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Post-mammoplasty connective tissue disease.

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694
POST-MAMMOPLASTY
CONNECTIVE TISSUE DISEASE
SHERYL A.
VAN
N U N E N , PAUL A. GATENBY, and ANTONY BASTEN
Three patients are described in whom autoimmune connective tissue disease developed within 2%
years after cosmetic mammary augmentation with silicone gel-filled, elastomer envelope-type prostheses.
Comparison is made with previously reported cases
concerning the complications after paraffin and processed petroleum were injected into the breast. Although
evidence for a causal relationship between the implantation and the development of connective tissue disease is
circumstantial, it is possible that these 3 patients represent examples of human adjuvant disease.
There have been a number of reports of the
occurrence of connective tissue disorders after injection of paraffin or processed petroleum into the breast
for cosmetic purposes (1-3). The clinical features were
not usually those of classic syndromes, although some
patients did develop systemic lupus erythematosus ( l ) ,
rheumatoid arthritis (2), and scleroderma (3). During a
3-year period, we have seen 3 patients with autoimmune connective tissue disorders, the onset of which
has been from 2 to 2% years after augmentation
mammoplasty with enclosed silicone gel in a silastic
envelope (Cronin-type prostheses) (4). The first patient has systemic lupus erythematosus; the second
has classic mixed connective tissue disease ( 5 ) ; the
third is considered to have rheumatoid arthritis with
From the Department of Clinical Immunology, Royal
Prince Alfred Hospital, Sydney, N.S.W., Australia.
Sheryl A. van Nunen, MBBS, FRACP: Clinical Immunology Registrar; Paul A. Gatenby, MBBS, PhD, FRACP, FRCPA: Staff
Specialist in Clinical Immunology; Antony Basten, MBBS, D Phil,
FRACP, FRCPA, FRCP: Professor of Immunology.
Address reprint requests to Dr. S. A. van Nunen, Department of Clinical Immunology, Royal Prince Alfred Hospital, Missenden Road, Camperdown, N.S.W. 2050, Australia.
Submitted for publication June 8, 1981; accepted in revised
form December 18, 1981.
Arthritis and Rheumatism, Vol. 25, No. 6 (June 1982)
Sjogren’s syndrome. The previous reports, together
with more recent concepts on the potential immunologic activity of silicone and its degradation products
(6), suggest that the association may well be more than
coincidental. Hopefully, a wider awareness of this
potential problem will lead to confirmation or refutation of the relationship.
CASE REPORTS
Patient 1. A 33-year-old white woman, who had
received uncomplicated bilateral augmentation mammoplasties 2% years earlier, was referred to our clinic with a 5month history of left-sided, pleuritic chest pain. She had
noted facial photosensitivity intermittently over the preceding year and arthralgia of 4 months’ duration that involved
the metacarpophalangeal and proximal interphalangeal
joints. She had had a second-trimester abortion just before
her visit.
Her general physical state was unremarkable. Breast
examination initially revealed uncomplicated mammary
prostheses, although subsequently intermittent tenderness
of the left breast-without periprosthetic thickening, but
accompanied by left axillary lymphadenopathy-developed.
Results of chest roentgenographic and routine biochemical
and hematologic studies were normal. Immunologic investigations are detailed in Table 1. The partial thromboplastin
time with kaolin was slightly elevated at 41 seconds (normal,
25-40), and a lupus anticoagulant was detected in the serum
(7). On the basis of the clinical and laboratory findings, a
diagnosis of systemic lupus erythematosus was made. Treatment with regular ibuprofen and short courses of up to 20 mg
prednisonelday has afforded adequate symptomatic relief for
the 3 years of observation.
Patient 2. A 31-year-old Chilean immigrant was seen
who had a 6-month history of up to 10 attacks daily of
Raynaud’s phenomenon. She had received bilateral mammary implants without complication at the time of surgery 2
years earlier. The symptoms of Raynaud’s phenomenon
were accompanied by arthralgia of the metacarpophalangeal
and proximal interphalangealjoints of both hands. She had
POST-MAMMOPLASTY CT DISEASE
695
noted dry eyes for 2 months and generalized swelling of her
fingers for 1 month. On examination, her fingers showed a
sausage-like appearance; the painful joints were tender.
Results of the Allan test were normal on both sides, but
provoked an attack of Raynaud's phenomenon. She had
abnormal results on a Schirmer test, with tear production of
0 mm in the right eye, and 3 mm in the left eye; however. slit
lamp examination was normal. Decreased salivary pooling
was noted. Breast examination revealed bilateral uncomplicated mammoplasties. Roentgenograms of the chest and
hands showed normal structures. and results of routine
hematologic and biochemical tests were normal. Immunologic studies are shown in Table 1. Labial salivary gland
biopsy disclosed a minor degree of lymphocytic infiltrate
consistent with Sjogren's syndrome.
The patient was considered to have mixed connective tissue disease. After a 6-week course of prednisone in
decremental dosages that began at 30 mg daily, her sicca
symptoms and arthralgia abated. The arthralgia is now well
controlled on naproxen, 250 mg twice daily; the Kaynaud's
symptoms require nicotinic acid and phenoxybenzamine
hydrochloride for symptomatic relief.
Patient 3. A 44-year-old white woman was referred
for assessment after she was admitted for a severe episode of
Raynaud's phenomenon that had resolved spontaneously.
She had received bilateral mammoplasties without complication 2 years earlier. For the 12 months before admission, she
had suffered from Raynaud's phenomenon; arthritis of the
left knee, left elbow, and right wrist; dry eyes and mouth.
Physical examination revealed active synovitis involving both temporomandibular joints as well as those
symptomatic peripheral joints referred to above. Effusions
were present in the left knee and elbow. Bilateral wasting of
the dorsal interossei was noted. Allan test results were
normal. Schirmer tests showed subnormal tear production in
both eyes, and punctate ulceration of the conjunctivae was
seen on slit lamp examination. Breast examination disclosed
no problems with the mammary implants.
Roentgenography of the involved joints showed a
decrease in lateral joint space in the left knee and reduction
in the joint space of both temporomandibular joints. The
hands appeared radiologically normal. The erythrocyte sedimentation rate was 60 mm/hr, and rheumatoid factor (latex
fixation test) was present at a titer of 1 :80 in the serum and
1 : 160 in the joint fluid. Labial gland biopsy demonstrated 3
minor salivary glands infiltrated with plasma cells and lymphocytes. A protein EPG disclosed a paraprotein of 15 gm/
liter, which, on immunoelectrophoresis, proved to be of
IgG-lambda type. However, no evidence of a plasma cell
dyscrasia was found on full skeletal survey or bone marrow
aspiration. A diagnosis was therefore made of a benign.
monoclonal gammopathy in association with a connective
tissue disorder that had the features of early rheumatoid
arthritis complicated by Sjogren's syndrome.
The patient was initially treated with artificial tears
and a 2-month course of prednisone. Complete relief of joint
symptoms occurred and was subsequently maintained by
250 mg penicillamine daily.
Table 1. Immunologic investigations performed before therapy on 3 patients with post-mammoplasty
connective tissue disease*
Laboratory tests
-
Fluorescent antinuclear
antibody
Cryocrit
Immunoglobulins (mg/dl)
IgG (normal = 740-1,400)
IgA (normal = 40-300)
IgM (normal = 60-200)
Delayed hypersensitivity
skin tests
Intradermal silicone skin tests
T cells (normal = 6 7 4 3 % )
B cells (normal = 9-19%)
T y cells (normal = 13-22%)
HLA typing
-
~
Patient 2
Patient 3
1:loo
I : 1oo,oO0
(homogeneous
and speckled)
8
I :50
(homogeneous
and speckled)
2
(homogeneous)
D N A antibodies
(KIA Amersham, normal
<25 unitslm1)f
RNP antibodies
RF latex
C3 (normal =: 55-1 10 mg/dl)
C4 (normal =: 20-50 mg/dl)
Immune complexes
(Clq binding assay)
Cryoglobulins
Type
~~
Patient 1
~
* - := negative; + = positive.
t RIA = rddioimmunoassay.
34
-
+
-
I37
1 :80
108
10
24
Not elevated
Not elevated
33
Not elevated
1:80
99
Mixed
pol yclonal
4%
Mixed
pol yclonal
-
1%
-
377
Normal
2,053
108
246
Normal
2.063
133
184
Normal
71
9
14
A3,29,B8,14,
DR3.-
61
8
7
A3.25,B 18.49.
DR2.DK3
70
17
21
A2,26.B35.DK5
2.065
151
.-
VAN NUNEN ET AL
696
Special investigations. A number of immunologic investigations were performed for all 3 patients (Table I ) .
Immune complexes were estimated by a Clq binding assay
(8) but were not elevated, despite suggestive evidence from
the rheumatoid factor and cryoglobulin assays. Delayed
hypersensitivity skin tests were performed with t h e following battery of antigens: streptokinase, 5 units; streptodornase, 1.25 units; mumps, purified protein derivative, 10
tuberculin units; candida, 1 :30; trichophytin, I : 100. Each
antigen was injected intradermally in a volume of 0.1 ml and
read at 48 hours. A normal delayed hypersensitivity response was defined as a >S-mm reaction (induration) to 2 or
more antigens (9). No patient showed any immediate or
delayed response when tested intradermally with 0.1 ml of
undiluted silicone gel. The numbers and proportions of T
cells and B cells were measured by E rosettes and surface Ig
labeling, respectively. The proportion of T cells bearing Fcy
receptors was estimated by the method of Moretta et a1 (10).
One patient had a minor reduction in this T cell subset; the
other 2 patients had values within the normal range. Ribonucleoprotein antibody was detected by the counterimmunoelectrophoresis method of Kumata and Tan ( I I ) . Serum was
examined for the presence of lupus-type anticoagulant activity, as described by Exner et al (7).
DISCUSSION
Early forms of cosmetic mammary augmentation involved direct instillation of paraffin and processed petroleum into the breast. After 1950, these
materials were supplanted by the organosilicon polymers, which may be synthesized as liquids, gels, or
rubber-like (elastomer) products (12).
Injection of paraffin and processed petroleum,
and silicone in the liquid form, were frequently associated with local, often intense, inflammatory reactions
(13). Consequently, their usage was largely discontinued; at present, enclosed saline or gel-filled silicone
elastomer envelopes, including those of the Cronin
type (41, are preferred. Although these implants are
associated with local inflammation (14-16), intense
reactions are comparatively infrequent.
In addition to local reactions, a number of
reports suggest that exposure to paraffin or processed
petroleum (1-3) and to silicone (17) may result in a
more generalized tissue response, possibly immunologic in nature. Thus, 9 patients have been described
since 1972 with connective tissue disease, the onset of
which occurred from 7 to 19 years after instillation of
these substances (1-3). In the majority of instances,
histopathologic evidence of local inflammation and
granuloma formation was found in the implantation
site ( 3 ) .
The 3 patients described in this report developed symptoms of connective tissue disease (mixed
connective tissue disease, rheumatoid arthritis with
Sjogren’s syndrome, and systemic lupus erythemato-
sus) within 2% years after silicone gel-filled, elastomer, envelope-type prostheses were inserted. The first
patient may have had a late local reaction to the
prosthesis in the left breast, but the other 2 patients
had no clinical signs of local inflammation, either at
the time of their operation or later. The occurrence of
Sjogren’s syndrome has not been documented previously, and this may therefore represent a new finding.
Elastorneric silicone has been used extensively
in the production of artificial heart valves, prosthetic
finger joints, arteriovenous shunts for dialysis patients, and ventricular shunts for hydrocephalics (18).
Furthermore, certain cardiac pacemakers incorporate
a form of silicone that vulcanizes at body temperature.
To date, however, there have been no reports of cases
of connective tissue disease after implantation of such
materials. Nor has an exacerbation of preexisting
disease of this kind been recorded. to our knowledge.
Although the time between implantation and onset of
disease was considerably less in our cases than in
previously described ones, the association may be
fortuitous. Nevertheless, the frequency with which the
procedure is performed would seem to justify reporting 3 further instances of connective tissue disease,
particularly since silicone or its products of degradation are known to exert significant effects on the
immune system (vide infra). Despite being informed of
a possible association between their disease and the
implants, none of our patients would submit to reversal of their mammoplasties.
Why the possible association between silicone
implants and connective tissue disease seems limited
to mammoplasties is unclear. The higher frequency of
usage of implants for many purposes other than mammary augmentation (18) makes it very unlikely that
this discrepancy is caused by a failure to detect a
significant association with connective tissue disease.
Conversely. it is conceivable that the form (i.e., the
gel-filled implant) and the amount of silicone used in
mammary implants may be significant contributing
factors. Thus, silicone has been detected in the tissues
surrounding a prosthesis, where it is thought to accumulate secondary to minor leaks or by the process of
“silicone sweat” (19) through the envelope enclosing
the prosthesis. The existence of a large deposit of
material could therefore lead to persistent slow leakage of potentially antigenic material (6), both locally
and into the lymphoid tissue draining the prosthesis.
In the present cases, no evidence for antigenicity was obtained by skin testing, although this
procedure is somewhat crude and does not necessarily
exclude an adjuvant effect by the silicone in native or
POST-MAMMOPLASTY CT DISEASE
altered form. Another way that silicone could provoke
an autoimmune response is by converting to silica (20).
which is known t o exert profound effects on the
immune system (21,22), including the development of
autoantibodies and connective tissue diseases such a s
scleroderma (23) a n d systemic lupus erythematosus
(24). Taken together, these findings provide a rational
basis for an association between mammary implants
and connective tissue disease. Nevertheless, the rarity
of this association could b e regarded as evidence for
the existence of additional susceptibility factorspossibly of host origin-required for the development
of overt disease (25). The nature of such factors
remains t o b e established but could, by analogy with
other immunopathologic disease, include disease susceptibility genes linked t o the major histocompatibility
complex. In view of the small number of cases
involved, t h e lack of a linkage with a particular
HLA haplotype in o u r report d o e s not exclude this
possibility.
It seems reasonable then t o suggest that silicone
gel-filled mammary implants could precipitate connective tissue disease in a susceptible host. T h u s , the
patients described here may represent further examples of human adjuvant disease.
ACKNOWLEDGMENTS
The authors are grateful to Dr. M. Stephen and Dr.
B. A. Frith, who referred 2 of the patients; to the laboratory
staff in the Immunology Department, who performed many
of the investigations; and to Lindsay Gatenby and Judy
Bonnefin, who typed the manuscript.
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