Juvenile onset systemic lupus erythematosus (JSLE) is a rare, multi-system autoimmune disorder that affects 0.7 per 100,000 children in the United States.^[1] The childhood form of SLE has greater disease activity, more severe organ manifestations and a higher incidence of renal, cardiovascular and neuropsychiatric involvement than seen in adult patients.^[2] Affected children have a higher medication burden with steroid-toxicity presenting a bigger problem for children than it does for adults with SLE.

Steroids can permanently impact a young person’s growth and pubertal development

The magnitude of the problem was highlighted in a recent interview with Joyce Chang, MD MSCE, pediatric rheumatologist at Boston Children's Hospital. Dr Chang highlighted the importance of reducing the use of glucocorticoids in JSLE, echoing the findings of recent UK studies looking at developing treat-to-target (T2T) guidelines.

T2T is a strategy whereby treatment is escalated until a specified target (e.g., remission) is achieved and re-escalated if that target is lost. The approach is routine clinical practice in an increasing number of disease areas, including rheumatoid arthritis and adult systemic lupus erythematosus.^[3] Eve Smith, PhD MBCHB and her team at Liverpool University are at the forefront of developing appropriate targets to enable T2T in JSLE patients and exploring the use of adult targets in this cohort. In adults, the focus is on establishing:

• Low disease activity
• Remission – based on the Definition Of Remission in SLE (DORIS)

 
The most widely used definition of low disease activity is the “lupus low disease activity state” (LLDAS), developed by the Asia Pacific Lupus Consortium. This definition focuses on the principle of “tolerable” disease activity on stable treatment, with low glucocorticoid doses (≤7.5mg/day) and reduced likelihood of adverse outcomes. Achievement of these goals in an adult setting is associated with reduced organ damage, fewer flares, reduced steroid-burden, improved quality of life and reduced healthcare costs.^[2]

TARGET LUPUS: Targeting disease, agreeing recommendations and reducing glucocorticoids through effective treatment in lupus

The study was overseen by TARGET LUPUS, a group set up to develop T2T studies in JSLE. With no robust treatment targets for JSLE, the study assessed the achievability of seven adult low disease activity and remission measures in a juvenile cohort. Four hundred and thirty children were included from the UK JSLE cohort study, which collects longitudinal data from 22 pediatric rheumatology centers across the UK. 

T2T effectively reduces the risk of flare and organ damage

This is an impressive study that resulted in complex analyses of large amounts of data around the low disease activity and remission targets. Rather than delve into the details, we are going to focus on what the results mean for the development of targets for JSLE and the potential impact on outcomes and quality of life for the children involved.

The key findings were:

• Low disease activity and remission targets achieved in 32% to 73% of patients depending on the measure used, demonstrating that adult targets are achievable in juvenile patients.
  
  • Factors contributing to non-achievement included requirement for ≥7.5mg per day of steroid doses, development of new features of lupus activity and major active organ involvement.
• Attaining any of the targets at any point and having a disease duration of > 1 year significantly reduced the hazard of severe flare.
  • Target attainment also significantly reduced the liklihood of new damage.
• Remission on-treatment was easier to achieve (42-61%) than remission off-treatment (21-31%).
• Attainment of low disease activity targets, remission on/off-treatment reduced and longer periods of time on target reduced the hazard of severe flare.
  • For example, increasing cumulative time in the LLDAS target from 10% to 80% reduced the hazards of severe flare from 0.68 to 0.05.
• The LLDAS definition of low disease activity performed best in terms of balancing attainment of targets and the impact of flare/damage.

Juvenile targets should include patient-reported quality of life assessments and a focus on reducing the burden of steroid-toxicity

This is the first study to investigate the use of adult definitions of low disease activity and remission in a pediatric cohort. The results demonstrate that a T2T approach to treating juvenile lupus can improve outcomes by reducing the risk of severe flare and new damage.
  
The TARGET team have also undertaken a qualitative study, exploring the views of patients and parents on both the T2T strategy and target development for juvenile lupus. While opinions varied as to the most appropriate definition of low disease activity, the majority agreed on two elements that should be included: a fatigue patient-reported outcomes measure and a focus on reducing glucocorticoid dosage.^[4]

Success of the T2T approach in juvenile lupus requires the longitudinal monitoring of targets to ensure attainment and long-term maintenance of those targets. Reducing glucocorticoid dosage is an important element in achieving all adult targets. One of the suggestions from the patient and parent study was the inclusion of aggressive steroid-sparing treatment strategies within a T2T trial. The authors highlighted the need for inclusion of a validated measure of steroid-toxicity, such as the pGTI, for T2T studies in children.^[4] It will be interesting to see how the inclusion of this instrument in future lupus studies helps the development of appropriate targets for juvenile lupus.
 

References

1. Valenzuela-Almada MO, Hocaoglu M, Dabit JY et. al. Epidemiology of Childhood-Onset Systemic Lupus Erythematosus: A Population-Based Study. Arthritis Care Research (Hoboken), 74(5): 728-732. doi.org/10.1002/acr.24827
2. Smith EMF, Tharmaratnam, K Al-Abadi E et. al. Attainment of low risk disease activity and remission targets reduces the risk of severe flare and new damage in childhood lupus Rheumatology 61: 3378-3389, 2022. doi.org/10.1093/rheumatology/keab915
3. Atar D, Birkeland KI and Uhlig T. ‘Treat to target’: moving targets from hypertension, hyperlipidaemia and diabetes to rheumatoid arthritis. Ann Rheum Dis. 69:629–30. doi.org/10.1136/ard.2010.128462
4. Smith EMF, Gorst SL, Al-Abadi E, Hawley DP et. al. ‘It is good to have a target in mind’: qualitative views of patients and parents informing a Treat to Target clinical trial in juvenile-onset systemic lupus erythematosus. Rheumatology, 60:5630-5641, 2021. doi.org/10.1093/rheumatology/keab173