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 Table of Contents  
ORIGINAL ARTICLE
Year : 2019  |  Volume : 2  |  Issue : 2  |  Page : 21-25

Vitamin D in rheumatoid arthritis and association of disease activity with various laboratory parameters


1 Department of Orthopaedics, NMCH, Patna, Bihar, India
2 Department of Orthopaedics, Ayushman Hospital, Hajipur, Bihar, India

Date of Submission24-Aug-2019
Date of Decision05-Sep-2019
Date of Acceptance10-Sep-2019
Date of Web Publication21-Oct-2019

Correspondence Address:
Dr. Ravi Kumar
Department of Orthopaedics, NMCH, Agamkuan, Patna - 800 007, Bihar
India
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/JODP.JODP_7_19

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  Abstract 


Background: The aim was to validate the association between Vitamin D level and rheumatoid arthritis (RA); evaluate association of stages of disease activity with various parameters such as serum Vitamin D level, RA factor level, anti-cyclic citrullinated peptide (CCP), erythrocyte sedimentation rate (ESR) and C-reactive protein (CRP) levels; and evaluate correlation of Vitamin D with various parameters and Disease Activity Score (DAS)-28 score with various parameters. Materials and Methods: This was a prospective comparative study. The sample size was of 100 patients with 50 each in case and control groups. Investigations such as ESR, CRP (quant), anti-CCP, and RA factor were undertaken for case group. Serum 25-hydroxyvitamin D concentration was analyzed for both case and control groups. Disease activity was measured in patients of RA using DAS-28. Mean of Vitamin D level in case and control groups were measured. Association of different stage of disease activity among cases was calculated with various laboratory parameters. Correlation coefficient of Vitamin D with various laboratory parameters and DAS-28 score with various laboratory parameters calculated. Results: The mean Vitamin D level in case group was 18.726 ng/ml, while in control group, it was 42.851 ng/ml. Association of various stages of disease activity was statistically highly significant for CRP and anti-CCP levels. Vitamin D was negatively correlated with serum ESR, while DAS-28 score was positively correlated with serum ESR, CRP, RA factor, and anti-CCP values. Conclusions: Vitamin D deficiency is more common in RA patients. CRP and anti-CCP markers are associated with disease activity. Moderate-to-strong positive linear correlation present between DAS 28 score & CRP and DAS 28 score & anti CCP values respectively.

Keywords: Disease Activity Score-28, rheumatoid arthritis, Vitamin D


How to cite this article:
Kumar R, Kunal K, Kumar N. Vitamin D in rheumatoid arthritis and association of disease activity with various laboratory parameters. J Orthop Dis Traumatol 2019;2:21-5

How to cite this URL:
Kumar R, Kunal K, Kumar N. Vitamin D in rheumatoid arthritis and association of disease activity with various laboratory parameters. J Orthop Dis Traumatol [serial online] 2019 [cited 2019 Nov 11];2:21-5. Available from: http://www.jodt.org/text.asp?2019/2/2/21/269584




  Introduction Top


Rheumatoid arthritis (RA) is an autoimmune disease with a worldwide prevalence of approximately 0.5%–1% among adults.[1],[2] RA investigators have noted that prevalence in North America and Europe may be higher than the prevalence in Asia.[3],[4] It is three times more common in females as compared to male. It is a more common chronic inflammatory disease which is characterized by inflammation of synovium of the joint which gradually leads to various articular and extra-articular manifestations. This eventually leads to enhanced morbidity and mortality in this subset of the population. The etiology of RA has been elusive. It could be due to either genetic or nongenetic factors such as environmental, hormonal, and infectious factors.[5]

No tests are specific for diagnosing RA. RA factor is not specific as it is found in almost 5% of the healthy population. Anti-cyclic citrullinated peptide (CCP) has similar sensitivity but better specificity. The presence of anti-CCP is more common in patients with aggressive disease. Levels of acute-phase reactants such as erythrocyte sedimentation rate (ESR) and C-reactive protein (CRP) are also elevated and invariably correlate with disease activity. Literature has limited reports depicting correlation between these parameters and disease activity.

A variety of tools for assessment of disease activity have been developed for use in clinical trials and in the office setting. Disease Activity Score in 28 joints (DAS-28) is being used as a measurement for assessing disease activity in patients with RA for the past several years.[6]

Vitamin D deficiency is now a pandemic. In the past, it has been associated with bone metabolism. Of late, various researches have been undertaken to ascertain the involvement of Vitamin D in autoimmune disorders such as multiple sclerosis, Type 1 diabetes mellitus, RA, systemic lupus erythematosus. This was further corroborated by literature reports which found involvement of Vitamin D in various biological processes that regulate immune responses.[7],[8] The stimulant was finding of Vitamin D receptors in monocytes[9],[10] and subsequently in dendritic cells and activated T-cells.In vitro studies have shown inhibitory effect of Vitamin D on pro-inflammatory activity of CD4+ Th1 cells and their production of interleukin (IL)-2, interferon- ]47;, and tumor necrosis factor-α.[11],[12] In addition to its anti-inflammatory effects, Vitamin D also promotes Th2 responses by enhancing IL-4, IL-5, and IL-10 production.[13] These effects of Vitamin D strongly suggests that Vitamin D could play important roles in autoimmunity. A circulating level of 25-hydroxyvitamin D (25[OH] D) of 75 nmol/L, or 30 ng/mL, is required to maximize Vitamin D's beneficial effects for health.

The aim was to validate the association between Vitamin D level and RA, evaluate association of various stages of disease activity with various laboratory parameters such as serum Vitamin D level, RA factor level, anti-CCP, and ESR and CRP levels and evaluate the correlation of Vitamin D with various laboratory parameters and similarly DAS-28 score with various laboratory parameters.


  Materials and Methods Top


This was a prospective comparative study done at a government tertiary care hospital. Written informed consent was obtained from each participant. Prior approval from the Institutional Review Board was taken. The sample size was of 100 patients with 50 each in case and control groups. The participants were from both male and female genders. The age group varied from 18 to 64 years. Inclusion criteria were diagnosed case of RA as per the American College of Rheumatology (ACR)-European League Against Rheumatism 2010 classification criteria.[14]

Exclusion criteria were:

  1. History of any other autoimmune disease
  2. Hepatorenal dysfunction
  3. On Vitamin D or calcium supplements over previous 6 months.


Controls were free from any systemic illness. After thorough history and clinical evaluation, investigations such as ESR, CRP (quant), anti-CCP, and RA factor were undertaken for case group. Serum 25(OH) D concentration (ng/ml) was analyzed for both case and control groups. The investigations were done from the hospital laboratory only.

Disease activity was measured in patients of RA using DAS-28 as per the guidelines of ACR; remission: DAS-28 ≤2.6, low disease activity: 2.6< DAS-28 ≤ 3.2, moderate disease activity: 3.2 <DAS-28 ≤5.1, and high disease activity: DAS-28 >5.1.

Statistical analysis was done using SPSS software (SPSS Inc., Chicago, United states). Mean of continuous variables and P values were calculated. In order to study the associations between two continuous variables, a Pearson's correlation coefficient was calculated. To study differences in mean findings of related continuous interval groups, an unpaired Student's t-test or a one-way analysis of variance was performed when relevant. Differences were considered to be of statistical significance at P < 0.05 and highly significant at P < 0.001.


  Results Top


Females comprised 80% (n = 40) of the case group, while in control, they were 6% (n = 3) and this difference was statistically significant (P < 0.001). Similarly, mean age in case group was: 41.42 ± 11.15 years, while in control, it was 27.88 ± 7.21 years with P < 0.001 which is statistically very significant [Table 1].
Table 1: Distribution of demographic data

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The mean Vitamin D level in case group was 18.726 ± 6.259 ng/ml, while in control group, it was 42.851 ± 14.516 ng/ml with P < 0.001 which is highly significant [Figure 1].
Figure 1: Comparison of mean Vitamin D level among cases and controlsFigure 2: Association of Disease Activity Score-28 with various laboratory parameters among cases

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Correlation of Vitamin D among cases with various parameters revealed a moderate-negative linear relationship (r: −0.315) between Vitamin D level and serum ESR with P = 0.026 which is significant. Low negative linear relationship was present on correlational analysis of Vitamin D with RA factor (r: −0.176). There was no correlation between Vitamin D level and DAS-28 score or CRP or even anti-CCP levels, respectively. Similarly, correlation of DAS-28 score with various parameters revealed positive linear relationship between DAS-28 score and ESR, CRP, RA factor, and anti-CCP, respectively, with P value as statistically significant (P = −0.001) for CRP and highly statistically significant (P = −<0.001) for anti-CCP [Table 2].
Table 2: Correlation of Vitamin D and Disease Activity Score-28 score with various parameters, respectively, among cases

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DAS revealed that out of total 50 cases; 18 cases each in remission and low activity groups, while 14 cases were in moderate activity group. None of the cases were in high activity group.

Low activity group (n = 18) had mean Vitamin D value of 18.036 ± 5.969 ng/ml, while moderate (n = 14) and remission groups (n = 18) had mean Vitamin D values as 18.222 ± 6.613 ng/ml and 19.808 ± 6.471 ng/ml, respectively, with P = 0.663. Low activity group had mean CRP value of 6.040 ± 7.847, while moderate and remission groups had mean CRP values as 36.766 ± 43.660 and 1.200 ± 1.200, respectively, with P < 0.001 which is highly significant. Low activity group had mean RA factor value of 21.574 ± 16.306, while moderate and remission groups had mean RA factor values as 86.453 ± 180.580 and 18.352 ± 24.230, respectively, with P = 0.102. Low activity group had mean anti-CCP value of 313.889 ± 347.189, while moderate and remission groups had mean anti-CCP values as 458.037 ± 342.880 and 33.481 ± 52.090, respectively, with P < 0.001 which is highly significant. Low activity group had mean ESR value of 41.611 ± 21.544, while moderate and remission groups had mean ESR values as 48.500 ± 32.477 and 32.389 ± 16.783, respectively, with P = 0.166 [Table 3] and [Figure 2].
Table 3: Association of Disease Activity Score-28 with various parameters among cases

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Figure 2: Association of Disease Activity Score-28 with various laboratory parameters among cases

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  Discussion Top


Our study had 80% (n = 40) females in case group, while control group had just 6% (n = 3) of females. High prevalence in case group can be attributed to the fact that RA is three times more common in females as compared to males. The onset is most frequent during the fourth and fifth decades of life, with 80% of all patients developing disease between the ages of 35 and 50. Even in our study, the mean age in case group was 41.42 years which happen to be consistent with the literature.

Our results show that the serum Vitamin D levels in case group are significantly lower than control group. Literature has been unanimous in fostering the relationship between levels of Vitamin D in RA. We selected nine studies which found low serum Vitamin D levels in RA [Table 4].
Table 4: Study listing low Vitamin D levels in rheumatoid arthritis

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Association of DAS-28 with Vitamin D revealed high mean Vitamin D level in remission group as compared to moderate activity group, but low activity group had the least mean Vitamin D level and the data were statistically not significant.

Numerous articles have been published revealing inverse association between RA disease activity and serum Vitamin D level. We have shortlisted seven studies and listed in [Table 5]. Similar to our study, few others also did not find association between Vitamin D deficiency and disease activity in RA like Craig et al. in 2010[15], Braun-Moscovici et al. in 2011,[16] and Baker et al. in 2012.[17]
Table 5: Study listing inverse association between Disease Activity Score-28 and Vitamin D levels

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Association of DAS-28 with other parameters, especially CRP and anti-CCP yielded results which were highly significant, thereby signifying role of CRP and anti-CCP as markers to judge disease activity in a patient of RA. Ruof and Stucki[18] found ESR and CRP as sensitive markers of disease activity in patients with RA.

There was negative correlation between Vitamin D and ESR and also between Vitamin D and RA factor. DAS-28 had positive correlation with CRP, anti-CCP, RA factor, and ESR. However, there was no correlation between Vitamin D and DAS-28. Our results are consistent with some studies.[19],[20] Other studies revealed that there is an inverse correlation between Vitamin D serum level and DAS-28 score.[21],[22]

To summarize, it appears that Vitamin D deficiency is highly prevalent in patients with RA and serum levels of CRP and anti-CCP are significant markers of disease activity. There was no correlation between Vitamin D levels and DAS-28 nor was there any association between DAS-28 and Vitamin D levels.

This study has some limitations which have to be pointed out:

  1. Small sample size
  2. Confounding factors such as climate, season, sun exposure, and nutritional status may have affected our results
  3. There might be association between Vitamin D level and medications for RA treatment (e.g., sulfasalazine, leflunomide, methotrexate, etc.).



  Conclusions Top


The study validates findings of various studies where low Vitamin D levels have been documented in RA but found no correlation between DAS-28 and Vitamin D which can be attributed to small sample size.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.



 
  References Top

1.
Scott DL, Wolfe F, Huizinga TW. Rheumatoid arthritis. Lancet 2010;376:1094-108.  Back to cited text no. 1
    
2.
Carmona L, Cross M, Williams B, Lassere M, March L. Rheumatoid arthritis. Best Pract Res Clin Rheumatol 2010;24:733-45.  Back to cited text no. 2
    
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Aviña-Zubieta JA, Choi HK, Sadatsafavi M, Etminan M, Esdaile JM, Lacaille D. Risk of cardiovascular mortality in patients with rheumatoid arthritis: A meta-analysis of observational studies. Arthritis Rheum 2008;59:1690-7.  Back to cited text no. 3
    
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Gonzalez A, Maradit Kremers H, Crowson CS, Nicola PJ, Davis JM 3rd, Therneau TM, et al. The widening mortality gap between rheumatoid arthritis patients and the general population. Arthritis Rheum 2007;56:3583-7.  Back to cited text no. 4
    
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Frank-Bertoncelj M, Klein K, Gay S. Interplay between genetic and epigenetic mechanisms in rheumatoid arthritis. Epigenomics 2017;9:493-504.  Back to cited text no. 5
    
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Fuchs HA, Brooks RH, Callahan LF, Pincus T. A simplified twenty-eight-joint quantitative articular index in rheumatoid arthritis. Arthritis Rheum 1989;32:531-7.  Back to cited text no. 6
    
7.
Cutolo M, Pizzorni C, Sulli A. Vitamin D endocrine system involvement in autoimmune rheumatic diseases. Autoimmun Rev 2011;11:84-7.  Back to cited text no. 7
    
8.
Peelen E, Knippenberg S, Muris AH, Thewissen M, Smolders J, Tervaert JW, et al. Effects of vitamin D on the peripheral adaptive immune system: A review. Autoimmun Rev 2011;10:733-43.  Back to cited text no. 8
    
9.
Veldman CM, Cantorna MT, DeLuca HF. Expression of 1,25-dihydroxyvitamin D(3) receptor in the immune system. Arch Biochem Biophys 2000;374:334-8.  Back to cited text no. 9
    
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Deluca HF, Cantorna MT. Vitamin D: Its role and uses in immunology. FASEB J 2001;15:2579-85.  Back to cited text no. 10
    
11.
Lemire JM, Archer DC, Beck L, Spiegelberg HL. Immunosuppressive actions of 1,25-dihydroxyvitamin D3: Preferential inhibition of Th1 functions. J Nutr 1995;125:1704S-8S.  Back to cited text no. 11
    
12.
Cippitelli M, Santoni A. Vitamin D3: A transcriptional modulator of the interferon-gamma gene. Eur J Immunol 1998;28:3017-30.  Back to cited text no. 12
    
13.
Boonstra A, Barrat FJ, Crain C, Heath VL, Savelkoul HF, O'Garra A, et al. 1alpha, 25-dihydroxyvitamin d3 has a direct effect on naive CD4(+) T cells to enhance the development of Th2 cells. J Immunol 2001;167:4974-80.  Back to cited text no. 13
    
14.
Aletaha D, Neogi T, Silman AJ, Funovits J, Felson DT, Bingham CO 3rd, et al. 2010 rheumatoid arthritis classification criteria: An American College of Rheumatology/European league against rheumatism collaborative initiative. Arthritis Rheum 2010;62:2569-81.  Back to cited text no. 14
    
15.
Craig SM, Yu F, Curtis JR, Alarcón GS, Conn DL, Jonas B, et al. Vitamin D status and its associations with disease activity and severity in African Americans with recent-onset rheumatoid arthritis. J Rheumatol 2010;37:275-81.  Back to cited text no. 15
    
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Braun-Moscovici Y, Toledano K, Markovits D, Rozin A, Nahir AM, Balbir-Gurman A. Vitamin D level: Is it related to disease activity in inflammatory joint disease? Rheumatol Int 2011;31:493-9.  Back to cited text no. 16
    
17.
Baker JF, Baker DG, Toedter G, Shults J, Von Feldt JM, Leonard MB. Associations between Vitamin D, disease activity, and clinical response to therapy in rheumatoid arthritis. Clin Exp Rheumatol 2012;30:658-64.  Back to cited text no. 17
    
18.
Ruof J, Stucki G. Validity aspects of erythrocyte sedimentation rate and C-reactive protein in ankylosing spondylitis: A literature review. J Rheumatol 1999;26:966-70.  Back to cited text no. 18
    
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Quraishi MK, Badsha H. Rheumatoid arthritis disease activity and vitamin D deficiency in an Asian resident population. Int J Rheum Dis 2016;19:348-54.  Back to cited text no. 19
    
20.
Yazmalar L, Ediz L, Alpayci M, Hiz O, Toprak M, Tekeoglu I. Seasonal disease activity and serum Vitamin D levels in rheumatoid arthritis, ankylosing spondylitis and osteoarthritis. Afr Health Sci 2013;13:47-55.  Back to cited text no. 20
    
21.
Svensson D, Nebel D, Nilsson BO. Vitamin D3 modulates the innate immune response through regulation of the hCAP-18/LL-37 gene expression and cytokine production. Inflamm Res 2016;65:25-32.  Back to cited text no. 21
    
22.
Rossini M, Maddali Bongi S, La Montagna G, Minisola G, Malavolta N, Bernini L, et al. Vitamin D deficiency in rheumatoid arthritis: Prevalence, determinants and associations with disease activity and disability. Arthritis Res Ther 2010;12:R216.  Back to cited text no. 22
    


    Figures

  [Figure 1], [Figure 2]
 
 
    Tables

  [Table 1], [Table 2], [Table 3], [Table 4], [Table 5]



 

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