Targeting GM-CSF in rheumatological conditions: risk of PAP

Rooney, Leah; Veale, Douglas J.; Orr, Carl; McCarthy, Cormac

doi:10.1016/s2665-9913(21)00145-4

Cited by 2 publications

(1 citation statement)

References 6 publications

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“…30 31 However, a more pronounced inhibition of the inflammatory biomarker, IL-6, was reported with mavrilimumab. 32 Previously, there have been theoretical safety concerns regarding anti-GM-CSF therapies due to the potential impairment of myeloid cell production and function that could result in PAP, 33 and the potential impact on immunological responses 34 that could result in increased infections or reactivation of latent infections such as TB, as observed with anti-TNFs. 35 36 However, there were no reports of PAP, the incidence of neutropenia or serious infections was ≤4% with either otilimab dose (COVID-19 infection was balanced across treatment groups and accounted for approximately half of serious infections) and there were no reports of active TB or reactivation of latent TB in these trials.…”

Section: Discussionmentioning

confidence: 99%

Anti-GM-CSF otilimab versus tofacitinib or placebo in patients with active rheumatoid arthritis and an inadequate response to conventional or biologic DMARDs: two phase 3 randomised trials (contRAst 1 and contRAst 2)

Fleischmann,

van der Heijde,

Strand

et al. 2023

Ann Rheum Dis

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ObjectivesTo investigate the efficacy and safety of otilimab, an antigranulocyte-macrophage colony-stimulating factor antibody, in patients with active rheumatoid arthritis.MethodsTwo phase 3, double-blind randomised controlled trials including patients with inadequate responses to methotrexate (contRAst 1) or conventional synthetic/biologic disease-modifying antirheumatic drugs (cs/bDMARDs; contRAst 2). Patients received background csDMARDs. Through a testing hierarchy, subcutaneous otilimab (90/150 mg once weekly) was compared with placebo for week 12 endpoints (after which, patients receiving placebo switched to active interventions) or oral tofacitinib (5 mg two times per day) for week 24 endpoints. Primary endpoint: proportion of patients achieving an American College of Rheumatology response ≥20% (ACR20) at week 12.ResultsThe intention-to-treat populations comprised 1537 (contRAst 1) and 1625 (contRAst 2) patients. Primary endpoint: proportions of ACR20 responders were statistically significantly greater with otilimab 90 mg and 150 mg vs placebo in contRAst 1 (54.7% (p=0.0023) and 50.9% (p=0.0362) vs 41.7%) and contRAst 2 (54.9% (p<0.0001) and 54.5% (p<0.0001) vs 32.5%). Secondary endpoints: in both trials, compared with placebo, otilimab increased the proportion of Clinical Disease Activity Index (CDAI) low disease activity (LDA) responders (not significant for otilimab 150 mg in contRAst 1), and reduced Health Assessment Questionnaire-Disability Index (HAQ-DI) scores. Benefits with tofacitinib were consistently greater than with otilimab across multiple endpoints. Safety outcomes were similar across treatment groups.ConclusionsAlthough otilimab demonstrated superiority to placebo in ACR20, CDAI LDA and HAQ-DI, improved symptoms, and had an acceptable safety profile, it was inferior to tofacitinib.Trial registration numbersNCT03980483,NCT03970837.

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Section: Discussionmentioning

confidence: 99%

Anti-GM-CSF otilimab versus tofacitinib or placebo in patients with active rheumatoid arthritis and an inadequate response to conventional or biologic DMARDs: two phase 3 randomised trials (contRAst 1 and contRAst 2)

Fleischmann,

van der Heijde,

Strand

et al. 2023

Ann Rheum Dis

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GMCSF: More an Inflammatory Immune ‘Cytokine’ Than a Growth Factor

Khullar,

Leishangthem,

Dhir

2024

Indian Journal of Rheumatology

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GMCSF, discovered in 1977, was one of the first growth factors for myelopoiesis. However, over time, it has been found to be redundant for basal myelopoiesis. Rather, its important function seems to be its effect on mature myeloid cells and the immune system. It is produced by a variety of cells, including macrophages, endothelial cells, T-cells etc. and works on the GMCSF receptor, which is mainly expressed by mature myeloid cells such as neutrophils, monocytes and macrophages. It has been found to be an important mediator of at least two autoimmune diseases: rheumatoid arthritis and multiple sclerosis. Animal models prove that GMCSF produced from T-cells play a crucial role in their pathogenesis of both these autoimmune diseases. This has led to the development of therapeutics which target GMCSF or its receptor. Clinical trials have been carried out in rheumatoid arthritis, which have shown modest efficacy. In addition, anti-GMCSF therapy has shown promise in giant cell arteritis.

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Targeting GM-CSF in rheumatological conditions: risk of PAP

Cited by 2 publications

References 6 publications

Anti-GM-CSF otilimab versus tofacitinib or placebo in patients with active rheumatoid arthritis and an inadequate response to conventional or biologic DMARDs: two phase 3 randomised trials (contRAst 1 and contRAst 2)

Anti-GM-CSF otilimab versus tofacitinib or placebo in patients with active rheumatoid arthritis and an inadequate response to conventional or biologic DMARDs: two phase 3 randomised trials (contRAst 1 and contRAst 2)

GMCSF: More an Inflammatory Immune ‘Cytokine’ Than a Growth Factor

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