Department of Internal Medicine, University of Michigan, Ann Arbor, MI.
2 Department of Epidemiology, University of Michigan, Ann Arbor, MI.
3 Center for Statistical Consultation and Research, University of Michigan, Ann Arbor, MI.
4 Department of Environmental Health Sciences, University of Michigan, Ann Arbor, MI.
5 Institute for Social Research, University of Michigan, Ann Arbor, MI.
6 Department of Internal Medicine, Wayne State University, Detroit, MI.
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ABSTRACT |
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breast implants; connective tissue diseases; orthopedic fixation devices
Abbreviations: ACR, American College of Rheumatology; ANA, antinuclear antibodies; CI, confidence interval; CNS, central nervous system; HCIA, Health Care Investment Analysts, Inc.; OR, odds ratio; UCTD, undifferentiated connective tissue disease; USF, United Scleroderma Foundation; WSU, Wayne State University
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INTRODUCTION |
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To examine potential risks of exposure to implanted medical devices, we adopted the International Classification of Diseases, Ninth Revision, Clinical Modification code 710.9 for unspecified diffuse connective tissue disease, commonly referred to as UCTD, which we reasoned would be the diagnostic code most often applied by rheumatologists and nosologists to women with "atypical" connective tissue disease manifestations. UCTD is generally applied to patients with less severe manifestations of illness than to those with defined rheumatic diseases. The adoption of this code enabled us to conduct a case-control study among women in Michigan and Ohio of associations between UCTD and silicone breast implants; other implanted, silicone-based medical devices; or other implanted, non-silicone-containing medical devices in parallel with a similar study of women with scleroderma (7).
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MATERIALS AND METHODS |
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Scleroderma and UCTD cases were recruited simultaneously, and a final diagnosis was determined after verification by review of the medical record. HCIA contacted 386 hospitals and requested that consent forms be sent to all women discharged during the study period with a diagnostic code of either 710.9 or 710.1 (scleroderma). Among these hospitals, 243 (63 percent) agreed to participate (representing 74 percent of inpatients), 114 (30 percent) declined due to staffing shortages, and 29 (8 percent) had closed or were operating under another hospital system. Of 254 Michigan and Ohio rheumatologists, 161 (63 percent) agreed to mail consent forms to their potentially eligible patients. In the initial phase of determining eligibility, 150 of 202 (74 percent) patients at the University of Michigan hospitals, 255 of 330 (77 percent) patients at WSU hospitals, and 230 of 527 (44 percent) patient members from the USF of Michigan agreed to participate. The response rate from patient mailings in Michigan and Ohio requesting participation was estimated to be between 75 and 80 percent after adjustment for duplicate names identified from the multiple sources, ineligible subjects, and incorrect mailing addresses.
We could not review the medical records of potential cases who did not agree to participate. However, although we were unable to estimate the exact proportion of all eligible cases with UCTD who were captured, an examination of recruitment at the University of Michigan and WSU hospitals and clinics, where access to inpatient and ambulatory patient medical records facilitated the identification of potentially eligible cases, revealed that 86 percent of cases participated and that participation did not differ by age group or disease severity.
Patients were considered to have UCTD if review of their medical record identified signs, symptoms, and/or laboratory abnormalities that suggested a systemic rheumatic disease, but these manifestations were not sufficient to meet American College of Rheumatology (ACR) classification criteria for any defined connective tissue disease (8). The diagnostic criteria emphasized documentation of Raynaud's phenomenon, keratoconjunctivitis Sjögren's syndrome, and unexplained polyarthritis. The medical record was reviewed for other clinical and laboratory manifestations not attributable to another disease, such as peripheral neuropathy, pleuritis or pericarditis, positive titer of antinuclear antibodies (ANA), or a false-positive serologic test for syphilis. The clinical investigators excluded the fibromyalgia syndrome, a symptom complex of diffuse body pain and fatigue accompanied by multiple tender points on physical examination (9
). Patients with calcinosis, Raynaud's phenomenon, esophageal dysmotility, sclerodactyly, and telangiectasias or limited forms of scleroderma were not considered to have UCTD. Those who had been given a previous diagnosis of scleroderma but who, after medical record review, did not satisfy the ACR criteria for scleroderma were eligible to be classified as UCTD. The date of diagnosis was defined as the date UCTD or scleroderma (for those who did not meet ACR criteria) was first mentioned in the medical record by the primary physician. If the medical record mentioned the diagnosis year but not the month, July was assigned as the month of diagnosis.
Selection of controls and questionnaire administration
The Institute for Social Research at the University of Michigan used random digit dialing telephone sampling to identify population-based adult female controls (10). Within each state, controls were frequency matched at a 3:1 control:case ratio to women with scleroderma on age at interview (within 5-year intervals), race/ethnicity, and geographic region. Since fewer UCTD cases than scleroderma cases were identified, the final control:UCTD ratio for this analysis was 10:1. An interview lasting at least 30 minutes was administered to all consenting, eligible cases and controls by using Computer Assisted Telephone Interview software (SurveyCraft PTY, Ltd., Montmorency, Victoria, Australia).
Inquiries were made regarding the presence and dates of breast implants and other implanted devices and/or materials. The types of implanted devices were grouped as silicone-containing (e.g., breast, artificial flexible joints as in hands and feet, shunts or catheters, pacemakers, pumps) and non-silicone-containing devices. The latter included artificial hip or knee joints, in which materials such as titanium-, cobalt-, and iron-based alloys; higher-molecular-weight polyethylene; and autocuring polymethacrylate bone cement are used, and metallic fixation devices for traumatic or neoplastic fractures.
Statistical analysis
The average age difference between cases at diagnosis (46.5 years) over the more than 10-year ascertainment period and controls at interview (51.0 years) was approximately 5 years, which resulted in an extended period of potential exposure for the controls. To adjust for this potential bias, adjusted odds ratios were calculated by post hoc individual case matching on year of birth by using conditional logistic regression. A stratum was created for each case on the basis of the month and year of UCTD diagnosis; included in the stratum was the case diagnosed in that month and all controls who were born in the same year as that case. Each case with the same year of birth had a unique month of diagnosis (and, thus, each stratum included only one case), but the cases with the same year of birth had the same set of matched controls. To adjust for this repeated use of controls, variance estimates were calculated by using the method of Barlow (11). This variance estimator uses the jackknife resampling method and has had practical application in the case-cohort design. Barlow used the PHREG procedure in SAS (SAS Institute, Inc., Cary, North Carolina) to obtain the parameter estimates.
Exposure was evaluated in each stratum. Cases were considered to be exposed only if their exposure date was before their date of diagnosis, and controls were considered to be exposed only if their exposure date was prior to the date of diagnosis of the case in that stratum. For controls in multiple strata, exposure was reevaluated in each stratum. The analysis assumed that within each birth-year cohort, the study cases were a random sample from all eligible UCTD cases, and the study controls were a random sample of subjects from the population in which the cases arose.
All responses of "don't know" or "refused" were excluded from the analysis of that risk factor. For exposures that no case experienced, conditional logistic regression calculations could not be performed. For each exposure category, each woman who reported exposure, but for whom the age at exposure was missing, was assigned an age at exposure randomly selected from the distribution of ages for all women in that category. It was required that assigned ages be less than the age at interview. Ages were imputed for one non-CNS shunt or catheter in one case and for 21 devices (one pacemaker; two non-CNS shunts or catheters; two non-silicone-containing artificial joints; three fixation devices; five intraocular lenses; six dental implants; one artificial artery, vein, or ligament; and one artificial heart valve) in 19 controls. Assignment of dates in this manner was based on the assumption that the probability of having an implanted device was age dependent and that the women with missing implant dates were likely to have received their implanted devices at ages similar to those reported by the other women with the same devices. This process of randomly assigning ages at exposure for missing values was repeated 10 times, and the regression analysis was performed for each data set, with different imputed values each time. The parameter estimates from the 10 analyses were averaged to obtain an overall parameter estimate, and an overall standard error was computed that incorporated the variation introduced by multiple imputation (12). Analysis of duration of exposure was performed for implanted medical devices by defining duration as the time interval between first implantation and diagnosis of UCTD for cases and for exposed controls in each stratum. Each subject was asked whether the implanted device was removed permanently, at which point the estimated duration of exposure was truncated.
The analysis addressed potential confounding by medical indication for the implanted device and to what extent medical surveillance bias may have resulted in a spurious association. The question to be addressed, with respect to the consideration of medical surveillance bias, is whether prior surgical intervention or a medical condition resulting in an implanted device influences the likelihood of diagnosing the outcome event of autoimmune disease. In addressing this potential source of bias, the analysis compared UCTD and scleroderma cases, in which each stratum, as in the comparison with random population controls, evaluated potential exposures prior to the date of diagnosis of UCTD. All analyses were performed by using the SAS statistical package (13).
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RESULTS |
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Among the final group of 205 cases, the maximum number of documented clinical or laboratory manifestations of connective tissue disease was 30, and the mean was 10. The most frequent manifestation was a positive ANA titer (87 percent). Polyarthralgia (63 percent), Raynaud's phenomenon (57 percent), polyarthritis (53 percent), rash (51 percent), elevated erythrocyte sedimentation rate (39 percent), Sjögren's syndrome (33 percent), puffy hands (30 percent), rheumatoid factor (29 percent), pleuritis (21 percent), and anticentromere antibody (17 percent) were examples of other recorded disease manifestations.
A total of 2,258 controls from both states were interviewed. The interview response rate for eligible controls was 80 percent in Michigan and 74 percent in Ohio. The 31 controls who did not report their date of birth and the 132 controls who reported in their medical history that their physician had previously diagnosed a connective tissue disease (scleroderma, systemic lupus, UCTD, or "mixed connective tissue disease," rheumatoid arthritis, seronegative spondyloarthropathy, myositis, Sjögren's syndrome, polymyalgia rheumatica, polyarteritis nodosa, or temporal arteritis) were excluded. The final subject pool consisted of 205 women with UCTD and 2,095 controls with similar mean ages and ethnicity (table 1).
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The intervals between surgical implantation and the diagnosis of UCTD were reviewed for artificial joints (mean = 4.5 years; range, 3.06.9 years), orthopedic fixation devices (mean = 12.1 years; range, 2.022.4 years), and non-CNS shunts (mean = 8.7 years; range, 1.019.0 years). The relation between duration of exposure and risk of UCTD was explored in the conditional logistic regression model. The odds ratio per year of exposure for metallic fixation devices was 1.02 (95 percent CI: 0.97, 1.07), and for exposures to silicone-containing devices (excluding breast implants), it was 1.03 (95 percent CI: 0.99, 1.08).
Analyses were performed to address concerns that the observed associations between implanted devices and UCTD may have been confounded by the underlying medical condition(s) that required a shunt or catheter, artificial joint, or fixation device (table 3). As expected, given that the study group was composed of women with UCTD, we observed significantly greater proportions of cases than controls with self-reported lung disease; kidney disease; heart disease or heart problems; liver disease; skin rashes, eczema, or other skin allergies; and neurologic diseases, including migraine headaches. The age- and year-of-birth-adjusted odds ratios for the silicone-containing or non-silicone-containing implant subgroups, when adjusted for any of the listed medical conditions, resulted in 12 percent reductions in the estimations of association. For any individual medical condition, the maximum reductions in adjusted odds ratios (1625 percent) were demonstrated for "heart disease or heart problems." Constraints of low prevalence of underlying disease conditions in conjunction with exposures to implants did not allow for adequate assessment of effect modification.
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DISCUSSION |
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Greenland and Finkle, in a case-control study (3), investigated the possibility of adverse effects from prosthetic nonbreast implants on the basis of a private health insurance claims database. Neither silicone-containing nor metal-containing bone and joint implants was associated with the diagnosis of "collagen disease not otherwise specified." The authors questioned whether the putative effects attributed to an implanted device may be due to a rare systemic reaction to foreign material, to the surgical procedure and perioperative medications, or to the medical condition requiring a prosthetic implant.
In a subsequent study, using a 5 percent sample of Medicare claims data and a case-control design, Greenland and Finkle (14) determined whether there was any association between connective tissue diseases, including UCTD, diagnosed in 19921994, and joint replacement surgery with silicone-, metal-, or polyethylene-containing devices. Metal-containing bone and joint implants were associated with an increased risk of UCTD (OR = 1.58, 95 percent CI: 1.33, 1.87). The observed associations with implants were not demonstrable in relation to other surgical procedures, such as hernia repair. In their most recent publication, Greenland and Finkle (4
) constructed retrospective cohorts defined by medical procedure with follow-up from 1991 to 1996. This study suggested that only the cohort with breast implants, when compared with a cohort receiving mastectomy and breast reconstruction without breast implants, was at increased risk of UCTD. Compared with the arthroscopic surgery cohort, the silicone bone and joint implant cohort, in contrast to the metal bone and joint implant cohort, exhibited increased risks of Sjögren's syndrome, systemic lupus, and polyarthropathy.
The limitations of these studies, based on random Medicare file sampling, were the truncated follow-up interval of less than 4 years and lack of information on potential confounding by prior medical history or preexisting medical conditions. In addition, there is the potential bias in the selection of controls undergoing other surgical interventions that may not be representative of the reference population at risk for implantation of a medical device (5).
An estimated 1525 percent of patients with rheumatic disease diagnosed at tertiary care centers in the United States present with clinical features that are not sufficiently specific to fulfill the ACR classification criteria for any defined connective tissue disease (15). The women in our study averaged 10 manifestations of rheumatic disease, the most common of which, namely a positive ANA, poly-arthralgia, Raynaud's phenomenon, rash, Sjögren's syndrome, puffy hands, and a sedimentation rate greater than 40 mm/hour, comprise the salient features cited in the reports of UCTD (16
). Alarcón et al. (17
) identified a cohort of UCTD patients with symptoms, physical findings, and laboratory abnormalities similar to those described in our cases. At 5 years of follow-up, the actuarial survival was estimated to be 94 percent, and 45 percent of the patients retained the clinical features of UCTD. The remaining surviving noncensored patients (n = 75) were classified as polyarthritis (9 percent), systemic lupus erythematosus (15 percent), isolated Raynaud's phenomenon (7 percent), rheumatoid arthritis (5 percent), scleroderma (4 percent), polymyositis or dermatomyositis (1 percent), or sarcoidosis (1 percent) or were in remission (13 percent) (18
).
Limitations of our study include its reliance on self-reported exposure data regarding implanted medical devices and the nonuniformity of the information on clinical examinations and laboratory tests recorded in the medical records. The exclusion of specific connective tissue diseases, including UCTD, among the controls was based on the telephone interview, and with the exception of Raynaud's phenomenon, individual signs and symptoms of rheumatic disease were not inventoried during the interview. Self-reported data are subject to recall bias, but there was no apparent basis for suspecting systematic suppression of information regarding exposures to implanted medical devices, particularly in light of the results of our previously reported validation study, which showed that 94 percent of women with breast implants correctly reported their implant status, regardless of whether or not an underlying rheumatic disease was present (6).
The comparison of UCTD with scleroderma patients may be viewed as overmatching because some patients presenting as UCTD may represent incipient scleroderma. However, because of our concern about recall and medical surveillance bias, we reasoned that such a comparison would be informative. Of interest were the associations that persisted for non-silicone-containing devices.
Perhaps a more serious concern is the extent of selection bias and nonrepresentative sampling of the cases. Because UCTD cases tend to be less severely disabled than patients with classically differentiated rheumatic diseases, it was important to develop a mechanism for identifying a spectrum of cases from multiple sources. When we initiated the study, there were increasing public concerns about adverse sequelae of breast implants, but not about other surgical implants. Although the recruitment of eligible patients referred to two academic medical centers in Michigan was determined to be 86 percent, the response rate by rheumatologists was only 63 percent, and that by the potentially eligible patients was between 75 and 80 percent.
Consideration of biologic plausibility may be presumptuous at this time, but the concept of environmental "triggers" in the natural history of scleroderma and other autoimmune disorders is well recognized (19). In recent publications, we reported that UCTD was associated with cumulative exposures to petroleum distillates, such as in paint thinners or removers, mineral spirits, and "other solvents" (20
, 21
). Autoimmune disease is the consequence of an immune response against self-antigens that eventually causes the dysfunction of target organs. Animal experiments on synthetic chemicals and metals in implanted devices are exploring biologic mechanisms that may be attributable to adjuvant immunologic effects, foreign-body inflammatory responses, or fragmentation of self-antigens by catalyzed oxidation reactions (22
, 23
).
Epidemiologic studies of breast implants and other implanted medical devices and their possible association with chronic diseases are methodologically challenging and frequently controversial. The studies conducted among populations in Michigan and Ohio are intended to stimulate new hypotheses, innovative approaches, and the fostering of understanding of the environmental determinants of autoimmune disease.
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ACKNOWLEDGMENTS |
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NOTES |
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REFERENCES |
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