Yves Allenbach

High risk of cancer in autoimmune necrotizing myopathies: usefulness of myositis specific antibody

Cancer can occur in patients with inflammatory myopathies. This association is mainly observed in dermatomyositis, and myositis-specific antibodies have allowed us to delineate patients at an increased risk. Malignancy is also reported in patients with necrotizing autoimmune myopathies, but the risk remains elusive. Anti-signal recognition particle or anti-HMGCR antibodies have been specifically associated with necrotizing autoimmune myopathies. We aimed at screening the incidence of cancer in necrotizing autoimmune myopathies. A group of patients (n = 115) with necrotizing autoimmune myopathies with or without myositis-specific antibodies was analysed. Malignancy occurred more frequently in seronegative necrotizing autoimmune myopathies patients and in HMGCR-positive patients compared to anti-signal recognition particle positive patients. Synchronous malignancy was diagnosed in 21.4% and 11.5% of cases, respectively, and incidence of cancer was higher compared to the general population in both groups. No specific type of cancer was predominant. Patients suffering from a synchronous cancer had a decreased median survival time. Cancer screening is necessary in seronegative necrotizing autoimmune myopathies and in HMGCR-positive patients but not in anti-signal recognition particle-positive patients.

Dermatomyositis With or Without Anti-Melanoma Differentiation-Associated Gene 5 Antibodies: Common Interferon Signature but Distinct NOS2 Expression.

The anti-melanoma differentiation-associated gene 5 (MDA5) autoantibody is specifically associated with dermatomyositis (DM). Nevertheless, anti-MDA5(+)-patients experience characteristic symptoms distinct from classic DM, including severe signs of extramuscular involvement; however, the clinical signs of myopathy are mild or even absent. The morphological and immunological features are not yet described in adulthood. Data concerning the pathophysiology of anti-MDA5 DM are sparse; however, the importance of the interferon (IFN) type I pathway involved in DM has been shown. Our aim was to define morphological alterations of the skeletal muscle and the intrinsic immune response of anti-MDA5-positive DM patients. Immunohistological and RT-PCR analysis of muscle biopsy specimens from anti-MDA5 and classic DM were compared. Those with anti-MDA5 DM did not present the classic features of perifascicular fiber atrophy and major histocompatibility complex class I expression. They did not show significant signs of capillary loss; tubuloreticular formations were observed less frequently. Inflammation was focal, clustering around single vessels but significantly less intense. Expression of IFN-stimulated genes was up-regulated in anti-MDA5 DM; however, the IFN score was significantly lower. Characteristic features were observed inxa0anti-MDA5 DM and not in classic DM patients. Only anti-MDA5 DM showed numerous nitric oxide synthase 2-positive muscle fibers with sarcoplasmic colocalization of markers of regeneration and cell stress. Anti-MDA5-positive patients demonstrate a morphological pattern distinct from classic DM.

Integrated classification of inflammatory myopathies

Inflammatory myopathies comprise a multitude of diverse diseases, most often occurring in complex clinical settings. To ensure accurate diagnosis, multidisciplinary expertise is required. Here, we propose a comprehensive myositis classification that incorporates clinical, morphological and molecular data as well as autoantibody profile. This review focuses on recent advances in myositis research, in particular, the correlation between autoantibodies and morphological or clinical phenotypes that can be used as the basis for an ‘integrated’ classification system.

224th ENMC International Workshop:: Clinico-sero-pathological classification of immune-mediated necrotizing myopathies Zandvoort, The Netherlands, 14-16 October 2016

224th ENMC International Workshop: Clinico-sero-pathological classification of immune-mediated necrotizing myopathies Zandvoort, The Netherlands, 14–16 October 2016 Yves Allenbach , Andrew L. Mammen , Olivier Benveniste , Werner Stenzel * on behalf of the Immune-Mediated Necrotizing Myopathies Working Group 3 a Department of Internal Medicine, Pitie Salpetrière Hospital, AP-HP Sorbonne university, Paris, France b National Institute of Arthritis and Musculoskeletal and Skin Diseases, National Institutes of Health, Bethesda, MD, USA c Department of Neuropathology, Charité-Universitätsmedizin, Berlin, Germany

JAK inhibitor improves type I interferon induced damage: proof of concept in dermatomyositis.

Dermatomyositis is an acquired auto-immune disease characterized by skin lesions and muscle-specific pathological features such as perifascicular muscle fibre atrophy and vasculopathy. Dermatomyositis patients display an upregulation of type I interferon-inducible genes in muscle fibres, endothelial cells, skin and peripheral blood. However, the effect of type I interferon on muscle tissue has not yet been determined. Our aim was to study the pathogenicity of type I interferon in vitro and to evaluate the efficacy of the type I interferon pathway blockade for therapeutic purposes. The activation of type I interferon in differentiating myoblasts abolished myotube formation with reduced myogenin expression while in differentiated myotubes, we observed a reduction in surface area and an upregulation of atrophy-associated genes. In vitro endothelial cells exposure to type I interferon disrupted vascular network organization. All the pathogenic effects observed in vitro were abolished by ruxolitinib. Finally, four refractory dermatomyositis patients were treated with ruxolitinib and improvement ensued in skin lesions, muscle weakness and a reduced serum type I interferon levels and interferon-inducbile genes scores. We propose JAK inhibition as a mechanism-based treatment for dermatomyositis, a finding that is relevant for the design of future clinical trials targeting dermatomyositis.

Expanding the spectrum of livedoid vasculopathy: peculiar neuromuscular manifestations.

Livedoid vasculopathy (LV) is a rare and recurrent chronic disorder mainly restricted to the skin. LV is characterized by recurrent purpura, livedo reticularis of the legs associated with painful ulcerations, resulting in atrophic, porcelain scars [1]. This disease is considered a thrombo-occlusive vasculopathy of superficial dermal micro-vessels due to either idiopathic cause or secondary to a defined state of thrombophilia [2]. Diagnosis is based on the characteristic skin lesions and presence of intraluminal thrombosis, endothelial cell hyperplasia and sub-intimal hyaline degeneration in dermal vessels [3]. LV is not a vasculitis sensu-stricto, as generally no inflammation occurs within the wall of the vessels, but perivascular inflammation may be present secondarily [4]. Neurological involvement in LV is rare and may expand its nosological spectrum. Symptoms comprise mononeuritis multiplex, and the underlying pathophysiology has been postulated to be the result of ischaemia [5,6]. However, vasculitis has been observed, in an association between LV and periarteritis nodosa (PAN) [7]. From a physiopathological point of view, this entity is surprising, as a general state of hypercoagulability leads to damage confined to the skin and much less frequently to the peripheral nervous system, but not to other tissues. Here, we describe LV patients with a peripheral neuropathy attributed to thrombotic vasculopathy without signs of vasculitis. Furthermore, we illustrate the involvement of the skeletal muscle, characterized by an extreme loss of capillaries, associated with peculiar perifascicular pathology. In a retrospective observational study, primary LV patients (n = 18, 10 females and mean age of 50.1 years) diagnosed by international criteria [8] were enrolled. We identified three patients, who had undergone combined nerve–muscle biopsy to explore peripheral neurological symptoms. Patients were 58, 44 and 22 years at time of the first skin manifestation (patient A, B and C, respectively). Neurological signs appeared respectively 10 (patients A), 20 (patient B) and 23 years after (patient C) the first skin manifestation. One patient (patient A) suffered from mononeuritis multiplex. Electroneurography confirmed popliteal sciatic nerve damage and showed injuries of median and ulnar nerves. Patient B suffered from sensory polyneuropathy of lower limbs. Patient C had bilateral dysesthaesia and hypaesthesia of the back of the right foot, and his EMG showed a motor and sensory axonal neuropathy. No proximal weakness was observed in any of the three patients, and all of them had normal CK levels. Other causes of peripheral neuropathy were excluded by extensive laboratory tests, and there was no history of drugs, neurotoxin exposure or association with cancer. All patients showed remarkably similar morphological alterations. A severe loss of myelinated axons, with only few thinly myelinated axons (with minimal signs of axonal regeneration) and endoneurial replacement by fibrous tissue, was the most prominent finding (Figure 1A,B). Furthermore, a relevant formation of collagen pockets on ultra-structural examination illustrated loss of un-myelinated axons (Figure 1C). All fascicles were equally affected. The second observation consisted of enlarged vessels with conspicuous engorgement mainly in the epineurium (Figure 1D). Importantly, in all cases, inflammatory infiltrates basically consisting of CD3 lymphocytes were detected around enlarged vessels in the epineurium (Figure 1D), however without signs of vasculitis. In addition, we found a remarkable vascular pathology mainly involving capillaries of the endoneurium. Alterations consisted of enlarged endothelial cells, which appeared thickened, occasional basal membrane duplication, apposition of endothelial cells layers, as well as necrosis of capillaries (Figure 1A,E,F). Indirect signs of neuropathy were also observed in all muscle biopsies with neurogenic features consisting of nuclear clumps, grouped atrophic fibres and fibre-type grouping (Figure 1G). Additional myopathic changes included split fibres, and round and hypertrophic fibres with internalized nuclei (Figure 1H). Although neurogenic changes are frequently associated with myopathic features especially during a chronic course of disease, we also detected myopathic changes not attributable to neu-

Non-invasive differentiation of idiopathic inflammatory myopathy with cardiac involvement from acute viral myocarditis using cardiovascular magnetic resonance imaging T1 and T2 mapping.

BackgroundIdiopathic inflammatory myopathy (IIM) is a group of autoimmune diseases with systemic myositis which may involve the myocardium. Cardiac involvement in IIM, although often subclinical, may mimic clinical manifestations of acute viral myocarditis (AVM). Our aim was to investigate the usefulness of the combined analysis of cardiovascular magnetic resonance (CMR) T1 and T2 mapping parameters measured both in the myocardium and in the thoracic skeletal muscles to differentiate AVM from IIM cardiac involvement.MethodsSixty subjects were included in this retrospective study (36 male, age 45u2009±u200916xa0years): twenty patients with AVM, twenty patients with IIM and cardiac involvement and twenty healthy controls. Study participants underwent CMR imaging with modified Look-Locker inversion-recovery (MOLLI) T1 mapping and 3-point balanced steady-state-free precession T2 mapping. Relaxation times were quantified after endocardial and epicardial delineation on basal and medial short-axis slices, as well as in different thoracic skeletal muscle groups present in the CMR field-of-view. ROC-Analysis was performed to assess the ability of mapping indices to discriminate the study groups.ResultsMapping parameters in the thoracic skeletal muscles were able to discriminate between AVM and IIM patients. Best skeletal muscle parameters to identify IIM from AVM patients were reduced post-contrast T1 and increased extracellular volume (ECV), resulting in an area under the ROC curve (AUC) of 0.95 for post-contrast T1 and 0.96 for ECV. Conversely, myocardial mapping parameters did not discriminate IIM from AVM patients but increased native T1 (AUC 0.89 for AVM; 0.84 for IIM) and increased T2 (AUC 0.82 for AVM; 0.88 for IIM) could differentiate both patient groups from healthy controls.ConclusionCMR myocardial mapping detects cardiac inflammation in AVM and IIM compared to normal myocardium in healthy controls but does not differentiate IIM from AVM. However, thoracic skeletal muscle mapping was able to accurately discern IIM from AVM.

Potential Pathogenic Role of Anti-Signal Recognition Protein and Anti-3-hydroxy-3-methylglutaryl-CoA Reductase Antibodies in Immune-Mediated Necrotizing Myopathies

Purpose of ReviewThis review provides an overview of the potential pathogenic roles of anti-SRP and anti-HMGCR in IMNM over the past 5 years.Recent FindingsIdiopathic inflammatory myopathies (IIM) are a group of acquired autoimmune disorders that mainly affect the skeletal muscle tissue. Classification criteria of IIM are comprised of polymyositis, dermatomyositis, inclusion body myositis and immune-mediated necrotizing myopathies. One important hallmark of autoimmune diseases is the detection of autoantibodies in patient sera. The anti-SRP (signal recognition particle) and anti-HMGCR (3-hydroxy-3-methylglutaryl coenzyme A reductase) antibodies are specifically associated with IMNM patients, and their detection has been described as related to disease severity. The muscles of IMNM patients are characterized by necrosis, atrophy and regenerating fibres with sparse inflammatory infiltrates.SummaryAlthough an important correlation between autoantibody titres, creatine kinase levels and disease progression/severity has been described in the last few years, the potential pathogenic roles of these autoantibodies have only recently been described.

Activated dendritic cells modulate proliferation and differentiation of human myoblasts

Idiopathic Inflammatory Myopathies (IIMs) are a heterogeneous group of autoimmune diseases affecting skeletal muscle tissue homeostasis. They are characterized by muscle weakness and inflammatory infiltration with tissue damage. Amongst the cells in the muscle inflammatory infiltration, dendritic cells (DCs) are potent antigen-presenting and key components in autoimmunity exhibiting an increased activation in inflamed tissues. Since, the IIMs are characterized by the focal necrosis/regeneration and muscle atrophy, we hypothesized that DCs may play a role in these processes. Due to the absence of a reliable in vivo model for IIMs, we first performed co-culture experiments with immature DCs (iDC) or LPS-activated DCs (actDC) and proliferating myoblasts or differentiating myotubes. We demonstrated that both iDC or actDCs tightly interact with myoblasts and myotubes, increased myoblast proliferation and migration, but inhibited myotube differentiation. We also observed that actDCs increased HLA-ABC, HLA-DR, VLA-5, and VLA-6 expression and induced cytokine secretion on myoblasts. In an in vivo regeneration model, the co-injection of human myoblasts and DCs enhanced human myoblast migration, whereas the absolute number of human myofibres was unchanged. In conclusion, we suggest that in the early stages of myositis, DCs may play a crucial role in inducing muscle-damage through cell–cell contact and inflammatory cytokine secretion, leading to muscle regeneration impairment.

In vivo pathogenicity of IgG from patients with anti-SRP or anti-HMGCR autoantibodies in immune-mediated necrotising myopathy

Objectives In autoimmunity, autoantibodies (aAb) may be simple biomarkers of disease or true pathogenic effectors. A form of idiopathic inflammatory myopathy associated with anti-signal recognition particle (SRP) or anti-3-hydroxy-3-methylglutaryl-CoA reductase (HMGCR) aAb has been individualised and is referred to as immune-mediated necrotising myopathy (IMNM). The level of aAb correlates with IMNM activity and disease may respond to immunosuppression, suggesting that they are pathogenic. We aimed to evaluate the pathogenicity of IgG from patients with anti-SRP or anti-HMGCR aAb in vivo by developing the first mouse model of IMNM. Methods IgG from patients suffering from anti-SRP or anti-HMGCR associated IMNM were passively transferred to wild-type, Rag2-/- or complement C3-/- mice. Muscle deficiency was evaluated by muscle strength on electrostimulation and grip test. Histological analyses were performed after haematoxylin/eosin staining or by immunofluorescence or immunohistochemistry analysis. Antibody levels were quantified by addressable laser bead assay (ALBIA). Results Passive transfer of IgG from patients suffering from IMNM to C57BL/6 or Rag2-/- mice provoked muscle deficiency. Pathogenicity of aAb was reduced in C3-/- mice while increased by supplementation with human complement. Breakage of tolerance by active immunisation with SRP or HMGCR provoked disease. Conclusion This study demonstrates that patient-derived anti-SRP+ and anti-HMGCR+ IgG are pathogenic towards muscle in vivo through a complement-mediated mechanism, definitively establishing the autoimmune character of IMNM. These data support the use of plasma exchanges and argue for evaluating complement-targeting therapies in IMNM.