Diagnostic and prognostic value of anti-cN1A antibodies in inclusion body myositis

Inclusion body myositis (IBM) is an acquired idiopathic inflammatory myopathy more commonly seen in individuals aged above 50. Unlike other idiopathic inflammatory myopathies, there is no response to immunosuppression/immunomodulation. The lack of response to such therapies led the focus away from considering IBM as a purely immune-mediated condition. However, the discovery of antibodies against cytosolic 5'-nucleotidase 1A (cN1A) in patients with IBM has reinvig-orated interest in autoimmunity as a key role in its pathogenesis. Over the last decade different methods have been developed to detect anti-cN1A antibodies. There has been an interest in whether these assays can be utilised in the diagnosis of IBM. Furthermore, there has been focus on whether anti-cN1A antibodies can be used to prognosticate and predict the clinical phenotype in IBM. Anti-cN1A antibodies appear to have a high specificity and moderate sensitivity for IBM. There have been some exploratory clinicopathological associations described in seropositive IBM patients, but sample sizes in most studies have been small so far. Antibody testing is yet to be standardised; which somewhat limits our ability to draw robust conclusions from current investi-gations. In this article we review the literature on anti-cN1A antibodies and discuss whether they have a role in clinical practice

Imaging biomarkers in the idiopathic inflammatory myopathies

Idiopathic inflammatory myopathies (IIMs) are a group of acquired muscle diseases with muscle inflammation, weakness, and other extra-muscular manifestations. IIMs can significantly impact the quality of life, and management of IIMs often requires a multi-disciplinary approach. Imaging biomarkers have become an integral part of the management of IIMs. Magnetic resonance imaging (MRI), muscle ultrasound, electrical impedance myography (EIM), and positron emission tomography (PET) are the most widely used imaging technologies in IIMs. They can help make the diagnosis and assess the burden of muscle damage and treatment response. MRI is the most widely used imaging biomarker of IIMs and can assess a large volume of muscle tissue but is limited by availability and cost. Muscle ultrasound and EIM are easy to administer and can even be performed in the clinical setting, but they need further validation. These technologies may complement muscle strength testing and laboratory studies and provide an objective assessment of muscle health in IIMs. Furthermore, this is a rapidly progressing field, and new advances are going to equip care providers with a better objective assessment of IIMS and eventually improve patient management. This review discusses the current state and future direction of imaging biomarkers in IIMs

Measuring change in inclusion body myositis: clinical assessments versus imaging.

Sporadic inclusion body myositis (sIBM) is a heterogeneous progressive inflammatory muscle disease impacting skeletal muscles in the head, neck, and limbs. Use of valid, reliable, sensitive, and standardised clinical and paraclinical outcome assessments (COA) are critical to inform both proactive clinical care and clinical trial design. Here we review clinical and imaging methods used to quantify muscle strength, size, or function in sIBM, and discuss their application to clinical practice and use in clinical trials. Considerations for future work to validate measures in this population are also discussed

Methotrexate Polyglutamation in a Myasthenia Gravis Clinical Trial

Introduction. Methotrexate (MTX) is an immunosuppressive and anti-inflammatory drug used to treat rheumatoid arthritis (RA) and other autoimmune conditions. MTX is transported into cells, where glutamate moieties are added and is retained as methotrexate polyglutamates (MTXPGs). In the RA literature, it has been reported that the degree of polyglutamation correlates with the anti-inflammatory effect of MTX in RA. There are no prior studies evaluating the relationship between MTXPGs and myasthenia gravis (MG) outcome measures. The objective of this study was to assess the correlation between methotrexate (MTX) polyglutamates (MTXPGs) with Myasthenia Gravis (MG) outcome measures. Methods.xAn analysis was done of blood drawn from patients enrolled in the 12-month randomized, placebo-controlled study of MTX in MG study. Red blood cell MTXPGs were measured via ultraperformance liquid chromatography and tandem mass spectrometry. MTXPG was correlated to MG outcome measures using Spearman Correlation Coefficient. A two-group t-test was used to determine the difference in MTXPG based on clinical outcome responder definitions. Results. Twenty-one polyglutamate samples were analyzed of subjects on MTX while eight samples were analyzed from subjects on placebo. Pentaglutamate had the strongest correlation with the MG-ADL (0.99), while tetraglutamate had the strongest correlation with the QMG (0.54). Triglutamate had the strongest correlation with MGC (0.76). Conclusion. There were variable correlations between MTXPG1-5 and MG outcomes (rho range: 0.08 to 0.99). There are strong correlations between MTXPG and the MG-ADL, QMG, and MGC. Long chain methotrexate polyglutamates correlate better with MG outcomes

The effects of an intronic polymorphism in TOMM40 and APOE genotypes in sporadic inclusion body myositis.

A previous study showed that, in carriers of the apolipoprotein E (APOE) genotype ε3/ε3 or ε3/ε4, the presence of a very long (VL) polyT repeat allele in "translocase of outer mitochondrial membrane 40" (TOMM40) was less frequent in patients with sporadic inclusion body myositis (sIBM) compared with controls and associated with a later age of sIBM symptom onset, suggesting a protective effect of this haplotype. To further investigate the influence of these genetic factors in sIBM, we analyzed a large sIBM cohort of 158 cases as part of an International sIBM Genetics Study. No significant association was found between APOE or TOMM40 genotypes and the risk of developing sIBM. We found that the presence of at least 1 VL polyT repeat allele in TOMM40 was significantly associated with about 4 years later onset of sIBM symptoms. The age of onset was delayed by 5 years when the patients were also carriers of the APOE genotype ε3/ε3. In addition, males were likely to have a later age of onset than females. Therefore, the TOMM40 VL polyT repeat, although not influencing disease susceptibility, has a disease-modifying effect on sIBM, which can be enhanced by the APOE genotype ε3/ε3

Applying the win ratio method in clinical trials of orphan drugs: an analysis of data from the COMET trial of avalglucosidase alfa in patients with late-onset Pompe disease

Background: Clinical trials for rare diseases often include multiple endpoints that capture the effects of treatment on different disease domains. In many rare diseases, the primary endpoint is not standardized across trials. The win ratio approach was designed to analyze multiple endpoints of interest in clinical trials and has mostly been applied in cardiovascular trials. Here, we applied the win ratio approach to data from COMET, a phase 3 trial in late-onset Pompe disease, to illustrate how this approach can be used to analyze multiple endpoints in the orphan drug context. Methods: All possible participant pairings from both arms of COMET were compared sequentially on changes at week 49 in upright forced vital capacity (FVC) % predicted and six-minute walk test (6MWT). Each participant’s response for the two endpoints was first classified as a meaningful improvement, no meaningful change, or a meaningful decline using thresholds based on published minimal clinically important differences (FVC ± 4% predicted, 6MWT ± 39 m). Each comparison assessed whether the outcome with avalglucosidase alfa (AVA) was better than (win), worse than (loss), or equivalent to (tie) the outcome with alglucosidase alfa (ALG). If tied on FVC, 6MWT was compared. In this approach, the treatment effect is the ratio of wins to losses (“win ratio”), with ties excluded. Results: In the 2499 possible pairings (51 receiving AVA × 49 receiving ALG), the win ratio was 2.37 (95% confidence interval [CI], 1.30–4.29, p = 0.005) when FVC was compared before 6MWT. When the order was reversed, the win ratio was 2.02 (95% CI, 1.13–3.62, p = 0.018). Conclusion: The win ratio approach can be used in clinical trials of rare diseases to provide meaningful insight on treatment benefits from multiple endpoints and across disease domains

A Bayesian comparative effectiveness trial in action: developing a platform for multisite study adaptive randomization

A grant from the One-University Open Access Fund at the University of Kansas was used to defray the author's publication fees in this Open Access journal. The Open Access Fund, administered by librarians from the KU, KU Law, and KUMC libraries, is made possible by contributions from the offices of KU Provost, KU Vice Chancellor for Research & Graduate Studies, and KUMC Vice Chancellor for Research. For more information about the Open Access Fund, please see http://library.kumc.edu/authors-fund.xml.Background In the last few decades, the number of trials using Bayesian methods has grown rapidly. Publications prior to 1990 included only three clinical trials that used Bayesian methods, but that number quickly jumped to 19 in the 1990s and to 99 from 2000 to 2012. While this literature provides many examples of Bayesian Adaptive Designs (BAD), none of the papers that are available walks the reader through the detailed process of conducting a BAD. This paper fills that gap by describing the BAD process used for one comparative effectiveness trial (Patient Assisted Intervention for Neuropathy: Comparison of Treatment in Real Life Situations) that can be generalized for use by others. A BAD was chosen with efficiency in mind. Response-adaptive randomization allows the potential for substantially smaller sample sizes, and can provide faster conclusions about which treatment or treatments are most effective. An Internet-based electronic data capture tool, which features a randomization module, facilitated data capture across study sites and an in-house computation software program was developed to implement the response-adaptive randomization. Results A process for adapting randomization with minimal interruption to study sites was developed. A new randomization table can be generated quickly and can be seamlessly integrated in the data capture tool with minimal interruption to study sites. Conclusion This manuscript is the first to detail the technical process used to evaluate a multisite comparative effectiveness trial using adaptive randomization. An important opportunity for the application of Bayesian trials is in comparative effectiveness trials. The specific case study presented in this paper can be used as a model for conducting future clinical trials using a combination of statistical software and a web-based application. Trial registration ClinicalTrials.gov Identifier: NCT02260388, registered on 6 October 201