IVIg increases interleukin-11 levels, which in turn contribute to increased platelets, VWF and FVIII in mice and humans.

The mechanisms of action of intravenous immunoglobulins (IVIg) in autoimmune diseases are not fully understood. The fixed duration of efficacy and noncumulative effects of IVIg in immune thrombocytopenia (ITP) and acquired von Willebrand disease (AVWD) suggest other mechanisms besides immunological ones. Additionally to the peripheral destruction of platelets in ITP, their medullary hypoproduction emerged as a new paradigm with rescue of thrombopoietin receptor agonists (TPO-RA). In an ITP mouse model, interleukin (IL)-11 blood levels increase following IVIg. IL-11 stimulates the production of platelets and other haemostasis factors; recombinant IL-11 (rIL-11) is thus used as a growth factor in post-chemotherapy thrombocytopenia. We therefore hypothesized that IVIg induces IL-11 over-production, which increases platelets, VWF and factor VIII (FVIII) levels in humans and mice. First, in an ITP mouse model, we show that IVIg or rIL-11 induces a rapid increase (72 h) in platelets, FVIII and VWF levels, whereas anti-IL-11 antibody greatly decreased this effect. Secondly, we quantify for the first time in patients with ITP, AVWD, inflammatory myopathies or Guillain-Barré syndrome the dramatic IL-11 increase following IVIg, regardless of the disease. As observed in mice, platelets, VWF and FVIII levels increased following IVIg. The late evolution (4 weeks) of post-IVIg IL-11 levels overlapped with those of VWF and platelets. These data may explain thrombotic events following IVIg and open perspectives to monitor post-IVIg IL-11/thrombopoietin ratios, and to assess rIL-11 use with or without TPO-RA as megakaryopoiesis co-stimulating factors to overcome the relative hypoproduction of platelets or VWF in corresponding autoimmune diseases, besides immunosuppressant.

[Myositis: From classification to diagnosis]. / Myosites : de la classification au diagnostic.

Idiopathic inflammatory myopathies, or IIM, are a group of acquired diseases that affect the muscle to a certain extent, and may also affect other organs. They include dermatomyositis, which can affect the muscle eventualy, with a typical skin rash; inclusion body myositis, with a purely muscular expression resulting in a slow progressive deficit; and the former group of "polymyositis", a misnomer that actually includes other categories of IIM, such as immune-mediated necrotizing myopathies, with a severe muscle involvement often presents from the onset of the disease; antisynthetase syndrome, which combines muscle damage, joint involvement and a potentially life-threatening lung disease; and overlapping myositis, which combines muscle damage with other organs involvement connected to another autoimmune disease. The diagnosis of IIM is based on rigorous clinical examination and interrogation, electromyographic data and immunological testing for myositis specific antibodies. This antibody dosage must be extended or repeated if necessary to classify correctly the muscle disease under investigation, as the available tests may not perform well enough. Muscle biopsy, although very informative, is not anymore systematically recommended when the clinic and the antibodies are typical. However, some forms of IIM are sometimes difficult to classify; in these cases, muscle biopsy plays a crucial role in the precise etiological diagnosis.

French expert opinion for the management of juvenile dermatomyositis.

A guideline group consisting of a pediatric rheumatologist, internists, rheumatologists, immunologists, a physiotherapist and a patient expert elaborated guidelines related to the management of juvenile dermatomyositis on behalf of the rare autoimmune and autoinflammatory diseases network FAI2R. A systematic search of the literature published between 2000 and 2015 and indexed in PubMed was undertaken. Here, we present the expert opinion for diagnosis and treatment in juvenile dermatomyositis.

Diagnostic potential of sarcoplasmic myxovirus resistance protein A expression in subsets of dermatomyositis.

AIMS: To elucidate the diagnostic value of sarcoplasmic expression of myxovirus resistance protein A (MxA) for dermatomyositis (DM) specifically analysing different DM subforms, and to test the superiority of MxA to other markers. METHODS: Immunohistochemistry for MxA and retinoic acid-inducible gene I (RIG-I) was performed on skeletal muscle samples and compared with the item presence of perifascicular atrophy (PFA) in 57 DM patients with anti-Mi-2 (n = 6), -transcription intermediary factor 1 gamma (n = 10), -nuclear matrix protein 2 (n = 13), -melanoma differentiation-associated gene 5 (MDA5) (n = 10) or -small ubiquitin-like modifier activating enzyme (n = 1) autoantibodies and with no detectable autoantibody (n = 17). Among the patients, nine suffered from cancer and 22 were juvenile-onset type. Disease controls included antisynthetase syndrome (ASS)-associated myositis (n = 30), immune-mediated necrotizing myopathy (n = 9) and inclusion body myositis (n = 5). RESULTS: Sarcoplasmic MxA expression featured 77% sensitivity and 100% specificity for overall DM patients, while RIG-I staining and PFA reached respectively 14% and 59% sensitivity and 100% and 86% specificity. In any subset of DM, sarcoplasmic MxA expression showed higher sensitivity than RIG-I and PFA. Some anti-MDA5 antibody-positive DM samples distinctively showed a scattered staining pattern of MxA. No ASS samples had sarcoplasmic MxA expression even though six patients had DM skin rash. CONCLUSIONS: Sarcoplasmic MxA expression is more sensitive than PFA and RIG-I expression for a pathological diagnosis of DM, regardless of the autoantibody-related subgroup. In light of its high sensitivity and specificity, it may be considered a pathological hallmark of DM per se. Also, lack of MxA expression in ASS supports the idea that ASS is a distinct entity from DM.

[Focal myositis: An unknown disease]. / Myosite focale : une maladie méconnue.

Focal myositis are inflammatory muscle diseases of unknown origin. At the opposite from the other idiopathic inflammatory myopathies, they are restricted to a single muscle or to a muscle group. They are not associated with extramuscular manifestations, and they have a good prognosis without any treatment. They are characterized by a localized swelling affecting mostly lower limbs. The pseudo-tumor can be painful, but is not associated with a muscle weakness. Creatine kinase level is normal. Muscle MRI shows an inflammation restricted to a muscle or a muscle group. Muscle biopsy and pathological analysis remain necessary for the diagnosis, showing inflammatory infiltrates composed by macrophages and lymphocytes without any specific distribution within the muscle. Focal overexpression of HLA-1 by the muscle fibers is frequently observed. The muscle biopsy permits to rule out differential diagnosis such a malignancy (sarcoma). Spontaneous remission occurs within weeks or months after the first symptoms, relapse is unusual.

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.

Diagnostic Utility of Auto-Antibodies in Inflammatory Muscle Diseases.

To date, there are four main groups of idiopathic inflammatory myopathies (IIM): polymyositis (PM), dermatomyositis (DM), immune-mediated necrotizing myopathy (IMNM) and sporadic inclusion body myositis; based on clinical presentation and muscle pathology. Nevertheless, important phenotypical differences (either muscular and/or extra-muscular manifestations) within a group persist. In recent years, the titration of different myositis-specific (or associated) auto-antibodies as a diagnostic tool has increased. This is an important step forward since it may facilitate, at a viable cost, the differential diagnosis between IIM and other myopathies. We have now routine access to assays for the detection of different antibodies. For example, IMNM are related to the presence of anti-SRP or anti-HMGCR. PM is associated with anti-synthetase antibodies (anti-Jo-1, PL-7, PL-12, OJ, and EJ) and DM with anti-Mi-2, anti-SAE, anti-TIF-1-γ and anti-NXP2 (both associated with cancer) or anti-MDA5 antibodies (associated with interstitial lung disease). Today, over 30 myositis specific and associated antibodies have been characterised, and all groups of myositis may present one of those auto-antibodies. Most of them allow identification of homogenous patient groups, more precisely than the classical international classifications of myositis. This implies that classification criteria could be modified accordingly, since these auto-antibodies delineate groups of patients suffering from myositis with consistent clinical phenotype (muscular and extra-muscular manifestations), common prognostic (cancer association, presence of interstitial lung disease, mortality and risk of relapse) and treatment responses. Nevertheless, since numerous auto-antibodies have been recently characterised, the exact prevalence of myositis specific antibodies remains to be documented, and research of new auto-antibodies in the remaining seronegative group is still needed.

[Autoantibody profile in myositis]. / Auto-anticorps au cours des myosites.

Patients suffering from muscular symptoms or with an increase of creatine kinase levels may present a myopathy. In such situations, clinicians have to confirm the existence of a myopathy and determine if it is an acquired or a genetic muscular disease. In the presence of an acquired myopathy after having ruled out an infectious, a toxic agent or an endocrine cause, physicians must identify which type of idiopathic myopathy the patient is presenting: either a myositis including polymyositis, dermatomyositis, and inclusion body myositis, or an immune-mediated necrotizing myopathy. Histopathology examination of a muscle biopsy is determinant but detection of autoantibody is now also crucial. The myositis-specific antibodies and myositis-associated antibodies lead to a serologic approach complementary to the histological classification, because strong associations of myositis-specific antibodies with clinical features and survival have been documented. The presence of anti-synthetase antibodies is associated with an original histopathologic pattern between polymyositis and dermatomyositis, and defines a syndrome where interstitial lung disease drives the prognosis. Anti-MDA-5 antibody are specifically associated with dermatomyositis, and define a skin-lung syndrome with a frequent severe disease course. Anti-TIF1-γ is also associated with dermatomyositis but its presence is frequently predictive of a cancer association whereas anti-MI2 is associated with the classical dermatomyositis. Two specific antibodies, anti-SRP and anti-HMGCR, are observed in patients with immune-mediated necrotizing myopathies and may be very useful to distinguish acquired myopathies from dystrophic muscular diseases in case of a slow onset and to allow the initiation of effective therapy.

[Usefulness of autoantibodies for the diagnosis of autoimmune myopathies]. / Apport des auto-anticorps au cours des myopathies auto-immunes.

INTRODUCTION: Idiopathic myopathies are a group of acquired muscular diseases considered as autoimmune disorders. Characteristic histopathologic features allow the classification into myositis (polymyositis, dermatomyositis, and inclusion body myositis) and immune-mediated necrotizing myopathies. But overlapping histological features may be observed between different idiopathic myopathies and even between acquired and genetic muscular diseases. In the group of idiopathic myopathies important discrepancies can be observed concerning extra-muscular involvement and prognosis. STATE OF ART: The discovery of myositis-specific antibodies and myositis-associated antibodies has led to a serologic approach complementary to histological classification, because striking associations of myositis-specific antibodies with clinical features and survival were observed. Here we reviewed the myositis-specific antibodies including autoantibodies directed against the aminoacyl tRNA-synthetase enzymes, the Mi-2 protein and the signal recognition particle, and the main myositis-associated autoantibodies, that can be tested in clinical practice. PERSPECTIVES: We will also focus on newly described dermatomyositis-associated antibodies (directed against: transcription intermediary factor 1 family proteins, small ubiquitin-like modifier activating enzyme, and melanoma differentiation-associated gene 5), and immune-mediated necrotizing myopathy-associated antibodies (directed against HMGcoA-reductase). CONCLUSION: Myositis-specific antibodies and myositis-associated antibodies are useful for the diagnosis of forms of autoimmune myopathies with distinct clinical features. They may help to define patients into clinical syndromes with specific outcomes and thus influence treatment strategies.

[Acquired necrotizing myopathies]. / Les myopathies nécrosantes acquises.

Necrotizing myopathies (MN) are defined by a specific histological pattern. They are characterized by a predominant muscle fibre necrosis and regeneration but with little or no associated inflammation. This histological pattern is observed in acquired myopathy but also in muscular dystrophy. Acquired NM can be secondary to drugs or toxics, and if not, autoimmune mechanisms have to be suspected. Necrotizing autoimmune myopathy is recognized as a subgroup of idiopathic inflammatory myopathies, different from other myositides. Generally, patients present a rapidly progressive and severe symmetrical proximal weakness with high serum creatine kinase level, associated in some patients with cardiac involvement. On the other hand, a slower progression may sometimes be observed, that could lead to erroneous diagnosis of muscular dystrophy. Necrotizing autoimmune myopathy may be associated to specific autoantibodies against signal recognition particle, or more recently described, against 3-hydroxy-3-methylglutaryl-coenzyme A reductase. Necrotizing auto-immune myopathy can also be described in association with connective tissue diseases such as lupus or sclerodermia. In remaining cases, cancer association may be observed. Necrotizing autoimmune myopathies are now considered as a new entity, treatable by immunosuppressants and which should not be misdiagnosed as a muscular dystrophy.

Diagnostic value of markers of muscle degeneration in sporadic inclusion body myositis.

Sporadic inclusion body myositis (s-IBM) is characterized histologically by the association of concomitant inflammatory and degenerative processes. We evaluated the sensitivity and specificity of different markers of the degenerative process in order to refine the histological diagnosis. We performed an immunohistochemical study with antibodies directed against ubiquitin, amyloid-beta precursor protein (AbetaPP), amyloid-beta (Abeta), SMI-31, SMI-310, Tar-DNA binding protein-43 (TDP-43) and p62 on s-IBM and control muscle biopsies. Based on conventional stains 36 patients with characteristic clinical features of s-IBM were subclassified as presumed definite s-IBM (d s-IBM, n = 17) or possible s-IBM (p s-IBM, n = 19) according to the presence or absence of vacuolated muscle fibers. Immunohistochemically, TDP-43 and p62 were the most sensitive markers, accumulating in all d s-IBM and in 31% and 37%, respectively, of the p s-IBM cases and thus enabling reclassification of these cases as d s-IBM. We recommend using TDP-43 and p62 antibodies in the histological diagnosis workup of s-IBM. The specificity of these markers has to be further validated in prospective series.

High frequency of venous thromboembolic events in Churg-Strauss syndrome, Wegener's granulomatosis and microscopic polyangiitis but not polyarteritis nodosa: a systematic retrospective study on 1130 patients.

OBJECTIVE: To determine the frequency and risk factors of venous thromboembolic events (VTE) in Wegener's granulomatosis (WG), microscopic polyangiitis (MPA) and, the so far unstudied, Churg-Strauss syndrome (CSS) and polyarteritis nodosa (PAN). METHODS: Retrospective, systematic analysis and comparisons were made between the characteristics of patients in the VTE group and non-VTE group. 1130 patients with WG, MPA, CSS or PAN were identified from the French Vasculitis Study Group cohort. RESULTS: During a mean follow-up of 58.4 (45.8) months, 83 VTE occurred in 74 (6.5%) patients, with a median vasculitis-VTE diagnosis interval of 5.8 months (-3 to +156). VTE occurred in seven of 285 (2.5%) patients with PAN, 19 of 232 (8.2%) with CSS, 30 of 377 (8%) with WG and 18 of 236 (7.6%) with MPA. Multivariate analysis retained age, male sex or previous VTE or stroke with motor deficit as being associated with a higher VTE risk. The adjusted odds ratio (95% confidence interval) for VTE was 2.88 (1.27 to 6.50) for patients with WG, MPA or CSS compared with PAN (p = 0.01). CONCLUSIONS: Our results suggest that, like WG and MPA, patients with CSS are at a greater risk of VTE, than those with PAN. The reasons for this difference remain to be elucidated.