Treat-to-Target in Systemic Lupus Erythematosus: History
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Contributor:
Dina Zucchi
,
Chiara Cardelli
,
Elena Elefante
,
Chiara Tani
,
Marta Mosca

Treat-to-target is a therapeutic approach based on adjustments to treatment at set intervals in order to achieve well-defined, clinically relevant targets. This approach has been successfully applied to many chronic conditions, and in rheumatology promising results have emerged for rheumatoid arthritis. For systemic lupus erythematosus (SLE), defining the most meaningful treatment targets has been challenging, due to disease complexity and heterogeneity. Control of disease activity, the reduction of damage accrual and the patient’s quality of life should be considered as the main targets in SLE, and several new drugs are emerging to achieve these targets. 

  • systemic lupus erythematosus
  • treat-to-target
  • remission

1. Introduction

Treat-to-target (T2T) is a therapeutic approach in which adjustments to treatment are made at set intervals in order to achieve a well-defined, clinically relevant target. T2T strategies include choosing a target and a method for measuring it, taking steps to achieve it, assessing the target at a pre-specified time point and changing the treatment if the target is not achieved [1]. The change in treatment does not necessarily have to be a switch of drugs but can be a change in lifestyle or an increase in the dose of previously introduced drugs.
The concept of T2T has been widely used in the treatment of chronic diseases such as diabetes, hypertension, hyperuricaemia and hyper-lipidaemia, using specific quantitative parameters as targets (glycated haemoglobin, blood pressure, uric acid and cholesterol levels, respectively), since in these patients the achievement of the targets can minimize organ damage and increase life expectancy [2].
The application of the T2T strategy to rheumatic diseases is more challenging, due to the complexity of the diseases and the absence of a specific or direct marker to assess disease activity. In clinical practice clinicians use composite scores that generally include not only biomarkers, but also physician’s assessed measures and patient-reported outcomes, and it is therefore difficult to identify a unique and ideal target. The T2T concept has been recently applied to rheumatoid arthritis (RA) with promising results; clinical remission, defined as the absence of signs and symptoms of significant inflammatory disease activity, was indicated by the European League Against Rheumatism (EULAR) recommendations as the primary target of the treatment strategy in RA, and low disease activity as an acceptable alternative therapeutic goal [3][4]. The efficacy of the T2T strategy in RA is supported by several clinical trials, including the FIN-RACo [5], the TICORA [6], the CAMERA [7] and the BeSt [8] study, confirming that this approach may improve the care of patients and provide useful guidance to healthcare professionals.
Systemic lupus erythematosus (SLE) is a more complex disease with respect to RA, due to the wide range of possible clinical manifestations, the relapsing–remitting course and the complexity of the composite scores used to assess disease activity.
In the T2T recommendations for SLE [9] different targets were identified, with particular emphasis on disease activity and damage prevention keeping the lowest glucocorticoid (GC) dosage and withdrawal if possible. In addition, the need to take into account the patient’s health-related quality of life (HRQOL) was underlined.
Although many targets have been identified in the T2T recommendations, at present the main available data on targets in SLE treatment concern remission, Lupus Low Disease Activity State (LLDAS) in non-renal and renal lupus and GC reduction.

2. Achievement of Remission and Low Disease Activity

Several definitions of remission have been developed, all of which include as main components the absence of clinical disease activity; treatment, particularly referring to GC doses; and, in some cases, serological activity [10][11][12][13][14].
One of the most notable differences with respect to the previous criteria from the same Task Force [15] is that serological markers (anti-dsDNA, C3 and C4) were not included.
This is because, although some studies have shown that abnormalities or changes in serology predict flare or response to treatment, abnormal serology was not an independent predictor of damage, late morbidity or mortality in most of them [16].
Where remission cannot be reached, the lowest possible disease activity represents a target for disease activity control in SLE. Different definitions of low disease activity have been proposed [17]. Recently, the Asia–Pacific Lupus Collaboration group has developed and validated a definition of LLDAS [18], which has been largely applied in clinical practice as well as in randomized controlled trials (RCTs).
Remission and LLDAS prevalence varied among studies and cohorts. Remission is the ultimate goal in SLE, but it could be difficult to achieve and even more difficult is to maintain over time [19]. Remission has been reported in 2.5% [11] to 90.4% [20] of patients in the different cohorts with a notable increase over the years, despite in cases of more stringent definitions where remission was achieved by a lower percentage of patients [21].
LLDAS prevalence was generally higher than remission, being reached by more than 80% of patients in several cohorts [20][22]; in addition, LLDAS was maintained over time by 33.5% to 52.5% of patients.
Reaching the targets of remission and LLDAS has proven to be linked to better outcomes in SLE, in terms of damage accrual, a reduction in the number of flares, GC withdrawal, better quality of life [23], reduced risk of cardiovascular disease [24], improved mortality [25] and also reduced direct healthcare costs [26].
One of the largest studies exploring the impact of achieving treatment targets on damage showed that reaching remission even as low as <25% at the time of follow-up and achieving LLDAS in 50% of follow-up visits led to a 50% reduction in damage accrual [27]. Several studies have also demonstrated that it is important to achieve remission as early as possible in the disease course (within one year from disease onset), to prevent early damage accrual and to prevent disease flares, to spare GC [28][29].
The attainment of treatment targets is not the only element to be considered. Growing evidence from the literature underlines that time spent in remission or LLDAS is a crucial point. So, it can be hypothesized that remission or LLDAS need to be a durable state to be considered a desirable treatment outcome [20]. In a cohort of Caucasian patients with SLE, two consecutive years appeared as the shortest duration of remission associated with a decrease in damage progression [30].
Data coming from different SLE cohorts confirmed that prolonged remission or LLDAS (defined as a 5-year consecutive period) are both associated with a lower risk of damage accrual, irrespective of other factors such as age, gender, racial group, serology or immunosuppressive treatment. In the LUMINA cohort, this protective effect was also shown on mortality, although statistical significance was not reached [14][31][32].
The definitions of both remission and LLDAS take into consideration ongoing GC treatment. Actually, GCs are responsible for much of the damage accrual, infections and premature mortality in SLE [33][34][35]. In this context, although reaching LLDAS is more frequent than remission, remission sounds intuitively preferable than LLDAS as it would probably lead to a lower GC burden over time.
The independent impact of different definitions of remission and LLDAS on damage accrual has been recently examined, for the first time, in a large multinational, multiethnic cohort (the Systemic Lupus International Collaborating Clinics (SLICC) inception cohort). Five mutually exclusive disease activity states were defined: remission off-treatment and on-treatment; low disease activity Toronto cohort (cSLEDAI-2K score of ≤ 2, without prednisone or immunosuppressants); and modified LLDAS (LLDAS definition without PGA) were compared to active disease. Achieving any of these possible targets was associated with a lower probability of damage accrual, even after adjusting for possible confounders and effect modifiers, highlighting the importance of treating-to-target in SLE. Moreover, in this cohort, a relatively high rate of remission was found, compared to LLDAS, thus encouraging the use of remission on- or off-treatment as the ideal target, with LLDAS being only an alternative target [36].
The association of remission and LLDAS and HRQOL is not unequivocal. Some studies have showed an association between remission or LLDAS achievement and better HRQOL in SLE patients, especially when a durable, stable remission is achieved [37][38]. Interestingly, major effects have been demonstrated on the physical component, whereas the mental component of quality of life seems to remain unchanged by remission [39]. However a recent study in a large Italian cohort has demonstrated that, although LLDAS is a satisfactory treatment target for the physician, it may not represent the ideal goal from the patient’s perspective, particularly when a low disease activity state “allows” the presence of ongoing arthritis and steroid therapy [40].
Therefore, it appears crucial to carry out a more comprehensive assessment of associated symptoms and conditions, such as fibromyalgia, mood disorders and fatigue [41][42]. In fact, the persistence of symptoms such as pain and fatigue, even when remission of SLE disease activity has been achieved, has largely emerged as an unmet need from patients’ perspectives [43][44].

3. Reaching Glucocorticoids Minimization and Withdrawal

It is well established that long-term GC use is associated in a dose-dependent manner with organ damage accrual including osteoporotic fractures, coronary artery disease, cataracts, avascular necrosis and stroke [45][46].
In a large SLE cohort it has been demonstrated that the current use of GCs at a dosage of 20 mg prednisone or more is associated with a five-fold increase in cardiovascular events [34]. Moreover, Ruiz-Irastorza et al. have demonstrated that with each increase of 10 mg per day of prednisone, there is an 11-fold increase in serious infections, in addition to an increased risk of avascular necrosis and the other numerous side-effects associated with exposure to supraphysiological doses of GCs [35].
Organ damage in SLE is associated with increased mortality [47]; therefore, according to the treat-to-target strategy and the EULAR recommendations, GC minimization and, when possible, complete GC withdrawal are considered important targets to be pursued [46][48]. However, GC tapering below 5 mg/day seems to be more difficult in older patients, in patients treated before 2000 and in cases of high disease activity and skin and musculoskeletal manifestations [49].The CORTICOLUP trial showed that the maintenance of long-term 5 mg prednisone prevents relapse [50]. In this RCT, patients in remission were randomized to GC withdrawal or maintenance; the proportion of patients experiencing a flare was significantly lower in the maintenance group as compared with the withdrawal group (4 patients vs. 17, p = 0.003). However, the majority of flares were mild–moderate. However, several real-life data suggest that GC discontinuation could be safe [51][52][53][54] in patients with long-term quiescent disease, and disease flares were not common in this subset of patients [51][52][53].
Although, with some caveats, therefore, the literature shows that GC withdrawal is feasible, particularly in patients with long-term remission or LLDAS.

4. Control of Lupus Nephritis

In the context of lupus nephritis (LN), people have more data available on the targets to be achieved and the timelines for achieving them. Recently, the EULAR recommendations for the management of LN have clearly defined specific goals of therapy [55].
In LN, the prediction of the long-term renal outcome at the early stages of the disease is of vital importance [56]. With this premise, adhering to a T2T strategy in clinical practice may facilitate the management and follow-up of LN patients, particularly when a clear target to be pursued is identified. Recently, the analyses of two important lupus trials, the MAINTAIN Nephritis trial [57] and the EuroLupus Nephritis Trial [58], have reported that proteinuria is the single best predictor of long-term (7 years) renal outcome in lupus patients, suggesting a possible use of proteinuria as a target to prevent renal damage in a T2T approach. Similarly, in a real-life situation, proteinuria at 12 months of follow-up was found to be the single best predictor of renal outcome at 7 years for an ethnically diverse group of patients with severe nephritis and a valid parameter for distinct histological classes, races, genders and anti-dsDNA [59].
A renal complete response, defined as proteinuria < 0.5–0.7 g/24 h with a glomerular filtration rate (GFR) normalization/stabilisation in 12 months from LN onset, is considered a clinically meaningful target to be achieved as it is associated with a good long-term renal prognosis.
However, in the meantime, at least an improvement in proteinuria should be obtained within 3 months in combination with a normalization/stabilization of GFR and a partial clinical response, defined as a reduction in proteinuria of at least 50%, should be achieved by 6 months. The time to reach the target could be extended for 6–12 months in patients with nephrotic-range proteinuria, to avoid premature treatment changes.

This entry is adapted from the peer-reviewed paper 10.3390/jcm12093348

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