ArticlePDF AvailableLiterature Review

The Effect of Vitamin D Supplementation on Rheumatoid Arthritis Patients: A Systematic Review and Meta-Analysis

Authors:

Abstract and Figures

Objective Observational studies have shown that vitamin D levels are inversely related to rheumatoid arthritis activity, yet evidence from population interventions remains inconsistent. Methods: The PubMed, Cochrane Library, Embase, CNKI, VIP, and Wanfang databases were searched for studies published before June 2020. Information was collected about the pain visual analog scale (VAS), Disease Activity Score 28 (DAS28), serum vitamin D level, tender joint count (TJC), swollen joint count (SJC), erythrocyte sedimentation rate (ESR), C-reactive protein (CRP), and parathyroid hormone (PTH) research data. Results: Six studies (n = 438) were included in the meta-analysis. Vitamin D supplementation resulted in a significant improvement in the DAS28 (weighted mean difference (WMD) = −0.41, 95% CI (−0.59, −0.23), P < 0.001), ESR (WMD = −3.40, 95% CI (−6.62, −0.18), P = 0.04) and TJC (WMD = −1.44, 95% CI (−2.74, −0.14), P = 0.03) but not in other outcomes. According to the subgroup analyses, VAS and serum vitamin D were improved in the European ethnic subgroups. TJC and serum vitamin D were improved in the Asian ethnic subgroups. TJC and serum vitamin D were improved in the duration ≤ 12 w subgroups, and the VAS and DAS28 in the duration > 12 w subgroup were different from those of the control group. With a vitamin D dose ≤50,000 IU, only serum vitamin D and TJC improved, and with a vitamin D dose> 50,000 IU, the VAS and DAS28 improved. Conclusions: Compared with placebo control interventions, vitamin D supplementation seemed to be an effective intervention for patients with rheumatoid arthritis. Different doses of vitamin D and durations of intervention produce different effects.
Content may be subject to copyright.
SYSTEMATIC REVIEW
published: 30 October 2020
doi: 10.3389/fmed.2020.596007
Frontiers in Medicine | www.frontiersin.org 1October 2020 | Volume 7 | Article 596007
Edited by:
Helena Canhao,
New University of Lisbon, Portugal
Reviewed by:
Garifallia Sakellariou,
University of Pavia, Italy
Wang-Dong Xu,
Southwest Medical University, China
*Correspondence:
Hongwu Wang
tjwanghw5555@163.com
Huaien Bu
buhuaien1976@163.com
Specialty section:
This article was submitted to
Rheumatology,
a section of the journal
Frontiers in Medicine
Received: 18 August 2020
Accepted: 12 October 2020
Published: 30 October 2020
Citation:
Guan Y, Hao Y, Guan Y, Bu H and
Wang H (2020) The Effect of Vitamin D
Supplementation on Rheumatoid
Arthritis Patients: A Systematic Review
and Meta-Analysis.
Front. Med. 7:596007.
doi: 10.3389/fmed.2020.596007
The Effect of Vitamin D
Supplementation on Rheumatoid
Arthritis Patients: A Systematic
Review and Meta-Analysis
Yuanyuan Guan 1, Yang Hao 2, Yun Guan 3, Huaien Bu 4
*and Hongwu Wang 4
*
1Graduate School, Tianjin University of Traditional Chinese Medicine, Tianjin, China, 2Department of Traditional Chinese
Medicine, Tianjin First Central Hospital, Tianjin, China, 3Crawford School of Public Policy, Asia and Pacific College, Australian
National University, Canberra, ACT, Australia, 4School of Health Sciences and Engineering, Tianjin University of Traditional
Chinese Medicine, Tianjin, China
Objective Observational studies have shown that vitamin D levels are inversely
related to rheumatoid arthritis activity, yet evidence from population interventions
remains inconsistent.
Methods: The PubMed, Cochrane Library, Embase, CNKI, VIP, and Wanfang databases
were searched for studies published before June 2020. Information was collected about
the pain visual analog scale (VAS), Disease Activity Score 28 (DAS28), serum vitamin D
level, tender joint count (TJC), swollen joint count (SJC), erythrocyte sedimentation rate
(ESR), C-reactive protein (CRP), and parathyroid hormone (PTH) research data.
Results: Six studies (n=438) were included in the meta-analysis. Vitamin D
supplementation resulted in a significant improvement in the DAS28 (weighted mean
difference (WMD) = −0.41, 95% CI (0.59, 0.23), P<0.001), ESR (WMD = −3.40,
95% CI (6.62, 0.18), P=0.04) and TJC (WMD = −1.44, 95% CI (2.74, 0.14), P
=0.03) but not in other outcomes. According to the subgroup analyses, VAS and serum
vitamin D were improved in the European ethnic subgroups. TJC and serum vitamin D
were improved in the Asian ethnic subgroups. TJC and serum vitamin D were improved in
the duration 12 w subgroups, and the VAS and DAS28 in the duration >12 w subgroup
were different from those of the control group. With a vitamin D dose 50,000 IU, only
serum vitamin D and TJC improved, and with a vitamin D dose>50,000 IU, the VAS and
DAS28 improved.
Conclusions: Compared with placebo control interventions, vitamin D supplementation
seemed to be an effective intervention for patients with rheumatoid arthritis. Different
doses of vitamin D and durations of intervention produce different effects.
Keywords: vitamin D, rheumatoid arthritis, inflammatory response, meta-analysis, health medicine
INTRODUCTION
Rheumatoid arthritis (RA) is a chronic autoimmune disease that manifests as a chronic
inflammatory response, and persistent synovitis leads to progressive deterioration and impairment
of joint function (1). RA bone fragility is caused by systemic inflammation, circulating
auto-antibodies and pro-inflammatory cytokine secretion, which together have harmful effects on
Guan et al. Vitamin D for Rheumatoid Arthritis
bone (2). The prevalence of RA is 1–2% of the world’s
population, and the prevalence in women is three times that
in men (3). Rheumatoid arthritis can occur at any age, but
patients around the ages of 40 and 50 are more susceptible.
According to the World Health Organization mortality database
of 31 countries, RA accounts for almost 18% of all deaths caused
by different types of arthritis and other musculoskeletal diseases,
but the exact cause of RA remains unknown (4,5).
Vitamin D (VD) is a fat-soluble hormone that promotes
calcium/phosphate metabolism in bones (6). Studies have found
that vitamin D has certain effects on other physiological functions
and pathological conditions. Specifically, vitamin D has been
widely indicated to have an effect on the immune system (7).
There is evidence that VD may be involved in rheumatoid
arthritis (RA). Studies have found that VD can prevent antigen
expression (8) and increase and regulate T cell activity (9).
Higgins et al. (10) found that VD controls the innate and
adaptive immune systems mainly through Toll-like receptors
(TLRs) and differentiation of T-cells, predominantly Th17 cells,
and that these Th17 cells have a crucial role in RA pathology.
Aslam et al. (11) found that VD is an important regulator
of various genes involved in the immune system. VD mainly
prevents the occurrence and development of rheumatoid arthritis
by inhibiting cytokine levels (12). In clinical applications, an
increasing number of physicians use VD as a supplement to treat
RA. The results have a certain effect on improving the symptoms,
laboratory indicators or prognosis of RA patients. At the same
time, studies on the potential role of VD supplementation in
RA treatment have produced inconsistent results. In view of
the differences in the current studies, a comprehensive and
systematic evaluation of the efficacy of VD as a supplement for
RA is necessary.
The aim of this systematic evaluation was to evaluate the
efficacy of VD as a supplement for RA compared with a placebo
control group and to determine the effects of different VD doses
and supplementation times on these patients.
METHODS
Research Strategy
We searched the PubMed, Cochrane Library, Embase, CNKI,
VIP, and Wanfang databases for studies published before
June 2020. The search terms were (1) “Vitamin D”[Mesh]
OR “Ergocalciferols”[Mesh] OR “Cholecalciferol”[Mesh]
OR “Calcifediol”[Mesh] OR “Ergocalciferol” OR “Vitamin
D Supplementation” OR “25-hydroxy-vitamin D”; (2)
“Arthritis”[Mesh] OR “Rheumatoid Arthritis”[Mesh] OR
“Rheumatoid Nodule” OR “Rheumatoid Vasculitis”; and (3)
#1 AND #2. The results were filtered for clinical trials and
Abbreviations: CI, confidence interval; CNKI, China National Knowledge
Infrastructure; PubMed, National Library of Medicine; VIP, VIP Database
for Chinese Technical Periodicals; MD, mean difference; PRISMA, Preferred
Reporting Items Systematic Reviews and Meta-Analyses; RR, risk ratio; RCT,
randomized controlled trial; SD, standard deviation; SE, standard error; WMD,
weighted mean difference; DAS28, Disease Activity Score 28; VAS, Pain Visual
Analog Scale; TJC, Tender joint count; SJC, Swollen joint count; ESR, Erythrocyte
sedimentation rate; CRP, C-reactive protein; PTH, Parathyroid hormone.
randomized clinical trials. The above search strategy was run
in PubMed and was tailored to each database when necessary.
Two independent reviewers selected and screened all results, and
in cases of disagreement, a third reviewer was asked for advice.
The reviewers applied the PRISMA statement guidelines for
reporting systematic reviews and meta-analyses (13).
Eligibility Criteria
The inclusion criteria for this systematic review were as follows:
(1) a randomized controlled trial (RCT) design related to the
therapeutic effect of VD as a supplement was used; (2) human
subjects were recruited; (3) VD supplementation was the main
intervention in the experimental group and was compared to
a standard treatment control condition; and (4) at least one
detail of the outcomes of interest was reported, including changes
in serum vitamin D level, tender joint count, swollen joint
count, ESR (erythrocyte sedimentation rate), VAS (pain visual
analog scale), DAS28 (Disease Activity Score 28), CRP (C-
reactive protein), PTH (parathyroid hormone). Data including
the mean and standard deviation of each group at baseline
and post-intervention, along with the number of participants
in each group, were able to be obtained. The exclusion criteria
were as follows: (1) duplicate publications; (2) non-intervention
designs (such as case-control studies, cohort studies, cross-
sectional studies, case reports and experiences, theory research,
and reviews); and (3) non-clinical tests and animal experiments.
Data Extraction
Two review authors independently screened the literature using
the predetermined inclusion criteria and extracted the data
from the trials. The following information was extracted:
participant characteristics, intervention and outcome data,
adverse effects, and methodological quality. The reviewers
resolved any disagreements about the extracted data from the
included studies by consensus and consulted a third review
author if the disagreements persisted.
Risk of Bias Assessment
The risk of study bias was assessed using the Cochrane
Handbook for Systematic Reviews. The risk of bias of the studies
was evaluated with regard to the following aspects: random
sequence generation, hidden methods utilization, blinding
method application, incomplete results management, selective
reporting of results, and other biases. Funnel diagrams were used
to detect publication bias.
Rating Quality of Evidence
The Grading of Recommendations, Assessment, Development
and Evaluation (GRADE) approach was used to rate the quality
of evidence for each outcome. The strength of the evidence was
categorized as high, moderate, low or very low (14). The GRADE
was used to rate the quality of evidence by the consensus of
two authors.
Frontiers in Medicine | www.frontiersin.org 2October 2020 | Volume 7 | Article 596007
Guan et al. Vitamin D for Rheumatoid Arthritis
Statistical Analysis
Extraction and Merging of Data
The Cochrane Collaboration’s Review Manager 5.3 software was
used to extract the relevant dichotomous or continuous data
from the literature for analysis. Risk ratios (RRs) were calculated
for dichotomous data, whereas the mean differences (MDs)
and standard deviations (SDs) were calculated for continuous
variables. The corresponding 95% confidence intervals (CIs) and
forest plots were used in both cases. In our meta-analysis, we used
SD values when the data were provided in the same unit. When
they were provided in different units, we performed a conversion.
The chi-squared and I2(inconsistency) tests were used to detect
heterogeneity. A P<0.10 or I2>50% indicated that there
was significant heterogeneity. The fixed-effect model was used
when P>0.10 and I2<50%, and the random-effect model was
used when P<0.10 or I250%. Subgroup analysis is used
to explore the influence of certain characteristics: geographic
regions, duration, supplemental dose.
Data Conversion
The final DAS28 and VAS values were evaluated as the main
results, and serum vitamin D level, TJC, SJC, ESR, CRP, and PTH
were evaluated as the secondary indicators. Some trials provided
the average value of the indicator but did not provide the SD. We
calculated the SD of the indicator using the following formulas:
(1) If the number of samples (n) and the standard error (SE) were
known, the SD was calculated as:
SD =SE×n
(2) Estimates of SD were calculated if the number of samples (n),
mean, and 95% CI (15,16) were known, where “a” and “b” are the
upper and lower confidence limits, respectively:
SD =amean/1.96n
SD =mean b/1.96n
RESULTS
Study Selection
A total of 625 study reports were screened, 165 of which were
excluded because they were duplicate publications. After the
reading of the titles and abstracts, an additional 352 articles were
excluded, and 44 articles were retained. Among them, 38 articles
did not meet the inclusion criteria, 20 studies did not have a
suitable control group, and 18 studies did not have data that
we were able to extract. Finally, six RCTs with a total of 438
participants were included. The PRISMA flow diagram is shown
in Figure 1.
Study Characteristics
The principal study characteristics are summarized in Table 1.
Six studies were published between 2011 and 2018. A total of
438 participants were included. The number of participants in the
individual studies ranged from 11 to 62. All of the included trials
were single-center studies. The included studies were conducted
in different geographical regions: North America (19), Europe
(2022) and Asia (17,18). The duration of the intervention
varied from 12 to 24 weeks. All participants had rheumatoid
arthritis. Only one trial applied vitamin D and calcium co-
supplementation (the same doses of calcium were also given to
the control groups) (18). The other studies provided vitamin D
supplementation alone.
Quality Assessment
Figure 2 provides an overview of the risk of bias for the included
studies based on the tools provided by the Cochrane Manual. All
the included studies used a double-blind approach and reported
dropouts. Most of the trials reported allocation concealment and
random allocation but did not specify the method used. Four
studies (17,18,21,22) reported automatic generation of random
sequences by a computer, while two studies (19,20) reported that
the division of participants into an experimental group and a
control group with random number tables. Studies that employed
selective reporting were unbiased but did include any description
to evaluate the existence of other biases. All the included trials
reported whether adverse events occurred. It is worth noting that
no adverse events occurred in the included trials.
Study Results
The Effect on the VAS
Five included RCT trials (17,18,2022) with a total of 416
participants provided data on the VAS. There was highly
significant heterogeneity among the five studies (I2=72%,
P=0.007). The VAS in the vitamin D supplement group
was lower than that in the control group, but the difference
was not significant [WMD = −2.85, 95% CI (6.90, 1.20),
P=0.17] (Figure 3A). However, vitamin D supplementation
produced significant decreases in the following subgroups:
Europe, duration >12 w, and vitamin D dose >50,000
IU (Table 2).
The Effect on the DAS28
DAS28 levels were reported in five trials (17,18,2022)
with a total of 416 participants. There was high heterogeneity
among the five studies (I2=87%, P<0.001). There was a
significant difference in the DAS28 between the rheumatoid
arthritis patients who received vitamin D supplementation
and the control group. [WMD = −0.41, 95% CI (0.59,
0.23), P<0.001] (Figure 3B). Nevertheless, the effects shown
in the Europe, duration >12 w, and vitamin D dose >
50,000 IU subgroups were significantly in favor of the control
group (Table 2).
The Effect on Serum Vitamin D Levels
Figure 3C shows the forest plot analysis of the effect on
serum vitamin D levels. Three RCTs were included (17,19,
21). There was a significant increase in the serum vitamin
D level in the vitamin D supplementation group [WMD =
23.37, 95% CI (16.15, 30.59), P<0.001]. We used a random
effects model for the quantitative serum vitamin D level data
and showed low heterogeneity (I2=0%, P<0.001). Similar
results were demonstrated in the duration 12 w, Europe
Frontiers in Medicine | www.frontiersin.org 3October 2020 | Volume 7 | Article 596007
Guan et al. Vitamin D for Rheumatoid Arthritis
FIGURE 1 | Study selection procedure according to the PRISMA statement (13).
and Asia, and vitamin D dose 50,000 IU or >50,000 IU
subgroups (Table 2).
The Effect on the TJC
Two trials reported a change in the TJC after the intervention
(17,21). In the comparison of the control and intervention
groups, the difference in TJC reduction was significant [WMD
= −1.44, 95% CI (2.74, 0.14), P=0.03] (Figure 3D) and
had low heterogeneity (I2=0%, P=0.37). Nevertheless, the
effects shown in the Europe and Vitamin D supplement >50,000
IU subgroups were not significantly different from those of the
control group (Table 2).
The Effect on the SJC
In terms of reducing the SJC (17,21), there was no significant
difference between the vitamin D supplementation group and the
control group [WMD = −0.75, 95% CI (1.58, 0.08), P=0.08]
(Figure 3E). There was low heterogeneity among the included
studies (I2=0%, P=0.56). The subgroup analyses suggested
similar findings for all subgroups of the intervention (Table 2).
Frontiers in Medicine | www.frontiersin.org 4October 2020 | Volume 7 | Article 596007
Guan et al. Vitamin D for Rheumatoid Arthritis
TABLE 1 | Randomized controlled trials included in the systematic review of the effects of vitamin D supplementation on rheumatoid arthritis.
References Sample Mean age Nation Supplemented Supplementation Time of Outcome Adverse event;
size (T/C) (T/C) dose of vitamin D intervention measured follow-up
Salesi and
Farajzadegan (17)
50/48 49.9 ±13/50 ±12.7 Iran 50,000 IU/weekly Vit D 12 week ①②③④⑤⑥ No
Gopinath and Danda
(18)
59/62 44.86 ±12.33/44.90 ±12.5 India 500 IU/weekly Vit D +Ca 12 week ④⑤⑥⑧ No
Hansen et al. (19) 11/11 63 ±12/53 ±11 America 50,000 IU/weekly Vit D 12 week ①⑨ No
Buondonno et al.
(20)
18/18 56 ±14/54 ±12 Italy 300,000 IU/day Vit D 12 week ④⑤⑥⑧⑨ No
Adami et al. (21) 51/51 58 ±13/58 ±12 Italy 100,000 IU/4 weeks Vit D 12 week ①②③⑤⑦ No
Soubrier et al. (22) 29/30 59.8 ±10.9/59.7 ±8.9 France 100,000 IU once Vit D 24 week ④⑤⑥⑧ No
Months were converted to weeks by using 1 mo =4 wk; years were converted by using 1 y =52 wk.
T,treatment group; C, control group; DAS28, Disease Activity Score 28; VAS, Pain visual analog scale; TJC, Tender joint count; SJC, Swollen joint count; ESR, Erythrocyte sedimentation
rate; CRP, C-reactive protein; PTH, Parathyroid hormone.
Serum vitamin D Level; Tender joint count; Swollen joint count; ESR; VAS (0–100); DAS 28; DAS 28-CRP; CRP; PTH.
The Effect on the ESR
The combined ESR results of the four studies (17,18,20,22)
comparing a vitamin D supplementation group with a control
group showed significant differences [WMD = −3.40, 95% CI
(6.62, 0.18), P=0.04), with low heterogeneity (I2=0%, P
=0.75) (Figure 3F). In the subgroup analysis, the levels in the
vitamin D supplementation group were lower than those in the
control group, but there was no significant difference (Table 2).
The Effect on CRP
Four studies (18,2022) reported CRP levels in 318 patients, and
157 of those patients underwent a vitamin D supplementation
intervention. The CRP levels decreased in the vitamin D
supplementation group compared with the levels in the control
group, but there was no significant difference [WMD = −1.03,
95% CI (4.25, 2.20), P=0.53] (Figure 3G). Similarly, no
significant differences were found between the vitamin D
intervention group and the control group in the subgroup
analysis (Table 2).
The Effect on PTH
Two trials (n=58) measured the effect of vitamin D
supplementation on PTH (19,20). Overall, we observed no
difference in PTH reduction between the intervention and
control groups [WMD =3.94, 95% CI (1.37, 9.24), P=0.15].
The heterogeneity was low (I2=40%, P=0.20) (Figure 3H). In
the subgroup analysis, it was found that there was a significant
difference between the vitamin D supplement group and the
control group for the Europe and vitamin D dose>50,000 IU
subgroups (Table 2).
Publication Bias
The publication bias of the six RCTs was evaluated with a funnel
plot. Figure 4 shows that the publication bias across the studies
was small.
Quality of Evidence
Table 3 presents the quality of evidence by outcome, assessed
with the GRADE system. The evidence quality was classified
as low for the DAS28, VAS, CRP, and PTH, very low
for the SJC, and moderate for the serum vitamin D level,
TJC, and ESR.
DISCUSSION AND CONCLUSION
Rheumatoid arthritis is characterized by persistent synovitis,
systemic inflammation and autoantibody production (23).
Genetic factors and environmental factors are closely related
to the incidence of rheumatoid arthritis (24,25). In developed
countries, the prevalence of adult rheumatoid arthritis has
increased yearly (26). Active rheumatoid arthritis that does not
receive interventional treatment can cause joint damage and even
disability (27). Decreased quality of life causes cardiovascular
disease and other complications (28,29). Vitamin D is a fat-
soluble hormone that has been extensively studied (30), but
recent studies have found that vitamin D has a wide range
of immune system activities (31) and that it may be related
to the pathogenesis of rheumatoid arthritis (32). Lee et al.
conducted a meta-analysis of the sensitivity of vitamin D levels
to RA and RA activity in rheumatoid patients, indicating that
vitamin D levels were negatively correlated with sensitivity to
RA and RA activities (33). There are also studies based on
rheumatoid arthritis that suggest that active vitamin D can
be used as a parameter for regulating inflammation and that
vitamin D has the potential to be a therapeutic biomarker
and can even be used to track the disease progression and
treatment effect of rheumatoid arthritis patients (34). In previous
systematic reviews, no studies have evaluated VD as a supplement
for the treatment of RA. In this study, through quantitative
synthesis, we found that compared with the control group, RA
patients treated with VD as complementary therapy seemed
to experience more beneficial effects on the DAS28, TJC, and
ESR. In contrast, the VAS, SJC, CRP and PTH showed no
benefits. However, although there were no overall beneficial
findings, several subgroups showed significant positive effects in
terms of demographic characteristics and interventions. Pain is
a symptom that rheumatoid arthritis patients urgently need to
Frontiers in Medicine | www.frontiersin.org 5October 2020 | Volume 7 | Article 596007
Guan et al. Vitamin D for Rheumatoid Arthritis
FIGURE 2 | Risk of bias summary: the review authors’ judgements about each risk of bias item for each included study.
improve. Previous studies have shown that nearly 90% of patients
with rheumatoid arthritis regard pain as the first symptom
requiring improvement (35). The VAS score is a commonly used
pain score in clinical work and can accurately reflect the degree
of pain experienced by patients (36). Based on our combined
research results, we found that VD supplementation did not
significantly reduce the VAS in rheumatoid arthritis patients.
However, in the subgroup analysis, we found that with a vitamin
D intervention time>12 w and vitamin D dose>50,000 IU, in
the VD intervention group, VAS was significantly reduced. Some
Frontiers in Medicine | www.frontiersin.org 6October 2020 | Volume 7 | Article 596007
Guan et al. Vitamin D for Rheumatoid Arthritis
FIGURE 3 | Effect of vitamin D supplementation on (A) Patient global pain score; (B) Disease Activity Score 28; (C) Serum vitamin D level; (D) Tender joint count; (E)
Swollen joint count; (F) Erythrocyte sedimentation rate; (G) C-reactive protein; and (H) Parathyroid hormone.
Frontiers in Medicine | www.frontiersin.org 7October 2020 | Volume 7 | Article 596007
Guan et al. Vitamin D for Rheumatoid Arthritis
TABLE 2 | Subgroup analyses.
Subgroups VAS DAS28 Serum vitamin D TJC SJC ESR CRP PTH
WMD 95% CI PWMD 95% CI PWMD 95% CI PWMD 95% CI PWMD 95% CI PWMD 95% CI PWMD 95% CI PWMD 95% CI P
Geographical regions
North America – – – – – – 22.26 [6.97,
51.49]
0.14 – – – – – – – – – 1.00 [10.19,
8.19]
0.83
Europe 9.26 [14.51,
4.00]
0.0006 0.54 [0.74,
0.34]
<0.001 20.35 [9.79,
30.91]
0.0002 0.90 [2.65,
0.85]
0.31 0.50 [1.68,
0.68]
0.41 3.25 [8.94,
2.43]
0.26 0.31 [3.71,
3.09]
0.86 6.40 [0.10,
12.90]
0.05
Asia 6.47 [0.13,
12.82]
0.05 0.07 [0.31,
0.46]
0.71 26.50 [15.98,
37.02]
<0.001 2.10 [4.04,
0.16]
0.03 1.00 [2.17,
0.17]
0.10 2.40 [6.30,
1.50]
0.23 7.50 [17.75,
2.75]
0.15 – – –
Duration
12 w 0.86 [5.53,
3.82]
0.72 0.06 [0.28,
0.17]
0.63 23.37 [16.15,
30.59]
<0.001 1.44 [2.74,
0.14]
0.03 0.75 [1.58,
0.08]
0.08 2.44 [6.14,
1.25]
0.20 1.04 [5.07,
2.99]
0.61 3.94 [1.37,
9.24]
0.15
>12 w 8.90 [17.02,
0.78]
0.03 1.00 [1.29,
0.71]
<0.001 – – – – – – – – – 3.40 [9.93,
3.13]
0.31 1.00 [6.38,
4.38]
0.72 – – –
Vitamin D dose
50,000 IU 6.47 [0.13,
12.82]
0.05 0.07 [0.31,
0.46]
0.71 26.01 [16.12,
35.91]
<0.001 2.10 [4.04,
0.16] 0.03 1.00 [2.17,
0.17]
0.10 2.40 [6.30,
1.50]
0.23 7.50 [17.75,
2.75]
0.15 1.00 [10.19,
8.19]
0.83
>50,000 IU 9.26 [14.51,
4.00]
0.0006 0.54 [0.74,
0.34]
<0.001 20.35 [9.79,
30.91]
0.0002 0.90 [2.65,
0.85]
0.31 0.50 [1.68,
0.68]
0.41 3.25 [8.94,
2.43]
0.26 0.31 [3.71,
3.09]
0.86 6.40 [0.10,
12.90]
0.05
FIGURE 4 | Funnel plot of six randomized controlled trials of vitamin D
supplementation for rheumatoid arthritis.
experimental studies have shown that vitamin D significantly
improves nociceptive thresholds and allodynia scores, supporting
the analgesic effect of vitamin D on rheumatoid arthritis
patients (37). The DAS28 score has important significance as
an evaluation indicator of the disease activity of rheumatoid
arthritis patients and whether vitamin D is effective after drug
treatment (38). Research analysis found that the DAS28 score of
patients with rheumatoid arthritis was effectively reduced after
vitamin D supplementation. In contrast, when the vitamin D
dose was 50,000 IU or the duration was 12 w, there was
no difference between the vitamin D supplement group and
the control group. This may be because large-dose and long-
term vitamin D supplementation can reduce the inflammatory
factor response (39). Mainly through the differentiation of Toll-
like receptors and T cells (mainly Th17 cells) to control the
innate and adaptive immune system. It can even be used as an
important regulator of various genes in the immune system. The
SJC, TJC, and ESR are closely related to the DAS28 score (40).
Through comprehensive analysis, it was found that the TJC and
ESR were significantly reduced in the vitamin D supplement
group, which was consistent with the study that found that
the DAS28 score was reduced. The ESR subgroup analysis
does not support this finding. This may be because the small
sample size reduced the reliability of the ESR subgroups. Further
research is needed to clarify this connection and explore its
potential explanation.
Our study also focused on the effect of vitamin D
supplementation on the self-inflammatory response and
hormonal immune response of rheumatoid arthritis patients.
Therefore, we systematically evaluated the levels of CRP and
PTH in rheumatoid arthritis patients and found no significant
improvement after VD supplementation. Bjorkman et al. (41)
and Moghimi et al. (42) reported results consistent with this
finding. CRP concentration is related to bone turnover but
not to vitamin D status. Serum vitamin D levels in patients
with rheumatoid arthritis may not be related to PTH secretion
or activity.
Frontiers in Medicine | www.frontiersin.org 8October 2020 | Volume 7 | Article 596007
Guan et al. Vitamin D for Rheumatoid Arthritis
TABLE 3 | Evidence quality rated using the GRADE approach.
Outcomes No. of studies Limitations Inconsistency Indirectness Imprecision Publication bias Evidence quality
DAS28a5 Seriousb,c SeriousdNot serious Not serious Not found ⊕ ⊕ ◦◦ Low
VASa5 SeriousbSeriousdNot serious SeriouseNot found ⊕ ⊕ ◦◦ Low
Serum vitamin D level 3 Seriousb,c Not serious Not serious Not serious Not found ⊕ ⊕ ⊕◦ Moderate
TJCa2 SeriousbNot serious Not serious Not serious Not assessedf⊕ ⊕ ⊕◦ Moderate
SJCa2 SeriousbNot serious Not serious SeriouseNot assessedf⊕◦◦◦ Very low
ESRa4 SeriousbNot serious Not serious Not serious Not found ⊕ ⊕ ⊕◦ Moderate
CRPa4 SeriouscNot serious Not serious SeriouseNot found ⊕ ⊕ ◦◦ Low
PTHa2 SeriouscSeriousdNot serious SeriouseNot found ⊕ ⊕ ◦◦ Low
aDAS28, Disease Activity Score 28; VAS, Patient global pain score; TJC, Tender joint count; SJC, Swollen joint count; ESR, Erythrocyte sedimentation rate; CRP, C-reactive protein;
PTH, Parathyroid hormone.
bStudy had reporting bias.
cStudy had attrition bias.
dSignificant heterogeneity was observed in this meta-analysis.
eWide confidence intervals, including values in favor of the experimental group and values in favor of the control group.
fNot assessed because a limited number of studies were included in the meta-analyses on TJC and SJC.
This study has several limitations. First, the overall sample size
of this study is limited. Some of the included studies have a small
sample size, and the level of evidence defined by GRADE method
is not high. Second, most studies included did not assess the
effects of sun exposure and dietary intake, and did not indicate
whether the patient’s rheumatoid arthritis was in the early or
late stage, which may have affected the results of the meta-
analysis. We conducted a sensitivity analysis of the included RCTs
and found that two studies may be the source of most of the
heterogeneity. In both studies, the study design was a single-
center study with a small number of participants, which may have
had an impact on the overall measurement results. In addition,
language and publication biases limited our research. Finally,
the evaluation included only randomized controlled trials. In the
future, more research diversity is needed, such as cooperation
between multiple centers, more rigorous clinical reports and
prospective research.
We summarize the research status of vitamin D
supplementation in patients with rheumatoid arthritis and
provide data to support future clinical treatment and trials
of rheumatoid arthritis. Although this study shows that
supplemental vitamin D can effectively control the DAS28,
TJC, and ESR levels of patients with rheumatoid arthritis, the
current evidence, potential bias due to the low quality of the
research methods and the observed clinical heterogeneity of
the examined studies suggest that these findings should be
carefully investigated.
CONCLUSION
Compared with the control interventions, vitamin D
supplementation seemed to be an effective intervention for
patients with rheumatoid arthritis. Different doses of vitamin
D and the duration of intervention will produce different
effects. More RCTs with rigorous research designs are needed
to determine the efficacy of vitamin D supplementation in the
treatment and improvement of symptoms and inflammatory
responses in patients with rheumatoid arthritis and to apply
vitamin D supplementation in daily interventions for rheumatoid
arthritis patients to improve the symptoms of rheumatoid
arthritis and other related chronic diseases.
DATA AVAILABILITY STATEMENT
All datasets generated for this study are included in the
article/Supplementary Material.
AUTHOR CONTRIBUTIONS
YuaG, YH, YunG, and HW: conceptualization and methodology.
YuaG and YH: data curation and formal analysis. YH and
YunG: investigation. HW and HB: project administration and
supervision. YuaG: software, writing – original draft, and writing
– review and editing. All authors contributed to the article and
approved the submitted version.
FUNDING
This project was supported by the National Key Research
and Development Program of China (approval No.:
2017YFC1703305) and the Basic Research on Health
Identification of Traditional Chinese Medicine in Tianjin
Colleges and Universities “Innovation Team Training Plan”
(approval No.: TD135049) during the 13th 5-year plan period.
SUPPLEMENTARY MATERIAL
The Supplementary Material for this article can be found
online at: https://www.frontiersin.org/articles/10.3389/fmed.
2020.596007/full#supplementary-material
Frontiers in Medicine | www.frontiersin.org 9October 2020 | Volume 7 | Article 596007
Guan et al. Vitamin D for Rheumatoid Arthritis
REFERENCES
1. Smolen JS, Aletaha D, McInnes IB. Rheumatoid arthritis. Lancet. (2016)
388:2023–38. doi: 10.1016/s0140-6736(16)30173-8
2. McInnes IB, Schett G. Mechanisms of disease the pathogenesis of rheumatoid
arthritis. N Engl J Med. (2011) 365:2205–19. doi: 10.1056/NEJMra1004965
3. van der Woude D, van der Helm-van Mil AHM. Update on the
epidemiology, risk factors, and disease outcomes of rheumatoid arthritis.
Best Pract Res Clin Rheumatol. (2018) 32:174–87. doi: 10.1016/j.berh.2018.
10.005
4. Kiadaliri AA, Felson DT, Neogi T, Englund M. Brief report: rheumatoid
arthritis as the underlying cause of death in thirty-one countries,
1987-2011: trend analysis of world health organization mortality
database. Arthritis Rheumatol. (2017) 69:1560–5. doi: 10.1002/art.
40091
5. Kiadaliri AA, Turkiewicz A, Englund M. Mortality from musculoskeletal
disorders including rheumatoid arthritis in Southern Sweden: a
multiple-cause-of-death analysis, 1998-2014. J Rheumatol. (2017)
44:571–9. doi: 10.3899/jrheum.161219
6. Bivona G, Agnello L, Ciaccio M. The immunological implication of the
new vitamin D metabolism. Central Euro J Immunol. (2018) 43:331–
4. doi: 10.5114/ceji.2018.80053
7. Medrano M, Carrillo-Cruz E, Montero I, Perez-Simon JA. Vitamin D: effect
on haematopoiesis and immune system and clinical applications. Int J Mol Sci.
(2018) 19:2663. doi: 10.3390/ijms19092663
8. Székely JI, Pataki Á. Effects of vitamin D on immune disorders
with special regard to asthma, COPD and autoimmune diseases: a
short review. Expert Rev Respir Med. (2012) 6:683–704. doi: 10.1586/
ers.12.57
9. Luo J, Wen H, Guo H, Cai Q, Li S, Li X. 1,25-dihydroxyvitamin D3
inhibits the RANKL pathway and impacts on the production of pathway-
associated cytokines in early rheumatoid arthritis. Biomed Res Int. (2013)
2013:101805. doi: 10.1155/2013/101805
10. Higgins MJ, Mackie SL, Thalayasingam N, Bingham SJ, Hamilton
J, Kelly CA. The effect of vitamin D levels on the assessment of
disease activity in rheumatoid arthritis. Clin Rheumatol. (2013)
32:863–7. doi: 10.1007/s10067-013-2174-x
11. Aslam MM, John P, Bhatti A, Jahangir S, Kamboh MI. Vitamin D
as a principal factor in mediating rheumatoid arthritis-derived immune
response. Biomed Res Int. (2019) 2019:3494937. doi: 10.1155/2019/34
94937
12. Gopal K, Thevarajah M, Ng CM, Raja J. Effects of vitamin D on disease activity
and serum interleukin-6 in rheumatoid arthritis. Int J Rheum Dis. (2019)
22:834–41. doi: 10.1111/1756-185x.13484
13. Moher D, Liberati A, Tetzlaff J, Altman DG. Preferred reporting items for
systematic reviews and meta-analyses: the PRISMA statement. Int J Surg.
(2010) 8:336–41. doi: 10.1016/j.ijsu.2010.02.007
14. Guyatt GH, Oxman AD, Vist GE, Kunz R, Falck-Ytter Y, Alonso-
Coello P, et al. GRADE: an emerging consensus on rating quality
of evidence and strength of recommendations. BMJ. (2008) 336:924–
6. doi: 10.1136/bmj.39489.470347.AD
15. Wan X, Wang W, Liu J, Tong T. Estimating the sample mean and
standard deviation from the sample size, median, range and/or interquartile
range. BMC Med Res Methodol. (2014) 14:135. doi: 10.1186/1471-2288-
14-135
16. Hozo SP, Djulbegovic B, Hozo I. Estimating the mean and variance from the
median, range, and the size of a sample. BMC Med Res Methodol. (2005)
5:13. doi: 10.1186/1471-2288-5-13
17. Salesi M, Farajzadegan Z. Efficacy of vitamin D in patients with active
rheumatoid arthritis receiving methotrexate therapy. Rheumatol Int. (2012)
32:2129–33. doi: 10.1007/s00296-011-1944-5
18. Gopinath K, Danda D. Supplementation of 1,25 dihydroxy
vitamin D3 in patients with treatment naive early rheumatoid
arthritis: a randomised controlled trial. Int J Rheum Dis. (2011)
14:332–9. doi: 10.1111/j.1756-185X.2011.01684.x
19. Hansen KE, Bartels CM, Gangnon RE, Jones AN, Gogineni J. An evaluation
of high-dose vitamin D for rheumatoid arthritis. J Clin Rheumatol. (2014)
20:112–4. doi: 10.1097/rhu.0000000000000072
20. Buondonno I, Rovera G, Sassi F, Rigoni MM, Lomater C, Parisi S,
et al. Vitamin D and immunomodulation in early rheumatoid arthritis:
a randomized double-blind placebo-controlled study. PLoS ONE. (2017)
12:e0178463. doi: 10.1371/journal.pone.0178463
21. Adami G, Rossini M, Bogliolo L, Cantatore FP, Varenna M, Malavolta N, et al.
An exploratory study on the role of vitamin D supplementation in improving
pain and disease activity in rheumatoid arthritis. Mod Rheumatol. (2019)
29:1059–62. doi: 10.1080/14397595.2018.1532622
22. Soubrier M, Lambert C, Combe B, Gaudin P, Thomas T, Sibilia J, et al. A
randomised, double-blind, placebo-controlled study assessing the efficacy of
high doses of vitamin D on functional disability in patients with rheumatoid
arthritis. Clin Exp Rheumatol. (2018) 36:1056–60.
23. Singh JA, Saag KG, Bridges SL, Akl EA, Bannuru RR, Sullivan MC, et al. 2015
American college of rheumatology guideline for the treatment of rheumatoid
arthritis. Arthritis Rheumatol. (2016) 68:1–26. doi: 10.1002/art.39480
24. Deane KD, Demoruelle MK, Kelmenson LB, Kuhn KA, Norris JM, Holers VM.
Genetic and environmental risk factors for rheumatoid arthritis. Best Practice
Res Clin Rheumatol. (2017) 31:3–18. doi: 10.1016/j.berh.2017.08.003
25. Traylor M, Curtis C, Patel H, Breen G, Lee SH, Xu XH, et al. Genetic
and environmental risk factors for rheumatoid arthritis. Best Pract Res Clin
Rheumatol. (2017) 31:3–18.
26. Salaffi F, Di Carlo M, Farah S, Di Donato E, Carotti M. Prevalence
of frailty and its associated factors in patients with rheumatoid
arthritis: a cross-sectional analysis. Clin Rheumatol. (2019)
38:1823–30. doi: 10.1007/s10067-019-04486-5
27. Abasolo L, Ivorra-Cortes J, Leon L, Jover JA, Fernández-Gutiérrez B,
Rodriguez-Rodriguez L. Contribution of the bone and cartilage/soft tissue
components of the joint damage to the level of disability in rheumatoid
arthritis patients: a longitudinal study. Clin Rheumatol. (2019) 38:691–
700. doi: 10.1007/s10067-018-4335-4
28. Blum A, Adawi M. Rheumatoid arthritis (RA) and cardiovascular disease.
Autoimmun Rev. (2019) 18:679–90. doi: 10.1016/j.autrev.2019.05.005
29. Kerekes G, Nurmohamed MT, González-Gay MA, Seres I, Paragh G, Kardos
Z, et al. Rheumatoid arthritis and metabolic syndrome. Nat Rev Rheumatol.
(2014) 10:691–6. doi: 10.1038/nrrheum.2014.121
30. Carlberg C. Nutrigenomics of Vitamin D. Nutrients. (2019)
11:676. doi: 10.3390/nu11030676
31. Manson JE, Cook NR, Lee IM, Christen W, Bassuk SS, Mora S, et al. Vitamin
D supplements and prevention of cancer and cardiovascular disease. N Engl J
Med. (2019) 380:33–44. doi: 10.1056/NEJMoa1809944
32. Bellan M, Sainaghi PP, Pirisi M. Role of vitamin D in rheumatoid arthritis. Adv
Exp Med Biol. (2017) 996:155–68. doi: 10.1007/978-3-319-56017-5_13
33. Lee YH, Bae SC. Vitamin D level in rheumatoid arthritis and its correlation
with the disease activity: a meta-analysis. Clin Exp Rheumatol. (2016) 34:
827–33.
34. Khajoei S, Hassaninevisi M, Kianmehr N, Seif F, Khoshmirsafa M,
Shekarabi M, et al. Serum levels of adiponectin and vitamin D correlate
with activity of rheumatoid arthritis. Mol Biol Rep. (2019) 46:2505–
12. doi: 10.1007/s11033-019-04682-1
35. Heiberg T, Kvien TK. Preferences for improved health examined in 1,024
patients with rheumatoid arthritis: pain has highest priority. Arthritis Rheum.
(2002) 47:391–7. doi: 10.1002/art.10515
36. Hawker GA, Mian S, Kendzerska T, French M. Measures of adult pain:
Visual Analog Scale for Pain (VAS Pain), Numeric Rating Scale for Pain
(NRS Pain), McGill Pain Questionnaire (MPQ), Short-Form McGill Pain
Questionnaire (SF-MPQ), Chronic Pain Grade Scale (CPGS), Short Form-
36 Bodily Pain Scale (SF-36 BPS), and measure of intermittent and constant
osteoarthritis pain (ICOAP). Arthritis Care Res. (2011) 63(Suppl. 11):S240–
52. doi: 10.1002/acr.20543
37. Poisbeau P, Aouad M, Gazzo G, Lacaud A, Kemmel V, Landel
V, et al. Cholecalciferol (Vitamin D3) reduces rat neuropathic
pain by modulating opioid signaling. Mol Neurobiol. (2019)
56:7208–21. doi: 10.1007/s12035-019-1582-6
38. van Riel PL, Renskers L. The Disease Activity Score (DAS) and the Disease
Activity Score using 28 joint counts (DAS28) in the management of
rheumatoid arthritis. Clin Exp Rheumatol. (2016) 34(Suppl. 101):S40–4.
39. Tabatabaeizadeh SA, Avan A, Bahrami A, Khodashenas E, Esmaeili H, Ferns
GA, et al. High dose supplementation of vitamin D affects measures of
Frontiers in Medicine | www.frontiersin.org 10 October 2020 | Volume 7 | Article 596007
Guan et al. Vitamin D for Rheumatoid Arthritis
systemic inflammation: reductions in high sensitivity C-reactive protein level
and neutrophil to lymphocyte ratio (NLR) distribution. J Cell Biochem. (2017)
118:4317–22. doi: 10.1002/jcb.26084
40. Prevoo ML, van ’t Hof MA, Kuper HH, van Leeuwen MA, van de Putte LB,
van Riel PL. Modified disease activity scores that include twenty-eight-joint
counts. Development and validation in a prospective longitudinal study
of patients with rheumatoid arthritis. Arthritis Rheum. (1995) 38:44–
8. doi: 10.1002/art.1780380107
41. Bjorkman MP, Sorva AJ, Tilvis RS. C-reactive protein and fibrinogen
of bedridden older patients in a six-month vitamin D supplementation
trial. J Nutr Health Aging. (2009) 13:435–9. doi: 10.1007/s12603-00
9-0080-3
42. Moghimi J, Sadeghi A, Malek M, Ghorbani R. Relationship
between disease activity and serum levels of vitamin D and
parathyroid hormone in rheumatoid arthritis. Endocr Regul. (2012)
46:61–6. doi: 10.4149/endo_2012_02_61
Conflict of Interest: The authors declare that the research was conducted in the
absence of any commercial or financial relationships that could be construed as a
potential conflict of interest.
Copyright © 2020 Guan, Hao, Guan, Bu and Wang. This is an open-access article
distributed under the terms of the Creative Commons Attribution License (CC BY).
The use, distribution or reproduction in other forums is permitted, provided the
original author(s) and the copyright owner(s) are credited and that the original
publication in this journal is cited, in accordance with accepted academic practice.
No use, distribution or reproduction is permitted which does not comply with these
terms.
Frontiers in Medicine | www.frontiersin.org 11 October 2020 | Volume 7 | Article 596007
... However, no improvement was observed in other parameters such as VAS (Patient Global Pain Score), SJC (Swollen Joint Count), CRP. Notably, in a subgroup analysis, a significantly improved VAS score was observed with vitamin D supplementation of more than 50,000 IU/week, for more than 12 weeks [45]. In another small cohort (61) study, supplementation with 1,00,000 IU/month, resulted in a significant decline in DAS and VAS scores in only vitamin D sufficient patients [46]. ...
Full-text available
Article
Vitamin D is an immunomodulatory hormone with an established role in calcium and phosphate metabolism and skeletal mineralization. Evidence showing its immunological benefits by regulating essential components of the innate and adaptive immune system is prevalent. Vitamin D deficiency is reported worldwide and is thereby found to be associated with various immune-related diseases. Rheumatoid Arthritis and COVID-19 are two such diseases, sharing a similar hyperinflammatory response. Various studies have found an association of lower Vitamin D levels to be associated with both these diseases. However, contrasting data is also reported. We review here the available scientific data on risk factor association and supplementation benefits of Vitamin D in Rheumatoid Arthritis and COVID-19, intending to critically evaluate the literature.
... However, improvement was not observed in other parameters such as VAS (Patient Global Pain Score), SJC (Swollen Joint Count), or CRP. Notably, in a subgroup analysis, a significantly improved VAS score was observed with vitamin D supplementation of more than 50,000 IU/week, for more than 12 weeks [40]. The pharmacological mechanism of 1,25D in RA has also been investigated. ...
Full-text available
Article
Immune cells, including dendritic cells, macrophages, and T and B cells, express the vitamin D receptor and 1α-hydroxylase. In vitro studies have shown that 1,25-dihydroxyvitamin D, the active form of vitamin D, has an anti-inflammatory effect. Recent epidemiological evidence has indicated a significant association between vitamin D deficiency and an increased incidence, or aggravation, of infectious diseases and inflammatory autoimmune diseases, such as rheumatoid arthritis, systemic lupus erythematosus, and multiple sclerosis. However, the impact of vitamin D on treatment and prevention, particularly in infectious diseases such as the 2019 coronavirus disease (COVID-19), remains controversial. Here, we review recent evidence associated with the relationship between vitamin D and inflammatory diseases and describe the underlying immunomodulatory effect of vitamin D.
Full-text available
Article
Although the management of rheumatoid arthritis (RA) has improved remarkably with new pharmacological therapies, there is still a significant part of patients not reaching treatment goals. Difficult-to-treat RA (D2TRA) is a complex entity involving several factors apart from persistent inflammation, thereafter requiring a holistic management approach. As pharmacological treatment options are often limited in D2TRA, the need for non-pharmacological treatments (NPT) is even more pronounced. The mechanism of action of non-pharmacological treatments is not well investigated, NPTs seem to have a complex, holistic effect including the immune, neural and endocrine system, which can have a significant additive benefit together with targeted pharmacotherapies in the treatment of D2TRA. In this review we summarize the current knowledge on different NPT in rheumatoid arthritis, and we propose a NPT plan to follow when managing D2TRA patients.
Full-text available
Article
Rheumatoid arthritis (RA), an autoimmune disease, is characterized by the presence of symmetric polyarthritis predominantly of the small joints that leads to severe cartilage and bone destruction. Based on animal and human data, the pathophysiology of osteoporosis, a frequent comorbidity in conjunction with RA, was delineated. Autoimmune inflammatory processes, which lead to a systemic upregulation of inflammatory and osteoclastogenic cytokines, the production of autoantibodies, and Th cell senescence with a presumed disability to control the systemic immune system’s and osteoclastogenic status, may play important roles in the pathophysiology of osteoporosis in RA. Consequently, osteoclast activity increases, osteoblast function decreases and bone metabolic and mechanical properties deteriorate. Although a number of disease-modifying drugs to treat joint inflammation are available, data on the ability of these drugs to prevent fragility fractures are limited. Thus, specific treatment of osteoporosis should be considered in patients with RA and an associated increased risk of fragility fractures.
Article
Background: The aim of this research was to assess if hand bone mineral density (HBMD) changes associated with the appearance of erosions in early rheumatoid arthritis (ERA), compared with the population-based control group. Additionally, we tried to identify if there are novel factors that associate with HBMD and erosive changes (EC), and if they are dissimilar. The study was conducted as the data are limited. Methods: The study group consisted of 83 ERA patients and 321 controls. Dual-Energy X-Ray Absorptiometry (DXA) machine was used to measure HBMD. EC of RA (rheumatoid arthritis) were assessed in X-rays of hands using Sharp scores. Life-style habits, inflammation markers were assessed to evaluate the effects of different factors. Results: The presence of ERA was associated with lower HBMD compared with controls (adjusted for age, gender, height and weight; b -0.01, p = 0.045). 76% (95% CI 65.3-84.6) of ERA patients had EC in hand X-ray. Smoking habits and higher BMI (body mass index) were associated with an increased likelihood of having RA specific EC. In ERA, decreasing of HBMD was associated with the elevation of interleukin-6 (IL-6) and rheumatoid factor (RF) positivity. Conclusions: In ERA, HBMD changes were not associated with the appearance of erosions. Factors that associate in ERA with HBMD changes and appearance of erosions differ. HBMD assessment together with serum IL-6 level could be useful in everyday clinical practice for better surveillance of ERA patients who do not have EC in hand X-rays.
Full-text available
Article
Background/objective: Rheumatoid arthritis (RA) patients might experience anxiety and depressive symptoms. Deficient vitamin D levels may be a trigger for these conditions. The aim of this study was to determine the frequency of depression, anxiety symptoms, and suicidal risk or ideation in patients with RA associated with vitamin D serum levels. Methods: In this cross-sectional study, we recruited RA patients older than 18 years, classified into 3 groups according to serum vitamin D levels: sufficient, ≥30 ng/mL; insufficient, 20-29 ng/mL; and deficient, <20 ng/mL. Based on the self-reported Plutchik and the Hospital Anxiety and Depression Scale, we evaluated the association of suicidal risk, depression, and anxiety with the vitamin D levels in RA and the Rheumatoid Arthritis Quality-of-Life Questionnaire. Results: We studied 72 patients with RA between January and October 2019. We found an inverse correlation between Plutchik score and suicidal risk with inadequate vitamin D levels, but not with the Hospital Anxiety and Depression Scale. Suicidal ideation was associated with a higher score on the Rheumatoid Arthritis Quality-of-Life Questionnaire. Conclusions: Despite the high prevalence of depressive and anxiety symptoms in RA patients, a Plutchik low correlation coefficient with inadequate serum levels of vitamin D was found. However, in the analysis of covariance, we were able to find that vitamin D levels remain associated with a reduction of reduction of suicide ideation. Further studies are needed to identify a risk profile for early psychological interventions to improve the quality of life in RA patients.
Full-text available
Article
Vitamin D plays an important role in maintaining a healthy mineralized skeleton. It is also considered an immunomodulatory agent that regulates innate and adaptive immune systems. The aim of this narrative review is to provide general concepts of vitamin D for the skeletal and immune health, and to summarize the mechanistic, epidemiological, and clinical evidence on the relationship between vitamin D and rheumatic diseases. Multiple observational studies have demonstrated the association between a low level of serum 25-hydroxyvitamin D [25(OH)D] and the presence and severity of several rheumatic diseases, such as rheumatoid arthritis (RA), systemic lupus erythematosus (SLE), spondyloarthropathies, and osteoarthritis (OA). Nevertheless, the specific benefits of vitamin D supplements for the treatment and prevention of rheumatic diseases are less accepted as the results from randomized clinical trials are inconsistent, although some conceivable benefits of vitamin D for the improvement of disease activity of RA, SLE, and OA have been demonstrated in meta-analyses. It is also possible that some individuals might benefit from vitamin D differently than others, as inter-individual difference in responsiveness to vitamin D supplementation has been observed in genomic studies. Although the optimal level of serum 25(OH)D is still debatable, it is advisable it is advisable that patients with rheumatic diseases should maintain a serum 25(OH)D level of at least 30 ng/mL (75 nmol/L) to prevent osteomalacia, secondary osteoporosis, and fracture, and possibly 40–60 ng/mL (100–150 nmol/L) to achieve maximal benefit from vitamin D for immune health and overall health.
Article
In this study, we assess the association between the occurrence of new fractures and vitamin D deficiency in Japanese patients with rheumatoid arthritis using our large IORRA cohort. The results suggest that vitamin D deficiency is a significant risk factor for new fractures in Japanese female patients over the age of 50 years with rheumatoid arthritis. Purpose: Both rheumatoid arthritis (RA) and menopause are known risk factors for the onset of osteoporosis. The occurrence of new clinical fractures in patients with RA can significantly lower quality of life. The purpose of this study was to investigate whether vitamin D deficiency in Japanese women with RA could be a risk factor for new fractures. Methods: Between 2011 and 2017, a total of 2567 female patients with RA over the age of 50 years (mean age, 65.9 years) were enrolled in a prospective observational study. Self-reported occurrences of new fractures were verified using patient medical records. Vitamin D deficiency was defined as serum 25(OH)D levels < 20 ng/mL. Cox proportional hazards models were used to analyze the independent contributions of various risk factors to the occurrence of a new fracture. Results: New clinical fractures were sustained by 205 patients in the included cases. Among them, new osteoporotic fractures were sustained by 139 patients (63 vertebral fractures and 76 non-vertebral fractures). Among all patients, the mean (SD) serum 25(OH)D level was 16.9 (5.89) ng/mL and the prevalence of vitamin D deficiency was 72.6%. A Cox proportional hazards model revealed that vitamin D deficiency was significantly associated with all new clinical fractures (hazard ratio, 1.44 [95% confidence interval 1.02‒2.05]; p = 0.0365) and all new osteoporotic fractures (hazard ratio, 1.75 [95% confidence interval 1.14‒2.69]; p = 0.0109). Conclusion: Vitamin D deficiency is a risk factor for new fractures in Japanese female patients over the age of 50 years with RA. Screening these patients for serum 25(OH)D could potentially be seminal to reducing their risk of fractures.
Full-text available
Article
Vitamin D [1,25(OH)2D—calcitriol] is basically a steroid hormone with pleiotropic biologic effects, and its impact on the regulation of immune system may influence several clinical conditions. Calcidiol (25OHD), as precursor of calcitriol, derives, for the most part (80%), from cutaneous cholesterol (7-dehydrocholesterol) under the action of UV-B (sunlight). Consequently, serum concentrations fluctuate during the year following the circannual rhythm of sun exposition. We will update about the available evidence regarding the complex influence of seasonal vitamin D changes on two different chronic connective tissue diseases, namely rheumatoid arthritis (RA) and systemic sclerosis (SSc). Notably, RA is an emblematic model of autoimmune disease with prevalent joint inflammatory features, while SSc is mainly an autoimmune progressive pro-fibrotic disease. However, in both conditions, low serum concentrations of 25OHD are involved in the pathogenesis of the diseases, and emerging data report their impact on clinical manifestations.
Full-text available
Article
Rheumatoid arthritis (RA) is a systemic multifactorial autoimmune disorder. The interactions between diverse environmental and genetic factors lead to the onset of this complex autoimmune disorder. Serum levels of vitamin D (VD) are involved in the regulation of various immune responses. Vitamin D is a key signaling molecule in the human body that maintains calcium as well as phosphate homeostasis. It also regulates the functions of the immune system and, thus, can play a substantial role in the etiology of various autoimmune disorders, including RA. Low serum VD levels have been found to be associated with a higher risk of RA, although this finding has not been replicated consistently. The molecular mechanisms by which VD influences autoimmunity need to be further explored to understand how variation in plasma VD levels could affect the pathogenesis of RA. This mini-review focuses on the influence of VD and its serum levels on RA susceptibility, RA-associated complexities, treatment, and transcriptome products of key proinflammatory cytokines, along with other cytokines that are key regulators of inflammation in rheumatoid joints.
Full-text available
Article
The impact of vitamin D on sensory function, including pain processing, has been receiving increasing attention. Indeed, vitamin D deficiency is associated with various chronic pain conditions, and several lines of evidence indicate that vitamin D supplementation may trigger pain relief. However, the underlying mechanisms of action remain poorly understood. We used inflammatory and non-inflammatory rat models of chronic pain to evaluate the benefits of vitamin D3 (cholecalciferol) on pain symptoms. We found that cholecalciferol supplementation improved mechanical nociceptive thresholds in monoarthritic animals and reduced mechanical hyperalgesia and cold allodynia in a model of mononeuropathy. Transcriptomic analysis of cerebrum, dorsal root ganglia, and spinal cord tissues indicate that cholecalciferol supplementation induces a massive gene dysregulation which, in the cerebrum, is associated with opioid signaling (23 genes), nociception (14), and allodynia (8), and, in the dorsal root ganglia, with axonal guidance (37 genes) and nociception (17). Among the identified cerebral dysregulated nociception-, allodynia-, and opioid-associated genes, 21 can be associated with vitamin D metabolism. However, it appears that their expression is modulated by intermediate regulators such as diverse protein kinases and not, as expected, by the vitamin D receptor. Overall, several genes—Oxt, Pdyn, Penk, Pomc, Pth, Tac1, and Tgfb1—encoding for peptides/hormones stand out as top candidates to explain the therapeutic benefit of vitamin D3 supplementation. Further studies are now warranted to detail the precise mechanisms of action but also the most favorable doses and time windows for pain relief.
Full-text available
Article
Rheumatoid arthritis (RA) is a chronic inflammatory disease in which numerous cells and mediators affect inflammatory conditions and disease severity. To compare the serum levels of adiponectin, vitamin D, copper, and zinc in patients with RA and to investigate the relationship between these parameters and RA severity. Ninety patients with RA and 30 healthy controls participated in this cross-sectional case-control study between November 2016 and April 2017; according to the ACR/EULAR criteria for RA. Serum levels of adiponectin were determined by ELISA; copper and zinc by colorimetric spectrophotometry; and vitamin D by HPLC. Kruskal-Wallis and Spearman tests were performed using SPSS software and data were depicted by GraphPad Prism software. Compared with healthy controls, the serum level of adiponectin was significantly increased, whereas vitamin D was significantly decreased in patients with RA. Adiponectin and vitamin D levels were inversely correlated in RA subgroups (P < 0.001, r = − 0.410). Adiponectin and vitamin D correlated with RA severity. Furthermore, no significant difference was found in copper and zinc levels between RA groups and controls. The definitive roles of adiponectin, vitamin D, copper, and zinc are not completely determined in RA development. Based on disease activity, these parameters can modulate inflammatory conditions, thus they have the potential to be used as promising therapeutic biomarkers to follow up the severity of disease, as well as the progression and treatment success in patients with RA.
Full-text available
Article
Nutrigenomics studies how environmental factors, such as food intake and lifestyle, influence the expression of the genome. Vitamin D3 represents a master example of nutrigenomics, since via its metabolite 1α,25-dihydroxyvitamin D3, which binds with high-affinity to the vitamin D receptor, the secosteroid directly affects the epigenome and transcriptome at thousands of loci within the human genome. Vitamin D is important for both cellular metabolism and immunity, as it controls calcium homeostasis and modulates the response of the innate and adaptive immune system. At sufficient UV-B exposure, humans can synthesize vitamin D3 endogenously in their skin, but today’s lifestyle often makes the molecule a true vitamin and micronutrient that needs to be taken up by diet or supplementation with pills. The individual’s molecular response to vitamin D requires personalized supplementation with vitamin D3, in order to obtain optimized clinical benefits in the prevention of osteoporosis, sarcopenia, autoimmune diseases, and possibly different types of cancer. The importance of endogenous synthesis of vitamin D3 created an evolutionary pressure for reduced skin pigmentation, when, during the past 50,000 years, modern humans migrated from Africa towards Asia and Europe. This review will discuss different aspects of how vitamin D interacts with the human genome, focusing on nutritional epigenomics in context of immune responses. This should lead to a better understanding of the clinical benefits of vitamin D.
Article
Patients with rheumatoid arthritis (RA) suffer cardiovascular events 1.5-2 fold than the general population, and cardiovascular (CV) events are leading cause of death in patients with RA. It is known that patients with RA have endothelial dysfunction, related with impaired function of endothelial progenitor cells (EPCs). The mechanistic pathways leading to endothelial function are complicated, but understanding these mechanisms may open new frontiers of management and therapies to patients suffering from atherosclerosis. Inflammation is a key factor in atherosclerosis, including endothelial function, plaque stabilization and post infarct remodeling; thus, inhibition of TNF-α may affect the inflammatory burden and plaque vulnerability leading to less cardiovascular events and myocardial infarctions. An aggressive management of inflammation may lead to a significant improvement in the clinical cardiovascular outcome of patients with RA. The clinical evidence that showed a reduced risk of CV events following treatment with anti-inflammatory agents may suggest a new approach to treat atherosclerosis, i.e., inhibition of inflammation using biological medications that were primarily aimed to treat the high scale inflammation of RA and other autoimmune-inflammatory diseases, but may be useful also to prevent progression of atherosclerosis.
Article
Objectives The aims of the present research were to assess the prevalence of frailty and its potential associated factors in a cohort of adult patients with rheumatoid arthritis (RA). Methods Consecutive RA patients and healthy controls were assessed according to the Survey of Health, Ageing and Retirement in Europe Frailty Instrument (SHARE-FI), and classified as frail, pre-frail, or non-frail. Chi-square, analysis of variance (ANOVA), and multinomial logistic regression analyses were used to test the prognostic value of frailty for the outcomes of interest. Results Two hundred and ten consecutive RA patients (65.7% female, mean age 60.4 years) and 100 healthy controls (63% female, mean age 59.1 years) were included. According to SHARE-FI criteria, 35 RA patients (16.6%) were categorized as frail, 68 (32.4%) as pre-frail, and 107 (51%) as non-frail, while 8 control subjects were categorized as frail, (8%), 17 as pre-frail (17%), and 75 as non-frail (75%) (chi-squared 12.8; P = 0.0016). The results from logistic regression analysis revealed that age (odds ratio [OR] = 1.12, 95% confidence interval [CI] = 1.07–1.17; P < 0.0001), comorbidities (OR = 1.51, 95% CI = 1.01–2.27; P = 0.0446), and high disease activity (OR = 1.10, 95% CI = 1.04–1.16; P = 0.0006) were independently associated with frailty in RA. Conclusions Frailty or pre-frailty are common in RA. The SHARE-FI may be a useful tool for the screening of frailty in RA and may summarize the results of a comprehensive RA assessment providing a marker of deficits accumulation.
Article
Aim Vitamin D3 or 25(OH)D3 may have a potential role in rheumatoid arthritis (RA) pathogenesis by inhibiting the expression of pro‐inflammatory cytokines including interleukin‐6 (IL‐6). The aim of this study is to determine the clinical factors of vitamin D deficiency in multi‐ethnic Malaysian RA patients and its association with disease activity, functional disability and serum IL‐6 levels. Method One hundred RA patients and 50 healthy controls, sex‐ and age‐matched, were recruited. Disease Activity Score of 28 joints and Health Assessment Questionnaire scores were assessed. Baseline serum 25(OH)D3 and IL‐6 were measured in all subjects. RA patients who were vitamin D deficient were given loading doses of vitamin D3 and repeated assessments were done. Results Vitamin D deficiency (<50 nmol/L) was found in 63% of RA patients and 76% of healthy controls. Chinese RA patients and healthy controls had significantly more sufficient 25(OH)D3 levels compared to Malays and Indians (P < 0.001). Serum 25(OH)D3 level was still negatively associated with body mass index in RA patients (P = 0.002) after adjustment for potential confounding variables. No significant association was seen between 25(OH)D3 levels and disease activity or serum IL‐6 levels in both pre‐ and post‐treatment groups. A negative association was observed between serum 25(OH)D3 and functional disability, including a 33% improvement post‐treatment (mean ± SD: 0.30 ± 0.46 to 0.20 ± 0.18). Conclusion Vitamin D deficiency is prevalent in Malaysian RA patients. This study suggests that vitamin D is not associated with disease activity or serum IL‐6 levels but it may have a role in functional disability in RA patients.
Article
Vitamin D is a neuro-hormone regulating calcium-phosphate homeostasis, cell proliferation, and immunomodulation. exogenous and endogenous Vitamin D is inactive, and two hydroxylations are required to produce the active hormone. The first hydroxylation is unique to the liver, while the second step occurs in kidney, brain, lung, prostate, placenta, and immune cells. Kidney-derived calcitriol regulates calcium homeostasis. active hormone produced by brain and immune cells mediates immune system response; lung calcitriol is involved in fighting respiratory tract infections; finally, prostate and placenta Vitamin D regulates cells growth and proliferation within such tissues. immune modulation by Vitamin D includes enhancing innate immune response, attenuating and stimulating Th1 and Th2 cell proliferation, respectively, and promoting self-tolerance. Hypovitaminosis D is a common finding in several autoimmune diseases. it is unclear whether hypovitaminosis D could be a consequence or a cause of autoimmune diseases and whether Vitamin D supplementation has an impact on these patients. Moreover, there is no consensus on oral cholecalciferol dosage for supplementation. More interventional studies are required to better define how Vitamin D could represent both a causation agent in autoimmunity and a target for therapeutic strategies in autoimmune patients.
Article
Rheumatoid arthritis (RA) is an autoimmune disease characterized by joint inflammation, which affects approximately 1% of the population. The benefit of early recognition and treatment has led to an increased interest in the early phases of disease. With the aim of classifying patients earlier in their disease course, new RA classification criteria have been developed. Much attention has been devoted to the identification in the prearthritis phase of arthralgia. The discovery of new risk factors and autoantibodies has led to new theories about the putative mechanisms involved in disease development. Finally, the outcome measures have also evolved, with more emphasis on sustained drug-free remission and patient-reported outcomes. This article reviews the new developments in RA research and discusses the latest insights into epidemiology, risk factors, predisease states, and outcomes.
Article
Background It is unclear whether supplementation with vitamin D reduces the risk of cancer or cardiovascular disease, and data from randomized trials are limited. Methods We conducted a nationwide, randomized, placebo-controlled trial, with a two-by-two factorial design, of vitamin D3 (cholecalciferol) at a dose of 2000 IU per day and marine n−3 (also called omega-3) fatty acids at a dose of 1 g per day for the prevention of cancer and cardiovascular disease among men 50 years of age or older and women 55 years of age or older in the United States. Primary end points were invasive cancer of any type and major cardiovascular events (a composite of myocardial infarction, stroke, or death from cardiovascular causes). Secondary end points included site-specific cancers, death from cancer, and additional cardiovascular events. This article reports the results of the comparison of vitamin D with placebo. Results A total of 25,871 participants, including 5106 black participants, underwent randomization. Supplementation with vitamin D was not associated with a lower risk of either of the primary end points. During a median follow-up of 5.3 years, cancer was diagnosed in 1617 participants (793 in the vitamin D group and 824 in the placebo group; hazard ratio, 0.96; 95% confidence interval [CI], 0.88 to 1.06; P=0.47). A major cardiovascular event occurred in 805 participants (396 in the vitamin D group and 409 in the placebo group; hazard ratio, 0.97; 95% CI, 0.85 to 1.12; P=0.69). In the analyses of secondary end points, the hazard ratios were as follows: for death from cancer (341 deaths), 0.83 (95% CI, 0.67 to 1.02); for breast cancer, 1.02 (95% CI, 0.79 to 1.31); for prostate cancer, 0.88 (95% CI, 0.72 to 1.07); for colorectal cancer, 1.09 (95% CI, 0.73 to 1.62); for the expanded composite end point of major cardiovascular events plus coronary revascularization, 0.96 (95% CI, 0.86 to 1.08); for myocardial infarction, 0.96 (95% CI, 0.78 to 1.19); for stroke, 0.95 (95% CI, 0.76 to 1.20); and for death from cardiovascular causes, 1.11 (95% CI, 0.88 to 1.40). In the analysis of death from any cause (978 deaths), the hazard ratio was 0.99 (95% CI, 0.87 to 1.12). No excess risks of hypercalcemia or other adverse events were identified. Conclusions Supplementation with vitamin D did not result in a lower incidence of invasive cancer or cardiovascular events than placebo. (Funded by the National Institutes of Health and others; VITAL ClinicalTrials.gov number, NCT01169259.)