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Pharmacological Research 117 (2017) 228–241

Contents lists available at ScienceDirect

Pharmacological Research
journal homepage: www.elsevier.com/locate/yphrs

Review

Vitamin D in autoimmune rheumatic diseases: A view inside gender


differences
Massimiliano Vasile a,b,1 , Clarissa Corinaldesi a,c,1 , Cristina Antinozzi a , Clara Crescioli a,∗
a
Department of Movement, Human and Health Sciences, University of Rome Foro Italico, 00135 Rome, Italy
b
Department of Internal Medicine and Medical Specialities, Sapienza University of Rome, 00161 Rome, Italy
c
Leeds Institute of Rheumatic and Musculoskeletal Medicine, University of Leeds, Leeds, UK

a r t i c l e i n f o a b s t r a c t

Article history: A large body of evidence highlights the role for vitamin D deficiency/insufficiency in rheumatic diseases,
Received 12 August 2016 a group of different pathologies mostly of autoimmune origin. Vitamin D and vitamin D receptor agonists
Received in revised form exquisitely modulate the immune system against over-reactivity towards tolerance; on this basis, vitamin
26 December 2016
D could be a good therapeutic candidate to control autoimmune processes in rheumatic diseases. Sim-
Accepted 29 December 2016
ilarly, to other autoimmune pathologies, rheumatic diseases show a significant female bias. This sexual
Available online 31 December 2016
dimorphism seems, in part, to rely on the different sex hormone-induced regulation on male and female
immune systems. Females, in fact, retain greater immune reactivity and competence likely due to estro-
Keywords:
Vitamin D gens, which, at variance with androgens, are associated with a greater resilience to infections but also to
Therapy a higher risk for autoimmunity. In this scenario, there is growing interest on vitamin D supplementation
Rheumatic diseases for prevention or therapy in rheumatic diseases in relation to gender and sexual hormones.
Autoimmunity The purpose of the review is to overview vitamin D status in rheumatic diseases, related to gender
Sex hormones and sex hormones. In particular, the main vitamin D immunoregulatory properties are summarized with
Gender some sex hormone-driven immune activities, in females and males immune systems. Topics onto vitamin
D receptor agonists as potential therapeutic agents in rheumatic disease are addressed, especially in view
of the role of vitamin D inadequacy in the pathogenesis of rheumatic diseases. So far, further clinical and
basic studies should be encouraged to confirm the high potential power of vitamin D receptor agonists
as novel pharmacological tools in rheumatic diseases particularly in light of personalized gender-related
therapeutic strategies.
© 2017 Elsevier Ltd. All rights reserved.

Contents

1. Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 229
2. Vitamin D . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 229
2.1. Vitamin D deficiency . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 230
2.2. Vitamin D and immune regulation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 231
3. Sexual dimorphism and (auto)immunity . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 231
3.1. Sex hormones . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 231
3.1.1. Androgens . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 231
3.1.2. Estrogens . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 232
4. Rheumatic diseases and sexual dimorphism . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 232
5. Vitamin D and rheumatic diseases . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 233

∗ Corresponding author at: Department of Movement, Human and Health Sciences, Section of Health Sciences, Unit of Endocrinology, University of Rome “Foro Italico”,
00135 Rome, Italy.
E-mail address: clara.crescioli@uniroma4.it (C. Crescioli).
1
These authors contributed equally.

http://dx.doi.org/10.1016/j.phrs.2016.12.038
1043-6618/© 2017 Elsevier Ltd. All rights reserved.
M. Vasile et al. / Pharmacological Research 117 (2017) 228–241 229

5.1. Effects of antirheumatic treatment on vitamin D metabolism . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 234


5.2. Potential multi-faceted beneficial effect of vitamin D supplementation: an example from idiopathic inflammatory myopathies . . . . . . . . . 234
5.2.1. Cross influence of estrogens and vitamin D . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 235
6. Conclusion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 236
Acknowledgments . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 236
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 236

1. Introduction biologic effects occurs through classical genomic mechanisms,


engaging direct interaction with specific vitamin D response ele-
An adequate vitamin D status is nowadays considered to be ment (VDRE) on a DNA sequence: mechanistically, 1,25(OH)D/VDR
essential in order to maintain good health and wellbeing, beside bound changes conformation of the receptor, which forms het-
calcium-phosphate homeostasis and bone metabolism regulation. erodimer with retinoid-X receptor (RXR) – or other putative
Skin exposure to sunlight and ultraviolet B (UVB) radiation is the transcription factors – and, recruiting tissue specific co-activators,
main source of vitamin D, while diet and dietary supplements help acts as a transcription factor directly onto VDRE in responsive gene
to gain a hormone optimal status when the sunlight is not sufficient. promoter regions. Of note, more than 1000 genes seem to be trig-
Adequate hormone levels should be ensured by this dual source in gered upon ligand binding with VDR that is widespread expressed
order to warranty health homeostasis. Nevertheless, severe vitamin [8–10].
D insufficiency is now emerging as a global health problem, lead- Conversely, rapid non genomic effects occur via a receptor
ing to different acute and chronic illnesses [1,2]. Past and recent anchorage in cell membrane and/or cytoplasm and induce rapid
literature has pointed out the link existing between vitamin D defi- signaling via second messenger signaling [11]. However, the exact
ciency and the onset/maintenance of several diseases. Vitamin D molecular mechanisms underlying vitamin D non genomic effects
seems to exert such an important pleiotropic effect, likely due to are still not fully understood. Vitamin D/VDR classical/genomic and
its fine immunomodulatory features. Vitamin D receptor (VDR) rapid/non genomic effects are depicted in Fig. 2.
agonists, indeed, have been recognized as powerful immunomod- Vitamin D status in human is evaluated by serum measurement
ulating agents, able to counteract inflammation which, in turn, of circulating 25(OH)D, which, having a quite long half-life in circu-
has been shown to be the “common soil” of several pathologies, lation (about 2 or 3 weeks), is easy to be detected and, importantly,
including rheumatic diseases (RD) [3]. Thus, it is not surprising that correlates with clinical status [12–15].
vitamin D inadequacy associates with metabolic and cardiovascu- Several factors are able to impact on circulating vitamin D,
lar illnesses, some types of neoplasia, adverse pregnancy or birth including geographic latitude, year season, life style (e.g., time spent
outcomes, neurocognitive disorders, autoimmune and, relevant for outdoors or dietary habit) or skin pigmentation. Caucasian and
this review, RD [4–6], which consist of many different disorders Asian population seem to produce higher vitamin D serum level
mainly of autoimmune origin. Great scientific interest is addressed in comparison to dark skin-toned African American or East Indian
to vitamin D and RD, which, like most of autoimmune diseases, are subjects [16,17].
characterized by an important gender bias toward females, from Severe air pollution as in large cities, unhealthy lifestyle, like
clinical presentation to onset, progression and outcome. immobility of elderly subjects, high protection sunscreens or cul-
To date, autoimmune response underlying RD seem to be under tural dress code can modulate the production of endogenous
the control of vitamin D and sexual hormones. The present review vitamin D [16]. Sex, ethnicity, body composition, alcohol consump-
aims to offer an oversight on the association between vitamin D tion, fish intake, season of blood draw dietary vitamin D intake,
status and RD related to gender and sex hormones, highlighting calcium supplements, physical activity, smoking status, history of
vitamin D inadequacy as factor involved in disease pathogenesis diabetes are some of the many variables affecting 25(OH)D serum
and vitamin D supplementation as potential tool in disease pre- level [18]. Age, indeed, is another factor influencing vitamin D level:
vention or treatment. in childhood and adolescence its level is lower [17], while in adult it
With this purpose, the following paragraphs will first summa- declines age-dependently, likely due either to age-related fall in the
rize how vitamin D regulates the immune response and how male precursor 7-dehydrocholesterol or general biological aging changes
and female immune systems differ in relation to sex hormones. [19,20].
Interestingly, vitamin D level likely differs upon gender too, with
2. Vitamin D some studies reporting higher level in males [18], and some others,
conversely, in females [17]. However, even though basal level of
The term vitamin D comprehends a group of natural molecules vitamin D seems not to really differ between males and females,
named “calciferols”, including cholecalciferol, or vitamin D3 , gender-specific determinants of 25(OH)D serum concentration,
ergocalciferol, or vitamin D2 and their intermediate and final potentially useful for preventive strategies, have been suggested
metabolites, [25(OH)D] and [1,25(OH)2 D], respectively. [21]. As from a previous study in an elderly German cohort, smok-
The exposure of epidermis to wavelength UVB light ing, monthly net income and physical activity were predictors in
(290–315 nm) converts the precursor 7-dehydrocholesterol in men, while body composition, sun exposure, total body fat per-
previtamin D3 ; non enzymatic processes originate vitamin D3, cent and vitamin D supplements had a higher predictive power
that circulates in blood transported by the specific vitamin D in women. Intact parathyroid hormone (iPTH) has been proven to
binding protein (DBP). Vitamin D3 undergoes first rapid conver- be a negative predictor for 25(OH)D concentration in both sexes
sion to 25-dihydroxyvitamin D3 /25(OH)D by 25-hydroxylase in [21].
liver; the active endogenous hormone, 1,25-dihydroxyvitamin To date, although some controversies existing on the definition
D3 /1,25(OH)D originates from a further hydroxylation by 1␣- of the optimal serum level – in part due to the lack of highly reliable
hydroxylase in kidney or other organs [7]. Scheme in Fig. 1 standard assays [12] – vitamin D insufficiency/deficiency undoubt-
summarizes those processes. edly represents a worldwide health problem [22] which deserves
Upon 1,25(OH)D binding with vitamin D receptor (VDR), a attention of researchers and clinicians as well.
specific zinc-finger nuclear receptor, the majority of vitamin D
230 M. Vasile et al. / Pharmacological Research 117 (2017) 228–241

Fig. 1. Vitamin D source.


The major amount of vitamin D3 (cholecalciferol) is produced by UV radiation (290–315 nm wavelength) from the precursor7-dehydrocholesterol present in the skin;
a minor amount comes from dietary supplementation by cholecalciferol and/or ergocalciferol (D2). In the liver, 25-hydroxylase enzyme rapidly converts vitamin D3 to
25-hydroxyvitamin D3/25(OH)D, that needs a further hydroxylation in the kidney to produce the final active hormone, 1,25-dihydroxyvitamin D3/1,25(OH)D (calcitriol).

Fig. 2. Biological actions of 1,25(OH)D.


1,25(OH)D interacts with the cytosolic/nuclear receptor protein (VDR) in the nucleus and with specific DNA sequences, the vitamin D responsive elements (VDRE), promoting
a slow response through a genomic mechanism (left side of the figure). In non genomic action(right side) 1,25(OH)D binds to a putative cell membrane receptor involving
a variety of second messengers and signal transduction mediators, i.e., activation of Map kinase, cyclic adenosin monophosphate (cAMP) or protein kinase C (PKC) activity
increase. This mechanism allows rapid responses.

2.1. Vitamin D deficiency ciated with this condition; cut-off values to diagnose vitamin D
insufficiency vary from 50 to 75 nM and are still a matter of debate
The definition of vitamin D deficiency is based on 10 ng/ml (or [23,24], also due to the high variability in current lab methods that
25 nM) concentration, as levels below this value result in clinical makes standardization quite difficult [25,26].
symptoms. Vitamin D insufficiency, conversely, is not easy to define Vitamin D inadequacy is currently a very common condition
on a medical basis because of the lack of overt symptoms asso- in healthy population, including young adults, elderly, general
M. Vasile et al. / Pharmacological Research 117 (2017) 228–241 231

medicine in patients and children as well [1]; in utero vitamin D Herein, we want to recapitulate and highlight that all those
insufficiency, causing, in turn, neonatal deficiency seems to be a vitamin D-triggered processes end in a shift towards to Treg
diffuse condition, as well [27]. and Th2 immune control and in a significant decrease of
Still, the widespread condition of obesity in the developed world Th1/Th17 cell response, essentially throughout DCs, induced to a
is another possible cause of vitamin D deficiency, since the adipose (self)amplification of their regulatory/tolerogenic role.
tissue is a storage of liposoluble vitamins. Hormone bioavailability So far, vitamin D-driven control of the immune system – leading
is, indeed, reduced by excess in body weight and fat [28], which act to polarization toward a net protolerogenic dominance – is likely a
as a reservoir. Obesity correlates negatively with vitamin D serum critical event to limit and contain autoimmune response, whereas
levels with some differences between males and females: every inadequate levels of this hormone could easily permit autoimmu-
second men and every third women showing BMI ≥ 40 are vitamin nity.
D deficient [29]. Of note and relevant for the topic of this review many RD
Currently, there is growing evidence on the close associa- of autoimmune origin are characterized by very low level of
tion between vitamin D deficiency and several human diseases vitamin D and sexual dimorphism, within the dynamic and gender-
i.e., neuropathy, malignancy, infertility, cardiovascular and kid- dependent dialogue between endocrine and immune systems. The
ney diseases, glucose metabolism and immunological dysfunctions following paragraphs are to recall some features and mechanisms
[4–6,30–36]. shared by autoimmune disturbances.
The link of vitamin D inadequacy with so many different dis-
eases likely relies on the ability of this hormone to exert widespread 3. Sexual dimorphism and (auto)immunity
effects through the interaction with VDR, virtually expressed in
almost all tissues and cells. Vitamin D, in fact, is well known to It is well known that diseases of autoimmune origin, including
modulate growth and differentiation of different cell types; impor- RD, take place from a disruption of immune tolerance to self-
tantly, the fine-tuned modulation exerted by this hormone onto antigens, characterized by cell- and antibody-mediated response,
immune system cells [6,36–39] underlies its tight association with and end in systemic or/and organ damage [54,55].
(auto)immune regulation and response. Remarkably, sexual dimorphism seems to play a pivotal role in
The immunomodulatory properties of vitamin D, its associa- development and maintenance of autoimmune diseases, in addi-
tion with immune regulation and autoimmunity will be shortly tion to numerous other factors, including genetic background,
addressed. environment, epigenetic mechanisms, X and Y chromosome signif-
icant influence [56–58]. A high female bias has been documented in
2.2. Vitamin D and immune regulation some autoimmune conditions, such as systemic, endocrine, neuro-
logical diseases, and RD as well; i.e., the prevalence of Sjoegren’s
Several extra-skeletal non-classical effects of vitamin D, such as syndrome (SS), systemic sclerosis (SSc), or rheumatoid arthritis
regulation of cell proliferation and differentiation have been rec- (RA) is higher in females, while males’ clinical presentation is asso-
ognized since quite a while. In particular, the regulatory effects on ciated with more severe disease manifestations [59].
immune system cells were introduced in 2007 highlighting the abil- It is quite difficult to exactly define gender related differences in
ity of this hormone to maintain tolerance and promote protective severity of symptoms or disability degree in autoimmunity, albeit
immunity [40]. some unquestionable variances exist between sexes.
Of note, almost all immune cell types, i.e., Females, generally, retain a higher immune reactivity due to
macrophages/monocytes, neutrophils, T and B cells and den- amplified T cell-mediated immune response, involving higher cell
dritic cells (DC) express VDR; DC, in particular, could be considered reactivity and survival [60]; also, resistance to target organ damage
as the primary immune cell target of vitamin D [41] to promote seems different [61].
hormone-induced tolerogenic effects [42–44]. The mechanisms underlying sexual dimorphism in autoimmune
Vitamin D, indeed, is capable to inhibit monocyte-derived response including RD still need to be fully understood, but clear
DC maturation and differentiation, and, consequently, to impair differences in immune systems of females and males have been
antigen process and presentation to T cells [45], inducing a simul- shown in most animal species and in humans as well [62].
taneous decline of T helper (Th)1 type proinflammatory cytokines,
such as interleukin (IL)-6, IL-23, IL-1, IL-8, IL-12, tumor necrosis fac- 3.1. Sex hormones
tor (TNF)␣ and interferon (IFN)␥ [39,46–48]. Those processes occur
along with an increase in Th2 type tolerogenic molecules, i.e., IL-10 The differential action of sex hormones onto immune system
or CCL22. cells might in part explain the sexual dimorphism in the immune
Furthermore, through the DC modulation, vitamin D suppresses response.
the activity of Th17, a T cell subset widely engaged in inflamma- Androgen and estrogen have been first identified as potentially
tory responses [39,45,49,50], and enhance regulatory T (Treg) cell responsible for the sex bias observed in the majority of autoimmune
expansion [39]. Direct effects of vitamin D onto T cell differentiation responses, since these hormones can directly affect the develop-
are not fully elucidated, direct suppression of B cell proliferation, ment/function of several immune cells, acting through androgen
differentiation and antibody production have been documented and estrogen receptors, expressed in progenitors and mature cells
[51]; in macrophages VDR agonists are able to counteract inflam- of the immune system [63]. Furthermore, sex hormones likely affect
matory molecules, such as cyclooxygenase 2 (COX-2) and inducible organ specificity of autoimmune disease and tolerance breakdown
nitric oxide synthase (iNOS), decreasing nitric oxide (NO) and by modulating lymphocyte homing to a target organ and antigen
prostaglandin (PG)E2 release [39]. Furthermore, the endogenous presentation and processing [64].
production of 1,25(OH)D by immune cells, like DC, macrophages, T The complexity of mechanisms involved in sex hormone and
cells, B cells likely regulates immune response within target tissues, immune system mutual influence should be taken in account in
where, i.e., IL-12 and IL-23 the production of some interleukins light of the conflicting observations existing on this topic.
and the expression of costimulatory molecules (CD40, CD80, CD86)
seem downregulated [45,52]. 3.1.1. Androgens
The fine-tuned biomolecular mechanisms associated with this Androgen effect on immune response depends on the type
effect are complex and well reported elsewhere [39,45,53]. of hormone, concentration and administration timing for exoge-
232 M. Vasile et al. / Pharmacological Research 117 (2017) 228–241

nous hormone intake. There are controversial reports on androgens complicated form display joint damage, severe pain, disability and
showing to exert opposite effects, either stimulatory [65] or sup- death [93]. Commonly, in RD there is also a detrimental involve-
pressive [66] onto immune function. I.e., T cell expansion is both ment of skeletal muscle which worsens disease disability [94]. In
inhibited or enhanced by dehydroepiandrosterone (DHEA) [67], the 2010 World Health Organization (WHO) Global Burden of Dis-
whereas T cell proliferation and differentiation is counteracted by ease Study, RD have been, indeed, reported to be the second leading
testosterone [68–70]. Also, supraphysiological doses of androgens cause of disability worldwide [95].
are able to decrease natural killer (NK) cells cytotoxic activity and As previously addressed, a high gender bias toward females has
suppress immunoglobulins [65,71,72]. Albeit some controversial been recognized for some autoimmune conditions, including RD
reports, it is generally accepted that androgens confer protection [55]. The mechanisms responsible for sexual dimorphism in RD still
against autoimmunity, considering that androgens are higher in have to be clarified, but, as for other autoimmune diseases, some
males who, in turn, show a lower autoimmune incidence. differences gender dependent seem due to, the variance existing
In line with this hypothesis, men and pregnant women seem, between female and male immune systems. Hormonal theory is,
indeed, to be more prone to develop protolerogenic Th2 driven indeed, a quite convincing explanation for bias female observed in
immune responses, while non-pregnant and post-menopausal autoimmunity. Studies document the role of estrogens, androgens
women display Th1 type immunity [63,73,74]. and prolactin in increasing susceptibility to RD, by affecting both
An overt autoimmunity development and early death occur in innate and adaptive immune systems [63,96,97]. Sex hormones,
male animals after gonadectomy, while mortality is reduced in i.e., are thought to be crucial for systemic lupus erythematosus
ovariectomized female mice after androgens [75]. Results from (SLE) regulation, a multifactorial and extremely polymorphic sys-
studies in humans did not clearly prove real benefit of androgens temic RD that mostly affects women at child-bearing age − showing
in autoimmune disease [76–79]. a female:male ratio 8–15:1 [98]; it tends to worsen during preg-
nancy and to remit after menopause, suggesting some association
between estrogen levels and disease severity [99,100]. Estrogen
3.1.2. Estrogens
and prolactin affect maturation and selection of autoreactive B
Estrogens (estrogen, estradiol and estriol in pregnancy), act-
cells, behaving then as immune-stimulators [101,102]. In partic-
ing through estrogen receptor (RE), are able to affect mitogenic
ular, 17␤-estradiol (E2) plays a pivotal role in SLE female bias
response, maturation, activation and cytokine secretion of several
and disease activity, although the underlying molecular mecha-
types of immune cells [63,80,81].
nisms are not yet clear [103]. An altered estrogen receptor (ER)
In particular, estrogens likely promote protective effect “con-
profile seems critical in disease pathogenesis as well, since in
taining” Th1-driven response [82,83], i.e., by facilitating CD25− to
T cells from SLE females ER␤ expression extent reflects disease
CD25+ Treg cell conversion [75], suppressing antigen presentation
activity [104]. Men with SLE show as well elevated serum lev-
[84] and simultaneously amplifying Th2 immune response [85].
els of estrogens − i.e., 16-hydroxyestrone and estrone − with
Estrogens have been reported to retain biphasic dose effects:
some subjects presenting hypoandrogenism and elevated levels
lowers levels, as post menopause, seem to facilitate Th1 immune
of luteinizing hormone (LH) [81,105]. In this context, we could
response, higher concentrations, as during pregnancy, suppresses it
explain the beneficial effects of vitamin D, which by decreasing
[86], driving to Th2 dominance; Th1 driven autoimmune response,
aromatase expression [106] reduces estrogen peripheral synthe-
in fact, usually tends to undergo remission during pregnancy [87].
sis from androgens. This observation is in line with the hypothesis
However, autoimmunity remission during pregnancy is a topic still
that SLE could be also sustained by the interplay between vita-
widely debated, because that condition also triggers some autoim-
min D deficiency – with reduced down-regulation of aromatases
mune diseases, such as diabetes or thyroiditis [61].
– and increased peripheral estrogen synthesis; this latter, in turn,
In animals and humans, the vulnerability of target organs
promotes B cell proliferation and overactivity [107]. Local hor-
to autoimmune response has been shown to be under estrogen
mone imbalance can also play a pivotal role as evidenced in
influence as well, with differential involvement of T and B cells,
RA, a disease characterized by chronic joint inflammation, func-
macrophages, lymphocyte homing, antigen presentation by DC and
tional impairment, disability, and premature mortality, presenting
consequent cytokine release [63,88].
a female to male ratio 2:1 in subjects aged from 55 to 64, with
To date, target organs show gender-dependent ability to resist
an upturned ratio in subjects over 75 [108]. In both male and
damage, likely due to some differences in complex different cel-
female RA patients, estrogens in synovial fluid are significantly
lular/biomolecular processes – from autophagy, to apoptosis, cell
elevated, likely due to local enzymatic aromatase increased activ-
survival or mitochondrial functions [89–91].
ity, which affects macrophage and fibroblast proliferation, key
Human studies on gender-related role of immune cells resident
cells in synovial inflammation [109]. Vitamin D deficiency could
in tissues/organs are currently quite limited. So far, it is a gen-
indirectly lead to a further increased risk for RA through estro-
eral opinion that estrogens confer females with greater resistance
gen levels: adequate vitamin D seems to counteract aromatase
[61] due to stronger immune responses (humoral and cellular) to
activity through the inhibition of macrophage-derived inflamma-
antigens and higher levels of CD4+ T cells, following allo- or auto-
tory cytokines, which strongly enhance enzyme activity [97,110].
antigenic challenge [92].
Estrogens are somehow associated with female predisposition to
The higher immune reactivity and greater immunocompetence,
SSc [111], a connective tissue disease, characterized by immune
while leading females to a greater resilience to some diseases (i.e.,
and vascular alteration, ending in skin and internal organ fibrosis
infections), make them more prone to autoimmunity [81].
[112], with 3:1 woman to man ratio [113,114]. Also, SSc severity
Generally, it could be summarized that estrogens, exert a dif-
seems linked to high prolactin and low dehydroepiandrosterone
ferent effect onto autoimmunity depending on several variables,
serum levels [115]. Spondyloarthropathies (SpA), characterized
i.e., age, reproductive capacity and, not least, type of autoimmune
by chronic inflammatory rheumatic diseases, include ankylosing
disease.
spondylitis (AS), the most typical form of spondyloarthropathy,
reactive arthritis, arthritis associated with psoriasis (psoriatic
4. Rheumatic diseases and sexual dimorphism arthritis), arthritis/spondylitis with Crohn disease and ulcerative
colitis (entheropatic spondyloarhtitis) – affect the axial spine and
The term RD largely encompasses over one hundred inflamma- occur more frequently in men (male to female ratio 3:1 in AS),at
tory, degenerative and autoimmune conditions which in their most variance with most RDs, [116] with a progressive fall in the sex ratio
M. Vasile et al. / Pharmacological Research 117 (2017) 228–241 233

as the age at onset increased [117]. Several hypothesis have been influenced by hormone sequestration in fat tissue as previously
proposed to explain sexual dimorphism involving testosterone, reported [155].
but data are conflicting [118–121] I.e., in a mouse model with an Albeit the literature reports conflicting results on the role of
arthropathy resembling human ankylosing enthesopathy the dis- vitamin D deficiency as an independent risk factor for RA onset
ease occurred in intact but not in castrated males; the latter ones [156,157], the risk decreases with longer light exposure, somehow
injected with testosterone developed arthropathy while females in confirming vitamin D role in disease pathogenesis [144,158–161].
the same condition did not [122]. Those data suggest that, albeit Of note, as from a retrospective investigation, severe vitamin D
androgens act as natural immunosoppressors, in this specific dis- deficiency in patients with early inflammatory arthritis signifi-
ease testosterone conversely seems to trigger/worsen autoimmune cantly associates with the higher probability of being diagnosed
overactivity critical in the development of joint disease. Neverthe- with RA [162]. In established RA, vitamin D deficiency is highly
less, no significant changes in testosterone serum levels were found prevalent and correlates with higher disease activity and lower
in men with AS [76,120,121], thus we could speculate a “local” functional status [144,163–166]; remarkably, 3-months adminis-
role for testosterone in the disease. Another evidence for andro- tration of alphacalcidiol improved RA clinical symptoms [167].
gen role in disease development emerges from women affected Vitamin D levels seem to play a role also in AS. Some authors
by breast cancer and treated with aromatase inhibitors: the con- reported no differences in vitamin D levels between AS patients
sequent increase in testosterone level seems to be responsible for and healthy controls, but after patients’ stratification according to
SpA promoting [123]. In patients with AS the different activation vitamin levels, Erythrocytes Sedimentation Rate (ESR), C Reactive
of the immune system, particularly Th17 axis, supports a distinct Protein (CRP), the disease activity was higher in the subgroups with
sexual dimorphism since males but not females show higher fre- low 25(OH)D, suggesting that vitamin D deficiency may worsen
quency of IL-17A and Th17 cells [124]. This gender related immune inflammatory process involved in the disease [168]. To date, results
profile underlying AS might encourage further studies searching for from a metanalysis confirm the association between lower vitamin
sex-specific therapies. SS is a RD characterized by chronic inflam- D and higher disease AS activity, even though data seem not suffi-
mation of the salivary and lacrimal glands [125] and it primarily cient enough to support an immunomodulatory role for vitamin D
affects women during the fourth and fifth decades of life, with 9:1 in this disease [169].
woman:man ratio [126]. Estrogens likely exert a protective role in The high incidence of vitamin D deficiency in SSc has been doc-
SS: while estrogen insufficiency promotes a SS-like autoimmune umented in several reports [170–173]. Albeit some paper reported
exocrinopathy [127–133] estrogen treatment apparently corrects no correlation between decreased vitamin D level and clinical fea-
the defects in lacrimal gland, typical of the disease [132,134–136]. tures of SSc [174], some others, conversely, found a tight correlation
Furthermore, studies on aromatase inhibition confirm that lack of between vitamin D levels and respiratory parameter, or, i.e., sever-
estrogens play a key role in SS pathogenesis [137]. Few studies ity of skin involvement [6].
evaluate gender-dependence in antiphospholipid syndrome (APS), Of note, in vitro studies from SSc human fibroblasts and in
another RD preponderant in females (2–5:1 female to male ratio) vivo studies from murine models show a significant reduction
and characterized by the association of antiphospholipid antibod- in VDR expression and signalling, dependent on TGF␤, which is
ies (aPL) with recurrent arterial and venous thrombosis and/or fetal deeply involved in fibrotic processes and downregulation of VDR
loss, mild to moderate thrombocytopenia [138,139]. Since men expression. Remarkably, the treatment with paricalcitol, a syn-
and women display different disease consequences – i.e., stroke thetic vitamin D analogue, exerted preventive and therapeutic
or pulmonary thromboembolism more prevalent in females, while potent antifibrotic effects, by restoring VDR signalling in SSc fibrob-
gastrointestinal involvement in males [140,141], – a role for sex lasts and reducing TGF␤-induced fibrosis [175].
hormones has been hypothesized. There are scarce and contradictory data about vitamin D levels
in SS from literature; however, some studies suggest a role for this
hormone in the pathogenesis of primary SS [176], showing plasma
D level lower in SS patients, especially in female subjects [177].
5. Vitamin D and rheumatic diseases Moreover, several clinical manifestation of SS (i.e. leukocytopenia,
lymphoma and peripheral neuropathy) associate with 25(OH)-D
As previously addressed, a consistent part of literature suggests severe deficiency and these observations led to the suggestion that
a correlation between some autoimmune RD, such as SLE, RA, SSc, vitamin D supplementation could be useful in SS [30,178]. As for
Polymyositis/Dermatomyositis (PM/DM) and low plasma vitamin SS, there are few studies documenting poor vitamin D status on
D levels [142,143]. In fact, although some discrepancy reported subjects with APS. In particular, the hypovitaminosis D was found
by some epidemiological studies [144], the role for vitamin D to cluster in APS patient with thrombosis, the main clinical feature
insufficiency in the pathogenesis of certain RD is supported by of the disease [179]. In fact, conversely, an in vitro study showed
epidemiologic, genetic and basic science studies [25,145,146]. Ade- that vitamin D inhibits the expression of the procoagulant protein,
quate vitamin D levels result in a more balanced Th1/Th2 response tissue factor, induced by the typical autoantibody of the syndrome
that hinder autoimmunity and self-reactive T cells [147]. Therefore, (anti-ß2GPI Abs) [180].
the idea that supplementation or vitamin D pharmacological dose The term “undifferentiated connective tissue disease” (UCTD)
intakes treatment to attenuate ongoing autoimmune disorders or includes a group of connective tissue diseases still lacking
even to prevent them has taken place. The following paragraphs specific features for connective tissue diseases but with spe-
highlight how vitamin D status can impact on some RD. cific signs and/or autoantibodies characteristic of autoimmune
Several studies pointed out vitamin D insufficiency as a risk fac- disease. Clinical manifestations of UCTD frequently include pol-
tor for SLE [148,149]; vitamin D deficiency seems, in fact, directly yarthralgy/polyarthritis, Raynaud phenomenon, serositis (pleuritis
linked with autoimmune phenomena parameters such as antinu- and pericarditis), photosensitive, rash, xerostomia or xeroph-
clear antibodies-ANA- positivity [150]. Moreover, SLE flares seem thalmia with the involvement of central nervous system. About 30%
triggered by seasonal declines in vitamin D level [151]. Some debate to 40% of patients with UCTD will evolve to defined CTD, charac-
exists on serum 25(OH)D level and disease activity [152], with some terized by increased intensity of immunological abnormalities and
reports documenting an inverse correlation, not confirmed by other new organ manifestations leading to a specific evolution to a RD
studies [153,154]. A tight association between disease activity and (SLE, mixed connective tissue disease, SSc, SS, PM/DM, RA and sys-
hypovitaminosis D is evident in overweight SLE patients, likely
234 M. Vasile et al. / Pharmacological Research 117 (2017) 228–241

temic vasculitis). In this scenario, vitamin D lower levels seem to by means of several anti-rheumatic drugs, in order to counteract
facilitate UCTD progression towards well-established CTDs [181]. adverse direct and indirect drug reactions.
An open-label trial of alfacalcidol improved the Th17/Treg
imbalance found in UCTD patients, supporting the idea that vita- 5.2. Potential multi-faceted beneficial effect of vitamin D
min D could be beneficial in the management of the disease [182]. supplementation: an example from idiopathic inflammatory
Summarizing, vitamin D deficiency has been reported in several myopathies
autoimmune rheumatic diseases (SSc, SpA, SS, APS, UCTD). In some
diseases, this deficiency was even related to the risk of RD devel- A pivotal role for vitamin D has been recognized in the
oping (SLE, APS, RA, SSc, UCTD) or to the degree of disease activity pathogenesis of autoimmune inflammatory myopathies (IM), a het-
(SLE, RA, SpA, SS, APS, UCTD). Moreover, the vitamin intake affects erogeneous group of autoimmune diseases subclassified in distinct
RA patients, immunological imbalance in UCTD patients and some subgroups: DM, PM, inclusion body myositis (IBM), necrotizing
aspects of SSc (fibrosis). Even if not so striking, these evidences are autoimmune myositis (NAM), and myositis associated with sys-
leading to a pressing need for therapeutic studies. temic disorders.
Chronic inflammation and infiltration by
immune/inflammatory cells in skeletal muscles are features
5.1. Effects of antirheumatic treatment on vitamin D metabolism shared by all IM subtypes [203,204]; in addition, all disease sub-
groups show common clinical and histological characteristics, as
Although many of the well-known side effects of immunosup- muscle weakness, fatigue, mononuclear cell infiltration, elevated
pression regard systems in which vitamin D plays a critical role – serum muscle enzymes and myofiber degeneration or fibrosis
i.e., cancer, hypertension, dysmetabolisms, liver-, gastrointestinal-, [205].
kidney- or bone injury – large evidences collected on the straight IM occur as primary pathologies or as disease overlapping other
relationship between immunosuppressive treatment in RD and RD, i.e., SS, SSc, SLE or RA [206,207].
alterations in vitamin D metabolism are still lacking. Previous studies show the relationship between lower serum
One of the first described consequences of immunosuppression levels of vitamin D and the presence of autoantibody, deregu-
is the alteration in bone turnover and metabolism ending in bone lated production of inflammatory molecules and several immune
loss, osteopenia, osteoporosis, osteomalacia [183]; of note, about abnormalities reinforcing the hypothesis that vitamin D is closely
20% of all osteoporosis cases are attributable to corticosteroids involved with immune system activities in the pathogenesis of IM
[183]. as well [149,208–210].
Chronic glucocorticoid therapy has been, in fact, associated with The 25(OH)D deficiency could be considered as a risk factor
a significant higher risk of bone loss and fracture, likely due, at for IM development, even though hypovitaminosis D could not be
least in part, to immunosuppression-induced alteration of vitamin excluded as a disease consequence. In particular, Azali et al. [210]
D homeostasis and status. To date, often no significant changes are report that IM patients at the early disease stage showed lower
reported in vitamin D levels, maybe in consequence of the simul- level of vitamin D vs. patients at the late disease stage, suggest-
taneous vitamin D and calcium supplementation given to patients. ing a critical role for this hormone at disease onset, when some
However, greater corticosteroid exposure has been associated with immunebioactive molecules start to trigger detrimental effects. In
low vitamin D levels and significant VDR expression negative this view, it is remarkable the ability of vitamin D to counteract
regulation in bone cells [184,185]. Recent evidences address an the activity of some molecules, such as Th1 type pro/inflammatory
important effect of glucocorticoids on the role pregnane X recep- cytokines and chemokines, widely engaged in IM pathogenesis.
tor (PXR) a nuclear receptor retaining 60% omology with VDR. PXR Despite extensive studies, the molecular mechanisms under-
activation has been shown to affect the expression of several genes lying IM pathogenesis have not been yet fully clarified but the
such as 24-hydroxylases, which increases degradation of 25(OH)D presence of B and NK cells in addition to DCs are well documented
and 1,25 (OH)2D causing an acceleration of vitamin D catabolism in all types of IM [211,212].
and leading to vitamin D deficiency [186–189]. DCs, in particular, seem to be involved in the stimulation of
At difference with glucocorticoids, the antimalarial drugs adaptive immune response and in the maintenance of autoimmune
chloroquine and hydroxychloroquine [190,191] as well as sul- lesions in IM. Myeloid (m)DCs have been found in PM and IBM
fasalazine [192] have been commonly linked to significant while plasmacytoid (p)DCs, the main source of IFN␣, a type I IFN,
variations of vitamin D circulating levels. are particularly present in muscle tissue of adult and juvenile DM.
In particular, chloroquine and hydroxychloroquine, used by In addition, genomic studies evidenced a marked overexpression
patients affected by connective tissue diseases and arthritides of type I IFN inducible gene in the peripheral blood of DM and PM
seem to inhibit the conversion of 25(OH)D to 1,25(OH)2 D [190], patients; of note type I IFN pathway is activated in different RD
as shown in SLE patients[193]; sulfasalazine, used in patients with [213].
arthritides, has been shown in vitro to enhance endogenous 1␣- As previously discussed, vitamin D stimulation of all type of DCs
hydroxylase mRNA levels[194]. reduced their ability to activate T cells and limited T cell response
There are conflicting reports on the relationship between cal- to self antigens, thus potentially leading to a significant improve-
cineurin inhibitors such as cyclosporine and tacrolimus vitamin D. ment in the treatment or prevention of autoimmune processes
While Reichel H et al. did not show any effect of cyclosporine treat- [43,214,215].
ment on vitamin D levels [195] opposites data have been collected As reported, in general, the higher incidence of autoimmune RD
form others [196] that showed the ability of this drugs to lead to a in women seems supported by possible links between vitamin D
vitamin D-resistant state due to suppressive effect on VDR, as also deficiency and increased synthesis of peripheral estrogens [216].
showed in animal studies [197–199]. Estrogens, indeed, can modulate immune response during inflam-
Few studies describe the effect of biologic therapies (goli- matory states or immune abnormalities and are also able to modify
mumab, adalimumab and rituximab) which seem not to interfere human monocytes, monocyte-derived DCs, blood myeloid and in
with vitamin D levels in RA patients [199–202]. particular, pDCs function [217].
These clear evidences depict how important is to monitor vita- In particular, also in women with IM a possible direct action
min D status in rheumatic patients not only at the time of the of estrogens on DCs may influence immunity and tolerance, and
diagnosis as already suggested, but even during the treatment an augmented synthesis of peripheral estrogens might correlate
M. Vasile et al. / Pharmacological Research 117 (2017) 228–241 235

with an increased disease severity; in fact, different studies support that vitamin D likely control muscular disease progression acting
an IM exacerbation during pregnancy, when important hormonal through double regulatory effect: on innate and adaptive immu-
changes occur [218]. nity on a side, and on hormonal level regulation on the other side.
However, pDCs are described to decline as pregnancy progresses These observations strongly encourage vitamin D supplementation
and further evidence indicates that both estradiol and progesterone during disease.
correlated with this change. In particular, while estrogens acti- In addition, restoring adequate levels of vitamin D might help to
vate pDC, progesterone likely inhibits their activity, hence, female minimize the effect of some critical inflammatory molecules, such
sex steroids seem to influence autoimmunity, immunity and toler- as the interferon ␥ inducible protein 10 (IP-10 or CXCL10), directly
ance through a fine-modulated opposite effects exerted onto DCs involved in autoimmune response since very early IM stages. This
function [219–221]. The sex-dependent differences observed in IM small chemokine, in fact, triggers organ infiltration by establishing
incidence – DM and PM affect women more frequently (female to a self-promoting inflammatory loop between resident and Th1 type
male ratio 2:1), at variance with IBM (male to female ratio 3:1) – immune cells, at disease onset [228–230]; of note, VDR agonists can
somehow confirm the pathophysiologic role for sex hormones in impair CXCL10 release by muscular and immune cells [231,232].
these diseases. Furthermore, antiestrogen medication, by inhibit- Corticosteroids combined with immunosuppressive drugs (as
ing proinflammatory cytokines involved in disease pathogenesis, steroid-sparing agents) aimed to target/suppress immune cell
such as TNF␣, has been anecdotally reported to improve DM [222]. activity represent the mainstay treatment in IM [233–255].
The tight association between sex hormones and IM disease is also Nevertheless, too often IM patients do not show satisfactory clin-
reflected by the hormonal dysfunctions influencing gonadal and ical improvement, as few recover muscle performance, while
sexual function, as reported in PM and DM subjects either female about 25% of subjects are refractory to those drugs and left
and males, also since pediatric age [223–225]. Vitamin D retains with disability [233–255]. Hence, immune system pharmacolog-
the ability to regulate the production and interfere with the action ical targeting seems not enough to gain real modifying-disease
of female hormones. effects.
Again, we want to underline that VDR agonists contribute to
5.2.1. Cross influence of estrogens and vitamin D restoring immune homeostasis through different actions: immune
As previously addressed, the interaction between hypovita- response polarization to protolerogenic Th2 phenotype; regulatory
minosis D and estrogen levels may be the route toward an increased effect through interplay with sex hormones; beneficial impact
risk of RA or SLE in both genders. We could summarize that gender directly at muscular tissue/cell level.
and vitamin D status together, somehow, contribute to the suscep- To date, in fact, the muscular component takes part in dialogue
tibility to develop and maintain RD. with the immune system during inflammation throughout highly
Understanding the biomolecular mechanism(s) underlying the immune-bioactive molecules (cytokines and chemokines); so far,
cross influence of sex hormones and vitamin D within the crosstalk skeletal muscle can be considered not only as the final target of
endocrine system/immune system might help to clarify potential detrimental processes, but as an active counterpart contributing as
therapeutic target(s) and, in turn, to design therapeutic strategies well to the IM and, hence, as an important therapeutic objective.
aimed at. Nevertheless, few evidences have been collected on the However, VDR expression in vivo in human muscle still remains
role of gonadal hormones/vitamin D interplay and its straight rel- controversy and debated [236], albeit its presence is unquestion-
evance in RD pathogenesis and treatment. However, a meaningful ably critical for skeletal muscle development, maintenance and
example on the critical role of hormonal collaboration is elegantly function [237,238].
given by data collected from studies on multiple sclerosis (MS), an Another aspect of vitamin D deficiency regards the high preva-
autoimmune disease characterized by vitamin D poor status and lence of diabetes reported IM [239,240]. In general, vitamin
showing high female bias. D inadequacy is reported as part in multifactorial pathogene-
From studies on autoimmune MS, estrogens seem to act in syn- sis of metabolic disturbances – from insulin resistance (IR), to
ergy with vitamin D to gain protective effect [226] through a mutual metabolic syndrome (MetS), type 1 or 2 diabetes (T1D, T2D)
interaction. [241,242]. Thus, supplementation with vitamin D in IM ideally
In particular, Kragt and coll. measured serum vitamin D (in could contribute to prevent overlapping disease condition. So far,
summer and winter) in a large prospective cohort of MS patients re-establishing adequate hormone levels might be advantageous
and healthy control subjects and showed that the higher vita- under different aspects: vitamin D supplementation retain the
min D concentration, observed in all subjects during summer, potential as multi-faceted beneficial therapeutic intervention in
inversely associated with lower disease-related disability and inci- IM.
dence only in women, who showed MS odd reduction by 19% for Moreover, gender related studies on VDR agonists in IMs over-
every 10 nmol/L serum D level. This result is in line with previ- lapping metabolic disturbance would be particularly desirable in
ous data obtained in experimental mice model with autoimmune view of a females/males personalized treatment.
encephalomyelitis (EAE, resembling human MS) documenting a Some molecules, as BXL-01-0029 or elocalcitol, showing less
protective role for vitamin D only in intact females, neither in or none hypercalcemic activity, seem suitable pharmacological
ovariectomized females nor in males. Fully restored vitamin D tools to be included – maybe as steroid-sparing agents – in
protective effect occurred in EAE ovariectomized females after the therapeutic regimen for IM treatment. In particular, safety
estrogen implant: vitamin D enhanced the biosynthesis of 17␤- and tolerability of elocalcitol (150??g/day P.O.) has been shown
estradiol, which, in turn, increased VDR expression, thus, enabling in a double-blind randomized study in 101 postmenopausal
vitamin D/estrogen to act in concert against inflammatory pro- osteoporotic women and in placebo-controlled phase IIa (119
cesses and drive toward disease remission [227]. So far, estrogens enrolled subjects) and follow-on phase IIb (514 patients) trials
are likely to be selectively permissive for vitamin D beneficial for the treatment of benign prostate hyperplasia (BPH) [243–246].
action. Furthermore, it is notable that elocalcitol has been recently doc-
So far, rather than a simple “one way” effect of one or the other umented to directly target and regulate biomolecular metabolic
hormone, a multi-faceted dynamic dialogue is likely the critical machinery of human skeletal muscle cells similarly to insulin
event in autoimmune response regulation. [247].
Therefore, hypothesizing that this kind of interplay would occur
in other autoimmune disease context such IMs, we could speculate
236 M. Vasile et al. / Pharmacological Research 117 (2017) 228–241

6. Conclusion gender and sex hormone level as important variables influencing


the final therapeutic effect. Albeit the many concerns existing, the
As previously addressed, the key event for therapeutic use of potential use of vitamin D or non-calcemic VDR agonists to prevent
VDR agonists relies on restoring immune homeostasis substantially or treat RD drives the attention to the latest challenge in autoim-
through its inhibitory effects on DC maturation and activation. munity: “resetting” rather than “ablating” the immune system with
In view of the tight link existing with RD progression, recently a therapeutic approach towards a personalized therapy in line with
recommendations for daily vitamin D intake have been provided. the emerging concept of gender-specific medicine.
I.e., in UCTD 1.0 ␮g/day alfacalcidol for 5 weeks repairs the
Treg/Th17 balance and raise the capacity of Treg cells to sup- Acknowledgments
press the proliferation of autologous CD4+ CD25− cells [182]. Since
quite a while, it is known that in RA alphacalcidiol administration The authors wish to thank Dr. Francesco Marampon, Depart-
(2 ␮g/day) acted as strongly as corticosteroids [167]. ment of Movement, Human and Health Sciences, University of
In 2013 Cutolo [216] still confirms the beneficial effect of ther- Rome Foro Italico, for his critical support during manuscript
apeutic vitamin D supplementation in some RD, like SLE and AR. reviewing.
Novel therapeutic VDR agonists without the undesired side effects
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