Therapeutic development in rare diseases shares many challenges, such as incomplete understanding of natural history to design clinical trials, and difficulties of recruiting patients to participation. To secure clinical studies and clinical research at national university hospitals in Japan, National University Hospital Clinical Research Promotion Initiative (NUH–CRPI) founded in October 2012. The topic group (TG2) promotes information sharing, standardization and coordination, and discusses the network of national university hospitals. They set up the web system of feasibility study assessing capacity in university hospitals for clinical trials in rare diseases. The support and training program for translational research that was initiated by the Ministry of Education, Culture, Sports, Science and Technology was launched in 2007. The second term of Translational Research Network Program started in 2012. In this program, they are setting up the patient registry system for screening for eligibility and enrollment in clinical trials.

Immune–mediated necrotizing myopathy (IMNM) is a subgroup of idiopathic inflammatory myopathies, characterized by usually subacutely progressive course, symmetrical and proximal muscle weakness and atrophy, highly elevated serum creatine kinase levels, and muscle fiber necrosis and regeneration with little or no lymphocytic inflammatory infiltration on muscle pathology. Two major autoantibodies, anti–signal recognition particle (SRP) and anti–3–hydroxy–3–methylglutaryl–coenzyme A reductase (HMGCR) antibodies, are known to be associated with IMNM. IMNM with those antibodies were initially reported in adults but are now known to be seen also in children. Anti–SRP antibodies seem to be more frequently seen in IMNM pateints than anti–HMGCR antibodies. Although anti–HMGCR necrotizing myopathy was first found in patients who were taking statins, majority of patients do not have history of statin use. Myositis associated with anti–aminoacyl tRNA synthetases (ARS) is pathologically characterized by perifascicular necrotizing myopathy with perimysial alkaline phosphatase activity. Clinically, patients typically develop triad of interstitial lung disease, mechanic's hands, and myositis, which is sometimes called anti–synthetase syndrome or anti–ARS syndrome. Of note, necrotizing muscle pathology can also be observed in a variety of other conditions, including myositis associated with anti–mitochondria M2 autoantibodies, malignancy, viral infections (HIV and hepatitis C), and connective tissue diseases. In addition, muscular dystrophy, such as dysferlinopathy or facioscapulohumeral muscular dystrophy, may also display similar muscle pathology. Not surprisingly, it can be clinically difficult to distinguish IMNM from muscular dystrophy especially in children. As IMNM is treatable by immunosuppressive therapy, it should not be misdiagnosed. Immunohistochemical analysis including MHC class I and C5b–9 may be useful as cytoplsmic upregulation of MHC class I in non–necrotic fibers and sarcolemmal deposition of membrane attack complex (C5b–9) are often observed in IMNM but not in muscular dystrophy. This review focuses on muscle pathological features of IMNM.

Immune–mediated necrotizing myopathy (IMNM) is recently defined subgroup of idiopathic inflammatory myopathies. IMNM is characterized by significant necrosis, with muscle fiber regeneration, but without or with little inflammatory cells on muscle biopsy. IMNM may be associated with myositis–specific autoantibodies against signal recognition particle (SRP), or against 3–hydroxy–3–methylglutaryl–coenzyme A reductase (HMGCR). Typical clinical features such as severe muscle weakness, highly elevated serum creatine kinase (CK) levels, as well as resistance to conventional immunosuppressive therapy. Severe limb muscle weakness, neck weakness, dysphagia, respiratory insufficiency and muscle atrophy were more frequently observed in patients with anti–SRP antibodies than that in with anti–HMGCR antibodies. The pathophysiological mechanisms of these diseases are poorly understood, and therapeutic strategies for treating patients have not yet been validated. Most patients in both types were initially treated with corticosteroids. Additional immunotherapies were needed in patients with anti–SRP antibodies. In addition, one third of IMNM therapy do not show known specific autoantibodies. This review provides an overview of this disease entity and focuses on its clinical features and immunotherapy.

Immune–mediated necrotizing myopathy (IMNM), characterized by necrosis and regeneration of muscle fibers in the absence of prominent inflammatory cells, is one of inflammatory myopathies. Autoantibodies against signal recognition particle (SRP) or 3–hydroxy–3–methylglutaryl–coenzyme A reductase (HMGCR) are regarded as serological markers for IMNM. SRP is a cytoplasmic ribonucleoprotein consisting of six proteins and 7S RNA. Recently, anti–SRP antibodies have been observed to entail a broad variety of neuromuscular phenotypes, collected under the heading “anti–SRP myopathy”. RNA immunoprecipitation is an original detection method for anti–SRP antibodies. One disadvantage is that RNA immunoprecipitation requires a complicated technique and is performed at only a limited number of facilities. Other conventional detection assays including enzyme–linked immunosorbent assay (ELISA) and line blot assay using a recombinant SRP protein are typically used. In contrast, Mammen et al. identified autoantibodies to HMGCR in patients with statin–induced myopathy. Although anti–HMGCR antibodies were originally identified by protein immunoprecipitation assay using radiolabeled culture cell extracts, many researchers agree that ELISA is a preferred standard method. Anti–SRP and anti–HMGCR antibody studies are not used in routine clinical practice because there is no convenient, widely accepted assay. Our goal was to establish accurate quantitative assays for IMNM–associated autoantibodies. We have developed new ELISAs for anti–SRP and anti–HMGCR with some modifications of previous studies. The advantage of ELISAs is its ability to provide quantitative results, which may be useful in evaluating disease activity. In addition, ELISAs can be performed easily and quickly and are particularly suitable for screening large numbers of sera. We believe that our ELISAs can substitute for an immunoprecipitation assay in the clinical settings.

We report herein the case of a 32–year–old pregnant woman with Guillain–Barré syndrome (GBS) who showed complications of paralytic ileus and deep vein thrombosis (DVT) in lower limbs. She developed paresthesia of the distal limbs and muscle weakness of limbs at 23 weeks of gestation. She became unable to walk one week after her initial symptoms. She was diagnosed with GBS on the basis of electrophysiological findings and lumbar puncture showing albuminocytologic dissociation. Intravenous immunoglobulin (IVIG) was administered for 5 days, and she showed smooth recovery after the IVIG treatment. Ten days after her admission, however, she developed paralytic ileus and DVT in the left common femoral vein–superficial femoral vein. The symptoms of ileus and DVT were improved with the procedure of intestinal tube and anticoagulant therapy with continuous infusion of heparin. She delivered vaginally a healthy newborn at 40 weeks' gestation after receiving a prophylactic placement of an inferior vena cava filter. She was discharged 2 weeks after delivery, and recovered without neurological sequelae. GBS associated with pregnancy is rare. However, paralytic ileus or DVT would be major complications and high mortality risk in these conditions.

Istradefylline improves motor symptoms and reduces OFF–time in Parkinson's disease patients with motor fluctuation. However, it is not known exactly who are appropriate target patients for istradefylline therapy. In the present study, we evaluated efficacy of istradefylline on Parkinson's disease patients with motor fluctuation and mild motor disability during ON–period. Fourteen Parkinson's disease patients with less than 16 of UPDRS part 3 score during ON–period completed an open label trial of 20mg/day istradefylline for 8 weeks. The istradefylline treatment significantly improved UPDRS part 3 score during ON–period and shortened daily OFF–time. Questionnaire for the patients revealed a high satisfaction level for the istradefylline treatment. Parkinson disease patients with mild motor disability during ON–period could be good candidates for istradefylline therapy.

We examined the data from the clinical research forms of sporadic amyotrophic lateral sclerosis (ALS) patients with mechanical ventilation, who had received the subsidy for the medical costs of the specified intractable disease treatment research program, in Tokyo, Japan. Comparing the implements of respiratory/dietary treatments between 2006 and 2012, the number of patients with ventilation, especially non–invasive ventilation (NIV) had increased in 2012 (55 in 2012 vs 5 in 2006). The duration from the onset to the beginning of ventilation in 2012 was shorter than that in 2006 (2.6 vs 3.7 years), and the installation term of tracheostomy with invasive ventilation (TIV) was longer (63.7 vs 42.7 months). The number of the patients who had percutaneous endoscopic gastrostomy (PEG) increased (257 in 2012 vs 130 in 2006), and patients receiving home care also increased especially in NIV patients (41 vs 0), but only 43.9% of them had doctor's visits to home.

When limited to the patients within 6 years from the onset, the onset ages were higher than those of all patients in both 2006 and 2016 (67.3 vs 59.5 in 2006, 68.9 vs 59.2 in 2012). More than 60% introduced either NIV or TIV within 2 years after onset, and more than 70% underwent ventilation before PEG.

This research indicates that it is necessary for TIV patients with progressing disability to receive and maintain the appropriate care environment for a long time, and for NIV patients to receive home medical care including emergency treatment and palliation. Moreover, since there are older patients with rapid disease progression, establishing the care support system at the beginning is obviously important.