A Clinical and Immunologic Evaluation of Women with Silicone Breast Implants and Symptoms of Rheumatic Disease

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 [2-11]. 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. Methods Patients 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 [15-17]. 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. Results 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 (Table 2). Other symptoms and clinical findings were seen less often. Table 1. Clinical and Laboratory Features of Patients and Controls Table 2. Clinical Features of Patients with Joint and Muscle Pain and Joint Swelling 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 (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 ( 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 (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 3. Characteristics of Patients with Scleroderma-like Illness 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