Immune–mediated necrotizing myopathy (IMNM) is a subgroup of idiopathic inflammatory myopathies, pathologically characterized by myofiber necrosis with little lymphocytic infiltration. Autoantibodies toward signal recognition particle (SRP) and 3–hydroxy–3–methylglutaryl–coenzyme A reductase (HMGCR) are two major autoantibodies specifically associated with IMNM. Anti–SRP autoantibody–associated IMNM patients are more likely to present with severe muscle weakness and atrophy, cervical muscle weakness, dysphagia, and respiratory insufficiency ; anti–HMGCR autoantibody–associated IMNM patients show a higher proportion of statin use, especially in elderly patients. It is occasionally challenging to distinguish from non–inflammatory myopathies such as muscular dystrophy without autoantibody testing when patients show a relatively slowly progressive course. RNA immunoprecipitation is the original detection method for anti–SRP antibodies, but it requires complicated techniques and is not suitable for clinical use. Therefore, immunoassays using recombinant 54kDa subunit protein of the SRP complex, e.g. immunodot assay and enzyme–linked immunosorbent assay, are commonly used in clinical settings. However, it should be kept in mind that false–negative results can occur in the assays because anti–SRP antibodies occasionally recognize epitopes other than the 54kDa subunit. The pathomechanism has been regarded to involve complement–mediated immunity. In light of recent advances in the pathogenesis, complement–targeting therapy for refractory patients is being discussed.

Dermatomyositis (DM) is characterized clinically by myositis and a unique set of skin eruptions and myopathologically by perifascicular atrophy and capillary C5b–9 depositions. In DM muscles, a set of proteins known to be induced by type I interferon, including myxovirus resistance protein A (MxA), are expressed. Sarcoplasmic MxA on immunohistochemistry is highly specific and sensitive for DM, and thus a useful diagnostic marker. In addition, an increasing number of reports have been recently describing the efficacy of JAK inhibitors, which block the type I interferon pathway, in patients with refractory DM. Therefore, DM can be regarded as muscle type I interferonopathy. Five DM–specific autoantibodies (DMSA) so far identified are against : TIF1–γ, MDA5, Mi–2, NXP–2, and SAE. In our cohort, 97% of DM cases confirmed by the sarcoplasmic MxA expression on muscle biopsy had one of DMSAs, suggesting that DMSA is a surrogate marker of muscle type I interferonopathy. Apparently, each DMSA is associated with a relatively specific phenotype. For example, anti–TIF1–γ autoantibodies are associated with malignancy and anti–MDA with clinically amyopathic DM. This indicates that DM may well be further subclassified by DMSA.

Antisynthetase syndrome (ASS) is characterized by the presence of anti–aminoacyl t–RNA synthetases (ARS). So far, 10 anti–ARS antibodies have been identified, including Anti–Jo–1, PL–7, EJ, OJ, PL–12, and KS autoantibodies. ASS was previously classified as DM because patients typically develop skin rash such as mechanic's hand, in addition to myositis and chronic idiopathic lung disease. However, a recently proposed classification of idiopathic inflammatory myopathies (IIMs) based upon pathological and serological features, in addition to clinical information, includes ASS as a distinct subtype of IIM. Mounting evidence indicates the correlation between autoantibodies and phenotypes also in ASS. Anti–Jo–1, PL–7, EJ, OJ autoantibodies are more closely associated with myositis rather than interstitial lung disease while anti–PL–12, KS autoantibodies are more closely correlated with interstitial lung disease. ASS is pathologically characterized by perifascicular necrosis and perifascicular pathology. Perifascicular necrosis may superficially resemble perifascicular atrophy, however, MxA is not expressed in myofibers in ASS, indicating ASS and DM have different pathomechanisms. Of note, anti–OJ autoantibodies, which are seen in 27% of ASS patients who received muscle biopsy, cannot be detected by line blot assay or ELISA.

Polymyositis (PM) has been a common clinical diagnosis for inflammatory myopathies without dermatitis, since Bohan and Peter established diagnostic criteria classifying polymyositis and dermatomyositis by the presence of dermatitis. In Japan, the diagnostic criteria of polymyositis and dermatomyositis for medical subsidies are also based on the presence of dermatitis, and there are a number of patients with “polymyositis”. However, clinical, pathological, and serological studies have revealed that the inflammatory myopathies without dermatitis are a heterogenous group, including sporadic inclusion body myositis (sIBM), immune–mediated necrotizing myopathy (IMNM), collagen disease related myositis, and PM. For adequate clinical decisions as well as high–quality studies, PM should be diagnosed based on strict diagnostic criteria including pathological examination, such as the European Neuromuscular Centre (ENMC) criteria. Among 972 cases that had been diagnosed as inflammatory myopathies in our laboratory between 2000 and 2019, about 2/3 cases (550/925) lacked dermatitis, and could be diagnosed as “polymyositis” by Bohan and Peter criteria. However, based on the ENMC criteria, only 1.7% (17/972) cases were classified as PM. Even after the diagnosis of PM was made by pathological examination, some patients may be reclassified as other diseases, especially as sIBM. The improvement of pathological examination further reduced the number of misdiagnosed “PM”. In addition, infiltration of CD8 positive cells surrounding non–necrotic fibers, a hallmark of PM and sIBM, is also observed in other myopathies. Some researchers doubt the existence of PM. Thus, PM is a shrinking entity.

Inclusion Body Myositis (IBM) is a chronic progressive muscular disease observed primarily in people aged 50 years or more. Weakness and atrophy are seen in the quadriceps and in the finger/wrist flexors. The inability to stand–up, cane–dependent gait, inability to open a plastic bottle, choking on food ingestion, and being wheelchair–bound appear to be the typical IBM milestones. Dysphagia may result in aspiration pneumonia. Falls and fractures associated with knee breaks are frequently seen.

Rimmed vacuoles and infiltration of mononuclear cells in non–necrotic fibers can be found in the muscle tissue of IBM patients. IBM is generally refractory to current therapy, such as steroids and immunosuppressant agents. Although IBM is rarely observed in Japan compared with Europe and the United States, it has been observed more frequently over the past 30 years in Japan. In a society where the number of elderly people increases, the number of individuals with IBM would also increase. This review provides an overview of the clinical features, pathobiological mechanisms, biomarkers, and therapeutic strategies for IBM.

The idiopathic inflammatory myopathies (IIMs) are a group of heterogenous conditions showing immune–mediated muscle damage. Increasing numbers of myositis–specific autoantibodies (MSAs) or myositis–associated autoantibodies (MAAs) have been shown to be associated with a majority of patients with IIMs year after year. It has been known that there are associations between these autoantibodies, especially MSAs, and characteristic clinical features. Anti–mitochondrial antibody (AMA) is a characteristic marker of primary biliary cirrhosis. We previously studied clinical features of IIMs associated with AMA and reported. In the report, we found that IIMs associated with AMA frequently include patients with a clinically chronic disease course, muscle atrophy, cardiopulmonary involvement and granulomatous inflammation. After we reported, several case repots mainly in Japanese literature and four case series in English literature have been reported on clinicopathological features of IIMs associated with AMA. Of the four case series, one is negative, one is partly supportive, and two are supportive to our findings. In this review, we summarized the findings of four case series in English literature in comparison with our previous report. We also discussed the reasons of the differences in findings among reports. Considering growing numbers of literature supporting association between AMAs and characteristic clinical features ; chronic disease course, muscle atrophy, and cardiac involvement, we believe AMA should be added to the growing list of myositis–associated antibodies.

Immune check point inhibitors have shown remarkable benefit in the treatment of a range of cancer types. As cancer treatment with these drugs has become more common, the safety management of immune–related adverse events (irAEs) due to cancer immunotherapy has become more important. Myositis is one of the representative neuromuscular irAEs. A variety of studies have demonstrated that myositis as an irAE is often accompanied by ocular muscle symptoms, which physicians have often termed “myasthenia-like” or “pseudo-myasthenic” symptoms. Physicians often recognize the unique clinical manifestations of irAE myositis and may hesitate to diagnose these patients as pre–existing myositis alone. To comprehensively characterize the inflammatory myopathy associated with programmed cell death 1 inhibitors (PD–1 myopathy), we studied 19 Japanese patients with PD–1 myopathy. PD–1 myopathy occurred 29 days on average after the first administration of PD–1 inhibitor. The initial manifestation of muscle weakness was ptosis in 10 patients. 15 patients had ptosis, 13 diplopia, 8 facial muscle weakness, 10 bulbar symptoms, 13 limb weakness, 14 neck weakness, 4 cardiac involvement, 6 respiratory involvement and 16 myalgia. Ocular, facial, cardiac and respiratory muscle involvement and myalgia were frequently observed. Serum creatine kinase was increased to 5,247 IU/L on average. Autoantibodies related to inflammatory myopathy were negative, while anti–striational antibodies were found in 13 (68%) patients. HLA–C*12:02 alleles were more frequently detected than healthy controls. Muscle pathology was characterized by multifocal necrotic myofibers with endomysial inflammation and expression of MHC class I. There are guidelines for the treatment of neuromuscular irAEs. For all but the minimum symptoms, therapy with PD–1 inhibitors should be withheld. Immunosuppressive therapy with corticosteroids was generally effective for muscle weakness. PD–1 inhibitor induced myositis and myasthenia gravis may share the same pathophysiology, suggesting an emerging clinical entity. Based on our clinical, histological and immunological findings, PD–1 myopathy is a discrete subset of inflammatory myopathy.

Statin intolerance is defined as “adverse events linked to statin administration that result in some un-tolerated impairments in daily life which justify statin cessation or dose reduction.” Statin–associated muscle symptoms (SAMS) include all muscle symptoms that appear as a result of statins. They include subjective symptoms such as muscle pain, or stiffness, as well as muscle discomfort. These symptoms show no bilateral differences in the trunk and proximal extremities and appear in relatively large muscles. There are two severe forms : rhabdomyolysis and reduced muscle strength in the trunk and extremities (statin–associated myopathy). SAMS appear within 4–6 weeks after the start of statin administration, but in rare cases muscle symptoms may appear several years later. When increasing the statin dose or switching to another statin, new SAMS may appear. In many cases SAMS may appear soon after statin administration is resumed after temporary cessation. CK levels of under 4x ULN are considered mild elevation, levels between≧4x and under 10x ULN are considered moderate elevation, and levels of v10x or higher are considered severe elevation. Assessment of muscle–related adverse events linked to statins are organized into four categories based on the serum CK level and whether SAMS are present. Statin–associated myopathy is characterized by muscle weakness, immune–mediated necrotizing myopathy in muscle biopsy, and the presence of autoantibodies to 3–hydroxy–3–methylglutaryl–coenzyme A reductase. Patients with statin–associated myopathy may have progressive weakness that must be controlled with immunosuppressive therapy.

Myositis, or idiopathic inflammatory myopathies (IIM), are heterogeneous diseases. The pathomechanisms of IIM can be caused by specific interactions between genetic and environmental risk factors, however, the details are not clear. This article reviews that have been made in our understanding of the studies of genetics in IIM, with particular focus on inclusion body myositis (IBM), immune–mediated necrotizing myopathies (IMNM), myositis specific autoantibodies (MSA) and PD–1 inhibitor–associated myopathies. The human leukocyte antigen (HLA) 8.1 ancestral haplotype (8.1 AH) is a key risk factor for major IIM phenotypes in Caucasian, and other genetic variants have been identified as risk factors in several IIM phenotypes. Owing to the rarity of IIM in Japan, there are few studies of genetic analysis. Since the HLA allele frequency varies greatly among ethnicity, it is necessary to proceed with research unique to Japanese.

Nakajo–Nishimura syndrome (NNS) is an autosomal recessive disease characterized by remittent fever, skin rash, emaciation of the face and upper body, and long gnarled fingers with contractures. Since Nakajo reported the first patients in Japan in 1939, only a few papers describing similar patients have been published. The detailed characteristics of NNS are unknown because it is very rare.

Arima et al. (2011) reported that proteasomal dysfunction due to a mutation of the proteasome subunit beta type 8 gene (PSMB8) encoding immunoproteasome subunit β5i caused various symptoms of NNS. Since then, reports of NNS have increased gradually. Nevertheless, some patients with NNS may be misdiagnosed with collagen–related diseases or inflammatory myopathies because they show similar symptoms to these diseases.

There is no established treatment for NNS, however, the administration of an anti–IL–6 receptor antibody and JAK inhibitor is possibly effective. If patients with NNS are diagnosed and treated early, they can maintain their activities of daily living.

難治性の疾患における持続中枢神経感作と言われる病態の疫学，基礎・臨床的な位置付けさらには患者のケアにむけての研究をまとめた．本総説は厚生労働研究班の各員の研究結果を示したものなので，必ずしもまとまりがない点に限界があるが，今までは疾患縦断的に診断治療がおこなわれてきた難治性疾患における中枢神経感作の役割を横断的にみたという意味でもわれわれの研究の結果は一部ではあるが解明したものといえる．結果として，中枢神経感作は種々の疾患，特に難治性のもので明らかに何らかの役割を呈していることが示せた．さらにその治療法の解明には至らぬまでも，患者ケアに繋がる方略を示せたものと考えられ，今後の研究の基盤となることが望まれる．

レストレスレッグス症候群患者375名を対象に，gabapentin enacarbil 600 mg（本剤）の有効性をランダム化，二重盲検，プラセボ対照，製造販売後臨床試験で検証した．主要評価項目であるベースラインから最終評価時のInternational Restless Legs Syndrome Rating Scale（IRLS）スコア変化量で有意な差は認められなかった［調整済み平均値の差（本剤群−プラセボ群）：−1.2，95%信頼区間：−2.6～0.2，p＝0.088］が，全評価時点のIRLSスコア変化量はプラセボ群に比べ本剤群で大きかった．本剤群で発現割合が10%以上の有害事象は傾眠，鼻咽頭炎，及び浮動性めまいであった．国内第II/III相試験との事後併合解析では，最終評価時のIRLSスコア変化量で有意な差が認められ（−1.7，p＝0.002），本剤600 mgには臨床効果があると考えた．