Immune-mediated necrotizing myopathy

Immune-mediated necrotizing myopathy (IMNM), also known as necrotizing autoimmune myopathy (NAM), is an emerging subtype of autoimmune myopathies (myositis). Unlike other forms, such as dermatomyositis, antisynthetase syndrome, or inclusion body myositis, muscle biopsy in most IMNM patients shows minimal or no inflammatory cell infiltration.

The disease can occur at any age but is more common in adults. It typically presents with subacute, rapidly progressive, symmetric weakness involving the shoulders, upper arms, hips, and thighs. Unlike dermatomyositis, patients usually do not have skin rashes, although rare cases with skin involvement have been reported. Serum creatine kinase (CK) levels are typically greater than 1,000 U/L, with most cases reaching at least 5,000 U/L. Approximately 60–70% of patients have autoantibodies against either HMG-CoA reductase (HMGCR) or the signal recognition particle (SRP). HMGCR antibody-positive disease is often associated with prior statin exposure, with onset typically at or after age 60 and symptoms appearing on average 2-3 years after starting statins. Statin-naïve cases also occur, particularly in pediatric patients, some of whom may have a slower progression resembling muscular dystrophy. Those with SRP autoantibodies usually present at a younger age, often in their mid-30s.

Immune mediated necrotizing myopathy symptoms

The following are common symptoms of IMNM:

  • Weakness in the hip and upper leg muscles, especially hamstrings, leading to frequent falls, difficulty walking, and trouble climbing stairs or standing from a seated position
  • Weakness in the shoulder and upper arm muscles, leading to difficulty combing or washing hair, trouble reaching for objects on high shelves, and needing help putting on or taking off a shirt or jacket.
  • Muscle pain or discomfort
  • Shortness of breath due to cardiac or respiratory muscle involvement.

Muscle pathology

Muscle biopsy in IMNM typically shows numerous necrotic and regenerating muscle fibers with no or minimal infiltration by immune cells. In approximately 20% of patients, there may be significant inflammation resembling polymyositis. The necrotizing pathology itself is nonspecific, as it can also be seen in other active myopathies, both acquired and hereditary. Abnormal accumulation of fibrous tissue surrounding muscle fibers is not a characteristic feature of IMNM, but may be present in chronic cases, mimicking muscular dystrophies. Unusual immune system activity (MHC class I and membrane attack complex) can be seen in IMNM, however, similar changes can also happen in some inherited muscle conditions, so these findings aren’t specific enough to confirm a diagnosis on their own.

The presence of necrotizing pathology in a patient with a subacute, rapidly progressive weakness should prompt testing for HMGCR and SRP antibodies. Diagnosis of IMNM without autoantibodies (seronegative) can be more challenging. A certain pattern seen under the microscope—called p62 staining—can help doctors identify IMNM. This pattern shows up in both people who test positive and those who test negative for specific antibodies, so it can be especially useful for diagnosing cases where blood tests don’t give clear answers.

Statins and muscle complications

Statins are commonly prescribed medications for lowering high cholesterol. Examples include atorvastatin, simvastatin, rosuvastatin, pravastatin, lovastatin, and fluvastatin. Muscle discomfort is a well-recognized side effect of these medications, reported in up to 25% of patients. This is considered a form of statin-associated muscle toxicity (toxic myopathy), as symptoms typically resolve after the medication is discontinued. In these cases, patients usually have no objective weakness, or only very mild weakness, and serum CK levels are normal or only mildly elevated.

In contrast, fewer than 1% of statin users develop profound weakness with CK levels greater than 1,000 U/L, and symptoms persist despite stopping the medication. This presentation represents an autoimmune attack on muscle, HMGCR antibody-positive IMNM, which is triggered by statin exposure. Toxic myopathy from statins typically appears within weeks to months of starting therapy, whereas statin-associated IMNM often develops after 2-3 years of exposure. Persistent weakness and CK ≥1,000 U/L in a statin-treated patient should prompt testing for HMGCR antibodies. In addition to discontinuing statin therapy, patients with statin-associated IMNM generally do not respond to corticosteroid therapy alone and require immunosuppressive treatment with at least two medications.

Diagnosis of IMNM

In patients with subacute, progressive, symmetric proximal weakness, serum CK ≥ 1,000 U/L, and electromyography showing myopathic changes, typically with fibrillation potentials and/or myotonic discharges, HMGCR and SRP antibodies should be tested in addition to a standard myositis antibody panel, regardless of statin exposure. It is important to note that while SRP antibodies are often included in commercial myositis antibody panels, HMGCR antibodies are generally not and must be specifically requested. In patients with the above clinical features and positive HMGCR or SRP antibodies, muscle biopsy may not be necessary. If antibodies are negative, muscle biopsy should be performed.

IMNM and malignancy

Seronegative IMNM is associated with an increased risk of malignancy and is termed paraneoplastic necrotizing myopathy when cancer is present. This form should be distinguished from cancer-associated dermatomyositis, which has characteristic skin features and different pathological findings. The risk of cancer in HMGCR antibody-positive IMNM remains controversial, with some studies reporting a mildly increased risk and others finding no significant association. In contrast, SRP antibody-positive IMNM is generally not linked to an increased risk of cancer.

Revised August 2025 by Teerin Liewluck, MD – neurology professor at Mayo Clinic, Rochester, MN, and TMA special volunteer.

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