Final Diagnosis

Immune-mediated necrotizing myopathy associated with anti-SRP autoantibody (anti-SRP myopathy)

Patient Follow-up

The patient was treated with Rituximab . Her blood CD3-CD19+ B cell number went down from 357 to <1 cells/μL (normal: 110–570). She continued to take prednisone 15 mg once daily and receive IVIg treatment every 3 weeks. She also underwent physical therapy. Her weakness slowly improved. Eighteen months later, her follow-up examination showed resolution of the weakness in the deltoid and quadriceps muscles. The weakness in the bilateral iliopsoas (3+/5), biceps (4/5), and triceps (4/5) muscles slightly improved.

Discussion

IMNM, also known as necrotizing autoimmune myopathy (NAM) , is a type of idiopathic inflammatory myopathy (IIM) [1, 2]. It is distinguished by its muscle biopsy features of myofiber necrosis with no or limited lymphocytic infiltrates [1–4]. The disease is categorized into three distinct clinical subtypes based on the autoantibody status: anti-SRP myopathy, anti-HMGCR myopathy, and autoantibody-negative (seronegative) IMNM [5]. A large study of 460 patients with IIM in Japan [6] showed that 177/460 (38.5%) patients had IMNM. Among the patients with IMNM, autoantibodies were detected in 115/177 (65%), with anti-SRP autoantibody in 69/177 (39%) and anti-HMGCR autoantibody in 46/177 (26%).

Although all subtypes of IMNM in adults manifest subacute, progressive, symmetric, proximal limb weakness and marked CK elevation, they are different in several aspects including weakness severity, extra-muscular manifestations, cancer association, and treatment response [5, 7]. Severe limb weakness, muscle atrophy, neck weakness, dysphagia, and respiratory insufficiency are more frequently seen in anti-SRP myopathy than in anti-HMGCR myopathy [6]. Extra-muscular manifestations , such as skin rash, arthritis, and Raynaud’s phenomenon, are rare in both seropositive subtypes. The seronegative subtype shows frequent occurrence of connective tissue diseases and a high rate of extra-muscular disease activity [8]. Anti-HMGCR myopathy can be seen in patients with or without statin exposure [9], with the percentage of statin-induced anti-HMGCR myopathy ranging from 14% to 63% in different cohorts [3, 10–13]. Comparing with statin-induced anti-HMGCR myopathy, statin-naïve anti-HMGCR myopathy shows a younger age at onset, a more severe disease, and a worse prognosis [8, 14]. The risk of cancer is markedly increased in seronegative IMNM , slightly increased in anti-HMGCR myopathy , but not increased in anti-SRP myopathy. No specific type of cancer is predominate [15]. It has been reported that seronegative IMNM can be induced by programmed death-1 (PD-1) inhibitors that are used as cancer immunotherapy [16].

Although IMNM is mainly seen in adults, it can also be seen in children. It is worth noting that children with anti-SRP myopathy and anti-HMGCR myopathy may present with slowly progressive proximal weakness, mimicking a limb girdle muscular dystrophy [17, 18]. It is thus advocated that the autoantibodies should be tested in children who have a muscular dystrophy phenotype but no family history or a confirmative gene test result [5]. Children with anti-SRP myopathy and anti-HMGCR myopathy can respond favorably to immunosuppressive therapy if diagnosed and treated early [17–19].

Although anti-SRP and anti-HMGCR autoantibodies are highly specific for IMNM, a muscle biopsy is still needed to establish the diagnosis and to exclude other diagnoses, especially in patients with seronegative IMNM. Pathologically, the morphology of anti-SRP, anti-HMGCR and seronegative IMNM is similar. The muscle biopsy shows randomly scattered necrotic fibers at different stages of resolution (Fig. 7.2a), but only minimal or no lymphocytic inflammation. The muscle may show significant chronic myopathic changes such as myofiber hypertrophy, interstitial fibrosis, abnormal internal architecture (Fig. 7.2b), and even rimmed vacuoles (Fig. 7.2c). Perimysial connective tissue damage, indicated by abnormal alkaline phosphatase reactivity, is usually absent but may be focally present in cases with abundant necrotic fibers (Fig. 7.2d). C5b-9 immunostain shows strong sarcoplasmic reactivity in necrotic fibers (Fig. 7.2e black arrow) and membranous staining on scattered viable myofibers (Fig. 7.2e blue arrow). Class I major histocompatibility complex expression is upregulated in individually scattered myofibers (Fig. 7.2f). In mild cases, rare necrotic/regenerating fibers (Fig. 7.3a) and scattered myofibers with MHC1 upregulation (Fig. 7.3b) may be the only abnormal findings. The amount of necrotic fibers on muscle biopsy does not always correlate with serum CK or autoantibody levels (Fig. 7.3).