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 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 LDA look like in Lupus, and how high should we set the bar?
Consensus on a validated definition of LDA for Lupus is rapidly emerging. The Lupus Low Disease Activity State, or LLDAS, proposed in 2016 by the Asia-Pacific Lupus Collaboration (APLC) group, 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 agents1.
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)1. 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 damage2, 3, and additional research has linked LLDAS improvement with improved quality of life for patients4. My own group is also working on an international multicentre prospective study to validate the association of LLDAS attainment with improving patient outcome measures and we look forward to reporting the results later this year.
Looking back to last year at LUPUS 2017, Michelle Petri from Johns Hopkins University, in Baltimore, USA, presented data showing that LLDAS is more attainable than remission5. 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 period5. As Petri concluded, this is good news for patients with lupus, given that LLDAS is a more feasible treatment target to achieve than remission5. Indeed, a recent study found that failure to attain LLDAS in early treatment of lupus is associated with adverse long term outcomes (REF)6.
New work also suggests that LLDAS is a relevant endpoint for clinical trials. A post hoc analysis of results from the Phase II MUSE trial of anifrolumab in patients with moderate to severe SLE showed that LLDAS correlated with traditional treatment response measures such as SRI, but was more stringent, and powerfully discriminated responders from non-responders7. Importantly, the utility of LLDAS as a clinical trial endpoint was also demonstrated in the recent trial comparing azathioprine and mycophenoate in non-renal active SLE8.
Should clinicians now be implementing treat-to-target regimens in clinical practice with LLDAS as their goal?
I think the answer is ‘yes’, but with caveats. Encouraging results of retrospective analyses of the association between LLDAS and reduced organ damage accrual published in peer reviewed journals are matched to many studies reported in abstract form that await publication, and ultimately the results from the prospective validation study currently under way. From our experience in RA, we know that prospective treat-to-target trials – escalating a patient’s treatment until they meet the preset criteria and demonstrating that outcomes with that approach are better than with standard care - have considerable impact. The key caveat to implementing a T2T approach in lupus today is whether we can achieve this with our currently available lupus treatments – this was the case in RA. Perhaps the full value of treat-to-target will only become clear once we have more effective drugs for lupus, again as the successes in RA have taught us.
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.
2. Golder et al. Arthritis Research & Therapy (2016) 18:260. DOI 10.1186/s13075-016-1163-2
3. 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.
4. 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.
5. Petri M. Comparison of Remission and Lupus Lows Activity State as Predictors of Organ Damage [abstract]. Presented at Lupus 2017. Available from http://lupus2017.org/program-information/interactive-program. Accessed March 16, 2017.
6. Piga M, Floris A, Cappellazzo G, et al. Failure to achieve lupus low disease activity state (LLDAS) six months after diagnosis is associated with early damage accrual in Caucasian patients with systemic lupus erythematosus. Arthritis Research & Therapy (2017) 19:247. DOI: https://doi.org/10.1186/s13075-017-1451-5.
7. Morand E, et al. "Lupus Low Disease Activity State (LLDAS) attainment discriminates responders in a systemic lupus erythematosus trial: post-hoc analysis of the Phase IIb MUSE trial of anifrolumab." Annals of the Rheumatic Diseases (2018): annrheumdis-2017.
8. Ordi-Ros J, Saez-Comet L, Perez-Conesa M. Enteric-coated mycophenolate versus azathioprine in patients with active systemic lupus erythematosus: a randomized clinical trial. Ann Rheum Dis 2017 Sep;76 (9):1575-1582.