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Background: Secondary inefficacy characterized by infusion reactions and anti-drug antibodies occur in 14% of SLE patients treated with repeat rituximab courses(1). Obinutuzumab is a next-generation humanized type-2 anti-CD20 therapy licensed for hematological malignancies which may overcome this issue(2).
Objectives: We set out to evaluate the clinical efficacy and safety of obinutuzumab in a cohort of rituximab resistant SLE patients.
Methods: We collated data from SLE patients receiving obinutuzumab for secondary non-response to rituximab in BILAG centres. Disease activity was assessed using BILAG-2004, SLEDAI-2K and serology before, and 6 months after, obinutuzumab 2x1000mg infusions alongside methylprednisolone 100mg. Flow cytometry where possible was carried out using a multiple gating highly sensitive strategy.
Results: All 9 patients included in the study received obinutuzumab alongside concomitant oral immunosuppression. At 6 months post-obinutuzumab, there were significant reductions in median SLEDAI-2K from 12 to 6 (p=0.014) and total BILAG-2004 score from 21 to 2 (p=0.009). Complement C3 and dsDNA titres improved significantly (both p=0.04). Non statistically significant numerical improvements were seen in C4 levels.
Of 8/9 patients receiving concomitant oral prednisolone at baseline (all >10mg/day), 5/9 had their dose reduced at 6 months; 4/8 were on 5mg/day and were in Lupus Low Disease Activity State. After obinutuzumab, 6/9 patients with peripheral B-cell data achieved complete depletion including 4/4 assessed with highly sensitive assays. 1/9 obinutuzumab non-responder required cyclophosphamide therapy. 1 unvaccinated patient died from COVID-19.
Baseline characteristics, disease activity and steroid doses before and after last obinutuzumab/rituximab.
| Patient | Ethnicity | Disease duration (Years) | Age (Years) | Total BILAG-2004 before Obi | Total BILAG-2004 after Obi | SLEDAI-2K before Obi | SLEDAI-2K after Obi | Prednisolone before Obi (mg) | Prednisolone after Obi (mg) |
|---|---|---|---|---|---|---|---|---|---|
| 1 | South Asian | 10.8 | 36.4 | 18 | 2 | 14 | 8 | 10 | 5 |
| 2 | South Asian | 6.3 | 24.4 | 24 | 2 | 12 | 4 | 30 | 10 |
| 3 | South Asian | 11.9 | 34.8 | 29 | 1 | 10 | 4 | 10 | 10 |
| 4 | South Asian | 8.2 | 41.9 | 21 | 1 | 6 | 0 | 15 | 15 |
| 5 | South Asian | 6.8 | 29.4 | 32 | 21 | 18 | 14 | 50 | 60 |
| 6 | White European | 17.5 | 37.0 | 12 | 8 | 8 | 8 | 15 | 5 |
| 7 | White European | 16.9 | 30.0 | 12 | 1 | 12 | 8 | 10 | 5 |
| 8 | Caribbean | 6.2 | 44.2 | 25 | 2 | 13 | 0 | 10 | 15 |
| 9 | Caribbean | 2.6 | 21.0 | 9 | 2 | 16 | 6 | 10 | 5 |
| Median (Q1, Q3 ) | NA | 8.2 (6, 12 ) | 34.8 (29,37 ) | 21 (12, 25 ) | 2 (1, 2 ) | 12 (10, 14 ) | 6 (4, 8 ) | 10 (10, 15 ) | 10 (5, 15 ) |
Conclusion: Obinutuzumab appears to be effective and steroid-sparing in renal and non-renal SLE patients with secondary non-response to rituximab. Obinutuzumab was shown to be effective in patients with severe renal and non-renal disease. Therefore, in those with previous responsiveness to B-cell depletion, switching to humanised type-2 anti-CD20 therapy is a logical approach following loss off efficacy.
REFERENCES:
[1]Vital EM, Dass S, Buch MH, Henshaw K, Pease CT, Martin MF, et al. B cell biomarkers of rituximab responses in systemic lupus erythematosus. Arthritis Rheum [Internet]. 2011 Oct [cited 2020 Oct 12];63(10):3038–47. Available from:
[2]Hassan SU, Md Yusof MY, Emery P, Dass S, Vital EM. Biologic Sequencing in Systemic Lupus Erythematosus: After Secondary Non-response to Rituximab, Switching to Humanised Anti-CD20 Agent Is More Effective Than Belimumab. Front Med [Internet]. 2020 Aug 27 [cited 2020 Sep 2];7:498. Available from:
Disclosure of Interests: Jack Arnold: None declared, Shouvik Dass Consultant of: Roche, Abbvie, UCB & Chugai, Employee of: Honoraria from Roche, Abbvie, UCB & Chugai, Sarah Twigg: None declared, Colin Jones: None declared, Benjamin Rhodes: None declared, Peter Hewins: None declared, Mithun Chakravorty: None declared, Philip Courtney: None declared, Michael Ehrenstein Grant/research support from: GSK, Employee of: Has received honoraria from GSK, Md Yuzaiful Md Yusof: None declared, Edward Vital Employee of: Has received honoraria from Roche