Lupus

LLDAS validated as a treat-to-target endpoint for SLE


Achieving lupus low disease activity state (LLDAS) for any period of time is associated with significant protection against subsequent disease flares and organ damage accrual in people with SLE, according to an Australian-led study.

Researchers say the study is the first to validate LLDAS as a treat-to-target endpoint, paving the way for LLDAS to become a standard measure in future SLE clinical trials, treat-to-target studies and clinical practice.

Speaking to the limbic, study co-investigator Professor Mandana Nikpour, a rheumatologist at St Vincent’s Hospital in Melbourne, said that in contrast to single-organ diseases, treatment endpoints were more elusive for complex multi-organ diseases such as SLE.

“Defining a treatment target for lupus has been challenging because of the heterogeneous nature of the disease, the fact that it can involve multiple organs,” she said.

A treatment target for lupus has to balance aspects related to both disease activity and treatment burden, she added.

“While someone can have what might be low disease activity they might still be on a lot of treatment – in particular corticosteroids – and that in itself can carry a risk of morbidity and side effects such as osteoporosis and weight gain,” she said.

According to Professor Nikpour, LLDAS is defined by several key measurable requirements that indicate low disease activity level, such as a Systemic Lupus Erythematosus Disease Activity Index-2K score of four or less, and a current prednisone (or equivalent) dose of 7.5 milligrams or less per day.

“This definition of low disease activity allows immunosuppressive drugs in standard doses and I think that’s important because in a lot of situations these drugs also have a ‘prednisone sparing’ effect and in turn facilitate reduction in prednisone dose.”

The definition also allows the concomitant use of antimalarial treatment, which is now staple treatment in all lupus patients long term unless there are compelling contraindications.

In the validation study, 1,707 patients from the Asia Pacific lupus collaboration cohort were recruited from the region and followed prospectively for a mean of 2·2 years to investigate the connection between LLDAS and disease flares and accrual of irreversible organ damage.

“We found a definite protective association against subsequent flare and accrual of organ damage in individuals who achieved the low disease activity state,” Professor Nikpour explained.

“We also found that if patients spend more than 50% of their period of follow up in that low disease activity state, they have an almost two-fold increased protection against damage compared to those that had less than 50% of their follow up in low disease activity state.”

A subgroup analysis revealed that the association of LLDAS with reduced organ damage accrual was observed regardless of study participants’ pre-existing damage or disease activity.

“So even in those individuals who entered the cohort with active disease and existing damage there is definitely a protective association with subsequent flare and damage accrual in those who attain the low disease activity state.”

Of the total cohort, 78% had at least one episode of LLDAS during follow-up while 62·7% of patients achieved at least one episode of sustained LLDAS. And 48·2% of this group sustained LLDAS for at least 12 months.

The 803 (47%) patients who spent at least 50% of their observed time in LLDAS had a lower SLEDAI-2K at recruitment and were significantly less likely to have ever had vasculitis or renal disease compared with those who spent less than 50% of the observed time in LLDAS.

The longer patients were in LLDAS the better they did but, equally importantly, Professor Nikpour noted that even a short period of time in LLDAS has a protective association with flare and subsequent damage accrual.

“We found that as little as three to six months of sustained LLDAS is protective, and the longer they’re in that sustained state the better they tend to do.”

The findings now provide ‘sufficient evidence’ of an association between LLDAS and protection against flare and damage accrual,  argued Professor Nikpour, referring to the question of whether doctors should adopt the treatment approach.

“From a clinical practice perspective we should be aiming to get our patients into that low disease activity state, or as close to it as we can, and striving to keep them there for as long as we can. Implicit in that is striving to have minimal disease activity as well as ensuring that prednisone equivalent doses are 7.5mg or less.”

Professor Nikpour said she would ultimately like to see a treat-to-target trial that compares the outcomes of flare and damage accrual with a target-drive approach to treatment using the LLDAS endpoint with standard care.

“I think that would be the final piece of evidence that would be required to really cement the low disease activity state that we have defined as a treatment target.”

The findings are published in Lancet Rheumatology.

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