Immune-Mediated Necrotizing Myopathy (IMNM): A Story of Antibodies.

Immune-mediated necrotizing myopathy (IMNM) is a rare and severe disease that corresponds to a specific entity of idiopathic inflammatory myopathy. Patients with IMNM suffer from proximal muscle weakness, and present high levels of creatine kinase and necrotic myofibers. Anti-Signal Recognition Particle (SRP) and anti-3-hydroxy-3-methylglutaryl-coenzyme A reductase autoantibodies (HMGCR) have recently been identified in two thirds of patients with IMNM and are used as a hallmark of the disease. In this review, we provide a detailed description of these antibodies and the tests used to detect them in the serum of patients. Based on in vitro studies and mouse models of IMNM, we discuss the role of autoantibodies in the pathogenesis of the disease. Finally, in the light of the latest knowledge, we conclude with a review of recent therapeutic approaches in IMNM.

Efgartigimod restores muscle function in a humanized mouse model of immune-mediated necrotizing myopathy.

OBJECTIVE: Immune-mediated necrotizing myopathies (IMNMs) are severe forms of myositis often associated with pathogenic anti-3-hydroxy-3-methylglutaryl-CoA reductase (HMGCR) autoantibodies (aAbs). Efgartigimod is an engineered human IgG1 Fc fragment that antagonizes the neonatal Fc receptor (FcRn), thereby preventing recycling and promoting lysosomal degradation of IgG, including aAbs. We evaluated the therapeutic effects of IgG reduction by efgartigimod in a humanized murine model of IMNM. METHODS: Disease was induced in C5-deficient (C5def) or Rag2-deficient (Rag2-/-) mice receiving co-injections of anti-HMGCR+ IgG from an IMNM patient and human complement. C5def mice were treated in a preventive setting with s.c. injections of efgartigimod and Rag2-/- mice in a curative setting after disease was induced by anti-HMGCR+ IgG injections. Anti-HMGCR aAbs levels were monitored in mouse serum and muscle tissue. Histological analysis was performed on muscle sections. Muscle force was assessed by grip test or measurement of gastrocnemius strength upon electrostimulation. RESULTS: Administration of efgartigimod rapidly reduced total IgG levels, including the level of pathogenic anti-HMGCR aAbs, in both serum (P < 0.0001) and muscle (P < 0.001). In the preventive setting, efgartigimod prevented myofibre necrosis (P < 0.05), thus precluding loss of muscle strength (P < 0.05). In the therapeutic setting, efgartigimod prevented further necrosis and allowed muscle fibre regeneration (P < 0.05). Hence, muscle strength returned to normal (P < 0.01). CONCLUSION: Efgartigimod reduces circulating IgG levels, including pathogenic anti-HMGCR+ IgG aAbs, in a humanized mouse model of IMNM, preventing further necrosis and allowing muscle fibre regeneration. These results support investigating the therapeutic efficacy of efgartigimod through a clinical trial in IMNM patients.

Prevention of Anti-HMGCR Immune-Mediated Necrotising Myopathy by C5 Complement Inhibition in a Humanised Mouse Model.

Introduction: immune-mediated necrotising myopathy (IMNM) is associated with pathogenic anti-signal recognition particle (SRP) or 3-hydroxy-3-methylglutaryl-CoA reductase (HMGCR) antibodies, at least partly through activation of the classical pathway of the complement. We evaluated zilucoplan, an investigational drug, and a macrocyclic peptide inhibitor of complement component 5 (C5), in humanized mouse models of IMNM. Methods: purified immunoglobulin G (IgG) from an anti-HMGCR+ IMNM patient was co-injected intraperitoneally with human complement in C57BL/6, C5-deficient B10 (C5def) and Rag2 deficient (Rag2-/-) mice. Zilucoplan was administered subcutaneously in a preventive or interventional paradigm, either injected daily throughout the duration of the experiment in C57BL/6 and C5def mice or 8 days after disease induction in Rag2-/- mice. Results: prophylactic administration of zilucoplan prevented muscle strength loss in C5def mice (anti-HMGCR+ vs. anti-HMGCR+ + zilucoplan: p = 0.0289; control vs. anti-HMGCR+ + zilucoplan: p = 0.4634) and wild-type C57BL/6 (anti-HMGCR+ vs. anti-HMGCR+ + zilucoplan: p = 0.0002; control vs. anti-HMGCR+ + zilucoplan: p = 0.0939) with corresponding reduction in C5b-9 deposits on myofibres and number of regenerated myofibres. Interventional treatment of zilucoplan after disease induction reduced the complement deposits and number of regenerated myofibres in muscles of Rag2-/- mice, although to a lesser extent. In this latter setting, C5 inhibition did not significantly ameliorate muscle strength. Conclusion: Early administration of zilucoplan prevents the onset of myopathy at the clinical and histological level in a humanized mouse model of IMNM.

Local Neuronal Synchronization in Frequent Nightmare Recallers and Healthy Controls: A Resting-State Functional Magnetic Resonance Imaging Study.

Nightmares are highly dysphoric dreams that are well-remembered upon awakening. Frequent nightmares have been associated with psychopathology and emotional dysregulation, yet their neural mechanisms remain largely unknown. Our neurocognitive model posits that nightmares reflect dysfunction in a limbic-prefrontal circuit comprising medial prefrontal and anterior cingulate cortices, hippocampus, and amygdala. However, there is a paucity of studies that used brain imaging to directly test the neural correlates of nightmares. One such study compared the regional homogeneity (ReHo) of resting-state functional magnetic resonance imaging blood-oxygen level-dependent signals between frequent nightmare recallers and controls. The main results were greater regional homogeneity in the left anterior cingulate cortex and right inferior parietal lobule for the nightmare recallers than for the controls. In the present study, we aimed to document the ReHo correlates of frequent nightmares using several nightmare severity measures. We acquired resting-state functional magnetic resonance imaging data from 18 frequent nightmare recallers aged 18-35 (3 males and 15 females) and 18 age- and sex-matched controls, as well as retrospective and prospective disturbed dreaming frequency estimates and scores on the Nightmare Distress Questionnaire. While there were inconsistent results for our different analyses (group comparisons, correlational analyses for frequency estimates/Nightmare Distress scores), our results suggest that nightmares are associated with altered ReHo in frontal (medial prefrontal and inferior frontal), parietal, temporal and occipital regions, as well as some subcortical regions (thalamus). We also found a positive correlation between retrospective disturbed dreaming frequency estimates and ReHo values in the hippocampus. These findings are mostly in line with a recent SPECT study from our laboratory. Our results point to the possibility that a variety of regions, including but not limited to the limbic-prefrontal circuit of our neurocognitive model, contribute to nightmare formation.

Attempted induction of signalled lucid dreaming by transcranial alternating current stimulation.

Neurophysiological correlates of self-awareness during sleep ('lucid dreaming') remain unclear despite their importance for clarifying the neural underpinnings of consciousness. Transcranial direct (tDC) and alternating (tAC) current stimulation during sleep have been shown to increase dream self-awareness, but these studies' methodological weaknesses prompted us to undertake additional study. tAC stimulation was associated with signal-verified and self-rated lucid dreams-but so was the sham procedure. Situational factors may be crucial to inducing self-awareness during sleep.

Predicting the affective tone of everyday dreams: A prospective study of state and trait variables.

Although emotions are reported in a large majority of dreams, little is known about the factors that account for night-to-night and person-to-person variations in people's experience of dream affect. We investigated the relationship between waking trait and state variables and dream affect by testing multilevel models intended to predict the affective valence of people's everyday dreams. Participants from the general population completed measures of personality and trauma history followed by a three-week daily journal in which they noted dream recall, valence of dreamed emotions and level of perceived stress for the day as well as prior to sleep onset. Within-subject effects accounted for most of the explained variance in the reported valence of dream affect. Trait anxiety was the only variable that significantly predicted dream emotional valence at the between-subjects level. In addition to highlighting the need for more fine-grained measures in this area of research, our results point to methodological limitations and biases associated with retrospective estimates of general dream affect and bring into focus state variables that may best explain observed within-subject variance in emotions experienced in everyday dreams.

Nightmare Severity Is Inversely Related to Frontal Brain Activity During Waking State Picture Viewing.

STUDY OBJECTIVES: Growing evidence suggests that nightmares have considerable adverse effects on waking behavior, possibly by increasing post-sleep negative emotions. Dysphoric reactions to nightmares are one component of nightmare severity for which the neural correlates are unknown. Here, we investigate possible neural correlates of nightmare severity in a sample of individuals who frequently recall nightmares. METHODS: Our principal measure of nightmare severity is nightmare distress as indexed by the Nightmare Distress Questionnaire (NDQ), and secondary measures are retrospective and prospective estimates of frequency of recalling dysphoric dreams (DD). We used high-resolution technetium 99m ethyl cysteinate dimer single photon emission computed tomography to assess regional cerebral blood flow (rCBF) while 18 individuals who were frequent nightmare recallers viewed negative and neutral pictures from the International Affective Picture System. We correlated rCBF with NDQ scores and DD recall frequency estimates. RESULTS: Negative correlations were observed between NDQ scores and rCBF during negative picture viewing in bilateral insula and anterior cingulate, right medial frontal gyrus, bilateral superior temporal gyrus, right inferior frontal and precentral gyri, and bilateral putamen. Retrospective DD recall correlated with rCBF activity primarily in regions overlapping those related to NDQ scores. Prospective DD recall was only weakly related to rCBF. Results for the neutral condition overlapped partially with those for the negative condition; in particular, NDQ and retrospective DD recall were related to rCBF in medial prefrontal and anterior cingulate gyri. CONCLUSIONS: Results point to a possible overlap in brain mechanisms involved in nightmare dysphoria (during sleep) and distress (during wakefulness) among individuals who frequently recall nightmares. They provide partial support for a neurocognitive model of nightmares. COMMENTARY: A commentary on this article appears in this issue on page 179.