“Revisionista” is my glamorous made up moniker for research criteria changes that make it easier to study how to improve the lives of autoimmune disease sufferers. The 2010 American College of Rheumatology’s revision of the study classification criteria for Rheumatoid arthritis is Revisionista. Substack’s AI image generator made me this vaguely Spanish, vaguely female, vaguely revolutionary image to go with this fake word, and I kind of love it. If your eyes just glazed over, bear with me. In 2010, the American College of Rheumatology changed their study classification criteria for Rheumatoid arthritis. They studied (also known as “validated”) how accurate and effective this classification change was. The American College of Rheumatology made this change because their old study classification criteria excluded subjects in the earlier stages of the disease process. This exclusion made it difficult to study early interventions that might prevent permanent joint damage. They wrote an article about their reasoning, their criteria changes, and their validation process here.
And what, you might ask, does this have to do with Palindromic rheumatism?
There is a subset of patients diagnosed with Palindromic rheumatism—anywhere from 10-66%, depending on the study classification criteria used—who eventually progress to meeting the criteria for Rheumatoid arthritis (Sanmartí et. al, 2021). Thus, Palindromic rheumatism may be one of the earliest signs of Rheumatoid arthritis in some patients. Last week, I briefly touched on a Canadian study of 154 participants with Early Rheumatoid Arthritis (ERA), who were evaluated for episodic joint inflammation prior to their early Rheumatoid arthritis diagnosis. If you want to learn more about Palindromic rheumatism, please read its Diagnosis Description here.
The Canadian study found that 42% of study participants experienced episodes of joint pain and swelling prior to their early Rheumatoid arthritis diagnosis. These episodes occurred less than 6 months prior to early Rheumatoid arthritis diagnosis in about half of participants, and up to a year prior to diagnosis for the other half of participants. Interestingly, this study was made possible by the Canadian Early Arthritis Cohort, abbreviated to a very belabored CATCH. This is a multi-center study with 3,700 participants with some form of early inflammatory arthritis. I’ll grudgingly forgive the awkward acronym, and unreservedly appreciate the effort at early research and intervention. Participants who were recruited from CATCH completed a questionnaire prior to their diagnosis of early Rheumatoid arthritis, in order to asses episodic joint inflammation.
There are drawbacks to this study design. Were the episodic joint symptoms experienced by participants inflammatory arthritis? If the episodes were inflammatory arthritis, were they consistent with any of the four—that’s right, four!—proposed, and unvalidated, diagnostic criteria for Palindromic rheumatism? The study authors note these unknowns. Considering that Palindromic rheumatism is poorly defined and, as a consequence, poorly studied, these drawbacks don’t negate the study’s findings. Those findings in brief: episodic joint inflammation can be an early indicator of Rheumatoid arthritis, and should be taken seriously.
(Ellingwood et. al, 2019)
A randomized clinical drug trial is ongoing in Spain
Sanmarti et. al proposed, in their 2021 case study and review article, that Palindromic rheumatism (PR)
may present a unique opportunity for therapeutic interventions that avoid the frequent progression to chronic polyarthritis. Randomized clinical trials with potentially-effective drugs in PR patients with a high risk for RA progression are warranted.
And they have designed a study comparing early treatment of antibody positive Palindromic rheumatism treated with hydroxychloroquine vs. abatacept. Why compare the effect of those two? Hydroxychloroquine has been shown to reduce the frequency and intensity of acute attacks in Palindromic rheumatism. Abatacept has been tested in patients with inflammatory joint pain:
Biological therapies which modulate the B or T cell response, such as rituximab or abatacept, may avoid progression to persistent arthritis, as already tested in patients with pre-RA or inflammatory arthralgia.
So what, specifically, does abatacept do in the body?
Abatacept: A “Fully Humanized Fusion Protein”
I don’t know about you, but the above quote sent a series of sinister Sci-Fi book covers flashing through my brain. Cue robot voice: “I am ful-ly hu-man-ized.” Here’s the dense explanation:
Abatacept (CTLA-4Ig) represents a soluble, recombinant, fully humanized fusion protein, comprising the extracellular domain of CTLA-4 and the Fc portion of IgG1. Abatacept binds to the costimulatory molecules CD80 and CD86 on antigen-presenting cells (APC), thereby blocking interaction with CD28 on T cells. In humans, Abatacept treatment was shown to be effective in patients with various autoinflammatory diseases including rheumatoid arthritis. Although the prevention of T-cell activation by interfering with signaling via CD28 still represents the main mechanism of action, Abatacept acts on additional cell populations including regulatory T cells (Treg), monocytes/macrophages, osteoclasts, and B cells.
(Bonelli & Scheinecker, 2018)
CTLA-4Ig = Cytotoxic T Lymphocyte antigen 4 Immunoglobulin; soluble = dissolvable; recombinant = made by combining genetic material; fully humanized fusion protein = lab-created by joining parts of two different genes; CD = the acronym for “Cluster of Differentiation” molecules and/or “Cluster of Designation” molecules. “CD” is used to name and study cell surface molecules for immunophenotyping of cells.
So, Abatacept binds to specific cell surface molecules on antigen-presenting cells (cells whose job it is to find non-self molecules and show them to the immune system) to prevent antigen-presenting cells from activating the immune system work of T-cells via the molecule CD28. I’m imagining a High School dance floor, two cells on opposite sides of the dance floor are drawn to each other, but two steps before they meet, the obnoxious jock swoops in to dance with the antigen-presenting cell, leaving the T cell awkwardly sidelined. That obnoxious jock is Abatacept, and we’re rooting for him, in this case, because he blocks the pathological inflammation of pre-Rheumatoid arthritis.
Why it Matters
Early detection and effective treatment options are a little intoxicating to consider when it comes to autoimmune disease. Recognition of Palindromic rheumatism as an early marker of Rheumatoid arthritis—wow—could make all the difference in a person’s disease prognosis.
This post concludes my look at Palindromic rheumatism. Next week, I’m back on more familiar ground with Polymyalgia rheumatica.
A Little Housekeeping—Notes
Substack added “Notes” to their feature upgrades a couple of months ago, and I have struggled with how, and whether, to use it. Finally, it clicked for me that this is the perfect spot to park autoimmune disease news and studies that don’t fit in with the topic or timing of regular AutoimmuneDx posts, but that I think are important to “note.” Ha! It worries me that it took me months to figure this out. If you’re interested, you can go to the Notes tab at the top of the home page, and scroll through. If not, just ignore. You may also receive email digests with my Notes in them (Substack was experimenting with this, and I don’t have control over whether this happens or not), so if this is too much traffic in your inbox, please forgive me, and delete with impunity.
References
Bonelli M, Scheinecker C. How does abatacept really work in rheumatoid arthritis? Curr Opin Rheumatol. 2018 May;30(3):295-300. doi: 10.1097/BOR.0000000000000491. PMID: 29401118.
Ellingwood L, Schieir O, Valois MF, Bartlett SJ, Bessette L, Boire G, Hazlewood G, Hitchon C, Keystone EC, Tin D, Thorne C, Bykerk VP, Pope JE; CATCH Investigators. Palindromic Rheumatism Frequently Precedes Early Rheumatoid Arthritis: Results From an Incident Cohort. ACR Open Rheumatol. 2019 Oct 21;1(10):614-619. doi: 10.1002/acr2.11086. PMID: 31872182; PMCID: PMC6917323.
Sanmartí R, Frade-Sosa B, Morlà R, Castellanos-Moreira R, Cabrera-Villalba S, Ramirez J, Salvador G, Haro I, Cañete JD. Palindromic Rheumatism: Just a Pre-rheumatoid Stage or Something Else? Front Med (Lausanne). 2021 Mar 25;8:657983. doi: 10.3389/fmed.2021.657983. PMID: 33842513; PMCID: PMC8026891.