Long-term outcome in mixed connective tissue disease: Longitudinal clinical and serologic findings

Abstract

Objective. To determine the long-term clinical and immunologic outcomes in a well-characterized cohort of 47 patients with mixed connective tissue disease (MCTD), including reactivity with U small nuclear RNP (snRNP) polypeptides.Methods. Patients were followed up over a period of 3-29 years with immunogenetic and systematic clinical and serologic analysis. Sera were analyzed for reactivity with snRNP polypeptides U1-70 kd, A, C, B/B , and D, for anti-U1 RNA, and for anticardiolipin antibodies (aCL).Results. The typical core clinical features of MCTD tended to develop over time; features of inflammation as well as Raynaud's phenomenon and esophageal hypomotility diminished, while pulmonary hypertension, pulmonary dysfunction, and central nervous system disease persisted, following treatment. A favorable outcome was observed in 62% of patients; 38% had continued active disease or had died, with death associated with pulmonary hypertension and aCL. All patients had autoantibodies to the U1-70 kd polypeptide of snRNP, and most were positive for anti-U1 RNA. An orderly progression of intramolecular spreading of autoantibody reactivity against snRNP polypeptides was observed, as was the novel finding of "epitope contraction" followed by disappearance of anti-snRNP autoantibodies during prolonged remission.Conclusion. These patients demonstrated the typical immunogenetic, clinical, and serologic findings of MCTD, and the condition rarely evolved into systemic lupus erythematosus or systemic sclerosis. The majority of patients had favorable outcomes, with pulmonary hypertension being the most frequent disease-associated cause of death. Intramolecular spreading of autoantibody reactivity against snRNP polypeptides was observed, followed by "epitope contraction" and ultimate disappearance of anti-snRNP autoantibodies during prolonged disease remission.

Structural Analysis of TCRα and β Chains from Human T‐Cell Clones Specific for Small Nuclear Ribonucleoprotein Polypeptides Sm‐D, Sm‐B and U1–70 kDa: TCR Complementarity Determining Region 3 Usage Appears Highly Conserved

“…The identical sequences and common motifs within the CDR3 of the TCR suggest that the autoreactive T cells have been selected by a limited number of epitopes on the autoantigens. The data described here supports preliminary findings on CDR3 usage [14,15].…”

A murine model of mixed connective tissue disease induced with U1 small nuclear RNP autoantigen

“…Although prior reports describe the ability of some anti-70K antibodies to directly react with lung tissue (11), the increasingly evident close relationship of the anti-70K responses to MCTD lung pathogenesis will require further study, work that may be facilitated by the use of this animal system. MCTD differs clinically from SLE both by having a higher prevalence of pulmonary manifestations and by having a dramatically lower prevalence of major end organ lupus manifestations seen in lupus, including GN, neuropsychiatric disease, and antiphospholipid syndrome (2,27). Results in our model indicate that induction of autoimmunity using the same antigen can yield either the MCTD or the SLE phenotype, depending on the innate immune context in which the immunization occurs.…”

“…In contrast to lupus, though, major end organ manifestations, including glomerulonephritis (GN), are not typical features of MCTD. Rather, lung disease, an uncommon manifestation of SLE, is the leading cause of death in MCTD (2). While animal models involving anti-RNP autoantibodies have been previously described (3)(4)(5)(6)(7), these models have either demonstrated no clinical disease or manifested double-stranded DNA (dsDNA) antibodies and GN, and thus have not been models of the distinctive features of MCTD.…”

Treatment of pulmonary fibrosis for twenty weeks with imatinib mesylate in a patient with mixed connective tissue disease

“…Later, a high prevalence of arthritis resembling rheumatoid arthritis was observed in patients with MCTD. Pulmonary involvement is commonly observed in patients with MCTD (2)(3)(4)(5)(6). The prevalence of interstitial lung disease has been suggested to be as high as 67%, based on findings of high-resolution computed tomography (HRCT) and gadolinium diethylenetriaminepentaacetic acid scans.…”

“…The prevalence of interstitial lung disease has been suggested to be as high as 67%, based on findings of high-resolution computed tomography (HRCT) and gadolinium diethylenetriaminepentaacetic acid scans. Ground-glass opacities were found in 48-78% of patients by HRCT (3,4). Although many of these patients are asymptomatic, interstitial lung disease can progress to severe, lifethreatening lung fibrosis in patients with MCTD.…”