The Story of Multiple Autoimmune Syndrome
A Synthesis of Lessons Learned
The available scientific research on Multiple autoimmune syndrome (when one person meets the study classification criteria for three or more autoimmune diseases) reveals a way of thinking about, and organizing, autoimmune disease that’s relevant across medical specialties, symptoms, signs, named disorders, and unnamed disorders. First, it must be noted that there is no standardized diagnostic criteria for rheumatological disorders. Yes, you read that right. The American College of Rheumatology and the European League Against Rheumatism abandoned the development of diagnostic criteria for rheumatological disorders in 2015. They decided to focus on research study classification criteria exclusively.
These are the criteria they use to determine which research subjects fit the Classification Criteria for Systemic Lupus Erythematosus, for example. They focused on classification criteria in an effort to improve research, as a foundation for improving clinical care for autoimmune symptom sufferers. They note that classification criteria and diagnostic criteria are not synonymous. I see this move by the American College of Rheumatology as an admission of how very little is actually known about autoimmune disease. It’s my opinion that research on named autoimmune diseases, as they are currently “organized,” is ultimately a confounding dead end.
So, what’s the alternative? The expert on Multiple autoimmune syndrome, Juan Manuel Anaya, and his various co-authors and partner institutions, presented a compelling story arch in their research into Multiple autoimmune syndrome. Anaya summed up the problems with, and the path forward for, autoimmune disease research. Then he followed the path he laid out in his subsequent research—publishing studies on novel genetic variations in Multiple autoimmune syndrome, and on familial autoimmunity. His foundational work is so compelling that I use it in this post to organize the rest of the studies on Multiple autoimmune syndrome.
The Problems with Autoimmune Disease Research
Phenotypes (signs of disease such as observable clinical presentations and test results) are shared among autoimmune diseases
Sjogren’s syndrome and Autoimmune thyroid disease, particularly Hashimoto’s thyroiditis, are the autoimmune diseases that are most associated with polyautoimmunity. Systemic Lupus Erythematosus is also significantly associated with polyautoimmunity, with multiple studies showing a consistent incidence of polyautoimmunity (where one person meets the study classification criteria for two or more autoimmune diseases) in approximately 40% of participants.
In contrast, Rheumatoid arthritis is one of the least associated with polyautoimmunity, of the autoimmune diseases studied. Multiple sclerosis has the lowest incidence of polyautoimmunity, of the autoimmune diseases studied. Unusually, the prevalence of polyautoimmunity in Multiple sclerosis, in men and women, was found to be comparable. Polyautoimmunity in rheumatological disorders typically has a female predominance.
Classification criteria lacks accuracy
By definition, polyautoimmunity is the epitome of inaccurate classification criteria. The same underlying pathological processes happening in one body equals two different autoimmune diseases? Only because of the way autoimmune disease is currently dis-organized, not because of the basic mechanisms of the disease.
Signs and symptoms of autoimmune diseases differ from patient to patient, and within a single patient over time
Studies have shown that patients with the same diagnosis have variable symptoms, and their test results may differ. Symptoms may change over time, so that an autoimmune disease that fits one set of classification criteria has the potential to change into fitting the classification criteria of a different autoimmune disease, over time, within the same person. Specifically, two studies showed a higher risk of polyautoimmunity with autoimmune gastritis and celiac disease in people over 65 compared to people under 65. Presenting signs and symptoms of these diseases vary by age, and should influence healthcare screening practices.
The Path Forward for Autoimmune Disease Research
Accurate Clinical and Immunological Databases
In the United States, there are two research registries that I have found for people with formal autoimmune disease diagnoses: the Autoimmune Registry and ARNet, through the Autoimmune Association. A research registry isn’t the same as an accurate clinical and immunological database, but in the absence of the autoimmune equivalent of the C.D.C’s cancer registries, these research registries are an important first step in understanding autoimmune disease prevalence.
Molecular Genetic Analyses
The research shows that female sex is strongly associated with polyautoimmunity. I am persuaded that Adipokines (cell signaling molecules produced in fat cells), such as leptin, are likely to be the key to understanding why women have a higher incidence of autoimmune disease than men.
The research also shows that autoimmune disease runs in families. One study on familial clustering of autoimmune diseases suggests that the most fruitful avenue for further study of polyautoimmunity is in genetic testing of sister/sister pairs in families with a clustering of autoimmune diseases. Another study on polyautoimmunity found that familial autoimmunity was associated with polyautoimmunity in Systemic sclerosis and Systemic Lupus Erythematosus. Familial autoimmunity may also occur earlier and be more severe in the younger generation.
Whole Exome Sequencing is the most comprehensive way to study genetic variations that contribute to the development of autoimmune disease, particularly in families with multiple members affected by polyautoimmunity. Genetics, as a defining factor of autoimmune disease, is critical to accurate diagnostics.
Identifying specific, dysfunctional immune system processes causing disease signs and symptoms
Classification of autoimmunity by IgG autoantibodies has the potential to be a meaningful tool in the search for accurate diagnosis, and an important direction for exploring treatment options by identifying the fundamental pathological process. Researchers recommended that IgG autoantibody analysis be included in all autoimmune disease research going forward.
The Absence of One Drug Stands Out
Study participants with polyautoimmunity and Multiple autoimmune syndrome took antimalarial agents, like hydroxychloroquine, less frequently or for less time. Whether this means that hydroxychloroquine has a protective effect against polyautoimmunity needs to be studied more. For those less familiar with autoimmunity treatment, hydroxychloroquine has been used in the treatment of autoimmune symptoms for decades. In contrast to its recent pandemic fame, hydroxychloroquine is uncontroversial for routine treatment of certain autoimmune diseases.
The Sinister Whisper of Common Bacteria
Human exposure to Mycobacterium avium subspecies paratuberculosis may be a common occurrence, and linked to many different autoimmune disorders. In the complex dance between genetic susceptibility and environmental exposures that predispose a person to autoimmune disorders, Mycobacterium could be one of the critical factors that tip the balance toward autoimmune disease. Surveillance of consumer products and drinking water supplies, including milk, other dairy products, infant formula, treated water supplies, and well water monitoring, is essential to understand the ubiquity of this resilient bacteria. It can survive standard water treatment practices in the United States, pasteurization and freeze drying. Determining prevalence is essential to identifying community strategies to reduce exposure.
Meaningful Terms Going Forward
Autoimmune tautology
The term autoimmune tautology means that all autoimmune disease originates from the same basic mechanisms.
Overt polyautoimmunity
The clinical coexistence of two or more autoimmune diseases fulfilling classification criteria.
Latent polyautoimmunity
The presence of autoantibodies, unrelated to a defined autoimmune disease, which does not fulfill classification criteria for any autoimmune disease.
Meaning-less Terms Best Left in the Past
Multiple autoimmune syndrome
Multiple autoimmune syndrome is the combination of at least three autoimmune diseases in the same patient. It’s possible that there’s an evolution happening in the research from the use of Multiple autoimmune syndrome to polyautoimmunity. Anaya argues that Multiple autoimmune syndrome is already encompassed by the term polyautoimmunity, and expresses a preference for polyautoimmunity over Multiple autoimmune syndrome.
Secondary Autoimmune Disease
Secondary autoimmune disease is diagnosed in a person who has already been diagnosed with a different autoimmune disease. The term makes research difficult because it’s hard to isolate what is applicable to which diagnosis. Secondary Sjogren’s syndrome, for example, isn’t useful for the definition, research, diagnosis and treatment of autoimmune disease. It obscures more than it clarifies. Anaya, again, argues:
Our results indicate that coexistence of autoimmune diseases is not uncommon and follows a grouping pattern. Polyautoimmunity is the term proposed for this association of disorders, which encompasses the concept of a common origin for these diseases.
Overlap Syndromes
Overlap syndromes are defined as the co-occurrence of several pieces of different, but well-defined autoimmune diseases, without meeting the classification criteria of a single autoimmune disease. It’s a controversial term that lacks classification criteria, and is therefor difficult, if not impossible, to study. Polyautoimmunity and the autoimmune tautology are better defined terms than Overlap syndromes.
Why it Matters
Polyautoimmunity is an inherent critique of the current system of autoimmune disease classification. By definition, it doesn’t have a place. It doesn’t fit in. That’s why polyautoimmunity is one of the most fruitful research avenues for characterizing the autoimmune disease process. Defining and using accurate terms is critical to studying and describing autoimmunity. The words we use to describe autoimmunity define how it’s studied. That certainly matters.