By Pantelis P. Pavlakis, MD, PhD
Assistant Attending Neurologist, Hospital for Special Surgery, and Assistant Professor of Neurology, Weill Cornell Medical College
SYNOPSIS: Inclusion body myositis (IBM) is a progressive myopathy characterized by prominent finger flexor and quadriceps involvement. Black patients with IBM have more prominent proximal weakness, in addition to finger flexion and quadriceps weakness. Female patients have less prominent finger flexion and quadriceps weakness and slower progression, whereas younger patients had a greater delay in diagnosis. There are variability and distinct clinical subsets among IBM patients, which can have implications in terms of timely diagnosis and possibly response to treatments.
SOURCE: Michelle EH, Pinal-Fernandez I, Casal-Domiguez M, et al. Clinical subgroups and factors associated with progression in patients with inclusion body myositis. Neurology 2023;100:e1406-e1417.
Inclusion body myositis (IBM) is a progressive myopathy, predominantly affecting finger flexors and quadriceps muscles. Half of patients eventually will develop dysphagia, while most patients will require assistive devices for ambulation at some point. Pathological features of IBM include endomysial inflammation with auto-invasive T-cells and rimmed vacuoles. Despite evidence of dysimmune responses in patients with IBM, trials of multiple immunomodulatory therapies have been unsuccessful. Over the years, multiple studies published have shown a consistent pattern of weakness predominantly involving finger flexors and quadriceps muscles. However, there has been variability regarding age of onset, initial presentation, clinical evolution, and rate of progression. There also are limited studies on the ethnic or racial composition of IBM patients and whether such subsets can differ in disease presentation or evolution.
The authors of this study retrospectively evaluated clinical, pathological, serological, and electrophysiological data of patients with sporadic IBM seen at the Johns Hopkins Myositis Center between 2003 and 2018. Patients meeting the Griggs (possible), European Neuromuscular Centre 2011 (probable), or Lloyd-Greenberg data-derived criteria were included. Patients with anti-synthetase syndrome (AS), immune-mediated necrotizing myopathy (IMNM), or dermatomyositis (DM) and positive myositis-specific antibodies were used as a control group.
Of 387 patients with a diagnosis of IBM, 335 met criteria for inclusion in this study. The control group consisted of 524 patients. Median age of onset (58.7 years) was higher in IBM patients compared to myopathy controls. Male sex (64%) and white race (84%) also were significantly more prevalent in the IBM group. Average time to diagnosis of IBM was 5.2 years, which was significantly longer compared to other forms of myositis. The presence of dysphagia at the time of symptom onset was less frequent in IBM (4%) compared to IMNM and DM (19% each). However, dysphagia was seen more commonly during the course of IBM (60%) and DM (53%) compared to IMNM (45%) and AS (38%). Although the mortality rate was higher in IBM compared to IMNM, it was not higher than the overall population of all patients with the various forms of myositis.
Patients with IBM had significantly more prominent finger flexor and quadriceps weakness compared to IMNM and showed a steady decline over the course of the disease. Arm abduction and hip flexion were significantly stronger in IBM patients during the first 10 years of the disease compared to the control group. More than half of IBM patients had initially received an alternate diagnosis at the time of symptom onset. Female sex, younger age at symptoms onset, less prominent finger flexor weakness, and absence of rimmed vacuoles on muscle biopsy were associated with an alternate diagnosis at symptoms onset.
Average time of muscle biopsy from symptoms onset was 5.5 years. The triad of endomysial inflammation, non-necrotic fiber infiltration, and rimmed vacuoles was present in 43% of biopsies, whereas 41% had two of these three features. Rimmed vacuoles were absent in 34% of biopsies. Electrodiagnostic data were present in 85% of patients; all patients had myopathic findings on electromyography (EMG), while 44% had mixed, neurogenic, and myopathic findings. Abnormal sural sensory responses were present in 31% of patients. The median creatine kinase (CK) level was 426 IU/L (interquartile range, 230-707).
NT5c1A antibodies were tested in 320 patients, of which 47% were positive. Patients positive for NT5c1A antibodies had higher median CK levels than seronegative IBM patients, but otherwise did not differ in terms of clinical characteristics, muscle biopsy, or electrodiagnostic findings.
Black patients had similar age of symptom onset and time from symptom onset to first visit. Compared to non-Black IBM patients, they had more prominent weakness in arm abduction, hip flexion, and knee flexion and were less likely to develop dysphagia during the disease course. NT5c1A antibodies were more frequently positive (68%), and neurogenic motor units were less frequently observed on EMG. Muscle biopsy findings did not differ across races.
Female patients had a longer time from symptoms onset to diagnosis. Compared to male patients with IBM, female patients had stronger finger flexors and knee extensors with slower decline in these muscle groups over time. Female patients were more likely to develop dysphagia during the course of the disease.
Younger patients had a longer time from symptoms onset to muscle biopsy and diagnosis, but otherwise did not differ in terms of strength, accounting for the longer time elapsed or biopsy findings.
COMMENTARY
This study shows that there are distinct patient subsets in IBM with variability in their presentation and clinical evolution. Although all patient groups present with the typical findings of quadriceps and finger flexor weakness, female patients have less prominent weakness in these muscle groups, whereas Black patients have more prominent proximal arm and leg weakness as well. Muscle biopsy can be helpful in diagnosis, but typical features, such as rimmed vacuoles, may not always be present, as in this study, where only 66% of biopsies had rimmed vacuoles present. The variability in clinical presentation and lack of sensitive biomarkers can lead to a delay in diagnosis of IBM, which commonly was seen in this study.
This is an important study showing that there are variability and distinct clinical subsets among patients with IBM. This suggests distinct underlying disease mechanisms with further implications regarding response to treatments and design of future clinical trials. This variability in presentation also can lead to a delay in diagnosis and initiation of appropriate treatment.
Although the typical pattern of quadriceps and finger flexion weakness should always raise the suspicion of IBM, a heightened index of suspicion is needed when evaluating patients with weakness, since individual presentation may differ according to the subtypes noted earlier. It also is important to bear in mind that pathological or serological markers can be of limited sensitivity, and their absence may not always reliably rule out a diagnosis of IBM in the appropriate clinical setting.
