Biologics and tsDMARDs have a role in lupus treatment, but questions remain

Biologics and targeted synthetic (ts) DMARDs could help to address significant unmet need in lupus, but key questions remain over their use in clinical practice, an expert says.

Speaking at the British Rheumatology Society’s annal conference in Glasgow, Consultant Rheumatologist Dr Natasha Jordan at the British Society for Rheumatology’s annual conference in Glasgow.

While there have been therapeutic advances for lupus in recent decades that have helped to improve outcomes, including a significant increase in five-year survival to more than 90% from the 50% seen in the 1950s, there is still much room for improvement, she said.

“Our management of lupus is sadly far from optimal. Early diagnosis is a challenge, [which] has been hampered further by the last two years, we still have a paucity of sensitive biomarkers, and [there is] still an over-reliance on steroids”.

Obvious unmet needs include difficult-to-control disease, such as lupus nephritis (LN) and moderate to severe extra renal disease, and more generally there is a need to prevent organ damage that leads to mortality and morbidity in a patients, she said.

According to Dr Jordan, who is based at Addenbrooke’s Hospital in Cambridge, steroids are dangerously overused in the treatment of lupus. “Steroids increase traditional cardiovascular risk factors, and in a disease where a leading cause of death is atherosclerosis, the last thing we want to do is then add to the traditional risk factors, and yet we continue do this,” she noted.

“It’s known that 15 years after a person is diagnosed with lupus the majority of their organ damage can be directly attributed to corticosteroids,” she said, further highlighting the need for new treatment strategies.

While life expectancy for lupus has improved, in the last 20 years it has not improved to the same degree as that seen in other inflammatory conditions, such as rheumatoid arthritis (RA), which Dr Jordan believes is largely down to a lack of newer therapies.

“We’ve had biologics in rheumatoid for almost 25 years, and in that time there’s been a flourishing of treatment for RA and other conditions, but lupus has really lagged behind and I think this is what is being reflected in mortality”.

The mean age of death for patients with lupus is 53 years, with clinical evidence from one study showing that 25% died from infection, 15% from atherosclerosis, 13% from active lupus and 9% from malignancy. This again highlights that treatment needs to be improved, particularly with regard to deaths from infections and atherosclerosis.

Studies also show that despite treatment advances the condition still has a significant impact on life. In one survey of more than 4,000 lupus patients published last year, of those who were diagnosed under the age of 25, almost 60% said the condition had had a negative impact on their career, almost 15% said they had to stop working on medical grounds, and over 70% said they were less active than people of the same age.

It was also revealed that 50% of patients were taking steroids on an ongoing basis (of whom 20% were on 5-15mg a day), that just 40% were on immunosuppression and that just 10% were on biologic therapy.

“So we have young patients, with a disease that if it doesn’t kill them, it’s going to negatively impact every aspect of their life, and in this day and age only 10% of them are on biologics. I think if you compare that to other rheumatic conditions, the percentage on biologics will be much higher, so there is room for targeted biologics and synthetic DMARDs in lupus”, she said.

Dr Jordan went on to outline several therapies either approved or showing promise as treatments for lupus, including the monoclonal antibody belimumab, which has been approved for lupus since 2011, has shown reductions in proteinuria and renal flares and success in LN, with less organ damage than standard of care in the long-term.

Trials are now assessing its sequential use following rituximab; while efficacy results have been mixed, the UK Beat Lupus trial has had encouraging results, not only showing a reduction in the pivotal biomarker for SLE, serum IgG anti-dsDNA antibody levels at 52 weeks, but also a reduction in severe flares compared to placebo after rituximab.

Also showing promise is ‘new kid on the block’ obinutuzumab, a second generation anti-CD20 with enhanced B cell depletion (90-100% in trials), which is currently being assessed in Phase III studies. A recent UK study using data from the BILAG registry looking at 9 patients who were given the drug after having failed rituximab has also shown encouraging results, with patients ending up on less steroids, she noted.

Anifrolumab, a first-in-class type I interferon receptor antibody, was recently approved by US and EU regulators for SLE, and a trial assessing its potential for LN is also underway.

Other new and potentially exciting therapies include voclosporin, a novel calcineurin inhibitor that impairs T cell activation and in trials showed “a really impressive drop in proteinuria” and good tolerability, and those targeting plasma cells in the bone marrow – CD19 targeted CAR T-cell therapy and daratumumab.

“There is a role for biologics and tsDMARDs in lupus, as we have several unmet needs in this disease,” Dr Jordan concluded. “But questions remain – which drug for which patient, what is the time course that we should be thinking of for particular treatments, should we combine treatment, and if a treatment is proven efficacious, will we be allowed to use it?”.

To improve outcomes for patients, “we need to aim for better remission, consider using combined agents, move away from corticosteroids, use our outcome measures in trials in a more sensitive way, and we need better biomarkers to guide our treatment,” she stressed.

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