Laura said:
Psyche, one of the papers I read - of the bunch I've been uploading to my brain - mentioned something about Raynaud's syndrome being related. Can you find anything on that for Lisa Guliani.
I received this paper and it made me think of Lisa. There is lupus in her family so she could have a spectrum of lupus. The infection part got my attention too. Other than the viral part, it talks about toxoplasmosis. There is also some correlation with solvents (paint stuff, etc), estrogen mimicking chemicals (pesticides, etc). The smoking part is total nonsense, it is amazing they didn't thought of self-medication. Anyhow, here it is FWIW:
Lupus (2012) 21, 241–250.
Environment and lupus-related diseases
Clinical manifestations of lupus are encountered in a variety of disease entities, including
isolated cutaneous lupus,
undifferentiated connective tissue disease, mixed connective tissue
disease, drug-induced lupus,
overlap syndrome, and systemic lupus erythematosus (SLE).
While each entity has been recognized as a specific disease with its own diverse clinical and
serological pattern, one could argue that many findings are common. Could it be that all of
these entities actually represent a spectrum of one disease? Could it be that rather than the
genetic predisposition and hence controlled factors that govern this spectrum of diseases, that
environmental factors associated with SLE could also play a role in the different entities of this
spectrum? The traditional environmental triggers in SLE include sunlight and ultraviolet (UV)
light, infections, smoking, and medications including biologics such as tumor necrosis factor
alpha (TNF-a) blockers. In this review, we update and further substantiate these traditional
factors in the various lupus-related syndromes. We will also discuss the association with vaccine
exposure, industrial estrogens, and other factors. Lupus (2012) 21, 241–250.
Introduction
Lupus erythematosus is a spectrum of diseases
characterized by diverse clinical and serological
manifestations. Multi-faceted triggers may play a
role.
The genetic pattern is complex and not yet
entirely deciphered, and it is probable that exposure
to various environmental agents can determine
which lupus syndrome in the spectrum will develop.
Furthermore, among patients with systemic lupus
erythematosus (SLE), the clinical subset, disease
activity and severity may be governed by genetics
and environmental load. The traditional environmental
factors known to influence the development
of lupus in the genetically prone individual are
exposure to sunlight and ultraviolet (UV) light,
infections, and medications including biologics
such as tumor necrosis factor alpha (TNF-a)
blockers.1,2 [...]
The spectrum of lupus
The lupus-related disease spectrum includes organ specific
disease, i.e. cutaneous lupus, undifferentiated
connective tissue disease (UCTD), mixed
connective tissue disease (MCTD) with specific
manifestations of lupus but of other autoimmune
diseases as well, drug-induced lupus, overlap
syndrome – for example SLE and antiphospholipid
syndrome (APS) – and SLE, the classic multisystemic
disease.
[skipped cutaneous and drug induced lupus, read it in the attached document]
Mixed connective tissue disease
MCTD, a discrete entity, is usually a benign syndrome
characterized by specific features of autoimmune
diseases: SLE, systemic sclerosis (SyS), RA [Rheumatoid Arthritis],
and myositis, in the restricted presence of elevated
titers of antibodies to RNP. This is an example
where only one antibody is exclusively required
for the basis of diagnosis. Features reported to be
characteristic of MCTD, occurring more commonly
than, for example, in typical SLE, include
severe
Raynaud’s phenomenon, an erosive arthritis,
multiple subcutaneous nodules in the peri-tendinous
regions of the forearms and hands, juxta-articular
calcinosis and pulmonary hypertension.25
A prominent histopathologic feature of MCTD
is a
widespread proliferative vasculopathy characterized
by intimal and medial proliferation which
results in narrowing of the lumen of small arteries
and larger vessels such as the aorta, coronary, pulmonary
and renal arteries. In addition, the titers of
antibodies to U1RNP are generally very high, usually
much higher than in SLE sera. It is reported
that MCTD is most closely correlated with the
presence of IgG antibodies to the 70 kDa and A
proteins and predominantly IgM antibodies to
the B’B peptides of the Sm system.25 There is
some serological evidence that the autoimmune
response to MCTD is distinctive from that in
SLE and other systemic rheumatic diseases. For
example, epitope mapping studies to determine
the fine specificity of antibodies to U1RNP have
shown differences between MCTD and lupus. An
important observation was that antibody reactivity
to a particular peptide on the A protein was found
in 94% of MCTD patients compared with 19% of
patients with SLE. Similarly, the specific epitope
recognition of a different autoantigen, hnRNP-A2
(or RA33) was also distinctive in MCTD. Amongst
207 patients fulfilling the American College of
Rheumatology (ACR) criteria for SLE followed
prospectively,
Raynaud’s phenomenon and myositis
were found to be prominent features in
anti-U1RNP-positive patients, with 55% of this
serological group fulfilling the clinical components
of MCTD criteria compared with only 3% of the
152 lupus patients without these antibodies.25,26
Reports describe MCTD patients with higher circulating
TNF-a levels than in patients with SLE. The
development of additional SLE- or SyS-associated
autoantibodies during the course of MCTD is very
unusual.26
In a retrospective observation over 8 years, some
MCTD patients went on to develop SLE or SyS. In
this report it was unclear if these patients really had
MCTD or evolving lupus with high titers of antibodies
to RNP.27
Although not pathognomonic for any of the diseases,
the antibody response against hnRNP-A2
(RA33) distinguishes MCTD patients from SLE
and RA patients by virtue of the difference in epitope
recognition.22
MCTD has a distinct genetic profile associated
with the HLA-DR4, -DR1, and (less prominently) -
DR2 molecules which is not identical to those
that are found most commonly in SLE, SyS, or
polymyositis/dermatomyositis – the three MCTDrelevant
diseases. Hence, it is reasonable to postulate
that
MCTD falls within the spectrum of
lupus-related diseases.26
In a literature search for environmental factors
associated with MCTD, surprisingly, no relevant
articles were found. Further investigation into
potential environmental triggers including drugs,
sun exposure, occupational risks, or hormonal
exposure is warranted in these patients.
Undifferentiated connective tissue disease
UCTDs are defined by a limited set of clinical and
serologic features that do not meet all the criteria
for connective tissue diseases (CTDs) as opposed to
MCTD which has set clinical and serological characteristics
and fulfil respective diagnostic criteria.
Cumulative evidence suggests that
some of these
patients will remain in the UCTD subset while
others will develop well-defined autoimmune diseases
over time. A subset of patients with UCTD
have a mild type of lupus and develop
clinical
manifestations suggesting lupus, but do not upon
presentation, fulfil four of 11 ACR criteria for the
definite diagnosis of SLE. It is known that autoantibodies
circulate in the blood years before the
onset of clinical disease.28 Possibly, in some individuals,
the UCTD lupus subset represents the gradual
onset of disease instead of a full-blown pattern.
Some patients usually have elevated titers to antidsDNA
antibodies upon presentation, and some
rheumatologists even initiate therapy at this point.
The majority of patients with SLE will develop the
classical disease usually within 2 years.
Compared with SLE, evidence for environmental
triggers of UCTD are sparse. Plasma levels of
25(OH)D3 in 161 UCTD patients were significantly
lower compared with controls. The presence of
dermatological symptoms (photosensitivity, erythema,
and chronic discoid rash) and pleuritis was
associated with low levels of vitamin D. During the
average follow-up period of 2.3 years, 21.7% of
UCTD patients developed well-established CTD.
Patients who progressed into CTDs had lower
vitamin D levels than those who remained in the
UCTD stage. These results suggest that vitamin
D deficiency in patients with UCTD may play a
role in the subsequent progression into well-defined
CTDs.29
Sporadic reports suggest that solvents are associated
with UCTD among other autoimmune
diseases. Yet it is difficult to establish a true relevance
due to lack of replication, an inability to
specify which solvents convey risk, and an absence
of increasing risk with increasing exposure.30 For
example, in one study, detailed information on
solvent exposure was ascertained from 205 women
who had at least two autoimmune related symptoms
but did not fulfil ACR criteria for defined
disease and were diagnosed between 1980 and
1992, and compared with 2095 population-based
controls.
Among 16 self-reported occupational
activities with potential solvent exposure, furniture
refinishing, perfume, cosmetic, or drug manufacturing,
rubber product manufacturing, work in a
medical diagnostic or pathology laboratory, and
painting or paint manufacturing were significantly
associated with UCTD. After expert review of selfreported
exposure to 10 specific solvents, paint
thinners or removers and mineral spirits were associated
with UCTD.31
Overlap syndromes – SLE and APS
The most common overlap syndrome in lupus related
diseases is SLE–APS. Some 40% of SLE
patients develop secondary
APS with clinical
manifestations of recurrent venous and arterial
events and/or recurrent fetal loss in the setting of
autoantibodies to cardiolipin, beta-2-glycoprotein
I, or lupus anticoagulant. The presence of SLE–
APS overlap can skew clinical lupus manifestations
and be associated with focal CNS findings
including stroke and seizures or cardiac disease
(Libman–Sacks endocarditis). As in SLE, circulating
antibodies are encountered prior to clinical disease.
Distinct polymorphisms of common genetic
factors have been associated with SLE and primary
APS, supporting the notion that these entities are
indeed variants within a continuum of the same
disease.32 The support for the influence of infectious
triggers in APS is vast and beyond the scope
of this chapter (and is reviewed elsewhere).33,34
In a recent study,
98 patients with APS were
screened for antibodies directed to several infectious
agents. The main finding in this study was
the significantly higher prevalence of IgM antibodies
to toxoplasma and rubella. This novel finding
suggests that these infections might be associated
with APS.
A current infection with certain agents,
i.e. toxoplasma and rubella, might either be related
to the pathogenesis of APS or alternatively to its
manifestations.35 We found that rubella antibodies
may be associated with neuropsychiatric lupus while
Epstein-Barr virus (EBV) exposure does not correlate
with APS.36,37
Mounting evidence suggests that SLE and APS
are yet another face to the spectrum of lupusrelated
disorders.38–41 While some common environmental
triggers are associated with increased
thrombophilia (smoking, estrogens), other environmental
triggers such as hydrazines, solvents, and
pesticides were associated with an increase risk of
developing SLE. In the Women’s Health Initiative
Observational Study,
women who had exposure to
pesticides had a higher risk of developing SLE and
RA;42 however, this result was contradicted in
some studies regarding pesticides.38
Individuals
exposed to solvents (e.g. nail polish, metal cleaning
products) have a higher risk of developing SLE.43
Clinical diversity of SLE
SLE is a multi-systemic autoimmune disease with
diverse patterns of clinical and serological manifestations.
SLE is characterized by autoantibody production.
44 At least 20 different autoantibodies have been
reported with neuropsychiatric involvement that
target brain-specific antigens and systemic antigens.40
Are clinical subsets influenced by exposure to
various environmental factors? Can environmental
triggers further influence the spectrum or pattern of
disease? Can exposure to infections influence the
clinical pattern of lupus disease?
SLE and infections/vaccines as triggers of disease
We have investigated the association of viral infections
and SLE. In previous studies, we compared
the titers of antibodies to infectious agents with
lupus clinical manifestations. The sera of 260 individuals
(120 patients with SLE and 140 geographic
controls) were evaluated for the titers of EBV,
cytomegalovirus (CMV), toxoplasma, rubella and
syphilis antibodies. Correlation analysis indicated
that rubella IgM antibody titers were marginally
positively associated with neuropsychiatric lupus
(NPSLE) manifested as psychosis.36
Exposure to EBV infection predicted a disease
phenotype of mild SLE disease with cutaneous
and joint manifestations and elevated titers of
anti-Ro antibodies. No evidence of severe disease
demonstrated as renal or neuropsychiatric involvement
was associated with prior EBV exposure.
These studies suggest that
in the genetically prone
individual, particular infectious exposure may skew
the patient toward specific organ involvement, or
may affect disease severity.37
Furthermore,
exposure to certain vaccines may
elicit an autoimmune effect in genetically prone
individuals. For example,
SLE has been diagnosed
in patients following vaccination with hepatitis B
virus and influenza.45
Following tetanus toxoid,
influenza vaccines and polio vaccine there were
anecdotal reports of autoantibody production and
even RA.46 In a study of 173 patients with SLE,
cervical samples were collected demonstrating
threefold findings of HPV infection in these
patients. This was associated with the immunosuppressive
therapy given to the patients,47 suggesting
that SLE patients should be vaccinated against
HPV. It should be noted that in sporadic cases
SLE developed following the HPV vaccine.45
SLE and hormonal triggers
There is no doubt that estrogen plays a direct role
in the immune system, as demonstrated in numerous
experimental lupus models.
Environmental
sources of estrogen including oral contraceptives,
hormonal replacement therapy, preparation for
in-vitro fertilization, preparation for sex reassignment
surgery, estrogens found in plastic bottles,
pesticides, alternative medicine (phytogens) and
probably other sources, may play an added role
in the development or exacerbation of lupus.5,48
In addition, blockade of estrogen effects with selective
estrogen receptor modulators may have a beneficial
effect on disease activity in lupus-prone
mice.49
While it has been traditionally thought that
exogenous estrogens in the form of oral contraceptives
may play a role in the development of lupus,
recent studies have shown a less dramatic effect and
the evidence to date is mixed, mostly regarding
a higher risk of developing thrombosis in menopausal
patients with SLE who are treated with
hormonal replacement.50 Global disease activity,
maximum SLEDAI score, incidence of flares, time
to first flare, and incidence of adverse events were
similar among women with SLE, irrespective of
the type of contraceptive utilized. Therapy with
estrogen as hormone replacement therapy for
post-menopausal women is predominantly related
to mild lupus flares.51
Recently, there has been much controversy
about the presence of estrogens in industry.
Phthalates, natural compounds found in mushrooms,
have an estrogenic effect.
Xenoestrogens, a
group of synthetic compounds that mimic estrogen,
could affect the endocrine system and stimulate the
immune system.5 In one study, SLE-prone mice
exposed chronically to xenoestrogens such as
DDT showed accelerated development of albuminuria.
49,52,53 More investigation is warranted on the
impact of these compounds on the immune system
and the development or even the exacerbation of
SLE. The effects of sex hormones are well established
in SLE, but have not been described in other
lupus-related syndromes. In anecdotal studies,
decreased androgen levels had an immunosuppressive
effect, causing dysregulation of the immune
system which in turn may lead to non-specific autoimmune
reactions.54
SLE and UV triggers
Photosensitivity is a known trigger for systemic
disease.
Recent evidence points to the possible
detrimental effect of exposure to artificial light.
UVA2 and UVB can exacerbate skin disease in
patients with lupus, while UVA1 may be protective.
Halogen lamps emit significant levels of UV radiation
and should be covered with glass prior to use.
Incandescent bulbs emit low-dose UV radiation.
Fluorescent bulbs emit varying levels of UV radiation,
and
patients should strive to use bulbs with
the lowest irradiance. UV exposure in doses similar
to those emitted from compact fluorescent light
bulbs induces DNA damage, tumor formation,
and erythema.55 In one study, patients with SLE
had an increased risk for blisters and/or rash after
2 h exposure to sunlight.43
Additional studies must be performed to determine
the lowest dose capable of causing damage in
photosensitive patients.55 The exacerbation of SLE
following exposure to cosmetic sun-tanning apparatus
has been reported.56 UVB not only induces
apoptosis, but also plays a role in the recruitment
and activation of opsonins including CRP and
MBL so as to facilitate the clearance of apoptotic
cells. The dose of UVB determines the rate of
apoptosis, the degree of autoantigen translocation
to the cell surface, and the level of cytokine
response.57
Paradoxically, the persistent abstention from sun
exposure in the general population has lead to
impaired immune system function related to vitamin
D deficiency.58 There is growing interest in this
topic, with many recent studies on the contribution
of vitamin D deficiency in SLE.59–63 Vitamin D
deficiency skews the immunologic response towards
loss of tolerance which is reversible. Most crosssectional
studies show an inverse relationship
between levels of vitamin D and disease activity.59
Data from a population-based cohort study of 123
recently diagnosed SLE patients found a trend
toward lower 25(OH)-D levels in cases compared
with controls, which was statistically significant in
Caucasians. Overall, 67% of the subjects were vitamin
D deficient, with mean levels significantly
lower among African Americans compared with
Caucasians. Critically low vitamin D levels (<
10 ng/ml) were found in 22 of the patients with
SLE, with the presence of renal disease being the
strongest predictor followed by photosensitivity.59
In a recent study of 378 patients with SLE an
inverse correlation was demonstrated between vitamin
D levels and disease activity.63 Vitamin D is
implicated in many biologic mechanisms unrelated
to calcium homeostasis. Of interest are the downregulating
mechanisms of interaction with the
adaptive and innate immunity through the regulation
of B cells, T cells, dendritic cells, and toll-like
receptors.60
SLE and occupational environmental triggers
Other potentially hazardous environmental agents
that may play a role in the development of lupus
include xenobiotic organic and inorganic compounds,
silica dust, silicone implants, organic
solvents, petroleum, and related by-products.
An example is hydrazine, a compound used in
agricultures and industry, synthesis of plastics,
anti-corrosives, rubber products, herbicides, photographic
supplies, preservatives, textiles, dyes, pharmaceuticals,
and in tobacco.5,64,65
Although silicone implants for augmentation
mammoplasty were reported in some lupus-related
cases, no causative effect was determined.66,67
[...]
In conclusion, exposure to various environmental
agents may determine which lupus-related
syndrome (cutaneous lupus, drug-induced lupus,
MCTD, UCTD, overlap syndrome, or SLE) will
develop. Cutaneous lupus is elicited by exposure
to UV light, drugs, exogenous estrogens, and smoking.
Over 80 drugs are implicated in drug-induced
lupus manifested by mild disease with elevated
titers of anti-histone antibodies. Exposure to biologics,
such as TNF-a blockers, leads to the development
of systemic severe disease with expected
elevated titers of anti-dsDNA antibodies. MCTD
is a distinct entity with features of lupus, and environmental
causes have not been reported. UCTD
may originate with initial findings of lupus and
hence may be influenced by environmental exposure,
as in the case of vitamin D deficiency and
possible occupational related agents. Infectious
agents will influence the clinical manifestations of
SLE. For example, exposure to rubella may be
involved in the development of neuropsychiatric
lupus, where exposure to EBV may be associated
with skin and joint involvement. Other recently
investigated triggers include exogenous estrogens,
as found in oral contraceptives, hormone replacement
therapy, sex reassignment surgery, phthalates
(plastics), and others. Deficient levels of vitamin D
and smoking have been linked to the development
of lupus. Environmental triggering factors of the
lupus spectrum are summarized in Table 1.
The extent of environmental factors on the
development of other lupus-related diseases is yet
to be discovered. Could it be that an environmental
load is responsible for systemic disease? While environmental
factors have been well-defined in cutaneous
lupus and SLE, information is lacking
regarding MCTD and overlap syndromes.
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