



REVIEW ARTICLE Year : 2019 | Volume : 14 | Issue : 5 | Page : 76-81 Autoimmune/autoinflammatory syndrome induced by adjuvants: what is it and why the controversy?



Sajal Ajmani

Arthritis and Rheumatology Clinic, New Delhi, India

Date of Web Publication 2-Dec-2019 Correspondence Address:

Dr. Sajal Ajmani

Arthritis and Rheumatology Clinic, New Delhi - 110 070

India

Source of Support: None, Conflict of Interest: None Check

DOI: 10.4103/0973-3698.272150

Abstract

Autoimmune/autoinflammatory syndrome induced by adjuvants (ASIA) is a group of autoimmune diseases with possible adjuvant-associated causes, such as siliconosis, macrophagic myofasciitis syndrome, Gulf War syndrome, sick building syndrome, and postvaccination autoimmune phenomena. Over time, an international registry with over 500 patients has been established for this conglomeration of rare syndromes. In spite of this, the very existence of ASIA has been debated at times and the diagnostic criteria have come under criticism. The cause-effect relationship between adjuvants and autoimmune phenomenon is difficult to prove due to lack of precisely defined time range between exposure and disease and also due to numerous exposures to adjuvants a person may have in his or her lifetime. The current article attempts at reviewing the clinical features, diagnostic criteria, and evidence for/against the existence of the disease.

Keywords: Adjuvant, autoinflammatory, Gulf War syndrome, macrophagic myofasciitis, sick building syndrome, siliconosis, vaccine

How to cite this article:

Ajmani S. Autoimmune/autoinflammatory syndrome induced by adjuvants: what is it and why the controversy?. Indian J Rheumatol 2019;14, Suppl S1:76-81

How to cite this URL:

Ajmani S. Autoimmune/autoinflammatory syndrome induced by adjuvants: what is it and why the controversy?. Indian J Rheumatol [serial online] 2019 [cited 2020 Sep 27];14, Suppl S1:76-81. Available from: http://www.indianjrheumatol.com/text.asp?2019/14/5/76/272150







Introduction



In 2011, Yehuda Shoenfeld et al. proposed the term autoimmune/autoinflammatory syndrome induced by adjuvants (ASIA) with the aim of grouping together a growing number of reports of diseases such as siliconosis, macrophagic myofasciitis syndrome (MMF), sick building syndrome (SBS), Gulf War syndrome (GWS), and postvaccination autoimmune phenomena, all of which are characterized by dysregulation of innate and adaptive immune system after adjuvant exposure.[1],[2],[3],[4] Adjuvants are agents that promote innate immune system pattern recognition receptor activation. They are commonly used in vaccines to increase their efficacy by boosting immune response.[5],[6] Conflicting reports of immune adverse events due to aluminum have been published, which is the most common adjuvant used in vaccines.[7],[8] Aluminum adjuvants are used in various vaccines such as tetanus, diphtheria, hepatitis A and B, Haemophilus influenzae, and pneumococcal vaccines. They are not used in the live vaccines such as measles, mumps, rubella, varicella, and rotavirus.[9] Substances such as silicone gel, acrylamides, hyaluronic acid, liquid paraffin, and methacrylate compounds which are not used in vaccines also have adjuvant-like properties.[10],[11],[12] This article intends to discuss the proposed criteria, clinical manifestations, pathogenesis, and evidence for/against the existence of ASIA.





Search Strategy



(MMF)Pubmed engine was used to search for articles with the MeSH terms 'ASIA AND syndrome', 'adjuvant AND autoimmune' and 'adjuvant AND autoinflammatory'. Around 60 articles were found to be relevant which were mostly case series and case reports. Among them, case series and articles on proposed pathogenesis were given preference.





Diagnostic Criteria



The criteria proposed by Shoenfeld et al. are shown in [Table 1].[1] There are four major and four minor criteria. The presence of any two major or one major plus two minor criteria is sufficient to establish the diagnosis. This criteria has come under criticism for not being specific.[13] Table 1: Proposed diagnostic criteria for autoinflammatory syndrome induced by adjuvants



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The first major criterion requires exposure to a vaccine, an adjuvant, or an infection. This criterion could easily include all human beings. The vaccines or infections which could trigger ASIA are not specified in this criterion. Furthermore, the time limit between exposure to these agents and ASIA has not been defined. Jara et al. suggested that the lag time for ASIA can vary from 2 days to 23 years.[4] Such a considerable time variation makes proving causality extremely difficult. The second major criterion includes symptoms which are nonspecific; most patients with autoimmune disorders have the symptoms mentioned, such as fever and fatigue. Hence, any patient presenting with fever, chronic fatigue, or autoimmunity could qualify as ASIA, because they are certain to have had exposure to triggers such as infection or vaccine at some point in their lifetime. The third major criterion is the improvement of symptoms once the causative agent is withdrawn. This obviously cannot be applied to vaccines because they cannot be withdrawn after administration but can apply to silicone breast implants (SBIs).



The minor criteria have faced similar criticism. The detection of antibodies to aluminum is not a standard diagnostic test. To develop such a test for clinical use, it would be essential to establish a reference interval for normal individuals in various populations. Clinical manifestations such as irritable bowel syndrome (IBS) are included as minor criteria. Since up to 11% of the population has IBS, this would decrease the specificity of the criteria as well.[14] Many patients with autoimmunity have the HLA haplotypes stated in the criteria, and these haplotypes are also commonly found in the general population, further reducing the specificity of the diagnostic criteria.[15] The last minor criterion includes any patient who has a known autoimmune disorder. Therefore, many patients with an autoimmune disorder may potentially qualify as having ASIA, provided they have the relevant haplotype and have ever had an infection.





Clinical Features



GWS is used to denote a chronic disorder characterized by a wide range of acute and chronic symptoms affecting military veterans of the 1990-1991 Gulf War. The symptoms include muscle pain, fatigue, rashes, diarrhea, insomnia, and cognitive problems [16]

MMF: A few patients who had received aluminum-containing vaccines presented months to years later with diffuse myalgias, arthralgias, or muscle weakness. On histopathological evaluation of their deltoid muscle biopsies, they were found to have inflammatory macrophage formations with aluminum-containing crystal inclusions and microscopic muscle necrosis. This histopathological finding is defined as MMF syndrome. Since deltoid is the most common site for administering vaccines, it appears that aluminum-containing vaccines result in these abnormalities [17]





The SBS: When occupants of a common building start complaining of subjective symptoms such as headache, inability to concentrate, bad odors, irritation of the eyes, nose and throat, lethargy, and less frequently, nausea, chest tightness, and dizziness, it is defined as the SBS [3]

Siliconosis: Includes symptomatic patients who have been exposed to silicone gel by either injection or implant placement. Patients with siliconosis usually present with fatigue, arthralgia, and myalgia. [18] In addition to these musculoskeletal symptoms, a few of them may have skin rash, alopecia, arthritis, fever, and lymphadenopathy. A significant number of patients develop symptoms similar to Sjögren's (sicca symptoms), lupus (arthralgia, skin rash, and fever), and rheumatoid arthritis (polyarthritis). [18] However, they do not have the corresponding autoantibodies, and in case of a rheumatoid arthritis like illness, there is absence of significant erosions

In addition to these musculoskeletal symptoms, a few of them may have skin rash, alopecia, arthritis, fever, and lymphadenopathy. A significant number of patients develop symptoms similar to Sjögren's (sicca symptoms), lupus (arthralgia, skin rash, and fever), and rheumatoid arthritis (polyarthritis). However, they do not have the corresponding autoantibodies, and in case of a rheumatoid arthritis like illness, there is absence of significant erosions Postvaccination phenomenon: Numerous autoimmune phenomena such as Guillain-Barré syndrome, multiple sclerosis, arthritis, and lupus following vaccines have been reported.[19]



Patients with ASIA typically present with nonspecific features such as arthralgia, fatigue, and myalgia. In 2011, an International ASIA registry was created. Recently, a case series of 500 patients was published from that registry by Watad et al.[20] In this case series, patients in whom the gap between the adjuvant exposure and disease onset was more than 5 years were excluded. Patients with nonspecific, self-limited symptoms within a few days after a vaccination were excluded as well. Common symptoms noted were arthralgia (73.8%), chronic fatigue (65.6%), myalgia (50.8%), sleep disturbance (43.8%), fever (38.8%), and neurological manifestations (35%). Other symptoms observed were sicca (19%) and Raynaud's phenomenon (19%). On examination, findings such as rash (12.8%), lymphadenopathy (28.2%), and mouth ulcers (6%) were present. The mean age at presentation was 43 years with a strong female preponderance (89%) and 46.6% were smokers. Patients with ASIA have been found to have a significant reduction in the ability to engage in personal, occupational, educational, or social activities.[21] Many patients report postexertional malaise lasting from days to weeks. Symptoms of cognitive impairment are also seen.



In 2006, McGonagle and McDermott proposed classification of autoimmune diseases into polygenic autoimmune, polygenic autoinflammatory, and mixed pattern diseases.[22] Examples of polygenic autoimmune disorders are rheumatoid arthritis and systemic lupus erythematosus, in which there is dysfunction of predominately dendritic, B and T cells. Polygenic autoinflammatory diseases have predominately innate immunity dysfunction such as inflammatory bowel disease and polymyalgia rheumatica. Diseases such as psoriasis and seronegative arthropathies with MHC Class-I associations are proposed to be intermediate with mixed innate-adaptive immune system dysfunction. Among the well-defined immune diseases mentioned in the earlier case series, polygenic autoimmune diseases represented 93% of the reported conditions. Among these, undifferentiated connective tissue disorder and Sjögren's syndrome had the highest prevalence with a percentage of 38.8% and 16.8%, respectively. A statistically significant association was found for HBV vaccine (odds ratio [OR]: 6.72). The polygenic autoinflammatory diseases represented 5.8% of the well-defined immune conditions, with giant cell arteritis, Crohn's disease, and polymyalgia rheumatica being the most common. A large number of patients (31%) had an undefined diagnosis of autoimmune/autoinflammatory disorder.



Concerning the autoantibody profile status, Watad et al. found that 54.4% of patients had a positive autoantibody test. The most common was antinuclear antibody (48%), followed by rheumatoid factor (7%) and anti-SSA (6%).[20] The median time between disease onset and exposure to adjuvant was 1 month, while for vaccine it was 1 week. Identified foreign materials were silicone (12.5%), hyaluronic acid (29.2%), mineral oils (20.8%), and polyacrylamide (37.5%). Among vaccines, 26.4% of patients had exposure to hepatitis B vaccine, 11% to influenza, and 10% to human papilloma virus (HPV) vaccine. Patients were treated with steroids, hydroxychloroquine, disease-modifying antirheumatic drugs, and few even required biologics.





Pathogenesis and Evidence For/against the Disease



Similar to the suggested mechanisms by which infections promote autoimmunity, vaccines are postulated to induce autoimmunity by molecular mimicry, epitope spreading, clonal expansion, and bystander activation.[23],[24] Among these, molecular mimicry has the maximum evidence.[25],[26],[27],[28],[29] It has been suggested that there is diminished immune tolerance on exposure of the immune system to adjuvants.[30] In such a situation, pathogen-derived antigens in vaccines which are similar to human proteins may induce an immune response against “self-proteins,” leading to autoimmunity.[8]



There have been many animal studies on the effects of adjuvants/vaccines. Khan et al. reported that intramuscular injection of aluminum-containing vaccine led to the appearance of aluminum deposits in organs, such as spleen and brain.[31] These deposits persisted even 1 year after the injection. Two other studies investigated the ability of aluminum hydroxide to induce ASIA in mice,[32],[33] both showing acceleration of lupus in mouse models. However, all three studies used doses of aluminum in excess of those that could be expected to be delivered through vaccination.[34] Studies have also examined the effect of Complete Freund's Adjuvant (CFA) in animal models.[32],[35],[36],[37],[38] In these studies, CFA was shown to induce autoimmune disease such as lupus and antiphospholipid antibody syndrome in genetically predisposed mice. However, CFA (which consists of inactivated mycobacteria and mineral oil) is not used in any vaccine; hence, the relevance of these studies is unclear.



In a study from Denmark, patients with allergic rhinitis who were being treated with immunotherapy (aluminum-containing allergen) were compared with those receiving conventional treatment such as antihistamines and nasal sprays.[39] In this large nationwide study, patients receiving immunotherapy (n = 18,841) had a 14% lower incidence of autoimmunity compared with those on conventional treatment (n = 428,484). However, unlike in immunotherapy, in addition to adjuvants, vaccines contain pathogen-derived antigenic particles with possible contaminants (both infectious and noninfectious) which are not there in immunotherapy.[8],[40],[41] Hence, this study cannot be taken as direct evidence against vaccine-induced autoimmune phenomenon.



ASIA after SBI is well documented.[21] Both local and distant complications have been reported. Patients can present with fatigue, arthralgias, and other nonspecific symptoms.[42] Removal of the implant leads to resolution of symptoms in 60%-80% of the patients.[43] It has been shown that silicon-containing particles are transported to regional lymph nodes, leading to an inflammatory reaction.[42] In 2013, de Boer et al. reported 32 patients who had developed ASIA after SBI.[44] The median time between exposure to adjuvants and the start of complaints was 10 years (2-24 years). A systemic autoimmune disease was diagnosed in 53% of the cases and organ-specific autoimmune disease in 22% of cases. Many patients with silicone-related ASIA would fulfill the criteria for chronic fatigue syndrome,[45] fibromyalgia,[46] undifferentiated connective tissue disease,[47] and/or sarcoidosis-like disease.[42],[48] Histopathological findings are similar to idiopathic sarcoidosis as a result of infiltration of silicones in lymph nodes, lungs, and various other tissues. It has also been suggested that patients with SBI are more likely to have autoimmune diseases such as Sjogren's syndrome, systemic lupus erythematosus, rheumatoid arthritis, and systemic sclerosis, though this is not certain.[42],49-52] A large epidemiological study from Israel was recently reported by Watad et al., in which 24,651 SBI patients were compared with 98,604 matched controls. They found that patients with SBI had an increased risk of developing autoimmune diseases as compared to the controls (OR: 1.21, 95% confidence interval: 1.17-1.26). The strongest associations were reported with sarcoidosis, Sjogren's syndrome, and systemic sclerosis.[12] A significant link between Guillain-Barrè syndrome and influenza immunization has been reported.[53]





Controversies in Vaccine-Related Autoimmune/autoinflammatory Syndrome Induced by Adjuvants



Most of the controversy to the existence and research in ASIA stems from its proposed association with vaccines.[8] In recent years, we have witnessed a rising opposition to vaccinations, mostly from people from nonscientific backgrounds. This puts public safety in grave danger because vaccinations are one of the most effective public health measures. There are many reports of people, even in developed countries, opting out of vaccinating their children.[54] However, that does not justify the medical community for going in the opposite extreme and disregarding any side effects which are reported. Any concern raised about the safety of a vaccine in the current climate is usually followed by immediate dismissal without a thorough analysis.[7],[8] This opposition to any question which is raised against vaccines is not called for because it is generally accepted that any medical intervention can lead to side effects even if very rarely. Vaccines are no exceptions, such as “Rotashield” vaccine which has been withdrawn due to a higher risk of adverse events.[55] It is fairly common for significant adverse effects to be initially reported through case reports and series. Furthermore, pharmaceutical companies have sometimes been found guilty of expediting vaccines to the market without adequate safety testing.[56],[57],[58] However, it needs to be stressed again that these serious adverse events have been reported at an extremely low occurrence rate. Immunization practices have enhanced the quality of human life by eradicating and controlling several communicable diseases.[7]



The mechanism of an autoimmune disease is thought to be as a result of a complex interplay between several environmental and genetic factors.[20] It is often difficult to prove a causation of a disease by a substance and usually requires at least two elements: an association to be found in different settings and a plausible mechanism.[20] The importance of addressing these connections between adjuvants and ASIA is not to criticize vaccination, but rather it is to develop even better vaccines if these connections are proven.





Conclusion



ASIA remains an enigmatic entity, raising many questions which are yet to be answered. More specific diagnostic criteria which help in studying the disease would go a long way in understanding the disease better and addressing the objections or queries raised by people in the scientific community.



Financial support and sponsorship



Nil.



Conflicts of interest



There are no conflicts of interest.







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Tables

[Table 1]



