Lupus Low Disease Activity State Useful Target

Large study shows LLDAS achieved by many patients

Pauline Anderson November 20, 2016


Contributing Writer, MedPage Today

Action Points

Almost 44% of patients with systemic lupus erythematosus (SLE) meet criteria for the lupus low disease activity state (LLDAS), according to a large study.

The results, published in Arthritis Research & Therapy, suggest that LLDAS is "a much more clinically attainable state than the stricter definitions of remission," said Vera Golder, a clinical research fellow and PhD student at Monash University in Melbourne, Australia.

"This study is important because, for the first time in SLE, we have defined a treatment target that is attainable and that will, with time, have a role akin to low disease activity in rheumatoid arthritis."

Current instruments used to measure disease activity in SLE are "complex," contributing to mixed results in clinical trials of new targeted therapies, Golder and colleagues explained. "This state of affairs has led to a call for definitions of treatment target states that can be used in clinical trials and clinical practice."

And given that definitions of remission "remain under debate," and that a recently reported stringent definition of remission occurs in only 2% of SLE patients, "using remission as a treatment target is not pragmatic."

Assessment tools include the SLE Responder Index (SRI), which includes criteria from three internationally validated indices -- the Safety of Estrogens in Lupus Erythematosus National Assessment-SLE Disease Activity Index (SELENA-SLEDAI), the Physician Global Assessment (PGA), and the British Isles Lupus Assessment Group (BILAG).

The study included 1,846 adult, mostly female, SLE patients from 12 centers in nine countries. The participants' mean age at diagnosis was 29.34, and the mean disease duration was 8.64 years. More than half of the subjects were of Chinese ethnicity.

Patients were considered to be in an LLDAS if they met the following criteria (slightly modified from the published definition as this was a cross-sectional analysis with no data from previous visits, the researchers noted):

SLEDAI 2000 (2 K) ≤4, with no activity in major organ systems and no hemolytic anemia or gastrointestinal activity;

Absence of flare as measured by the SLE flare index (SFI);

A SELENA-SLEDAI PGA of ≤1 (on a scale of 0–3);

Current prednisolone (or equivalent) dose ≤7.5 mg daily, and;

Not exceeding the maximum recommended doses of immunosuppressant therapy.

All patients fulfilled at least one criterion of LLDAS. The most common (by 99.6%) related to immunosuppressive medications, and the least common (63.4%) was SLEDAI-2 K ≤4, without activity in a major organ system. About 43.9% of participants met all five criteria.

In multivariable logistic regression analysis, variables that were significantly negatively associated with LLDAS included disease duration ≤1 year (OR 0.31, 95 % CI 0.19-0.49, P < 0.001) and a history of discoid rash (OR 0.66, 95 % CI 0.49-0.89, P = 0.006) or renal disease (OR 0.60, 95 % CI 0.48-0.75, P < 0.001).

The results showed that patients from countries with a high gross domestic product (GDP) purchasing power parity (PPP) per capita were significantly more likely to be in LLDAS than patients with lower GDP (PPP) per capita (OR 1.57, 95 % CI 1.25–1.98, p < 0.001). The researchers noted that it is important to include an index of socioeconomic wealth in analyzing predictors of LLDAS.

The fact that all patients met at least one LLDAS criterion, but only 44% met all five "supports the value of including multiple variables in the definition of LLDAS," Golder et al wrote.

If reaching or maintaining LLDAS translates into improved patient outcomes, this new definition could represent a treatment target to use in clinical trials of novel therapies, the team said.

"Conversely, the fact that the majority of patients did not meet criteria for LLDAS speaks to the inadequate state of current treatment of SLE."

A next step in validating LLDAS as an outcome measure in SLE is evaluating whether LLDAS attainment or maintenance is associated with protection from long-term adverse outcomes, the researchers added.

"Clinicians should watch for the results of a prospective study of LLDAS in almost 2,000 patients, which is now nearing completion," Golder told MedPage Today. "This will hopefully provide further validation for the use of LLDAS not only in research but also in routine clinical practice."

A limitation of the study was its cross-sectional design, the researchers noted. The published definition of LLDAS requires the absence of new disease manifestations, which is not possible to measure in a cross-sectional study.

Asked for his opinion of the study, Ronald van Vollenhoven, MD, PhD, chief of the Unit for Clinical Therapy Research, Inflammatory Diseases, at the Karolinska Institute in Stockholm, Sweden, called the research an important contribution to the process of identifying suitable outcomes for SLE, both for use in clinical trials as an appropriate primary or secondary outcome, and for clinicians to use in a treat-to-target approach to patients.

"This very good study demonstrated that the LLDAS, which is being developed in parallel to definitions for remission in SLE, can be attained in a meaningful proportion of patients," he added.

Also commenting, Michelle Petri, MD, of Johns Hopkins University and Hopkins Lupus Center, said, "LLDAS combines both low disease activity and a limit on prednisone, so it includes two desirable outcomes in SLE. For that reason, I think it is more clinically meaningful than SRI or BICLA [BILAG-Based Composite Lupus Assessment]."

The Asia-Pacific Lupus Collaboration receives project support grants from GlaxoSmithKline, UCB, and Janssen.

Golder and colleagues reported having no competing interests.