Raynaud's Phenomenon Can Act As An Early Warning System in Systemic Sclerosis,
but only when genetic signatures can be identified and validated.
It’s not breaking news that in the numerous studies on genetic variations found in study participants with Systemic sclerosis, the genetic variant picture is not particularly clear. What is clear is that there is a real scientific focus on characterizing genetic variations found in study participants with Systemic sclerosis. Why? According to Keret et. al, Systemic sclerosis has the highest mortality rate among all rheumatological autoimmune diseases. I wrote about how the old news adage, “If it bleeds, it leads,” also applies to autoimmune disease research here. Between 2020 and 2023, several comprehensive review articles were published that compiled charts on research studies on systemic sclerosis and associated genetic variations. They can be found here, here and here. The authors of these reviews have compiled the available scientific research to draw conclusions about classifying Systemic sclerosis by its genetic variation signatures. The picture they paint is very, very weedy. In today’s post, I aspire to transcend the weeds. But first, some background.
Raynaud’s Phenomenon, In a Nutshell
Blood vessels that are compromised in such a way as to affect blood flow to peripheral areas of the body; for example, the fingers and toes. Affected areas may turn white due to lack of blood flow. There are many hypothesized causes for Raynaud’s phenomenon, and the causes can vary from person to person. It is an associated symptom in several autoimmune diseases, as well as non-autoimmune conditions. (Pauling et. al, 2019)
Raynaud’s Phenonmenon/Syndrome is not specific to a diagnosis of Systemic sclerosis, but it occurs in 90% of patients with Systemic sclerosis (Yang et. al, 2020).
Systemic Sclerosis, In a Nutshell
Just a reminder for new readers: Systemic sclerosis is one of two sub-types of Scleroderma. Systemic sclerosis is, itself, broken down into two sub-types. A growing body of evidence suggests that Systemic sclerosis (SSc) can be further split into categories based on known genetic variants:
identifying the genetic background may provide a better understanding of SSc diagnosis, intrinsic classification, and therapeutic monitoring
(Yang et. al, 2020)
There’s scientific evidence of a complex interplay between Systemic sclerosis, genetic variations, and autoantibodies.
Unlike with other autoimmune diseases, Systemic sclerosis has no slam dunk Human Leukocyte Antigen (HLA) associations, which have been shown to vary by ethnicity in study participants with Systemic sclerosis. But an analysis of studies by Yang et. al, found that non-HLA genetic variations were correlated to different auto-antibodies in participants with Systemic sclerosis. I’ll say that in another way: these authors found that variations on a particular gene co-occur, almost exclusively, with a particular autoantibody. Specifically, anti-topoisomerase antibodies (ATA), anti-centromere antibodies (ACA), and anti-RNA polymerase antibodies (ARA). The tables below are really useful for seeing study size, number and type, along with the genetic and autoantibody connections noted—if you read nothing else in the table, compare the first and sixth columns. I like to look at the Locus/SNP (Single Nucleo-Peptide) column to see if the specific site of the variation repeat in different studies. If they do, then it lends more weight to the findings.
(Yang et. al, 2020)
(Yang et. al, 2020)
Anti-topoisomerase antibodies (ATA) and anti-RNA polymerase antibodies (ARA) are considered to be very specific to a diagnosis of Systemic sclerosis, but the connection with associated genetic variants has the potential to solidify a diagnosis. In the case of anti-centromere antibodies (ACA), which can be positive in other autoimmune diseases, an accompanying genetic variation has the potential to provide a convincing diagnosis of Systemic sclerosis. Perhaps more importantly, the genetic variations, along with their associated autoantibodies, provide a more comprehensive picture of cellular and immune dysfunction, and how to target treatment to that specific dysfunction.
Risk of Systemic sclerosis multiplies with the number of associated genetic variations:
Recent evidence suggests that BANK1, IRF5, and STAT4 risk alleles {non-Mendelian genetic variation} display a multiplicatively increased risk of dcSSc {diffuse cutaneous Systemic sclerosis, one of two sub-types of Systemic sclerosis}
(Yang et. al, 2020)
The Aspirational Real-Life Translation
A person walks into a clinic…with Raynaud’s Phenomenon. This person is years away from developing Systemic sclerosis. The primary care provider they see is able to diagnose Raynaud’s Phenomenon, and provide genetic screening to predict the later development of Systemic sclerosis, including multiplicative risk due to more than one risk-related genetic variant in that person. Early, targeted treatment for the specific genetic variation present, prevents progression to Systemic sclerosis. The evidence isn’t there yet, but it’s closing in.
And this concludes my look at Scleroderma. You can check out the Diagnosis Description here. For those who are new to AutoimmuneDx, I am currently writing posts based on reader-requests for more information and analysis on particular autoimmune diagnoses. I base my posts on the questions, concerns and—yes, feelings—that come up while completing a Diagnosis Description (you can read more about what goes into a Diagnosis Description here). Diagnosis Descriptions are designed to be a catalog of information that effectively describes and organizes the scientific evidence on autoimmune disease for people without a medical background. If you would like me to take a closer look at a particular diagnosis, please leave a comment below. If you don’t feel comfortable commenting publicly, email me at autoimmunedx@gmail.com. Because I have a curious mind and a medical background, I sometimes get too wrapped up in the weeds of autoimmune disease, so if you would like me to clarify a post, a concept, a word, or anything in-between, please don’t hesitate to leave a comment or send an email.
References
Keret S, Rimar D, Lansiaux P, Feldman E, Lescoat A, Milman N, Farge D; MATHEC working group. Differentially expressed genes in systemic sclerosis: Towards predictive medicine with new molecular tools for clinicians. Autoimmun Rev. 2023 Jun;22(6):103314. doi: 10.1016/j.autrev.2023.103314. Epub 2023 Mar 12. PMID: 36918090.
Pauling JD, Hughes M, Pope JE. Raynaud's phenomenon-an update on diagnosis, classification and management. Clin Rheumatol. 2019 Dec;38(12):3317-3330. doi: 10.1007/s10067-019-04745-5. Epub 2019 Aug 16. PMID: 31420815.
Yang C, Tang S, Zhu D, Ding Y, Qiao J. Classical Disease-Specific Autoantibodies in Systemic Sclerosis: Clinical Features, Gene Susceptibility, and Disease Stratification. Front Med (Lausanne). 2020 Nov 19;7:587773. doi: 10.3389/fmed.2020.587773. PMID: 33330547; PMCID: PMC7710911.