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Abstract：
OBJECTIVE: Characteristics of myositis with anti-Ku antibodies are poorly understood. The purpose of this study was to elucidate the pathologic features of myositis associated with anti-Ku antibodies, compared with immune-mediated necrotizing myopathy (IMNM) with anti-signal recognition particle (SRP) and anti-3-hydroxy-3-methylglutaryl-coenzyme A reductase (HMGCR) antibodies, in muscle biopsy-oriented registration cohorts in Japan and Germany.
METHODS: We performed a retrospective pathology review of patients with anti-Ku myositis samples diagnosed in the Japanese and German cohorts. We evaluated histologic features and performed HLA phenotyping.
RESULTS: Fifty biopsied muscle samples in the Japanese cohort and 10 in the German cohort were obtained. After exclusion of myositis-specific autoantibodies or other autoimmune connective tissue diseases, 26 samples (43%) of anti-Ku antibody-positive myositis were analyzed. All the samples shared some common features with IMNM, whereas they showed expression of MHC class II and clusters of perivascular inflammatory cells more frequently than the anti-SRP/HMGCR IMNM samples (71% vs 7%/16%; p < 0.005/<0.005; 64% vs 0%/0%; p < 0.005/<0.005). Anti-Ku myositis biopsies could be divided into 2 subgroups based on the extent of necrosis and regeneration. The group with more abundant necrosis and regeneration showed a higher frequency of MHC class II expression and perivascular inflammatory cell clusters. HLA phenotyping in the 44 available patients showed possible associations of HLA-DRB1*03:01, HLA-DRB1*11:01, and HLA-DQB1*03:01 (p = 0.0045, 0.019, and 0.027; odds ratio [OR] 50.2, 4.6, and 2.8; 95% CI 2.6-2942.1, 1.1-14.5, and 1.0-7.0) in the group with less conspicuous necrosis and regeneration. On the contrary, in the group of more abundant necrosis and regeneration, the allele frequencies of HLA-A*24:02, HLA-B*52:01, HLA-C*12:02, and HLA-DRB1*15:02 were lower than those of healthy controls (p = 0.0036, 0.027, 0.016, and 0.026; OR = 0.27, 0, 0, and 0; 95% CI 0.1-0.7, 0-0.8, 0-0.8, and 0-0.8). However, these HLA associations did not remain significant after statistical correction for multiple testing.
CONCLUSIONS: While anti-Ku myositis shows necrotizing myopathy features, they can be distinguished from anti-SRP/HMGCR IMNM by their MHC class II expression and clusters of perivascular inflammatory cells. The HLA analyses suggest that anti-Ku myositis may have different subsets associated with myopathologic subgroups.
METHODS: We performed a retrospective pathology review of patients with anti-Ku myositis samples diagnosed in the Japanese and German cohorts. We evaluated histologic features and performed HLA phenotyping.
RESULTS: Fifty biopsied muscle samples in the Japanese cohort and 10 in the German cohort were obtained. After exclusion of myositis-specific autoantibodies or other autoimmune connective tissue diseases, 26 samples (43%) of anti-Ku antibody-positive myositis were analyzed. All the samples shared some common features with IMNM, whereas they showed expression of MHC class II and clusters of perivascular inflammatory cells more frequently than the anti-SRP/HMGCR IMNM samples (71% vs 7%/16%; p < 0.005/<0.005; 64% vs 0%/0%; p < 0.005/<0.005). Anti-Ku myositis biopsies could be divided into 2 subgroups based on the extent of necrosis and regeneration. The group with more abundant necrosis and regeneration showed a higher frequency of MHC class II expression and perivascular inflammatory cell clusters. HLA phenotyping in the 44 available patients showed possible associations of HLA-DRB1*03:01, HLA-DRB1*11:01, and HLA-DQB1*03:01 (p = 0.0045, 0.019, and 0.027; odds ratio [OR] 50.2, 4.6, and 2.8; 95% CI 2.6-2942.1, 1.1-14.5, and 1.0-7.0) in the group with less conspicuous necrosis and regeneration. On the contrary, in the group of more abundant necrosis and regeneration, the allele frequencies of HLA-A*24:02, HLA-B*52:01, HLA-C*12:02, and HLA-DRB1*15:02 were lower than those of healthy controls (p = 0.0036, 0.027, 0.016, and 0.026; OR = 0.27, 0, 0, and 0; 95% CI 0.1-0.7, 0-0.8, 0-0.8, and 0-0.8). However, these HLA associations did not remain significant after statistical correction for multiple testing.
CONCLUSIONS: While anti-Ku myositis shows necrotizing myopathy features, they can be distinguished from anti-SRP/HMGCR IMNM by their MHC class II expression and clusters of perivascular inflammatory cells. The HLA analyses suggest that anti-Ku myositis may have different subsets associated with myopathologic subgroups.
摘要：
目的：抗Ku抗体对肌炎的特征了解甚少。这项研究的目的是阐明与抗Ku抗体相关的肌炎的病理特征，与抗信号识别颗粒（SRP）和抗3-羟基-3-甲基戊二酰辅酶A还原酶（HMGCR）抗体的免疫介导的坏死性肌病（IMNM）相比，在日本和德国的面向肌肉活检的登记队列中。
方法：我们对在日本和德国队列中诊断的抗Ku肌炎患者样本进行了回顾性病理学回顾。我们评估了组织学特征并进行了HLA表型分析。
结果：在日本队列中获得了50个活检肌肉样本，在德国队列中获得了10个活检肌肉样本。排除肌炎特异性自身抗体或其他自身免疫性结缔组织疾病后，分析了抗Ku抗体阳性肌炎的26个样品(43%)。所有样本都与IMNM共享一些共同功能，而与抗SRP/HMGCRIMNM样本相比，他们显示MHCII类和血管周围炎症细胞簇的表达更频繁(71%vs7%/16%;p<0.005/<0.005;64%vs0%/0%;p<0.005/<0.005)。根据坏死和再生的程度，抗Ku肌炎活检可分为2个亚组。坏死和再生更丰富的组显示出更高频率的MHCII类表达和血管周围炎症细胞簇。44例患者的HLA表型分析显示HLA-DRB1*03:01、HLA-DRB1*11:01和HLA-DQB1*03:01可能相关(p=0.0045、0.019和0.027;比值比[OR]50.2、4.6和2.8;95%CI2.6-2942.1、1.1-14.5和1.0-7.0)在坏死和再生较不明显的组中。相反,在更丰富的坏死和再生组中，HLA-A*24:02,HLA-B*52:01,HLA-C*12:02和HLA-DRB1*15:02的等位基因频率低于健康对照组(p=0.0036,0.027,0.016和0.026;OR=0.27,0,和0;95%CI0.1-0.7,0-0.8,0-0.8和0-0.8).然而,在对多重检验进行统计学校正后,这些HLA相关性并不显著.
结论：虽然抗Ku肌炎显示坏死性肌病特征，它们可以通过其MHCII类表达和血管周围炎症细胞簇与抗SRP/HMGCRIMNM区分开。HLA分析表明，抗Ku肌炎可能具有与肌病理学亚组相关的不同亚群。
方法：我们对在日本和德国队列中诊断的抗Ku肌炎患者样本进行了回顾性病理学回顾。我们评估了组织学特征并进行了HLA表型分析。
结果：在日本队列中获得了50个活检肌肉样本，在德国队列中获得了10个活检肌肉样本。排除肌炎特异性自身抗体或其他自身免疫性结缔组织疾病后，分析了抗Ku抗体阳性肌炎的26个样品(43%)。所有样本都与IMNM共享一些共同功能，而与抗SRP/HMGCRIMNM样本相比，他们显示MHCII类和血管周围炎症细胞簇的表达更频繁(71%vs7%/16%;p<0.005/<0.005;64%vs0%/0%;p<0.005/<0.005)。根据坏死和再生的程度，抗Ku肌炎活检可分为2个亚组。坏死和再生更丰富的组显示出更高频率的MHCII类表达和血管周围炎症细胞簇。44例患者的HLA表型分析显示HLA-DRB1*03:01、HLA-DRB1*11:01和HLA-DQB1*03:01可能相关(p=0.0045、0.019和0.027;比值比[OR]50.2、4.6和2.8;95%CI2.6-2942.1、1.1-14.5和1.0-7.0)在坏死和再生较不明显的组中。相反,在更丰富的坏死和再生组中，HLA-A*24:02,HLA-B*52:01,HLA-C*12:02和HLA-DRB1*15:02的等位基因频率低于健康对照组(p=0.0036,0.027,0.016和0.026;OR=0.27,0,和0;95%CI0.1-0.7,0-0.8,0-0.8和0-0.8).然而,在对多重检验进行统计学校正后,这些HLA相关性并不显著.
结论：虽然抗Ku肌炎显示坏死性肌病特征，它们可以通过其MHCII类表达和血管周围炎症细胞簇与抗SRP/HMGCRIMNM区分开。HLA分析表明，抗Ku肌炎可能具有与肌病理学亚组相关的不同亚群。
