|Ahead of print publication
Sporadic inclusion body myositis in the rheumatology clinic
Fernando Henrique Carlos de Souza, Gustavo Luiz Behrens Pinto, Jean Marcos de Souza, Pablo Arturo Olivo Pallo, Leonardo Santos Hoff, Samuel Katsuyuki Shinjo
Division of Rheumatology, Faculdade de Medicina FMUSP, Universidade de Sao Paulo, SP, Brazil (BR), Brazil
Samuel Katsuyuki Shinjo,
Division of Rheumatology, Laboratório de Miopatias Inflamatórias, Faculdade de Medicina FMUSP, Universidade de Sao Paulo, SP
Source of Support: None, Conflict of Interest: None
Sporadic inclusion body myositis (sIBM) is a progressive and insidious skeletal muscle disorder characterized classically by the quadriceps, wrist, and finger flexor weakness. The main irreversible complications of sIBM are dysphagia and walking difficulties. The disease affects more men than women, and the symptom onset mainly occurs between 50 and 70 years of age. Due to its slow progression, sIBM diagnosis is frequently delayed and therefore misdiagnosed as other muscle diseases. sIBM remains refractory to treatment (e.g., glucocorticoid, and immunosuppressive/immunomodulatory/immunobiological drugs). Although there have been no robust clinical trials, training exercise/physiotherapy should be prescribed regularly in sIBM patients.
Keywords: Idiopathic inflammatory myopathies, inclusion body myositis, myopathies, myositis, review
| Introduction|| |
Sporadic inclusion body myositis (sIBM) is a rare disorder characterized by late-onset muscle disease with distinct classical features, which include progressive muscle weakness and hypo/atrophy of the quadriceps and flexors of the fingers, histopathology with infiltration of cytotoxic T-cells.,
sIBM is acquired inflammatory muscle disease and it should not be mistaken for hereditary inclusion body myopathies (not myositis). These later are hereditary diseases with autosomal recessive or dominant inheritance. To distinguish these groups, it is rather to define them as sporadic or hereditary.
The prevalence varies considerably depending on the region under analysis, and according to a recent meta-analysis, the prevalence is 45.6 cases/million habitants. It affects more men than women at a ratio of 2~3:1. The average age reported is 61–66 years, and sIBM is even less common in non-Caucasian individuals.,
sIBM has been associated with different systemic autoimmune diseases, such as rheumatoid arthritis, Sjögren's syndrome, systemic lupus erythematosus, and others., HIV-infected patients may have histological abnormalities on muscle biopsy equal to sIBM. A higher incidence of cancer has been found in some but not all population-based studies.,, Furthermore, patients with sIBM have more comorbidities, such as hypertension, dyslipidemia, diabetes mellitus, neoplasia, and osteoporosis.,,,
Although the mechanisms for the development of disease are still incompletely understood, there are two main theories for the pathophysiology of sIBM: one involving autoimmunity and another with a neurodegenerative perspective.
The postulate of autoimmunity is reinforced by the increased incidence of other autoimmune diseases in these patients. An important finding related to the immune system was the identification of cytotoxic CD8+ T-cell endomysial infiltrates capable of surrounding and invading nonnecrotic muscle fibers., Another evidence of autoimmunity was the discovery of the antibody anti-cytosolic 5'-nucleotidase 1A (cN1A) in 2011.
The neurodegenerative perspective of the disease is built on the lack of response to glucocorticoids and immunosuppressive drugs, and the finding of protein aggregates in muscle fibers, frequently associated with other neurodegenerative diseases. Aggregates of β-amyloid, hyperphosphorylated tau, heavy chain neurofilament, and Tar-DNA-binding protein-43 (TDP-43) ubiquitin, among others, have been described in muscle immunohistochemical studies of patients with sIBM.,, Important data to corroborate this hypothesis is the degeneration of myocyte nuclei, which generates rimmed vacuoles and leads to anomalous displacement of DNA-binding proteins to the cytoplasm of muscle fibers.
It is important to emphasize that these two hypotheses are not mutually exclusive, and possible link mechanisms between these two main theories are still being elucidated. There is also evidence about genetic defects in autophagy and mitochondrial dysfunction, as possible mechanisms involved in the pathophysiology of sIBM.,
| Methods|| |
The present study was performed by searching the sentence “inclusion body myositis” for research works available on the Medline (PubMed) from 2000 to 2020. The following articles were selected for our revision: English version, reviews, original articles, controlled clinical trials, and case series.
The most common clinical manifestation in sIBM is asymmetric proximal and distal muscle weakness, of slow progression toward disability, generally of >12 months of evolution.
Patients initially report symptoms related to muscle groups that are particularly affected in sIBM: quadriceps (difficulty rising from a chair and difficulty in climbing stairs and falls), finger flexors and ankle dorsiflexors (falls and foot drop).,,,,, On physical examination, muscle weakness is typically accompanied by atrophy in the quadriceps muscles and impaired grip strength in finger flexors [Figure 1].
|Figure 1: Clinical features of patients with inclusion body myositis. (a) Atrophy of finger flexors; (b) thigh atrophy. Figures from the author's personal archive|
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Dysphagia is found in 42%–65% of patients, which is associated with high morbidity and mortality because of nutritional deficiency, weight loss, aspiration pneumonia, and reduction of quality of life.,,
Finally, other findings on physical examination in individuals with sIBM, which may be useful at the time of differential diagnosis, show greater weakness of elbow flexion than shoulder abduction; greater muscle weakness in the quadriceps than the hips, and finger flexion is ever weaker than shoulder abduction.,,,
As the recognition of sIBM is a subtype of systemic autoimmune myopathies, many diagnostic criteria have been developed and suggested. However, Griggs et al. criteria and the European Neuromuscular Centre (ENMC) IBM research diagnostic criteria of 2011 are used widely in clinical research and practice.,
Griggs et al. criteria are based on the clinical and laboratory data [Table 1] and consider definite sIBM if all three pathological features (mononuclear cell invasion of nonnecrotic muscle fibers, rimmed vacuoles, and either amyloid deposits or 15–18 nm tubule filaments by electronic microscopy) are present and independent of the clinical features. They also define possible sIBM if clinical features exist, with inflammatory myopathy but without rimmed vacuoles and amyloid or tubule filaments.
The ENMC research diagnostic criteria of 2011, which are based in the clinical, laboratory, and pathological features [Table 2], recognize three main groups of patients: those with classical clinical and pathological features (clinic and pathologically defined sIBM), those with classical clinical features but limited pathological changes (clinically defined sIBM), and patients with characteristic lower and upper and limb patterns of weakness but not both (probable sIBM).
|Table 2: European Neuromuscular Centre 2011 sporadic inclusion body myositis diagnostic criteria|
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Subsequently, Lloyd et al. assessed the sensitivity and specificity of all available diagnostic criteria for sIBM and showed that all diagnostic groups had high specificity (≥97%) but varied substantially in their sensitivities (11%–84%). The probable IBM group from the ENMC 2011 criteria was the best performing category with a sensitivity of 84%.
Before the muscle for biopsy, it is relevant not to choose either a muscle which is so involved by the disease process (e.g., atrophic muscles) or a muscle which is so little affected or submitted to electromyogram (EMG) recently.
A classical biopsy finding in sIBM is characterized by atrophic muscle fibers, infiltration of nonnecrotic myofibers by predominant of CD8+ T-cells in an endomysial and perivascular pattern, and rimmed vacuoles [Figure 2]. Increased numbers of cytochrome c oxidase-negative fibers are also frequently noted in the muscle biopsies of individuals with sIBM. Moreover, the major histocompatibility complex I is upregulated on immunostaining [Figure 2]. Cytoplasmic inclusions of β-amyloid may be visualized using Congo red and polarized light.
|Figure 2: Inclusion body myositis – typical histological finding in muscle biopsy legends: *Infiltration of muscle endomysium by immune cells – hematoxylin and eosin staining; **Deep invasion of non-necrotic myofiber by immune cells – hematoxylin and eosin staining; ***Rimmed vacuoles in Gomori trichrome stained|
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In addition, abnormal sarcoplasmic deposition of TDP-43 or p62 immunostaining may help to discriminate individuals with polymyositis that are going to convert sIBM, but there has been no study to elucidate p62 utility in inflammatory myopathies.
Electroneuromyography can be useful in distinguishing neuropathy from myopathy weakness. Needle electromyography typically shows an irritative myopathy that is related to fibrillation potentials., EMG findings of sIBM include irritability of the muscle fibers at rest and during needle insertion and myopathic motor unit potentials during contraction., However, neuropathic features can also be found in approximately one-third of the IBM patients caused by reinnervation of denervated., In some cases, the neurogenic motor unit action potentials in sIBM may be appropriately dense to minimize the myopathic changes, leading to a misdiagnosis of motor neuron disorders.
Magnetic resonance imaging
The evaluation of the muscle condition has many benefits in sIBM. It is one of the tools used to guide diagnosis because the pattern of involvement may suggest the clinical hypothesis and might be used to guide biopsy and the acquisition of images may serve as a monitoring method. Up to date, magnetic resonance imaging (MRI) is the cornerstone for muscle assessment in systemic autoimmune myopathies in general.,
The pattern of muscular involvement in sIBM as seen by MRI has been studied extensively in many cross-sectional studies, most of them depicting it as a disease that most often affects the anterior compartment of the thighs.,, Frequently, there is an important degree of atrophy and fatty infiltration, mainly in the quadriceps femoris muscles and relatively sparing the rectus femoris and the posterior compartment., Some studies also reported a high degree of fatty infiltration and atrophy in the gastrocnemius muscles., The girdle muscles are affected less frequently, and in the forearm, there is a striking predilection for the flexor digitorum profundus (forearm). In general, the pattern of involvement seems to be so solid that an MRI-based criterion was already proposed, with good specificity and moderate sensibility. [Figure 3] shows a typical thigh MRI from a patient with sIBM.
|Figure 3: Magnetic resonance in a patient with inclusion body myositis T1 – axial section of thigh (a: Proximal; b: Medium; c: Distal). A significant “melted” appearance with fatty infiltration/fibrous tissue and atrophy is observed in the distal part of the thigh|
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Anti-cN1A (or anti-NT5C1A) is a highly specific antibody detected in sIBM patients: studies have shown a sensitivity of 33%–76% and a specificity of 87%–100%. Interestingly, anti-cN1A antibodies are also detected in 20%–30% of individuals with juvenile dermatomyositis, systemic lupus erythematosus, and Sjögren's syndrome but not in adults with other systemic autoimmune myopathies., Therefore, anti-cN1A antibody testing may be useful to differentiate an atypical case of sIBM from other forms of adult myopathies and should not be used as a screening test for sIBM (given the low-moderate sensitivity). Anti-cN1A does not seem to related to disease severity or to a specific clinic pathological phenotype of sIBM. They also have not been comprised as diagnostic criteria for sIBM.
Other autoantibodies detected less frequently are antinuclear antibodies, anti-Ro, anti-La, and rheumatoid factor. Myositis-specific autoantibodies are usually negative in individuals with sIBM.,
Levels of creatine phosphokinase serum are usually <10 times the normal limit., Erythrocyte sedimentation rate is frequently normal. All patients with suspected sIBM should also have a complete blood workup to rule out other causes of myopathy, including endocrine and electrolyte disorders.
The management of sIBM remains the main challenge because of the coexistence of inflammatory and degenerative courses. No effective treatment has been known so far, and the standard regimens used for other types of inflammatory myopathies do not stabilize sIBM.,
Glucocorticosteroids, azathioprine, methotrexate, or β-interferon-1a are not effective in sIBM.,, Moreover, Benveniste et al.. demonstrated that 71 individuals who received prednisone associated with intravenous human immunoglobulins, azathioprine, or methotrexate (median duration of 40.8 months) were more affected on disability measures than controls.
A double-blinded, placebo-controlled study with methotrexate (5–20 mg/week) showed in 44 patients no difference in development and muscle strength at 48 weeks but did show decreased serum creatine phosphokinase activity.
In a pilot study, interferon was well tolerated at low doses, and the adverse event profile was similar to placebo. However, no differences were shown in muscle strength or mass at 6 months.
Similar results were found in biopsies from a placebo-controlled study with intravenous human immunoglobulin and glucocorticoids that down-modulated inflammatory mediators but miscarried to block nitric oxide stress in the muscle and in an analogous in-vitro model. It can be related to stabilization or even temporary, mild upgrading of muscle strength and upgraded dysphagia in several individuals with sIBM.
A small clinical study demonstrated that oxandrolone had a doubtful substantial effect in improving whole-body strength and a relevant effect in refining upper-extremity strength. In 10 patients who completed a trial of simvastatin, the management appeared safe and well tolerated, but none of them showed a substantial clinical upgrading.
In a prospective, randomized, double-blind, placebo-controlled trial, 22 individuals received oral rapamycin and 22 received placebos over 12 months. No difference in the main outcome (quadriceps strength) was recognized, but significantly less fatty replacement was found in the quadriceps and hamstrings. Improvements in sIBM weakness composite index and the forced vital capacity were noted in the dynamically treated limb.
Etanercept and anakinra failed to demonstrate improvement., Barohn et al. used etanercept (25 mg two times a week) for 17.0 months, and there was no alteration between the treated group and the placebo group at 6 and 12 months when observing at elbow flexors or at 6 months when observing at handgrip. In the treated individuals, there was a minor but important improvement in handgrip at 12 months.
In a minor pilot study with anakinra, four individuals with biopsy-proven sIBM were treated for 7.7 months. However, no upgrading in muscle strength or steadying was observed in any of the individuals based on grip strength and medical research council dimensions.
Alemtuzumab (0.3 mg/kg/day for 4 days) led to a slowdown of disease development up to 6 months, improved the strength of some individuals, and reduced endomysial inflammation and stressor molecules. In a post hoc analysis, a downregulation of inflammatory markers was noted without an effect on numerous crucial markers of cell stress and degeneration, which could possibly explain the inadequate long-term effect of this treatment.
A global, randomized, double-blind placebo-controlled trial with bimagrumab (anti-activin type II receptor antibody) showed no improvement in the 6-min walking distance test after 52 weeks of treatment.
A long-term open-label study with canakinumab (150 mg subcutaneous injection, bi-monthly for 4 months, and then monthly) showed minor but not clinically considerable, stabilizing profits in two of five individuals with sIBM.
The rationale behind attempting to treat IBM with physical exercise is the notion that this entity is a complex and multifactorial disease that should be tackled in a multidisciplinary manner. Despite the promising results reported in case studies and even clinical experience, the evidence sustaining physical training in sIBM is still fragile. Most studies are not controlled or randomized, and the heterogeneity of the training protocols makes it difficult to grasp the ideal intervention. Currently, there is limited evidence to funding the safety of physical exercise in sIBM. Based on the conflicting and low-quality evidence, physical exercise might slightly improve muscle strength or, at least, reduce the speed of decline.
Many previous studies addressed home-based programs, especially resistive training or combined (resistive and aerobic) exercises.,, These protocols established the safety of exercise training in sIBM and some of them presented gains in strength and functionality. One study also evaluated aerobic exercise in community-based facilities and, although underpowered to grasp differences between groups, was able to find strong size effects of the intervention regarding improvement in VO2 peak.
Moreover, one randomized clinical trial evaluated the effect of blood-flow restricted resistance training over physical function and was unable to reach the primary endpoint. Even still, the authors emphasize that they could find differences regarding the amount of loss of knee extensor strength between groups, suggesting that the exercise had a protective role in the subjects. In summary, there is a scientific penumbra regarding physical exercise in sIBM that calls for high-quality randomized controlled trials. Efforts to homogenize the interventions are welcome for these trials, but from what science indicates so far, an individual approach might be more suitable in the real-life clinical practice.
Nutrition and supplementation
Considering the mechanisms underlying the pathogenesis of sIBM, some clinicians empirically prescribe combinations of L-carnitine, coenzyme Q10, B complex vitamins, and creatine for patients. Although those substances may participate in one or more pathways involved in the muscle metabolism and mitochondrial respiratory chain, we could not find evidence for benefits in the literature, not even considering those with low quality. At present, no ongoing trials were found to be registered in ClinicalTrials.gov concerning supplementation in sIBM.
The classical sIBM manifestations are characterized by proximal leg or distal arm weakness. The most important differential diagnoses are the other inflammatory myopathies, neuromuscular diseases, and neurological diseases that can affect the lower motor neuron [Table 3].
|Table 3: Differential diagnosis of patients with inclusion body myositis|
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Some important demographic considerations and clinical features can help to differentiate sIBM from other diseases. For instance, the age at onset of sIBM is generally 50 years and older, is more prevalent in men than women, and its evolution is slow and chronic, particularly over 12 months, unlike other subgroups of systemic autoimmune myopathies with an acute or subacute course., Hereditary inclusion body myopathies, for instance, usually occurs at the age between 30 and 40 years. Asymmetric distribution and arrangement of proximal and distal muscle weakness observed in sIBM is particularly uncommon in other groups of myopathies, and a greater atrophy of quadriceps (especially vastus medialis), flexor muscle of the fingers, and thenar and hypothenar muscles also are frequently found only in sIBM., On the other hand, sparing of hypothenar, thenar, and finger extensor muscles sets sIBM besides a myotomal diseases, such as amyotrophic lateral sclerosis. On physical examination, the presence of cramps, fasciculation, hyperreflexia, and/or neurogenic signs suggests neuromuscular disease. Finally, individuals with sIBM usually do not respond to glucocorticoid therapies.,
In hereditary inclusion body myopathies, there is sparing of the quadriceps muscles, even in the progressive disease phases. Weakness and atrophy of the foot extensors show as reduced foot dorsiflexion at an early phase of the disease, presenting as walk complications. Afterward, girdle and axial muscles convert more complicated.
Therefore, when considering differential diagnoses, multidisciplinary discussion with an expert in neuromuscular disease is crucial for the correct diagnosis and treatment.
A suggested diagnostic chart built on clinical outcomes is presented in [Figure 4].
|Figure 4: Suggested diagnostic approach to muscle weakness in the Rheumatology setting. *Present in physical examination. If relevant family history is present, consider first an inherited disease. Metabolic myopathies include: glycogenosis, mitochondrial, and lipid storage myopathies.‡Systemic connective tissues diseases.‡Depending on the context, relevant different diagnosis may include muscular dystrophies, motor neuron disease, infectious myopathies, and toxic myopathies|
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The natural progression of the sIBM consists of slowly advanced weakness of the lower and upper limbs, with a yearly decline of 10% for pinch strength and of 4% for knee extension. Younger age at diagnosis may be related to a rapid deterioration of grip strength, while an older age at diagnosis may be related to a rapid deterioration of knee extension strength.
Most patients may experience walking difficulties and up to a half will be bound to a wheelchair as the disease progress. Dysphagia is also a common complication of the disease, contributing to cachexia and muscle wasting.,
Mortality in sIBM is a matter of controversy. A population-based study showed an increased mortality risk for patients with sIBM, while two cohort studies did not show differences in life expectancy.,, Dysphagia and aspiration pneumonia contribute to premature death.
Financial support and sponsorship
Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq) #303379/2018-9 and Faculdade de Medicina da USP - SP to SKS.
Conflicts of interest
There are no conflicts of interest.
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[Figure 1], [Figure 2], [Figure 3], [Figure 4]
[Table 1], [Table 2], [Table 3]