Mixed Connective Tissue Disease: Still Crazy After All These Years
Section snippets
Diagnostic criteria
Four sets of diagnostic criteria have been published, those of Sharp [6], Kasukawa [7], Alarcon-Segovia [8], and Kahn [9], summarized in a review by Smolen and Steiner [10]. These four diagnostic criteria have been evaluated [11] alongside ACR criteria for other well-defined ARDs, and Alarcon-Segovia's [8] and Kahn's [9] criteria were concluded to be comparable to the highest sensitivity (62.5% [increased to 81.3% if “myositis” is replaced with “myalgia”]) and specificity (86.3%) when tested in
A benign disease course?
Studies have shown that MCTD is not a benign disease, and vital organs, such as the lungs, can be involved. It has a mortality rate that exceeds that of SLE, according to one report [4]. The clinical course of MCTD was observed in a retrospective study of 47 patients who fulfilled the Kasukawa criteria [7] and did not evolve into another ARD [14]. Their clinical and serologic information had been collected from presentation, diagnosis, and follow-up for more than 3 years (mean 15 years). Mean
A disease entity or part of autoimmune rheumatic disease evolution?
A number of studies have been undertaken to answer this question but have produced conflicting results. Selection criteria and length of follow-up differ between groups, and many patients were selected on serologic rather than clinical grounds. Furthermore, many of the studies are retrospective.
Gendi and colleagues [4], using a prospective study of patients with the greatest disease duration, concluded that only 36% of patients presenting with high titers of anti-RNP and clinical features of
Autoantibodies
Sharp [1] described MCTD around the presence of anti–U1-RNP antibodies; however, they are not diagnostic because they occur in other ARDs, including PM/DM, RA, lupus, and scleroderma. In addition, they are not always found in patients with typical MCTD symptoms. Here we summarize the nature of these antinuclear antibodies.
Eukaryotic cells contain small nuclear RNAs complexed with several proteins to make small nuclear ribonucleoproteins. The most commonly described snRNPs are U1, U2, U3, U4/6,
Human leukocyte antigen association
There are variable associations between ARD and major histocompatibility complexes (MHC). RA, for example, has been strongly associated with an epitope found on DR4 subtypes DRB1*0401, 0404, 0405, and DR1 subtype DRB1*0101 [50].
A few studies have demonstrated an association with MCTD and human leukocyte antigen (HLA) DR4 [51], [52]. A study comparing haplotypes of patients with SLE (fulfilling the ARA criteria) and MCTD (fulfilling the Alarcon-Segovia criteria) showed that there was a DR4
Summary
The controversy about the existence of MCTD challenges us to reflect upon the question of disease nomenclature and its utility. We identify individual diseases and give them labels as a matter of convenience and because we believe they may provide a guide to outcome and thus help us to decide what we can tell our patients about future possible complications. For patients in whom problems are straightforward (eg, an attack of measles or mumps), this approach is useful because the outcome is
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Cited by (39)
Facts and controversies in mixed connective tissue disease
2018, Medicina ClinicaDefinition and classification of lupus and lupus-related disorders
2018, Dubois' Lupus Erythematosus and Related SyndromesOrofacial manifestations in patients with inflammatory rheumatic diseases
2016, Best Practice and Research: Clinical RheumatologyCitation Excerpt :Mixed connective tissue disease (MCTD) is part of the spectrum of undifferentiated connective tissue diseases and overlap syndromes. It can be a contentious diagnosis, and debate exists on whether MCTD is a separate entity or whether it should be classified as an undifferentiated connective disease [65]. There is at least a consensus view that a diagnosis of MCTD should only be made when there is evidence of anti-U1 ribonucleoprotein antibody positivity.
Mixed connective tissue disease
2016, Best Practice and Research: Clinical RheumatologyCitation Excerpt :The concept of mixed connective tissue disease (MCTD) as a separate immune-mediated connective tissue disease (CTD) was first introduced by Gordon C. Sharp and coworkers > 40 years ago, but there is still no consensus regarding the disease definitions, the classification criteria, or the relationship with other CTDs [1]. Some rheumatologists argue that MCTD is a distinct disease entity; others believe that it represents an overlap syndrome or an early and unspecific phase of an evolving, more distinct CTD; however, few studies still disregard the whole concept [2–4]. In their initial report, Sharp and coworkers described MCTD as a mild disease with favorable outcomes and an excellent response to oral prednisolone [1].
Imaging of pulmonary involvement in rheumatic disease
2015, Rheumatic Disease Clinics of North AmericaCitation Excerpt :A rare but striking presentation of LIP in SS occurs when there is associated pulmonary amyloid deposition; on HRCT there are multiple bizarrely shaped nodules (which may appear calcified) often adjacent to cysts, with no particular zonal predilection.124–126 There is continuing debate about whether MCTD represents a distinct entity or a simply an “overlap syndrome” with features of, most commonly, SSc, SLE, and PM/DM.127–129 There is support for the latter hypothesis in that the thoracic manifestations of MCTD generally represent an overlap of features found in the other CTDs listed previously.
Derailed B cell homeostasis in patients with mixed connective tissue disease
2013, Human ImmunologyCitation Excerpt :Long-term follow-up studies revealed that other symptoms, such as serositis, pulmonary involvement (interstitial lung disease, pleural effusion, pulmonary arterial hypertension) cutaneous involvement, neuropsychiatric disease, and glomerulonephritis, might also develop in MCTD [3–8]. Autoantibodies to U1-ribonuclear protein (U1-RNP) in high-titer are associated with MCTD [9]. It is composed of U1-RNA, containing a partially double-stranded secondary structure, and proteins that are specific to the U1-RNP complex including U1-A, U1-C, and U1-70 kDa [10].