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.

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.

Cytosolic 5'-nucleotidase 1A autoantibody profile and clinical characteristics in inclusion body myositis.

OBJECTIVES: Autoantibodies directed against cytosolic 5'-nucleotidase 1A have been identified in many patients with inclusion body myositis. This retrospective study investigated the association between anticytosolic 5'-nucleotidase 1A antibody status and clinical, serological and histopathological features to explore the utility of this antibody to identify inclusion body myositis subgroups and to predict prognosis. MATERIALS AND METHODS: Data from various European inclusion body myositis registries were pooled. Anticytosolic 5'-nucleotidase 1A status was determined by an established ELISA technique. Cases were stratified according to antibody status and comparisons made. Survival and mobility aid requirement analyses were performed using Kaplan-Meier curves and Cox proportional hazards regression. RESULTS: Data from 311 patients were available for analysis; 102 (33%) had anticytosolic 5'-nucleotidase 1A antibodies. Antibody-positive patients had a higher adjusted mortality risk (HR 1.89, 95% CI 1.11 to 3.21, p=0.019), lower frequency of proximal upper limb weakness at disease onset (8% vs 23%, adjusted OR 0.29, 95% CI 0.12 to 0.68, p=0.005) and an increased prevalence of excess of cytochrome oxidase deficient fibres on muscle biopsy analysis (87% vs 72%, adjusted OR 2.80, 95% CI 1.17 to 6.66, p=0.020), compared with antibody-negative patients. INTERPRETATION: Differences were observed in clinical and histopathological features between anticytosolic 5'-nucleotidase 1A antibody positive and negative patients with inclusion body myositis, and antibody-positive patients had a higher adjusted mortality risk. Stratification of inclusion body myositis by anticytosolic 5'-nucleotidase 1A antibody status may be useful, potentially highlighting a distinct inclusion body myositis subtype with a more severe phenotype.

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.

High dose subcutaneous immunoglobulin for idiopathic inflammatory myopathies and dysimmune peripheral chronic neuropathies treatment: observational study of quality of life and tolerance.

BACKGROUND: In patients with autoimmune diseases who still derive benefit from high dose intravenous immunoglobulin (IVIg) treatment, some physicians resort to subcutaneous (SC) Ig as a replacement therapy. OBJECTIVE: To collect quality of life (QoL) and tolerance data on SCIg in patients for whom the switch from IVIg to SCIg is essential to maintain treatment. METHODS: This observational study included patients with either idiopathic inflammatory myopathies (IIM) or chronic dysimmune peripheral neuropathies (CDPN) treated with IVIg, who had been switched to SCIg administration for at least three months. The main objective was to describe the impact of SCIg on QoL after six months, using the generic Short-Form 36 questionnaire (SF-36). The secondary objectives were to evaluate SCIg tolerance and clinical efficiency. RESULTS: Eight centres recruited 12 IIM patients and two centres recruited 11 CDPN patients. Neither the physical nor the mental health SF-36 component summaries showed any QoL deterioration during the six-month study period and all IIM and CDPN patients remained clinically stable during the same period. The most frequent adverse effects were injection site reactions (50%), cutaneous tissue disorders (18.2%), and nervous system disorders (13.6%). Two serious adverse events (myocarditis and cerebrovascular accident) occurred in two patients. CONCLUSION: In these rare inflammatory diseases, high dose SCIg administration (which can be home based) has no deleterious effect on patient QoL. It appears to be a safe and efficient alternative to hospital-based IVIg.

[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.

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.

[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.

Long-term outcome of patients with polymyositis/ dermatomyositis and anti-PM-Scl antibody.

BACKGROUND: To date, no series has analysed long-term outcome in patients with polymyositis/dermatomyositis (PM/DM) with anti-PM-Scl antibody. OBJECTIVES: The aims of the present study were: (i) to assess clinical features and long-term outcome, including organ complications, functional course and mortality rate, in patients with isolated PM/DM with anti-PM-Scl antibody; and (ii) to evaluate prevalence, characteristics and long-term outcome of interstitial lung disease (ILD) in patients with isolated PM/DM with anti-PM-Scl antibody. METHODS: The medical records of 20 consecutive patients with isolated PM/DM with anti-PM-Scl antibody were reviewed. RESULTS: Two patients (10%) achieved remission of PM/DM, whereas 14 (70%) improved and four (20%) had a worsened clinical status. Short-term recurrences (during tapering of therapy) occurred in nine patients and long-term recurrences (after discontinuation of therapy) in three patients. Moreover, patients with PM/DM with anti-PM-Scl antibody exhibited severe complications, as follows: oesophageal involvement (n = 4) requiring enteral feeding in three cases, ventilatory insufficiency (n = 3) requiring mechanical ventilation in two cases; three other patients had cancer. Interestingly, patients with PM/DM with anti-PM-Scl antibody often presented symptoms that are usually found in antisynthetase syndrome, i.e. hyperkeratotic rhagadiform hand symptoms (n = 2; 10%), Raynaud's phenomenon (n = 8; 40%), arthralgia/arthritis (n = 7; 35%) and ILD (n = 12; 60%). In our cohort, the associated ILD often required combined therapy of steroids and immunosuppressive agents. CONCLUSIONS: Our series suggests that the presence of anti-PM-Scl antibody is not a good prognostic factor in patients with PM/DM, as there appears to be an association with lung and oesophageal involvement; in addition, anti-PM-Scl antibody may coexist with malignancy in patients with PM/DM. Furthermore, anti-PM-Scl antibody-positive patients with PM/DM often exhibit 'mechanic's hands', Raynaud's phenomenon and joint involvement. Our latter findings raise the possibility that the immunogenetic background influences the autoantibody status of these patients; HLA-DR3 has, in fact, been found in association with antisynthetase syndrome antibodies and with anti-PM-Scl antibodies.

[Severe MDA5 dermatomyositis associated with cancer and controlled by JAK inhibitor]. / Dermatomyosite à anticorps anti-MDA5 sévère associée à un cancer et contrôlée par inhibiteur de JAK.

Dermatomyositis is an idiopathic inflammatory myopathy with various clinical and serological profiles, including poor prognosis forms for which aggressive immunosuppressive treatment is warranted. We report the case of a 60-year-old woman referred to our hospital for an anti-melanoma differentiation-associated 5 gene antibody-positive dermatomyositis (MDA5 DM) with rapidly progressive interstitial pneumonia, typical cutaneous features and muscular impairment. Treatment with high-dose methylprednisolone, cyclophosphamide and gamma globulin was performed, but the patient remained corticodependant. Blood detection of positive interferon signature justified the administration of an anti-JAK1/2, leading to the clinical remission and the regression of the interferon signature. After 12 months of follow up, a small cell carcinoma was discovered, raising the question of a paraneoplastic syndrome, for which the most recent datas are quite reassuring for this kind of MDA5 DM. The presentation of this case is of twofold interest: describing one of the first report of successful treatment of intereronopathy MDA5 DM with ruxolitinib and highlighting an association with a cancer, which is not expected for this phenotype of dermatomyositis.

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.

[New classifications and pathophysiology of the inflammatory myopathies]. / Nouvelles classifications et physiopathologie des myopathies inflammatoires.

SCOPE: Review on new classifications of myositis linked with their different pathophysiology. CURRENT SITUATION AND SALIENT POINTS: The classification of myositis refined recently, taking into account clinical (such as isolated muscle involvement or not, association with cancer...), immunological (presence or absence of auto-antibodies) and pathological criteria. This new classification has the ability to separate different clinical and physiopathological entities, having actually different prognosis factors. The most common inflammatory myopathies include dermatomyositis (DM), polymyositis (PM), inclusion body myositis (IBM), but also, overlap myositis (defined, among others, by the presence of auto-antibodies), and myositis associated to cancers. These myopathies may be also distinguished by their histological features which also reflect their different underlying pathogeneses. The mechanism of DM is complement-mediated microangiopathy, the inflammatory infiltrate being secondary to ischaemic damage. In PM the muscle fibres are damaged by cytotoxic CD8 T lymphocytes. IBM may be a degenerative disease with accumulation of a variety of proteins within the fibres. The inflammatory infiltrate, which is similar to that seen in PM, may be secondary to accumulated proteins. PERSPECTIVES: These diseases with different pathogeny and prognosis should be treated by specific approaches. That is the reason why we initiated specific clinical trials for respectively inclusion body myositis and overlap myositis.

[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.

[A complex case of diabetes due to LMNA mutation]. / Un diabète particulièrement compliqué.

INTRODUCTION: Laminopathies (diseases related to A/C mutations of lamines) are rare genetic diseases with an extensive phenotypic spectrum, including lipodystrophic syndromes-characterized by a selective loss of adipose tissue-of which the partial Dunnigan family type is the most frequent. CASE REPORT: We report on a 55-year-old woman with diabetes and long-term disabling myalgia. Her cushingoid morphotype, associated with cutaneous lipo-atrophy and muscle hypertrophy in addition to a genetic heritage, led us to the diagnosis of complex partial familial lipodystrophy heterozygous LMNA_c.82C>T, p.Arg28Trp mutation. CONCLUSION: Familial partial lipodystrophic syndromes may have varied phenotypes, mainly cardio-metabolic, which could mimic a particularly severe type 2 diabetes. The diagnostic work-up of this disease has to include a careful investigation of gait troubles and paroxysmal conduction that could lead to sudden death, as well as a genetic examination. In some cases, recombinant leptin can be proposed.

[Usefulness of rehabilitation in inflammatory myopathies]. / Intérêt de la rééducation fonctionnelle au cours des myopathies inflammatoires.

Rehabilitation, for a long time not recommended, seems today to hold a prominent place within the therapeutic arsenal of inflammatory myopathies. The difficulty of its evaluation, apart from the low prevalence of these diseases, lies in a triple heterogeneity: first that distinguishing the different forms of inflammatory myopathies and the phase where they are active; second, that concerning the endpoint considered to assess the efficiency of the intervention; lastly, the diversity of the rehabilitation programs that can be undertaken. Between 1993 and 2016, about 30 studies estimating the rehabilitation of inflammatory myopathies have been published, among which five randomized controlled trials, four controlled trials, 15 open studies, and seven case reports. All these studies evidence the safety of rehabilitation and some show a significant improvement of the criteria estimating the activity of the disease, its functional impact or the impairment of quality of life and the limitation in daily life activities triggered by the disease. The rehabilitation, whether aerobic, anaerobic or mixed, must today systematically be associated with the pharmaceutic treatment proposed to patients affected by inflammatory myopathies. Other studies are necessary to optimize the rehabilitation methods, to understand their effects and action, and to quantify their impact and provide more trustworthy evidence.

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.

Significant response to immune therapies in a case of subacute necrotizing myopathy and FKRP mutations.

Necrotizing myopathies can be encountered in various conditions as acquired myopathies (toxic or autoimmune) or muscular dystrophies. We report a twenty-year-old Caucasian woman who presented with clinical findings suggestive of an inflammatory myopathy: subacute onset of lower limb muscle weakness, myalgia, weight loss and absence of family history. The serum creatine kinase level was elevated at 4738 IU/L (normal range, 25-175 IU/L). Muscle biopsy was consistent with necrotizing myopathy. The patient showed significant clinical improvement following corticosteroid, azathioprine and intravenous immunoglobulin treatments. Biological tests revealed no specific autoantibodies associated with necrotizing autoimmune myopathies. Immunohistochemical staining for sarcolemmal proteins in muscle biopsy samples finally led to a diagnosis of limb-girdle muscular dystrophy 2I (fukutin-related protein gene mutations). The response to immune therapies suggested a possible inflammatory component associated with the muscular dystrophy and highlighted the potential benefit of corticosteroid treatment in patients with LGMD2I and subacute onset.

Nef and Gag synthetic peptide priming of antibody responses to HIV type 1 antigens in mice and primates.

T epitope mapping in human immunodeficiency virus proteins provides a useful tool for AIDS vaccine design. We have previously shown that four peptides selected from the Gag polyprotein of HIV-1 were able to prime mice for in vitro lymphoproliferative responses. These responses were shown to be MHC restricted, and a pool of these peptides was able to prime mice for a subsequent humoral response to HIV-1 Gag proteins. Here we show that two of these Gag peptides are able to prime the anti-HIV-1 IgG response to heat-inactivated HIV-1 in B10Sc.Cr mice. Furthermore, we extended this study in the nonhuman primate model, and show efficient priming of the IgG response to heat-inactivated HIV-1 using the pool of four Gag peptides in baboons. Further mapping of "nonself" peptides is extended to the HIV-1 Nef protein. Three potential Nef T epitopes located at positions 137-145, 98-107, and 81-95 are also shown to prime the IgG response to HIV-1 in the mouse model, although T cell proliferation to recall peptides in vitro was not detectable. Although they have not yet been defined as major helper T epitopes in humans, using classic in vitro stimulation assays, the fact that most of them are able to prime IgG responses in animals without detectable in vitro proliferative responses does not rule out their functional helper capacity in humans.