MCTD: Is It Just Letters?

The Great Debate in Adult Rheumatology at ACR Convergence 2024

WASHINGTON, D.C.—At a Great Debate session at ACR Convergence 2024, speakers argued vigorously about the validity and utility of mixed connective tissue disease (MCTD) as a distinct disease entity in rheumatology.

Dr. Christopher-Stine

Lisa Christopher-Stine, MD, MPH, professor of medicine and neurology at Johns Hopkins University School of Medicine, Baltimore, maintained that MCTD should be considered a distinct disease entity, as did Oliver Distler, MD, director of the Department of Rheumatology, University Hospital Zurich.

Arguing the con position was Peter Izmirly, MD, professor at New York University Grossman School of Medicine and co-director of the NYU Lupus Clinic, along with Judith James, MD, PhD, professor and chair of the Arthritis and Clinical Immunology Program, Oklahoma Medical Research Foundation, Oklahoma City.

Origins of MCTD

In 1972, Sharp et al. first characterized a rheumatic syndrome that they called MCTD. As described, the syndrome had some overlapping features with systemic sclerosis, systemic lupus erythematosus (SLE) and inflammatory myositis. Patients often reported arthralgias/arthritis, swollen hands, Raynaud’s phenomenon, esophageal dysmotility and/or myositis, but renal, pulmonary, cerebral or vasculitis symptoms were rare. Dr. Sharp reported that the syndrome had a favorable prognosis, requiring only low levels of corticosteroids.¹

Another key characterization was antibodies to the U1 ribonucleoprotein particle (U1-RNP), required for diagnosis. Although the antibody could be found in patients qualifying for other rheumatic diagnoses, titers were high in MCTD, and no other extractable nuclear antigen antibodies were present.

Newer Conceptions of MCTD

Characterization of MCTD has changed somewhat since Dr. Sharp’s initial description, which the con team used as a critique. Dr. Christopher-Stine acknowledged that later evidence has shown that MCTD patients are not always steroid responsive, internal organs, such as the kidney and lungs, actually are sometimes affected and the disease course isn’t always as benign as initially described. But she still defended MCTD as a disease entity with specific autoreactive immune cells, autoantibodies, clinical phenotype and genetics.

Interestingly, although MCTD was initially characterized as having a benign course, anti-U1-RNP antibodies in the context of another, already diagnosed connective tissue disease, such as systemic sclerosis, may actually increase the risk of such complications as pulmonary artery hypertension, interstitial lung disease and kidney involvement.^2,3 

Researchers have proposed four different overlapping sets of classification criteria for MCTD, all of which include high titer U1-RNP antibodies, Raynaud’s phenomenon and varying levels of myositis, systemic sclerosis and SLE-type features. But it remains unclear which of these is the most sensitive or specific.^4-7

One salient point of agreement: Members of both teams pointed to different kinds of evidence that MCTD is often misdiagnosed. MCTD is often conflated with undifferentiated connective tissue disease (UCTD), a condition in which symptoms and lab results suggest some sort of connective tissue disease, but not quite enough to meet diagnostic criteria for an established rheumatic illness.

CTD Heterogeneity & Overlapping Syndromes

Ever since Dr. Sharp’s initial description, some in the rheumatology community have questioned the validity of the disease category.

Dr. Peter M. Izmirly

Dr. Izmirly argued that patients with MCTD would be better classified as either having an already defined autoimmune disease (e.g., systemic sclerosis, SLE or an inflammatory myositis) or two more or more overlapping diseases. Or, in some cases, they might not yet qualify for any such diagnosis, but should be thought of as having an intermediary, prodromal phase stage that may eventually develop into disease that is more easily characterized, but is not yet a distinct disease entity.

In contrast, Dr. Christopher-Stine contended that although it is true that a subgroup of patients may eventually evolve into a phenotype better described as a different connective tissue disease, MCTD still deserves to be characterized as a distinct clinical entity.

Dr. Izmirly shared data that a significant percentage of MCTD patients also meet criteria for SLE, systemic sclerosis or inflammatory myositis, and suggested that they might be better characterized as having one of these other illnesses. He also noted the highly overlapping nature of the classification criteria for MCTD with both SLE and systemic sclerosis classification criteria. Moreover, when patients diagnosed with MCTD are followed past five years, their chances of qualifying for one of these other illnesses increases.^8-10

Dr. Distler

Yet CTD categories in rheumatology are inherently somewhat imperfect and heterogeneous, a point argued by Dr. Distler in support of MCTD as a distinct clinical entity. “We try to group patients into categories to make them as similar as possible to call them a disease, but there was never the aim to have a super unique phenotype with only once clinical presentation,” he said. “These diseases are very heterogeneous clinically, molecularly and in their outcomes.”

Dr. Distler also noted that most classification criteria clearly state that they are not meant to apply to patients in whom another disease might better explain their clinical presentation, for instance, systemic sclerosis. Just because a patient might technically qualify for more than one category of rheumatic disease does not necessarily imply that the disease category (e.g., MCTD) has no clinical or research utility.

How to Characterize a Disease

As part of his argument, Dr. Izmirly contrasted, “The description of rheumatoid arthritis preceded by 100 years or so the actual discovery and association of rheumatoid factor and later [cyclic citrullinated peptide] antibodies, but in MCTD the identification of the antibody actually shaped the description of the disease.”

Dr. Izmirly noted that U1-RNP antibodies are seen in 38% of patients diagnosed with SLE, 8% of patients with systemic sclerosis, 5.5% of patients with inflammatory myositis, as well as 0.2% of healthy women, although not necessarily at high titers. However, overlapping antibody positivity is not an uncommon situation in rheumatic diseases.

Interestingly, both teams used data on the impact of anti-U1-RNP antibodies to help make their case. Dr. Distler noted that U1-RNP antibody positivity is associated with a unique phenotype in patients with systemic sclerosis, one associated with increased inflammation and poorer prognosis. However, other patients do bear the more classic characteristics of MCTD, and looking at U1-RNP as purely a subset marker of another disease may miss those patients.^11,12

In multiple areas of rheumatology, experts have debated how to deal with disease subsets. For example, disease course, outcomes and pathophysiology may vary somewhat between seronegative and seropositive patients with rheumatoid arthritis, and in some cases the two groups might be better separated out for research purposes. Similarly, SLE is known for its dramatic disease heterogeneity. In some cases, being more specific about emerging intradisease subsets may reveal clues to pathophysiology and targeted treatment.^13,14

Dr. James

The challenge of defining such disease subsets has become even more complex with the advent of modern laboratory tools, such as genomics and machine learning. To help make her case that MCTD is better conceptualized as a disease subset of other rheumatic diseases, Dr. James shared different kinds of molecular data, for example, demonstrating similar immunotypes and serotypes between patients with MCTD and SLE, with most MCTD patients exhibiting an interferon signature, similar to SLE patients.¹⁵

Implications of Categorization

So should MCTD be considered a distinct disease entity on equal footing with its disease cousins like systemic sclerosis? Or might U1-RNP positivity be better thought of as a marker to stratify subsets in other diseases? In one sense, the distinction may be more of a linguistic or philosophical one, as much about the underlying pathophysiology is still unclear. However, practically speaking, the language used does have significant implications, as both teams argued, for both research efforts and current patient care.

“These categories help us stratify and communicate in clinical practice,” said Dr. Distler. Moreover, he pointed out that classification systems are ultimately developed to help develop better clinical trials. He argued that the debate itself has led to an unfortunate dearth of research on MCTD, and Dr. Christopher-Stine added that this has impaired the development of targeted treatment strategies.

Dr. James noted that because the U.S. Food and Drug Administration has not specifically approved any therapies for MCTD, patients sometimes can’t get approved for specific medications if they have the diagnosis on record. Moreover, they often can’t qualify for participation in clinical trials, even if they also meet criteria for a diagnosis, such as SLE or systemic sclerosis, because they have a concurrent autoimmune disease. “We’re doing our patients a disservice by giving them another diagnosis that keeps them from actively participating in studies and potentially getting new therapies,” she noted.

Dr. James shared some key learning points that have broader implications, irrespective of whether one finds the pro or con arguments more convincing. She remarked that patients positive for U1-RNP antibodies may need additional screening, such as echocardiograms, pulmonary function tests and chest X-ray or computed tomography scan, regardless of whether they have a diagnosis of MCTD or another connective tissue disease.

Dr. James also added that it’s very common for patients to present with symptoms of multiple autoimmune diseases, although usually practitioners focus on just one. “Sometimes that helps our patients, but other times not so much,” she said. “We need paths to trials and insurance coverage for medications for patients who don’t clearly follow just one set of classification criteria.”

Ruth Jessen Hickman, MD, a graduate of the Indiana University School of Medicine, is a medical and science writer in Bloomington, Ind.

References

1. Sharp GC, Irvin WS, Tan EM, et al. Mixed connective tissue disease—An apparently distinct rheumatic disease syndrome associated with a specific antibody to an extractable nuclear antigen (ENA). Am J Med. 1972 Feb;52(2):148–159.
2. Chevalier K, Chassagnon G, Leonard-Louis S, et al. Anti-U1RNP antibodies are associated with a distinct clinical phenotype and a worse survival in patients with systemic sclerosis. J Autoimmun. 2024 Jun;146:103220.
3. Xiang W, Dong R, Li M, et al. The role of anti-U1 RNP antibody in connective tissue disease-associated pulmonary arterial hypertension: A systematic review and meta-analysis. J Clin Med. 2022 Dec;12(1):13.
4. Tanaka Y, Kuwana M, Fujii T, et al. 2019 Diagnostic criteria for mixed connective tissue disease (MCTD): From the Japan research committee of the ministry of health, labor, and welfare for systemic autoimmune diseases. Mod Rheumatol. 2021 Jan;31(1):29–33.
5. Kasukawa R. Mixed connective tissue disease. Intern Med. 1999 May;38(5):386–393.
6. Alarcón-Segovia D, Villarreal M. Classification and diagnostic criteria for mixed connective tissue disease. In: Kasukawa R, Sharp GC, et al., Eds. Mixed Connective Tissue Disease and Antinuclear Antibodies. Elsevier Science, Amsterdam. 1987:33–40.
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12. Elhai M, Sritharan N, Boubaya M, et al. Stratification in systemic sclerosis according to autoantibody status versus skin involvement: A study of the prospective EUSTAR cohort. Lancet Rheumatol. 2022 Nov;4(11):e785–e794.
13. Nordberg LB, Lillegraven S, Aga AB, et al. Comparing the disease course of patients with seronegative and seropositive rheumatoid arthritis fulfilling the 2010 ACR/EULAR classification criteria in a treat-to-target setting: 2-year data from the ARCTIC trial. RMD Open. 2018 Nov 16;4(2):e000752.
14. Sinicato NA, Postal M, Appenzeller S, et al. Defining biological subsets in systemic lupus erythematosus: Progress toward personalized therapy. Pharmaceut Med. 2017 Apr;31(2):81–88.
15. Barturen G, Babaei S, Català-Moll F, et al. Integrative analysis reveals a molecular stratification of systemic autoimmune diseases. Arthritis Rheumatol. 2021 Jun;73(6):1073–1085.