Systemic lupus erythematosus (SLE) is a chronic inflammatory autoimmune disease with fluctuating periods of relative inactivity and disease flares.1,2 It is marked by inflammation and tissue injury, and commonly progresses to irreversible organ damage.3,4 Notably, approximately 30 to 50% of people with SLE will develop organ damage within 5 years of diagnosis, and 50% or more will within 10 years following diagnosis.5,6

Unpredictable and heterogeneous,7 there is no clear understanding of what the “disease story” is with SLE. There is no cure1 for SLE, nor strongly correlated biomarkers8 to determine success beyond what patients are reporting to us as patient-reported outcomes and the overall patient experience. This presents challenges in the way we as clinicians assess outcomes, design clinical trials and set treatment targets – specific parameters that we can measure quantitatively such as blood pressure or glucose level, as we have with other conditions.9,10

However, we do know what we want to achieve for patients. We want to be able to control the symptoms so patients can enjoy important moments in life. We want to protect them as much as we can from organ damage. There are no second chances to prevent organ damage, and early intervention is crucial. 


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Disease Modification Has Remained Undefined in SLE

While the concept of disease modification is familiar to rheumatologists in treating rheumatoid arthritis (RA) and other rheumatic diseases, that is not the case with SLE, where disease modification is not universally understood nor accepted.8 In SLE, symptom-relieving treatments may be recommended to “put out fires,” but may or may not control the source of the disease, and, in the case of corticosteroids, can contribute to long-term organ damage when used over time.11-14 

To date, no widely accepted definition of disease modification has been established in SLE, and there are no guidelines that define the term.8 Without this definition, it is difficult to determine whether a specific treatment is having the desired treatment impact and modifying the natural progress of the disease.8 A formal definition is essential to demonstrate a medicine’s capacity to modify the course of SLE, help identify which treatments can be considered disease-modifying at different time during the course of the disease, and provide an opportunity to harmonize future clinical trial outcomes, which will ultimately help improve patient care and patient outcomes.8  Having a clear definition of disease modification will help physicians explain to patients the role of their medication in the shared-decision making process, how their medication is important to their long-term outcome, and the importance of treatment adherence.

Data show that while SLE control has improved, outcomes remain suboptimal.15 Severe flares still occur in some patients, regardless of whether they are on antimalarials, corticosteroids, or immune system suppressing drugs.16 Organ damage progression still occurs on standard of care,17 and high corticosteroid cumulative exposure is associated with late organ damage accrual.18 For all these reasons, patients deserve a definition of disease modification in SLE.

Our Proposed Definition: A First Step in Transforming Lupus Care

In a paper recently published in Lupus Science & Medicine, I, along with 11 other global lupus experts, conceptualised a framework and criteria for defining disease modification in SLE. We reviewed established definitions of disease modification in other conditions and identified a meaningful effect on both disease manifestations, such as signs, symptoms, and patient-reported outcomes, and disease outcomes, including long-term remission or progression of damage as the key principles of disease modification, indicating a positive effect on the natural course of SLE. Based on these findings and the treatment goals and outcome measures for SLE, including lupus nephritis (LN), we suggested a definition of disease modification based on disease activity indices and organ damage outcomes, with organ damage as a key anchor.8

Roger Levy, MD

The inclusion of organ damage prevention in the proposed definition is a critical component. Patients with SLE-associated organ damage have worse health-related quality of life (HRQOL) and increased healthcare costs, morbidity, and mortality versus patients with SLE who have lesser or no organ damage.19-21

The proposed definition is: Disease modification in lupus requires minimising disease activity with the fewest treatment-associated toxicities and slowing or preventing organ damage progression (or, in the case of LN, progression to end-stage kidney disease).8 

This definition could be applied to clinical trials and clinical practice to establish treatment targets. In the paper, we propose using specific measures of disease activity and damage at baseline and at least every year to determine whether a treatment is able to minimize disease activity with the fewest treatment-associated toxicities and, at year 5 or later, to evaluate slowing or preventing organ damage progression. In turn, interim measures for years 2 through 5 could determine whether an intervention is on track for achieving disease modification at the 5-year mark.8

Treat to Target: Aligning Short and Long-Term Goals for Better Outcomes

Defining disease modification also marks an important step in allowing for the application of a treat-to-target (T2T) strategy to SLE and LN, which has been effective other diseases, including RA.22 With the T2T approach, treatment is adjusted at set intervals, as long as the patient is achieving a well-defined, clinically relevant target.23

Typically, short-term symptom resolution and quality of life are key objectives when making treatment decisions. While these are certainly important goals, as physicians we must also recognise the need to think about the lives of people with SLE and LN on a continuum, which means long-term management and maintaining health for as long as possible while trying to avoid future complications.

By focusing on the underlying mechanism of disease, T2T seeks to shift the treatment mindset from targeting only present symptoms to also managing the underlying disease, which may be active despite no symptoms, and can lead to irreversible kidney damage. It means thinking beyond symptom-relieving treatments like corticosteroids earlier given that they do not modify the underlying cause of disease and also contribute to organ damage.8,11,14

An additional advantage of disease modification as part of the T2T approach is that it may facilitate earlier treatment, which could ultimately lead to improved long-term patient outcomes and avoidance of the need for transplantation, or development of advanced or end-stage kidney disease.8 With T2T, we have an opportunity to make an impact on the millions of lives affected by lupus, balancing current symptom management with targeting the underlying progression of the disease.

Addressing Barriers and Sparking Future Debate

There are many benefits to defining disease modification in SLE, but there may be challenges in the wide adoption of it and the T2T approach. Some physicians have not been updated on the different ways in which the underlying cause of disease can be targeted as treatments are rapidly evolving. There may also be a perception that currently available lupus treatments are fundamentally “disease modifiers.” However, the proposed definition of disease modification includes the important criteria of slowing or preventing organ damage, and not all SLE treatments can do this.  

Our hope is that this publication of a preliminary definition of disease modification in SLE, which also provides criteria for a medication to be classified as a disease-modifying therapy, serves as a foundation for an exchange of ideas that could lead to further refinement of this concept in SLE. While more formal evaluation and testing will be needed before a consensus definition can be adopted, as we note in the paper, our work should spark debate on how to achieve disease modification in SLE and the criteria that must be met for a drug to be classified as disease-modifying.8

Several SLE treatments may fit the proposed definition, and that is the focus of an ongoing review. Though there is no one-size-fits-all treatment strategy for SLE,7 it is vital that we help our patients understand the visible and invisible impacts of SLE and how available treatment options address both, especially when there is so much new information coming out about SLE. Wherever disease modification in SLE ultimately lands, what remains true is the continued need for ongoing conversations with patients about short- and long-term treatment goals and working together to achieve the best possible outcomes.

References

  1. American College of Rheumatology. Lupus, 2020. Accessed April 28, 2022. https://www.rheumatology.org/I-Am-A/Patient-Caregiver/Diseases.
  2. Gyori N, Giannakou I, Chatzidionysiou K, et al. Disease activity patterns over time in patients with SLE: analysis of the Hopkins lupus cohort. Lupus Sci Med. 2017;4:e000192.
  3. Liu S, Davidson A. Taming lupus-a new understanding of pathogenesis is leading to clinical advances. Nat Med. 2012;18:871–82.
  4. Samansky GB. Sunlight-induced pathogenesis in systemic lupus erythematosus. J Invest Dermatol. 1985;85:179–80.
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  9. European Medicines Agency. Guideline on the Clinical Investigation of Medicines for the Treatment of Alsheimer’s Disease. Updated: February 22, 2018. Accessed April 28, 2022. https://www.ema.europa.eu/en/documents/scientific-guideline/guideline-clinical-investigation-medicines-treatment-alzheimers-disease-revision-2_en.pdf  
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