Differential immunoglobulin class-mediated responses to components of the U1 small nuclear ribonucleoprotein particle in systemic lupus erythematosus and mixed connective tissue disease

Abstract

Summary Objective To determine whether patients with Systemic Lupus Erythematosus (SLE) and Mixed Connective Tissue Disease (MCTD) possess differential IgM-and IgG-specific reactivity against peptides from the U1 small nuclear ribonucleoprotein particle (U1 snRNP). Methods The IgM- and IgG-mediated responses against 15 peptides from subunits of the U1 snRNP were assessed by indirect ELISAs in sera from patients with SLE and MCTD and healthy individuals (n = 81, 41 and 31, respectively). Additionally, 42 laboratory tests and 40 clinical symptoms were evaluated to uncover potential differences. Binomial logistic regression analyses (BLR) were performed to construct models to support the independent nature of SLE and MCTD. Receiver Operating Characteristic (ROC) curves corroborated the classification power of the models. Results We analyzed IgM and IgG anti-U1 snRNP titers to classify SLE and MCTD patients. IgG anti-U1 snRNP reactivity segregates SLE and MCTD from non-disease controls with an accuracy of 94.1% while IgM-specific anti-U1 snRNP responses distinguish SLE from MCTD patients with an accuracy of 71.3%. Comparison of the IgG and IgM anti-U1 snRNP approach with clinical tests used for diagnosing SLE and MCTD revealed that our method is the best classification tool of those analyzed (p ≤ 0.0001). Conclusions Our IgM anti-U1 snRNP system along with lab tests and symptoms provide additional molecular and clinical evidence to support the hypothesis that SLE and MCTD may be distinct syndromes.

Can SLE classification rules be effectively applied to diagnose unclear SLE cases?

“…In congruency with previous reports (Vlachoyiannopoulos et al, 1996; Luyckx et al, 2005; Somarelli et al, 2011; Watanabe et al, 2012; Gunnarsson et al, 2013; Mesa et al, 2013; Zidan et al, 2013), our statistical analysis of 205 variables documented for SLE and MCTD patients revealed 35 clinical manifestations and 18 molecular features significantly different between the two conditions ( Figure 2 ). The high prevalence of skin rashes and renal disease in SLE and high incidence of myositis and muscle weakness in MCTD patients that emerged from our statistical analysis were reassuringly consistent with typical clinical manifestations associated with each of these autoimmune conditions (Uthman et al, 1996; Belibou et al, 2012; Szodoray et al, 2012; Watanabe et al, 2012; Gunnarsson et al, 2013; Zidan et al, 2013).…”

“…It is remarkable, though, that novel studies for IgM reactivity for different subunits of the U1 small nuclear ribonucleoprotein were important contributors to the most accurate classification rule(s) derived in this study. These tests, recently reported by us as a potential blood markers for differentiating SLE and MCTD patients (Mesa et al, 2013), had not been performed yet when the expert rheumatologists classified the study patients as having either SLE or MCTD. Their presence in our novel Lu-vs-M rule suggests that the analyses in this study are doing more than statistically characterizing the internal “mental map” that the expert rheumatologists were using to make their decisions.…”

“…All 55 MCTD patients evaluated in this study were defined as unclear cases given that none of them fulfilled all four MCTD classification criteria sets and/or fulfilled at least one SLE classification criteria set. All the individuals included represent well characterized patients that have been the subject of previous publications (Maldonado et al, 2006; Perkins et al, 2008; Somarelli et al, 2011; Mesa et al, 2013; Carpintero et al 2015). …”

“…For example, MCTD patients typically express elevated autoantibodies targeting U1 small nuclear ribonucleoprotein (snRNP) specific proteins known as U1-70K, U1A and U1C while those with SLE show anti-Smith (Sm) and anti-dsDNA antibodies (Luyckx et al, 2005). Though some SLE patients develop anti-U1 snRNP response, they are able to retain IgM reactivity against these antigens while those with MCTD switch to an IgG response (Vlachoyiannopoulos et al, 1996; Somarelli et al, 2011; Mesa et al, 2013). Likewise, severe renal and central nervous system (CNS) manifestations are observed in SLE patients (Zidan et al, 2013) while lung and heart pathologies are frequent in MCTD subjects (Watanabe et al, 2012; Gunnarsson et al, 2012).…”

A evolução do diagnóstico da doença mista do tecido conjuntivo

“…Já o anticorpo IgG foi secretado de forma mais abundante em LES do que na DMTC, e a reatividade foi semelhante para ambas doenças. A partir da combinação da IgM com o anticorpo anti-U1C, observou-se que foi possível a realização da diferenciação de pacientes que possuíam DMTC dos que possuíam LES, com uma precisão de 71,3% 4,23 . Pacientes com DMTC são menos propensos do que pacientes com LES a reter anticorpos IgM U1, e o elevado nível de IgG específica para U1 é típico para DMTC, transmitindo alta especificidade 23 .…”