O. Benveniste

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.

Resistant myasthenia gravis and rituximab: A monocentric retrospective study of 28 patients.

This retrospective study evaluated the efficiency and tolerance of rituximab in the management of resistant myasthenia gravis (MG). All patients who received rituximab for the treatment of MG between 2004 and 2015 at Pitié-Salpétrière University Hospital (Paris, France) were included. The efficacy of rituximab was evaluated every 6 months by the myasthenic muscle score (MMS), the Myasthenia Gravis Foundation of America - Clinical Classification (MGFA-CC), the MGFA Therapy Status and the Postintervention Status (PIS). All rituximab-related side effects were noted. Twenty-eight patients were included: 21 with anti-acetylcholine receptor antibodies, 3 with anti-muscle-specific tyrosine kinase antibodies and 4 seronegatives. The mean age at day 1 of RTX was 50.6u2009±u200912.0 years. Patients previously received 1-4 immunosuppressants. The mean follow-up was 27.2 months (range: 6-60 months). The mean total dose of rituximab was 4.8u2009±u20092.5u2009g. The initial median MMS (58.8 points) improved significantly at M6 (74.5u2009±u200915.0 points; pu2009<u20090.0001) and remained stable thereafter: at M12: 75.9u2009±u200914.0 points (pu2009=u20090.00014), at M36: 72.5u2009±u200913.1 points (pu2009=u20090.0013). Among 16 patients with initial severe symptoms (MGFA-CC class IV), 14 improved. The PIS showed efficacy in about 50% of patients: at M6, 12/28 (43%) patients were considered improved. This benefit remained stable thereafter: at M12: 12/24, at M24: 7/17, at M36: 6/12. One patient developed a delayed progressive multifocal leukoencephalopathy. Based on the PIS, rituximab may be efficient in 50% of patients with MG resistant to immunosuppressants.

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-

Quickly progressive amyotrophy of the thigh: An unusual cause of rapid chondrolysis of the knee.

While rapidly destructive OA is more recognized in hip, we report the case of a 50-year-old woman who presented a rapid chondrolysis in the patellofemoral joint in a context of rapid loss of muscular strength. She had arthralgia, myalgia and proximal muscular deficit of the limbs. Creatine phospho kinase level was elevated and electromyogram exam showed a myogenic syndrome. Neither immune nor visceral disease was highlighted. As we suspected a polymyositis, we started corticosteroids and physiotherapy, then methotrexate and intravenous immunoglobulin. Concomitantly to the worsening of the muscular deficit and atrophy of hamstrings, she developed a persistent and disabling knee pain. Initial radiographs and magnetic resonance imaging (MRI) showed only a patellofemoral dysplasia and tiny cartilage damages. Because of aggravation of myalgia, we treated by mycophenolate mofetyl then rituximab. One year later, the knee remained painful and swollen. MRI showed signs of advanced osteoarthritis including an important loss of cartilage with an atrophy of hamstrings. Several articular corticosteroids injections were done. In the same time, the evolution of the muscular disease was unusual. Another histological analysis of muscle has highlighted a genetic myopathy due to mutation of calpain. Immunosuppressive treatments were stopped and a total joint replacement was performed. We show for the first time a case of rapid chondrolysis of patellofemoral joint related to a severe genetic myopathy.

Deep characterization of the anti-drug antibodies developed in Fabry disease patients, a prospective analysis from the French multicenter cohort FFABRY

BackgroundFabry disease (OMIM #301500) is an X-linked disorder caused by alpha-galactosidase A deficiency with two major clinical phenotypes: classic and non-classic of different prognosis. From 2001, enzyme replacement therapies (ERT) have been available. We aimed to determine the epidemiology and the functional characteristics of anti-drug antibodies. Patients from the French multicenter cohort FFABRY (nxa0=u2009103 patients, 53 males) were prospectively screened for total anti-agalsidase IgG and IgG subclasses with a home-made enzyme-linked immunosorbent assay (ELISA), enzyme-inhibition assessed with neutralization assays and lysoGb3 plasma levels, and compared for clinical outcomes.ResultsAmong the patients exposed to agalsidase, 40% of men (nu2009=u200918/45) and 8% of women (nu2009=u20092/25) had antibodies with a complete cross-reactivity towards both ERTs. Antibodies developed preferentially in men with non-missense GLA mutations (relative risk 2.88, pu2009=u20090.006) and classic phenotype (58.6% (17/29) vs 6.7% (1/16), pu2009=u20090.0005). Specific anti-agalsidase IgG1 were the most frequently observed (16/18 men), but the highest concentrations were observed for IgG4 (median 1.89xa0μg/ml, interquartile range (IQR) [0.41–12.24]). In the men exposed to agalsidase, inhibition was correlated with the total IgG titer (ru2009=u20090.67, pu2009<u20090.0001), especially IgG4 (ru2009=u20090.75, pu2009=u20090.0005) and IgG2 (ru2009=u20090.72, pu2009=u20090.001). Inhibition was confirmed intracellularly in Fabry patient leucocytes cultured with IgG-positive versus negative serum (median: 42.0 vs 75.6%, pu2009=u20090.04), which was correlated with IgG2 (ru2009=u20090.67, pu2009=u20090.017, nu2009=u200912) and IgG4 levels (ru2009=u20090.59, pu2009=u20090.041, nu2009=u200912). Plasma LysoGb3 levels were correlated with total IgG (ru2009=u20090.66, pu2009=u20090.001), IgG2 (ru2009=u20090.72, pu2009=u20090.004), IgG4 (ru2009=u20090.58, pu2009=u20090.03) and IgG1 (ru2009=u20090.55, pu2009=u20090.04) titers. Within the classic group, no clinical difference was observed but lysoGb3 levels were higher in antibody-positive patients (median 33.2xa0ng/ml [IQR 20.6–55.6] vs 12.5 [10.1–24.0], pu2009=u20090.005).ConclusionAnti-agalsidase antibodies preferentially develop in the severe classic Fabry phenotype. They are frequently associated with enzyme inhibition and higher lysoGb3 levels. As such, they could be considered as a hallmark of severity associated with the classic phenotype. The distinction of the clinical phenotypes should now be mandatory in studies dealing with Fabry disease and its current and future therapies.

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.