Imaging swallowing function and the mechanisms driving dysphagia in inclusion body myositis

Sporadic inclusion body myositis (IBM) is a progressive condition which commonly affects patients aged above 40. IBM does not respond to immunosuppression and no proven treatments are available. Up to 80% of patients develop some degree of swallowing impairment during the disease course. Dysphagia is a source of marked morbidity in IBM and predisposes patients to life-threatening complications such as aspiration pneumonia. The pathophysiology behind dysphagia in IBM is not fully understood. Evidence from imaging demonstrates that impaired swallowing is predominantly underpinned by oropharyngeal deficits. Changes in cricopharyngeal physiology is thought to be an important factor influencing dysphagia in IBM. However, it is unclear whether this is secondary to structural changes within the cricopharyngeus itself or driven by impairment of the muscles promoting pharyngeal clearance. The approach to dysphagia in IBM patients is limited by a lack of validated instruments to reliably assess swallowing function and an absence of effective therapeutic interventions derived from controlled trials targeting dysphagia. Imaging modalities such as the video fluoroscopic swallowing study (VFSS) are commonly used to evaluate dysphagia in IBM. Whilst VFSS is a commonly used technique in clinical practice; cumulative radiation exposure with repeated testing can be a limitation. Alternative imaging techniques could be developed further as outcome measures for assessing swallowing. In this review, we provide an overview of imaging techniques used to assess swallowing and the insight provided from such investigations into the mechanisms behind dysphagia in IBM. We suggest future directions for evaluation and outcome measurement of dysphagia in this population

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

Two emerging phenotypes of atypical inclusion body myositis: illustrative cases

OBJECTIVES: Sporadic inclusion body myositis (IBM) is the most common acquired myopathy in those aged above 50. It is classically heralded by weakness in the long finger flexors and quadriceps. The aim of this article is to describe five atypical cases of IBM, outlining two potential emerging clinical subsets of the disease. METHODS: We reviewed relevant clinical documentation and pertinent investigations for five patients with IBM. RESULTS: The first phenotype we describe is young-onset IBM in two patients who had symptoms since their early thirties. The literature supports that IBM can rarely present in this age range or younger. We describe a second phenotype in three middle-aged women who developed early bilateral facial weakness at presentation in tandem with dysphagia and bulbar impairment followed by respiratory failure requiring non-invasive ventilation (NIV). Within this group, two patients were noted to have macroglossia, another possible rare feature of IBM. CONCLUSIONS: Despite the classical phenotype described within the literature IBM can present in a heterogenous fashion. It is important to recognise IBM in younger patients and investigate for specific associations. The described pattern of facial diplegia, severe dysphagia, bulbar dysfunction and respiratory failure in female IBM patients requires further characterisation. Patients with this clinical pattern may require more complex and supportive management. Macroglossia is a potentially under recognised feature of IBM. The presence of macroglossia in IBM warrants further study, as its presence may lead to unnecessary investigations and delay diagnosis

Imaging evaluation of the upper limbs in inclusion body myositis: an unmet need

Inclusion body myositis (IBM) is an acquired myopathy belonging to the spectrum of idiopathic inflammatory myopathies. It commonly presents in individuals aged above 50 years of age. Characteristic clinical features of IBM include weakness of the quadriceps and finger flexors. There are currently no effective drug treatments for IBM. However as more clinical drug trials are being conducted it is important that more precise outcome measures are developed to track disease progression and assess treatment effects. Imaging techniques such as magnetic resonance imaging (MRI) and ultrasound have been increasingly used to study intramuscular changes within the thigh and calf muscles. In particular quantitative MRI assessments of the lower limb have started to be employed as endpoints for clinical trials in IBM patients. However, in comparison to the lower limb, there is a relative lack in robust imaging biomarkers for the upper limb muscles. It is prudent that this paucity is addressed as the majority of IBM patients have forearm involvement and, in many individuals, upper limb weakness is their main source of disability. Imaging focussed studies thus far indicate preferential flexor digitorium profundus involvement. In this review, we discuss the imaging modalities that have been used to evaluate intramuscular changes and the possible techniques which could be developed further as upper limb biomarkers for IBM

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

Quantitative muscle magnetic resonance imaging as a biomarker for inclusion body myositis in clinical trials: exploring the in vivo effects of arimoclomol

OBJECTIVES: To investigate the intramuscular effects of arimoclomol using quantitative magnetic resonance imaging (qMRI) of the thighs in a subset of inclusion body myositis (IBM) participants from a multicentre, randomised, double-blind, placebo-controlled trial, and to further evaluate the utility of qMRI assessments as outcome measures. METHODS: Eighteen participants (10 placebo, 8 arimoclomol-treated) were recruited to undergo an MRI at baseline, 12 and 20 months. Spearman correlations between baseline clinical measures and qMRI measurements [fat fraction (FF), remaining muscle area (RMA), magnetisation transfer ratio (MTR), muscle water T2 (T2m) and fat fraction apparent (FFa)] were used to evaluate construct validity. A mixed model repeated measures (MMRM) strategy was employed to estimate mean changes, in order to determine treatment effects on qMRI biomarkers and evaluate responsiveness to disease progression over time. Longitudinal analyses examined Spearman correlations between changes in qMRI and changes in clinical assessments at the last available follow-up. RESULTS: Baseline FF, RMA, MTR and FFa of the thigh and quadriceps demonstrated strong construct validity. No significant treatment effects on the qMRI measures were detected. FF, RMA and FFa demonstrated strong responsiveness to disease progression (standardised response means>0.8, p<0.05) at 20 months. Longitudinal changes in thigh T2m were strongly correlated with changes in myometry and modified timed up and go velocity. CONCLUSIONS: Arimoclomol had no significant effects on the qMRI measurements evaluated, consistent with clinical outcomes from the main trial. The qMRI measurements demonstrated both validity and responsiveness, further supporting their potential utility as biomarkers in IBM

Measurement properties of the Inclusion Body Myositis Functional Rating Scale

OBJECTIVES: To evaluate the validity, reliability, responsiveness and meaningful change threshold of the Inclusion Body Myositis (IBM) Functional Rating Scale (FRS). METHODS: Data from a large 20-month multicentre, randomised, double-blind, placebo-controlled trial in IBM were used. Convergent validity was tested using Spearman correlation with other health outcomes. Discriminant (known groups) validity was assessed using standardised effect sizes (SES). Internal consistency was tested using Cronbach's alpha. Intrarater reliability in stable patients and equivalence of face-to-face and telephone administration were tested using intraclass correlation coefficients (ICCs) and Bland-Altman plots. Responsiveness was assessed using a standardised response mean (SRM). An receiver operator characteristic (ROC) curve anchor-based approach was used to determine clinically meaningful IBMFRS change. RESULTS: Among the 150 patients, mean (SD) IBMFRS total score was 27.4 (4.6). Convergent validity was supported by medium to large correlations (rs modulus: 0.42-0.79) and discriminant validity by moderate to large group differences (SES=0.51-1.59). Internal consistency was adequate (overall Cronbach's alpha: 0.79). Test-retest reliability (ICCs=0.84-0.87) and reliability of telephone versus face-to-face administration (ICCs=0.93-0.95) were excellent, with Bland-Altman plots showing good agreement. Responsiveness in the worsened group defined by various external constructs was large at both 12 (SRM=-0.76 to -1.49) and 20 months (SRM=-1.12 to -1.57). In ROC curve analysis, a drop in two IBMFRS total score points was shown to represent a meaningful decline. CONCLUSIONS: When administered by trained raters, the IBMFRS is a reliable, valid and responsive tool that can be used to evaluate the impact of IBM and its treatment on physical function, with a 2-point reduction representing meaningful decline. TRIAL REGISTRATION NUMBER: NCT02753530