Immune-mediated necrotizing myopathy (ORPHA:206569)
A rare form of idiopathic inflammatory myopathy characterized by acute or subacute, severe, symmetrical, proximal muscle weakness usually associated with muscle-specific antibodies (anti-HMGCR or anti-SRP). Histopathological characteristics include myocyte necrosis and regeneration without significant inflammation, and C5b-9 deposition on non-necrotic myofibers.
Epidemiology
The incidence of idiopathic inflammatory myopathy as a whole ranges from 1.16 to 19/million/year and the prevalence ranges from 2.4 to 33.8 per 100 000 inhabitants. Although the prevalence and annual incidence are not known, immune-mediated necrotizing myopathy (IMNM) represents roughly 10% of the idiopathic inflammatory myopathies.
Clinical description
Age of onset typically ranges from 30 to 70 years of age, although pediatric onset is possible. The main presenting feature of IMNM is subacute severe symmetrical proximal myopathy with a markedly elevated creatine kinase (CK) level. The main clinical symptom is upper and lower limb weakness causing difficulty in moving from a sitting position, climbing stairs, or lifting objects. The neck flexor, pharyngeal, and respiratory muscles may also be involved. Other manifestations include fatigue, weight loss, dysphagia and dyspnea. Interstitial lung disease and cardiac involvement have also been reported (especially in patients with anti-SRP antibodies).
Etiology
The disease is thought to be related to an immune response possibly triggered by drug therapy (statins), viral infections, or cancer. The pathophysiological mechanisms are partially deciphered. A specific genetic background has been identified (HLA-DRB1*11:01 allele in adult patients with anti-HMGCR autoantibodies). The production of autoantibodies is a major feature of the disease. Several studies point toward a direct pathogenic role of these autoantibodies, potentially through the activation of the complement cascade.
Diagnostic methods
Diagnosis is based on the clinical picture with the presence of auto-antibodies (anti-SRP or anti-HMGCR) and/or a muscle biopsy showing minimal or no inflammatory infiltrates and marked muscle necrosis, unlike other inflammatory myopathies. Electromyography (EMG) shows myopathic findings. Creatine kinase (CK) levels are often more than 10 times above the upper limit of normal at the time of onset of muscle weakness. Magnetic resonance imaging (MRI) may show diffuse or patchy edema within muscles and damage-like muscle fatty replacement. Anti-SRP and anti-HMGCR autoantibodies are frequently associated with this condition. Currently, seronegative IMNM represents 20-30% of the cases.
Differential diagnosis
Differential diagnoses include other inflammatory myopathies. In children, the progressive form of the disease may mimic muscular dystrophy.
Management and treatment
Treatment of the underlying cause, if identified, is essential (statin withdrawal, or malignancy). IMNM patients generally respond well to multiple-agent, long-term immunosuppressive therapies starting by high dose corticosteroids. The therapeutic strategy relies on an induction therapy combining high dose corticosteroids and other immunosuppressive agents (methotrexate, rituximab or intravenous immunoglobulins (IVIg)), followed by a maintenance therapy with the lowest tolerated dose of corticosteroids and the immunosuppressive agent. The maintenance therapy should be administered for at least 2 years in which there is well-controlled disease. Exercise is recommended to improve muscle strength. Response to therapy should be assessed clinically on the basis of muscle strength and biologically on CK levels.
Prognosis
IMNM is the most severe idiopathic inflammatory myopathy in terms of muscle damage, and relapses are frequent. Early age of onset is a poor prognosis factor for muscle strength recovery. There is an association with cancer risk in patients with seronegative IMNM and, to a lesser extent, in patients with anti-HMGCR IMNM.

                            Last update: 
                            February 2021


                            - Expert reviewer(s): 
                            Dr Céline ANQUETIL  - Pr Olivier BENVENISTE