Autoimmunity Reviews 22 (2023) 103287

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Autoimmunity Reviews
journal homepage: www.elsevier.com/locate/autrev

Autoimmune/inflammatory syndrome induced by adjuvants (ASIA)

in 2023☆
Jan Willem Cohen Tervaert a, b, *, Manuel Martinez-Lavin c, Luis J. Jara d, e, Gilad Halpert f, g,
Abdulla Watad h, Howard Amital h, Yehuda Shoenfeld g
a
Division of Rheumatology, Department of Medicine, Faculty of Medicine and Dentistry, University of Alberta, Edmonton, Alberta, Canada
b
School for Mental Health and Neurosciences (MHeNs), Maastricht University, Maastricht, the Netherlands
c
Chief Rheumatology Department, National Institute of Cardiology, Mexico City, Mexico
d
Rheumatology Division, National Institute of Rehabilitation Luis Guillermo Ibarra Ibarra, Mexico City, Mexico
e
Universidad Nacional Autónoma de Mexico, Mexico City, Mexico
f
Department of Molecular Biology, Ariel University, Ariel, Israel
g
Zabludowicz Center for Autoimmune Diseases, Sheba Medical Center, Tel-Hashomer, Ramat Gan 52621, Affiliated to Sackler Faculty of Medicine, Tel Aviv University,
Tel Aviv 69978, Israel
h
Department of Medicine ’B’ and Zabludowicz Center for Autoimmune Diseases, Sheba Medical Center, Tel-Hashomer, Ramat Gan 52621, Affiliated to Sackler Faculty
of Medicine, Tel Aviv University, Tel Aviv 69978, Israel

A R T I C L E I N F O A B S T R A C T

Keywords: In 2011, a syndrome entitled ASIA (Autoimmune/inflammatory Syndrome Induced by Adjuvants; Shoenfeld’s
Autoimmunity/autoinflammatory syndrome syndrome) was first described. ASIA aimed to organize under a single umbrella, the existing evidence regarding
induced by adjuvants certain environmental factors which possess immune stimulatory properties, in order to shed light on a common
ASIA
pathway of autoimmune pathogenesis. Such environmental immune stimulators, or adjuvants, include among
Silicone breast implants
others: aluminum salts as in vaccines, various medical implants, as well as various infectious agents. After the
Explantation
Fibromyalgia launch of the ASIA syndrome, the expansion and recognition of this syndrome by different researchers from
Chronic fatigue syndrome/myalgic different countries began. During the past decades, evidence had been accumulating that (auto)immune symp­
encephalomyelitis toms can be triggered by exposure to environmental immune stimulatory factors that act as an adjuvant in
COVID-19 vaccination genetically susceptible individuals. A panoply of unexplained subjective and autonomic-related symptoms has
Autoimmunity been reported in patients with ASIA syndrome. The current review summarizes and updates accumulated
Autonomic nervous system knowledge from the past decades, describing new adjuvants- (e.g. polypropylene meshes) and vaccine- (e.g. HPV
Small fiber neuropathy
and COVID vaccines) induced ASIA. Furthermore, a direct association between inflammatory/autoimmune
HPV vaccine
diseases with ASIA syndrome, will be discussed. Recent cases will strengthen some of the criteria depicted in
ASIA syndrome such as clear improvement of symptoms by the removal of adjuvants (e.g. silicone breast im­
plants) from the body of patients. Finally, we will introduce additional factors to be included in the criteria for
ASIA syndrome such as: (1) dysregulated non-classical autoantibodies directed against G-protein coupled re­
ceptors (GPCRs) of the autonomic nervous system and (2)) small fiber neuropathy (SFN), both of which might
explain, at least in part, the development of ‘dysautonomia’ reported in many ASIA patients.

1. ASIA syndrome characteristics described [1], but the idea of such an immune-mediated disease was not
a new one. During the past decades, evidence had been accumulating
In 2011, a syndrome entitled ASIA (Autoimmune/inflammatory that (auto)immune symptoms can be triggered by exposure to envi­
Syndrome Induced by Adjuvants; Shoenfeld’s syndrome) was first ronmental immune stimulatory factors that act as an adjuvant in

☆
A report from the 13th International Congress on Autoimmunity. From 10 to 13 June 2022 this congress was held in Athens, Greece. The conference was attended
by more than 1000 delegates from more than 60 different countries.
* Corresponding author at: Division of Rheumatology, Department of Medicine, Faculty of Medicine and Dentistry, University of Alberta, Edmonton, Alberta,
Canada.
E-mail address: cohenter@ualberta.ca (J.W. Cohen Tervaert).

https://doi.org/10.1016/j.autrev.2023.103287
Received 10 January 2023; Accepted 30 January 2023
Available online 3 February 2023
1568-9972/© 2023 The Authors. Published by Elsevier B.V. This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/).
J.W. Cohen Tervaert et al.
susceptible individuals [2,3]. Adjuvants are compounds that, when
introduced into the body, enhance a specific immune reaction resulting
in higher titters of antibodies, for instance against specific pathogens
[4]. Well-known examples of adjuvants are aluminum hydroxide,
squalene, and silica as well as various infectious agents [5]. During the
last decade, it became clear that human medical implants, including
injectables such as silicones and polypropylene meshes may act as ad­
juvants as well [2,6–8].
Typical clinical symptoms of ASIA are: chronic fatigue, arthralgias,
myalgias, pyrexia, sicca symptoms, cognitive impairment, and or
(atypical) neurological symptoms (Table 1; Fig. 1). Typically, patients
present with severe fatigue, nonrestorative sleep, and a majority
reporting post-exertional malaise as is observed in ME/CFS [9,10]. Sleep
disturbances such as problems falling asleep and/or staying asleep are
common with poor sleep quality being linked to greater fatigue. Another
early symptom is the occurrence of arthralgias and most patients fulfill
the 2016 criteria for fibromyalgia [11]. Patients often suffer from severe
morning stiffness, myalgias and/or muscle weakness. Weakness can be
severe and may render the patient bedridden. Furthermore, most pa­
tients report pyrexia and night sweats, while others report dry eyes and/
or a dry mouth. Dry eyes are often severe and may result in blurred
vision and/or a keratitis sicca if left untreated. Symptoms of cognitive
impairment are not infrequent [12] manifesting as mental fogginess,
memory deficits, absent-mindedness, anomic dysphasia, and inatten­
tion. In some patients, the neurological manifestations are very dis­
turbing and patients may present with a stroke or multiple sclerosis-like
attacks. Patients may suffer from allergies and gastrointestinal symp­
toms such as abdominal pain with changes in bowel movement patterns
typical of irritable bowel syndrome. New-onset Raynaud’s phenomenon
can be present as well, while in other instances pain and burning sen­
sations (“pins and needles”) of the skin points towards a diagnosis of
small fiber neuropathy. Patients may have recurrent hives or ill-defined
skin rashes, unexplained (sometimes severe) pruritus and/or alopecia.
Cardiovascular complaints include signs of orthostatic intolerance such
as dizziness, and disturbed balance as observed in postural tachycardia
syndrome (POTS). Finally, a substantial number of patients have inter­
stitial cystitis.
After the launch of the ASIA Syndrome in 2011 [1], the expansion
and recognition of this syndrome by different researchers from different
countries began. In 2012, a special issue of the LUPUS journal was
Table 1
Criteria for the diagnosis of autoimmune/inflammatory syndrome induced by
adjuvants (ASIA).
Major criteria
• Exposure to an external stimulus (implants such as silicone and mesh are classic
adjuvants) prior to clinical manifestations
• The appearance of ‘typical’ clinical manifestations such as:
• Chronic fatigue, unrefreshing sleep or sleep disturbances
• Myalgia, Myositis or muscle weakness
• Arthralgia and/or arthritis
• Cognitive impairment, memory loss
• Pyrexia
• Sicca (dry mouth, dry eyes)
• Neurological manifestations (especially associated with demyelination)
• Removal of inciting agent induces improvement
• Typical biopsy of involved organs
Minor criteria
• The appearance of autoantibodies or antibodies directed at the suspected adjuvant.
• Other clinical manifestations (i.e., irritable bowel syndrome, Raynaud’s
phenomenon)
• Specific HLA associations (i.e. HLA DRB1, HLA DQB1)
• Evolvement of an autoimmune disease (i.e. multiple sclerosis, rheumatoid arthritis,
Sjogren syndrome, systemic sclerosis)
Criteria for the diagnosis of autoimmune/inflammatory syndrome induced by
adjuvants (ASIA) [1,2]. Patients are considered to have ASIA when either two
major or one major and two minor criteria are present.
2
Autoimmunity Reviews 22 (2023) 103287
dedicated to ASIA. In this special issue, a series of articles from different
countries were published and provide the clinical and experimental
bases for support the existence of ASIA [13]. More than a decade has
passed since the initial description of the ASIA syndrome. New cases
from ASIA have been described and new adjuvants have been added.
Substances other than silicone and mineral oil, previously described
[13], may be associated with the development of ASIA syndrome after
injection of bioimplants for aesthetic purposes, such as, hyaluronic acid,
methacrylate, polyacrylamide, polyalkylimide, and metals in implants
as used in orthopedic surgery and/or in birth control devices [14–17].
2. Metals-induced ASIA syndrome
Mercury has been associated with autoantibody production and
immune tissue mediated-complex injury. A case of ASIA syndrome
associated to liquid metal mercury injected subcutaneously was
described [18]. In 2019, a new case of ASIA syndrome associated with
metallosis [16] was reported. The authors presented the case of a 51-
year-old woman with a 6-month history of asthenia, anorexia, weight
loss, headaches, nausea, vomiting, hand and foot paresthesia, instability
and pain in her hip. She referred impaired memory, fatigue, difficulty
concentrating and apathy due to intoxication with metal ions from hip
metallosis. Blood tests showed high levels of chromium (7.6 μg/l) and
cobalt (1.5 μg/l), confirming the diagnosis of metallosis with systemic
manifestations. Surgical debridement was performed and the hip pros­
thesis was replaced with a new one. Histology of the bursae was
compatible with the xanthogranulomatous inflammatory process with
histiocytic granulomas. After 6 months of follow-up, most clinical
manifestations disappeared. This case highlights the importance of
follow-up and continuous monitoring of patients with a hip prosthesis
[16,19].
In 2021, it was reported that ASIA could also be induced by Essure
sterilization [17]. The essure device is a small, flexible insert with an
inner stainless-steel coil wrapped in polyethylene terephthalate (PET)
fibers and an outer coil of Nickel-Titanium alloy to anchor the device. All
material components of Essure have been demonstrated to have adju­
vant activity. Indeed, surgical removal of the device results in marked
improvement of ASIA symptoms [17].
An interesting review about aluminum, an adjuvant used in multiple
vaccines, and its possible relationship with Myalgic Encephalomyelitis/
Chronic Fatigue Syndrome (ME/CFS) has been published in 2019 [20].
The authors present epidemiological, clinical and experimental evidence
that ME/CFS constitutes a major type of adverse effect of vaccines,
especially those containing poorly degradable particulate aluminum
adjuvants. Once the aluminum-containing vaccine is injected, instead of
rapidly solubilizing in the extracellular space, it accumulates at the in­
jection site, forming aluminum conglomerates. This delay in solubili­
zation allows the injected aluminum particles to be quickly captured by
cells of the immune system and transported to different organs,
including the brain, where aluminum stimulates the inflammatory
response and causes chronic neurotoxicity. Something similar happens
in the syndrome of macrophagic myofasciitis (MMF) [20]. Therefore,
post-immunization ME/CFS represents one of the main manifestations of
ASIA syndrome [20].
In 2020, another case of ASIA syndrome was published [21]. A 38-
year-old woman with no health problems, underwent a dental proced­
ure and received a porcelain-fused-to-metal (PFM) crown. The metal
component of the crown was a chrome and cobalt alloy (Cr-alloy). One
month later she developed profound fatigue, xerostomia, sleeping dis­
orders, depression, acne, hair loss, facial pain, headaches, tinnitus,
dizziness, heart palpitations, and cognitive impairment. She visited
various specialists, including oral and maxillofacial specialists, ear nose
and throat physicians, and neurologists, all of whom found nothing
abnormal. Blood analysis was within normal limits. Since the patient’s
symptoms began shortly after her procedure, the authors decided to
remove the PFM crown. Five months later the patient improved her
J.W. Cohen Tervaert et al.
clinical picture [21]. This case demonstrates that to determine the
diagnosis of ASIA it is necessary to consider not only the elements
implanted for aesthetic purposes, but also curative ones. If no other
cause is identified that explains the non-specific symptomatology, the
probable causal agent must be removed.
An experimental model of the ASIA syndrome has recently been
published. The aim of this study was to investigate cognitive and
behavioral changes in sheep subjected to repetitive inoculation with
products containing aluminum. Twenty-one lambs were assigned to
three groups: control, adjuvant only, and vaccine. Sixteen inoculations
were administered over a period of 349 days. Animals in the vaccine and
adjuvant-only groups exhibited individual and social behavioral
changes. Affiliative interactions were significantly reduced and aggres­
sive interactions and stereotypies were significantly increased. Some of
these alterations observed in this experimental model are similar to
those observed in the ASIA syndrome [22].
It is worth mentioning that aluminum salts and other metals are
known to be part of the components in tattoo ink – another adjuvant
found to be associated with ASIA syndrome [23].
3. Mineral oil-induced ASIA syndrome
The first case of methyl methacrylate injection in the buttocks for
cosmetic reasons resulting in ASIA complicated by seronegative anti­
phospholipid syndrome and lymphoma has recently been described
[24]. ASIA syndrome associated to mineral oil (ASIA-MO), and other
substances are the result of the interplay of genetic and environmental
factors. ASIA-MO has been reported in many countries, especially on the
Latin American continent, and are used illegally and surreptitiously.
This practice constitutes a real health problem and endangers the health
and life of patients [25]. The clinical spectrum of ASIA-MO is very
heterogeneous and varies between mild and severe clinical manifesta­
tions. The clinical manifestations can be nonspecific, such as fatigue,
fever, polyarthralgia, myalgia, depression, sleep disorders, and chronic
pain, leading to poor quality of life. These manifestations have been
observed in approximately 60% of ASIA-MO patients. 40% of patients
have systemic manifestations that met criteria for different autoimmune
diseases, such as SLE, systemic sclerosis (SSc), rheumatoid arthritis (RA),
dermatomyositis (DM), and overlap syndrome. These clinical manifes­
tations are similar to those observed in other cases of ASIA syndrome.
3
Autoimmunity Reviews 22 (2023) 103287
Fig. 1. Clinical features of the autoimmune/inflam­
matory syndrome induced by adjuvants (ASIA).
Mesh-induces ASIA (Autoinflammatory/autoimmu­
nity Syndrome induced by Adjuvants) presents with
neurological/musculoskeletal, immunological, and/
or vascular manifestations.
ANA = antinuclear antibodies; ANCA = anti-neutro­
phil cytoplasmic antibodies (from Ref [119]: Cohen
Tervaert JW, Osman M. Autoimmune/inflammatory
syndrome induced by adjuvants (ASIA or Shoenfeld’s
syndrome) due to polypropylene mesh implants. In:
Watad A, Bragazzi NL, Shoenfeld Y (Eds): The auto­
immune/inflammatory syndrome induced by adju­
vants (ASIA). 2023: in press).
4. ASIA registries: associations between ASIA, autoimmune/
auto-inflammatory diseases and lymphomas
Through the ASIA syndrome International Registry (established in
2011) up to December 2016, 300 patients were identified [26]. The
mean age at disease onset was 37 years, and the mean duration between
adjuvant stimuli and the development of autoimmune conditions was
16.8 months (a range of: 3 days to 5 years). Arthralgia, myalgia, chronic
fatigue, sleep disturbances, weakness, sicca symptoms, fever. Arthritis
and neurological manifestations were the most frequently reported
symptoms. Clinically well-defined diseases were observed in 89% of
patients. Undifferentiated connective tissue disease (UCTD) was the
most frequent disease, followed by fibromyalgia and/or chronic fatigue
syndrome. Other autoimmune diseases that were observed included:
SLE, vasculitis, mainly giant cell arteritis (GCA), ANCA-associated
vasculitis, Behçet’s disease, Henoch-Schoenlein purpura, polyarteritis
nodosa, and cutaneous sarcoidosis. Cases of type 1 diabetes mellitus
(DM1) were related to exposure to the HBV and HPV vaccines, whereas
autoimmune liver diseases were associated with HBV vaccination. In the
HBV group, the most frequent diagnosis was UCTD; in HPV, fibromy­
algia; and in influenza, UCTD or GCA. The materials identified as ad­
juvants were: cosmetic fillers of mineral oil, hyaluronic acid,
polyalkylimide (PAL), polyacrylamide gel (PAC) and collagen. Metallic
implants and silicone breast implants were also found. Vaccines iden­
tified as adjuvants were hepatitis B virus (HBV) vaccine, human papil­
lomavirus (HPV) vaccine, influenza vaccine, and other vaccines
(hepatitis A virus; diphtheria, tetanus, pertussis, measles, mumps, and
rubella [27].
Between 2011 and 2016, 4479 ASIA cases have been identified [28].
Severe cases of ASIA were mostly associated with HPV vaccine, influ­
enza vaccine, silicone, and mineral oil injections [28].
Another study investigated the different subtypes of autoimmune
diseases (autoimmune vs auto-inflammatory or intermediate states) in
500 patients accumulated from 2016 to 2019 in the ASIA Syndrome
International Registry [29]. The mean age of the patients was 43 ± 17
years, and the majority (89%) were women. 69% of patients had well-
defined autoimmune diseases. Polygenic autoimmune diseases were
significantly higher than autoinflammatory disorders (92.7% vs. 5.8%,).
Polygenic autoimmune diseases were found to be significantly related to
HBV vaccine exposure, whereas polygenic autoinflammatory diseases
J.W. Cohen Tervaert et al.
were significantly associated with exposure to influenza vaccination.
Polygenic autoimmune diseases included: vasculitides such as ANCA-
associated vasculitis, rheumatoid arthritis, SLE, UCTD, Sjogren’s syn­
drome, systemic sclerosis/morphea, dermatomyositis, antiphospholipid
syndrome, recurrent polychondritis, MCTD, multiple sclerosis/optic
neuritis/ neuromyelitis optica, diabetes mellitus type 1, Guillain-Barré
syndrome, dysautonomic neuropathy, postural orthostatic tachycardia
syndrome (POTS), autoimmune liver diseases, transverse myelitis,
autoimmune encephalitis, hemolytic anemia, autoimmune thyroiditis,
adrenal insufficiency, inflammatory polyradiculopathy, primary biliary
cholangitis, chronic inflammatory demyelinating polyneuropathy, ce­
liac disease fibromyalgia, ME/CFS, sarcoidosis, panniculitis, alopecia,
macrophagic myofasciitis, inflammatory polyarthritis, autoimmune
recurrent abortions, and/or juvenile idiopathic arthritis. Polygenic
autoinflammatory diseases include: giant cells arteritis/polymyalgia
rheumatica (GCA/PMR), Adult Still’s disease, and inflammatory bowel
disease (IBD). Mixed pattern diseases include: ankylosing spondylitis,
psoriasis, Behçet’s disease, psoriatic arthritis, undifferentiated-
spondylarthritis. In relation to the treatments used, the majority of
ASIA syndrome patients were treated with oral or parenteral steroids
and with hydroxychloroquine. Other patients were treated with disease-
modifying antirheumatic drugs (DMARDs) and <10% were treated with
biologicals [29].
Recently, a 70-year old patient was reported who developed a severe
relapse of PMR after a trivalent influenza vaccine [30]. Furthermore, the
association between ASIA syndrome and the development of PMR/GPA
was reported in 12 patients older than 50 years, vaccinated against
Influenza (Influenza vaccine [I.V.]) [31]. Of 358 GCA/PMR patients
recruited since 2002, 10 (2.8%) patients had GCA/PMR after I.V. Two
patients developed PMR 10 days after vaccination. Patients with post-I.
V. GCA/PMR had the DRB1*13:01 haplotype more frequently than those
with familial GCA/PMR or with GCA/PMR without a known trigger. It is
of interest that the post-I.V. GCA/PMR generally appeared to be self-
limited. This study confirms that post-I.V. GCA/PMR may be part of
the ASIA syndrome spectrum [32]. Thus, I.V. can trigger GCA or PMR,
especially in people at higher spontaneous risk, such as those with a
personal or family history of GCA/PMR. Whether the presence of the
DRB1*13:01 allele further increases the risk of post-I.V. GCA/PMR
through a stronger vaccine-induced immune reaction warrants further
investigation [31].
In 2020, cases of ASIA syndrome associated with autoimmune
endocrine diseases were described [33]. These diseases were: sub-acute
thyroiditis (n = 54), Hashimoto’s thyroiditis (n = 2), primary ovarian
failure/primary ovarian insufficiency (n = 11), autoimmune diabetes
type 1 (n = 13), and auto-immune adrenal gland insufficiency (n = 1)
[33].
In a recent review five diseases, including sarcoidosis, Sjögren’s
syndrome, undifferentiated connective tissue disease, silicone implant
incompatibility syndrome (SIIS), and immune-related adverse events
(irAEs) were identified as classical examples of ASIA [34]. These entities
occur in genetically predisposed individuals (HLA-DRB1 and PTPN22
gene), in which the adjuvant induces an hyperstimulation of the immune
system eventually leading to the development of autoimmune diseases
[34].
It has been suggested that chronic activation of the immune system
by adjuvants may also lead to the development of lymphoma and form
part of the ASIA spectrum [35]. Indeed, a large number of reports
indicate an increased risk of lymphoma, particularly of the anaplastic
large cell type in patients with breast implants [36,37]. In addition,
patients with ASIA syndrome associated with a silicone breast implant
may develop other forms of non-Hodgkin lymphomas such as Epstein-
Barr virus positive large B cell lymphoma and/or intravascular large
B-cell lymphoma [8,38,39]. In addition, the FDA recently issued a safety
communication stating that also squamous cell carcinoma linked to
breast implants occur [39].
4
Autoimmunity Reviews 22 (2023) 103287
5. ASIA due to medical implants
Supporting evidence from the literature underlines the development
of ASIA in susceptible patients after breast or testicular implantation,
rhinoplasty, polypropylene mesh implantation for hernia repair or for
reinforcement of a weak pelvic floor, tension free vaginal tape implan­
tation for stress incontinence, Essure sterilizations, implantation of
prosthetic materials for arthroplasty, and/or metal implants as used in
orthopedic surgery [2,7,16,17] (Fig. 2). At present, clues underpinning
patients’ susceptibility to development of ASIA after implantation of
medical devices remain to be elucidated. Several factors, however, have
been postulated [2]. Patients with an allergic past medical history are at
a greater risk of developing ASIA after implantation. Furthermore, pa­
tients with an established autoimmune disease or a familial predispo­
sition to autoimmune disease are at risk of developing symptoms after
silicone breast implantation (“SBI”). It is important to note the interplay
between immunogenetic (i.e., human leukocyte antigens “HLA”) factors
as well as environmental factors such as smoking and obesity in the
development of medical device induced ASIA.
In general, commonly used biomaterials for implantation are non-
immunogenic and non-toxic. However, implanted biomaterials trigger
a foreign body reaction (FBR) resulting in granulomatous inflammation
[40,41]. Immediately after the implantation of a biomaterial, a layer of
host proteins is absorbed, resulting in the attraction of phagocytes
(predominantly macrophages of the pro-inflammatory M1 subtype)
[42]. Such process is dependent on the presence of activated mast cells
and histamine [43] which plays a pivotal role in pain, at times severe, at
the site of implantation secondary to sensitization of the transient re­
porter potential channel V1 (TRPV1), a nociceptor [44]. Furthermore,
microbial biofilms form on implants [45,46] and contribute to the
chronic inflammatory response. Importantly, the biomaterial may
deliver a “danger signal” to the immune system and subsequently result
in an enhanced immune response [47,48]. As such, the biomaterials act
as an adjuvant in the development of an adaptive immune response to an
antigen [2,14].
6. Explantation of the medical implant that causes ASIA, results
in amelioration of symptoms
A major criterion of ASIA includes the improvement of symptoms
and signs that ensued after implantation (such as chronic fatigue or
widespread pain) upon explantation. The cessation or reduction of
symptoms after removal (also called “dechallenge”) is an extremely
important observation in diagnosing ASIA as well as determining
causation. Such improvement has been documented in patients with
silicone breast implants ([49–60], mesh implants [7]. Essure devices
[17], arthroplasty [16] and/or metal implants [14]. Most case series
describing the improvement of ASIA after medical device explantation,
have been published on breast implants. In 2017, de Boer et al. reviewed
the literature regarding symptoms after SBI explantation [49]. Eleven
case reports with a total of 19 patients and 12 case series with a total of
703 patients (of which clinical symptoms were well described after
explantation in 603 patients) who underwent explantation were found.
In total (case reports + case series), 469 of 622 patients (75%) experi­
enced improvement of silicone-related complaints after explantation
[49]. During the last 5 years several new case series regarding the effects
of explantation in >2000 patients have been published [50–60].
Improvement of symptoms have been reported in 50–98% of the pa­
tients. Importantly, in the study by Spit et al. [52] patients with symp­
toms that underwent explantation (n = 152) were compared with
patients who did not want to remove their implants (n = 180). A sig­
nificant improvement occurred in 30% of patients who underwent
explantation whereas in the non-removal group 12% reported a signif­
icant improvement (OR = 2.86; CI 1.31–6.24). No significant differences
were found between women with only moderate improvement, no
change and/or deterioration between the removal and non-removal
J.W. Cohen Tervaert et al. Autoimmunity Reviews 22 (2023) 103287

Fig. 2. Autoimmune/inflammatory Syndrome Induced by Adjuvants (ASIA) due to implants and/or fillers.
Typical examples of implant-related or filler-related examples of ASIA are shown.
Upper three from left to right: mesh, gluteal biopolymer injections, arthroplasty.
Lower three from left to right: Silicone breast implants, essure and metal implants.

group. Magno-Padron et al. [57] reported that 60% of their patients did
not want to undergo an explantation. The most common reasons for this
were costs (64%) and/or cosmetic reasons (30%).
7. Which patients are likely to benefit from explantation?
As stated above, it is clear that not all SBI patients benefit from
explantation.
Several factors can be postulated that might influence the outcome of
explantation, e.g., implant characteristics, disease characteristics,
duration, surgery, post-explantation reconstruction and/or other
factors.
7.1. Implant characteristics
Breast implants can have a different filling material (silicone,
hydrocellulose or saline), can have a different outer silicone shell that
has either a smooth surface or a textured surface and can have a different
shape (round or anatomic). Not much is known regarding these char­
acteristics and outcome after explantation. Katsnelson et al. [54],
however, found in their study that capsular inflammation was more
often present in silicone-gel filled implants compared to saline implants,
whereas capsular inflammation was more severe in implants with a
textured surface when compared to patients with smooth implants. This
might be relevant since Wee et al. [53] found in their large group of
explanted patients that patients with capsular contracture had a signif­
icantly better outcome compared to those without a capsular contrac­
ture. Wee et al. [53], however, did find similar improvement in
symptoms between removal of saline and silicone-gel filled implants.
systemic autoimmune diseases such as Sjogren syndrome, sarcoidosis,
systemic sclerosis, rheumatoid arthritis, systemic lupus erythematosus,
anti-phospholipid syndrome, eosinophilic granulomatosis with poly­
angiitis and/or different other forms of vasculitis. Epidemiologic evi­
dence for an increased occurrence of these autoimmune diseases has
been clearly reported [51]. Watad et al. [61] studied 24,651 women
with silicone breast implants and found that women with breast im­
plants had a 45% increased risk for being diagnosed with at least one
autoimmune/rheumatic disorder, compared to those without breast
implants (n = 98.604). In medical-implant induced ASIA patients with a
well-established systemic autoimmune disease (such as rheumatoid
arthritis or systemic sclerosis), recovery after explantation is often not
complete and –as expected because the breakdown of immune tolerance
is not recovered by explantation - disease modifying drugs are needed to
treat the complicating autoimmune disease [49].
7.3. Duration: time between implantation and explantation
Brawer [62] reported in 2000 that improvement of systemic symp­
toms was less likely to occur when the length of time of implantation
increased. In addition, Spit et al. [52] recently found that that the
likelihood for improvement of Breast Implant Illness/Autoimmune In­
flammatory Syndrome Induced by Adjuvants (ASIA) due to silicone
implant incompatibility syndrome declines with the duration of expo­
sure to SBI. Fifty-nine percent of women who removed their implants
within 10 years after implantation showed significant improvement,
whereas this was only 33% in women who had their implants for over
10 years, suggesting that the duration of exposure to gel bleed and
increasing amounts of gel bleed over the years may be related to
outcome.

7.2. Disease characteristics

A substantial number of SBI patients may develop well-defined

5
J.W. Cohen Tervaert et al.
7.4. Surgery
There is controversy whether explantation of SBI should be accom­
panied by a capsulectomy [59,60]. In 2012, Kappel and Pruijn [63]
reported a study in which women after explantation with capsulectomy
(n = 22) were compared with women after explantation without cap­
sulectomy (n = 13). Symptoms improved in both groups; however, the
improvement was more pronounced in the women who had undergone a
capsulectomy [63]. Experience of the surgeon might be another factor
that plays a role. Indeed, amazing results were recently published
demonstrating that nearly all patients improve after explantation
[53–55,60].
7.5. Post-explantation reconstruction
After explantation, a new implant can be placed (saline, hydro­
cellulose or silicone-gel filled), a reconstruction with autologous mate­
rial can be performed or no reconstruction can be done. Cohen Tervaert
compared the results of women that were followed in the Reinaert
Clinic, Maastricht, the Netherlands, after explantation and who did not
undergo a reconstruction (n = 60), women with an autologous recon­
struction (n = 7), and women who choose to have a new (hydro­
cellulose) implant (n = 19). Initial improvement was 72% for women
without reconstruction, 68% for women with a new implant, versus 72%
for women with autologous reconstruction. Relapses, however, occurred
frequently (47%) in the patients with a new implant, whereas this
occurred only infrequently in the other two groups. Similar results were
reported by Brawer [62], i.e., a low relapse rate if no reconstruction was
done and a high relapse rate when new (saline) implants were placed
(46% relapse).
7.6. Other factors
Many other factors such as smoking, age, BMI, and/or comorbidity
could play a role regarding outcome after explantation. In the study by
Wee et al. [53] it was found that explantation in obese patients resulted
in a greater improvement than explantation in patients with a normal
BMI. The authors speculate that the inflammatory response triggered by
leaked silicones was greater in obese patients than in patients with a
normal BMI since obesity is a proinflammatory condition.
In summary, from these studies it can be concluded that women who
developed symptoms after breast implantation have significant
improvement of symptoms and quality of life when the breast implants
are removed. Improvement in the ASIA symptoms (fatigue, arthralgia,
muscle pain and weakness, cognitive impairment, alopecia, widespread
pain and allergies) after removal of breast implants also provides con­
firming evidence of causation. These symptoms would not be expected
to improve spontaneously after removal of breast implants if they were
not caused by the device. Similar symptoms as found in ASIA are re­
ported by patients with “idiopathic” chronic fatigue syndrome (ME/
CFS) and/or “idiopathic” fibromyalgia, but spontaneous improvements
are extremely rarely observed in these patients. Improvement upon
explantation of the medical device points to a different pathophysiology
for the autoimmune-like symptoms seen in patients with implants than
in patients with idiopathic ME/CFS and/or fibromyalgia. All of the
above studies support the evidence that ASIA in patients with an
implanted medical device is caused by these implants.
8. Post-HPV vaccination illness: another ASIA syndrome facet
Vaccination has been one of the most effective public health mea­
sures in the history of medicine. This strategy has prevented or attenu­
ated several dreaded diseases. Nevertheless, any substance designed to
chronically stimulate the immune system, may produce untoward re­
actions in predisposed individuals. This immune system hyperstimula­
tion may be more pronounced after multiple inoculations or with the use
6
Autoimmunity Reviews 22 (2023) 103287
of vaccine adjuvants. Vaccines are given to large population of healthy
individuals; therefore, constant safety surveillance is a priority. Open
debate on vaccine untoward reactions should not be taken as an anti-
vaccine crusade [64].
Starting in 2014, independent clinicians from different parts of the
world described a chronic syndrome of dysautonomia and neuropathic
pain occurring soon after human papilloma virus (HPV) vaccination
[65]. Differing from these reports, the European Medicine Agency [66]
and the United Kingdom Medicines and Healthcare Products Regulatory
Agency [67] found no evidence supporting the existence of such syn­
drome. This section updates the controversial HPV vaccination syn­
drome status and discusses the fact that HPV vaccine adverse events
were already present in the pivotal randomized preclinical studies but
were minimized or ignored by the investigators.
9. Post-HPV vaccination syndrome clinical features
Independent practitioners from different countries have described
the following symptom-cluster occurring soon after HPV vaccination:
Disabling fatigue, headache, widespread pain, fainting, gastrointestinal
dysmotility, limb weakness, memory impairment episodes of altered
awareness, and abnormal movements. Different clinical diagnoses have
been proposed to explain this syndrome including: ME/CFS, postural
orthostatic tachycardia, complex regional pain or fibromyalgia. These
are overlapping entities with similar proposed pathogenetic features.
Dysautonomia and neuropathic pain are common elements to these
syndromes [65].
10. Similar Post-HPV vaccination symptoms are steadily
reported over the years
In 2015, Martínez-Lavín et al. reported a questionnaire-based study
on symptoms cluster appearing after HPV vaccination. Patients who had
an illness onset soon after HPV vaccination were asked to enumerate
their main symptoms. The most common presenting complaints were
musculoskeletal pain (66%), fatigue (57%), headache (57%), dizziness/
vertigo (43%), and paresthesia/allodynia (36%) [68]. After these data
publication, the investigators kept receiving similar post-HPV vaccina­
tion adverse events reports. Table 2 list the original published cohort
compared with the post-publication group. Both groups show similar
post-vaccination cluster of symptoms.
11. HPV vaccine adverse events were already present in the
pivotal preclinical trials but were minimized or ignored by the
investigators
In the pivotal preclinical VIVIANE randomized trial, the group of
2881 mid-adult women injected with the bivalent HPV vaccine had
more deaths in the four-year follow-up period than the 2871 women
who received “aluminum placebo” (14 versus 3, p = 0.012). Neverthe­
less, this hard to believe, but significant, statistical difference was
improperly overruled by a post hoc unblinded investigators opinion
concluding that no deaths were related to vaccination [69]. Later on, a
Cochrane meta-analysis confirmed the higher fatality rate in women
aged 25 to 45 who received HPV vaccine (relative risk 2.36, 95% con­
fidence interval 1.1 to 5.0). Again, the hard-statistical data were over­
ruled by experts’ assessment concluding there was no pattern in the
cause or timing of deaths [70].
A safe vaccine should not have a biological gradient of adverse
events. Nine valent HPV vaccine has more than twice the virus-like
particles and aluminum adjuvant as the four valent dose. In the largest
HPV vaccine trial (14,149 participants), those who received the nine
valent dose had more vaccine related systemic adverse events than those
receiving the four valent dose (29.5% versus 27.3%, P = 0.003) and had
more serious systemic adverse events (3.3% versus 2.6%, P = 0.01) [71].
These worrisome incongruities arising from two key HPV vaccine
J.W. Cohen Tervaert et al. Autoimmunity Reviews 22 (2023) 103287

Table 2 13. ASIA syndrome and post-covid-19 vaccination

Clinical features of patients who had the onset of a chronic illness soon after HPV
vaccination. Unlike antimicrobial agents used to treat infected persons, vaccines
Cohort 1 Cohort 2 p are applied to healthy subjects to prevent infectious; therefore, adverse
n = 45 n = 37 effects acquire great relevance. Nevertheless, adverse effects do not
Demographic features outweigh the demonstrated advantages vaccines offer humanity by
Age (mean ± SD) 19 ± 6 19 ± 11 0.100 preventing diseases that constitute a significant economic, social, and
Female (%) 98 95 0.438 family burden [74,75].
Age at vaccination time (mean ± SD) 14 ± 5 16 ± 10 0.255
Mass vaccination campaigns against COVID-19 began in January
Quadrivalent vaccination (%) (gardasil) 79 43 0.003
Bivalent vaccination (%) (cervarix) 21 5 0.051 2021. At present >5.3 billion persons, and it is considered that currently
Time elapsed between HPV vaccination and 2.9 ± 69% of the population has been vaccinated with one or more doses,
symptom onset (weeks) 2.3 ± 3.1 5.3 0.370 however, the lack of access to vaccines in some countries is a challenge
for health authorities [76].
Most common presenting complaints (%) The efficacy of vaccines against COVID-19 have been widely
Musculoskeletal pain 66 73 0.438 demonstrated in the population and are responsible for the significant
Fatigue 57 54 0.534
decrease in hospitalization, admission to the intensive care unit, and
Headache 57 54 0.563
Dizziness/vertigo 43 27 0.080
death [77]. In relation to rheumatic diseases, a EULAR study showed
Paresthesias/allodynia 36 30 0.475 that in 5121 participants, adverse events were observed in 37%, and
Nausea/vomiting 27 16 0.138 relapses of rheumatic diseases was observed in 4.4% of patients [78].
The World Health Organization has defined a post-vaccine adverse event
Most frequent complaints at survey time (%) as follows: any adverse medical event that follows immunization, even if
Fatigue/tiredness 88 86 0.615 not necessarily causally related to the use of the vaccine. Therefore, a
Muscle pain 76 81 0.288 minority of people may develop adverse effects after applying any
Headache 74 73 0.583
Muscle weakness 69 89 0.024
vaccine, including autoimmune syndromes [79].
Thinking or remembering problem 63 64 0.412 In April 2021, the first cases of immunothrombosis with autoimmune
Dizziness 63 70 0.174 thrombocytopenia were described after the Astra Zeneca vaccine, now
Pain/cramps in the abdomen 60 38 0.084 known as VITT (Vaccine-Induced Immune Thrombotic Thrombocyto­
Numbness/tingling 60 70 0.299
penia) syndrome [80]. Of interest, none of these patients had previously
Nausea 60 54 0.534
received heparin. This complex interaction caused in a minority of
vaccinated persons to adverse effects, either anaphylaxis or autoim­
Questionnaire score
% of cases fulfilling fibromyalgia 2010 diagnostic
munity due to cytokine activation. Immune activation followed by this
criteria 53 59 0.370 vaccine, can lead to the formation of antiplatelet factor 4 (PF4) anti­
COMPASS 31 score 43 ± 21 45 ± 20 0.616 bodies, with platelet activation and subsequently the coagulation
10.3 ± cascade [80,81]. After intramuscular inoculation of the Adenovirus-
S-LANSS score 7.6 15 ± 6.7 0.026
vectored DNA vaccine, a chain of events develops, including microvas­
% of cases with S-LANSS score > 12 and
musculoskeletal pain 83 76 0.324 cular damage, microhemorrhage and platelet activation with PF4
% of cases able to go to school (or work) on a release. PF4-DNA cargo dispersion can break immunological tolerance,
regular basis 7 6 0.645 leading to rare PF4-driven autoimmunity [82]. Acute management of
Outstanding clinical features of patients who had the onset of a chronic illness this new syndrome consisted of parenteral anticoagulants, corticoste­
soon after HPV vaccination. Cohort 1 = 45 patients published in the original roids, intravenous immunoglobulin (IVIG), and eculizumab. A long-term
case-series compared to cohort 2 composed by 37 individuals who reported their follow-up suggest that VITT appears to be a highly prothrombotic con­
symptoms after publication of the original case-series. dition and direct oral anticoagulants appear to be safe and effective
[83].
preclinical randomized trials remain unaccounted for. After the initial publication of the VITT Syndrome, various authors
confirmed the existence of this new entity [84,85]. In addition, auto­
12. Post-HPV vaccination syndrome: postulated pathogenesis immune syndromes were described, such as autoimmune neurological
diseases [85,86], thrombocytopenia [87], de novo cutaneous and/or
Dorsal root ganglia are key neural sites where different types of systemic vasculitis and/or dermatomyositis [88–90]. A recent study,
foreign substances including viruses, immune complexes or vaccines can evaluated immune mediated disease flares or new disease onset within
induce neuropathic pain and dysautonomia. Recent studies in mice have 28 days of SARS-CoV-2 vaccination in five large tertiary centers in
shown that after vaccination dorsal root ganglia sensory neurons are countries with early vaccination adoption: Israel, UK, and USA [91]. The
able to sequester and retain antigen-specific antibodies released by authors, described 27 cases, that included 17 flares and 10 patients with
antibody-secreting plasma cells [72]. Trapped vaccine-induced antigen- new disease onset. 23/27 patients, received the BNT - 162b2 vaccine, 2/
specific antibodies could theoretically cross-react with dorsal root 27 the mRNA-1273 and 2/27 the ChAdOx1 vaccines. The mean age was
ganglia epitopes thus inducing neuropathic pain and dysautonomia in 54.4 ± 19.2 years and 55% of cases were female. 21 cases (78%) had at
predisposed individuals. A different animal model demonstrates that least one underlying autoimmune/rheumatic disease prior the vacci­
aluminum adjuvant can damage dorsal root ganglia [73]. nation. In relation with a flare or activation, four episodes occurred after
In summary, clinicians from different places, circumstances, and receiving the second-dose and in one patient they occurred both after
times had reported a similar syndrome of neuropathic pain and dysau­ the first and the second-dose. In those patients with a new onset disease,
tonomia following HPV vaccination. HPV vaccine adverse events were two occurred after the second-dose and in one patient occurred both
already evident in the randomized preclinical trials. Much more after the first (new onset) and second-dose (flare). Over 80% of cases had
research is needed to define post-HPV vaccination adverse reactions and excellent resolution of inflammatory features, mostly with the use of
their possible pathogenesis. Beyond causality assessment, there is an corticosteroid therapy [91].
urgent duty to provide proper medical care to those youngsters who The first systematic review of the literature on the different new-
have developed a disabling illness after HPV vaccination. onset autoimmune phenomena after the application of various vac­
cines against COVID-19 was published in 2022 [92]. All the

7
J.W. Cohen Tervaert et al.
autoimmune syndromes identified in this review were of a new onset. A
total of 277 cases were identified. The autoimmune entities identified
were: Guillain-Barre syndrome (151 cases), VITT (93 cases); Autoim­
mune liver diseases (8 cases); Immune thrombocytopenic purpura (7
cases); IgA nephropathy (5 cases); Autoimmune polyarthritis (2 cases);
rheumatoid arthritis (2 cases); Graves’ disease (2 cases); Diabetes Mel­
litus type I (4 cases); and Systemic Lupus Erythematosus (3 cases). The
association between the COVID-19 vaccine and the development of
autoimmune syndromes is a matter of study. So far, no components of
COVID-19 vaccines have been identified as being responsible for these
rare immune-mediated adverse events. In this regard, 3 mechanisms
have been proposed: 1. Molecular mimicry. 2. Production of autoanti­
bodies and 3. Vaccine adjuvants. Molecular mimicry is based on immune
cross-reactivity, caused by the similarity between vaccine components
and specific human proteins, which would trigger an immune system
response against pathogenic antigens and similar human proteins in
susceptible individuals and cause autoimmune diseases. In fact, only a
minority of individuals develop autoimmunity after vaccination against
COVID-19, which supports the concept of a genetic predisposition for
the development of vaccine-induced autoimmunity [92,93]. Several
candidates for “adjuvants” of the immune response have been proposed,
such as: Polyethylene glycol (PEG) 2000, present in lipid layer
BNT162b2 and mRNA-1273, Polysorbate 80 (ChAdOx1 nCoV-19), and
anti-spike antibodies developed after exposure to the SARS-CoV-2 virus
that stimulate the production of anti-idiotypic antibodies after the anti-
COVID vaccine [91,92]. Interestingly, RNA in vaccines might contribute
to the development of vasculitis as has been demonstrated in a patient
who developed de novo ANCA associated vasculitis after receiving a
RNA containing vaccine [94].
It has recently been proposed that COVID 19 vaccination can trigger
autoimmune phenomena, probably inducing age-associated B cells (ABC
cells). ABC cells (double negative, CD11c + T-bet+ B cells) are impli­
cated in the increased production of (autoreactive) immunoglobulin
production occurring in advanced age, autoimmune diseases, and
infections.TLR-7 increases ABC cell activity. TLR-7 and TLR-9 increase
Interferon I production.TLR-7/8 and TLR-9 are stimulated by mRNA/
DNA from SARS-CoV-2 vaccine. Therefore, vaccine-stimulated ABC cells
may be responsible for the production of autoantibodies and the
development of post-vaccine autoimmune syndromes [95]. However,
the exact mechanism of the development of post-vaccination autoim­
mune syndromes against COVID-19 is not yet established.
After the description of this great diversity of autoimmune syn­
dromes after COVID-19 vaccine, it is clear that although the “adjuvants”
have not been identified, the vaccines against COVID-19 contain mate­
rials that hyperstimulate the immune system and can present clinical
manifestations and meet the minimum criteria for the diagnosis of ASIA
syndrome. Indeed, various researchers have described ASIA syndrome
post-vaccine against COVID-19. The first reports on post-Covid 19
vaccination ASIA syndrome were published almost simultaneously in
August and September 2021 [96,97]. The first 3 patients developed
subacute thyroiditis after inactivated SARS-CoV-2 vaccine (Corona­
Vac®) and the other 2 patients developed Graves’ disease after
BNT162B2 (Pfizer-BioNTech) SARS-CoV-2 vaccination. All patients
developed thyroid disease a few days (2–7 days) after the application of
the COVID-19 vaccines [96,97]. None of these patients had a history of
prior autoimmune thyroid disease. These cases have been observed by
other authors in different parts of the world [98]. In 2022, another case
of ASIA syndrome with isolated adrenocorticotropic hormone (ACTH)
deficiency (IAD) following mRNA vaccination against COVID-19 was
published [99]. The patient was treated with hydrocortisone, with rapid
improvement and without recurrence of his symptoms [99]. A case of
atypical Kawasaki disease was described in an 18-year-old patient, as an
adverse event after the application of the COVID-19 vaccine. This case,
as well as several of those previously described, meet the sufficient
criteria to be diagnosed as ASIA syndrome [100]. In 2022, case-series of
post-Covid-19 vaccination autoimmune syndromes have continued to be
8
Autoimmunity Reviews 22 (2023) 103287
published. A recent report described 7 cases of demyelinating neuro­
logical disease (3 of them were new onset), 1 to 21 days after receiving
vaccines against COVID-19 (Moderna (n = 3) or Pfizer (n = 4) SARS-
CoV-2 mRNA vaccines. These patients developed neurologic symptoms
and MRI findings consistent with active CNS demyelination of the optic
nerve, brain, and/or spinal cord [85]. The first case of a concurrent
antineutrophil cytoplasmic autoantibody and anti-glomerular basement
membrane glomerulonephritis after COVID-19 vaccination has been
published [101].
Fortunately, autoimmune syndromes induced or stimulated by the
COVID-19 vaccine are rare, short-lived and respond quickly to steroids
and other treatments, including immunomodulatory drugs and therefore
have a good prognosis [74,75]. However, it is necessary to follow these
patients in order to determine if these autoimmune phenomena
observed after the COVID-19 vaccine are really transitory or if it is the
beginning of a chronic autoimmune disease, which will present with
lifelong exacerbation and remission periods. Jara et al. experience on
this topic has been recently published [102] and it is expanded in
Table 3.
14. ASIA-induced dysautonomia: association with
autoantibodies directed against autonomic nervous system
receptors
As already been suggested in 2011 [1], the major and minor criteria
of ASIA syndrome include, at least in part, the appearance of subjective
and non-specific clinical manifestations such as: chronic fatigue, sleep
disturbance, dry mouth, cognitive impairment, memory loss and irrita­
ble bowel syndrome – in genetically predispose subjects following
exposure to external stimuli (e.g. viruses and adjuvants). Notably,
removal of such inciting agents, should induce clinical improvement [1].
Recently, Shoenfeld’s group and others found that adjuvants such as
silicone can cause autonomic-related manifestations in both animal and
humans and might lead to an ‘autoimmune dysautonomia’ condition in
genetically predispose subjects [103,104]. Silicone breast implant in­
compatibility syndrome (SIIS) is a classic example of ASIA-induced
dysautonomia condition in genetically predispose subjects [34,105].
The silicone adjuvant can cause chronic stimulation of both the innate
and adaptive immune system resulting in the production of classical
autoantibodies and occasionally in the development of a rare-type of T
cell lymphoma [106]. Moreover, using a large population-based study, a
significant increase in the development of various autoimmune and
rheumatic diseases in women with silicone breast implants (SBI) as
compared with sex and aged matched controls was demonstrated [61].
Women with SBI can suffer from a panoply of autonomic-related
manifestation such as: palpitations, dry eyes and mouth, depression,
chronic fatigue, widespread pain, cognitive impairments, hearing loss
etc. [2,103]. Unfortunately, these subjective symptoms are neglected by
most clinicians and rheumatologists, as the routine laboratory tests for
these patients show normal results. Recently, significant changes in the
circulating level of non-classical autoantibodies directed against G
protein coupled receptors (GPCRs) of the autonomic nervous system
(such as: anti-β1 adrenergic receptor, anti-endothelin receptor type A
and anti-angiotensin II type 1 receptor) in symptomatic women with SBI
were demonstrated as compared to healthy women [103]. GPCRs
comprise the largest family of integral membrane proteins and func­
tional antibodies (agonists or antagonists) directed against them are
involved in physiological processes and pathological conditions in our
body [107,108]. It has been postulated that dysregulation in the level
and function of these anti-GPCRs autoantibodies might explain some of
the subjective/autonomic-related manifestations reported by women
with SBI. Of note, the removal of SBI from these symptomatic subjects,
as one of the major criteria of ASIA syndrome [1], lead to a clear
improvement in their autonomic symptoms and clinical status (53, vide
supra and unpublished new data) – strengthening the introduction of
SIIS as a classical example of ASIA syndrome [34,105].
J.W. Cohen Tervaert et al. Autoimmunity Reviews 22 (2023) 103287

Table 3 candidate for therapeutic intervention, have been suggested

Demographic, clinical, and laboratory characteristics of patients with autoim­ [108,111–114]. Of note, the presence of anti-GPCRs autoantibodies is
mune diseases associated to COVID-19 vaccines (n = 45). not the only objective parameter found in various clinical entities which
Syndromeordisease Number Brand Time to Antibodies express the ASIA syndrome. An additional clinical objective finding is
cases Vaccine presentation positive for instance the presence of small fiber neuropathy (SFN)
(days) [2,109,114,115]. SFN is defined as structural damage of thin myelinated
Astra- A-delta and unmyelinated C-fibers, specifically in the distal termination
GuillainBarré RF: 2
Syndrome (Miller 11
Zeneca: 8
30 (1–60) SS-A: 1 of the nerves [116]. The aetiology of SFN can be attributed to toxic,
Sputnik V: 2
Fisher 4 cases) ANA: 1 metabolic, immune-mediated or genetic factors [116]. Clinical charac­
Sinovac: 1
Sputnik V: 1 teristic of this syndrome includes neuropathic pain and autonomic-
Astra- related manifestations such as: fatigue, anxiety, depression etc. [115].
Zeneca:1 AQP-4: 5 Overall, the observation of autonomic-related symptoms, autoanti­
NeuromyelitisOptica 5 Pfizer 20 (5–50) Anti- bodies directed against GPCRs of the autonomic nervous system and/or
BioNTech:1 RBBP9: 1
Moderna:1
SFN in genetically predispose subjects, introduce these new parameters
Sputnik V:1 as additional factors to be included in the criteria for ASIA syndrome.
Astra-
AL: 1
Zeneca: 3
Longitudinal Myelitis 4 26 (1–63) ANA: 1 15. Conclusions
Pfizer
AQP-4: 1
BioNTech:1
Transverse myelitis 1 Sputnik V 1 ANA: 1 From its launch in 2011 until today, the ASIA syndrome (Shoenfeld’s
Autoimmune Astra-
Anti- syndrome) have been dramatically expanded and recognized by many
4 22 (10–60) NMDA: 3
encephalitis Zeneca: 3 researchers. New cases of ASIA associated with new adjuvants (e.g.
Gab-Ab: 1
Astra- Anti-Musk:
polypropylene meshes) were described. New subtypes of the ASIA syn­
Myasthenia Gravis 1 7 drome have been introduced, related to exposure to different types of
Zeneca:1 1
Astra-
Anti-CCP: 9
vaccines (e.g., HPV and COVID vaccines) in genetically predisposed
Neuropathy 2 Zeneca:1 17 (1− 33) individuals, i.e., HLA DRB1 haplotypes [117,118]. Recent evidence
ANA 1
Janssen:1
describing a clear association between the removal of a specific adjuvant
ANA: 1
Vasculitis ANCA 2
Pfizer
5 (3–7) p-ANCA: 2 (e.g. silicone implants, mesh, Essure sterilization devices, metal im­
BioNTech: 2
RF: 1 plants or even porcelain-fused-to-metal dental crowns) followed by
Anti-SSA: 1 symptoms relieve/disappearance in ASIA patients, strengthen some of
ANA: 2
the criteria of ASIA syndrome. Finally, new findings, such as a potential
Atypical Kawasaki Astra- COOMBS:
disease
2
Zeneca: 2
41 (22–60)
cold
dysfunction of autoantibodies directed against GPCRs of the autonomic
antibodies: nervous system and the presence of SFN, are being suggested as new
1 criteria for ASIA and as an explanation for the dysautonomia that is often
Astra- Anti-CCP: 1 reported in ASIA patients.
Rheumatoid Arthritis 1 1
Zeneca:1 RF: 1
Autoinmune Astra-
1 2 ESR: 80
Polyarthritis Zeneca: 1
Sinovac:1 Declaration of Competing Interest
Ferritin:
Still’s disease 2 Astra- 30 (1–60)
>2000
Zeneca:1
Dr. Cohen Tervaert appeared as expert witness in court for patients
ANA: 2
Anti-TSH-R: with adverse effect due to biomaterials. Dr. Shoenfeld appeared as
Pfizer expert witness in court for patients with adverse effect due to vaccines.
3
Graves’ disease 3 BioNTech: 2 3 (2–6)
TSI: 1
Sputnik V:1
Anti TPO: 3 Data availability
Anti-Tg: 1
Astra-
Subacute thyroiditis 2 Zeneca:1 4 (1–7) Anti-TPO: 1 Data will be made available on request.
Sputnik:1
Astra-
VITT 4 2.5 (1− 10) References
Zeneca: 4

F: Female, M: Male, RF: Rheumatoid Factor, Anti SS-A: anti–Sjögren’s-syn­
drome-related antigen A autoantibodies, ANA: Antinuclear antibodies, AQP4:
anti- aquaporin-4 antibody, Anti-RBBP9: Anti-RB binding protein 9, LA: Lupus
anticoagulant, Anti-NMDA: anti-N-methyl-D-aspartate, Anti-GAB: Anti-glutamic
acid decarboxylase antibody, Anti-Musk: Anti-muscle-specific kinase antibodies,
Anti-CCP: Anti-citrullinated protein antibodies, p-ANCA: perinuclear- anti­
neutrophil cytoplasmic antibodies, ESR: erythrocyte sedimentation rate, anti-
TSH-R: anti-Thyroid-stimulating hormone- Receptor, TSI: thyroid stimulating
immunoglobulin, anti-TPO: anti-thyroid peroxidase antibodies, anti-Tg: antith­
yroglobulin antibodies, VITT: Vaccine-induced immune thrombotic
thrombocytopenia.
It is worth mentioning, that such autonomic-related manifestations
were reported in other ‘suspected autoimmune dysautonomic-related
conditions’ such as: ME/CFS, fibromyalgia, acute/post/long-COVID,
postural orthostatic tachycardia syndrome (POTS), HPV vaccine syn­
drome etc. [109,110]. Importantly, the involvement of anti-GPCRs au­
toantibodies in the pathogenesis of these syndromes and even as a
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