Version July 2025
INTRODUCTION —
Sporadic inclusion body myositis (IBM) is an idiopathic inflammatory myopathy, a group of diseases that includes polymyositis, dermatomyositis, the antisynthetase syndrome, and necrotizing autoimmune myopathy.
Despite some similarities, the clinicopathologic manifestations of IBM are clearly distinct from the other myositis subtypes (table 1). (See "Overview of and approach to the idiopathic inflammatory myopathies", section on 'Major disease subtypes'.)
Because IBM does not respond to immunosuppression, distinguishing IBM from other forms of idiopathic inflammatory myopathy may help these patients avoid unnecessary exposure to immunosuppressive agents.
The clinical manifestations and diagnosis of IBM will be reviewed here. The treatment and prognosis of IBM are discussed separately. (See "Management of inclusion body myositis".)
PATHOGENESIS —
Sporadic inclusion body myositis (IBM) is a progressive muscle degenerative disease of unclear etiology [1,2]. Several mechanisms (eg, autoimmunity, neurodegeneration, mitochondrial dysfunction) have been implicated in its pathogenesis.
●Autoimmunity – Evidence supporting a role for autoimmunity in disease pathogenesis includes the following [3]:
•Linkage to the human leukocyte antigen (HLA) locus in genome-wide association studies
•Intense infiltration of T cells on muscle biopsies
•Association with anti-NT5C1A antibodies
The use of these findings to help establish a diagnosis of IBM is discussed below. (See 'Muscle biopsy findings' below and 'In patients with finger flexor weakness' below.)
●Neurodegeneration – Like other neurodegenerative disorders, IBM manifests in older patients and does not respond to immunosuppression [3-5].
Also like other neurodegenerative disorders, IBM is characterized by the accumulation of intracellular proteins. These proteins accumulate due to defects in autophagy, which is the process by which organelles and proteins are targeted for lysosomal destruction.
Two types of proteins accumulate:
•Proteins that directly participate in autophagy (eg, p62)
•Proteins that are targeted by autophagy (eg, TAR deoxyribonucleic acid [DNA]-binding protein 43 [TDP-43]).
Identifying these specific protein accumulations in muscle biopsies may assist in diagnosing IBM [6]. (See 'Muscle biopsy findings' below.)
●Mitochondrial respiratory chain dysfunction – Cytochrome C oxidase is a key component of the mitochondrial respiratory chain, which generates adenosine triphosphate (ATP). Muscle biopsies from patients with IBM often demonstrate cytochrome C oxidase deficiency [7].
Identifying cytochrome C oxidase deficiency may assist in diagnosing IBM, but this finding is also associated with mitochondrial myopathies and some neurodegenerative disorders [8,9]. (See 'Muscle biopsy findings' below.)
EPIDEMIOLOGY —
Sporadic inclusion body myositis (IBM), while uncommon, is the most common acquired idiopathic inflammatory myopathy in individuals over the age of 50 [10]. In one study of adults older than 50 years, the estimate of prevalence was as high as 180 per million adults [11,12].
In the general population, IBM has an estimated prevalence of 15 to 70 cases per million adults [10-12].
The mean age at onset of symptoms is approximately 60 years, with a range from the fifth to the ninth decade. However, patients may start to develop the initial symptoms of IBM in their late 30s.
IBM affects males more often than females, unlike the other idiopathic inflammatory myopathies, which preferentially affect females [13]. (See "Clinical manifestations of dermatomyositis and polymyositis in adults", section on 'Epidemiology'.)
CLINICAL FEATURES
Symptoms and signs
●Time course – Patients with sporadic inclusion body myositis (IBM) present with the insidious onset of weakness. The average duration of symptoms before diagnosis is approximately five years [10,14].
●Proximal muscle weakness – Like patients with polymyositis, dermatomyositis, antisynthetase syndrome, and necrotizing autoimmune myopathy, patients with IBM commonly present with slowly progressive proximal leg weakness, with difficulty getting up out of a chair or frequent falls. Patients may also describe increasing difficulty climbing stairs, carrying heavy groceries, or picking up their children due to proximal muscle involvement.
In our experience, it is not unusual for patients to initially assume their symptoms are due to aging.
●Distal muscle weakness – Unlike dermatomyositis, antisynthetase syndrome, and necrotizing autoimmune myopathy, distal muscle involvement can occur in IBM.
•Upper extremity – The earliest examination finding of IBM is weakness of distal finger flexion, which may be subtle. Weakness of the distal finger flexor muscles occurs in approximately 95 percent of patients [15,16]. Patients may also initially present with weakness of grip strength, leading to difficulty opening jars.
On examination, patients with distal finger flexor weakness may have "scooping" or scalloping of the medial forearm flexor compartment (picture 1).
•Lower extremity – The characteristic lower extremity physical examination finding is knee extensor weakness, which eventually occurs in all patients with IBM. However, this is a later finding and generally occurs after the development of finger flexor weakness.
On examination, patients with knee extensor weakness often have quadriceps atrophy.
Patients with IBM may also present with weakness of the ankle dorsiflexors or tibialis anterior, leading to a foot drop or an inability to walk on the heels, respectively [15-17]. (See "Foot drop: Etiology, diagnosis, and treatment", section on 'Physical examination'.)
●Other neurologic features
•Dysphagia – Dysphagia due to involvement of the cricopharyngeal muscle occurs in approximately half of patients. Rarely, patients with IBM may present with dysphagia, which may precede extremity weakness by up to seven years [14,18-20].
•Facial muscles – Facial muscles (especially muscles controlling eye closure) may be involved, but the oculomotor muscles are spared.
•Muscle atrophy – Muscle atrophy progresses in parallel with the duration and severity of weakness. Muscle atrophy associated with IBM is greater than would be expected for the same degree of weakness in polymyositis.
•Deep tendon reflexes – Deep tendon reflexes also decrease in parallel with the decline in strength.
•Myalgias – Myalgias may accompany the weakness but are usually mild [21].
Laboratory abnormalities
●Creatine kinase – Early in the disease course, creatine kinase (CK) is often mildly elevated, usually less than 10 times normal [22]. CK elevations greater than 15 times the upper limit of normal should prompt evaluation for alternate diagnoses.
Normalization of serum CK without an improvement in weakness is a hallmark of IBM. Later in the disease course, CK levels normalize as muscles atrophy. Glucocorticoids can also lead to a reduction in CK level without improvement in muscle strength.
●Acute phase reactants – Acute phase reactants (eg, erythrocyte sedimentation rate [ESR], C-reactive protein [CRP]) are usually normal.
APPROACH TO INITIAL EVALUATION
In whom to suspect — The diagnosis of sporadic inclusion body myositis (IBM) should be considered in patients who meet the following criteria:
●Older than 35 years
●Muscle weakness developing over 6 to 12 months (or longer)
●Bilateral (but often asymmetric) muscle involvement
A normal creatine kinase (CK) does not exclude a possible diagnosis of IBM. (See 'Laboratory abnormalities' above.)
However, patients with rapid-onset or unilateral weakness and patients younger than 35 years are unlikely to have IBM, and they should be evaluated for alternative causes of weakness. (See 'Differential diagnosis' below and "Approach to the patient with muscle disorder (myopathy)".)
An approach to the diagnosis of IBM is outlined below and in the algorithm (algorithm 1).
Establish history of weakness — The medical history serves to identify clinical manifestations of IBM as well as identify other possible causes of muscle weakness.
Most patients with an idiopathic inflammatory myopathy, such as IBM, will note difficulty performing specific activities.
We perform a thorough history with particular attention to the following symptoms:
●Insidious onset of falls due to weakness of knee extensors and/or foot drop, typically in the absence of sensory complaints
●Difficulty standing from the floor or a low chair
●Loss of dexterity of hands or grip strength due to finger flexor weakness
●Dysphagia
Patients with generalized fatigue, reduced endurance, joint dysfunction, pain, and other conditions may complain of weakness. A careful history will help distinguish true muscle weakness form other conditions. (See "Approach to the patient with muscle disorder (myopathy)", section on 'Distinguishing true weakness from other conditions'.)
Determine distribution of weakness — The physical examination helps determine the distribution of muscle weakness and atrophy. Patients with IBM will typically have both distal and proximal muscle weakness. However, other muscle groups may also be involved.
●Quadriceps and forearm flexor weakness – Knee extensor (ie, quadriceps) and forearm flexor (ie, wrist and finger flexor) muscle weakness and wasting are clinical hallmarks of IBM and differentiate IBM from the other idiopathic inflammatory myopathies [23].
•Asymmetric finger and wrist flexor weakness greater than deltoid weakness – To detect subtle weakness of distal finger flexion (typically the earliest examination finding), the clinician should isolate and specifically examine flexion at the distal interphalangeal (DIP) joint. Distal finger flexion may be tested by asking the patient to mimic hanging on to a wall with just the fingertips.
•Knee extensor weakness greater than hip flexor weakness – Knee extensor and hip flexor weakness is not subtle. With severe knee extensor weakness, patients may walk with the leg hyperextended (genu recurvatum).
●Proximal muscle weakness – Patients with IBM will also have symmetric, proximal muscle weakness, most notably affecting hip flexion.
Patients with hip flexion weakness are typically unable to stand from a chair without pushing off with their arms.
However, hip flexion weakness (and proximal muscle weakness, in general) is also seen with the other idiopathic inflammatory myopathies (eg, polymyositis).
●Other muscle involvement – Other muscles that are commonly affected include:
•Orbicularis oculi (leading to weakness with eye closure)
•Triceps (leading to weakness with arm extension)
•Tibialis anterior (leading to foot drop) [24].
Identify risk factors for alternate diagnoses
●Medications and illicit drugs – A variety of prescription and illicit drugs may cause myopathy, myositis, neuropathy, or other disorders that cause muscle weakness.
Drugs associated with drug-induced myopathy include:
•Glucocorticoids
•HMG-CoA reductase inhibitors
•Alcohol
•Cocaine
Drug-induced myopathies are discussed in detail elsewhere. (See 'Acute weakness' below and "Drug-induced myopathies".)
●Associated diseases – Some diagnoses are known to be associated with IBM.
•Autoimmune diseases – Up to 15 percent of patients with IBM patients have an underlying autoimmune disorder (eg, systemic lupus erythematosus, Sjögren’s disease, systemic sclerosis (scleroderma), Hashimoto thyroiditis, variable immunoglobulin deficiency, sarcoidosis, and idiopathic thrombocytopenia purpura) [25,26].
•Other diseases – There is also association of IBM with some lymphoproliferative disorders (eg, T-cell large granular lymphocytic leukemia) and chronic viral infections (eg, human immunodeficiency virus [HIV], hepatitis C) [27-29].
IBM is not associated with myocarditis, interstitial lung disease, or an increased risk of malignancy. The presence of these diagnoses should prompt an evaluation for dermatomyositis and polymyositis (both of which are associated with these findings). (See "Diagnosis and differential diagnosis of dermatomyositis and polymyositis in adults", section on 'Subsequent evaluation based on clinical presentation'.)
●Family history – Some hereditary myopathies (eg, limb-girdle muscular dystrophy [LGMD], hereditary IBM) have proximal and distal muscle weakness and/or muscle biopsy features that may be misdiagnosed as IBM. (See 'Subacute weakness' below.)
Laboratory testing to identify alternative diagnoses — There is no definitive diagnostic laboratory test for IBM. The purpose of laboratory testing is primarily to exclude an alternative diagnosis associated with weakness.
●Creatine kinase – A normal serum CK does not preclude a diagnosis of IBM. However, most patients will have mild to moderate elevations of plasma muscle enzyme levels (ie, serum CK less than 10-fold higher than normal).
Patients with CK levels greater than 15-fold higher than normal should be evaluated for other causes.
●Other laboratory tests – The following laboratory tests may help identify alternate causes of weakness:
•Potassium
•Calcium
•Magnesium
•Phosphate
•Thyroid-stimulating hormone
•Alkaline phosphatase
Abnormal values may suggest a potential cause of muscle weakness other than IBM. For example, an elevated alkaline phosphatase level should prompt evaluation for Paget disease, which can be seen in hereditary IBM. (See "Clinical manifestations and diagnosis of Paget disease of bone".)
Similarly, hypokalemia, hypocalcemia, hypomagnesemia, hypophosphatemia, and hypothyroidism are also associated with muscle weakness. If present, these abnormalities should be corrected prior to trying to evaluate a patient for IBM (see relevant topics for discussion).
The use of anti-NT5C1A antibody testing to establish the diagnosis of IBM in patients who present with finger flexor weakness is discussed below. (See 'In patients with finger flexor weakness' below.)
Electromyography to identify irritable myopathy — In patients with typical history and examination features suggestive of IBM, an electromyogram (EMG) may not be necessary for diagnosis (and is not used in diagnostic criteria). However, an EMG is often useful at excluding alternative diagnoses and can help suggest the diagnosis based on its association with both an irritable myopathy and neuropathic changes on EMG:
●Irritable myopathy – An irritable myopathy demonstrates increased insertional activity, fibrillations, positive waves, and early recruitment of short-duration, small-amplitude polyphasic motor unit action potentials (MUAPs).
An irritable myopathy is characteristic of all idiopathic inflammatory myopathies, including IBM. A patient without an irritable myopathy is unlikely to have IBM and should be evaluated for other diagnoses. (See 'Differential diagnosis' below.)
●Neuropathic changes – Neuropathic changes are characterized by a mix of short- and long-duration, small- and large-amplitude polyphasic MUAPs.
An EMG that demonstrates evidence of both an irritable myopathy and neuropathic changes is highly suggestive of a diagnosis of IBM in a patient with a typical presentation who also has finger flexor weakness [21,22,30,31]. However, patients with other presentations should undergo muscle biopsy to confirm the diagnosis. (See 'In patients with finger flexor weakness' below and 'Muscle biopsy' below.)
Neuropathic changes in the absence of an irritable myopathy are not consistent with an idiopathic inflammatory myopathy. Patients with isolated neuropathic changes or fasciculations should be evaluated for alternate diagnoses [32]. (See 'Differential diagnosis' below.)
The use of EMG or nerve conduction study is discussed in detail elsewhere. (See "Overview of electromyography" and "Overview of nerve conduction studies".)
Magnetic resonance imaging in patients with equivocal findings — We perform magnetic resonance imaging (MRI) in patients who present with findings that are not clearly consistent with an idiopathic inflammatory myopathy such as IBM (eg, equivocal weakness, mildly elevated muscle enzymes).
MRI of the thigh in patients with IBM typically shows edema, atrophy, and fatty replacement of the anterior compartment with relative sparing of the medial and posterior compartments [33-35].
MRI has the advantage of sampling wide areas of muscle, as opposed to muscle biopsies, which are subject to sampling error. A completely normal MRI makes the diagnosis of an idiopathic inflammatory myopathy (including IBM) much less likely. However, MRI cannot, by itself, distinguish IBM from other idiopathic inflammatory myopathies.
ESTABLISHING THE DIAGNOSIS —
Most patients will require a biopsy to establish a diagnosis of sporadic inclusion body myositis (IBM). However, in some patients presenting with finger flexion weakness (in addition to characteristic clinical findings), a diagnosis may be established in the absence of a biopsy. (See 'In patients with finger flexor weakness' below.)
Our approach to establishing a diagnosis of IBM uses elements of several diagnostic criteria, which have been developed based on expert opinion and consensus groups [36-39]. While these criteria are essential for research and for clinical trials, their use for diagnosis is limited by a lack of sensitivity (table 2) [15].
In patients with finger flexor weakness — Finger flexor weakness is a feature of IBM that is not generally associated with the other idiopathic inflammatory myopathies.
In a patient with a typical presentation (eg, over the age of 35, presenting with slowly progressive, bilateral muscle weakness) who also presents with finger flexor weakness, we take the following approach to establishing the diagnosis:
●Electromyography – We start by obtaining an EMG. In a patient with a typical presentation including finger flexor weakness, the presence of an irritable myopathy and neuropathic changes is suggestive of IBM.
●Anti-NT5C1A antibody testing – In a patient with a typical presentation including finger flexor weakness, the presence of antibodies against cytoplasmic 5’-nucleotidase 1A (NT5C1A) is suggestive of a diagnosis of IBM.
Anti-NT5C1A antibodies may help establish the diagnosis of IBM in a patient with a typical clinical presentation that includes finger flexor weakness.
However, anti-NT5C1A antibodies may be present at low levels in patients with other idiopathic inflammatory myopathies and cannot be used in isolation to establish a diagnosis of IBM.
•Presence in other muscle diseases – In a study of 593 patients presenting for evaluation of an inflammatory myopathy, anti-NT5C1A antibodies were predominantly found in patients with IBM (64 percent). However, these antibodies were also found in patients with dermatomyositis (21 percent), the antisynthetase syndrome (12 percent), immune mediated necrotizing myopathy (12 percent), undifferentiated myositis (24 percent), and noninflammatory muscle disease (6 percent) [40].
•Presence in other autoimmune diseases – Anti-NT5C1A antibodies are also detected in approximately 20 percent of patients with systemic lupus erythematosus and Sjögren's disease who lack muscle involvement [41,42].
●Quadriceps weakness – In a patient with a typical presentation including finger flexor weakness, knee extension (quadriceps) weakness greater than hip flexion weakness is highly suggestive of a diagnosis of IBM. (See 'Determine distribution of weakness' above.)
Because strength examinations can be subjective, EMG or anti-NT5C1A antibody tests can be helpful to establish a diagnosis of IBM.
Additionally, in patients who are younger than 50 who meet these criteria, we still obtain a muscle biopsy to confirm the diagnosis rather than relying on strength testing alone. We prefer this approach given the lower prevalence of IBM among younger patients.
The European Neuromuscular Centre (ENMC) criteria include knee extension weakness greater than hip flexion weakness as part of their definition of "clinically defined" IBM (table 2) [15]. However, this finding has only 47 percent sensitivity for IBM [43]. The low sensitivity of this finding is caused by two factors:
•Knee extension weakness can occur late in the disease course.
•The absence of knee extension weakness, or knee extension weakness that is not greater than hip flexion weakness, does not exclude a diagnosis of IBM.
If these tests fail to confirm a diagnosis of IBM, we proceed to muscle biopsy. The absence of anti-NT5C1A antibodies and/or quadriceps weakness is not adequate to rule out IBM. (See 'Muscle biopsy' below.)
In patients without finger flexor weakness — In patients presenting without finger flexor weakness, we perform both an EMG and biopsy of an affected muscle group.
●Electromyogram – If an irritable myopathy is not detected on EMG, other diagnoses should be considered. (See 'Differential diagnosis' below and 'Electromyography to identify irritable myopathy' above.)
●Muscle biopsy – In patients who have an irritable myopathy on EMG, a muscle biopsy is still required to distinguish IBM from other idiopathic inflammatory myopathies (eg, dermatomyositis, antisynthetase syndrome, immune-mediated necrotizing myopathy), which may have overlapping clinical presentations. (See 'Muscle biopsy' below.)
●Other tests – Knee extension (quadriceps) weakness greater than hip flexion weakness is suggestive of a diagnosis of IBM. However, in the absence of finger flexion weakness (and in patients younger than 50 years), we still obtain a muscle biopsy to confirm the diagnosis.
Additionally, in the absence of finger flexion weakness, anti-NT5C1A antibodies and EMG findings are not adequate to confirm a diagnosis of IBM.
Muscle biopsy — For most patients, a muscle biopsy will be required to establish a diagnosis of IBM.
Considerations for muscle biopsy — We biopsy muscles that are only moderately weak (4 or 4+ on the Medical Research Council [MRC] scale). Very weak muscles likely have extensive atrophy and fibrofatty replacement. Biopsies of muscles with extensive atrophy are less likely to be diagnostic. For this reason, MRI, ultrasound, and EMG may be useful in guiding the selection of a muscle for biopsy.
Immunohistologic and electron-microscopic evaluation of the tissue require freshly frozen muscle and special fixatives. A discussion of the technical aspects of muscle biopsy is discussed in detail elsewhere. (See "Diagnosis and differential diagnosis of dermatomyositis and polymyositis in adults", section on 'Muscle biopsy'.)
The best diagnostic information can be expected from a laboratory that frequently processes muscle biopsy specimens and whose staff is provided with detailed clinical information. This may be facilitated by a discussion between the clinician requesting the biopsy, the surgeon, and pathologist prior to the procedure or by referral of the patient to a center with the necessary laboratory facilities.
Muscle biopsy findings — To consider a diagnosis of IBM, a muscle biopsy should demonstrate, at minimum, histologic characteristics of an inflammatory myopathy. The absence of histologic evidence of an inflammatory myopathy makes a diagnosis of IBM less likely.
To establish a diagnosis of IBM, the muscle biopsy should also have one or more features that are more specific for IBM.
●Indicative of an inflammatory myopathy – IBM is unlikely if a muscle biopsy does not demonstrate histologic evidence of an inflammatory myopathy [30]. Evidence of an inflammatory myopathy includes the following:
•Endomysial inflammatory cell infiltrate – All inflammatory myopathies (including IBM) are characterized by an infiltrate of CD8+ T lymphocytes and macrophages in the endomysium (ie, the connective tissue surrounding individual muscle fibers) (picture 2 and picture 3 and picture 4). Major histocompatibility complex I (MHC-I) is upregulated on immunostaining. These findings do not differentiate IBM from polymyositis [44].
•Myofiber degeneration, regeneration, and necrosis – Variable muscle fiber size (representing myofiber degeneration and regeneration) with scattered atrophic fibers is common to all forms of inflammatory myopathy, including IBM (picture 5).
●More specific for IBM – The following findings are suggestive of IBM in the presence of histologic evidence of an inflammatory myopathy.
•Sarcoplasmic "rimmed" vacuoles – Sarcoplasmic "rimmed" vacuoles are red-rimmed with modified trichrome stain and blue-rimmed with hematoxylin and eosin stain (H&E). Rimmed vacuoles are considered the pathologic hallmark of IBM. However, as many as 20 to 30 percent of IBM muscle biopsies lack this finding.
•Tubulofilaments – On electron microscopy, inclusions consisting of 15 to 18 nm tubulofilaments may be detected in the sarcoplasm and myonuclei. These tubulofilaments are not present in other inflammatory myopathies.
•Amyloid deposits – Amyloid deposits in vacuolated fibers identified by Congo red staining of frozen sections are occasionally observed in IBM muscle biopsies [45].
•TDP-43- and p62-positive protein aggregates – These protein aggregates are much more common than amyloid deposits in IBM muscle biopsies. The presence of these protein aggregates in muscle fibers increases diagnostic certainty for IBM [6,46,47].
•Cytochrome C oxidase-negative fibers – Cytochrome C oxidase-negative fibers are suggestive of mitochondrial abnormalities, which are characteristic of IBM. However, cytochrome C oxidase-negative fibers are also associated with mitochondrial myopathies and some neurodegenerative disorders [7].
Muscle biopsy interpretation
●Findings diagnostic or highly suggestive of IBM – The presence of sarcoplasmic "rimmed" vacuoles is diagnostic of IBM in a patient who meets the following criteria [36]:
•Characteristic clinical presentation for IBM (with or without finger flexion weakness)
•Histologic evidence of an inflammatory myopathy (see 'Muscle biopsy findings' above)
The combination of cyclooxygenase (COX)-negative fibers with TDP-43- and p62-positive protein aggregates is a less common finding, but it is also highly suggestive of IBM [48].
●Indeterminate findings – The specificity of other combinations of findings described as "more specific for IBM" has not been well established. While each of these findings is suggestive of IBM, they can also be found in patients with other muscle diseases. Therefore, these findings must be interpreted in the context of the patient's clinical presentation. Furthermore, the absence of these more specific findings does not exclude a diagnosis of IBM.
●Exclusionary findings – At minimum, patients with IBM should have at least endomysial inflammation on muscle biopsy. In a large cohort of 335 IBM patients, fewer than 5 percent lack endomysial inflammation on biopsy [49]. However, patients with many years of symptoms may have only evidence of muscle atrophy. A completely normal muscle biopsy makes a diagnosis of IBM much less likely.
Approach to the equivocal muscle biopsy — In cases where the biopsy does not clearly establish a diagnosis of IBM, we suggest that the patient undergo additional tests for other diagnoses that can have biopsy features that overlap with IBM. Such tests include the following:
●Myositis-specific antibody testing. (See "Overview of and approach to the idiopathic inflammatory myopathies", section on 'Myositis-specific autoantibodies'.)
●Genetic testing for muscular dystrophy, particularly dystrophic disorders such as limb-girdle and facioscapulohumeral muscular dystrophies, which can have a prominent endomysial inflammatory cell infiltrate on muscle biopsy. Oculopharyngeal muscle dystrophy can have intranuclear inclusions that can are reminiscent of the "rimmed" vacuoles seen in IBM. (See "Limb-girdle muscular dystrophy", section on 'Genetic testing' and "Facioscapulohumeral muscular dystrophy", section on 'Genetic confirmation' and "Oculopharyngeal, distal, and congenital muscular dystrophies", section on 'Genetics'.)
If these tests do not yield a diagnosis, alternatives include:
●Repeat biopsy – Biopsies are subject to sampling variability, and histologic features absent in early disease may appear on subsequent biopsies.
●Empiric therapy – Patients who are treated empirically for an inflammatory myopathy should be reassessed clinically after three to six months. Patients who fail to respond to empiric therapy in this scenario are likely to have IBM.
The initial therapy of an inflammatory myopathy and assessment of treatment response are discussed elsewhere. (See "Initial treatment of dermatomyositis and polymyositis in adults".)
●Serial clinical re-evaluation – To look for evidence of evolving features that may support a diagnosis of IBM. In most cases, patients will eventually develop finger flexor weakness, which helps confirms a diagnosis of IBM.
Choosing between these alternatives should be driven by shared decision-making between the clinician and patient. Empiric therapy may be a reasonable option for patients with high levels of inflammation on biopsy; however, because of sampling error, a single biopsy may not reveal the true extent of inflammation present in the muscles [15,36-39,43].
DIFFERENTIAL DIAGNOSIS —
Many patients may complain of weakness in the absence of objective evidence of weakness or muscle breakdown. The evaluation of such patients is discussed in detail elsewhere. (See "Approach to the patient with muscle disorder (myopathy)", section on 'Distinguishing true weakness from other conditions'.)
For patients who present with objective evidence of muscle weakness, the approach to the differential diagnosis depends on whether the patient presents with acute (ie, developing over less than one month) or subacute weakness, as discussed below.
Acute weakness — Patients who complain of weakness developing over less than 1 month are unlikely to have sporadic inclusion body myositis (IBM), and should be evaluated for alternate diagnoses, such as drug-induced myopathies and rhabdomyolysis.
●Drug-induced myopathies – Like IBM, patients with a drug-induced myopathy may present with muscle weakness, myalgias, and fatigue associated with creatine kinase (CK) elevation.
Additionally, drugs that affect lysosomal function (eg, colchicine, chloroquine, hydroxychloroquine) may also produce vacuolar changes similar to the rimmed vacuoles associated with IBM.
However, drug-induced myopathies typically develop over several weeks, rather than months. Other than the time course, drug-induced myopathies may be clinically indistinguishable from IBM. Differentiating drug-induced myopathies from IBM generally requires a muscle biopsy.
Drug-induced myopathies are discussed in detail elsewhere. (See 'Identify risk factors for alternate diagnoses' above and "Drug-induced myopathies".)
●Rhabdomyolysis – Like IBM, patients with rhabdomyolysis may present with muscle weakness and myalgias associated with a CK elevation.
However, rhabdomyolysis generally presents acutely and is associated with muscle pain and swelling following an inciting event. Additionally, myoglobinuria is a feature of rhabdomyolysis, but not IBM.
The evaluation and diagnosis of rhabdomyolysis is discussed in detail elsewhere. (See "Rhabdomyolysis: Clinical manifestations and diagnosis", section on 'Evaluation and diagnosis'.)
Subacute weakness — While it is beyond the scope of this review to provide a comprehensive list of all possible alternative causes of subacute weakness (table 3), we present several disorders that can resemble IBM here. Broadly, these diagnoses may be categorized into diseases associated with muscle inflammation versus diseases where muscle inflammation is generally absent.
●Without inflammation on muscle biopsy – These diagnoses can be distinguished from IBM by the absence of inflammation on muscle biopsy, in addition to other clinical features:
•Hereditary inclusion body myopathy – The term hereditary inclusion body myopathy (hIBM) is used to describe a group of rare muscle disorders that may be autosomal dominant or recessive. Other names for hIBM include familial distal myopathy and distal myopathy with "rimmed vacuole formation.
Like IBM, patients with hIBM present with slowly progressive muscle weakness, with proximal or distal muscle group involvement, and muscle biopsies show a vacuolar myopathy with inclusions [36,50-52].
However, the onset of weakness is usually in early adulthood, and the quadriceps muscles are relatively spared compared with patients with IBM. The family history may also help distinguish these rare heritable disorders from IBM.
Additionally, muscle biopsies in patients with hIBM typically do not demonstrate evidence of inflammation. However, hIBM type 2 (also known as GNE myopathy) may be associated with endomysial inflammation (see below for discussion).
•Multisystem proteinopathy – Multisystem proteinopathy (MSP) is a variant of hIBM associated with Paget disease of bone and frontotemporal dementia or neurodegeneration of other neuronal subtypes [53].
MSP is most commonly caused by an autosomal dominant mutation in the valosin-containing protein (VCP) gene [54,55]. However, mutations in other genes, including hnRNPA1, hnRNPA2B1, and Matrin-3, can also result in MSP.
Additionally, mutations in the SQSTM1/p62 gene have been associated with amyotrophic lateral sclerosis (ALS), MSP, and IBM [56]. (See 'Pathogenesis' above.)
MSP can be distinguished from other forms of hereditary and spontaneous IBM both clinically and by the absence of inflammation on muscle biopsy.
•Amyotrophic lateral sclerosis – ALS is a progressive neurodegenerative disorder associated with weakness and both upper motor neuron (eg, hyperreflexia, spasticity) and lower motor neuron (eg, muscle atrophy, fasciculations) manifestations.
Some patients with IBM present with predominantly distal or asymmetric muscle involvement that mimics ALS.
ALS can be distinguished from IBM by muscle biopsy and electromyography, which will demonstrate primarily neurogenic features [57].
The evaluation of ALS is discussed in detail elsewhere. (See "Diagnosis of amyotrophic lateral sclerosis and other forms of motor neuron disease".)
●With inflammation on muscle biopsy – Endomysial inflammation may be the only histologic finding in muscle biopsies from patients with IBM. However, endomysial inflammation is also a characteristic of other diagnoses, including polymyositis, granulomatous myositis, and some muscular dystrophies.
In patients with only endomysial inflammation on muscle biopsy, differentiating IBM from other diagnoses may rely on the clinical presentation. In some cases, additional testing (eg, myositis-specific antibodies, genetic testing, repeat muscle biopsy) may be required. (See 'Muscle biopsy interpretation' above.)
•GNE myopathy – GNE myopathy (also known as hIBM type 2) is the most common form of hIBM (discussed above).
GNE myopathy is caused by an autosomal recessive mutation in the gene for UDP-N-acetylglucosamine 2-epimerase/N-acetylmannosamine kinase (GNE).
Unlike other forms of hIBM, GNE myopathy has been reported to be associated with endomysial inflammation on muscle biopsy [52,58,59].
Like other forms of hIBM, the diagnosis can often be distinguished from IBM by the patient's presentation and family history. In particular, patients with GNE myopathy typically start to develop symptoms between 20 and 40 years of age, whereas IBM typically presents in older patients [60].
•Polymyositis – Many patients initially diagnosed as having "treatment-resistant" polymyositis actually have IBM. This is because IBM and polymyositis can share both clinical and histologic features, and true polymyositis is becoming increasingly rare [61].
Clinically, both IBM and polymyositis present with proximal muscle weakness. However, the weakness of PM develops over several months, while IBM is more insidious. Also, only IBM is associated with both finger flexor weakness and quadriceps weakness. Other differences are discussed in the table (table 1)
When IBM cannot be distinguished from polymyositis, we suggest a six-month trial of immunosuppression with serial evaluations to assess for evolving features and treatment response. (See 'Approach to the equivocal muscle biopsy' above.)
The diagnosis and treatment of polymyositis is described in detail elsewhere. (See "Diagnosis and differential diagnosis of dermatomyositis and polymyositis in adults", section on 'Differential diagnosis' and "Initial treatment of dermatomyositis and polymyositis in adults", section on 'Initial therapy'.)
•Muscular dystrophy – Other inherited myopathies that present with weakness and variable levels of rimmed vacuoles and/or inflammation on muscle biopsy include oculopharyngeal muscular dystrophy (OPMD), facioscapulohumeral dystrophy (FSHD), limb-girdle muscular dystrophy (LGMD), distal muscular dystrophy, and myofibrillar myopathies.
The correct diagnosis can usually be established based on the earlier age of onset, the pattern of weakness, and/or family history.
The diagnosis of a muscular dystrophy is confirmed by genetic testing.
These diagnoses are discussed in detail elsewhere. (See "Oculopharyngeal, distal, and congenital muscular dystrophies" and "Limb-girdle muscular dystrophy" and "Facioscapulohumeral muscular dystrophy".)
SOCIETY GUIDELINE LINKS —
Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Inclusion body myositis".)
INFORMATION FOR PATIENTS —
UpToDate offers two types of patient education materials, "The Basics" and "Beyond the Basics." The Basics patient education pieces are written in plain language, at the 5th to 6th grade reading level, and they answer the four or five key questions a patient might have about a given condition. These articles are best for patients who want a general overview and who prefer short, easy-to-read materials. Beyond the Basics patient education pieces are longer, more sophisticated, and more detailed. These articles are written at the 10th to 12th grade reading level and are best for patients who want in-depth information and are comfortable with some medical jargon.
Here are the patient education articles that are relevant to this topic. We encourage you to print or e-mail these topics to your patients. (You can also locate patient education articles on a variety of subjects by searching on "patient info" and the keyword(s) of interest.)
●Beyond the Basics topics (see "Patient education: Polymyositis, dermatomyositis, and other forms of idiopathic inflammatory myopathy (Beyond the Basics)")
SUMMARY AND RECOMMENDATIONS
●Epidemiology – Sporadic inclusion body myositis (IBM) is the most common acquired idiopathic inflammatory myopathy in individuals older than 50 years. IBM affects males more than females, and the mean age of onset of symptoms is 60 years. However, patients may start to develop the initial symptoms of IBM in their late 30s. (See 'Epidemiology' above.)
●Clinical presentation – IBM is associated with an insidious onset of both proximal and distal muscle weakness. Distal finger flexor and knee extension weakness is more characteristic of IBM than the other inflammatory myopathies. Individuals may also present with dysphagia or facial muscle weakness. (See 'Symptoms and signs' above.)
●Laboratory findings – IBM initially presents with mild creatine kinase (CK) elevation (ie, less than 10 times normal), which resolves with time. Acute phase reactants are normal. (See 'Laboratory abnormalities' above.)
●Evaluation – IBM should be considered in patients older than 35 years who present with bilateral muscle weakness developing over 6 to 12 months (or longer), even in the absence of CK elevation.
The evaluation focuses on identifying objective evidence of proximal and distal (ie, knee extensor and finger flexor) muscle weakness and identifying potential alternative explanations for muscle weakness. (See 'Approach to initial evaluation' above.)
●Diagnosis – IBM is a clinicopathologic diagnosis. For most patients, a muscle biopsy is required to establish a diagnosis of IBM. (See 'Establishing the diagnosis' above.)
However, for patients presenting with characteristic clinical findings (including finger flexion weakness), the presence of any of the following is adequate to establish a diagnosis:
•Electromyography demonstrating both irritable myopathy and neuropathic changes
•Presence of antibodies against cytoplasmic 5’-nucleotidase 1A (NT5C1A)
•Knee extension weakness greater than hip flexor weakness (in patients >50 years old)
●Muscle biopsy – To consider a diagnosis of IBM, the muscle biopsy should demonstrate evidence of an inflammatory myopathy (ie, mononuclear inflammatory cells invading non-necrotic muscle fibers and/or myofiber degeneration, regeneration, and necrosis).
In a patient with a characteristic clinical presentation and histologic evidence of an inflammatory myopathy, the finding of sarcoplasmic "rimmed" vacuoles on muscle biopsy is diagnostic of IBM.
Other findings suggestive of a diagnosis of IBM include tubulofilaments, amyloid deposits, TDP-43- and p62-positive protein aggregates, and cytochrome C oxidase-negative fibers.
However, a nondiagnostic muscle biopsy does not exclude the possibility of IBM. In such patients, additional evaluations may be required to establish (or exclude) the diagnosis. (See 'Approach to the equivocal muscle biopsy' above.)
●Differential diagnosis – Patients who complain of weakness developing over less than one month are unlikely to have IBM and should be evaluated for alternate diagnoses such as drug-induced myopathies and rhabdomyolysis. Polymyositis and some muscular dystrophies are associated with subacute weakness and endomysial inflammation on biopsy. Other diagnoses may be excluded by the absence of inflammation on muscle biopsy. (See 'Differential diagnosis' above.)
ACKNOWLEDGMENT —
The UpToDate editorial staff acknowledges Marc L Miller, MD, who contributed to an earlier version of this topic review.
