Introduction

Silicone breast implants have been a powerful tool in both cosmetic and reconstructive surgery since the 1960s. Thus far, silicone implants have been considered safe, with accepted known risks.^1,2 However, media and social awareness are now fuelling growing scepticism about the safety of silicone breast implants. Over the past 20 years, there has been an increasing pool of literature proposing a link between silicone implants and autoimmune-related symptoms³ known colloquially as breast implant illness (BII). This association was reported as early as 1964 by Miyoshi and colleagues⁴ and has various names including human adjuvant disease, silicone implant incompatibility syndrome and, more recently, autoimmune inflammatory syndrome induced by adjuvants (ASIA).⁵

Currently, BII is not a defined disease and has no established diagnostic criteria or widely accepted treatment options. A recent article by Rohrich and colleagues⁶ reviewed the safety of silicone breast implants, while Magnusson and colleagues have analysed the scientific validity of BII.⁷ This supplementary review provides clinicians with available and relevant information to form a framework for discussing the evidence behind the diagnosis, investigation and management of patients who present with symptoms of BII.

Methods

We performed a literature search using MEDLINE®, the Cochrane Database of Systematic Reviews, the Cochrane Central Register of Controlled Trials (CENTRAL), the Database of Abstracts of Reviews of Effect (DARE) and Pubmed in September 2018. The search terms ‘autoimmune inflammatory syndrome induced by adjuvants’, ‘breast implants’ and ‘silicone’ were used alone and in combination.

Articles were excluded if they did not specifically focus on the potential relationship between silicone breast implants and symptoms of an undefined autoimmune disorder. Also excluded were articles that focused on well-defined autoimmune or connective tissue diseases, those that focused on silicone in medical devices other than breast implants, those pertaining to breast malignancies and non-English language papers. Further, additional citations were solicited from references in the selected articles.

Results

A total of 110 studies were screened and assessed for eligibility, of which 34 are included in this review. These studies were published between 1987 and 2017. They include three case reports, 12 case series, 14 retrospective cohort studies, four case control studies and one prospective cohort study (Table 1). Eighteen studies were found regarding the explantation of implants relating to ASIA or other defined autoimmune diseases. Of these, there were three case reports, five cases series, eight retrospective cohort studies and two prospective cohort studies (Table 2).

Discussion

Polydimethylsiloxane (PDMS) is the basic material of breast implants and is part of the family of polyorganosiloxanes (silicones).⁴⁴ Although silicone is considered to be biologically inert, it undergoes oxidation to silica when exposed to reactive oxygen radicals released by activated local macrophages.^45–47 Studies have demonstrated a link between silica and silicon exposure with the development of autoimmune conditions via the induction of a type two inflammatory response.^35,48

Silicone levels

Studies have shown that silicone levels are significantly higher in the peri-implant capsule in patients with saline-filled breast implants, while levels in adjacent breast tissue are the same compared with control breast tissue. Despite this, saline implants have not been linked with the development of BII.^49–51 Comparatively, the levels of silicone in both the peri-implant capsule and adjacent breast tissue are significantly higher in patients with silicone-filled breast implants and have been associated with symptoms of BII.^49,50 This observation speculates a possible dose-dependent pathogenesis for the symptoms of BII.

Silicone and autoimmune disease

The link between silicone breast implants and autoimmune disorders has historically been controversial. Following the moratorium on breast implants in 1992, the United States Institute of Medicine (IOM) released its report on the safety of silicone breast implants.⁵² This report noted that there was no evidence to implicate silicone breast implants with the development of autoimmune disease.⁵² When the US Food and Drug Administration (FDA) approved silicone-gel breast implants in 2006, it recognised that data on rare events and long-term outcomes were limited. To clarify this, each manufacturer of silicone-gel breast implants is required to conduct a number of post-approval studies to characterise the long-term safety profile of its devices.⁵³ In response, MENTOR® and Allergan produced core studies with a follow-up period of eight and 10 years, respectively.^54,55 These studies did not demonstrate an association with autoimmune disease.⁵³

More recently, larger post-approval studies have been conducted to evaluate the incidence of rare adverse events. A study by Singh and colleagues assessed 55,279 patients with a minimum five-year follow-up who had Allergan implants, comparing the incidence of targeted adverse events to patients with saline implants and national norms. This study showed that Allergan Natrelle® (Northshore Corporate Centre, 4/810 Pacific Hwy, Gordon NSW 2072) round silicone implants did not significantly increase the risk of any systemic disease compared with both national norms and saline implants.⁵⁶ Another study by Coroneos and colleagues assessed both Allergan and MENTOR® (a business of Johnson & Johnson Medical Pty Ltd 1–5 Khartoum Road, Macquarie Park NSW 2113) implants with a total of 99,993 patients, with a follow-up period of two years for Allergan and seven years for MENTOR® implants. They found that women with silicone breast implants had rates of Sjögren’s’ syndrome, scleroderma and rheumatoid arthritis that were greater than double those in the general population. Furthermore, both the Allergan and MENTOR® groups showed a higher incidence of patient-reported rheumatological symptoms in the revision-reconstruction cohort.⁵⁷ These authors also countered the common criticism of patient-reported data. They suggested that although the accuracy of the findings might be difficult to interpret, the results represent a significant proportion of women who present with symptoms who nevertheless still require clinical evaluation and management.

In the studies we reviewed, there was a wide range in duration of latency periods between exposure and disease. In an analysis of 300 patients, Watad and colleagues⁵⁸ showed a mean latency period of 31 months (range 1 week to 60 months). In their cohort of 200 patients, Colaris and colleagues³⁸ showed a median latency period of four years (range 1–39 years) and several smaller studies had latency periods ranging from 5 to 15 years.^4,35,55 The aforementioned post-approval studies by Allergan and MENTOR® would therefore have captured data pertaining to ASIA; however, the FDA analysis was looking for an association with known autoimmune diseases and not a yet-to-be-defined syndrome such as BII.

The incidence of concomitant autoimmune conditions was assessed in several publications. A retrospective study of 300 patients with silicone breast implants referred to a rheumatology clinic for musculoskeletal complaints found similar incidences of human adjuvant disease and known connective tissue disease (10.6% and 11%, respectively).¹⁵ In other studies in which all patients met the criteria for ASIA, the incidence of concomitant autoimmune conditions ranged from 10 per cent to 53 per cent.^{4,12,13,21,35,38}

A meta-analysis by Janowski and colleagues⁵⁹ showed no association between silicone breast implants and autoimmune or connective tissue disorders, supporting the safety of silicone breast implants. This is in keeping with three prior meta-analyses, which also found no increased risk of connective tissue diseases following silicone breast implantation.^60–62

However, in the meta-analysis by Janowsky and colleagues, several smaller studies^11,63,64 and a significant study of 10,830 patients by Hennekens and colleagues⁶⁵ were excluded as the patients’ symptoms were self-reported.⁵⁹ In their analysis, Janowsky and colleagues found the relative risk of connective tissue, autoimmune or rheumatic disorders to be slightly elevated when the data from Hennekens and colleagues study were included, but when the data were excluded the results were equivocal.⁵⁹ Janowsky and colleagues expounded on the shortcomings of self-reported data in light of the controversial nature of public awareness and concern over the potential health effects of breast implants, justifying the exclusion of this large study. In short, this meta-analysis failed to establish an association between silicone breast implants and autoimmune or connective tissue disorders.

Although the medical literature has failed to link silicone-gel breast implants with ‘known’ autoimmune or connective tissue disorders, there are numerous studies that examine the link between silicone breast implants and a collective group of symptoms that may be autoimmune in nature and are colloquially known as BII.

Clinical findings

The symptom profile of ASIA has been reported by numerous studies. The most common symptoms experienced include chronic fatigue, myalgia, arthralgia, fever and generalised weakness (Table 3).

A common belief is that the symptomatology of ASIA is non-specific and therefore possibly related to any number of conditions or circumstances in the normal population. This generalisation has been difficult to dispel, as only a limited number of controlled studies have assessed the incidence of symptoms in patients with silicone breast implants compared with those without. Giltay and colleagues¹¹ presented an age-matched study of 235 patients with silicone breast implants and 210 patients who had undergone an aesthetic operation without the use of silicone. They found that patients with silicone breast implants had a significantly higher rate of symptoms, especially arthralgia, dry eyes and skin abnormalities. Of note, this study was excluded from the meta-analysis by Janowsky and colleagues due to the use of self-reported outcomes. Englert and colleagues²⁸ presented a study of 458 patients with silicone breast implants and a control group of 687 patients who had undergone plastic surgery without the use of silicone. Although they found a higher rate of a ‘cluster’ of symptoms including night sweats, lethargy, impaired cognition, myalgia, breast pain, reflux and paraesthesia in the ‘exposed’ group, these symptoms were also found in the ‘non-exposed’ group, albeit at a lower frequency.

Diagnostic criteria

Despite having a varied presentation and symptomatology, several authors have described diagnostic criteria for ASIA. Miyoshi and colleagues were the first to do so for a condition they called human adjuvant disease. In 2011, Shoenfeld and colleagues refined this by introducing major and minor criteria.⁵ In 2015, Alijotas-Reig further modified this by replacing subjective terms from Shoenfeld’s criteria with objective terms to minimise false-positive diagnoses⁶⁶ (Table 4).

These diagnostic criteria should guide clinical recognition of common symptom groupings that patients may present with. Rather than a tool to exclude or confirm a diagnosis of ASIA, these criteria should direct counselling and appropriate investigation. In their discussion, Shoenfeld and colleagues aptly described the clinical signs and symptoms as ‘enigmatic’, but ‘nevertheless prominent’.⁵

Risk factors

The development of autoimmunity is believed to result from complex multifactorial interactions involving both a genetic predisposition and external triggers. To better characterise ASIA and rationalise why some individuals exposed to silicone develop post-exposure autoimmune symptoms, Soriano and colleagues described four groups of patients deemed to be at risk of developing ASIA after vaccination based on their review of the literature.⁶⁷ These groups were identified. They were patients with:

1. a prior documented autoimmune reaction to an adjuvant

2. an established autoimmune condition

3. a history of allergic conditions/atopic disorders

4. a genetic predisposition to autoimmune disorders.

From their own review of the literature, Goren and colleagues suggested that these same groups would be at risk of developing ASIA following exposure to silicone.³ The commentary provided by these two papers reflects the current literature surrounding risk factors for post-exposure autoimmune syndromes, but both papers acknowledge the need for larger epidemiological studies to validate these concepts.

In addition to a genetic predisposition, external factors such as smoking and obesity have been linked to the development of autoimmune syndromes.^68–70 Having an appreciation of these potential risk factors adds to our understanding and gives depth to our discussion with patients presenting with symptoms of BII (Table 5).

Serological markers

The role of serological markers in the diagnosis and management of connective tissue and autoimmune diseases is well established. Many investigators have hoped to discover unique patterns of markers to diagnose and characterise ASIA. To date, no specific pattern of serological markers has been identified. In their case series of 156 patients with breast implants and rheumatic disease complaints, Bridges and colleagues found that most women had normal results from serological tests. These tests included immunoglobulins, complement, C-reactive protein, rheumatoid factor and autoantibodies.⁹ The Dutch Working Party on Silicone Breast Implants reported a cohort study of 63 women who underwent mastectomy followed by immediate reconstruction with silicone breast implants. They found no difference in symptoms between antinuclear antibody-positive or -negative patients.²³ Despite this, serological investigation is vital in the workup of a patient presenting with symptoms of an autoimmune condition and future research endeavours may yet discover a significant serological marker for BII.

Imaging

Although BII has been commonly reported in the presence of an intact and uncomplicated implant,²⁵ thorough imaging will define the integrity of the implant, delineate the containment of a silicone rupture within a fibrous capsule, highlight silicone lymphadenopathy and identify a mass or peri-prosthetic fluid. If on imaging an implant appears intact and uncomplicated, patients presenting with BII often still request explantation. However, if imaging identifies an abnormality, this will direct further investigation to exclude traumatic, inflammatory or malignant conditions. Ultrasound and CT scanning have a role, but MRI is the investigation of choice for assessing the integrity of the implant. The current recommendations from the FDA are for MRI screening of asymptomatic patients with breast implants at three years post-implantation and every two years thereafter.⁵³ In its recent draft, the FDA has recommended an ultrasound or MRI at five to six years postoperatively, then every two years thereafter.⁷⁴

Implant integrity

Although it has been proposed that the risk of ASIA is greater and symptoms are more severe in patients with ruptured implants,⁷⁵ ASIA has been described in patients with intact implants.²⁵ Gaubitz and colleagues explored this further in their MRI study of 90 patients with silicone breast implants. They found that symptoms and signs of an autoimmune response did not differ between those with or without ruptured implants.²⁵

Considering that a patient with silicone implants is exposed to silicone from the shell and silicone bleeding,^76–78 the integrity of an implant should not determine the presence and course of an autoimmune response.

Medical therapy

Medical therapy with prednisolone alone and in combination with agents such as hydroxychloroquine, allopurinol, cetirizine and tacrolimus has been used for patients presenting with symptoms of ASIA.⁴ Alijotas-Reig and colleagues presented a case series of 45 patients with ASIA from biomaterials. Of these patients 42 per cent had silicone breast implants. Medium-high doses of prednisolone (0.5–1mg/kg/day) were typically used, with some patients requiring long-term corticosteroid therapy to manage their symptoms. They found that almost 100 per cent of patients were symptom free within a few months and 70 per cent remained symptom free at two years when treatment was withdrawn. Although promising, within this small sample, 22 per cent (10/45) of patients also had complete surgical removal of the offending biomaterial, with 60 per cent of this group demonstrating an improvement in symptoms.⁴

In line with a multifactorial model of pathogenesis for a post-exposure autoimmune syndrome, Colaris and colleagues explored the role of vitamin D as an immune regulator in patients with ASIA.⁷⁹ Based on their literature review and measurement of vitamin D levels in 135 patients with ASIA, they found that vitamin D deficiency was related to the presence of auto-antibodies in patients with ASIA, as well as those with other autoimmune diseases such as autoimmune thyroid disease, connective tissue disorders, inflammatory arthritides and multiple sclerosis. Although speculative in nature, the authors acknowledge the limitations of the study and suggest that more robust trials are required to assess the role of vitamin D supplementation.⁷⁹

Explantation

The explantation of silicone implants is often patient driven, unless there are clear indications such as an implant rupture. There remains uncertainty in offering explantation, due to the perceived lack of pathology, the lack of evidence for its efficacy and concerns over aesthetic outcomes.

In their literature review, de Boer and colleagues proposed that explantation of a silicone implant improves symptoms by reducing autoimmune and inflammatory processes, while reducing nociceptive signals from the physical presence of an implant.⁴⁶ They reviewed studies that assessed outcomes following explantation for patients with symptoms from silicone breast implants. From their review, there were 11 case studies, which demonstrated an improvement in symptoms in 12/19 (63%) of patients.⁴⁶ They were also able to collate 703 patients from 12 case series with a reported improvement in symptoms after explantation in 603/703 (76%) of patients. Overall this represented a 75 per cent rate of improvement in symptoms following explantation. Although promising, it is difficult to interpret, as this overall rate was not reached through statistical methodology and simply represents an average of a collection of different studies. In addition, these studies often did not state whether patients also received medical therapy. Many of these studies relied on self-reported outcomes and suffered from selection bias based on their recruitment strategies. Maijers and colleagues recruited their patients through a national media campaign,³⁶ while Cuellar and colleagues recruited patients referred to a rheumatology clinic.¹⁵ A study by Peters and colleagues was based on consecutive cases of patients requesting explantation.²¹ The data are therefore difficult to interpret, despite appearing to strongly support the role of capsulectomy and explantation.

The way in which the explantation and capsulectomy are performed has not been consistently reported and there is no evidence to support an en-bloc capsulectomy over a total capsulectomy that removes the capsule in components or even explantation without a capsulectomy. However, in line with the theory of an adjuvant inciting an autoimmune response,⁵ understanding the permeating nature of silicone within a fibrous capsule⁸⁰ and acknowledging silicone bleed as a real phenomenon,^76–78 an en-bloc style capsulectomy and explantation theoretically would provide the most thorough technique to remove any potential local source of silicone while minimising silicone contamination to the surgical field. De Boer and colleagues even suggested that the persistence of symptoms following capsulectomy may reflect the presence of residual silicone perpetuating the production of autoantibodies.⁴⁶

Most patients presenting to a surgeon seeking explantation surgery would usually have contemplated the potential aesthetic impact. A thorough exploration of a patient’s sense of body image and emotional readiness for surgery should be completed.⁸¹ If a patient expresses deep regret or fear of losing their breast implants, these concerns should be explored until it is clear that the patient understands and accepts the aesthetic ramifications of explantation surgery. A discussion of the merits and limitations of immediate or delayed options in restoring form and/or volume to the breasts should also be conducted.

Conclusion

Breast implant illness remains a condition of marked debate. This review serves to outline the literature surrounding BII so that clinicians have the relevant information at hand to discuss with their patients. Patients with possible BII can present in a number of ways with mild to severe and even debilitating symptoms. The uncertain nature of a BII diagnosis has repercussions in establishing satisfactory management pathways for these patients. Regardless of the true nature of BII, clinicians have a responsibility to assess these patients to exclude other pathology and also offer counselling and appropriate management guided by the available literature to date. A multidisciplinary approach is recommended to assess and support these patients and surgery is a key component to be considered in their overall management.

Conflict of interest

The authors have no conflicts of interest to disclose.

Funding declaration

The authors received no financial support for the research, authorship, and/or publication of this article.

Revised: August 29, 2020 AEST