Elsevier

Autoimmunity Reviews

Volume 13, Issue 7, July 2014, Pages 770-777
Autoimmunity Reviews

Review
Optimizing outcome in SLE: treating-to-target and definition of treatment goals

https://doi.org/10.1016/j.autrev.2014.01.055Get rights and content

Abstract

Patients affected with systemic lupus erythematosus (SLE) display poor-long term prognosis and increased mortality in respect of general population. This may be due to continuous organ damage accrual which is fostered both by persistent disease activity (mainly in the short term) and prolonged corticosteroid exposure (mainly in the long term). The effort of defining novel therapeutic goals to which patients should be treated in order to have their prognosis improved is named treat-to-target.

Remission in SLE was shown to be associated with better outcome and prolonged survival; in clinical practice, patients may experience either complete or clinical remission, which are defined as complete clinical/serological healing or no clinical signs of lupus with active serology, respectively. The main treat-to-target in SLE is complete remission, however since longitudinal observations suggest that clinical remission or low disease activity even with minimal corticosteroid intake do improve patients prognosis and survival as well, they may be assumed as acceptable alternative targets.

Suitable therapeutic strategies have to be defined in order for these goals to be achieved including early diagnosis, effective treatment and proper corticosteroid tapering which in turn require development of more reliable serum biomarkers for early disease detection and less toxic targeted therapies with a steroid-sparing potential.

Introduction

Survival of patients with systemic lupus erythematosus (SLE) has dramatically improved over the last 50 years, increasing from 50% at 10 years in the fifties to more than 90% in 2000s [1], possibly owing to earlier diagnosis and more appropriate treatment schemes [2]. However, SLE patients still display a 4.6-fold higher standardized mortality rate compared with general population [3]. Causes of death have been varying deeply along with the increase in survival rates, with less patients dying due to acute disease and a greater percentage succumbing to cardiovascular events, infections or cancer [2], [4], [5]. Notably, persistent disease activity is associated with increased organ damage which in turn is predictive of more damage and death [6], [7], [8] (Fig. 1). Hence, several needs are still unmet among SLE population in that long-term prognosis remains poor; therefore, new methodological strategies should be found out aiming to prolong remission and minimize damage accrual. The aim of our paper is to shed more light on optimizing strategies in SLE focusing on treat-to-target, importance of early treatment and judicious corticosteroid use, which might reduce damage accrual and improve disease outcome.

Section snippets

Treat-to-target

Treat-to-target may be defined as a therapeutic strategy aimed to treat patients to a goal which is capable of improving disease outcome. The basis according to which one may pinpoint the best target to be treated to is mostly provided by clinical trials [9], [10]. As an example, current guidelines for diabetes and cardiovascular disease management outline the treatment thresholds which confer the highest probability of survival to patients at risk of adverse events (e.g. a total LDL-cholesterol

SLE disease activity

Lupus activity can be defined as a variable which represents the sum of all abnormalities due to ongoing immune inflammatory pathways involved in SLE which are mostly reversible.

Lupus activity may be distinguished into clinical and serological disease activity (Table 1), which encompass inflammatory/non-inflammatory manifestations affecting any district in the body and persistent serological abnormalities, among which the presence of autoantibodies, especially anti-dsDNA antibodies, low C3

SLE and organ damage

Damage in SLE is defined as an irreversible tissue injury occurring after diagnosis of SLE and lasting at least 6 months [31]; it is evaluated through the SLICC (Systemic Lupus International Collaborating Clinics) damage index (SDI), which encompasses 12 organ systems [31]. Interestingly, disease activity tends to generally decline over time, along with a parallel worsening in diverse damage domains [32], [33], [34]. Therefore, since lupus patients live longer, they tend to accumulate more

Organ damage predicts poor outcome

Damage is one of the major determinants of poor long term prognosis and death in SLE patients. It can also lead to disability and productivity loss.

Remission is associated with a better outcome

Results from a large multicentric inception cohort of SLE patients prospectively followed for 5 years showed that disease remission and particularly early remission is predictive for a better outcome in SLE [15], whereas long term prognosis remains poor in active patients [15], [74]. As an example, it is worth noting that renal survival is increased in patients who achieve either complete or partial disease remission in comparison with severely-affected patients, whereas overall survival at 20 

Remission in SLE

Remission in SLE is not clearly defined by any of the available disease activity scores [77]. According to SLEDAI, remission may be defined as a SLEDAI = 0, whereas SLEDAI  3 was referred to as persistent disease activity [78], [79], thus raising the question what significance be given to serologic abnormalities such as anti-double stranded (ds)DNA antibodies or complement levels.

SLE activity measures are not commonly used in routine follow-up visits, thus if we look at clinical practice, at least

Definition of treatment goals

Long-term complete remission is the primary target that SLE patients should be treated to, since durable remission is associated with a better outcome in terms of reduced disease flares and damage accrual. However, complete remission is often hard to accomplish for the majority of SLE patients, whereas clinical remission without corticosteroids or with a minimal dose of corticosteroids could be acceptable alternative targets. Though it is not included in the SLE wish-list, low disease activity

Early treatment and the window of opportunity in SLE

It is worth noting that clinical recommendations for lupus management all agree on the need of early initiation of adequate therapy [86], [87], [88], [89], regardless of which organ is affected and what drug is specifically proposed for treatment. As aforementioned, the sooner the treatment is started, the higher is the chance of achieving persistent remission and improve patients prognosis [74]. Data on early intervention in humans are currently limited, however existing studies clearly show

Conclusions

Achievement of a more favorable outcome in SLE is closely due to tight control of disease activity and prolonged remission. Patients should be treated to complete remission since it is associated with the best outcome; however, clinical remission or even low disease activity with low doses of steroids are acceptable alternative therapeutic targets. Early diagnosis is essential in order for patients to be efficiently treated (better if within 3–5 months from clinical disease onset) and enter an

Take-home messages

  • Treat to target refers to treating patients to a definite value of disease, which significantly improves a patient's condition.

  • Complete remission is the main treat-to-target in SLE, yet partial remission or low disease activity may be acceptable.

  • Early treatment in SLE prevents organ damage and is predictive of durable remission.

  • Tight balance between therapeutic harm and benefit has to be provided and prompt corticosteroids withdrawal is recommended.

  • More reliable biomarkers and outcome measures

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      Citation Excerpt :

      The effectiveness of this strategy on other diseases led to the search for therapeutic targets in patients with Systemic Lupus Erythematosus (SLE) in the last few years [2]. The 2014 recommendations on the treat-to-target strategy in SLE suggested that the therapeutic targets should be remission and, when this is not possible, the lowest possible level of disease activity, since SLE disease activity is associated with adverse patient outcomes, including damage accrual and mortality [1,4–9]. Thus, there was a need to define low disease activity (LDA) and remission, not only for their use in clinical practice but also as outcomes in randomized controlled trials (RCT) [3].

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