Autoimmune/auto-inflammatory syndrome induced by adjuvant (ASIA) in patients refusing breast implant explantation: two case reports and a review of the literature

Abstract Autoimmune/auto-inflammatory syndrome induced by adjuvant (ASIA) is a pathological condition that could affect some women after breast augmentation surgery. ASIA presents with a large group of unspecific symptoms, which could deteriorate patients’ physical and psychological well-being. Herein, we present a mini-review of this condition and report two patients with autoimmune disturbances emerging soon after silicone breast implantation. Breast implants are safe for most women, but they could potentiate autoimmune reactions and provoke subjective complaints in a minor group of susceptible patients. It is unclear if the autoimmune reactions in our cases developed de novo after silicone placement or if the adjuvant had just potentiated an underlying subclinical autoimmune disease. The patients insisted on preserving their breast implants; therefore, immunosuppressive therapy was applied with beneficial effects on clinical symptoms. Identifying high-risk patients and ensuring appropriate medical monitoring is possible via screening for several antibodies, e.g. anti-nuclear and anti-phospholipid antibodies, rheumatoid factor and antistreptolysin-O titer, in all patients planning breast augmentation surgery. In the case of ASIA, short- or long-term medical treatment could be a practical approach in patients who refuse breast implant explantation. The proper education of women about the possible risks and benefits of breast implantation surgery is essential for making an informed choice.


Introduction
Autoimmune/auto-inflammatory syndrome induced by adjuvant (ASIA) or Shoenfeld's syndrome is a recently described disorder that includes a large group of similar symptoms emerging after the use of external substances [1].The main complaints of patients with ASIA include myalgia, arthralgia, chronic fatigue, fever, sleep disturbances, alopecia, lymphadenopathy, cognitive and other neurological disturbances, etc. [1,2].Currently used criteria for diagnosis of ASIA provided by Shoenfeld et al. require the presence of two major criteria or one major and two minor criteria [1][2][3].The major ASIA criteria are exposure to adjuvants, "typical" clinical symptoms, improvement after the adjuvant removal, and/or specific pathological changes in the affected organs (Figure 1).The minor criteria include the presence of auto-antibodies or antibodies against the adjuvant, other clinical symptoms, particular HLA genotype, and/or the evolvement of autoimmune disease [1][2][3].The main environmental adjuvants associated with autoimmunity in genetically susceptible individuals are aluminum hydroxide and silicone [4].Silicone has long been considered an inert material unable to provoke immune reactions and, therefore, is widely used in breast implants and other medical applications [5,6].However, silicone particles could migrate outside the implant ('silicone bleeding'); thus, they might induce cytokine disturbances and alterations in humoral and cell immunity [6,7].The use of silicone breast implants is entirely safe in most women; nevertheless, some patients may develop autoimmune reactions -the so-called siliconosis or human adjuvant disease [2,8,9].The complaints of some breast implant carriers do not fulfill the specific criteria for well-defined connective tissue diseases [1][2][3], but the symptoms and their evolution might correspond to ASIA.
ASIA is a rare clinical condition but should be considered in patients with breast implants and mixed rheumatologic and neurologic symptoms.However, the available information about ASIA patients worldwide is still scarce.Here, we present two cases of Bulgarian women with probable ASIA and provide a short review of the literature focused on the unresolved questions on this topic.

Methodology of literature search
Literature search was performed in PUBMED with key words: breast implant, siliconosis, ASIA.Only case reports with sufficient clinical data in English published after the definition of ASIA in 2011 were included.

Patient 1
A 32-year-old patient was referred to a rheumatologist because of progressive muscle and joint pain as well as joint stiffness.The complaints had started two and a half years ago shortly after an augmentation mammoplasty with silicone implants.She had been treated with non-steroidal anti-inflammatory drugs but the pain in the knees and small joints persisted.The patient suffered also from recurrent tonsillitis, but its treatment did not improve the condition.The patient did not have other concomitant diseases or symptoms.Laboratory investigations revealed lymphopenia, increased titers of antinuclear antibodies (ANA) (Table 1), anti-streptolysin (ASO) and rheumatoid factor (RF). Radiological investigations showed asymmetric joint space narrowing of wrists as well as sacroiliitis.No other medical abnormalities were found.Overlapping connective tissue disease was suspected and treatment with corticosteroids (methylprednisolone 8 mg/daily with subsequent reduction up to 2 mg/daily) and azathioprine (50 mg/daily) was started.The breast implants of the patient were replaced with a different silicone model, because of her firm refusal to remove the silicone.Several months thereafter, the patient continued Figure 1.autoimmune/auto-inflammatory syndrome induced by adjuvant (aSia) in women with breast silicone implantssuggested screening and therapeutic approach (criteria according to Schoenfeld and agmon-levin, 2011 [1]).aiD -autoimmune disturbances; ana -anti-nuclear antibodies; RF-rheumatoid factor; aSo-antistreptolysin-o titer; acl -anticardiolipin antibodies; mRi -magnetic resonance imaging; + yes; − no.
immunosuppressive therapy and the clinical complaints were slightly reduced, while the immunological indices remained elevated.Antimalarial treatment was also started but had to be discontinued because of retinal abnormalities.Treatment with azathioprine was replaced by leflunomide (20 mg/daily reduced to 10 mg/ daily), while the low-dose corticosteroid treatment (2 mg/daily) was continued, which led to a significant improvement in clinical symptoms without any side effects.The lymphopenia, inflammatory disturbances and ANA improved (Table 1), while RF levels (41.97 U/ mL/<20/) were still above the upper reference ranges.

Patient 2
A 31-year-old patient was admitted to the Department of Rheumatology because of persisting fever up to 40 °C, pain in small joints, progressive microcytic hypochromic anemia, diffuse hair loss and strongly elevated ESR (sedimentation rate of erythrocytes) and C-reactive protein in the last two months.The symptoms had started soon after the insertion of breast silicone implants because of cosmetic indications.The patient had been initially referred to the Department of Infectious Diseases, but no signs of local breast or systemic infection were established, and antibiotic treatment was ineffective.The patient was with significantly increased levels of anti-nuclear antibodies (Table 1), while rheumatoid factor (RF, 13.44 U/mL/<20/) and antistreptolysin-O (ASO, 173.5 IU/mL/>200/) titers were normal.High-dose corticosteroid treatment (pulse therapy with 1000 mg methylprednisolone i.v. and subsequently methylprednisolone 8 mg p.o. daily with gradual reduction) was applied leading to a rapid decrease of acute phase proteins and significant improvement of clinical symptoms and anemia.An acute autoimmune reaction induced by silicone was suspected and the patient was referred to a plastic surgeon.However, the patient refused breast implant explantation.She was under antimalarial (hydroxychloroquine 200 mg/daily) and corticosteroid treatment (methylprednisolone 2 mg p.o. daily) for about a year (Table 1).The therapy was stopped by the patient herself without recurrence of the clinical symptoms.Soon after the discontinuation of treatment the patient became pregnant and delivered a healthy child after an uncomplicated pregnancy.The anti-nuclear antibodies (ANA) levels were normal in the postpartum period.

Discussion and literature review
Herein, we present two cases of women with autoimmune disturbances soon after cosmetic operations for silicone breast implantation.Both of them fulfilled the ASIA criteria.The severity of the clinical manifestations differed in the patients, but the immunosuppressive therapy was effective despite the preservation of breast implants.It is unclear if the autoimmune reactions were newly developed after silicone implantation or if the adjuvant had just potentiated an underlying subclinical autoimmune disease [10] Silicone has been used for many years in plastic surgery, but a dispute over its safety is still ongoing.A large-meta-analysis conducted twenty years ago concluded that silicone breast implants are not associated with an increased risk of autoimmune connective-tissue diseases [8].Similar results were obtained by Sánchez-guerrero et al. after 14 years of follow-up of the Nurses' Health Study cohort [11].However, a recent healthcare system data analysis, including electronic records of more than 123 000 women, has shown that patients with silicone breast implants are at significantly increased risk of being diagnosed with at least one autoimmune or rheumatic disorder [6].Thus, the presence of silicone breast implants has been associated with a significantly increased prevalence of Sjögren's syndrome, systemic sclerosis, sarcoidosis, multiple sclerosis, and fibromyalgia/chronic fatigue syndrome (OR > 1.3) [6].Additionally, numerous case series have reported different autoimmune and rheumatologic complications in women with silicone breast implants [2,12,13].

ASIA: unresolved questions
A large meta-analysis has tried to summarize the current research on the contradictory ASIA topic.Compared to noncarriers, breast implant carriers are at a slightly elevated risk for rheumatoid arthritis and Sjogren syndrome [14].However, these results are inconclusive because of limiting factors.Adjustment for important confounders is lacking in most papers; complaints are often self-reported, and very few studies have distinguished silicone implants from other breast implants [14].The different prevalence of some disorders might be related to the silicone implant per se or to the specific demographic, lifestyle, and reproductive characteristics of the women who prefer cosmetic surgery compared to other women [14,15].Nevertheless, similar results were obtained by the recent analyses of the largest FDA Breast Implant Postapproval Studies database [16].The authors described strong associations between silicone implants and the increased risk of Sjogren syndrome, scleroderma and rheumatoid arthritis.This study was also criticized for methodological flaws emphasizing on the low follow-up rate of participants with breast augmentation and the need of more rigorous analysis [16,17].
Our cases showed direct chronological associations between the silicone breast implant placement and the development of autoimmune disturbances and subjective complaints.Thus, breast implants are safe for most women, but they could induce or amplify autoimmune reactions and nonspecific subjective complaints in a minor group of susceptible patients.

Pathophysiological mechanisms
The published case reports in the literature suggest that systemic symptoms and immunological disturbances could emerge soon or late after silicone implantation, though implant ageing and rupture might be related to more severe clinical manifestations (Table 2).The proposed pathophysiological mechanisms include autoimmune response provoked by silicone and/or nociceptive activation related to the breast implant volume [2,18].'Silicone bleeding' might activate surrounding macrophages and enhance a humoral and cellular immune response leading to subclinical inflammation [19,20].On the other hand, the breast implant as a chronic nociceptive signal could stimulate different neurotransmitters in the nervous system and provoke clinical symptoms similar to alterations found in idiopathic fibromyalgia [2,18].Since our patients were ANA-positive, the first mechanism is more likely irrespective of the relatively shorter silicone exposure period.

Risk
goren et al. have identified several main risk groups of patients prone to developing ASIA after silicone implantation [21].They include patients with established autoimmune conditions, history of allergic or atopic disturbances, previous adjuvant-induced autoimmune reactions, and women with genetic predisposition, concomitant illnesses or habits increasing the risk of autoimmunity [21].Our patients did not fall into these categories; however, no HLA testing, immunologic or other specific investigations had been provided before breast implant operations.The high risk of autoimmune disorders in young women might justify the evaluation of several antibodies, e.g.anti-nuclear and anti-phospholipid antibodies, rheumatoid factor and antistreptolysin-O titer in all patients planning breast augmentation surgery.

Management
Since ASIA is a recently defined syndrome, consensus statements focused on its management are lacking.Removing or replacing the silicone breast implant is the logical first therapeutic step leading to the reduction of ASIA symptoms in about 60% to 75% of patients [18,22,23].However, in patients with autoimmune disorders, the explantation might not be effective or sufficient (Table 2), so that additional treatment is usually needed [18].Moreover, some individuals might refuse explantation because of cosmetic or financial reasons, like our patients; thus, immunosuppressive therapy might be necessary.At present, the long-term effects of that approach are not apparent.The effects of possible alternatives in case of breast implant explantation, such as replacement with a saline breast implant or autologous tissue reconstruction, are also poorly investigated [18].Therefore, some authors have recommended more conservative management of patients with silicone-induced ASIA [24,25].Medical treatment might be initiated to diminish clinical complaints in most women (Figure 1).MRI of the breasts and possible explantation in case of silicone leakage would be strongly recommended in medication-resistant patients [24,25].Additionally, ASIA should always be considered as a "diagnosis of exclusion" because unspecific symptoms like fever and fatigue might be associated with serious underlying oncologic or systemic diseases irrespective of the presence of breast implants [26].

Conclusions
The complaints of both described patients with silicone-induced ASIA improved significantly in response to immunosuppressive therapy despite the preservation of silicone breast implants.Additionally, a normal pregnancy was observed.However, the proper education women about the possible risks and benefits of breast implantation surgery, as well as potential complications, is crucial.Screening for several antibodies, e.g.anti-nuclear and anti-phospholipid antibodies, rheumatoid factor and antistreptolysin-O titer in all patients planning breast augmentation surgery could help to identify high-risk patients and ensure appropriate monitoring by rheumatologist.In the case of ASIA, the patients should have the opportunity to make an informed choice between different treatment options.

Table 1 .
laboratory characteristics of the investigated patients before and after treatment.

Table 2 .
case reports* of the autoimmune/auto-inflammatory syndrome induced by adjuvant (aSia) in women with breast implantation.