{
  "abstract": "Introduction: Anti–IL-6 therapy with tocilizumab (TCZ) is ineffective in a proportion of patients with idiopathic multicentric Castleman disease (iMCD), particularly the TAFRO subtype, and rescue options remain limited. Evidence for mTOR inhibition comes mainly from cohorts in which iMCD-TAFRO was underrepresented.\n\nMethods: Eight Japanese patients with refractory iMCD (iMCD-TAFRO, n=6; iMCD-NOS, n=1) or TAFRO syndrome without iMCD (n=1) received add-on sirolimus (1–2 mg/day). Five had active refractory iMCD-TAFRO at initiation and formed the efficacy set; Case 5 (sirolimus for glucocorticoid sparing), Case 1 (iMCD-NOS) and Case 3 (TAFRO syndrome without iMCD) are reported descriptively. Response was defined as improvement in at least one refractory feature (CRP <0.3 mg/dL, platelets >15×10 ⁴ /µL, improvement of anasarca, or a ≥50% rise in eGFR) at 3 and 12 months.\n\nResults: In the efficacy set, 4/5 responded at 3 months (80%; 95% CI 28–99) and 3/4 evaluable at 12 months (75%; 95% CI 19–99); a prespecified TAFRO-phenotype analysis (n=6, including Case 3) gave 5/6 (83%; 95% CI 36–100) and 4/5 evaluable (80%; 95% CI 28–99). Under a prespecified stringent definition additionally requiring CRP normalization and no escalation of concomitant immunosuppression, proportions fell to 3/5 (60%) and 2/4 evaluable (50%), each reclassification resting on a single criterion. All six responders eventually discontinued sirolimus without relapse during available follow-up. Glucocorticoids were withdrawn in all four responders receiving prednisolone, TCZ intervals were extended to ≥5 weeks in three patients, and both patients with dialysis-dependent active disease stopped hemodialysis. Exploratory paired single-cell RNA sequencing in one TAFRO-phenotype patient showed reductions in inflammatory monocytes and B cells with lower cytotoxic and proliferative programs.\n\nDiscussion: Given the very small sample, wide confidence intervals and the sensitivity of the estimates to the response definition, add-on sirolimus should be regarded as a hypothesis-generating adjunctive rescue option on top of standard treatment, not a substitute, in refractory iMCD-TAFRO.",
  "abstract_shown": true,
  "affiliations": [
    "Department of Immunology and Rheumatology, Division of Advanced Preventive Medical Sciences, Nagasaki University Graduate School of Biomedical Sciences",
    "Clinical Research Center, Nagasaki University Hospital",
    "Division of Hematology, Mayo Clinic",
    "Division of Translational Medicine and Human Genetics, University of Pennsylvania",
    "Myeloma Center, Winthrop P. Rockefeller Cancer Institute, University of Arkansas for Medical Sciences",
    "DEJIMA Infectious Disease Research Alliance (DIDA), Nagasaki University",
    "Biomedical Research and Career Support Office, Nagasaki University"
  ],
  "article_type": "research article",
  "arxiv": null,
  "author_total": 9,
  "authors": [
    {
      "affs": [
        0,
        1
      ],
      "name": "Remi Sumiyoshi"
    },
    {
      "affs": [
        0
      ],
      "name": "Tomohiro Koga"
    },
    {
      "affs": [
        0
      ],
      "name": "Toru Michitsuji"
    },
    {
      "affs": [
        0
      ],
      "name": "Masataka Umeda"
    },
    {
      "affs": [
        0
      ],
      "name": "Ayuko Takatani"
    },
    {
      "affs": [
        2
      ],
      "name": "Yoshito Nishimura"
    },
    {
      "affs": [
        3
      ],
      "name": "David C Fajgenbaum"
    },
    {
      "affs": [
        4
      ],
      "name": "Frits van Rhee"
    },
    {
      "affs": [
        1,
        5,
        6
      ],
      "name": "Atsushi Kawakami"
    }
  ],
  "bibtex": "https://research.draconitic.com/paper/6qp837xsqqmfa.bib",
  "cited_by": 0,
  "doi": "10.3389/fimmu.2026.1963440",
  "fulltext_url": "https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13719344/?tool=EBI",
  "id": "6qp837xsqqmfa",
  "issns": [
    "1664-3224"
  ],
  "landing_url": "https://www.frontiersin.org/articles/10.3389/fimmu.2026.1963440/full",
  "language": "eng",
  "licence": "CC-BY-4.0",
  "licence_label": "CC BY 4.0",
  "licence_source": "article",
  "licence_url": "https://creativecommons.org/licenses/by/4.0/",
  "metadata_licence": null,
  "native_subjects": [
    [
      "heading",
      "Original Research"
    ],
    [
      "openalex",
      "2745|IgG4-Related and Inflammatory Diseases"
    ]
  ],
  "openalex": "W7222760227",
  "pdf_url": "https://www.frontiersin.org/journals/immunology/articles/10.3389/fimmu.2026.1963440/pdf",
  "pmcid": "PMC13719344",
  "pmid": "42964130",
  "published": "2026-10-16",
  "publisher": "Frontiers Media SA",
  "ris": "https://research.draconitic.com/paper/6qp837xsqqmfa.ris",
  "sources": [
    {
      "first_seen": "2026-10-30T12:19:17Z",
      "native_id": "10.3389/fimmu.2026.1963440",
      "source": "crossref",
      "url": "https://www.frontiersin.org/articles/10.3389/fimmu.2026.1963440/full"
    },
    {
      "first_seen": "2026-10-31T12:21:36Z",
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  ],
  "subjects": [
    {
      "field": "biology",
      "origin": "issn:1664-3224",
      "subfield": "immunology"
    }
  ],
  "title": "Add-on sirolimus in refractory iMCD-TAFRO: a TAFRO-enriched 8-patient case series with paired single-cell profiling",
  "title_text": "Add-on sirolimus in refractory iMCD-TAFRO: a TAFRO-enriched 8-patient case series with paired single-cell profiling",
  "type": "peer-reviewed",
  "updated_at": "2026-11-03T12:20:25Z",
  "url": "https://research.draconitic.com/paper/6qp837xsqqmfa",
  "venue": "Frontiers in Immunology",
  "versions": []
}