Anti-HMGCR autoantibodies in European patients with autoimmune necrotizing myopathies: inconstant exposure to statin

Yves Allenbach, Laurent Drouot, Aude Rigolet, Jean Luc Charuel, Fabienne Jouen, Norma B Romero, Thierry Maisonobe, Odile Dubourg, Anthony Behin, Pascal Laforet, Tania Stojkovic, Bruno Eymard, Nathalie Costedoat-Chalumeau, Emmanuelle Campana-Salort, Anne Tournadre, Lucile Musset, Brigitte Bader-Meunier, Isabelle Kone-Paut, Jean Sibilia, Laurent Servais, Olivier Fain, Claire Larroche, Elisabeth Diot, Benjamin Terrier, Raphael De Paz, Antoine Dossier, Dominique Menard, Chafika Morati, Marielle Roux, Xavier Ferrer, Jeremie Martinet, Sophie Besnard, Remi Bellance, Patrice Cacoub, Laurent Arnaud, Bernard Grosbois, Serge Herson, Olivier Boyer, Olivier Benveniste, French Myositis Network, Yves Allenbach, Laurent Drouot, Aude Rigolet, Jean Luc Charuel, Fabienne Jouen, Norma B Romero, Thierry Maisonobe, Odile Dubourg, Anthony Behin, Pascal Laforet, Tania Stojkovic, Bruno Eymard, Nathalie Costedoat-Chalumeau, Emmanuelle Campana-Salort, Anne Tournadre, Lucile Musset, Brigitte Bader-Meunier, Isabelle Kone-Paut, Jean Sibilia, Laurent Servais, Olivier Fain, Claire Larroche, Elisabeth Diot, Benjamin Terrier, Raphael De Paz, Antoine Dossier, Dominique Menard, Chafika Morati, Marielle Roux, Xavier Ferrer, Jeremie Martinet, Sophie Besnard, Remi Bellance, Patrice Cacoub, Laurent Arnaud, Bernard Grosbois, Serge Herson, Olivier Boyer, Olivier Benveniste, French Myositis Network

Abstract

Necrotizing autoimmune myopathy (NAM) is a group of acquired myopathies characterized by prominent myofiber necrosis with little or no muscle inflammation. Recently, researchers identified autoantibodies (aAb) against 3-hydroxy-3-methylglutaryl-coenzyme A reductase (HMGCR) in patients with NAM, especially in statin-exposed patients. Here we report what is to our knowledge the first European cohort of patients with NAM.The serum of 206 patients with suspicion of NAM was tested for detection of anti-HMGCR aAb using an addressable laser bead immunoassay. Forty-five patients were found to be anti-HMGCR positive. Their mean age was 48.9 ± 21.9 years and the group was predominantly female (73.3%). Statin exposure was recorded in 44.4% of patients. Almost all patients had a muscular deficit (97.7%), frequently severe (Medical Research Council [MRC] 5 ≤3 in 75.5%). Subacute onset (<6 mo) was noted for most of them (64.4%). Nevertheless, 3 patients (6.6%) had a slowly progressive course over more than 10 years. Except for weight loss (20%), no extramuscular sign was observed. The mean CK level was high (6941 ± 8802 IU/L) and correlated with muscle strength evaluated by manual muscle testing (r = -0.37, p = 0.03). Similarly, anti-HMGCR aAb titers were correlated with muscular strength (r = -0.31; p = 0.03) and CK level (r = 0.45; p = 0.01). Mean duration of treatment was 34.1 ± 40.8 months, and by the end of the study no patient had been able to stop treatment.This study confirms the observation and description of anti-HMGCR aAb associated with NAM. The majority of patients were statin naive and needed prolonged treatments. Some patients had a dystrophic-like presentation. Anti-HMGR aAb titers correlated with CK levels and muscle strength, suggesting their pathogenic role.

Figures

FIGURE 1
FIGURE 1
Correlation between CK level and muscular deficit in patients with NAM. For each patient the muscular deficit is given as the Medical Research Council score of the weakest muscular group using manual muscular testing (MMT MRC).
FIGURE 2
FIGURE 2
Histologic and immunohistologic analysis of muscle biopsies from anti-HMGCR+ patients. A, Muscle biopsy from a NAM patient showing rare necrotizing fiber (arrow) with some atrophic fibers (arrowheads) (hematin eosin stain). B, Muscle biopsy from another patient showing a high number of necrotized fibers (arrow) with important numbers of regenerative fibers (arrowhead). C, Muscular infiltrates are sometimes present (arrow) and in low intensity as represented here (arrow) for 1 patient. D, Immunohistologic analysis showing C5b9 deposits decorating some necrotic and non-necrotic fibers (arrows). E, Immunohistologic analysis of MHC class I expression showing a representative case of MHC overexpression on 2 fibers (arrows). F, A few patients may have diffuse and intense MHC overexpression not only on necrotic fibers (arrows) but also on non-necrotic fibers (arrowheads).
FIGURE 3
FIGURE 3
Correlation between muscular deficit and CK level with anti-HMGCR aAb titer. For each patient, we analyzed the correlation between the anti-HMGCR aAb titer and muscular deficit given as the MRC score of the weakest muscular group using manual muscular testing (MMT MRC) (A) or CK level (B).

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