Long-term safety and efficacy of weekly subcutaneous tocilizumab monotherapy in patients with rheumatoid arthritis who had an inadequate response to subcutaneous tocilizumab every other week: Results from the open-label extension of the SHINOBI study

Ogata, Atsushi; Tanaka, Yoshiya; Ishii, Tomonori; Kaneko, Motohide; Miwa, Hiroko; Ohsawa, Shino; Yamakawa, Reiji

doi:10.1080/14397595.2018.1533514

Cited by 10 publications

(3 citation statements)

References 23 publications

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“…The combined results indicate that the IL-6R/STAT3 signaling axis is preferentially but not exclusively active in ABC-DLBCL, and a negative prognosticator for both subtypes; STAT3 phosphorylation correlates with activation of the upstream kinase JAK2. IL-6R is a therapeutic target in rheumatoid arthritis (RA); a neutralizing antibody targeting the IL-6R, tocilizumab (trade name: Actemra), is approved for the treatment of RA in adult patients (Ogata et al, 2012(Ogata et al, , 2018 and has also recently received FDA approval for the treatment of cytokine release syndrome related to CAR T-cell therapy (Le et al, 2018). We sought to examine a possible benefit of tocilizumab monotherapy in MISTRG6 mice that harbor spleen-and bone marrow-colonizing lymphomas due to intravenous transplantation of serially passaged primary DLBCL cells; this patient-derived xenograft is positive for the IL-6R and also positive for phosphorylated STAT3 (Fig 4).…”

Section: Il-6 Signaling Contributes To Myc-driven Lymphomagenesis In mentioning

confidence: 99%

The IL ‐6 signaling complex is a critical driver, negative prognostic factor, and therapeutic target in diffuse large B‐cell lymphoma

et al. 2019

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Interleukin‐6 (IL‐6) is a growth factor for normal B cells and plasma cell‐derived malignancies. Here, we show that the IL‐6 signaling pathway is also active in a subset of diffuse large B‐cell lymphoma (DLBCL) patients with particularly poor prognosis. Primary DLBCL cells and DLBCL cell lines expressing IL‐6R engraft and form orthotopic lymphomas in humanized mice that ectopically produce human IL‐6, and in mice reconstituted with a human immune system. We show that a subset of DLBCL cases have evolved mechanisms that ensure constitutive activation of the IL‐6 signaling pathway, i.e., the expression of both chains of the IL‐6R, the expression of the cytokine itself, and the mutational inactivation of a negative regulator of IL‐6 signaling, SOCS1. IL‐6 signaling promotes MYC‐driven lymphomagenesis in a genetically engineered model, and treatment with the IL‐6R‐specific antibody tocilizumab reduces growth of primary DLBCL cells and of DLBCL cell lines in various therapeutic settings. The combined results uncover the IL‐6 signaling pathway as a driver and negative prognosticator in aggressive DLBCL that can be targeted with a safe and well‐tolerated biologic.

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Section: Il-6 Signaling Contributes To Myc-driven Lymphomagenesis In mentioning

confidence: 99%

The IL ‐6 signaling complex is a critical driver, negative prognostic factor, and therapeutic target in diffuse large B‐cell lymphoma

et al. 2019

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“…In the MRA229JP study, which was a study evaluating the efficacy and safety of TCZ-SC (162 mg every 2 weeks) versus TCZ-IV (8 mg/kg every 4 weeks) in patients with rheumatoid arthritis, it was suggested that serum TCZ trough concentrations tended to decrease with increasing body weight, body surface area, and body mass index (BMI). American College of Rheumatology 20 responses were consistently lower in patients treated with TCZ-SC than in patients treated with TCZ-IV in patients with body weight ≥70 kg or BMI ≥25 kg/m 2 [ 10 ]. In fact, the BMI of the patient in Case 6 was 32.3 kg/m 2 .…”

Section: Discussionmentioning

confidence: 99%

Long-term clinicopathological characteristics of TAFRO syndrome and its relapse: a case series study

Yoshimura,

Mizuno,

Ikuma

et al. 2024

Clinical Kidney Journal

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Introduction This study aimed to analyze the clinical course of TAFRO syndrome in patients through extended follow-up, focusing on recurrent cases and long-term remission. Methods This was a retrospective case series study. We assessed the clinical course of patients diagnosed with TAFRO syndrome between January 2012 and September 2022 at Toranomon Hospital or Toranomon Hospital Kajigaya, excluding those patients who died during the initial hospitalization. Results Twelve patients were included. Baseline characteristics, laboratory findings, treatment modalities, and outcomes were assessed. During the median follow-up period of 1 474 days, two patients experienced recurrence following a reduction in tocilizumab (TCZ) dose, while two achieved remission for over 400 days without TCZ treatment. The remaining eight patients maintained remission under the continued TCZ therapy. Recurrence diagnosis was complicated by the non-simultaneous presentation of the five manifestations of TAFRO syndrome. The patients who experienced recurrence showed milder manifestations and faster recovery than the initial onset. Glomerular endotheliopathy was evident in kidney biopsies during recurrence, which was similar to the initial presentation. In a case where only inflammation preceded other manifestation, a kidney biopsy was pivotal in distinguishing TAFRO syndrome relapse from other inflammatory conditions such as infection. Pretreatment serum IL-6 levels were within the reference range only in patients who experienced long-term remission without TCZ treatment. Conclusions This is the first study to perform kidney biopsies on recurrent TAFRO cases, highlighting recurrence after TCZ dosage reduction, non-simultaneous manifestation of symptoms, the utility of kidney biopsies in recurrence diagnosis, and potential non-IL-6 pathogenesis factors. Pretreatment serum IL-6 levels may help identify patients suitable for maintenance therapy without TCZ. Further investigation is warranted to identify stratified treatment approaches based on individual etiologic factors.

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“…There are several limitations to this study. First, although subcutaneous injection of tocilizumab every week (QW) has been approved since June 2017 in Japan for treatment of RA with inadequate response to subcutaneous injection every other week, 43 44 no patients participating in this study were treated with the QW dosing regimen of tocilizumab. If we had used the QW in this study, more favourable outcomes might have been induced in the tocilizumab group.…”

Section: Discussionmentioning

confidence: 99%

Tofacitinib versus tocilizumab in the treatment of biological-naïve or previous biological-failure patients with methotrexate-refractory active rheumatoid arthritis

Mori

Urata²,

Yoshitama

et al. 2021

RMD Open

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ObjectivesTo compare effectiveness between tofacitinib and tocilizumab treatments for biological disease-modifying antirheumatic drug (bDMARD)-naïve patients or previous bDMARD-failure patients with active rheumatoid arthritis (RA) refractory to methotrexate (MTX).MethodsWe used two ongoing real-world registries of patients with RA who had first started tofacitinib or tocilizumab between August 2013 and February 2019 at our institutions. Clinical disease activity index (CDAI)-based improvements at 12 months were used for comparisons between tofacitinib and tocilizumab treatments, separately for bDMARD-naïve and previous bDMARD-failure patients.ResultsA total of 464 patients with RA with high or moderate CDAI were enrolled (247 with tofacitinib and 217 with tocilizumab). After adjustments for treatment-selection bias by propensity score matching, we showed that tofacitinib was more likely to induce and maintain ≥85% improvement in CDAI (CDAI85), CDAI70 and remission at 12 months compared with tocilizumab in bDMARD-naïve patients. After adjusting for concurrent use of MTX and prednisolone, the ORs of tofacitinib versus tocilizumab were 3.88 (95% CI 1.87 to 8.03) for CDAI85, 2.89 (95% CI 1.43 to 5.84) for CDAI70 and 3.31 (95% CI 1.69 to 6.48) for remission. These effects were not observed in bDMARD-failure patients. In tofacitinib treatment for bDMARD-failure patients, the number of previously failed bDMARD classes was not associated with CDAI-based improvements. The rate of overall adverse events was similar between both treatments. Similar ORs were obtained from patients adjusted by inverse probability of treatment weighting.ConclusionsCompared with tocilizumab, tofacitinib can induce greater improvements during the first 12-month treatment in bDMARD-naïve patients, but this difference was not observed in previous bDMARD-failure patients.

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Long-term safety and efficacy of weekly subcutaneous tocilizumab monotherapy in patients with rheumatoid arthritis who had an inadequate response to subcutaneous tocilizumab every other week: Results from the open-label extension of the SHINOBI study

Cited by 10 publications

References 23 publications

The IL ‐6 signaling complex is a critical driver, negative prognostic factor, and therapeutic target in diffuse large B‐cell lymphoma

The IL ‐6 signaling complex is a critical driver, negative prognostic factor, and therapeutic target in diffuse large B‐cell lymphoma

Long-term clinicopathological characteristics of TAFRO syndrome and its relapse: a case series study

Tofacitinib versus tocilizumab in the treatment of biological-naïve or previous biological-failure patients with methotrexate-refractory active rheumatoid arthritis

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