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MANCHESTER, England — Two new randomized controlled trials (RCTs) assessing the role of rituximab in the treatment of various stages of systemic lupus erythematosus (SLE) have the green light to start, experts involved in their planning announced at the British Society for Rheumatology (BSR) 2025 Annual Meeting.

The STRATIFY Lupus study will recruit people with established SLE to investigate whether it is possible to personalize treatment with rituximab followed by belimumab based on baseline serum immunoglobulin A2 (IgA2) anti–double-stranded DNA (dsDNA) antibody concentrations. Meanwhile, the First-Line Rituximab in Systemic Lupus Trial (FIRST) will study the use of rituximab in people newly diagnosed with SLE.

“We’re in quite an exciting position in lupus in the UK at the moment because we have not one, but two national-scale RCTs that are about to start,” said Edward Vital, MBChB, PhD, a professor in autoimmune connective tissue diseases and an honorary consultant rheumatologist at the University of Leeds, Leeds, England; the chair of the BSR’s Special Interest Group for SLE; and the chair of the British Isles Lupus Assessment Group (BILAG).

“These trials are very difficult to get funding for, and they are even more difficult to execute. So, it is something we are all going to have to focus on together, especially those of us who are sites or are referring patients to sites,” added Vital, the co-lead investigator for FIRST.

STRATIFY Lupus

Michael Ehrenstein, MBBS, PhD, professor in rheumatology at University College London (UCL) and consultant rheumatologist for UCL Hospital, London, England, agreed that conducting clinical trials in lupus was “incredibly challenging from a recruitment point of view.”

Ehrenstein is the co-lead investigator for the STRATIFY Lupus trial alongside Muhammad Shipa, MBBS, also of UCL, who has noted that the trial would be the first ever biomarker-enriched trial for patients with SLE.

STRATIFY Lupus comes 10 years after funding for the phase 2 BEAT-LUPUS trial was obtained. The results of that trial were published in 2021 and showed that giving the anti–B-cell activating factor drug belimumab after the B-cell–depleting therapy rituximab was “safe,” said Ehrenstein, and the combination vs rituximab alone significantly reduced the risk for severe flares of disease in people who had refractory SLE.

A subsequent exploratory analysis published 2 years later found that baseline serum IgA2 anti-dsDNA was predictive of a major clinical response to the use of belimumab after rituximab. The difference in achieving a major clinical response at 1 year with the combination was 48% vs 35% for rituximab alone, a difference of just 13%. But when these data were stratified according to whether serum IgA2 anti-dsDNA levels had been high or low at baseline, the major clinical response rates were 64.3% with the combination vs 16.7% for rituximab alone, a difference of 48%.

“The delta jumps from 13% to 48%,” Ehrenstein said. “Wouldn’t it be great to have trials in lupus where you have a delta of 48% between the two arms? That would cause incredible excitement.”

Trial Setup and Design

STRATIFY Lupus will officially be set up in June, with a target accrual of 66 patients with established SLE and high levels of IgA2 anti-dsDNA antibodies. Recruitment is expected to take 2 years, with the first patients enrolled in February or March next year.

The current plan is that after an initial 4- to 8-week screening period, during which all patients will receive treatment with rituximab, patients will be randomly allocated to receive belimumab as well as rituximab or to continue with rituximab alone.

“The idea is that, if you treated patients with belimumab after rituximab, those with high levels of IgA2 anti-dsDNA antibody would be much more likely to respond compared [with] if you just treated with rituximab, which is the standard of care at the moment,” Ehrenstein said. Similar to BEAT-LUPUS, the primary endpoint will be major clinical response at 1 year.

This is personalized medicine, he added. The results of the trial could potentially help guide clinicians and their patients to decide on the best course of treatment. If IgA2 anti-dsDNA levels are low, “you just continue with what you were going to do anyway, which is give them rituximab. If they’re high, you give them belimumab, and then you follow it with rituximab.”

Safety and Protocol Challenges

One of the concerns of using belimumab and rituximab together has been safety, and specifically the possibility of a higher rate of serious infections than rituximab alone. In fact, the prescribing information for belimumab states that the two should not be used in combination.

However, looking at data from the phase 3 randomized, controlled BLISS-BELIEVE trial in context with other trials such as BEAT-LUPUS and CALIBRATE in lupus nephritis, Ehrenstein said, “We were able to persuade [belimumab manufacturer] GSK [GlaxoSmithKline] that we thought that giving belimumab may well make rituximab safer and certainly wouldn't cause any issue.”

Notably, he added, with the study population enriched to be potentially more likely to obtain a clinical response, the benefit-to-risk ratio should be tipped more in favor of the combination than rituximab alone.

There could be some protocol and recruitment challenges, Ehrenstein said, such as whether rituximab would still be the go-to for the standard of care, with evidence mounting for the role of mycophenolate mofetil in refractory lupus and a potentially increased uptake of the B-cell–depleting drug obinutuzumab (Gazyva). And because only 30%-50% of patients with refractory SLE may have high IgA2 anti-dsDNA levels, considerably more patients would need to be screened than was the case for BEAT-LUPUS. Competition from other teams conducting clinical trials in lupus was also a consideration for obtaining sufficient accrual.

Trialing First-Line Rituximab

Switching to discuss the FIRST trial, Md Yuzaiful Md Yusof, MBChB, PhD, consultant rheumatologist and senior research fellow at the University of Leeds and Leeds Teaching Hospitals NHS Trust, Leeds, England, noted that a grant of £2.6 million has been secured from the National Institute for Health and Care Research (NIHR) to fund the trial.

Although “there is a long way ahead,” hopefully when the trial reports in 2029, it will show whether there is a benefit to using rituximab earlier in the course of the disease, Md Yusof said.

The rationale is that in the first year of diagnosis, compared with later time points, patients with SLE have “the worst disease activity” and “tend to use a lot of glucocorticoids” and tend to have high healthcare costs, he said.

“Also, as we all know that, if we treat our patients late, this also may affect long-term outcomes, including organ damage, health, quality of life, etc.,” he added.

FIRST will be a multicenter, double-blind, superiority trial that will aim to recruit 128 patients within 12 months of a diagnosis of moderate to severe SLE across 20 sites in the United Kingdom.

Patients will receive standard care treatment, including oral immunosuppressants, and be randomly allocated to treatment with either rituximab or placebo.

Primary Endpoint

The primary endpoint of FIRST will be cumulative time spent in Lupus Low Disease Activity State (LLDAS) at 12 months rather than response using the SLE Disease Activity Index 2000. LLDAS is the cumulative time where SLE disease activity is adequately controlled on an acceptable dose of glucocorticoids, and it is a meaningful clinical endpoint according to people living with the disease, Md Yusof said.

Vital, the co-lead investigator for the trial, later said, “I increasingly think that our concept of response has been a mistake in the world of lupus.” Indeed, the main trials that have been conducted with rituximab in the past, and which largely yielded negative results, used response assessment at set time points as their primary endpoints, but it has long been known that everyone is fluctuating up and down in their response over the course of treatment, Vital observed.

His comment was in response to some unpublished data from the BILAG Biologics Register (BILAG BR) that had been presented by Ian Bruce, MD, professor of rheumatology at the University of Manchester, Manchester, England, and pro vice chancellor of Medicine, Health, and Life Sciences at Queen’s University Belfast, Belfast, Ireland. These data showed that there appear to be six distinct trajectories of response to rituximab, one of which showed an initial response to treatment but then a flare at about 9 months, which resolved by 12 months.

So, “if you choose your landmark at 6 months, they would all be responders. If you choose your landmark at 12 months, they’ll be responders. You might actually miss the flare if you were tracking them that way,” Bruce said.

Inclusion criteria for FIRST are a diagnosis of SLE within the past 12 months and aged 5 years or older. Treatment with a first immunosuppressant can occur at screening or not more than 4 weeks prior, so long as patients have a minimum of one BILAG-A grade, two BILAG-B grades, or one BILAG-B grade plus mucocutaneous involvement with physician intent to treat with immunosuppression.

So far, 24 groups have come forward to participate in the study, but there is still room for more teams to get involved, Md Yusof said.

STRATIFY Lupus is being funded by Versus Arthritis and the NIHR’s Efficacy and Mechanism Evaluation (EME) Researcher-led Program, with contributions from Lupus UK and belimumab being provided by GSK. Ehrenstein had received consultancy fees from AbbVie, GSK, and UCB, and grant/research support from GSK. Ehrenstein and Shipa are named on a UCL patent application for the use of IgA2 anti-dsDNA antibodies as a biomarker in SLE.

FIRST is being funded by the NIHR.

Md Yusof had received consultancy, advisory board, or speaker fees from Alumis, Aurinia, GSK, Novartis, Roche, UCB, and Vifor.

Vital is the co-lead investigator for FIRST and sits on the steering committee of the Lupus Forum, which is supported with educational grants and other donations from various companies, including AbbVie, AstraZeneca, Aurinia, Biogen, Bristol Myers Squibb (BMS), GSK, Merck, Novartis, Roche, Otsuka, and UCB.

BILAG-BR had received funding support from Roche, GSK, and Lupus UK. Bruce had received research and clinical trial funding from AstraZeneca, GSK, Janssen, and Otsuka. He had also received honoraria, consultation, advisory board, or speaker fees from AstraZeneca, BMS, Eli Lilly & Company, GSK, Novartis, and UCB.

Sara Freeman is a medical journalist based in London, England.