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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.To describe a novel autoantibody biomarker of iRMD and report associated clinicopathological characteristics.This retrospective cohort study evaluated archived sera from 10 adult patients at tertiary care centers at the Mayo Clinic, Rochester, Minnesota, and BrighamWomen'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.Diagnosis of iRMD.Detection of a common autoantibody in serum of patients sharing similar clinical and myopathological features.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.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.

A 72-year-old man had mild proximal weakness that developed into progressive camptocormia, head drop, numbness, and significant muscle wasting. What is your diagnosis?

Objectives To investigate immune-mediated necrotizing myopathy (IMNM) association with cancer and its clinical implications. Methods IMNM cases were identified 1 January 2000 to 31 December 2020 matching sex and age controls (4:1). Results A total of 152 patients with IMNM were identified and among serologically tested, 60% (83/140) were HMGCR-IgG+, 14% (20/140) were SRP-IgG+ and 26% (37/140) were seronegative. Cancer rates were not significantly different between serological subgroups; 18.1% (15/83) HMGCR-IgG+, 25% (5/20) SRP-IgG+ and 30% (11/37) seronegative (P = 0.34). Cancer screening was performed within 12 months from IMNM diagnosis in 88% (134/152) (whole-body CT plus FDG-PET CT in 53, CT alone in 72 and FDG-PET alone in 9). FDG-PET/CT was positive in 73% (25/34) of cancers. Increasing age was the only risk associated with cancer (P = 0.02). The odds of developing cancer at ±3 or ±5 years from IMNM diagnosis was not higher than controls (OR = 0.49; CI: 0.325–0.76). Lifetime IMNM diagnosis of cancer was less compared with controls (OR = 0.5 CI: 0.33–0.78, P = 0.002). Most patients responded to treatment (137/147, P Conclusions Greater cancer risk is not observed in IMNM vs controls. Cancer screening in IMNM should be individualized based on age-personal and family history, including consideration of FDG-PET/CT. Immune-treatment response did not differ with cancer.

ObjectiveTo describe a novel autoantibody biomarker of Immune mediated rippling muscle disease (iRMD).BackgroundiRMD is a rare immunotherapy-responsive myopathy characterized by wave-like muscle contractions (rippling) and percussion/stretch-induced muscle mounding. However, serological biomarker of this disease is lacking.Design/MethodsA Retrospective review was done to identify iRMD patients with stored sera in Mayo Neuroimmunology laboratory. Archived sera from IRMD patients were evaluated for a common biomarker of IRMD using phage immunoprecipitation sequencing (PhIP-Seq).ResultsArchival sera from 10 patients with clinical diagnosis of iRMD were retrieved. Whole human proteome PhIP-Seq identified peptides corresponding to different regions of the cavin-4 in sera of iRMD patients. Eight of the ten iRMD cases were positive for cavin-4 IgG by immunofluorescent cell-based-assay (CBA) using cavin-4-transfected COS7 cells. The cavin-4-reactive IgG in all 8 positive sera was of IgG1 subclass. None of the disease control sera (98 immune-mediated myopathy/neuromuscular junction disorders, 20 autoimmune CNS diseases and 123 healthy subjects) contained cavin-4-reactive IgG. Furthermore, none of the iRMD patients' sera were positive for caveolin-3 IgG. The majority of seropositive cases were males (6/8, 75%) with median age of 51 years (range 18-76). Three seropositive patients had co-existing myasthenia gravis (38%). Creatine Kinase was elevated in 6/7 tested patients (median 771 U/L, range: 132-2625 U/L). Muscle biopsy was performed in 7 of the 8 cavin-4 IgG seropositive patients; 6/6 specimens analyzed immunohistochemically revealed a mosaic pattern of sarcolemmal cavin-4 immunoreactivity. Three of 6 seropositive patients who received immunotherapy had complete resolution of symptoms; one had mild improvement and two had no change.ConclusionsCavin-4 IgG is a novel and specific serological autoantibody biomarker identified in iRMD. Depletion of cavin-4 expression in iRMD patient muscle biopsies suggests the potential role of this autoantigen in disease pathogenesis.