Editorial theme | Treat-to-target in SLE

High rates of remission with novel targeted agents have been achieved with many rheumatic diseases; however, treatment of systemic lupus erythematosus (SLE) remains difficult. While there are clinical trials underway to investigate novel therapies, the final efficacy results remain awaited. In the interim, treatment outcomes could be optimized for patients with SLE by adopting specific treatment strategies, such as the treat-to-target (T2T) strategy, that prevent damage accrual and reduce flares and mortality.¹

In this first article in our editorial theme on treatment goals, we examine the T2T strategy and consider the advantages and disadvantages of its use when managing patients with SLE. Further information on the clinical considerations for SLE can be found in our related article here.

EULAR/ACR recommendations on treatment goals²

The 2019 European Alliance of Associations for Rheumatology (EULAR)/American College of Rheumatology (ACR) recommendations state that the goals of treatment should be to aim for remission or low disease activity and prevention of flares in all organs, maintained with the lowest possible dose of glucocorticoids. The guidelines state that achieving complete remission is infrequent and suggests the use of Lupus Low Disease Activity State (LLDAS) as a treatment goal to allow a comparable decrease in damage accrual and prevention of flares.

For further information on the EULAR/ACR recommendations for management of SLE, please see our related article here.

What is T2T?¹

T2T is a strategy that has been used successfully in other diseases, including diabetes and rheumatoid arthritis. The T2T strategy involves four steps, as outlined in Figure 1.

Figure 1. T2T strategy for the treatment of SLE* 

SLE, systemic lupus erythematosus; T2T, treat-to-target.
*Adapted from Parra Sánchez, et al.¹

For SLE, monitoring intervals are suggested of 3−6 months, while assessing disease activity, response to treatment, and damage (both from disease and as a result of therapy).

T2T has been suggested as an effective strategy for the treatment of SLE, although this has yet to be formally assessed in a clinical trial against standard care. To make T2T a viable option, defined treatment goals are needed along with therapeutic options to achieve these goals.

T2T endpoints¹

The main goal when treating SLE is to achieve remission, ideally without immunosuppressive agents and no serological activity. However, this can be very challenging to achieve in some patients with the current therapeutic options available. LLDAS is considered as an attainable intermediate goal in the SLE T2T strategy and the benefits of attaining and maintaining LLDAS in patients have been shown in a several studies, such as the Hopkins Lupus Cohort and the Asia-Pacific collaborative study.

The Definition of Remission in SLE (DORIS) is more stringent than LLDAS, with a SLE Disease Activity Index (SLEDAI) index score of 0 being necessary, whereas LLDAS allows up to 4 points. The maximum dose of glucocorticoids is also lower in DORIS at <5 mg daily prednisolone compared with ≤7.5 mg daily prednisolone in LLDAS (Table 1).

Table 1. Definitions of the T2T endpoints LLDAS and DORIS*

Benefit of using T2T¹

The effect on outcomes, such as health-related quality of life (HRQoL), survival, and prevention of long-term organ damage, using LLDAS and DORIS has been investigated in several studies. In the Asia-Pacific Collaborative study, patients who spent >50% of their time in LLDAS demonstrated a significant reduction in the cumulative organ damage and had a relative risk of 0.47 (p = 0.005) of having ≥1 increase in the Systemic Lupus International Collaborating Clinics (SLICC)/ACR Damage Index.

DORIS has also been shown to be associated with decreased organ damage, flares, and improved patient QoL; therefore, either endpoint is thought to be suitable as a treatment goal for patients with SLE.

Impact on patient-reported outcomes⁶

Achieving remission in SLE is associated with an improvement in HRQoL, which is a key endpoint from a patient’s perspective. Two cohort studies found that long-term remission ≥5 years was associated with improvements in HRQoL when using the SF-36 and LupusPRO tools. Using LLDAS as an endpoint has also shown similar results.

Treatments facilitating T2T¹

Recent advances in the understanding of SLE pathogenesis have enabled the development of targeted therapies for patients who respond inadequately to conventional treatments, making T2T feasible in routine patient management. An overview of SLE management has previously been published on the Lupus Hub, here.

Challenges in adopting T2T in clinical practice¹

Patients may be resistant to the T2T strategy if the rationale behind it is not properly explained as it may involve an increased number of visits to the clinic for monitoring purposes and more frequent changes of medication. This could potentially lead to reduced trust in the primary physician and increased non-compliance with prescribed medication. In addition, treatments that are achieving moderate success in treating SLE may be stopped in favor of a less successful agent under the T2T model as the primary endpoint was not met. This approach may also lead to the use of more expensive medication more quickly than standard of care if an adequate response is not attained. As treatment options for SLE remain limited this may lead to rapid exhaustion of treatment options.

T2T trials¹

As the T2T strategy has not yet been compared against standard of care in a prospective study, an ongoing study, the Lupus-BEST trial (NCT05714930), aims to assess the impact on organ damage accrual and improve HRQoL. The trial will consist of three arms; standard of care, T2T with a goal of DORIS, and T2T with a goal of LLDAS. The design of this trial should allow assessment of which endpoint is feasible, along with calculation of the benefit-risk ratio of each treatment arm and the impact on adverse events and organ damage.

Conclusion 

SLE is a heterogenous disease that makes treatment challenging. However, the adoption of clinical strategies such as T2T has the potential to improve not only the number of flares and decrease the amount of damage accrual but also improve a patient’s HRQoL. With several novel therapies on the horizon, T2T strategies for SLE management are more viable as there are sufficient therapeutic options for patients. LLDAS is the more clinically achievable treatment goal currently, but with the advent of novel agents for the treatment of SLE, DORIS may become more achievable for a larger group of patients. Despite the challenges of implementing the T2T strategy in the clinic, it has the potential to greatly improve treatment outcomes for patients and upcoming trials should provide further information on the benefits and caveats of using this strategy.