Autoimmune/Autoinflammatory Syndrome Induced by Adjuvants (ASIA) is a relatively new syndrome, introduced in 2011. Diagnosis of ASIA is based on major and minor criteria encompassing generalized signs and symptoms such as persistent fatigue, cognitive difficulties, neurological deficits, myalgias/arthralgias, and dry mouth. As the name implies, an immune adjuvant is requisite, although the adjuvant itself may or may not be identified. ASIA is thought to be a rare entity, which makes the identification and study of those affected challenging. Knowledge of ASIA may help clinicians identify patients with underlying immune dysregulation.
Autoimmune/Autoinflammatory Syndrome Induced by Adjuvants (ASIA) was first proposed as a distinct syndrome in 2011.1 In a seminal paper in the Journal of Autoimmunity, Shoenfeld and Agmon-Levin outlined 4 conditions as representative of autoimmune/autoinflammatory conditions triggered by an adjuvant. They described this entity as ASIA, or Shoenfeld syndrome.
The prototypical conditions used to define ASIA were siliconosis, Gulf War Syndrome (GWS), macrophagic myofasciitis syndrome (MMS), and postvaccination phenomena. All 4 represent manifestations of underlying autoinflammatory or autoimmune reactions. Since 2011, several more conditions have emerged under the designation of ASIA, including narcolepsy, postural orthostatic hypotension (POTS), sick building syndrome, chronic fatigue syndrome (CFS), and fibromyalgia.2-6
Shoenfeld is an internist, researcher, and practicing clinician in autoimmunity for over 30 years. The “discovery” of ASIA is an anachronism in today’s evidence-based medical paradigm. It was largely through empirical evidence and ongoing research that he deduced the existence of an immune hyperreactive state, not yet designated as a known disease or syndrome. The combining of autoimmune and autoinflammatory states into 1 entity is indicative of his clinical, rather than mechanistic, focus. It may not be coincidence that his stated specialty is rheumatoid arthritis. Rheumatoid diseases are now recognized as having 2 distinct pathophysiologies: autoimmune or autoinflammatory.7 While the dominant molecular underpinnings of each are distinctly different, there may be a continuum between autoinflammation and autoimmunity.8 This continuum is implied in the clinical description of ASIA as being an autoimmune and/or an autoinflammatory reaction.
Clinically, patients with ASIA often present with generalized complaints, such as persistent fatigue, myalgia, arthralgia, neurologic symptoms, cognitive impairment/memory loss, or dry mouth. Any of these symptoms, in the absence of identifiable pathology, qualify as 1 of the major criteria developed by Shoenfeld/Agmon-Levin.
In addition to presenting symptoms, a patient can have any 1 major criteria or 2 minor criteria to qualify as having ASIA (Figure). The major criteria are: 1) exposure to an external stimulus (infection, vaccine, silicone, adjuvant) prior to symptom manifestation; 2) histologically normal tissue on biopsy; and 3) normalization of symptoms upon removal of inciting agent/adjuvant. The minor criteria are: 1) autoantibodies or antibodies directed toward the adjuvant; 2) other clinical manifestations (eg, irritable bowel syndrome); 3) presence of specific human leukocyte antigen (HLA) subtypes; and 4) evolution to overt autoimmune disease.1
Integrative or alternative practitioners are more likely to see patients with symptom constellations that do not fit into any known disease process. Often patients seek integrative and alternative medicine when conventional medicine fails to diagnose or adequately treat their persistent symptoms. It is likely that patients suffering from ASIA disproportionately seek help from integrative/alternative practitioners. Identification of ASIA in these patients can help practitioners tailor appropriate treatments.
For example, studies suggest that those with myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) or fibromyalgia (FM) use complementary, alternative, or integrative medicine (CAIM) at higher rates than the general public.9
Studies suggest results of treatments for ME/CFS and FM by CAIM providers are as good as or better than symptom management from conventional medicine.10,11 Interestingly, at least some cases of ME/CFS may be manifestations of ASIA.12 By extension, patients with ASIA may derive benefit in seeing CAIM practitioners. Not coincidentally, CAIM practitioners often do not need a formal conventional diagnosis of a disease process to apply appropriate therapies.
As of 2010, 23.5 million people were living with a diagnosis of an autoimmune disease in the United States.13 According to the National Institutes of Health, “Autoimmune diseases can affect almost any part of the body, including the heart, brain, nerves, muscles, skin, eyes, joints, lungs, kidneys, glands, the digestive tract, and blood vessels.”14
When seeking help for given symptoms, patients typically see a medical professional who specializes in the most predominant symptoms. Thus, some patients will see an endocrinologist for Hashimoto’s thyroiditis, Grave’s disease, or type I diabetes mellitus, while others with primarily rheumatic, gastrointestinal, or respiratory symptoms will seek care from a rheumatologist, gastroenterologist, or pulmonologist, respectively. In both autoimmune and autoinflammatory conditions, there can be symptom crossover between many organs and systems that confound the diagnostic picture. If there is no predominant organ or system, as is the case with fatigue, the diagnosis of underlying autoimmune or autoinflammatory process may not be apparent.
For these reasons there is growing recognition that autoimmunology is a distinct discipline.15 Given the disparate specialists who see autoimmunity as one of many disease processes in their respective specialty, it is not surprising that patients who present with generalized symptoms (ie, ASIA), who do not warrant criteria for a given autoimmune disease, may evade diagnosis. That is, unless (and until) the autoimmune/autoinflammatory reaction grows more severe and the criteria for an overt disease process reaches the tipping point.
This brings us to a telling minor criterion for ASIA: “evolvement to an autoimmune disease.” This implies that before the overt disease process develops, there may be an autoimmune or autoinflammatory state not quite reaching disease status. Indeed, there is evidence that autoantibody titers can be high for many years before overt autoimmune disease diagnosis.16 Recognizing ASIA before the evolution of overt disease processes may lead to earlier treatment.
What is an Adjuvant?
In immunology, adjuvants are substances that increase an immune response.17 They are largely exogenous substances that may be intended as adjuvants (eg, aluminum hydroxide in vaccines), or unintended as adjuvants (eg, plasticizers).18 To be clear, adjuvants are not always associated with adverse reactions. Many herbs traditionally used to “bolster immune function” act as adjuvants.19-22 In the diagnosis of ASIA, an adjuvant is assumed to incite the autoreactivity, but the actual adjuvant substance may not be identified for every patient.
Adjuvant substances affect immune response in complex ways that involve both the innate and humoral aspects of immunity. Innate responses may be augmented by increased cytokine secretion with secondary activation of antigen-presenting cells (APCs), activation of the inflammasome, and direct activation of innate cells through effects on several different receptors (eg, Toll-like receptors, NOD-like receptors). In addition, adjuvants can enhance humoral response by promoting dendritic cell attraction to T cells and increasing the uptake of antigens by APCs.23
Adjuvant substances, including intended adjuvants in vaccines (eg, aluminum hydroxide), foreign materials to the body (eg, silicone), organisms (eg, Epstein-Barr Virus [EBV]), or toxicants incidental to modern living (eg, mercury, crude petroleum oils) can act as immunogenic stimulants. Why then are autoimmune diseases and ASIA not more ubiquitous, given the billions of people exposed to the wide distribution of adjuvants in the world? The reason for this has only recently come to light: there appear to be requisite genetic components.24,25
One area of the genome encoding for major histocompatibility complexes (MHCs)—the locus known as the human leukocyte antigen (HLA) system—is of particular importance. HLA encodes for proteins involved in antigen presentation. As such, it is intimately involved in pathogen recognition and autoimmunity. Encoding of HLAs is highly diverse between individuals and populations. Polymorphisms in HLA, especially HLA-DRB1, account for both the rarity and greater susceptibility of some individuals to developing autoimmune reactions.26
As mentioned, Shoenfeld and Agon-Levin included 4 conditions in the original criteria for ASIA: siliconosis, GWS, MMS, and postvaccination phenomena. The common symptoms between these conditions make up 1 of the major criteria for diagnosis of ASIA (Figure). Here is a brief look at these prototypical ASIA conditions.
Several authors have proposed that the silicone in implantation devices can act as an adjuvant to the immune system in those with genetic susceptibility, possibly alone or perhaps with a concomitant infectious agent.27 Silicone was considered an inert substance and assumed not to elicit any immune reactions. However, both rodent and human studies have disproved this assumption.28-31 Despite this, when there are reactions to silicone, they are mostly limited to the area around the implant itself, rather than systemic.32-34
In those who do associate symptom development with breast implantation, there is a fairly consistent trend in the types of systemic symptoms reported.
Several studies have shown that women with silicone breast implants have significantly higher incidence of arthralgia, myalgia, fatigue, and impaired cognition.35-37 Given that hundreds of millions of silicone breast implants have been surgically placed in the past 30-plus years, these reactions are considered a rarity. However, in those who do associate symptom development with breast implantation, there is a fairly consistent trend in the types of systemic symptoms reported.
In a 2016 publication by Colaris and colleagues, 100 women who received silicone breast implants and had been diagnosed with ASIA in the Netherlands (2014) were compared to a matched cohort of 100 women with what was then called “adjuvant breast disease” due to silicone breast implants, diagnosed at Baylor College of Medicine between 1985 and 1992.38 The authors found that despite the 30-year difference between the cohorts, the symptoms between the 2 cohorts were similar. In this same publication, the authors reviewed the literature and found that in 18 other published cohorts, many symptoms post-silicone breast implant coincided with ASIA. These symptoms included fatigue, myalgia, arthralgia, pyrexia, cognitive dysfunction, sicca, and/or neurological symptoms.
Siliconosis is somewhat controversial. The Food and Drug Administration (FDA) has found no evidence for any association between autoimmune diseases and silicone implants or injections. Indeed, studies reviewing incident autoimmune diseases, including systemic lupus erythematosus and mixed connective tissue disease, have not found any causal relationship.39,40 However, the FDA has not addressed the possibility of a nonclassical inflammatory reaction, such as ASIA.
Again, implants are generally considered safe. However, according to the FDA, they are not considered lifetime devices. The longer an implant is in place, the higher the risk of its rupture or leakage, with increased rates at 6 to 10 years post-implantation.41 The FDA recommends women with silicone-filled implants be screened for silent rupture 3 years after implantation and every 2 years thereafter.42
Various authors have posed unanswered questions regarding ASIA in women with silicone breast implants. These questions all remain unanswered. Does the implant need to leak or rupture to stimulate a reaction?43 Why doesn’t removal result in reversal of symptoms 100% of the time?44 Is there a requisite coadjuvant or additional antigenic stimuli needed to trigger ASIA?45
Systemic reactions to implanted silicone devices remain rare. However, knowledge of ASIA allows a practitioner to recognize possible reactions to silicone injections or implants, even if years or decades have passed since the procedure. For more information on the topic, see the 2013 review titled “Silicone implant incompatibility syndrome (SIIS): A frequent cause of ASIA (Shoenfeld’s syndrome).”46
Macrophagic myofasciitis syndrome (MMS)
MMS is perhaps the most well-studied autoimmune condition induced by a vaccine adjuvant. It presents mostly as myalgia, chronic fatigue, poor sleep, and cognitive difficulties. Aluminum oxyhydroxide (alum), a commonly used vaccine adjuvant since 1927, is the causative agent.47,48
The signature muscle pathology, macrophagic myofasciitis (MMF), is a granulomatous lesion found at the site of previous intramuscular injection(s) with alum-containing vaccines. The lesion is marked by persistence of alum-laden macrophages and inflammation in the muscle for years or decades. Systemic symptoms of MMS often appear years after the vaccines are administered, making a causal association less than obvious without a detailed and thorough patient history.
In retrospect, the 'perfect storm' of events that led to the discovery of MMS was extraordinary.
The mechanism of immune stimulation by aluminum is not ultimately known.49 However, there is ample evidence that the nanosized particles of alum once thought to be inert and remain extracellular50 actually may travel via immune cells to distant organs, even passing into the brain, where they may incite immune reactivity.51-53
The first cases of MMS emerged in the mid- to late-1990s. In 1998, a consortium of French physicians published a paper describing a rare condition marked by diffuse myalgias and fatigue.54 In the course of disease workup in these patients, muscle biopsies were taken. The deltoid muscle biopsy consistently found granulation tissue largely made up of macrophages that contained aluminum intracellularly.55 In addition, 100% of these adults had received hepatitis B, hepatitis A, and/or tetanus toxoid vaccine in the given muscle. It is now well-established that aluminum hydroxide (alum), a common vaccine adjuvant, can accumulate in muscle tissue and lead to MMS in select vaccine recipients.56
In retrospect, the “perfect storm” of events that led to the discovery of MMS was extraordinary. A review by Gheradi and Authier summed it up: “It is now clear that rapid emergence of MMF in France resulted from the specific combination of 3 factors: (1) replacement of the subcutaneous route by the i.m. route of vaccination in the early 1990s; (2) widespread extension of HBV [hepatitis B] primo-vaccination to the French adult population in the same time; and (3) the choice of the deltoid muscle (also used for i.m. vaccination) for routine muscle biopsy in France whereas biceps brachialis and quadriceps femoris muscles are preferred in most other countries.”49 Given the rarity of MMS, the entity itself may have gone completely unrecognized if it were not for this unique situation in the late 1990s in France.
Since then, there have been approximately 1,000 cases of MMS in France, with a few cases also reported in other countries.57-61 While the incidence of MMS appears to be extraordinarily rare, many patients with MMS also fit the criteria for chronic fatigue syndrome (CFS) and, by extension, ASIA.62 In one study of 30 consecutive MMS patients, 87% fit the criteria for CFS, leading the authors to suggest that patients with CFS be questioned regarding aluminum-containing vaccinations and the vaccinated muscle biopsied if appropriate.63
As with all autoimmune conditions, there is a necessary genetic susceptibility to MMS. In 2002 Sandrine Guis and colleagues published a case series of 10 patients with MMS, 6 of whom had polymorphisms in HLA-DRB1*01.63 Since then, polymorphisms of HLA-DRB1 have been implicated in many autoimmune reactions, including MMS, while other HLA haplotypes may actually confer protection from autoimmune reactions.27
Only some vaccines contain alum. According to the Centers for Disease Control and Prevention (CDC), “Aluminum is present in U.S. childhood vaccines that prevent hepatitis A, hepatitis B, diphtheria-tetanus-pertussis (DTaP, Tdap), Haemophilus influenzae type b (Hib), human papillomavirus (HPV), and pneumococcus infection … In the United States, vaccines against measles, mumps, rubella, chickenpox, rotavirus, polio, and seasonal influenza vaccines do not contain added adjuvants.”64
Gulf War syndrome
Gulf War Syndrome (GWS) shares many symptoms with MMS—in particular chronic fatigue, cognitive dysfunction, and musculoskeletal pain. There is little dispute that the entity exists, but great dispute surrounds its causation.
In establishing GWS as a prototypical presentation of ASIA, Shoenfeld relied heavily on one study by Asa that implicated squalene as the offending adjuvant substance found in anthrax vaccinations.65 The findings of that study were striking. Of the 144 veterans with GWS studied, 95% of those deployed to the Gulf War and 100% of those who did not deploy had antibodies to squalene.1 This association led to the conjecture that squalene is acting as an adjuvant for a generalized autoinflammatory reaction (ie, GWS). However, this hypothesis is far from conclusive, and since its publication in 2000, the association of GWS with squalene has not been strongly corroborated.66-68
While GWS was used as a prototypical ASIA condition, it is difficult to diagnosis GWS and to discern possible adjuvants. GWS is marked by general symptoms that may have various causes, depending on the patient’s genome and exposures. Also, because GWS occurs in veterans with such a wide variety of environmental exposures, from ammunition aerosols to pesticides that come into direct contact with skin and clothing, determining a single causative agent for what may be a manifestation of multiple conditions may very well not be possible.69-73
Vaccines, and the herd immunity that is inherent in their widespread adoption, have lessened the morbidity and mortality of many infectious diseases. While vaccines are safe for the vast majority of recipients, there are those with genetic susceptibilities who may develop autoimmune/autoinflammatory reactions, or ASIA. Postvaccination phenomena causing autoimmunity are considered rare, so much so the association is questioned by immunologists.74 However, the link between autoimmune reactions and vaccinations, while rare, is plausible and deserves sober consideration. Cases of post-vaccine phenomena frequently present as arthritis, neurological complaints, fatigue, encephalitis, and vasculitis.75
While vaccines are safe for the vast majority of recipients, there are those with genetic susceptibilities who may develop autoimmune/autoinflammatory reactions, or ASIA.
As stated above, MMS is perhaps the most well-delineated ASIA condition causally linked to adjuvant (alum) from vaccinations. However, there are other examples of vaccines and autoimmune disease associations. For example, systemic lupus erythematosus (SLE) has been associated with hepatitis B vaccination,76 HPV vaccination,77,78 and H1N1 vaccination.79 Of course, association is not causation, and in some of these cases there was reason to believe that a latent or low-level autoimmunity was already present.
Infectious agents, or their metabolic products (eg, lipopolysaccharide) are generally accepted as possible causative factors in developing autoimmunity. It stands to reason that vaccines, which have antigenic stimuli necessary for efficacy, may also be a trigger for autoimmunity. Whether the autoimmune reaction is caused by antigenic stimuli, vaccine adjuvant, both, or a requisite coinfection/stimulation is an unanswered question.
Since 2011 there have been several case reports of ASIA following vaccinations. In 2012, ASIA was reported in a case series of 93 people, all of whom had received the hepatitis B vaccine.80 In 2014, Shoenfeld and colleagues determined that of 19 cases of chronic fatigue and fibromyalgia following hepatitis B vaccination, all 19 also met criteria for ASIA.4 In that case series, factors for ASIA were determined as adverse events during vaccination, high autoantibody titers, or a family history of autoimmune disease. Of note, hepatitis B vaccination was also the most common vaccination in adults developing MMS, reviewed above.
Untoward reactions to the HPV vaccine need special consideration. Unlike many of the prophylactic vaccines that impart immunity to common diseases and have been used for decades, the HPV vaccine was relatively recently adopted. In a paper published in January 2017, reviewing adverse events of HPV using the World Health Organization Adverse Event (AE) reporting system (VigiBase), the authors concluded: “Cluster analysis reveals additional reports of AEs following HPV vaccination that are serious in nature and describe symptoms that overlap those reported in cases from the recent safety signals (POTS, CRPS, and CFS), but which do not report explicit diagnoses. While the causal association between HPV vaccination and these AEs remains uncertain, more extensive analyses of spontaneous reports can better identify the relevant case series for thorough signal evaluation.”81
Postural orthostatic hypotension (POTS),3,2,82 complex regional pain syndrome(CRPS)83 and CFS12 are all considered conditions that meet the criteria for ASIA. It should be emphasized that, given the tens of millions of doses of HPV vaccine administered around the world, reports of these adverse events are exceedingly rare. However, their commonality as ASIA-designated conditions, as well as their rarity, lends support to the hypothesis that these adverse events represent some type of autoreactivity.
Several other cases of post-HPV adverse events have been reported, including overt autoimmune disease as well as ASIA.82,84-90 Anovulation as a presenting autoimmune reaction has received particular attention.91,92 According to the CDC there is no association of anovulation with HPV vaccines of any type. Anovulation may be due to many factors including extreme exercise, stress, low body mass index (BMI), and glucose dysregulation.
Over the years there have been hundreds of case reports on a variety of vaccinations associated with autoimmune diseases or ASIA. For a complete update of ASIA cases, most of which are postvaccination phenomena, refer to the January 2017 publication, “Autoimmune/inflammatory syndrome induced by adjuvants (Shoenfeld syndrome)–an update.”5
It is thought that infectious agents (eg, EBV, HPV, Hepatitis B) or their byproducts (eg, lipopolysaccharide) are the most common triggers of autoimmunity. Whether through incidental exposure, infection with the organism, or exposure in the form of antigens found in a vaccine, exposure to organisms is something that is universal and unavoidable. The relative rarity of autoimmunity appears to be due to the need for particular genetic susceptibility. As personalized medicine evolves and research determines who may be susceptible, it is quite possible that we will better define who is at risk for developing autoimmune/autoinflammatory reactions.
This review of ASIA focuses on the presence of 2 components—adjuvant and genetic predisposition—in triggering an autoimmune/autoinflammatory reaction. There are other influences on immune reactivity that should be mentioned. Hormones like estrogen influence susceptibility, which may explain why women are more likely than men to be diagnosed with an overt autoimmune disease. Nutritional status may also influence autoimmune responses. For example, vitamin D deficiency may increase risk and lead to more severe symptoms.93,94
There is no “screening” for ASIA, per se. There are also no blood markers required for diagnosis. Clinicians need to be attentive to both the criteria and possible adjuvant exposures. The challenge is that symptoms may appear many years after exposure to an adjuvant substance. To be clear, ASIA is not without its skeptics, and a lack of any timeline for the development of symptoms is a major critique.95
As personalized medicine becomes the norm, perhaps knowing the patient’s genomics will help clinicians gauge an appropriate level of suspicion. Recently 4 characteristics of higher risk individuals were proposed: 1) history of postvaccination immune phenomena; (2) personal history of autoimmunity; (3) history of strong allergic reactions; and (4) tendency to develop autoimmunity (genetics, presence of autoantibodies, strong family history of autoimmunity).96 Many of these risk factors can be discerned through a thorough medical history. All clinicians should keep in mind the possibility of ASIA in patients presenting with arthralgias, myalgias, chronic fatigue, sleep disturbance, neurological/cognitive complaints, and unexplained respiratory and skin disorders.
Ultimately, the diagnosis of ASIA is based on meeting 2 major criteria or 1 major and 2 minor criteria. This means that autoantibodies do not need to be high to meet the criteria. As with all syndromes, ASIA is a symptom complex defined by given criteria. Being familiar with ASIA helps clinicians recognize the associated symptoms and consider treatment options that may have been overlooked, such as therapies geared toward correcting immune dysregulation.
There are many questions to be answered: Will newer adjuvants be safer and less likely to incite autoimmune/inflammatory reactions in those who are vulnerable? What other substances in our environment act as adjuvants? Do any of the additional substances or excipients in vaccines play a role as unintended adjuvants?
Patients who have conditions not diagnosed as disease yet present with multiple symptoms may seek CAIM providers because of lack of resolution with conventional medicine. Complementary, alternative, or integrative medicine practitioners may recognize and address an autoimmune/autoinflammatory reaction (ASIA) long before any overt autoimmune disease is diagnosed. Better tracking, awareness, recognition, and reporting of ASIA by all clinicians is needed to assess its prevalence. Further understanding of the precise genetics behind higher risk for immune dysregulation may help identify—and spare—those at highest risk of ASIA or autoimmune disease.
Figure: ASIA Criteria
> Exposure to an external stimulus (infection, vaccine, silicone, adjuvant) prior to clinical manifestations
> The appearance of ‘typical’ clinical manifestations:
> Removal of inciting agent induces improvement
> Typical biopsy of involved organs
> The appearance of autoantibodies or antibodies directed at the suspected adjuvant
> Other clinical manifestations (eg, irritable bowel syndrome)
> Specific HLA (ie, HLA DRB1, HLA DQB1)
> Evolvement of an autoimmune disease (eg, multiple sclerosis, systemic sclerosis)