Type I IFN response associated with mTOR activation in the TAFRO subtype of idiopathic multicentric Castleman disease

Pai, Ruth-Anne Langan; Japp, Alberto Sada; Gonzalez, Michael; Rasheed, Rozena; Okumura, Mariko; Arenas, Daniel; Pierson, Sheila K; Powers, Victoria; Layman, Awo Akosua Kesewa; Kao, Charlly; Hákonarson, Hákon; Rhee, Frits van; Betts, Michael R.; Kambayashi, Taku; Fajgenbaum, David C

doi:10.1172/jci.insight.135031

Cited by 45 publications

(49 citation statements)

References 40 publications

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“…Patients with idiopathic multicentric Castleman’s disease who have progressive organ dysfunction and who do not have a response to anti–interleukin-6 therapy are often treated with combination cytotoxic chemotherapy to nonspecifically eliminate hyperinflammatory cells. 81 Other elevated serum cytokines and cellular signaling pathways that could be considered for therapeutic targeting include CXCL13, CXCL10 (interferon-inducible protein 10 [IP-10]), VEGF-A, 82 type I interferon, 83 mTOR complex 1 (mTORC1), 84 and JAK-STAT3. These findings have led to treatment with the mTORC1 inhibitor sirolimus in patients with idiopathic multicentric Castleman’s disease who do not have a response to anti–interleukin-6 therapy.…”

Section: Monogenic or Autoimmune Cytokine Stormmentioning

confidence: 99%

Cytokine Storm

Fajgenbaum¹,

2020

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Grade 1 Mild; asymptomatic or mild symptoms; clinical or diagnostic observations only; intervention not indicated. Grade 2 Moderate; minimal, local or noninvasive intervention indicated; limiting ageappropriate instrumental ADL*. Grade 3 Severe or medically significant but not immediately life-threatening; hospitalization or prolongation of hospitalization indicated; disabling; limiting self care ADL**. Grade 4 Life-threatening consequences; urgent intervention indicated. Grade 5 Death related to AE. A Semicolon indicates 'or' within the description of the grade. A single dash (-) indicates a Grade is not available. Not all Grades are appropriate for all AEs. Therefore, some AEs are listed with fewer than five options for Grade selection. Grade 5 Grade 5 (Death) is not appropriate for some AEs and therefore is not an option. Definitions A brief Definition is provided to clarify the meaning of each AE term. A single dash (-) indicates a Definition is not available. Navigational Notes A Navigational Note is used to assist the reporter in choosing a correct AE. It may list other AEs that should be considered in addition to or in place of the AE in question. A single dash (-) indicates a Navigational Note has not been defined for the AE term. Activities of Daily Living (ADL) *Instrumental ADL refer to preparing meals, shopping for groceries or clothes, using the telephone, managing money, etc. **Self care ADL refer to bathing, dressing and undressing, feeding self, using the toilet, taking medications, and not bedridden. Table of Contents Blood and lymphatic system disorders .

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Section: Monogenic or Autoimmune Cytokine Stormmentioning

confidence: 99%

Cytokine Storm

Fajgenbaum¹,

2020

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“…Furthermore, data extracted into ACCELERATE have served as critical correlative data for translational research performed on biospecimens around the world; patient data and tissue biospecimens collected from ACCELERATE have been used in published and ongoing translational and clinical studies that have led to treatment guidelines, critical biological insights, and the discovery of therapeutic targets ( Figure 6 ). 14 , 15 , 16 , 17 , 18 , 19 Overall, ACCELERATE patient data and tissue samples have enabled translational research studies that shed light on iMCD pathogenesis and will serve as an engine for future discovery.…”

Section: Resultsmentioning

confidence: 99%

“…In the past 3 years, data and tissue samples collected for ACCELERATE have been used in 5 published studies that have identified key cell types, signaling pathways, chemokines, therapeutic targets, and optimal treatment approaches. 14 , 15 , 16 , 17 , 19 The ACCELERATE model may also be helpful for other rare disease research studies.…”

Section: Discussionmentioning

confidence: 99%

ACCELERATE: A Patient-Powered Natural History Study Design Enabling Clinical and Therapeutic Discoveries in a Rare Disorder

Pierson

Khor

Ziglar

et al. 2020

Cell Reports Medicine

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Summary Geographically dispersed patients, inconsistent treatment tracking, and limited infrastructure slow research for many orphan diseases. We assess the feasibility of a patient-powered study design to overcome these challenges for Castleman disease, a rare hematologic disorder. Here, we report initial results from the ACCELERATE natural history registry. ACCELERATE includes a traditional physician-reported arm and a patient-powered arm, which enables patients to directly contribute medical data and biospecimens. This study design enables successful enrollment, with the 5-year minimum enrollment goal being met in 2 years. A median of 683 clinical, laboratory, and imaging data elements are captured per patient in the patient-powered arm compared with 37 in the physician-reported arm. These data reveal subgrouping characteristics, identify off-label treatments, support treatment guidelines, and are used in 17 clinical and translational studies. This feasibility study demonstrates that the direct-to-patient design is effective for collecting natural history data and biospecimens, tracking therapies, and providing critical research infrastructure.

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“…Notably, 14/18 (78%) iMCD‐TAFRO patients responded to a combination including anti‐IL‐6 therapy (siltuximab or tocilizumab) and 9/13 (69%) responded to anti‐IL‐6 therapy±corticosteroids, according to the case report authors' assessments; three patients who responded to anti‐IL‐6 ± corticosteroids relapsed before the time of publication (Table 3). 17‐29 We also assessed all of the iMCD‐TAFRO and iMCD‐NOS cases with HyperV or HV histopathology at UAMS that were treated with anti‐IL‐6 therapy±corticosteroids. Here, 4/4 iMCD‐TAFRO and 7/7 iMCD‐NOS patients responded, according to the investigator's assessment of clinical and laboratory abnormalities.…”

Section: Resultsmentioning

confidence: 99%

“…therapy (siltuximab or tocilizumab) and 9/13 (69%) responded to anti-IL-6 therapy±corticosteroids, according to the case report authors' assessments; three patients who responded to anti-IL-6 ± corticosteroids relapsed before the time of publication (Table 3). [17][18][19][20][21][22][23][24][25][26][27][28][29] We also assessed all of the iMCD-TAFRO and iMCD- Anti-IL-6 + rituximab or cyclosporine ± CS iMCD-TAFRO 5 5 3…”

Section: Real-world Datamentioning

confidence: 99%