Role of Vitamin D in rheumatoid arthritis and its association with neuropathic pain: a systematic review and meta-analysis

• Background: Rheumatoid arthritis (RA) is the most common autoimmune disease found in about 1% of adults worldwide. The cause of RA is unknown but there is a combination of genetic and multiple environmental factors dietary resulting in systemic inflammation. Vitamin D not only plays a major role in the regulation of bone mineral homeostasis but also plays a role in in the regulation of the immune response through a different mechanism, these data support a vitamin D deficiency role in the development and progression of RA and other autoimmune diseases. Long-term vitamin D deficiency may lead to decreased immune response and chronic inflammation, which may cause disabling pain. Individuals with vitamin D deficiency often report increased pain perception, which has been referred to hyperinnervation and hypersensitivity in nerve fibers.

• Background: Rheumatoid arthritis (RA) is the most common autoimmune disease found in about 1% of adults worldwide. The cause of RA is unknown but there is a combination of genetic and multiple environmental factors dietary resulting in systemic inflammation. Vitamin D not only plays a major role in the regulation of bone mineral homeostasis but also plays a role in in the regulation of the immune response through a different mechanism, these data support a vitamin D deficiency role in the development and progression of RA and other autoimmune diseases. Long-term vitamin D deficiency may lead to decreased immune response and chronic inflammation, which may cause disabling pain. Individuals with vitamin D deficiency often report increased pain perception, which has been referred to hyperinnervation and hypersensitivity in nerve fibers.
• Methods: We searched the PUBMED, EMBASE, and •

Results
Systematic review of 8 articles found that the serum vitamin D level in the RA group was significantly lower than that in the control group. In addition, vitamin D deficiency was more observed in RA patients with neuropathic pain.

• Conclusion
This systematic review and meta-analysis suggest that vitamin D plays a key role in the susceptibility and activity of RA. following key words and subject terms were used in the search: "vitamin D," "level," "deficiency", "rheumatoid arthritis," "RA" and "neuropathic pain" All references cited were also reviewed to identify additional studies not indexed by the electronic databases.

Criteria for meta-analysis
Studies were considered eligible if: (1) they were case-control studies with patients with RA diagnosed on the basis of diagnosed according to ACR 1987 or ACR/EULAR classification criteria; (2) they provided data on vitamin D levels and/or vitamin D deficiency in case and control groups; or (3) NP symptoms such as burning, tingling, numbness and throbbing sensations in any extremity (4) they provided data on the relation between serum vitamin D levels and RA activity based on disease activity score 28 (DAS28). Disease activity is classified based on the DAS28 value as remission (<2.6), low (2.6 to <3.2), moderate (≥3.2 to 5.1), and high (≥5.1). Course of disease, whether or not being new patients, immunosuppression, hormone or calcium treatment maybe have effect on the relationship between vitamin D level and RA, and may cause heterogeneity to affect the authenticity of testing results. However, for inclusion criteria, we did not limit studies based on this information in order to include as many studies as we can to examine a generalized finding.
We excluded studies if: (1) they contained overlapping or insufficient data; or (2) they were reviews or case reports. (3) systemic disease associated with neuropathy (diabetes, hypothyroidism, amyloidosis, liver disease, chronic kidney failure); (4) neurological disease; (5) metabolic bone disease such as hyperthyroidism, hyperparathyroidism or osteomalacia; and (6) use of any medication that could affect vitamin D levels or NP (psychiatric medications such as antidepressants, anxiolytics or sleeping pills).

Studies included in the meta-analysis
We identified 269 studies using electronic and manual searching methods, and 33 of these were selected for full text review based on the title and abstract. Nineteen of these were excluded, because they had data on other diseases, no control group, or no vitamin D data. Thus, 14 articles met the inclusion criteria (11).
Thus, A total of 8 articles; including 434 psoriatic cases and 214 controls, were chosen from 33 results in searching the role of the vitamin D level in the RA and if its deficiency associated with neuropathic pain (NP)?
The first article which examine the development of NP in patients with RA and the relationship between NP and vitamin D found that vitamin D deficiency was associated with increased NP in patients with RA where Seventy-five of the eligible patients were female (80.6%), and 31 (33.3%) were diagnosed with NP according to the LANSS.
There was a negative correlation between vitamin D levels and the LANSS score (P = 0.001). The prevalence of NP was 5.8 times higher among patients with serum The second one examined the prevalence of vitamin D insufficiency and the associations of vitamin D concentration with disease status in African Americans with rheumatoid arthritis (RA) and showed that Vitamin D insufficiency is common in African Americans with recent-onset RA. Unadjusted associations of circulating vitamin D with baseline pain, swollen joints, and DAS-28 were explained by differences in season, age, and gender and were not significant in multivariate analyses. In contrast to reports of Northern Europeans with early inflammatory arthritis, there are not strong associations of 25(OH)-D concentration with symptoms or disease severity in African Americans with RA (14).
The 3 rd article was the first multicenter European survey which add new evidences that vitamin D insufficiency/deficiency is frequent in RA patients with statistically significant differences among several countries as mean serum concentration of 25(OH)D in RA patients (17.62 ± 9.76 ng/ml) was found significantly lower if compared to the levels obtained in matched controls (18.95 ± 9.45 ng/ml) (p = 0.01), with statistically significant differences among several European countries. Negative correlations were found between 25(OH)D serum levels and DAS28-CRP (p b 0.001), RAID (p = 0.05) and HAQ (p = 0.04) scores in the RA patients' group. Negative correlations were also found in the cohort of enrolled RA patients between 25(OH)D serum concentrations and SRS (p = 0.04), HRS (p = 0.02) and GRS (p = 0.02) domains of the D-PRO questionnaire (15).
The 4 th article aimed to assess vitamin D levels in rheumatoid arthritis (RA) patients and to find their relation to clinical parameters, fibromyalgia syndrome (FMS), quality of life (QoL) and disease activity. This study included 63 RA patients and 62 controls. Clinical examination and laboratory investigations were performed. For patients, the Disease Activity Score (DAS-28), QoL index, Health Assessment Questionnaire II (HAQ II) and Modified Larsen score were calculated. 25-OH-vitamin D was measured in patients and controls. This study suggested that special attention is required regarding vitamin D levels in RA patients with FMS and decreased QoL. Vitamin D should be corrected and supplementation considered among the RA management armamentarium (16). Meta-analysis of this study revealed that: • RA patients had lower vitamin D level than control subjects as regard the mean value of vitamin D blood level. • The prevalence of NP was 5.8 times higher among patients with serum vitamin D levels below 20 ng/mL than in patients with vitamin D levels ≥ 30 ng/mL. • Vitamin D is considered as a clinical biomarker for RA. • Vitamin D deficiency may be linked to disease severity in RA. • Low vitamin D concentration is associated with arthritis, muscle pain and chronic widespread pain. • Vitamin D supplementation may be needed both for the prevention of osteoporosis as well as for pain relief in patients with RA.

Conclusion
In conclusion, this review summarizes the literature on the effect of different vitamin D levels and it was concluded that its deficiency could influence the physical health and quality of life, moreover it may be one of the causes leading to worsening of RA clinically and also affected the laboratory investigations. In addition, vitamin D deficiency was more observed in RA patients with neuropathic pain as vitamin D is considered an essential neuro-steroid with a major role in central and peripheral nervous system physiology, and its deficiency contribute to hyperinnervation and hypersensitivity in nerve fibers.