The limited number of studies of serum proteins and paraproteins in women with silicone implants, and the lack of a controlled study taking into account CTD as an additional possible risk factor for serum protein abnormalities, prompted this case–controlled investigation. Paraproteinemia is most often associated with MGUS, which in turn may be a precursor of MM, macroglobulinemia, amyloidosis, or related diseases [21
]. Subjects with MGUS often have autoantibodies [22
] or autoimmune manifestations [23
], and subjects with rheumatic diseases are reported to have higher rates of MGUS [15
]. A critical aspect of our case–control study design was therefore to match subjects not only by age, but also by CTD diagnosis to minimize possible confounding. We also used highly sensitive agarose gel electrophoretic and immunofixation electrophoresis methods to maximize detection of serum paraproteins. Because it is possible that FMS patients may differ from inflammatory CTD in the risk of paraproteinemia, we analyzed the women in each group without FMS and found that excluding them does not alter the primary findings of the study.
Although serum paraproteins occurred somewhat more frequently in our study of 74 women with CTD and silicone implants compared with those having CTD without silicone implants (9.5% versus 5.4%), the difference was not statistically significant. Furthermore, since all paraproteins occurred at very low serum concentrations (≤1 g/l), our cases probably represent MGUS [24
]. Without additional testing (including bone marrow biopsy, urinary free light-chain assessment, chromosomal studies, and bone surveys) and without follow-up regarding the persistence of paraprotein bands [21
], we could not completely rule out an ongoing malignant process. Nevertheless, none of the subjects reported progression to MM or other hematologic malignancies for up to 2 years after study enrollment. Overall, our findings do not support a major role for silicone implants in inducing monoclonal gammopathies in humans and are consistent with conclusions of prior investigations of silicone implants and MGUS [13
] or MM [29
We observed higher prevalence of paraproteinemia in women with CTD both with and without silicone implants (8.0% and 4.5%, respectively) than those reported for similarly aged women with any type of breast implants (1.4–1.7%) in one study [14
]. Our prevalence rates of paraproteinemia, however, were lower than those reported by the same authors for similarly aged women with breast implants (10.4–15.8%) in another study [16
]. MGUS is known to increase in prevalence with age, but our observed prevalence rates are higher than those reported in the literature for 'healthy' adult subjects/populations with ages up to the 70 s (0.5–3.0%) [32
]. Our finding of three to five times higher prevalence of serum paraproteins over those expected for our age group in the case–control study is, in part, probably related to the combined use of both a highly sensitive protein stain and highly sensitive immunofixation electrophoresis. Using similar analytical methods (Helena agarose electrophoresis and Sebia immunofixation electrophoresis), Kyle and colleagues [35
] recently reported a relatively high (3.2%) prevalence of MGUS in a population-based study of 21,463 subjects ≥50 years of age. The age-adjusted rates of MGUS were significantly higher in men than in women (4.0% versus 2.7%) and the prevalence of MGUS increased with age to 5.3% in subjects ≥70 years old. Since these rates are approximately twice that observed earlier, they suggest that the screening methods used in many previous studies were less sensitive than current techniques [35
]. In addition to using highly sensitive detection techniques, the high prevalence of paraproteinemia in our study may also be related to the reportedly high prevalence (~3–6%) of paraproteins in subjects with CTD [15
] and the relatively high prevalence of CTD (6%) in subjects with MGUS [22
]. Regardless of silicone implant exposure, all of our newly identified paraproteinemia cases occurred in women with CTD, resulting in an overall 7.4% prevalence in this group (13/176).
While the total number of cases with paraproteinemia was small in our study, we also observed biclonal cases more often (15% or two out of 13 paraproteinemia cases) than expected from previous investigations in the general population (~2% of MGUS cases) [31
]. Interestingly, both of our biclonal cases occurred in myositis subjects with no silicone implants. The distribution of heavy chain types of the serum paraproteins identified in our study for women with silicone implants and CTD in all 13 cases combined was similar to that we found in women with silicone implants, CTD, and previously diagnosed paraproteins, and similar to that in those described in earlier MGUS case series (71–73% versus 83% for IgG, and 11–14% versus 17% IgM in our population) [13
]. We found no IgA paraprotein (0% versus 11–14% in earlier reports for MGUS [31
]) but this may be due to our comparatively small sample size.
The etiology of MGUS and MM is poorly understood, but case reports and epidemiological studies have shown an increasedassociation with chronic inflammatory conditions [12
]. Autonomous growth with clonal B-cell expansion and selection mediated by chronic antigen stimulation have been hypothesized to contribute to the development of MM. Silicone has been reported to trigger a variety of inflammatory and immunological (both humoral and cellular) responses in humans [39
] and experimental animals [43
]. Experimentally, plasma cell tumors (peritoneal plasmacytomas) could be induced in up to 80% of genetically susceptible mice with intraperitoneal injection of silicone gels and oils [9
]. It is unlikely that our inability to detect significantly increased numbers of paraproteinemia cases in conjunction with prior silicone implants in women with CTD was related to inadequate exposure to silicone. The 15.4-year mean duration of silicone implant exposure (median 15.8 years, range 0.9–31.3 years) in our case–control study approached the exposure time of women with previously diagnosed CTD and MGUS/MM (mean 17.4 years, median 16.8 years, range 10.2–29.0 years), and both groups had a high rate of implant rupture or leak (≥52% and ≥71%, respectively).
Unexpected findings were the significantly lower serum total protein and α1
-globulin, β-globulin, γ-globulin, and IgG levels in those with silicone implants compared with those without silicone implants, in both the presence and absence of CTD. We have found no comprehensive study of the serum protein profile in silicone implants subjects in the literature, and the results reported for selected serum proteins and/or protein fractions are conflicting. Hypergammaglobulinemia has been reported in both women with silicone implants [11
] and in mouse models of silicone exposure [9
]. In contrast, the total gammaglobulin levels in 2,721 consecutive women with silicone implants [47
], and the IgG, IgA and IgM levels in 156 women with silicone implants and rheumatic disease complaints [48
], were found to be normal. Furthermore, the proportions of increased or decreased IgG, IgA, and IgM levels between well-matched groups of 298 'healthy' women with and without breast implants were similar in the Women's Health Study [14
]. Our findings of lower γ-globulin and immunoglobulin levels in women with silicone implants compared with those in women without implants are thus at variance with these earlier observations. Since all serum globulin fractions tended to be lower with silicone implant exposure in both subjects with various CTD and in healthy subjects, CTD is an unlikely contributor. The etiology of this possible effect of silicone implants remains unclear and requires further study.
Limitations of our study include comparatively small sample sizes, heterogeneity of women regarding the type and length of their silicone implant exposure and CTD diagnoses, lack of quantitative information regarding markers of autoimmune diseases, incomplete information regarding possible treatment effects (type and dose of medications), lack of data for the possible presence of abnormal urinary free light chains, unavailability of bone marrow studies, and lack of extended follow-up regarding the possible development of additional paraproteins and/or possible conversion into MM.