Classes I & II Are Associated with Localized Scleroderma
Human Leukocyte Antigen Associations with Eosinophilic fasciitis: is this study even relevant?
I’ve been going back and forth about whether to write about a study on Human Leukocyte Antigen associations in 211 participants with Localized scleroderma. For more information on Human Leukocyte Antigens and their association with autoimmune disease, you can read a post I wrote here.
On the one hand, Yes, it’s relevant!
Eosinophilic fasciitis may be a severe sub-type of Localized scleroderma, which is, in turn, a sub-type of Scleroderma. You can read more about Slceroderma in its Diagnosis Description here. Much of the treatment and management of Eosinophilic fasciitis is informed by research on the two types of Sclerodermas: Systemic sclerosis and Localized scleroderma. Studies on Human Leukocyte Antigen associations have the potential to differentiate Eosinophilic fasciitis from its Sclerodermal cousins, or to strengthen the evidence for a shared disease-contributing mechanism. The mostly-finished Diagnosis Description for Eosinophilic fasciitis can be found here.
On the other hand, No, the connections are too flimsy!
I was disappointed to read that the study I had set aside on HLA associations with Localized scleroderma was unable to include participants with Deep morphea. The participants included in this study had either Linear or Generalized morphea, which are two of several sub-types of Localized scleroderma. There simply were not enough participants with Deep morphea for the study authors to include DNA analysis in this study. Eosinophilic fasciitis may be a severe form of Localized scleroderma, and it may be synonymous with a separately-identified sub-type known as Deep Morphea. It’s unclear how closely- or distantly-related Eosinophilic fasciitis is to Linear or Generalized morphea.
But, wait!
I remembered from this review article that Eosinophilic fasciitis (EF) is often found with morphea (Localized scleroderma)
About 29–40% of patients with EF simultaneously present morphea.
(Mazilu et. al, 2023)
Except they don’t cite their sources for these percentages, so I wasn’t able to check whether the Linear and Generalized morphea sub-types were found in conjunction with Eosinophilic fasciitis in large enough numbers to consider them linked. But, there are two studies of Eosinophilic fasciitis in the last decade that may list Localized scleroderma (Morphea) associations:
In a study of 34 participants with Eosinophilic fasciitis, 14 (41%) had what the authors refer to as “Morphea-like lesions.” (Lebeaux et. al, 2012)
In a separate study of 63 participants, 21 (35%) had “concurrent plaque morphea.” (Wright et. al, 2016)
The rabbit hole is deep and winding with this one…because “morphea-like lesions” and “plaque morphea” are not defined in the 5 sub-types of Localized scleroderma used in the study on Human Leukocyte Antigen (HLA) associations. Paradoxically, the authors appear to include 25 participants with “Plaque morphea” in their study, despite the fact that “Plaque morphea” is not included in the 5 sub-types they purportedly used to characterize the participant’s lesions, and “Plaque morphea” is not further defined in their publication. The categorical confusions are telling and lead me to conclude that HLA associations to Linear and Generalized morphea (and undefined “Plaque morphea”) are relevant to Eosinophilic fasciitis, should be explored in discussions of Eosinophilic fasciitis, but may later lead to differentiations when Eosinophilic fasciitis is better studied—hopefully in a comprehensive genetic analysis of all Localized scleroderma sub-types.
The Study
Class II
The table below summarizes the study’s findings, and in case you look at tables like these and can feel your eyes glaze over and your attention wander, I’ll review in verbal form what is so striking about these results. The Human Leukocyte Antigen is a variation that appears on the surface of cells in certain people. Class II Human Leukocyte Antigens appear on antigen-presenting cells only, as opposed to Class I Human Leukocyte Antigens, which appear on all cells with a nucleus in a particular person. This chart shows that participants with Localized scleroderma (morphea) have Human Leukocyte Antigen Class II genetic variations on
DRB1*03:01 in greater numbers compared to the control group, specifically a 27% rate in patients with Localized scleroderma compared to an 18% rate in control participants without autoimmune disease
DRB1*04:04 in greater numbers compared to the control group, specifically a 13% rate in patients with Localized scleroderma compared to a 6% rate in control participants without autoimmune disease
DQA1*03:00 was present in 26% of Localized scleroderma participants, but was spectacularly non-existent in the control group without autoimmune disease
DQA1*04:01 in lesser numbers compared to the control group, specifically a 3% rate in patients with Localized scleroderma compared to a 12% rate in control participants without autoimmune disease. This could indicate a possible protective function of the DQA1*04:01 variant.
DQB1*02:01 in greater numbers compared to the control group, specifically a 32% rate in patients with Localized scleroderma compared to a 20% rate in control participants without autoimmune disease
The total absence of DQA1*03:00 in the control group vs. the 26% presence in the Localized scleroderma group is striking. The authors also found that HLA DRB1*04 was associated with caucasian race, which due to the high number of caucasian participants in the study, implied that “the association in the overall group was driven by the Caucasian patients.” That means this particular HLA association may be less useful for characterizing disease in other races, but more research is needed (always!).
(Jacobe et. al, 2014)
Class I
Class I Human Leukocyte Antigens are antigens that are present on all cells in the body that have a nucleus (that central sphere of genes found in the middle of most cells). I explain more about Human Leukocyte Antigens and its classes here. The study found an association between HLA B*37 and Localized scleroderma that was statistically significant regardless of caucasian race.
(Jacobe et. al, 2014)
Why It Matters
Identifying Human Leukocyte Antigen associations that make a person more susceptible to different autoimmune diseases is one piece of the diagnostic puzzle, which can improve the speed and accuracy of diagnosis. More importantly, it’s the kind of information that can define the molecular-level disease process. Being able to define the molecular-level disease process is the foundation for the development and/or use of targeted treatment.
I try hard to keep my weekly posts to five minutes of reading time, and I almost never succeed. This week is no exception—I’ve run out of time to write about the evidence for post-treatment resolution of symptoms in Eosinophilic fasciitis. So, I’ll save that for next week’s post. Thank you, as always, for reading. 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. 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. 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
Jacobe H, Ahn C, Arnett FC, Reveille JD. Major histocompatibility complex class I and class II alleles may confer susceptibility to or protection against morphea: findings from the Morphea in Adults and Children cohort. Arthritis Rheumatol. 2014 Nov;66(11):3170-7. doi: 10.1002/art.38814. Erratum in: Arthritis Rheumatol. 2015 Mar;67(3):751. PMID: 25223600; PMCID: PMC4211936.
Lebeaux D, Francès C, Barete S, Wechsler B, Dubourg O, Renoux J, Maisonobe T, Benveniste O, Gatfossé M, Bourgeois P, Amoura Z, Cacoub P, Piette JC, Sène D. Eosinophilic fasciitis (Shulman disease): new insights into the therapeutic management from a series of 34 patients. Rheumatology (Oxford). 2012 Mar;51(3):557-61. doi: 10.1093/rheumatology/ker366. Epub 2011 Nov 25. PMID: 22120602.
Mazilu D, Boltașiu Tătaru LA, Mardale DA, Bijă MS, Ismail S, Zanfir V, Negoi F, Balanescu AR. Eosinophilic Fasciitis: Current and Remaining Challenges. Int J Mol Sci. 2023 Jan 19;24(3):1982. doi: 10.3390/ijms24031982. PMID: 36768300; PMCID: PMC9916848.
Wright NA, Mazori DR, Patel M, Merola JF, Femia AN, Vleugels RA. Epidemiology and Treatment of Eosinophilic Fasciitis: An Analysis of 63 Patients From 3 Tertiary Care Centers. JAMA Dermatol. 2016;152(1):97–99. doi:10.1001/jamadermatol.2015.3648