Silicate antibodies in Danish women with silicone breast implants

B. Jensen1,2,, A. Wiik3, I. Hechmann Wittrup1, S. Friis2, G.-Q. Shen4, H. Bliddal1, J. K. McLaughlin5,6, B. Lykke Thomsen2, B. Danneskiold-Samsøe1 and J. H. Olsen2,6

1 Parker Institute, Frederiksberg Hospital, Ndr. Fasanvej 57, 2000 Frederiksberg,
2 Danish Cancer Society, Division for Cancer Epidemiology, Strandboulevarden 49, 2100 Copenhagen Ø,
3 Department of Autoimmunology, Statens Serum Institut, Artillerivej 5, 2300 Copenhagen S, Denmark,
4 Specialty Laboratories, 2211 Michigan Avenue, Santa Monica, CA 90404-3900,
5 International Epidemiology Institute, 1455 Research Blvd., Rockville, MD 20850 and
6 Department of Medicine, Vanderbilt University Medical Center, Vanderbilt-Ingram Comprehensive Cancer Center, Nashville, TN 37232, USA


    Abstract
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 Abstract
 Introduction
 Materials and methods
 Results
 Discussion
 References
 
Objectives. To use a new immunological assay to evaluate silicate antibody levels in women with and without silicone breast implants (SBIs).

Methods. Women (n=186) were identified through Danish population-based registers and categorized into six groups defined by prior breast surgery (breast implantation/breast reduction/no breast surgery) and by the presence or absence of prior hospital diagnoses of soft-tissue rheumatism (muscular rheumatism, ICD-8 codes 717.90 and 717.99). The women underwent blood tests, a silicate antibody assay and a clinical examination. Severity of rheumatic symptoms/signs was scored from 1 (none) to 5 (severe).

Results. The level of silicate antibodies was not significantly different between the three groups with prior soft-tissue rheumatism (P > 0.5), with the lowest value among women with SBIs. Among women who had no prior diagnosis of soft-tissue rheumatism, silicate antibody levels were highest in women with SBIs (P < 0.01). No significant correlations were observed between silicate antibody levels and symptom severity scores.

Conclusions. Silicate antibodies were not consistently associated with SBIs and were not correlated with rheumatic symptoms. The clinical relevance of these antibodies remains questionable.

KEY WORDS: Silicate antibodies, Breast implants, Silicone, Symptom severity.


    Introduction
 Top
 Abstract
 Introduction
 Materials and methods
 Results
 Discussion
 References
 
Recent reviews of the epidemiological literature conclude that there is currently no evidence of an association between silicone breast implants (SBIs) and connective tissue diseases (CTDs) or other diseases [14]. Some clinical reports have suggested that women with SBIs may suffer from ‘atypical CTD’ [57]; however, the available epidemiological evidence provides no support for this hypothesis [8].

A systemic influence of silicone has been hypothesized on the basis of the detection of antibodies in sera of women with SBIs [9, 10] and patients with ventriculoperitoneal shunts [11], but others have been unable to detect anti-silicone antibodies in patients with SBIs [12, 13]. Higher levels of silicone derivatives in tissue and sera of women with SBIs than in controls have been suggested to be indicative of degradation of silicone in humans [1417], but these findings have been questioned [18]. Animal studies have indicated that silicones in vivo may be broken down to silicates and silica [15, 19], but human data are lacking.

A method for detecting and quantifying a specific humoral immune response to silicate in patients with SBIs was developed recently [14]. Using this assay, levels of silicate-specific antibodies of immunoglobulin (Ig) G or IgM isotype were found to be increased in the sera of 30% of symptomatic women with SBIs compared with 2% of healthy women without SBIs [14]. The reported symptoms were fatigue, fibromyalgia, insomnia, skin disorders, joint pain, muscle cramps, arthritis, allergies, arrhythmia and overt connective tissue disease [14, 20]. We used this new assay to examine the levels of silicate antibodies in women with SBIs and controls.


    Materials and methods
 Top
 Abstract
 Introduction
 Materials and methods
 Results
 Discussion
 References
 
The investigation of silicate antibodies in women with SBIs was part of a cross-sectional clinical study in Denmark. Using the Danish National Hospital Register of Patients (NHP) and the Central Population Registry (CPR), six groups of women had been identified previously [21]. They were selected according to a history of breast surgery (silicone breast implantation/breast reduction/no breast surgery) and the presence or absence of a prior hospital diagnosis of muscular rheumatism (a non-specific soft-tissue diagnostic entity; ICD-8 codes 717.90 and 717.99). Validation of the diagnosis of muscular rheumatism revealed that the diagnosis applied primarily to soft-tissue rheumatism [21, 22]. No specific pattern of symptoms suggestive of an atypical CTD was found among the women with SBIs [21, 22].

Study group A comprised 27 women with SBIs who had an NHP diagnosis of soft-tissue rheumatism subsequent to their breast implantation and prior to entering the current study (study group A). The five other groups were matched on age, date of muscular rheumatism and/or date of breast surgery, all within 5 yr intervals, with this index group of women with SBIs. Thus, we selected two comparison groups of women with an NHP diagnosis of soft-tissue rheumatism who had previously undergone breast reduction surgery (study group B; n=28), or who had undergone neither breast implant nor reduction surgery (study group C; n=26) (Table 1Go). In addition, three groups of women without prior soft-tissue rheumatism were selected: women (n=23) with SBIs (study group D), women (n=26) who had undergone breast reduction (study group E), and women (n=56) from the background population (identified from CPR) who had no record of breast implant or reduction surgery (study group F).


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TABLE 1. Characteristics of the six study groups (A–F)

 
Study participants underwent a thorough clinical examination, blood collection and an interview focusing on possible rheumatic complaints. Standard blood tests indicative of inflammatory rheumatic diseases were performed on all participants. A Likert rheumatic scale for symptom severity rating from 1 (no symptoms or signs) to 5 (severe symptoms and severe signs) was applied on the basis of self-reported symptoms and clinical signs.

Enzyme immunoassay for silicate antibodies
Patient samples were sent to Dr G.-Q. Shen, Specialty Laboratories, California for silicate antibody analysis. Samples were blinded as to the patients' implant status, symptoms and diagnoses. Details of the assay are described elsewhere [14].

Sodium silicate (Na2SiO3) adsorbed onto bovine serum albumin (BSA)-precoated plates served as the antigen in an enzyme immunoassay (EIA) to detect and quantitate silicate-reactive antibodies of IgG or IgM isotype in plasma. Plates were precoated with 200 µl per well of 0.5% fat-free BSA in distilled water (dH2O) for 2 h, and washed three times with dH2O. One half of each plate was coated with 200 µl Na2SiO3 per ml dH2O and the other half (left uncoated and washed with dH2O) served as a control well without added silicate. After overnight incubation at 38°C in zip-lock bags, the plates were washed three times with dH2O, air-dried, wrapped in Parafilm, and stored at -20°C until use. Portions (200 µl) of plasma, diluted 1:1000 in 0.5% BSA in phosphate-buffered saline (PBS)–Tween 20, 0.05% (a dilution found to be optimal and uniformly used in subsequent assays), were added to the appropriate wells; the plates were incubated overnight with shaking at room temperature. Following incubation, the plates were washed three times with PBS–Tween. Portions (200 µl) of alkaline phosphatase-conjugated goat anti-human IgG or goat anti-human IgM (diluted 1:2000 and 1:4000 respectively) were added to the plates. After incubation at room temperature for 1 h with shaking, the plates were washed three times with PBS–Tween, blot-dried, and, after addition of 200 µl substrate buffer containing 1 mg p-nitrophenyl phosphate disodium per ml to all wells, shaken at 300 r.p.m. for 10–15 min at room temperature. Optical density of the plates was read at 405 nm on a Molecular Devices reader linked to the Softmax computer program (Sunnyvale, CA, USA). Absorbance readings of the background values were subtracted from the samples. Using a standard curve [14], measurements of optical density were converted to EIA arbitrary units.

Statistical methods
Non-parametric statistical methods were used for comparisons: the Mann–Whitney U-test for comparison of continuous variables between groups and Fisher's exact test for differences in dichotomous variables. Spearman's rank correlation coefficient (rs) was used for correlation analyses. Statistical analyses were performed using the statistical package SPSS (SPSS, Chicago, IL, USA).

Informed consent was obtained from all participants. The protocol was approved by the local ethics committee.


    Results
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 Abstract
 Introduction
 Materials and methods
 Results
 Discussion
 References
 
Characteristics of participants are presented in Table 1Go. Age distributions were similar in the three groups of women who had previously been hospitalized for soft-tissue rheumatism (P > 0.5 for both comparisons). Among these women, those with SBIs had significantly lower median symptom severity scores, compared with women with breast reduction (P=0.04) and women without breast surgery (P=0.03). No significant differences in age and symptom severity scores were observed between the three groups of women with no prior diagnosis of soft-tissue rheumatism (all P-values >0.1).

Silicate antibody levels in the study groups are shown in Fig. 1Go. Levels of silicate antibodies were not significantly different between the three groups with prior muscular rheumatism (A vs B and A vs C, P > 0.5 for both comparisons) (Table 1Go). Among the three groups of women with no prior soft-tissue rheumatism, silicate antibody levels were higher in women with SBIs (D vs E and D vs F, P < 0.01 for both comparisons).



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FIG. 1. Silicate antibody levels in the six study groups. The asterisk indicates a level of 167 EIA units. (+r) and (-r) indicate women with and without a prior diagnosis of soft-tissue rheumatism according to the files of the National Hospital Register of Patients. CPR, Central Population Register.

 
Correlations between silicate antibody levels and symptom severity scores were close to zero for all study groups (group A, rs=-0.09, P=0.66; group B, rs=-0.13, P=0.50; group C, rs=-0.18, P=0.34; group D, rs=0.11, P=0.63; group E, rs=0.04, P=0.85; group F, rs=-0.20, P=0.14). No significant differences were observed among the study groups with regard to standard blood tests.


    Discussion
 Top
 Abstract
 Introduction
 Materials and methods
 Results
 Discussion
 References
 
Our pairwise comparisons revealed significantly higher silicate antibody levels among women with SBIs who had no prior soft-tissue rheumatism, whereas women with SBIs who had prior soft-tissue rheumatism had lower silicate antibody levels compared with control groups. These findings indicate that the silicate antibody test cannot be used as a specific test for reaction to SBIs.

In the study by Shen et al. [14], a cut-off of 10 EIA units was applied to define silicate antibody positivity. In our study we did not apply a cut-off value in order to avoid loss of information. However, when we did so for purposes of comparison between studies, we found that women who had silicate antibody levels exceeding 10 EIA units were evenly distributed among the six study groups (groups A–F: 11.1, 7.1, 11.5, 17.4, 11.5 and 14.3% respectively; P > 0.35 for all pairwise comparisons) and their rheumatological diagnoses showed no unique rheumatic pattern. The primary diagnosis among these women was soft-tissue rheumatism; none had classic connective tissue disease.

With respect to the potential clinical relevance of the presence of silicate antibodies, women with SBIs and prior soft-tissue rheumatism had fewer rheumatic signs and symptoms than controls with prior soft-tissue rheumatism even though their silicate antibody levels were similar to those of controls. However, women with SBIs without prior soft-tissue rheumatism had significantly higher levels of silicate antibodies, although their rheumatic complaints were similar to those of controls. For all six study groups, we found no association between symptom severity scores and silicate antibody levels. Apparently, silicate antibody levels were not associated with the clinical parameters that we evaluated in the present study. In the study by Shen et al. [14], levels of silicate antibodies were higher among women with SBIs who had rheumatic symptoms compared with those who did not. However, in contrast to our study, patients were not scored according to the severity of their symptoms, and the analysis was based solely on self-reported symptoms with no clinical examination. Our finding of lower symptom severity scores among the women with SBIs who had prior soft-tissue rheumatism deserves comment because of its potential implications for studies of associations between SBIs and ill-defined rheumatic diseases. Doctors and patients may be more likely to suspect soft-tissue rheumatism when a woman has a breast implant. Furthermore, these women may have a lower threshold for seeking medical attention, as evidenced by their generally higher rates of hospitalization/out-patient contacts [23].

Exposure to silicone through medical devices other than breast implants is unlikely in this study. Only one woman who had a low silicate antibody level (2 EIA units) had insulin-dependent diabetes and was thus exposed repeatedly to silicone syringes; none had artificial heart valves or joint prostheses. While it is unclear whether the silicone of breast implants and other medical devices may degrade to metabolites such as silicon and silicate, direct environmental exposure to these substances is a possibility. Certain foods and beverages (notably vegetables, grain, rice and beer), and perhaps also drinking water [24], have been shown to contain high levels of silicon [25]. Magnesium silicate, a constituent of talc, has been found in pericapsular scars of patients with SBIs; this is considered to be due to iatrogenic contamination with talc from surgical gloves [26]. Thus, any type of surgery involving the use of surgical gloves with talc powder may lead to deposition of silicates. Furthermore, certain analgesics, antacids and prepared foods contain silicates [25].

To summarize, silicate antibodies were not consistently associated with SBIs in our study and were not correlated with rheumatic symptoms. The clinical relevance, if any, of silicate antibodies is questionable. We recommend that future silicate antibody studies consider this and also take into account other possible confounders that may influence silicate levels.


    Notes
 
Correspondence to: B. Jensen, P. G. Ramms Allé 1 3.th, 2000 Frederiksberg, Copenhagen, Denmark. E-mail: bjensen{at}aab11.dk Back


    References
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 Abstract
 Introduction
 Materials and methods
 Results
 Discussion
 References
 

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Submitted 3 September 2002; Accepted 16 January 2003





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