Organized Autoimmunity and Reactive Arthritis
Just threading the needle of a new autoimmune disease classification system.
A Conversation About Reactive Arthritis, Mostly with Myself
In my last post, I used Reactive Arthritis as an example of how to organize autoimmune disease differently. I’m calling the system I’m developing “Organized Autoimmunity.” Organized Autoimmunity doesn’t rely on the, frankly, disorganized symptomatology, body system, medical specialty, physician last name, or whatever other identifier was thrown into the current “system.” Organized Autoimmunity relies on classification by
sex predominance (is an autoimmune disease primarily found in genetic females, males, or equally in both?)—F, M, or B.
inherited gene variations that cause increased susceptibility—I
gene triggering environmental exposures (infections, toxins, stress)—E
multiple interactive and destructive immune system pathologies—M
Based on this classification system, I called Reactive Arthritis a BIEM (Both sexes are predominant, there is Inherited genetic susceptibility (mediated by HLA-B27), known triggering Environmental exposures of viral gastroenteritis and gonorrhea, and Multiple interactive and destructive immune system pathologies. A gracious reader reached out to me to discuss the historical context of Reactive Arthritis (first known as Reiter’s Syndrome). It was originally thought to exclusively occur in men, and was only associated with bacterial infections, originally gonorrhea, and gastrointestinal bacterial infections. As an example of how to organize autoimmunity better, Reactive arthritis turns out to provide an excellent example.
Incorrect Assumption of Male Predominance
It’s easy to imagine how male predominance is, historically, mistakenly assumed. Original disease recognition is based on the connection between enough men presenting for treatment of gonorrhea, for example, then simultaneously, or later, developing a reactive arthritis as a result. This doesn’t necessarily mean that women are not equally likely to be affected by a similar disease process, but it requires the surveillance of enough women contracting gonorrhea, and seeking treatment for it, and then developing a reactive arthritis, in order for any given clinician (Dr. Reiter) to take notice.
There could be any number of reasons that a pattern of recognition in men is originally higher: perhaps the prevalence of gonorrhea in the female population is lower at the time of disease discovery; Dr. Reiter may specialize in the treatment of men only; perhaps disease prevalence at the time is equal in women, but they do not seek treatment; perhaps women do not report recent sexually transmitted bacterial infection in connection with seeking treatment elsewhere for arthritic symptoms; perhaps women’s pain symptoms are ignored by male clinicians. All of these factors, and probably many more, could affect the original recognition and characterization of an autoimmune disease. What’s logically objectionable about what happened with Reactive Arthritis is the assumption that it was a male disease, to the possible exclusion of consideration of its presence in women.
Returning to the present for a moment. A quick check of the CDC shows a higher prevalence of gonorrhea in men during the period of 2013 through 2020. Prior to that, there appears to be a period of slight female predominance.
Based on the above chart it’s easy to see how, depending on the period of time, the prevalence of a disease could be overestimated in certain populations, and autoimmune reactions could be seen in only one sex, especially when we know how small sample populations for autoimmune disease usually are.
With regard to sex prevalence, the way that Organized Autoimmunity works in a research and clinical environment is more accountable. For prior, named autoimmune diseases, where sex prevalence has been scientifically studied, a disease would be classified by sex prevalence. This classification would occur based on the available scientific evidence, regardless of the biological sex of the individual affected by the disease. Here’s why that’s important: it’s a way to provide an automatic check and balance on the potential for changes in the data. For instance, if a clinician starts to see that a disease classically known as a FIEM suddenly has a number of males fitting the same IEM categories, there may be a reason to question the past science on sex predominance, or to consider a different disease process, or some other phenomenon at work (for instance, males may be more triggered to a particular autoimmune disease by a particular infectious agent that’s circulating more widely at the time). If an autoimmune disease is organized by sex predominance, these kinds of changes in disease pattern are more readily recognized and then more easily studied.
In contrast to already-characterized and studied autoimmune diseases, Organized Autoimmunity would classify newly recognized autoimmune diseases by the sex of the patient. In this way, just by virtue of organizing the autoimmune disease consistently, there is automatic data on sex prevalence, which can exist at an individual physician level (I have six patients with this autoimmune disease, and five out of the six are women) up to a country or worldwide level with the presence of accurate registries. As more data accumulates, the sex prevalence of the IEM portions of the disease will become clearer.
But back to Reactive arthritis, is it really predominant in both sexes? I wasn’t able to do extensive research in the time that I had, but expert sources and some recent, but questionable research, creates a mixed picture. The Global Autoimmune Institute reports male sex and bacterial sexually transmitted infections as risk factors, pointing to a 2015 study out of Kosova on 100 participants. This study showed a male predominance (66% male to 34% female). But, when the study considered infective agent, urogenital causes had a male predominance of 2:1 whereas “enteral” causes were roughly equal among the sexes with a slight female predominance. This is an observational cross-sectional study, which is a type of study that is most susceptible to hidden bias. There’s potential bias in what people are most likely to seek treatment for: visible bacterial growth, redness, and inflammation on private areas, as well as burning with urination, compared to a stomach bug. So is the male sex predominance a true finding in this particular study or just a function of who is affected by what, how likely they are to seek treatment for it, and how likely it is that their symptoms will be recognized as a Reactive arthritis?
The Autoimmune Association states that “Women and men are equally likely to develop reactive arthritis in response to foodborne infections. However, men are more likely than are women to develop reactive arthritis in response to sexually transmitted bacteria.” Here again, it pays to classify disease by sex predominance so that infectious agent can also be systematically cross-compared to sex prevalence.
Gene Triggering Environmental Exposures
In using Reactive Arthritis as an example in my last post, I wasn’t being rigorous. I threw out viral gastroenteritis as an environmental trigger based on a recollection of a study that I had read without double checking. Bacterial infections, historically, have been associated with Reactive arthritis, so was I misremembering this study on viral causative agents when they were really bacterial? That’s entirely possible.
The Autoimmune Association only notes bacterial infections in their description. The Global Autoimmune Institute does not specify the type of causative infection. UptoDate has a section on “viral arthritis” that notes “Other viruses that may be arthrotropic include parvoviruses [15], enteroviruses [1], and chikungunya virus, which can cause an autoimmune reaction in the synovia [16]; both parvovirus and enteroviruses have been isolated from joint fluid.” Viral arthritis is a more general term referring to any joint pain caused by a virus, whether destructively autoimmune or not.
I didn’t have time for an extensive search of the research to date on bacterial vs. viral causes in Reactive arthritis. Unless Reactive arthritis is defined by the specific presence of a bacterial infection…oh wait, nope, the American College of Rheumatology says, there is no Diagnostic Classification Criteria for Rheumatological disorders. So, a bacterial vs. viral cause of Reactive arthritis is still an open question.
It’s also important to ask what kind of bias exists toward the recognition of bacterial infection compared to viral infection? Bacterial infections are often more externally obvious and more easily tested. They also have a readier treatment, antibiotics, and so clinicians are more likely to test for them because they have a solution to offer. These considerations make selection bias for bacterial causes more likely.
What would help clear up this confusion, and lead to better research, diagnostics and treatment? Organized Autoimmunity. Gene triggering environmental exposures, such as infections, sub-classified as bacterial or viral based on comprehensive patient assessment and testing. There is a way to impose order on the current chaos of autoimmunity. It’s just that the right system needs to be developed, scientifically validated, popularized into clinical acceptance, and then implemented. No problem.