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.

症例は32歳女性，妊娠23週であった．四肢遠位部の痺れ感，四肢脱力を自覚後に運動麻痺が進行して歩行困難となり第11病日当科入院となった．四肢腱反射消失，髄液検査で蛋白細胞解離を認め，神経伝導検査では遠位潜時の延長と伝導速度遅延と時間的分散がみられたことよりGuillain–Barré症候群（Guillain–Barré syndrome：GBS）と診断し免疫グロブリン静注療法を施行した．GBSの症状は改善を示したが，第22病日より麻痺性イレウスと下肢深部静脈血栓症を合併した．イレウス管留置と抗凝固療法により回復し第119病日に経膣分娩し第132病日自宅退院した．妊娠合併GBSでは妊娠に伴う生理的変化もありイレウスや下肢深部静脈血栓症など合併症の頻度も増えると考えられ注意が必要である．

Istradefyllineはウエアリング・オフのあるParkinson病患者の運動症状を改善する．しかし実臨床ではistradefyllineが有効でないこともしばしばあり，どのような患者にistradefyllineが有用なのか迷うことも多い．そこでウエアリング・オフがあり，オン時の運動症状が軽度なParkinson病患者（オン時のUPDRSパートIIIスコアが15点以下）を対象にistradefylline 20mg/日の有効性をオープンラベル試験にて評価した．14例の患者が8週間の試験を終了できた．Istradefyllineの追加投与により，オン時のUPDRSパートIIIスコアが有意に低下し，オフ時間が有意に短縮した．そのうちの13例は試験終了時にParkinson病症状の改善を自覚しており，istradefyllineの内服継続を希望した．ウエアリング・オフがあり，オン時の運動症状が軽度でドパ反応性が保たれている患者でのistradefyllineの有用性が示唆された．

2006年度と2012年度の難病医療費助成申請時の臨床調査個人票を用い，人工呼吸器装着中の孤発性筋萎縮性側索硬化症患者の人工呼吸・栄養療法の導入状況と療養環境を比較した．その結果，人工呼吸器装着者，特に非侵襲的換気療法（non–invasive ventilation, NIV）装着者が増加した．NIVと気管切開下侵襲的換気療法（tracheostomy with invasive ventilation, TIV）導入までの期間が短縮し，TIVの装着期間は63.7ヶ月と長くなった．また，胃・腸ろうの造設率は増加した．在宅療養者が増加したが，NIV患者への往診率は43.9%と低かった．発症6年以内の患者に限定した比較では，人工呼吸器導入は6割以上が発症後2年以内で，7割以上が胃・腸ろう導入より先だった．以上より，長期TIV患者の療養環境の構築と維持，およびNIV患者の緊急時対応と終末期緩和ケアが充実した在宅医療体制整備の必要性が示唆された．また，比較的高齢患者が急速に進行することから，発症初期から進行を把握し，療養支援体制を確立する必要性が明らかになった.