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A Clinical and Immunologic Evaluation of Women With Silicone Breast Implants and Symptoms of Rheumatic Disease Alan J. Bridges; Carol Conley; Grace Wang; David E. Burns; and Frank B. Vasey Annals of Internal Medicine 15 June 1993 ; Volume 118 Issue 12 p 929-936 Objective: To describe the clinical and serologic features of women with silicone breast implants who were referred for symptoms of rheumatic disease. Design: A case series. Setting: University and private rheumatology practices. Patients: A total of 156 women with silicone breast implants and rheumatic disease complaints. Controls for the serologic studies included women with silicone implants and no rheumatic symptoms (n = 12) and women with fibromyalgia without silicone implants (n = 174). Measurements: Complete physical examination and testing for immunoglobulins; complement; C-reactive protein; rheumatoid factor; and autoantibodies by indirect immunofluorescence, immunodiffusion, and Western blot. Results: Three subgroups of patients were defined based on clinical and laboratory findings: joint and muscle pain (n = 95), joint swelling (n = 32), and connective tissue disease (n = 29). Most women had normal immunologic studies. The patients with joint swelling had mild, asymmetric, rheumatoid-factor-negative synovitis that did not meet American College of Rheumatology criteria for rheumatoid arthritis. Fourteen patients had a scleroderma-like illness and anti-centromere or anti-PM-Scl antibodies by Western blot. Ten patients had a positive Western blot for BB' polypeptide, a small nuclear ribonucleoprotein (snRNP), but did not meet criteria for systemic lupus erythematosus. No autoantibodies to known disease-related polypeptides were detected on Western blot in the control groups. Conclusion: Most women with silicone implants and rheumatic complaints had normal results of serologic tests and nonspecific symptoms, suggesting no serious connective tissue disease. However, a subset of women had clinical signs and serologic tests that were unusual even for referred patients. These observations suggest, but cannot establish, that some women with silicone breast implants may develop atypical immunologic reactions. Millions of women have had breast augmentation with silicone prostheses or injections. Most women have not developed serious problems, and breast augmentation or breast reconstruction after cancer surgery can serve an important psychological role to improve self-image [1]. With longer follow-up, however, questions have been raised by patients, some investigators, and health officials about the safety of silicone implants, including issues of silicone gel bleeding, shedding of silicone from the prosthesis envelope, prosthesis rupture, tissue fibrosis, and rheumatic disease. These issues have not been investigated adequately. Silicone implants have been associated with the development of rheumatic disease in a number of case reports and small series [2,3,4,5,6,7,8,9,10,11]. One uncontrolled study suggested that no relationship existed between silicone implantation and rheumatic disease because among 125 respondents no patients had rheumatoid arthritis and connective tissue disease [12]. Data suggest that the derivatives of elemental silicon, silica and silicone, can "trigger" the immune system and cause fibrotic and connective tissue diseases, but no controlled studies have been done of the immune system in women with silicone implants [13]. We evaluated the clinical and serologic features of a large group of women with silicone implants who were referred with symptoms of rheumatic disease.
Consecutive patients (n = 166) with silicone implants referred between October 1990 and March 1992 to three rheumatologists for evaluation of rheumatic symptoms were entered into the study. The geographic referral areas of the participating rheumatologists were central Missouri; Houston, Texas; and Tampa, Florida. Most of the patients were referred by other physicians who knew of the authors' interest in silicone and rheumatic disease. Ten patients with rheumatic disease complaints that preceded breast implant surgery were not included in the study. Controls included women with silicone implants without clinical symptoms (n = 12) and women with fibromyalgia (diagnosis based on criteria of Yunus and colleagues [14]) and no silicone implants (n = 174). The institutional review boards at the participating institutions approved the project. Diagnostic Criteria The diagnoses of systemic lupus erythematosus, rheumatoid arthritis, and systemic sclerosis were made according to American College of Rheumatology criteria [15,16,17]. Skin sclerosis was subdivided into diffuse, intermediate, or limited cutaneous involvement according to Barnett [18]. The Sjogren syndrome and sicca symptoms were diagnosed according to criteria developed by Fox and colleagues [19]. Polymyositis was diagnosed according to criteria developed by Bohan and Peter [20]. Mixed connective tissue disease was diagnosed according to criteria developed by Porter and colleagues [21]. Joint swelling was confirmed by a rheumatologist according to American College of Rheumatology criteria [22]. Immunologic Studies Immunoglobulin (IgG, IgM, IgA), complement (C3, C4), rheumatoid factor, and C-reactive protein levels were performed using the nephelometric technique (QM300 Protein Analysis System, Kallestad Diagnostics; Chaska, Minnesota) [23]. Control sera from Kallestad Diagnostics were used to calibrate the nephelometer. Normal ranges for each test were determined by Kallestad Diagnostics. Antinuclear antibody (ANA) testing was performed using HEp-2 cells as tissue substrate (Kallestad Diagnostics). Serum ANA titers of 1:80 or greater were considered positive. Testing for antibodies to double-stranded DNA (ds-DNA) was performed by indirect immunofluorescence technique using Crithidia luciliae as substrate (Kallestad Diagnostics). Titers of anti-ds-DNA antibody greater than 1:10 were considered positive. Testing for antibodies to Sm, ribonucleoprotein (RNP), SSA/Ro, SSB/La, Scl-70, and PM-Scl antigens were performed by double immunodiffusion [24]. The presence of autoantibodies to cellular antigens was further assessed by Western blot using Jurkat or HeLa cells as substrate [25]. Human sera were used at a dilution of 1:100. Each experiment included standard sera that detected disease-related polypeptides for Sm, U1RNP, Scl-70, centromere, PM-Scl, SSA/Ro, and SSB/La antigens. Statistical Analysis Kruskal-Wallis and chi-square tests were used to examine the data for statistically significant differences between groups.
Patients (n = 156) with silicone implants ranged in age from 22 to 72 years (mean, 44.6 years). The implants had been in place from 1 to 26 years (mean, 9.4 years). Age and exposure to silicone implants did not differ between patients and silicone implant controls (P > 0.2). We separated patients into three groups based on clinical and laboratory findings: joint and muscle pain, joint swelling, and connective tissue disease. Joint and Muscle Pain Group Clinical Features Ninety-five women (60%) had joint and muscle pain (Tables 1 and 2). All patients had diffusely tender muscles and joints. Ninety-two percent of these women complained of overwhelming fatigue, whereas 21% had lymphadenopathy on physical examination (see Table 2). Other symptoms and clinical findings were seen less often. Table 1. Clinical and Laboratory Features of Patients and Controls Laboratory Features Four patients with joint and muscle pain had elevated IgG levels, and two patients had elevated levels of IgM. One patient had an IgA deficiency. The mean immunoglobulin levels (IgG, IgM, IgA) of the 95 women were within the normal range (see Table 1). Comparison of immunoglobulin levels (IgG, IgM, IgA) between patients with joint and muscle pain and controls showed no statistical differences (P > 0.2 for all comparisons). All patients had normal levels of complement. Nine patients had elevated levels of rheumatoid factor (>60 IU/mL), and six patients had elevated levels of C-reactive protein (> 1.0 IU/mL). Mean levels of rheumatoid factor and C-reactive protein for the patient subgroup were within the normal range. The proportion of patients with joint and muscle pain and abnormal levels of immunoglobulin, ANA, rheumatoid factor, and C-reactive protein did not differ from controls (P > 0.2 for all comparisons). No autoantibodies were found in sera of patients with joint or muscle pain that consistently detected common polypeptide bands on Western blot that differed from controls. Joint Swelling Group Clinical Features Thirty-two women (21%) had joint swelling, which was mild, asymmetric, and involved both small and large joints (see Tables 1 and 2). The wrists and ankles were most commonly involved. No patient met American College of Rheumatology criteria for rheumatoid arthritis [16]. Most of the patients had fatigue (see Table 2). Pulmonary symptoms consisting of cough, shortness of breath, pleuritic chest pain, or abnormal pulmonary function testing were noted in approximately 20% of patients. Other clinical findings were less common. Laboratory Features Three patients with joint swelling had an elevated rheumatoid factor level (67, 105, and 247 IU/mL). Five patients had elevated C-reactive protein levels, and two patients had elevated levels of IgM. All patients had normal levels of complement. The mean values of the immunoglobulin, rheumatoid factor, and C-reactive protein levels were within the normal range (see Table 1). The proportion of patients with joint swelling and abnormal levels of immunoglobulin, ANA, rheumatoid factor, and C-reactive protein did not differ from controls (P > 0.15 for all comparisons). There were no autoantibodies in sera of patients with joint swelling that consistently detected common polypeptide bands on Western blot that differed from controls. Connective Tissue Disease Group Clinical Features Twenty-nine women (19%) had findings suggestive of a connective tissue disease (Tables 3 and 4). Fatigue was the most common symptom. Twenty-one percent had pulmonary symptoms including dyspnea, cough, pleuritic chest pain, pleural effusions, interstitial lung disease, or abnormal results of pulmonary function testing. Lymphadenopathy, sicca symptoms, rash, mucosal ulceration, and alopecia were noted less frequently.
Table 4. Characteristics of Patients with Connective Tissue Disease Laboratory Features Immunoglobulin levels were abnormal in eight patients with connective tissue disease: One patient had IgA deficiency and seven patients had elevated levels of immunoglobulin (IgG-4, IgM-2, IgA-1). Although the mean immunoglobulin levels were within the normal range, the IgM level was significantly higher in the group with connective tissue disease compared to the control group of patients with fibromyalgia (P = 0.04). The proportion of patients with abnormal immunoglobulin levels was significantly higher in the connective tissue disease group compared with the groups with joint pain and joint swelling and with controls (P = 0.05). Five patients had elevated levels of rheumatoid factor and one patient had an elevated C-reactive protein level. The proportion of patients with abnormal rheumatoid factor and C-reactive protein levels did not differ from controls (P > 0.2). Scleroderma-like Subgroup Table 3 shows the clinical and laboratory features of the 14 patients with a scleroderma-like illness. Four patients had diffuse cutaneous involvement, and five patients had intermediate cutaneous involvement. Three patients had limited cutaneous involvement typical of calcinosis, Raynaud phenomenon, esophageal dysfunction, sclerodactyly, and the telangiectasias syndrome (CREST). Nine of the 14 patients with a scleroderma-like illness had Raynaud phenomenon. Four of the nine patients with intermediate or diffuse cutaneous scleroderma had lung involvement characterized by dyspnea, pleural effusions, or abnormal pulmonary function tests. Seven patients with a scleroderma-like illness had negative or low-titer ANA tests. One patient had elevated IgG levels and one patient had elevated IgM. Three patients had a positive rheumatoid factor. Figure 1 shows the Western blot patterns of the patients with a scleroderma-like illness. Sera from eight patients had antibodies to centromere-related polypeptide bands on Western blot. Sera from two patients had antibodies to PM-Scl-related polypeptide bands on Western blot. Sera from five patients showed antibodies to disease-related polypeptides despite a negative or low-titer ANA test result (see Table 3). No patient had antibodies to Scl-70-related polypeptide (topoisomerase I). Four patients showed no connective tissue disease-related polypeptide bands on Western blot.
Table 4 shows the findings of 15 patients with other forms of connective tissue disease. Three patients had systemic lupus erythematosus defined by American College of Rheumatology criteria [15]. Two patients with systemic lupus erythematosus had a low-titer ANA test result with a positive result of Western blot for antibodies to connective tissue disease-related polypeptides. Two patients had antibodies to ds-DNA. The patient with mixed connective tissue disease had anti-RNP antibodies in high titer. No other patient had specific autoantibodies by immunodiffusion. Ten patients were diagnosed with early connective tissue disease based on the detection of autoantibodies on Western blot, specifically anti-BB' polypeptide antibodies Figure 2. BB' polypeptide is a member of the small nuclear ribonucleoproteins (snRNP); autoantibodies to this polypeptide are found characteristically in systemic lupus erythematosus associated with Sm antigen reactivity by immunodiffusion but may be found in mixed connective tissue disease or scleroderma associated with RNP antigen reactivity [25,26,27]. The patients in this study had nonspecific findings of connective tissue disease (fatigue, myalgias, arthralgias, and joint swelling), a negative or low-titer result of ANA test, negative immunodiffusion test results, and did not meet criteria for systemic lupus erythematosus (see Table 4). None of the controls (women with silicone implants and no rheumatic disease symptoms and women with fibromyalgia) had autoantibodies to BB' polypeptide or other connective tissue disease-related polypeptides.
The goal of this study was to survey the clinical and serologic features of a large group of women with silicone breast implants who were referred for rheumatic disease symptoms. Despite limitations in the design of this case-series study, we made some important observations. We showed that most women with silicone breast implants and symptoms of rheumatic disease have normal results of common immunologic tests. However, some women had findings that were unusual even for patients referred to rheumatologists. For example, 10 women (6.4% of the study patients) had autoantibodies to BB' polypeptide, a distinctly unusual autoantibody response characteristically found only in patients with connective tissue disease [27,28,29]. Our study did not investigate the epidemiologic relationship of silicone exposure to the development of rheumatic disease. Our study sample did not reflect the general population of women with silicone breast implants because each patient in our study was referred with existing symptoms of rheumatic disease. Therefore, the degree of risk for development of rheumatic disease cannot be ascertained from this study. In addition, the observation that most women with silicone breast implants had no detectable serologic abnormalities supports the hypothesis that serious connective tissue disease associated with silicone breast implants is uncommon. We found no evidence for autoantibody production by immunofluorescence or Western blot in most of the study patients and in none of the asymptomatic controls. The findings suggest that most women with silicone breast implants and rheumatic disease symptoms do not have serologic findings consistent with serious connective tissue disease such as scleroderma or systemic lupus erythematosus. Nevertheless, our observations support the possibility that atypical autoimmune illness may be associated with silicone exposure in a small number of women. A large prospective controlled study will be needed to answer this question. Rheumatoid arthritis was relatively uncommon among study patients. None of the women met the 1987 revised criteria for rheumatoid arthritis [16]. Women with joint swelling and silicone breast implants in this study had an asymmetric polyarthritis that was negative for the rheumatoid factor and was not associated with laboratory evidence of inflammation. Only 3 of 32 patients had elevated levels of rheumatoid factor. Of those women who had radiographs of the hands (n = 32), no joint erosions were found. In data obtained from another study of consecutive patients with rheumatic disease from a similar referral area, 13% of referred women (total = 97) had rheumatoid arthritis, of whom 12 had elevated levels of rheumatoid factor [30]. The large group of patients with seronegative asymmetric polyarthritis and the lack of rheumatoid-factor-positive rheumatoid arthritis among the 156 women with rheumatic disease symptoms and silicone breast implants is quite unusual and suggests that women with silicone breasts implants are not at increased risk for rheumatoid arthritis. Similar conclusions were reported from a case-control study of 349 women with rheumatoid arthritis [31]. The high proportion of patients with a scleroderma-like illness in this study was also unusual. From a similar referral area, only 1 patient with scleroderma was diagnosed among 97 women referred with rheumatic diseases [30]. A high proportion of patients with a scleroderma-like illness is consistent with the accumulation of connective tissue disease cases associated with silicone reported in the literature [2,3,4,5,6,7,8,9,10,11] and a recent study by Press and colleagues [32]. These observations, although not obtained from controlled epidemiologic studies, support a hypothesis that silicone may, like other occupational and environmental exposures, be a "trigger" for a scleroderma-like illness in small numbers of patients [33]. Atypical clinical and serologic features of the patients with a scleroderma-like illness also supports an association between silicone implants and scleroderma. Idiopathic scleroderma is accompanied by Raynaud phenomenon in more than 95% of patients [34,35], whereas only 67% of our patients with a scleroderma-like illness in this study had Raynaud phenomenon. Most studies report that nearly 100% of patients with idiopathic scleroderma have a positive ANA test [16,36,37], whereas only 7 of our 12 (58%) patients with a scleroderma-like illness had a positive ANA test. Antibodies to Scl-70 are typically found in 30% to 100% of patients with diffuse and intermediate cutaneous scleroderma [16,35,37]. Seven patients in this study had diffuse or intermediate cutaneous scleroderma and none had anti-Scl-70 antibodies. Anticentromere antibodies are typically found only in patients with limited scleroderma (CREST) [16,36,37], whereas the patients with scleroderma in this study had antibodies to centromere or PM-Scl on Western blot. Anti-PM-Scl antibodies are typically found in a small percentage of patients with the polymyositis-scleroderma overlap syndrome [38,39]; neither patient with anti-PM-Scl antibodies had evidence of myositis. Thus, certain clinical and serologic features of patients with a scleroderma-like illness and silicone implants differed from patients with idiopathic scleroderma reported in the medical literature. Autoantibodies to BB' polypeptide were found in a subgroup of our patients. To our knowledge, autoantibodies to BB' polypeptide are found only in patients with connective tissue disease [27,28,29]. Most patients with autoantibodies to BB' polypeptide have systemic lupus erythematosus and react with Sm antigen by immunodiffusion [27,29]. Autoantibodies to BB' polypeptide may be found in serum from patients with mixed connective tissue disease or scleroderma associated with autoantibodies directed toward other snRNP polypeptides and RNP antigen by immunodiffusion [27,29]. Sera with autoantibodies to BB' polypeptide alone are unusual [28]. The 10 patients with BB' autoantibodies reported in this study had nonspecific clinical features; had a negative or low-titer ANA test; had negative immunodiffusion tests; and did not meet defined criteria for systemic lupus erythematosus, mixed connective tissue disease, or scleroderma [15,17,21]. It is not clear whether these patients have early systemic lupus erythematosus or have an atypical autoantibody response or if they represent a new subgroup of patients with connective tissue disease. Nevertheless, this finding is important because these women initially were believed to have no evidence of connective tissue disease until the presence of autoantibodies was assessed by Western blot. Sensitive testing by Western blot may be necessary to detect autoantibodies suggestive of connective tissue disease in patients with silicone implants. Follow-up of patients with these antibodies will be necessary to further define the significance. Clearly, many questions remain about the relationship of silicone exposure and pathogenesis of rheumatic disease. The hypotheses raised by this study and others should be tested in large, population-based studies. Acknowledgments: The authors thank Frederick W. Miller, MD, PhD, Lori A. Love, MD, PhD, and Dr. Charles L. Puckett, MD, for scientific review. Dr. John Hewitt and Jane Johnson performed the statistical analyses. Grant Support: In part by grants from the Department of Medicine, University of Missouri-Columbia, and by the St. Petersburg Medical Clinic Foundation.
From the University of Missouri-Columbia, the University of South Florida, and the James A. Hailey Veterans Administration Hospital, Tampa, Florida. Requests for Reprints: Alan J. Bridges, MD, H6/367 Clinical Sciences Center, University of Wisconsin Hospital, 600 Highland Avenue, Madison, WI 53792.
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