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Association of Silicone Breast Implants, Breast Cancer and Anti-RNA Polymerase III Autoantibodies in Systemic Sclerosis: Case-Based Review

Authors De Angelis R , Di Battista J , Smerilli G , Cipolletta E, Di Carlo M , Salaffi F 

Received 19 May 2020

Accepted for publication 9 July 2020

Published 21 September 2020 Volume 2020:12 Pages 207—213

DOI https://doi.org/10.2147/OARRR.S262428

Checked for plagiarism Yes

Review by Single anonymous peer review

Peer reviewer comments 3

Editor who approved publication: Professor Chuan-Ju Liu



Rossella De Angelis, Jacopo Di Battista, Gianluca Smerilli, Edoardo Cipolletta, Marco Di Carlo, Fausto Salaffi

Rheumatology Clinic, Department of Clinical and Molecular Sciences, Marche Polytechnic University, Jesi, Ancona, Italy

Correspondence: Rossella De Angelis
Rheumatology Clinic, “Carlo Urbani” Hospital, Jesi, Ancona 60035, Italy
Email [email protected]

Abstract: Some case reports and small case series of patients with silicone breast implant (SBI) have reported the development of systemic sclerosis (SSc) many years later, despite conflicting evidence of this association in the literature. Recently, patients with SSc and anti-RNA polymerase III antibodies positivity have been associated with previous silicone implants and/or breast cancer, showing clinical features that differ from the classic SSc, such as rapid and diffuse cutaneous involvement and scleroderma renal crisis (SRC). The specific autoimmune reaction is not yet fully understood, although knowledge in this regard is increasing. We describe a case that can support these previous observations, strengthening this association which must be taken into account. Clinicians should be aware of this new clinical entity, given the widespread use of silicone implants.

Keywords: systemic sclerosis, silicone breast implant, anti-RNA polymerase III antibodies, cancer

Introduction

Systemic sclerosis (SSc) is a complex, chronic autoimmune disease, affecting skin and various internal organs, whose pathogenesis appears to be attributable to genetic and environmental factors.15 It focuses on microvasculature and cells involved in synthesizing components of connective tissue, such as fibroblasts, and those responsible for innate and adaptive immune response, leading to small vessels damage and abnormal collagen overproduction.4

Exposure to various environmental factors such as polyvinyl chloride and silica has been thought to play a role in the development of the disease.3,6 Therefore, silicone breast implants (SBI) have been suggested as a cause for a range of autoimmune diseases including SSc, even if a definite relationship between the two conditions has not yet been conclusively proven,69 mostly due to a lack of consistent estimates and adequate adjustment for potential confounders.3,7 However, research among the literature reveals several SSc case reports following SBI.7,1014

The SSc-related autoantibodies that are detectable with commercially available enzyme-linked immunosorbent assay kits (ELISAs) are anti-topoisomerase I (Topo-I), anti-centromere antibody (ACA) and anti-RNA polymerase III (RNAP III).15 SSc patients with RNAP III positivity are thought to be associated with diffuse cutaneous involvement, renal crisis and malignancies concomitant to SSc onset,16 particularly breast cancer.16,17

More recently, a higher frequency of anti-RNAP III antibody in patients with SBI history than in patients with anti-Topo-I antibody or ACA was noted.15 Since the measurement kit of the anti-RNAP III antibody was not commercially available until recently, it is possible that the association of this antibody with SBI has not been sufficiently valued and is currently underestimated.

Herein, we report a patient who developed SSc several years after the diagnosis of breast cancer and subsequent silicone implants, found to be positive for anti-RNAP III antibodies.

Case Presentation

A 54-year-old woman was admitted to our hospital on April 2018 with a seven-month history of swelling and skin thickening of both hands and forearms (Figure 1), and arthralgia. She had no Raynaud’s phenomenon (RP), digital tip ulcers, pitting scars, dysphagia, and dyspnea or sicca syndrome. Physical examination showed an afebrile patient, without synovitis or lung crackles. Her modified Rodnan’s total skin thickness score (MRSS) was 12. Her history disclosed left breast intraductal comedonic-type carcinoma diagnosed in 2002 (p53 positive, estrogen receptor negative, progesterone receptor negative, erbB2 negative), TNM classification (extension, lymph node involvement and metastasis): pT1a, pN1mi, pMx. She underwent left mastectomy with lymph node resection and subsequent textured bilateral silicone breast implant (SBI). From January to April 2003, she went through chemotherapy treatment according to the FEC regimen (90) given once every three weeks for six cycles (5-fluorouracil 600 mg/mq - epirubicin 90 mg/mq- cyclophosphamide 600 mg/mq). No rupture of SBI was demonstrated by Magnetic Resonance Imaging – MRI (last exam performed in May 2017). Last breast ultrasound assessment revealed mild signs of capsulitis surrounding the left implant. Detailed autoantibodies analysis showed positivity of the anti-nuclear antibodies (ANA, 1:640 titer, granular pattern, indirect immunofluorescence assay) and anti-RNAP III antibodies (>70 index score [normal range, 0–7], fluorescence enzyme immune assay-FEIA) but not in otheranti-extractable nuclear antigens (ENA) and anti-dsDNA antibodies. Rheumatoid factor (RF) and anti-citrullinated protein antibodies (ACPA) were negative as well. Nailfold videocapillaroscopy revealed a typical scleroderma pattern with prominent disorganization of the microvascular structure, neoangiogenesis and well detectable areas without capillaries (Figure 2). A diagnostic workup (chest high-resolution computed tomography-HRCT and abdomen ultrasound) for possible underlying neoplasm was negative. These clinical, laboratory and instrumental findings led to the diagnosis of anti-RNAP III antibody-positive SSc with exclusive skin involvement. Initially treated with low-dose prednisone (5 mg/day) and methotrexate (MTX) 10 mg/weekly, the patient’s condition rapidly worsened. Clinical evaluation showed diffuse cutaneous involvement with further centripetal progression involving the forearms, thighs and chest with no signs of pulmonary or cardiac disease. On December 2018, the patient developed severe pruritus, melanodermia and joint contractures due to skin traction. Laboratory tests showed persistence of ANA positivity (1:640 granular/nucleolar pattern, indirect immunofluorescence assay) with an increased title of anti-RNAP III (123 U/mL, fluorescent enzyme immune assay-FEIA). No abnormal findings could be detected by chest HRCT, pulmonary function tests (PFTs) and diffusion lung CO. MTX was stopped and infusion with iloprost was started for seven days in association with mycophenolate mofetil (1.5 g/day). Low-dose prednisolone (10 mg⁄day) was employed for her painful edema and sclerosis. The patient experienced slowly progressive subjective improvement, with decreased pruritus, arthralgia and stiffness, and improvement of mRSS 26->20. The titer of anti-RNAP III decreased (123 ->90 IU/mL, fluorescent enzyme immunoassay-FEIA). ANA positivity remained (1:1280 speckled, indirect immunofluorescence assay). The provisional Composite Response Index for early diffuse cutaneous SSc (CRISS), based on the modified Rodnan skin thickness score, patient and physician global assessments and the Health Assessment Questionnaire disability index, showed that the patient had improved since the start of combination therapy with iloprost, mycophenolate mofetil and prednisone.

Figure 1 Hands’ photograph of the 54-year-old woman shows thickening of the skin, flexion contractures of the interphalangeal joints and oedema.

Figure 2 Nailfold capillaroscopy (200 x magnification): Capillary abnormalities revealing a “scleroderma pattern”: (A and B) architectural derangement with bushing and enlarged capillaries, (C) microaneurysms and (D) loss of capillaries.

Patient’s written consent was obtained on October 3rd, 2019, according to international ethical guidelines, for details to be used in the manuscript. Institutional approval was not required to publish.

Discussion

So far, seven cases with SSc, anti-RNAP III and SBI have been described,15,1820 and are summarized in Table 1. All were women, mostly with diffuse disease. Two cases with scleroderma renal crisis (SRC) have been observed, one of them following SBI rupture. Two cases (including the present) have a previous history of breast cancer. The median time from implant to symptoms onset for all cases was 18.0 years. Amongst organ involvement, three-sevenths had interstitial lung disease (ILD), one gastrointestinal (GI) involvement. Other clinical manifestations were Raynaud’s phenomenon (RP), pleural effusion and arthritis.

Incidence and Prevalence of SSc After SBI Exposure

In the past few decades, there has been a growing body of evidence linking SBIs to autoimmunity, although this issue has generated considerable controversy ranging from veiled criticism to substantial denial that SBIs can be associated with health-damaging outcomes.1,21,22 However, a large patient-reported study of breast implant outcomes found an increased risk of certain rare harms, including autoimmune diseases such as SSc,5 and a real-world analysis physician-made demonstrated a significant association between having SBI and an increased risk to be diagnosed with autoimmune/rheumatic disorders, also SSc (OR>1.5, p<0.05) (2). In the light of these data, the debate has re-opened.2,5 It should be noted that this condition falls into the so-called “ASIA” (Autoimmune/inflammatory Syndrome Induced by Adjuvants) syndrome, systematically described by Shoenfeld and Agmon-Levin, who proposed provisional diagnostic criteria.23

Focusing particularly on SBI and SSc, six meta-analyses3,8,9,21,24,25 were reported in the medical literature. Perkins et al24 included 13 epidemiology studies and provided a relative risk (RR) estimate for the possible association between SBI and CTDs. The meta-analysis summary RR was 0.76 for CTD in general (95% confidence interval [CI]: 0.55, 1.04; homogeneity p-value = 0.073) and was 0.98 for SSc (95% CI: 0.57, 1.64; homogeneity p = 0.006). Regardless of the studies aggregated in this meta-analysis, no significant increase in scleroderma risk was found.

Hochberg et al25 limited examination to the three case-control studies, which specifically addressed the hypothesis relative to SSc. They found a pooled crude odds ratio of 1.07 (95% CI: 0.60, 1.89), and a pooled adjusted odds ratio of 1.04 (95% CI: 0.58, 1.88), concluding that there is no evidence of a significant association between SBI and the development of SSc.

Wong et al, based on data from case-control studies, representing a combined database of approximately 4000 cases of connective tissue disease, found a relative risk (95% confidence intervals) of 0.82 (0.50–1.35) for SSc, indicating that there was no increased risk associated with SBI.8

Whorton et al included a qualitative review of the epidemiologic studies and a quantitative summary (meta-analysis) of the case-control studies. Neither the case-control studies, nor the other epidemiologic data support the hypothesis that SSc is associated with or causally related to breast implants.9 Janowsky et al found no evidence of an association between breast implants in general, or silicone gel-filled breast implants specifically, and any of the individual connective tissue diseases, all definite connective-tissue diseases combined, or other autoimmune or rheumatic conditions. In particular, the relative risk for SSc was 1.01 (95% confidence interval, 0.59 to 1.73).21 Finally, the meta-analysis of Rubio Rivas included four case-control studies overall OR 1.68 (95% CI 1.65–1.71; p < 0.001) and six cohort studies overall RR 2.13 (95% CI 0.86–5.27; p = 0.10). This study, unlike the previous ones, has notably shown that a potential role of SBI inducing SSc cannot be excluded, as results achieved statistical significance when analyzing case-control studies.3

Mechanisms of Autoimmune Reaction

After being introduced in 1962, SBIs have been surgically implanted in millions of women, mainly for cosmetic purposes, with a percentage of up to about 30% used as part of breast reconstructions after mastectomy.26 Silicone implants were initially considered biologically inert, but nowadays that concept is outdated, as various silicone-induced immunological effects have been reported.1,2 Silicone gel can migrate from the outer shell after implant failure, but, very importantly, the so-called “bleed gel”, which is the migration of material through the “intact” prosthesis, has been demonstrated.1 In this view, Bekerecioglu et al looked at the capsular tissue around silicone implants in asymptomatic patients, finding significantly higher concentrations of immunoglobulins (IgG and IgM) as well as anti-silicone antibodies in tissues.27

There are various mechanisms by which SBI induce autoimmune reactions, including dysregulation of the innate as well as adaptive immunity in genetically susceptible individuals. Macrophages capable of trapping silicone-containing particles have been shown to induce the release of IL-1b, activate inflammasome and B cells, thus generating an imbalance of regulatory T-cells, response T-cells and the T-helper 17 subpopulation.2,28,29

It should be noted that the cellular immune response directed against collagen (type I and III), fibronectin and fibrinogen was found to occur more frequently and intensely in women with SBIs,30 and it should be emphasized that ANAs and a variety of other antibodies were detected in SBI recipients.31

Focusing on the autoimmune reaction to the RNAP III antigen, the triggering mechanisms have not yet been fully clarified. RNAP III is a cytosolic DNA sensor involved in innate immune responses, able to recognize external cytosolic dsDNA such as bacteria and viruses, and then modify it into dsRNA. Through other steps, the nuclear factor – jB and the response paths of interferon type I can be activated.32

Taken together, it is assumed that chronic inflammation induced by innate immune response to adjuvants could aberrantly activate RNAP III and break immune tolerance, leading to the production of autoantibody to RNAP III antigen.15 In most of the cases, supporting this idea, chronic inflammatory signs were seen in computed tomography, such as calcifications around SBI [Saigusa] or capsulitis (present case), so the evidence for a causal effect between SBI and autoimmunity is still being accumulate.2,4 Silicone adjuvant action may be enhanced after rupture, facilitating this chain of events.18

Breast Cancer, SSc and RNAP III

The incidence of breast cancer in SSc patients is extremely variable and discordant when referring to the literature data. Discrepancies are related to study methods and heterogeneity among the studied populations.4

Indeed, several case series and/or retrospective cohort studies describe a short delay between breast cancer and SSc diagnosis in a subgroup of patients.4,17,3336 A significant proportion of patients (61.4%) are diagnosed with cancer between one year before and one year after SSc diagnosis.34 In the study by Colaci et al, the median time between these two conditions was 2.5 years.35 The percentage of women with breast cancer diagnosis synchronous to the onset of SSc was found to be 6.0% (95% CI 3.0–12.0) in a cohort of patients with SSc and malignancy.16

These findings might suggest common pathogenesis pathways between these two diseases,4,37 involving both the female susceptibility and the influence of the same hormonal factors.4

In general, the frequency of solid tumors in anti-RNAP III patients is higher than in controls (p = 0.012), particularly for breast cancers (p = 0.03) (16).

The temporal relationship between the diagnosis of SSc with specific autoantibodies RNAP III patients and breast cancer17,38,39 is confirmed by other studies,36,40 suggesting this subtype of SSc as a paraneoplastic disease with a common underlying mechanism with cancer.4,16,17 To support the paraneoplastic genesis, a specific nucleolar expression of RNAP III was observed in the malignant cells from these patients, signifying a link between cancer-related autoantigen and autoimmune response.41 Interestingly, other authors found that the polymerase III polypeptide A (POLR3A) locus is genetically altered in six of eight patients’ cancers, including breast cancers, with antibodies to RNAP III, but not in other SSc patients, bringing further hypotheses to support the close link between the two conditions.42

Therefore, due to this close temporal relationship, a malignancy screening at the time of diagnosis for anti-RNAP III patients with SSc is recommended.16

Our case, together with the one described by Saigusa,15 given the late-onset of SSc with respect to the diagnosis of breast cancer, along with the absence in the literature of such long sequence, cannot be ascribed to a paraneoplastic syndrome.

Clinical Characteristics

The largest population study from the EUSTAR registry found that anti-RNAP III in SSc patients were associated in multivariable analysis with renal crisis and diffuse cutaneous involvement,16 confirming other studies about the clinical characterization of SSc with anti-RNAP III patients, which is commonly associated with rapidly progressive skin fibrosis43 and renal involvement.18 No association was found relating to RP, gastrointestinal (GI) involvement, lung fibrosis on plain radiographs and HRCT.16

In our reviewed case-series, patients did not develop RP during the clinical course of the disease, except those with SRC (Table 1). Three-eighths patients had interstitial lung disease (ILD), and two with pleural effusion. The number of cases described is limited in order to establish why only a few developed lung involvement, and it is therefore difficult to draw conclusions. Nevertheless, it is interesting to argue about SRC, which has been found to be significantly associated with the presence of anti-RNAP III in SSc in a large data-base,16 and appears to be related to rapid disease progression. This scenario might reinforce the characterization of anti-RNAP III as markers of an SSc subset particularly prone to microangiopathic complications.16

Table 1 Summary of Literature Reported Cases of Systemic Sclerosis (SSc), Anti-RNAP and Silicone Breast Implant (SBI)

Finally, there is no conclusive evidence of health status improvement in SSc women after replacement or removal of SBIs.18,44 It should be noted, however, that some authors observed a significant relief from systemic symptoms in approximately 75% of SBI recipients after explantation (45), but this appears to be successful when explantation is combined with immunosuppressive therapy (45). Inclusion of silicone particles from surrounding tissues could explain why explantation alone is not successful in all patients (45). On this issue, there is a need for more research.

Conclusions

So far, the relationship between SBI and SSc appearance with the above-mentioned characteristics may have been missed because: (i) RNAP III antibody testing was not commercially available until recently, and (ii) it took more than 20 years for the development of SSc after SBI in most of the described cases. Studies including subjects with at least a 10–15-year follow-up should be adequately designed in the future to avoid an underestimation of risk.44,45 As previously pointed out, SBI could influence the development of SSc in a certain subset of patients with anti-RNAP III, which seems to be a peculiar property of this antibody.15 Given the widespread use of silicone implants, along with the advance in implant technology, it is important to be aware of this clinical entity over time.46 We emphasize the recommendation to search for the autoantibody profile in each patient undergoing silicone implant surgery, to learn some of the possible prognostic factors relating to their health or pathologic status. With RNAP III antibodies, the opportunity for SBI especially for cosmetic reasons must be carefully considered.

Disclosure

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. The authors report no conflicts of interest for this work.

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