Importance Immune-mediated rippling muscle disease (iRMD) is a rare myopathy characterized by wavelike muscle contractions (rippling) and percussion- or stretch-induced muscle mounding. A serological biomarker of this disease is lacking. Objective To describe a novel autoantibody biomarker of iRMD and report associated clinicopathological characteristics. Design, Setting, and Participants This retrospective cohort study evaluated archived sera from 10 adult patients at tertiary care centers at the Mayo Clinic, Rochester, Minnesota, and Brigham & Women's Hospital, Boston, Massachusetts, who were diagnosed with iRMD by neuromuscular specialists in 2000 and 2021, based on the presence of electrically silent percussion- or stretch-induced muscle rippling and percussion-induced rapid muscle contraction with or without muscle mounding and an autoimmune basis. Sera were evaluated for a common biomarker using phage immunoprecipitation sequencing. Myopathology consistent with iRMD was documented in most patients. The median (range) follow-up was 18 (1-30) months. Exposures Diagnosis of iRMD. Main Outcomes and Measures Detection of a common autoantibody in serum of patients sharing similar clinical and myopathological features. Results Seven male individuals and 3 female individuals with iRMD were identified (median [range] age at onset, 60 [18-76] years). An IgG autoantibody specific for caveolae-associated protein 4 (cavin-4) was identified in serum of patients with iRMD using human proteome phage immunoprecipitation sequencing. Immunoassays using recombinant cavin-4 confirmed cavin-4 IgG seropositivity in 8 of 10 patients with iRMD. Results for healthy and disease-control individuals (n = 241, including myasthenia gravis and immune-mediated myopathies) were cavin-4 IgG seronegative. Six of the 8 individuals with cavin-4 IgG were male, and the median (range) age was 60 (18-76) years. Initial symptoms included rippling of lower limb muscles in 5 of 8 individuals or all limb muscles in 2 of 8 sparing bulbar muscles, fatigue in 9 of 10, mild proximal weakness in 3 of 8, and isolated myalgia in 1 of 8, followed by development of diffuse rippling. All patients had percussion-induced muscle rippling and half had percussion- or stretch-induced muscle mounding. Four of the 10 patients had proximal weakness. Plasma creatine kinase was elevated in all but 1 patient. Six of the 10 patients underwent malignancy screening; cancer was detected prospectively in only 1. Muscle biopsy was performed in 7 of the 8 patients with cavin-4 IgG; 6 of 6 specimens analyzed immunohistochemically revealed a mosaic pattern of sarcolemmal cavin-4 immunoreactivity. Three of 6 patients whose results were seropositive and who received immunotherapy had complete resolution of symptoms, 1 had mild improvement, and 2 had no change. Conclusions and Relevance The findings indicate that cavin-4 IgG may be the first specific serological autoantibody biomarker identified in iRMD. Depletion of cavin-4 expression in muscle biopsies of patients with iRMD suggests the potential role of this autoantigen in disease pathogenesis.

中文翻译：

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鉴定小窝相关蛋白 4 自身抗体作为成人免疫介导的波纹肌肉疾病的生物标志物。

重要性 免疫介导的涟漪肌病 (iRMD) 是一种罕见的肌病，其特征是波状肌肉收缩（涟漪）和敲击或拉伸引起的肌肉隆起。缺乏这种疾病的血清学生物标志物。目的描述一种新的iRMD自身抗体生物标志物并报告相关的临床病理特征。设计、设置和参与者这项回顾性队列研究评估了 10 名成年患者的存档血清，这些患者在 2000 年被神经肌肉专家诊断为 iRMD和 2021 年，基于电无声敲击或拉伸引起的肌肉波纹和敲击引起的快速肌肉收缩，有或没有肌肉隆起和自身免疫基础。使用噬菌体免疫沉淀测序评估血清的常见生物标志物。大多数患者的肌病理学与 iRMD 一致。中位（范围）随访时间为 18（1-30）个月。iRMD的暴露诊断。主要结果和措施 在具有相似临床和肌病理学特征的患者血清中检测到常见的自身抗体。结果 确定了 7 名男性和 3 名女性患有 iRMD（发病时的中位 [范围] 年龄，60 [18-76] 岁）。使用人蛋白质组噬菌体免疫沉淀测序在 iRMD 患者的血清中鉴定出一种针对小窝相关蛋白 4 (cavin-4) 的 IgG 自身抗体。使用重组 cavin-4 的免疫测定证实 10 名 iRMD 患者中有 8 名出现 cavin-4 IgG 血清学阳性。健康和疾病控制个体（n = 241，包括重症肌无力和免疫介导的肌病）的结果为 cavin-4 IgG 血清阴性。8 名具有 cavin-4 IgG 的个体中有 6 名是男性，中位（范围）年龄为 60（18-76）岁。最初的症状包括 8 人中有 5 人出现下肢肌肉波动或 8 人保留延髓肌肉中有 2 人出现所有肢体肌肉，10 人中有 9 人出现疲劳，8 人中有 3 人出现轻度近端无力，8 人中有 1 人出现孤立性肌痛，随后发展弥漫的涟漪。所有患者都有敲击引起的肌肉波纹，一半有敲击或拉伸引起的肌肉隆起。10 名患者中有 4 名出现近端无力。除 1 名患者外，所有患者的血浆肌酸激酶均升高。10 名患者中有 6 名接受了恶性肿瘤筛查；癌症仅在 1 人中前瞻性检测到。8 名患有 cavin-4 IgG 的患者中有 7 人进行了肌肉活检；免疫组化分析的 6 个标本中有 6 个显示肌膜 cavin-4 免疫反应性的马赛克模式。结果为血清阳性并接受免疫治疗的 6 名患者中有 3 名症状完全消退，1 名轻度改善，2 名无变化。结论和相关性 研究结果表明，cavin-4 IgG 可能是 iRMD 中鉴定的第一个特异性血清学自身抗体生物标志物。