Anti-NT5c1A Autoantibodies as Biomarkers in Inclusion Body Myositis.

Adam Amlani,May Y Choi,Claire E Barber,Lauren Brady,Michelle Jung,Mark Tarnopolsky,Ignacio Garcia-De La Torre,Marvin J Fritzler,Michael Mahler,Ann E Clarke,Heinrike Schmeling

doi:10.3389/fimmu.2019.00745

Abstract

Objective: Sporadic Inclusion Body Myositis (sIBM) is an inflammatory myopathy (IIM) without a specific diagnostic biomarker until autoantibodies to the cytosolic 5′-nucleotidase 1A (NT5c1A/Mup44) were reported. The objectives of our study were to determine the sensitivity and specificity of anti-NT5c1A for sIBM, demonstrate demographic, clinical and serological predictors for anti-NT5c1A positivity and determine if anti-nuclear antibody (ANA) indirect immunofluorescence (IIF) staining on HEp-2 cells is a reliable screening method for anti-NT5c1A.Methods: Sera from sIBM patients and controls were stored at −80°C until required for analysis. IgG antibodies to NT5c1A were detected by an addressable laser bead immunoassay (ALBIA) using a full-length human recombinant protein. Autoantibodies to other autoimmune myopathy antigens (Jo-1, OJ, TIF1y, PL-12, SAE, EJ, MDA5, PL7, SRP, NXP2, MI-2) were detected by line immunoassay (LIA), chemiluminescence immunoassay (CIA) or enzyme linked immunosorbent assay (ELISA) and ANA detected by IIF on HEp-2 substrate. Demographic, clinical and serological data were obtained by chart review.Results: Forty-three patients with sIBM, 537 disease control patients with other autoimmune, degenerative and neuromuscular diseases, and 78 healthy controls were included. 48.8% (21/43) of sIBM patients were positive for anti-NT5c1A. The overall sensitivity, specificity, positive predictive value, and negative predictive value of anti-NT5c1A for sIBM were 0.49, 0.92, 0.29, and 0.96, respectively. Compared to sIBM, the frequency of anti-NT5c1A was lower in both the disease control group (8.8%, OR 0.10 [95%CI: 0.05–0.20], p < 0.0001) and in the apparently healthy control group (5.1%, OR 0.06 [95%CI: 0.02–0.18], p < 0.0001). In the univariable analysis, sIBM patients with more severe muscle weakness were more likely to be anti-NT5c1A positive (OR 4.10 [95% CI: 1.17, 14.33], p = 0.027), although this was not statistically significant (adjusted OR 4.30 [95% CI: 0.89, 20.76], p = 0.069) in the multivariable analysis. The ANA of sIBM sera did not demonstrate a consistent IIF pattern associated with anti-NT5c1A.Conclusions: Anti-NT5c1A has moderate sensitivity and high specificity for sIBM using ALBIA. The presence of anti-NT5c1A antibodies may be associated with muscle weakness. Anti-NT5c1A antibodies were not associated with a specific IIF staining pattern, hence screening using HEp-2 substrate is unlikely to be a useful predictor for presence of these autoantibodies.

Highlights

Sporadic Inclusion Body Myositis is one subset of idiopathic inflammatory myopathies (IIM) that is characterized by a clinical presentation of asymmetrical muscle involvement, predominantly affecting the long finger flexors, quadriceps muscles and posterior oropharynx [1, 2]
The frequency of anti-NT5c1A in the Sporadic Inclusion Body Myositis (sIBM) group was 21/43 or 48.8% [95% CI: 33.9, 63.8]; while the frequency of anti-NT5c1A in the non-sIBM disease comparator groups was 8.8% ([95% CI: 6.4, 11.1]) and in the healthy control group was 5.1% ([95% CI: 0.2, 10.0])
There was no positive anti-NT5c1A sera identified within the RA, primary Sjögren’s syndrome (SjS), or juvenile dermatomyostis (JDM) cohorts

Summary

Introduction

Sporadic Inclusion Body Myositis (sIBM) is one subset of idiopathic inflammatory myopathies (IIM) that is characterized by a clinical presentation of asymmetrical muscle involvement, predominantly affecting the long finger flexors, quadriceps muscles and posterior oropharynx [1, 2]. In the absence of a reliable diagnostic biomarker, the prevalence is suspected to be underestimated due to diagnostic challenges in differentiating sIBM from other IIMs [3]. Previous reports have suggested diagnostic criteria for sIBM, the highest diagnostic sensitivity and specificity requires a combination of clinical, electrodiagnostic and pathological assessment [1, 2]. Treatment of sIBM is notoriously challenging given the lack of response to conventional immunosuppression [1, 2]. SIBM is not responsive to immunosuppression, the immune system is thought to play a significant role in the pathogenesis given documented clonal expansion of T and B cells, findings of plasma cells in pathological specimens, and the association of sIBM with HLA-DR3 [2, 4]. The precise pathogenesis of sIBM remains unclear with respect to the interplay of these factors

Methods

Results

Conclusion