Autoinflammatory Syndrome Induced by Adjuvants: An Overview

Introduction:

The autoinflammatory syndrome induced by adjuvants (ASIA), also known as Shoenfeld's syndrome, involves different autoimmune conditions that can be triggered by exposure to substances with adjuvant activity, such as vaccines, medical implants, and others. Vaccines employ adjuvants to enhance the immune response. While vaccines are generally safe and effective, some genetically susceptible individuals may experience general symptoms, produce autoantibodies, or worsen existing conditions.

What Is Autoinflammatory Syndrome?

Autoinflammatory syndromes are a group of rare disorders characterized by recurrent fever episodes and inflammation in the skin, mucous membranes, joints, and other body tissues. These conditions have a distinct clinical presentation with sudden and intense inflammation, but they are not caused by infections or autoimmune reactions. Instead, many of these syndromes are linked to genetic abnormalities that disrupt the body's innate immune response, leading to excess cytokine production and inflammasome activation. As a result, these disorders typically respond to treatments targeting specific cytokines like interleukin (IL)-1 or tumor necrosis factor (TNF)-α rather than immunosuppressive medications.

What Is Autoinflammatory Syndrome Induced by Adjuvants (ASIA)?

Autoinflammatory syndrome induced by adjuvants (ASIA) is a condition that was introduced by Shoenfeld and his team in 2011. They proposed criteria to help diagnose ASIA syndrome. It includes a group of immune-related diseases that have similar symptoms and a history of exposure to adjuvants. Adjuvants are substances used in vaccines to enhance the immune response. Some of the common symptoms seen in these diseases are muscle pain, joint pain, fatigue, dry mouth, and neurological problems like memory loss and cognitive issues. The conditions MMF (macrophagic myofasciitis syndrome), post-vaccination phenomena, GWS (Gulf War syndrome), and silicosis are examples of ASIA-related diseases. The use of aluminum-based adjuvants is associated with post-vaccination phenomena and MMF, while squalene adjuvant exposure is linked to GWS.

What Are the Functions of Adjuvants?

Adjuvants can be made from various substances like oils, mineral salts, lipopolysaccharides, and peptidoglycan. They are molecules used to boost specific immune responses to vaccines. They do not trigger an immune response themselves but help create a strong reaction against the vaccine's antigens. It is commonly used in medicine, especially in vaccine production. They increase the vaccine's effectiveness, allowing for fewer doses to achieve adequate immunity.

Adjuvants act as depots, keeping the vaccine's antigens in the body for a longer time and delivering them to areas with many immune cells, like lymph nodes. This strengthens the immune response, which might not be as strong without adjuvants. These molecules influence both the adaptive and innate arms of the immune system by activating specific receptors. This leads to the production of cytokines and enhances the response to the antigens. It also helps dendritic cells and antigen-presenting cells function better, further improving the adaptive immune response.

Edelman's classification divides adjuvants into three distinct groups:

1. Active immune stimulants that boost the immune response to the antigen,

2. Carriers that support T-cell assistance.

3. Vehicle adjuvants that introduce the antigens and trigger immune response activation.

What Are the Common Adjuvants for Autoinflammatory Syndrome Induced by Adjuvants?

Some patients experienced severe reactions following vaccines, mainly targeting HPV (human papillomavirus), HBV (hepatitis B virus), and seasonal influenza. Other products containing adjuvants that resulted in severe clinical manifestations include silicone implants and mineral oil fillers.

1. Aluminum Adjuvants in Vaccines: Aluminum hydroxide is used in some vaccines, along with viral antigens, as an adjuvant. Aluminum's ability to boost the immune response allows for the use of smaller amounts of antigens. However, this increased immunogenicity can lead to heightened reactogenicity, which is not always harmless and may involve pathological stimulation.

2. Silicone Implants: Silicone implants, previously considered inert, have been used in medical devices like breast implants for many years. However, studies have suggested a possible link between silicone exposure and autoimmune diseases, with patients developing autoimmune conditions and autoantibodies after exposure to silicone implants. The removal of implants has been associated with improved clinical manifestations, supporting the connection between silicone and autoimmunity.

3. Mineral Oil Fillers: Mineral oil injections, commonly used for cosmetic purposes in some countries, have been identified as a leading cause of ASIA syndrome. The proposed mechanism involves chronic inflammation induction, leading to granuloma formation (the development of organized immune cell clusters as a response to chronic inflammation) and dermal thickening.

What Are the Symptoms of Autoinflammatory Syndrome Induced by Adjuvants?

The common symptoms that have been reported in individuals with ASIA include:

• Persistent and unexplained fatigue and weakness are often reported by individuals with ASIA.

• Chronic muscle and joint pain, sometimes resembling arthritis-like symptoms, may occur.

• Headaches, dizziness, and cognitive difficulties have been associated with ASIA in some cases.

• Skin manifestations, such as rashes or lesions, can be observed in affected individuals.

• Some individuals may experience gastrointestinal symptoms like abdominal pain, nausea, or diarrhea.

• ASIA may be accompanied by flu-like symptoms, including fever, chills, and body aches. Recurrent or persistent fever may be present in some individuals with ASIA.

• Enlarged lymph nodes, commonly in the neck, armpit, or groin, may be observed.

• Some individuals may develop symptoms that resemble other autoimmune disorders, such as rheumatoid arthritis (an autoimmune condition causing joint inflammation and pain).

How Can Autoinflammatory Syndrome Induced by Adjuvants Be Diagnosed?

The criteria for diagnosing autoinflammatory syndrome induced by adjuvants (ASIA) are categorized into major and minor criteria.

• Major Criteria: This criteria include exposure to an external stimulus, such as silicone implants or mesh, before the appearance of clinical symptoms. The typical clinical manifestations include chronic fatigue, muscle pain or weakness, joint pain, cognitive impairment, fever, dry mouth, dry eyes, and neurological issues. Improvement after removing the inciting agent and a typical biopsy of affected organs also contribute to the major criteria.

• Minor Criteria: These criteria includes the presence of antibodies or autoantibodies directed at the suspected adjuvant, additional clinical manifestations like IBS (irritable bowel syndrome) or Raynaud's phenomenon, specific HLA (human leukocyte antigens) associations (HLA DRB1, HLA DQB1), and the development of autoimmune diseases like multiple sclerosis, rheumatoid arthritis, Sjogren syndrome, or systemic sclerosis. Meeting both major and minor criteria aids in diagnosing ASIA and helps in identifying individuals who may have adverse reactions related to vaccine adjuvants.

How Is Autoinflammatory Syndrome Induced by Adjuvants (ASIA) Managed?

Some general approaches to managing ASIA-like symptoms are listed below:

1. Symptomatic Treatment: Medications such as nonsteroidal anti-inflammatory drugs (NSAIDs) may be prescribed to help alleviate pain and inflammation during acute episodes.

2. Corticosteroids: In more severe cases, corticosteroids may be used to dampen the immune reaction and alleviate inflammation. However, long-term use of corticosteroids results in side effects and is typically reserved for short-term symptom management.

3. Vitamin D Supplementation: It is crucial to fix any vitamin D deficiency or insufficiency. Vitamin D has a regulatory function within the immune system, so some doctors recommend vitamin D supplements for their patients.

4. Biologic Therapies: For individuals with persistent and severe symptoms, targeted biologic therapies may be considered. These medications, such as IL-1 (interleukin-1) inhibitors, can help modulate the immune system and decrease inflammation. Biologic therapies are used cautiously and are usually reserved for some cases where other treatments have not yielded the desired results or when the condition is significantly impacting the individual's quality of life.

5. Supportive Care: Supportive care is an integral part of managing ASIA. This may include addressing specific symptoms like skin rashes, joint pain, or gastrointestinal issues and providing psychological support to individuals coping with chronic symptoms.

Conclusion:

ASIA is considered a rare condition, and the vast majority of individuals do not experience adverse effects from vaccine adjuvants and medical plants. The concept of the autoinflammatory syndrome induced by adjuvants (ASIA) has developed in response to the worry about possible adverse reactions to adjuvants used in vaccines. The use of vaccines is essential for preventing infectious diseases, but it is also important to be aware of and deal with any potential side effects. The scientific community is constantly trying to understand the causes, mechanisms, and management of ASIA, a topic that is still being researched.