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
The definition of vitamin D deficiency is based on 10 ng/ml (or
25 nM) concentration, as levels below this value result in clinical
symptoms. Vitamin D insufficiency, conversely, is not easy to define
on a medical basis because of the lack of overt symptoms asso-
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
[23,24], also due to the high variability in current lab methods that
makes standardization quite difficult [25,26].
Vitamin D inadequacy is currently a very common condition
in healthy population, including young adults, elderly, general
 M. Vasile et al. / Pharmacological Research 117 (2017) 228–241
medicine in patients and children as well [1]; in utero vitamin D
insufficiency, causing, in turn, neonatal deficiency seems to be a
diffuse condition, as well [27].
Still, the widespread condition of obesity in the developed world
is another possible cause of vitamin D deficiency, since the adipose
tissue is a storage of liposoluble vitamins. Hormone bioavailability
is, indeed, reduced by excess in body weight and fat [28], which act
as a reservoir. Obesity correlates negatively with vitamin D serum
levels with some differences between males and females: every
second men and every third women showing BMI ≥ 40 are vitamin
D deficient [29].
Currently, there is growing evidence on the close associa-
tion between vitamin D deficiency and several human diseases
i.e., neuropathy, malignancy, infertility, cardiovascular and kid-
ney diseases, glucose metabolism and immunological dysfunctions
[4–6,30–36].
The link of vitamin D inadequacy with so many different dis-
eases likely relies on the ability of this hormone to exert widespread
effects through the interaction with VDR, virtually expressed in
almost all tissues and cells. Vitamin D, in fact, is well known to
modulate growth and differentiation of different cell types; impor-
tantly, the fine-tuned modulation exerted by this hormone onto
immune system cells [6,36–39] underlies its tight association with
(auto)immune regulation and response.
The immunomodulatory properties of vitamin D, its associa-
tion with immune regulation and autoimmunity will be shortly
addressed.
2.2. Vitamin D and immune regulation
Several extra-skeletal non-classical effects of vitamin D, such as
regulation of cell proliferation and differentiation have been rec-
ognized since quite a while. In particular, the regulatory effects on
immune system cells were introduced in 2007 highlighting the abil-
ity of this hormone to maintain tolerance and promote protective
immunity [40].
Of note, almost all immune cell types, i.e.,
macrophages/monocytes, neutrophils, T and B cells and den-
dritic cells (DC) express VDR; DC, in particular, could be considered
as the primary immune cell target of vitamin D [41] to promote
hormone-induced tolerogenic effects [42–44].
Vitamin D, indeed, is capable to inhibit monocyte-derived
DC maturation and differentiation, and, consequently, to impair
antigen process and presentation to T cells [45], inducing a simul-
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-
tor (TNF)␣ and interferon (IFN)␥ [39,46–48]. Those processes occur
along with an increase in Th2 type tolerogenic molecules, i.e., IL-10
or CCL22.
Furthermore, through the DC modulation, vitamin D suppresses
the activity of Th17, a T cell subset widely engaged in inflamma-
tory responses [39,45,49,50], and enhance regulatory T (Treg) cell
expansion [39]. Direct effects of vitamin D onto T cell differentiation
are not fully elucidated, direct suppression of B cell proliferation,
differentiation and antibody production have been documented
[51]; in macrophages VDR agonists are able to counteract inflam-
matory molecules, such as cyclooxygenase 2 (COX-2) and inducible
nitric oxide synthase (iNOS), decreasing nitric oxide (NO) and
prostaglandin (PG)E2 release [39]. Furthermore, the endogenous
production of 1,25(OH)D by immune cells, like DC, macrophages, T
cells, B cells likely regulates immune response within target tissues,
where, i.e., IL-12 and IL-23 the production of some interleukins
and the expression of costimulatory molecules (CD40, CD80, CD86)
seem downregulated [45,52].
The fine-tuned biomolecular mechanisms associated with this
effect are complex and well reported elsewhere [39,45,53].
231
Herein, we want to recapitulate and highlight that all those
vitamin D-triggered processes end in a shift towards to Treg
and Th2 immune control and in a significant decrease of
Th1/Th17 cell response, essentially throughout DCs, induced to a
(self)amplification of their regulatory/tolerogenic role.
So far, vitamin D-driven control of the immune system – leading
to polarization toward a net protolerogenic dominance – is likely a
critical event to limit and contain autoimmune response, whereas
inadequate levels of this hormone could easily permit autoimmu-
nity.
Of note and relevant for the topic of this review many RD
of autoimmune origin are characterized by very low level of
vitamin D and sexual dimorphism, within the dynamic and gender-
dependent dialogue between endocrine and immune systems. The
following paragraphs are to recall some features and mechanisms
shared by autoimmune disturbances.
3. Sexual dimorphism and (auto)immunity
It is well known that diseases of autoimmune origin, including
RD, take place from a disruption of immune tolerance to self-
antigens, characterized by cell- and antibody-mediated response,
and end in systemic or/and organ damage [54,55].
Remarkably, sexual dimorphism seems to play a pivotal role in
development and maintenance of autoimmune diseases, in addi-
tion to numerous other factors, including genetic background,
environment, epigenetic mechanisms, X and Y chromosome signif-
icant influence [56–58]. A high female bias has been documented in
some autoimmune conditions, such as systemic, endocrine, neuro-
logical diseases, and RD as well; i.e., the prevalence of Sjoegren’s
syndrome (SS), systemic sclerosis (SSc), or rheumatoid arthritis
(RA) is higher in females, while males’ clinical presentation is asso-
ciated with more severe disease manifestations [59].
It is quite difficult to exactly define gender related differences in
severity of symptoms or disability degree in autoimmunity, albeit
some unquestionable variances exist between sexes.
Females, generally, retain a higher immune reactivity due to
amplified T cell-mediated immune response, involving higher cell
reactivity and survival [60]; also, resistance to target organ damage
seems different [61].
The mechanisms underlying sexual dimorphism in autoimmune
response including RD still need to be fully understood, but clear
differences in immune systems of females and males have been
shown in most animal species and in humans as well [62].
3.1. Sex hormones
The differential action of sex hormones onto immune system
cells might in part explain the sexual dimorphism in the immune
response.
Androgen and estrogen have been first identified as potentially
responsible for the sex bias observed in the majority of autoimmune
responses, since these hormones can directly affect the develop-
ment/function of several immune cells, acting through androgen
and estrogen receptors, expressed in progenitors and mature cells
of the immune system [63]. Furthermore, sex hormones likely affect
organ specificity of autoimmune disease and tolerance breakdown
by modulating lymphocyte homing to a target organ and antigen
presentation and processing [64].
The complexity of mechanisms involved in sex hormone and
immune system mutual influence should be taken in account in
light of the conflicting observations existing on this topic.
3.1.1. Androgens
Androgen effect on immune response depends on the type
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
showing to exert opposite effects, either stimulatory [65] or sup-
pressive [66] onto immune function. I.e., T cell expansion is both
inhibited or enhanced by dehydroepiandrosterone (DHEA) [67],
whereas T cell proliferation and differentiation is counteracted by
testosterone [68–70]. Also, supraphysiological doses of androgens
are able to decrease natural killer (NK) cells cytotoxic activity and
suppress immunoglobulins [65,71,72]. Albeit some controversial
reports, it is generally accepted that androgens confer protection
against autoimmunity, considering that androgens are higher in
males who, in turn, show a lower autoimmune incidence.
In line with this hypothesis, men and pregnant women seem,
indeed, to be more prone to develop protolerogenic Th2 driven
immune responses, while non-pregnant and post-menopausal
women display Th1 type immunity [63,73,74].
An overt autoimmunity development and early death occur in
male animals after gonadectomy, while mortality is reduced in
ovariectomized female mice after androgens [75]. Results from
studies in humans did not clearly prove real benefit of androgens
in autoimmune disease [76–79].
3.1.2. Estrogens
Estrogens (estrogen, estradiol and estriol in pregnancy), act-
ing through estrogen receptor (RE), are able to affect mitogenic
response, maturation, activation and cytokine secretion of several
types of immune cells [63,80,81].
In particular, estrogens likely promote protective effect “con-
taining” Th1-driven response [82,83], i.e., by facilitating CD25− to
CD25+ Treg cell conversion [75], suppressing antigen presentation
[84] and simultaneously amplifying Th2 immune response [85].
Estrogens have been reported to retain biphasic dose effects:
lowers levels, as post menopause, seem to facilitate Th1 immune
response, higher concentrations, as during pregnancy, suppresses it
[86], driving to Th2 dominance; Th1 driven autoimmune response,
in fact, usually tends to undergo remission during pregnancy [87].
However, autoimmunity remission during pregnancy is a topic still
widely debated, because that condition also triggers some autoim-
mune diseases, such as diabetes or thyroiditis [61].
In animals and humans, the vulnerability of target organs
to autoimmune response has been shown to be under estrogen
influence as well, with differential involvement of T and B cells,
macrophages, lymphocyte homing, antigen presentation by DC and
consequent cytokine release [63,88].
To date, target organs show gender-dependent ability to resist
damage, likely due to some differences in complex different cel-
lular/biomolecular processes – from autophagy, to apoptosis, cell
survival or mitochondrial functions [89–91].
Human studies on gender-related role of immune cells resident
in tissues/organs are currently quite limited. So far, it is a gen-
eral opinion that estrogens confer females with greater resistance
[61] due to stronger immune responses (humoral and cellular) to
antigens and higher levels of CD4+ T cells, following allo- or auto-
antigenic challenge [92].
The higher immune reactivity and greater immunocompetence,
while leading females to a greater resilience to some diseases (i.e.,
infections), make them more prone to autoimmunity [81].
Generally, it could be summarized that estrogens, exert a dif-
ferent effect onto autoimmunity depending on several variables,
i.e., age, reproductive capacity and, not least, type of autoimmune
disease.
4. Rheumatic diseases and sexual dimorphism
The term RD largely encompasses over one hundred inflamma-
tory, degenerative and autoimmune conditions which in their most
complicated form display joint damage, severe pain, disability and
death [93]. Commonly, in RD there is also a detrimental involve-
ment of skeletal muscle which worsens disease disability [94]. In
the 2010 World Health Organization (WHO) Global Burden of Dis-
ease Study, RD have been, indeed, reported to be the second leading
cause of disability worldwide [95].
As previously addressed, a high gender bias toward females has
been recognized for some autoimmune conditions, including RD
[55]. The mechanisms responsible for sexual dimorphism in RD still
have to be clarified, but, as for other autoimmune diseases, some
differences gender dependent seem due to, the variance existing
between female and male immune systems. Hormonal theory is,
indeed, a quite convincing explanation for bias female observed in
autoimmunity. Studies document the role of estrogens, androgens
and prolactin in increasing susceptibility to RD, by affecting both
innate and adaptive immune systems [63,96,97]. Sex hormones,
i.e., are thought to be crucial for systemic lupus erythematosus
(SLE) regulation, a multifactorial and extremely polymorphic sys-
temic RD that mostly affects women at child-bearing age − showing
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
and prolactin affect maturation and selection of autoreactive B
cells, behaving then as immune-stimulators [101,102]. In partic-
ular, 17␤-estradiol (E2) plays a pivotal role in SLE female bias
and disease activity, although the underlying molecular mecha-
nisms are not yet clear [103]. An altered estrogen receptor (ER)
profile seems critical in disease pathogenesis as well, since in
T cells from SLE females ER␤ expression extent reflects disease
activity [104]. Men with SLE show as well elevated serum lev-
els of estrogens − i.e., 16-hydroxyestrone and estrone − with
some subjects presenting hypoandrogenism and elevated levels
of luteinizing hormone (LH) [81,105]. In this context, we could
explain the beneficial effects of vitamin D, which by decreasing
aromatase expression [106] reduces estrogen peripheral synthe-
sis from androgens. This observation is in line with the hypothesis
that SLE could be also sustained by the interplay between vita-
min D deficiency – with reduced down-regulation of aromatases
– and increased peripheral estrogen synthesis; this latter, in turn,
promotes B cell proliferation and overactivity [107]. Local hor-
mone imbalance can also play a pivotal role as evidenced in
RA, a disease characterized by chronic joint inflammation, func-
tional impairment, disability, and premature mortality, presenting
a female to male ratio 2:1 in subjects aged from 55 to 64, with
an upturned ratio in subjects over 75 [108]. In both male and
female RA patients, estrogens in synovial fluid are significantly
elevated, likely due to local enzymatic aromatase increased activ-
ity, which affects macrophage and fibroblast proliferation, key
cells in synovial inflammation [109]. Vitamin D deficiency could
indirectly lead to a further increased risk for RA through estro-
gen levels: adequate vitamin D seems to counteract aromatase
activity through the inhibition of macrophage-derived inflamma-
tory cytokines, which strongly enhance enzyme activity [97,110].
Estrogens are somehow associated with female predisposition to
SSc [111], a connective tissue disease, characterized by immune
and vascular alteration, ending in skin and internal organ fibrosis
[112], with 3:1 woman to man ratio [113,114]. Also, SSc severity
seems linked to high prolactin and low dehydroepiandrosterone
serum levels [115]. Spondyloarthropathies (SpA), characterized
by chronic inflammatory rheumatic diseases, include ankylosing
spondylitis (AS), the most typical form of spondyloarthropathy,
reactive arthritis, arthritis associated with psoriasis (psoriatic
arthritis), arthritis/spondylitis with Crohn disease and ulcerative
colitis (entheropatic spondyloarhtitis) – affect the axial spine and
occur more frequently in men (male to female ratio 3:1 in AS),at
variance with most RDs, [116] with a progressive fall in the sex ratio
 M. Vasile et al. / Pharmacological Research 117 (2017) 228–241
as the age at onset increased [117]. Several hypothesis have been
proposed to explain sexual dimorphism involving testosterone,
but data are conflicting [118–121] I.e., in a mouse model with an
arthropathy resembling human ankylosing enthesopathy the dis-
ease occurred in intact but not in castrated males; the latter ones
injected with testosterone developed arthropathy while females in
the same condition did not [122]. Those data suggest that, albeit
androgens act as natural immunosoppressors, in this specific dis-
ease testosterone conversely seems to trigger/worsen autoimmune
overactivity critical in the development of joint disease. Neverthe-
less, no significant changes in testosterone serum levels were found
in men with AS [76,120,121], thus we could speculate a “local”
role for testosterone in the disease. Another evidence for andro-
gen role in disease development emerges from women affected
by breast cancer and treated with aromatase inhibitors: the con-
sequent increase in testosterone level seems to be responsible for
SpA promoting [123]. In patients with AS the different activation
of the immune system, particularly Th17 axis, supports a distinct
sexual dimorphism since males but not females show higher fre-
quency of IL-17A and Th17 cells [124]. This gender related immune
profile underlying AS might encourage further studies searching for
sex-specific therapies. SS is a RD characterized by chronic inflam-
mation of the salivary and lacrimal glands [125] and it primarily
affects women during the fourth and fifth decades of life, with 9:1
woman:man ratio [126]. Estrogens likely exert a protective role in
SS: while estrogen insufficiency promotes a SS-like autoimmune
exocrinopathy [127–133] estrogen treatment apparently corrects
the defects in lacrimal gland, typical of the disease [132,134–136].
Furthermore, studies on aromatase inhibition confirm that lack of
estrogens play a key role in SS pathogenesis [137]. Few studies
evaluate gender-dependence in antiphospholipid syndrome (APS),
another RD preponderant in females (2–5:1 female to male ratio)
and characterized by the association of antiphospholipid antibod-
ies (aPL) with recurrent arterial and venous thrombosis and/or fetal
loss, mild to moderate thrombocytopenia [138,139]. Since men
and women display different disease consequences – i.e., stroke
or pulmonary thromboembolism more prevalent in females, while
gastrointestinal involvement in males [140,141], – a role for sex
hormones has been hypothesized.
5. Vitamin D and rheumatic diseases
As previously addressed, a consistent part of literature suggests
a correlation between some autoimmune RD, such as SLE, RA, SSc,
Polymyositis/Dermatomyositis (PM/DM) and low plasma vitamin
D levels [142,143]. In fact, although some discrepancy reported
by some epidemiological studies [144], the role for vitamin D
insufficiency in the pathogenesis of certain RD is supported by
epidemiologic, genetic and basic science studies [25,145,146]. Ade-
quate vitamin D levels result in a more balanced Th1/Th2 response
that hinder autoimmunity and self-reactive T cells [147]. Therefore,
the idea that supplementation or vitamin D pharmacological dose
intakes treatment to attenuate ongoing autoimmune disorders or
even to prevent them has taken place. The following paragraphs
highlight how vitamin D status can impact on some RD.
Several studies pointed out vitamin D insufficiency as a risk fac-
tor for SLE [148,149]; vitamin D deficiency seems, in fact, directly
linked with autoimmune phenomena parameters such as antinu-
clear antibodies-ANA- positivity [150]. Moreover, SLE flares seem
triggered by seasonal declines in vitamin D level [151]. Some debate
exists on serum 25(OH)D level and disease activity [152], with some
reports documenting an inverse correlation, not confirmed by other
studies [153,154]. A tight association between disease activity and
hypovitaminosis D is evident in overweight SLE patients, likely
233
influenced by hormone sequestration in fat tissue as previously
reported [155].
Albeit the literature reports conflicting results on the role of
vitamin D deficiency as an independent risk factor for RA onset
[156,157], the risk decreases with longer light exposure, somehow
confirming vitamin D role in disease pathogenesis [144,158–161].
Of note, as from a retrospective investigation, severe vitamin D
deficiency in patients with early inflammatory arthritis signifi-
cantly associates with the higher probability of being diagnosed
with RA [162]. In established RA, vitamin D deficiency is highly
prevalent and correlates with higher disease activity and lower
functional status [144,163–166]; remarkably, 3-months adminis-
tration of alphacalcidiol improved RA clinical symptoms [167].
Vitamin D levels seem to play a role also in AS. Some authors
reported no differences in vitamin D levels between AS patients
and healthy controls, but after patients’ stratification according to
vitamin levels, Erythrocytes Sedimentation Rate (ESR), C Reactive
Protein (CRP), the disease activity was higher in the subgroups with
low 25(OH)D, suggesting that vitamin D deficiency may worsen
inflammatory process involved in the disease [168]. To date, results
from a metanalysis confirm the association between lower vitamin
D and higher disease AS activity, even though data seem not suffi-
cient enough to support an immunomodulatory role for vitamin D
in this disease [169].
The high incidence of vitamin D deficiency in SSc has been doc-
umented in several reports [170–173]. Albeit some paper reported
no correlation between decreased vitamin D level and clinical fea-
tures of SSc [174], some others, conversely, found a tight correlation
between vitamin D levels and respiratory parameter, or, i.e., sever-
ity of skin involvement [6].
Of note, in vitro studies from SSc human fibroblasts and in
vivo studies from murine models show a significant reduction
in VDR expression and signalling, dependent on TGF␤, which is
deeply involved in fibrotic processes and downregulation of VDR
expression. Remarkably, the treatment with paricalcitol, a syn-
thetic vitamin D analogue, exerted preventive and therapeutic
potent antifibrotic effects, by restoring VDR signalling in SSc fibrob-
lasts and reducing TGF␤-induced fibrosis [175].
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].
Moreover, several clinical manifestation of SS (i.e. leukocytopenia,
lymphoma and peripheral neuropathy) associate with 25(OH)-D
severe deficiency and these observations led to the suggestion that
vitamin D supplementation could be useful in SS [30,178]. As for
SS, there are few studies documenting poor vitamin D status on
subjects with APS. In particular, the hypovitaminosis D was found
to cluster in APS patient with thrombosis, the main clinical feature
of the disease [179]. In fact, conversely, an in vitro study showed
that vitamin D inhibits the expression of the procoagulant protein,
tissue factor, induced by the typical autoantibody of the syndrome
(anti-ß2GPI Abs) [180].
The term “undifferentiated connective tissue disease” (UCTD)
includes a group of connective tissue diseases still lacking
specific features for connective tissue diseases but with spe-
cific signs and/or autoantibodies characteristic of autoimmune
disease. Clinical manifestations of UCTD frequently include pol-
yarthralgy/polyarthritis, Raynaud phenomenon, serositis (pleuritis
and pericarditis), photosensitive, rash, xerostomia or xeroph-
thalmia with the involvement of central nervous system. About 30%
to 40% of patients with UCTD will evolve to defined CTD, charac-
terized by increased intensity of immunological abnormalities and
new organ manifestations leading to a specific evolution to a RD
(SLE, mixed connective tissue disease, SSc, SS, PM/DM, RA and sys-
234 M. Vasile et al. / Pharmacological Research 117 (2017) 228–241
temic vasculitis). In this scenario, vitamin D lower levels seem to
facilitate UCTD progression towards well-established CTDs [181].
An open-label trial of alfacalcidol improved the Th17/Treg
imbalance found in UCTD patients, supporting the idea that vita-
min D could be beneficial in the management of the disease [182].
Summarizing, vitamin D deficiency has been reported in several
autoimmune rheumatic diseases (SSc, SpA, SS, APS, UCTD). In some
diseases, this deficiency was even related to the risk of RD devel-
oping (SLE, APS, RA, SSc, UCTD) or to the degree of disease activity
(SLE, RA, SpA, SS, APS, UCTD). Moreover, the vitamin intake affects
RA patients, immunological imbalance in UCTD patients and some
aspects of SSc (fibrosis). Even if not so striking, these evidences are
leading to a pressing need for therapeutic studies.
5.1. Effects of antirheumatic treatment on vitamin D metabolism
Although many of the well-known side effects of immunosup-
pression regard systems in which vitamin D plays a critical role –
i.e., cancer, hypertension, dysmetabolisms, liver-, gastrointestinal-,
kidney- or bone injury – large evidences collected on the straight
relationship between immunosuppressive treatment in RD and
alterations in vitamin D metabolism are still lacking.
One of the first described consequences of immunosuppression
is the alteration in bone turnover and metabolism ending in bone
loss, osteopenia, osteoporosis, osteomalacia [183]; of note, about
20% of all osteoporosis cases are attributable to corticosteroids
[183].
Chronic glucocorticoid therapy has been, in fact, associated with
a significant higher risk of bone loss and fracture, likely due, at
least in part, to immunosuppression-induced alteration of vitamin
D homeostasis and status. To date, often no significant changes are
reported in vitamin D levels, maybe in consequence of the simul-
taneous vitamin D and calcium supplementation given to patients.
However, greater corticosteroid exposure has been associated with
low vitamin D levels and significant VDR expression negative
regulation in bone cells [184,185]. Recent evidences address an
important effect of glucocorticoids on the role pregnane X recep-
tor (PXR) a nuclear receptor retaining 60% omology with VDR. PXR
activation has been shown to affect the expression of several genes
such as 24-hydroxylases, which increases degradation of 25(OH)D
and 1,25 (OH)2D causing an acceleration of vitamin D catabolism
and leading to vitamin D deficiency [186–189].
At difference with glucocorticoids, the antimalarial drugs
chloroquine and hydroxychloroquine [190,191] as well as sul-
fasalazine [192] have been commonly linked to significant
variations of vitamin D circulating levels.
In particular, chloroquine and hydroxychloroquine, used by
patients affected by connective tissue diseases and arthritides
seem to inhibit the conversion of 25(OH)D to 1,25(OH)2 D [190],
as shown in SLE patients[193]; sulfasalazine, used in patients with
arthritides, has been shown in vitro to enhance endogenous 1␣-
hydroxylase mRNA levels[194].
There are conflicting reports on the relationship between cal-
cineurin inhibitors such as cyclosporine and tacrolimus vitamin D.
While Reichel H et al. did not show any effect of cyclosporine treat-
ment on vitamin D levels [195] opposites data have been collected
form others [196] that showed the ability of this drugs to lead to a
vitamin D-resistant state due to suppressive effect on VDR, as also
showed in animal studies [197–199].
Few studies describe the effect of biologic therapies (goli-
mumab, adalimumab and rituximab) which seem not to interfere
with vitamin D levels in RA patients [199–202].
These clear evidences depict how important is to monitor vita-
min D status in rheumatic patients not only at the time of the
diagnosis as already suggested, but even during the treatment
by means of several anti-rheumatic drugs, in order to counteract
adverse direct and indirect drug reactions.
5.2. Potential multi-faceted beneficial effect of vitamin D
supplementation: an example from idiopathic inflammatory
myopathies
A pivotal role for vitamin D has been recognized in the
pathogenesis of autoimmune inflammatory myopathies (IM), a het-
erogeneous group of autoimmune diseases subclassified in distinct
subgroups: DM, PM, inclusion body myositis (IBM), necrotizing
autoimmune myositis (NAM), and myositis associated with sys-
temic disorders.
Chronic inflammation and infiltration by
immune/inflammatory cells in skeletal muscles are features
shared by all IM subtypes [203,204]; in addition, all disease sub-
groups show common clinical and histological characteristics, as
muscle weakness, fatigue, mononuclear cell infiltration, elevated
serum muscle enzymes and myofiber degeneration or fibrosis
[205].
IM occur as primary pathologies or as disease overlapping other
RD, i.e., SS, SSc, SLE or RA [206,207].
Previous studies show the relationship between lower serum
levels of vitamin D and the presence of autoantibody, deregu-
lated production of inflammatory molecules and several immune
abnormalities reinforcing the hypothesis that vitamin D is closely
involved with immune system activities in the pathogenesis of IM
as well [149,208–210].
The 25(OH)D deficiency could be considered as a risk factor
for IM development, even though hypovitaminosis D could not be
excluded as a disease consequence. In particular, Azali et al. [210]
report that IM patients at the early disease stage showed lower
level of vitamin D vs. patients at the late disease stage, suggest-
ing a critical role for this hormone at disease onset, when some
immunebioactive molecules start to trigger detrimental effects. In
this view, it is remarkable the ability of vitamin D to counteract
the activity of some molecules, such as Th1 type pro/inflammatory
cytokines and chemokines, widely engaged in IM pathogenesis.
Despite extensive studies, the molecular mechanisms under-
lying IM pathogenesis have not been yet fully clarified but the
presence of B and NK cells in addition to DCs are well documented
in all types of IM [211,212].
DCs, in particular, seem to be involved in the stimulation of
adaptive immune response and in the maintenance of autoimmune
lesions in IM. Myeloid (m)DCs have been found in PM and IBM
while plasmacytoid (p)DCs, the main source of IFN␣, a type I IFN,
are particularly present in muscle tissue of adult and juvenile DM.
In addition, genomic studies evidenced a marked overexpression
of type I IFN inducible gene in the peripheral blood of DM and PM
patients; of note type I IFN pathway is activated in different RD
[213].
As previously discussed, vitamin D stimulation of all type of DCs
reduced their ability to activate T cells and limited T cell response
to self antigens, thus potentially leading to a significant improve-
ment in the treatment or prevention of autoimmune processes
[43,214,215].
As reported, in general, the higher incidence of autoimmune RD
in women seems supported by possible links between vitamin D
deficiency and increased synthesis of peripheral estrogens [216].
Estrogens, indeed, can modulate immune response during inflam-
matory states or immune abnormalities and are also able to modify
human monocytes, monocyte-derived DCs, blood myeloid and in
particular, pDCs function [217].
In particular, also in women with IM a possible direct action
of estrogens on DCs may influence immunity and tolerance, and
an augmented synthesis of peripheral estrogens might correlate
 M. Vasile et al. / Pharmacological Research 117 (2017) 228–241
with an increased disease severity; in fact, different studies support
an IM exacerbation during pregnancy, when important hormonal
changes occur [218].
However, pDCs are described to decline as pregnancy progresses
and further evidence indicates that both estradiol and progesterone
correlated with this change. In particular, while estrogens acti-
vate pDC, progesterone likely inhibits their activity, hence, female
sex steroids seem to influence autoimmunity, immunity and toler-
ance through a fine-modulated opposite effects exerted onto DCs
function [219–221]. The sex-dependent differences observed in IM
incidence – DM and PM affect women more frequently (female to
male ratio 2:1), at variance with IBM (male to female ratio 3:1) –
somehow confirm the pathophysiologic role for sex hormones in
these diseases. Furthermore, antiestrogen medication, by inhibit-
ing proinflammatory cytokines involved in disease pathogenesis,
such as TNF␣, has been anecdotally reported to improve DM [222].
The tight association between sex hormones and IM disease is also
reflected by the hormonal dysfunctions influencing gonadal and
sexual function, as reported in PM and DM subjects either female
and males, also since pediatric age [223–225]. Vitamin D retains
the ability to regulate the production and interfere with the action
of female hormones.
5.2.1. Cross influence of estrogens and vitamin D
As previously addressed, the interaction between hypovita-
minosis D and estrogen levels may be the route toward an increased
risk of RA or SLE in both genders. We could summarize that gender
and vitamin D status together, somehow, contribute to the suscep-
tibility to develop and maintain RD.
Understanding the biomolecular mechanism(s) underlying the
cross influence of sex hormones and vitamin D within the crosstalk
endocrine system/immune system might help to clarify potential
therapeutic target(s) and, in turn, to design therapeutic strategies
aimed at. Nevertheless, few evidences have been collected on the
role of gonadal hormones/vitamin D interplay and its straight rel-
evance in RD pathogenesis and treatment. However, a meaningful
example on the critical role of hormonal collaboration is elegantly
given by data collected from studies on multiple sclerosis (MS), an
autoimmune disease characterized by vitamin D poor status and
showing high female bias.
From studies on autoimmune MS, estrogens seem to act in syn-
ergy with vitamin D to gain protective effect [226] through a mutual
interaction.
In particular, Kragt and coll. measured serum vitamin D (in
summer and winter) in a large prospective cohort of MS patients
and healthy control subjects and showed that the higher vita-
min D concentration, observed in all subjects during summer,
inversely associated with lower disease-related disability and inci-
dence only in women, who showed MS odd reduction by 19% for
every 10 nmol/L serum D level. This result is in line with previ-
ous data obtained in experimental mice model with autoimmune
encephalomyelitis (EAE, resembling human MS) documenting a
protective role for vitamin D only in intact females, neither in
ovariectomized females nor in males. Fully restored vitamin D
protective effect occurred in EAE ovariectomized females after
estrogen implant: vitamin D enhanced the biosynthesis of 17␤-
estradiol, which, in turn, increased VDR expression, thus, enabling
vitamin D/estrogen to act in concert against inflammatory pro-
cesses and drive toward disease remission [227]. So far, estrogens
are likely to be selectively permissive for vitamin D beneficial
action.
So far, rather than a simple “one way” effect of one or the other
hormone, a multi-faceted dynamic dialogue is likely the critical
event in autoimmune response regulation.
Therefore, hypothesizing that this kind of interplay would occur
in other autoimmune disease context such IMs, we could speculate
235
that vitamin D likely control muscular disease progression acting
through double regulatory effect: on innate and adaptive immu-
nity on a side, and on hormonal level regulation on the other side.
These observations strongly encourage vitamin D supplementation
during disease.
In addition, restoring adequate levels of vitamin D might help to
minimize the effect of some critical inflammatory molecules, such
as the interferon ␥ inducible protein 10 (IP-10 or CXCL10), directly
involved in autoimmune response since very early IM stages. This
small chemokine, in fact, triggers organ infiltration by establishing
a self-promoting inflammatory loop between resident and Th1 type
immune cells, at disease onset [228–230]; of note, VDR agonists can
impair CXCL10 release by muscular and immune cells [231,232].
Corticosteroids combined with immunosuppressive drugs (as
steroid-sparing agents) aimed to target/suppress immune cell
activity represent the mainstay treatment in IM [233–255].
Nevertheless, too often IM patients do not show satisfactory clin-
ical improvement, as few recover muscle performance, while
about 25% of subjects are refractory to those drugs and left
with disability [233–255]. Hence, immune system pharmacolog-
ical targeting seems not enough to gain real modifying-disease
effects.
Again, we want to underline that VDR agonists contribute to
restoring immune homeostasis through different actions: immune
response polarization to protolerogenic Th2 phenotype; regulatory
effect through interplay with sex hormones; beneficial impact
directly at muscular tissue/cell level.
To date, in fact, the muscular component takes part in dialogue
with the immune system during inflammation throughout highly
immune-bioactive molecules (cytokines and chemokines); so far,
skeletal muscle can be considered not only as the final target of
detrimental processes, but as an active counterpart contributing as
well to the IM and, hence, as an important therapeutic objective.
However, VDR expression in vivo in human muscle still remains
controversy and debated [236], albeit its presence is unquestion-
ably critical for skeletal muscle development, maintenance and
function [237,238].
Another aspect of vitamin D deficiency regards the high preva-
lence of diabetes reported IM [239,240]. In general, vitamin
D inadequacy is reported as part in multifactorial pathogene-
sis of metabolic disturbances – from insulin resistance (IR), to
metabolic syndrome (MetS), type 1 or 2 diabetes (T1D, T2D)
[241,242]. Thus, supplementation with vitamin D in IM ideally
could contribute to prevent overlapping disease condition. So far,
re-establishing adequate hormone levels might be advantageous
under different aspects: vitamin D supplementation retain the
potential as multi-faceted beneficial therapeutic intervention in
IM.
Moreover, gender related studies on VDR agonists in IMs over-
lapping metabolic disturbance would be particularly desirable in
view of a females/males personalized treatment.
Some molecules, as BXL-01-0029 or elocalcitol, showing less
or none hypercalcemic activity, seem suitable pharmacological
tools to be included – maybe as steroid-sparing agents – in
the therapeutic regimen for IM treatment. In particular, safety
and tolerability of elocalcitol (150??g/day P.O.) has been shown
in a double-blind randomized study in 101 postmenopausal
osteoporotic women and in placebo-controlled phase IIa (119
enrolled subjects) and follow-on phase IIb (514 patients) trials
for the treatment of benign prostate hyperplasia (BPH) [243–246].
Furthermore, it is notable that elocalcitol has been recently doc-
umented to directly target and regulate biomolecular metabolic
machinery of human skeletal muscle cells similarly to insulin
[247].
236 M. Vasile et al. / Pharmacological Research 117 (2017) 228–241
6. Conclusion
As previously addressed, the key event for therapeutic use of
VDR agonists relies on restoring immune homeostasis substantially
through its inhibitory effects on DC maturation and activation.
In view of the tight link existing with RD progression, recently
recommendations for daily vitamin D intake have been provided.
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-
press the proliferation of autologous CD4+ CD25− cells [182]. Since
quite a while, it is known that in RA alphacalcidiol administration
(2 ␮g/day) acted as strongly as corticosteroids [167].
In 2013 Cutolo [216] still confirms the beneficial effect of ther-
apeutic vitamin D supplementation in some RD, like SLE and AR.
Novel therapeutic VDR agonists without the undesired side effects
on calcium mobilization ending in hypercalcemia and hypercalci-
uria seem to be useful in SLE treatment [248]. Again in SLE [85,249]
and in RA [228,250] the administration of 1,25(OH)D (5 mcgr/kg
on alternate days) or analogous compounds (BXL-219, MC 1288,
Ro 63-2023, Ro 26-2) has been shown to arrest immunological
progression and prevent clinical onset, by inhibiting IL-12 produc-
tion and Th1 cell infiltration while favoring CD4+ CD25+ regulatory
T-cells frequency.
So far, albeit scattered evidences and proposal for vitamin D
supplementation are largely present and reviewed in literature for
most RD and autoimmune diseases [251], the controversy exist-
ing on a real effect of VDR agonists in human RD treatment cannot
be ignored [143,149,167] and some authors suggest that enthu-
siasm for a vitamin D panacea should be tempered [252]. Thus,
it is undeniable the need for suitable controlled trials with suffi-
cient power to determine efficacy and safety of vitamin D and its
analogues in RD. The current effort of many Companies from all
around the world is focused on searching for molecules with dis-
tinct separation between immunomodulatory and hypercalcemic
potency, throughout chemical modifications especially in the A-
ring, containing the 1␣-hydroxyl group, or in side chain − i.e., chain
modifications altering VDR susceptibility to 24-hydroxylation are
able to affect their biological selectivity. By those conformational
changes, the novel molecules should be characterized by a clear
dissociation between the beneficial and adverse effects, such as
hypercalcemia and hypercalciuria. A comprehensive review on
licensed and marketed vitamin D analogues for therapeutic applica-
tions is beyond the aim of this review and elsewhere reported [253].
Another concern regards the lack of consensus on supplementary
or therapeutic doses for vitamin D intake, since quite high hormone
concentrations are necessary to gain clinical effects in RDs and in
autoimmunity in general. Furthermore, supraphysiological doses
of vitamin D are required to reach effective concentration (about
10−10 M) at local cell/tissue level [45,254]. Since 1997, the Insti-
tute of Medicine (IOM) of the US National Academy recommended
a vitamin D intake 200 IU for children and adults under 50 years
of age, 400 IU for adults 50–70 years old, 600 IU for adults older
than 70 years. In 2010, IOM revised and renewed recommendations
indicating 600–800 IU as average daily intake to meet human body
basic needs, increasing to approximately 800–1000 IU/day when
sunlight is insufficient [255–257]. European authorities advise even
for higher doses, since vitamin D intoxication is a very rare event.
In fact, hypercalcemia and hyperphosphatemia are reported with
doses higher than 50,000 IU per day (raising serum 25(OH)D to
150 ng/ml), whereas 10,000 IU for 5 months did not cause any toxic
effect [258–261]. Furthermore, the lack of standardization in meth-
ods for hormone measurement and the high number of variables
influencing vitamin D status represent as well a substantial part
of the current “classical” problems to face in order to achieve con-
sistent response and disease remission. On the other side, in light
of the reported observations, it should be mandatory to include
gender and sex hormone level as important variables influencing
the final therapeutic effect. Albeit the many concerns existing, the
potential use of vitamin D or non-calcemic VDR agonists to prevent
or treat RD drives the attention to the latest challenge in autoim-
munity: “resetting” rather than “ablating” the immune system with
a therapeutic approach towards a personalized therapy in line with
the emerging concept of gender-specific medicine.
Acknowledgments
The authors wish to thank Dr. Francesco Marampon, Depart-
ment of Movement, Human and Health Sciences, University of
Rome Foro Italico, for his critical support during manuscript
reviewing.
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