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How to use the Lupus Low Disease Activity State (LLDAS) in clinical trials
  1. Ioannis Parodis1,2,
  2. Mandana Nikpour3
  1. 1 Division of Rheumatology, Department of Medicine, Karolinska Institutet, Stockholm, Sweden
  2. 2 Rheumatology, Karolinska University Hospital, Stockholm, Sweden
  3. 3 Department of Medicine, University of Melbourne, Fitzroy, Victoria, Australia
  1. Correspondence to Dr Ioannis Parodis, Division of Rheumatology, Department of Medicine, Karolinska Institutet, 171 77 Solna, Sweden; ioannis.parodis{at}

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Recently, two different studies1 2 applied the criteria of the Lupus Low Disease Activity State (LLDAS)3 to the data sets of the BLISS-524 and BLISS-765 phase III trials of belimumab. The studies reported similar LLDAS attainment frequencies at key time points; however, not identical. We herein discuss possible explanations in order to guide future usage of the LLDAS.

In the study by Parodis et al,1 LLDAS at week 52 was achieved by 10.0% of the patients in BLISS-52 and 7.1% in BLISS-76, with a greater percentage within patients who received belimumab 10 mg/kg compared with patients who received placebo in BLISS-52 (11.9% vs 6.2%; p=0.030), but not in BLISS-76 (8.3% vs 6.4%; p=0.473). In the study by Oon et al,2 LLDAS at week 52 was attained by 12.5% and 14.4% in the belimumab 10 mg/kg arm versus 5.8% and 7.8% in the placebo arm in BLISS-52 (p=0.02) and BLISS-76 (p=0.04), respectively.

The small-scale differences in the two studies can be traced to the criteria used for the retrospective calculation of the LLDAS (table 1). Comparing the two setups, Parodis et al did not rely on British Isles Lupus Assessment Group (BILAG) evaluations claiming that the rationale for the development of LLDAS included the notion that the highly detailed BILAG index renders its use cumbersome in everyday practice.3 In contrast, Oon et al 2 used BILAG information collected as a part of the BLISS studies. More specifically, Oon et al defined criterion 1 as (i) a Systemic Lupus Erythematosus Disease Activity Index 2000 (SLEDAI-2K) score≤4, (ii) zero score in the Safety of Estrogens in Lupus Erythematosus National Assessment (SELENA)-SLEDAI items seizures, psychosis, organic brain syndrome, visual disturbance, cranial nerve disorder, lupus headache, cerebrovascular accident, vasculitis, urinary casts, haematuria, proteinuria, pyuria, pleurisy, pericarditis and fever, and (iii) BILAG D or E only for the neurological, renal and cardiac systems, with no evidence of active haemolysis. The same study defined criterion 2 as (i) no new SELENA-SLEDAI items with score>0 and (ii) no BILAG items with new activity, irrespective of organ system, while Parodis et al defined criterion 2 as no new moderate or severe flare according to the SELENA-SLEDAI Flare Index (SFI).6

Table 1

Definitions of the LLDAS criteria used in the two post hoc studies

In fact, neither absence of new flares based on the SFI used by Parodis et al nor BILAG D/E scores used by Oon et al are validated interpretations of the LLDAS criterion 2. In retrospective settings, such assumptions may be inevitable, especially since the initial publication of the derivation of LLDAS3 does not clarify what one should consider ‘new features’ of SLE disease activity. The discrepancies in the two studies underscore the importance of prospective evaluation of the LLDAS where possible. In prospective settings, no new lupus disease activity could be a clinician-assessed item in the case report form.

Despite the similar results in the two studies, the authors emphasised different points. Oon et al stressed the discriminatory performance of LLDAS when the belimumab and placebo arms were compared, while Parodis et al discussed the overall low LLDAS attainment rates. Indeed, a stringent outcome might be advantageous in trials of powerful therapies where the active treatment could generate higher rates of LLDAS achievers compared with the BLISS trials, but low attainment rates across all arms might impede approval by drug regulatory agencies despite adequate separation between the active substance and placebo arms.

The LLDAS was designed to reflect low SLE disease activity rather than changes in lupus activity; it can, therefore, be considered a more clinically relevant outcome in SLE studies compared with the SLE Responder Index (SRI)-4, and should preferably be assessed prospectively. Perhaps the time has come to put forth a standardised approach to the calculation the LLDAS components to ensure uniformity across both prospective and retrospective studies.

Ethics statements


The authors would like to thank GlaxoSmithKline (Uxbridge, UK) for granting access to the data from the BLISS-52 and BLISS-76 trials ( identifiers NCT00424476 and NCT00410384, respectively) through the Clinical Study Data Request consortium.



  • Handling editor Josef Smolen

  • Contributors IP and MN contributed to the conception and design of the work. IP drafted the manuscript. IP and MN revising the work critically for important intellectual content and approved the final version prior to submission. IP and MN agree to be accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved.

  • Funding IP is supported by the Swedish Research Council, Professor Nanna Svartz Foundation (2017-00213 and 2018-00250), Swedish Rheumatism Association, King Gustaf V’s 80-year Foundation, Stockholm County Council and Karolinska Institutet Foundations. MN is supported by an NHMRC Career Development Fellowship (APP1126370).

  • Competing interests None declared.

  • Provenance and peer review Not commissioned; internally peer reviewed.