Hereditary and sporadic inclusion body myositis

Author(s): Lisa Williams, MD

Originally published:11/27/2012

Last updated:03/24/2017

1. Disease/Disorder:

Definition

Sporadic inclusion body myositis (s-IBM) and Hereditary inclusion body myositis (h-IBM) are subtypes of idiopathic inflammatory myositis (IIM) first described in 1971 by Yunis and Samaha. s-IBM and h-IBM are distinguished from other inflammatory myopathies clinically by their pattern of weakness, selective muscle wasting and progressive course. It is pathologically distinct by a combination of inflammatory and myodegenerative features with multi-protein aggregates in muscle tissue.1 S-IBM is an idiopathic slowly progressive inflammatory myopathy characterized by proximal muscle weakness and atrophy most prominent in wrist and finger flexors in the forearm, as well as the quadriceps, resulting in severe disability. h-IBM has a similar onset and clinical course with the notable exception of relative sparing of quadriceps musculature.

Etiology

The etiology of inclusion body myositis (IBM) is complex and likely multifactorial. It is believed IBM has an autoimmune component, however, it responds poorly to immune therapy leaving suggestion of a more complex etiology which may include muscle fiber degradation, inflammation, and the accumulation of abnormal proteins in muscle fibers leading to a secondary immune response.1,2 The trigger for these events has not been definitively identified; however, it is likely related to gene expression and oxidative stress in the milieu of aging muscle.2-4

Epidemiology including risk factors and primary prevention

  • s-IBM is the most common acquired myopathy in patients aged over 45 years old.5
  • s-IBM most commonly presents in the sixth decade of life.4
  • It occurs more frequently in men than women.6,7
  • Prevalence estimates range from 4 to 71 cases per million, with variability associated with geographic location. However, a high rate of misdiagnosis has been reported.1 Prevalence variation may be due to the HLA-DRB1 allele.
  • There are no identifiable risk factors for s-IBM, which can be modified to prevent onset or progression.

Patho-anatomy/physiology

  • There are 3 pathophysiologic components of s-IBM, which result in the following clinical findings:
    • Muscle fiber degradation.
    • Abnormal gene expression with subsequent protein mis-folding and accumulation.
  • Protein unfolding, mis-folding, and accumulation is a prominent feature resulting from oxidative stress and abnormal genetic expression.
    • In general, known causes of misfolded proteins include oxidative stress, aging, molecular crowding, and toxins.
    • These abnormal proteins accumulate in the cytoplasm and nucleus of the muscle fiber.
  • Inflammation is likely a response to misfolded proteins.
    • Major histocompatibility complex (MHC) class 1 and II are upregulated in the muscle fiber. Normally, this is not expressed.4,6
    • Muscle fibers that express MHC class 1 then become antigen presenting, which stimulates an inflammatory response.8
    • Cytotoxic CD8 positive cytotoxic T cells accumulate in the cytoplasm and nuclei of muscle fibers expressing MCC class I antigens.9,10,11 The inflammatory cell invasion of the non-necrotic muscle fibers is seen in inflammatory myopathies and suggests a primary role of inflammation.
    • This lymphocytic inflammatory component has been clearly demonstrated; however, s-IBM does not respond to anti-inflammatory or immunosuppressive agents. This argues against a primary role of inflammation in the disease and separates it from polymyositis and dermatomyositis.
  • Abnormal protein formation leads to inclusion bodies identified histologically and muscle atrophy identified clinically.
    • As multiprotein aggregates form, lysosome-like vacuoles develop, possibly as an attempt to degrade these proteins.4,5
    • Inclusion bodies are composed of amyloid beta, amyloid beta precursor protein, and phosphorylated tau protein, which have staining patterns consistent with beta-pleated sheet conformation.4,5
    • Increased cholesterol deposition at sites of abnormal protein accumulation suggests impaired cholesterol transport and may promote further amyloid deposition.
  • Mitochondrial deoxyribonucleic acid (MtDNA) abnormalities at the histologic level have been noted. Mitochondrial dysfunction has a role in sIBM progression .1,10,11
  • Genetic susceptibility in sIBM has shown increasing evidence.
    • Likely polygenic including both HLA and non-HLA forms.
    • There is a strong association with HLA-DRB1 * 03:01 which may portend a more severe phenotype and early age of onset.1
    • The TOMM 40 gene on chromosome 19 plays a role in mitochondrial membrane function may influence age of onset.
  • hIBM
    • Aassociated with mutations in the VCP, GNE and MYHC2A genes.
    • Shares pathologic features of sIBM.

Disease progression including natural history, disease phases or stages, disease trajectory (clinical features and presentation over time)

Inclusion body myositis (IBM) is a slowly progressive disease. Muscle deterioration by manual muscle testing (MMT) has been estimated at 3.5% per year with the greatest decline in the quadriceps muscle.

  • Initial presentation will likely include difficulty rising from sit to stand and weak grasp.12
  • Weakness in the quadriceps group and wrist/finger flexors progresses and may result in falls and impaired activities of daily living.
  • Dysphagia is common and worse in the later stages of disease, however, 15% may present with dysphagia as initial symptom.1
  • Because of the late onset of the disorder and the slowly progressive nature of the process, patients may attribute early decline in functional status over years to the normative process of aging. This may contribute to a delay in diagnosis.
  • Natural history studies have shown the life expectancy is not significantly decreased compared to the general population.
  • In end stage severe disease, Weakness, dysphagia and respiratory involvement can be debilitating and result in failure to thrive and respiratory infections.1

Specific secondary or associated conditions and complications

IBM is more frequent in patients with autoimmune disorders, such as rheumatoid arthritis, systemic lupus erythematosus, and Sjogren’s syndrome.1,6

B. Essentials of Assessment

History

  • Initial presentation involves both proximal and distal muscle weakness. There is a predilection for weakness of the non-dominant hand and a distinctive pattern of asymmetric weakness affecting the flexors of the distal phalanges with sparing of the intrinsic hand muscles.
  • Patients may also have mild facial weakness.1
  • Falls may be noted secondary to quadriceps weakness. This may result in difficulty ascending and descending stairs, and subjective report of knees giving out or buckling (less frequently noted in the h-IBM form). Recent studies have found a correlation between knee extensor strength and functional lower limb measures including the six minute walk test.1
  • Patients often complain of progressive difficulty with functional tasks requiring strength and endurance of involved muscle groups, such as grooming hair, climbing stairs, grasping kitchen items, and rising from a seated position.
  • Swallowing dysfunction occurs in 51-65% of cases,1more commonly found later in disease progression.
  • Sleep disordered breathing (SDB) due to weakness of the oropharyngeal muscles is now recognized as a common problem in IBM and a restrictive lung disease pattern noted by reduced vital capacity and nasal inspiratory pressures have been found in up to 75% of patients with IBM. Diaphragmatic weakness may also be involved.1
  • Cardiac involvement is not typical of IBM. However, There have been rare reported cases of cardiomyopathy and conduction abnormalities.1

Physical examination

Prominent findings on physical examination include:

  • Observable atrophy of quadriceps (except in h-IBM) and forearm musculature (scalloped forearms), in particular the wrist/finger flexor group is commonly effected.12
  • Weak knee extension, hip flexion, and grasp are usually seen.
    • The pattern of quadriceps and long finger flexor weakness is common and diagnostic; this combination is rarely seen in other diseases.
    • Typically, if finger flexor strength is less than shoulder abduction, and quadriceps strength is less than hip flexors, IBM is suggestive rather than polymyositis or dermatomyositis.
  • Normal sensation is common, although it has been noted that up to 30% of patients with IBM also have a sensory neuropathy.1
  • Diminished patellar reflex is seen secondary to quadriceps wasting and reduced brachioradialis reflex may be seen with forearm wasting.

Functional assessment

  • Mobility decreases slowly. A longitudinal study by Benveniste et al. noted that average progression to wheelchair use took 14 years from date of diagnosis.5
  • Self-care abilities also diminish slowly.
  • There is no evidence that s-IBM effects cognition, behavior, or affect. However, attention should be paid to effective coping skills, because the patient deals with loss of functional ability in the setting of a chronic progressive disease.7

Laboratory studies

Creatine kinase (CK) and aldolase may be normal or mildly elevated, usually <10X the normal value.1,6,8

Autoantibody testing has become an important tool for the diagnosis of IBM. Antibodies to cystosolic 5’-nucleotidase 1A (anti-cN1A) can be found in 33-55% of patients with IBM compared to <5% prevalence in other inflammatory IIM. Although, anti-cN1A reactivity may also be seen with a similar proportion in other autoimmune diseases such as Sjogren’s syndrome (SS) and systemic lupus erythematosus (SLE) and a high antibody titer is less reliable in patients who have associated autoimmune disease.13,14,15

Imaging

Magnetic resonance imaging (MRI) with T1 and T2 weighted (STIR images) will reflect atrophy of affected skeletal muscles and compliments the physical examination and can assist with sights of target for muscle biopsy.4 The pattern of weakness and edema seen on MRI has been shown to be highly specific and distinguishable from other myopathies. Features on MRI in the upper limbs include forearm flexor involvement with preference for the flexor digitorum profundus (FDP) and sparing of the flexor digitorum superficialis (FDS) and forearm extensors are seen. In the lower limbs, quadriceps are involved early with sparing of adductors and hamstrings even in the later stage of disease.16,17

Muscular ultrasound (US) will reveal muscle atrophy. Flexor digitorum profundus and flexor carpi ulnaris echo intensity in muscle US is a sensitive diagnostic indicator of s-IBM when compared to s-IBM mimicking diseases.16,17

Muscle biopsy is the definitive diagnostic procedure for s-IBM.

  • The biopsy should be taken from a moderately effected, proximal muscle not previously studied by needle electromyography.
  • Biopsy consistent with s-IBM will show the following are shown to be highly specific:
    • Inflammatory lymphocytic changes including CD8 + T-cell lymphocytic endomysial infiltration with invasion of non-necrotic muscle fibers
    • Myodegenerative changes including rimmed vacuoles, congophilic inclusions and multi-protein aggregates.
    • Mitochondrial changes including increased numbers of ragged red fibers, cytochrome C-oxidase negative fibers and Succinic dehydrogenase (SDH) stained fibers.10,11
  • Upregulated expression of MHC-II antigens, in combination with MHC-I, has been shown to have a high specificity for IBM compared to MHC-I alone, and should be included routinely in the muscle biopsy for inflammatory myopathy.1,5,6
  • Other non-specific findings may include: Accumulation of amyloid,5,6 which is seen as apple green biregringent deposits with Congo red staining viewed under polarized light. Tubulofilaments in the nucleus and cytoplasm seen on electron microscopy.5,6

Supplemental assessment tools

Electromyography plays a crucial role in clinical practice and may be used to clarify the nature of this disease and differentiate a myopathy from a neuropathy. However EMG findings in IBM are non-specific and have been excluded from the most recent diagnostic research criteria for IBM.1,13

  • Abnormal spontaneous activity can be seen commonly (56-100%) and includes fibrillations, positive sharp waves and less frequently reported are myotonic and myokymic discharges.
  • Myopathic motor units are not specific to s-IBM. They are identifiable on needle electromyography with decreased amplitude, short duration, and polyphasic. With later stages of disease the motor unit action potential duration may become larger and longer secondary to muscle fiber necrosis followed by regeneration. These findings can be misconstrued as neuropathic, however, careful attention to the recruitment pattern will distinguish myopathic motor units which will have early recruitment from neurogenic which will have reduced.
  • There also may be a sensory axonal neuropathy found on electrodiagnostic studies in up to 30% of cases.12
  • Single Fiber EMG studies may show mildly increased fiber density, abnormal jitter and blocking, however, these findings are non-specific.
  • EMG examination of the flexor muscles including the FDP should be included.

Early predictions of outcomes

  • Older age at the time of diagnosis is associated with more rapid progression.5,6
  • Men tend to have a more rapid progression and later symptom onset than women.5
  • Life expectancy does not change with diagnosis or treatment.5
  • There is some evidence that patients treated with immunosuppressive agents progress more rapidly to use of assistive mobility devices. It is not clear whether there is a causative relationship or if this reflects an artifact of aggressive treatment of those more severely affected.5

Environmental

There are no environmental risk factors associated with h-IBM or s-IBM.

Social role and social support system

As with any myopathy, communication with the patient and family regarding functional deficits needs to occur.

Professional Issues

Open and honest discussion with the patient and family regarding the course of this disease is necessary. Because life expectancy is not shortened and there are no treatments at this time that improve strength, ongoing communication regarding adaptive equipment and environmental modifications to improve quality of life is appropriate.

In individuals identified as having h-IBM, appropriate genetics counseling of family members is recommended for potential issues in family planning.

C. Rehabilitation Management and Treatments

Available or current treatment guidelines

  • Presently, there are no effective pharmacologic treatments that alter the course of the disease. Appropriate adaptive equipment including orthotics, wheelchairs, and assistive lift devices will improve the quality of life.
  • Patients typically respond poorly to treatment with steroids or other immunotherapeutic agents.1,5,6 Some patients may show a temporary improvement or period of stabilization, however, the disease will progress despite this treatment.17,18 Muscle biopsy subsequent to this treatment notes progression of amyloid deposition and vacuolization.1 These are still used as empiric agents, and may have a positive effect in those with comorbid autoimmune disorders. As it is difficulty to predict which subsets of patients may respond to treatment, current practice is to offer only supportive treatment .1 If a trial of immunosuppressive therapy is used, tolerability and efficacy are carefully monitored.1

At different disease stages

Rehabilitation

  • Rehabilitation efforts may improve function and quality of life. Goals include maximizing functional independence through environmental adaptation, task modification, and provision of mobility aids.
  • Exercise-based therapy is safe for strength and endurance with no subsequent increase in CK.20,21
  • Orthotics may help prolong independent mobility and prevent falls.
    • Ground reaction force ankle foot orthosis (AFO), limited dorsiflexion range of motion AFO, or standard knee-ankle-foot orthosis with locking mechanism in knee extension during gait may be helpful in patients with dorsiflexion weakness and varying degrees of quadriceps weakness.
    • Knee orthoses, such as a Swedish knee cage, may prevent genurecurvatum to stabilize knee during gait.
  • Tendon transfers (extensor carpi radialis longus / brachioradialis to finger flexors) can improve function and reduce disability.1
  • Assistive devices may include straight cane, quad cane, and walker; however, diminished finger/wrist flexor strength may make this difficult. Lofstrand crutches with elbow support or a platform walker may be an option also.
  • Environmental modifications to optimize accessibility is appropriate as disease progresses and functional impairments emerge.

Dysphagia Management:

  • Various treatmentand management strategies including cricopharyngeal myotomy, botulinum toxin injections or insertion of a PEG tube to maintain nutrition exist, however, there are no currently established guidelines.1

Coordination of care

All members of the rehabilitation team should be actively involved in the ongoing management of patients with IBM, including the physical therapist, occupational therapist, speech therapist, orthotist, nutritionist, social worker, psychologist, neurologist, physiatrist and otolaryngologist.

Emerging/unique Interventions

There have been no studies to date showing that treatment modifies course of the disease.

Translation into practice: practice “pearls”/performance improvement in practice (PIPs)/changes in clinical practice behaviors and skills

Rehabilitation medicine impacts patients with IBM through ongoing functional evaluation and provision of adaptive equipment to optimize function and quality of life.

Weakness and atrophy in the quadriceps or wrist/finger flexor groups suggest s-IBM.

Coinciding sensory neuropathy may disguise underlying myopathy and result in a delay in diagnosis.

Diagnosis is made by characteristic findings on muscle biopsy.

Distinguishing s-IBM from polymyosits and dermatomyositis is important to direct treatment and management.

D. Cutting edge/emerging and unique concepts and practice

Cutting edge concepts and practice

  • Cytotoxic agents, antithymocyte globulin, and interferon-beta need further study. Initial studies lack power and results are equivocal.1,2
  • Intravenous immunoglobulin has not demonstrated effectiveness.18 It may improve dysphagia mildly. Further study is needed.
  • Oxandrolone, a synthetic androgen, has no clear beneficial effect, although some studies suggest mild improvement in upper extremity strength.21
  • Coenzyme Q10 and carnitine are used empirically with no evidence of benefit.
  • Diagnostic testing including Anti CM1A is useful the use of genetic testing is emerging.14,15

E. Gaps in the evidence-based knowledge

Gaps in the evidence-based knowledge

There is debate regarding whether inflammation leads to muscle fiber degeneration or whether fiber degeneration leads to an inflammatory response. Lack of response to corticosteroids and immunotherapy would seem to indicate that muscle fiber degeneration with secondary inflammation is the more likely scenario.5

References

  1. Needham M, Mastaglia F. Sporadic inclusion body myositis: A review of recent clinical advances and current approaches to diagnosis and treatment. Clinical Neurophysiology. 2016;127:1764–1773.
  2. Needham M, Mastaglia FL. Inclusion body myositis: current pathogenetic concepts and diagnostic and therapeutic approaches. Lancet Neurol. 2007;6:620-631.
  3. Askanas V, Engel WK. Inclusion-body myositis and myopathies: different etiologies, possibly similar pathogenic mechanisms. Curr Opin Neurol. 2005;15:525-531.
  4. Askanas V, Engel WK. Inclusion-body myositis, a multifactorial muscle disease associated with aging: current concepts of pathogenesis. Curr Opin Rheumatol. 2007;19:500-559.
  5. Benveniste O, Guiguet M, Freebody J, et al. Long-term observational study of sporadic inclusion body myositis. Brain. 2011;134:3176-3184.
  6. Dalakas MC, Karpati G. The inflammatory myopathies. In: Disorders of Voluntary Muscle, 8th edition. Eds G. Karpati, D. Hilton-Jones, K. Bushby, R.C. Griggs. Cambridge: Cambridge University Press, 2010;427-52.
  7. McDonald CM, Han JJ, Carter GT. Myopathic disorders. In: Braddom R, ed. Physical Medicine and Rehabilitation. 4th ed. Elsevier Saunders: Philadelphia, PA, 2011.
  8. Griggs RC, Askanas V, DiMauro S, et al. Inclusion body myositis and myopathies. Ann Neurol. 1995;38:705-713.
  9. Atluri RB. Inflammatory Myopathies. Mo Med. 2016;113(2):127-30.
  10. Catalán-García M, Garrabou G, Morén C, Mitochondrial DNA disturbances and deregulated expression of oxidative phosphorylation and mitochondrial fusion proteins in sporadic inclusion body myositis. Clin Sci (Lond). 2016;130(19):1741-51.
  11. Rygiel K, Miller J, Grady JP, et al. Mitochondrial and inflammatory changes in sporadic inclusion body myositis. Neuropathol Appl Neurobiol. 2015;41(3):288-303. 12.Amato AA, Russell JA. Inflammatory myopathies. In: Neuromuscular Disorders. AA Amato and JA Russell eds. McGraw-Hill Medical: New York City, NY. 2008:681-719.
  12. Herbert MK, Stammen-Vogelzangs J, Verbeek MM, et al. Disease specificity of autoantibodies to cytosolic 5’-nucleotidase 1A in sporadic inclusion body myositis versus known autoimmune diseases. Ann Rheum Dis. 2015;75(4):696-701.
  13. Benveniste O, Stenzel W, Allenbach Y. Advances in serological diagnostics of inflammatory myopathies. Curr Opin Neurol. 2016;5:662-73.
  14. Limaye VS, Lester S, Blumbergs P, et al. Anti- C N1A antibodies in South Australian patients with inclusion body myositis. Muscle Nerve. 2016 Apr;53(4):654-5.
  15. Lundberg IE, Miller FW, Tjärnlund A, et al. Diagnosis and classification of idiopathic inflammatory myopathies. J Intern Med. 2016;280(1):39-51.
  16. Noto Y, Shiga K, Tsuji Y, Kondo M, Tokuda T, et al. Contrasting echogenicity in flexor digitorum profundus-flexor carpi ulnaris: a diagnostic ultrasound pattern in sporadic inclusion body myositis. Muscle Nerve. 2014;49(5):745-8.
  17. Dalakas MC, Sonies B, Dambrosia J, et al. Treatment of inclusion body myositis with IVIg: a double blind placebo controlled study. Neurology. 1997;48:712-716
  18. Rose MR. 188th ENMC international workshop: inclusion body myositis, 2–4 December 2011, Naarden, The Netherlands. Neuromuscul Disord. 2013;23 (12):1044–55.
  19. Lilleker J, Murphy S, Cooper R. Selected aspects of the current management of myositis. Ther Adv Musculoskelet Dis. 2016.;8(4):136-44.
  20. Arnadottir S, Alexanderson H, Lundberg IE, et al. Sporadic inclusion body myositis: pilot study on the effects of a home exercise program on muscle function, histopathology and inflammatory reaction. J Rehabil Med. 2003;35:31-35.
  21. Rutkove SB, Parker RA, Nardin RA, et al. A pilot randomized trial of oxandralone in inclusion body myositis. Neurology. 2002;58:1081-1087.

Original Version of the Topic

Lisa Williams, MD. Hereditary and sporadic inclusion body myositis. 11/27/2012.

Author Disclosure

Lisa Williams, MD
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