ASIA syndrome: Adverse reaction or autoimmunity?

Introduction: Adjuvant-Induced Autoimmune / Auto-inflammatory Syndrome (ASIA) is an immune-mediated condition by the exposure of material previously considered inert, such as silicone, aluminum salts, mineral oils, hyaluronic acid and metallic implants. In addition to a genetic component, there is a risk of development of an undifferentiated connective tissue disease, which varies clinically and laboratorially depending on the adjuvant material used. Patients and methods: This paper addresses two cases reported, in caucasian subjects, born and residents in Madeira Island, Portugal. In this article are described two different histological patterns occurring in ASIA patients, due to mammoplasty with silicone.
Conclusion: Although ASIA does not meet the diagnostic requirements for connective tissue disease, there is a close relationship with the development of autoimmune conditions. These cases aim to alert the medical community to the existence of this entity, encourage the notification of situations arising from exposure to adjuvants and investigate the presence of a genetic predisposition and a suggestive histological pattern in excisional biopsies of satellite adenomegalies.

Introduction

The adjuvant-induced autoimmune / autoinflammatory syndrome (ASIA) is an entity, recognised in 2011 by Shoenfeld, which encompasses autoimmune phenomena that are induced after exposure to adjuvants, that is, substances that enhance an immune response, whether innate and adaptive. This hyperactivation phenomenon of the immune system can culminate in autoimmune reactions or a chronic inflammatory state. The conditions used to define this syndrome are: siliconosis, Gulf War syndrome (GWS), macrophage myofasciitis syndrome (SMM) and post-vaccination phenomena.[1-5]

The ASIA diagnoses are often late and with considerable controversy. The gross histopathological examination of focal lesions and the tissue surrounding the foreign implanted elements, often provide direct information. Typically, there is fibroblast and collagen deposition, infiltration of macrophages, lymphocytes, and foreign body giant cells with apparent granulomas. There may be lymphoid hyperplasia.

This syndrome has the following manifestations: myalgia, arthralgia, chronic asthenia and xerostomia, as well as neurological symptoms, which include cognitive disorders and memory loss. The clinic of this entity varies between men and women, particularly depending on the adjuvants to which they were exposed. Like autoimmune conditions, this entity has an epigenetic component, which often evolves into a condition of undifferentiated connective tissue disease.

Patients considered to have ASIA have at least 2 major criteria (exposure to external stimulus that precedes the clinic; typical manifestations; improvement of symptoms with the removal of the provocative agent; suggestive biopsy of the organs involved) or 1 major and 2 minor criteria (self- antibodies or antibodies against adjuvant; other clinical manifestations; HLA-DRB1 or HLA-DQB1 haplotypes; evolution to autoimmune disease).[1-3]

Since the recognition of this entity, more than 4000 cases have been notified and reported. However, it remains challenging to establish a temporo-causal relationship between symptomatology and suspected symptoms, given the scarcity of reported cases.

Case series of a cluster of cases

CASE 1: A 42-year-old Caucasian woman with a personal history of fibromyalgia, hepatitis C, hepatitis B, who had been abstinent for 15 years from drug addictive habits, who had had bilateral breast silicone implants for 9 years (Figure 1). Oriented to Internal Medicine, due to asthenia, non-selective anorexia, fever and weight loss of about 20 kg in 12 months. Objectively, it denoted axillary and inguinal adenopathies. Analytically unchanged. Pathological anatomy of excision of axillary adenopathy revealed a pattern of follicular immunoreactivity. The patient started corticosteroid therapy, with regression of adenomegalies.

Figure 1.

Chest radiograph of 42-year-old female patient with bilateral breast implants for nine years, oriented to internal medicine due to asthenia, non-selective anorexia, fever and weight loss.

CASE 2: Caucasian woman, 53 years old, with a history of mastectomy (2001) due to neoplasia and then by mammoplasty with silicone (2003), anterior uveitis (2007). In 2008, a patient reported weight loss, extreme asthenia and a cervical nodule. Analytically unchanged. Computed tomography: multiple non-necrotizing cervical lymphadenopathies and micro-nodules in the lung. PETscan suggested metastatic lymphadenopathies (Figure 2). Fine needle aspiration revealed non-necrotizing granulomatous and caseous lymphadenitis. Antituberculostatics were started empirically (interrupted 5 months after poor response). Bronchoalveolar lavage, respiratory function tests and cultural exam did not show any changes. There was regression of adenopathy with corticosteroids.

Figure 2.

PETscan suggesting metastic lymphadenopathies of a 53-year-old female patient with mammoplasty following mastectomy due to breast cancer, oriented to internal medicine due to weight loss, asthenia and cervical nodule.

Discussion

Silicone, once considered an inert material, like other adjuvants, is capable to enhance antigen-specific immune response that can spread into lymph nodes, lungs, liver, and other tissues. Later inducing immunoreactivity phenomena manifested with an extensive complex pattern of symptoms, leading to the definition of “siliconosis”, also known as “adjuvant disease”, in the early 90 s. There is some debate as whether silicon-based reaction is an acquired or cross-reactive entity, or even a direct immune reaction stimulated after non-specific polyclonal activation. However, silicone has proven to be immunogenic for delayed-type hypersensitivity reactions.[4,5]

ASIA by silicone does not meet all diagnostic criteria for a connective tissue disease, but its relationship is unequivocal given that 0.8% of exposed individuals are at risk of manifesting a diffuse connective tissue disease (DCTD).

Balk et al. have demonstrated a possible association between silicone implants and a variety of DCTD such as dermatomyositis, polymyositis, scleroderma. Authors also report a possible association between autoimmune symptoms with silicone breast implantation and Human Leukocyte Antigen (HLA) genotype positive for HLA-DR5 and HLA-DQ2.

Thus, the link between silicone and autoimmunity involves a broader spectrum of autoimmune manifestations. In 2016 more than 200 cases of ASIA were reported after exposure to silicone implants, despite modifications in the silicone implants’ constituents in the last century.

Since there are no screening methods or diagnostic/laboratory markers for ASIA, this entity continues to represent an exclusion diagnosis. These cases aim to alert the medical community to the existence of this entity, to encourage the notification of situations resulting from the exposure of adjuvants, as well as to emphasize the need to create prospective controlled studies that confirm the development of autoimmune processes with other adjuvants to be identified. In view of the findings described in the respective clinical cases, the authors highlight the need to investigate the presence of a suggestive histological pattern in excisional biopsies of satellite adenomegalies, identify individuals with HLA genotype predisposition, as well as the existence of a hormonal component that can justify the prevalence of this syndrome in feminine gender.