Akinori Uruha

Clinical features and prognosis in anti-SRP and anti-HMGCR necrotising myopathy

Objective To elucidate the common and distinct clinical features of immune-mediated necrotising myopathy (IMNM), also known as necrotising autoimmune myopathy associated with autoantibodies against signal recognition particle (SRP) and 3-hydroxy-3-methylglutaryl-coenzyme A reductase (HMGCR). Methods We examined a cohort of 460 patients with idiopathic inflammatory myopathies (IIMs) through a muscle biopsy-oriented registration study in Japan. Study entry was strictly determined by the comprehensive histological assessment to exclude other neuromuscular disorders. Anti-SRP and anti-HMGCR antibodies were detected by RNA immunoprecipitation and ELISA, respectively. Results Of 460 patients with IIM, we diagnosed 73 (16%) as having inclusion body myositis (IBM). Of 387 patients with IIMs other than IBM, the frequencies of anti-SRP and anti-HMGCR antibodies were 18% and 12%, respectively. One patient had both autoantibodies. Severe limb muscle weakness, neck weakness, dysphagia, respiratory insufficiency and muscle atrophy were more frequently observed in patients with anti-SRP antibodies than in those with anti-HMGCR antibodies. Serum creatine levels were markedly higher in the patients with autoantibodies than in those without. Histology was characterised by necrosis and regeneration of muscle fibres and was consistent with IMNM except in 1 HMGCR-positive IBM patient. Most patients were initially treated with corticosteroids; however, additional immunosuppressive drugs were required, especially in the patients with anti-SRP antibodies. Rates of unsatisfactory neurological outcome were similar in the 2 autoantibody groups. Conclusions Anti-SRP antibodies are associated with severe neurological symptoms, more so than are anti-HMGCR antibodies. Although these autoantibodies are independent serological markers associated with IMNM, patients bearing either share common characteristics.

Hepatitis C virus infection in inclusion body myositis A case-control study

Objective: To clarify whether there is any association between inclusion body myositis (IBM) and hepatitis C virus (HCV) infection. Methods: We assessed the prevalence of HCV infection in 114 patients with IBM whose muscle biopsies were analyzed pathologically for diagnostic purpose from 2002 to 2012 and in 44 age-matched patients with polymyositis diagnosed in the same period as a control by administering a questionnaire survey to the physicians in charge. We also compared clinicopathologic features including the duration from onset to development of representative symptoms of IBM and the extent of representative pathologic changes between patients with IBM with and without HCV infection. Results: A significantly higher number of patients with IBM (28%) had anti-HCV antibodies as compared with patients with polymyositis (4.5%; odds ratio 8.2, 95% confidence interval 1.9–36) and the general Japanese population in their 60s (3.4%). Furthermore, between patients with IBM with and without HCV infection, we did not find any significant difference in the clinicopathologic features, indicating that the 2 groups have essentially the same disease regardless of HCV infection. Conclusion: Our results provide the statistical evidence for an association between IBM and HCV infection, suggesting a possible pathomechanistic link between the 2 conditions.

Sarcoplasmic MxA expression: A valuable marker of dermatomyositis.

Objective: To evaluate the diagnostic value of myxovirus resistance A (MxA) expression in the cytoplasm of myofibers in the diagnosis of dermatomyositis (DM). Methods: We assessed the sensitivity and specificity of the sarcoplasmic expression of MxA in muscles with DM by immunohistochemistry in consecutive cases of DM (n = 34) and other idiopathic inflammatory myopathies (n = 120: 8 with polymyositis, 16 with anti–tRNA-synthetase antibody–associated myositis, 46 with immune-mediated necrotizing myopathy, and 50 with inclusion body myositis) and compared them with conventional pathologic hallmarks of DM, including perifascicular atrophy (PFA) and membrane attack complex (MAC) deposition on endomysial capillaries. Results: The sensitivity and specificity of sarcoplasmic MxA expression were 71% and 98%, respectively. While the specificity was almost comparable to that of PFA and capillary MAC deposition, the sensitivity was higher, with PFA showing 47% sensitivity and 98% specificity and capillary MAC deposition showing 35% sensitivity and 93% specificity. Of note, in patients with DM with typical skin rash but no PFA, 44% of the samples showed sarcoplasmic MxA expression, which was higher than the 17% sensitivity of capillary MAC deposition in the population. Conclusions: Sarcoplasmic MxA expression detected by immunohistochemistry is a more sensitive marker of DM than the conventional hallmarks, indicating its practical utility in the diagnosis of DM. It may well be included in the routine immunohistochemistry panel for myositis. Classification of evidence: This study provides Class II evidence that immunohistochemistry-detected sarcoplasmic MxA expression accurately identifies patients with dermatomyositis.

Perifascicular necrosis in anti-synthetase syndrome beyond anti-Jo-1.

Sir, The papers by Mescam-Mancini et al. (2015) and Stenzel et al. (2015) are of particular interest, at least partially addressing the important question whether anti-synthetase syndrome is pathologically distinct from other idiopathic inflammatory myopathies. Mescam-Mancini et al. (2015) beautifully demonstrated that patients with anti-Jo-1 antibodies, one of the anti-aminoacyl-tRNA synthetase (ARS) antibodies, characteristically show perifascicular necrosis on muscle pathology. However, they did not deal with anti-synthetase syndrome patients with anti-ARS antibodies other than anti-Jo-1, raising a question whether perifascicular necrosis is characteristic only of myopathies associated with anti-Jo-1 antibodies or is observed also in those associated with other anti-ARS antibodies. We have analysed muscle samples from patients with anti-Jo-1 antibodies ( n …

Pediatric necrotizing myopathy associated with anti-3-hydroxy-3-methylglutaryl-coenzyme A reductase antibodies

Objective. Antibodies against 3-hydroxy-3-methylglutaryl-coenzyme A reductase (HMGCR) have recently been associated with immune-mediated necrotizing myopathy, especially in patients with statin exposure. As the data are very limited concerning phenotypes and treatment in paediatric patients, we aimed to identify the paediatric patients positive for anti-HMGCR antibodies and clarify their features and therapeutic strategies. Methods. We screened 62 paediatric patients who were clinically and/or pathologically suspected to have inflammatory myopathy for anti-HMGCR antibodies. We further re-assessed the clinical and histological findings and the treatment of the patients positive for anti-HMGCR antibodies. Results. We identified nine paediatric patients with anti-HMGCR antibodies (15%). This was more frequent than anti-signal recognition particle antibodies (four patients, 6%) in our cohort. The onset age ranged from infancy to 13 years. Five patients were initially diagnosed with muscular dystrophy, including congenital muscular dystrophy. Most patients responded to high-dose corticosteroid therapy first but often needed adjuvant immunosuppressants to become stably controlled. Conclusion.Paediatric necrotizing myopathy associated with anti-HMGCR antibodies may not be very rare. Phenotypes are similar to those of adult patients, but a chronic slowly progressive course may be more frequent. Some patients share the clinicopathological features of muscular dystrophy indicating that recognizing inflammatory aetiology would be challenging without autoantibody information. On the other hand, most patients responded to treatment, especially those who were diagnosed early. Our results suggest the importance of early autoantibody testing in paediatric patients who have manifestations apparently compatible with muscular dystrophy in addition to those who have typical features of inflammatory myopathy.

HLA-DRB1 alleles in immune-mediated necrotizing myopathy

Immune-mediated necrotizing myopathy (IMNM), also known as necrotizing autoimmune myopathy, is a histologic entity characterized by marked necrosis in the absence of prominent lymphocytes.1 Risk factors or triggers for IMNM include statin treatment, cancer, and connective tissue disease (CTD).1,2 Although autoantibodies against signal recognition particle (SRP) or 3-hydroxy-3-methylglutaryl-coenzyme A reductase (HMGCR) are regarded as markers for IMNM, they are not always detected in sera of pathologically defined patients with IMNM. The autoimmune mechanisms of IMNM are not elucidated.

Necklace cytoplasmic bodies in hereditary myopathy with early respiratory failure

Background In hereditary myopathy with early respiratory failure (HMERF), cytoplasmic bodies (CBs) are often localised in subsarcolemmal regions, with necklace-like alignment (necklace CBs), in muscle fibres although their sensitivity and specificity are unknown. Objective To elucidate the diagnostic value of the necklace CBs in the pathological diagnosis of HMERF among myofibrillar myopathies (MFMs). Methods We sequenced the exon 343 of TTN gene (based on ENST00000589042), which encodes the fibronectin-3 (FN3) 119 domain of the A-band and is a mutational hot spot for HMERF, in genomic DNA from 187 patients from 175 unrelated families who were pathologically diagnosed as MFM. We assessed the sensitivity and specificity of the necklace CBs for HMERF by re-evaluating the muscle pathology of our patients with MFM. Results TTN mutations were identified in 17 patients from 14 families, whose phenotypes were consistent with HMERF. Among them, 14 patients had necklace CBs. In contrast, none of other patients with MFM had necklace CBs except for one patient with reducing body myopathy. The sensitivity and specificity were 82% and 99%, respectively. Positive predictive value was 93% in the MFM cohort. Conclusions The necklace CB is a useful diagnostic marker for HMERF. When muscle pathology shows necklace CBs, sequencing the FN3 119 domain of A-band in TTN should be considered.

PLASMA IP-10 LEVEL DISTINGUISHES INFLAMMATORY MYOPATHY

Discrimination of idiopathic inflammatory myopathy (IIM) from other muscle diseases is at times difficult in clinical practice even after muscle biopsy.1

Think worldwide: hereditary myopathy with early respiratory failure (HMERF) may not be rare

Respiratory failure in adult myopathy patients is rare. Nevertheless, it is often a characteristic clinical feature that can be a clue for the diagnosis of a certain group of muscle diseases, including Pompe disease and congenital myopathy. Two reports by Palmio et al 1 and Pfeffer et al 2 suggest that hereditary myopathy with early respiratory failure (HMERF) may not be rare and is distributed worldwide. HMERF was first described as adult-onset myopathy with acute …

A 62-Year-Old Woman with A History of Muscle Pain and Skin Rash for 1 Month: Correspondence

The patient was a 62-year-old woman who presented at the hospital with a one-month history of muscle pain and skin rash. Before this visit, she had experienced fever for 2 months. She had no other underlying medical condition except for rheumatoid arthritis which had been treated for over 20 years. Physical examination revealed mild symmetrical proximal muscle weakness of both upper and lower extremities (Medical Research Council grade 4). Erythema was observed in lower legs. Serum creatine kinase (CK) was 2048 U/L (normal range 32–180 U/L). Muscle biopsy was performed in the left tibialis anterior muscle.