Overlap Syndromes vs. The Autoimmune Tautology
We have a winner.
What are Overlap Syndromes?
I first encountered the term “Overlap Syndrome” in the study Hydroxychloroquine is associated with a lower risk of polyautoimmunity: data from the RELESSER Registry, while investigating Multiple autoimmune syndrome. (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 authors of the Hydroxycholorquine… study define Overlap Syndrome this way:
Overlap syndrome is defined as the co-occurrence of manifestations of several recognized and diagnostically confirmed autoimmune diseases in the same patient [3], although this area remains open to debate [4]. One example would be MCTD {Mixed Connective Tissue Disease}, which shares clinical characteristics with SLE {Systemic Lupus Erythematosus}, SSc {Systemic sclerosis}, PM/DM {Polymyositis/Dermatomyositis} and RA {Rheumatoid arthritis}. Patients with this condition also have high ANA {anti-nuclear antigen} titres (anti-RNP {ribo-nucleic protein}), and their main symptoms are polyarthritis, hand oedema, RP {Raynaud’s phenomenon}, sclerodactyly, myositis and oesophageal hypomobility [5]. The subject of whether this disease is a separate entity or a transitional syndrome remains controversial [6]. The main objections are as follows: (i) patients can progress to another well-defined SARD {systemic autoimmune rheumatic disease}; (ii) anti-RNP antibodies are not exclusive to this condition, and the most typical clinical manifestations of MCTD co-occur with other antibodies; and (iii) there are no widely accepted classification criteria [7, 8].
(Mena-Vázquez N et al, 2020)
Righto. There’s that question answered, done and dusted.
Except…is “Overlap Syndrome” a diagnostically useful term? Does it clarify or confuse autoimmune disease? I think it confuses more than it clarifies, and here’s why: it’s like the basket of kittens at the top of this post. Overlap syndrome, as a concept, is just an ill-defined catchall basket for a group of different, probably related, chaotic and unpredictable signs and symptoms (the metaphorical kittens). It’s a way to provide a diagnosis without really providing a diagnosis for a collection of autoimmune disease signs and symptoms that follow a loose pattern, but don’t fit neatly anywhere else, and don’t add up to any one named autoimmune disease. Perhaps most damning is that a lack of classification criteria means that Overlap Syndromes can’t be coherently studied. If you can’t study it, you can’t know its severity, prevalence, mechanism of action, and efficacy of treatments.
The fascinating story of Antisynthetase syndrome…
illustrates how this Overlap Syndrome came to be defined by its unique autoantibodies. I’d never heard of Antisynthetase syndrome—it doesn’t appear on the Global Autoimmune Institute’s or Autoimmune Association’s list of autoimmune disorders. Digging further, I found that it has historically been considered a subtype of myositis (muscle inflammation due to autoimmunity), despite the fact that studies have found that myositis is the presenting symptom in only about a quarter of patients. Interstitial lung disease is the most common presenting symptom. (Aggarwal, 2020)
The first antisynthetase autoantibody was found in 1980 and named Jo-1, after the patient John P. Since 1980, seven other antisynthetase autoantibodies have been identified, and named after the first patient in which they were found. Signs and symptoms of Antisynthetase syndrome vary, depending on the particular autoantibody found in the patient’s system. Signs and symptoms are consistent with individual autoantibodies, but vary significantly enough between the eight known autoantibodies that disease sub-types can be classified by the autoantibody that is present in the patient’s system. Unfortunately, the role the autoantibodies play in disease expression is still unknown. (Aggarwal, 2020)
“The Autoimmune Tautology” Throws Down “Overlap Syndrome”
The Autoimmune Tautology means “the same idea:” that all autoimmune disease originates from the same basic mechanisms. I contend that there are four interwoven disease-causing mechanisms that all autoimmune disease could be coherently classified by in order to improve research, diagnostics, and treatments: 1. sex predominance (is an autoimmune disease primarily found in genetic females, males, or equally in both?); 2. inherited gene variations that cause increased susceptibility; 3. gene triggering environmental exposures (infections, toxins, stress); 4. multiple destructive and interactive immune system processes.
Antisynthetase syndrome started as an Overlap syndrome, then it became defined by its identifiable autoantibodies. Now it is named by a specific, and basic mechanism of the autoimmune tautology, its destructive autoantibodies classified under 4. multiple destructive and interactive immune system processes. It is an evolving example of how a disease process can go from an ill-defined basket of various signs and symptoms (Overlap Syndrome) to a better-defined and identified disease. It became a disease that can be coherently studied.
I Propose a New Autoimmune Disease Classification System…
Because why not? And can it get any worse than the status quo? Maybe don’t answer that. It relies on a problematic shorthand—acronyms. I’ll have to consider how to improve that. I think autoimmune disease could be better organized into FIEMs, MIEMs, and BIEMs. Then sub-classification systems used to identify specific genes (I), specific environmental exposure (E), and specific immune system pathologies (M).
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
For example, Antisynthetase syndrome could be classified as a MIM—Male predominance(?), known gene variation(?) (which can then be sub-listed into a more specific gene classification system), environmental exposure unidentified (in this hypothetical case), and autoantibody to antisynthetase antigens (also ripe for sub-classification). With improved technology, I think it’s possible for these categories to be studied and known, and I think they represent the categories with the most potential for causal relationship to be found and organized coherently.
If you’re still wondering what the hell I’m talking about. I don’t blame you. I’m still working it out in my head, too. So, here’s another example.
Reactive arthritis alternatively classified as a BIEM. Affects both sexes, known inherited genetic association (HLA-B27), known environmental exposure (viral gastroenteritis of various types, Gonorrhea), and multiple interactive and destructive immune system pathologies. Why is this alternative classification useful? It could be used to find other BIEM autoimmune diseases to compare and contrast to Reactive arthritis. It could be used to identify susceptible individuals. It could be used as a research tool to quickly identify and study the unknowns of a disease. My proposed classification system is a work in progress, for sure. The comparison between the coherence of the autoimmune tautology and the confusion of overlap syndromes in the classification of autoimmune disease is revelatory. We definitely have a winner.
References
Huang K, Aggarwal R. Antisynthetase syndrome: A distinct disease spectrum. J Scleroderma Relat Disord. 2020 Oct;5(3):178-191. doi: 10.1177/2397198320902667. Epub 2020 Feb 18. PMID: 35382516; PMCID: PMC8922626.
Kelly A, Panush RS. Diagnostic uncertainty and epistemologic humility. Clin Rheumatol. 2017 Jun;36(6):1211-1214. doi: 10.1007/s10067-017-3631-8. Epub 2017 Apr 22. PMID: 28432522.
Mena-Vázquez N, Fernández-Nebro A, Pego-Reigosa JM, Galindo M, Melissa-Anzola A, Uriarte-Isacelay E, Olivé-Marqués A, Aurrecoechea E, Freire M, Tomero E, García-Villanueva MJ, Stoye C, Salas-Heredia E, Bernal-Vidal JA, Salgado E, Blanco R, Javier Novoa F, Ibáñez-Barcelo M, Torrente-Segarra V, Narvaez J, Calvet J, Moriano Morales C, Ramon Vazquez-Rodriguez T, Garcia de la Peña P, Bohórquez C, Andreu-Sánchez JL, Cobo-Ibañez T, Bonilla G, Lozano-Rivas N, Montilla C, Toyos FJ, De la Fuente JLM, Expósito L, Ruiz-Lucea ME, Vals E, Manero-Ruiz J, Bernal-Vidal JA, Rua-Figueroa I. Hydroxychloroquine is associated with a lower risk of polyautoimmunity: data from the RELESSER Registry. Rheumatology (Oxford). 2020 Aug 1;59(8):2043-2051. doi: 10.1093/rheumatology/kez562. PMID: 31808534; PMCID: PMC7382602.