Low levels of vitamin-D are associated with neuropathy and lymphoma among patients with Sjögren’s syndrome
Highlights
► Vitamin-D levels of Sjogren's syn. patients do not differ from the healthy population. ► Peripheral neuropathy was diagnosed in 23% of Sjogren’s syn. patients in this cohort. ► Lymphoma was diagnosed in 4.3% of Sjogren’s syn. patients. ► Peripheral neuropathy and lymphoma were associated with lower vitamin-D levels.
Introduction
Sjögren’s syndrome (SS) is a slowly progressing autoimmune disease affecting the exocrine glands of predominantly middle aged women. This syndrome can present alone as primary SS (pSS) or in the context of underlying connective tissue disease as secondary SS. The prevalence of SS is reported to be between 0.1 and 4.8% depending on different reports from different geographical and ethnical areas [1], [2]. Extra glandular manifestations appear in up to a half of the patients with Sjögren’s syndrome, may involve the joints, skin, lung, central and peripheral nervous system, and may associate with various autoantibody profiles [3]. An increased incidence of lymphoma in SS patients, mainly of B-cell origin, is repeatedly demonstrated in large epidemiological studies [4], [5]. While the etiology of SS is unknown, genetic, environmental, and hormonal factors are considered to play a major role in its pathogenesis [6], [7]. Vitamin-D is a pro-hormone with important impact on bone and mineral homeostasis. During the last two decades vitamin-D has been linked to the development of cardiovascular diseases [8], cancer [9], [10], glucose intolerance [11], and all cause mortality [12]. Some of these conditions are associated with genetic polymorphisms in vitamin-D metabolism-related genes [10]. In addition, vitamin-D has been found to possess immune-regulatory and immune-suppressive effects in vitro and in vivo [13]. At least some of vitamin-D’s immune-modulatory properties are ascribed to its effect on immune cells of the innate and adaptive systems, including macrophages, dendritic cells, and T and B lymphocytic cells, all of which harbor vitamin-D receptors. Noteworthy are DCs, which are a primary target for the immunomodulatoric activity of vitamin-D [14], [15]. Vitamin-D has been shown to inhibit DC-dependent T-cell activation, and promote tolerogenic properties that favor the induction of regulatory rather that effector T-cells. Low vitamin-D levels, and higher prevalence of vitamin-D deficiency are consistently demonstrated in several autoimmune diseases, such as type I diabetes mellitus [16], rheumatoid arthritis [17], [18], autoimmune thyroid diseases [19], [20] mixed connective tissue disease [21], systemic lupus erythematosus [22], [23], [24], the anti-phospholipids syndrome (APS) [25] and systemic sclerosis [26]. Moreover, in several of these autoimmune diseases, vitamin-D levels correlated with disease severity, as well as clinical and serological markers. This could also explain the striking latitude differences found in several autoimmune diseases, which have an inverse correlation with vitamin-D status [27], [28]. Several experiments showed that vitamin-D supplementation can improve disease related symptoms in animal models of autoimmune diseases [29], as well as in patients suffering from AD’s [16], [30], [31], [32].
To date, two small case–control studies have evaluated vitamin-D levels in patients with SS, with inconclusive results. In one, which involved 25 pSS patients and 15 healthy controls from Hungary, vitamin-D levels were similar 79.9 vs. 71.5 nmol/l (p = 0.4), respectively. The authors indicated also, that no significant differences in vitamin-D levels were detected in pSS patients with and without extraglandular manifestations [33]. The second study, conducted in 1990, however, did suggest the presence of an abnormal vitamin-D3 metabolism in pSS patients [34]. In this Danish work, Muller K. and his colleagues demonstrated normal 1, 25-OH D3 levels, but lower 25-OH D3 levels, in 41 pSS patients compared to normal controls. Serum levels of Gc globulin (the main vitamin-D3 binding protein in the blood) and the distribution of its phenotypes did not differ from the normal subjects, as well. In their follow-up article in 1999, which dealt with the same 41 pSS patients, again, 25-OH D3 levels, and not 1, 25-OH D3, inversely correlated with clinical manifestations, and levels of immune-inflammatory markers [35].
In light of the uncertainty regarding the vitamin-D-SS relationship, we conducted a case–control study comparing vitamin-D levels of patients with pSS from several European countries with their matched healthy controls. In addition, we aimed to evaluate the association between vitamin-D concentrations and different manifestations of SS.
Section snippets
Study population
Serum samples were drawn from 176 consecutive pSS patients (including 169 females), treated in several European autoimmune-rheumatic medical centers. All patients were diagnosed with pSS according to the revised international classification criteria for Sjögren’s syndrome [36]. Patients were documented for demographical (age, gender), glandular and extraglandular, clinical (xerostomia, xerophthalmia, salivary gland enlargement, fever, fatigue, fibromyalgia, joint/muscle symptoms,
Vitamin-D levels in patients compared to healthy controls
Vitamin-D levels (mean ± standard deviation) of 176 patients with pSS were comparable to those of 163 healthy controls: 21.2 ± 9.4 vs. 22.4 ± 10 ng/ml, respectively (p = 0.2). In addition, the rate of vitamin-D levels lower than 20 ng/ml or lower than 10 ng/ml were 50% vs. 44.7% (p = 0.29), and 12.5% vs. 11.3% (p = 0.23) among patients and controls, respectively.
Vitamin-D levels and demographic parameters among patients with pSS
Among patients with pSS, there was no significant correlation between vitamin-D levels and gender. Mean vitamin-D levels were 21 ± 8.9
Discussion
According to our results, vitamin-D levels of patients with primary Sjögren’s syndrome are not lower than those measured in the equivalent healthy population. However, lower vitamin-D levels among pSS patients did correlate inversely with older age. This finding is supported by previous studies, including ours, demonstrating decreasing vitamin-D levels with age in patients with other autoimmune diseases such as celiac disease [38] as well as in the healthy general population [39], [40], [41].
Conclusions
In the current study we found that although levels of vitamin-D were comparable between patients with pSS and healthy controls, low levels of this vitamin correlated with peripheral neuropathy and the presence of lymphoma among the pSS patients. These inverse associations have been documented in other conditions thereby suggesting a role for vitamin-D in the process of neuronal damage and lymphoproliferative diseases. These findings may warrant the need for a tighter monitoring of vitamin-D
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Both authors have equally contributed to this manuscript.