In recent years, the concept of treatment-to-target (T2T), originally applied to diseases such as diabetes mellitus, has been introduced into the treatment of rheumatoid arthritis (RA). The overall concept implies that a specific therapeutic target is decided upon within the physician-patient interaction and that subsequent therapeutic interventions are assessed, at appropriate time intervals, against that target. Failure to achieve the target would in general be a trigger for changes in therapy. For RA, commonly chosen targets are ‘remission’ or ‘low disease activity’, defined by reference to the disease activity score (DAS) or other global disease activity indices. Various studies in RA have shown that a targeted approach to treatment yields better clinical results.

In 2013, an international expert panel, consisting of rheumatologists, nephrologists, dermatologists, clinical immunologists, and patient representatives, was convened and developed T2T guidance for systemic lupus erythematosus (SLE). SLE therapy is inherently more complex than the above-mentioned diseases because the disease is, by definition, multi-organ in nature. Instruments to measure global disease activity in SLE do exist but there is no agreed-upon preferred instrument for clinical use and it is generally recognized that each instrument has both inherent strengths and weaknesses. Disease ‘flares’ are clinically important aspects of SLE but although there are various flare instruments. Despite these challenges, the international T2T/SLE task force succeeded in establishing both Overarching Principles and eleven Specific Recommendations that were based on an extensive systematic literature search and subsequently finalized through Delphi-style interactions within the 35-member panel. These Principles and Recommendations have been published (Van Vollenhoven, ARD 2014) and have been extensively cited and included in treatment recommendations for SLE.
Treatment of SLE has also been more limited compared to treatment for the inflammatory joint diseases, with reliance mainly on corticosteroids, antimalarials, and conventional immunosuppressives. However, the regulatory approval of belimumab (Benlysta) has provided clinicians with one important new therapeutic option for their patients, and the current late-stage development of additional biological immunomodulatory therapies makes it likely that the therapeutic armamentarium will undergo significant changes in the coming years.

Thus, the development of T2T guidance for SLE has now been completed, but with the understanding that this is a first step in a longer-term process. One of the key recommendations from this endeavor was the identification of remission as a key therapeutic goals in SLE (as it is in rheumatoid arthritis). However, during the panel’s deliberations, it was also recognized that as of yet no generally accepted definition of remission in SLE has been established. It was acknowledged that a EULAR panel studying current guidelines for management of SLE in clinical practice had briefly investigated the issue without resolving it (M. Mosca, personal communication), but no other initiatives are currently underway to achieve a more clear definition of this very important outcome in SLE.

Therefore, the T2T/SLE panel identified as a very high priority the continued work on establishing a scientifically robust and practically applicable definition of remission in SLE. This project was initiated during 2014. An initial meeting was held in Berlin on March 5, 2014, and a large international meeting was held in Zurich on August 28, 2014. The latter meeting was attended by multiple patient representatives, medical specialists from four relevant specialties, representing 17 different countries on four continents. The meeting resulted in a blue-print for research work to test a series of remission definitions on multiple data sets, work that has now been started in several centers.

Subsequently, a second meeting of the entire task force was held in August, 2015 in Zurich, Switzerland. This meeting was attended by over 60 specialists, mostly rheumatologists but also nephrologists, dermatologists, and clinical immunologists; as well as by patient representatives. The delegates came from countries in North-, Central- and South-America, Europe, Asia, and Australia. The meeting resulted in a clearly articulated framework for testing definitions of remission in appropriate datasets. Thus, the task force agreed on eight key statements regarding remission in SLE and on the following three principles to guide the further development of remission definitions:

1. Definitions of remission will be worded as follows: Remission in SLE is a durable state characterized by …………………. (insert descriptor for symptoms, signs, routine labs).
2. For defining remission a validated index must be used, e.g., clinical-SLEDAI = 0, BILAG2004 D/E only, clinical ECLAM =0; with routine laboratory assessments included, and supplemented with Physician Global Assessment.
3. Distinction is made between remission off therapy and remission on therapy: Remission-off-therapy requires the patient to be on no other treatment for SLE than maintenance antimalarials; and Remission-on-therapy allows patients to be on stable maintenance antimalarials, low-dose corticosteroids (prednisone <5 mg/d), maintenance immunosuppressives and/or maintenance biologics.

Based on these principles, the task force agreed that testing should now be done of the various possible definitions of remission in appropriate data sets, including registries and clinical trials, determining 1) the metric characteristics and 2) the construct validity of each definition (i.e., based on cSLEDAI with/without serology, based on BILAG with/without serology; studying various durations; on/off treatment; etc). This work will result in the identification of the most suitable definitions for remission-on-treatment and remission-off-treatment for use in future clinical trials and observational studies. The task force agreed that the most appropriate outcomes (dependent variables) for such testing would be: Death, Damage, Flares, and measures of Health-related quality of life.

Since this task-force meeting concluded a number of research groups (including the groups of Dr. Doria in Padua, Dr. Petri in Baltimore, Dr. Voskuijl in Amsterdam, and the applicant’s own research group) have initiated these studies and results of several such analyses have been communicated at congresses and/or submitted for publication. It is anticipated that by the middle of 2018 at least five such analyses will be available for closer examination in the task force.

Steering Committee

Prof.dr. R. van Vollenhoven, Amsterdam Rheumatology & immunology Center, the Netherlands
Prof.dr. R. Cervera, Department of Autoimmune Diseases, Hospital Clinic, Barcelona, Spain
Prof.dr. F. Houssiau Department of Rheumatology, Université Catholique de Louvain, Bruxelles, Belgium
Prof.dr. M. Mosca, Rheumatology Unit, University of Pisa, Pisa, Italy
Prof.dr. G. Bertsias, Department of Internal Medicine, University of Crete, Heraklion, Greece
Prof.dr. N. Costedoat, Service de Médicine Interne 2, Hôpital Pitié-Salpêtrière, Paris, France
Prof.dr. T. Dörner, Department of Medicine/Rheumatology and Clinical Immunology, Charite University Hospital, Berlin, Germany
Prof.dr. M. Schneider, Department of Rheumatology, Heinrich-Heine-University Duesseldorf, Düsseldorf, Germany
Prof.dr. A. Voskuijl, Amsterdam Rheumatology & immunology Center, the Netherlands