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A Comparison of Autoantibody Production in Asymptomatic and Symptomatic Women with Silicone Breast Implants GISELE ZANDMAN-GODDARD, MIRI BLANK, MICHAEL EHRENFELD, BORIS GILBURD, JAMES PETER, and YEHUDA SHOENFELD ABSTRACT. Objective. We previously reported an increased preponderance of a broad range of autoantibodies in symptomatic women with silicone breast implants. The objective of this study was to investigate the frequency of autoantibody production in asymptomatic compared to symptomatic women with silicone implants. One hundred twenty-two asymptomatic women were recruited to our center for autoantibody detection through an advocate dealing with breast implant liabilities. Methods. Autoantibody detection in 86 asymptomatic women was done blindly on a panel of 15 different antibodies (dsDNA, ssDNA, histones, SSA/Ro, SSB/La, RNP, cardiolipin, phosphatidylserine, pyruvate dehydrogenase, Scl-70, NC-1, silicone, collagen I, II, and IV). Clinical variables, specific questioning about related silicone implant symptoms, and a rheumatological examination were performed blindly by a certified rheumatologist. The findings were recorded and at a later stage compared with positive autoantibody detection. The normal control group consisted of age and sex matched Israeli women without known autoimmune disease. In the positive control group were symptomatic women previously tested for antibody production. The autoantibodies were assessed by ELISA. Values from individual patients were considered positive only when greater than 3 standard deviations above the control mean. Results. The mean ages of 86 asymptomatic and 116 symptomatic women were 46.2 ± 11.2 and 45.7 ± 8.3 years, respectively. Breast implants were in place for a mean period of 8.2 ± 5.0 years in the asymptomatic group and 15.0 ± 5.6 years in the symptomatic group. The incidence of increased titers of autoantibodies ranged from 2 to 13% for 13 different autoantibodies among asymptomatic women. Among symptomatic women, 20% harbored 4 autoantibodies and 8% had 6 autoantibodies. The most common antibodies in the asymptomatic group were: dsDNA 8%; ssDNA 9%; SSB/La 13%; silicone 9%; collagen II 9%. No autoantibodies were found for NC-1, Scl-70, or RNP. Among the symptomatic group, the most common autoantibodies were histone ribosomal phosphate, SSA, SSB, Scl-70, cardiolipin, phosphatidylserine, GM2-ganglioside, and NC-1. Comparison of autoantibody incidence in asymptomatic and symptomatic women with silicone breast implants revealed an increased incidence of anti-SSB/La and anticollagen II in both groups. Polyclonality was more prominent in the group of symptomatic women with silicone breast implants, but also evident in 3 asymptomatic women. Conclusion. The mean duration of implant in the asymptomatic group was significantly less compared with the symptomatic group (p < 0.01). The development of autoantibodies may be related to implant duration. (J Rheumatol 1999;26:73-7) Key Indexing Terms: AUTOANTIBODIES AUTOIMMUNE DISEASES SILICONE IMPLANTS
From the Department of Medicine B and the Research Unit of Autoimmune Diseases, Department of Medicine C, Sheba Medical Center, Tel-Hashomer, affiliated to the Sackler Faculty of Medicine, Tel Aviv University, Israel; and Specialty Laboratories, Inc., Santa Monica, CA, USA. Supported by a research grant given by the Chief Scientist of the Ministry of Health, Israel. G. Zandman-Goddard. MD; M. Blank, PhD, Department of Medicine B and Research Unit of Autoimmune Diseases; M. Ehrenfeld, MD, Department of Medicine C; B. Gilburd, PhD, Department of Medicine B; J. Peter, MD, Specialty Laboratories, Inc.; Y. Shoenfeld, MD, Head, Department of Medicine B. Address reprint requests to Dr. Y. Shoenfeld, Department of Medicine B, Sheba Medical Center, Tel Hashomer, 52 621 Israel; Email: shoenfel@tau.post.ac.il Submitted June 13, 1996 revision accepted June 18, 1998.
Silicone implants for augmentation mammoplasty in women may be associated with autoimmune phenomena1-15. Research and lawsuits are innumerable, and there are at least 850,000 women with these implants in the United States alone16-22. Studies have shown no or only a slightly increased related risk of autoimmune disease among women with these implants20,21,23-25. However, women have developed autoimmune diseases, the most common being scleroderma6-8,10-12. Many women share common symptoms that do not fulfill the criteria for autoimmune disease, but may present a distinct entity. Common syndromes and diseases are fibromyalgia, chronic fatigue syndrome, autoimmune- like disease resembling rheumatoid arthritis, systemic lupus erythematosus, and Sjögren's syndrome26.
In addition, several studies have shown higher frequencies of autoantibodies in small groups of symptomatic implant patients27-30. In a previous study, we reported an increased preponderance of a broad range of autoantibodies in symptomatic women with silicone breast implants31. To pursue these findings, we investigated the frequency of autoantibody production in asymptomatic women with silicone implants.
MATERIALS AND METHODS Patients. One hundred twenty-two asymptomatic women were recruited to our center for autoantibody detection through an advocate dealing with breast implant liabilities. These women had not previously approached a physician for rheumatological or autoimmune disease symptoms. None were known to have autoimmune disease. Autoantibody detection by ELISA was done blindly in 86 asymptomatic women on a panel of 15 different antibodies (dsDNA, ssDNA, histones, SSA/Ro, SSB/La, RNP, cardiolipin, phosphatidylserine, pyruvate dehydrogenase (PDH), Scl-70, noncollagenous domain of alpha-3 chain of type IV collagen (NC-1), silicone, collagen I, II and IV).
Clinical variables, specific questioning about known silicone implant symptoms, and a rheumatological examination were performed blindly by a certified rheumatologist. Silicone implant syndrome was defined as evidence of one or more of the following: polyarthralgia, joint swelling, morning stiffness, sensation of tingling, fatigue, rash, and fibrositis. The findings were recorded to be compared later with positive autoantibody detection.
The healthy control group consisted of 50 age and sex matched Israeli women without known autoimmune disease. The positive control group consisted of 116 symptomatic age matched women previously tested for antibody production31.
Autoantibody detection. The following autoantibodies were assessed by ELISA. Values from individual patients were considered positive only when they were greater than 3 standard deviations (SD) above the control mean.
Detection of anti-DNA antibodies. Polystyrene plates (Nunc) were coated sequentially with polymicron: L-lysine (50 µg/ml in water). We added dsDNA 2.5 µg/ml in Tris buffered saline (TBS) followed by S l nuclease treatment (3 U/ml in 37°C). After exposure to L-glutamate (50 µg/ml), the plates were additionally blocked in 5% bovine serum for 2 h at room temperature. Between each step, extensive washings with TBS 0.05%-Tween 20 were performed. The diluted sera (1:200) were added. Bound autoantibodies were detected using goat anti-IgG conjugated to alkaline phosphatase (Jackson Immuno Research Laboratories, West Grove, PA, USA) and its substrate p-nitrophenylphosphate. Color was read in a Titertek Multiskan spectrophotometer ELISA reader at 405 nm. Values 3 SD above the mean of 10 normal mice sera were considered positive for autoantibody detection. In the detection of anti-ssDNA, the dsDNA was boiled for 10 min and immediately cooled at 40°C and used for coating. No S 1 nuclease treatment was employed. Detection of antiphospholipid (anticardiolipin and antiphosphatidyl ) antibodies. Antiphospholipid activity in sera of the immunized mice was detected by ELISA as follows: 96 well ELISA plates (Nunc, Roskilde, Denmark) were coated with a phospholipid (cardiolipin, phosphatidylserine; Sigma, St. Lous, MO, USA) at concentrations of 50 µg/ml in ethanol. The plates were left open at 40°C until evaporation. Following blocking with 5% bovine serum in phosphate buffered saline (PBS) a 1:200 dilution of the mice sera were incubated for 2 h. Wells were extensively washed with PBS. The diluted sera were added and the autoantibodies were detected as described for anti-DNA antibodies.
Detection of antipyruvate dehydrogenase antibodies. Anti-PDH antibodies (employed as a non-relevant antigen) were detected in an ELISA as described32.
Detection of anti-histone, anti-SSA/Ro, anti-SSB/La, and anti-RNP antibodies. Anti-histone, anti-SSA/Ro, and anti-SSB/La antibodies were detected in an ELISA as described33. Antibodies to RNP were detected using Enzyme ImmunoAssay diagnostic kits (Eldan Tech, Israel).
Detection of other antibodies. Antibodies to Scl-70, anti-glomerular basement membrane (anti-GBM), collagen type I, II and IV were tested by ELISA kits at Specialty Laboratories, Santa Monica, CA, USA.
Detection of antisilicone antibodies by 2 methods. In the first method, developed in our laboratory, dimethylpolysiloxane (the material used for the outer envelope of the breast implant) in its liquid form was used for coating the plates. In the second method, the plates were first coated with bovine serum albumin, then a second coat with silica was used (Specialty Laboratories).
Statistical analysis. Differences in the frequency of autoantibody levels were determined by ANOVA test analysis.
RESULTS One hundred twenty-two asymptomatic women with silicone breast implants were evaluated (Table 1). The mean age of 86 women was 46.2 ±11.2 years (range 23-72). Breast implants were in place for a mean period of 8.2 ±5.0 years (range 1-22). The indications for breast augmentation with silicone breast implants in 85 women were cosmetic only (69%), reconstruction after mastectomy for cancer of the breast (27%), or fibrocystic disease (4%). A comparison of the clinical characteristics between the asymptomatic group and the symptomatic women revealed a similar mean age, but the asymptomatic women had a shorter breast implant duration (15 ± 5.2 yrs, and 8.2 ± 5 yrs, respectively; p < 0.01).
The incidence of increased titers of autoantibodies ranged from 2 to 13% for 13 different antibodies (Table 2). The most commonly found antibodies were dsDNA 8%; ssDNA 9%; SSB/La 13%; silicone 9%; collagen II 9%. No antibody detection was found for NC-1, Scl-70, or RNP. The
*p < 0.01.
these asymptomatic women would need prolonged followup to determine if they become seropositive. The time interval remains undetermined and further studies would be required. Other investigators have found increased autoantibody production in symptomatic women with breast implants27-30,34-40. Cuellar, et al found the frequency of dsDNA antibodies (detected by ELISA) in women with silicone breast implants was 8.5%30, a result similar to ours. To our knowledge, no previous study on the presence of multiple autoantibodies in asymptomatic women has been done.
Teuber, et al have shown that autoantibodies to collagen types I and II are found in women with silicone breast implants41. These autoantibodies were increased in the asymptomatic as well as the symptomatic group of women. It is yet to be determined if these autoantibodies are specific or represent a reaction to the scar tissue that develops surrounding the implant. However, antibodies to collagen were not found in patients with Wegener's granulomatosis. Moreover, epitope mapping studies have shown that such reactivity is unique to women with implants42.
Furthermore, polyclonality was more prominent in the group of symptomatic women with silicone breast implants. Those women with 7 or more autoantibodies developed autoimmune disease. However, asymptomatic women with 2-4 autoantibodies developed clinical manifestations associated with silicone implant syndrome.
In conclusion, asymptomatic women with silicone breast implants may harbor one or more autoantibodies. The development of autoantibodies and clinical symptoms associated with silicone breast implants may be related to the duration of implant. Women as well as physicians may not be aware of clinical manifestations of silicone implant syndrome, delaying physician consultation diagnosis. Consistent with our findings, it would be unfair to adhere to strict criteria for autoimmune diseases in determining morbidity in women with silicone implants. Further followup studies are necessary to evaluate the association of autoantibody production and autoimmune phenomena in asymptomatic women. ACKNOWLEDGMENT We thank Professor M.E. Gershwin for his critical reading and suggestions. REFERENCES 1. Shon AR, Schubert W. Silicone breast implants and immune disease. Ann Plast Surg 1992; 28:491-50. 2. Kumagai Y, Abe C, Shiokawa Y. Scleroderma after cosmetic surgery: four cases of human adjuvant disease. Arthritis Rheum 1979; 22:532-7. 3. van Nunen SA, Gatenby PA, Basten A. Post-mammoplasty connective tissue disease. Arthritis Rheum 1982; 25:694-7. 4. Okano Y, Nishikai M, Sato A. Scleroderma, primary biliary cirrhosis and Sjögren's syndrome after cosmetic breast augmentation with silicone injection: a case report of possible human adjuvant disease. Ann Rheum Dis 1984; 43:520-2. 5. Pock KM, Feng PH, Tey BH. Autoimmune disease developing after augmentation mammoplasty: report of 3 cases. J Rheumatol 1984; 11:98-100. 6. Kumagai Y, Shiokawa YM, Medsger TA Jr, Rodnan GP. Clinical spectrum of connective tissue disease after cosmetic surgery. Arthritis Rheum 1984; 27:1-12. 7. Varga J, Schumacher R, Jimenez SA. Systemic sclerosis after augmentation mammoplasty with silicone implants. Ann Intern Med 1989; 111:377-83. 8. Spiera H. Scleroderma after silicone augmentation mammoplasty. JAMA 1988;260:236-8. 9. Brozena SJ, Fenske NA, Cruse W, et al. Human adjuvant disease following augmentation mammoplasty. Arch Dermatol 1988;124:1383-6. 10. Sahn EE, Garen PD, Silver RM, Maize JC. Scleroderma following augmentation mammoplasty. Arch Dermatol 1990; 126:1198-202. 11. Marik PE, Kark AL, Zambakieas A. Scleroderma after silicone augmentation mammoplasty. S Afr Med J 1990;77:212-3. 12. Spiera H, Kerr D. Scleroderma following silicone implantation: a cumulative experience of 12 cases [abstract]. Arthritis Rheum 1992; 35 Suppl:S68. 13. Endo LP, Edwards L, Longly S, Corman C, Panush RS. Silicone and rheumatic diseases. Semin Arthritis Rheum 1987; 17:112-8. 14. Vasey FB, Seleznick MJ, Webb RW, Havice D, Germain BF. Clinical manifestations of fifty consecutive women with silicone implants and connective tissue disease [abstract]. Arthritis Rheum 1992; 35 Suppl: R7. 15. Vasey FB, Seleznick MJ, Webb RW, Havic D, Bernard FG. 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N Engl J Med 1995; 332:1666-70. 22. Cook RR, Delongchamp RR, Woodbury M, Perkins LL, Harrison MC. The prevalence of women with breast implants in the United States — 1989. J Clin Epidemiol 1995; 48:519-25. 23. Hochberg MC, Perlmutter D, Medsger TA Jr, et al. Lack of association between augmentation mammoplasty and systemic sclerosis (scleroderma). Arthritis Rheum 1996; 39:1125-31. 24. Hennekens CH, Lee I-M, Cook NR, et al. Self-reported breast implants and connective tissue diseases in female health professionals. JAMA 1996; 275:616-21. 25. Rose NR. The silicone breast implant controversy: the other courtroom. Arthritis Rheum 1996; 39:1615-8. 26. Borenstein D. Siliconosis: a spectrum of illness. Semin Arthritis Rheum 1994; 24 Suppl 1:1-7. 27. Press RI, Peebles CL, Kumagai Y, Ochs RL, Tan EM. Antinuclear autoantibodies in women with silicone breast implants. Lancet 1992; 340:1304-7. 28. Solomon G. A clinical and laboratory profile of symptomatic women with silicone breast implants. Semin Arthritis Rheum 1994; 24 Suppl 1:29-37. 29. Bridges AJ. Autoantibodies in patients with silicone implants. Semin Arthritis Rheum 1994; 24 Suppl 1:54-60. 30.Cuellar ML, Scopelitis E, Tenenbaum SA, et al. Serum antinuclear antibodies in women with silicone breast implants. J Rheumatol 1995; 22:230-40. 31.Bar-Meir E, Teuber SS, Lin HC, et al. Multiple autoantibodies in patients with silicone breast implants. J Autoimmunity 1995; 8:267-77. 32. Zurgil N, Bakimer R, Moutsopoulos M, et al. Antimitochondrial (pyruvate dehydrogenase) autoantibodies in autoimmune rheumatic diseases. J Clin Immunol 1992; 12:201-9. 33.Shoenfeld Y, Hou Lin S, Gabriel JE, et al. Production of autoantibodies by human-human hybridoma. J Clin Invest1982;70:295-8. 34. Bridges AJ, Conley C, Wang G, et al. A clinical and immunological evaluation of women with silicone breast implants and rheumatic disease. Ann Intern Med 1993; 118:929-36. 35. Morse JH, Spiera H. Autoimmune diseases, immunoglobulin isotypes, and lymphocytic subsets in 30 females with breast augmentation mammoplasty [abstract]. Arthritis Rheum 1992; 35 Suppl:S65. 36. Muhanna A, Rubin L, Keystone E, et al. Silicone breast implants and rheumatic disease — clinical and immunological investigations [abstract]. Arthritis Rheum 1992; 35 Suppl: S65. 37. Bridges AJ, Anderson JD, Burns DE, Kemple K, Kaplan JD, Lorden T. Autoantibodies in patients with silicone implants. CTMI 1996; 210:277-81. 38. Zandman-Goddard G, Ehrenfeld M, Shoenfeld Y. Silicone augmentation mammoplasty and autoimmune diseases. Harefuah 1993;125:360-4. 39. Peter J. Silicon(e) breast implant syndromes: evidence of cellular and humoral immunity. Lupus 1995; 4 Suppl 2:139. 40. Sanchez-Guerrero J, Schur PH. Sergent JS, Liang MH. Silicone breast implants and rheumatic disease. Clinic, immunological and epidemiologic studies. Arthritis Rheum 1994; 37:158-68. 41. Teuber SS, Rowley SH, Yoshida SH, Ansari AA, Gershwin ME. Anti-collagen autoantibodies are found in women with silicone breast implants. J Autoimmun 1993; 6:367-77. 42. Rowley MJ, Cook AD, Teuber SS, Gershwin ME. Antibodies to collagen: comparative epitope mapping in women with silicone breast implants, systemic lupus erythematosus and rheumatoid arthritis. J Autoimmunity 1994; 7:775-89. |
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