Discussion
Our systematic literature search showed that being in remission or LDA, regardless of the definitions used, was associated with better outcomes in patients with SLE, the most commonly reported outcomes being lower damage accrual, fewer flares and a better HRQoL. The association with a lower mortality rate was less consistently reported.
In terms of mortality, LDA was associated with lower mortality in two studies, one from the Toronto Lupus Cohort,7 which had a more stringent definition of LDA (SLEDAI ≤2 without treatment) and the other from Norway40 (which allowed a SLEDAI ≤4, excluding new activity and major organ activity, and allowing prednisone ≤7.5 mg/day and immunosuppressive drugs on maintenance dose); similarly, remission was associated with lower mortality in a study from Mexico4 and in one from the UK.5 However, in the GLADEL14 and the LUMINA20 cohorts, the association between remission and LDA and mortality was not statistically significant, although the trend was in the protective direction. This lack of association between achieving these outcomes and mortality could be due to a relatively short follow-up time in these cohorts. The Toronto Lupus Cohort compared remission and LDA and found no statistically significant difference between the two states in terms of mortality.7
Remission was associated with a lower risk of damage accrual in several cohorts from Asia, Europe, North America (USA-Canada) and Latin America3 7 14–16 18 27 34–37 ; however, the minimum time on remission needed to prevent damage accrual has yet to be determined. According to the Padua cohort, being in remission for less than 1 year was not protective against damage,16 whereas according to the Hopkins cohort, being in remission even less than 25% of the follow-up time prevented the accrual of damage.18,18 According to the GLADEL cohort, being in remission prevented not only the accrual of any damage but also the accrual of severe damage (an increase in the SDI of at least 3 points) and from non-glucocorticoid (GC)-related damage and severe damage.14 Additionally, the longer the duration of remission, the lower the probability of damage accrual.16 Similarly, LDA (regardless of how it was defined) has been associated with less damage accrual7 11 14 15 17 18 20 34 38 40 43; however, in the Padua cohort, being on LDA for less than 1 year did not prevent the accrual of damage.17 In the Hopkins cohort, being in LDA for less than 25% of the follow-up did not prevent the accrual of damage.18 Being in LDA prevented also severe damage accrual, non-GC and GC-related damage14; furthermore, the longer the duration of LDAS, the less the damage accrued.20 In the Toronto cohort, being on remission and LDA (SLEDAI ≤2 without treatment) did not differ in terms of the risk of damage accrual7; however, in the Padua cohort, being in remission was associated with a lower risk of damage that being on LLDAS (which allowed a SLEDAI ≤4, excluding new activity and major organ activity, and allowing prednisone ≤7.5 mg/day and immunosuppressive drugs on maintenance dose).17 Probably, the difference in the definitions used in both cohorts could explain these results. Consistent with these results, prolonged remission was associated with a lower probability of cardiovascular events.30
Being in remission or LDA reduced the risk of any flares, being those mild-moderate or severe.7 26 27 38 43 Only in the Toronto cohort remission and LDA (SLEDAI ≤2 without treatment) were compared, but no differences were found.7
Patient perspective is important in defining the optimal treatment target. In previous reports, the association between disease activity and HRQoL has been low or absent.44 Notably, remission and LDA have been found to be associated with a better HRQoL in cross-sectional and longitudinal studies regardless of whether generic or lupus-specific measures were used.3 24 25 29 31–33 39 42 43 These associations were more consistently reported in the physical than in the mental domains, probably because the mental domains are affected also by comorbid conditions such as depression, fibromyalgia and anxiety. It has been suggested that specific measures may ascertain better QoL dimensions specific to patients with SLE.44
Finally, remission and LDA could reduce hospitalisation rate; this has been reported in the Peruvian Almenara Lupus cohort28; LDA could also reduce annual medical cost as reported in a study from an Australian cohort.41 It is important to point out that this information needs to be confirmed in other populations.
Taking together, being on remission or on LDA, regardless of the definitions used, is associated with better outcomes, including mortality, damage, flares, HRQoL, hospitalisation and cost. It is important, however, to point out that a uniform definition of both states is desirable in order to make these results comparable. The current definition of remission, as proposed by the DORIS group, takes into account two physician disease activity measures (clinical SLEDAI=0 and PGA<0.5) as well as treatment (prednisone daily dose not higher than 5 mg/day and/or immunosuppressive drugs on maintenance dose),1 and, even not all the studies used this definition, the large majority used 2015 or 2021 DORIS definitions1 2 or a very similar definition. LDA should be different enough from remission in order to define a group of patients with a better prognosis than those with active disease, but, not as good as the prognosis of those on remission; in this context, the definition proposed by APLC is a good option as it allows a higher level of disease activity (SLEDAI ≤4 and PGA≤1), excludes activity in major organs and new activity, and also allows a higher dose of prednisone (7.5 mg/day) and keeping the immunosuppressive drugs on maintenance dose.6 Additionally, in the KORNET cohort from Korea, LLDAS, but not LDA (SLEDAI ≤2 without treatment) or MDA (minimal disease activity) were predictive of good outcomes.43 However, more information is needed in order to determine if being on remission is better than being on LDA. About the duration of these states, it seems that achieving these states even for a short period of time is associated with better outcomes, but the longer the patient remains on these states, the better the outcomes will be.
These analyses have some limitations; first, as the studies included used different definitions for remission and LDA, a meta-analysis could not be performed. Second, the duration of follow-up in some studies reviewed was not long enough for the assessment of mortality. Third, there are only a few studies for some of the outcomes assessed; this precludes us from making stronger conclusions.
The main strength of this report is the inclusion of several different populations from across the world and several outcomes, allowing us to evaluate the real impact of remission and LDA in the prognosis of patients with SLE.
In conclusion, being in remission or LDA (regardless of the definition) is associated with improved outcomes in patients with SLE. These results reinforce the relevance of these outcomes for the management of patients with SLE.
In order to facilitate the implementation of a T2T strategy in SLE, it is important to have an uniform definition of remission1 and LDA.