Welcome to the 13th International Congress on Autoimmunity interactive program

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Patients with ASIA present with complaints such as fatigue, cognitive impairment, arthralgias, myalgias, pyrexia, dry eyes, and dry mouth. During the last decennium, it has been postulated that these symptoms in patients with foreign body implants are due to a chronic inflammatory process and an adjuvant effect of the implanted biomaterial. Ultimately, these inflammatory reactions result in (an increase of) allergies, autoimmune diseases, immune deficiency, and/or lymphomas. Pre-existent allergic disease has been found to be an important risk factor for the development of ASIA after foreign body implantation. Explantation of the foreign body results in the majority of patients in an amelioration of the symptoms.

The best-studied example of foreign body implantation that may result in ASIA is silicone-breast implantation (SBI). Previously, we calculated from the literature that explantation of the SBI improved silicone-related complaints in 75 % of the patients (469 of 622). In patients with autoimmune diseases, however, additional (immunosuppressive) therapy is needed. There is some evidence that explantation with total capsulectomy may result in better results than explantation without capsulectomy, although good prospective studies are lacking. Recently, thousands of patients have been described demonstrating that SBI explantation results in an amelioration of ASIA symptoms. Several possibilities which could clarify why patients improve after explantation have been postulated. Firstly, the inflammatory response could be reduced after explantation, supporting a causal role for SBI in the pathogenesis of ASIA. Secondly, explantation of the implants may remove a nociceptive stimulus, which may be a causative factor for many complaints as well. Recently, studies have been published that not only suggest recovery of symptoms but also improvement of objective measures after explantation, suggesting that SBI indeed causes ASIA. Options for the reconstruction of the explanted breast such as autologous tissue and/or the use of saline- or hydrocellulose-filled breast implants will be discussed.

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To date, around 60% of the world population has been protected by vaccines against SARS-CoV-2, signifcantly reducing the devastating efect of the pandemic and restoring social economic activity through mass vaccination. Multiple studies have demonstrated the efectiveness and safety of vaccines against COVID-19 in healthy populations, in people with risk factors, in people with or without SARS-CoV-2 infection, and in immunocompromised people. According to the criteria for post-vaccine adverse events established by the World Health Organization, a minority of individuals may develop adverse events, including autoimmune syndromes. The exact mechanisms for the development of these autoimmune syndromes are under study, and to date, a cause-efect relationship has not been established. Many of these autoimmune syndromes meet sufcient criteria for the diagnosis of Adjuvant-Induced Autoimmune Syndrome (ASIA syndrome). The descriptions of these autoimmune syndromes open new perspectives to the knowledge of the complex relationship between the host, its immune system, with the new vaccines and the development of new-onset autoimmune syndromes. Fortunately, most of these autoimmune syndromes are easily controlled with steroids and other immunomodulatory medications and are short-lived. Rheumatologists must be alert to the development of these autoimmune syndromes, and investigate the relationship between autoimmune/infammatory symptoms and vaccination time, and assess their therapeutic response.

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A clear association between the clinical picture of symptomatic women with silicone breast implants and dysregulated immunity was in dispute for decades. Recently, our group found, in a large-population based study, that women with silicone breast implant (SBI) have a significant increased risk to develop autoimmune diseases. Moreover, we reported a significant change in the titters of circulating IgG autoantibodies directed against G-protein coupled receptors (GPCRs) of the autonomic nervous system in symptomatic women with SBI, which might explain some of their subjective and autonomic-related manifestations. So far, the potential pathogenic functional effects of autoantibodies derived from symptomatic women with SBI have not been explored. In the current study, we describe for the first time, the in vitro and in-vivo functional activity of purified IgG antibodies derived from symptomatic women with SBI. Our in vitro studies shows that while healthy-derived IgG reduces the secretion of pro-inflammatory cytokines (TNFα and IL-6) by human monocytes in response to bacterial lipopolysaccharide (LPS), IgG derived from SBI women increases the production of these cytokines. Importantly, we directly injected IgGs derived from symptomatic women with SBI (suffering from autonomic-related manifestations such as cognitive impairment and depression) into mice brains. Behavioral studies demonstrated a specific and transient significant increment (about 60%) in the time spent at the center of the open field arena as compared with mice injected with IgG from healthy women (without SBI), apparently indicating anxiolytic outcome of SBI-IgG. This effect was accompanied with a strong trend of reduction of the locomotor activity of the SBI-IgG treated mice, indicating an apathic behavior masked by an anxiolytic-like behavior. Our study is the first to show the pathogenic functional activity of IgG autoantibodies in symptomatic women with SBI, emphasizing the importance of these antibodies as potential targets for antibody-depleting therapies in silicone breast implant related illness.

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Abstract.
Vaccination is one of the most successful public health programs in the history of medicine. As result of global immunization campaigns, several dreaded diseases have been eradicated. Nevertheless, modern excessive vaccination with persistent immune system hyperstimulation can theoretically lead to the development of autoimmune illnesses in predisposed individuals. Unfortunately, vaccine safety has become a medical dogma; vaccine adverse event reports are often shunned as anti-vax propaganda.

Independent clinicians from different parts of the world have described the onset of a chronic debilitating illness soon after HPV vaccination. This illness is characterized by headache, fatigue, widespread pain, dizziness nausea and abnormal limb movements, among other vexing symptoms. This constellation of symptoms and signs has been labeled with different diagnoses such as complex regional pain syndrome, postural orthostatic tachycardia syndrome, myalgic encephalomyelitis/chronic fatigue syndrome, or fibromyalgia. Profound dysautonomia and small fiber neuropathy have been reported in these cases.

This purported Post-HPV vaccination syndrome resemble other contested vaccine-related illnesses such as Macrophagic Myofasciitis and Gulf War Illness. We propose that vaccine-triggered, immune-mediated autonomic dysfunction and small fiber neuropathy could lead to the development of these post- vaccination syndromes in genetically susceptible individuals. Dorsal root ganglia may play a key role in the pathogenesis of these syndromes. These para-vertebral ganglia house the pain-transmitting small nerve fiber nuclei, each individual nucleus is enveloped by immune-competent glial cells. Lymphocytes, macrophages, and different pro-nociceptive mediators populate DRG. Communicating nerves tightly link DRG with the para-vertebral sympathetic chain. Dorsal root ganglia are able to actively trapped antigen specific antibodies including vaccines. We proposed that in susceptible individuals vaccines may be trapped at the dorsal root ganglia inducing inflammation, dysautonomia and small fiber neuropathy.

Background and Aims

Granulomatosis with polyangiitis (GPA) is a small vessel necrotizing vasculitis associated with the anti-neutrophil cytoplasmic antibodies (ANCA), affecting various organs including breasts. Here we aim to describe the first ever case of potentially silicone-induced PR3+ GPA arising in a patient with breast implants who developed GPA five weeks after the COVID-19 vaccination.

Methods

Clinical data of the patient was collected.

Results

35-year old female presented at our outpatient clinic with a two-month history of tender and swollen right breast, polyarthralgia, myalgia and elevated inflammatory markers. MRI revealed a concentric subcapsular thickening of the right breast without an implant rupture. In the following days she progressively developed arthritis, paresthesia, hyperalgesia, left foot drop (clinically mononeuritis multiplex) and acral ischemia leading to gangrene of distal left fifth finger. Further, full blown GPA glomerulonephritis along with the presence of anti-PR3 antibodies developed. She was treated with high doses of glucocorticoids, IVIG, vasodilators, low-molecular-weight heparin, and surgical removal of breast implants. Histological examination of the implants revealed presence of granulomatous vasculitis with an intense fibrinoid necrosis of vessel walls. After the surgery the patient received intravenous cyclophosphamide and rituximab.

Conclusions

We suspect a two-hit model: a chronic adverse immune system reaction to silicone that was acutely exacerbated by vaccine-trigged immune activation leading to severe GPA. Our case shows that silicone breasts implants should be considered as an environmental trigger of GPA.

Background and Aims

The pathophysiological mechanism of the clinical symptomatology in chronic disorders such as complex regional pain syndrome, fibromyalgia, chronic fatigue syndrome, silicone breast implants related symptoms, and post COVID syndrome have not been clearly defined yet. The course of the pain in part of the syndromes, the absence of evident tissue damage, and the predominant autonomic dysfunction features are shared similarities between them.

Methods

The production of autoantibodies following a trigger in these syndromes were previously described. For instance, trauma as a trigger of complex regional pain syndrome, infectious agents in fibromyalgia, chronic fatigue syndrome, and the post COVID syndrome, and the immune stimulation by silicone in women with breast implants.

Results

The autoantibodies produced, were shown to be directed against the autonomic nervous system receptors leading to the amplification of the perception of pain and to various clinical symptoms seen in patients diagnosed with these syndromes. Therefore, autoantibodies targeting the autonomic nervous system resulting in autonomic dysfunction is probably the most comprehensive explanation of the pathophysiology of the disorders mentioned.

Conclusions

We introduce hereby a new notion uniting complex regional pain syndrome, fibromyalgia, chronic fatigue syndrome, silicone breast implants related symptoms, and post COVID syndrome, namely “autoimmune autonomic dysfunction syndromes”. We believe that our notion is more precise in classifying the syndromes under one title, due to its etiological, pathophysiological, and clinical properties. The suggested term would facilitate both lab and clinical studies aimed for better diagnosis and treatment options for the syndromes included.

Background and Aims

The "Autoimmune/Autoinflammatory Syndrome Induced by Adjuvants" (ASIA syndrome) described in 2011 by Shoenfeld and Agmon-Levin consists of heterogeneous clinical features and immunological dysfunctions triggered by exposure to an adjuvant in genetically predisposed subjects

Methods

We present a case of patient with autoimmune thyroiditis and familial history of autoimmune diseases who developed ASIA syndrome after silicone breast implants.

Results

A 37-year-old women presented in January 2019 with arthralgia, sicca syndrome, fatigue, + ANA, +SSA and +Acla IgG antibodies. The nailfold capillaroscopy was normal. Two years prior she had cosmetic silicone breast implants procedure that was complicated with fluid collection in right breast that needed drainage three times. She was treated with prednisolone by the surgeon due to right breast capsulitis. The family history revealed that patient mother has systemic lupus erythematosus and secondary Sjogren’s syndrome, while grandmother has cutaneous lupus. Over the course of the next two years she didn’t have regular follow up visits due to COVID 19 and diagnostic procedures towards systemic autoimmune diseases were not completed. In September 2021, she had + ANA and + anticentromere antibodies both in sera and breast fluid, sicca syndrome, arthralgia, abnormal capillaroscopic findings and reduced diffusing capacity of the lungs for carbon monoxide (DLCO). Computed tomography of the chest and heart ultrasound were normal. There were no SSA or Acla antibodies. The antimalarial and corticosteroid therapy were started.

Conclusions

: In women with organ specific autoimmune disease and familial autoimmune disease background, silicone breast implants should be carefully considered due to ASIA syndrome development.

Background and Aims

We performed a prospective follow-up of 119 aesthetic/reconstructive breast surgeries, checking every female before, 3, 6 and 12 months after the operation.

Methods

In 90 cases silicone breast implants (SBI) were used, 29 cases of breast surgery without silicone (BSWS) constituted control group. Blood serum levels of: prolactin, TSH, thyroid hormones, calcitriol, testosterone, estrogens and 9 various autoantibodies were measured. ASIA questionnaire interview was taken before and year after surgery. Local tissue specimens obtained from 12 females during and 6 months after operation were histologically analyzed.

Results

Only in SBI (but not in BSWS) significant increase in anti-TSHR autoantibodies occurred (both regarding seropositive cases number, and average anti-TSHR concentration which exceeded normal range). 18,5% of SBI patients (but no one among BSWS) showed significant gain in anti-MCV and anti-cardiolipin autoantibodies (but within normal ranges). Autoantibodies mentioned positively correlated with each other and negatively – with testosterone. While expecting surgery, stress-related/psychogenic hyperprolactinemia manifested in 50% of cases (both in SBI and BSWS), disappearing in 3 months. After a year number of females positive for ASIA critheria increased (both in SBI and BSWS), perhaps resulting from post-operation immune system hyperstimulation. Bioptates showed perifocal inflammation, silicone-containing microgranulomas and CD3/CD4+ lymphocyte infiltration. Hence, SBI may increase anti-thyroid autoimmunity in healthy recipients, presumably due to its adjuvant effect. Before surgery calcitriol level was low-normal, with significant increase 12 months after SBI, probably reflecting vitamin D activating compensatory response to adjuvant effect.

Conclusions

SBI-related risk of autoimmune thyropathies should be taken into account among contraindications and during dispensary observation.