Inclusion body myositis: therapeutic approaches.

The idiopathic inflammatory myopathies are a heterogeneous group of diseases that include dermatomyositis (DM), polymyositis (PM), inclusion body myositis (IBM) and other less common myopathies. These are clinically and histopathologically distinct diseases with many shared clinical features. IBM, the most commonly acquired inflammatory muscle disease occurs in individuals aged over 50 years, and is characterized by slowly progressive muscle weakness and atrophy affecting proximal and distal muscle groups, often asymmetrically. Unlike DM and PM, IBM is typically refractory to immunotherapy. Although corticosteroids have not been tested in randomized controlled trials, the general consensus is that they are not efficacious. There is some suggestion that intravenous immunoglobulin slows disease progression, but its long-term effectiveness is unclear. The evidence for other immunosuppressive therapies has been derived mainly from case reports and open studies and the results are discouraging. Only a few clinical trials have been conducted on IBM, making it difficult to provide clear recommendations for treatment. Moreover, IBM is a slowly progressive disease so assessment of treatment efficacy is problematic due to the longer-duration trials needed to determine treatment effects. Newer therapies may be promising, but further investigation to document efficacy would be expensive given the aforementioned need for longer trials. In this review, various treatments that have been employed in IBM will be discussed even though none of the interventions has sufficient evidence to support its routine use

Juvenile dermatomyositis. Where are we now?

Juvenile onset idiopathic inflammatory myopathy (IIM) has many similarities and distinct differences from adult-onset disease. This review will focus on recent developments in understanding and treatment of juvenile dermatomyositis (JDM), the most common disease sub-type of IIM in childhood. JDM is a systemic immune mediated vasculopathy, increasingly recognised as a group of distinct phenotypes with variable presentation and outlook. This overview will describe long-term outlook and disease course including health-related quality of life and emerging treatments

Use of type I interferon-inducible mRNAs as pharmacodynamic markers and potential diagnostic markers in trials with sifalimumab, an anti-IFNα antibody, in systemic lupus erythematosus

Type I interferons are implicated in the pathogenesis of systemic lupus erythematosus (SLE). Type I interferon-inducible mRNAs are widely and concordantly overexpressed in the periphery and involved tissues of a subset of SLE patients, and provide utility as pharmacodynamic biomarkers to aid dose selection, as well as potential indicators of patients who might respond favorably to anti-IFNα therapy in SLE. We implemented a three-tiered approach to identify a panel of type I interferon-inducible mRNAs to be used as potential pharmacodynamic biomarkers to aid dose selection in clinical trials of sifalimumab, an anti-IFNα monoclonal antibody under development for the treatment of SLE. In a single-dose escalation phase 1 trial, we observed a sifalimumab-specific and dose-dependent inhibition of the overexpression of type I interferon-inducible mRNAs in the blood of treated subjects. Inhibition of expression of type I interferon-inducible mRNAs and proteins was also observed in skin lesions of SLE subjects from the same trial. Inhibiting IFNα resulted in a profound downstream effect in these SLE subjects that included suppression of mRNAs of B-cell activating factor belonging to the TNF family and the signaling pathways of TNFα, IL-10, IL-1β, and granulocyte-macrophage colony-stimulating factor in both the periphery and skin lesions. A scoring method based on the expression of type I interferon-inducible mRNAs partitioned SLE patients into two distinct subpopulations, which suggests the possibility of using these type I interferon-inducible genes as predictive biomarkers to identify SLE patients who might respond more favorably to anti-type I interferon therapy

Autoantibodies and the type I interferon system in idiopathic inflammatory myopathies

Idiopathic inflammatory myopathies (IIM), also known as myositis, are rare autoimmune diseases, characterized by proximal muscle weakness and inflammatory cells in skeletal muscle tissue. The most common subgroups are polymyositis (PM), dermatomyositis (DM) and inclusion body myositis (IBM). New subgroups have been recognized, such as immunemediated necrotizing myopathy (IMNM) and the antisynthetase syndrome (ASS). Autoantibodies are common and some of them specific for myositis. The most frequent is the anti-Jo-1 autoantibody, which is associated not only with myositis but also with interstitial lung disease (ILD) and arthritis. The etiology of IIM is still unknown but environmental and genetic factors are believed to contribute to disease susceptibility. Accumulating data indicate a role of the type I interferons (IFNs) in myositis. The treatment of IIM (glucocorticoids and immunomodulatory drugs) has limited effect. New treatments are needed, thus increased understanding of molecular disease mechanisms in IIM is required. The overall aim of my thesis was to get an increased understanding of molecular mechanisms that are involved in IIM with a focus on the type I IFN system, autoantibodies and mechanisms that may induce immune reactivity, to be able to subclassify patients. Several new observations were made. Firstly, we found that line blot is a suitable serological test in myositis and is a reliable alternative to more time-consuming assays such as immunoprecipitation (paper I). Secondly, we concluded that smoking is associated with IIM patients who are either anti-Jo-1 autoantibody and/or HLA-DRB1*03 positive (paper II). These associations point towards a gene-environment interaction in the pathogenesis for IIM. Thirdly, we found that a high IFN score was not only associated with the subset DM, as previously reported, and IBM, but also with autoantibody monospecificity against RNA-binding proteins or with autoantibody multispecificity (paper III). Furthermore, we identified IFN-α in sera as a trigger for activation of the type I IFN pathway in peripheral blood, which supports IFN-α as a possible target for therapy in these patients. Finally, we found that PM and DM are associated with dysregulation of endothelial progenitor cell (EPC) phenotype and function that may be attributed, at least in part, to aberrant IL-18 and type I IFN pathways (paper IV). In conclusion, this thesis confirms a role of the type I IFN system in myositis, especially in subgroups of patients, based on their autoantibody status, and implicates a relationship between the type I IFN system and endothelial disruption. Furthermore, smoking may be a trigger in the pathogenesis of IIM in genetic susceptible persons. However, the implication of our findings to disease prognosis and treatment remain to be determined

Characterization of immune specificities in idiopathic inflammatory myopathies

Idiopathic inflammatory myopathies (IIM or myositis) are a group of rheumatic autoimmune diseases characterised by skeletal muscle inflammation and weakness, and are associated with high morbidity and mortality. The diagnosis integrates several subgroups of muscular disorders with autoimmune backgrounds, where identifying myositis-specific and associated autoantibodies play an essential role. The spectrum of these autoantibodies may reflect different clinicopathological mechanisms involved in the disease for the various subgroups of IIM. The high heterogeneity and complexity in myositis represent a clinical challenge and due to the rarity of the disease, the pathophysiological mechanism behind IIM remains elusive. The aims of this thesis were to 1) study the mechanisms of disease associated with the group of IIM and anti-Jo-1 autoantibodies in terms of T cell functionality and local autoantibody production; 2) to gain a deeper understanding of T cell infiltrate in the muscle tissue at a single-cell level; 3) to characterise the autoantibody subgroups and identify new associations of risk HLA alleles, and 4) to study the prevalence of anti-FHL1 autoantibody and clinical manifestations in cross-sectional and longitudinal cohorts. In Paper I, we identified histidyl–tRNA synthetase (HisRS) reactive CD4+ T cells in the bronchoalveolar lavage fluid and germinal centre-like structures in the lungs of patients with IIM/anti-synthetase syndrome and the HLA-DRB1*03 allele. Thereby, we identified a potential link between autoreactive T cells and the formation of autoantibodies originating from the lung. In Paper II and V, we detected anti-four-and-a-half-LIM domain 1 (FHL1) autoantibodies in patients with IIM from Australia and Sweden in a cross-sectional and longitudinal approach. In Paper V, we also evaluated the autoantibody levels against FHL1 over time and reported the correlation between FHL1 levels and disease severity. We found that anti-FHL1 autoantibodies were present in patients with IIM who were previously autoantibody-negative, thus adding a novel autoantibody that supports IIM diagnosis. In Paper III, we classified IIM autoantibody co-expression patterns and determined the underlying HLA allele variations. In Paper IV, we used single-cell mRNA sequencing to explore T cell infiltration in the muscle of patients with IIM. We identified a muscle T cell signature containing genes associated with tissue homing and tissue residency. Moreover, we identified immunosuppression-resistant T cell clones in blood and muscle. In conclusion, this thesis contributes to the understanding of the pathophysiology of IIM from the perspective of the tissue-specific T cells, HLA variations, and autoantibodies diversity. Our findings also propose new avenues for further research, which could facilitate the development of a personalised treatment or new biomarkers

Studies on autoantibodies and inflammatory markers in patients with idiopathic inflammatory myopathies

Idiopathic Inflammatory myopathies (IIM), commonly known as myositis, are chronic autoimmune diseases characterized by low muscle strength and low muscle endurance as main features. However, a high number of patients may develop extra muscular manifestations such as interstitial lung disease, skin rash or arthritis. There are known genetic and environmental risk factors for developing these conditions, but the cause is not fully understood. To date, it is considered that myositis is driven by an autoimmune component. In this sense, the production of autoantibodies is characteristic in most patients and each of these autoantibodies is strongly linked to specific clinical manifestations. However, the implications of positive autoantibodies as prognostics tools beyond the association with clinical features has not been fully studied. Moreover, different methods have been used to detect these autoantibodies and new methods, usually employed in the daily clinical setting, require validation. In addition to the autoantibodies, the role of inflammatory markers as predictors of subjective health perception has been overlooked in patients with myositis. The aim of this thesis was to validate an autoantibody assay commonly used in the clinic, a line blot assay, as well as to explore the usefulness of autoantibodies as predictors of response to treatment and organ damage, and to investigate the association of inflammatory markers with patient reported outcomes. A validation of a line bot test was conducted using an immunoprecipitation-based algorithm as comparator in a cohort of well-characterized patients with myositis. The prevalence of relevant clinical associations with both assays was compared between patients. A moderate agreement between the assays was found, and the clinical features of patients with detected autoantibodies by the line blot assay were consistent with known clinical phenotypes (Paper I). By using a longitudinal Swedish electronic database (SweMyoNet), dermatomyositis specific autoantibodies (DMSA) were found as predictors for moderate level of response to treatment; initial doses of glucocorticoids and shorter time lag from first symptoms to diagnosis were also predictors of response to treatment (Paper II). In a longitudinal study, based on a large international electronic database (MyoNet), patients with anti-PM/Scl autoantibodies accumulated damage more pronounced than seronegative patients, and patients with DMSA accumulated less pronounced damage than seronegative patients. Furthermore, a strong correlation between severity of muscle damage and functional disability was found, especially in patients with immune-mediated necrotizing myopathies (Paper III). By analyzing data from MyoNet, we found a longitudinal correlation between Patient Global Assessment (PatGA) and inflammatory markers, namely C-reactive protein (CRP) and erythrocyte sedimentation rate (ESR) (Paper IV). Altogether, the findings of this thesis indicate that the line blot assay is useful to detect the most frequent autoantibodies in patients with a known myositis diagnosis. The results of this thesis also suggest that autoantibodies are useful as predictors of response to treatment and of organ damage, and that inflammatory markers are associated with subjective health perception status measured by the Patient Global Assessment scale in patients with myositis

Treatment for inclusion body myositis

Background Inclusion body myositis (IBM) is a late-onset inflammatory muscle disease (myopathy) associated with progressive proximal and distal limb muscle atrophy and weakness. Treatment options have attempted to target inflammatory and atrophic features of this condition (for example with immunosuppressive and immunomodulating drugs, anabolic steroids, and antioxidant treatments), although as yet there is no known effective treatment for reversing or minimising the progression of inclusion body myositis. In this review we have considered the benefits, adverse effects, and costs of treatment in targeting cardinal effects of the condition, namely muscle atrophy, weakness, and functional impairment. Objectives To assess the effects of treatment for IBM. Search methods On 7 October 2014 we search ed the Cochrane Neuromuscular Disease Group Specialized Register, the Cochrane Central Register for Controlled Trials (CENTRAL), MEDLINE, and EMBASE. Additionally in November 2014 we searched clinical trials registries for ongoing or completed but unpublished trials. Selection criteria We considered randomised or quasi-randomised trials, including cross-over trials, of treatment for IBM in adults compared to placebo or any other treatment for inclusion in the review. We specifically excluded people with familial IBM and hereditary inclusion body myopathy, but we included people who had connective tissue and autoimmune diseases associated with IBM, which may or may not be identified in trials. We did not include studies of exercise therapy or dysphagia management, which are topics of other Cochrane systematic reviews. Data collection and analysis We used standard Cochrane methodological procedures. Main results The review included 10 trials (249 participants) using different treatment regimens. Seven of the 10 trials assessed single agents, and 3 assessed combined agents. Many of the studies did not present adequate data for the reporting of the primary outcome of the review, which was the percentage change in muscle strength score at six months. Pooled data from two trials of interferon beta-1a (n = 58) identified no important difference in normalised manual muscle strength sum scores from baseline to six months (mean difference (MD) -0.06, 95% CI -0.15 to 0.03) between IFN beta-1a and placebo (moderate-quality evidence). A single trial of methotrexate (MTX) (n = 44) provided moderate-quality evidence that MTX did not arrest or slow disease progression, based on reported percentage change in manual muscle strength sum scores at 12 months. None of the fully published trials were adequately powered to detect a treatment effect. We assessed six of the nine fully published trials as providing very low-quality evidence in relation to the primary outcome measure. Three trials (n = 78) compared intravenous immunoglobulin (combined in one trial with prednisone) to a placebo, but we were unable to perform meta-analysis because of variations in study analysis and presentation of trial data, with no access to the primary data for re-analysis. Other comparisons were also reported in single trials. An open trial of anti-T lymphocyte immunoglobulin (ATG) combined with MTX versus MTX provided very low-quality evidence in favour of the combined therapy, based on percentage change in quantitative muscle strength sum scores at 12 months (MD 12.50%, 95% CI 2.43 to 22.57). Data from trials of oxandrolone versus placebo, azathioprine (AZA) combined with MTX versus MTX, and arimoclomol versus placebo did not allow us to report either normalised or percentage change in muscle strength sum scores. A complete analysis of the effects of arimoclomol is pending data publication. Studies of simvastatin and bimagrumab (BYM338) are ongoing. All analysed trials reported adverse events. Only 1 of the 10 trials interpreted these for statistical significance. None of the trials included prespecified criteria for significant adverse events. Authors\u27 conclusions Trials of interferon beta-1a and MTX provided moderate-quality evidence of having no effect on the progression of IBM. Overall trial design limitations including risk of bias, low numbers of participants, and short duration make it difficult to say whether or not any of the drug treatments included in this review were effective. An open trial of ATG combined with MTX versus MTX provided very low-quality evidence in favour of the combined therapy based on the percentage change data given. We were unable to draw conclusions from trials of IVIg, oxandrolone, and AZA plus MTX versus MTX. We need more randomised controlled trials that are larger, of longer duration, and that use fully validated, standardised, and responsive outcome measures