HomeHealth articlesimmune-mediated necrotizing myopathyWhat Is Immune-Mediated Necrotizing Myopathy?

Immune - Mediated Necrotizing Myopathy - Causes, Clinical Features, Diagnosis, and Treatment

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Immune-mediated necrotizing myopathy is an autoimmune neuromuscular disorder that affects day-to-day activities. Read this article to know more.

Medically reviewed by

Dr. Abhishek Juneja

Published At January 25, 2023
Reviewed AtAugust 10, 2023

Introduction

Immune-mediated necrotizing myopathy (IMNM) or autoimmune necrotizing myopathy (NAM) is a neuromuscular disorder that causes significant necrosis (cell death) within the muscle tissues resulting in severe muscle weakness and fatigue. It is a very recent discovery, described first in 2004. There are no infectious etiologies for this kind of myopathy; it is a sickness of a confounded immune system. Hence, this is differentiated from other variants of myopathies and is found to be autoimmune.

Who Is Susceptible to Immune-Mediated Necrotizing Myopathy?

IMNM is a rare disorder with a prevalence of around 9 to 14 cases per 100,000 individuals, with just about 10 percent of the patients carrying anti-SRP or anti-HMGCR antibodies. Patients with anti-SRP antibodies tend to be younger (mean age of 40) than anti-HMGCR presenting patients (mean age of 55). The condition shows gender predilection towards the female sex. There are two types of anti-HMGCR patients; medical statins trigger one, and another one is not. Two of the most significant epidemiological findings state that the Asian patient population had similar mean age in both variants, with the anti-SRP being the most prevalent, and that the gender bias is reduced in statin-exposed anti-HMGCR patients. Other myositis variants show a clear predominance over the black populations compared to Caucasians and Asians; in IMNM, that dominance is absent. An approximation states that the total number of patients is 6300 in the United States.

What Causes Immune-Mediated Necrotizing Myopathy?

The exact cause of IMNM remains a mystery, but a close association has been noted between the type of MHC (major histocompatibility complex) allele and anti-HMGCR myopathy. Adults show an association with a particular allele (DRB1*11:01) that increases the probability of disease occurrence in whites by 24.5 percent, blacks by 56.5 percent, and Asians by 3.7 percent. Another allele (DRB1*07:01) has been associated with disease appearance in children. In the Japanese population, anti-SRP myopathy is associated with an HLA (human leukocyte antigen) allele (DRB1*08:03).

For individuals with anti-HMGCR myopathy, research has proved that statin exposure is the prime causality candidate, with an 89 percent probability of developing IMNM above 50 years. Alternative statin supplements are present in various Asian delicacies, including oyster mushrooms, red yeast rice, and pu-erh tea. Hence, a possible weaker association of statin and prevalence in the Asian population after statin exposure (14 to 38 percent) may point towards an alternative method of alimentary exposure to medical statins. Alternatively, the US has a prevalence of 38 to 63 percent and Europeans with 44 percent.

Statins are known to increase the expression of HMGCR (an enzyme related to cholesterol synthesis), which results in aberrant protein processing and subsequent neoantigen synthesis. Additionally, statin binding might make HMGCR-protein more immunogenic and is presented by the MHC molecules to the immune system.

Viral infections may trigger IMNM in a seasonal pattern, as viral seasons show the development of anti-SRP myopathy. Studies show that viral exposure may generate an immune response against the proteins through molecular mimicry as certain subunits of HMGCR and SRP proteins are homologous (similar) to varicella-zoster virus and the human papillomavirus-type 58, respectively. IMNM patients show myofiber necrosis which has been hypothesized to have resulted from antibody-dependent complement-mediated cell death. Recent studies claim that the two antibodies (anti-HMGCR and anti-SRP) show direct toxic effects and induce muscle atrophy, increases ROS (reactive oxygen species) and pro-inflammatory cytokines (TNF and IL-6), and impair myoblast fusion by rescuing interleukin (4 and 13) production. The hypothesis has not been proven in animals.

What Are the Clinical Features of Immune-Mediated Necrotizing Myopathy?

The clinical features of IMNM are:

  • Symmetric proximal muscle weakness.

  • Interstitial lung disease.

  • Polymyositis (severe muscle weakness and inflammation).

  • Weakness in breathing, swallowing, and distal muscles.

  • Muscle pain (myalgia).

  • Inability to climb stairs or board vehicles.

  • Difficulty in doing activities that require raising the arm (hair maintenance, managing upper shelves).

  • Dysphagia (difficulty in swallowing).

  • Severe and debilitating fatigue.

  • Weight loss.

  • Difficulty in recovering from a fall.

How to Diagnose Immune-Mediated Necrotizing Myopathy?

Diagnosis of IMNM is based on analyzing various aspects of the disease, out of which the autoantibody assays are the cornerstone of recognition. The physician recognizes the clinical features and further tests are ordered.

1) Autoantibodies:

Autoantibody testing differentiates between anti-HMGCR and anti-SRP myopathies. The screening assays are done with ELISA (enzyme-linked immunosorbent assay), line blot assay, dot blot assay, and ALBIA (addressable laser bead immunoassay). Confirmatory tests are done using the patient’s serum to immunoprecipitate radio-labeled proteins by IVTT (in vitro transcription and translation) or RNA (ribonucleic acid) immunoprecipitation, where autoantibodies recognize a complex within the antibodies.

2) Muscle Strength:

Since the loss of muscle strength is one of the most important chief complaints and a major criterion for provisional diagnosis, it is essential to document the degree of muscle weakness. The MRC scale (medical research council) is widely accepted to measure muscle strength, where grade 5 signifies normal strength and grade 0 signifies no muscle contraction. Although limited in its capability to measure muscle strength accurately, the MRC scale in studies reflects an average score of grade 4, which corresponds to moderate weakness with the active movement against gravity and resistance.

3) Creatinine Kinase (CK):

CK is a muscle enzyme (normal range is between 5 to 25 IU/L) and is greatly elevated in IMNM patients. The median value peaks at 4700 IU/L (international units per litre) and 700 IU/L in anti-HMGCR and anti-SRP myopathy, respectively.

4) Muscle Magnetic Resonance Imaging:

MRI can be implemented to show the distribution and severity of active and chronic muscle damage. However, it cannot differentiate between the two subtypes of IMNM. Fatty replacement minimal fascial edema after muscle loss is a common MRI finding, along with generalized muscle edema and muscle atrophy.

5) Muscle Biopsy:

Muscle biopsy followed by staining and microscopic examination shows features like:

  • The deposition of a membrane attack complex on the membrane of the non-necrotic muscle cell (more evident in anti-HMGCR type).

  • Perifascicular atrophy.

  • Non-necrotic fibers.

  • Affected region invaded by lymphocytic infiltration (CD4+, CD8+, and CD123+ plasmacytoid dendritic cells).

Other tests like EMG (electromyogram), barium swallow, pulmonary function tests, chest X-ray, HRCT (high-resolution computed tomography), and other cancer screening tests (colonoscopy, mammogram, PAP smear, and PET scan) can be performed.

How to Treat Immune-Mediated Necrotizing Myopathy?

The treatment of IMNM can be categorized into induction and maintenance stages. The primary aim of IMNM is to induce remission and maintain that state.

  • Induction Stage: Oral steroid therapy like Methotrexate, Rituximab, and IVIG (intravenous immune globulin). Methotrexate can be supplemented with Azathioprine, Mycophenolate, Tacrolimus, Cyclosporine, or Cyclophosphamide.

  • Maintenance Stage: Tapered doses of oral corticosteroid therapy, Methotrexate (for two years), Rituximab (for two years), and IVIG.

What Is the Prognosis of Immune-Mediated Necrotizing Myopathy?

The prognosis is worse in patients with persistent muscle weakness despite immunosuppressive therapy. Around half of all patients report significant weakness after two years of therapy.

Conclusion:

Immune-mediated necrotizing myopathy is a rare autoimmune disorder with possible cancer association within three years of diagnosis, known as cancer-associated myositis. Children with IMNM may present with dystrophy-like features, which may be reversed with immunosuppressive therapy. Trials and studies are required to study the disease further to form a uniform diagnostic and treatment plan.

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Dr. Abhishek Juneja
Dr. Abhishek Juneja

Neurology

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