Clinical manifestations and diagnosis of immune-mediated necrotizing myopathy

INTRODUCTION — Immune-mediated necrotizing myopathy (IMNM), also referred to as necrotizing autoimmune myopathy (NAM), is a distinct subgroup of the idiopathic inflammatory myopathies (IIMs). While its clinical presentation may be similar to traditional IIMs such as dermatomyositis (DM) or polymyositis (PM), IMNM has specific histopathologic findings and distinct clinical correlates.

The clinical manifestations, diagnosis, and management of IMNM will be discussed in this topic. Separate topic reviews on related content include the following:

●(See "Pathogenesis of inflammatory myopathies".)

●(See "Overview of and approach to the idiopathic inflammatory myopathies".)

●(See "Clinical manifestations of dermatomyositis and polymyositis in adults".)

●(See "Diagnosis and differential diagnosis of dermatomyositis and polymyositis in adults".)

●(See "Initial treatment of dermatomyositis and polymyositis in adults".)

●(See "Treatment of recurrent and resistant dermatomyositis and polymyositis in adults".)

●(See "Malignancy in dermatomyositis and polymyositis".)

●(See "Cutaneous dermatomyositis in adults: Overview and initial management".)

●(See "Management of refractory cutaneous dermatomyositis in adults".)

●(See "Clinical manifestations and diagnosis of inclusion body myositis".)

●(See "Management of inclusion body myositis".)

NOMENCLATURE AND CLASSIFICATION CRITERIA — Immune-mediated necrotizing myopathy (IMNM) had been erroneously labeled "polymyositis" (PM) for decades, despite early descriptions of a distinct myopathy featuring necrosis with scant or absent inflammatory infiltrates indicative of IMNM [1-3]. It was eventually recognized as a distinct entity from PM in 1989, but it was not recognized as a subcategory within the idiopathic inflammatory myopathies (IIMs) in the years that followed [4-6]. Despite the relative paucity of a traditional lymphocytic inflammatory infiltrate observed on muscle biopsy, an immunologic/autoimmune process is indirectly implied by the disease's frequent association with prototypic autoantibodies (notably anti-signal recognition particle [anti-SRP] and anti-3-hydroxy-3-methylglutaryl coenzyme A reductase [anti-HMGCR]), in addition to its presence in association with other connective tissue diseases and its general response to immunosuppressive agents. The term "immune-mediated" is more often used for this group of necrotizing myopathies rather than "autoimmune," although many experts would likely believe them to be interchangeable terms, and thus the terms IMNM and necrotizing autoimmune myopathy (NAM) are also used interchangeably.

The understanding of IMNM with the combination of muscle necrosis and regeneration as a discrete ontological category within the IIMs was initially described in 2004 [4]. The European Alliance of Associations for Rheumatology/American College of Rheumatology (EULAR/ACR) classification criteria for adult and juvenile IIMs and their major subgroups use a classification tree developed to distinguish subgroups of patients classified with IIM according to specific clinical and histologic criteria [7]. However, this schema did not include enough patients with IMNM to allow for distinct subcategorization; thus, within this classification schema, it remains a provisional classification, still grouped with PM [8].

EPIDEMIOLOGY — Immune-mediated necrotizing myopathy (IMNM) has been described in children as well as adults. In the adult population, the age range is from young adulthood to older adult with a median age of approximately 40 to 50 years [9,10] depending on the geographic cohort studied. As in most autoimmune diseases, a female predominance across worldwide geographic cohorts has been recognized. In general, females are affected approximately three times more often than males [9-13].

Prevalence — True estimates of the frequency of IMNM are variable, owing to the evolving recognition and reclassification of this entity, thereby distinguishing it from polymyositis (PM). From the perspective of subspecialists including rheumatologists and neurologists, PM now accounts for only 5 percent of idiopathic inflammatory myopathy (IIM) patients [14]. In addition to the reclassification of many PM cases as IMNM, there is also a growing recognition that there is an increasing incidence of IMNM over time, with a notable increase beginning in the late 2000s, which may be associated with increasing statin use in the general population worldwide, although this is not conclusively linked [15]. Among residents of Olmsted County, Minnesota, the prevalence of IMNM in 2010 was 1.85 per 100,000 people at least 50 years old [16]. In the same population, the prevalence of IMNM was found to be one-tenth of that of inclusion body myositis.

Subtypes — Three major subtypes of IMNM based on autoantibodies include anti-signal recognition particle (anti-SRP) autoantibody IMNM, anti-3-hydroxy-3-methylglutaryl coenzyme A reductase (anti-HMGCR) autoantibody IMNM, and seronegative IMNM [17]. IMNM may also be associated with certain myositis-associated autoantibodies or with cancer.

●Anti-SRP-positive IMNM – Anti-SRP-positive IMNM is estimated to comprise between 22 and 39 percent of all IMNM cases [12,18]. The SRP is a cytoplasmic ribonucleoprotein (RNP) made up of six polypeptide chains, of 72, 68, 54, 19, 14, and 9 kDa, and one molecule of 7SL ribonucleic acid (RNA), a protein complex initiating protein translocation [19,20]. Some studies have reported a predilection for the anti-SRP-positive disease to start in the autumn, suggesting a possible infectious etiology as the initial immunologic trigger [21]; however, other studies have not identified a clear seasonal onset [6]. The clinical phenotype associated with anti-SRP autoantibodies is discussed below. (See 'Clinical significance' below.)

●Anti-HMGCR-positive IMNM – Several studies support the association of anti-HMGCR autoantibodies with IMNM with and without statin use [9,11,12,22-27]. While HMGCR is the known pharmacologic target of lipid-lowering drugs commonly known as "statins," the autoantibodies that target HMGCR can be found in both statin-exposed and statin-naïve individuals. The percentage of statin-exposed patients among anti-HMGCR autoantibody patients varies widely across numerous global geographic cohorts [28]. In addition, the ratio of statin-exposed patients among anti-HMGCR antibody-positive patients has declined from approximately 63 to 73 percent to somewhere from 15 to 44 percent from the early 2010s to the early 2020s [11,22,29,30]. The clinical phenotype associated with anti-HMGCR autoantibodies is discussed below. (See 'Clinical significance' below.)

Anti-HMGCR IMNM is rare among statin users, with an estimated incidence of approximately 2 to 3 of every 100,000 statin-treated patients [31]. Most patients with statin exposure, including those with self-limited statin intolerance, do not develop anti-HMGCR IMNM [32].

The duration of statin use prior to the onset of weakness varies widely from approximately 6 months to 3 years [15,24,33-35]. As an example, in a cohort from the Czech Republic, the average duration of statin use prior to the onset of symptoms was 32 months (range 2 months to 6.5 years) [15]. Another cohort from the United States noted a median duration of statin therapy of 38 months before the onset of muscle symptoms [34]. In addition, up to one in three patients do not appear to develop the symptoms of myopathy until after the statin has been discontinued [24,36].

Atorvastatin is the statin most commonly associated with anti-HMGCR-positive IMNM, even when controlling for its prescribing popularity for lipid reduction [15,34,37,38]. No clear dose-dependent effect has been described, and even low doses of statins (such as 10 mg of simvastatin) have been found to trigger IMNM [33]. Type 2 diabetes mellitus may be associated with an increased susceptibility to anti-HMGCR-positive IMNM, particularly in the setting of atorvastatin [39].

●Seronegative IMNM – Seronegative IMNM makes up approximately 25 to 40 percent of IMNM cohorts worldwide [17,40]. It is generally recognized as a patient with elevated creatine kinase (CK), proximal muscle weakness, absent myositis-specific and myositis-associated autoantibodies, exclusion of toxins or other possible etiologies, and a muscle biopsy consistent with IMNM. It is unknown if such patients are truly seronegative or rather possess autoantibodies that have not yet been discovered or described.

●Other associated autoantibodies – IMNM may be associated with other autoantibodies such as anti-Ro52, anti-PM-Scl, antimitochondrial (AMA), anti-U1-RNP, or an antisynthetase antibody [40], or it may be unaccompanied by any known autoantibodies. (See 'Clinical significance' below and "Overview of and approach to the idiopathic inflammatory myopathies", section on 'Myositis-specific autoantibodies' and "Overview of and approach to the idiopathic inflammatory myopathies", section on 'Myositis-associated autoantibodies'.)

Of note, AMAs have been reported in concert with IIMs and are associated with, but not exclusive for, IMNM histologically [17,41,42]. AMA-positive IMNM is a rare disease entity, which can occur independently or along with other autoimmune conditions, most notably primary biliary cholangitis [42-45]. (See "Overview of and approach to the idiopathic inflammatory myopathies", section on 'Myositis-associated autoantibodies' and "Clinical manifestations, diagnosis, and prognosis of primary biliary cholangitis", section on 'Associated autoimmune conditions'.)

●Cancer-associated IMNM – The association of cancer and IMNM is discussed further below. (See 'Possible association with malignancy' below.)

CLINICAL MANIFESTATIONS

Muscle-related symptoms — Phenotypically, while there is variation in onset, severity, and chronicity among the immune-mediated necrotizing myopathy (IMNM) subsets, most patients generally present with subacute proximal limb muscle weakness and a high serum creatine kinase (CK) level in the absence of characteristic skin findings for dermatomyositis (DM) or overt connective tissue disease overlap features such as Raynaud phenomenon or an inflammatory arthritis.

●Proximal muscle weakness – The clinical hallmarks of IMNM include subacute proximal weakness and a high serum CK level, which are often very severe, with some bedbound within weeks after onset of symptoms [10,46,47]. Weakness is symmetric, often involving the shoulder and hip girdle limb muscles; with disease progression, muscle weakness may also affect the truncal muscles. Neck flexor weakness is more common than neck extensor involvement; however, on occasion, neck extensor weakness may be so severe that it results in a dropped head syndrome [48]. Some patients have slowly evolving disease, which can mimic muscular dystrophy, especially in younger patients [12]. (See "Limb-girdle muscular dystrophy" and "Duchenne and Becker muscular dystrophy: Clinical features and diagnosis".)

Differentiating features between the subsets include early weakness, prominent oropharyngeal dysphagia, and irreversible muscle damage in patients with anti-signal recognition particle (anti-SRP) autoantibodies, whereas in patients with anti-3-hydroxy-3-methylglutaryl coenzyme A reductase (anti-HMGCR) autoantibodies and statin exposure, weakness may be of later onset. In comparison with anti-SRP myopathy, statin-associated HMGCR autoantibody-positive IMNM, in particular, more often affects people over age 50. (See 'Clinical significance' below.)

●Pharyngeal muscle involvement – Pharyngeal muscles may be affected, causing nasal speech, voice hoarseness, nasal regurgitation, dysphagia, and, in the most critical cases, aspiration pneumonia. Dysphagia is common in both anti-HMGCR IMNM [9,24,49] and anti-SRP IMNM [12], and clinicians should suspect statin-associated IMNM in any patient who develops weakness with concomitant dysphagia while taking statins. While weakness may also be observed with self-limited, nonimmune-mediated statin myopathy, dysphagia is not a typical clinical feature noted. (See "Statin muscle-related adverse events", section on 'Other muscular toxicity'.)

●Facial muscle weakness – Although ocular muscles are typically spared, facial muscle weakness may be present but is usually mild [48] and is more common in anti-SRP IMNM patients [50]. As an example, patients may not be able to fully bury their eyelashes when attempting to tightly closer their eyes, or they may not be able to whistle.

●Myalgias – While diffuse myalgias may be present, severe muscle pain, especially in the absence of weakness, is typically not a predominant symptom [48]. Myalgias in the absence of weakness have rarely been observed [11], although, in the author's personal experience, some patients who are treated and regain strength do complain of persistent pain of unclear etiology. Rarely, elevated CK can be observed in the absence of weakness [11], particularly at the onset of the illness, which may suggest that regeneration is outpacing degeneration at that time.

●Dyspnea – Dyspnea has also been described in large cohort studies, and this may be related to diaphragmatic muscle involvement more often than frank interstitial lung disease (ILD) [50]. IMNM has been reported as a clinical phenotypic mimic of muscular dystrophy, especially with a subacute onset in an early age group with a persistent CK elevation in the absence of initial symptoms [11,51].

●Other connective tissue disease features – Arthritis, arthralgia, and Raynaud phenomenon are reported but are less commonly associated with IMNM compared with other idiopathic inflammatory myopathies (IIMs) [52].

Additional information regarding phenotypic variations with respect to different autoantibody profiles is presented below. (See 'Clinical significance' below.)

Other organ involvement

●Interstitial lung disease – While anti-HMGCR-positive IMNM is generally not associated with ILD, limited data suggest that there may be an increased risk in patients who are anti-SRP autoantibody positive. One observational study reported ILD in approximately one-quarter of their anti-SRP-positive IMNM patients [6]. Some cases were clinically quiescent; however, imaging features of ILD were noted.

●Cardiac involvement – There have been conflicting reports of whether anti-SRP-positive IMNM is associated with cardiac features; however, it appears that cardiac involvement is present in at least a minority of cases [6,21,53]. In one of the larger observational studies, the type and frequency of abnormalities on the electrocardiogram (ECG) of patients with anti-SRP antibodies were similar to those found in a large series of patients with polymyositis (PM) and DM, including prior evidence of myocardial infarctions and conduction blocks [53]. Myocarditis or pericarditis was not a typical feature. By contrast, anti-HMGCR IMNM has largely been unassociated with myocarditis, cardiomyopathy, or other cardiac manifestations with the exception of rare reports of a small number of atrial tachyarrhythmias [11] and systolic heart failure [54]. While rare, cardiac involvement is becoming increasingly recognized as a manifestation of IIMs, thus lowering the threshold for cardiac evaluation in this population [54].

●Cutaneous features – In general, IMNM is not classically associated with skin findings. However, there are scattered reports of DM-like rashes among patients who are positive for the anti-HMGCR antibody, including heliotrope rash and nonpruritic, erythematous macular rashes that were present around typical areas where DM rashes are found such as the neck, upper chest, and the extensor surfaces of the interphalangeal and metacarpophalangeal joints [55]. The author has noted nonspecific facial rashes as well as typical heliotrope and Gottron papules in some patients with the anti-HMGCR antibody. Similar rashes are not typical of anti-SRP-positive IMNM.

Possible association with malignancy — An increased rate of malignancy has been well established among patients with IIMs, especially with DM (see "Malignancy in dermatomyositis and polymyositis"). Malignancy can be found in concert with IMNM, but the true association with IMNM is less clear based on limited observational data with variable findings [2,56]. However, there may be a higher frequency of malignancy among patients who are anti-HMGCR positive [57,58].

DIAGNOSTIC APPROACH

When to suspect IMNM — The diagnosis of immune-mediated necrotizing myopathy (IMNM) should be considered in a patient who presents with subacute proximal muscle weakness and a high serum creatine kinase (CK) level, in the absence of characteristic skin findings for dermatomyositis (DM) or overt connective tissue disease overlap features such as Raynaud phenomenon or inflammatory arthritis. In addition, a history of statin use (that may be either recent or longstanding) may further raise the index of suspicion, especially if muscle weakness persists despite statin discontinuation.

Evaluation

History and physical examination — The initial clinical history should include attention to the following:

●Onset – Patients should be asked about the seasonal onset and duration of symptoms, associated viral prodromal symptoms, and location and severity of weakness.

●Functional limitations – They should be questioned about their ability to carry out various activities of daily living that they commonly perform such as climbing stairs, getting up from a chair, getting out of a vehicle, bathing, washing their hair, and carrying heavy groceries or other objects.

●Features of muscle symptoms – The severity and distribution of myalgia should be assessed. True muscle weakness should be distinguished from complaints of fatigue or shortness of breath with exertion and from limitation due to concomitant disease. (See "Approach to the patient with muscle weakness".)

●Extramuscular involvement – Patients should be asked about a history of dysphagia, which may suggest esophageal involvement, cough or shortness of breath, or palpitations that may occur due to cardiopulmonary involvement.

●Malignancy symptoms – Patients should also be queried regarding whether they have been experiencing any symptoms suggesting malignancy and what screening and other testing have been performed.

●Statin or other medication exposures – The use of statins, or the timing and use of any other drugs that may cause myopathy, should be determined.

●Concomitant autoimmune diseases – Patients should be asked about other autoimmune diseases. The co-occurrence of other nonrheumatologic autoimmune diseases such as thyroiditis and type 1 diabetes has been described in IMNM [11].

Careful examination of the muscles, joints, and skin is necessary. A general physical examination should be performed, with attention to the heart and lungs, which should be auscultated for evidence of palpitations or interstitial disease. A thorough joint examination should be carried out to detect signs of a concomitant inflammatory arthritis. A comprehensive neurologic and neuromuscular examination is critical to determine the severity and distribution of weakness and of muscle tenderness as well as the presence or absence of other abnormal neurologic findings.

Laboratory testing

Routine laboratory testing — We obtain the following routine laboratory tests:

●Creatine kinase – CK is the most sensitive muscle enzyme and should be tested and followed in all patients with suspected IMNM. The level of serum CK can vary widely but is often well above 1000 international units/L. However, in contrast to DM or polymyositis (PM), it is our experience that patients with IMNM may have relatively preserved muscle strength even when the CK is well above 1000 international units/L.

●Complete blood count with differential.

●Comprehensive metabolic panel.

●Erythrocyte sedimentation rate (ESR) and/or C-reactive protein (CRP) – The CRP and/or ESR are often normal or only mildly elevated, even in patients with active muscle disease [59]. Markedly elevated CRP and/or ESR in a patient with an inflammatory myopathy should raise the suspicion of a coexisting infection, underlying malignancy, or a connective tissue disease associated with interstitial lung disease (ILD) [59].

●Thyroid-stimulating hormone (TSH).

●Tests for hepatitis B and C viruses and human immunodeficiency virus (HIV) – These tests are performed to help exclude virus-induced myositis, but also because knowledge of the patient's hepatitis history may be needed to assess for safety of certain medications, which can reactivate previous quiescent disease.

Autoantibody testing — The approach to autoantibody testing is included in an algorithm (algorithm 1).

●Myositis-specific autoantibodies (often available as a panel) including anti-Jo-1 – Anti-signal recognition particle (anti-SRP) and anti-3-hydroxy-3-methylglutaryl coenzyme A reductase (anti-HMGCR) are the prototypic myositis-specific autoantibodies associated with IMNM and can be helpful in narrowing down the differential diagnosis.

Serologic tests for myositis-specific autoantibodies are often available as a panel to eliminate the need to order the numerous autoantibody tests individually. However, the results are often not available for several weeks, and treatment decisions may be required before the specific serologic profile is known. In some clinical settings, specific autoantibody tests can be ordered individually and may be available more quickly. HMGCR enzyme-linked immunosorbent assays (ELISAs) are usually not included in myositis-specific panels and thus testing must be ordered separately; results are often readily available within days.

There is still wide variability with no standardization across laboratories that defines antibody positivity. However, when assayed in a reputable laboratory in the correct clinical context, autoantibodies targeting SRP and HMGCR are highly specific for IMNM. Additional information regarding other myositis-specific autoantibodies can be found separately. (See "Overview of and approach to the idiopathic inflammatory myopathies", section on 'Myositis-specific autoantibodies'.)

●Myositis-associated autoantibodies in selected patients – Specific myositis-associated autoantibodies may be considered in selected patients, particularly those who may have overlap features of other systemic rheumatic diseases. (See "Overview of and approach to the idiopathic inflammatory myopathies", section on 'Myositis-associated autoantibodies'.)

We specifically check antimitochondrial autoantibodies (AMA) in patients who are negative for myositis-specific autoantibodies to risk stratify patients with possible IMNM for cardiac involvement.

Clinical significance — The clinical phenotypes of several subtypes of IMNM are described below:

●Anti-SRP positive – Anti-SRP testing can be complicated by false negatives on some platforms and false positives on others; thus, testing with immunoprecipitation in labs like Oklahoma Medical Research Foundation may be warranted when there is a high clinical suspicion of the disease and all other antibodies associated with IMNM have been ruled out.

Severe limb muscle weakness, neck weakness, dysphagia, respiratory insufficiency, and muscle atrophy have been more frequently described in patients with anti-SRP antibodies than in those with anti-HMGCR antibodies [12,18]. In some instances, a presymptomatic period of elevated CK in the absence of objective muscle weakness may predate the symptomatic phase of the disease [60].

●Anti-HMGCR positive – Assays for anti-HMGCR autoantibodies have a reported specificity and sensitivity of approximately 94 to 100 percent and 95 to 99 percent, respectively [28]. While anti-HMGCR autoantibodies are highly specific, the co-occurrence of anti-HMGCR autoantibodies with other myositis-specific autoantibodies, particularly with anti-SRP, as well as other disease (eg, inclusion body myositis, systemic sclerosis, and myasthenia gravis) has been reported.

A wide range of phenotypes of anti-HMGCR myopathy have been described. It most commonly occurs in patients with adult-onset disease and is characterized by subacute, progressive, and proximal muscle weakness and highly elevated CK levels (eg, 1000 to 20,000 international units/L range). Many patients have a history of an exposure to statins, and their symptoms often do not resolve with discontinuation of the offending medication. Fatigue and myalgia are reported in 20 to 60 percent of patients, and truncal weakness has been highlighted as a clinical feature. Dysphagia is reported in 15 to 30 percent of patients [61]. An association of disease severity with autoantibody titer has been described.

●Relevant myositis-associated autoantibodies

•Anti-U1-RNP autoantibodies – Patients with anti-U1-ribonucleoprotein (RNP) myositis characteristically present with proximal weakness and necrotizing muscle biopsies. Unlike the other IMNM subtypes, arthritis, dermatitis, and ILD are common extramuscular clinical features in this group [62]. Pericarditis and glomerulonephritis were also noted in patients with anti-U1-RNP-positive myositis, which is suggestive of a lupus overlap and atypical of the other IMNMs. (See "Overview of and approach to the idiopathic inflammatory myopathies", section on 'Myositis-associated autoantibodies'.)

•Antimitochondrial autoantibodies – Cardiac involvement with arrhythmia and heart failure, often necessitating an implantable cardioverter-defibrillator (ICD), is an important clinical hallmark in patients with AMA-positive IMNM. The cardiac manifestations often precede muscle symptoms, increasing the risk of misdiagnosis [42,43].

●Seronegative – Patients with seronegative IMNM may have clinical features suggestive of a distinct subgroup with features that differ from those with seropositive IMNM. Data from a retrospective review of 64 patients reported that when compared with seropositive IMNM, seronegative IMNM was characterized by female prevalence (1:3), common occurrence of associated connective tissue disorders (22 versus 9 percent), and higher rates of extramuscular disease activity (50 versus 16 percent) [40].

Testing for myopathy — The approach to testing for IMNM is the same as that for other idiopathic inflammatory myopathies (IIMs) and is discussed in detail separately (see "Diagnosis and differential diagnosis of dermatomyositis and polymyositis in adults", section on 'Testing for myopathy'). Testing includes electromyography (EMG), magnetic resonance imaging (MRI) of the bilateral thighs, and muscle biopsy in selected patients. Additional information regarding such testing specific to IMNM is discussed below.

Electromyography — EMG testing is generally indistinguishable from other IIMs (see "Diagnosis and differential diagnosis of dermatomyositis and polymyositis in adults", section on 'Electromyography'). Findings include a myopathic process with muscle membrane irritability. EMG testing in IMNM may reveal a "noisier" examination at rest (in comparison with DM) with florid abnormal spontaneous activity observed in the form of positive sharp waves, fibrillation potentials, complex repetitive discharges, and even pseudomyotonic discharges, in addition to the myopathic units [48]. The myotonic/pseudomyotonic discharges can be seen in IMNM and are not indicative of clinical myotonia. They are more common in statin-associated anti-HMGCR IMNM [50].

Skeletal muscle imaging — MRI is the most common imaging performed for IMNM. Noncontrast studies with T1 and short tau inversion recovery (STIR) fat-suppressed sequences of bilateral thighs or whole-body MRI (if available) is preferred. Patients with active IMNM have generalized muscle edema (seen as hyperintensities on STIR sequences that are associated with ongoing inflammation or myofiber necrosis (image 1)), atrophy, and fatty infiltration (seen on T1-weighted images and that can begin early after onset of the disease), with minimal fascial edema (in contrast to patients with DM) [18]. Additionally, patients with IMNM may have less involvement of the anterior compartment of the thigh compared with patients with inclusion body myositis. Selective involvement of paraspinal and gluteal muscles in the hip and posterior and medial compartments of the thigh has been reported in anti-HMGCR-positive IMNM. STIR signal increase can be patchy and asymmetric [28].

The muscle MRIs of patients with anti-SRP myopathy demonstrate more fatty replacement and atrophy than those with anti-HMGCR myopathy, suggesting that anti-SRP IMNM is often a more severe form of myopathy. One caveat is that, owing to a more severe nature of the disease in younger (and usually statin-naïve) patients, some younger patients with HMGCR IMNM and no statin exposure can also demonstrate severe fatty replacement [18].

Muscle biopsy in selected patients — There is wide disparity among experts in terms of whether muscle biopsy should be routinely obtained in cases of suspected IMNM [7].

Many physicians may now forgo a muscle biopsy with a convincing clinical phenotype and a known myositis-specific autoantibody, especially anti-HMGCR autoantibodies. However, patients without a known myositis-specific autoantibody and those for whom autoantibody testing was unavailable or the results of such testing were equivocal, as well as patients who have atypical or nonspecific clinical symptoms, require a muscle biopsy to help confirm the diagnosis.

The histopathologic hallmarks of IMNM include necrosis of muscle fibers and/or regeneration with a paucity or absence of lymphocytic infiltrates [63,64]. Although major histocompatibility complex (MHC) class I upregulation, myofiber degeneration, necrosis, and macrophage infiltration can be seen in IMNM (features similar to DM), perivascular inflammation and perifascicular atrophy are not seen [17]. This is in contrast to other IIMs such as DM, PM, and inclusion body myositis, as those entities are usually associated with an inflammatory infiltrate on muscle biopsy [50]. The histologic pattern of MHC class I expression and complement deposition may help in distinguishing IMNM from dystrophies [12]. The amount of myofiber complement deposition may be associated with clinical severity [65].

Establishing the diagnosis — The diagnosis of IMNM is typically established histologically and serologically, as the clinical phenotypic elements may be ostensibly indistinguishable from other IIMs.

In patients presenting with subacute proximal muscle weakness in the setting of elevated muscle enzymes, the diagnosis of IMNM is based upon the results of testing that include the confirmation of myopathy with either EMG or MRI of the thighs, followed by additional serologic testing to help distinguish IMNM from other IIMs. The presence of anti-SRP and/or anti-HMGCR autoantibodies are the prototypic myositis-specific autoantibodies associated with IMNM. The presence of anti-HMGCR autoantibodies in the setting of a convincing clinical history, including statin use, may obviate the need for muscle biopsy. However, in many cases, a muscle biopsy is required to confirm a histopathologic diagnosis.

Differential diagnosis — IMNM should be differentiated from other conditions that cause muscle weakness and elevated muscle enzymes. The differential diagnosis is the same as for that of the IIMs (eg, DM, PM, and antisynthetase syndrome), which is discussed in detail separately (see "Diagnosis and differential diagnosis of dermatomyositis and polymyositis in adults", section on 'Testing for myopathy'). Additional considerations include statin-associated rhabdomyolysis, motor neuron disease, myasthenia gravis, and the muscular dystrophies, as well as other systemic rheumatic diseases and a variety of inherited, metabolic, drug-induced (especially stain-related), endocrine, and infectious myopathies.

POSTDIAGNOSTIC CONSIDERATIONS — Additional studies are important in the evaluation of a given patient once the diagnosis of immune-mediated necrotizing myopathy (IMNM) has been established. Our approach to additional testing include the following considerations:

●Assessment for pulmonary involvement – Pulmonary function tests with assessment for restrictive lung disease (with ascertainment of total lung capacity as well as the assessment of the diffusion capacity) are warranted at baseline in all patients with anti-signal recognition particle (anti-SRP)-positive IMNM. However, at a minimum, any patient with shortness of breath or unexplained fatigue or cough should also have PFT with a follow-up high-resolution computed tomography (CT) scan of the chest if abnormal.

●Screening for malignancy – Because of the possible association with malignancy, we also recommend age- and sex-appropriate screening for adult patients (eg, mammograph and colonoscopy).

●Avoidance of statins in selected patients – While statins are not necessarily contraindicated in most forms of idiopathic inflammatory myopathy (IIM), they are absolutely contraindicated in patients with known anti-3-hydroxy-3-methylglutaryl coenzyme A reductase (anti-HMGCR)-positive IMNM, whether previously associated with statin exposure or not. PCSK9 inhibitors appear to be safe cholesterol-lowering agents, however, in this patient population [66].

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: Dermatomyositis and polymyositis".)

SUMMARY AND RECOMMENDATIONS

●Nomenclature and classification criteria – Immune-mediated necrotizing myopathy (IMNM), also referred to as necrotizing autoimmune myopathy (NAM), is a distinct subgroup of the idiopathic inflammatory myopathies (IIMs). While its clinical presentation may be similar to traditional IIMs such as dermatomyositis (DM) or polymyositis (PM), IMNM has specific histopathologic findings and distinct clinical correlates. For decades prior, IMNM had been erroneously labeled as PM. (See 'Nomenclature and classification criteria' above.)

●Epidemiology – IMNM has been described in children as well as adults. In the adult population, the age range is from young adulthood to older adult with a median age of approximately 40 to 50 years. In general, females are affected approximately three times more often than men. (See 'Epidemiology' above.)

●Subtypes – Three major subtypes of IMNM based on autoantibodies include anti-signal recognition particle (anti-SRP) autoantibody IMNM, anti-3-hydroxy-3-methylglutaryl coenzyme A reductase (anti-HMGCR) autoantibody IMNM, and seronegative IMNM. IMNM may also be associated with certain myositis-associated autoantibodies or may be associated with cancer. (See 'Subtypes' above.)

●Clinical manifestations – Most patients present with subacute proximal limb muscle weakness and a high serum creatine kinase (CK) level in the absence of characteristic skin findings for DM or overt connective tissue disease overlap features such as Raynaud phenomenon or an inflammatory arthritis. (See 'Muscle-related symptoms' above.)

●Evaluation

•History and physical exam – The initial evaluation begins with a careful history, physical examination, and a laboratory evaluation with particular attention to:

-Onset and duration of symptoms

-Severity and distribution of muscle symptoms

-Functional limitations

-Extramuscular involvement

-Malignancy symptoms

-Statin or other medication exposures

-Concomitant autoimmune disease

•Laboratory testing – CK is the most sensitive muscle enzyme and should be tested and followed in all patients with suspected IMNM. Additional laboratory testing should include a complete blood count, comprehensive metabolic panel, erythrocyte sedimentation rate (ESR) and/or a C-reactive protein (CRP), thyroid-stimulating hormone (TSH), and tests for hepatitis B and C viruses and HIV. (See 'Routine laboratory testing' above.)

Autoantibody testing should include myositis-specific autoantibodies, which are often available as a panel. Anti-SRP and anti-HMGCR autoantibodies are the prototypic myositis-specific autoantibodies associated with IMNM.

●Testing for myopathy – The approach to additional testing for myopathy includes electromyography (EMG), MRI of the bilateral thighs, and muscle biopsy. (See 'Testing for myopathy' above.)

●Establishing the diagnosis – In patients presenting with subacute proximal muscle weakness in the setting of elevated muscle enzymes, the diagnosis of IMNM is based upon the results of testing that include the confirmation of myopathy with either EMG or MRI of the thighs, followed by additional serologic testing to help distinguish IMNM for other IIMs. The presence of anti-HMGCR autoantibodies in the setting of a convincing clinical history, including statin use, may obviate the need for a muscle biopsy. However, in many cases, a muscle biopsy is required to confirm a histopathologic diagnosis. (See 'Establishing the diagnosis' above.)

●Postdiagnostic considerations – Postdiagnostic considerations include an assessment for pulmonary involvement (eg, interstitial lung disease [ILD]) and age- and sex-appropriate malignancy screening. Statin use is contraindicated in patients with known anti-HMGCR-positive IMNM. (See 'Postdiagnostic considerations' above.)