# Chapter IV:

# Rheumatology:

# Clinical Case Definitions/Diagnoses

***and Clinical Associations***

# Principal Author:

# Peter Tugwell, MBBS, MD, MSc, FRCP \[Canada and United Kingdom\]

# Professor and Chairman, Department of Medicine

# University of Ottawa

# Ottawa, Ontario, Canada

# Chapter IV: Rheumatology: Clinical Case Definitions/Diagnoses and Clinical Associations

I. Introduction IV-2

II\. Classic Accepted Connective Tissue Diseases IV-3

Clinical Case Definition IV-4

Strength of Association IV-4

Methodology IV-4

Study Results Reported for Accepted Diagnoses IV-7

# III. Atypical Presentations of Connective Tissue Diseases:

Undifferentiated Connective Tissue Disease (UCTD) IV-16

Clinical Case Definition IV-16

Strength of Association IV-17

Methodology IV-17

Study Results Reported for Atypical Presentations (UCTD) IV-17

# IV. Atypical Presentations of Connective Tissue Diseases;

Proposed Systemic Silicone Related Diseases (SSD) IV-18

Clinical Case Definition IV-18

V. Symptoms IV-24

Clinical Case Definition IV-24

Strength of Association IV-25

Methodology IV-25

Study Results Reported for Symptoms IV-26

VI\. Concluding Comments IV-41

References IV-43

Table 1 IV-47

Appendix A IV-A-75

Appendix B IV-B-82

# Rheumatology: Clinical Case Definitions/Diagnoses and Clinical Associations

# 1. Introduction

The charge from the court to the Panel is to assess whether existing
studies, research and reported observations provide a reasonable
scientific basis for one to conclude that silicone breast implants cause
or exacerbate \"classic\" connective tissue diseases, atypical
presentations, symptoms or immune system dysfunctions.

The following Scope was specified in Order No 31E:

• Classic connective tissue disease such as systemic lupus
erythematosus, Sjögren\'s syndrome

etc.

• Atypical presentations of connective tissue diseases.

• Symptoms (a listing of symptoms and signs was appended)

• Immune system dysfunctions (this category of immune system dysfunction
is not addressed here since it is reviewed in detail in the Immunology
Chapter).

The categories specified in Order No 31E (classic connective tissue
disease, atypical presentations, symptoms and signs), require
case-definitions that can be used for clinical diagnosis. Clinical
diagnosis is the crucial process that labels patients and classifies
their diseases (Sackett, 1991). The word \"disease\" is an ambiguous
term but in this context it can usefully be conceptualized as an agreed
upon case definition of a \"target disorder\" that is the objective of
the diagnostic process. Target disorders consist of clusters of symptoms
(manifestations of the target disorder that the subjects themselves
perceive either spontaneously or on questioning), signs (manifestations
perceived by their clinicians during an examination) and
laboratory/radiological findings (results that reflect maladaptive
alterations in structure or function). The above approach is consistent
with that described by Dr. Robert Willkens in his September 10th 1996
submission to Judge Robert E. Jones (Willkens, 1996) in which he states:
\"The scientific methodology of arriving at a hypothesis by observation,
in the matter of symptoms in patients who have previously undergone
silicone breast implantation would seem appropriate and incontestable. A
clinician considers the history of the development of symptoms, performs
a physical examination, obtains laboratory studies such a x-rays,
electrocardiograms and additional studies in establishing a diagnosis.
But in arriving at a specific diagnosis he must consider all those
conditions which might

present with some or all of the findings and finally the diagnostician
selects the diagnosis which best fits the findings on the basis of
common knowledge. This process in called differential diagnosis.
Cardinal elements of arriving at a correct diagnosis are objective
determinations in any of the facets of the examination. (Degown and
Degown, 1969). In arriving at a diagnosis the physician is encouraged to
employ the principle called the Law of Parsimony that encourages the
choice of a single disease to explain the patient\'s disease
manifestations. This \"law\" must be applied cautiously since the
experienced clinician recognizes the likelihood of multiple disorders
contributing to the patient\'s symptoms. The clinician must then
differentiate, if he can, the patient\'s symptoms as unique to a disease
which he designates as being present.\"

The Findings of Fact Documents, and the supporting material submitted by
both legal parties provided an excellent review of the clinical studies
themselves, their strengths and weaknesses. There is no dispute that
there is sound documentation of the presence of a wide variety of
connective tissue/autoimmune diseases and symptoms in women with
silicone breast implants. However, this does not automatically lead to
the conclusion that silicone breast implants are the cause of the
clinical conditions. In such a large number of women with implants all
of these conditions will occur independently in this population. To
support the hypothesis that silicone breast implants are causing
additional cases of connective tissue/autoimmune diseases, it is
necessary to demonstrate an increased incidence of these conditions in
women with silicone breast implants, compared to women without such
implants. This is best assessed through estimating the strength of the
association. Although the case series and case reports are critical to
establishing a clinical case definition, assessing the strength of
association requires studies with appropriate control groups using
cohort, case-control, or cross-sectional designs (see also Epidemiology
Chapter).

The remainder of this chapter is structured to review each category
(Classic/Accepted Diagnosis, Atypical Presentations of Connective Tissue
Disease, Symptoms and Signs) first for the Clinical Case
Definition/Diagnosis and then for a review of the Strength of
Association.

The categories of systemic disease specified in Order no 31E will now be
reviewed.

**II. Classic/Accepted Connective Tissue Diseases, Such As Systemic
Lupus Erythematosus, Sjögren\'s Syndrome Etc.**

# Clinical Case Definition/Diagnosis

We have interpreted the word \'classic\' to include established
connective tissue/autoimmune diseases that are described in the major
textbooks and accepted by the majority of the rheumatology medical
community. We have added the term autoimmune to include diseases such as
Hashimoto\'s Thyroiditis, Multiple Sclerosis and Myasthenia Gravis which
are included in the submissions submitted by legal counsel.

Established/Classic Connective Tissue/Autoimmune Diseases include:
Ankylosing Spondylitis; Arthritis Associated with Inflammatory Bowel
Disease; Chronic Fatigue Syndrome; Dermatomyositis Polymyositis;
Fibromyalgia; Hashimoto\'s Thyroiditis; Localized or Discoid Lupus;
Mixed Connective Tissue Disease; Morphea Multiple Sclerosis; Myasthenia
Gravis; Polyarteritis Nodosa; Polychondritis; Polyrnyalgia Rheumatica;
Psoriatic Arthritis; Raynaud\'s Disease/Phenomenon; Rheumatoid Arthritis
Sarcoidosis; Scleroderma; Sjögren\'s Syndrome; Systemic Lupus
Erythematosus; Temporal Arteritis; Vasculitis; Wegener\'s
Granulomatosis.

Explicit criteria have been established for a number of these (i.e.
Dermatomyositis/Polymyositis; Fibromyalgia; Rheumatoid Arthritis;
Scleroderma; Sjögren\'s Syndrome; Systemic Lupus Erythematosus) (The
Arthritis Foundation, 1997). The standard textbooks describe in a
reasonably consistent fashion, the case definition for each cluster, or
constellation of the symptoms, signs and diagnostic test results.

# Strength of Association

# Methodology

The basic methodology for assessing the Strength of Association is
described here for all three categories (Classic/Accepted, Atypical
Presentations and Symptoms and Signs).

# 1) Literature Search

Three methods were used to identify potentially relevant studies: 1)
screening of all legal submissions supplied by the Kobayashi legal firm;
2) a search of computerized bibliographical databases; and 3) a review
of references cited in the retrieved articles.

For the computerized search, four search strategies designed to focus on
different subsets of rheumatological/autoimmune disease, were run on
five bibliographic databases. MEDLINE (1966-

September 1998), Current Contents (January 1997 - week 13 1998),
HealthSTAR (1990 -December 1996), and Biological Abstracts (1990 -
September 1996) were searched using OVID version 3.0. EMEBASE (1980-
April 1997) was searched using Silver Platter\'s WinSPIRS version 2.0.
The search strategies were initially developed for MEDLINE and then
modified to search the indices of the other databases. In an attempt to
retrieve any studies pertaining to atypical presentations, symptoms or
neurological disorders that may have been missed, MEDLINE
(1996-­September 1998), Toxline (1965-Sept 1998) via Internet Grateful
Med. and Dissertation Abstracts (1997-1998) from Dissertation Services
at: http: //www.umii.com were searched with a fifth strategy to capture
these less uniform terms. (See Appendix A for details).

# 2) Study Selection

The panel received over 3600 documents from the legal councils of the
parties. One thousand six hundred articles were identified through the
computerized searches. Some were duplicates.

The titles of all legal submissions were screened independently by two
reviewers. Each citation was categorized as: potentially relevant,
insufficient information to make a judgment, or ineligible. All
citations classified, by one or both of the reviewers, as potentially
relevant or as insufficient information to make a judgment were
retrieved and classified as eligible or ineligible according to
predetermined inclusion criteria. All ineligible citations were coded
according to the reason for exclusion. Disagreements were resolved
through discussion and consensus. A final list of included citations
from the legal submissions was generated.

The titles and abstracts of computerized database search printouts were
screened independently by two reviewers, and categorized as eligible or
ineligible according to the same predetermined criteria. Disagreements
were resolved through discussion and consensus. A final list of included
citations from the database search was generated.

A priori selection criteria were:

a\) human studies;

b\) total number of participants equal to or greater than ten;

c\) appropriate control group of either healthy or unexposed women,
fulfilling the requirements of the study design (i.e. cohort,
case-control, or cross-sectional studies);

d\) for multiple publications of the same data, only one publication
using the same data was

included in the review;

e\) no language restrictions were imposed;

f\) no restrictions were imposed on publication dates for the legal
submissions and computerized database searches were limited to
1962-1998.

# 3) Data Extraction

A standard form (see appendix B) was used to collect information from
the selected manuscripts, regarding study design, population
characteristics, exposure to implants (type, duration, complications,
explantation, outcome measure (self-report and/or diagnostic criteria)
and results. In particular, the types of breast implants included
silicone gel-filled, saline-filled or polyurethane­coated. Information
was extracted independently by two reviewers. Discrepancies in data
extraction were discussed and resolved through consensus.

# 4) Data Synthesis

The magnitude of the association between breast implants (exposure) and
a connective tissue disease under consideration (outcome) is expressed
as a relative risk (RR) or an odds ratio (OR). The RR is obtained
directly from a cohort study and the OR from case-control and
cross-sectional studies. If the estimates were corrected for the effects
of confounding factors they are called adjusted estimates, otherwise
unadjusted. In addition to the point estimate, the 95% confidence
interval (CI) estimate are used, which defines a range within which the
true value for the association between exposure and outcome is most
likely to be found. If the study provided adjusted RRs or ORs, they were
reported, otherwise unadjusted RRs and ORs were calculated and reported.
These calculated risk estimates and confidence intervals should be
interpreted with caution, since in many instances the number of cases
reported are small and approximate methods need to be used.

A RR or OR of 1.0 indicates no observed association between exposure and
outcome; a number appreciably larger than 1.0 indicates a likely
increase in risk associated with the exposure, whereas a number
appreciably smaller than 1.0 indicates a likely risk reduction. As
indicated in the Epidemiology

Chapter, the decision that a value is \'appreciably\' larger than 1.0 is
generally based on whether the lower boundary of the 95% confidence
interval exceeds 1.0 for increased risks or the upper boundary is less
than 1.0 for decreased risks.

For meta-analysis of adjusted effects, approximate large-sample
statistical methods were used. These methods are outlined in Appendix B,
Section B.1 of the Epidemiology Chapter.

# Study Results Reported For Accepted Diagnoses

Twenty studies using cohort, case-control or cross-sectional designs
were identified, namely: (Burns, 1996; Dugowson, 1992; Edworthy, 1998;
Englert, 1996; Friis, 1997; Gabriel, 1994; Goldman, 1995; Hennekens,
1996; Hochberg, 1996; Lacy, 1997; Macdonald, 1996; Nyren, 1998a; Nyren,
1998b; Park, 1998; Sanchez-Guerrero, 1995; Strom, 1994; Teel 1997;
Wells, 1994; Winther, 1998; Wolfe, 1995). Details regarding these
studies may be found in Table 1.

Although some individual studies show some degree of elevation of risk,
as given by the relative risk or odds ratio, these are not substantial
or consistent for any of these conditions. For the studies reported
here, no risk estimate has a lower confidence interval greater than one.

The details, analysis and results for the following diagnoses are given
in the Epidemiology Chapter.

# *Dermatomyositis/Polymyositis*-see Epidemiology Chapter for details

# Friis 1997

Goldman 1995

Hennekens 1996

Nyren 1998a

Sanchez-Guerrero 1995

Teel 1997

# *Rheumatoid Arthritis*-see Epidemiology Chapter for details

# Dugowson 1992

Edworthy 1998

Friis 1997

Gabriel 1994

Goldman 1995

Hennekens 1996

Nyren 1998

Park 1998

Sanchez-Guerrero 1995

Wolfe 1995

# *Scleroderma*-see Epidemiology Chapter for details

# Burns 1996

Edworthy 1998

Englert 1996

Friis 1997

Gabriel 1994

Goldman 1995

Hennekens 1996

Hochberg 1996

Lacey 1997

Nyren 1998

Sanchez-Guerrero 1995

Wells 1994

# *Sjögren\'s Syndrome* - see Epidemiology chapter three for details

# Edworthy 1998

Friis 1997

Gabriel 1994

Goldman 1995

Hennekens 1996

Nyren 1998a

Sanchez-Guerrero 1995

# *Systemic Lupus Erythematosus* - see Epidemiology Chapter for details

# Edworthy 1998

Friis 1997

Goldman 1995

Hennekens 1996

Nyren 1998a

Sanchez-Guerrero 1995

Strom 1994

Wells 1994

Diagnoses not discussed in the Epidemiology chapter are divided into and
discussed in the following categories:

1\) Diagnoses for which there are no data reported;

2\) Diagnoses for which there is no study reporting an estimate with a
lower confidence limit of greater than one (or the limit could not be
calculated with information provided);

3\) Diagnoses for which there are discordant results (i.e. at least one
but not all studies report an estimate with a lower confidence limit of
greater than one); and

4\) Diagnoses for which there are concordant results (i.e. all studies
report an estimate with a lower confidence limit of greater than one).

# 1) Diagnoses for which there are no data reported

# Morphea

# 2) Diagnoses for which there is no study reporting an estimate with a lower confidence limit of greater than one

# Ankylosing Spondylitis

Friis 1997 Design: Cohort

Implant Type: any

Factors Controlled: none

Frequencies: 0 cases in 2570 exposed (0.0%); unexposed not reported

Relative Risk: na

Gabriel 1994 Design: Cohort

Implant Type: any

Factors Controlled: Design - age, duration of medical care, index year

Frequencies: 0 cases in 749 exposed (0.0%); 3 cases in 1498 unexposed
(0.26%)

Relative Risk (adjusted/calculated): 0.29 (0.01, 5.52)

Nyren 1998a Design: Cohort

Implant Type: any

Factors Controlled: none

Frequencies: 1 case in 7442 exposed (0.01%); 0 cases in 3353 unexposed
(0.0%)

Relative Risk (unadjusted/calculated): 1.35 (0.06, 33.18)

# Arthritis Associated with Inflammatory Bowel Disease

Gabriel 1994 Design: Cohort

Implant Type: any

Factors Controlled: Design - age, duration of medical care, index year

Frequencies: 1 case in 749 exposed (0. 13%); 0 cases in 498 unexposed
(0.0%)

Relative Risk (adjusted/calculated): 2.00 (0.08, 48.90)

# Chronic Fatigue Syndrome

Macdonald Design: Case-Control

1996 Implant Type: any

Factors Controlled: Design - neighbourhood, age

Frequencies: 1 exposure in 35 cases (2.86%); 2 exposures in 35 controls
(5.71%)

Odds Ratio (adjusted/calculated): 0.49 (0.01,9.84)

# Fibromyalgia

Nyren 1998a Design: Cohort

Implant Type: any

Factors Controlled: Analysis - age, length of follow up

Frequencies: 9 cases in 7442 exposed (0.12%); 5 cases in 3353 unexposed
(0.15%)

Relative Risk (adjusted/article): 1.0 (0.3, 3.0)

Wolfe 1995 Design: Case-Control

Implant Type: silicone breast implants

Factors Controlled: Analysis - age

Frequencies: 4 exposures in 533 cases (0.57%); 4 exposures in 1134
controls

(0.35%)

Relative Risk (adjusted/article): 2.11 (0.51, 8.77)

# Hashimoto\'s Thyroiditis

Friis 1997 Design: Cohort

Implant Type: any

Factors Controlled: none

Frequencies: 0 cases in 2570 exposed (0.0%); unexposed not reported

Relative Risk: na

Gabriel 1994 Design: Cohort

Implant Type: any

Factors Controlled: Design - age, duration of medical care, index year;
Analysis -age, index year

Frequencies: 10 cases in 749 exposed (1.34%); 21 cases in 1498 unexposed

(1.40%)

Relative Risk (adjusted/article): 1.00 (0.47, 2.13)

# Localized or Discoid Lupus

Friis 1997 Design: Cohort

Implant Type: any

Factors Controlled: none

Frequencies: 0 cases in 2570 exposed (0.0%); unexposed not reported

Relative Risk: na

Nyren 1998a Design: Cohort:

Implant Type: any

Factors Controlled: none

Frequencies: I case in 7442 exposed (0.01%); 0 cases in 3353 unexposed
(0.0%)

Relative Risk (unadjusted/calculated): 1.35 (0.06, 33.18)

*Mixed Connective Tissue Disease*

Goldman Design: Cross-Sectional

1995 Implant Type: any

Factors Controlled: Analysis-age at first visit, income

Frequencies: 0 cases in 150 exposed (0.0%); 49 cases in 4097 unexposed
(1.20%)

Odds Ratio (unadjusted/article): 0.00 (0.00, 2.68)

Sanchez- Design: Cohort

Guerrero Implant Type: any

1995 Factors Controlled: none

Frequencies: 0 cases in 1183 exposed (0.0%); 0 cases in 86,318

unexposed (0.0%)

Relative Risk (unadjusted/calculated): 17.55 (0.35, 884.24)

Teel l997 Design: Case-Control

Implant Type: any

Factors Controlled: none

Frequencies: 0 exposed in 3 cases (0.0%); 40 unexposed in 3249 controls

Odds Ratio (unadjusted/calculated): 11.32 (0.58, 222.74)

# Multiple Sclerosis

Nyren 1998b Design: Cohort

Implant type: any

Factors Controlled: Analysis - age, follow-up

Frequencies: 3 cases in 7429 exposed (0.04%); 4 cases in 3351

unexposed (0. 12%)

Relative Risk (adjusted/article): 0.5 (0.2, 0.9)

Winther 1998 Design: Cohort

Implant type: unspecified

Factors Controlled: none

Frequencies: 2 cases in 1135 exposed (0. 18%); 2 cases in 7071

unexposed (0.03%)

Relative Risk (unadjusted/calculated): 6.23 (0.88, 44.18)

# Myasthenia Gravis

Winther 1998 Design: Cohort

Implant type: unspecified

Factors Controlled: none

Frequencies: 0 cases in 1135 exposed (0.0%); 1 case in 7071 unexposed
(0.01%)

Relative Risk (unadjusted/calculated): 2.08 (0.08, 50.91)

# Polyarteritis Nodosa

Friis 1997 Design: Cohort

Implant Type: any

Factors Controlled: none

Frequencies: 0 cases in 2570 exposed (0.0%); unexposed not reported

Relative Risk: na

Nyren 1998a Design: Cohort

Implant Type: any

Factors Controlled: none

Frequencies: 0 cases in 7442 exposed (0.0%); 0 cases in 3353 unexposed
(0.0%)

Relative Risk (unadjusted/calculated): 0.45 (0.01, 22.71)

# Polychondritis

Gabriel 1994 Design: Cohort

Implant Type: any

Factors Controlled: Design - age, duration of medical care, index year

Frequencies: 1 case in 749 exposed (0. 13%); 0 cases in 1498 unexposed
(0.0%)

Relative Risk (adjusted/calculated): 6.00 (0.24, 147.01)

# Polymyalgia Rheumatica

Gabriel 1994 Design: Cohort

Implant Type: any

Factors Controlled: Design - age, duration of medical care, index year

Frequencies: 2 cases in 749 exposed (0.27%); 1 case in 1498 unexposed
(0.07%)

Relative Risk (adjusted/calculated): 4.00 (0.36, 44.04)

Friis 1997 Design: Cohort

Implant Type: any

(combined Factors Controlled: none

with Temporal Frequencies: 3 cases in 2570 exposed (11.7%); 10 cases in
11023 unexposed

Arteritis) (0.09%)

Relative Risk (unadjusted/calculated): 1.29 (0.35, 4.67)

# Psoriatic Arthritis

Friis 1997 Design: Cohort

Implant Type: any

Factors Controlled: none

Frequencies: 0 cases in 2570 exposed (0.0%); unexposed not reported

Relative Risk: na

Gabriel 1994 Design: Cohort

Implant Type: any

Factors Controlled: Design - age, duration of medical care, index year

Frequencies: 0 cases in 749 exposed (0.0%); 1 case in 1498 unexposed
(0.07%)

Relative Risk (adjusted/calculated): 0.67 (0.03, 16.33)

Nyren 1998a Design: Cohort

Implant Type: any

Factors Controlled: none

Frequencies: 0 cases in 7442 exposed (0.0%); 2 cases in 3353 unexposed
(0.06%)

Relative Risk (unadjusted/calculated): 0.09 (0.00, 1.88)

# Raynaud\'s Disease/Phenomenon

Giltay 1994 Design: Cohort

Implant Type: silicone gel-filled

Factors Controlled: Design - age, year of operation

Frequencies: 12 cases in 325 exposed (3.69%); 7 cases in 210 unexposed
(3.33%)

Relative Risk (adjusted/calculated): 1. 11(0.44, 2.77)

Park 1994 Design: Cohort

Implant Type: silicone gel-filled

Factors Controlled: Design - Augmentation - \"similar aged\";
Reconstruction -

partially matched on age, stage of disease and time of operation

Frequencies:

Augmentation: 1 case in 110 exposed (0. 91%); 3 cases in 128 unexposed
(2.34%)

Reconstruction: 7 cases in 207 exposed (3.38%);5 cases in 88 unexposed
(5.68%)

Relative Risk (adjusted/calculated):

Augmentation: 0.39 (0.04, 3.68);

Reconstruction: 0.60 (0.19, 1.82)

Wells 1994 Design: Cohort

Implant Type: silicone breast implants

Factors Controlled: none

Frequencies: 1% cases in exposed group; 0% cases in unexposed group

Relative Risk: na

# Sarcoidosis

Friis 1997 Design: Cohort

Implant Type: any

Factors Controlled: none

Frequencies: 0 cases in 2570 exposed (0.0%); unexposed not reported

Relative Risk: na

Nyren 1998a Design: Cohort

Implant Type: any

Factors Controlled: none

Frequencies: 2 cases in 7442 exposed (0.03%); 2 cases in 3353

unexposed (0.06%)

Relative Risk (unadjusted/calculated): 0.45 (0.06,3.20)

# Temporal Arteritis

Friis 1997 Design: Cohort

(combined with Implant Type: any

Polymyalgia Factors Controlled: none

Rheumatica) Frequencies: 3 cases in 2570 exposed (0. 12%); 10 cases in
11023

unexposed (0.09%)

Relative Risk (unadjusted/calculated): 1.29 (0.35, 4.67)

Nyren 1998a Design: Cohort

Implant Type: any

Factors Controlled: none

Frequencies: 1 case in 7442 exposed (0.01%); 0 cases in 3353 unexposed
(0.0%)

Relative Risk (unadjusted/calculated): 1.35 (0.06, 33.18)

# Vasculitis

Gabriel 1994 Design: Cohort

Implant Type: any

Factors Controlled: Design - age, duration of medical care, index year

Frequencies: 0 cases in 749 exposed (0. 0%); 2 cases in 1498 unexposed
(0.13%)

Relative Risk (adjusted/calculated): 0.40 (0.02, 8.32)

# Wegener\'s Granulomatosis

Friis 1997 Design: Cohort

Implant Type: any

Factors Controlled: none

Frequencies: 0 cases in 2570 exposed (0.0%); 0 cases in 11023 unexposed
(0.0%)

Relative Risk (unadjusted/calculated): 4.29 (0.09, 216.04)

A meta-analysis was possible for four diagnoses, and the results, as
given by the pooled relative risk and confidence interval, are as
follows:

Relative Risk (95% Confidence Interval)

# Multiple Sclerosis

(including unadjusted estimates)

Nyren 1998b 0.5 (0.2, 0.9)

Winther 1998 6.23 (0.88, 44.18)

Overall 0.69 (0.34, 1.40)

# Raynaud\'s Disease/Phenomenon

Giltay 1994 1.11 (0.44, 2.77)

Park 1994 Augmentation 0.39 (0.04, 3.68)

Overall 0.96 (0.41, 2.25)

# Fibromyalgia

Nyren 1998 1.0 (0.3,3.0)

Wolfe 1995 2.11 (0.51, 8.77)

Overall 1.34 (0.55, 3.29)

# Polymyalgia Rheumatica

(including unadjusted estimates)

Gabriel 1994 4.00 (0.36, 44.04)

Fries 1997 1.29 (0.35, 4.67)

Overall 1.66 (0.53, 5.21)

# 3) Diagnoses for which there are discordant results (i.e. at least one but not all studies report an

*estimate with a lower confidence limit of greater than one)*

None

# 4) Diagnoses for which there are concordant results (i. e. all studies report an estimate with a lower confidence limit of greater than one)

None

# This data does not provide any evidence for an association between silicone breast implants and

these Classic/Accepted connective tissue diseases.

**III. Atypical Presentations of Connective Tissue Diseases:
Undifferentiated Connective Tissue Disease (UCTD)**

Two constellations of symptoms, signs and laboratory test abnormalities
have been proposed that are not in the majority of textbooks, namely
Undifferentiated Connective Tissue Disease and Systemic Silicone Related
Disease.

# Clinical Case Definition/Diagnosis

In order to be able to study such atypical presentations there needs to
be an accepted case definition that has been shown to differ from other
conditions in its constituent clinical presentation, impact upon
prognosis, severity or response to therapy.

Undifferentiated connective tissue disease provides a good example of
how a case definition is established and the natural history assessed.
The term has been used since the early 1980s (Leroy, 1980; Rich, 1984;
Strongwater, 1989) to describe patients who do not meet the criteria for
other accepted connective tissue diseases, but who have a constellation
of the symptoms that are found in the accepted connective tissue
diseases.

An important study (Williams, 1998) has been conducted to standardize
the case definition, and to follow a cohort of 410 patients with well
defined and undifferentiated connective tissue diseases over 5 years to
assess the natural history and outcome. The case definition was defined
by a group of experienced rheumatologists under the auspices of the
Coordinating Center of the Cooperative Systemic Studies of the Rheumatic
Diseases, funded under the National Institute of Arthritis,
Musculoskeletal and Skin Diseases. A protocol was developed at the
Coordinating Center with the assistance and approval of participating
clinics and under the direction and guidance of an external advisory
committee. Early Undifferentiated Connective Tissue Disease was defined
as patients with disease manifestations of less than one year in
duration that met at least one of the following criteria: 1) Raynaud\'s
phenomenon; 2) isolated keratoconjunctivitis SICCA; 3) unexplained
polyarthritis (including possible and probable rheumatoid arthritis); or
4) at

least three other criteria that could not be attributed to other disease
processes, which included myalgias, rash, pleuritis, pericarditis,
central nervous system symptoms, pulmonary symptoms, peripheral
neuropathy, elevated erythrocyte rate, and a false positive serologic
test for syphilis.

The above group of investigators followed 115 undifferentiated patients
over five years. Thirty four patients were lost to follow-up. Of the
remaining 81 patients, the five year actuarial survival was 94%, similar
to patients with rheumatoid arthritis, systemic lupus erythematosus or
dermatomyositis/polymyositis. Ten patients experienced complete
remission, 34 patients persisted with undifferentiated disease, 18
patients went on to fulfill the diagnostic or classification criteria
for a specific disease. The response to therapy of patients with UCTD is
not well documented with the exception of one study by Wise (1996) in
which patients with UCTD (defined as having two to three criteria for
Systemic Lupus Erythematosus (SLE)), respond as well to methotrexate, as
do those who meet the full criteria for SLE.

The Panel is comfortable with including UCTD as a constellation given
that it has a case definition, is distinct from the other established
connective tissue diseases, has been studied longitudinally, and has
substantive symptoms, which in many patients have been shown to be
stable over time. In addition, the criteria do not require the presence
of silicone gel. This allows studies to be conducted to assess its
putative association with silicone gel (Liang, 1996).

# Strength of Association

# Methodology

The same methods were applied as for the Classic/Accepted diseases and
the results are shown below.

# Study Results Reported For Atypical Presentations: UCTD

UCTD was included explicitly in one case control study (Liang, 1996) and
although not analyzed separately would possibly apply to a number of the
patients included in cross sectional or cohort studies. (Edworthy, 1998;
Friis, 1997; Gabriel, 1994; Giltay, 1994; Hennekens, 1996; Nyren, 1998;
Park, 1998; Wells, 1994)

# The study addressing this outcome had an estimate with lower confidence interval greater

than one indicating no appreciably increased risk.

Liang 1996 Design: Case Control

Implant Type: unspecified

Factors Controlled: Design - age, race, geographic location:

Analysis - year of birth

Frequencies: 3 exposures in 205 cases (1.46%); 27 exposures in 2220
controls (1.21%)

Odds Ratio (adjusted/article): 2.27 (0.67, 7.71)

This study was only available as an abstract. The study found only 3
cases out of 205 women with implants. The confidence limits for the
adjusted odds ratio are very wide with the lower bound of 0.67, well
below the criteria level of 1.0 for defining an appreciable association.
This is insufficient to substantiate an association with silicone breast
implants.

# IV. Atypical Presentation of Connective Tissue Diseases: Proposed Systemic Silicone Related Disease (SSRD)

# Clinical Case Definitions

The second constellation of atypical presentation of connective tissue
diseases for which a case definition has been proposed, that is not in
the majority of textbooks, is that of the proposed Systemic Silicone
Related Disease.

The history of SSRD being proposed as a disease is well summarized in
the Findings of Fact from the plaintiffs. In the early 1990s,
rheumatologists were reporting an increasing number of case series of
women with implants with a wide variety of rheumatological symptoms. It
was noted that many of these women did not have classical connective
tissue disease and it was suggested that perhaps they were experiencing
an atypical disease (Bridges, 1993; Love, 1992).

Weiner et al, (1992) reported on 50 patients with Silicone Breast
Implants (SBIs) all of whom had arthralgias, and many of whom had
myalgias, neuralgias, recurrent flu-like sensations and profound
fatigue. Sixty percent reported dry eyes/mouth and Anti-nuclear
Antibodies (ANAs) were positive in 70% of women. None met ACR criteria,
and none responded to traditional therapy.

Osborn (1992) described symptoms of breast pain and hardening, fatigue,
weakness, muscle aches, widespread pain, and breast lumps in 50% of 100
women with Silicone Breast Implants. Less than 20% met American College
of Rheumatology (ACR) criteria for classical Connective Tissue

Disease (CTD). Subsequently, Osborn and colleagues (1993) reported a
series of 126 women with rheumatological complaints, none of whom
fulfilled ACR criteria for classical Connective Tissue Disease.

Vasey (1994) reported the clinical findings of 50 Silicone Breast
Implant patients between 1977 and 1991. The most common clinical
findings included chronic fatigue, muscle pain, joint pain, joint
swelling and lymphadenopathy. Twenty percent were judged to have
classical connective tissue disease.

By 1995, the reports of atypical connective tissue disease were growing
and the literature contained an increasing number of case series.
Freundlich (1994) reviewed 50 consecutive women with Silicone Breast
Implant and found 50% had complaints of dry eyes and dry mouth. The same
year, Borenstein described symptoms of fatigue, myalgias and arthralgias
reported by a proportion of 100 patients, who on average reported the
onset of clinical symptoms 5.6 years after mammaplasty. In 1995, Davis
reported on 343 patients with arthralgias (71%), chronic fatigue (85%),
dry eyes (69%) and numbness (69%). Mease and colleagues (1995) reported
a series of 128 symptomatic women with Silicone Breast Implants. The
average interval between implantation and onset of symptoms was 5.8
years. The authors concluded that their results suggested the presence
of a syndrome marked by fatigue, polyarthralgias, myalgias, cognitive
dysfunction, SICCA syndrome, rash, chest wall pain, sleep and mood
disturbance and occasional serologic abnormalities. Baker reported on
145 patients with Silicone Breast Implant who reported symptoms of
Sjögren\'s syndrome, alopecia, arthralgia and skin rashes which seemed
to represent a clustering that is different from fibromyalgia or primary
generalized osteoarthritis. Cuellar (1995) reported on 813 patients with
Silicone Breast Implants, many with an ill-defined connective tissue
diseases. Predominant complaints were malaise, fatigue, lymphadenopathy,
arthralgia and myalgia.

Solomon reported similar findings in 1994 on his first 176 patients. By
1996 he reported on a patient base of 639 symptomatic women. The mean
implant duration was 12.4 years. Four hundred and fifty six of the women
had a history of Baker Grade IV contracture and 216 had documented
implant rupture. The most frequently reported symptoms were fatigue,
cognitive dysfunction, arthralgias, and dry mouth. Three hundred and
thirty two of the patients had their implants removed. Of these, 215
were followed for six months following explantation with clinical
improvement seen in 36%. Solomon (1994) concluded that these women had a
unique disease which tends to occur in women with long-standing implants
who have antecedent pathology in the form of capsular contracture

and implant rupture.

The Executive Committee of the Silicone Related Disorders Research Group
(1996) have

proposed the following set of preliminary operational criteria for a
syndrome/disease that they term Systemic Silicone Related Disease.

*Inclusion Criteria: *

A. Presence of a silicone gel filled breast implant either currently or
in the past

B. Presence of local disease: Any of the following

1 . Capsular contracture (Baker 11 or greater)

# 2. Rupture documented by imaging technique (sonograrn or MRI), operative findings, or presence of siliconoma

# 3. Persistent (more than 6 weeks) chest wall pain

# 4. Persistent (more than 6 weeks) breast pain unrelated to menses

# 5. Axillary adenopathy

# 6. Entrapment neuropathy or thoracic outlet syndrome documented by physical exam (positive Adson\'s sign) or by electrodiagnostic studies

# 7. Immune mediated skin rash (petechiae, telangiectasia, or poikiloderma not related to sun

exposure) on the chest wall

# 8. Histopathologic finding in capsule of immune granuloma (foamy macrophages, plasma cells, or

lymphoid infiltrates)

To be considered definite SSRD, both A and B must be present unless the
implant is polyurethane coated in which case only A must be present.

*Exclusion Criteria: *

A. Presence of classic connective tissue disease

1 . Rheumatoid Arthritis by ACR criteria

2\. Systemic Lupus Erythematosis by ACR criteria

3\. Primary Systemic Sclerosis (PSS) by ACR criteria or biopsy

4\. Mixed Connective Tissue Disease with positive anti-RNP antibody

5\. Dermatomyositis/Polymyositis by Bohan criteria

6\. Primary Sjögren\'s Syndrome by Fox Criteria

B. Presence of local or metastatic malignancy excluding skin cancer or
carcinoma in situ.

C. Exposure to another environmental agent or drug know to produce
systemic rheumatic disease

D. Documented chronic and persistently active infection prior to
implantation. Does not exclude

patients with positive serologies for past viral or bacterial infection
who lack evidence of active infection at time of implantation.

*Major Criteria: *

(Defined as those signs or symptoms present in 50% or more women in 2 or
more published series). The symptom must be either objectively
verifiable or sufficiently severe to interfere with activities of daily
living, vocational activities, and/or recreational activities.

A. Symmetrical myalgia with 4-11 tender points, including four or more
tender points above the waist. Ascertainment of tender points includes
appropriate negative control points.

B. Chronic fatigue of six month duration or longer interfering with
activities of daily living or occupational and/or recreational
activities.

C. Cognitive dysfunction of six month duration or longer which can
either be objectively demonstrated on neuropsychiatric testing or which
is of sufficient severity to interfere with activities of daily living
and occupational and/or recreational activities.

D. Objective SICCA complex defined by abnormal Schirmer testing,
abnormal Rose Bongal

staining, salivary scintography, sialogram or abnormal labial biopsy.

*Minor Criteria: *

(Defined as those signs, symptoms or laboratory findings seen in 50% or
more symptomatic women in two or more published series without objective
confirmation or in 25-50% of symptomatic women with objective
confirmation).

A. Local disease (see above) after onset of systemic disease. (This
criteria may only be applied to

patients with polyurethane implants who did not satisfy inclusionary
criteria B)

B. Arthralgia (pain lasting for six months or longer in four or more
upper extremity joints which do

not have radiographic evidence of osteoarthritis).

C. Enthesopathy in 2 or more sites in the upper extremities

D. Subjective SICCA complex (2 of 3: dry eye, dry mouth, dry vagina)

E. Cerebello-vestibular dysfunction demonstrated on physical examination
or by electrophysiologic

testing.

F. Non-scarring alopecia not attributable to pregnancy

G. Raynaud\'s phenomenon with observed 2 or 3 color change

H. Photosensitive skin rash

I. Immune mediated skin rash (petechiae, telangiectasia, or livedo
reticularis) involving both the trunk and extremities)

J. Improvement of two Major or one Major and four Minor criteria within
18 months of

explantation

K. Positive ANA at a titer of 1: 40 or greater on a Hep-2 cell line

L. Elevated ESR (Westergren\>25)

M. Abnormal quantitative immunoglobulins (one or more isotypes)

*Definite SSRD requires: *

1\) Presence of the inclusion criterion

2\) Absence of the exclusion criterion

3\) Presence of three major criteria, or presence of two major criteria
and four minor criteria, or presence of one major and seven minor
criteria.

These criteria were derived from the clinical experience with 639
patients reported by Solomon and the patients that had been seen by
other members of the Silicone Related Disorders Study Group, a
non-profit clinical research organization. The requirement that there be
a history of breast implant is of concern to the Panel, since the
requirement of the inclusion of the putative cause of silicone exposure
as one of the criteria, does not allow the criteria set to be tested
objectively without knowledge of the presence of implants thus incurring
\'incorporation bias\' (Sackett, 1979).

Another concern of the Panel is that there are few objective signs and
that the constellation proposed is not unique. The majority of
components of the proposed SSRD criteria are already part of other
accepted diseases (e.g, scleroderma, Sjögren\'s, lupus, fibromyalgia,
chronic fatigue syndrome) with the only differentiating feature being
that SSRD requires the presence of a breast implant.

A consensus statement was developed following a meeting of a consensus
panel of nine practicing rheumatologists with extensive experience with
patients having silicone exposure in October 1995. An abstract at the
1996 ACR describes the application of preliminary operational criteria
to 100 cases with what is termed atypical connective tissue disease
(ACTD), another 60 cases with implants and no systemic complaints, and
37 patients with a diagnosis of fibromyalgia without implants. The
authors

state that \"the selection of the cases of ACTD were obtained by random
or consecutive selection from four university based urban practices.\"
The exact criteria for the selection of these patients are not stated in
this abstract. All charts were reviewed by two of the authors and a
given patient was considered to have fulfilled these putative criteria
for SSRD if the two reviewers found the documentation to meet these
criteria. Sensitivity and specificity were calculated. An abstract from
the 1996 ISEE Annual Conference provides similar information although
some patients with classic connective disease are included. This latter
abstract describes the approach but does not include any results. This
study does not provide the needed information around patients presenting
with none or a more of the exact symptoms proposed to assess whether
these are more frequent in those with implants. The patients with
implants but no symptoms are by definition not going to contribute to
this, and the patients with fibrositis will have been selected out on
the basis of their own constellation of signs and symptoms.

The authors have called for a large multicenter disease classification
study, but this has not been completed to our knowledge. Such a study
will require an evaluation of a representative sample of women with
implants (that are not self selected from those with complaints)
compared with a matched population group to examine the frequency of the
presence of the proposed criteria.

The Panel has carefully considered the above information, as well as
presentations at the hearings by Drs. Solomon and Silverman,
complemented by Plaintiff Exhibit 434 by Solomon (1996) that presents
evidence in support of there being a unique atypical connective tissue
disease in women with silicone breast implants.

The Panel has concluded that they do not yet support SSRD being included
in the list of accepted diseases for the following reasons:

1\. That the requirement of the inclusion of the putative cause
(silicone exposure) as one of the criteria does not allow the criteria
set to be tested objectively without knowledge of the presence of
implants thus incurring incorporation bias.

2\. There are few objective signs, and the constellation proposed is not
unique. That is a majority of

components of the proposed SSRD criteria are already part of other
accepted diseases (e.g.

scleroderma, Sjögren\'s, lupus, fibromyalgia, chronic fatigue syndrome)
with the only differentiating

feature being that SSRD requires the presence of a breast implant.

3\. There is no proven association of the criteria set, with the
putative cause - exposure to silicone gel and/or silica, through well
controlled studies. If a cohort design is used, this requires study of a
representative sample of women with implants that are not self selected
from those with complaints compared with a matched population group to
examine the frequency of such symptoms. Although this conclusion is
subject to revision if the appropriate well designed studies are
conducted. The Panel, on balance, concludes that at present the
scientific basis is insufficient to accept this as a established disease
or syndrome.

# V. Symptoms

# Clinical Case Definition

The mandate from Judge Pointer in Order 31E states: Listed in the
appendix to this order are various diseases, symptoms, conditions or
complaints that have sometimes been asserted as possibly associated with
silicone gel implants. To the extent you believe appropriate - and
without being asked to address separately each of these diseases,
symptoms, conditions, and complaints- you are encouraged to comment on
the scientific basis, if any, for any such claimed linkage. The Appendix
to Order 31E from Judge Pointer lists the following symptoms and signs
reported in women exposed to Silicone Breast Implants, but in whom the
accepted criteria for any of the above conditions are not met:

Allergies; Alopecia; Arthralgias; Breathing difficulties/shortness of
breath/pulmonary symptoms; Bruising easily; Burning in
chest/heartburn/esophageal symptoms; Chronic fatigue/low energy; Chronic
inflammation; Cognitive dysfunctions/memory problems; Concentration
difficulties; Constipation; Coughing; Diarrhea; Decrease in sex drive;
Fever/low grade; Flu-like feelings; Headaches; Heart palpitations; Hot
flashes; Incontinence; Infections Lymphadenopathy; Malaise/general; Mood
swings/irritability/anxiety/panic attacks; Mucosal ulcers; Muscle
cramps; Muscle weakness; Myalgias ; Nausea/vomiting; Neurologic
deficits; Night sweats; Pain (abdominal, back, chest, intestinal, joint,
muscle); Paraesthesia/numbness and tingling; Sensitivity to heat/cold;
SICCA symptoms (dry eyes/mouth/skin/vagina); Skin changes/rashes/hives;
Sleep disorders; Sore throat; Stiffness; Swallowing
difficulties/dysphagia; Swelling/fluid retention/bloating;
Tenderness/tender points; TMJ problems;

Urination/frequency/burning/incontinence; Vertigo/dizziness/ringing in
ears/vestibular dysfunction; Vision problems/blurred vision/light
sensitivity; Weight loss; Weight gain.

The more than 50 case reports and clinical series describing these in
the Findings of Fact of the Plaintiffs were reviewed. The precision of
the Case Definition of the symptoms and signs varied across the studies,
with few providing reproducible definitions or evidence of validation by
medical records and/or rheumatologist\'s evaluation

# Prognosis

The prognosis influences the clinical importance of symptoms and signs
in patients not fulfilling criteria for a Classic/Accepted Disease. For
this review the author\'s categorization was accepted. It is known that
in most cases single symptoms or signs are not predictive of accepted
connective diseases -for example polyarthralgias have numerous causes
and rarely and in the majority no diagnosis is ever made (Williams,
1998; Mukeji, 1993). In patients presenting with monoarthritis of three
months duration that do not have the associated features to meet the
criteria for an accepted connective tissue diseases, the majority fail
to attain a definitive diagnosis in the ensuing two years (Blocka,
1987). In patients with Raynaud\'s Phenomenon two studies have reported
that only 3-19% go on to attain diagnoses of defined connective tissue
diseases (Harper, 1982; Fitzgerald, 1988; Williams, 1998).

The same is true of individuals with positive anti-nuclear antibodies.
As described in the chapter on immunology, Aho et al showed that in
healthy women less than one in 100 with a positive Anti­nuclear
Antibodies will develop systemic lupus erythematosus. Schoenfeld et al,
found that over five years only 12% of women with a high level of
Anti-nuclear Antibodies developed symptoms and none had developed an
established connective tissue disease. Thus the evidence to date
suggests that the majority of these symptoms and signs resolve
spontaneously, and the abnormal laboratory tests do not lead to
symptomatic disease in the majority of patients.

# Strength of Association

# Methodology

The same methods were applied as for the Classic/Accepted diseases and
the results are listed below.

The symptoms and signs in the eligible controlled studies were
categorized according to the Appendix

to Order 31E. Some categories included a number of different symptoms or
signs. It should be appreciated that many studies do present the results
as a frequency of symptoms rather than by individual women, so that
women with multiple symptoms will be represented in several analyses

# Study Results Reported for Symptoms

Nine cohort studies reporting endpoints, which could be classified
according to the appendix of order

31E were found. (Edworthy, 1998; Friis, 1997; Gabriel, 1994; Giltay,
1994; Kim, 1998; Nyren,

1998b; Park, 1998; Wells, 1994; Winther, 1998)

Symptoms are divided into the following categories:

1\) Symptoms for which there are no data reported

2\) Symptoms for which there is no study reporting an estimate with a
lower confidence limit

of greater than one (or the limit could not be calculated with
information provided).

3\) Symptoms for which there are discordant results (i.e. at least one
but not all studies report

an estimate with a lower confidence limit of greater than one).

4\) Symptoms for which there are concordant results (i.e. all studies
report an estimate with a

lower confidence limit of greater than one).

# 1) Symptoms for which there are no data reported

# Allergies

*Bruising Easily*

*Burning In Chest/Heartburn/Esophageal Symptoms*

*Chronic Inflammation*

*Cognitive Dysfunction/Memory Problems*

*Coughing*

*Decrease in Sex Drive*

*Diarrhea*

*\"Flu-Like \" Feelings*

*Heart Palpitations*

*Hot Flashes*

*Incontinence*

*Infections*

*Malaise (General)*

*Muscle Cramps*

*Nausea/Vomiting*

*Night Sweats*

*Pain (Abdominal, Back, Chest, Intestinal, Joint, Muscle)*-see
arthralgias, myalgias

*Sensitivity To Heat/Cold*

*Sleep Disorders*

*Sore Throat*

*Tenderness/Tender Points-*see myalgias

*TMJ problems*

*Urination - Frequency/Burning/Incontinence*

*Vision Problems - Blurred Vision/Light Sensitivity*

# 2) Symptoms for which there is no study reporting a point estimate with a lower confidence limit of greater than one.

# Alopecia

Wells 1994 Study Type: Cohort

Implant Type: silicone breast implants

Factors Controlled: Analysis - age, year of operation

Endpoint: [hair loss arms and legs]{.underline}

Frequencies: 0% cases in exposed group; 1% cases in unexposed group

Odds Ratio (adjusted/article): (Relative Risk not reported) 0.32
(0.01,8.30)

# Breathing Difficulties/Shortness of Breath/Pulmonary Symptoms

Giltay 1994 Study Type: Cohort

Implant Type: silicone gel-filled

Factors Controlled: Design - age, year of operation

Endpoint: [pleuritis]{.underline}

Frequencies: 4 cases in 235 exposed (1.7%); 5 cases in 210 unexposed
(2.38%)

Relative Risk (adjusted/calculated): 0.71 (0.19, 2.63)

Wells 1994 Study Type: Cohort

Implant Type: silicone breast implants

Factors Controlled: Analysis - age, year of operation

Endpoint: [breathing difficult]{.underline}

Frequencies: 2% cases in exposed group; 7% cases in unexposed group

Odds Ratio(adjusted/article): (Relative Risk not reported) 0.22 (0.067,
0.731)

# Chronic Fatigue/Low Energy

Park 1998 Study Type: Cohort

Implant Type: silicone gel-filled

Endpoint: fatigue

Factors Controlled: Design - Augmentation - \"similar aged\";
Reconstruction -

partially matched on age, stage of disease and time of operation

Frequencies:

Augmentation - 13 cases in 110 exposed (11. 82%);

8 cases in 128 unexposed (6.25%)

Reconstruction -28 cases in 207 exposed (13.53%);

15 cases in 88 unexposed (17.05%)

Relative Risk (adjusted/calculated):

Augmentation - 1.89 (0.81, 4.39)

Reconstruction - 0.79 (0.45, 1.41)

Wells 1994 Study Type: Cohort

Implant Type: silicone breast implants

Factors Controlled: Analysis - age, year of operation

Endpoint: [easily tire]{.underline}

Frequencies: 15% cases in exposed group; 11% cases in unexposed group

Odds Ratio(adjusted/article): (Relative Risk not reported) 1.379
(0.547,3.310)

# Concentration Difficulties

Edworthy Study Type: Cohort

1998 Implant Type: silicone gel-filled

Factors controlled: none

Endpoint: [thought problems]{.underline}

Frequencies: 32% cases in exposed group; 17% cases in unexposed group

Relative Risk (adjusted/calculated): 1.88 (confidence interval not
available)

*Constipation*

Park 1998 Study Type: Cohort

Implant Type: silicone gel-filled

Factors Controlled: Design - Augmentation - \"similar aged\",
Reconstruction -

partially matched on age, stage of disease and time of operation

Endpoint: [constipation]{.underline}

Frequencies:

Augmentation - 4 cases in 110 exposed (3.62%);

2 cases in 128 unexposed (1.56%)

Reconstruction - 8 cases in 207 exposed (3.82%);

4 cases in 88 unexposed (4.55%)

Relative Risk (adjusted/calculated):

Augmentation - 2.33 (0.43, 12.46)

Reconstruction - 0.85 (0.26, 2.75)

# Fever (Low Grade)

Wells 1994 Study Type: Cohort

Implant Type: silicone breast implants

Factors Controlled: Analysis - age, year of operation

Endpoint: [persistent fever]{.underline}

Frequencies: 1% cases in exposed group; 0% cases in unexposed group

Odds Ratio (adjusted/article): (Relative Risk not reported) 1.099
(0.164, 7.381)

# Headaches

Edworthy Study Type: Cohort

1998 Implant Type: silicone gel-filled

Endpoint: headache

Factors controlled: none

Frequencies: 18% cases in exposed group; 8% cases in unexposed group

Relative Risk (unadjusted/calculated): 2.25 (confidence interval not
available)

# Mood Swings/Irritability/Anxiety/Panic Attacks

Park 1998 Study Type: Cohort

** **Implant Type: silicone gel-filled

Factors Controlled: Design - Augmentation - \"similar aged\";
Reconstruction -

partially matched on age, stage of disease and time of operation

Endpoint: [psychiatric]{.underline}

Frequencies:

Augmentation - 2 cases in 110 exposed (1.82%);

0 cases in 128 unexposed(0.0%)

Reconstruction - 3 cases in 207 exposed (1.45%);

1 cases in 88 unexposed (1.14%)

Relative Risk (adjusted/calculated):

Augmentation - 5.81 (0.28, 119.76)

Reconstruction - 1.28 (0.13, 12.09)

# Mucosal Ulcers

Gabriel 1994 Study Type: Cohort

Implant Type: any

Factors Controlled: Design - age, duration of medical care, index year;
Analysis -

age, index year

Endpoint: [oral ulcers ]{.underline}

Frequencies: 25 cases in 749 exposed (3.34%); 39 cases in 1498 (2.60%)
unexposed

Relative Risk (adjusted/article): 0.69 (0.29, 1.63)

Giltay 1994 Study Type: Cohort

Implant Type: silicone gel-filled

Factors Controlled: Design - age, year of operation; Analysis - none

Endpoint: [mouth ulcers for at least three weeks]{.underline}

Frequencies: 4 cases in 235 (1.70%) exposed; 2 cases in 210 (0.95%)
unexposed

Relative risk (adjusted/calculated): 1.79 (0.33, 9.66)

# Muscle Weakness

Gabriel 1994 Study Type: Cohort

Implant Type: any

Factors Controlled: Design - age, duration of medical care, index year

Endpoint: [symmetric muscle weakness]{.underline}

Frequencies: 1 case in 749 exposed (0. 13%); 5 cases in 1498 unexposed
(0.33%)

Relative Risk (adjusted/article): 0.43 (0.04, 2.67)

# Neurologic Deficits

Nyren 1998b Study Type: Cohort

Implant Type: any

Factors Controlled: Design - none; Analysis - age, follow-up time for
all endpoints

except neuritis of the optic nerve, Guillian-Barre syndrome for which no
factors

were adjusted and amyotropic lateral sclerosis

Endpoint: diseases [on nerve roots and plexuses ]{.underline}

[ ]{.underline}Frequencies: 3 cases in 7425 exposed (0.04%); 1 case in
3351 unexposed (0.03%) Relative Risk (adjusted/article): 1.5 (0.6,3.9)

# Endpoint: [mononeuritis of the upper limb]{.underline}

Frequencies: 8 cases in 7425 (0.11%) exposed; 8 cases in 3351 unexposed
(0.24%)

Relative Risk (adjusted/article): 0.5 (0.2,1.03)

# Endpoint: [mononeuritis of the lower limb]{.underline}

Frequencies: 7 cases in 7425 exposed (0.09%); 3 cases in 3351 unexposed
(0.09%)

Relative Risk (adjusted/article): 1.3 (0.6,2.5)

# Endpoint: [Guillian-Barre Syndrome]{.underline}

Frequencies: 1 case in 7425 exposed (0.01%); 0 cases in 3351 unexposed
(0.0%)

Relative Risk (unadjusted/calculated): 1.35 (0.06, 33.23)

# Endpoint: [neuritis of the optic nerve]{.underline}

Frequencies: 0 cases in 7425 exposed (0.0%); 0 cases in 3351 unexposed
(0.0%)

Relative Risk (unadjusted/calculated): 0.45 (0.01, 22.74)

# Endpoint: [amyotropic lateral sclerosis]{.underline}

Frequencies: 0 cases in 7425 exposed (0.0%); 0 cases in 3351 unexposed
(0.0%)

Relative Risk (unadjusted/calculated): 0.45 (0.01, 22.74)

Winther 1998 Study Type: Cohort

Implant Type: unspecified

Factors Controlled: none

Endpoint: motor neuropathy

Frequencies: 0 cases in 1135 exposed (0.0%); 1 case in 7071 unexposed
(0.01%)

Relative Risk (unadjusted/calculated): 2.08 (0.08, 50.91)

Endpoint: [peripheral neuropathies]{.underline}

Frequencies: 9 cases in 1135 exposed (0.79%); 53 cases in 7071 unexposed

(0.75%)

Relative Risk (unadjusted/calculated): 1.06 (0.52, 2.14)

Endpoint: optical retino- and neuropathy

Frequencies: 0 cases in 1135 exposed (0.0%); 1 case in 7071 unexposed
(0.01%)

Relative Risk (unadjusted/calculated): 2.08 (0.08, 50.91)

# Paraesthesia/Numbness and Tingling

Edworthy Study Type: Cohort

1998 Implant Type: silicone gel-filled

Factors controlled: none

Endpoint: [numbness in extremities]{.underline}

Frequencies: 26% cases in exposed group; 15% cases in unexposed group

Relative Risk (unadjusted/calculated): 1.73 (confidence interval not
available)

# Swallowing Difficulties/Dysphagia

Park 1998 Study Type: Cohort

Implant Type: silicone gel-filled

Factors Controlled: Design \--Augmentation - \"similar aged\";
Reconstruction­

partially matched on age, stage of disease and time of operation

Endpoint: dysphagia

Frequencies:

Augmentation - 2 cases in 110 exposed (1.82%);

0 cases in 128 unexposed (0.0%)

Reconstruction - 1 case in 207 exposed (0.48%);

0 cases in 88 unexposed (0.0%)

Relative Risk (adjusted/calculated):

Augmentation - 5.81 (0.28, 119.76)

Reconstruction - 1.28 (0.05, 31.21)

*Swelling/Fluid Retention/Bloating*

Park 1998 Study Type: Cohort

Implant Type: silicone gel-filled

Factors Controlled: Design \--Augmentation - \"similar aged\";
Reconstruction­

partially matched on age, stage of disease and time of operation

Endpoint: [edema]{.underline}

Frequencies:

Augmentation - 6 cases in 110 exposed (5.54%);

2 cases in 128 unexposed (1.56%)

Reconstruction - 32 cases in 207 exposed (15.46%),­

20 cases in 88 unexposed (22.73%)

Relative Risk (adjusted/calculated):

Augmentation - 3.49 (0.72, 16.95)

Reconstruction - 0.68 (0.41, 1.12)

# Vertigo/Dizziness/Ringing in Ears/Vestibular Dysfunction

Kim 1998 Study Type: Case-Control

Implant Type: silicone breast implants

Factors Controlled: Design-age

Endpoint: [progressive sensorineural hearing loss or Meniere\'s
disease]{.underline}

Frequencies: 5 exposures in 119 cases ( 4.20%); 3 exposures in 100
controls

(3.0%)

Odds Ratio (adjusted/calculated): 1.45 (0.27, 9.54)

Nyren 1998b Study Type: Cohort

Implant Type: any

Factors Controlled: Analysis-age, follow-up time

Endpoint: [Meniere\'s disease]{.underline}

Frequencies: 3 cases in 7425 exposed (0.04%); 1 case in 3351 unexposed
(0.03%)

Relative Risk (adjusted/article): 0.8 (0.4, 1.4)

Winther 1998 Study Type: Cohort

Implant Type: unspecified

Factors Controlled: none

Endpoint: [Meniere\'s disease]{.underline}

Frequencies: 1 case in 1135 exposed (0.09%); 3 cases in 7071 unexposed
(0.04%)

Relative Risk (unadjusted/calculated): 2.08 (0.22, 19.95)

# Weight gain

Wells 1994 Study Type: Cohort

Implant Type: silicone breast implants

Factors Controlled: Analysis - age, year of operation

Endpoint: [weight gain \> 10 lbs]{.underline}

Frequencies: 10% cases in exposed group; 3% cases in unexposed group

Odds Ratio (adjusted/article): (Relative Risk not reported) 1.307
(0.370, 4.619)

# Weight loss

Wells 1994 Study Type: Cohort

Implant Type: silicone breast implants

Factors Controlled: Analysis - age, year of operation

Endpoint: [weight loss \> 10 lbs]{.underline}

Frequencies: 2% cases in exposed group; 4% cases in unexposed group

Odds Ratio (adjusted/article): (Relative Risk not reported) 0.419
(0.105, 1.676)

Park 1998 Study Type: Cohort

Implant Type: silicone gel-filled

Factors Controlled: Design \--Augmentation - \"similar aged\";
Reconstruction -

partially matched on age, stage of disease and time of operation

Endpoint: [weight loss]{.underline}

Frequencies:

Augmentation - 0 cases in 110 exposed (0.0%);

0 cases in 128 unexposed (0.0%)

Reconstruction - 4 cases in 207 exposed (1.93%);

2 cases in 88 unexposed (2.27%)

Relative Risk (adjusted/calculated):

Augmentation - 1.16 90.02, 58.09)

Reconstruction - 0.85 (0.16, 4.56)

# 3) Symptoms for which there are discordant results (i.e. at least one but not all studies report an estimate with a lower confidence limit of greater than one).

# Arthralgias

Six studies reported arthralgias; some with increases in odds ratios,
but only in Giltay 1994 did one of the analyses (of painful joints for
at least three months) have a lower confidence limit exceeding 1 (1.37).
The frequency of 8.5% in the unexposed group and of 19.57% in the
exposed group are much higher than in other studies suggesting a
different population.

Edworthy Study Type: Cohort

1998 Implant Type: silicone gel-filled

Factors controlled: none

Endpoint: [hand pain]{.underline}

[ ]{.underline}Frequencies: 26% cases in exposed group; 18% cases in
unexposed group

Relative Risk (unadjusted/calculated): 1.44 (confidence interval not
available)

Friis 1997 Study Type: Cohort

Implant Type: any

Factors Controlled: none

Endpoint: [arthritis not further specified]{.underline}

Frequencies: 2 cases in 2570 (0.08%) exposed; 8 cases in 11023 unexposed
(0.07%)

Relative risk (unadjusted/calculated): 1.07 (0.23, 5.05)

Endpoint: [rheumatism not further specified]{.underline}

Frequencies: 1 case in 2570 exposed (0.04%); 1 case in 11023 unexposed
(0.01%)

Relative Risk (unadjusted/calculated): 4.29 (0.27,68.55)

Gabriel 1994 Study Type: Cohort

Implant Type: any

Factors Controlled: Design - age, duration of medical care, index year;

Analysis - age, index year

Endpoint: [any arthritis ]{.underline}(includes swelling of wrist,
swelling of three or more joints,

symmetric joint swelling or any other documented arthritis or synovitis)

Frequencies: 25 cases in 749 exposed (3.34%); 39 cases in 1498 unexposed
(2.60%)

Relative Risk (adjusted/article): 1.38 (0.84, 2.28)

Giltay 1994 Study Type: Cohort

Implant Type: silicone gel-filled

Factors Controlled: Design - age, year of operation; Analysis - none

Endpoint: [painful joints for at least three months]{.underline}

Frequencies: 46 cases in 235 exposed (19.57%); 18 cases in 210 unexposed

(8.57%)

Relative risk (adjusted/calculated): 2.28 (1.37, 3.81)

Endpoint: [Swelling of joints for at least one week]{.underline}

Frequencies: 14 in 235 (5.96%) exposed; 10 in 210 unexposed (4.76%)

Relative Risk (adjusted/calculated): 1.25 (0.57,2.76)

Park 1998 Study Type: Cohort

Implant Type: silicone gel-filled

Factors Controlled: Design-Augmentation - \"similar aged\";
Reconstruction -

partially matched on age, stage of disease and time of operation

Endpoint: [joint pain]{.underline}

[ ]{.underline}Frequencies:

Augmentation - 11 cases in 110 exposed (10.00%);

12 cases in 128 unexposed (9,38%)

Reconstruction - 31 cases in 207 exposed (14.98%);

13 cases in 88 unexposed (14.77%)

Relative Risk (adjusted/calculated):

Augmentation - 1.07 (0.49, 2.32)

Reconstruction - 1.01 (0.56, 1.84)

Wells 1994 Study Type: Cohort

Implant Type: [silicone breast implant]{.underline}

[ ]{.underline}Factors Controlled: Analysis - age, year of operation

Endpoint: [arthritis]{.underline}

Frequencies: 0% cases in exposed group; 1% cases in unexposed group

Odds Ratio (adjusted/article): (Relative Risk not reported) 1.159
(0.149, 9.040)

Endpoint: [painful joints]{.underline}

Frequencies: 11% cases in exposed group; 5% cases in unexposed group

Odds Ratio (adjusted/article): (Relative Risk not reported) 1.929
(0.521, 7.142)

Endpoint: [swollen joints]{.underline}

Frequencies: 5% cases in exposed group; 3% cases in unexposed group

Odds Ratio (adjusted/article): (Relative Risk not reported) 1.477
(0.263, 8.291)

# Lymphadenopathy/Swollen and Tender Glands

Park did not find an association; Wells found a small increase in the
frequency of swollen or tender glands under the arms with a lower
confidence limit of 1. 129 and 1.752 respectively. If this is a true
increase, it is still not possible to know if these signs and symptoms
occurred shortly after surgery or whether they were related to the
primary indication for the implant.

Park 1998 Study Type: Cohort

Implant Type: silicone gel-filled

Factors Controlled: Design - Augmentation - \"similar aged\";
Reconstruction -

partially matched on age, stage of disease and time of operation

Endpoint: lymphadenopathy

Frequencies:

Augmentation - 1 case in 110 exposed (0.91%); 0 cases in 128

unexposed (0.0%)

Reconstruction - 0 cases in 207 exposed (0.0%); 1 case in 88

unexposed (1.14%)

Relative Risk (adjusted/calculated):

Augmentation - 3.49 (0.14, 84.73)

Reconstruction - 0.14 (0.01, 3.47)

Wells 1994 Study Type: Cohort

Implant Type: silicone breast implants

Factors Controlled: Analysis - age, year of operation

Endpoint: [swollen glands neck]{.underline}

Frequencies: 10% cases in exposed group; 5% cases in unexposed group

Odds Ratio (adjusted/article): (Relative Risk not reported) 1.982
(0.570, 6.894)

Endpoint: [tender glands neck]{.underline}

Frequencies: 10% cases in exposed group; 7% cases in unexposed group

Odds Ratio (adjusted/article): (Relative Risk not reported) 1.433
(0.472, 4.354)

Endpoint: [swollen glands under arm]{.underline}

Frequencies: 8% cases in exposed group; 1% cases in unexposed group

Odds Ratio (adjusted/article): (Relative Risk not reported) 7.082
(1.129,44.439)

Endpoint: [tender glands under arm]{.underline}

Frequencies: 14% cases in exposed group; 3% cases in unexposed group

Odds Ratio (adjusted/article): (Relative Risk not reported) 6.898
(1.752, 27.154)

# Myalgias

Friis 1997 is the only one of the three studies that has a raised odds
ratios with a lower confidence limit that exceeds 1. Edworthy has a
raised summary relative risk but the information was not available to
allow a calculation of the confidence limits. This sample includes a
variety of conditions including \"muscular rheumatism, fibrositis and
myalgia\" so that these patients appear heterogeneous.

Edworthy Study Type: Cohort

1998 Implant Type: silicone gel-filled

Factors controlled: none

Endpoint: [muscle pain]{.underline}

[ ]{.underline}Frequencies: 25% cases in exposed group; 16% cases in
unexposed group

Relative Risk (adjusted/calculated): 1.56 (confidence interval not
available)

Friis 1997 Design: Cohort

Implant Type: any

Factors Controlled: none

Endpoint: muscular rheumatism, fibrositis, myalgia

Frequencies: 63 cases in 2570 exposed (2.45%); 169 cases in 11023

unexposed (1.53%)

Relative Risk (adjusted/calculated): 1.60 (1.20, 2.13)

Park 1998 Study Type: Cohort

Implant Type: silicone gel-filled

Factors Controlled: Design - Augmentation - \"similar aged\";
Reconstruction­

partially matched on age, stage of disease and time of operation

Endpoint: [muscle pain]{.underline}

Frequencies:

Augmentation - 7 cases in 110 exposed (6.36%);

7 cases in 128 unexposed (5.47%)

Reconstruction - 17 cases in 207 exposed (8.21%);

3 cases in 88 unexposed (3.41%)

Relative Risk (unadjusted/calculated):

Augmentation - 1.16 (0.42, 3.2 1)

Reconstruction - 2.41 (0.72, 8.01)

Wells 1994 Study Type: Cohort

Implant Type: silicone breast implants

Factors Controlled: Analysis - age, year of operation

Endpoint: [muscle pain]{.underline}

[ ]{.underline}Frequencies: 15% cases in exposed group; 9% cases in
unexposed group

Odds Ratio (adjusted/article): (Relative Risk not reported) 1.396
(0.541, 3.600)

# SICCA Symptoms (Dry Eyes/Mouth/Skin/Vagina)

Giltay 1994 found an increase frequency of 8.5% versus 1.9% in 52 cases
with a relative risk of 2.20 and a lower confidence limit of 1.25 in the
symptom of \"regularly burning eyes\"; Gabriel also found a slightly
increased frequency of 3.3% versus 2.6% in five cases giving a relative
risk of 1.42, but the confidence limits straddle 1(0. 92, 2.2 1);
however, these were for the symptoms of dryness of the eyes and mouth
with no mention of the symptom of burning.

Gabriel 1994 Study Type: Cohort

Implant Type: any

Factors Controlled: Design - age, duration of medical care, index year;

Analysis -(SICCA only) age, index year

Endpoint: [salivary gland enlargement]{.underline}

Frequencies: 2 cases in 749 exposed (0.27%); 3 cases in 1498 unexposed
(0.20%)

Relative Risk (adjusted/article): 1.42 (0.22, 7.98)

Endpoint: [SICCA ]{.underline}

Frequencies: 25 cases in 749 exposed (3.34%); 39 cases in 1498 unexposed
(2.60%) Relative Risk (adjusted/article): 1.42 (0.92, 2.21)

Giltay 1994 Study Type: Cohort

Implant Type: silicone gel-filled

Factors Controlled: Design - age, year of operation

Endpoint: [regularly burning eyes]{.underline}

Frequencies: 37 cases in 235 exposed (8.51); 15 cases in 210 unexposed
(1.90)

Relative risk (adjusted/article): 2.20 (1.25, 3.90)

# Skin Changes/Rashes/Hives

Photosensitivity: Giltay 1994 reported an increased frequency of \'skin
abnormalities worsened by sun exposure of 8.5% versus 1.9% relative risk
of 4.47 (1.55, 12.86). Gabriel, found a frequency of 0.4% in exposed and
unexposed. Park found a raised frequency in augmentation cases but a
lower frequency in the reconstruction patients; this lack of consistency
may be due to the small numbers of implants in this study leading to
imprecise estimates.

Gabriel 1994 Study Type: Cohort

Implant Type: any

Factors Controlled: Design - age, duration of medical care, index year;

Analysis - age, index year only for endpoint photosensitivity

Endpoint: [malar or discoid rash]{.underline}

Frequencies: 1 case in 749 exposed (4.41%); 5 cases in 1498 unexposed
(3.34%)

Relative Risk (adjusted/article): 0.43 (0.04, 2.67)

Endpoint: [photosensitivity]{.underline}

Frequencies: 3 cases in 749 exposed (0.40%); 6 cases in 1498 unexposed
(0.40%)

Relative Risk (adjusted/article): 1.12 (0.28, 4.50)

Giltay 1994 Study Type: Cohort

Implant Type: silicone gel-filled

Factors Controlled: Design - age, year of operation

Endpoint: [skin abnormalities worsened by sun exposure]{.underline}

Frequencies: 20 cases in 235 exposed (8.51%): 4 cases in 210 unexposed
(1.90%)

Relative risk (adjusted/calculated): 4.47 (1.55, 12.86)

Park 1998 Study Type: Cohort

Implant Type: silicone gel-filled

Factors Controlled: Design - Augmentation - \"similar aged\";
Reconstruction -

partially matched on age, stage of disease and time of operation

Endpoint: [photosensitivity]{.underline}

Frequencies:

Augmentation - 5 cases in 110 exposed (4.55%);

3 cases in 128 unexposed (2.34%)

Reconstruction - 7 cases in 207 exposed (3.38%);

5 cases in 88 unexposed (5.68%)

Relative Risk (adjusted/calculated):

Augmentation - 1.94 (0.47, 7.93)

Reconstruction - 0.60 (0.19, 1.82)

Endpoint: [telangiectasia]{.underline}

Frequencies:

Augmentation - 3 cases in 110 exposed (2.72%);

2 cases in 128 unexposed (1.56%)

Reconstruction - 2 cases in 207 exposed (0.97%);

1 case in 88 unexposed (1. 14%)

Relative Risk (adjusted/calculated):

Augmentation - 1.77 (0.24, 15.41)

Reconstruction - 0.85 (0.06, 23.96)

Endpoint: [rash]{.underline}

Frequencies:

Augmentation - 3 cases in 110 exposed (2.73%);

3 cases in 128 unexposed (2.34%)

Reconstruction - 8 cases in 207 exposed (3.68%);

8 cases in 88 unexposed (9.09%)

Relative Risk (adjusted/calculated):

Augmentation - 1.16 (0.24, 5.65)

Reconstruction - 0.43 (0.16, 1.10)

Endpoint: sclerodactyly

Frequencies:

Augmentation - 0 cases in 110 exposed;

12 cases in 128 unexposed

Reconstruction - 1 case in 207 exposed;

0 cases in 88 unexposed

Relative Risk (adjusted/calculated):

Augmentation - 0.05 (0.00, 0.78)

Reconstruction - 1.28 (0.05, 31.21)

Endpoint: [abnormal pigment]{.underline}

Frequencies:

Augmentation - 2 cases in 110 exposed (1.82%);

2 cases in 128 unexposed (1.56%)

Reconstruction - 3 cases in 207 exposed (1.45%);

1 case in 88 unexposed (1.14%)

Relative Risk (adjusted/calculated):

Augmentation - 1.16 (0.17, 8.12)

Reconstruction - 1.28 (0.13, 12.09)

Wells 1994 Study Type: Cohort

Implant Type: silicone breast implants

Factors Controlled: Analysis - age, year of operation

Endpoint: [rashes]{.underline}

Frequencies: 4% cases in exposed group; 4% cases in unexposed group

Odds Ratio (adjusted/article): (Relative Risk not reported) 1.067
(0.273, 4.168)

Endpoint: [skin thickening]{.underline}

Frequencies: 2% cases in exposed group; 7% cases in unexposed group

Odds Ratio (adjusted/article): (Relative Risk not reported) 0.206
(0.043, 0.992)

Endpoint: [skin tightness]{.underline}

Frequencies: 12% cases in exposed group; 19% cases in unexposed group

Odds Ratio (adjusted/article): (Relative Risk not reported) 0.582
(0.264, 1.284)

# Stiffness

Gabriel 1994 found an increased frequency of 4% versus 2.3% with a
relative risk of 1.80 and a lower confidence limit of 1.0. The
significance and importance of this is unclear. Wells 1994 did not find
an association.

Gabriel 1994 Study Type: Cohort

Implant Type: any

Factors Controlled: Design - age, duration of medical care, index year;
Analysis -

age, index year

Endpoint: [morning stiffness ]{.underline}

[ ]{.underline}Frequencies: 30 cases in 749 exposed (4.01%); 35 cases in
1498

unexposed (2.34%)

Relative Risk (adjusted/article): 1.80 (1.10, 2.93)

Wells 1994 Study Type: Cohort

Implant Type: silicone breast implants

Factors Controlled: Analysis - age, year of operation

Endpoint: [general stiffness]{.underline}

Frequencies: 10% cases in exposed group; 10% cases in unexposed group

Odds Ratio (adjusted/article): (Relative Risk not reported) 0.930
(0.382, 2.265)

# Symptoms for which there are consistent results

# None

Few studies have adequate numbers of patients, and although some
individual studies show some degree of elevation of relative odds or
relative risks, these are not substantial in a consistent fashion in any
of these conditions.

# VI. Concluding Comments

In this chapter the clinical case definitions have been reviewed for the
three clinical categories of Classic/Accepted Diagnosis., Atypical
Presentations of Connective Tissue Diseases, and Symptoms and Signs
listed in the Appendix to the Court Order 31E. The prognosis of many of
the Classic/Accepted diseases is poor with most patients being subjected
to sustained morbidity with symptoms, reduction in ability to carry out
their activities of daily living and reduced psychosocial well-being.

In none of the Classic/Accepted diagnosis was there any \'appreciable\'
association (as defined in the Epidemiology Chapter) with silicone
breast implants demonstrated.

The atypical syndrome of Undifferentiated Connective Tissue Disease
(UCTD) as defined by the criteria of Williams, also has sustained
morbidity in a proportion of patients. In the one study of this, there
were few implants and no appreciable association was found.

Patients with one or more symptoms and signs but who do not meet the
criteria for a specified Classic/Accepted connective tissue disease or
the criteria for UCTD as defined by Williams, have a better prognosis
and do not usually progress to a defined disease. There are few symptoms
and signs for which a single study found an appreciable association, but
in all cases there were other studies of the same symptom or sign that
did not confirm this association. Additional caution in accepting any
association in these studies is needed compared to the studies of the
Classic/Accepted diagnosis and UCTD, since different symptoms are
included in some of the categories, the numbers of cases are small, a
single woman with more than one symptom will be represented in the
analysis of each symptom that the woman has experienced.

Other atypical syndromes have been suggested, some of which include the
presence of a silicone breast implant and none of which (with the
exception of UCTD as stated above) have stringent, objective diagnostic
criteria. Including the exposure (i.e. breast implants), in the disease
definition precluded the rigorous scientific evaluation of this proposed
entity, since there is no possibility of comparing women with and
without the syndrome to estimate each group\'s frequency of implants.
Furthermore, many of the signs and symptoms including the rheumatologic
and psychological complaints are so common in the general population and
as presenting complaints in physician\'s offices, that a possible
increased frequency of these complaints among those with implants would
be difficult to discern.

The literature submitted by the court was reviewed for information on
the effect of silicone breast implants on the clinical course and
immunologic parameters in women with diagnosed connective tissue
disease. No substantive data was found that allowed a rigorous
assessment of any differences in the clinical course from those with the
conditions but without implants; thus no conclusion can be reached due
to the uncertainty arising from a lack of research addressing this
question.

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261-268.

Winther JF, Bach FW, Friis S, et al: Neurologic disease among women with
breast implants \[see comments\]. *Neurology *1998;50: 951-955.

Wise CM, Vuyyuru S, Roberts WN: Methotrexate in nonrenal lupus and
undifferentiated connective tissue disease-a review of 36 patients.
*Journal of Rheumatology. *1996;23: 1005-1010.

Wolfe P: Silicone breast implants and the risk of fibromyalgia and
rheumatoid arthritis. *Arthritis and Rheumatism *1995;38: S265.

**Table 1: Description of Included Studies**

**Study Methods Participants Interventions Outcomes**

**Burns Case Control Study Country**: Michigan USA **Implant Type**
**Diagnosis**

**(1996) Cases: **N = 274 Unspecified: N = 1(control) Systemic sclerosis
(1980 ACR

**Study Dates Controls**: N= 1184 Silicone gel filled: N = 14 (2
criteria or subject exhibited signs

Cases of scleroderma diagnosed cases, 12 controls) and symptoms
characteristic of

between 1985-1991. Mean age at interview: cases 54.3 years, Saline: N =
1 (control) SSc: sclerodactyly or thick tight

Data collection August 1992 - May controls 52.6 years. Polyurethane
coated: N = 2 skin, and at least one other

1993\. Income \>\$ 15,000: cases 74.8 0/., controls (controls)
manifestation of CREST.

81.5% (p\<.05) Separate analysis for Silicone gel Excluded linear or
localized SSc -

** Group Selection **High school education: cases 85%, controls filled
implants: yes morphea)

[Case Definition]{.underline}: Women diagnosed 84.3%

with systemic sclerosis in Michigan Race - non black: cases 83.9%,
controls **Exposure**

between 1985-1991 were recruited 88.1% Rupture described: yes (1 case

from hospitals, rheumatologists and Reconstruction due to breast cancer:
cases had ruptured;no ruptures reported

United Scleroderma Foundation. 50%, controls 50% among controls although
6

[Control Definition]{.underline}: Females, Separate analysis for breast
cancer subjects: experienced encapsulation,

identified through random digit no hardness, scar tissue or

dialing, were frequency matched to Years since implantation: cases (n=2)
1 and unspecified problems)

cases on age (5 yr. Intervals), race 12 years., controls (n=14) median
8.8 years Explantation described: no

and geographic region. Cases with breast implants: 0.7% Duration
described: yes

Controls with breast implants: 1.2% Excluded injections: no (they

** Group Determination **were enumerated as \"injections to

[Cases]{.underline}: medical records were **Response Rate** a body
part\" and reported

reviewed by a rheumatologist to [Cases]{.underline}: Investigators
estimate that 80 - 87% separately)

determine eligibility of incident cases in Michigan from 1985-91

[Controls]{.underline}: self report (telephone were identified. 75-80%
of these responded

interview) to mailing, 93% of whom agreed to

participate.

** Ascertainment of Exposure **[Controls]{.underline}: 80%

[Cases]{.underline}: self report (telephone

interview)

[Controls]{.underline}: same

To determine the accuracy of self

reporting of breast implants a

validation study was carried out on

a separate population. (94%

accurate with respect to presence or

absence of implant)

**Blinding**

Subjects were unaware of the

research hypothesis and in the case

of the validation study, investigators

were blind to implant status.

**Study Methods Participants Interventions Outcomes**

**Dugowson** **Case Control Study** **Country**: Seattle, Washington USA
**Implant Type** **Diagnosis**

\(1992\) **Cases**: N = 300 Unspecified Rheumatoid Arthritis (criteria
not

**Study Dates Controls**: N = 1456 reported)

Not reported **Exposure**

Cases with breast implants: 0.3% Rupture described: no

** Group Selection **Controls with breast implants 0.8% Explantation
described: no

[Case Definition]{.underline}: Women with new Duration described: no

onset of rheumatoid arthritis **Response Rate** Excluded injections: not
reported

[Control Definition]{.underline} : Similarly aged Cases: 86%,

women were recruited co- [Controls]{.underline}: Number of subjects in
original

operatively with a breast cancer pool from which controls were drawn is
not

study reported

** Group Determination**

not reported

** Ascertainment of exposure **

** **[Cases: ]{.underline}self report (questionnaire)

-history of implants prior to reference

date (first physician visit for

rheumatoid arthritis)

[Controls: ]{.underline}self report (questionnaire)

\- history of implants prior to a

reference date chosen randomly

from cases

**Blinding **

not reported

**Study Methods Participants Interventions Outcomes**

**Edworthy**

**(1998)**

**Retrospective Cohort Study**

**Study Dates**

1978-1986 - Subjects were

identified who underwent cosmetic

surgery during this period ,

No dates reported for recruitment

and examination of these women.

1982-1993 - data base searched for

hospitalization rates and service

use during this time period.

**Group Selection **

[Exposed ]{.underline}: Women, identified

through the Alberta Health

Registry, who had obtained breast

implants, other than for

reconstructive purposes, between

1978 and 1986.

[Unexposed ]{.underline}: Women, from the

same source, who had undergone

non silicone related cosmetic

surgery.

**Group Determination **

[Exposed ]{.underline}: Alberta Health Registry

procedural codes, medical records

(for verification of implant type),

self report (questionnaire)

[Unexposed ]{.underline}: Alberta Health

Registry procedural codes, self

report

**Ascertainment of Outcome **

[Exposed ]{.underline}: Direct measurement

(physical exam for those with a

history or symptoms of disease),

lab values, self report

(questionnaire and for those

attending physical exam, a detailed

history)

[Unexposed ]{.underline}: same

**Blinding**

Rheumatologist\'s Physical

assessment

**Country**: Alberta, Canada

**Exposed**: N = 1,576

**Unexposed**: N = 727

Median Age at Assessment: Exposed

(Silicone gel filled) 42 years, Unexposed

46 years

Median Years of Education: Exposed 12,

Unexposed 13

Married: Exposed 80. 1,% Unexposed

73.7%

Mean Duration of Exposure: 13.5 years

Reconstruction Due to Breast Cancer: 0%

**Response Rate**

Of the 9200 implantations and 7400 other

cosmetic surgeries identified, 60% had a

current address. Of those contacted 3152

implanted women 34% of those identified)

and 2670 controls (36% of those

identified) responded. Of those who

responded, 41% of implanted subjects and

69% of controls declined. An

additional 9% of implanted subjects and

4% of controls were ineligible.

**Implant Type**

Unspecified (N=86)

Silicone gel filled (N= 1, 112)

Saline (N=352)

Meme (N=26)

Only Silicone get filled implants

appear to have been included in

the analyses.

**Exposure**

Rupture Described: no

Explantation Described: no

Duration Described: yes

Excluded Injections yes

**Diagnosis **

Rheumatoid Arthritis (ACR tree

criteria)

Systemic Lupus Erythematosus

(ARA 4 of 11 criteria)

Scleroderma (ACR criteria,

CREST or variants of)

Sjögren\'s Syndrome (clinical signs

of dry eyes, dry mouth, history of

parotitis),

Atypical Connective Tissue

Disease (cases which did not

conform to expected patterns of

presentation and had a greater

than 50% certainty of having any

CTD)

**Lab Values **

ANAs (indirect

immunofluorescence using HEp-2

cells, considered positive if \> 1: 40

dilution)

**Symptoms**

Thought problems

Numbness in extremities

Muscle pain

Headache

Hand pain

**Study Methods Participants Interventions Outcomes**

**Englert**

** (1996)**

**Case Control Study **(Update of

Englert 1994)

**Study Dates**

Study initiated 1989. Scleroderma

diagnosis must have been made

prior to Dec 31,1988 (study time

frame 1974-1988) Controls must

have attended General practitioner

since Jan 1990.

**Group Selection**

[Case Definition]{.underline}: Patients with SSc

who resided in Sydney for at least 6

consecutive months within study

time frame. Excluded were patients

with mixed CTD morphea or other

localized form of SSc. Cases were

recruited from hospitals, death

certificates, physicians, Scleroderma

Association of NSW and medical

laboratories performing ANA tests.

If patient migrated to Sydney, the

major reason must not have been for

scleroderma management, and the

diagnoses must have been made

prior to emigration

[Control Definition]{.underline}: Sydney residents

(for at least 6 consecutive months)

were recruited from 28 randomly

selected general practices and were

age and sex stratified (5 years) with

a living case.

Those with scleroderma CREST or

a psychiatric history were excluded.

**Group Determination**

[Cases]{.underline}: medical records

[Controls: ]{.underline}medical records

**Ascertainment of Exposure**

Cases: medical records (GP and for

those with implants surgeon\'s

records) for deceased and medical

records plus self report (interview)

for living subjects

[Controls: ]{.underline}medical records plus self

report (interview)

**Country**: Sydney, Australia

Cases: N = 532

Controls: N = 253

Explantation: cases 50%, controls 20% Dates of implantation: cases
1978-1983, controls 1973-1990 Cases with breast implants: 0.9% Controls
with breast implants: 1.2 -1.6%

Response Rate not reported

**Implant Type**

Unspecified 10%

Silicone gel filled 80%

(analysed separately)

Saline: 10%

Exposure

Rupture described: no

Explantation described: yes

Duration described: yes

Excluded injections: not reported

**Diagnosis **

Systemic Sclerosis (ACR criteria or patient had sclerodyctaly plus 2 of
the following: Raynaud\'s phenomenon, oesophageal dysmotolity,
calcinosis, telangiectasia(e), bilateral basal pulmonary fibrosis or
elevated ANA)

**Blinding **

Both physicians and patients were blind to each others responses
regarding mammaplasty status

**Study Methods Participants Interventions Outcomes**

**Friis**

**(1997)**

**Retrospective Cohort Study**

**Study Dates**

Identification of subjects 1977­

1992

Follow up to Dec3l/93

**Group Selection**

[Expose ]{.underline}: Women from Danish

Central Hospital Register who had

received implants between 1977

and 1992 for cosmetic or

reconstructive purposes.

[Unexposed ]{.underline}: Women from the same

source who had undergone breast

reduction surgery or correction for

mammoptosis or women who had

been diagnosed with breast cancer

but had not received an implant.

Breast cancer controls were

matched to the reconstruction

patients in: age, disease (localized,

regional, metastatic), and calendar

time (5 years)

**Group Determination**

[Exposed ]{.underline}: medical records

(information on breast surgery

confirmed by authors)

[Unexposed ]{.underline}: same as exposed

**Ascertainment of Outcome**

Exposed: medical records

(diagnosis of definite CTD

validated by rheumatologists)

[Unexposed ]{.underline}: same as exposed

**Blinding**

Not reported

**Country: **Denmark

**Exposed**: cosmetic N = 1,335,

reconstruction N = 1,435

**Unexposed**: breast reduction N = 7,07 1, mamoptosis N = 472 (not
analysed), breast cancer N= 3,952

Median Age at Entry: Exposed: cosmetic 31 years, reconstruction 45
years; Unexposed: reduction 31 years, mamoptosis 28 years, breast cancer
47years Median Length of Follow up: Exposed: cosmetic 8.4 years;
reconstruction 7.2 years Unexposed: reduction 7.6 years, mammoptosis 6.2
years, breast cancer 5.3 years Reconstruction due to breast cancer: 52%
(analysed separately)

**Response Rate** All eligible women from the register were entered into
the study. They were followed until the time of death, emigration or Dee
31 1993, whichever came first.

**Implant**

Unspecified: 16% Silicone get filled: 84% (no separate analysis) Note:
Percentages are based on an earlier sampling study

**Exposure **

Rupture described: no

Explantation described: no

Duration described: no

Excluded Injections: not reported

**Diagnosis**

(All cases represented rheumatic

disease requiring hospitalization

and were classified according to

ICD 8)

Rheumatoid Arthritis (ICD 712.09 -39, 712.59) Dermatomyositis /
Polymyositis (ICD 716.09, 716.19)

Systemic Sclerosis (ICD 734.0­.09)

Systemic Lupus Erythematosis (ICD 734.19)

Sjögren Syndrome (ICD 734.90)

Polymyalgia Rheumatica and Ternperal Arteritis (446.30-39)

Muscular Rheumatism Including Fibrositis and Myalgia (717.90 717.99)

Arthritis Not Further Specified (715.99)

Rheumatism Not Further Specified (718.99)

CTD Not Further Specified (734.91,734.99)

**Study Methods Participants Interventions Outcomes**

**Gabriel**

**(1994)**

**Retrospective Cohort Study**

**Study Dates**

Exposed: implantation occurred

between January 1964 to December

1991

Follow up: to December 31 1991

**Group Selection**

[Exposed ]{.underline}: All women in Olmstead

county whose medical records

indicated that they had received a

breast implant.

[Unexposed ]{.underline}: Age matched (3 years)

Olmstead women who had

undergone a medical evaluation

within 2 years of date of matched

case implantation. For each woman

who had undergone reconstruction

following mastectomy for breast

cancer an additional 2 controls were

selected who had undergone

mastectomy but had not received an

implant (analysis of data using this

control group was not reported).

**Group Determination**

[Exposed: ]{.underline}medical records

[Unexposed ]{.underline}: same

**Ascertainment of Outcome**

[Exposed ]{.underline}: Medical records reviewed

by trained nurses for evidence of

clinical features, and laboratory and

radiographic studies necessary to

make diagnoses.

[Unexposed]{.underline}: same

**Blinding**

Not reported

**Country**: Olmsted county Minnesota

USA

**Exposed**: N = 749

**Unexposed**: N = 1498

Mean age: exposed 34.4 +/- 10.5 years, unexposed 34.3 +/- 10.5 years
Caucasian: exposed 96.8%, unexposed 92.8% (p\<.05) Marital status -
single: exposed 15.21/e, unexposed 2 1.0% (p\<.05) History of smoking:
exposed 53.5%, unexposed 45.6% (p\<.05) Mean years since implantation or
index visit: exposed 7.8 +/- 5.5 years, unexposed: 8.3 +/- 5.8 years
(36% of cohort followed for at least 10 years) Reconstruction Due to
Breast Cancer: 17% (analysed both separately and combined) Bilateral
implants: 83%

**Response Rate** All eligible records included. Follow up continued to
Dec 31 1991, death or date of last health care visit.

**Implant Type**

Uuspecified: N=2

Silicone gel filled: 78.3%

Saline: 5.2%

Double Lumen: 6.7%

Polyurethane coated: 9.6%

Combination of Silicone and

Saline: 6.7%

Perras Papillion: N=2

**Exposure **

Rupture described: no

Explantation described: no

Duration described: yes. 23.6% of exposed women had undergone\> 1
surgical breast implantation procedure

Excluded Injections: yes

**Diagnosis **

determined from clinical features,

lab and radiographic studies

Systemic sclerosis (ACR criteria)

Rheumatoid arthritis (ACR criteria)

Scleroderma (ACR criteria)

Sjögren

SLE

Dermatomyositis

Polymyositis

Vasculitis

Ankylosing spondylitis

Psoriatic arthritis

Arthritis associated with inflammatory bowel disease

Polychondritis

Polymyalgia rheumatica

Any CTD (combined endpoint including all of the above)

Hashimoto\'s thyroiditis

Primary bilary cirrhosis

Sarcoidosis

**Lab Values **

Antinuclear Antibodies (values

considered abnormal at the time the

test was performed)

**Symptoms **

any arthritis (swelling of the wrist,

swelling of 3 or more joints,

symmetric joint swelling or any

other documented arthritis or

synovitis)

SICCA (dry eyes, dry mouth, or

keractoconjunctivitis)

serositis (serosal inflammation such

as pleuritis and pericarditis)

malar or discoid rash

oral ulcers

photosensitivity

salivary gland enlargement

symmetric muscle weakness

morning stiffness

**Study Methods Participants Interventions Outcomes**

**Gfltay Retrospective Cohort Study **Country: The Netherlands **Implant
Type Diagnosis**

**(1994) Exposed: **N = 235 Implant: Silicone gel filled Probable
inflammatory disease

**Study Dates Unexposed**: N = 2 10 excluded polyurethane coated with
onset 1 or more years

Surgery performed Jan 1978 - Dec following surgery (subjects self

1990\. Mean age: exposed 43 years ; unexposed Exposure reported symptoms
on

Questionnaire regarding rheumatic 43 years Rupture described: no
questionnaire were assessed by

symptoms June 1992 Mean years since implantation: 6.5 years Explantation
described: no rheumatologist regarding

(range 2-14 years) for all subjects Duration described: yes likelihood
to have disease; likely

**Group Selection** Mean interval between surgery and Excluded
Injections: yes subjects were further assessed via

[Exposed]{.underline} : All patients who received symptom onset: exposed
5.1 years phone, plus medical records;

silicone breast implants at Free unexposed 5.9 years criteria not
reported.)

University Hospital, Amsterdam. Reconstruction due to breast cancer:
23.8%

[Unexposed]{.underline}: Age matched females (not analysed separately)
**Symptoms**

who had an operation not involving Bilateral: 68.5% Raynaud\'s
phenomenon

silicone in the same year in the same painful joints ( \> 3 months)

department. **Response Rate** swollen joints (1+ weeks)

[Exposed]{.underline}: 82% regularly burning eyes

**Group Determination **[Unexposed]{.underline}: 73% mouth ulcers (3+
weeks)

[Exposed]{.underline}: medical records, pleuritis

[Unexposed]{.underline} : same skin abnormalities worsened by

sunlight

** Ascertainment of Outcome **combined endpoint - subjects with

[Exposed]{.underline}: Self report - mailed at least one symptom arising
after

questionnaire and for those surgery

suspected of rheumatic disease,

medical records

[Unexposed]{.underline}: same

** Blinding**

Not reported

**Study Methods Participants Interventions Outcomes**

**Goldman**

**(1995)**

**Cross Sectional Study**

**Study Dates **

1982 - May 1992 - Medical records of office visits between these dates

provided data regarding both

exposure and outcome. (1982-1986

prior to computerization - some

incomplete data)

**Group Selection**

Both exposed and unexposed subjects were identified from all female
patient records in one referral based rheumatology practice.

**Group Determination: **

[Exposed]{.underline}: Medical records -historical, physical or
radiologic evidence of a breast implant.

[Unexposed]{.underline}: Medical records - no evidence of breast implant

**Ascertainment of outcome **

[Exposed]{.underline}: Medical records -independent chart review to
confirm rheumatological diagnoses

[Unexposed]{.underline}: same

**Blinding**

Not reported

**Country**: Atlanta, Georgia USA

**Exposed**: N = 150

**Unexposed**: N = 4079

Mean age (at 1 st visit): exposed: 43.8, unexposed 47.2 (p\<.04) SES
(mean income based on ZIP code): exposed \$43,744, unexposed \$39,524
(p\<0.0001) Race \"primarily Caucasian\" Mean years since implantation:
exposed who did develop disease 8.3, exposed with no disease 9.9% of
cohort with breast implants: 3.5

**Response Rate **

100% of eligible records reviewed

**Implant Type **

Unspecified (11%)

Silicone get fitted (85%) (no separate analysis)

Saline (4%)

**Exposure**

Ruptured described: no

Explantation described: no

Duration described: yes

Injections excluded: yes

**Diagnosis **

Patients were diagnosed according to ACR and Arthritis Foundation
criteria. No year was reported for ICD codes. Rheumatoid Arthritis (ICD
714)

Systemic Lupus Erythematosus (ICD 710.0)

Systemic Sclerosis - including CREST (ICD 710.1)

Sjögren\'s (ICD 710.2)

Dermatomyositis / Polymyositis (ICD 710.3, 710.4)

Mixed Connective Tissue Disease (ICD 710.9)

Rheumatoid Arthritis and Connective Tissue Disease (combined endpoint
comprised of all the above)

**Study Methods Participants Interventions Outcomes**

Hennekens

\(1996\)

**Cross Sectional Study**

**Study Dates**

Sept 1992 - May 1995 -Questionnaire regarding both exposure and disease
was mailed to prospective participants. Aug 1, 1995 - forms completed
Dec 31 1991 - only CTDs diagnosed prior to this date were included in
the analysis.

**Group Selection**

Female health professionals age 18 - 99 residing in the USA or Puerto
Rico, who completed mailed questionnaires for participation in the
Women\'s Health Study. Excluded were women who reported an implant or
CTD prior to 1962 or who provided unclear or missing information
regarding implant surgery, CTD and dates

**Ascertainment of Exposure**

[Exposed]{.underline}: self report (questionnaire) - women who reported
ever having had a breast implant along with the year of procedure

[Unexposed: ]{.underline}self report (questionnaire) - those not
reporting an implant

**Ascertainment of Outcome**

[Exposed]{.underline}: self report

(questionnaire)

[Unexposed]{.underline}: same

**Blinding**

Not reported

**Country**: USA and Puerto Rico

**Exposed**: N = 10,830

**Unexposed**: N = 384,713

Mean age: 51.7 years. Caucasian: 90.7% Reconstruction due to breast
cancer: 18% (estimated from report of implantation the same year as
diagnosis of breast cancer. No separate analysis of these cases) Cohort
with breast implants: 3.6%

**Response Rate**

24% (whole cohort)

**Implant Type**

Unspecified

**Exposure**

Rupture described: no

Explantation described: no

Duration described: yes

Excluded Injection: no

**Diagnosis **

All diseases were self reported. No diagnostic criteria were used
Rheumatoid Arthritis Systemic Lupus Erythematosus Sjögren\'s
Dermatomyositis / Polymyositis Other Connective Tissue Disease
(including Mixed) Any Connective Tissue Disease (combined endpoint
comprised of all the above)

**Study Methods Participants Interventions Outcomes**

Hochberg

\(1996\)

**Case Control Study**

**Study Dates**

July 1990 - summer of 1991 -eligible cases mailed questionnaires. 1993 -
data collected from an additional 18 of the eligible cases Dec 1991 -
cases diagnosed after this date were excluded July 1993 - Dec 1994 -
controls interviewed

**Group Selection **

[Case Definition ]{.underline}: Women with a clinical diagnosis of SSc
Identified at 3 university based scleroderma research centers: 1)
Baltimore-Washington - seen at scleroderma center, referred by
rheumatologists, or members of Scleroderma Foundation; 2) Pittsburgh -
all patients seen by faculty members at U of Pittsburgh were
consecutively enrolled; 3) San Diego/Orange County - patients followed
by faculty members UCSD or community based rheumatologists. Patients \<
18 years at diagnoses or Residing outside USA were excluded.

[Control Definition]{.underline}: Race and sex matched local controls
were identified through random digit dialing and frequency matched to
cases in 3 strata: age \< 45, 45-64 and 65+. Women with a self reported
diagnosis of CTD were excluded.

**Group Determination **

[Cases: ]{.underline}medical records

[Control]{.underline}s: self report (telephone interview

**Ascertainment of exposure **

[Cases: ]{.underline}self report (self administered questionnaire),

**Country**: USA (Multicenter)

**Cases**: N = 837

**Controls**: N = 2507

Mean Age at Interview: cases: 55.3 +/- 12.9 years controls: 55.6 +/- 15.
5years SES -% High School Graduates: cases 86.6%, controls: 85.3%%
Caucasian: cases 90.4%, controls 90.9% Mean Duration of SSc: cases 10.0
+/- 7.2 Median years since implantation: cases: 11 years (time to
disease), controls: 10 years (time to interview)

Complications related to implants: Cases 0%, Controls 16% (hardening
N\~2, shifting N=2, leakage N= 1) Explantation: cases 36% (Diagnosis of
scleroderma N=2, hardening N= 1, leakage N=1) controls.032% (breast pain
N= 1) Breast surgery (related to benign breast masses, breast cancer,
fibrocystic disease and mastitis): cases 17.9%, controls 18.5% Cases
with implants: 1.3% Controls with implants: 1.2%

**Response Rate**

[Cases]{.underline}: Baltimore 61.9% Pittsburgh 78.4%

San Diego 100%

[Controls]{.underline}: 90% of those eligible

**Implant Type**

Silicone get-filled

**Exposure**

Rupture described: yes

Explantation described: yes

Duration described: yes

Excluded Injections: yes

**Diagnosis **

Systemic Sclerosis (no diagnostic

criteria reported)

**Study Methods Participants Interventions Outcomes**

[Controls: ]{.underline}self report (telephone

interview)

**Blinding**

Not reported

**Study Methods Participants Interventions Outcomes**

**Kim**

\(1998\)

Case Control Study

**Study Dates**

Questionnaires collected between

July 1995 and Jan 1996

**Group Selection**

[Case Definition: ]{.underline}Female patients

with a diagnosis of either Meniere\'s

disease or progressive sensorineural

hearing loss who had undergone

prior Western blot analysis for

reactivity to 68 kD.

[Control Definition: ]{.underline}Women waiting

for outpatient lab results at an

ambulatory care center matched to

cases on age.

**Group Determination**

[Cases]{.underline}: Identified from a single

clinical practice.

[Controls]{.underline}: Mailed questionnaire.

Those reporting a history of hearing

loss were excluded.

[Ascertainment of Outcome]{.underline}

[Cases: ]{.underline}Self report - mailed

questionnaire.

[Control ]{.underline}: questionnaire

**Blinding**

not reported

**Country: **La Jolla California USA

**Cases**: N=119

**Controls**: N=100

Mean Age: cases - Meniere\'s - 48.5 years,

cases - PSNHL - 50.2 years controls 49.7

years

Mean time from implantation to disease:

9.23 years (range 2 months to 24 years)

Cases with breast implants: 4.2%

Controls with breast implants: 3%

**Response Rate**

[Cases]{.underline}: 64.7%

[Controls]{.underline}: not reported

**Implant Type**

\"Silicone breast implants\"

**Exposure**

Rupture described: no

Explantation described: no

Duration described: no

Injections excluded: yes

**Diagnoses **

Meniere\'s Disease (no criteria reported)

Progressive Sensorineural Hearing Loss

(PSNHL no criteria reported)

**Lab Values **

Anti-68kD antibodies (Western blot

analysis) - This variable was analysed

both on its own and in combination with

Meniere\'s Disease or PSNHL

**Study Methods Participants Interventions Outcomes**

**Lacey** **Case Control Study** **Country**: Michigan USA **Implant
Type** **Diagnosis**

**(1997)** Cases: N = 189 Unspecified N=4 Systemic Sclerosis (1980 ACR

**Study Dates **Controls: N = 1043 Silicone gel filled N=11 criteria or
subject exhibited signs

1985 - 1992 diagnosis of SSc (separate analysis provided) and symptoms
characteristic of

Cases with implants: 1.1% SSc: sclerodactyly or thick tight

**Group Selection** Controls with implants: 1.2% **Exposure** skin, and
at least one other

[Case Definition]{.underline}: Women Rupture described: no manifestation
of CREST -

diagnosed with SSc in Ohio **Response Rate** Explantation described: no
Excluded linear or localized SSc -

[Control Definition]{.underline}: Ohio women Not reported Duration
described: no morphea)

selected by random digit dialing Excluded injections: no (data re

matched to cases on age injections was recorded but does

geographic location and race not appear to have been

analysed)

** Group Determination**

[Cases]{.underline}: medical records - reviewed

by rheumatologist

[Controls]{.underline}: self report

**Ascertainment of Exposure**

[Cases]{.underline}: self report -telephone

questionnaire

[Controls]{.underline}: self report - telephone

questionnaire

** Blinding**

** **Blind expert reviewed self reported

exposure data

**Study Methods Participants Interventions Outcomes**

**Liang Case Control Study Country: **Michigan and Ohio, USA **Implant
Type Diagnosis**

**(1996)** Cases: N = 205 Unspecified Undifferentiated Connective Tissue

**Study Dates** Controls: N = 2220 Disease (Either the referring

Diagnoses 1980-1992 **Exposure** physician diagnosis or HCIA

Mean age at interview: Cases: 52.3 Rupture described: no discharge code
was UCTD (ICD 9

**Group Selection **Controls: 51.4 Explantation described: no 10.9) or
the patient fulfilled all of

[Case Definition]{.underline}: All women 18+ Mean age at diagnoses:
cases 41.6, Duration described: no the following: 1) was diagnosed as

years in Michigan and Ohio Caucasian: cases 90.7%, controls 89.4%
Excluded injections: not reported having Systemic Sclerosis but did

Diagnosed with UCTD between Cases with breast implants: 1. 5% not meet
the ACR criteria, 2) did

1980 and 1992 Controls with breast implants: 1.2% not meet the
diagnostic criteria for

Control Definition: Identified another CTD and 3) had a

through random digit dialing **Response Rate** minimum of 2 signs,
symptoms or

Frequency matched to cases within Not reported lab values suggestive of
a CDT.)

each state on age race and

geographic location.

**Group Determination**

[Cases]{.underline}: medical records - National

Hospital discharge database,

university hospital databases,

mailing list of rheumatologists,

Scleroderma, Foundation

[Controls]{.underline}: self report

**Ascertainment of Exposure: **

[Cases]{.underline}: self report - telephone

interview

[Controls]{.underline}: self report - telephone

interview

**Blinding**

Yes - blind review of self reported

occupational hobby exposure

**Study Methods Participants Interventions Outcomes**

**MacDonald** **Case Control Study** **Country**: Minnesota USA
**Implant Type** **Diagnosis**

**(1996) Cases**: N = 35 Silicone gel filled (1 case 1 Chronic Fatigue
Syndrome (8 of

**Study Dates** **Controls**: N = 35 control - numbers available to 10
symptoms identified in 1988

Diagnosis: Post Jan 1988 analysed separately) CDC criteria, more than
once or

Interviews conducted Oct/93 - Median Age at Disease Onset: cases 37
Saline (1 control) persistently for at least 6 months)

Jun/94 Median Duration of Illness: cases 54.3

months **Exposure**

**Group Determination** Mean Years Since Implantation: cases 11, Rupture
described: no

[Case Definition]{.underline}: patients from the controls not reported
Explantation described: no

Minnesota Regional CFS Research Subjects with any breast implant: cases
Duration described: yes

Program Registry whose disease 3%, controls 6% Excluded injections: not

onset occurred after Jan 1988 and Reconstruction due to breast cancer:
not reported

were residents of Minneapolis St. reported

Paul or St. Cloud. They were

diagnosed after medical **Response Rate**

psychometric and psychiatric [Cases]{.underline}: 83%

assessment could not establish [Controls]{.underline}: 58%

another explanation for fatigue.

Two investigators, a psychiatrist

and an infectious disease specialist,

had to agree on the diagnosis.

[Control Definition]{.underline}: matched to

cases on neighborhood (calling

households with same 3 digit

prefix as cases) gender and age (5

years)

**Group Determination**

[Cases]{.underline}: medical records

[Controls]{.underline}: self report - telephone

interview

**Ascertainment of Exposure**

[Cases]{.underline}: self report - telephone

interview

[Controls]{.underline}: self report - telephone

interview

**Blinding**

Not reported

**Study Methods Participants Interventions Outcomes**

Nyren

\(1998\)

**Retrospective Cohort Study**

**Study Dates**

Breast surgery took place from 1965 -1993 Follow up from Jan 1 1972 -
Dec 31 1993

**Group Selection **

[Exposed]{.underline}: All records in the National Swedish Inpatient
register that contained the surgical code for breast augmentation with
foreign material. These were divided into 2 subcohorts - those with a
diagnosis of breast cancer and those who had received implants for other
reasons (mainly cosmetic)

[Unexposed]{.underline}: All records, of patients who had received
breast reduction surgery, were selected from the same source. From
these, 1 woman was selected as a control for each subject in the
cosmetic implant group. They were matched on age (5 years), hospital and
calendar year at operation (2 years).

**Group Determination **

[Exposed]{.underline}: Medical records -National Swedish Inpatient
Register

[Unexposed]{.underline}: same

**Ascertainment of Outcome **

[Exposed]{.underline}: Medical Records - records were reviewed to
confirm diagnoses

[Unexposed]{.underline}: same

**Blinding**

Not reported

**Country**: Sweden

**Exposed**: N = 7442

**Unexposed**: N = 3353

Mean years since operation: exposed cosmetic 10.3 years, exposed
reconstruction 6.0 years, unexposed: 9.9 years Reconstruction Due to
Breast Cancer: 53 (separate analysis provided)

**Response Rate **

Medical records - 100% of those eligible. Censoring occurred at date of
immigration, death or end of follow up.

**Implant Type**

Unspecified 7% Silicone gel filled

56% (no separate analysis)

Saline 24%

Double Lumen 12%

Polyurethane Coated \<0.1%

**Exposure**

Rupture Described: no

Explantation Described: no

Duration Described: yes

Excluded Injections: not reported

**Diagnosis **

Determined via ICD 8 and ICD 9

codes in Swedish Inpatient Register

Sjögren\'s Syndrome (ICD 8

734,90, ICD 9 710C)

Systemic Lupus Erythematosis

(ICD8 734,10 ICD9 710A)

Systemic Sclerosis (ICD8

734,00,01,09 ICD 9 710B)

Dermatomyositis (ICD8 716,00

ICD 9 710D)

Rheumatoid Arthritis (ICD8

712,00,10,20,38,39 ICD9

714A,B,C,D 719D)

All Definite CTD (combined

outcome included the proceeding

diagnoses)

Fibromyalgia (ICD8 712,50

717,98 718,99 ICD 9 729A)

Polymyositis (ICD 8 716. 10, ICD

9 710E)

Polyrnyalgia Rheumatica (ICD 8

446.38, ICD 9 725)

Polyarteritis Nodosa (codes na)

Temporal Arteritis (ICD 8 446.30,

ICD 9 446F)

Other Specified CTD (ICD

8734.98, ICD 9710W)

CTD or Collagenosis without

further specification (ICD 8

734.91,734.99, ICD 9710)

Sarcoidosis (ICD 8 135, ICD 9

135\)

Localized Lupus (ICD 8 695.40,

ICD 9 695E)

Ankylosing Spondylitis (ICD 8

712.40, ICD 9 720A)

Psoriatic Arthritis (ICD 8 696.0,

713D, ICD 9 696A)

**Study Methods Participants Interventions Outcomes**

**Nyren**

**(1998b)**

**Retrospective Cohort Study**

**Study Dates**

Breast surgery took place from 1965

to 1993.

Follow up from Jan 1972 to Dec

1993

**Group Selection**

[Exposed]{.underline}: All records in the National

Swedish Inpatient register that

contained the surgical code for

breast augmentation with foreign

material. These were divided into 2

subcohorts - those with a diagnosis

of breast cancer and those who had

received implants for other reasons

(mainly cosmetic).

[Unexposed: ]{.underline}

All records, of patients who had

received breast reduction surgery,

were selected from the same source.

From these, 1 woman was selected

as a control for each subject in the

cosmetic implant group. They were

matched on age (5 yrs), hospital and

calendar year at operation (2 yrs).

[Group Determination]{.underline}

[Exposed]{.underline}: Medical records - National

Swedish Inpatient Register

[Unexposed]{.underline}: same

**Ascertainment of Outcome**

[Exposed]{.underline}: Medical Records - records

were reviewed to confirm diagnoses

[Unexposed]{.underline}: same

**Blinding**: not reported

**Country**: Sweden

**Exposed**: N = 7433

**Unexposed**: N = 3353

Mean follow up: exposed cosmetic 10.3 years; exposed reconstruction 6.0
years; unexposed 9.9 years

\% Reconstruction Due to Breast Cancer: 53 (separate analysis provided)

**Response Rate**

All eligible records included. Censoring occurred at date of
immigration, death or end of follow up.

**Implant Type** Type Unspecified

7% Silicone Gel Filled 56% (no separate analysis)

Saline 24%

Double Lumen 12%

Polyurethane Coated \<0.1%

**Exposure**

Injections Excluded: no mention

Rupture Described: no

Explantation Described: no

Duration Described: yes

**Diagnoses**

Multiple Sclerosis (ICD-7 345.00, ICD-8

340.99, ICD-9 340)

Neuritis of the Optic Nerve (ICD-7345.10,

ICD-8341.01, ICD-9341A)

Amyotrophic Lateral Sclerosis (ICD­

7356.10, ICD-8 348.00, ICD-9 335C)

Diseases of the Nerve Roots and Plexuses

(ICD-9 353)

Mononeuritis of the Upper Extremity

-Lesion of the Median Nerve (ICD-7

368.01, ICD-8 357.01, ICD-9354B)

-Lesion of the Ulnar Nerve (ICD-7 368.00,

ICD-8 357.00, ICD-9 354C)

-Lesion of the Radial Nerve (ICD-7 368.02,

ICD-8 354.01, ICD-9 354D)

Mononeuritis of the Lower Extremity (ICD­

9 355)

Guillian-Barre Syndrome (ICD-7 364.20,

ICD-8 354.01, ICD-9 357A)

Meniere\'s Disease (ICD-7 395, ICD-8 385,

ICD-9 368A)

**Study Methods Participants Interventions Outcomes**

**Park**

**(1998)**

**Retrospective Cohort Study**

**Study Dates**

Implantation took place from 1982­

1991\. No other dates reported.

**Group Selection**

[Exposed]{.underline}: 1) Augmentation Group -

All women in SE Scotland who had

received silicone gel implants for

reasons other than reconstruction

following mastectomy, between

1982 and 1991 were approached to

participate. 2) Reconstruction Group

\- All women from the same region

who had undergone reconstruction

with silicone gel implants following

mastectomy for breast cancer.

Patients who had locally advanced

or metabolic disease at the time of

initial diagnoses were excluded.

Only those patients who had

survived 1 year following their

operations were eligible.

[Unexposed]{.underline}: 1) Augmentation

Control Group (a) Examination

controls - Women attending the

plastic surgery out patient

department who were of similar age

as augmentation group. 2)

Augmentation Control Group (b)

Blood Sample [Controls]{.underline} - Women of

similar age as augmentation group

recruited anonymously from local

maternity unit. 3) [Reconstruction]{.underline}

[Controls ]{.underline}- Patients from the data

base of the Breast Unit were

matched to reconstruction patients

on age (6 months), stage of disease

at diagnosis and time of operation (3

months).

**Group Determination**

[Exposed]{.underline}: medical records -

operating books

[Unexposed]{.underline}: medical records

Ascertainment of Outcome:

[Exposed: ]{.underline}

Direct measurement (medical exam

and seroloical analysis), medical

**Country**: Scotland

**Exposed**: Augmentation Group N = I 10,

Reconstruction Group N = 207

**Unexposed**: Augmentation -

Examination Controls N = 128, Blood Controls N = 203, Reconstruction
Controls N=88 Mean Age: Exposed: Augmentation Group 34.1 years,
Reconstruction Group 55.2 years, Unexposed: Augmentation (a) Examination
Controls 33.6 years, (b) Blood Controls 31.2 years, Reconstruction
Controls 55.8 years Mean Years Since Implantation: Augmentation Group
5.9 Reconstruction Group 5.3 Reconstruction Due to Breast Cancer: 64%
(separate analysis) Cosmetic: 36% Bilateral: 77% Unilateral: 32%

**Response Rate**

[Augmentation Group ]{.underline}59%

[Augmentation controls ]{.underline}(both groups) not reported

[Reconstruction Group]{.underline} 72%

[Reconstruction controls]{.underline} 50%

**Implant Type**

Silicone gel filled (average size

258 ml)

**Exposure**

Rupture Described: yes

Explantation Described: yes

Duration Described: yes

Excluded Injections yes

**Diagnosis **

Rheumatoid Arthritis (ACR

criteria)

**Lab Values**

Positive ANA (human cell culture,

titre \<40 considered normal)

**Symptoms **

joint pain

muscle pain

fatigue

Raynaud\'s phenomenon

dysphagia

weight loss

constipation,

psychiatric

photosensitivity

rash

edema

lyphadenopathy

sclerodactyly

abnormal pigment

telangectasia

**Study Methods Participants Interventions Outcomes**

records, and self report (medical history and quality of life
questionnaire)

[Unexposed]{.underline}: same

**Blinding**

Not reported

**Study Methods Participants Interventions Outcomes**

**Sanchez**

**(1995)**

**Retrospective Cohort Study**

**Study Dates**

1976 - rheumatic conditions which

occurred since this date were

enumerated

1990 - Implantation must have

taken place prior to this date.

1992- Information regarding

exposure was collected via mailed

questionnaires.

1980-1992 - Information regarding

rheumatic conditions was collected

via mailed questionnaires

(biannually).

1992 - Participants who had

completed the 1992 biannual

questionnaire and had reported

rheumatic disease prior to June 1

1990 were sent a screening

questionnaire regarding CTD.

**Group Selection**

Participants in Nurses Health Study

assembled in June 1976 - married

female RNs age 30-55 residing in

11 US states.

[Exposed]{.underline}: women reporting any

breast implants or injections on

questionnaire (surgery prior to

1990\)

[Unexposed]{.underline}: reporting no implants or

injections on questionnaire

**Group Determination**

[Exposed]{.underline}: self report (mailed

questionnaire). Self report validated

in a random sample by blinded

physician medical record review.

[Unexposed]{.underline}: self report (mailed

questionnaire)

Ascertainment of Outcome:

[Exposed]{.underline}: self report (questionnaire),

medical records - Women who had

reported CTD were then sent a

screening questionnaire including 30

criteria based symptoms, (sensitivity

83 -96%, specificity 83-93%) for

detecting RA, SLE, SSc, Sjögren\'s,

**Country**: United States

**Exposed**: N = 1183

**Unexposed**: N = 86318

SES: All nurses

Caucasian: 95% (whole cohort)

Reconstruction Due to Breast cancer: 33%

(no separate analysis)

Bilateral: 79%

Exposed subjects with 2+ operations: 23%

Mean years since implantation: 9.9 (+/- 6.4)

Cohort with breast implants: 1.4%

**Response Rate **

Whole cohort:

1976 baseline questionnaire 70%,

1992 biennial questionnaire 81%, Supplementary questionnaire to those
who reported breast implants in 1992 - 97.2%, Screening questionnaire to
those who had reported disease 90%

**Implant Type **

Unspecified: 5% Silicone gel filled: 74% (analysed separately)

Saline: 14%

Double lumen: 6%

Polyurethane coated: 1%

**Exposure**

Rupture described: no

Explantation described: no

Duration described: yes

Excluded Injections: yes

**Diagnosis **

Rheumatoid Arthritis (ACR criteria)

Scleroderma (ACR criteria)

Sjögren\'s Syndrome (Fox et al criteria)

Polymyositis / Dermatomyocitis (Bohan and Peter criteria)

Systemic Lupus Erythematosus (ACR criteria)

Mixed Connective Tissue Disease

(Alarcon, Sigovis and Cardiel criteria)

Definite CTD (combined endpoint

comprised of all the above)

Self Reported Connective Tissue

Disease (women with possible

early, milder or atypical forms of

CTD who did not meet the

standard classification criteria)

**Symptoms**

Self Reported Signs or Symptoms

of CTD

Documented Signs or Symptoms of CTD

Inflammatory Myosotis, and Mixed Connective Tissue Disease. Those who
had a positive questionnaire (at least 2 swollen joints for \>6 weeks or
3 positive answers) had their medical records reviewed by 2
rheumatologists. Date of onset was defined as date of diagnosis in
chart. Less stringent criteria were used for a separate analysis -
patients who reported rheumatic disease on any biennial questionnaire,
patients who had a positive screening questionnaire, or patients who had
any 1 of 41 signs, symptoms or laboratory features on the medical record
abstraction form were included.

[Unexposed]{.underline}: same

**Blinding**

Data regarding implant history was entered by blinded researchers.
Medical records regarding outcome were reviewed by blinded physicians.

**Study Methods Participants Interventions Outcomes**

**Strom**

**(1994)**

**Case Control Study**

**Study Dates**

1985-1987 - Cases and controls identified for a general risk factor
study not involving implants. June 1992 - Sept 1992 Subjects were
contacted again to be interviewed regarding breast implantation prior to
the index date of the previous study.

**Group Selection **

[Case Definition: ]{.underline}Outpatients with a new (incident) or
recent (within 3 years) clinical diagnosis of SLE or lupus-like illness
were identified from Philadelphia rheumatology practices (73%) and local
Lupus Foundation (27%). Cases without matched controls were excluded

[Control Definition: ]{.underline}

[Internal Controls]{.underline} - Friends of cases, matched on sex and
age (5 years) were randomly selected from alphabetical order and random
number table.

[External Controls ]{.underline}- Population based controls from the
Cancer and Steroid Hormone study which studied events diagnosed from
1980 -1982.

**Group Determination**

[Cases]{.underline}: medical records (not specified) [Controls
]{.underline}(internal): self report (not specified) - excluded those
with SLE

**Ascertainment of Exposure**

[Cases]{.underline}: self report (telephone interview) [Controls
]{.underline}(internal): same

**Blinding**

not reported

**Country**: Philadelphia, USA

**Cases**: N = 133

**Controls**: Internal Controls N = 100,

External Controls N = 4754

Years since implantation: cases: 8 years (only 1 case)

Cases with breast implants: 0.75% Controls with breast implants:
internal controls 0, external controls 0. 17

**Response Rate** [Cases]{.underline}:

Original Study - 89% Implant Study - cases 75.9% of original subjects

[Controls: ]{.underline}Original Study - 85.1% Implant Study 77.6% of
original subjects

**Implant Type**

Unspecified

**Exposure **

Rupture described: no

Explantation described: no

Duration described: yes

Excluded injections: no (external controls)

**Diagnosis **

Scleroderma (4 or more revised

ARA criteria)

**Study Methods Participants Interventions Outcomes**

**Teel Case Control Study** **Country**: Washington State, USA **Implant
Type** **Diagnoses**

**(1997)** Cases: N = 427 Unspecified: N = 5 (1 case, 4 Systemic Lupus
Erythematosus

**Study Dates** **Controls**: \"Pre-existing\" N = 1688; \"New\"
controls) (ACR criteria)

Cases diagnosed between Jan 1983 N = 1577 Silicone Get-Fitted: N = 32 (4
Systemic Sclerosis/Crest (ACR

and Dec 1991. \"Pre existing control cases, 28 controls) criteria)

group\" interviewed between 1986 Mean age at reference date: cases 45.2
Saline: N = 8 (1 case, 7 controls) Sjögren\'s Syndrome (ACR criteria)

and 1991. \"New\" control group years; \"pre-existing\" controls 48.1
years; Separate analysis for Silicone Polymyositis (Bohan criteria)

selected from 1994 - 1996. \"new\" controls 41.7 years Gel-Filled
implants: no Mixed Connective Tissue Disease

Race - Caucasian: cases 79.9%; \"pre (Sharp criteria)

**Group Selection** existing\" controls 89.1%; \"new\" controls
**Exposure** Any Connective Tissue Disease

[Case Definition]{.underline} 93.7% Rupture described: no (all cases
combined)

Female residents of King\'s County Body Mass Index: cases 23.2; \"pre-
Explantation described: no

diagnosed by a rheumatologist as existing\" controls 23.5; \"new\"
controls 23.2 Duration described: no

having one of five connective tissue Ever Married: cases 83. 1%; \"pre
existing\" Injections excluded: not reported

diseases. controls 91.0%; \"new\" controls 81.4%

Education: cases 13.9 years; \"pre existing\"

[Control Definition]{.underline} controls 13.9 years; \"new\" controls
14.1

\"Pre existing\" controls had been years

identified through random digit Breast Cancer: : cases 1.6%, \"pre
existing\"

dialing for previous epidemiologic controls 2.3 O/o; \"new\" controls
1.3%

studies. Cases with breast implants: 1.4%

\"New\" controls were selected by Controls with breast implants: \"pre

random digit dialing and matched existing\" 1.0%; \"new\" 1.1%

to cases on age and year of

diagnosis. **Response Rate**

All controls were residents of King [Cases]{.underline}: 80.3%

County at their reference dates. [Control]{.underline} : \"pre
existing\" controls 79.0%;

Those with a history of CTD prior \"new controls\" 79.0%

to reference date were excluded.

**Group Determination**

** **[Cases]{.underline}: Medical records were

reviewed by trained research

assistants. Cases were classified as

definite (case met all diagnostic

criteria and had been diagnosed by

rheumatologist) or probable

(rheumatologist made diagnosis but

case fell one feature short of

requisite criteria or criteria were met

but rheumatologist had labeled the

disease as probable). 96% of

probable cases were re-abstracted to

confirm eligibility

[Controls]{.underline}: \"Pre existing\" controls -

self report (not clear if interview or

questionnaire). \"New\" controls - self

report - mailed questionnaire (non

respondents administered same

questionnaire by phone)

**Ascertainment of Exposure**

[Cases]{.underline}: Self report - mailed

questionnaire (non respondents

administered same questionnaire by

phone)

­[Controls]{.underline}: \"Pre existing\" controls -

self report - interview \"New\"

controls same as for cases.

**Blinding **

Not reported.

**Study Methods Participants Interventions Outcomes**

**Wells**

**(1994)**

**Retrospective Cohort Study**

**Study Dates**

1970-1990 - dates of implantation

Oct 13 1990 - Questionnaire

regarding symptoms was mailed to

both exposed and unexposed plastic

surgery patients.

July 11 1991 - Second questionnaire

was mailed to non responders. (In

addition, a telephone follow up for

which no dates were reported, was

conducted with a random sample of

\- responding women.)

**Group Selection**

Subjects age 20 - 60 who had not

undergone silicone chin or nose

implant or collagen injections

selected from a single plastic surgery

practice­

[Exposed]{.underline}: women who had \"silicone

breast implants\" for aesthetic or

reconstructive purposes.

[Unexposed]{.underline}: Women who had a

cosmetic procedure (blepharoplasty,

rhinoplasty or liposuction) other

than breast implants. Those who

subsequently obtained breast

implants were excluded.

**Group Determination**

[Exposed]{.underline}: medical records

[Unexposed]{.underline}: same

**Ascertainment of Outcome**

[Exposed]{.underline}: self report - mailed

questionnaire and for a random

sample of non responders (n=8)

telephone survey

[Unexposed]{.underline}: same (telephone survey

n=19)

**Blinding**

not reported

**Country**: Florida, USA

**Exposed**: N = 222

**Unexposed**: N = 80

Median age: exposed 37(+/- 0.67),

unexposed 46.5 (+/-1.63)

Caucasian: 98% (of all subjects)

Median year of operation: exposed 1986 (+/-0.48), unexposed 1988
(+/-0.31). 8% of implant group had surgery \>10 years ago.

None of controls had surgery \> than 7 years previously.

Good health before surgery: exposed 98%, unexposed 100%

Prevalence of allergies: exposed 38%, unexposed 32%

History of breast cancer: 0 in Cohort

**Response Rate**

[Exposed: ]{.underline}59%

[Unexposed: ]{.underline}46%

**Implant Type**

Silicone gel filled (assume -article states \"silicone breast implants\"

**Exposure**

Rupture described: no

Explantation described: no

Duration described: yes

Excluded Injections: yes

**Diagnosis**

Systemic sclerosis

Raynaud\'s phenomenon

Arthritis (not defined whether RA or not)

Note: study looked at self reported diagnoses only, no criteria
reported.

**Symptoms **

easily tired

muscle pain

swollen glands neck

tender glands neck

swollen glands under arm

tender glands under arm

rashes

skin thickening

skin tightness

change in skin colour

hair loss arms and legs

persistent fever

change in hand colour with cold

breathing difficulty

weight loss \> 10 lbs.

weight gain \> 10 lbs.

swollen joints

painful joints

general stillness

Note: patients were asked if they experienced these outcomes either
before or after surgery. Only those symptoms reported as being post
surgical which were not present before hand were analysed.

**Study Methods Participants Interventions Outcomes**

**Winther Retrospective Cohort Study: Country: Denmark Implant Type**
**Diagnoses**

**(1998) **Study Dates: Breast surgery took **Exposed**: N = 1335
Silicone breast implants (All cases represented neurologic disease

place between 1977- 1992. Follow Unexposed: N = 7071 requiring
hospitalization and were classified

up to Dec 31 1993 according to ICD 8)

Median Age at Entry: Exposed 31; **Exposure** Multiple Sclerosis (ICD
340, Poser criteria)

**Group Selection** Unexposed 31 Injections Excluded: yes Other
Demyelinating CNS Neuropathies

Exposed: Women identified through Median Length of Follow up: Exposed
8.5 Rupture Described: no (ICD 341)

Danish Central National Register yrs; Unexposed 7.7 yrs Explantation
Described: no Motor Neuropathy (ICD 348, includes

of Patients (NRP) who had received Duration Described: yes ALS)

implants at public hospitals between **Response Rate** Peripheral
Neuropathies

for cosmetic reasons. All eligible records included. Follow up -Brachial
Neuropathy (ICD 352)

[Exposed]{.underline}: Women from the same continued to Dec 31 1993,
death or date of Sciatic Neuropathy (ICD 353.99)

source who had undergone breast last health care visit. Polyneuropathy
(ICD 354, includes

reduction surgery. Guillian Barre)

Neuropathy, NOS (ICD 355.09)

**Group Determination **Other Peripheral Neuropathies (ICD

[Exposed]{.underline}: NRP records (ICD-8 357.99)

38500, 38540) Optical Retino, - and Neuropathy (ICD 367)

[Unexposed]{.underline}: NRP records (ICD-8 Meniere\'s Disease (ICD
385.99)

38400, 38460) Myasthenia Gravis (ICD 733.09)

** Ascertainment of Outcome **

** **[Exposed]{.underline}: NRP records. Hospital

medical records were reviewed to

validate neurologic diagnoses

obtained form NRP

[Unexposed]{.underline}: NRP records. Hospital

medical records were reviewed to

validate neurologic diagnoses for

which an increased occurrence was

observed in the exposed cohort

** Blinding**

Medical records reviewed by

blinded neurologist

**Study Methods Participants Interventions Outcomes**

Wolfe

\(1995\)

**Case Control Study**

**Study Dates**

not reported

[Case Definition: ]{.underline}patients with fibromyalgia, patients with
rheumatoid arthritis

[Control Definiton: ]{.underline}Two groups - 1) patients with
osteoarthritis, 2) women randomly selected from the general population

**Group Determination**

not reported

**Ascertainment of Exposure**

[Cases]{.underline}: self report - mailed

questionnaires

[Controls: ]{.underline}Osteoarthritis controls -

self report - mailed questionnaires, community controls - self report -

telephone interview

**Blinding**

not reported

**Country**: Kansas, USA

**Cases**: Fibromyalgia (FM) N = 533,

Rheumatoid Arthritis (RA) N = 637

**Controls**: Osteoarthritis (OA) N = 477,

Community N = 655

Mean age at interview: cases: RA 64.4 years, FM 51.6 years controls: OA
67.4 years, community 55.3 years Mean age at disease onset: Cases: RA
47.1 years, FM 38.5 years Controls: OA 52.7 years Cases with implants:
Fibromyalgia 1.31%, Rheumatoid Arthritis 0.47% Controls with implants:
Community controls 0.31%. Osteoarthritis controls 0.42

**Response Rate**

not reported

**Implant Type**

Unspecified (referred to as silicone breast implants but not specific
about the filling)

**Exposure**

Rupture described: no

Explantation described: no

Duration described: no

Excluded injections: not reported

**Diagnosis **

Rheumatoid Arthritis (criteria not reported)

Fibromyalgia (criteria not reported)

# APPENDIX A

**SEARCH STRATEGY**

**`APPENDIX A`**

**`SEARCH STRATEGY`**

Set Search 1

001 breast implants/

002 (breast adj3 implant\$).tw.

003 (breast adj3 (augmentation or reconstruction)).tw.

004 (breast adj3 prosthes#s).tw.

005 or/1‑3

006 breast/ or breast\$.tw.

007 implants, artificial/

008 prosthesis/

009 exp silicones/ or silicone\$.tw.

010 or/7‑9

011 (5 or 6) and 10

012 mammaplasty/ or mammaplasty.tw.

013 surgery, plastic/

014 breast/su

015 or/12‑14

016 (augment\$ or implast\$).tw.

017 (reconstruct\$ or cosmetic or prosthes#s).tw.

018 15 and (16 or 17)

019 5 or 11 or 18

020 exp arthritis, rheumatoid/

021 (felty\$ adJ2 syndrome).tw.

022 (caplan\$ adJ2 syndrome).tw.

023 rheumatoid nodule.tw.

024 (sjogren\$ adJ2 syndrome).tw.

025 (sicca adj2 syndrome).tw.

026 still\$ disease.tw.

027 (spondylitis adJ2 ankylosing).tw.

028 bechterew\$ disease.tw.

029 (arthritis adJ2 rheumat\$).tw.

030 or/20‑29

031 19 and 30

032 scleroderma, circumscribed/

033 ((scleroderma adj localized) or progressive or diffuse or sy

034 exp sclerodenna, systemic/

035 ((crest or crst) adj syndrome).tw.

036 morphea.ti,ab,sh. or dermatosclerosis.tw.

037 sclerodacty\$.tw.

038 exp calcinosis/ or calcinosis.tw.

039 exp esophageal motility disorders/

040 esophag\$.tw.

041 ataxia telangiectasia/

042 telangiectasia, hereditary hemorrhagic/

043 telangiectasia.tw.

044 osler‑rendu.tw.

045 louis‑bar.tw.

046 raynaud\'s disease/ or raynaud\$.tw.

047 or/32‑46

048 19 and 47

049 48

Set Search 2

001 breast implants/

002 (breast adj3 implant\$).tw.

003 (breast adj3 (augmentation or reconstruction)).tw.

004 (breast adj3 prosthes#s).tw.

005 or/1‑3

006 breast/ or breast\$.tw.

007 implants, artificial/

008 prosthesis/

009 exp silicones/ or silicone\$.tw.

010 or/7‑9

011 (5 or 6) and 10

012 mammaplasty/ or mammaplasty.tw.

013 surgery, plastic/

014 breast/su.

015 or/12‑14

016 (augment\$ or implast\$).tw.

017 (reconstruct\$ or cosmetic or prosthes#s).tw.

018 15 and (16 or 17)

019 5 or 11 or 18

020 exp lupus erythematosus, systemic/

021 (lupus adj (nephritis or erythematosus or disseminatus)).tw.

022 libman‑sacks.tw.

023 antiphospholipid syndrome/

024 antiphospholipid.tw.

025 or/20‑24

026 19 and 25

027 dermatomyositis/ or dermatomyositis.tw.

028 19 and 27

029 polymyositis/

030 myositis.ti,ab,sh. or polymyositis.tw.

031 20 or 30

032 19 and 31

033 arthritis, psoriatic/

034 (psoriatic adJ2 (arthrit\$ or arthropathica)).tw.

035 33 or 24

036 19 and 35

037 28

Set Search 3

001 breast implants/

002 (breast adj3 implant\$).tw.

003 (breast adj3 (augmentation or reconstruction)).tw.

004 (breast adj3 prosthes#s).tw.

005 or/1‑3

006 breast/ or breast\$.tw.

007 implants, artificial/

008 prosthesis/

009 exp silicones/ or silicone\$.tw.

010 or/7‑9

011 (5 or 6) and 10

012 mammaplasty/ or mammaplasty.tw.

013 surgery, plastic/

014 breast/su

015 or/12‑14

016 (augment\$ or implast\$).tw.

017 (reconstruct\$ or cosmetic or prosthes#s).tw.

018 15 and (16 or 17)

019 5 or 11 or 18

020 exp vasculitis/

021 angiitis.tw.

022 vasculitis, allergic cutaneous/

023 vasculitis.tw,sh.

024 arteritis.tw.

025 (thrombophlebitis or phlebitis).tw.

026 thromboangiitis.tw.

027 (behcet\$ or churg‑strauss).tw.

028 wegener\$.tw.

029 mucocutaneous lymph.tw.

030 or/20‑29

031 19 and 30

032 exp inflammatory bowel diseases/

033 ulcerative colitis.tw.

034 crohn\$.tw.

035 (colitis or ileitis or enteritis).tw.

036 (rectocolitis or proctocolitis).tw.

037 inflammatory bowel.tw.

038 or/32‑37

039 19 and 38

040 polychondritis, relapsing/

041 polychondritis.tw.

042 40 or 41

043 19 and 42

044 fibromyalgia/

045 (fibromyalgia or fibrositis).tw.

046 muscular rheumatism.tw.

047 fatigue syndrome, chronic/

048 chronic fatigue.tw.

049 myalg\$.tw.

050 encephalomyelitis.tw.

051 encephalomyelitis.tw.

052 or/44‑51

053 19 and 52

054 53

Set Search 4

001 breast implants/

002 (breast adj3 implant\$).tw.

003 (breast adj3 (augmentation or reconstruction)).tw.

004 (breast adj3 prosthes#s).tw.

005 or/ 1 ‑3

006 breast/ or breast\$.tw.

007 implants, artificial/

008 prosthesis/

009 exp silicones/ or silicone\$.tw.

010 or/7‑9

011 (5 or 6) and 10

012 mammaplasty/ or mammaplasty.tw.

013 surgery, plastic/

014 breast/su

015 or/12‑14

016 (augment\$ or implast\$).tw.

017 (reconstruct\$ or cosmetic or prosthes#s).tw.

018 15 and (16 or 17)

019 5 or 11 or 18

020 connective tissue diseases/

021 exp cartilage diseases/

022 cellulitis/

023 exp collagen diseases/

024 cutis laxa/

025 dupuytren\'s contracture/

026 homocystinuria/

027 marfan syndrome/

028 mixed connective tissue disease/

029 exp mucinoses/

030 neoplasms, connective tissue/

031 noonan syndrome/

032 osteopoikilosis/

033 exp panniculitis/

034 pseudoxanthorna elasticum/

035 mctd.tw.

036 sharp syndrome.tw.

037 human adjuvant.tw.

038 mixed connective tissue.tw.

039 sclerosis‑like.tw.

040 fibrous banding.tw.

041 skin thickening. tw.

042 arthralgia/

043 (arthralgia or polyarthralgia).tw.

044 or/20‑43

045 19 and 44

046 scleroderma, circumscribed/

047 ((scleroderma adj localized) or progressive or diffuse or sy

048 exp scleroderma, systemic/

049 ((crest or crst) adj syndrome).tw.

050 morphea.ti,ab,sh. or dermatosclerosis.tw.

051 sclerodacty\$.tw.

052 exp, calcinosis/ or calcinosis.tw.

053 exp esophageal motility disorders/

054 esophag\$.tw.

055 ataxia telangiectasia/

056 telangiectasia, hereditary hemorrhagic/

057 telangiectasia.tw.

058 osler‑rendu.tw.

059 louis‑bar.tw.

060 raynaud\'s disease/ or raynaud\$.tw.

061 or/46‑60

062 19 and 61

063 45 not 62

064 63

Set Search 5

001 breast implants/

002 breast adj3 implant\$).tw.

003 (breast adj3 (augmentation or reconstructio

004 (breast adj3 prosthes#s).tw.

005 or/1‑3

006 breast/ or breast\$.tw.

007 implants, artificial/

008 prosthesis/

009 exp silicones/ or silicone\$.tw.

010 or/7‑9

011 (5 or 6) and 10

012 mammaplasty/ or mammaplasty.tw.

013 surgery, plastic/

014 breast/su

015 or/12‑14

016 (augment\$ or implast\$).tw.

017 (reconstruct\$ or cosmetic or prosthes#s).tw

018 15 and (16 or 17)

019 5 or 11 or 18

020 randomized controlled trial.pt.

021 controlled clinical trial.pt.

022 controlled clinical trials/

023 exp cross‑sectional studies/

024 cross‑sectional.tw.

025 prospective.tw.

026 retrospective. tw.

027 exp cohort studies/

028 exp case‑control studies/

029 or/20‑28

030 19 and 29

031 control\$.tw.

032 19 and 31

033 30 or 32

034 limit 33 to human

035 exp arthritis, rheumatoid/

036 exp calcinosis/

037 exp scleroderma, systemic/

038 exp esophageal motility disorders/

039 exp lupus erythematosus, systemic/

040 arthritis, psoriatic/

041 vasculitis.tw.

042 exp inflammatory bowel diseases/

043 fibromyalgia/

044 fatigue syndrome, chronic/

045 connective tissue diseases/

046 mixed connective tissue disease/

047 exp collagen diseases/

048 exp cartilage diseases/

049 neoplasms, connective tissue/

050 exp Mucinoses/

051 cellulitis/

052 scleroderma.tw.

053 antiphospholipid syndrome/

054 polymyositis/

055 arteritis.tw.

056 (colitis or ileitis).ti,ab,rw,sh. or enteri

057 exp panniculitis/

058 arthralgia/

059 telangiectasia.tw.

060 raynaud\'s disease/ or raynaud\$.tw.

061 or/35‑50

062 34 not 61

063 2 or 3 or 4 or 6 or 12 or 14

064 63 and 9

065 1 or 64

066 breast implantation/

067 65 or 66

068 29 and 67

069 31 and 67

071 limit 71 to human

Toxline Search

001 (breast implant\$ or breast) and silicone\$

002 exclude medline

Dissertation Abstracts

001 breast implant

002 breast implants

003 breast and silicone

**APPENDIX B**

**DATA EXTRACTION FORMS**

**SILICONE BREAST IMPLANTS AND CONNECTIVE TISSUE DISEASE**

**CASE CONTROL STUDY**

  -------------------- -------------------------------------------------------- ------------------------ -- ------------ ------- -- ---------------- ------- -- ------ ------- -- -------------- ------- -- ------------------- ------- -- ---------------- ------- -- -------------- ------- -- -------------------------- -- -- ----------------------- --
  **Identification**   Article \# Review \# Reviewer                                                                                                                                                                                                                                                                                                      
                                                                                                                                                                                                                                                                                                                                                          
  **Title**                                                                                                                                                                                                                                                                                                                                               
                                                                                                                                                                                                                                                                                                                                                          
  **Investigator**                                                                                                                                                                                                                                                                                                                                        
                                                                                Year                                                                                                                                                                                                                                                                      
  **Setting**          Location                                                 Language                                                                                                                                                                                                                                                                  
                                                                                                            Study Name                                                                                                                                                                                                                                    
  **Dates of**                                                                                                                                                                                                                                                                                                                                            
  **Enrolment**                                                                                                                                                                                                                                                                                                                                           
  **Diagnoses**        ' SSc                                                    ' ACR                                                                                                                                                                                                                                                                     
                       ' Morphea                                                ' ACR                       ' RA         ' ACR      ' SLE            ' ACR      ' FM   ' ACR      ' Sjögren\'s   ' ACR      ' Dermatomyositis   ' ACR      ' Polymyositis   ' ACR      ' Vasculitis   ' ACR      ' Ankylosing Spondylitis         ' Psoriatic Arthritis   
                       ' Arthritis Associated With Inflammatory Bowel Disease                                                                                                                                                                                                                                                                             
                       ' Polychondritis                                                                                                                                                                                                                                                                                                                   
                       ' Mixed Connective Tissue Disease                                                                                                                                                                                                                                                                                                  
                       ' Raynaud\'s Phenomenon                                                                                                                                                                                                                                                                                                            
                       ' Any Connective Tissue Disease (Combined Endpoint)                                                                                                                                                                                                                                                                                
                       ' Other                                                                              ' Other                                                                                                                                                                                                                                       
  Implant              ' Implant Type Unspecified                               ' Injection - Silicone                                                                                                                                                                                                                                                    
                       ' Silicone Gel Filled                                    ' Injection - Collagen      ' Saline                ' Double lumen                                                                                                                                                                                                        
                       ' Polyurethane coated                                                                                                                                                                                                                                                                                                              
  -------------------- -------------------------------------------------------- ------------------------ -- ------------ ------- -- ---------------- ------- -- ------ ------- -- -------------- ------- -- ------------------- ------- -- ---------------- ------- -- -------------- ------- -- -------------------------- -- -- ----------------------- --

Comments:
\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_

\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_

# \_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_

**Methodology**

  --------------- -------------------------------- ---------------------- -- ---------------------------- --------------- -- ------------------ ------------------ -- -- -- -- -- -- -- -- -- -- -- -- -- -- --------------------- -- -- ---------------------------- -- -- ---------------------- -- -- --------------------- -- -- ----------- -- -- ------------- -- ------------------------------ ------------------ -- --------------------------- --------------------- -- -- --
                  Cases                            Control                                                                                                                                                                                                                                                                                                                                                                                                                           
  \# Identified                                                                                                                                                                                                                                                                                                                                                                                                                                                                      
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                     
  \# Excluded                                                                                                                                                                                                                                                                                                                                                                                                                                                                        
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                     
  Group N                                                                                                                                                                                                                                                                                                                                                                                                                                                                            
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                     
  Group           Case Definition                  Control Definition                                                                                                                                                                                                                                                                                                                                                                                                                
  Selection                                                                                                                                                                                                  ' Randomly Selected         ' Excluded Hist of Disease         ' Community Controls         ' Hospital Controls         ' Matched         ' Unmatched      Excluded cases with Dx prior   ' Single Control      to implants? ' Y ' N ' NA   ' Multiple Controls         
  Group           ' Direct Measurement             ' Direct Measurement                                                                                                                                                                                                                                                                                                                                                                                                              
  Determination   ' Medical Records                ' Medical Records         ' Self Report                ' Self Report                                                                                                                                                                                                                                                                                                                                                              
  Ascertainment   ' Direct Measurement             ' Direct Measurement                                                                                                                                                                                                                                                                                                                                                                                                              
  of Exposure     ' Medical Records                ' Medical Records         ' Self Report                ' Self Report      Blinding ' Y ' N   Blinding ' Y ' N                                                                                                                                                                                                                                                                                                                     
  Exposure        Rupture Described ' Y ' N                                                                                                                                                                                                                                                                                                                                                                                                                                          
                  Explantation Described ' Y ' N                             Duration Described ' Y ' N                                                                                                                                                                                                                                                                                                                                                                              
                  Excluded Injections ' Y ' N                                                                                                                                                                                                                                                                                                                                                                                                                                        
  --------------- -------------------------------- ---------------------- -- ---------------------------- --------------- -- ------------------ ------------------ -- -- -- -- -- -- -- -- -- -- -- -- -- -- --------------------- -- -- ---------------------------- -- -- ---------------------- -- -- --------------------- -- -- ----------- -- -- ------------- -- ------------------------------ ------------------ -- --------------------------- --------------------- -- -- --

**Subject Characteristics**

<table>
<tbody>
<tr class="odd">
<td><p><strong>Characteristic</strong></p></td>
<td><p><strong>Cases</strong></p></td>
<td><p><strong>Controls</strong></p></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
</tr>
<tr class="even">
<td><p>Age</p></td>
<td></td>
<td></td>
<td><p>SES (Define)</p></td>
<td></td>
<td></td>
<td><p>% Family History of</p>
<p>Disease</p></td>
<td></td>
<td></td>
<td><p>% Caucasian</p></td>
<td></td>
<td></td>
<td><p>% Rupture</p></td>
<td></td>
<td></td>
<td><p>% Explantation</p></td>
<td></td>
<td></td>
<td><p>Yrs Since Implantation</p></td>
<td></td>
<td></td>
<td><p>% Reconstruction Due to</p>
<p>Breast Cancer</p></td>
<td></td>
<td></td>
<td><p>% Cosmetic</p></td>
<td></td>
<td></td>
<td><p>% Bilateral</p></td>
<td></td>
<td></td>
</tr>
<tr class="odd">
<td><p>% Unilateral</p></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
</tr>
</tbody>
</table>

**Group Differences: **

**Data Analysis**: ' All subjects ' Excludes ascertainment exposure
unknown

+-------+-------+------+-------+-------+-------+-------+-------+
| **    | **N** |      |       | **Cr  | **    | **Fa  | **Tra |
| Expos |       |      |       | ude** | Adjus | ctors | nslat |
| ure** |       |      |       |       | ted** | Adjus | ion** |
|       |       |      |       |       |       | ted** |       |
+-------+-------+------+-------+-------+-------+-------+-------+
|       |       |      |       | **OR  | **OR  |       |       |
|       |       |      |       | (     | (     |       |       |
|       |       |      |       | CI)** | CI)** |       |       |
+-------+-------+------+-------+-------+-------+-------+-------+
|       |       | Case | Co    |       |       | ' Age |       |
|       |       |      | ntrol |       |       |       |       |
+-------+-------+------+-------+-------+-------+-------+-------+
|       |       |      |       |       |       | '     |       |
|       |       |      |       |       |       | Educ  |       |
|       |       |      |       |       |       | ation |       |
+-------+-------+------+-------+-------+-------+-------+-------+
|       | E     |      |       |       |       | '     |       |
|       |       |      |       |       |       | I     |       |
|       |       |      |       |       |       | ncome |       |
+-------+-------+------+-------+-------+-------+-------+-------+
|       |       |      |       |       |       | '     |       |
|       |       |      |       |       |       | Ma    |       |
|       |       |      |       |       |       | rital |       |
|       |       |      |       |       |       | S     |       |
|       |       |      |       |       |       | tatus |       |
+-------+-------+------+-------+-------+-------+-------+-------+
|       | E     |      |       |       |       | '     |       |
|       |       |      |       |       |       | Race  |       |
+-------+-------+------+-------+-------+-------+-------+-------+
|       |       |      |       |       |       | '     |       |
+-------+-------+------+-------+-------+-------+-------+-------+
|       | T     |      |       |       |       | '     |       |
+-------+-------+------+-------+-------+-------+-------+-------+
|       |       |      |       |       |       |       |       |
+-------+-------+------+-------+-------+-------+-------+-------+
|       |       | Case | Co    |       |       | ' Age |       |
|       |       |      | ntrol |       |       |       |       |
+-------+-------+------+-------+-------+-------+-------+-------+
|       |       |      |       |       |       | '     |       |
|       |       |      |       |       |       | Educ  |       |
|       |       |      |       |       |       | ation |       |
+-------+-------+------+-------+-------+-------+-------+-------+
|       | E     |      |       |       |       | '     |       |
|       |       |      |       |       |       | I     |       |
|       |       |      |       |       |       | ncome |       |
+-------+-------+------+-------+-------+-------+-------+-------+
|       |       |      |       |       |       | '     |       |
|       |       |      |       |       |       | Ma    |       |
|       |       |      |       |       |       | rital |       |
|       |       |      |       |       |       | S     |       |
|       |       |      |       |       |       | tatus |       |
+-------+-------+------+-------+-------+-------+-------+-------+
|       | E     |      |       |       |       | '     |       |
|       |       |      |       |       |       | Race  |       |
+-------+-------+------+-------+-------+-------+-------+-------+
|       |       |      |       |       |       | '     |       |
+-------+-------+------+-------+-------+-------+-------+-------+
|       | T     |      |       |       |       | '     |       |
+-------+-------+------+-------+-------+-------+-------+-------+
|       |       |      |       |       |       |       |       |
+-------+-------+------+-------+-------+-------+-------+-------+
|       |       | Case | Co    |       |       | ' Age |       |
|       |       |      | ntrol |       |       |       |       |
+-------+-------+------+-------+-------+-------+-------+-------+
|       |       |      |       |       |       | '     |       |
|       |       |      |       |       |       | Educ  |       |
|       |       |      |       |       |       | ation |       |
+-------+-------+------+-------+-------+-------+-------+-------+
|       | E     |      |       |       |       | '     |       |
|       |       |      |       |       |       | I     |       |
|       |       |      |       |       |       | ncome |       |
|       |       |      |       |       |       |       |       |
|       |       |      |       |       |       | L\)   |       |
|       |       |      |       |       |       | Ma    |       |
|       |       |      |       |       |       | rital |       |
|       |       |      |       |       |       | S     |       |
|       |       |      |       |       |       | tatus |       |
+-------+-------+------+-------+-------+-------+-------+-------+
|       |       |      |       |       |       | '     |       |
|       |       |      |       |       |       | Ma    |       |
|       |       |      |       |       |       | rital |       |
|       |       |      |       |       |       | S     |       |
|       |       |      |       |       |       | tatus |       |
+-------+-------+------+-------+-------+-------+-------+-------+
|       | E     |      |       |       |       | '     |       |
|       |       |      |       |       |       | Race  |       |
+-------+-------+------+-------+-------+-------+-------+-------+
|       |       |      |       |       |       | '     |       |
+-------+-------+------+-------+-------+-------+-------+-------+
|       | T     |      |       |       |       | '     |       |
+-------+-------+------+-------+-------+-------+-------+-------+
|       |       |      |       |       |       |       |       |
+-------+-------+------+-------+-------+-------+-------+-------+

**SILICONE BREAST IMPLANTS AND CONNECTIVE TISSUE DISEASE**

**COHORT STUDY**

  -------------------- -------------------------------------------------------- ------------------------ -- ------------ ------- -- ---------------- ------- -- ------ ------- -- -------------- ------- -- ------------------- ------- -- ---------------- ------- -- -------------- ------- -- -------------------------- -- -- ----------------------- --
  **Identification**   Article \# Review \# Reviewer                                                                                                                                                                                                                                                                                                      
                                                                                                                                                                                                                                                                                                                                                          
  **Title**                                                                                                                                                                                                                                                                                                                                               
                                                                                                                                                                                                                                                                                                                                                          
  **Investigator**                                                                                                                                                                                                                                                                                                                                        
                                                                                Year                                                                                                                                                                                                                                                                      
  **Setting**          Location                                                 Language                                                                                                                                                                                                                                                                  
                                                                                                            Study Name                                                                                                                                                                                                                                    
  **Dates of**                                                                                                                                                                                                                                                                                                                                            
  **Enrolment**                                                                                                                                                                                                                                                                                                                                           
  **Diagnoses**        ' SSc                                                    ' ACR                                                                                                                                                                                                                                                                     
                       ' Morphea                                                ' ACR                       ' RA         ' ACR      ' SLE            ' ACR      ' FM   ' ACR      ' Sjögren\'s   ' ACR      ' Dermatomyositis   ' ACR      ' Polymyositis   ' ACR      ' Vasculitis   ' ACR      ' Ankylosing Spondylitis         ' Psoriatic Arthritis   
                       ' Arthritis Associated With Inflammatory Bowel Disease                                                                                                                                                                                                                                                                             
                       ' Polychondritis                                                                                                                                                                                                                                                                                                                   
                       ' Mixed Connective Tissue Disease                                                                                                                                                                                                                                                                                                  
                       ' Raynaud\'s Phenomenon                                                                                                                                                                                                                                                                                                            
                       ' Any Connective Tissue Disease (Combined Endpoint)                                                                                                                                                                                                                                                                                
                       ' Other                                                                              ' Other                                                                                                                                                                                                                                       
  **Implant**          ' Implant Type Unspecified                               ' Injection - Silicone                                                                                                                                                                                                                                                    
                       ' Silicone Gel Filled                                    ' Injection - Collagen      ' Saline                ' Double lumen                                                                                                                                                                                                        
                       ' Polyurethane coated                                                                                                                                                                                                                                                                                                              
  -------------------- -------------------------------------------------------- ------------------------ -- ------------ ------- -- ---------------- ------- -- ------ ------- -- -------------- ------- -- ------------------- ------- -- ---------------- ------- -- -------------- ------- -- -------------------------- -- -- ----------------------- --

**Comments: **
\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_

\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_

\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_

**Methodology**

Design: ' Prospective Cohort ' Retrospective Cohort

' Internal Cohort ' External Cohort

  --------------- ---------------------- ---------- --------------------- -------------------- ---------- --------------- -- --- ------------- -- --------------------- -- -- --------------------- -- ------------------------- ----- -- -- -- ----------------------- ----- -- -- -- ------------------------ ----- -- -- -- ------------------------ ----- -- --
                  Exposed                (Cohort)                         Unexposed                                                                                                                                                                                                                                                                              
  \# Identified                                                                                                                                                                                                                                                                                                                                                  
  (Describe)                                                                                                                                                                                                                                                                                                                                                     
  \# Excluded                                                                                                                                                                                                                                                                                                                                                    
  (Describe)                                                                                                                                                                                                                                                                                                                                                     
  Group N                                                                                      All S\'s                                                                                                                                                                                                                                                          
  Accounted ?                                                                                                                                                                                                                                                                                                                                                    
  Group                                                                                                                                                                                                                                                                                                                                                          
  Selection                                                                                                                                       Exposure:                                            Injections Excluded ' Y   ' N            Rupture Described ' Y   ' N            Explantation Desc. ' Y   ' N            Duration Described ' Y   ' N      
  Group           ' Direct Measurement              '                     Direct Measurement                                                                                                                                                                                                                                                                     
  Determination   ' Medical Records                 '                     Medical Records                 ' Self Report      '   Self Report      Blinding ' Yes ' No         Blinding ' Yes ' No                                                                                                                                                                
  Ascertainment   ' Direct Measurement              '                     Direct Measurement                                                                                                                                                                                                                                                                     
  of Outcome      ' Medical Records                 '                     Medical Records                 ' Self Report      '   Self Report                                                                                                                                                                                                                     
                  Blinding ' Yes ' No               Blinding ' Yes ' No                                                                                                                                                                                                                                                                                          
  Outcome                                                                                                                                                                                                                                                                                                                                                        
                                                                                                                                                                                                                                                                                                                                                                 
                                                                                                                                                                                                                                                                                                                                                                 
  --------------- ---------------------- ---------- --------------------- -------------------- ---------- --------------- -- --- ------------- -- --------------------- -- -- --------------------- -- ------------------------- ----- -- -- -- ----------------------- ----- -- -- -- ------------------------ ----- -- -- -- ------------------------ ----- -- --

**Subject Characteristics**

<table>
<tbody>
<tr class="odd">
<td><p><strong>Characteristic</strong></p></td>
<td><p><strong>Cohort</strong></p></td>
<td><p><strong>Exposed</strong></p></td>
<td><p><strong>Unexposed</strong></p></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
</tr>
<tr class="even">
<td><p>Age</p></td>
<td></td>
<td></td>
<td></td>
<td><p>SES (Define)</p></td>
<td></td>
<td></td>
<td></td>
<td><p>% Family History of</p>
<p>Disease</p></td>
<td></td>
<td></td>
<td></td>
<td><p>% Caucasian</p></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
</tr>
<tr class="odd">
<td><p>% Rupture</p></td>
<td></td>
<td></td>
<td></td>
<td><p>% Explantation</p></td>
<td></td>
<td></td>
<td></td>
<td><p>Yrs Since Implantation</p></td>
<td></td>
<td></td>
<td></td>
<td><p>% Reconstruction Due to</p>
<p>Breast Cancer</p></td>
<td></td>
<td></td>
<td></td>
<td><p>% Cosmetic</p></td>
<td></td>
<td></td>
<td></td>
<td><p>% Bilateral</p></td>
<td></td>
<td></td>
<td></td>
</tr>
<tr class="even">
<td><p>% Unilateral</p></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
</tr>
</tbody>
</table>

**Group Differences: **

Data Analysis: ' All subjects ' Loss to follow up excluded

  ------------- ------- --- --- ------ ------------ -------------- ----------------------- ----------------- -------------- -- -- -- -- ---------- ---------- -- --
  **Outcome**   **N**                  **Crude**    **Adjusted**   **Factors Adjusted **   **Translation**                                                       
  **and**                              **OR/RR **   **OR/RR**                                                **Exposure**               **(CI)**   **(CI)**      
  Outcome               D   D   T/PY                               ' Age                                                                                         
                                                                   ' Education                                                                                   
                E                                                  ' Income                                                                                      
                                                                   ' Marital Status                                                                              
  Exposure      E                                                  ' Race                                                                                        
                                                                   '                                                                                             
                T                                                  '                                                                                             
                                                                   '                                                                                             
  Outcome               D   D   T/Py                               ' Age                                                                                         
                                                                   ' Education                                                                                   
                E                                                  ' Income                                                                                      
                                                                   ' Marital Status                                                                              
  Exposure      E                                                  ' Race                                                                                        
                                                                   '                                                                                             
                T                                                  '                                                                                             
                                                                   '                                                                                             
  Outcome               D   D   T/Py                               ' Age                                                                                         
                                                                   ' Education                                                                                   
                E                                                  ' Income                                                                                      
                                                                   ' Marital Status                                                                              
  Exposure      E                                                  ' Race                                                                                        
                                                                   '                                                                                             
                T                                                  '                                                                                             
                                                                   '                                                                                             
  ------------- ------- --- --- ------ ------------ -------------- ----------------------- ----------------- -------------- -- -- -- -- ---------- ---------- -- --