paijit ASAVATANABODEE Rheumatic Disease Unit, Department of Medicine, Phramongkutklao Hospital, Bangkok, Thailand
Abstract Background: Serum vitamin D level was inversely associated with the risk of developing new onset rheumatoid arthritis (RA) and disease activity, but some conflicting results have been reported. Objective: To examine the serum vitamin D status in Thai RA patients and possible independent factors affecting serum 25 hydroxyvitamin vitamin D (25(OH)D) and the associations of serum 25(OH)D level and the disease activity and functional status in Thai RA patients. Methods: A cross-sectional study was performed in 239 Thai RA patients. The blood levels of 25(OH)D2 and D3 were measured by chemiluminescent immunoassay. Disease activity was assessed according to tender and swollen joint counts, erythrocyte sedimentation rate (ESR), visual analog scale for global patient assessment, Disease Activity Score-28 (DAS-28) and Thai Health Assessment Questionnaire (Thai HAQ). Result: The mean vitamin D level was 28.79 ng/mL. There were no associations between 25(OH)D levels and number of tender and swollen joint counts, DAS-28 score, HAQ score or rheumatoid factor (RF) and/or anticyclic citrulinated peptide (CCP) positivity. After multivariated analysis, Bangkok residents, non-farmer, obesity and non-vitamin D supplementation were the predictors for vitamin D insufficiency in Thai patients with RA. Conclusion: There are no associations of serum 25(OH)D levels with disease activity or functional status in Thai RA patients. The factors associated with vitamin D insufficiency are Bangkok resident, non-farmer, obesity and not taking vitamin D supplementation. Key words: disease activity, obesity, rheumatoid arthritis, Thai, vitamin D.
INTRODUCTION Nowadays vitamin D deficiency and vitamin D insufficiency constitute common problems in many populations worldwide and approximately 10 million people are affected. In Thailand, the prevalence of vitamin D levels below 30 ng/mL affects premenopausal and postmenopausal women to the level of at least 77.8% and 60.2%, respectively.1 Preliminary studies suggest that
Correspondence: Dr Rattapol Pakchotanon, Phramongkutklao Hospital, 4th floor, Rheumatic Disease Unit, 315 Ratchavithi Road, Phayathai, Ratchathevee, Bangkok 10400, Thailand. Email: [email protected]
the prevalence of vitamin D below 20 ng/mL and below 30 ng/mL in rheumatoid arthritis (RA) are approximately 43–52%2,3 and 84%, respectively. The discovery of vitamin D receptors (VDRs) on several immune cells and local vitamin D metabolism within the immune cells are evidence that vitamin D plays an important role in immune regulation which suppresses T cell and B cell proliferation and inhibits the expression of pro-inflammatory cytokines.4 Moreover, vitamin D deficiency may be a risk factor for development and severity of autoimmune rheumatic diseases.5,6 Most studies in many European countries and the United States found that serum vitamin D level was inversely associated with the risk of developing new
© 2013 Asia Pacific League of Associations for Rheumatology and Wiley Publishing Asia Pty Ltd
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onset RA and disease activity, but some conflicting results have been reported.2,3,7–12Therefore, this study aimed to investigate the association between serum 25OH vitamin D (25(OH)D) levels and disease activity and functional status in Thai RA patients and to estimate the prevalence and determinants of vitamin D deficiency and vitamin D insufficiency in Thai RA patients.
MATERIALS AND METHODS Study design This was a cross-sectional study.
Study population The subjects were enrolled from the rheumatic clinic in Phramongkutklao Hospital, Bangkok, Thailand between August 2011 and January 2012. All study subjects had to be over 18 years, provide informed written consent and meet the American College of Rheumatology RA classification criteria 1987. The exclusions were the patients who had overlapping syndrome except secondary Sjogren’s syndrome. We also excluded patients with fibromyalgia, neuropathic pain, polyneuropathy, end-stage renal disease (ESRD) and taking active forms of vitamin D.
Vitamin D status The serum was collected at the time of study enrollment. The serum 25(OH)D was measured using a commercial chemiluminescent immunoassay kit (The LIAISONâ 25 OH Vitamin D 2 and 3 assay, Venus Co., Italy; unit: ng/mL). The definition of vitamin D deficiency, vitamin D insufficiency and normal vitamin D levels are defined as the serum 25(OH)D concentration ≤ 20 ng/mL, between 20–30 ng/mL and ≥ 30 ng/mL, respectively. Serum intact parathyroid hormone (iPTH) was measured using a commercial electrochemiluminescent immunoassay (Roche Co., Basel, Switzerland; unit: pg/mL). The sera were collected into ethylenediaminetetraacetic acid (EDTA) tubes and kept at 20°C until their measurement.
Clinical evaluation Baseline patient characteristics were collected, including age, sex, occupation, workplace, body mass index (BMI), current smoking, current alcoholic drinking, comorbidities and disease duration from the diagnosis of RA. RA-specific treatments were collected, including the current glucocorticoids and disease-modifying antirheumatic drugs (DMARDs). The patients were
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interviewed regarding current use of calcium and vitamin D (calciferol) supplements.
Measures of RA disease activity, severity and functional status The evaluation included subcutaneous nodules (present or absent) and tender and swollen joint counts (0–28). Rheumatoid factor (RF immunoglobulin G [IgG], IU/ mL) was determined by the immunoturbidimetric method and RF > 14 IU/mL was defined as positive. Anti-cyclic citrulinated peptide (anti-CCP IgG, IU/mL) was determined by the enzyme-linked immunosorbent assay (ELISA) method and anti-CCP > 5 IU/mL was defined as positive. Erythrocyte sedimentation rate (ESR, mm/h) was assessed with the Westergren method. Visual analog scale (VAS; 0–10) for global patient assessment (GPA) and Disease Activity Score-28 (DAS28) were collected for measuring the disease activity. Thai Health Assessment Questionnaire (Thai HAQ) was also collected for measuring functional status.
Statistical analysis The data were analyzed statistically using a computer statistical program (SPSS for Windows version 13.0; SPSS Inc., Chicago, IL, USA). Associations between the serum 25(OH)D levels and disease activity and functional status were examined by univariate and multivariate linear regression analysis. The determinant factors affecting serum 25(OH)D levels below 20 and 30 ng/ mL were examined by univariate logistic regression analysis. The significant variables from univariate analysis were further examined by multivariate logistic regression analysis for odds ratios. Chi-square tests were used for categorical data. Differences were considered significant at P < 0.05.
RESULTS Patient characteristics The study included 239 Thai RA patients. These were mostly female (87.4%) with a mean (SD) age of 58.85 (12.56) years and median disease duration of 84 (range 48–132) months. Baseline demographic, health and disease-specific characteristics of study participants are shown in Table 1. The average BMI (SD) was 22.90 (4.15).
RA disease characteristics, disease activity and severity Subcutaneous nodules were infrequently present (28.1%). The positivity of RF and anti-CCP antibodies
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Table 1 Baseline demographic, health and disease-specific characteristics of Thai RA patients Number (%) Sociodemographic data Female Age (years) Disease duration (months) Occupation Housewife, retired Officer Self-employed Farmer Income (THB/month) Resident Bangkok Urban Rural Current smoking Current alcohol use RA disease characteristics Subcutaneous nodules RF-positive Anti-CCP-positive RF level (IU/mL) Anti-CCP level (IU/mL) < 4 DMARDS use Biological agents use Prednisolone (mg/week) Tender joints Swollen joints ESR (mm/h) GPA (0–100) HAQ (0–3) DAS-28
Mean (SD)
Median
Percentile 25th
Percentile 75th
209 (87.4) 58.85 (12.56) 112.79 (203.03)
60.00 84.00
51.00 48.00
68.00 132.00
8000.00
0.00
20000.00
136.44 (105.45) 116.22 (137.62)
64.00 74.30
25.70 8.00
209.70 181.00
10.75 (18.78) 3.76 (5.81) 3.03 (4.25) 49.11 (30.15) 28.63 (23.71) 0.8 (0.85) 4.07 (1.48)
0.00 1.00 2.00 45.00 24.00 0.50 3.90
0.00 0.00 0.00 24.00 10.00 0.13 2.83
17.50 5.00 4.00 67.00 44.00 1.31 5.08
110 (49.8) 72 (32.6) 25 (11.3) 14 (6.3) 12567.32 (15659.86) 98 (41.4) 60 (25.3) 79 (33.3) 9 (3.8) 5 (2.1) 66 (28.1) 137 (74.1) 62 (71.3)
212 (88.7) 14 (5.9)
Anti-CCP, anti-cyclic citrulinated peptide; DAS-28, Disease Activity Score-28; ESR, erythrocyte sedimentation rate; GPA, Global Health Assessment; HAQ, Health Assessment Questionnaire; RF, rheumatoid factor; SD, standard deviation.
was 74.1% and 71.3% respectively. Both anti-CCP antibodies and RF were positive in 57.1% of patients and only 26.2% of patient had negative results in both serologies. Eighty-eight percent of patients were taking less than four DMARDs regularly and 5.9% of patients were on biological DMARDs. The average dose of prednisolone was 10.75 mg per week. The mean (SD) tender joint and swollen joint counts were 3.76 (5.81) and 3.03 (4.25), respectively. The mean (SD) plasma level of ESR was 49.11 (30.15). Most patients (41.7%) had moderate disease activity and the mean (SD) DAS-28 score was 4.07 (1.48). The mean (SD) HAQ score was 0.80 (0.85).
Prevalence of vitamin D deficiency, insufficiency and adequacy The mean (SD) vitamin D levels was 28.79 (11.3) ng/ mL. The proportion of these patients with vitamin D
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deficiency (≤ 20 ng/mL), vitamin D insufficiency (20– 30 ng/mL) and normal vitamin D levels (≥ 30 ng/mL) were 13.4%, 51% and 35.6%, respectively. The prevalence of vitamin D levels below 30 ng/mL in Bangkok residents, urban and rural residents were 74.5%, 66.7% and 50.6%, respectively (data not shown). The median dose of vitamin D (calciferol) intake was 5600 IU (range 2800–5600) per week (data not shown). The average weekly vitamin D (calciferol) intake in patients with vitamin D deficiency, vitamin D insufficiency and normal vitamin D levels were 4675, 5269.6 and 9285.7 IU per week, respectively. Twenty-five percent of patients were not using any vitamin D supplement. Most patients (46.8%) used 5600 IU of vitamin D (calciferol) supplement per week. Only 15.6% of patients use over 20 000 IU of vitamin D (calciferol) supplement per week (Table 2). Most patients took elemental
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Number (%)
Mean (SD)
Vitamin D level (ng/mL) 28.79 (11.13) ≤ 20 32 (13.4) 20–30 122 (51.0) ≥ 30 85 (35.6) Vitamin D supplementation (IUs/week) No 58 (24.5) 2800 25 (10.5) 5600 111 (46.8) 8400 6 (2.5) 20 000 27 (11.4) 22 800 5 (2.1) 25 600 2 (0.8) 40 000 3 (1.3)
Vitamin D supplementation (%)
Weekly vitamin D supplementation (IU/week)
62.5 72.9 84.7
4675.00 5269.42 9285.71
Table 2 Vitamin D status (vitamin D deficiency, insufficiency and normal level) and vitamin D (calciferol) supplementation in Thai RA patients
SD, standard deviation.
calcium supplements of 600 mg per day. There were 6% of patients who had clinical osteoporotic fractures. Serum 25(OH)D levels and parathyroid hormone (PTH) levels were inversely correlated (b = 0.147, P = 0.024). In contrast, the study did not show the cutoff values of serum 25(OH)D levels to predict the significant change of serum PTH by using the area under the receiver operating curve (AUROC) approach. The AUROC was estimated to be 0.54 (95% CI: 0.42–0.62).
The associations between the serum 25(OH)D levels and disease activity and functional status in patients with RA There was no association between serum 25(OH)D levels with DAS-28. There were no associations between the serum 25(OH)D levels and number of tender joint counts and swollen joint counts, GPA, Thai HAQ, RF levels, anti-CCP levels or positivity of RF and/or antiCCP (Table 3).
The determinant factors affecting serum 25 (OH)D levels in patients with RA In univariate analyses, the study found that female, non-farmer, Bangkok residents, obesity (BMI ≥ 25 Kg/ mm2) and non-vitamin D supplementation were associated with serum 25(OH)D levels below 30 ng/mL (P = 0.33, 0.007, 0.008, 0.013 and 0.019, respectively) (Table 4). After multivariate adjustments for sex, occupation, residents, BMI and vitamin D supplementation, the Bangkok residents, non-farmer, obesity and non-vitamin D supplementation were the determinant
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Table 3 Univariate associations of serum 25-OH vitamin D level with measures of disease activity or severity and functional status of patients with RA Measures of disease Subcutaneous nodules RF-positive Anti-CCP-positive RF level Anti-CCP level Tender joints Swollen joints GPA (0–100) HAQ (0–3) DAS-28
b 0.014 0.033 0.037 0.208 0.310 0.018 0.057 0.140 0.003 0.003
t 0.841 2.396 1.711 0.055 0.308 0.414 1.785 0.974 0.628 0.345
P 0.359 0.122 0.191 0.956 0.759 0.680 0.076 0.331 0.534 0.731
Anti-CCP, anti-cyclic citrulinated peptide; b, coefficient of the regression model; DAS-28, Disease Activity Score-28; ESR, erythrocyte sedimentation rate; GPA, Global Health Assessment; HAQ, Health Assessment Questionnaire; RF, rheumatoid factor.
factors (OR 2.03; 95% CI: 1.07–3.84, OR 4.54; 95% CI: 1.12–18.48, OR 2.09; 95% CI: 1.04–4.17, OR 2.54; 95% CI: 1.17–5.70, respectively) for serum 25 (OH)D levels below 30 ng/mL in patients with RA (Table 5). The study found no determinant factors of vitamin D levels below 20 ng/mL due to the small number of patients (data not shown). More than 60% of patients taking vitamin D (calciferol) at least 20 000 IU per week had serum vitamin D levels ≥ 30 ng/mL, while only 20% of patients not taking vitamin D (calciferol) had serum vitamin D levels ≥ 30 ng/mL (Table 6).
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Table 4 The determinant factors affecting serum 25-OH vitamin D levels below 30 ng/mL in patients with RA by univariate logistic regression analysis
Table 6 Vitamin D (calciferol) supplementation and vitamin D status (vitamin D deficiency, insufficiency and normal levels) in Thai RA patients.
The determinant factors
Weekly vitamin D supplementation (IU/week)
Vitamin D deficiency (≤ 20 ng/ mL) n = 32 (%)
Vitamin D insufficiency (20–30 ng/ mL) n = 122 (%)
Normal vitamin D level (≥ 30 ng/ mL) n = 85 (%)
No supplementation 2800 5600 8400 20 000 22 800 25 600 40 000
12 (20.7)
33 (56.9)
13 (22.4)
4 (16.0) 14 (12.6) 0 (0) 1 (3.7) 0 (0) 0 (0) 1 (33.3)
16 (64) 58 (52.3) 3 (50) 9 (33.3) 1 (20.0) 0 (0) 1 (33.3)
5 (20) 39 (35.1) 3 (50) 17 (63)* 4 (80)* 2 (100) 1 (33.3)
Female Age (years) Duration of disease (months) Non-farmers Income ≥ 12.993 THB/month (Thai GDP) Bangkok residents Obesity (BMI ≥ 25 kg/m2) Weekly cumulative dose of prednisolone (mg) Non-vitamin D (calciferol) supplementation
P
OR
95% CI
0.033 0.281 0.506
2.39 1.00 1.01
1.07–5.02 0.97–1.01 1.0–1.01
0.007 0.094
5.22 1.73
1.58–17.27 0.91–3.28
0.008 0.013
2.15 2.24
1.22–3.79 1.19–4.23
0.831
1.0
0.98–1.01
0.019
2.28
1.15–4.52
BMI, body mass index, CI, confidence interval; OR, odds ratio; THB, Thai Baht; Thai GDP, Thai gross domestic product (GDP) in year 2011 (reference: Office of the National Economic and Social Development Board).
Table 5 The independent determinant factors affecting serum 25-OH vitamin D levels below 30 ng/ml in patients with RA by multivariate logistic regression analysis Independent determinant factors Bangkok residents Non-farmers Obesity (BMI ≥ 25 Kg/m2) Non-vitamin D (calciferol) supplementation
P
Adjusted OR
95% CI
0.030 0.034 0.038 0.019
2.03 4.54 2.09 2.54
1.04–4.17 1.12–18.48 1.04–4.17 1.17–5.70
Sex, occupation, residents, BMI and vitamin D supplementation were adjusted for the multivariate analysis. BMI, body mass index; CI, confidence interval; OR, odds ratio.
DISCUSSION Although Thai RA patients have a higher year-round exposure to sunlight, the current study shows that vitamin D deficiency and insufficiency are still common in Thai RA patients. In order to compare the current study result with previous research, the definition of vitamin D levels from previous research is then required in the current study. This study demonstrated lower rates of vitamin D deficiency and vitamin D insufficiency in Thai RA patients than the results of RA patients in the United States and European countries. These studies found the prevalence of vitamin D deficiency and vitamin D insufficiency were 43–52% and 84%, respec-
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*P ≤ 0.001 Fisher exact test compared with no vitamin D supplementation.
tively.2,3 The important factor that may account for the difference is the latitude which influences the zenith angle of the sun. Thailand is closer to the equator than these countries. Cutaneous vitamin D syntheses can occur all year round. Conversely, cutaneous vitamin D synthesis is markedly reduced during November through February in countries located above 37° latitude because of the decreasing number of UVB photons reaching the earth’s surface.13 Soontrapa and colleagues found the prevalence of vitamin D levels below 35 ng/mL in normal Thai postmenopausal women was 60.2% and in elderly women who live in urban or rural areas were 65.1% and 17.4%, respectively.1,14,15 In contrast, most participants in the current study were middle-aged or elderly women who demonstrate higher prevalence of vitamin D levels below 30 ng/mL in urban or rural areas. There are some factors that may account for the differences observed between the two populations. First, Thai RA patients mostly had moderate disease activity and might spend less time outdoors. Second, most of the RA patients took prednisolone, and anti-malarial agents (chloroquine or hydroxychloroquine) which increases the metabolism of vitamin D and anti-malarial agents’ effects on cutaneous vitamin D synthesis.16,17 Finally, poor nutritional status of RA patients may affect vitamin D intake and absorption. This study did not find an association between disease activity and serum vitamin D level. Previous studies in the United States and European countries found an inverse relationship between serum vitamin D levels
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and disease activity and functional status in RA patients.2,3,8,9 In contrast to the current study population who were exclusively Thai, this may be caused by the difference in genetic predisposition factors. Previous studies found the association between vitamin D receptor gene (VDR) polymorphisms and risk of RA susceptibility and severity, especially in RA patients in the United States and European countries.11 Although this study did not show the determinant factors of vitamin D deficiency in Thai RA patients, it found independent factors which were associated with vitamin D insufficiency were Bangkok residents, nonfarmer, obesity and not taking vitamin D (calciferol) supplementation. The effect of Bangkok residents and being a non-farmer may be indirectly explained by less sun exposure in comparison with the residents in rural areas and farmers.1,14,15 In addition, the current study also found an association between obesity and vitamin D insufficiency. This association has also been reported by Rossini et al.3 This can be explained by obesity decreasing bioavailability of vitamin D from any sources because of its deposition in body fat compartments.18 In addition, this study found most patients taking vitamin D (calciferol) supplementation at least 20 000 IU per week have normal serum vitamin D levels. Alternatively, some patients had vitamin D inadequacy although they were taking vitamin D supplementation at least 20 000 IU per week. According to US recommendations for vitamin D (calciferol) supplementation, this should be at higher dosages (at least 3000–6000 IUs per day) for patients at risk or taking prednisolone to maintain normal levels of vitamin D.19 Because Thai RA patients have lower incidences of vitamin D deficiency and more adequate sun exposure, which is a better source of vitamin D, Thai patients may need the lower limited amount of vitamin D supplementation than Europeans or Americans to maintain normal vitamin D levels.20 There are many limitations to the current study that may affect the different results between this study and previous research. First, this study did not have normal healthy controls so the differences in prevalence of vitamin D levels below 20 or 30 ng/mL between RA patients and a Thai normal population cannot be demonstrated. Second, the lack of an association between serum vitamin D levels with disease activity or functional status in this study may be caused by a lower number of patients and the lower rates of vitamin D deficiency compared with previous studies.2,3 In addition, RA disease activity in this study was influenced by several confounding factors, such as current DMARDs
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and steroid use and longer disease duration. These confounders might obscure the effects of vitamin D. In contrast, a previous study by Patel et al.21 in which DMARDs therapy was controlled, their study showed the association between vitamin D levels with early RA disease activity. Furthermore, in the current study, the patients who took vitamin D supplements were not separated from those who did not take vitamin D supplements. This may confound the association between RA activity and serum vitamin D levels. Finally, the study design was a cross-sectional study which may not be suitable for demonstrating the effects of vitamin D in controlling disease activity. Case control or prospective studies may be suitable for answering this question, as well as the study by Andjelkovic et al. which organized an open label trial on active RA patients. Their result showed a positive effect of vitamin D adjunctive therapy with DMARDs in controlling disease activity in RA.9 Further investigations are needed to reveal more information about vitamin D deficiency or insufficiency in RA patients.
CONCLUSION Vitamin D deficiency and vitamin D insufficiency are common in Thai RA patients. There is no association between serum 25(OH)D levels with disease activity or functional status in Thai RA patients. The factors associated with vitamin D insufficiency are Bangkok residency, non-farmer, obesity and not taking vitamin D supplementation. In Thai RA patients, adequate vitamin D (calciferol) supplementation is crucial to maintain normal serum vitamin D levels in addition to sun exposure and a vitamin D-rich diet intake.
ACKNOWLEDGEMENTS The authors would like to thank Ms Dollapas Punpanich for her help with statistical analysis. This study was supported by the grant from Thai rheumatism association.
DISCLOSURE None.
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2 Kerr GS, Sabahi I, Richards JS et al. (2011) Prevalence of vitamin D insufficiency/deficiency in rheumatoid arthritis and associations with disease severity and activity. J Rheumatol 38 (1), 53–9. 3 Rossini M, Maddali Bongi S, La Montagna G et al. (2010) Vitamin D deficiency in rheumatoid arthritis: prevalence, determinants and associations with disease activity and disability. Arthritis Res Ther 12 (6), R216. 4 Baeke F, Takiishi T, Korf H, Gysemans C, Mathieu C (2010) Vitamin D: modulator of the immune system. Curr Opin Pharmacol 10 (4), 482–96. 5 Schwalfenberg GK (2011) A review of the critical role of vitamin D in the functioning of the immune system and the clinical implications of vitamin D deficiency. Mol Nutr Food Res 55 (1), 96–108. 6 Adorini L, Penna G (2008) Control of autoimmune diseases by the vitamin D endocrine system. Nat Clin Pract Rheumatol 4 (8), 404–12. 7 Sokka T (2005) Rheumatoid arthritis databases in Finland. Clin Exp Rheumatol 23 (5 Suppl 39), S201–4. 8 Cutolo M, Otsa K, Laas K et al. (2006) Circannual vitamin D serum levels and disease activity in rheumatoid arthritis: Northern versus Southern Europe. Clin Exp Rheumatol 24 (6), 702–4. 9 Andjelkovic Z, Vojinovic J, Pejnovic N et al. (1999) Disease modifying and immunomodulatory effects of high dose 1 alpha (OH) D3 in rheumatoid arthritis patients. Clin Exp Rheumatol 17 (4), 453–6. 10 Craig SM, Yu F, Curtis JR et al. (2010) Vitamin D status and its associations with disease activity and severity in African Americans with recent-onset rheumatoid arthritis. J Rheumatol 37 (2), 275–81. 11 Lee YH, Bae SC, Choi SJ, Ji JD, Song GG (2011) Associations between vitamin D receptor polymorphisms and susceptibility to rheumatoid arthritis and systemic lupus erythematosus: a meta-analysis. Mol Biol Rep 38 (6), 3643–51.
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12 Baker JF, Baker DG, Toedter G, Shults J, Von Feldt JM, Leonard MB (2012) Associations between vitamin D, disease activity, and clinical response to therapy in rheumatoid arthritis. Clin Exp Rheumatol 30 (5), 658–64. 13 Holick MF (2003) Vitamin D: a millenium perspective. J Cell Biochem 88 (2), 296–307. 14 Soontrapa S, Pongchaiyakul C, Somboonporn C, Somboonporn W, Chailurkit LO. (2001) Prevalence of hypovitaminosis D in elderly women living in urban area of Khon Kaen province, Thailand. J Med Assoc Thai 84 (Suppl 2), S534–41. 15 Soontrapa S, Boonsiri P, Khampitak T (2009) The prevalence of hypovitaminosis D in the elderly women living in the rural area of Khon Kaen Province, Thailand. J Med Assoc Thai 92 (Suppl 5), S21–5. 16 Need AG, O’Loughlin PD, Morris HA, Coates PS, Horowitz M, Nordin BE (2008) Vitamin D metabolites and calcium absorption in severe vitamin D deficiency. J Bone Miner Res 23 (11), 1859–63. 17 Zhou C, Assem M, Tay JC et al. (2006) Steroid and xenobiotic receptor and vitamin D receptor crosstalk mediates CYP24 expression and drug-induced osteomalacia. J Clin Invest 116 (6), 1703–12. 18 Wortsman J, Matsuoka LY, Chen TC, Lu Z, Holick MF (2000) Decreased bioavailability of vitamin D in obesity. Am J Clin Nutr 72 (3), 690–3. 19 Holick MF, Binkley NC, Bischoff-Ferrari HA et al. (2011) Evaluation, treatment, and prevention of vitamin D deficiency: an Endocrine Society clinical practice guideline. J Clin Endocrinol Metab 96 (7), 1911–30. 20 Holick MF (2004) Sunlight and vitamin D for bone health and prevention of autoimmune diseases, cancers, and cardiovascular disease. Am J Clin Nutr 80 (Suppl 6), 1678S–88S. 21 Patel S, Farragher T, Berry J, Bunn D, Silman A, Symmons D (2007) Association between serum vitamin D metabolite levels and disease activity in patients with early inflammatory polyarthritis. Arthritis Rheum 56 (7), 2143–9.
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