International Journal of Rheumatic Diseases 2013
ORIGINAL ARTICLE
Serum vitamin D level and disease activity in patients with recent onset rheumatoid arthritis Zahra ZAKERI,1 Mahnaz SANDOUGHI,1 Mohammad A. MASHHADI,1 Vajihollah RAEESI1 and Sogol SHAHBAKHSH2 1
Department of Internal Medicine, Ali-Ebne-Abitaleb Hospital, Zahedan University of Medical Sciences, Zahedan, and 2Tehran University of Medical Sciences (TUMS), Tehran, Iran
Abstract Introduction: Rheumatoid Arthritis (RA) is one of the most prevalent autoimmune diseases. Due to the significance of the relationship between serum vitamin D levels and autoimmune diseases, this study aimed to determine the relationship between serum vitamin D level and the severity of disease activity in patients with newly diagnosed RA. Method: This cross-sectional study was conducted on 66 patients meeting the American College of Rheumatology – European League Against Rheumatism classification criteria for RA. It was performed in 2012 using simple sampling. The disease activity was measured based on Disease Activity Score of 28 joints – erythrocyte sedimentation rate (DAS28-ESR) and serum 25-OH vitamin D (25(OH)D) levels using the chemiluminescent immunoassay method. In addition, the levels of ESR and C-reactive protein (CRP), the duration of morning stiffness, and the number of joints with tenderness and swollen were calculated as well. The data were analyzed using the Pearson correlation coefficient. Results: In this study, 10 patients were male (15.2%) and 56 were female (84.8%). The average age of the participants was 45.2 15.3 years. The average level of 25(OH)D in the patients’ serum was 30.5 28.9 ng/mL and the mean DAS28-ESR was 5.6 1.1. The correlation coefficient showed that there was an inverse relationship between 25(OH)D and DAS28-ESR, the number of tender and swollen joints, global patient assessment and duration of morning stiffness (P < 0.01). However, the average 25(OH)D level was not related to ESR (P = 0.779) and CRP (P = 0.269). Conclusion: The results of this analysis indicated that patients with more active RA have a lower serum vitamin D level. Key words: disease activity, rheumatoid arthritis, vitamin D.
INTRODUCTION Rheumatoid arthritis (RA) is an autoimmune disease and the most common cause of inflammatory arthritis.
Correspondence: Assistant Professor Mahnaz Sandoughi, Rheumatologist, Department of Internal Medicine, Ali-EbneAbitaleb Hospital, Zahedan University of Medical Sciences, Zahedan, Iran. Email: [email protected]
It is seen as chronic and destructive polyarthritis with extra-articular manifestations. The prevalence of the disease is 0.5–1% and women are affected three times more than men.1 The etiology of RA is still unknown. Although various studies have argued that a combination of environmental and genetic factors is necessary for the development of this disease, they cannot adequately explain the symptoms of the disease. The presence of vitamin D receptors in the immune system cells and the production of vitamin D by active
© 2013 Asia Pacific League of Associations for Rheumatology and Wiley Publishing Asia Pty Ltd
Z. Zakeri et al.
dendritic cells suggest that vitamin D contributes to the regulation of the immune system.2 The synthesis of 1,25(OH)2D3 outside of the kidneys and the synthesis of 24,25(OH)2D3 in the synovial fibroblasts of patients with RA indicate that the consumption of the substrate of 25(OH)D is increased.3,4 In addition, it is reported that vitamin D binding protein (VDBP) expression decreases in patients with RA and 1,25(OH)2D3 connects to VDBP, consequently prevents cell proliferation, production of immunoglobulins and release of cytokines. It also leads to bone resorption by activating the osteoclasts.5 Based on this evidence, vitamin D is known as one of the factors contributing to the pathogenesis of RA. Various studies show the relationship between vitamin D level and autoimmune diseases and it is suggested that vitamin D can be used for controlling such diseases.6,7 Most cohort studies indicate that low consumption of vitamin D is accompanied by greater incidence of RA,8,9 although no other studies confirm the existence of this relationship.10,11 Moreover, the results of the majority of analyses to find the relationship between vitamin D level and activity of RA show that low vitamin D level is accompanied by more activity of RA disease12–17; however, not all of the studies approve of this finding.18–21 The literature provides no compelling justification for the lower vitamin D3 level in patients with more active RA and the involvement of confounding factors is suspected. Among the confounding factors is the presence of more bone destruction in more active patients, which is accompanied by increased parathyroid hormone (PTH) and inhibition of the production of 1,25(OH)2D3. In addition, patients with more active arthritis may be less exposed to sunlight due to their functional limitations. Above all, simultaneous drug consumption can affect the assessment of disease activity and vitamin D level, which is not addressed in some studies. The present study aims to analyze the relationship between vitamin D3 levels and activity of RA in newly diagnosed patients who have not been treated with disease-modifying anti rheumatic drugs (DMARDs), corticosteroid or vitamin D supplements.
METHODS This analytical observational study was conducted on 66 patients with RA referred to Zahedan rheumatology clinics with their consent, whose symptoms had appeared in the past 6 months. After the local ethics
2
committee approved this study, random sampling was performed until the desired volume was obtained. The patients were diagnosed with RA by a rheumatologist based on the American College of Rheumatology – European League Against Rheumatism (ACR-EULAR) classification criteria. Physical conditions and medical history of all the patients were obtained. Thereof, patients with systemic or chronic diseases and individuals who were taking DMARDs, corticosteroid or vitamin D supplements during the past month, were excluded from the study. The study was done in spring and summer in 2012. Disease activity was measured based on DAS28-ESR (Disease Activity Score 28 joint counts – erythrocyte sedimentation rate). One of the components of DAS28ESR is global patient assessment which is analyzed by a visual analogue score (VAS) of 0–100. All of the analyses were carried out by one person. C-reactive protein (CRP: mg/dL) was assessed using a quantitative method called turbidimetry and ESR (mm/h) was measured by the Westegren method. In order to determine the vitamin D level, blood samples were obtained in the morning after at least 8 h of fasting. The levels of 25(OH)D were also measured using a chemiluminescent immunoassay method with a DiaSorin kit (DiaSorin Ltd., Dartford, UK). A comparison was also made between the average vitamin D3 level and the average disease activity based on DAS28ESR. Another comparison was also drawn between vitamin D levels, ESR and CRP levels, durations of morning stiffness and numbers of tender and swollen joints. The data were analyzed using SPSS ver.18 (SPSS Inc., Chicago, IL, USA) and Pearson correlation coefficient and the t-test or their non-parametric equivalents were also used for statistical analysis.
RESULTS The average age of the participants was 45.2 15.3 years, among whom 10 individuals (15.2%) were male and 56 individuals (84.8%) were female. The mean serum 25(OH)D levels and the mean DAS28-ESR levels of patients were 30.5 28.9 ng/mL (median = 17.8) and 5.6 1.1, respectively. The correlation coefficient of the two variables was obtained at 0.790 using the Pearson correlation coefficient, which indicated that there is an inverse relationship between 25(OH)D levels and the severity of RA. In addition, more severe cases of RA were accompanied by lower serum 25(OH)D levels (P < 0.01). The average number of joints with tenderness was 14.9 9.3
International Journal of Rheumatic Diseases 2013
Vitamin D and recent onset RA
(median = 17.0) and correlation coefficient associated with vitamin D level was 0.764, which indicated that there is an inverse relationship between 25(OH)D levels and the number of tender joints (P < 0.01). The mean ESR was 29.9 23.7 (median = 23.5) and the mean CRP was 11.3 16.6 mg/dL (median = 5.6). The correlation coefficients of 25(OH)D level for ERS and CRP were 0.035 and 0.135, respectively. This finding showed that 25(OH)D level is not related to ESR (P = 0.779) or CRP (P = 0.269). In this study, the relationship of patient global assessment (which is assessed by VAS), BMI, and the number of swollen joints with serum vitamin D level was examined and the following coefficients were obtained using the Pearson correlation coefficient: 0.709, 0.116, and 0. 586, respectively. This finding suggests that 25(OH)D level is inversely related to the level of VAS and the number of swollen joints. Moreover, with higher levels of VAS and increase in the number of swollen joints, the serum 25(OH)D level was lower (P < 0.001). Nonetheless, no relationship was found between BMI and 25(OH)D level (P = 0.356) (Table 1). The serum vitamin D levels in patients with morning stiffness of more than and less than an hour were 14.7 13.7 ng/mL (median = 11.2) and 48.9 31.8 ng/mL (median = 44.9), respectively. The values indicated that the serum vitamin D level in patients with morning stiffness less than an hour is higher than that of the patients with morning stiffness more than an hour (P < 0.001).
DISCUSSION In the present study, there was an inverse relationship between the average serum vitamin D level and Table 1 Correlation coefficient of some variables with vitamin D serum level. Variables
Mean SD
Median
DAS Tender joint (no.) Swollen joint (no.) VAS ESR CRP BMI
5.6 1.1 14.9 9.3
5.9 17.0
0.790 0.764
0.01 0.01
5.5 3.8
4.0
0.586
0.01
70.0 23.5 5.6 25.4
0.709 0.035 0.138 0.116
0.01 0.77 0.26 0.35
61.2 29.9 11.3 25.1
19.9 23.7 16.6 3.1
Correlation coefficient
P-value
DAS, disease activity score; VAS, visual analog scale; ESR, erythrocyte sedimentation rate; CRP, C-reactive protein; BMI, body mass index.
International Journal of Rheumatic Diseases 2013
DAS28-ESR, the number of tender and swollen joints and global patient assessment. However, there was no relationship between the average serum vitamin D level and ESR or CRP. Moreover, the serum vitamin D level in patients with morning stiffness more than an hour was much lower than the patients with morning stiffness less than an hour. Our finding is in concordance with the results of the study conducted by Pater et al.12 In this study, the serum vitamin D level in 309 patients with inflammatory polyarthritis for less than 4 months was measured. At the beginning of the study, vitamin D level was lower in patients experiencing more disease activity and after a 1-year follow-up, the incidence of RA was higher among the individuals with lower serum vitamin D levels. These patients had lower Health Assessment Quenstionnaire (HAQ) levels and more tender joints. Similar to the present study, these patients were not treated by DMARDs and did not suffer from the disease for a long time. In addition, the results of the study by Turhano glu et al.13 revealed that there was a significant relationship between serum 25(OH)D level and disease activity (DAS28), CRP and HAQ. Nonetheless, new case patients were not included in this study and the simultaneous consumption of confounding drugs was also not studied. Oelzner et al.14 found an inverse relationship between the activity of RA and serum 1,25(OH)2 vitamin D levels and PTH level. It was found that this relationship was not caused by corticosteroids or the menopausal conditions of patients. In Moghimi’s study,15 a relationship was found between higher disease activity and lower vitamin D level; however, this correlation was not associated with PTH level and duration of disease. Pincus et al.17 found an inverse relationship between ESR, CRP and serum vitamin D levels, but the present study does not support this finding. In contrast to the results of the present study, the study by Craig et al.18 on African-American RA patients with recent onset diseases, there were no multivariate associations of 25(OH)D with any disease activity measures at baseline or at 3 years. Moreover, findings of Braun-Moscovici et al.19 indicated that regardless of the consumption of DMARDs, there is no relationship between RA and serum 25(OH)D levels. Likewise, Baker et al.20 did not report the existence of a relationship between vitamin D levels and RA activity. However, their study compared disease activity between individuals with hypovitaminosis D and normal vitamin D levels, while the present study focused on the comparison of the average DAS28 score and serum vitamin D levels.
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A factor that affects the assessment of the activity of RA is the role of vitamin D3 in pain perception. In analyzing disease activity using the DAS28 method, one of the components, VAS, is subjectively analyzed. The results of the study of Higgins22 indicated that in using the DAS28 assessment method, no relationship was found between vitamin D3 level and disease activity regardless of the VAS results. The present study indicates that low vitamin D3 level is linked to DAS28 with both subjective (VAS) and objective (number of swollen and tender joints) components. In this study there are some limitations in answering the question whether low vitamin D is causal or consequential for RA activity. Choosing patients with newly diagnosed RA minimizes the risk of the involvement of relevant factors affecting bone health. However, an exact evaluation requires the analysis of bone resorption markers, which was not done in this research. Moreover, the duration of sunlight exposure in patients was not measured, although choosing recent-onset RA patients without co-morbidity in the first two seasons of year had a diminished effect on these confounding factors. Therefore, it seems that low serum vitamin D3 level is a motivation factor instead of being a consequence of RA activity. In summary, to assess the relationship of vitamin D3 levels and RA activity, further studies with the exact exclusion of confounding factors and by using different assessment methods are required.
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REFERENCES 1 Shah A, St Clair EW (2012) Rheumatoid arthritis. In: Longo DL, Fauci AS, Kasper DL, Hauser SL, Jameson J, Loscalzo J (eds) Harrison’s Principles of Internal Medicine, 18th edn, pp 2738–51. Mc CrawHill Medical, New York, NY. 2 Cutalo M, Otsa K, Uprus M, Paolino S, Seriolo B (2007) Vitamin D in Rheumatoid arthritis. Autoimmun Rev 7, 59–64. 3 Mawer EB, Hayes ME, Still PE et al. (1991) Evidence for nonrenal synthesis of1,25-dihydroxyvitamin D in patients with inflammatory ar-thritis. J Bone Miner Res 6, 733–9. 4 Hayes ME, Bayley D, Still P (1992) Differential metabolism of 25-dihydroxyvitamin D3 by cultured synovial fluid macro-phages and fibroblast-like cells from patients with arthritis. Ann Rheum Dis 51, 220–6. 5 Yan X, Zhao Y, Pan J et al. (2012) Vitamin D-binding protein (group-specific component) has decreased expression in rheumatoid arthritis. Clin Exp Rheumatol 30, 525–33. 6 Orbach H, Zandman Goddard G, Amital H et al. (2007) Novel biomarkersin autoimmune diseases; prolactin,
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ferritin, vitamin D, and TPA levels in autoimmune diseases. Ann N Y Acad Sci 1109, 385–400. Arnson Y, Amital H, Shoenfeld Y (2007) Vitamin D and autoimmunity: new a etiological and therapeutic considerations. Ann Rheum Dis 66, 1137–42. Merlino LA, Curtis J, Mikuls TR, Cerhan JR, Criswell LA, Saag KG (2004) Vitamin D intake is inversely associated with rheumatoid arthritis: results from the Iowa Women’s Health Study. Arthritis Rheum 50, 72–7. Song GG, Bae SC, Lee YH (2012) Association between vitamin D intake and the risk of rheumatoid arthritis: a meta-analysis. Clin Rheumatol 31, 1733–9. Costenbader KH, Feskanich D, Holmes M, Karlson EW, Benito-Garcia E (2008) Vitamin D intake and risks of systemic lupus erythematosus and rheumatoid arthritis in women. Ann Rheum Dis 67, 530–5. Hiraki LT, Munger KL, Costenbader KH, Karlson EW (2012) Dietary intake of vitamin D during adolescence and risk of adult-onset systemic lupus erythematosus and rheumatoid arthritis. Arthritis Care Res (Hoboken) 64, 1829–36. 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, 2143–9. Turhanoglu AD, Guler H, Yonden Z, Aslan F, Mansuroglu A, Ozer C (2011) The relationship between vitamin D and disease activity and functional health status in rheumatoid arthritis. Rheumatol Int 31, 911–4. Oelzner P, M€ uller A, Deschner F et al. (1998) Relationship between disease activity and serum levels of vitamin D metabolites and PTH in rheumatoid arthritis. Calcif Tissue Int 62, 193–8. Moghimi JA, Sadeghi M, Malek M, Ghorbani R (2012) Relationship between disease activity and serum levels of vitamin D and parathyroid hormone in rheumatoid arthritis. Endocr Regul 46, 61. Kostoglou-Athanassiou I, Athanassiou P, Lyraki A, et al. (2012) Vitamin D and rheumatoid arthritis. Ther Adv Endocrinol Metab 3, 181–7. Pincus T, Sokka T (2009) Laboratory tests to assess patients with rheumatoid arthritis: advantages and limitations. Rheum Dis Clin North Am 35, 731–4. 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, 275–81. Braun-Moscovici Y, Toledano K, Markovits D, Rozin A, Nahir AM, Balbir-Gurman A (2009) Vitamin D level: is it related to disease activity in inflammatory joint disease? Rheumatol Int 31, 493–9. 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, 658–64.
International Journal of Rheumatic Diseases 2013
Vitamin D and recent onset RA
21 Baykal T, Senel K, Alp F, Erdal A, Ugur M (2011) “Is there an association between serum 25-hydroxyvitamin D concentrations and disease activity in rheumatoid arthritis?”. Bratisl Lek Listy 113, 610–11.
International Journal of Rheumatic Diseases 2013
22 Higgins MJ, Mackie SL, Thalayasingam N, Bingham SJ, Hamilton J, Kelly CA (2013) The effect of vitamin D levels on the assessment of disease activity in rheumatoid arthritis. Clin Rheumatol 23, 1–5.
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ORIGINAL ARTICLE
Serum vitamin D level and disease activity in patients with recent onset rheumatoid arthritis Zahra ZAKERI,1 Mahnaz SANDOUGHI,1 Mohammad A. MASHHADI,1 Vajihollah RAEESI1 and Sogol SHAHBAKHSH2 1
Department of Internal Medicine, Ali-Ebne-Abitaleb Hospital, Zahedan University of Medical Sciences, Zahedan, and 2Tehran University of Medical Sciences (TUMS), Tehran, Iran
Abstract Introduction: Rheumatoid Arthritis (RA) is one of the most prevalent autoimmune diseases. Due to the significance of the relationship between serum vitamin D levels and autoimmune diseases, this study aimed to determine the relationship between serum vitamin D level and the severity of disease activity in patients with newly diagnosed RA. Method: This cross-sectional study was conducted on 66 patients meeting the American College of Rheumatology – European League Against Rheumatism classification criteria for RA. It was performed in 2012 using simple sampling. The disease activity was measured based on Disease Activity Score of 28 joints – erythrocyte sedimentation rate (DAS28-ESR) and serum 25-OH vitamin D (25(OH)D) levels using the chemiluminescent immunoassay method. In addition, the levels of ESR and C-reactive protein (CRP), the duration of morning stiffness, and the number of joints with tenderness and swollen were calculated as well. The data were analyzed using the Pearson correlation coefficient. Results: In this study, 10 patients were male (15.2%) and 56 were female (84.8%). The average age of the participants was 45.2 15.3 years. The average level of 25(OH)D in the patients’ serum was 30.5 28.9 ng/mL and the mean DAS28-ESR was 5.6 1.1. The correlation coefficient showed that there was an inverse relationship between 25(OH)D and DAS28-ESR, the number of tender and swollen joints, global patient assessment and duration of morning stiffness (P < 0.01). However, the average 25(OH)D level was not related to ESR (P = 0.779) and CRP (P = 0.269). Conclusion: The results of this analysis indicated that patients with more active RA have a lower serum vitamin D level. Key words: disease activity, rheumatoid arthritis, vitamin D.
INTRODUCTION Rheumatoid arthritis (RA) is an autoimmune disease and the most common cause of inflammatory arthritis.
Correspondence: Assistant Professor Mahnaz Sandoughi, Rheumatologist, Department of Internal Medicine, Ali-EbneAbitaleb Hospital, Zahedan University of Medical Sciences, Zahedan, Iran. Email: [email protected]
It is seen as chronic and destructive polyarthritis with extra-articular manifestations. The prevalence of the disease is 0.5–1% and women are affected three times more than men.1 The etiology of RA is still unknown. Although various studies have argued that a combination of environmental and genetic factors is necessary for the development of this disease, they cannot adequately explain the symptoms of the disease. The presence of vitamin D receptors in the immune system cells and the production of vitamin D by active
© 2013 Asia Pacific League of Associations for Rheumatology and Wiley Publishing Asia Pty Ltd
Z. Zakeri et al.
dendritic cells suggest that vitamin D contributes to the regulation of the immune system.2 The synthesis of 1,25(OH)2D3 outside of the kidneys and the synthesis of 24,25(OH)2D3 in the synovial fibroblasts of patients with RA indicate that the consumption of the substrate of 25(OH)D is increased.3,4 In addition, it is reported that vitamin D binding protein (VDBP) expression decreases in patients with RA and 1,25(OH)2D3 connects to VDBP, consequently prevents cell proliferation, production of immunoglobulins and release of cytokines. It also leads to bone resorption by activating the osteoclasts.5 Based on this evidence, vitamin D is known as one of the factors contributing to the pathogenesis of RA. Various studies show the relationship between vitamin D level and autoimmune diseases and it is suggested that vitamin D can be used for controlling such diseases.6,7 Most cohort studies indicate that low consumption of vitamin D is accompanied by greater incidence of RA,8,9 although no other studies confirm the existence of this relationship.10,11 Moreover, the results of the majority of analyses to find the relationship between vitamin D level and activity of RA show that low vitamin D level is accompanied by more activity of RA disease12–17; however, not all of the studies approve of this finding.18–21 The literature provides no compelling justification for the lower vitamin D3 level in patients with more active RA and the involvement of confounding factors is suspected. Among the confounding factors is the presence of more bone destruction in more active patients, which is accompanied by increased parathyroid hormone (PTH) and inhibition of the production of 1,25(OH)2D3. In addition, patients with more active arthritis may be less exposed to sunlight due to their functional limitations. Above all, simultaneous drug consumption can affect the assessment of disease activity and vitamin D level, which is not addressed in some studies. The present study aims to analyze the relationship between vitamin D3 levels and activity of RA in newly diagnosed patients who have not been treated with disease-modifying anti rheumatic drugs (DMARDs), corticosteroid or vitamin D supplements.
METHODS This analytical observational study was conducted on 66 patients with RA referred to Zahedan rheumatology clinics with their consent, whose symptoms had appeared in the past 6 months. After the local ethics
2
committee approved this study, random sampling was performed until the desired volume was obtained. The patients were diagnosed with RA by a rheumatologist based on the American College of Rheumatology – European League Against Rheumatism (ACR-EULAR) classification criteria. Physical conditions and medical history of all the patients were obtained. Thereof, patients with systemic or chronic diseases and individuals who were taking DMARDs, corticosteroid or vitamin D supplements during the past month, were excluded from the study. The study was done in spring and summer in 2012. Disease activity was measured based on DAS28-ESR (Disease Activity Score 28 joint counts – erythrocyte sedimentation rate). One of the components of DAS28ESR is global patient assessment which is analyzed by a visual analogue score (VAS) of 0–100. All of the analyses were carried out by one person. C-reactive protein (CRP: mg/dL) was assessed using a quantitative method called turbidimetry and ESR (mm/h) was measured by the Westegren method. In order to determine the vitamin D level, blood samples were obtained in the morning after at least 8 h of fasting. The levels of 25(OH)D were also measured using a chemiluminescent immunoassay method with a DiaSorin kit (DiaSorin Ltd., Dartford, UK). A comparison was also made between the average vitamin D3 level and the average disease activity based on DAS28ESR. Another comparison was also drawn between vitamin D levels, ESR and CRP levels, durations of morning stiffness and numbers of tender and swollen joints. The data were analyzed using SPSS ver.18 (SPSS Inc., Chicago, IL, USA) and Pearson correlation coefficient and the t-test or their non-parametric equivalents were also used for statistical analysis.
RESULTS The average age of the participants was 45.2 15.3 years, among whom 10 individuals (15.2%) were male and 56 individuals (84.8%) were female. The mean serum 25(OH)D levels and the mean DAS28-ESR levels of patients were 30.5 28.9 ng/mL (median = 17.8) and 5.6 1.1, respectively. The correlation coefficient of the two variables was obtained at 0.790 using the Pearson correlation coefficient, which indicated that there is an inverse relationship between 25(OH)D levels and the severity of RA. In addition, more severe cases of RA were accompanied by lower serum 25(OH)D levels (P < 0.01). The average number of joints with tenderness was 14.9 9.3
International Journal of Rheumatic Diseases 2013
Vitamin D and recent onset RA
(median = 17.0) and correlation coefficient associated with vitamin D level was 0.764, which indicated that there is an inverse relationship between 25(OH)D levels and the number of tender joints (P < 0.01). The mean ESR was 29.9 23.7 (median = 23.5) and the mean CRP was 11.3 16.6 mg/dL (median = 5.6). The correlation coefficients of 25(OH)D level for ERS and CRP were 0.035 and 0.135, respectively. This finding showed that 25(OH)D level is not related to ESR (P = 0.779) or CRP (P = 0.269). In this study, the relationship of patient global assessment (which is assessed by VAS), BMI, and the number of swollen joints with serum vitamin D level was examined and the following coefficients were obtained using the Pearson correlation coefficient: 0.709, 0.116, and 0. 586, respectively. This finding suggests that 25(OH)D level is inversely related to the level of VAS and the number of swollen joints. Moreover, with higher levels of VAS and increase in the number of swollen joints, the serum 25(OH)D level was lower (P < 0.001). Nonetheless, no relationship was found between BMI and 25(OH)D level (P = 0.356) (Table 1). The serum vitamin D levels in patients with morning stiffness of more than and less than an hour were 14.7 13.7 ng/mL (median = 11.2) and 48.9 31.8 ng/mL (median = 44.9), respectively. The values indicated that the serum vitamin D level in patients with morning stiffness less than an hour is higher than that of the patients with morning stiffness more than an hour (P < 0.001).
DISCUSSION In the present study, there was an inverse relationship between the average serum vitamin D level and Table 1 Correlation coefficient of some variables with vitamin D serum level. Variables
Mean SD
Median
DAS Tender joint (no.) Swollen joint (no.) VAS ESR CRP BMI
5.6 1.1 14.9 9.3
5.9 17.0
0.790 0.764
0.01 0.01
5.5 3.8
4.0
0.586
0.01
70.0 23.5 5.6 25.4
0.709 0.035 0.138 0.116
0.01 0.77 0.26 0.35
61.2 29.9 11.3 25.1
19.9 23.7 16.6 3.1
Correlation coefficient
P-value
DAS, disease activity score; VAS, visual analog scale; ESR, erythrocyte sedimentation rate; CRP, C-reactive protein; BMI, body mass index.
International Journal of Rheumatic Diseases 2013
DAS28-ESR, the number of tender and swollen joints and global patient assessment. However, there was no relationship between the average serum vitamin D level and ESR or CRP. Moreover, the serum vitamin D level in patients with morning stiffness more than an hour was much lower than the patients with morning stiffness less than an hour. Our finding is in concordance with the results of the study conducted by Pater et al.12 In this study, the serum vitamin D level in 309 patients with inflammatory polyarthritis for less than 4 months was measured. At the beginning of the study, vitamin D level was lower in patients experiencing more disease activity and after a 1-year follow-up, the incidence of RA was higher among the individuals with lower serum vitamin D levels. These patients had lower Health Assessment Quenstionnaire (HAQ) levels and more tender joints. Similar to the present study, these patients were not treated by DMARDs and did not suffer from the disease for a long time. In addition, the results of the study by Turhano glu et al.13 revealed that there was a significant relationship between serum 25(OH)D level and disease activity (DAS28), CRP and HAQ. Nonetheless, new case patients were not included in this study and the simultaneous consumption of confounding drugs was also not studied. Oelzner et al.14 found an inverse relationship between the activity of RA and serum 1,25(OH)2 vitamin D levels and PTH level. It was found that this relationship was not caused by corticosteroids or the menopausal conditions of patients. In Moghimi’s study,15 a relationship was found between higher disease activity and lower vitamin D level; however, this correlation was not associated with PTH level and duration of disease. Pincus et al.17 found an inverse relationship between ESR, CRP and serum vitamin D levels, but the present study does not support this finding. In contrast to the results of the present study, the study by Craig et al.18 on African-American RA patients with recent onset diseases, there were no multivariate associations of 25(OH)D with any disease activity measures at baseline or at 3 years. Moreover, findings of Braun-Moscovici et al.19 indicated that regardless of the consumption of DMARDs, there is no relationship between RA and serum 25(OH)D levels. Likewise, Baker et al.20 did not report the existence of a relationship between vitamin D levels and RA activity. However, their study compared disease activity between individuals with hypovitaminosis D and normal vitamin D levels, while the present study focused on the comparison of the average DAS28 score and serum vitamin D levels.
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A factor that affects the assessment of the activity of RA is the role of vitamin D3 in pain perception. In analyzing disease activity using the DAS28 method, one of the components, VAS, is subjectively analyzed. The results of the study of Higgins22 indicated that in using the DAS28 assessment method, no relationship was found between vitamin D3 level and disease activity regardless of the VAS results. The present study indicates that low vitamin D3 level is linked to DAS28 with both subjective (VAS) and objective (number of swollen and tender joints) components. In this study there are some limitations in answering the question whether low vitamin D is causal or consequential for RA activity. Choosing patients with newly diagnosed RA minimizes the risk of the involvement of relevant factors affecting bone health. However, an exact evaluation requires the analysis of bone resorption markers, which was not done in this research. Moreover, the duration of sunlight exposure in patients was not measured, although choosing recent-onset RA patients without co-morbidity in the first two seasons of year had a diminished effect on these confounding factors. Therefore, it seems that low serum vitamin D3 level is a motivation factor instead of being a consequence of RA activity. In summary, to assess the relationship of vitamin D3 levels and RA activity, further studies with the exact exclusion of confounding factors and by using different assessment methods are required.
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REFERENCES 1 Shah A, St Clair EW (2012) Rheumatoid arthritis. In: Longo DL, Fauci AS, Kasper DL, Hauser SL, Jameson J, Loscalzo J (eds) Harrison’s Principles of Internal Medicine, 18th edn, pp 2738–51. Mc CrawHill Medical, New York, NY. 2 Cutalo M, Otsa K, Uprus M, Paolino S, Seriolo B (2007) Vitamin D in Rheumatoid arthritis. Autoimmun Rev 7, 59–64. 3 Mawer EB, Hayes ME, Still PE et al. (1991) Evidence for nonrenal synthesis of1,25-dihydroxyvitamin D in patients with inflammatory ar-thritis. J Bone Miner Res 6, 733–9. 4 Hayes ME, Bayley D, Still P (1992) Differential metabolism of 25-dihydroxyvitamin D3 by cultured synovial fluid macro-phages and fibroblast-like cells from patients with arthritis. Ann Rheum Dis 51, 220–6. 5 Yan X, Zhao Y, Pan J et al. (2012) Vitamin D-binding protein (group-specific component) has decreased expression in rheumatoid arthritis. Clin Exp Rheumatol 30, 525–33. 6 Orbach H, Zandman Goddard G, Amital H et al. (2007) Novel biomarkersin autoimmune diseases; prolactin,
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ferritin, vitamin D, and TPA levels in autoimmune diseases. Ann N Y Acad Sci 1109, 385–400. Arnson Y, Amital H, Shoenfeld Y (2007) Vitamin D and autoimmunity: new a etiological and therapeutic considerations. Ann Rheum Dis 66, 1137–42. Merlino LA, Curtis J, Mikuls TR, Cerhan JR, Criswell LA, Saag KG (2004) Vitamin D intake is inversely associated with rheumatoid arthritis: results from the Iowa Women’s Health Study. Arthritis Rheum 50, 72–7. Song GG, Bae SC, Lee YH (2012) Association between vitamin D intake and the risk of rheumatoid arthritis: a meta-analysis. Clin Rheumatol 31, 1733–9. Costenbader KH, Feskanich D, Holmes M, Karlson EW, Benito-Garcia E (2008) Vitamin D intake and risks of systemic lupus erythematosus and rheumatoid arthritis in women. Ann Rheum Dis 67, 530–5. Hiraki LT, Munger KL, Costenbader KH, Karlson EW (2012) Dietary intake of vitamin D during adolescence and risk of adult-onset systemic lupus erythematosus and rheumatoid arthritis. Arthritis Care Res (Hoboken) 64, 1829–36. 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, 2143–9. Turhanoglu AD, Guler H, Yonden Z, Aslan F, Mansuroglu A, Ozer C (2011) The relationship between vitamin D and disease activity and functional health status in rheumatoid arthritis. Rheumatol Int 31, 911–4. Oelzner P, M€ uller A, Deschner F et al. (1998) Relationship between disease activity and serum levels of vitamin D metabolites and PTH in rheumatoid arthritis. Calcif Tissue Int 62, 193–8. Moghimi JA, Sadeghi M, Malek M, Ghorbani R (2012) Relationship between disease activity and serum levels of vitamin D and parathyroid hormone in rheumatoid arthritis. Endocr Regul 46, 61. Kostoglou-Athanassiou I, Athanassiou P, Lyraki A, et al. (2012) Vitamin D and rheumatoid arthritis. Ther Adv Endocrinol Metab 3, 181–7. Pincus T, Sokka T (2009) Laboratory tests to assess patients with rheumatoid arthritis: advantages and limitations. Rheum Dis Clin North Am 35, 731–4. 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, 275–81. Braun-Moscovici Y, Toledano K, Markovits D, Rozin A, Nahir AM, Balbir-Gurman A (2009) Vitamin D level: is it related to disease activity in inflammatory joint disease? Rheumatol Int 31, 493–9. 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, 658–64.
International Journal of Rheumatic Diseases 2013
Vitamin D and recent onset RA
21 Baykal T, Senel K, Alp F, Erdal A, Ugur M (2011) “Is there an association between serum 25-hydroxyvitamin D concentrations and disease activity in rheumatoid arthritis?”. Bratisl Lek Listy 113, 610–11.
International Journal of Rheumatic Diseases 2013
22 Higgins MJ, Mackie SL, Thalayasingam N, Bingham SJ, Hamilton J, Kelly CA (2013) The effect of vitamin D levels on the assessment of disease activity in rheumatoid arthritis. Clin Rheumatol 23, 1–5.
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