Sporadic Inclusion Body Myositis

Sporadic inclusion body myositis (IBM) is an acquired muscle disease that typically affects patients more than age 45. The etiology is unknown and thought to be autoimmune; however, it is refractory to immunomodulatory treatment. The disease process results in slowly progressive and often asymmetric weakness with finger flexors and knee extensors preferentially affected. No effective treatments exist yet. In this review, we provide an update focused on the last 2 years of published data.

Etiology and Pathophysiology

Theories of pathogenesis include mitochondrial dysfunction, protein aggregation, myofiber degeneration, and autoimmunity. Recent studies have investigated autophagy, endoplasmic reticulum (ER) dysfunction, mitochondrial dysfunction, and the potential biomarker CD8⁺/T-bet⁺.

Muscle inflammation in IBM suggested an autoimmune process; however, transcription profiling suggests changes in muscle may contribute to pathopysiology. Transcriptome analysis of IBM and Jo-1-associated myositis show differential expression of messenger RNAs (mRNAs) that control muscle proliferation and differentiation, potentially altering phenotypes of these muscle diseases.¹ Another possible contributing factor is p62/sequestosome 1 (SQSTM1). The distribution of p62, phosphorylated p62, and ubiquitin-linked p62 in muscle specimens, from 16 people with IBM, suggests the 3 proteins work together to cause selective autophagy. Preventing binding of ubiquitinated p62 to microtubule-associated protein light chain 3 (LC3) stopped autophagy early in the process.²

Abnormal calcium homeostasis in the ER may result from immune-mediated sarcolemmal damage that increases proteolysis and impairs protein translation. A fourfold increase in levels of calpain-1, a calcium-activated protease, and decreased expression of calpain-3, which maintains normal calcium homeostasis, have been seen in individuals with IBM.³ In the context of myostatin expression, ER stress has been observed. In a human muscle cell line, increased secreted myostatin precursors were preferentially retained in the ER, causing stress. Mature myostatin secretion also increased in the context of ER stress.⁴ Aggregates of p62 and TAR DNA-binding protein 43 (TDP-43) and mitochondrial abnormalities are seen in IBM. In a muscle biopsy study of 10 people with IBM and 10 healthy individuals, TDP-43 aggregates were closely associated with mitochondria, which showed decreased complexes I and III in IBM compared with controls.⁵ In the context of TDP-43 aggregation, ER stress is seen, which suggests TDP-43 aggregation may cause ER stress that may cause myofiber degeneration.⁶

Mass cytometry and deep immune profiling of peripheral blood from people with IBM and healthy donors suggests CD8⁺/T-bet⁺ cells as a potential biomarker with more than 51.5% cells showing 94.4% sensitivity and 88.5% specificity for the diagnosis of IBM.⁷ Prospective studies are needed to determine diagnostic value of this potential biomarker.

Genetics

Muscle biopsy tissue from 16 people with IBM showed proteins most frequently found in vacuoles were associated with autophagy and protein folding. Rare mutations in coiled-coil domain-containing protein 1 (FYCO1), an autophagy adaptor protein were overrepresented in IBM. The FYCO1 mutation may impair autophagy, leading to rimmed vacuole formation.⁸ In a study of 252 people with IBM, the human leukocyte antigen (HLA) region was found most closely associated with IBM.⁹ Whole exome sequencing of 42 people with IBM in a case-control study did not identify pathogenic variants; however, 7 single-nucleotide polymorphisms (SNP) were found that increased susceptibility for IBM, and 2 of these were on the HLA gene.¹⁰ In a study of 9 people with IBM, mitochondrial DNA (mtDNA) from muscle was compared with that from 4 individuals with necrotizing myopathy and healthy individuals. Muscle tissue from those with IBM had 67% less mtDNA than that of healthy people, and mtDNA deletions were seen in 4 of the 9 people with IBM.¹¹

Diagnostic Studies

The diagnosis of IBM is based on the combination of clinical history, physical examination, and results of laboratory tests (eg, creatine kinase [CK], autoantibodies), histophathology, electrophysiology, and imaging. There is no definitive test, and CK levels are usually mildly to moderately elevated (< 10x upper limit of normal) but can be normal. If CK levels are high (> 15x upper limit of normal) other conditions are more likely.

Histopathology

In 18 people with IBM, expression of LC3B, p62, α-synuclein, and TDP-43 in muscle was seen. In addition, dystrophic changes, endomysial inflammation, rimmed vacuoles, and β-amyloid deposition are characteristic on histopathology.¹² In a study of 19 people with IBM who had muscle strength testing, MRI, and biopsies at the tibialis anterior, vastus lateralis, and biceps brachii, the weakest muscle, on average, was the vastus lateralis, which showed more atrophy and more edema. The biceps brachii showed the most inflammation despite an intermediate degree of weakness. Inflammation was seen with all degrees of muscle weakness.¹³ Vacuolation may be seen in many muscle disorders, including IBM where rimmed vacuoles are frequently observed. Expression of lysosome-associated membrane protein 2 (LAMP2), p62, and LC3 is seen in people with Pompe’s disease, IBM, necrotizing myopathy, and healthy individuals, but p62 staining is seen in all specimens from those with IBM, and in fibers negative for all other markers, suggesting p62 may serve an important role in vacuole characterization.¹⁴

Autoantibodies

Autoantibodies against cytoplasmic 5’-nucleotidase 1A (cN1A) are an important serologic marker for IBM. First described in people with IBM, anti-cN1A antibodies have been found in healthy people and individuals with other diagnosis, usually at much lower levels. People with systemic lupus erythematosus and Sjögren’s syndrome, however, also have a high frequency of anti-cN1A antibodies (20% and 36%, respectively).¹⁵ Multiple studies have been completed to establish sensitivity and specificity of anti-cN1A antibody status for the diagnosis of IBM. Anti-cN1A is moderately sensitive (range: 36-80%) and moderately to highly specific (range: 87-96%).^15-24

A retrospective study of cN1A antibody status pooled clinical data from 311 people with IBM and found that people who were positive for anti-cN1A antibody had higher adjusted mortality risk, lower likelihood of proximal upper limb weakness at onset, and increased cytochrome oxidase-deficient fibers on muscle histology test results.²⁵ In a small study of 40 people with clinicopathologically or clinically defined IBM, the sensitivity of the anti-cN1A antibody was 50%. People who were anti-cN1A positive were more likely to be more than age 60 at onset; however, no other association between cN1A status and clinical, laboratory, or pathologic features was identified.¹⁶ On cell-based assay, 35.8% (29/67) of people with IBM were anti-cN1A positive. In vitro and in vivo models suggest passive immunization with anti-cN1A autoantibodies may affect protein degradation within myofibers.²⁴

Although anti-cN1A antibodies are an important marker for IBM, these antibodies also occur in healthy people and people with other autoimmune diseases. In juvenile myositis, anti-cN1A antibody positivity is found in 27% of children affected and is associated with more severe disease. Anti-cN1A antibodies are also present in 27% of children with juvenile idiopathic arthritis and 12% of healthy children.²⁶ In a study of 193 people with primary Sjögren’s syndrome and 252 with systemic lupus erythematosus (SLE), 12% and 10%, respectively, had anti-cN1A antibodies. People who are antibody-positive or -negative reported similar frequency of muscular symptoms. In both Sjögren’s and SLE, people who were anti-cN1A antibody positive were more likely to have multiple autoimmune diseases.²³ In a study of 314 Japanese individuals with various systemic autoimmune conditions, including dermatomyositis, SLE, systemic sclerosis, Sjögren’s syndrome, polymyositis, mixed connective tissue disease, and IBM, all groups had lower frequencies of anti-cN1A antibody positivity compared with IBM, and anti-cN1A antibody positivity was present in 11% of people with dermatomyositis, 10% for polymyositis, 6% for SLE, 8% for systemic sclerosis, and 4% for Sjögren’s syndrome.²¹

Electrophysiology

Electrophysiologic studies such as EMG and nerve conduction studies may be helpful in the diagnosis of IBM. A retrospective analysis of EMG findings in 16 people with IBM was performed (10 clinicopathologically defined and 6 probable).²⁷ Abnormal spontaneous activity was seen in 63% of patients. Patients who fulfilled criteria for clinicopathologically defined IBM were more likely to have pseudo-neurogenic motor units and less often had abnormal spontaneous activity. Patients with probable IBM were more likely to have abnormal spontaneous activity as well as myopathic motor units. In a summary of 7 studies on EMG abnormalities in people with IBM spontaneous activity was seen in 60% to 100% , myopathic motor units in 65% to 100%, and either mixed or neurogenic motor units in 14% to 86%. Abnormal nerve conduction studies were seen in 6% to 32%.²⁸

Imaging

Both ultrasound and MRI are increasingly used to evaluate muscle diseases and may be particularly helpful for evaluating distal weakness seen in IBM.²⁹ Findings on MRI in people with IBM include hyperintensity on short tau inversion recovery (STIR) sequences because of muscle edema and intramuscular lipid accumulation seen as hyperintensity on T1-weighted sequences.^13,30 Ultrasound is useful for diagnosis of muscle diseases including IBM; sensitivity depends on clinician experience.³¹ Ultrasound findings in IBM include increased muscle echointensity in all muscles with more severe findings seen in muscles characteristically affected by IBM.³² Both ultrasound and MRI help identify a selective pattern of muscle involvement in IBM of upper extremity abnormalities in the flexor digitorum profundus with relative sparing of finger extensors, and prominent lower extremity abnormalities in the quadriceps. Other imaging modalities with promise for evaluating IBM include ¹⁸F-florbetapir PET to differentiate IBM from other types of myositis and ultrasound to quantify muscle shear modulus in order to monitor muscle changes.^33,34 Further development and validation of these techniques is needed.

Disease Management

Exercise

In studies of self-reported function, functional capacity, and muscle strength in people with IBM, using the 36-Item Short Form Survey (SF-36), a 2-minute walk test, timed up-and-go (TUG) test, 30-second chair-stand performance, and quantitative strength testing of knee and leg extensors, TUG test results most closely predicted self-reported physical function.³⁵

In a 9-week animal model study, 12 rats received chloroquine as an experimental IBM model and then had 1 week of exercise adaptation followed by 8 weeks of exercise (3 sessions/week). Resistance exercise appeared to decrease amyloid deposition in the soleus muscles, autophagy, and atrophy.³⁶

In a randomized controlled trial of blood-flow restricted resistance training, individuals with IBM were randomly assigned to do blood-flow restricted resistance training (twice weekly for 12 weeks) or no exercise. The primary outcome was self-reported physical function measured by the SF-36. Participants also completed a 2-minute walk test, TUG test, 30-second chair-stand, test, the Inclusion Body Myositis Functional Rating Scale (IBMFRS), and quantitative muscle strength testing of knee extensors. No effect of exercise was observed. Leg strength in those who exercised, however, was stable compared with those who did not exercise, in whom leg strength declined.³⁷ It should be noted that based upon Rasch analysis of psychometric properties of the IBMFRS, optimized versions have been proposed.³⁸

The feasibility and effect of a community-based aerobic exercise program for people with Charcot–Marie–Tooth disease (CMT) 1A and IBM have been reported. A randomized single-blinded crossover trial compared a 12-week aerobic exercise program to a control period. The primary outcome was peak oxygen uptake during maximal exercise. Muscle strength, function, and patient-reported measures functioned as secondary outcomes. A total of 23 people with CMT and 17 people with IBM participated, and those with IBM had a strong effect size regarding VO₂, whereas those with CMT had a moderate effect size. This study suggests that aerobic training was safe and improved aerobic capacity.³⁹

Pharmacologic Treatment in Development

In a small unblinded trial, 6 people with IBM received intramuscular injection of an adeno-associated virus (AAV)-delivered follistatin isoform. Injections were tolerated by participants and showed some benefit in 4 of 6 people measured by 6-minute walk distance (6MWD) test.⁴⁰ There are, however, methodologic concerns regarding steroid use and an exercise protocol that may have confounded results of this study.⁴¹

After a promising pilot safety study,⁴² a large randomized double-blind placebo-controlled phase 2 study^a of arimoclomol for treating IBM has begun. In a randomized double-blind placebo-controlled study,^b bimagrumab was well tolerated by participants with IBM, but the primary endpoints of improvements on the 6MWD test or muscle strength were not achieved.⁴³ Rapamycin is an mTOR inhibitor that can deplete T effector cells, preserve T regulatory cells, and induce autophagy, potentially to restore abnormal protein degradation pathways evident in IBM. In a randomized double-blind placebo-controlled trial of rapamycin for IBM,^c the primary endpoint of quantitatively measured improved quadricep strength was not met. There were, however, improvements in secondary endpoints (eg, 6MWD and fat muscle replacement on MRI).⁴⁴ An open-label extension of this study is ongoing to further assess these findings.

Conclusion

Although understanding continues to grow and significant progress has been made in understanding IBM, the precise mechanism remains elusive. Advances in diagnosis of IBM may lead to earlier diagnosis. Recent developments and ongoing clinical trials give hope towards the future.