|
Serum levels of interleukin-6 and Vitamin D at the onset of multiple sclerosis and neuromyelitis optica: A pilot study
Fereshteh Ashtari1, Reyhanehsadat Madanian1, Sayyed Hamid Zarkesh2, Arshia Ghalamkari1
1 Isfahan Neuroscience Research Center, School of Medicine, Isfahan University of Medical Science, Isfahan, Iran
2 Department of Immunology, School of Medicine, Isfahan University of Medical Sciences, Isfahan, Iran
| Date of Submission | 09-Sep-2021 |
| Date of Decision | 07-Feb-2022 |
| Date of Acceptance | 10-May-2022 |
| Date of Web Publication | 27-Sep-2022 |
Correspondence Address:
Mr. Arshia Ghalamkari
Isfahan Neuroscience Research Center, School of Medicine, Isfahan University of Medical Science, Isfahan
Iran
 Source of Support: None, Conflict of Interest: None  | Check |
DOI: 10.4103/jrms.jrms_796_21
Background: Interleukin-6 (IL-6) is an important mediator in the acute phase of inflammatory diseases such as neuromyelitis optica (NMO) and multiple sclerosis (MS). The level of IL-6 is higher in cerebrospinal fluid and serum of NMO patients compare to MS. Vitamin D has a regulatory effect on IL-6, so it may have a negative correlation with IL-6 in the acute phase of these diseases. This study was performed to evaluate the serum levels of IL-6 and Vitamin D in NMO and MS patients at the onset of disease to find differences that may help in early diagnosis. Materials and Methods: This case–control study was done on patients with the first episode of optic neuritis, transverse myelitis, and area postrema syndrome who were referred to Kashani MS Center in Isfahan, Iran, between January 2018 and January 2020. The serum levels of Vitamin D and IL-6 were assessed using enzyme-linked immunosorbent assay in blood sample taken at the time of first presentation in patients who had a definitive diagnosis of NMO and MS during subsequent workup. Results: During a 2-year follow-up, definitive diagnosis of NMO was given in 25 cases, and they were compared with 25 cases that were randomly selected from patients with definite MS. Nineteen patients in the NMO group and 21 patients in the MS group were female. The mean age of patients in the NMO and MS groups was 29.64 ± 1.47 and 30.20 ± 1.42, respectively (P = 0.46). The mean of serum level of Vitamin D was 24.88 ± 15.2 in NMO patients and 21.56 ± 18.7 in MS patients without significant difference (P = 0.48). The mean of IL-6 was 30.1 ± 22.62 in the NMO group and 23.35 ± 18.8 in the MS group without significant difference (P = 0.28). The serum levels of Vitamin D were insufficient in both groups. No correlation between Vitamin D and IL-6 levels was found in our study (P > 0.05). Conclusion: Our results showed that serum IL-6 levels were higher at the onset of NMO disease compared with MS. The serum levels of Vitamin D were low in both groups and there was no association between serum levels of Vitamin D and IL-6 in either group. Future studies with large sample size are needed to confirm these findings.
Keywords: Interleukin-6, multiple sclerosis, Vitamin D
How to cite this article:
Ashtari F, Madanian R, Zarkesh SH, Ghalamkari A. Serum levels of interleukin-6 and Vitamin D at the onset of multiple sclerosis and neuromyelitis optica: A pilot study. J Res Med Sci 2022;27:67 |
How to cite this URL:
Ashtari F, Madanian R, Zarkesh SH, Ghalamkari A. Serum levels of interleukin-6 and Vitamin D at the onset of multiple sclerosis and neuromyelitis optica: A pilot study. J Res Med Sci [serial online] 2022 [cited 2023 Mar 25];27:67. Available from: https://www.jmsjournal.net/text.asp?2022/27/1/67/356940 |
| Introduction | |  |
Multiple sclerosis (MS) is the most common autoimmune disease of the central nervous system (CNS) among the young adults.[1],[2] Various aspects of the immune system are impaired in this disease. The activity of Th1 and Th17, which produces pro-inflammatory cytokines such as interleukin (IL)-6, is increased,[3] and regulatory T-cells, which control inflammation, are suppressed.[4] In addition, there is evidence of abnormal activity in B-cells.[5] In other words, MS is an inflammatory disease of the CNS, and inflammatory factors such as IL-6 are increased in the lesions.[6]
Neuromyelitis optica (NMO) is another inflammatory disease of the CNS that was previously considered a severe variant of MS. Although it is now recognized as a distinct disease, its clinical manifestations including optic neuritis, transverse myelitis, and area postrema syndrome are also common symptoms of MS.[7],[8],[9] In a significant number of patients, the antibodies against aquaporin-4 (AQP4) confirm the diagnosis.[9] However, the antibody is absent in 20%–40% of cases, and the similarity of the common clinical symptoms in both diseases may lead to misdiagnosis.[7],[10]
AQP4-AB is a specific biomarker in NMO disease, and once enters the CNS, leads to the activation of a complement cascade that damages neural tissue.[11] IL-6 is an important mediator in the acute phase response and may induce AQP4-immunoglobulin G (IgG) secretion, reduces blood–brain barrier integrity, activates pro-inflammatory T-cells, and may induce NMO disease activity.[12] Studies have shown increased IL-6 levels in cerebrospinal fluid (CSF) and serum of NMO and MS patients[13],[14] In the acute phase of disease, the CSF levels of IL-6 in NMO patients are higher than in MS and other inflammatory neurologic diseases.[14] Indeed, the association between CSF level of IL-6 with disability was reported in NMO patients.[15] Therefore, inhibition of ILs may be effective in controlling the disease. Recently, satralizumab, an anti-IL-6 monoclonal antibody, has been approved for the treatment of NMO.[16]
Vitamin D deficiency is one of the possible environmental risk factors in MS and NMO. Besides having a significant role in calcium and phosphorus homeostasis, Vitamin D plays a role in regulating the immune system and has anti-inflammatory effects.[17]
Recent studies have shown the positive effect of Vitamin D3 on various clinical parameters in MS patients. Vitamin D plays an essential role in repairing damaged myelin peptides and regulating T-cell proliferation. It also has a positive immune-modulating effect on pro-inflammatory cytokines such as IL-6 and low Vitamin D levels may associate with disease activity in NMO patients.[18] A study in patients with rheumatoid arthritis showed a better response to IL-6 antibody therapy in the presence of adequate serum Vitamin D.[19] Based on these effects, Vitamin D deficiency may be associated with high level of IL-6 and increase disease activity. Although Vitamin D deficiency is one of the risk factors of MS and IL-6 levels may be high in MS patients, the role of IL-6 is more prevalent in NMO and may play a role in disease progression and even in the onset of the disease. To the best of our knowledge, no studies have been performed at the onset of NMO and MS to assess serum levels of Vitamin D and IL-6. This study was performed to compare serum levels of Vitamin D and IL-6 at the first presentation of NMO and MS disease. We aimed to find a correlation between Vitamin D levels and IL-6 levels at the onset of these diseases.
| Materials and Methods | | |
This is a case–control study to assess serum levels of Vitamin D and IL-6 in MS and NMO patients at the disease onset.
All patients with the first episode of optic neuritis, myelitis, and area postrema syndrome that were referred to Kashani MS Center, affiliated to Isfahan University of Medical Sciences (IUMS), between January 2018 and December 2019, were selected. Inclusion criteria were: The age over 18 years, presence of the first episode of optic neuritis, myelitis, or area postrema syndrome, not receiving corticosteroids during the past 4 weeks, and no underlying diseases including diabetes mellitus, collagen vascular, and cardiovascular diseases.
This study was approved by the IUMS Ethics Committee (no: IR.MUI.REC.1396.2.014), and patients provided informed written consent before enrollment.
Before receiving corticosteroids, a demographic questionnaire was completed and 7 ml of blood was taken from a peripheral vein of each participant. The serum of these samples was separated and kept at 20°C. The patients were then treated with 1000 mg intravenous methylprednisolone for 5 consecutive days. Additional workup including brain and cervical magnetic resonance imaging, AQP4-AB, and vasculitis tests, and if necessary, CSF analysis was used to aid in diagnosis. The patients were followed up for 2 years to confirm the diagnosis of MS according to the McDonald criteria[20] and NMO based on the international consensus diagnostic criteria for NMO spectrum disorders.[21]
Finally, among the patients who were followed up, 25 cases were definitively diagnosed with NMO disease and 95 definite MS.
Twenty-five cases were randomly selected from 95 MS patients and compared with 25 NMO patients. Demographic characteristics (e.g., age and gender) and serum levels of Vitamin D and IL-6 were measured in these patients by enzyme-linked immunosorbent assay (Boster Biological Technology Co., Ltd. Wuhan, China). Regard to our laboratory reference, Vitamin D3 level <10 ng/mL was defined as Vitamin D deficiency, 10–30 ng/mL was defined as Vitamin D insufficiency, and more than 30 ng/mL was defined as Vitamin D sufficiency.
All data were entered to the Statistical Package for the Social Sciences version 22 (SPSS crop. Chicago, IL, USA). Qualitative variables data have been shown as frequency (percentage), and for quantitative variables, data were shown as mean ± standard deviation. To assess normal distribution, Kolmogorov–Smirnov test was performed on different variables; the Mann–Whitney U-test is used to compare differences between nonparametric groups when the dependent variable is either ordinal or continuous, and for categorical groups, Pearson's Chi-square test was used.
| Results | | |
In this study, 135 patients with the first episode of optic neuritis, myelitis, or area postrema syndrome were evaluated. After a complete evaluation, NMO was definitively diagnosed in 25 patients and MS definitively in 95 patients. Fifteen patients have no specific diagnosis and were classified as clinically isolated syndrome. Twenty-five patients from the MS group were randomly selected and compared with the NMO group.
Nineteen patients in the NMO group and 21 patients in the MS group were female. The mean age of patients in the NMO and MS groups was 29.64 ± 1.47 and 30.20 ± 1.42, respectively (P = 0.46).
There was no significant difference between serum levels of Vitamin D and IL-6 in the two groups (P = 0.48 and 0.28, respectively) [Table 1]. Moreover, based on the bivariate Pearson correlation test, the serum level of Vitamin D and IL-6 was not correlated (P > 0.05).
| Discussion | | |
Our study showed that the serum level of Vitamin D was insufficient in the new-onset MS and NMO groups, without any significant difference.
This result was consistent with a study by Gao et al., which found a low level of 25-OH D in NMO patients.[22]
As our research, a study in Indonesia found that despite being near the equator, the prevalence of Vitamin D deficiency is high in MS and NMO patients.[23]
Min et al. showed a correlation between disability score and relapse rate with Vitamin D status in NMO patients.[24] On the other hand, another study in the Thai population showed low serum level of Vitamin D in NMO patients without any correlation with disease activity.[25]
In addition, the immunoregulatory effect of Vitamin D in NMO has been reported by Wu Y.[18] The positive effect of Vitamin D supplementation on the improvement of symptoms during the treatment of acute relapse in NMO patients has been reported.[26]
Ascherio et al. showed a low level of Vitamin D as an important risk factor for long-term activity and progression in MS patients.[27]
Although the relationship between Vitamin D deficiency and the degree of disability in NMO patients has been contradictory, the result of our study showed that Vitamin D deficiency might be common in NMO, the same as MS. It makes sense to evaluate Vitamin D levels in NMO patients and to take supplements if low levels are detected.
In our study, serum IL-6 level was higher in the NMO group than in the MS group, with no significant difference. Perhaps, the reason for the lack of significant difference was the small sample size.
IL-6 is one of the stimulating factors, which differentiates B-cells from plasma cells and leads to the production of immunoglobulin.[12] It is recognized as an important cytokine in inflammatory diseases of CNS and is produced by different cells. IL-6 increases the survival of plasmablasts that produce AQP4-IgG antibodies, that can cause further tissue damage.[12] High concentrations of CSF IL6 have been reported in initial NMO attacks and suggested CSF IL-6 as an early diagnostic marker of NMO disease.[8] Although a prognostic marker for NMO patients has not yet been established, CSF levels of IL-6 may be considered a biomarker for NMO activity.
The modulatory effect of Vitamin D on IL-6 has been reported recently during COVID-19 infection.[17] In addition, Wesselink et al. found an inverse relationship between Vitamin D and IL-6 levels in the first 2 years after diagnosis of colorectal cancer.[28] We evaluated the association between serum levels of Vitamin D and IL-6 but found no such association.
Considering all these cases, maintaining a high serum level of Vitamin D using supplements to reduce IL-6 levels and disease activity in NMO patients should be recommended.
| Conclusion | | |
Our study showed higher serum level of IL-6 at the onset of NMO disease compared with MS but not significantly, and Vitamin D insufficiency in both diseases.
Based on our findings, there was no association between serum levels of Vitamin D and IL-6 in either group. As our study is a pilot study with small sample size, future studies with larger sample sizes are needed to evaluate the correlation between serum IL-6 levels and Vitamin D at the onset of these diseases.
Financial support and sponsorship
Nil.
Conflicts of interest
There are no conflicts of interest.
| References | | |
| 1. | Kawachi I, Lassmann H. Neurodegeneration in multiple sclerosis and neuromyelitis optica. J Neurol Neurosurg Psychiatry 2017;88:137-45.  |
| 2. | Hirst C, Ingram G, Swingler R, Compston DA, Pickersgill T, Robertson NP. Change in disability in patients with multiple sclerosis: A 20-year prospective population-based analysis. J Neurol Neurosurg Psychiatry 2008;79:1137-43. |
| 3. | Dhib-Jalbut S. Pathogenesis of myelin/oligodendrocyte damage in multiple sclerosis. Neurology 2007;68:S13-21. |
| 4. | Venken K, Hellings N, Broekmans T, Hensen K, Rummens JL, Stinissen P. Natural naive CD4+CD25+CD127low regulatory T cell (Treg) development and function are disturbed in multiple sclerosis patients: Recovery of memory Treg homeostasis during disease progression. J Immunol 2008;180:6411-20. |
| 5. | Wekerle H. B cells in multiple sclerosis. Autoimmunity 2017;50:57-60. |
| 6. | Schönrock LM, Gawlowski G, Brück W. Interleukin-6 expression in human multiple sclerosis lesions. Neurosci Lett 2000;294:45-8. |
| 7. | Jarius S, Franciotta D, Paul F, Ruprecht K, Bergamaschi R, Rommer PS, et al. Cerebrospinal fluid antibodies to aquaporin-4 in neuromyelitis optica and related disorders: Frequency, origin, and diagnostic relevance. J Neuroinflammation 2010;7:52. |
| 8. | Uzawa A, Mori M, Arai K, Sato Y, Hayakawa S, Masuda S, et al. Cytokine and chemokine profiles in neuromyelitis optica: Significance of interleukin-6. Mult Scler 2010;16:1443-52. |
| 9. | Trebst C, Jarius S, Berthele A, Paul F, Schippling S, Wildemann B, et al. Update on the diagnosis and treatment of neuromyelitis optica: Recommendations of the Neuromyelitis Optica Study Group (NEMOS). J Neurol 2014;261:1-16. |
| 10. | Cree B. Neuromyelitis optica: Diagnosis, pathogenesis, and treatment. Curr Neurol Neurosci Rep 2008;8:427-33. |
| 11. | Dos Passos GR, Sato DK, Becker J, Fujihara K. Th17 cells pathways in multiple sclerosis and neuromyelitis optica spectrum disorders: Pathophysiological and therapeutic implications. Mediators Inflamm 2016;2016:5314541. |
| 12. | Chihara N, Aranami T, Sato W, Miyazaki Y, Miyake S, Okamoto T, et al. Interleukin 6 signaling promotes anti-aquaporin 4 autoantibody production from plasmablasts in neuromyelitis optica. Proc Natl Acad Sci U S A 2011;108:3701-6. |
| 13. | Narikawa K, Misu T, Fujihara K, Nakashima I, Sato S, Itoyama Y. CSF chemokine levels in relapsing neuromyelitis optica and multiple sclerosis. J Neuroimmunol 2004;149:182-6. |
| 14. | Uzawa A, Mori M, Ito M, Uchida T, Hayakawa S, Masuda S, et al. Markedly increased CSF interleukin-6 levels in neuromyelitis optica, but not in multiple sclerosis. J Neurol 2009;256:2082-4. |
| 15. | Barros PO, Cassano T, Hygino J, Ferreira TB, Centurião N, Kasahara TM, et al. Prediction of disease severity in neuromyelitis optica by the levels of interleukin (IL)-6 produced during remission phase. Clin Exp Immunol 2016;183:480-9. |
| 16. | Yamamura T, Kleiter I, Fujihara K, Palace J, Greenberg B, Zakrzewska-Pniewska B, et al. Trial of satralizumab in neuromyelitis optica spectrum disorder. N Engl J Med 2019;381:2114-24. |
| 17. | Orrù B, Szekeres-Bartho J, Bizzarri M, Spiga AM, Unfer V. Inhibitory effects of Vitamin D on inflammation and IL-6 release. A further support for COVID-19 management? Eur Rev Med Pharmacol Sci 2020;24:8187-93. |
| 18. | Wu Y, Cai Y, Liu M, Zhu D, Guan Y. The potential immunoregulatory roles of vitamin D in neuromyelitis optica spectrum disorder. Mult Scler Relat Disord 2020;43:102156. |
| 19. | Kim H, Baek S, Hong SM, Lee J, Jung SM, Lee J, et al. 1,25-dihydroxy vitamin D3 and interleukin-6 blockade synergistically regulate rheumatoid arthritis by suppressing interleukin-17 production and osteoclastogenesis. J Korean Med Sci 2020;35:e40. |
| 20. | McDonald WI, Compston A, Edan G, Goodkin D, Hartung HP, Lublin FD, et al. Recommended diagnostic criteria for multiple sclerosis: Guidelines from the International Panel on the diagnosis of multiple sclerosis. Ann Neurol 2001;50:121-7. |
| 21. | Wingerchuk DM, Banwell B, Bennett JL, Cabre P, Carroll W, Chitnis T, et al. International consensus diagnostic criteria for neuromyelitis optica spectrum disorders. Neurology 2015;85:177-89. |
| 22. | Gao M, Yao X, Ding J, Hong R, Wu Y, Huang H, et al. Low levels of vitamin D and the relationship between vitamin D and Th2 axis-related cytokines in neuromyelitis optica spectrum disorders. J Clin Neurosci 2019;61:22-7. |
| 23. | Kusumadewi W, Imran D, Witjaksono F, Pakasi TA, Rusmana AI, Pangeran D, et al. Low vitamin D-25(OH) level in Indonesian multiple sclerosis and neuromyelitis optic patients. Mult Scler Relat Disord 2018;25:329-33. |
| 24. | Min JH, Waters P, Vincent A, Cho HJ, Joo BE, Woo SY, et al. Low levels of vitamin D in neuromyelitis optica spectrum disorder: Association with disease disability. PLoS One 2014;9:e107274. |
| 25. | Jitprapaikulsan J, Siritho S, Prayoonwiwat N. Vitamin D level status in Thai neuromyelitis optica patients. J Neuroimmunol 2016;295-296:75-8. |
| 26. | Koduah P, Paul F, Dörr JM. Vitamin D in the prevention, prediction and treatment of neurodegenerative and neuroinflammatory diseases. EPMA J 2017;8:313-25. |
| 27. | Ascherio A, Munger KL, White R, Köchert K, Simon KC, Polman CH, et al. Vitamin D as an early predictor of multiple sclerosis activity and progression. JAMA Neurol 2014;71:306-14. |
| 28. | Wesselink E, Balvers M, Bours MJ, de Wilt JH, Witkamp RF, van Baar H, et al. The association between circulating levels of vitamin D and inflammatory markers in the first 2 years after colorectal cancer diagnosis. Therap Adv Gastroenterol 2020;13:1756284820923922. |
[Table 1]
|
Search Pubmed for