Atypical Presentations for Inclusion Body Myositis

By Michael Rubin, MD

Professor of Clinical Neurology, Weill Cornell Medical College

SYNOPSIS: Inclusion body myositis, the most common acquired myopathy, often is misdiagnosed or diagnosed after a delay of many years. Atypical presentations are not unusual, and clinicians should maintain a high degree of suspicion for this disorder when patients present with slowly progressive muscle weakness in an unusual pattern.

SOURCE: Alamr M, Pinto MV, Naddaf E. Atypical presentations of inclusion body myositis: Clinical characteristics and long-term outcomes. Muscle Nerve 2022;66:686-693.

Considered the most common acquired myopathy, with a prevalence of 18 per 100,000 in persons older than age 50 years, inclusion body myositis (IBM) is characterized by the insidious onset and slow progression of muscle weakness, characteristically affecting knee extensors and long finger flexors. More likely to be asymmetric, distal, and slowly progressive compared to polymyositis and dermatomyositis, muscle pain, if present, usually is mild. Dysphagia, eventually present on formal testing in most patients, often is the presenting symptom. What are the clinical characteristics and long-term outcomes in patients with atypical onset IBM?

A retrospective review of the electronic medical records of the Mayo Clinic, Rochester, MN, was undertaken to identify atypical onset IBM patients seen between Jan. 1, 2015, and Dec. 31, 2020. Based on the 2011 European Neuromuscular Center (ENMC) criteria, typical IBM presentations fulfill one of three categories: clinico-pathologically defined, clinically defined, and probable IBM.

For this study, atypical IBM presentations thus were defined as onset with dysphagia; asymptomatic or minimally symptomatic hyperCKemia (CK: creatine kinase); or weakness affecting the distal lower limb, proximal upper limb, axial, or facial muscles. All patients underwent open surgical muscle biopsy, and, for inclusion in the study, atypical presentation required one of the following: fulfillment of any category of the ENMC criteria at a later stage of their disease; muscle biopsy consistent with IBM, requiring the presence of autoaggressive inflammation, rimmed vacuoles, and protein aggregates; or findings of autoaggressive inflammation with either rimmed vacuoles or congophilic inclusions, together with other cardinal IBM features not included in ENMC criteria (such as muscle magnetic resonance imaging [MRI] pattern or cytosolic nucleotidase 1A [cN-1A] antibody status) after alternative causes had been excluded. Statistical analysis comprised the Fisher exact test/chi-squared test and the Wilcoxon rank sum/Kruskal Wallis tests, with P < 0.05 considered significant.

Among 357 patients with IBM, of which 55% (n = 196) were clinico-pathologically defined, 18% (n = 66) clinically defined, and 13% (n = 45) probable IBM, 307 (86%) had typical onset, leaving 14% (n = 50) with atypical onset, of which 38 patients had IBM based on ENMC criteria at a later stage, and 10 had biopsy-defined diagnosis.
Of the remaining two patients, one had autoaggressive inflammation with rimmed vacuoles and no congophilic inclusions, quadriceps atrophy without weakness, marked distal involvement of the vastus medialis and vastus lateralis on muscle MRI, and elevated cN-1A antibodies, while the other had autoaggressive inflammation and several congophilic inclusions with no rimmed vacuoles, with dysphagia, and with markedly elevated cN-1A antibodies.

Atypical presentations comprised dysphagia in 50%, hyperCKemia in 24%, foot drop in 12%, predominantly proximal arm weakness in 6%, and with axial weakness (head drop or camptocormia) or facial diplegia in 4% each. The median age at diagnosis was 70.5 years, with a median of nine years from symptom onset to diagnosis.

Among 26 patients (52%) who received treatment because of initial diagnostic uncertainty, only a single patient experienced any benefit, with mild improvement of dysphagia. Over time, like typical IBM, most patients noted progression and spread of their weakness. Atypical presentations are not uncommon in IBM, and heightened awareness will improve early diagnosis, precluding unnecessary testing and ineffective treatment efforts.

COMMENTARY

Controversy remains as to whether IBM is myodegenerative or immune-mediated in origin. Not all studies have found NT5c1A autoantibodies to be as highly specific and sensitive a serologic marker for IBM as originally reported, since they also are present in dermatomyositis, anti-synthetase syndrome, and immune-mediated necrotizing myopathy. NT5c1A autoantibodies are not associated with malignancy or interstitial lung disease, although an association is reported between IBM and lymphoproliferative disorders, such as T cell large granular lymphocytic leukemia. “Immunosenescent’’ T cells, which are chronically overstimulated and with no capacity to undergo apoptosis, are seen with a high prevalence in IBM muscle and may be a biomarker for IBM. Having lost the capacity for apoptosis, these T cells likely will not respond to conventional immunotherapy, and a therapeutic trial currently is underway to determine if depleting these cells will alter the course of IBM.¹

REFERENCE

Perez-Rosendahl M, Mozaffar T. Inclusion body myositis: Evolving concepts. Curr Opin Neurol 2022;35:604-610.