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Vitamin D and spondyloarthritis Expert Review of Clinical Immunology Downloaded from informahealthcare.com by Chinese University of Hong Kong on 02/13/15 For personal use only.

Expert Rev. Clin. Immunol. 10(12), 1581–1589 (2014)

Xavier Guillot*, Cle´ment Prati and Daniel Wendling Department of rheumatology, Besanc¸on University Hospital, Boulevard Fleming, 25030, Besanc¸on, France *Author for correspondence: [email protected]

In cross-sectional studies, vitamin D deficiency is frequent in spondyloarthritic patients and associated with increased spondyloarthritis (SpA) activity and structural damage. Experimental studies also show that vitamin D interferes with molecular pathways critically involved in SpA, especially regarding entheseal inflammation and ossification (involving cytokines such as IL-23 and sclerostin). Vitamin D deficiency might also affect the course of the disease through periodontal and gut inflammation, leading to increased functional impairment. Therefore, Vitamin D receptor selective agonists could represent a promising therapeutic pathway in this pathology. Randomised-controlled intervention studies are required in order to further elucidate complex relationships between vitamin D deficiency and SpA. KEYWORDS: disease activity • gut inflammation • IL-23 • sclerostin • spondyloarthritis • VDR • vitamin D

Vitamin D deficiency is a key focus in public health. Cross-sectional studies suggest a high frequency of vitamin D deficiency and inverse correlations between 25-hydroxy-vitamin D (25OHD) levels and disease activity in inflammatory conditions such as rheumatoid arthritis (RA), spondyloarthritis (SpA) and systemic lupus erythematosus [1–8]. The aim of this article is to review current published data about relationships between vitamin D and SpA: pathophysiological links, epidemiological associations between SpA and vitamin D deficiency, correlations between 25OHD levels and SpA activity assessed by bath ankylosing spondylitis disease activity index (BASDAI), erythrocyte sedimentation rate (ESR) (mm) and C-reactive protein (CRP) (mg/l) levels. The screening was performed on PubMed and in abstracts from the main rheumatology congresses (ACR, EULAR). Keywords were vitamin D, cholecalciferol, Vitamin D receptor (VDR), spondyloarthritis, ankylosing spondylitis, IL 23, interleukin 23, Wint, Wnt, sclerostin (SOST), Dickkopf and DKK 1 used alone and in combination. References from the articles were screened in order to find additional relevant publications. We selected clinical trials and experimental studies which assessed relationships between vitamin D and spondyloarthritis, or could be suggestive of such links. Because of the great heterogeneity of the studies and the large field of investigation, we did not perform a systematic review as defined in the informahealthcare.com

10.1586/1744666X.2014.972944

PRISMA statement. As for clinical studies dealing with vitamin D deficiency prevalence in spondyloarthritis, we only considered controlled trials. Studies related to epidemiological associations between vitamin D deficiency and SpA were excluded if numerical results were not clearly indicated and when mean serum 250HD levels were greater or equal to 30 ng/ml in samples including patients supplemented with oral vitamin D. Genetic associations between vitamin D metabolic pathway & spondyloarthritis

As concerns pathophysiological links between SpA and vitamin D deficiency, genetic associations have been found between VDR polymorphisms such as Fok1 (assessed in genomic DNA from peripheral leukocytes) and acutephase reactant levels as well as spinal bone mass density (assessed using both dual x-ray absorptiometry and quantitative computed tomography in order to exclude vertebral ossification bias) in 71 male axial SpA patients (fulfilling NY and ESSG criteria and without inflammatory bowel disease) compared to 54 healthy controls. These associations were not found in female SpA patients (n = 33), maybe due to a shorter sample size. Included female subjects also had normal estrogen levels (premenopausal) and less severe SpA according to New York criteria [9]. However, such associations between disease frequency, activity and VDR polymorphisms have also been described

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in RA patients, so these findings are probably not disease specific but suggest a wide role of vitamin D metabolism in inflammatory diseases [10]. Genetic associations have also been described between vitamin D-binding protein polymorphisms (assessed in peripheral blood leukocytes) and the prevalence of some specific phenotypes such as peripheral joint involvement (OR 0.6; p = 0.01) or uveitis (OR 2.04; p = 0.02) in 223 SA (modified NY criteria) compared to 239 ethnically matched healthy controls. However, the authors found no significant correlation between the susceptibility to SpA and vitamin Dbinding protein polymorphisms [11]. A genetic association has also been found between a CYP27-B1 gene (encoding 25OHD-1a hydroxylase) polymorphism and HLA B27-associated anterior uveitis in a study comparing 159 B27-positive patients with anterior uveitis, 138 B27-negative healthy controls and 100 B27-positive healthy controls. The authors found a significantly higher prevalence of the G allele in HLA B27-associated anterior uveitis patients compared to B27-positive healthy controls. As no B27-negative anterior uveitis group was included, it is difficult to determine if this genetic association was specific for B27-positive uveitis or only for uveitis [12]. A metabolomic study also showed that a vitamin D3 metabolite was downregulated in a small sample including 18 SpA patients (compared to nine healthy controls) [13]. In all of these studies, SpA subjects were compared to healthy controls. All these results should be replicated and further validated by studies including inflammatory, non-SpA, controls in order to assess if these findings are SpA-specific. These data also have not been confirmed in genome-wide association studies so far [14]. Vitamin D might interfere with bone metabolism in spondyloarthritis

In certain forms of rickets, patients develop spine hyperostosis and ankylosis mimicking syndesmophytes [15]. In SpA, two opposite effects on bone metabolism have been described: on the one hand, an increased osteoporosis and vertebral fracture prevalence related to cytokine-induced trabecular bone resorption via RANK-ligand pathway up-regulation [16,17], on the other hand an increased bone formation on enthesis through bone morphogenic proteins [18], transforming growth factor b [19] and most notably Wint pathway [20–24]. In 30 active SpA patients, Wint inhibitor-sclerostin (SOST) serum levels significantly increased after 1 year under TNF-blocker treatment with a concomitant increase in lumbar spine bone mineral density (BMD) [23]. Interestingly, a 2-year vitamin D supplementation also increased SOST serum levels in 66 elderly male healthy subjects versus placebo-treated controls after adjustment for season of measurement, physical activity and total body bone mineral content. However, this effect was not observed in 86 age-matched post-menopausal women. Baseline SOST levels were not significantly different between men and women. [25]. Discrepancies between men and women in SOST serum levels have already been described and attributed to an inhibitory effect of estrogens [26]. In postmenopausal women, a negative 1582

correlation has been described between SOST and follicle stimulating hormone (FSH) levels [27]. Therefore, the observed sex-related differences in SOST serum level evolution under vitamin D supplementation might have been related to elevated FSH serum levels in postmenopausal women. In male subjects, the increase in SOST levels under vitamin D supplementation was possibly mediated through an observed serum parathormone (PTH) level decrease, as PTH has been shown to downregulate SOST expression in osteocytes [28] and subsequently in the serum [29]. As concerns BMD, the authors found no correlation between SOST serum levels and BMD at baseline in both sexes. However, in most cross-sectional studies, high SOST serum levels are associated with higher BMD, lower bone remodeling and lower fracture risk [30,31]. SOST serum level changes after vitamin D supplementation have not been assessed in SpA patients yet. Epidemiological associations between vitamin D deficiency & spondyloarthritis (frequency of vitamin D deficiency, disease activity & structural progression)

In controlled, cross-sectional studies, 25OHD serum levels were significantly lower in 161 SpA patients (including 48 ankylosing spondylitis) as compared to 92 healthy controls [32], in 100 axial SpA (modified NY criteria) versus 58 healthy controls [33] and in 44 axial SpA patients versus 39 healthy controls [34]. In another controlled study, the authors found no significant difference in mean 250HD levels between 38 SpA patients and 52 healthy controls [35]. Serum 25OHD levels also negatively correlated with BASDAI, CRP and ESR levels [32,36–38]. However, these results were not confirmed in crosssectional studies including 128 SpA patients (modified NY criteria) and 100 axial SpA patients compared to 58 healthy controls respectively [33,39]. A retrospective study including 178 SpA patients (Amor criteria) also found no significant association between 25OHD levels and disease activity [40]. A negative correlation was found with tumor necrosis factoralpha (TNF-a) serum levels in 58 established-SpA patients (NY and ESSG criteria) compared to 58 age and sex-matched healthy controls [38]. Potential confounders such as seasonal variations (one study conducted in winter [32] and two studies in summer [37,38]), age [33,34,36–38], physical activity (physically active patients within the 12 previous months [33,36–38]) and BMI [33,38] were only partly assessed. As concerns vitamin D intake, patients receiving oral vitamin D supplementation were clearly excluded in only two studies [34,36]. In two other studies, patients receiving ‘drugs known to affect bone metabolism’ (without further precision) were excluded [37,38]. None of the SpA patients was treated with TNF-blockers. All the studies were cross-sectional except one retrospective study [40], and all studies were controlled except two ones [39,40]. In the French DESIR cohort, including 708 patients suffering from recent-onset inflammatory back pain suggestive of spondyloarthritis, at baseline, patients with serum 25OHD levels lower than 20 ng per ml showed significantly more prevalent X-ray sacroiliitis (104/358 vs 81/342; p < 0.03), BASDAI greater Expert Rev. Clin. Immunol. 10(12), (2014)

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Table 1. Vitamin D deficiency and spondyloarthritis: main studies. Study population

Endpoints

Design/methods

Associations

Ref.

104 axial SpA (NY+ESSG) – 54 healthy controls (matched for age, sex, BMI

VDR polymorphisms (Fok1 and Bsml)

Cross-sectional (consecutive inclusions) Bi-centric Genomic study Adjustment factors: BMI, pain, inflammation markers

Fok1 FF polymorphism (only in male patients, n = 71): – mean CRP 22 mg/L vs ff: 7 mg/L; p = 0.02 – significantly lower spine BMD (p = 0.01) and 25OHD levels (p = 0.002)

223 axial SpA (modified NY criteria, B27 95.3%) – 239 ethnicity-matched controls

VDBP polymorphisms

Retrospective Genomic study

– 3 SNP: peripheral arthritides OR 0.6; p = 0.01 – 1 SNP: uveitis OR 2.04; p = 0.02

[11]

159 patients with B27-positive-associated anterior uveitis 138 B27-negative healthy controls 100 B27-positive healthy controls

CYP27B1 polymorphism (1-a hydroxylase gene)

Case-control design

rs703842 A>G polymorphism HLA B27-positive uveitis versus HLA B27-positive healthy controls: OR = 0.62; p = 0.03

[12]

18 axial SpA (modified NY criteria) – nine healthy controls

Vitamin D3 metabolites (mass spectrometry)

Cross-sectional Metabolomic study

One vitamin D3 metabolite significantly lower in SA patients

[13]

161 SpA (113 undifferentiated/ 48 axial SpA; ESSG criteria) – 92 healthy controls

25OHD levels Disease activity (ESR, CRP, BASDAI)

Cross-sectional Controlled for seasonal variations

25OHD: 18 mg/L (AS) vs 24.3 mg/L (controls); p = 0.004 ESR: r = –0.428 (Spearman); p = 0.002 CRP: r = –0.592; p < 0.001 BASDAI: NS

[32]

100 axial SpA – 58 healthy controls

25OHD levels Disease activity (ESR, CRP, BASDAI)

Cross-sectional

25OHD: 21.7 mmol/L vs 32.7 mmol/L; p < 0.0001 ESR, CRP, BASDAI : NS

[33]

44 male axial SpA 39 age-matched healthy controls

25OHD levels Disease activity (measured parameter?)

Cross-sectional No vitamin D supplementation

25OHD: 19.2 ng/ml versus 26.6 ng/ml Disease activity: NS (measured parameter: NA)

[34]

38 axial SpA – 52 healthy controls

25OHD levels

Cross-sectional

25OHD: 21.6 ng/ml versus 20.1 ng/ml (NS)

[35]

99 axial SpA (modified NY criteria) – 42 healthy controls

25OHD levels Disease activity (ESR, CRP, BASDAI)

Cross-sectional Seasonal control Exclusion of vitamin D supplements

25OHD: 26.8 ng/ml versus 31.1 ng/ml (NS) ESR: r = –0.366 (Pearson); p < 0.001 CRP: r = –0.344; p < 0.001 BASDAI: r = –0.304; p = 0.002

[36]

70 axial SpA (modified NY criteria) – 70 age- and sexmatched healthy controls

25OHD3 and 1,25(OH) 2D3 levels Disease activity (ESR, CRP, BASDAI)

Cross-sectional Physically active patients Sunlight exposure NA

1,25(OH)2D3: 31 vs 42 pg/ml; p < 0.05 25OHD3: NS ESR: 23 vs 7 mm ; p < 0.05 CRP/1,25(OH)2D3: r = –0.711 ; p < 0.01 (Spearman) BASDAI/1,25(OH)2D3: r = –0.547 ; p < 0.01

[37]

58 axial SpA (modified NY and ESSG criteria) – 58 age and sex-matched healthy controls

25OHD3 and 1,25(OH) 2D3 levels Disease activity (ESR, CRP, TNF-a, BASDAI)

Cross-sectional Physically active patients Sunlight exposure NA

1,25(OH)2D3: 27 vs 43 pg/ml; p < 0.05 25OHD3: 19 vs 29 ng/ml; p < 0.05 ESR/1,25(OH)2D3: r = –0.57; p < 0.001 (Spearman) CRP/1,25(OH)2D3: r = –0.702; p < 0.001 BASDAI/1,25(OH)2D3: r = –0.567; p < 0.001 Serum TNF-a/1,25(OH)2D3: r = –0.521; p < 0.001

[38]

[9]

BASDAI: Bath ankylosing spondylitis disease activity index; BMD: Bone mineral density; CRP: C-reactive protein; ESR: Erythrocyte sedimentation rate; SpA: Spondyloarthritis; VDR: Vitamin D receptor.

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Table 1. Vitamin D deficiency and spondyloarthritis: main studies (cont.). Study population

Endpoints

Design/methods

Associations

Ref.

128 active axial SpA (modified NY criteria)

Disease activity (ESR, CRP, BASDAI)

Cross-sectional No control group

Mean 250HD: 24.4 ng/ml 250HD< 20 ng/ml: 26% 25OHD (nmol/L)/ESR, CRP, BASDAI: NS

[39]

178 SpA (Amor criteria)

Disease activity (BASDAI, CRP)

Retrospective No control group

Mean 25OHD: 24.8 ng/ml CRP, BASDAI: NS

[40]

708 patients with early inflammatory back pain suggestive of axial SpA. Male: 46.2% Mean age: 33.8 +/– 8.6

Disease activity (BASDAI, BASFI, BASMI, ASDAS) X-ray sacroiliitis

Cross-sectional (data at baseline) Adjusted for season and ethnicity (not for sex nor for age)

25OHD < 20 ng/ml/ BASDAI > 40 /ASDAS CRP > median value /higher BASMI /more prevalent x-ray sacroiliitis

[41]

BASDAI: Bath ankylosing spondylitis disease activity index; BMD: Bone mineral density; CRP: C-reactive protein; ESR: Erythrocyte sedimentation rate; SpA: Spondyloarthritis; VDR: Vitamin D receptor.

than 40 (226/358 vs 193/342; p < 0.03) and ankylosing spondylitis disease activity score (ASDAS) CRP higher than the median value (182/358 vs 151/342; p < 0.01). These patients also showed significantly more prevalent abdominal obesity (71/358 vs 49/342; p < 0.03), low HDL cholesterol rates (103/358 vs 72/342; p < 0.01) and more prevalent metabolic syndrome (26/358 vs 14/342; p < 0.04) [41]. All the data from analyzed studies are summarized in TABLE 1. We considered seven published articles [32,33,35–39] and three abstracts from international rheumatology conferences [34,40,41]. Six studies were excluded: A South-African study showed no difference in 25OHD levels between 74 SpA patients (modified New York Criteria) versus 70 non-age-matched healthy controls (which were 10 years older on average) and no correlation between serum 25OHD levels and disease activity assessed by the BASDAI score. The authors assessed season and sunlight exposure as potential confounders. However, the patients had ‘stable doses of vitamin D supplements for 3 months prior to their assessment’ with no more information and SpA patients as well as healthy controls showed normal mean 250HD concentrations (30.79 ng/ml vs 30.73 ng/ml respectively in summer, 29.57 ng/ml vs 29.82 ng/ml in winter). These values were higher than those found in the other studies related to the topic [32–40]. Therefore, we considered that the results were probably biased by vitamin D supplementation and by a mean 10-year difference in age between SpA patients (which were younger) and healthy controls [42]. We also excluded two articles which showed significant associations between 250HD levels and BASDAI [43] and BASDAI, CRP and ESR [44] but with no quantitative assessment of these associations. Another study was excluded because the authors only presented grouped results from a sample of patients including 85 rheumatoid arthritis, 22 psoriatic arthritis and 14 axial SpA patients [45]. Two other studies were excluded due to insufficient sample size [46] and inappropriate outcomes [47]. In a recent article, evidence concerning relationships between vitamin D deficiency and SpA (vitamin D deficiency prevalence in SpA, disease activity) was systematically reviewed [48]. All the selected studies had 1584

a cross-sectional design, and most of them didn’t control for important confounding factors such as sunlight exposure, physical impairment and vitamin D supplementation. The quality and design of the studies were also insufficient (sample sizes, outcomes, statistical analysis and bias assessment), so the data couldn’t be pooled. SpA patients showed significantly lower 25OHD serum levels in 7/11 studies and 25OHD levels inversely correlated with various disease activity measures in 5/11 studies. No effect size could be calculated due to a great heterogeneity between studies and a lack of details in result reporting. No causal relationship between vitamin D deficiency and SpA prevalence and activity could be shown because of the cross-sectional design of the studies and mostly non-assessed confounding factors. Indeed, many potential confounders such as decreased sunlight exposure in patients with active SpA might interfere with these associations. Vitamin D deficiency might also be related to gut inflammation and malabsorption in SpA, and so be rather a consequence than a cause of these diseases. Therefore, non-biased longitudinal randomized controlled trials are required in order to demonstrate a causal link between vitamin D deficiency and SpA (disease onset, activity and structural severity). Vitamin D supplementation in spondyloarthritis

In inflammatory joint diseases, vitamin D supplementation using high-dose loading treatment (a single oral dose of cholecalciferol 300 000 IU followed by oral cholecalciferol 800–1000 IU daily for 6 months) has been shown to be more efficient for reaching serum 250HD and PTH level normalization (i.e., 30 ng/ml or greater and 79.9 pg/ml or lower respectively) as compared to the same regimen with low-dose loading treatment (100 000 IU) or without any loading treatment [49]. The same authors had previously shown that in the same sample of autoimmune/inflammatory rheumatic disease patients (including rheumatoid arthritides, polymyalgia rheumatica, spondyloarthritides and other connective tissue diseases), average PTH concentration was increased irrespective of plasma 250HD range, suggesting an impaired vitamin D metabolism. Therefore, the authors suggested that in these patients, vitamin D Expert Rev. Clin. Immunol. 10(12), (2014)

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Vitamin D & spondyloarthritis

supplementation might be targeted to reach PTH suppression and not merely to usual therapeutic thresholds (i.e., 30 ng/ml) [50]. There are pathophysiological and epidemiological links between vitamin D deficiency and SpA but prospective randomized controlled trials are required to further assess the interest of vitamin D supplementation in this disease. It seems logical to monitor serum 25OHD levels in these patients and to target vitamin D global health therapeutic threshold (30– 44 ng/ml) vitamin D poisoning occurring at levels greater than 150 ng/ml [51,52]. Whether or not a threshold higher than 30–40 ng/ml should be targeted in order to reach sufficient local 1,25(0H) 2D3 concentrations in lymphoid microenvironment and subsequent optimal cholecalciferol immunomodulatory effects is still debated [53]. The therapeutic effects of vitamin D supplementation in SpA patients have not been demonstrated in wellconducted clinical trials so far. In an open-label study, six psoriatic arthritis patients treated with 1,25(OH) 2D3 (2 mg/day) for 6 months showed significant improvement in tender joint count, physician pain visual analogic score and ESR. However, we excluded this study from analysis due to an insufficient sample size [54]. No longitudinal intervention study with an appropriate design and sample size has been conducted in the field so far.

Vitamin D deficiency

Periodontal inflammation Citrullination

Sunlight exposure Sarcopenia Functional impairment

Enthesitis (bone formation)

IL-23

Gut (inflammation, malabsorption)

Bone (osteoporosis)

Smoking?

Spondyloarthritis (onset, activity, radiological progression)

Figure 1. Potential interactions between vitamin D deficiency and spondyloarthritis. Relationships between vitamin D deficiency and spondyloarthritis are complex with numerous potential confounders. Vitamin D deficiency, by promoting periodontal inflammation, could induce the citrullination of peptides such as vimentin via pathogens holding peptidyl deiminases such as Porphyromonas gingivalis [56]. Citrullinated vimentin has been associated with diseases radiological progression in SpA [55]. Vitamin D deficiency might also be associated with x-ray sacroiliitis [41]. In many cross-sectional studies, vitamin D deficiency is also more frequent in SpA patients and associated with increased disease activity [41]. Reciprocally, structural damage and functional impairment in SpA might aggravate vitamin D deficiency by reducing sunlight exposure. Gut inflammation is independently associated with disease activity (BASDAI) in axial SpA [70]. Malabsorption induced by this condition aggravates vitamin D deficiency. Vitamin D deficiency is significantly more prevalent in inflammatory bowel diseases and might in turn increase gut inflammation [6]. In SpA, the effects on bone are dual: Bone resorption driven by cytokines and RANKligand pathway [17] and new bone formation in enthesis, involving Wint pathway [20]. Vitamin D might inhibit Wint pathway through sclerostin up-regulation [25]. IL-23 is up-regulated in SpA and is notably produced by inflamed gut macrophages. It induces Th-17 response in enthesis through a specific IL-23R+ T-cell subset [64]. Vitamin D supplementation might down-regulate gut inflammation and IL-23 production [63,75].

Expert Commentary & five-year view

Interactions between SpA and vitamin D deficiency are numerous and complex. Recent epidemiological data showed more prevalent periodontal inflammation in SpA patients as compared to healthy controls, which could favor disease onset and activity via peptide citrullination in the same manner as in RA. Citrullinated vimentin levels have also been shown to correlate with radiological progression in SpA [55]. This indirectly suggests potential links between vitamin D deficiency, periodontitis and peptidic citrullination. In a model of periodontal cell culture, 1,25(OH)2D3 supplementation halved P. gingivalisinduced IL-8-mediated inflammation [56]. In this context, vitamin D supplementation might have therapeutic effects in SpA (FIGURE 1). 1,25(OH)2D3 modulates immune cell proliferation, differentiation [57,58] and cytokine gene transcription [59] through VDR interaction with VDR-response elements on target-gene promoters [60]. Furthermore, monocytes, dendritic cells and informahealthcare.com

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T-lymphocytes express 1a-hydroxylase and produce 1,25(OH) 2D3 locally in the immune cell microenvironment, which exerts autocrine and paracrine immunomodulatory effects [60–62]. Data from in vitro studies show that 1,25(OH)2D3 induces a shift from a pro-inflammatory T-helper 1 (Th-1), Th-17 to an antiinflammatory Th-2 and T-reg cytokinic profile (FIGURE 2) [63]. These pathways are known to be critically involved in SpA pathogenesis, especially interleukin 12/interleukin 23 (IL-12/IL23) [64] and interleukin 6/interleukin 17 (IL-6/IL-17) [65] pathways. IL-23 is a key cytokine in SpA pathophysiology. IL-23 receptor polymorphisms are associated with SpA [66,67]. Furthermore, B27 protein misfolding might induce IL-23 production through endoplasmic reticulum stress or autophagy [68,69]. In SpA, besides associated inflammatory bowel diseases, subclinical intestinal inflammation is frequent [70], and IL-23 has been shown to be overexpressed in inflamed gut [71,72]. A specific IL-23-responsive Th-17 cell subset has recently been identified in cell cultures from SpA murine models [64,73]. Therefore, new therapeutic strategies targeting IL-23 pathway could be promising in SpA. In a 1585

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compared to nine age- and sex-matched non-treated controls. IL-6 and TNF-a 1α-hydroxylase gene transcription levels were also signifiTh-1 response: cell-mediated 25-et 1α– ↓Proliferation immunity, intracellular pathogens cantly down-regulated in peripheral blood hydroxylases Th-1 ↓IL-2 et IFNγ (viruses), auto-immune diseases mononuclear cells in paricacitol-treated ↓IL-12 patients [74]. By contrast, in treated Dendritic Th-2 response: antibodypatients, serum calcium and phosphorus cells ↑↓IL-4 ? ↑GATA-3 mediated immunity, bactéria and ↑IL-5 levels did not show any significant varia↑Th-2 parasites, allergic response ↓Proliferation ↑IL-10 tion. These anti-IL-6 and anti-TNF-a ↓Differenciation effects in patients suffering from chronic ↓T cell stimulation Tr-1 lymphocytes: suppressor ↑IL-10 ↑Tr-1 kidney diseases suggest potential theraeffect on the immune response 25OHD3 peutic effects in inflammatory rheumatic ↑Cathelicidin diseases such as spondyloarthritis, as ↑Chemotactism Treg: effector T cell regulation, ↑Phagocytosis immune tolerance TNF-a and IL-6 are key molecular ↓CMH-2↓TLR9-4-2 ↑FoxP3 pathways in this pathology. Further↑Treg ↓IL-1 ↓TNF-α more, another VDR partial agonist, MacroBXL-62, compared to 1,25(OH)2D3, Th-17 response: pro↓RORγT phage significantly down-regulated IL-12/ inflammatory effect, auto↓Th-17 ↓IL-6 immunity, extracellular pathogens IL-23 p40 subunit, TNF-a, IL-6 and ↓IL-23 interferon-g (IFN-g) expression both at ↓Proliferation the transcriptional and protein levels in ↓Plasma cell differenciation B cell peripheral blood mononuclear cells and ↓Immunoglobulin production in lymphocyte-enriched lamina propria mononuclear cells from inflammatory Figure 2. Vitamin D effects on immune cells. In vitro studies show that 1,25(OH)2D3 inhibits B- and T-cell proliferation and differentia- bowel disease patients (Crohn’s disease tion, both directly and indirectly through dendritic cell (DC) and macrophage modulation. and ulcerative colitis). BXL-62 also It shifts the immune response from a Th-1/Th-17 pro-inflammatory toward a Th-2/Treg showed significantly higher therapeutic anti-inflammatory profile [6,63]. By down-regulating IL-12/IL-23, IL-6 and IL-17 pathways, vitamin D might play a role in effects compared to 1,25(OH)2D3 in spondyloarthritis (disease prevalence, activity, severity, enthesitis formation) and vitamin D murine dextran-sodium sulfate-induced supplementation (maybe using immunomodulating selective agonists such as paricacitol) colitis (clinical symptom improvement could hold therapeutic promise in SpA. at normocalcemic doses) [75]. This 1,25(OH)2D3, by up-regulating anti-bacterial peptide cathelicidin in macrophages, might VDR agonist, especially by interfering also have an influence on intracellular pathogens which might trigger agents involved in with IL-23 pathway and gut inflammaSpA onset [48]. tion without inducing hypercalcemia, might hold therapeutic promise in SpA murine model of colitis, vitamin D supplementation significantly patients. Longitudinal controlled intervention studies using down-regulated IL-23 p19 subunit in inflamed gut tissue and vitamin D supplementation in SpA (usual pharmacological showed therapeutic effects [63]. By down-regulating IL-23 forms or selective VDR agonists) are required in order to production in the inflamed gut, vitamin D might decrease further investigate the complex relationships between vitasubsequent IL-23 responsive cell-mediated enthesis inflammation, min D and SpA and potential therapeutic effects of vitamin which is the key feature in SpA pathogenesis and disease D analogs in this pathology. progression. These immunomodulatory properties require high 1,25(OH) Financial & competing interests disclosure 2D3 levels in the immune cell microenvironment. These levels The authors have no relevant affiliations or financial involvement could only be achieved using very high vitamin D intakes, with any organization or entity with a financial interest in or finanwhich could result in non-acceptable hypercalcemia risks. cial conflict with the subject matter or materials discussed in the manRecently, selective VDR agonists have been developed such as uscript. This includes employment, consultancies, honoraria, stock paricacitol (19-nor-1,25-hydroxy-vitamin D2). In eight dialyzed ownership or options, expert testimony, grants or patents received or male patients, paricacitol administration during 5 months sig- pending, or royalties. nificantly reduced serum IL-6, TNF-a and hs-CRP levels as No writing assistance was utilized in the production of this manuscript. Lymphocytes

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Key issues • In vitro studies show that vitamin D might interfere with key molecular pathways involved in SpA onset, activity and radiologic progression. • Vitamin D supplementation might notably down-regulate IL-23 and up-regulate sclerostin pathways. • Vitamin D deficiency could also be involved in SpA-associated gut and periodontal inflammation. • Many cross-sectional studies show that vitamin D deficiency is frequent in SpA patients and suggest an inverse correlation between 25OHD levels and SpA activity, radiological progression.

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• However, many confounders should be assessed (sunlight exposure, functional impairment, BMI, malabsorption, vitamin D supplementation) in longitudinal controlled studies (cohort studies and interventional studies). • Vitamin D receptor selective agonists such as paricacitol and BXL-62 could exert immunomodulatory properties in the immune cell microenvironment without inducing hypercalcemia and should be evaluated as a potential therapeutic option in this pathology.

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Durmus B, Altay Z, Baysal O, Ersoy Y. Does vitamin D affect disease severity in patients with ankylosing spondylitis? Chin Med J (Engl) 2012;125(14):2511-15 Guillot X, Semerano L, Saidenberg-Kermanac’h N, et al. Vitamin D and inflammation. Joint Bone Spine 2010;77:552-7 A review article showing complex pathophysiological links between vitamin D and inflammation. In in-vitro models, 1,25(OH)2D3 notably down-regulates some cytokinic pathways known to be critically involved in Spondyloarthritis (SpA). Agmon-Levin N, Theodor E, Segal RM, Shoenfeld Y. Vitamin D in systemic and organ-specific autoimmune diseases. Clin Rev Allergy Immunol 2013;45(2):256-66

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Pludowski P, Holick MF, Pilz S, et al. Vitamin D effects on musculoskeletal health, immunity, autoimmunity, cardiovascular disease, cancer, fertility, pregnancy, dementia and mortality-a review of recent evidence. Autoimmun Rev 2013; 12(10):976-89

Jung KH, Kim TH, Sheen DH, et al. Associations of vitamin d binding protein gene polymorphisms with the development of peripheral arthritis and uveitis in ankylosing spondylitis. J Rheumatol 2011;38:2224-9 Steinwender G, Lindner E, Weger M, et al. Association between polymorphism of the vitamin D metabolism gene CYP27B1 and HLA-B27-associated uveitis. Is a state of relative immunodeficiency pathogenic in HLA B27-positive uveitis? PLoS One 2013; 8(4):e62244

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Fischer R, Trudgian DC, Wright C, et al. Discovery of candidate serum proteomic and metabolomic biomarkers in ankylosing spondylitis. Mol Cell Proteomics 2012; 11(2):M111.013904

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International Genetics of Ankylosing Spondylitis Consortium (IGAS)1. Cortes A, Hadler J, Pointon JP, et al. Identification of multiple risk variants for ankylosing spondylitis through high-density genotyping of immune-related loci. Nat Genet 2013; 45(7):730-8

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Demirbilek H, Aydogdu D, Ozon A. Vitamin D-deficient rickets mimicking

ankylosing spondylitis in an adolescent girl. Turk J Pediatr 2012;54:177-9 16.

Lukik IK, Grcevic D, Kovacic N, et al. Alteration of newly induced enchondral bone formation in adult mice without tumour necrosis factor receptor 1. Clin Exp Immunol 2005;139(2):236-44

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Kim HR, Kim HY, Lee SH. Elevated serum levels of soluble receptor activator of nuclear factor-kB ligand (sRANKL) and reduced bone mineral density in patients with ankylosing spondylitis (AS). Rheumatology 2006;45(10):1197-200

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Lories RJ, Luyten FP. Bone morphogenetic proteins in destructive and remodeling arthritis. Arthritis Res Ther 2007;9:207

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Lories RJ, Derese I, De Bari C, Luyten FP. Evidence for uncoupling of inflammation and joint remodeling in a mouse model of spondylarthritis. Arthritis Rheum 2007;56: 489-97

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Appel H, Ruiz-Heiland G, Listing J, et al. Altered Skeletal Expression of Sclerostin and Its Link to Radiographic Progression in Ankylosing Spondylitis. Arthritis Rheum 2009;60(11):3257-62

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Heiland GR, Appel H, Poddubnyy D, et al. High level of functional dickkopf-1 predicts protection from syndesmophyte formation in patients with ankylosing spondylitis. Ann Rheum Dis 2012;71:572-4

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Haynes KR, Pettit AR, Duan R, et al. Excessive bone formation in a mouse model of ankylosing spondylitis is associated with decreases in Wnt pathway inhibitors. Arthritis Res Ther 2012;14:R253

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Saad CG, Ribeiro ACM, Moraes JCB, et al. Low sclerostin levels: a predictive marker of persistent inflammation in ankylosing spondylitis during anti-tumor necrosis factor therapy? Arthritis Res Ther 2012;14:R216

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Diarra D, Stolina M, Polzer K, et al. Dickkopf-1 is a master regulator of joint remodeling. Nat Med 2007;13(2):156-63

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Guillot, Prati & Wendling

Dawson-Hughes B, Harris SS, Ceglia L, Palermo NJ. Effect of supplemental vitamin D and calcium on serum sclerostin levels. Eur J Endocrinol 2014;170(4):645-50 A longitudinal intervention study suggesting that vitamin D supplementation might interfere with bone formation and Wint pathway through sclerostin inhibition.

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Clarke BL, Drake MT. Clinical utility of serum sclerostin measurements. Bonekey Rep 2013;2:361

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Ardawi MS, Al-Kadi HA, Rouzi AA, Qari MH. Determinants of serum sclerostin in healthy pre- and postmenopausal women. J Bone Miner Res 2011;26(12):2812-22

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Bellido T, Ali AA, Gubrij I, et al. Chronic elevation of parathyroid hormone in mice reduces expression of sclerostin by osteocytes: a novel mechanism for hormonal control of osteoblastogenesis. Endocrinology 2005;146:4577-83 Drake MT, Srinivasan B, Modder UI, et al. Effects of parathyroid hormone treatment on circulating sclerostin levels in postmenopausal women. Journal Clin Endocrinol Metab 2010;95:5056-62 Szulc P, Bertholon C, Borel O, et al. Lower fracture risk in older men with higher sclerostin concentration: a prospective analysis from the MINOS study. J Bone Miner Res 2013;28:855-64 Garnero P, Sornay-Rendu E, Munoz F, et al. Association of serum sclerostin with bone mineral density bone turnover, steroid and parathyroid hormones, and fracture risk in postmenopausal women: the OFELY study. Osteoporos Int 2013;24:489-94 Erten S, Kucuksahin O, Sahin A, et al. Decreased plasma vitamin D levels in patients with undifferentiated spondyloarthritis and ankylosing spondylitis. Intern Med 2013;52(3):33-44 Memerci Baskan B, Dogan YP, Sivas F, et al. The relation between osteoporosis and vitamin D levels and disease activity in ankylosing spondylitis. Rheumatol Int 2010; 30(3):375-81 Muntean LM, Simon SP, Font P, et al. Vitamin D deficiency in men with ankylosing spondylitis. Ann Rheum Dis 2011;70(Suppl 3):334

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Franck H, Keck E. Serum osteocalcin and vitamin D metabolites in patients with ankylosing spondylitis. Ann Rheum Dis 1993;52(5):343-6

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Durmus B, Altay Z, Baysal O, Ersoy Y. Does vitamin D affect disease severity in

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ankylosing spondylitis. Am J Med 1997; 103(3):233-41

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Lange U, Jung O, Teichmann J, Neeck G. Relationship between disease activity and serum levels of vitamin D metabolites and parathyroid hormon in ankylosing spondylitis. Osteoporos Int 2001;12:1031-5

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Teichmann J, Voglau MJ, Lange U. Antibodies to human tissue transglutaminase and alterations of vitamin D metabolism in ankylosing spondylitis and psoriatic arthritis. Rheumatol Int 2010;30(12):1559-63

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Lange U, Teichmann J, Strunk J, et al. Association of 1.25 vitamin D3 deficiency, disease activity and low bone mass in ankylosing spondylitis. Osteoporos Int 2005;16(12):1999-2004

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Arends S, Spoorenberg A, Bruyn GA, et al. The relation between bone mineral density, bone turnover markers, and vitamin D status in ankylosing spondylitis patients with active disease: a cross-sectional analysis. Osteoporosis Int 2011;22(5):1431-9

Zhao S, Duffield SJ, Moots RJ, Goodson NJ. Systematic review of association between vitamin D levels and susceptibility and disease activity of ankylosing spondylitis. Rheumatology (Oxford) 2014;53(9):1595-603



A recent systematic review article suggesting frequent vitamin D deficiency and inverse correlations between 25OHD levels and disease activity in SpA. The overall poor quality and heterogeneity of the studies prevented from pooling data and calculating any effect-size. All the studies were crosssectional. No causal relationship could be shown.

49.

Sainaghi PP, Bellan M, Nerviani A, et al. Superiority of a high loading dose of cholecalciferol to correct hypovitaminosis d in patients with inflammatory/autoimmune rheumatic diseases. J Rheumatol 2013; 40(2):166-72

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Sainaghi PP, Bellan M, Antonini G, et al. Unsuppressed parathyroid hormone in patients with autoimmune/inflammatory rheumatic diseases: implications for vitamin D supplementation. Rheumatology (Oxford) 2011;50(12):2290-6

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Holick MF. Vitamin D deficiency. NEngl JMed 2007;357:266-81

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Bischoff-Ferrari HA, Shao A, Dawson-Hughes B, et al. Benefit-risk assessment of vitamin D supplementation. Osteoporos Int 2010;21(7):1121-32



A recent meta-analysis suggesting 30– 44 ng/ml being a target 25OHD serum level for global health (non-vertebral fracture, fall, cardiovascular event and colorectal cancer prevention). Some of these protective effects might be related to vitamin D immunomodulatory properties.

53.

Braun-Moscovici Y, Toledano K, Markovits D, et al. Vitamin D level: is it related to disease activity in inflammatory joint disease? Rheumatol Int 2011;31(4): 493-9

Meyer O, Dawidowicz K, Wabo S. L’Actualite´ rhumatologique. Elsevier Masson Publishing; Paris, France: 2011. p. 243

54.

Lee YS, Schlotzhauer T, Ott SM, et al. Skeletal status of men with early and late

Huckins D, Felson DT, Holick M. Treatment of psoriatic arthritis with oral 1,25-dihydroxyvitamin D3 : a pilot study. Arthritis Rheum 1990;33(11):1723-7

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Wendling D, Prati C. Spondyloarthritis and smoking: towards a new insight into the

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Rostom S, Gossec L, Kolta S, et al. Prevalence of vitamin D deficiency in spondyloarthropathy. Ann Rheum Dis 2009;68(Suppl 3):648

41.

Hmamouchi I, Paternotte S, Borderie D, et al. Vitamin D deficiency is associated with a more active and severe disease in early axial spondyloarthritis: data from the DESIR cohort. 77th Annual Meeting of the American College of Rheumatology/ 48th Annual Meeting of the Association of Rheumatology Health Professionals, San Diego, CA, 25–30 October 2013. Arthritis Rheum 2013. 65 (Suppl 10):S649



A cross-sectional study from a large French cohort showing inverse correlations between 25OHD levels and SpA activity and x-ray sacroiliitis.

42.

Yazmalar L, Ediz L, Alpayci M, et al. Seasonal disease activity and serum vitamin D levels in rheumatoid arthritis, ankylosing spondylitis and osteoarthritis. Afr Health Sci 2013;13(1):47-55

43.

Hmamouchi I, Allali F, Hamdaoui B. The relation between disease activity, vitamin D levels and bone mineral density in men patients with ankylosing spondylitis. Rheumatol Rep 2013;5:e3-7-11

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Baykal T, Alp F Ugur M. The correlation between serum vitamin D levels and parathyroid hormone and disease activity in patients with ankylosing spondylitis. Osteoporosis Int 2011;22:937-41X

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Vitamin D & spondyloarthritis

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A review article showing pathophysiological links between SpA, peptidic citrullination, and periodontitis. Vitamin D deficiency could play a role in this relationship by inducing periodontitis. Tang X, Pan Y, Zhao Y. Vitamin D inhibits the expression of interleukin-8 in human periodontal ligament cells stimulated with Porphyromonas gingivalis. Arch Oral Biol 2013;58(4):397-407 Lemire JM, Adams JS, Sakai R, Jordan SC. 1 alpha,25-dihydroxyvitamin D3 suppresses proliferation and immunoglobulin production by normal human peripheral blood mononuclear cells. J Clin Invest 1984;74(2):657-61 Rigby WF, Stacy T, Fanger MW. Inhibition of T lymphocyte mitogenesis by 1,25-dihydroxyvitamin D3 (calcitriol). J Clin Invest 1984;74(4):1451-5 D’Ambrosio D, Cippitelli M, Cocciolo MG, et al. Inhibition of IL-12 production by 1,25-dihydroxyvitamin D3. Involvement of NF-kappaB downregulation in transcriptional repression of the p40 gene. J Clin Invest 1998;101(1):252-62 Hewison M, Freeman L, Hughes SV, et al. Differential regulation of vitamin D receptor and its ligand in human monocyte-derived dendritic cells. J Immunol 2003;170:5382-90 Fritsche J, Mondal K, Ehrnsperger A, et al. Regulation of 25-hydroxyvitamin D31 alpha-hydroxylase and production of 1 alpha,25-dihydroxyvitamin D3 by human dendritic cells. Blood 2003;102(9):3314-16



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An original research article showing vitamin D supplementation therapeutic effects in trinitrobenzene sulfonic acid-induced murine colitis, notably down-regulating IL-23 p19 subunit protein expression in colonic cellular extracts (Western blot).

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Sherlock JP, Buckley CD, Cua DJ. The critical role of interleukin-23 in spondyloarthropathy. Mol Immunol 2014; 57(1):38-43



A review article showing that IL-23 might be the key mediator involved in enthesitis and gut inflammation in SpA.

65.

Hreggvidsdottir HS, Noordenbos T, Baeten DL. Inflammatory pathways in spondyloarthritis. Mol Immunol 2014; 57(1):28-37

66.

Dong H, Li Q, Zhang Y, et al. IL23R gene confers susceptibility to ankylosing spondylitis concomitant with uveitis in a Han Chinese population. PLoS One 2013; 8(6):e67505

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Sigmundsdottir H, Pan J, Debes GF, et al. DCs metabolize sunlight-induced vitamin D3 to ‘program’ T cell attraction to the epidermal chemokine CCL27. Nat Immunol 2007;8:285-93 Daniel C, Sartory NA, Zahn N, et al. Immune modulatory treatment of trinitrobenzene sulfonic acid colitis with calcitriol is associated with a change of a T helper (Th) 1/Th17 to a Th2 and

disease activity in SpA. These effects might be in part related to malabsorption and subsequent vitamin D deficiency.

regulatory T cell profile. J Pharmacol Exp Ther 2008;324:23-33

disease. Expert Rev Clin Immunol 2013;9: 511-16

Kadi A, Costantino F, Izac B, et al. Brief report: the IL23R nonsynonymous polymorphism rs 11209026 is associated with radiographic sacroiliitis in spondyloarthritis. Arthritis Rheum 2013; 65(10):2655-60 DeLay ML, Turner MJ, Klenk EI, et al. HLA-B27 misfolding and the unfolded protein response augment interleukin-23 production and are associated with Th17 activation in transgenic rats. Arthritis Rheum 2009;60(9):2633-43 Ciccia F, Accardo-Palumbo A, Rizzo A, et al. Evidence that autophagy, but not the unfolded protein response, regulates the expression of IL-23 in the gut of patients with ankylosing spondylitis and subclinical gut inflammation. Ann Rheum Dis 2014; 73(8):1566-74

70.

Van Praet L1, Van den Bosch FE, Jacques P, et al. Microscopic gut inflammation in axial spondyloarthritis: a multiparametric predictive model. Ann Rheum Dis 2013;72(3):414-17



An article showing an independent association between gut inflammation and

Special Report

71.

Ciccia F, Bombardieri M, Principato A, et al. Overexpression of interleukin-23, but not interleukin-17, as an immunologic signature of subclinical intestinal inflammation in ankylosing spondylitis. Arthritis Rheum 2009;60(4):955-65

72.

Benham H, Rehaume LM, Hasnain SZ, et al. Interleukin-23 mediates the intestinal response to microbial b-1,3-glucan and the development of spondyloarthritis pathology in SKG mice. Arthritis Rheumatol 2014; 66(7):1755-67

73.

Sherlock JP, Joyce-Shaikh B, Turner SP, et al. IL-23 induces spondyloarthropathy by acting on ROR-gt+ CD3+CD4-CD8entheseal resident T cells. Nat Med 2012; 18(7):1069-76



The identification of a new IL-23R+, RORgT+, CD3+CD4–CD8– entheseal resident T-lymphocyte subset.

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Donate-Correa J, Dominguez-Pimentel V, Mendez-Perez ML, et al. Selective vitamin D receptor activation as an anti-inflammatory target in chronic kidney disease. Mediators Inflamm 2014;2014:670475



An article showing immunomodulatory properties of a vitamin D receptor selective agonist in hemodialyzed patients. These results suggest potential therapeutic effects in inflammatory rheumatic diseases such as SpA.

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Laverny G, Penna G, Vetrano S, et al. Efficacy of a potent and safe vitamin D receptor agonist for the treatment of inflammatory bowel disease. Immunol Lett 2010;131(1):49-58



An experimental controlled study showing the impact of a vitamin D receptor partial agonist (BXL-62) on IL-23 production and gut inflammation in peripheral blood mononuclear cells and intestinal cells from patients suffering from inflammatory bowel diseases, as well as therapeutic effects in a murine model of colitis.

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Vitamin D and spondyloarthritis.

In cross-sectional studies, vitamin D deficiency is frequent in spondyloarthritic patients and associated with increased spondyloarthritis (SpA) activ...
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