Low disease activity and remission in SLE: How to achieve the Holy Grail?

WRITTEN BY

Eric Morand

Many physicians treating lupus agree that remission is the ultimate treatment goal in systemic lupus erythematosus (SLE), but remission is an extremely high hurdle to achieve with the current treatment armamentarium. So what should physicians aim for in the treatment of lupus?

One option is to treat to a target of low disease activity (LDA). We can think of potential progress towards remission in lupus as moving from the outer circles of a dartboard towards the central ‘bullseye’. With progressive improvement in treatment response, a patient achieves a step-wise improvement in outcome – from active disease, to reduced activity, to LDA, to remission-on-treatment, to remission-off-treatment. With each advance in disease control, the rate of damage accrual will fall, theoretically reaching zero if off-treatment remission is achieved.

Experience in rheumatoid arthritis (RA) has shown us that the adoption of remission as the overall goal, even though it is achieved only by a minority, leads to the achievement of LDA in a larger proportion of patients. This lowers the impact of disease in the cohort as a whole.

 

So what do remission and LLDAS look like, and how high should we set the bar?

The recently proposed Definitions Of Remission in SLE (DORIS) criteria are based on clinical disease activity (SLEDAI-2K score of 0), serological activity (complement and anti-dsDNA antibodies), corticosteroid treatment and immunosuppressive treatment1. Whereas clinical remission on treatment allows serological activity, prednisone <5 mg per day and immunosuppressive treatment, remission-off-treatment is more stringent and rules out serological activity, and prednisone and immunosuppressive use. However, a retrospective analysis of prospectively collected data, using the DORIS criteria, has confirmed the difficulty of achieving and sustaining remission – even when the less stringent remission-on-treatment definition is used1,2.

An alternative measure is the Lupus Low Disease Activity State, or LLDAS, proposed in 2016 by the Asia-Pacific Lupus Collaboration (APLC) group.  LLDAS is defined by a SLEDAI-2K ≤4, with no activity in major organ systems, haemolytic anaemia or gastrointestinal activity; no new lupus disease activity compared with previous assessment; a SELENA-SLEDAI physician global assessment (scale 0-3) of ≤1; a current prednisolone (or equivalent) dose ≤7.5 mg daily; and well tolerated standard maintenance doses of immunosuppressive drugs and approved biological agents3.

A single centre cohort study showed that patients who spent more than 50% of their observed time in LLDAS had significantly reduced organ damage accrual compared with patients who spent less than 50% of their time in LLDAS (p=0.0007)3.  A number of groups have confirmed retrospectively that LLDAS is attainable in cohorts of lupus patients and is associated with protection from adverse outcomes including organ damage4,5, and additional research has linked LLDAS improvement with improved quality of life for patients6.

At LUPUS 2017, Michelle Petri from Johns Hopkins University, in Baltimore, USA, is presenting data showing that LLDAS is more attainable than remission7. In addition, organ damage rates in patients achieving LLDAS more than 50% of the time they were on treatment were similar to those seen in patients achieving remission-on-treatment criteria for the same time period7. As Petri concludes, this is good news for patients with lupus, given that LLDAS is a more feasible treatment target to achieve than remission7.

In another presentation at LUPUS 2017, my own group will be presenting data suggesting that LLDAS is a relevant endpoint for clinical trials.

 

Should clinicians now be implementing treat to target regimens in clinical practice with LLDAS as their goal?

I think the answer is ‘almost’. Although recent findings are encouraging, we need to see results of retrospective analyses published in peer reviewed journals, and ultimately results from prospective validation trials currently under way of the association between LLDAS and reduced organ damage accrual. From our experience in RA, we know that prospective treat-to-target trials – escalating a patient’s treatment until they meet the LLDAS criteria and demonstrating that outcomes with that approach are better than with standard care - have considerable impact. Whether we can achieve this with our currently available lupus treatments – as happened in RA – remains to be seen. Perhaps the full value of treat-to-target will only become clear once we have more effective drugs for lupus.

In the meantime, the promise of a target that is meaningfully associated with protection from damage and is attainable in a feasible proportion of patients has the potential to dispel the therapeutic nihilism that has surrounded lupus for so long. The data may not yet support widespread use of the treat-to-target approach in clinical practice, but we can certainly start discussing it with our patients, trying it out in our cohorts and reporting our results. With the likely acceptance of the treat-to-target approach converging with the development of new, more effective drugs for lupus, we are well placed for a possible transformation in the therapeutic landscape for patients with lupus. 

 

 

References

1.     van Vollenhoven RVoskuyl A, Bertsias G et al. A framework for remission in SLE: consensus findings from a large international task force on definitions of remission in SLE (DORIS). Ann Rheum Dis. 2016 Nov 24. pii: annrheumdis-2016-209519. doi: 10.1136/annrheumdis-2016-209519. [Epub ahead of print]

2.     Wilhelm, T. R., Magder, L. S. & Petri, M. Remission in systemic lupus erythematosus: durable remission is rare. Ann Rheum Dis. 2016 Aug 24. pii: annrheumdis-2016-209489. doi: 10.1136/annrheumdis-2016-209489. [Epub ahead of print]

3.     Franklyn KLau CSNavarra SV et al. Definition and initial validation of a Lupus Low Disease Activity State (LLDAS). Ann Rheum Dis. 2016 Sep;75(9):1615-21.

4.     Golder et al. Arthritis Research & Therapy (2016) 18:260. DOI 10.1186/s13075-016-1163-2

5.     Ugarte-Gil M, Wojdyla D, Pons-Estel GJ, et al. Remission and Low Lupus Disease Activity Status (LLDAS) Protect Lupus Patients from Damage Occurrence: Data from a Multi-Ethnic, Multinational Latin American Lupus Cohort [abstract]. Arthritis Rheumatol. 2016; 68 (suppl 10). http://acrabstracts.org/abstract/remission-and-low-lupus-disease-activity-status-lldas-protect-lupus-patients-from-damage-occurrence-data-from-a-multi-ethnic-multinational-latin-american-lupus-cohort/. Accessed March 16, 2017.

6.     Golder V, Kandane-Rathnayake R, Hoi AY, et al. Association of the Lupus Low Disease Activity State (LLDAS) with Health-Related Quality of Life [abstract]. Arthritis Rheumatol. 2016; 68 (suppl 10). http://acrabstracts.org/abstract/association-of-the-lupus-low-disease-activity-state-lldas-with-health-related-quality-of-life/. Accessed March 16, 2017.

7.     Petri M. Comparison of Remission and Lupus Lows Activity State as Predictors of Organ Damage [abstract]. To be presented at Lupus 2017. Available from http://lupus2017.org/program-information/interactive-program. Accessed March 16, 2017.