Survey of epidemiological studies from 1970 - 1998

1. Case-control studies
There have been a number of case-control studies (see Table 1). The major studies of scleroderma have been from Burns et al. (1996); Hochberg et al. (1996); Englert et al., (1996). In all three studies, the calculated odds ratios were approximately unity, but the confidence intervals were wide. The study by Hochberg et al. of 837 females had the narrowest 95% confidence interval after adjustment. Other studies as shown in the table have been undertaken on rheumatoid arthritis, SLE and connective tissue disease in general (e.g. Williams et al., 1997). The results, however, were similar to those with scleroderma. Most of the studies have been too small to provide useful data.

2. Cohort studies
Summaries of the major cohort studies conducted are listed in Table 2. These studies are of greater interest as, they give information on absolute risk. Thus in the study by Gabriel et al., (1994), none out of 749 women receiving an implant had developed either rheumatoid arthritis or scleroderma. In the Nurses Health Study (Sanchez-Guerrero et al.), 86,000 women without implants were compared for their risk of connective tissue disease with 1183 women with implants with an observed relative risk of approximately unity. The largest study to date is the Women's Health Cohort Study of 10,830 women who had had a breast implant and 384,000 without such an implant who answered self-completed questionnaires on the occurrence of connective tissue disease. The level of increased risk for all disorders considered was small, although the risk for scleroderma only just excluded unity. This major study has been criticised as it relied entirely on self-reported diagnosis which is very hazardous in dealing with connective tissue disease. It might be expected, if this bias was not random, then it might possibly be in favour of the implanted women reporting more disease given the publicity. Further, such women may have been more likely to seek medical care for non-specific complaints compared to women who had not received an implant.

One interesting study comparing the risk of connective tissue disease in women receiving a breast reconstruction with a silicone implant to those receiving breast augmentation from their own tissue (Schusterman et al., 1993) showed only one case of connective tissue disease in both groups. Clearly, however, with such numbers, it was impossible to rule out either a marked protective or a marked risk effect.

There have been two recent publications on the long-term connective tissue disease risk following silicone breast implants. These two large prospective studies are relevant to be considered alongside the above. The results of neither of these studies (Edworthy et al. 1998, Nyren et al. 1998) provide support for any increased risk of connective tissue disease following implantation.

3. Case studies
A number of case series have also been reported commenting either on the frequency of implants in series of women with a connective tissue disease (Table 3 ) or frequency of connective tissue disease in series of women with an implant (Table 4). In the absence of any comparative data, these data are difficult to interpret.

Table 1: Case-control studies

First Author (year)	Case Disease	Criteria	Number studied (Response rate)	Controls Source	Number studied (Response rate)	Method	Implant (%)		RR* (95%Cl)
							Cases	Control
Dugowson (1992 Abs)	RA	(N/S)	300 (86%)	Similarly aged women	1456 (N/S)	Questionnaire	1 (0.3)	12 (0.8)	0.40 (0.05-3.13)
Burns (1994)	SSc	ACR	274 (59%)	Random digit dialling. Age race & geography matched	1184 (100%)	Telephone interview	2 (0.7)	12 (1.0)	1.30 (0.27-6.23)
Strom (1994)	SLE	ARA	113 (67%)1	Age & sex matched friends	100 (66%)	Telephone interview	1 (0.8)	0	4.50 (0.2-27.3)
Englert (1996)2	SSc	ARA	532 (74%)	General Practice	252 (87%)	Medical records and telephone interview	3 (0.6)	3(1.2)3	0.47 (0.11-2.06)
Hochberg (1996)	SSc	Clinical diagnosis	837 (N/S)	Random digit dialling. Age & race matched	2507 (90%)4	Cases-mailed questionnaire Controls - telephone interview	11 (1.3)	31 (1.2)	1.1 (0.55-2.24)
Williams (1997)	New cohort of early CTD RA=38 SLE=53 SSc=40 Other 1992	Various	323 (N/S)	Population survey of 40,000 US huseholds	(N/S)	Cases-clinical interview Controls- N/S	2 (0.6)	N/S (0.8)	1.15 (0.23-3.41)

* - Relative risk - adjusted figures presented where available
1 - Assume equal response rate in males (not included above) and females
2 - Supersedes previous publication Englert et al. Aust NZ J Med 1994: 24; 74-80
3 - Many different exposure definitions used, data broadly similar
4 - Participation rate of eligible women
N/S - Not stated
SSc - Scleroderma (sometimes referred to as systemic sclerosis)
RA - Rheumatoid arthritis
SLE - Systemic lupus erythematosus
CTD - Connective tissue disease
ACR(ARA) - American College of Rheumatology (formerly American Rheumatism Association) published criteria

Abs - Abstract

Table 2: Cohort studies

First Author (year)	SBI Cohort Selection	Number Recruited (response)	Non-Implant Recruited (response)	Number Recruited (response)	Disease Data Source	Disease(s) Ascertained	N (%) in SBI	N (%) in Non-SBI	RR* (95% Cl)
Schusterman (1993)	SBI after mastectomy	250 (98%)	Autogenous implants	353 (97%)	Record review, phone follow-up	CTD	1 (0.4)	1 (0.3)	1.1 (0.1-17.2)
Teich Alasia (1993)	SBI after mastectomy	102 (N/S)	Mastectomy without SBI	102 (N/S)	Medical record review	RA	2 (0.2)	2 (0.2)	1.0 (0.1-7.0)
Gabriel (1994)	SBI after mastectomy	749 (N/S)	Mastectomy without SBI	1498 (N/S)	Medical record review	CTD	5 (0.6)	10 (0.7)	1.1 (0.3-3.0)
Giltay (1994)	SBI at Surgical Department	235 (82%)	Age matched female; other cosmetic operation	210 (73%)	Questionnaire	Non-specific rheumatic complaints	11 (6.0)	15 (7.1)	0.6 (0.3-1.4)
Wells (1994)	SBI at Plastic Surgeion's Practice	222 (43%)	Women after other cosmetic operations	80 (26%)	Questionnaire	Arthritis	11 (5.0)	2 (3.0)	1.2 (0.15-9.0)
Sanchez-Guerrero (1995)	Nurses with SBI (Health Study)	876 (75%)	Nurses with no implants (Health study)	86,318 (N/S)	Questionnaire	Definite CTD	1 (0.1)	543 (0.6)	0.3 (0.0-1.9)
Hennekens (1996)	Women's Health Study reported SBI	10,380 (N/S)5	Women with no implant	3487,713 (N/S)	Questionnaire	CTD	231 (2.1)	1157 (3.0)	1.2 (1.08-1.4)
Friis (1997)	Nation-wide Register Cosmetic SBI and surgical reconstruction	2570 (99%)5	Women having operations for breast cancer or breast reduction	11023 (9%)	Medical record review	Definite CTD	10 (0.4)	25 (0.2)	1.7 (0.8-3.6)6
Edworthy (1998)	Population based registry	1576 (17%) 1113 (12%)	Women after cosmetic operations	727 (10%)	Questionnaire and follow up physician assessment	Symptoms and AID	(3.2)	(5)	1.001 (0.45-2.22)
Nyren (1998)	National Registry	7442	Breast reduction	3353	Medical Records review	??? CTD	1 16	3 11	0.8 (0.5-1.4)

* - Adjusted figures presented where available
5 - No information was given on the type of implant
6 - Estimated value from the combined totals
N/S - Not stated

Table 3: Case Series of CTD Patients

First Author (year)	Case Disease	Criteria	Number Studied (response)	Exposure Data Source	Implants (%)
Wigley (1992)7 Abs	SSc	(N/S)	741 (N/S)8	Questionnaire	5 (0.7%)7
Wigley (1992)7 Abs	SSc	(N/S)	741 (N/S)8	Questionnaire	5 (0.7%)7
Goldman (1995)	RA/CTD	ARA	721 (N/S)	Medical record review	12 (7.9%)
Hochberg (1995)	SSc	ACR	210 (62%)	Questionnaire	2 (1.0%)

7 - Subsequently presented as a case-control study (See Hochberg, Appendix 1)
8 - Values from the combine totals of a multicentre study
N/S - Not standard

Table 4: Case Series of Implanted Patients

First Author (year)	SBI Cohort Selection	Number Studied (response)	Disease Data Source	Disease Ascertained	N (%)
De Cholnoky (1970)	Plastic Surgery	5036 (69%)	Survey	CTD	0
Weisman (1987)	Cosmetic Surgery Practice	125 (33%)	Questionnaire/ Telephone survey	Miscellaneous Rheumatic Complaints	35 (30.4%) Nil with CTD
Cruz (1992)	Plastic Surgery	1681 (99%)	Survey	SLE	1 (0.8%)
Peters (1993)	Plastic Surgery	500 (N/S)	Physician diagnosis	CTD	RA= 1 (0.2%) SSc= 1 (0.2%) SLE= 2 (0.4%)
McLaughlin (1994)	Hospital Cosmetic Surgery Department	924 (N/S)	Hospital discharge records	RA	2 (0.2%)

N/S - Not standard

3. References
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Dugowson CE, Daling J. Koepsell TD et al. . Silicone breast implants and risk for rheumatoid arthritis. Arth Rheum 1992; 35:S66.

Edworthy S M, Martin L, Barr S G et al. A Clinical Study of the Relationship between Silicone Breast Implants and Connective Tissue Disease. Journal of Rheumatology 1998; 25:254-60.

Englert H. Morris D, March L. Scleroderma and silicone gel breast prostheses - the Sydney study revisited. Aust NZ J Med 1996, 26 349-355

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Schusterman MA, Kroll SS, Reece GP. Miller MJ, Ainslie N. Halabi S et al. . Incidence of autoimmune disease in patients after breast reconstruction with silicone gel implants versus autogenous tissue: a preliminary report. Ann Eng J Med 1995; 332: 1666-1670.

Strom BL, Reidenberg MM, Freundich B. Schinnar R. Breast silicone implants and risk of systemic lupus erythematosus. J Clin Epid 1994; 47(10) 1211-1214

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Weisman MH, Vecchione TR, Albert D. Moore LT. Mueller MR. Connective-tissue disease following breast augmentation: a preliminary test of the human adjuvant disease hypothesis. Plast Reconstr Surg 1998; 82: 626-30

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Wolfe F. Silicone breast implants and the risk of fibromyalgia and Rheumatoid Arthritis. 59th National Scientific Meeting of the American college of Rheumatology, San Francisco October 7 1995. 7