Environment and systemic lupus erythematosus

Abstract

Systemic lupus erythematosus (SLE) is a chronic autoimmune disease with a wide range of clinical manifestations and a relapsing-remitting course. SLE pathogenesis is the result of complex interactions between ethnic, genetic, epigenetic, immunoregulatory, hormonal and environmental factors, and several aspects of these multifactorial connections are still unclear. Overall, for the disease development, an environmental trigger may induce immunological dysfunction in genetically predisposed individuals. This review aims to summarise the most relevant data on the impact of environmental factors on the incidence of SLE and on disease activity and damage in patients with an established diagnosis of SLE.

Full text

1104 Clinical and Experimental Rheumatology 2024
1Rheumatology Unit, Department of
Clinical and Experimental Medicine,
University of Pisa;
2Department of Medical Biotechnologies,
University of Siena, Italy.
Chiara Cardelli, MD*
Dina Zucchi, MD*
Elena Elefante, MD PhD
Viola Signorini, MD
Marina Menchini
Chiara Stagnaro, MD
Marta Mosca, MD, PhD
Chiara Tani, MD, PhD
*Contributed equally.
Please address correspondence to:
Chiara Tani
U.O. di Reumatologia,
Dipartimento di Medicina
Clinica e Sperimentale,
Università di Pisa,
via Roma 67,
56126, Pisa, Italy
E-mail: chiara.tani@unipi.it
Received on February 29, 2024; accepted
in revised form on April 22, 2024.
Clin Exp Rheumatol 2024; 42: 1104-1114.
© Copyright CliniCal and
ExpErimEntal rhEumatology 2024.
Key words: systemic lupus
erythematosus, environment,
smoking, infections
Competing interests: none declared.
ABSTRACT
Systemic lupus erythematosus (SLE) is
a chronic autoimmune disease with a
wide range of clinical manifestations
and a relapsing-remitting course. SLE
pathogenesis is the result of com plex in-
teractions between ethnic, genetic, epi-
genetic, immunoregulatory, hor monal
and environmental factors, and several
aspects of these multifactori al connec-
tions are still unclear. Overall, for the
disease development, an environmen-
tal trigger may induce immunological
dysfunction in genetically predisposed
individuals. This review aims to sum-
marise the most relevant data on the
impact of environmental factors on the
incidence of SLE and on disease activ-
ity and damage in patients with an es-
tablished diagnosis of SLE.
Introduction
Systemic lupus erythematosus (SLE)
is a complex, chronic autoimmune
disease with a broad spectrum of clini-
cal manifestations, that mainly affects
young women (1). The aetiology of
SLE is multifactorial, encompassing
genetic, epigenetic and environmental
factors. The role of genetics in SLE
is suggested by mouse models, famil-
ial linkage studies and concordance of
the disease in twins (2-4). However, a
recent metastudy on SLE concordance
in twins revealed high rates of discord-
ance (up to 75% in monozygotic and to
95% in dizygotic twins) (5), conrming
the key role of environmental factors in
SLE susceptibility. This narrative re-
view focuses on the main environmen-
tal factors involved in the development
and course of SLE.
Environmental factors
involved in SLE
Ultraviolet (UV) light
Among environmental factors, UV ra-
diation exposure is recognised as a risk
factor for the development and reacti-
vation of SLE. Whereas UVC, with its
short wavelength, does not penetrate
the atmospheric ozone layer, UVA
(320–400 nm) and UVB (280–320 nm)
are environmentally relevant.
UVA penetrates the deeper dermis and
is weakly absorbed by cells: its role in
SLE pathogenesis is still unclear. In-
deed, some studies have found that UVA
induces a reduction in disease activity
in SLE patients and in patients with
cutaneous lupus erythematosus (CLE)
(6); conversely, other studies have
shown that UVA exposure induces lu-
pus skin lesions (7, 8). In contrast, UVB
is unable to penetrate the epidermal lay-
er and is more absorbed by DNA and
cellular proteins; therefore, UVB is the
most effective inducer of keratinocytes
apoptosis. Several phototesting studies
demonstrated as UVB and/or UVA can
induce skin lesions in patients with dif-
ferent subtypes of LE (9), proving that
UV radiation exposure may induce or
exacerbate skin manifestations, while
their role as risk factors for the devel-
opment of SLE remains unclear. Only a
few case-control studies have been able
to examine UV radiation exposure and
risk of SLE (10, 11).
As we know, UV radiation causes DNA
damage and apoptosis of keratinocytes;
apoptotic keratinocytes, known as “sun-
burn cells”, are characterised by eosin-
ophilic cytoplasm and pyknotic nuclei
and can be found as early as eight hours
after UV exposure (12). UVA induces
keratinocytes apoptosis mainly through
mitochondrial oxidative damage lead-
ing to increased production of reac-
tive oxygen species (13). Conversely,
UVB induces apoptosis through DNA
damage with strand breaks and pyrimi-
dine dimers formation (14). Kuhn et
al. showed that, after a single UV light
exposure, apoptotic cells accumulate
in the skin of patients with CLE, com-
Review
Environment and systemic lupus erythematosus
C. Cardelli1,2, D. Zucchi1,2, E. Elefante1, V. Signorini1, M. Menchini1,
C. Stagnaro1, M. Mosca1, C. Tani1

1105
Clinical and Experimental Rheumatology 2024
SLE and environment / C. Cardelli et al.
pared to controls, suggesting impaired
or delayed clearance (15).
Another mechanism through which UV
induces skin injury is by increasing au-
toantigens production in the epidermis,
such as Ro52, IF116, Sm, RNP, Ku and
ribosomal-P (16). Moreover, UV light
increases the expression of chemokines
and induces keratinocytes and immune
cells to release pro-inammatory cy-
tokines such as interferon (IFN) and
tumour necrosis factor alpha (TNFα).
Furthermore, even in healthy skin, UV
induces the upregulation of proteins
that act as autoantigens in SLE patients,
suggesting that chronic or intense UV
exposure can increase the tendency to
autoantigen exposure (16).
Silica
Of the chemical agents that act as trig-
gers for SLE development, silica has
been the most studied. Silica is com-
monly found in nature as quartz; expo-
sure to respirable crystalline silica (<10
μm) occurs most often in occupational
settings.
Several epidemiological studies have
shown that silica exposure is related to
the development of autoimmune diseas-
es such as rheumatoid arthritis, ANCA-
associated vasculitis, systemic sclerosis
and SLE (17). Both Parks et al. (18) and
Morotti et al. (19) reported that occupa-
tional silica exposure may be associated
with SLE, particularly in patients with
silicosis. The dose-response has been
associated with increasing intensity or
duration of exposure (18, 20); these
ndings are conrmed by other popu-
lation-based studies (21, 22). Interest-
ingly, patients with SLE and silicosis
are predominantly middle-aged and
elderly men, in which the age of SLE
onset has been found to be between 40
and 63 years (23).
Smoking
Cigarette smoking has also been associ-
ated with the development and progres-
sion of several autoimmune diseases,
including SLE (24).
The pathogenetic link between smok-
ing and SLE development remains de-
bated; potential mechanisms include
oxidative stress, increased cytokine-
driven systemic inammation and im-
paired T- and B-cell function, epige-
netic modications. In particular, ciga-
rette smoke increases CD95 expression
on B and T lymphocyte cell surfaces
(25); CD95 plays a central role in im-
mune homeostasis, being an essential
membrane receptor for transmitting
apoptosis signals in lymphocytes; as a
consequence, its increased expression
could be responsible for increased ap-
optosis leading to an overburdening of
apoptotic debris clearance mechanisms,
a major driver of autoimmunity in SLE.
Other potential cellular mechanisms in-
clude reduction and functional impair-
ment of natural killer cells and impair-
ment of Th17 and Th22 cells functions.
The causal association between smok-
ing and disease onset risk, antibodies
prole, organ damage and treatment ef-
cacy in SLE patients has been the fo-
cus of extensive investigations in recent
years.
The relationship between smoking ex-
posure and the risk of developing the
disease is still debated; the presence
of possible confounders and the low
incidence of the disease in the general
population would require big cohorts
to be followed and analysed to draw
sound conclusions; to overcome these
difculties, several metanalysis have
been published in the last years.
In 2019, a metanalysis of 9 case-control
studies by Parisis et al. (26) found a sig-
nicantly increased risk of SLE in cur-
rent-smokers compared to never-smok-
ers and in ever- versus never-smokers,
while former-smokers were not at in-
creased risk of SLE. Data on passive
smoking remain scarce and controver-
sial. In the same study, no over-risk of
anti-dsDNA, anti-Sm or anti-SSA posi-
tivity was observed according to smok-
ing status.
More recently, Chua et al. (27) pub-
lished a metanalysis using a Bayesian
approach, including 12 studies for a total
of 3234 individuals who developed SLE
and 288336 control subjects; the study
conrmed the association between cur-
rent smoking and the risk to develop
SLE; interestingly, in this meta-regres-
sion analysis, publication time, age and
gender did not have a signicant effect
on the disease occurrence risk.
Moreover, in 2006, Simard et al. (28)
investigated whether early-life expo-
sure to cigarette smoke was associated
with subsequent SLE development; to
this end, they examined approximately
18000 adults free of SLE at baseline
who provided information on perinatal
exposures; in total, 236 incident SLE
cases were identied, but maternal cig-
arette smoking did not increase the risk
of SLE nor did paternal smoking during
participants’ childhood.
The association between tobacco smok-
ing and morbidity and organ damage
has been poorly studied.
In the 1990s, Ward and Studenski’s
study showed a signicant association
between smoking and the development
of end-stage renal disease (29).
More recently, Montes et al. (30) inves-
tigated the chronic damage accrual ex-
pressed by the SLICC/DI in a cohort of
SLE patients exposed or not to tobacco
smoke. They found that being “never
exposed” to smoking confers a 22%
relative risk reduction of progressing to
an SDI score >0 compared to an “ever
exposed” status.
In 2022, a systematic review was pub-
lished to summarise the available evi-
dence on the effects of tobacco smoking
on developing a cardiovascular disease
(CVD) in SLE patients (31). The authors
included a total of 10 studies on 6984
participants. Compared to never-smok-
ers, the risk of developing CVD in cur-
rent-smokers was signicantly higher.
In the last years, growing evidence has
suggested that tobacco smoking could
also have an impact in the effectiveness
of therapies in SLE patients.
The most recent data on this topic were
reviewed by Parisis et al. (26); in 11
observational studies of CLE or SLE
patients, tobacco smoking signicantly
reduced the therapeutic effectiveness
of hydroxychloroquine (HCQ) in cu-
taneous lesions. However, some stud-
ies evaluated the correlation between
plasmatic HCQ levels and tobacco
smoking, and no signicant differences
were found between smokers and non-
smokers (32-35).
One single study evaluated the effect
of tobacco smoking on the clinical re-
sponse to belimumab (36). In a pro-
spective follow-up study that included
active SLE patients starting belimum-

1106 Clinical and Experimental Rheumatology 2024
SLE and environment / C. Cardelli et al.
ab, the authors observed that current
smokers showed decreased probability
and prolonged time to attain clinical re-
sponse compared to non-smokers. The
same group also demonstrated that cur-
rent or former smokers showed a higher
probability of unchanged/worsened
mucocutaneous manifestations com-
pared to never-smokers, while no im-
pact of smoking on belimumab efcacy
in articular SLE was reported (37).
In conclusion, available evidence sug-
gests that tobacco smoking exposure
is associated with SLE disease risk,
its clinical progression/damage and re-
sponse to treatment. However, it is im-
portant to note that the available studies
refer to a wide range of geographical lo-
cations, vary widely in smoking expo-
sure collection methods and SLE phe-
notype; thus, large prospective studies
could be encouraged to better explore
the complex interaction between the
disease and tobacco smoke. Moreover,
there is a large and intriguing area relat-
ed to the possible impact of heated to-
bacco products and electronic cigarette
smoking, for which no studies exist yet.
Infections
Exogenous microbial agents, such as
bacteria or viruses, interact with and
sometimes overcome the human im-
mune system, potentially leading to
autoimmunity. Among microbiological
agents, viruses in particular have been
implicated as potential triggers of au-
toimmune conditions (38, 39). Overall,
viral infections could interact with in-
nate and acquired immune responses
and lead to an aberrant response or lack
of immune control, facilitating the de-
velopment of SLE and other autoim-
mune diseases. From an aetiopathoge-
netic point of view, the mechanism of
molecular mimicry by specic micro-
bial agents might play a role in the de-
velopment of SLE.
Several studies on the association with
Epstein-Barr virus (EBV) have been
conducted over the years, with con-
icting results (40). The main ndings
on the positive association come from
studies focusing on seroconversion
rates in SLE patients.
Some papers reported an association
between SLE and not only seroconver-
sion but also the presence of EBV ge-
nome in peripheral blood lymphocytes
in children and teenagers (41, 42). Con-
cerning adults, a study involving 196
SLE patients tested for previous infec-
tions demonstrated that all but one had
been exposed to EBV, whereas no dif-
ferences were observed between SLE
patients and controls in seroconversion
against CMV, HSV-2, or VZV, support-
ing the possible role of EBV in the de-
velopment of SLE (43). Similar results
emerged from another case-control
study, where a signicant difference
between SLE patients and controls was
also found in EBV viral load, with the
EBV-DNA positivity rate tending to de-
cline with age in the latter but not in the
former (44).
In 2014, Hanlon et al. published a
metanalysis of 25 case-control studies
to determine whether prior EBV in-
fection occurs more frequently in SLE
patients compared to matched controls:
although publication bias cannot be
excluded, the metanalysis supports the
hypothesis that EBV infection predis-
poses to SLE development (45). Indeed,
signicantly higher seroprevalence of
anti-viral capsid antigen (VCA) IgG,
anti-early antigen (EA)-D IgG and anti-
VCA IgA emerged in cases compared
with controls.
A seroprevalence of almost 100% sug-
gests a signicant, although not entire-
ly clear, role of EBV infection in SLE
pathogenesis. The likelihood that EBV
infection causes SLE in some patients
is supported by the possible molecular
mimicry of the EBV peptide PPPGRRP
by the human spliceosome peptide
SmB’/B’s PPPGMRPP (46). Moreover,
the presence of a dominant epitope in the
C-terminal region of SmD, which ex-
hibits a striking resemblance to a region
of the EBV nuclear antigen coding for
the EBNA1 protein (47), has previously
been demonstrated, thus raising hypoth-
eses on the possible role of the immune
response to EBV in the induction of
anti-SmD antibodies (48). Besides, the
cross-reactivity of spontaneously devel-
oped anti-ribosomal P protein antibod-
ies with the B/B´ and D constituents of
the Sm complex has been proven (49).
Recently, potential underlying molecu-
lar mechanisms have been investigated
by genetic and transcriptomic analy-
ses: lower latent EBV markers and
higher lytic EBV markers were found
in lymphoblastoid cell lines (LCLs) of
SLE patients compared to healthy indi-
viduals, suggesting an EBV nuclear an-
tigen 2 (EBNA2)-mediated molecular
pathway in which SLE risk loci may in-
crease the tendency of LCLs to switch
to the lytic phase (50).
A case-control study published a few
months ago, with data on serological,
molecular and sequence markers of
EBV infection in SLE patients, demon-
strated a 24-fold higher chance of hav-
ing SLE in the presence of anti-EBV-
EA-D IgG antibodies (51). Further-
more, higher titres of anti-EBV-EA-D
IgG were identied as independent
factor associated with lymphopenia and
SLE haematological manifestations,
while a higher titre of anti-VCA IgG as
an independent factor associated with
alopecia in SLE.
Regarding other infections, the Caro-
lina Lupus Study showed that the risk
of SLE increased with a history of shin-
gles and with frequent colds in the three
years prior to diagnosis (52). A recent
systematic review suggested a potential
association between COVID-19 and
new onset of systemic autoimmune dis-
eases, mostly myositis and SLE (53),
although given the few cases and the
short follow-up period no rm conclu-
sions can be drawn to date.
It should be noted that infections might
not only be associated with the devel-
opment of SLE, but also act as triggers
for disease ares over time. Among the
viral infections of most interest, inu-
enza was found to be a risk factor for a
SLE are according to a recent study,
with an incidence ratio for ares of
25.75 during the risk interval compared
to the control interval (54).
Even more, the possibility that the in-
fection itself acts as a mimicker for a
SLE are (55) should not be under-
estimated. SLE patients, in fact, are a
population at increased infection risk
due to both the aberrant immune system
and glucocorticoids and other immuno-
suppressants used to treat the disease.
Although prognosis has considerably
improved over the years, infections still
remain a major cause of hospitalisation

1107
Clinical and Experimental Rheumatology 2024
SLE and environment / C. Cardelli et al.
and mortality in patients with SLE, es-
pecially in the early phase of disease
(56-58).
Although controversial, the crucial in-
terplay between SLE and infections
must draw attention to the importance
of preventive measures such as vacci-
nation.
Exogenous hormones
Sex hormones may play a role in patho-
genesis, clinical features and manage-
ment of SLE.
A correlation between incident SLE and
use of combined oral contraceptives
was described by Bernier et al. (59) in
a large ten-year cohort. Data from this
study suggested a possible acute ef-
fect of sexual hormones in susceptible
women, as an increased risk of SLE
was observed particularly in women
who had recently started hormone ther-
apy and increased with the dose of ethi-
nylestradiol.
A unique population is represented by
transgender women receiving female
sex hormones before or after sexual
reassignment surgery. Few cases of
transgender women who have been
diagnosed with lupus following use of
exogenous female sex hormones were
reported (60-64). None of them had a
previous lupus diagnosis, and renal in-
volvement was described in three cases
(60, 63, 64). Despite the low number,
these data focused on the potential rela-
tionship between female sex hormones
and SLE in susceptible individuals.
It is known that SLE predominantly af-
fects women, and patients may require
hormone therapy during their life. Sev-
eral clinical trials have investigated the
effects of hormone therapies in SLE pa-
tients, with a particular attention to oral
contraceptives and menopause hormo-
nal therapy.
In a randomised controlled trial (RCT)
on 162 SLE women, patients were
randomised to combined oral contra-
ceptive, progestin-only pill or copper
intrauterine device (65). The results
demonstrated the absence of inuence
of these contraceptive methods on dis-
ease activity and adverse events in this
SLE subgroup. In another RTC on 183
SLE women, the authors observed that
combined hormonal oral contracep-
tives did not increase the risk of disease
are compared to placebo (66).
In both studies, all patients had stable
disease and those with medium/high
titre of antiphospholipid antibodies
(aPL) were excluded, as well as pa-
tients with history of thrombosis. Of
note, in the rst study (65) thrombosis
occurred in four patients (two for each
group receiving hormones), and all
four patients had low aPL titres.
Conversely, studies on effects of com-
bined contraceptives on aPL-positive
patients showed an increased risk of
thrombosis. A large multicentre popu-
lation-based case-control study, named
RATIO (Risk of Arterial Thrombo-
sis In relation to Oral contraceptives)
(67), showed an increased risk of arte-
rial events in combined users compared
with non-users. In particular, lupus an-
ticoagulant (LAC) resulted a major risk
factor for arterial thrombotic events,
and the risk of myocardial infarction
and ischemic stroke increased further in
women who used combined oral con-
traceptives.
As a matter of the fact, scientic soci-
eties (EULAR and ACR) support the
use of combined hormonal contracep-
tives in patients with stable/inactive
SLE and negative aPL, while in women
with positive aPL contraception with
combined hormones should be discour-
aged and progesterone only contracep-
tion carefully weighed against the risk
of thrombosis (68, 69). Moreover, ACR
conditionally recommends against the
use of transdermal oestrogen-progestin
patch, since it results in greater estro-
gen exposure than oral or transvaginal
methods (70).
In SLE patients with menopausal symp-
toms, hormone replacement therapy
(HRT) seems to improve vasomotor
symptoms (71), and several studies
have investigated HRT impact in SLE
women.
In RCTs no signicant increase in se-
vere disease ares (72, 73) or cardio-
vascular (CV) events (74) was reported
in SLE patients receiving HRT com-
pared to controls. However, Buyon et
al. observed a small increase in mild-
moderate ares in SLE HRT group with
respect to placebo (1.14 vs. 0.86 ares/
person-year for HRT and placebo, re-
spectively) (73). We must acknowledge
that women with high disease activity,
previous thrombosis or aPL-positivity
were excluded from most studies.
As stated in the previously mentioned
EULAR and ACR recommendations
(68, 69), HRT should be reserved for
the management of severe and disa-
bling menopausal vasomotor symp-
toms, preferably in SLE women with
stable/inactive disease and negative
aPL, while in patients with positive aPL
the use of HRT should be discouraged
or carefully weighed against thrombot-
ic and CV risks.
Diet
Some macronutrients and micronutrients
seem to have antioxidant, anti-inam-
matory and immunomodulatory effects,
and over the years several studies have
investigated their impact on rheumatic
and musculoskeletal diseases (RMDs)
and SLE (75). However, we must con-
sider that most of the studies are pilot or
small samples studies, and thus reliable
conclusions cannot be drawn.
Overall, a healthy, balanced diet is in-
tegral to lifestyle improvement for peo-
ple with RMDs (76). However, patients
should be informed that consuming spe-
cic food types is unlikely to have large
benets for RMD outcomes.
CV risk is known to be higher in SLE
patients, and mediterranean diet has
been reported to down-regulate inam-
matory biomarkers related to atherogen-
esis in subjects at high CV risk (77). A
cross-sectional study on 280 SLE pa-
tients showed that greater adherence to
the mediterranean diet correlated with
benecial effect on disease activity and
CV risk (78).
In overweight women with corticoster-
oid-dependent SLE, Davies et al. (79)
analysed the inuence of low glycae-
mic index diet and calorie restricted
diet in a 6-week controlled trial. Both
diets led to signicant weight loss, im-
proved waist and hip measurements and
reduced fatigue. In addition, no disease
ares were observed during the study
period, conrming the safety of this di-
etary regimen.
Omega-3 fatty acids are involved in
serotonin synthesis (80), and effects of
omega-3 supplementation in SLE have

1108 Clinical and Experimental Rheumatology 2024
SLE and environment / C. Cardelli et al.
been investigated in few studies, with
controversial results. Some papers re-
ported benets from omega-3 supple-
mentation in SLE patients, while other
studies did not conrm these results, as
shown in Table I.
Vitamin D is often considered an anti-
inammatory agent, and has effects on
proliferation, apoptosis and function of
immune system cells that are involved
in SLE pathophysiology (87). Vitamin
D deciency is common in SLE, since
the use of medications such as glucocor-
ticoids and renal failure can alter its me-
tabolism (87). In addition, all SLE pa-
tients are advised to avoid sunlight, and
vitamin D deciency is also reported as
a potential risk factor for SLE (88).
In clinical setting, adding vitamin D to
the traditional pharmacological regi-
men in SLE has been found benecial
in some studies, whereas other studies
failed to replicate these results, as de-
tailed in Table II.
Lastly, only a few studies have evalu-
ated the association between different
types of diet and the risk of SLE. Ac-
cording to a recent prospective study,
no association was found between
dietary patterns and risk of SLE oc-
currence (98). However, a subsequent
study suggested that a diet high in car-
bohydrates and low in fat may be asso-
ciated with an increased risk of SLE in
African-American women (99).
Gut microbiota
Increasing studies have shown that gut
microbiota dysbiosis, inducing inam-
mation and immune system sensitisa-
tion, represents a signicant risk factor
for the development of autoimmune
diseases, such as SLE (100).
In 2014, Hevia et al. (101) observed a
lower Firmicutes/Bacteroidetes (F/B)
ratio in SLE patients than in healthy
people. This nding was conrmed by
subsequent studies (102-105); further-
more, a French study observed that F/B
ratio was signicantly lower in active
SLE patients compared to patients in
remission (102). A signicant decrease
in Lactobacillus was also found in SLE
patients compared with healthy con-
trols (105).
Recently, Xiang et al. (106) realised a
metanalysis including 11 case-control
studies that examined 373 SLE pa-
tients and 1288 healthy controls. They
observed that SLE patients had fewer
Ruminococcaceae, but higher levels
of Enterobacteriaceae and Entero-
coccaceae. A two-sample Mendelian
randomisation study (107) found that
Bacilli, Eggertella and Lactobacilla-
les were positively correlated with the
risk of SLE, whereas Bacillales, Act-
inobacteria, Coprobacter and Lachno-
spira were negatively correlated with
SLE risk.
Another crucial factor involved in SLE
pathogenesis is the impairment of in-
testinal barrier: indeed, leaky gut has
been observed in patients with SLE.
This nding was demonstrated by two
studies that observed how calprotectin
levels in SLE stool samples were sig-
nicantly increased compared to con-
trols (108, 109). Moreover, Azzouz et
al. (108) observed that serum soluble
CD14, α1-acid glycoprotein and li-
popolysaccharides levels were higher
in SLE patients than in healthy sub-
jects, suggesting the presence of intesti-
nal bacterial displacement.
Molecular mimicry is another poten-
tial mechanism linking gut microbiota
with SLE, and several microorganisms
are involved: B. thetaiotaomicron, con-
taining Ro60, induces T- and B-cell re-
sponses against human Ro60 and glo-
merular immune complexes deposition;
E. gallinarum and R. intestinalis induce
anti-β2GP1 antibodies secretion; O.
splanchnicus, presenting a peptide sim-
ilar to human Sm antigen epitope, in-
creases IFN-γ and IL-17A production;
A. muciniphila has a peptide that, mim-
icking human Fas antigen, binds to IgG
produced by memory B cells; lastly, R.
gnavus cross-reacts with anti-dsDNA
antibodies.
Gut microbiota dysbiosis leads to both
cytokines and immune cells dysregula-
tion, contributing to the development
and progression of SLE. Briey, E. gal-
linarum and Ruminococcus are associ-
ated with an increase in Th17 cells and
a reduction of Treg, with a Th17/Treg
imbalance; E. gallinarum and L. reuteri
increase the number of plasmacytoid
dendritic cells and promote the produc-
tion of IFN-I, one of the most important
pathogenetic factors in SLE (110).
Drug-induced SLE
Drug-induced lupus (DIL) was rst
described in 1945 by Hoffman, who re-
ported lupus-like symptoms due to sul-
fadiazine treatment (111). Since then,
Table I. Principal interventional studies on omega3 supplementation in SLE.
Reference n Types of intervention Duration Conclusions
Westberg et al. 1990 (81) 17 Omega-3 vs. olive oil rened 6 months Short-term benecial effect on disease activity
(placebo group)
Duffy et al. 2004 (82) 52 Omega 3 with/without copper 24 weeks Improvement in disease activity (SLAM-R)
vs. copper vs. placebo
Wright et al. 2008 (83) 60 Omega-3 vs. olive oil 24 weeks Improvement in disease activity (SLAM-R, BILAG) and
(placebo group) endothelial function; reduction in oxidative stress
Bello et al. 2013 (84) 85 Omega-3 vs. starch 12 weeks No improvement in disease activity, endothelial function,
(placebo group) nor decrease in inammatory markers
Arriens et al. 2015 (85) 50 Omega-3 vs. olive oil rened 6 months Improvement in PGA, SF-36 and some circulating
(placebo group) inammatory markers; no impact on disease activity
Curado Borges et al. 2016 (86) 49 Omega-3; no placebo group 12 weeks No impact on IL-6, IL-10, leptin and adiponectin; signicant
decrease of CRP levels and impact on cholesterol levels

1109
Clinical and Experimental Rheumatology 2024
SLE and environment / C. Cardelli et al.
the list of drugs potentially involved in
the genesis of DIL has been expanding.
DIL is not a typical allergic drug reac-
tion, but is the result of a drug-induced
self-tolerance breakdown process (112).
According to studies of the early 2000s,
15000–30000 cases of DIL are esti-
mated to occur annually in the United
States, meaning that up to 10% of SLE
cases may be drug-induced.
Overall, compared to idiopathic SLE,
DIL tends to develop in elderly people
(partly because more exposed to drugs),
has a lower female predominance (with
a female-to-male ratio ranging from
4.3:1 to 1:1) and presents with a “lupus-
like syndrome” usually characterised
by fewer and milder clinical symptoms.
Arnaud et al. recently updated the
list of drugs associated with DIL. In
12166 DIL cases from the WHO phar-
macovigilance database, 118 putative
drugs were identied, and among these
42 had not been previously reported in
association with DIL. DIL was consid-
ered denite for nine drugs: procaina-
mide, hydralazine, minocycline, quini-
dine, isoniazid, terbinane, methyldo-
pa, dihydralazine and chlorpromazine
(113). Although less used nowadays,
procainamide and hydralazine are asso-
ciated with the highest risk of DIL, with
an estimated 20% incidence and 5–8%
risk per year of treatment (114).
In a recent matched case-control study
conducted on incident cases of CLE
and SLE in the Danish National Patient
Register, new plausible associations
were observed with some common
drugs: fexofenadine hydrochloride,
metoclopramide hydrochloride, metro-
nidazole hydrochloride and levothyrox-
ine sodium (115).
Moreover, a French pharmacoepidemi-
ological study suggested a link between
statin exposure and DIL, with a reported
OR >1 for each statin but uvastatin
(116).
Several anticonvulsants have been re-
ported to be associated to DIL, includ-
ing carbamazepine (117) and valproic
acid-induced lupus (118).
From a rheumatological perspective, it
is worth noting that, according to the
WHO pharmacovigilance database,
since 2007 onwards, anti-TNF agents
have been the drugs most commonly
associated with systemic DIL (113). We
can speculate if anti-TNF treatment may
unmask an underlying SLE in patients
with a baseline higher risk of overlap
syndrome, rather than cause de novo
drug-induced lupus (112).
Anti-TNF are known to induce autoan-
tibody production. Specically, in pro-
spective placebo-controlled trials, anti-
Table II. Principal interventional studies on vitamin D supplementation in SLE.
Reference n Types of intervention Duration Conclusions
Ruiz-Irastorza et al. 2010 (89) 60 Oral vitamin D3; no placebo group 24 months Benecial effect on fatigue; no effect on SLE
severity
Terrier et al. 2012 (90) 20 Vitamin D3 100000 IU/week for 4 weeks, 6 months Benecial effect on immunological and
followed by 100000 IU/month for 6 months; inammatory markers
no placebo group
Petri et al. 2013 (91) 1006 In patients with levels <40 ng/mL vitamin 128 weeks A 20 ng/mL increase in vitamin D level was
D2 50000 IU/week plus calcium/vitamin associated with decrease in the odds of having a
D3 200 IU twice daily high disease activity score and of having clinically
important proteinuria; no evidence of additional
benet of vitamin D beyond a level of 40 ng/ml
Aranow et al. 2015 (92) 54 Vitamin D3 4000 IU/day (high dose group) 12 weeks No effect on IFN signature in vitamin D-decient
or 2000 IU/day (low dose group) SLE patients
Andreoli et al. 2015 (93) 34 Vitamin D3 25000 IU/month (standard 24 months Neither regimen of supplementation affects disease
regimen) or 300000 IU initial bolus activity or SLE serology
followed by 50000 IU/month (intensive
regimen) for one year and then switched to
the other regimen in the second year
Piantoni et al. 2015 (94) 34 Vitamin D3 25000 IU/month (standard 24 months Enhancement of T-reg cells
regimen) or 300000 IU initial bolus followed
by 50000 IU/month (intensive regimen) for
one year and then switched to the other
regimen in the second year
Marinho et al. 2016 (95) 24 Vitamin D3 at variable dosage during the 6 months Reduction in SLEDAI and improvement in the
study period Treg/Th17 ratio
Karimzadeh et al. 2017 (96) 90 Vitamin D3 50000 IU/week for 12 weeks 6 months No effects on disease activity
and then 50000 IU/month for 3 months vs.
placebo
Al-Kushi et al. 2018 (97) 81 Corticosteroid treatment with vitamin D3 6 months Vitamin D and calcium supplementation
1400 IU/day and calcium carbonate 1250 signicantly improved the bone mineral density in
mg/day vs. corticosteroid treatment without vitamin D-decient patients; no effect on immune
supplementation vs. no corticosteroid markers or disease activity
treatment

1110 Clinical and Experimental Rheumatology 2024
SLE and environment / C. Cardelli et al.
dsDNA antibodies were induced in 20%
of iniximab, 15% of etanercept, 10-
12% of adalimumab and 4% of certoli-
zumab pegol patients. On the contrary,
in TNF-α antagonist-induced lupus-like
syndrome (TAILS), anti-histone an-
tibodies are less common (positive in
only 17–57% of patients). Moreover, in
a review of 72 patients with TAILS, the
presence of 12% anti-Ro/La, 10% anti-
Sm and 7% anti-RNP antibodies was
reported (119).
However, despite a quite high propor-
tion of patients developing autoanti-
bodies during anti-TNF treatment, the
development of a clinically relevant
lupus-like syndrome is much more in-
frequent and has been estimated to oc-
cur at a rate between 0.5 and 1%. Ac-
cording to a French study, iniximab
and adalimumab carry a higher risk of
TAILS than etanercept (120). From a
clinical point of view, TAILS, compared
to other DIL forms, is characterised by a
higher frequency of cutaneous manifes-
tations (up to 72% of patients).
Concurrent use of immunosuppres-
sants may reduce the risk of developing
autoantibodies and potentially TAILS.
Isolated induction of autoantibodies
is not an indication for discontinuing
therapy. Finally, a few studies investi-
gate if patients can switch to other anti-
TNF without recurrence of TAILS: 10
patients who tolerated long-term treat-
ment with similar-acting agents with-
out recurrence of TAILS have been
reported in the literature (121).
Anecdotal cases of DIL and ares of
preexisting SLE induced by chemo-
therapy (paclitaxel, capecitabine and
doxorubicin) have been described (122-
124).
A greater interest is currently being di-
rected towards immune checkpoint in-
hibitors (ICIs), known to be associated
with the risk of developing autoim-
mune rheumatic manifestations. How-
ever, DIL seems a rare event in patients
receiving ICIs. In the FDA Adverse
Event Reporting System, among 4870
rheumatic events reported with ICIs,
only 18 cases of SLE, 7 cases of CLE,
2 cases of lupus-like syndrome and 1
case each for lupus nephritis and cen-
tral nervous system lupus were identi-
ed (125). Only PD1/PDL1 were asso-
ciated with DIL (mainly nivolumab in
12 cases, followed by pembrolizumab
in 4 cases).
Such as idiopathic lupus, DIL can be
classied in systemic and cutaneous
DIL. Among skin-limited DIL, SCLE
has been mostly reported (126), while
discoid form of DIL seems to be very
rare (127).
In a population-based case-control study
of 234 SCLE incident cases in Sweden,
38% could be attributed to drug expo-
sure, with people <50 years at higher
risk compared to older ones (126). The
highest association was found for terbi-
nane, followed by anti-TNF. Among
anti-hypertensive drugs, ACE-inhibitors
resulted associated with SCLE. This
study also showed an association be-
tween proton pump inhibitors (PPIs)
exposure and SCLE, further conrmed
in a recent study on the French phar-
macovigilance database where, among
60 cases of DIL associated with PPIs,
79.6% were skin-limited (128).
The epidemiology and clinical spectrum
of DIL evolve with changes in the phar-
macopoeia. Rheumatologists should be
aware of this clinical entity, as prompt
discontinuation of the causative drug
can lead to rapid improvement of clini-
cal manifestations.
Conclusion
Although the exact patterns of SLE
onset and disease progression are not
fully understood, signicant progress
has been made over the years in under-
standing this complex disease. Besides
historically known environmental fac-
tors, recent advances have been made
in deciphering triggers and drivers that
contribute to the development of SLE.
In this review we summarised the most
recent literature investigating environ-
mental factors potentially involved in
the disease onset and clinical expres-
sion; despite the big amount of data
available, the causal relationship be-
tween certain exposures and the disease
onset or progression remains frequently
elusive and not fully demonstrated. In-
deed, epidemiological research on SLE
is difcult due to the low prevalence of
the disease, its scattered distribution,
and the inuence of several socio-eco-
nomic factors on disease expression and
evolution. For instance, environmental
studies may suffer from serious weak-
nesses, including the lack of adjustment
for individual confounding factors and
the inaccuracy in capturing the relevant
exposure at the time of disease induc-
tion. Thus, environmental-epidemiolo-
gy studies often lack sufcient power to
detect important effects.
Moreover, many environmental-epide-
miology studies are cross-sectional. In
such designs, the simultaneous assess-
ment of outcome and exposure can give
rise to difculties in determining the
temporal aspects of the causal associa-
tion between exposure and outcome.
Lastly, it is important to note that the
available studies refer to a wide range
of geographical locations and vary
widely in exposure collection methods
and SLE phenotypes.
In conclusion, high quality research
designs that could help identify the en-
vironmental components of the causal
pathways leading to SLE and its clinical
phenotype are still scarce and should be
strongly encouraged.
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