Achieving Low Disease Activity in SLE

Dec 07, 2016

Less than half of patients with systemic lupus erythematosus reach low disease activity. Why? Experts say focus on disease duration, phenotype and other accepted predictive factors.

A systemic lupus erythematosus diagnosis can bring a significant level of disease activity and damage over time, but it’s possible for some patients to achieve a low disease activity state, researchers show in a new study.

In a recent study published in Arthritis Research & Therapy, investigators determined disease duration, phenotype and national social wealth are positive predictors of lupus low disease activity state (LLDAS).

This identification, said Vera Golder, a doctoral candidate with Monash University in Australia, could change how providers treat systemic lupus erythematosus (SLE) in certain patient populations. This is the first multi-national study to focus on the new definition of LLDAS.

“LLDAS represents a much more attainable clinical target state than the strict definitions of remission, and we believe it will have a role akin to [low disease activity] in rheumatoid arthritis,” Golder said. “This has implications not only for clinical trial design, but also for routine clinical practice with clinicians having an achievable goal to work towards.”

Currently, targeted therapies for systemic lupus erythematosus are insufficient. Long-term glucocorticoid use and non-specific immune-suppressants don’t offer enough to prevent significant morbidities or shorten life expectancy. Add in inaccurate disease activity-measuring mechanisms, and you have mixed results for any new targeted therapies being tested in clinical trials.

Low-Level Disease as a Target

And, with only 2% of SLE patients ever reaching the official definition of remission, the specialty is looking for better targeted treatment options. LLDAS is one of the targets because previous research has shown patients who spend more time in LLDAS experience less damage and have improved long-term outcomes.

To be considered LLDAS, certain criteria must be met:

  • Lupus Disease Activity Index ≤4, with no activity in major organ systems (renal, central nervous system, cardiopulmonary, vasculitis, as well as no anemia or gastrointestinal activity.
  • No new features of lupus disease activity compared to previous assessments.
  • A Safety of Estrogens in Lupus Erythematosus National Assessment physician global assessment ≤1.
  • Current prednisolone (or equivalent) dose ≤7.5 mg daily.
  • Well-tolerated standard maintenance doses of immunosuppressive drugs and approved biologic agents, excluding investigational drugs.

Results

All total, 1,846 patients (93% female) from nine countries were recruited and assessed in this longitudinal study. The mean age was 29, and the mean disease duration was 8.6 years at the time of recruitment. More than 50% of patients were of Chinese descent, and 7% were Caucasian. The remainder came from the ethnic groups native to the Asian region. Of the entire group, 44% met the criteria for an LLDAS designation.

According to study data, more than half of participants had a history of malar rash, arthritis, and hematologic and immunologic manifestations, and 803 patients had renal disease histories. At the time of recruitment, 694 patients had irreversible damage. In addition, 1,430 patients were on a daily mean 11 mg dose of prednisolone.

Based on the data, researchers discovered patients with shorter disease durations were less likely to be in LLDAS (OR 0.31, 95% CI 0.19-0.49, p<0.001). LLDAS was also less common in patients with a history of discoid rash (OR 0.66, 95% CI 0.49-0.89, p=0.006), renal disease (OR 0.60, 95% CI 0.48-0.75, p<0.001), elevated double stranded DNA (OR 0.65, 95% CI 0.53-0.81, p<0.001) or hypocomplementaemia (OR 0.52, 95% CI 0.40-0.67, p<0.001).

Alongside the impact of various morbidities, investigators also found higher national social wealth, measured by gross domestic product per capita was also positively linked to LLDAS. However, there was no link to ethnicity identified.

Significance

Achieving and maintaining LLDAS, as well as translating it into improved patient outcomes, supports considering it a lupus treatment target for novel clinical trials.

Participants were either identified as being in LLDAS or not. One of the biggest factors that kept patients out of LLDAS was a daily glucocorticoid dose >7.5 mg. Disease duration of less than 1 year was also negatively associated with LLDAS, supporting an existing observation that patients with new disease are more likely to have active disease.

Investigators said their research further highlighted treatment practices in tertiary lupus centers - lower use of immuno-suppressants could be related to limited healthcare access or reduced availability of medications in some Asian countries.

From an economic perspective, high national social wealth was strongly linked to a five-year survival among lupus patients. Unfortunately, the benefit of national wealth didn’t translate to personal socioeconomic status. Education level also didn’t predict the likelihood of LLDAS.

Limitations

This study does have limitations, however. Researchers weren’t able to determine whether time spent in LLDAS is associated with less damage accrual due to the cross-sectional nature of the current analysis - even though a previous retrospective single-center validation study demonstrated it did.

Additionally, the published LLDAS definition requires the absence of new disease manifestations, but that’s not possible to measure in a cross-sectional study. Instead, researchers substituted it with a requirement for the absence of flare as measured using the more stringent SELENA-SLEDAI flare index.

Lastly, investigators modified the identification of the “well-tolerated immunosuppressive” LLDAS component because of an inability to determine any dose change or tolerance at the time of recruitment. Consequently, a higher number of patients fulfilled this requirement, meaning the use of the original definition in the longitudinal study could have resulted in a lower overall LLDAS frequency.

To further this research, Golder said, a large multinational perspective study is currently underway to assess whether LLDAS is associated with protection from damage accrual, which will further validate its use as a treatment target.

 

References:

Golder, Vera, et al. “Frequency and predictors of the lupus low disease activity state in a multi-national and multi-ethnic cohort,” Nov. 9, 2016. Arthritis Research & Therapy. DOI: 10.1186/s13075-016-1163-2.

Franklyn K, et al. “Definition and initial validation of a Lupus Low Disease Activity State (LLDAS),” Annals of the Rheumatic Diseases. Oct. 12, 2015. DOI: 10.1136/annrheumdis-2015-207726

 

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