Adjuvant-induced autoimmune syndrome triggered by silicone breast implants: systematic review

GIACOMAZZO, CAIO MUNARETTO; SAKAI, CAROLINE NODA; ARAUJO, RAYANE MERLLY GANDOLFI DE; ONO, MARIA CECILIA CLOSS; DUARTE-DA-SILVA, ALFREDO BENJAMIN; FREITAS, RENATO DA SILVA

doi:10.5935/2177-1235.2022RBCP.626-pt

Review article • Rev. Bras. Cir. Plást. 37 (4) • Oct-Dec 2022 • https://doi.org/10.5935/2177-1235.2022RBCP.626-en linkcopy

Adjuvant-induced autoimmune syndrome triggered by silicone breast implants: systematic review

Authorship SCIMAGO INSTITUTIONS RANKINGS

ABSTRACT

Adjuvant-induced autoimmune syndrome (ASIA) and its diagnostic criteria were described by Shoenfeld in 2011, relating symptoms of autoimmunity to adjuvants, such as silicone, present in breast implants. This systematic review aimed to gather data from the literature on symptomatology, incidence and proposed treatments for ASIA caused by silicone breast implants (SBI). Searches were carried out in PubMed, LILACS, Embase and Cochrane databases, using the descriptors “Autoimmune Syndrome Induced by Adjuvants,” “Breast implant,” and “Silicone Implant Incompatibility Syndrome.” The search strategy generated 95 articles, of which 20 were included in the review. The authors suggest three main theories to explain the development of the syndrome: genetic predisposition, silicone bleeding and the formation of a periprosthetic capsule. The most frequently described clinical manifestations include chronic fatigue, arthralgia, myalgia, and cognitive and sleep disorders. There is no consensus on laboratory findings and associated risk factors; recent studies propose expanding the diagnostic criteria initially described. Adequate treatment remains controversial, ranging from medications to prosthesis explantation. Although the reviewed articles suggest the existence of ASIA related to SBI, its precise pathophysiology is unknown, the symptoms reported are nonspecific, and the time between exposure and the onset of manifestations is uncertain. This systematic review concludes that, to date, there is not enough scientific evidence to establish the causality of the development of adjuvant-induced autoimmune syndrome resulting from silicone breast implants.

Keywords:
Breast implants; Silicone elastomers; Adjuvants; immunologic; Autoimmunity; Systematic Review

RESUMO

A síndrome autoimune induzida por adjuvantes (ASIA) e seus critérios diagnósticos foram descritos por Shoenfeld em 2011, relacionando sintomas de autoimunidade a adjuvantes, como o silicone, presente em próteses mamárias. Essa revisão sistemática objetivou reunir dados da literatura sobre a sintomatologia, a incidência e os tratamentos propostos para ASIA causada por implantes mamários de silicone (IMS). Foram realizadas pesquisas nas bases de dados PubMed, LILACS, Embase e Cochrane, utilizando os descritores “Autoimmune Syndrome Induced by Adjuvants”, “Breast implant” e “Silicone Implant Incompatibility Syndrome”. A estratégia de busca gerou 95 artigos, dos quais 20 foram incluídos na revisão. São as três as principais teorias sugeridas pelos autores para explicar o desenvolvimento da síndrome: predisposição genética, silicone bleeding e a formação de uma cápsula periprótese. As manifestações clínicas mais frequentemente descritas incluem fadiga crônica, artralgia, mialgia, distúrbios cognitivos e do sono. Não há consenso sobre os achados laboratoriais e os fatores de risco associados, além disso, estudos recentes propõem a ampliação dos critérios diagnósticos inicialmente descritos. O tratamento adequado permanece controverso, envolvendo desde o uso de medicações até o explante da prótese. Apesar dos artigos revisados sugerirem a existência da ASIA relacionada aos IMS, sua fisiopatologia precisa é desconhecida, os sintomas relatados são inespecíficos e o tempo entre a exposição e o surgimento das manifestações é incerto. Por meio dessa revisão sistemática, conclui-se que, até o presente momento, não existem evidências científicas suficientes para estabelecer a causalidade do desenvolvimento da síndrome autoimune induzida por adjuvantes decorrente de implantes mamários de silicone.

Descritores:
Implante mamário; Elastômeros de silicone; Adjuvantes imunológicos; Autoimunidade; Revisão sistemática

INTRODUCTION

Silicone breast implants (SBI) have been used in medical practice since 1962 in reconstructive and aesthetic surgery¹. For a long time, silicone was considered a biologically inert and harmless substance². However, in recent years, the presentation of a series of symptoms of autoimmune diseases common by patients with breast implants has led authors to correlate the symptoms with the presence of the implant. In 1964, Miyoshi had already described this association³ and, more recently, in 2011, Schoenfeld & Agmon-Levin⁴ described and proposed criteria for what they called adjuvant-induced autoimmune syndrome (ASIA)⁴.

ASIA involves a group of immune-mediated diseases related to previous exposure to adjuvants. Diseases include squalene-related Gulf War Syndrome; macrophagic myofasciitis, related to aluminum hydroxide; and siliconosis, related to silicone, which is present in breast implants and other materials frequently used in medical practice. The emergence of the syndrome is associated with the interaction between environmental factors, previous exposure to adjuvants, induction of autoimmunity and loss of immune tolerance in genetically predisposed individuals²,⁴.

The diagnostic criteria for ASIA proposed by Shoenfeld & Agmon-Levin include, as major criteria, exposure to external stimuli, as adjuvants, the subsequent appearance of clinical symptoms of autoimmune diseases involving the musculoskeletal, joint and nervous systems, improvement of symptoms after removal of the causal agent and typical biopsy presentation of the involved organs. And, as minor criteria, the presence of autoantibodies, certain human leukocyte antigens (HLA), involvement of autoimmune diseases and other clinical manifestations¹.

OBJECTIVE

Through a systematic review of the medical literature, this work aimed to gather information about ASIA in patients with silicone breast implants, compiling Dice about pathophysiology, symptomatology and treatments currently available.

METHODS

The topic was reviewed systematically to obtain the best available evidence. The PRISMA5 protocol cannot be followed, as many articles relevant to the subject were not systematic reviews or randomized clinical trials.

Articles were obtained by searching PubMed, Cochrane, LILACS and Embase databases. The search descriptors were used in the following systematization: (Autoimmune Syndrome Induced by Adjuvants) AND ((Breast implant) OR (Silicone Implant Incompatibility Syndrome)). The search was not limited by publication date, language, or study design.

Inclusion criteria included studies published in indexed journals that addressed the topic of ASIA associated with silicone breast implants or silicone implant incompatibility syndrome. Exclusion criteria were: (i) Studies dealing with lymphoma or other neoplasms; (ii) Studies in animal models; (iii) Study type: case reports or case series with less than three cases; (iv) Language: study not available in English, Spanish or Portuguese; (v) Study not published or in the pre-publication phase; (vi) ASIA syndrome caused by another adjuvant; (vii) Breast implants of materials other than silicone.

After searching the databases, all articles found were initially screened based on their titles. Studies whose titles permeated the themes of ASIA and breast implants or SIIS were included for analysis, and duplicate articles were excluded. Then, the selected articles had their abstracts read, and those that met the inclusion criteria, and did not fit the exclusion criteria, were kept. Finally, the articles were read in full; the appropriate ones were selected for the literature review. Three independent researchers screened and selected articles; an agreement was necessary to exclude any articles. The search was not limited by the publication date, language or study design, and all articles on the topic were published until March 2021, when the article selection process took place.

The present study does not require approval by the Ethics Committee and application of the Free and Informed Consent Form, as it is a secondary study, which does not involve tests on patients, data obtained directly from patients and tests on animal models.

RESULTS AND DISCUSSION

The search strategy generated 95 articles, 28 of which were repeated. In the end, 20 articles (21%) were selected (Figure 1) based on a database search for the literature review (Annex 1).

Figure 1
Flowchart of the search and selection of articles.

Pathophysiology

Adjuvants are substances capable of increasing the specific antigen-immune response; for this, they mimic molecules preserved throughout evolution, binding to receptors and potentiating the activity of antigen-presenting cells³,⁴.

The silicone implant incompatibility syndrome and the other diseases encompassed by ASIA share a common background: the genetic predisposition of affected individuals to develop autoimmunity after exposure to adjuvants³,⁶.

The pathogenesis that leads to autoimmunity after SBI implantation is still unclear, but some plausible mechanisms have already been proposed. The expression of HLA-DRB1 and HLA-DQB1 antigens seems to be linked to the onset of autoimmunity in patients with breast implants⁶. Furthermore, SIIS may be related to the phenomenon of silicone bleeding, in which silicone molecules cross the limits of the implant and can be dispersed throughout the body even with an intact prosthesis⁷. Bleeding silicone can also transform the foreign body reaction expected in the formation of the periprosthetic capsule, after implant insertion, into a chronic inflammatory process⁸.

Silicone molecules trigger an inflammatory process, which consists of the capture of particles by macrophages, triggering the production of cytokines and reactive oxygen species (ROS). Subsequent apoptosis of these cells releases the particles, restarting the process. Another mechanism is the production of interleukin (IL)-17, which stimulates intense migration of neutrophils, the secretion of enzymes and ROS. Furthermore, the transport of silicone-containing particles to lymph nodes may result in an adjuvant effect⁷-⁹.

In normal individuals, the formation of the periprosthetic capsule depends on the production of tumor necrosis factor α (TNF-α) and tissue growth factor β (TGF-β), produced by macrophages and T lymphocytes. These factors stimulate the multiplication of fibroblasts and extracellular matrix deposition, resulting in capsule formation and subsequent fibrotic reaction. In predisposed individuals, the continuous activation of macrophages and the predominance of T helper lymphocytes 17 concerning regulatory T lymphocytes are associated with the chronicity of inflammatory reactions and autoimmunity⁸.

Another theory suggests the participation of infectious agents as triggers for the development of pathological immune-mediated responses to adjuvants. In it, the adjuvant effect of microbial molecules, through the non-antigenic activation of the immune system and the expression of several regulatory cytokines, can trigger the disease³.

Clinical manifestations

Typically, chronic fatigue is the most prevalent symptom, affecting up to 98% of patients¹⁰,¹¹. The manifestation may be present from awakening and not improve after rest, compromising daily activities¹,¹². However, there are disagreements in the literature, and a recent study showed a lower prevalence in patients with SBI concerning a control group (18.2% vs. 47.7%, p=0.03)¹³.

Sleep disturbances are frequent complaints involving both the initiation and maintenance of sleep. This manifestation, which can affect up to 78% of cases¹⁰, is associated with cognitive disorders and memory alterations, commonly reported in the syndrome¹,¹².

Arthritis and arthralgia may be present as early symptoms of the syndrome¹,¹². Studies differ as to their prevalence, ranging from 31.8% to 91%¹⁰,¹³,¹⁴. In most cases, there is morning stiffness lasting more than one hour¹,¹².

Furthermore, up to 90% of patients may have myalgia or muscle weakness, with electromyography alterations in up to 53% of cases¹,¹². Again, there are discrepancies between publications; a study in Argentina indicated this symptom as less frequent in patients with SBI than in their control group (18.2% vs. 75%, p<0.0001)¹³.

Xerostomia and xerophthalmia are other important complaints, affecting 75% of patients¹,³,⁸. 30-50% of patients develop Raynaud’s phenomenon; in some cases, there are changes in nail capillaroscopy¹,³,¹⁰,¹².

Allergic manifestations such as nasal and eye itching, rhinorrhea, sneezing, coughing and skin symptoms are reported in 50-80% of patients¹,¹⁰,¹².

Less frequent symptoms related to ASIA include fever, respiratory tract symptoms, recurrent cystitis, livedo reticularis, alopecia and gastrointestinal tract disorders¹,¹⁰,¹²,¹⁴.

Some studies suggest a correlation of ASIA with other rheumatological disorders, such as fibromyalgia and rheumatoid arthritis¹¹,¹³,¹⁵, more frequently, but also with lupus, scleroderma, Sjögren, among others¹⁴,¹⁶.

The average time between exposure to SBI and the manifestation of symptoms is not consensual in the literature, ranging from 4 to 16.1 years¹⁰,¹¹,¹³,¹⁷. There are descriptions of cases in which the onset of symptoms occurred in just one year after exposure, and another reaching 42 years¹⁰,¹³,¹⁵,¹⁷.

Laboratory Findings

The presence of autoantibodies is common in ASIA. Antinuclear factor (ANA) can be found in up to 56% of cases1,3,18. Other antibodies include anti-Ro, anti-La, anti-dsDNA, anti-Scl-70, anticardiolipin, cyclic citrullinated peptide antibody, rheumatoid factor IgM, an anti-neutrophil cytoplasmic antibody can be found, although less frequently¹,¹⁸.

Specific HLA alleles, such as HLA-DRB1 and HLA-DQB1, constantly related to rheumatologic diseases, are frequently found in ASIA carriers¹⁷.

Vitamin D deficiency is described in some studies and may be present in up to 50% of patients with the syndrome¹,¹²,¹⁹.

Diagnostic Criteria

In his original work, Shoenfeld suggested using major and minor criteria for diagnosing ASIA (Chart 1).

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Chart 1
Shoenfeld’s diagnostic criteria.

Risk factors

The risk factors that predispose to the emergence of the syndrome are still not well elucidated in the literature. It is believed that patients with previously documented autoimmune diseases, especially those related to HLA-DRB1 and the PTPN22 gene, and those with a family predisposition to develop autoimmune diseases⁶,¹¹, are more affected by the syndrome¹,¹¹.

Studies suggest that patients with a history of atopy also seem to have a greater predisposition to developing ASIA1,2,11. Previous episodes of an autoimmune reaction to adjuvants, such as those that occurred after immunization with vaccines containing adjuvants²,²⁰, and some environmental factors such as smoking and obesity are cited as possible risk factors¹.

Treatment

No drug treatment cures the syndrome, but some medications such as corticosteroids, hydroxychloroquine, minocycline and doxycycline can help reduce symptoms¹,¹².

In patients who have allergic symptoms, the use of antiallergics can contribute to the improvement of the condition. In those with vitamin D deficiency, vitamin 1 replacement is recommended. Patients who smoke should also be instructed to quit smoking¹. Patients with the syndrome who manifest symptoms related to fibromyalgia should be encouraged to practice physical activities¹.

The silicone explant can be advised in patients with multiple complaints and refractory to drug treatments. Studies show that 60 to 80% of patients show improvement in symptoms, especially fatigue, arthralgia and myalgia, after removing the breast implant¹,⁶,¹⁰,¹²,¹⁴,²¹. It is believed that patients who do not show improvement in symptoms after removing the silicone implant have the material spread throughout the body¹.

Study limitations

The recent description of ASIA added to the lack of consensus on this entity’s existence, making studies on the subject scarce. The search in the databases was not able to include studies with strong scientific evidence, such as clinical trials and meta-analyses. At the same time, the studies included in the review were mostly carried out in specialized immunology and rheumatology centers, which could generate a selection bias and compromise external validity. The long time between implantation and manifestation of symptoms allows the existence of a confounding bias, in which the trigger of autoimmunity could be the exposition to an adjuvant other than SBI. Excluding articles by language may limit access to relevant knowledge.

CONCLUSION

Since silicone breast implants are widely used in plastic surgery, breast augmentation and reconstruction, the autoimmune syndrome induced by adjuvants becomes a topic of great relevance.

The autoimmune character, the wide spectrum of symptoms and the variable time between the silicone implant and the clinical manifestations make the diagnosis of ASIA inaccurate.

In addition, the pathophysiology and risk factors related to the development of the syndrome remain unclear. The history of previous autoimmune diseases was the most prevalent risk factor in the studies reviewed; however, it is not known whether ASIA acts as an aggravating factor or a trigger for the development of autoimmunity symptoms.

The diagnosis of ASIA through the criteria proposed by Shoenfeld lacks consensus and validation in the academic environment, as well as the definitive treatment because even the prosthesis explant was ineffective for all patients.

It is concluded that, despite some evidence, the correlation between silicone breast implants and adjuvant-induced autoimmunity syndrome cannot be confirmed, and further studies with strong scientific evidence are needed.

Annex 1 Main characteristics of the selected articles.

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Author Year Title Article type Relevant findings Tervaert, J. W. C. et al. 2017 Silicone breast implants and autoimmune rheumatic diseases: Myth or reality Revision It associates IMSs with a group of patients with complaints of fatigue, cognitive disorders, arthralgia, myalgia, fever, xerophthalmia and xerostomia. It indicates that silicone molecules can migrate from the implant through the body, inducing a chronic inflammatory process and that the IMS explant results in the improvement of symptoms in most patients. Goren, I. et al. 2015 Autoimmune/inflammatory syndrome induced by adjuvant (ASIA) evolution after silicone implants. Who is at risk? Revision It relates IMS and autoimmunity, suggesting ways to identify individuals at higher risk for developing silicone-induced ASIA and thus recommending avoiding IMS in some cases (e.g., individuals with a previous diagnosis of autoimmune diseases or genetic predisposition to immune system hyperactivity). Alijotas-Reig, J. 2015 Human adjuvant-related syndrome or autoimmune/inflammatory syndrome induced by adjuvants. Where have we come from? Where are we going? A proposal for new diagnostic criteria. Opinion article It proposes new diagnostic criteria for ASIA based only on objective clinical and laboratory data to be discussed and validated. Schoenfeld, Y; Agmon-Levin, N. 2010 ‘ASIA’ - Autoimmune/inflammatory syndrome induced by adjuvants Revision Discusses the role of adjuvants in the pathogenesis of immune-mediated diseases. Borba, V. et al. 2020 Classical Examples of the Concept of the ASIA Syndrome. Revision It describes the diagnostic criteria proposed by Shoenfeld and the manifestations of autoimmunity that may be present in the syndrome. Studies conducted by the authors themselves are cited, which found antibodies against G protein-coupled receptors of the autonomic nervous system circulating in the serum of patients with ASIA and improvement of symptoms after silicone explantation. Caravantes, C. et al. 2020 Breast Prosthesis Syndrome: Pathophysiology and Management Algorithm Revision It mentions the pathophysiological mechanisms involved in developing silicone-related autoimmune and inflammatory diseases and their relationship with human genetic variability. Basetto, F. et al. 2012 The periprosthetic capsule and connective tissue diseases: A piece in the puzzle of autoimmune/autoinflammatory syndrome induced by adjuvants Revision It seeks to understand the immunological mechanisms responsible for the emergence and development of autoimmune diseases in patients with breast implants, focusing on the role of cytokines in susceptible individuals. Medina. F. M. et al. 2016 Implantes mamarios, eventos adversos y complicaciones poco frecuentes: hallazgos por mamografía, ecografía y resonancia magnética. Revision Summarizes the main complications related to breast implants. It describes the main clinical manifestations of ASIA and possible findings that can be found in imaging studies in patients with silicone implants who manifest the syndrome. Colaris, M. J. L. et al. 2016 Two hundreds cases of ASIA syndrome following silicone implants: a comparative study of 30 years and a review of current literature Case series and Review It compares two cohort studies with a sample of 100 patients each, with an interval of 30 years between them. It concludes that silicone can be a chronic stimulus for the immune system and that no major changes in the clinical manifestations were reported over the last three decades. Khoo, T. et al. 2019 Silicone breast implants and depression, fibromyalgia and chronic fatigue syndrome in a rheumatology clinic population Controlcase This study analyzed the medical records of patients from a Rheumatology clinic. In the described data, we looked for whether the patients had silicone breast implants and compared them with a control group of patients from the same clinic without implants. Compared to the control group, patients had a higher incidence of fibromyalgia and chronic fatigue. Tervaert, J. W. C. et al. 2018 Autoinflammatory/autoimmunity syndrome induced by adjuvants (ASIA; Shoenfeld’s syndrome): A new flame Revision The study indicates the main symptoms of ASIA and relates them to the chronic inflammatory process by the foreign body reaction to the implant. It also indicates the pre-existence of allergic diseases as an important risk factor for the development of the syndrome and the silicone explant as a way to alleviate the symptoms. Tessel, R. R. et al. 2016 AB0923 Prevalence of Rheumatologic Symptoms and Specific Rheumatic Diseases in Patients with History of Breast Implants. Controlcase The study aimed to compare a group of patients with breast implants and a control group of patients without an implant. Both groups were being followed up with rheumatologists. Patients with breast implants had a higher incidence of arthritis compared to the control group. Maijers, M. C. et al. 2014 Women with silicone breast implants and unexplained systemic symptoms: A descriptive cohort study Case series It indicates the main signs and symptoms of ASIA and points out that most women with the syndrome have a history of allergies. It also states that 69% of them have reduced symptoms after explantation, and this option should be considered for the referred patients. Lastra, O. L. V. et al. 2019 Autoimmune/inflammatory syndrome induced by adjuvants due to silicone breast implant and rheumatic diseases Case series It points to the prevalence of ASIA associated with IMS at 15%. The main associated rheumatologic diseases were systemic sclerosis, fibromyalgia and rheumatoid arthritis. A family history, allergies and smoking association was also observed in patients with the syndrome. Tervaert, J. W. C. et al. 2013 Silicone implant incompatibility syndrome (SIIS): A frequent cause of ASIA (Shoenfeld’s syndrome). Case series The study provides a brief explanation of the adjuvants and the immunological mechanisms triggered by them. Patients referred to the Maastricht University Medical Center were investigated for the presence of breast implants and followed up. According to the symptoms presented, they were diagnosed with ASIA. Soriano, A. et al. 2014 Long-term inflammatory conditions following silicone exposure: The expanding spectrum of the autoimmune/inflammatory syndrome induced by adjuvants (ASIA) Opinion article It compiles information on the relationship between silicone and autoimmunity and its probable pathophysiology due to the material’s not completely inert nature. Finally, it discusses the need to assess the predisposition to autoimmune diseases by HLA genotyping and to screen for rheumatologic diseases prior to surgeries for cosmetic purposes. Shoenfeld, Y. et al. 2013 Autoimmune (auto-inflammatory) syndrome induced by adjuvants-ASIA. Revision The study addresses the different types of adjuvants, the way they interfere with the immune response and the different manifestations they can trigger. These manifestations are described as being part of a single syndrome: ASIA. Colafrancesco, S. et al. 2013 Unraveling the soul of autoimmune diseases: Pathogenesis, diagnosis and treatment adding dowels to the puzzle Opinion article It discusses the pathogenesis of adjuvant-induced autoimmune diseases, their interactions with genetic components, and immune defects, and points to environmental and hormonal factors as possible triggers. Meroni, P. L. 2011 Autoimmune or auto-inflammatory syndrome induced by adjuvants (ASIA): Old truths and a new syndrome? Revision Pavlov-Dolijanovic, S.; Stupar, NV 2017 Women with silicone breast implants and autoimmune inflammatory syndrome induced by adjuvants: description of three patients and a critical review of the literature Case series and Review The article questions whether the silicone molecule is inert due to the wide symptomatology and diagnosis of ASIA in the cases in the article.

References

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³ Alijotas-Reig J. Human adjuvant-related syndrome or autoimmune/inflammatory syndrome induced by adjuvants. Where have we come from? Where are we going? A proposal for new diagnostic criteria. Lupus. 2015;24(10):1012-8.
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» https://doi.org/10.1016/j.jaut.2010.07.003
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⁷ Caravantes-Cortes MI, Roldan-Valadez E, Zwojewski-Martinez RD, Salazar-Ruiz SY, Carballo-Zarate AA. Breast Prosthesis Syndrome: Pathophysiology and Management Algorithm. Aesthetic Plast Surg. 2020;44(5):1423-37. DOI: 10.1007/s00266-020-01663-9
» https://doi.org/10.1007/s00266-020-01663-9
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⁹ Medina, Ch FM, Calle JA, Ledesma OEG, Echeverry JC. Implantes Mamarios, Eventos Adversos Y Complicaciones Poco Frecuentes: Hallazgos Por Mamografía, Ecografía Y Resonancia Magnética. Rev Colomb Radiol. 2016;27(2):4434-40.
¹⁰ Colaris MJL, de Boer M, van der Hulst RR, Cohen Tervaert JW. Two hundreds cases of ASIA syndrome following silicone implants: a comparative study of 30 years and a review of current literature. Immunol Res. 2017;65(1):120-8.
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¹³ Rojas Tessel R, Alonso Lopez D, Buschiazzo E, Juarez R V, Aciar M; Crespo Espindola ME. Prevalence of Rheumatologic Symptoms and Specific Rheumatic Diseases in Patients with History of Breast Implants. Ann Rheum Dis. 2016;75(Suppl 2):1217.
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» https://doi.org/10.1016/j.jaut.2010.10.004
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Publication Dates

Publication in this collection
30 Jan 2023
Date of issue
Oct-Dec 2022

History

Received
26 Aug 2021
Accepted
13 Dec 2021

Este é um artigo publicado em acesso aberto (Open Access) sob a licença Creative Commons Attribution, que permite uso, distribuição e reprodução em qualquer meio, sem restrições desde que o trabalho original seja corretamente citado.

Major Criteria
Exposure to an external stimulus (silicone, infection, vaccine) prior to the manifestations Appearance of typical manifestations:
o Myalgia, myositis, or muscle weakness
o Chronic fatigue, non-restorative sleep, sleep disturbances
o Neurological manifestations (especially associated with demyelination)
o Cognitive deficit, memory loss
o Heartburn, xerostomia
Improvement after the removal of the external factor
Histological findings of Organs involved organs that suggest autoimmunity
Minor Criteria
Appearance of autoantibodies or antibodies against the suspected adjuvant. Other clinical manifestations (e.g., irritable bowel syndrome)
Specific HLA (e.g., HLA DRB1, HLA DQB1) Involvement of another autoimmune disease

Author	Year	Title	Article type	Relevant findings
Tervaert, J. W. C. et al.	2017	Silicone breast implants and autoimmune rheumatic diseases: Myth or reality	Revision	It associates IMSs with a group of patients with complaints of fatigue, cognitive disorders, arthralgia, myalgia, fever, xerophthalmia and xerostomia. It indicates that silicone molecules can migrate from the implant through the body, inducing a chronic inflammatory process and that the IMS explant results in the improvement of symptoms in most patients.
Goren, I. et al.	2015	Autoimmune/inflammatory syndrome induced by adjuvant (ASIA) evolution after silicone implants. Who is at risk?	Revision	It relates IMS and autoimmunity, suggesting ways to identify individuals at higher risk for developing silicone-induced ASIA and thus recommending avoiding IMS in some cases (e.g., individuals with a previous diagnosis of autoimmune diseases or genetic predisposition to immune system hyperactivity).
Alijotas-Reig, J.	2015	Human adjuvant-related syndrome or autoimmune/inflammatory syndrome induced by adjuvants. Where have we come from? Where are we going? A proposal for new diagnostic criteria.	Opinion article	It proposes new diagnostic criteria for ASIA based only on objective clinical and laboratory data to be discussed and validated.
Schoenfeld, Y; Agmon-Levin, N.	2010	‘ASIA’ - Autoimmune/inflammatory syndrome induced by adjuvants	Revision	Discusses the role of adjuvants in the pathogenesis of immune-mediated diseases.
Borba, V. et al.	2020	Classical Examples of the Concept of the ASIA Syndrome.	Revision	It describes the diagnostic criteria proposed by Shoenfeld and the manifestations of autoimmunity that may be present in the syndrome. Studies conducted by the authors themselves are cited, which found antibodies against G protein-coupled receptors of the autonomic nervous system circulating in the serum of patients with ASIA and improvement of symptoms after silicone explantation.
Caravantes, C. et al.	2020	Breast Prosthesis Syndrome: Pathophysiology and Management Algorithm	Revision	It mentions the pathophysiological mechanisms involved in developing silicone-related autoimmune and inflammatory diseases and their relationship with human genetic variability.
Basetto, F. et al.	2012	The periprosthetic capsule and connective tissue diseases: A piece in the puzzle of autoimmune/autoinflammatory syndrome induced by adjuvants	Revision	It seeks to understand the immunological mechanisms responsible for the emergence and development of autoimmune diseases in patients with breast implants, focusing on the role of cytokines in susceptible individuals.
Medina. F. M. et al.	2016	Implantes mamarios, eventos adversos y complicaciones poco frecuentes: hallazgos por mamografía, ecografía y resonancia magnética.	Revision	Summarizes the main complications related to breast implants. It describes the main clinical manifestations of ASIA and possible findings that can be found in imaging studies in patients with silicone implants who manifest the syndrome.
Colaris, M. J. L. et al.	2016	Two hundreds cases of ASIA syndrome following silicone implants: a comparative study of 30 years and a review of current literature	Case series and Review	It compares two cohort studies with a sample of 100 patients each, with an interval of 30 years between them. It concludes that silicone can be a chronic stimulus for the immune system and that no major changes in the clinical manifestations were reported over the last three decades.
Khoo, T. et al.	2019	Silicone breast implants and depression, fibromyalgia and chronic fatigue syndrome in a rheumatology clinic population	Control case	This study analyzed the medical records of patients from a Rheumatology clinic. In the described data, we looked for whether the patients had silicone breast implants and compared them with a control group of patients from the same clinic without implants. Compared to the control group, patients had a higher incidence of fibromyalgia and chronic fatigue.
Tervaert, J. W. C. et al.	2018	Autoinflammatory/autoimmunity syndrome induced by adjuvants (ASIA; Shoenfeld’s syndrome): A new flame	Revision	The study indicates the main symptoms of ASIA and relates them to the chronic inflammatory process by the foreign body reaction to the implant. It also indicates the pre-existence of allergic diseases as an important risk factor for the development of the syndrome and the silicone explant as a way to alleviate the symptoms.
Tessel, R. R. et al.	2016	AB0923 Prevalence of Rheumatologic Symptoms and Specific Rheumatic Diseases in Patients with History of Breast Implants.	Control case	The study aimed to compare a group of patients with breast implants and a control group of patients without an implant. Both groups were being followed up with rheumatologists. Patients with breast implants had a higher incidence of arthritis compared to the control group.
Maijers, M. C. et al.	2014	Women with silicone breast implants and unexplained systemic symptoms: A descriptive cohort study	Case series	It indicates the main signs and symptoms of ASIA and points out that most women with the syndrome have a history of allergies. It also states that 69% of them have reduced symptoms after explantation, and this option should be considered for the referred patients.
Lastra, O. L. V. et al.	2019	Autoimmune/inflammatory syndrome induced by adjuvants due to silicone breast implant and rheumatic diseases	Case series	It points to the prevalence of ASIA associated with IMS at 15%. The main associated rheumatologic diseases were systemic sclerosis, fibromyalgia and rheumatoid arthritis. A family history, allergies and smoking association was also observed in patients with the syndrome.
Tervaert, J. W. C. et al.	2013	Silicone implant incompatibility syndrome (SIIS): A frequent cause of ASIA (Shoenfeld’s syndrome).	Case series	The study provides a brief explanation of the adjuvants and the immunological mechanisms triggered by them. Patients referred to the Maastricht University Medical Center were investigated for the presence of breast implants and followed up. According to the symptoms presented, they were diagnosed with ASIA.
Soriano, A. et al.	2014	Long-term inflammatory conditions following silicone exposure: The expanding spectrum of the autoimmune/inflammatory syndrome induced by adjuvants (ASIA)	Opinion article	It compiles information on the relationship between silicone and autoimmunity and its probable pathophysiology due to the material’s not completely inert nature. Finally, it discusses the need to assess the predisposition to autoimmune diseases by HLA genotyping and to screen for rheumatologic diseases prior to surgeries for cosmetic purposes.
Shoenfeld, Y. et al.	2013	Autoimmune (auto-inflammatory) syndrome induced by adjuvants-ASIA.	Revision	The study addresses the different types of adjuvants, the way they interfere with the immune response and the different manifestations they can trigger. These manifestations are described as being part of a single syndrome: ASIA.
Colafrancesco, S. et al.	2013	Unraveling the soul of autoimmune diseases: Pathogenesis, diagnosis and treatment adding dowels to the puzzle	Opinion article	It discusses the pathogenesis of adjuvant-induced autoimmune diseases, their interactions with genetic components, and immune defects, and points to environmental and hormonal factors as possible triggers.
Meroni, P. L.	2011	Autoimmune or auto-inflammatory syndrome induced by adjuvants (ASIA): Old truths and a new syndrome?	Revision
Pavlov-Dolijanovic, S.; Stupar, NV	2017	Women with silicone breast implants and autoimmune inflammatory syndrome induced by adjuvants: description of three patients and a critical review of the literature	Case series and Review	The article questions whether the silicone molecule is inert due to the wide symptomatology and diagnosis of ASIA in the cases in the article.

Autor	Ano	Título	Tipo do artigo	Achados relevantes
Tervaert, J. W. C. et al.	2017	Silicone breast implants and autoimmune rheumatic diseases: Myth or reality	Revisão	Associa IMSs a um grupo de paciente com queixas de fadiga, distúrbios cognitivos, artralgia, mialgia, febre, xeroftalmia e xerostomia. Indica que moléculas de silicones podem migrar do implante pelo corpo, induzindo um processo inflamatório crônico e que o explante do IMS resulta na melhora dos sintomas na maioria dos pacientes.
Goren, I. et al.	2015	Autoimmune/inflammatory syndrome induced by adjuvant (ASIA) evolution after silicone implants. Who is at risk?	Revisão	Relaciona IMS e autoimunidade, sugerindo meios para identificar indivíduos com maior risco para desenvolver ASIA induzida por silicone e, assim, recomenda evitar o IMS em alguns casos (ex: indivíduos com diagnóstico prévio de doenças autoimunes ou predisposição genética para hiperatividade do sistema imune).
Alijotas-Reig, J.	2015	Human adjuvant-related syndrome or autoimmune/inflammatory syndrome induced by adjuvants. Where have we come from? Where are we going? A proposal for new diagnostic criteria.	Artigo de opinião	Propõe novos critérios diagnósticos para ASIA baseados somente em dados clínicos e laboratoriais objetivos para serem discutidos e validados.
Schoenfeld, Y; Agmon-Levin, N.	2010	‘ASIA’ - Autoimmune/inflammatory syndrome induced by adjuvants	Revisão	Discute o papel dos adjuvantes na patogênese de doenças imunomediadas.
Borba, V. et al.	2020	Classical Examples of the Concept of the ASIA Syndrome.	Revisão	Descreve os critérios diagnósticos propostos por Shoenfeld e as manifestações de autoimunidade que podem estar presentes na síndrome. São citados estudos conduzidos pelos próprios autores, que tiveram o achado de anticorpos contra receptores acoplados à proteína G do sistema nervoso autônomo circulantes no soro dos pacientes com ASIA e melhora dos sintomas após o explante do silicone.
Caravantes, C. et al.	2020	Breast Prosthesis Syndrome: Pathophysiology and Management Algorithm	Revisão	Menciona os mecanismos fisiopatológicos envolvidos no desenvolvimentos das doenças autoimunes e inflamatórias relacionadas ao silicone, assim como a relação com a variabilidade genética humana.
Basetto, F. et al.	2012	The periprosthetic capsule and connective tissue diseases: A piece in the puzzle of autoimmune/autoinflammatory syndrome induced by adjuvants	Revisão	Procura entender os mecanismos imunológicos responsáveis pelo surgimento e desenvolvimento de doenças autoimunes em pacientes com implantes mamários, focando no papel das citocinas em indivíduos suscetíveis.
Medina. F. M. et al.	2016	Implantes mamarios, eventos adversos y complicaciones poco frecuentes: hallazgos por mamografía, ecografía y resonancia magnética.	Revisão	Resume as principais complicações relacionadas às próteses mamárias. Descreve as principais manifestações clínicas da ASIA e possíveis achados que podem ser encontrados em exames de imagem nos pacientes com implante de silicone que manifestam a síndrome.
Colaris, M. J. L. et al.	2016	Two hundreds cases of ASIA syndrome following silicone implants: a comparative study of 30 years and a review of current literature	Série de casos e Revisão	Compara dois estudos de coorte com casuística de 100 pacientes cada, há um intervalo de 30 anos entre a realização deles. Conclui que o silicone pode ser um estímulo crônico para o sistema imune e que não existem alterações maiores das manifestações clínicas relatadas ao longo das últimas três décadas.
Khoo, T. et al.	2019	Silicone breast implants and depression, fibromyalgia and chronic fatigue syndrome in a rheumatology clinic population	Caso controle	Nesse estudo, foram analisados prontuários médicos de pacientes de uma clínica de Reumatologia. Procurou-se nos dados descritos se as pacientes tinham implantes mamários de silicone e comparou-se com um grupo controle, de pacientes da mesma clínica, sem implantes. Em comparação ao grupo controle, as pacientes apresentaram maior incidência de fibromialgia e fadiga crônica.
Tervaert, J. W. C. et al.	2018	Autoinflammatory/autoimmunity syndrome induced by adjuvants (ASIA; Shoenfeld’s syndrome): A new flame	Revisão	O estudo indica os principais sintomas da ASIA e os relaciona ao processo crônico inflamatório pela reação de corpo estranho ao implante. Também indica a pré-existência de doenças alérgicas como importante fator de risco para o desenvolvimento da síndrome e o explante do silicone como forma de amenizar os sintomas.
Tessel, R. R. et al.	2016	AB0923 Prevalence of Rheumatologic Symptoms and Specific Rheumatic Diseases in Patients with History of Breast Implants.	Caso controle.	O objetivo do estudo foi comparar um grupo de pacientes com implantes mamários e um grupo controle de pacientes sem implante. Ambos os grupos estavam em acompanhamento com reumatologistas. As pacientes com implantes mamários apresentaram maior incidência de artrite em relação ao grupo controle.
Maijers, M. C. et al.	2014	Women with silicone breast implants and unexplained systemic symptoms: A descriptive cohort study	Série de casos	Indica os principais sinais e sintomas da ASIA e aponta que a maioria das mulheres com a síndrome apresentavam histórico de alergia. Ainda refere que 69% delas têm redução dos sintomas após explante, devendo essa opção ser considerada para as pacientes referidas.
Lastra, O. L. V. et al.	2019	Autoimmune/inflammatory syndrome induced by adjuvants due to silicone breast implant and rheumatic diseases	Série de casos	Aponta a prevalência de ASIA associada a IMS em 15%. As principais doenças reumatológicas associadas foram esclerose sistêmica, fibromialgia e artrite reumatoide. Foi ainda observada associação de história familiar, alergias e tabagismo nos pacientes com a síndrome.
Tervaert, J. W. C. et al.	2013	Silicone implant incompatibility syndrome (SIIS): A frequent cause of ASIA (Shoenfeld’s syndrome).	Série de casos	O estudo faz uma breve explicação sobre os adjuvantes e os mecanismos imunológicos desencadeados por ele. Pacientes que foram encaminhadas ao Centro Médico da Universidade de Maastricht foram investigados para a presença de próteses mamárias e acompanhadas. De acordo com a sintomatologia apresentada, foram diagnosticadas com ASIA.
Soriano, A. et al.	2014	Long-term inflammatory conditions following silicone exposure: The expanding spectrum of the autoimmune/inflammatory syndrome induced by adjuvants (ASIA)	Artigo de opinião	Compila informações sobre a relação do silicone com a autoimunidade, assim como sua provável fisiopatologia pela natureza não completamente inerte do material. Por fim, debate a necessidade de avaliação da predisposição a doenças autoimunes, por genotipagem HLA e rastreio de doenças reumatológicas, anteriormente a cirurgias com propósito cosmético.
Shoenfeld, Y. et al.	2013	Autoimmune (auto-inflammatory) syndrome induced by adjuvants-ASIA.	Revisão	O estudo aborda os diferentes tipos de adjuvantes, o modo como interferem na resposta imunológica e as diferentes manifestações que podem desencadear. Essas manifestações são descritas como fazendo parte de uma única síndrome: ASIA.
Colafrancesco, S. et al.	2013	Unraveling the soul of autoimmune diseases: Pathogenesis, diagnosis and treatment adding dowels to the puzzle	Artigo de opinião	Debate a patogênese de doenças autoimunes induzidas por adjuvantes e suas interações com componentes genéticos, defeitos imunes e aponta fatores ambientais e hormonais como possíveis gatilhos.
Meroni, P. L.	2011	Autoimmune or auto-inflammatory syndrome induced by adjuvants (ASIA): Old truths and a new syndrome?	Revisão
Pavlov-Dolijanovic, S.; Stupar, NV	2017	Women with silicone breast implants and autoimmune inflammatory syndrome induced by adjuvants: description of three patients and a critical review of the literature	Série de casos e Revisão	O artigo questiona se a molécula de silicone é de fato inerte pela ampla sintomatologia e diagnóstico de ASIA realizado nos casos do artigo.

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[2] ² Goren I, Segal G, Shoenfeld Y. Autoimmune/inflammatory syndrome induced by adjuvant (ASIA) evolution after silicone implants. Who is at risk? Clin Rheumatol. 2015;34(10):1661-6.

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[7] ⁷ Caravantes-Cortes MI, Roldan-Valadez E, Zwojewski-Martinez RD, Salazar-Ruiz SY, Carballo-Zarate AA. Breast Prosthesis Syndrome: Pathophysiology and Management Algorithm. Aesthetic Plast Surg. 2020;44(5):1423-37. DOI: 10.1007/s00266-020-01663-9
» https://doi.org/10.1007/s00266-020-01663-9

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[10] ¹⁰ Colaris MJL, de Boer M, van der Hulst RR, Cohen Tervaert JW. Two hundreds cases of ASIA syndrome following silicone implants: a comparative study of 30 years and a review of current literature. Immunol Res. 2017;65(1):120-8.

[11] ¹¹ Khoo T, Proudman S, Limaye V. Silicone breast implants and depression, fibromyalgia and chronic fatigue syndrome in a rheumatology clinic population. Clin Rheumatol. 2019;38(5):1271-6.

[12] ¹² Cohen Tervaert JW. Autoinflammatory/autoimmunity syndrome induced by adjuvants (ASIA; Shoenfeld’s syndrome): A new flame. Autoimmun Rev. 2018;17(12):1259-64.

[13] ¹³ Rojas Tessel R, Alonso Lopez D, Buschiazzo E, Juarez R V, Aciar M; Crespo Espindola ME. Prevalence of Rheumatologic Symptoms and Specific Rheumatic Diseases in Patients with History of Breast Implants. Ann Rheum Dis. 2016;75(Suppl 2):1217.

[14] ¹⁴ Maijers MC, de Blok CJ, Niessen FB, van der Veldt AA, Ritt MJ, Winters HA, et al. Women with silicone breast implants and unexplained systemic symptoms: a descriptive cohort study. Neth J Med. 2013;71(10):534-40.

[15] ¹⁵ Lastra OLV, Dominguez MdPC, Jara LJ, Ramirez GM. Autoimmune/inflammatory syndrome induced by adjuvants due to silicone breast implant and rheumatic diseases. Ann Rheum Dis. 2019;78(Suppl 2):2111.

[16] ¹⁶ Cohen Tervaert JW, Kappel RM. Silicone implant incompatibility syndrome (SIIS): a frequent cause of ASIA (Shoenfeld’s syndrome). Immunol Res. 2013;56(2-3):293-8.

[17] ¹⁷ Soriano A, Butnaru D, Shoenfeld Y. Long-term inflammatory conditions following silicone exposure: the expanding spectrum of the autoimmune/inflammatory syndrome induced by adjuvants (ASIA). Clin Exp Rheumatol. 2014;32(2):151-4.

[18] ¹⁸ Shoenfeld Y, Maślińska M. Autoimmune (auto-inflammatory) syndrome induced by adjuvants - ASIA. Reumatologia. 2013;51(2):101-7.

[19] ¹⁹ Colafrancesco S, Agmon-Levin N, Perricone C, Shoenfeld Y. Unraveling the soul of autoimmune diseases: pathogenesis, diagnosis and treatment adding dowels to the puzzle. Immunol Res. 2013;56(2-3):200-5.

[20] ²⁰ Meroni PL. Autoimmune or auto-inflammatory syndrome induced by adjuvants (ASIA): old truths and a new syndrome? J Autoimmun. 2011;36(1):1-3. DOI: 10.1016/j.jaut.2010.10.004
» https://doi.org/10.1016/j.jaut.2010.10.004

[21] ²¹ Pavlov-Dolijanovic S, Vujasinovic Stupar N. Women with silicone breast implants and autoimmune inflammatory syndrome induced by adjuvants: description of three patients and a critical review of the literature. Rheumatol Int. 2017;37(8):1405-11.