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Autoimmune/Inflammatory Syndrome Induced by Silicone Breast Implant and
Risk Factors Associated to Autoimmune Diseases
Vera-Lastra O1,2*, Cruz-Domínguez MP2,3, Medrado Ramírez G4, Medina G2,5, Amigo MC6, Peralta-Amaro
AL1,2, Gayosso-Rivera JA1, Jara LJ 2,7
1Department of Internal Medicine, High Specialty Medical Unit, Specialties Hospital, Dr. Antonio Fraga Mouret, National Medical
Center La Raza, Mexico; 2Postgraduate Studies Division, Faculty of Medicine, National Autonomous University of Mexico, Mexico;
3Department of Rheumatology, High Specialty Medical Unit, Specialties Hospital, Dr. Antonio Fraga Mouret, National Medical
Center La Raza, Mexico; 4Department of Rheumatology, Hospital General de México, "Dr. Eduardo Liceaga", Mexico;
5Translational Research Unit, High Specialty Medical Unit, Specialties Hospital, Dr. Antonio Fraga Mouret, National Medical
Center La Raza, Mexico; 6Department of Rheumatology, Centro Médico ABC (The American British Cowdray Medical Center),
Mexico ; 7Department of Health Research and Education, High Specialty Medical Unit, Specialties Hospital, Dr. Antonio Fraga
Mouret, National Medical Center La Raza, Mexico
ABSTRACT
Autoimmune Rheumatic Diseases (ARD) have been associated with Silicon Breast Implant (SBI) as part of the
spectrum of Autoimmune/Inflammatory Syndrome Induced by Adjuvants (ASIA). Silicone is an adjuvant that may
bleed and subsequently may be a chronic stimulus to the immune system.
Objective: To determine the prevalence of autoimmune diseases (AID) and risk factors associated to patients with
ASIA induced by SBI (ASIA-SBI).
Patients and methods: This study was performed between 2012 and 2018, in a tertiary referral center, from a cohort
of 210 patients with ASIA. We selected those patients with ASIA-SBI and clinical manifestations of any ARD. We
investigated family history of AID, smoking, allergies and comorbidities. Statistical analysis: Chi square and Odds
Ratio (OR).
Results: There were 45 women with current age 50 (29-75) years, mean time of appearance of clinical manifestations
after SBI was 8.8 ± 5.5 years. We found systemic sclerosis (SSc) 10 patients, rheumatoid arthritis (RA) 8,
undifferentiated connective tissue syndrome (UCTDS) 6, fibromyalgia (FM) 5, systemic lupus erythematosus (SLE) 4,
Sjogren syndrome (SS) 3, angioedema/urticaria 3, overlap syndrome 2, and one of each of the following: Takayasu
arteritis, Still disease, tunnel carpal syndrome and antiphospholipid syndrome. We observed family history of ARD
42%, allergy history 37.5% and smoking 35.5%. In ASIA-SBI patients, family history and smoking had a significant
association with SSc OR 6.0 (CI 1.2-29), p<0.02 and RA OR 7.1 (CI 1.3-37.2), p<0.022.
Conclusions: In patients with ASIA-SBI, family history of AID and smoking were associated with SSc and RA. In
addition to SBI, environmental and genetic factors should be taken into account for the development of AID.
Keywords: Autoimmune/Inflammatory syndrome induced by adjuvants (ASIA); Silicone breast implant (SBI);
Autoimmune rheumatic disease (ARD); Systemic sclerosis (SSc); Rheumatoid arthritis (RA); Systemic lupus
erythematosus SLE); Undifferentiated connective tissue syndrome (UCTD) and risk factors
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ISSN: 2161-1149
Rheumatology: Current Research Research Article
*Correspondence to: Olga Vera-Lastra, Department of Internal Medicine, High Specialty Medical Unit, Specialties Hospital, Dr. Antonio Fraga
Mouret, National Medical Center La Raza, Mexico, Tel: (55) 5724 5900; E-mail: olgavera62@yahoo.com.mx
Received: May 17, 2019; Accepted: July 1, 2019; Published: July 08, 2019
Citation: Vera-Lastra O, Cruz-Domínguez MP, Medrado Ramírez G, Medina G, Amigo MC, Peralta-Amaro AL, Gayosso-Rivera JA, Jara LJ (2019)
Autoimmune/Inflammatory Syndrome Induced by Silicone Breast Implant and Risk Factors Associated to Autoimmune Diseases. Rheumatology
(Sunnyvale). 9:248.
Copyright: © 2019 Vera-Lastra O, et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License,
which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
Rheumatology (Sunnyvale), Vol.9 Iss.1 No:1000248 1
INTRODUCTION
Autoimmune/Inflammatory Syndrome Induced by Adjuvants
(ASIA) is a new syndrome which includes the following:
siliconosis, Gulf War syndrome, macrophagic myofasciitis
syndrome, and post-vaccination phenomena. Siliconosis
comprises a broad spectrum of clinical entities, including
Silicone Breast Implant (ASIA-SBI) [1,2]. In epidemiological
studies, the association of SBI and autoimmune diseases (AID)
has been controversial [3,4]; however some studies, support the
association between SBI and AID [5,6]. Recently, a study that
included a large number of patients (99,993) with SBI, found a
significant association between SBI and diseases such as Sjogren
syndrome (SS), systemic sclerosis (SSc), and rheumatoid arthritis
(RA) [7]. In this regard, it has been reported that silicones may
develop oxidization to silica and also silicon-containing gel
induces an increase of immune response activity [8]. The
mechanism through which silicones produce autoimmunity is
similar to the model proposed for other adjuvants by the
activation of innate and adaptive immunity and activation of the
Th1 and Th17 response with release of interleukin 17 that
stimulates fibroblasts leading to fibrosis [9,10]. Therefore,
disorders in the modulation of cytokines can be responsible in
susceptible individuals, for a perpetuation of the inflammatory
response which can locally lead to capsule contracture and at the
systemic level to possible triggering of AID [11]. Hence, silicone
present in the breast prosthesis acts as an adjuvant [8,12].
However, the presence of other environmental factors associated
with SBI-AID has been scarcely studied.
MATERIALS AND METHODS
Patients and methods
This study was performed in a tertiary referral center from 2012
to 2018, from a cohort of 210 patients with ASIA according to
Shoenfeld´s criteria [1]. The inclusion criteria were: patients
with SBI, clinical manifestations of any AID and criteria for
ASIA. Exclusion criteria: patients with SBI plus other adjuvants
such as vaccines, mineral oil and other modelant substances,
patients with rheumatic disease prior to SBI.
We retrospectively analyzed files of patients that met criteria for
ASIA- SBI. This study was approved by local Committee of the
Hospital. In our ASIA clinic, all patients are investigated for
ARD clinical manifestations and autoantibodies are determined.
Clinical manifestations of ARD were evaluated and classified
according to established criteria of The American College of
Rheumatology (ACR)/European League Against Rheumatism
(EULAR) for RA, SLE, SSc, SS, inflammatory myopathies,
vasculitis, antiphospholipid syndrome (APS). We also
investigated overlap connective tissue disease syndrome
(OCTDS), undifferentiated connective tissue syndrome
(UCTDS); other rheumatic diseases such as fibromyalgia (FM),
and diseases of allergic origin i.e. angioneurotic edema (AE) and
urticaria.
We also evaluated personal and family history of AID, tobacco
smoking, coexisting allergies and comorbidities such as
autoimmune hypothyroidism, depression, anxiety and others.
We also evaluated the following: antinuclear antibodies (ANA)
determined by indirect immunofluorescence, with normal
values less than 1:80, antibodies to double stranded DNA (Anti
sdDNA), anti-topoisomerase I (formerly called Scl-70), anti-
centromere (ACA), Sjogren ’ s syndrome antibodies-A (SSA) or
anti- Ro, Sjogren’ s syndrome antibodies-B (SSB) or anti-La,
rheumatoid factor (RF), anticyclic citrullinated peptide (ACPA),
anti-cardiolipin antibodies (aCL), lupus anticoagulant (LAC)
and thyroid peroxidase antibodies (TPO). We also measured C-
reactive protein (C-RP), erythrocyte sedimentation rate (ESR),
cell blood count, liver function, and urine. Histological studies
(lymph node biopsy, breast prosthesis and skin) and imaging
studies (Magnetic Resonance Imaging (MRI), computed
tomography (CT), ultrasound of breasts and mammography)
were undertaken for determining affection of SBI. We also
analyzed medical and surgical treatments used in these patients.
Statistical analysis
Descriptive statistics was used to summarize the baseline
demographic and clinical characteristics of ASIA-SBI.
Continuous variables were presented as a mean ± standard
deviation (SD) value, and discrete variables were reported as
median (minimum-maximum). We used chi square and Odds
Ratio (OR) with confidence intervals at 95% for the analysis of
ASIA-SBI and risk factor for development of AID.
RESULTS AND DISCUSSION
We studied 45 female patients with ASIA-SBI (all patients
received different types of implants from different
manufacturers for cosmetic purposes). One of these patients had
additionally implants of silicon in buttocks and in right eye. The
median current age was 50 (29-75) years and the age at
placement of the prostheses was 30 (15-43) years. The mean
disease course is 11 ± 4.9 years. Table 1 shows demographic
data, associated factors and comorbidities. Family history of
AID and tobacco smoking were statistically significant risk
factors for the development of systemic sclerosis and rheumatoid
arthritis. The most frequent comorbidities were hypothyroidism
of autoimmune origin and depression.
Table 2 shows patients with SBI who met criteria for some AID.
SSc was the most frequent, followed by RA, UCTD and SLE.
Regarding rheumatic diseases, FM was found in 5 patients
(11%), without an association to rheumatic diseases; in addition
we found FM in ASIA-SBI associated to other rheumatic
diseases in another 5 patients. We also observed three patients
with angioneurotic edema (AE), one patient with Takayasu
arteritis, and one with adult onset Still's disease (AOSD), among
others.
The principal immunological laboratory findings were ANA
with low to medium levels in the majority of cases, although in
some cases they were high. In all SSc patients there were more
ACE than anti Scl-70. All patients with RA had positive RF and
SLE patients showed ANA with homogeneous pattern or diffuse
patterns, as well as anti dsDNA, and anti RNP. Patients with
ASIA – SBI and FM had low levels of ANA and other
autoantibodies such as anti Ro, anti La and anti RNP. The range
Vera-Lastra O, et al.
Rheumatology (Sunnyvale), Vol.9 Iss.1 No:1000248 2
of numbers of ANA was from 1 to 5. We also noted increased C-
RP and ESR (Table 3).
The most common adverse reactions after silicone breast
implant (SBI) were capsular contracture, rupture and infection
(Figure 1). The main histological findings were chronic
granulomatous inflammation and body type reactions from
implant fibrous capsule to silicone corpuscles (Figure 2).
Regarding treatment, all patients were managed according to
main rheumatic disease. Patients with SSc received methotrexate
(MTX), mycophenolate mophetil, calcium channel blockers,
proton pump inhibitor, and non-steroids anti-inflammatory
drugs (NSAIDs). Patients with RA received MTX and low doses
of prednisone during short periods and f lares. Patients with SLE
received chloroquine, prednisone and one case of
neuropsychiatric lupus received methylprednisolone pulses and
bimonthly cyclophosphamide over a year. UCTDS patients were
treated with steroids or NSAIDs and patients with FM were
treated with antidepressants (inhibitors of serotonin recapture),
NSAIDs and psychological therapy. All of the above treatments
provided complete response in some patients or incomplete
control with remissions and exacerbations of AID.
Prosthesis removal was done in 16 patients due to shrinking
and/or breakage, with manifestations of pain. In addition, two
patients had infections, with re-implantation of new prosthesis
in 8 patients, with improvement of symptoms in 5.
We evaluated 45 patients with ASIA-SBI that developed various
ARD, being SSc, RA, UCTD and SLE the most frequent,
followed by SS, OCTD, AE, AODS and APS. In ASIA-SBI
patients, family history and smoking had a significant
association for developing of SSc and RA.
These ARD especially SSc are more frequent than those
observed in others studies [2,13]. The majority of these patients
had family history of ARD such as RA (2 patients),
granulomatosis with polyangiitis (one patient), and SLE (3
patients). One patient had asthma and two patients were allergic
to drugs. None of them had history of working exposure to
silicon. Several causative agents have been proposed as etiology
of SSc, chemicals have been the most suggested ones. Among
them, silica and SBI have been related to SSc development;
however, this association has been controversial. Different meta-
analyses did not find an increased risk of the association of SBI
and SSc, yet, these meta-analyses have some biases [14,15]. Rubio
Rivas et al. [16] found an increased risk of SBI to induce SSc.
Recently in a large post approval study a significant association
between SBI and AID such as SSc, SS and RA was found [7].
However, in several studies, some confounding factors were not
taken into account, such as lifestyle, smoking, exposure to
ultraviolet light, history of cancer and family history among
others, which are important in the development of AID [7,17].
In our patients, the average time from placement of SBI to first
manifestations of SSc was greater than 8 years, which indicates a
long period for the appearance of SSc. Our patients also had a
family history of AID which implies a close interaction between
environmental factors, genetic factors and the immune system.
The second ARD was RA, this disease was observed in 8
patients, 4 patients had family history of ARD and 4 patients
had history of smokingThe association of working exposure and
AID is well recognized for silica, and suspected for others
chemical substances. Among heavy smokers, both silica and
other inorganic dust exposures have been associated with
increased risk of RA [18]. In addition to the family history for
RA, environmental factors such as smoking have been associated
with triggering of RA, however, there are other candidates such
as silicone [19,20]. Silicon and SBI may cause autoimmune
responses which lead to the development of RA [2,21,22].
Recently a strong association between SBI and RA with a
Standardized incidence ratio (SIR) of 5.96 was found [7].
In the present study, a case of AOSD also was associated with
SBI. In our patient there was a previous history of probable
systemic onset juvenile idiopathic arthritis, who in adolescence
received SBI and later developed AOSD. With regard to this
disease there are some case reports attributed to SBI [23,24].
With respect to SLE, we found 4 cases, with a broad spectrum of
autoantibodies, including antibodies against factor VIII and
manifestations of bleeding with diagnosis of acquired
hemophilia plus SLE in one patient. Another patient had severe
neuro-psychiatric manifestations. The other two patients had
hematological SLE and cutaneous and articular conditions. One
patient had history of heavy smoking and another of family
history of ARD. In experimental models of murine lupus, it has
been demonstrated that implantation of silicone influences the
immune response and the production of different
autoantibodies [25]. It has been reported that some of the
patients with SBI developed clinical manifestations that did not
meet established criteria for SLE, but had various self-antibodies
as anti-Ro [26]. Other studies have reported the association of
SBI and SLE, as well as the generation of various autoantibodies
[27].
With regard to SS, an epidemiological study investigated the risk
of ARD and SBI patients finding a relative risk of 2.0 [28].
Recently, it was reported that SS had a significant association
with SBI with a SIR of 8.14 [7].
We had 2 cases with overlap syndrome (one had SSc, RA and SS
and the other, RA and SSc), this association has also been
reported in cases with SBI [29,30]. On the other hand, several
cases or series of cases have shown that patients with SBI met
criteria for ASIA and also for non-specific manifestations of
definite diseases of connective tissue and presence of ANA,
entity which can be termed UCTD [30-32]. The majority of
these patients had comorbidities, such as autoimmune
hypothyroidism and one case had infertility with low levels of
anti mullerian hormone not associated with the use of
immunosuppressants. In relation to other AID, we found a case
of Takayasu arteritis with clinical manifestation of fever of
unknown origin, adenopathies and lack of pulses; there are no
prior reports of association with SBI in the literature. Some
studies have only reported systemic vasculitides associated to
anti-neutrophil cytoplasmic antibodies (ANCA) and SBI [2].
With respect to rheumatic diseases, we found 5 patients with
FM, who had non-specific manifestations of connective tissue or
Vera-Lastra O, et al.
Rheumatology (Sunnyvale), Vol.9 Iss.1 No:1000248 3
UCTD. In addition, we also found another 5 cases of secondary
FM associated with some AID. In these cases there is an overlap
of manifestations being pain, fatigue and neurological disorders
(cognitive alterations) the most prevalent. Recently Khoo [33]
reported 30 patients with SBI in whom 10% had FM; we found
a higher frequency in our study. FM shares some manifestations
with ASIA criteria. Factors of atopy and hyperimmune state as
well as low levels 5-Hydroxyindoleacetic acid (5-HIAA) a
serotonin metabolite have related to ASIA and FM respectively
[34]. Other factors have also been implicated, such as surgery for
exchange of SBI. Hence, SBI can be considered as trigger of FM
[34]. Further, SBI surgery and depression can be stressful events
for the patient and can be considered risk factors for suicide
[33,34]. In this context, we observed one suicide in our study.
We found criteria for mild to moderate depression in 6 patients
and for severe in 2.
Another disease observed was angioneurotic edema where there
was a history of allergy to drugs and food in all patients. This
entity has already been reported in patients with SBI [29].
Finally, we consider that there are patients who are not
candidates for SBI placement, such as patients with family
history of AID and allergies or atopic patients as previously
described [30]. We suggest that before these patients undergo
placement of SBI they should be tested for immune markers of
AID. In general, all women who want prostheses should have a
thorough history and physical examination, emphasizing AID.
Our study has some limitations in that it has a retrospective
design and with its different biases. We evaluated a select group
of patients who were referred because they had some complaints
of AID; however, there are many women who have undergone
SBI placement who do not have clinical manifestations of
autoimmunity or these are minimal.
Table 1: Demographic data, associated factors and comorbidities in
patients with ASIA-silicone breast implant.
Different type of cases Number
Percentage
(%)
Sex-Female 45 100 (%)
Current age (Years) -- --
Median (Range) 50 (29-75)
Age at placement SBI -- --
Median (Range) 30 (15-43)
Mean time from onset of symptoms (Years) 8.8 ± 5.5 --
Mean disease course of disease. 11 ± 4.9 --
Family history of rheumatic disease * 19 42%
Allergies 17 37.5
Tobacco smoking * 16 35.5
Deaths 1 2.2
Comorbidities -- --
Autoimmune hypothyrodism 10 22
Depression 8 17.7
Systemic arterial hypertension 7 15.5
Obesity 5 11.1
Asthma 2 4.4
Neuropathies 1 2.2
Thyroid cancer 1 2.2
Infertility (Low levels of anti-mullerian
hormone) 1 2.2
Infertility and pituitary adenoma 1 2.2
* A Chi-square analysis showed a significant association between
family history and tobacco smoking with an increased risk for
systemic sclerosis: OR 6.0 (CI 1.2-29), p<0.02 and rheumatoid
arthritis: OR 7.1 (CI 1.3-37.2), p<0.022.
Table 2: Autoimmune disease in patients with ASIA-silicon breast
implant. N=45.
Autoimmune rheumatic diseases
Rheumatic disease Patients
Percentage
(%)
Systemic sclerosis 10 22
Rheumatoid arthritis 8 17.7
Undifferentiated connective tissue diseases 6 13.3
Systemic lupus erythematosus 4 8.8
Sjogren syndrome 3 6.6
Overlap syndrome 2 4.4
Vasculitis: Takayasu arteritis 1 2.2
Adult Still's disease 1 2.2
Antiphosfolipid syndrome 1 2.2
Allergies and rheumatic disease -- --
Angioneurotic edema/urticaria 3 6.6
Fibromyalgia (FM) * 5 11.1
Carpal tunnel syndrome 1 2.2
Vera-Lastra O, et al.
Rheumatology (Sunnyvale), Vol.9 Iss.1 No:1000248 4
*Fibromyalgia associated to ASIA- SBI was found in 5 patients.
Fibromyalgia associated to other AID was found in other 5 patients
Table 3: Laboratory findings in patients with ASIA-Silicone breast
implant. N=45.
Autoantibody
Number of
patients Percentage (%)
Anti-nuclear antibodies 37 82.2
Anti-centromere antibodies
(ACE) 10 22.2
Anti SCl 70 4 8.8
Anti Ro/La 3 6.6
Anti RNP 6 13.3
Anti-cardiolipin antibodies 1 2.2
Anti - Factor VIII adquired 1 2.2
Anti-cyclic citrullinated
peptide (ACPA) 7 15.5
Rheumatoid factor 8 17.7
C-reactive protein increased 33 73.3
Erythrosedimentation rate
increased 31 68
Complement C3/C4 levels
low 3 7.6
Silicone Breast Implant N=45
Figure 1: Silicone breast implant, A-contracture of silicone breast
implant grade III, B- contracture of silicone breast implant grade IV
and rupture with chronic presence of silicone (like-caseous material).
Figure 2: Histological findings of a silicone breast implant removed
from a patient, A-Hematoxylin and eosin stain 4X. Chronic
granulomatous inflammation with accumulations of histiocytes
surrounded by mature lymphocytes is observed. Courtesy of Socrates
García Gutierrez MD Department of Pathological Anatomy. Hospital
de Especialidades, Centro Médico Nacional La Raza, B- Hematoxylin
and eosin stain 40X.
This figure (*) shows multinucleated giant cell, surrounded by
histiocytes. Courtesy of Socrates García Gutierrez MD.
Department of Pathological Anatomy. Hospital de
Especialidades, Centro Médico Nacional La Raza.
CONCLUSION
In patients with ASIA-SBI, family history of AID and
environmental factors were associated with AID. Environmental
and genetic factors for the development of AID must be taken
into account in patients undergoing SBI in order to prevent the
development of ASIA-SBI.
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