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Silicones are widely used materials in many fields of medicine and largely are believed to be biologically inert. However, some investigators have reported that silicone implants are associated with an increased incidence of autoimmune disorders. In this study, we evaluated the capsular tissue of silicone implants and the sera of implant patients and controls for antisilicone antibodies and nonspecific immunoglobulins (IgG, IgA, IgM, and IgE). Our study group included 15 patients (eight men and seven women) undergoing reconstructive procedures for burn scars, in whom we used silicone implants, and 15 sex-matched controls undergoing reconstructive surgery for burn scars without using silicone implants. By immunofluorescence, we discovered strong capsular binding of IgG and weak capsular binding of IgM; antisilicone antibody levels were significantly higher in capsular tissue than elsewhere. Serum IgE also was higher in patient vs control subject sera. In conclusion, silicone materials do lead to an immune response consisting of antisilicone antibodies most evident immediately adjacent to the implant itself.
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ORIGINAL ARTICLE
The association between silicone implants
and both antibodies and autoimmune diseases
Mehmet Bekerecioglu & Ahmet Mesut Onat &
Mustafa Tercan & Hakan Buyukhatipoglu &
Metin Karakok & Daghan Isik & Omer Bulut
Received: 15 October 2006 /Revised: 18 May 2007 /Accepted: 21 May 2007
#
Clinical Rheumatology 2007
Abstract Silicones are widely used materials in many fields
of medicine and largely are believed to be biologically inert.
However, some investigators have reported that silicone
implants are associated with an increased incidence of auto-
immune disorders. In this study, we evaluated the capsular
tissue of silicone implants and the sera of imp lant patients
and controls for antisilicone antibodies and nonspecific im-
munoglobulins (IgG , IgA, IgM, and IgE). Our study group
included 15 patients (eight men and seven women) under-
going reconstructive procedures for burn scars, in whom we
used silicone implants, and 15 sex-matched controls under-
going reconstructive surgery for burn scars without using
silicone implants. By immunofluorescence, we discovered
strong capsular binding of IgG and weak capsular binding of
IgM; antisilicone antibody levels were significantly higher in
capsular tissue than elsewhere. Serum IgE also was higher in
patient vs control subject sera. In conclusion, silicone ma-
terials do lead to an immune response consisting of anti-
silicone antibodies most evident immediately adjacent to the
implant itself.
Keywords Antisilicone antibody
.
Capsular tissue
.
Immunoglobulins
.
Silicone
Introduction
Currently, silicones are used commonly in medicine. An
increasing number of patients receive silicone implants
during the course of plastic surgery. These implants may
cause foreign body reactions and local or systemic symp-
toms. Silicone imp lants have been accused of precipitating
rheumatic disorders and nervous and pulmonary system
dysfunction by means of auto-antibodies and abnormalities
in cellular immunity [1]. Several researchers have investigat-
edtheroleofsiliconeinimmunity[2, 3]. Studies have iden-
tified several kinds of antibodies (antinuclear antibodies,
rheumatoid factor, anticardiolipin antibodies IgG and IgM,
anti-Ro and anti-La) in silicone-implant patients [4, 5]and
higher levels of certain other antibodies (antisilicone anti-
bodies) [6]. In this study, we examined both for nonspecific
immunoglobulins (IgG, IgA, IgM, and IgE) and for specific
antisilicone antibodies in blood and capsular tissue samples.
The aim of this study was to identify specific and nonspecific
Ig expression in capsular tissue and in the sera of patients
with silicone implant expanders.
Clin Rheumatol
DOI 10.1007/s10067-007-0659-1
M. Bekerecioglu
:
D. Isik
:
O. Bulut
Department of Plastic and Reconstructive Surgery,
Gaziantep University School of Medicine,
Gaziantep, Turkey
A. M. Onat
Department of Rheumatology,
Gaziantep University School of Medicine,
Gaziantep, Turkey
H. Buyukhatipoglu (*)
Department of Internal Medicine,
Gaziantep University School of Medicine,
Gaziantep, Turkey
e-mail: buyukhatip@yahoo.com
M. Karakok
Department of Pathology,
Gaziantep University School of Medicine,
Gaziantep, Turkey
M. Tercan
Department of Plastic and Reconstructive Surgery,
Haydarpasa Numune Training Hospital,
Istanbul, Turkey
Materials and methods
We included 15 patients, eight men and seven women, who
had undergone reconstructive operative procedures between
January 1997 and December 2002. All patients had burn scar
contractures. Study and control groups consisted of healthy
individuals, except for their burn scars. Baseline serum Ig A,
G, M, and E levels were measured for all subjects. Anyone
who had a history of allergic or rheumatological diseases or
high baseline levels of any of the antibodies of interest was
excluded. Tissue expanders were placed adjacent to normal
tissue. Mean tissue expander volume was 250 cc (70450 cc).
Only one tissue expander was used per patient. The expanders
were left in place from 8 to 12 weeks (mean 9.3 weeks).
Evaluation of capsular tissue
We collected capsular tissue samples in patients with silicone
tissue expanders at the expansion ends of healthy tissue. Five-
micron frozen sections of capsular tissue were stained for
IgG, IgA, IgM, and IgE by immunofluorescence (Dako Lab,
Denmark). Capsular tissue samples were homogenized and
then incubated for 4 h with rabbit antibodies to human IgG.
Silicone capsule antibodies were expressed in optical density
units. Antisilicone antibodies in capsular tissue were detected
by ELISA (Sigma BioSciences, St. Louis).
Evaluation of serum
Blood samples were studied for immunoglobulins (Pharmacia
and Upjohn Diagnostics, Freiburg, Germany). Silicone anti-
bodies were identified by ELISA (Beckman Instruments,
Fullerton) [7].
Control group
A control group consisted of 15 patients (eight men and seven
women) undergoing reconstructive surgery for burn scar
contractures without using any silicone products. They had
no rheumatologic or immunological disease. Blood samples
were collected as part of the routine preoperative assessment.
Tissue samples were collected during the surgical procedure.
Statistical analysis
Between-group analyses were performed using Mann
Whitney U tests. Spearmans co rrelation tests were con-
ducted to investigate for bivariate correlations. Data were
analyzed using SPSS software (version 13.0). All analyses
were two-tailed, and p<0.05 was set as the threshold for
statistical significance.
Results
Patients with tissue expanders vs controls
a. Capsular tissue
Patient characteristics are shown in Table 1. Capsular
tissues exhibited stro ng immunofluorescence for IgG and
limited immunofluorescence for IgM, but there was no
detectable binding at all for IgA or IgE (Table 1, Fig. 1). In
Table 1 Demographic characteristics and antibody results in silicone-implant patients
Patients Serum Tissue Silicon antibody
Biochemical analysis Immunofluorescence technique ELISA
a
Number Age/sex IgG g/l IgM g/l Ig E IU/ml IgA g/l Ig G Ig M Ig E IgA Serum Tissue
1 25/M 8.57 0.92 175.4 1.42 ++ + ––0.012 0.310
2 32/M 9.63 0.56 107.2 3.66 ++ + ––0.022 0.620
3 17/F 8.03 2.44 220.4 1.15 ++ + ––0.032 0.256
4 42/M 12.46 1.51 170.9 2.77 ++ + ––0.009 0.608
5 12/F 10.03 3.00 141.5 4.20 ++ + ––0.005 0.762
6 54/M 17.11 2.97 238.1 1.02 ++ + ––0.032 0.437
7 14/F 9.58 1.46 344.3 3.97 ++ + ––0.043 0.651
8 4/F 13.05 0.73 224.8 2.17 ++ + ––0.065 0.873
9 15/M 14.70 2.65 218.5 1.83 ++ + ––0.053 0.597
10 33/M 9.80 3.05 162.7 4.49 ++ + ––0.029 0.486
11 30/F 10.71 0.93 229.1 1.23 ++ + ––0.071 0.629
12 28/M 9.93 1.16 256.4 1.11 ++ + ––0.048 0.695
13 21/M 12.04 1.41 167.3 3.09 ++ + ––0.026 0.572
14 14/F 9.57 2.38 182.3 2.61 ++ + ––0.081 0.773
15 35/F 9.98 1.53 242.6 1.79 ++ + ––0.046 0.698
M Male, F female, ++ strong positive immunofluorescence, + weak positive immunofluorescence
a
Values of IgG binding to silicone capsular tissue expressed in optical density units
Clin Rheumatol
the figure, strong immunofluorescence is demarcated with
two plus signs and weak immunofluorescence with a single
plus sign. Levels of capsular antisilicone antibodies were
significantly higher in silicone-implant patients (0.59±0.16
vs 0.030±0.012; p<0.001). Control patient characteristics
are presented in Table 2. Capsular tissues in control patients
did not exhibit any immunofluorescence.
b. Serum
Only IgE levels were significantly higher in the sera of
silicone-implant patients vs controls (205.3±56.9 vs 32.4±
8.7; p<0.001). Levels of other immunoglobulins were in
the normal range. Antisilicone antibodies were slightly
higher in silicone-implant patients; however, the difference
between means was not statistically significant (0.038±
0.022 vs 0.032±0.018; p =0.24). Bivariate correlations
between serum IgE and antisil icone antibodies, both in
serum and capsular tissue, were not statistically significant.
Discussion
Polydimethylsiloxane (PDMS) is the simplest silicone
structure in medical usage. Silicone is highly biocompati-
ble, nontoxic, nonallergic, and resistant to biodegradation.
Silicones can simulate different soft tissues as a liquid, gel,
or rubber by varying the length and degree of cross-linking
of the PDMS chains.
After a silicone implant is placed, a tissue response occurs.
This reaction generally is limited to a mild foreign-body
reaction, which then is followed by encapsulation. Capsular
tissue forms around any nondegradable material that is too
large to be engulfed by macrophages and that is so inert that it
causes no more than a local foreign body reaction [8].
This study is different from prior studies in that we
examined for the presence of antisilicone antibodies and
nonspecific immunoglobulins in the capsular tissue, itself,
something which has never been studied before. In several
animal models, silicone gel has been discovered to increase
antigenicity. There have been a few reports demonstrating
antibodies to silicone in human serum: Pastor et al. [4]and
Wolf et al. [6] found increased levels of antisilicone anti-
bodies in the majority of their patients but did not identify a
relationship between these antibody levels and autoimmune
disease. Goldblum et al. [9] detected increased IgG levels
Fig. 1 IgG staining of capsular tissue by immunofluorescence (×400
magnification) 183×116 mm (72×72 DPI)
Table 2 Demographic characteristics and antibody results in controls
Controls Serum Tissue Silicon antibody
Biochemical analysis Immunofluorescence technique ELISA
a
Number Age/sex IgG g/l IgM g/l Ig E IU/ml IgA g/l Ig G Ig M Ig E IgA Serum Tissue
1 5/F 11.41 2.71 23.12 1.19 –– 0.019 0.027
2 40/M 9.01 1.44 43.28 1.07 –– 0.012 0.015
3 19/M 9.37 1.71 41.76 2.26 –– 0.022 0.031
4 24/M 13.81 0.83 32.78 1.20 –– 0.015 0.010
5 32/F 12.07 0.96 33.45 1.81 –– 0.017 0.020
6 11/F 11.72 1.47 54.27 2.75 –– 0.030 0.028
7 14/F 9.87 1.73 21.38 1.39 –– 0.036 0.041
8 23/M 13.46 1.62 35.67 3.01 –– 0.035 0.047
9 15/M 11.65 2.06 31.29 1.93 –– 0.032 0.024
10 30/M 12.08 1.14 23.65 1.32 –– 0.031 0.033
11 29/F 11.56 0.94 26.33 1.70 –– 0.054 0.055
12 13/F 12.65 3.51 28.91 2.62 –– 0.039 0.046
13 15/M 14.13 1.35 34.68 1.78 –– 0.036 0.029
14 35/M 9.69 0.78 27.72 1.14 –– 0.018 0.027
15 16/F 10.59 2.56 29.43 2.06 –– 0.014 0.018
M Male, F female
a
Values of IgG binding to silicone capsular tissue expressed in optical density units
Clin Rheumatol
against silicone medical implants [10]. However, these stud-
ies evaluated serum samples only.
In the present study, we identified significantly increased
antisilicone antibodies in capsular tissue. We also discovered
IgG and IgM antibodies, by IFA, in capsular tissues in silicone-
implant patients. The levels of serum antisilicone antibody
levels were slightly higher in implant patients vs controls, but
this increase was not statistically significant. Nevertheless, if the
sample size had been greater, the difference might have been
significant. Evans et al. [11] reported that normal individuals
have basal antisilicone antibody levels; however , they also
reported that antisilicone antibody levels were significantly
higher in their breast-implant patients. Microscopic evidence
of silicone has been discovered in other bodily tissues in
breast-implant patients [12]. Furthermore, Iannello [13]
identified silicone compounds in the blood and liver of those
with silicone implants. Combining the results of our study and
previous studies, we might conclude that silicone particles,
albeit in very small quantities, scatter throughout body tissues,
leading the human body to produce specific antibodies. This
body reaction seems to be related to the amount of silicone
exposed in blood, body tissues, and the capsule. We identified
a significantly greater react ion in capsular tissue than
elsewhere. On the other hand, we discovered elevated serum
IgE levels possibly because of a foreign body reaction. There
was no correlation between serum IgE levels and the levels of
capsular or serum antisilicone antibodies.
Whether silicone implants lead to the development of
rheumatologic or immunologic disorders remains unknown.
Several authors have speculated about the likelihood of a
relationship. Karlson [14] reported on the activation of the
immune system in female silicone-implant recipients. In
other studies, several types of auto-antibodies have been
found to be increased [9, 15, 16], and a single study
identified an increased prevalence of rheumatic conditions in
females with breast implants [17]. On the other hand, Peters
et al. [18] identified no increase in antinuclear antibodies in
those with silicone implants.
To summarize, taken together, the previous reports and
the results of our study suggest that silicone implants cause a
negligible and nonspecific foreign body reaction. However,
we feel that these antibodies against the silicone implants
have little or no clinical importance. To determine any
causative association between silicone implants and autoim-
mune disease, furt her long-term studies are warranted.
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Human adjuvant disease or autoimmune disease after implantation of foreign material occurs subsequent to injection or implantation of paraffin/silicone and, possibly, silicone polymers. Patients develop signs, symptoms, and laboratory abnormalities suggestive but not diagnostic of a connective-tissue or autoimmune disease. The purpose of this paper is to present a thorough review of the literature, case studies, and guidelines for the possible identification of these patients. While previously reported in the Japanese literature, at the present time there are still many questions surrounding this disorder. The condition has not as yet been well-established, and further research is needed to explore these relationships in the U.S. population.
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Silicone implants have been associated with the development of multiple organ system abnormalities, including rheumatic disorders, nervous system, pulmonary dysfunction associated with autoantibodies and abnormalities of cellular immunity. In this regards a number of case reports and series of articles have been described. We hypothesized that an immune reaction to silicone breast implants would include the host reactivity against silicone and the macromolecules within the microenvironment of the implant, and these autoantibodies may react with other tissue antigens far from the site of the implant. To test this hypothesis 520 Symptomatic women with Silicone Implants which have developed Silicone related Immunological disorders and have typically complained of breast pain, Myalgia-Arthralgia, fatigue, or generalized pain, were examined by their physician. Blood samples were obtained and examined for the presence of Silicone antibodies, Myelin Basic Protein and human serum albumin antibodies. These samples were then compared to 520 matched controls without implants. At least at the level of two standard deviation silicone specific antibodies, IgG, IgA IgM, IgE and IgG+IgA+IgM antibodies were detected above the mean of normal controls. When these antibodies were classified based on the specialty of the examining physician, the % of patients with Silicone Antibodies were varied; general practice 51.6, Rheumatology 58.7, and Plastic Surgery 83.3, which may relate to the severeness of the disease. Being that a large % of patients demonstrated very high levels of Myelin Basic Protein Antibodies, possible cross reactive antibodies were sought. However, absorption of highly positive sera for Silicone Antibodies with MBP did not change the levels of Silicone Antibodies. On the other hand, Silicone-HSA was able to reduce the antibody values significantly. This reduction in antibody levels by Silicone is the best indication for the specificity of these antibodies. Moreover when data for silicone antibodies and MBP antibodies was analyzed in patients some with high and others with medium or low levels of silicone antibodies, MBP antibodies did not correspond to the silicone antibody levels. Similarly human serum albumin antibodies which was significantly higher in patients with silicone implants did not correlate with levels of silicone antibodies. These results indicate that immune reaction to silicone and different tissue antigens do occur and they are initiated through different mechanisms. And since predominant antibody class against silicone, MBP and HSA was IgM, clonal activation of IgM is possible which certainly warrants further investigation.
Article
There is currently no proven cause-and-effect relationship between breast implants and autoimmune connective tissue disease. However, there is a growing concern that immunological sensitization to silicone could potentially develop in certain susceptible patients and that this could contribute to the development of autoimmune connective tissue disease. In this article I review the current status of this potential relationship. The following areas are discussed: chemistry of silicone, potential mechanisms for an immune response, implant failure, epidemiological and antibody studies of autoimmune connective tissue disease, and recent information on certain neurological findings in a group of patients with breast implants. Current large-scale epidemiological studies should help to define any potential relationship between breast implants and autoimmune connective tissue disease.
Article
The present study was conducted to determine if 200 patients with silicone-gel implants demonstrated elevated levels of autoantibodies, compared with a similar group of 100 age-matched control subjects without breast implants. These results were then compared with 29 patients who had demonstrated implant rupture. Differences in the frequency of autoantibody levels were determined by the chi-squared test. Differences in autoantibody titers were determined by Wilcoxon's signed rank test. Differences were considered significant with p > 0.05. The prevalence of a positive antinuclear antibody (ANA) test (dilution 1:100) in the 200 patients with breast implants was 26.5% compared with 28% in the 100 control subjects. In 29 patients with implant rupture, only 17.2% tested ANA positive. These values were not significantly different. In addition, there were no significant differences between the ANA titers of positive patients in each group. In each of the three groups, all patients who tested ANA positive were analyzed to assess the frequency and titer of other autoantibodies, including anti-DNA, anti-cardiolipin, anti-SSA, anti-SSB, anti-SM, anti-RNP, and anti-Scl-70. There were no significant differences between the frequency or titer of any of these autoantibody levels in each of the three groups of patients. These studies strengthen the concept that there is no conclusive evidence that silicone-gel implants are related to the development of connective tissue disease.
Article
Microscopic silicone in various tissues in the bodies of females with breast implants has led to the possible incrimination of these implants with connective-tissue disorders. Current technology precludes accurate silicone measurements, but all compounds containing the element silicon (which would include silicone) may be measured accurately. Direct positive correlations of silicon assays with silicone measured levels were confirmed by adding known amounts of silicone oil as a control. With the ubiquitous nature of organosilicons (food containers, syringes, etc.), we hypothesized that baseline silicon levels could be detected in tissues of cadavers without silicone breast augmentation. Ten cadavers were examined. Tissue samples were derived from subcutaneous fat, nipple, breast tissue, liver, spleen, and axillary nodes. Nine of 10 cadavers had silicon levels in various tissues. Measurements were performed by direct current atomic emission spectroscopy. The baseline data were compared with those from four augmented patients who underwent capsulectomies and implant removal. Silicon levels were fivefold higher in the augmented patients than in the nonaugmented cadavers. No difference in levels was noted if the patient had an intact or ruptured implant and/or was symptomatic versus asymptomatic for immunologic disease. This study was designed to measure baseline silicon levels in the normal population. It also has established an accurate level of measurement of tissue silicone.
Article
There have been several anecdotal reports that silicone breast implants are associated with an increased incidence of autoimmune disease. Based upon these data as well as the theoretical potential of silicon and silicone immune interactions, we hypothesized that an immune response to a silicone breast implant would include host reactivity against components of the microenvironment within the implant milieu. To test this hypothesis, we obtained detailed histories and performed examinations of 57 consecutive, self-referred patients concerned about their breast implants. Eleven of these women were excluded for various reasons including previous exposure to bovine collagen. The remaining 46 women, as well as 45 normal women of approximately the same age and living in the same geographic region, were tested using a sensitive ELISA for the presence of autoantibodies to human native type I collagen, denatured type I collagen, native type II collagen and denatured type II collagen. Known positive and negative sera were included in all assays and the ELISA was performed and interpreted blindly. Positive sera were defined as an ELISA value of three standard deviations above the mean of the normal controls. Using these stringent criteria, there was a statistically significant incidence of antibodies to collagen in women with silicone breast implants. In fact, 35% of women with silicone breast implants had such antibodies; this is higher than we have observed in any other autoimmune disease and is similar to that of chronic erosive rheumatoid arthritis. We believe that silicone breast implants, in genetically susceptible hosts, may pose a significant risk for immunopathology.
Article
Although initially it was thought that polydimethylsiloxane (silicone) was biologically inert, recent published studies have demonstrated varying levels of IgG antibody reactive with this structure in humans. The objective of our study was to determine whether silicone implanted in humans results in a measurable immune response directed against a 3700 mol wt hydroxyl terminated silicone molecule and whether that response could be correlated with the level of presumed silicone exposure as inferred by clinical history. In a blind study, sera from 111 patients, with and without breast implants, were sent to a laboratory using an enzyme-linked immunosorbent assay to determine specific anti-silicone IgG antibody levels. Test results showed that patients with implants demonstrated statistically significant elevation in anti-silicone antibodies compared with the unimplanted control groups. The highest anti-silicone antibody levels were measured in implanted women with either frank implant ruptures or leakage of their silicone gel implants.
Article
In the past 10 years, there have been multiple published reports associating silicone breast implants with scleroderma, morphea, SLE, rheumatoid arthritis, CREST syndrome and "human adjuvant disease." The alleged offending material, silicone, is a synthetic polymer containing a silicon-oxygen backbone. Beginning with the heating of SiO2 in the presence of carbon, elemental silicon is produced. Methylchloride is added and the resulting product is hydrolyzed to form low molecular weight prepolymers which are linked to form linear silicone polymers and cross-linked to yield silicone rubbers or elastomers. The polymeric and hydrophobic characteristics of silicone and the presence of electrostatic charges and organic sidegroups make silicone a potentially ideal immunogen, leading to cross-reactivity with autoantigens. Silicon is an essential constituent of proteoglycans which theoretically could result in immunological cross-reactions between silicone and connective tissues. Although the literature contains numerous examples of silicone-associated autoimmune disease, there is no consistent pattern of immunological abnormalities observed. There are, however, some intriguing and interesting observations. Further large-scale studies are needed to determine if a link between silicone exposure and autoimmunity exists. Also, since the inducing events of autoimmune diseases are unknown, studies on silicone could provide a model for autoimmune diseases associated with toxicological factors.