Edward M Vital1, Shouvik Dass1, Maya H Buch1, Andrew C Rawstron2, Paul Emery1. 1. NIHR Leeds Biomedical Research Unit, Leeds Teaching Hospitals NHS Trust, Leeds, UK Leeds Institute of Rheumatic and Musculoskeletal Medicine, University of Leeds, Leeds, UK. 2. Haematological Malignancy Diagnostic Service, Leeds Teaching Hospitals NHS Trust, Leeds, UK.
Abstract
OBJECTIVES: Since clinical non-response to 2×1000 mg rituximab has previously been found to be associated with incomplete B cell depletion, we determined, in a randomised controlled proof of concept study, whether patients with initial incomplete B cell depletion would benefit from an additional infusion of rituximab at week 4. METHODS: Patients with active rheumatoid arthritis despite methotrexate received a first infusion of rituximab 1000 mg and were tested for persistent B cells using highly sensitive flow cytometry on day 15. All received a second infusion of 1 g (according to license), but patients with persistent B cells were subsequently randomised double-blind to receive, 2 weeks later, either a third infusion of 1000 mg rituximab or placebo. Clinical response was determined by European League Against Rheumatism (EULAR) and American College of Rheumatology (ACR) criteria. RESULTS: Baseline characteristics were balanced between groups. Treatment with 3×1000 mg rituximab resulted in significantly greater depletion (lower B cell and plasmablast numbers between 8 and 28 weeks) paralleled by significantly better EULAR and ACR20 response rates at 40 weeks (p=0.035 and p=0.027, respectively) and 52 weeks (p=0.021 and p=0.043, respectively) compared with 2×1000 mg. Immunoglobulin titres remained stable in both arms, and adverse event rates were balanced. CONCLUSIONS: In rituximab-treated patients with incomplete B cell depletion (predictive of poor response), an extra 1000 mg infusion of rituximab at 4 weeks produced both better depletion and clinical responses than placebo with no worsening of safety. Degree of depletion is an important, but modifiable, determinant of response. Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://group.bmj.com/group/rights-licensing/permissions.
OBJECTIVES: Since clinical non-response to 2×1000 mg rituximab has previously been found to be associated with incomplete B cell depletion, we determined, in a randomised controlled proof of concept study, whether patients with initial incomplete B cell depletion would benefit from an additional infusion of rituximab at week 4. METHODS: Patients with active rheumatoid arthritis despite methotrexate received a first infusion of rituximab 1000 mg and were tested for persistent B cells using highly sensitive flow cytometry on day 15. All received a second infusion of 1 g (according to license), but patients with persistent B cells were subsequently randomised double-blind to receive, 2 weeks later, either a third infusion of 1000 mg rituximab or placebo. Clinical response was determined by European League Against Rheumatism (EULAR) and American College of Rheumatology (ACR) criteria. RESULTS: Baseline characteristics were balanced between groups. Treatment with 3×1000 mg rituximab resulted in significantly greater depletion (lower B cell and plasmablast numbers between 8 and 28 weeks) paralleled by significantly better EULAR and ACR20 response rates at 40 weeks (p=0.035 and p=0.027, respectively) and 52 weeks (p=0.021 and p=0.043, respectively) compared with 2×1000 mg. Immunoglobulin titres remained stable in both arms, and adverse event rates were balanced. CONCLUSIONS: In rituximab-treated patients with incomplete B cell depletion (predictive of poor response), an extra 1000 mg infusion of rituximab at 4 weeks produced both better depletion and clinical responses than placebo with no worsening of safety. Degree of depletion is an important, but modifiable, determinant of response. Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://group.bmj.com/group/rights-licensing/permissions.
Entities:
Keywords:
B cells; DMARDs (biologic); Rheumatoid Arthritis; Treatment
Authors: Joerg Ermann; Deepak A Rao; Nikola C Teslovich; Michael B Brenner; Soumya Raychaudhuri Journal: Nat Rev Rheumatol Date: 2015-06-02 Impact factor: 20.543
Authors: Jasvinder A Singh; Alomgir Hossain; Amy S Mudano; Elizabeth Tanjong Ghogomu; Maria E Suarez-Almazor; Rachelle Buchbinder; Lara J Maxwell; Peter Tugwell; George A Wells Journal: Cochrane Database Syst Rev Date: 2017-05-08
Authors: Jasvinder A Singh; Alomgir Hossain; Elizabeth Tanjong Ghogomu; Ahmed Kotb; Robin Christensen; Amy S Mudano; Lara J Maxwell; Nipam P Shah; Peter Tugwell; George A Wells Journal: Cochrane Database Syst Rev Date: 2016-05-13
Authors: Jasvinder A Singh; Alomgir Hossain; Elizabeth Tanjong Ghogomu; Amy S Mudano; Lara J Maxwell; Rachelle Buchbinder; Maria Angeles Lopez-Olivo; Maria E Suarez-Almazor; Peter Tugwell; George A Wells Journal: Cochrane Database Syst Rev Date: 2017-03-10
Authors: C Fiehn; J Holle; C Iking-Konert; J Leipe; C Weseloh; M Frerix; R Alten; F Behrens; C Baerwald; J Braun; H Burkhardt; G Burmester; J Detert; M Gaubitz; A Gause; E Gromnica-Ihle; H Kellner; A Krause; J Kuipers; H-M Lorenz; U Müller-Ladner; M Nothacker; H Nüsslein; A Rubbert-Roth; M Schneider; H Schulze-Koops; S Seitz; H Sitter; C Specker; H-P Tony; S Wassenberg; J Wollenhaupt; K Krüger Journal: Z Rheumatol Date: 2018-08 Impact factor: 1.372
Authors: Diana G Adlowitz; Jennifer Barnard; Jamie N Biear; Christopher Cistrone; Teresa Owen; Wensheng Wang; Arumugam Palanichamy; Ezinma Ezealah; Debbie Campbell; Chungwen Wei; R John Looney; Inaki Sanz; Jennifer H Anolik Journal: PLoS One Date: 2015-06-05 Impact factor: 3.240