Lupus (2017) 0, 1–7

journals.sagepub.com/home/lup

UPDATE

Autoimmune/inflammatory syndrome induced by adjuvants

(Shoenfeld’s syndrome) – An update
A Watad1,2,3, M Quaresma3, S Brown2, JW Cohen Tervaert4, I Rodrı́guez-Pint5, R Cervera5, C Perricone6 and
Y Shoenfeld1,3,7
1
Department of Medicine B, Sheba Medical Center, Tel-Hashomer, Israel; 2Sackler Faculty of Medicine, Tel-Aviv University, Israel; 3Zabludowicz
Center for Autoimmune Diseases, Sheba Medical Center, Israel; 4Clinical and Experimental Immunology, Reinaert Clinic, The Netherlands;
5
Department of Autoimmune Diseases, Hospital Clinic, Spain; 6Reumatologia, Dipartimento di Medicina Interna e Specialita Mediche, Sapienza
Universita di Roma, Italy; and 7Incumbent of the Laura Schwarz-Kipp Chair for Research of Autoimmune Diseases, Tel-Aviv University, Israel

Autoimmune/inflammatory syndrome induced by adjuvants (ASIA) has been widely

described in many studies conducted thus far. The syndrome incorporates five immune-
mediated conditions, all associated with previous exposure to various agents such as vaccines,
silicone implants and several others. The emergence of ASIA syndrome is associated with
individual genetic predisposition, for instance those carrying HLA-DRB1*01 or HLA-DRB4
and results from exposure to external or endogenous factors triggering autoimmunity. Such
factors have been demonstrated as able to induce autoimmunity in both animal models and
humans via a variety of proposed mechanisms. In recent years, physicians have become more
aware of the existence of ASIA syndrome and the relationship between adjuvants exposure
and autoimmunity and more cases are being reported. Accordingly, we have created a registry
that includes at present more than 300 ASIA syndrome cases that have been reported by
different physicians worldwide, describing various autoimmune conditions induced by diverse
adjuvants.
In this review, we have summarized the updated literature on ASIA syndrome and the
knowledge accumulated since 2013 in order to elucidate the association between the exposure
to various adjuvant agents and its possible clinical manifestations. Furthermore, we especially
referred to the relationship between ASIA syndrome and systemic lupus erythematosus (SLE)
and antiphospholipid syndrome (APS). Lupus (2017) 0, 1–7.

Key words: Autoimmune/inflammatory syndrome induced by adjuvants/ASIA syndrome; sys-

temic lupus erythematosus/SLE; antiphospholipid syndrome/APS; adjuvants; vaccines;
human papilloma virus vaccine (HPVv); mineral oil; silicone

Introduction War syndrome (GWS) probably induced by squa-

lene, siliconosis and the sick building syndrome
Autoimmune/inflammatory syndrome induced by (SBS).2,3 All these conditions share similar clinical
adjuvants (ASIA) was first presented by Shoenfeld manifestations including myalgia, myositis, arthral-
et al. in 2011, suggesting major and minor criteria gia, neurological manifestations, dry mouth and
for diagnosis.1 Shoenfeld’s syndrome incorporates cognitive alterations, fever and chronic fatigue syn-
five immune-mediated conditions induced by the drome (CFS).4 Despite the fact that CFS can be
exposure to agents with adjuvant characteristics. induced by many and various agents surrogating
These conditions are as follows: the post- as adjuvants including infections, vaccines and
vaccination phenomena, the macrophagic myofas- others, it was found recently that the cellular metab-
ciitis syndrome (MMF), both most likely induced by olite response is homogenous.5
aluminum hydroxide acting as an adjuvant, the Gulf The emergence of these conditions results from a
complex interplay between genetic predisposition
and the exposure to environmental factors trigger-
Correspondence to: Y Shoenfeld, Zabludowicz Center for ing autoimmunity.6–8 These factors seem to be able
Autoimmune Diseases, Sheba Medical Center (affiliated to Tel-Aviv
University), Tel-Hashomer 5265601, Israel.
to induce autoimmunity both in animal models9
Email: shoenfel@post.tau.ac.il and in humans10 via a variety of proposed mechan-
Received 19 October 2016; accepted 5 December 2016 isms, including alteration of the host’s immune
! The Author(s), 2017. Reprints and permissions: http://www.sagepub.co.uk/journalsPermissions.nav 10.1177/0961203316686406
 Shoenfeld’s syndrome – An update
A Watad et al.
2
system, polyclonal activation of B cells, and effects
on cellular immunity.11
From its initial presentation in 2011 to 2016
more than 4000 ASIA syndrome cases have been
identified,2 varying from mild to severe clinical
manifestations, with the majority of severe cases
related to vaccines (especially against human pap-
illoma virus ‘‘HPV’’ and seasonal influenza), sili-
cone implants and mineral oil fillers.2 Moreover,
more than 300 ASIA cases have been documented
in the ASIA syndrome registry established and
managed by the Zabludowicz Center for
Autoimmune Diseases at the Chaim Sheba
Medical Center (in preparation).
In our review, we aimed to summarize the current
literature and knowledge about ASIA syndrome
collected since 2013 in order to elucidate the associ-
ation between the exposure to various adjuvant
agents and its possible clinical manifestations.
ASIA syndrome and silicone
Silicone implants have been used since the 60s in a
variety of medical devices such as intraocular
lenses, artificial heart valves, testicular prostheses,
joints and breast implants.12 Despite its proven
record of safety, a possible association between sili-
cone exposure and autoimmune diseases in genet-
ically prone individuals has been repeatedly
described in many studies.2,11,13,14 Autoimmune
diseases and phenomena in patients following sili-
cone implants have been proven in clinical reports
as well as in experimental animal models.15–17
Silicone can act as an immunologic adjuvant, to
enhance antigen-specific immune response and can
spread in lymph nodes, lung, liver and other tis-
sues.18,19 This leads to enhanced production and
activation of both B and T cells1,20 and to high
levels of IgG antibodies and Th1/Th17 cells in the
silicone capsule.21 Silicone may also induce an
immunogenic response via cross-reactions with glu-
cosaminoglycans, natural, and silicone-containing
molecules found in connective tissues.22
Silicone implantations have led to a significant
increase of heterogeneous symptoms such as body
aches, morning stiffness, abnormal fatigue,
impaired cognition, depression, headache, dry
eyes, dry mouth, skin abnormalities including hair
loss, paresthesia, swollen and tender axillary
glands, and unexplained fever, resembling fibro-
myalgia and chronic fatigue syndrome.18,21,23–27
Analysis of these sets of manifestations led to the
definition of ‘‘siliconosis’’.25 Silicone implant
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rupture, leakage through the shell ‘‘bleeding’’,
elastomer fragmentation, capsular fibrosis and cap-
sular contracture are well-studied local adverse
events following silicone implantation.23 Pain and
symptoms of chronic fatigue are more frequently
reported in patients with ruptured versus unrup-
tured implants.27 However, magnetic resonance
imaging-based studies of unselected women with
implants have observed relatively high numbers of
undiagnosed implant ruptures.28,29 Balk et al.30
have demonstrated the possible association
between silicone implants and a variety of connect-
ive tissue diseases (CTDs) such as dermatomyositis,
polymyositis, scleroderma, Raynaud’s phenomena
and several other CTDs.30
Maijers et al.31 have recently identified 52
women with silicone breast implants and unex-
plained systemic symptoms who reported fatigue,
arthralgia, myalgia, or morning stiffness after a
symptom-free period. Seventy-five percent of these
women reported pre-existent allergies. A significant
improvement of symptoms was reported in 36 of 52
women (69%) following silicone extraction.
Therefore, it seems that the link between silicone
and autoimmunity involves a broader spectrum of
autoimmune manifestations ‘‘formes frustes’’ rather
than well-defined autoimmune diseases.32
Eventually, these non-specific rheumatic clinical
manifestations evolve into a well-defined auto-
immune disease.33
In 2016 more than 200 cases of ASIA syndrome
were identified following exposure to silicone
implants.34 The authors showed that despite modi-
fications in the silicone implants’ components
during the past half century, silicone still produces
a chronic stimulus of the immune system yielding
similar clinical manifestations as observed in many
large cohorts of patients.14,34
The chronic stimulation induced by silicone is
linked with the higher risk for lymphoma.35
Indeed, chronic stimulation of B cells by the sili-
cone implants may lead to the formation of pseudo-
lymphoma which precede the development of the
well-defined non-Hodgkin lymphoma.36,37. Most of
the autoimmune diseases and especially noted in
Sjögren’s disease are associated with higher rates
of non-Hodgkin.38
Women with breast implants may also have a
small but increased risk of developing anaplastic
large cell lymphoma in the scar capsule adjacent
to the implant.36
Diverse categories of individuals were identified
to be more prone to have autoimmune diseases39
and therefore to have more risk for silicone-induced
ASIA syndrome.40 These include those with prior

documented autoimmune reaction to an adjuvant,
with established autoimmune conditions who are
prone to develop autoantibodies upon presentation
of exogenous adjuvants, with history of allergic
conditions or atopic disorders.40,41
Young et al.42 reported that silicone breast-
implanted women with autoimmune symptoms
were positive for HLA-DR5 and HLA-DQ2 when
compared to asymptomatic women with silicone
implants. This raises the possibility that HLA geno-
type might serve as a marker for women who are
predisposed to develop autoimmune symptoms fol-
lowing exposure to silicone gel breast implants.42
Therefore, physicians should be aware of the pos-
sible implications of silicone implantation in these
potentially predisposed individuals and even to
consider the extraction of the silicone implants in
those presenting rheumatic clinical manifestation.40
Recently, a statistically significant improvement
in somatic pain, vitality and mental health among
explanted patients suffering from autoimmune dis-
eases was reported.43 However, the extraction of
the silicone breast implants in patients who have
developed an autoimmune disease appears to be
successful when combined with immunosuppressive
therapy.43
ASIA syndrome and vaccines
Emerging evidence supports that vaccines are
rarely responsible for inducing specific6,44,45 and
non-specific10 auto-inflammatory manifestations,
particularly in genetically predisposed individ-
uals.46 Severe disease exacerbations of chronic
rheumatic diseases following immunization were
frequently reported in the literature.2,47,48
These post-vaccination phenomena are recog-
nized as being part of the ASIA syndrome,1 and
result from specific immunogenic properties of
adjuvants commonly used in vaccine formula-
tions.49,50 The main adjuvants involved are alumi-
num salts such as aluminum hydroxide.51 Other
vaccine components in some instances no longer
used, like thimerosal, an ethyl mercury preservative
used in multi-dose presentations of inactivated vac-
cines such as influenza, diphtheria-tetanus-pertussis
and hepatitis B vaccine (HVB-V), have also been
linked to autoimmunity.52
The vaccine adverse event reporting system
(VAERS), a national post-marketing surveillance
program developed in the United States, consists
of a database of patients’ and physicians’ spontan-
eous reports of adverse reactions associated with
Shoenfeld’s syndrome – An update
A Watad et al.
3
vaccines, and provides useful information on auto-
immune post-vaccination phenomena. Geier et al.45
have analyzed the VAERS for serious autoimmune
adverse events associated with the quadrivalent
HPV vaccine (HPV4-V) administered from 2006
to 2012 to subjects aged between 18 and 39 years
old. The authors observed that arthritis (OR ¼ 2.5),
vasculitis (OR ¼ 4), SLE (OR ¼ 5.3) and neuro-
logical conditions (OR ¼ 1.8), were significantly
more reported following the HPV4-V administra-
tion. The median onset of symptoms varied
between 6 and 55 days from the post-vaccination
period, which reinforces the existence of a time-
causal relationship. HPV4-V consists of purified
virus-like particles (VLPs) from HPV type 6, 11,
16 and 18 major capsid proteins, and is absorbed
on an aluminum-containing adjuvant. Most of the
autoimmune side effects related to this vaccine are
attributed to its adjuvant and were reproduced in
animal models.53,54
In 2014 McGarvey et al.55 analyzed the relation-
ship between the most frequent autoimmune dis-
eases reported in the VAERS in the last 20 years,
and the common genetic signaling pathways acti-
vated by specific vaccines. Guillain-Barré syndrome
(GBS) was the most common condition since more
than 1990 cases were identified mainly following
the administration of H1N1 and HBV vaccine.
Rheumatoid arthritis (RA) was also commonly
reported and associated especially with Lyme and
seasonal influenza vaccines. While in the VAERS,
SLE was correlated with HPV, seasonal influenza
and HBV vaccine, idiopathic thrombocytopenic
purpura (ITP) was found more frequently reported
following MMR and varicella zoster vaccines
exposure. Vaccine ingredients such as neomycin,
polymyxin B and deoxycolic acid, may also play a
pathogenic role in autoimmunity by the interaction
with dendritic cells through MAPK1 pathways.56
Autoimmune phenomena such as arthralgia,
myalgia, myocarditis, pericarditis, as well as dis-
eases of unclear etiology such as fibromyalgia and
chronic fatigue syndrome, occur in higher frequen-
cies after vaccine administration.10,57,58
Additionally, well-defined autoimmune diseases,
for instance immune-mediated myopathies,59,60
SLE,60,61 RA,62,63 Sjögren’s syndrome,4 multiple
sclerosis,64,65 acute disseminated encephalomyeli-
tis,66,67 transverse myelitis,68 inflammatory bowel
diseases,69 have all been linked to various vaccines
exposure. The most common vaccines to be related
to ASIA syndrome are those directed to influenza
virus,70 HPV,71 HBV,63 diphtheria-tetanus-
pertussisDTP,72 MMR73 and Bacillus Calmette-
Guerin (BCG).74 Murine models study, recently
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 Shoenfeld’s syndrome – An update
A Watad et al.
4
reviewed by Ruiz et al.,53 support the existence of
adjuvant-induced autoimmune diseases and give a
clue regarding the most plausible biological mech-
anisms involved in the ASIA syndrome.
Several types of vasculitis have been associated
with various vaccinations. Soriano et al.75 have
detailed 10 cases of giant cell arthritis associated
with polymyalgia rheumatica in previously healthy
individuals within three months of influenza vac-
cine. In all the cases, the patients were healthy
and had unremarkable family history for auto-
immunity before the immunization.
Although most epidemiological studies conclude
that there are no evident safety concerns related to
vaccines, there are reports showing a different scen-
ario. Research in the field of vaccinomics as well as
intense pharmacovigilance and the development of
new methodological strategies of immunization are
mandatory. The awareness of ASIA syndrome as a
consequence of vaccines exposure as well as the
identification of individuals at high risk of develop-
ing an autoimmune disease and therefore more
prone to have ASIA is considerable in order to pre-
vent non-essential vaccinations.41
ASIA syndrome and SLE
The development of SLE disease following expos-
ure to diverse adjuvants such as HBV and strepto-
coccal vaccines has been described in many case
reports and series as well as in animal
models.53,76,77 Soldevilla et al. described a case of
a 58-year-old female with SLE in prolonged clinical
remission who was admitted to the hospital due to
a severe flare of her disease with SLEDAI score of
15, three months following two doses of HPV vac-
cine.78 Another similar case of a flare of SLE in a
17-year-old female who completed two doses of
HPV vaccine was reported.78 Two months follow-
ing vaccination, the patient developed arthralgia,
pruritic rashes, proteinuria, elevated erythrocyte
sedimentation rate (ESR) and C-reactive protein
(CRP), low levels of serum complement C3 and
C4, and high titers of ANA and anti-dsDNA.
Kidney biopsy showed Class III lupus nephritis.
Hess et al. also reported a flare in two out of 109
SLE patients immunized with influenza A/New
Jersey/76 virus vaccine.79
Anti-dsDNA antibodies were significantly
increased in MRL mice after implantation of sili-
cone gel compared to the control animals, and
rheumatoid factor titers were modestly increased
in implanted lupus prone mice model (MRL-lpr/
Lupus
lpr mice).15 We have found that immunization of
mice model of lupus (NZB/WF1) mice with HBV
vaccine induced an acceleration of the kidney dis-
ease manifested by high anti-dsDNA antibody
levels (p < 0.01), early onset of proteinuria
(p < 0.05), histological damage and deposition of
HBs antigen in the kidney.80 The immunization
with HBV vaccine and/or aluminum had decreased
cell counts mainly of the red cell lineage (p < 0.001),
memory deficits (p < 0.01), and increased activated
microglia in various brain areas compared to mice
immunized with Phosphate-buffered saline (PBS).
Satoh et al.81 described the induction of lupus auto-
antibodies in pristane-treated mice (anti-RNP/Sm,
anti-Su, and anti-ribosomal P) in different genetic
background mouse species. Furthermore, a similar
spectrum of autoantibodies has been reported fol-
lowing exposure to squalene, however less effi-
ciently than with pristane.82,83 Finally, SLE can
be induced by diverse adjuvants including various
vaccines as well as silicone implantation. Therefore,
there is a need to be mindful of such associations in
order to recognize those individuals at high risk
who might undergo preventive measures.
ASIA syndrome and APS
Interestingly, vaccines such as tetanus toxoid and
seasonal influenza, were found to be associated
with the production of antiphospholipid antibodies
in both human and animal models.84,85 Induction
of APS was possible in two non-prone mouse strain
(BALBc and C57BL/6) mice that were hyper-
immunized with tetanus toxoid boosted with alumi-
num hydroxide and complete Freud’s adjuvants
(CFA) that are commonly used in other vac-
cines.84,85 In these animal models, APS was asso-
ciated with the development of prolonged
coagulation time, thrombocytopenia and fetal
loss. These findings suggest that APS may be
induced by adjuvants and is associated with ASIA
syndrome.86 Therefore, likewise SLE, also APS can
be induced after the exposure to vaccines and there
may be a need to detect anti-phospholipid antibo-
dies as a screening for APS before vaccination in
individuals with high risk for autoimmunity.
Conclusions
Shoenfeld’s syndrome seems to have a relatively high
frequency and a causal relationship between adju-
vant materials. The development of ASIA syndrome

and its clinical manifestations has been suggested by
the case reports, case series, epidemiological studies
and animal models conducted thus far. The ASIA
syndrome registry currently contains more than 300
cases of diverse autoimmune conditions induced by
various adjuvants, and this number is rising steadily
due to the high awareness among physicians world-
wide of the existence of this syndrome that has
increased significantly in recent years.
Therefore, being mindful of such correlation is
very important for a better diagnosis, prevention
and treatment of ASIA syndrome following expos-
ure to adjuvants. It is important to perform a risk
stratification of individuals by identification of
those with genetic predisposition through the detec-
tion of specific alleles of Human Leukocyte Antigen
(HLA) in order to prevent essential vaccination,
silicone implantation or other adjuvant exposure.
Declaration of Conflicting Interests
The authors declared the following potential con-
flicts of interest with respect to the research, author-
ship, and/or publication of this article: Professor
Shoenfeld has acted as an expert witness in
medico-legal cases.
Funding
The authors received no financial support for the
research, authorship, and/or publication of this
article.
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