B-Cell Depletion Predicts Rituximab Response in Systemic Lupus Erythematosus

B-cell depletion may be used to guide anti-CD20 therapy in systemic lupus erythematosus (SLE), according to a study published in the Annals of the Rheumatic Diseases.¹

While rituximab is an important treatment for SLE, its efficacy has not been confirmed in phase 3 randomized controlled trials (RCTs), so it is used on an off-label basis.^1-3 Certain properties of rituximab — such as inefficient B-cell killing ability — may have contributed to the failure of RCTs to demonstrate its efficacy in SLE.¹

In a previous study, Edward Vital, MRCP, PhD, from the University of Leeds in the United Kingdom, and colleagues found that B-cell depletion as measured by highly sensitive flow cytometry correlated with response to rituximab treatment in SLE. In patients with a good initial response to rituximab, those with B-cell depletion did not require retreatment.⁴

Some patients experienced a type of rituximab retreatment failure known as secondary non-depletion and non-response (2NDNR) – which may be mediated by immunogenicity to rituximab and is characterized by a lack of clinical response, CD20+ B-cell non-depletion, and severe infusion reaction that lasts >24 hours.¹

Researchers from the NIHR Doctoral Research Fellow Program at the University of Leeds, United Kingdom, sought to determine the risk factors for primary and secondary non-response to rituximab in patients with SLE. Other goals were to (1) validate B-cell depletion as a predictor of rituximab response, and (2) to investigate other anti-CD20 agents as alternative treatments.¹

A total of 117 patients were enrolled and treated with an initial cycle of intravenous (IV) rituximab (1000 mg) and methylprednisolone (100 mg), administered as 2 doses 2 weeks apart. All patients had refractory and active disease as measured by the British Isles Lupus Assessment Group (BILAG)-2004.¹

After the first cycle, 50%, 32%, and 18% of patients had major, partial, and no clinical response, respectively, as measured by BILAG.¹

Independent predictors for major BILAG response to rituximab were younger age (odds ratio [OR], 0.97; P =.045) and B-cell depletion at 6 weeks (OR, 3.22; P =.016).¹

Patients with normal complement levels and lower plasmablasts prior to rituximab treatment were more likely to experience complete B-cell depletion. The risk of serious infection was not increased with B-cell depletion.¹

Of 77 initial responders who relapsed and were retreated with rituximab, 72 had available follow-up data. The response rate for cycle 2 was 85% (61 of 72 patients). The majority of cycle 2 non-responders met criteria for 2NDNR and were positive for anti-rituximab antibodies. Risk factors for 2NDNR included higher plasmablasts before rituximab treatment (P <.001) and lack concurrent immunosuppressant use (P =.023).¹

A total of 5 patients with 2NDNR were treated with humanized anti-CD20 agents, ocrelizumab or ofatumumab. All experienced B-cell depletion and major clinical response.¹

Summary and Applicability

Patients with SLE who relapse after an initial good response to rituximab may fail retreatment with rituximab due to B-cell non-depletion, known as 2NDNR. Researchers investigated the risk factors for primary non-response and 2NDNR, as well as management of 2NDNR using alternative anti-CD20 agents.

“B-cell depletion in SLE is often incomplete. Failure to clinically respond to rituximab may often be because B-cell depletion was inadequate, rather than because the choice of B-cells as a therapeutic target was inappropriate. Therefore, rituximab non-responders may still be amenable to B-cell targeted therapies, such as ofatumumab or obinutuzumab,” Dr Vital told Rheumatology Advisor. 

“We don’t know exactly what the mechanism is by which B-cells are resistant to depletion in SLE,” he added. “We need to understand this to decide how we could improve the efficacy of rituximab.”

Limitations and Disclosures

More than 60% of patients were receiving concurrent immunosuppressant agents, which may have influenced treatment efficacy rates.

Dr Vital reports financial relationships with Roche, GSK and AstraZeneca.

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