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Correspondence to Dr Manuel Francisco Ugarte-Gil; [email protected]

Key messages

What is already known about this subject?

  • Remission and low disease activity (LDA) have been reported as potential targets in the systemic lupus erythematosus (SLE) treatment.

What does this study add?

  • Remission and LDA (regardless of the definitions used) are associated with better outcomes.

How might this impact on clinical practice or future developments?

  • Remission and LDA should be considered as the target for the management of patients with SLE.

  • However, it is important to have a uniform definition of both.

Introduction

A treat-to-target (T2T) strategy has been proposed for several chronic diseases in order to improve the affected patients’ treatment, and thus, their outcome; in systemic lupus erythematosus (SLE), however, a uniform definition of treatment goals is lacking.

The ideal goal is remission, which was defined in 2015 and modified in 2021 by the DORIS (Definition Of Remission In SLE) group as the absence of clinical disease activity (Clinical Systemic Lupus Erythematosus Disease Activity Index (SLEDAI)=0 and Physician Global Assessment (PGA)<0.5), with no or minimal intake of glucocorticoids (prednisone daily dose not higher than 5 mg/day) and/or immunosuppressive drugs on stable maintenance dose.1 2 However, some modifications of this definition have been reported in the literature.

Nevertheless, as remission state is not achieved frequently,3–5 low disease activity (LDA) has been proposed as an alternative target. To this end, there are several definitions about LDA in the literature; for example, the Asia Pacific Lupus Consortium (APLC) has introduced the lupus low disease activity state (LLDAS): SLEDAI≤4, which allows a low level of disease activity, without activity in major organ systems or new disease activity, PGA≤1, prednisone daily dose not higher than 7.5 mg/day and/or immunosuppressive drugs on maintenance dose.6 The Toronto Lupus Cohort investigators have proposed using the term low disease activity (LDA by Toronto Lupus Cohort): SLEDAI (excluding serology)≤2, without prednisone and immunosuppressive drugs.7

All these definitions allow the use of antimalarials.

The probability of patients achieving these states seems to vary according to a number of factors including race/ethnicity, in particular African ancestry,8 9 age at diagnosis,10 previous disease activity,8 10 11 major organ involvement10 12 and treatment.8–10 Furthermore, the clinical impact of achieving such states in several clinical outcomes has been examined.13 The outcome most frequently evaluated has been organ damage accrual; in fact, in several cohorts, remission and/or LDA have been found to prevent damage, but the exact definitions used for these states have not been uniform.3 6 7 11 14–20

One of the main challenges is to validate whether all these definitions are indeed predictive of outcomes such as organ damage, death, recurrent flares, number of hospitalisations and quality of life (QoL), and which of them would be the better option. Therefore, our aim was to perform a systematic review of the current literature to assess the impact of the existing definitions of remission/LDA on relevant outcomes of patients with SLE.

Methods

Search strategies

A systematic review according to the PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analysis) guidelines21 was carried out. The protocol was registered with PROSPERO (CRD42020162724).

We used the electronic databases PubMed (1946-week 2, April 2021), Cochrane library (1985-week 2, week 2, April 2021) and EMBASE (1974-week 2, April 2021) were searched. We used the Medical Subject Heading (MeSH) terms and Key words in all possible combinations using Boolean operators with the following search strategy: ‘systemic lupus erythematosus’, ‘lupus’, ‘SLE’, ‘remission’, ‘low disease activity status’, ‘low lupus disease activity status’, ‘minimal disease activity’. References of all included full-text articles were hand-searched in order to find additional references from the articles that seem to be relevant for the review. Details of the full search strategy are listed in online supplemental table 1.

These articles were downloaded into EndNote software (V.9.3.2); duplicates were deleted. Two independent teams examined each selected article and performed data extraction independently (MFU-G and CR-S or CM-P and GP-E). In case of disagreement, a third investigator was consulted. Discrepancies were resolved by consensus. The literature review team also made every effort to identify multiple publications from a single cohort.

Criteria for the selection of studies

We included both observational studies (case–control, cross-sectional or cohort) and clinical trials on adults or children with SLE in LDA (using a validated definition) or remission (as defined by available criteria) and reporting different disease outcomes in the follow-up (mortality, damage, flare, health-related QoL (HRQoL), risk of cardiovascular disease, hospitalisations and direct healthcare cost). A minimum sample size of 100 patients was required for an article to be included. Patients needed to have similar duration of follow-up in studies that reported flare rates (using a validated definition) as percentages; alternatively, reported flares per person-years was used in cases where patients had unequal follow-up duration. Damage data, as assessed by the validated instrument (the Systemic Lupus International Collaborating Clinics/American College of Rheumatology Damage Index (SDI)), were considered.

Studies published only as abstracts were excluded.

Articles written in English or Spanish were included. Case reports, case series, editorials, comments, letters and reviews were excluded.

Data extraction

Two reviewers independently screened all articles and applied the eligibility criteria to identify appropriate studies for inclusion; the selected articles were then abstracted, also independently, using a predetermined form. Information was collected on the study characteristics (study design, country, sample size), the number of participants, gender, age, major clinical variables (damage), definition of LDA/remission used, flare rates or flares per person-years, HRQoL scores, HRQoL instruments, hospitalisation rates, mortality rates, direct healthcare cost, definitions of cardiovascular disease and rates or risk of cardiovascular disease. If the same article reported more than one definition of the states or more than one outcome, all of them were included in the respective analyses.

Evaluation of the quality of the studies

The quality of the studies identified was assessed using the Newcastle-Ottawa Scale (NOS) for cohort and case–control studies a tool specifically developed to assess the quality of observational studies.15 The scoring system covers three major domains: selection of cohorts or cases and controls (maximum four points), comparability of selected groups (maximum two points) and ascertainment of either the exposure or the outcome of interest (maximum three points): the resulting score ranges from 0 to 9; a higher score represents a better methodological quality. While there is no validated cut-off value to discern between studies of good or poor quality, studies with a score of ≥7 were arbitrarily defined as being of high quality.22

Strategy for analysis synthesis

Due to the diversity of remission and LDA definitions, outcomes, heterogeneity of the results and of the different statistical tests performed in the selected articles, a meta-analysis was felt not to be feasible for most of the outcome variables; therefore, the studies selected were summarised using a narrative synthesis approach. A description and rationale were provided for grouping studies for synthesis (eg, according to outcomes type). Established metrics were used to measure the direction and magnitude effect of association between remission/LDA and outcomes (eg, OR, risk ratio (RR), HR, among others) when they were available. Summary tables and structured narrative were employed to descriptively summarise and compare each included study and to examine the heterogeneity across studies.23

Results

Study selection and characteristics of studies included

Our search identified 7497 articles, of which 31 studies met the inclusion criteria.3–5 7 11 14–18 20 24–43 The study selection process and reasons for exclusion are shown in figure 1. Four studies were cross sectional, 27 were longitudinal, 12 (38.7%) were from Europe, 10 (32.3%) from Asia and Australia, 5 (16.1%) from Latin America and 4 (12.9%) from the USA and Canada. The large majority of studies were of high quality according to NOS (table 1).

View Image - Figure 1. PRISMA flowchart.Enlarge this image.

Figure 1. PRISMA flowchart.

Table 1

Characteristics of the articles included in this systematic review

Remission
AuthorsCountry/regionYear of publicationPatientsEthnicity, %Cross-sectional or longitudinalFollow-up yearsNOS
CaucasianAsianMestizo/HispanicAfrican descentOthers
Drenkard et al4Mexico1996667NRNRNRNRNRLongitudinal11.65
Medina-Quiñones et al5UK201653255.318.0NR10.96.8Longitudinal12.07
Polachek et al7*Canada2017620NRNRNRNRNRLongitudinal4.07
Zen et al16Italy2017293100.00.00.00.00.0Longitudinal7.07
Ugarte-Gil et al14*Latin America2017135041.8NR42.711.73.8Longitudinal2.48
Tsang-A-Sjoe et al15*The Netherlands201718368.3NRNRNR31.7Longitudinal5.08
Mok et al3Hong Kong20177690.0100.00.00.00.0Longitudinal≥5.07
Petri et al18*USA2018135655.0NRNR38.07.0Longitudinal3.87
Tani et al11*Italy2018115NRNRNRNRNRLongitudinal≥5.08
Poomsalood et al24*Thailand2019237NRNRNRNRNRCross-sectionalNR7
Alarcon et al20*USA201955828.00.035.037.00.0LongitudinalNR8
Ugarte-Gil et al25USA2019483NRNRNRNRNRLongitudinalNR7
Mathian et al26*France2019407NRNRNRNRNRLongitudinal1.07
Golder et al27Asia Pacific2019170710.187.7NRNR2.2Longitudinal2.26
Reátegui-Sokolova et al28*Peru2019315NRNRNRNRNRLongitudinalNR9
Margiotta et al29Italy2019136NRNRNRNRNRCross-sectionalNR7
Fasano et al30Italy2019294NRNRNRNRNRLongitudinal9.07
Goswami et al31India2019126NRNRNRNRNRLongitudinal0.57
Tsang-A-Sjoe et al15The Netherlands201915469.5NRNRNR30.5Longitudinal2.07
Ugarte-Gil et al33*Peru2020208NRNRNRNRNRLongitudinal2.29
Floris et al34 *Italy2020116100.00.00.00.00.0Longitudinal1.58
Saccon et al35Italy2020646NRNRNRNRNRLongitudinal5.09
Jakez-Ocampo et al36Mexico2020132NRNRNRNRNRCross-sectionalNR6
Nikfar et al37Iran2021193NRNRNRNRNRLongitudinal8.08
LDA
AuthorsCountry/ regionYear of publicationPatientsEthnicity, %Cross-sectional or longitudinalFollow-up yearsNOS
CaucasianAsianMestizo/ HispanicAfrican descentOthers
Polachek et al7*Canada2017620NRNRNRNRNRLongitudinal4.07
Ugarte-Gil et al14*Latin America2017135041.8NR42.711.73.8Longitudinal2.48
Tsang-A-Sjoe et al15*The Netherlands201718368.3NRNRNR31.7Longitudinal5.08
Golder et al39Asia Pacific201714228.090.0NRNR2.0Cross-sectionalNR7
Tani et al11*Italy2018115NRNRNRNRNRLongitudinal≥58
Zen et al17Italy2018293100.00.00.00.00.0Longitudinal7.09
Petri et al18*USA2018135655.0NRNR38.07.0LongitudinalNR7
Poomsalood et al24*Thailand2019237NRNRNRNRNRCross-sectionalNR7
Alarcon et al20 *USA201955828.00.035.037.00.0LongitudinalNR8
Ugarte.Gil et al25*USA2019483NRNRNRNRNRLongitudinalNR7
Mathian et al26*France2019407NRNRNRNRNRLongitudinal1.07
Golder et al38Asia Pacific2019170710.187.7NRNR2.2Longitudinal2.26
Reategui-Sokolova et al28*Peru2019315NRNRNRNRNRLongitudinalNR9
Ugarte-Gil et al33*Peru2020243NRNRNRNRNRLongitudinal2.27
Sharma et al40Norway2020206100.00.00.00.00.0Longitudinal10.06
Yeo et al41Australia202020052.039.5NRNR8.5Longitudinal2.19
Floris et al34*Italy2020116100.00.00.00.00.0Longitudinal1.58
Louthrenoo et al42Thailand2020337NRNRNRNRNRLongitudinal3.28
Kang et al43Korea2021299NRNRNRNRNRLongitudinal4.08

*These articles were included for remission and LDA.

LDA, low disease activity; NOS, Newcastle-Ottawa Scale; NR, not reported.;

Remission and LDA rates

The rates of remission and LDA varied depending on both the definition used and the population studied. Remission was more frequent in European populations being as high as 88.1% in one study, but it was as low as 3.5% when the definition excluded patients under treatment and a duration of the remission of at least 7 years. LDA was also more frequent in European populations; however, the rate depended on the definition used; as expected, the less stringent the definition, the more frequently this outcome was achieved. These data are depicted in online supplemental table 2.

Mortality

Six studies including 3933 patients evaluated mortality as an outcome, two evaluated the impact of remission and LDA on mortality, two only LDA, one only remission and one compared remission and LDA. Among the four studies reporting the impact of LDA on mortality, two of them reported a reduction on mortality (HR 0.3% and 1.4% in those in LDA and 6.9% in those active) and two did not, although the trend was similar (HR 0.30 and 0.81, p: not significant). Among the three studies evaluating the impact of remission (compared with those not on remission) on mortality; two of them reported a reduction on mortality (HR 0.08% and 5% in those in remission and 17.7% in those not in remission), whereas the other did not (HR 0.56, p value not significant). In another report, remission was not statistically different from LDA in terms of the mortality rate. These data are depicted in table 2.

Table 2

Impact of remission and LDA on mortality*

AuthorsPatientsFollow-up yearsRemissionImpact
Disease activity indexImmunological activityPGAPDN daily doseIS useAM useMinimal duration
Drenkard et al466711.6Lack of clinical disease activity (no formal index was used)AllowedNRNot allowedNot allowedNot allowed1 yearHR 0.08, p<0.001
Medina-Quiñones et al553212BILAG C, D, ENot allowedNR0Not allowedAllowed3 years5% vs 17.7% (not on remission), p<0.001
Polachek et al76204SLEDAI=0Not allowedNRNot allowedNot allowedAllowed1 yearRemission vs LDA: 0.5% vs 2.5%, p=0.15 year 2
Ugarte-Gil et al1413502.4SLEDAI=0Not allowedNR≤5AllowedAllowedAt least onceMortality (reference active) HR 0.56, p=0.2623
AuthorsPatientsFollow-up yearsLDAImpact
Disease activity indexExclusion of new activityMajor organ exclusionPGAPrednisone daily doseIS drug useAntimalarial useMinimal duration
Polachek et al76204SLEDAI<=2YesNoNRNot allowedNot allowedAllowed1Remission+LDA vs active 1.4% vs 6.9, p=0.02 (year 2), 3.6% vs 13.3%, p=0.004
Ugarte-Gil et al1413502.4SLEDAI<=4NoNoNR<=7.5AllowedAllowedAt least onceExcluding remission. Mortality (reference active) HR 0.81, p=0.6476
Alarcon et al2020558NRSLAM<=3NoNoNR<=7.5Not allowedAllowedNRDuration on LDAS RR 0.303, p=0.1360
Sharma et al4020610SLEDAI<=4YesYesNR<=7.5AllowedAllowed50%HR 0.31, p<0.01
Sharma et al4020610SLEDAI<=4YesYesNR<=7.5AllowedAllowed30%HR 0.36, p<0.05
Sharma et al4020610SLEDAI<=4YesYesNR<=7.5AllowedAllowed70%HR 0.25, p<0.01

*If an article included more than one definition, a row per definition is included.

AM, antimalarials; IS, immunosuppressive drug; LDA, low disease activity; LDAS, low disease activity status; NR, not reported; PDN, prednisone; PGA, Physician Global Assessment; RR, risk ratio; SLAM, Systemic Lupus Activity Measure; SLEDAI, Systemic Lupus Erythematosus Disease Activity Index.

Damage accrual

Sixteen studies including 8288 patients evaluated damage accrual. In the majority of studies, both remission and LDA prevented damage accrual when compared with patients who did not attain these states (risk measures between 0.04 and 0.95 for remission and between 0.07 and 0.90 for LDA, depending on the definition). In most of the studies, LDA also included those patients who were on remission; however, depending on the definition used, there could be a difference between those in remission and those in LDA, being better to be on remission. These data are depicted in tables 3 and 4.

Table 3

Impact of remission on damage

AuthorsPatientsFollow-up yearsRemissionImpact
Disease activity indexImmunological activityPGAPDN daily doseIS useAM useMinimal duration
Polachek et al76204SLEDAI=0Not allowedNRNot allowedNot allowedAllowed1 year∆SDI: 0.1 vs 0.2 (remission vs LDA only) at year 2; p=0.18
Zen et al16*2937C-SLEDAI=0AllowedNR≤5AllowedAllowed1 year1 year (reference <1 year) OR 0.947, p=0.946
Zen et al16*2937C-SLEDAI=0AllowedNR≤5AllowedAllowed2 years2 years (reference <1 year) OR 0.228, p=0.028
Zen et al16*2937C-SLEDAI=0AllowedNR≤5AllowedAllowed3 years3 years (reference <1 year) OR 0.116, p=0.001
Zen et al16*2937C-SLEDAI=0AllowedNR≤5AllowedAllowed4 years4 years (reference <1 year) OR 0.118, p=0.005
Zen et al16*2937C-SLEDAI=0AllowedNR≤5AllowedAllowed5 years≥5 years (reference <1 year) OR 0.044, p<0.001
Ugarte-Gil et al14*13502.4SLEDAI=0Not allowedNR≤5AllowedAllowedAt least onceNew damage (reference active) HR 0.60, p=0.0042
Ugarte-Gil et al14*13502.4SLEDAI=0Not allowedNR≤5AllowedAllowedAt least onceNew damage non-GC (reference active) HR 0.51, p=0.0006
Ugarte-Gil et al14*13502.4SLEDAI=0Not allowedNR≤5AllowedAllowedAt least onceNew severe damage non-GC (reference active) HR 0.31, p=0.0101
Ugarte-Gil et al14*13502.4SLEDAI=0Not allowedNR≤5AllowedAllowedAt least onceNew damage GC (reference active) HR 0.99, p=0.9697
Tsang-A-Sjoe et al151835C-SLEDAI=0AllowedNR≤5AllowedAllowed5 yearsProlonged remission (5 years) OR=0.20, p=0.001
Mok et al3769NRC-SLEDAI=0Allowed<0.5≤5AllowedAllowed5 yearsNo remission or remission <5 years OR damage 2.42, p<0.001
Petri et al18*1356NRC-SLEDAI=0Allowed<0.5≤5AllowedAllowedNRLess than 25% RR 0.54, p<0.0001, 25%–50% on remission RR 0.47, p<0.0001, 50%–75% RR 0.43, p<0.0001, >=75%, RR 0.45, p=0.0019 (reference not remission)
Petri et al18*1356NRC-SLEDAI=0Allowed<0.50AllowedAllowedNRLess than 25% RR 0.60, p<0.0001, 25%–50% on remission RR 0.66, p=0.023, 50%–75% RR 0.63, p=0.035, >=75%, RR=0.58, p=0.12 (reference not remission)
Golder et al27*17072.2C-SLEDAI=0Allowed<0.50AllowedAllowedNRHR 0.64, p=0.020 (>=50% vs <50%)
Golder et al27*17072.2C-SLEDAI=0Allowed<0.50Not allowedAllowedNRHR 0.60, p=0.022 (>=50% vs <50%)
Golder et al27*17072.2C-SLEDAI=0Allowed<0.5<=5AllowedAllowedNRHR 0.49, p<0.0001 (>=50% vs <50%)
Golder et al27*17072.2C-SLEDAI=0Allowed<0.5<=5Not allowedAllowedNRHR 0.58, p=0.0005 (>=50% vs <50%)
Golder et al2727*17072.2C-SLEDAI=0Not allowed<0.50AllowedAllowedNRHR 0.62, p=0.076 (>=50% vs <50%)
Golder et al27*17072.2C-SLEDAI=0Not allowed<0.50Not allowedAllowedNRHR 0.59, p=0.083 (>=50% vs <50%)
Golder et al27*17072.2C-SLEDAI=0Not allowed<0.5<=5AllowedAllowedNRHR 0.63, p=0.0083 (>=50% vs <50%)
Golder et al27*17072,2C-SLEDAI=0Not allowed<0.5<=5Not allowedAllowedNRHR 0.65, p=0.043 (>=50% vs <50%)
Saccon et al35*6465 yearsAnyAllowedAny<=5AllowedAllowed1 yearOR 0.952 (p=0.828)
Saccon et al35*6465 yearsAnyAllowedAny<=5AllowedAllowed2 yearsOR 0.858 (p=0.471)
Saccon et al35*6465 yearsAnyAllowedAny<=5AllowedAllowed3 yearsOR 0.912 (p=0.668)
Saccon et al35*6465 yearsAnyAllowedAny<=5AllowedAllowed4 yearsOR 0.391 (p<0.001)
Saccon et al35*6465 yearsAnyAllowedAny<=5AllowedAllowed5 yearsOR 0.620 (p=0.010)
Saccon et al35*6465 yearsAnyAllowed<0.5AllowedAllowedAllowed1 yearOR 0.808 (p=0.185)
Saccon et al35*6465 yearsAnyAllowed<0.5AllowedAllowedAllowed2 yearsOR 0.560 (p<0.001)
Saccon et al35*6465 yearsAnyAllowed<0.5AllowedAllowedAllowed3 yearsOR 0.427 (p<0.001)
Saccon et al35*6465 yearsAnyAllowed<0.5AllowedAllowedAllowed4 yearsOR 0.226 (p<0.001)
Saccon et al35*6465 yearsAnyAllowed<0.5AllowedAllowedAllowed5 yearsOR 0.377 (p<0.001)
Saccon et al35*6465 yearsC-SLEDAI=0AllowedAnyAllowedAllowedAllowed1 yearOR 0.766 (p=0.119)
Saccon et al35*6465 yearsC-SLEDAI=0AllowedAnyAllowedAllowedAllowed2 yearsOR 0.454 (p<0.001)
Saccon et al35*6465 yearsC-SLEDAI=0AllowedAnyAllowedAllowedAllowed3 yearsOR 0.512 (p<0.001)
Saccon et al35*6465 yearsC-SLEDAI=0AllowedAnyAllowedAllowedAllowed4 yearsOR 0.173 (p<0.001)
Saccon et al35*6465 yearsC-SLEDAI=0AllowedAnyAllowedAllowedAllow ed5 yearsOR 0.382 (p<0.001)
Saccon et al35*6465 yearsAnyAllowed<0.5<=5AllowedAllowed1 yearOR 0.764 (p=0.101)
Saccon et al35*6465 yearsAnyAllowed<0.5<=5AllowedAllowed2 yearsOR 0.495 (p<0.001)
Saccon et al35*6465 yearsAnyAllowed<0.5<=5AllowedAllowed3 yearsOR 0.430 (p<0.001)
Saccon et al35*6465 yearsAnyAllowed<0.5<=5AllowedAllowed4 yearsOR 0.294 (p<0.001)
Saccon et al35*6465 yearsAnyAllowed<0.5<=5AllowedAllowed5 yearsOR 0.363 (p<0.001)
Saccon et al35*6465 yearsC-SLEDAI=0Allowed<0.5AllowedAllowedAllowed1 yearOR 0.857 (p=0.326)
Saccon et al35*6465 yearsC-SLEDAI=0Allowed<0.5AllowedAllowedAllowed2 yearsOR 0.514 (p<0.001)
Saccon et al35*6465 yearsC-SLEDAI=0Allowed<0.5AllowedAllowedAllowed3 yearsOR 0.459 (p<0.001)
Saccon et al35*6465 yearsC-SLEDAI=0Allowed<0.5AllowedAllowedAllowed4 yearsOR 0.243 (p<0.001)
Saccon et al35*6465 yearsC-SLEDAI=0Allowed<0.5AllowedAllowedAllowed5 yearsOR 0.397 (p<0.001)
Saccon et al35*6465 yearsC-SLEDAI=0AllowedAny<=5AllowedAllowed1 yearOR 0.888 (p<0.471)
Saccon et al35*6465 yearsC-SLEDAI=0AllowedAny<=5AllowedAllowed2 yearsOR 0.497 (p<0.001)
Saccon et al35*6465 yearsC-SLEDAI=0AllowedAny<=5AllowedAllowed3 yearsOR 0.548 (p<0.001)
Saccon et al35*6465 yearsC-SLEDAI=0AllowedAny<=5AllowedAllowed4 yearsOR 0.251 (p<0.001)
Saccon et al35*6465 yearsC-SLEDAI=0AllowedAny<=5AllowedAllowed5 yearsOR 0.411 (p<0.001)
Saccon et al35*6465 yearsC-SLEDAI=0Allowed<0.5<=5AllowedAllowed1 yearOR 0.800 (p=0.167)
Saccon et al35*6465 yearsC-SLEDAI=0Allowed<0.5<=5AllowedAllowed2 yearsOR 0.479 (p<0.001)
Saccon et al35*6465 yearsC-SLEDAI=0Allowed<0.5<=5AllowedAllowed3 yearsOR 0.438 (p<0.001)
Saccon et al35*6465 yearsC-SLEDAI=0Allowed<0.5<=5AllowedAllowed4 yearsOR 0.296 (p<0.001)
Saccon et al35*6465 yearsC-SLEDAI=0Allowed<0.5<=5AllowedAllowed5 yearsOR 0.384 (p<0.001)
Jakez-Ocampo et al36NR (case control)NRC-SLEDAI=0AllowedNRNot allowedNot allowedNot allowed10 yearsRemission group: 0.68±0.67, control group 1.05±0.87 (p=0.016). No difference between those on remission with or without serological activity.
Floris et al341161.5C-SLEDAI=0Allowed<0.5AllowedAllowedAllowedNROR=0.07, p=0.015
Nikfar et al371938C-SLEDAI=0Allowed<0.5<=5Not allowedAllowed5 yearsOR=0.62, p=0.047

*If an article included more than one definition, a row per definition is included.

AM, antimalarials; C-SLEDAI, Clinical Systemic Lupus Erythematosus Disease Activity Index; IS, immunosuppressive drug; LDAS, low disease activity status; LLDAS, lupus low disease activity state; NR, not reported; PDN, prednisone; PGA, Physician Global Assessment.;

Table 4

Impact of LDA on damage

AuthorsPatientsFollow-up yearsLDAImpact
Disease activity indexExclusion of New activityMajor Organ ExclusionPGAPDN daily doseIS useAM useMinimal duration
Polachek et al76204SLEDAI<=2NoNoNRNot allowedNot allowedAllowed1 yearRemission+LDA vs active: 0.15 vs 0.52, p<0.001 (year 2); 0.25 vs 0.88, p<0.001 (year 4)
Ugarte-Gil et al14*13502.4SLEDAI<=4NoNoNR<=7.5AllowedAllowedAt least onceExcluding remission new damage (reference active) HR 0.66, p=0.0158
Ugarte-Gil et al14*13502.4SLEDAI<=4NoNoNR<=7.5AllowedAllowedAt least onceExcluding remission new severe damage (reference active) HR 0.54, p=0.0614
Ugarte-Gil et al14*13502.4SLEDAI<=4NoNoNR<=7.5AllowedAllowedAt least onceExcluding remission new severe damage (reference active) HR 0.54, p=0.0614
Ugarte-Gil et al14*13502.4SLEDAI<=4NoNoNR<=7.5AllowedAllowedAt least onceExcluding remission new damage non-GC (reference active) HR 0.62, p=0.0067
Ugarte-Gil et al14*13502.4SLEDAI<=4NoNoNR<=7.5AllowedAllowedAt least onceExcluding remission new severe damage non-GC (reference active) HR 0.35, p=0.0206
Ugarte-Gil et al14*13502.4SLEDAI<=4NoNoNR<=7.5AllowedAllowedat least onceExcluding remission new damage GC (reference active) HR 1.34, p=0.3333
Tsang-A-Sjoe et al151835SLEDAI<=4NoYes<=2/10<=7.5AllowedAllowed>50% on LLDAS: OR=0.52, p=0.046
Tani et al11*115At least 5SLEDAI<=4NoYes<=1<=7.5AllowedAllowed100% of the follow-up∆SDI: 0.11 vs 0.63; p<0.001
Tani et al11*115at least 5SLEDAI<=4NoYes<=1<=7.5AllowedAllowed50%∆SDI: 0.25 vs 0.78; p=0.004
Zen et al17*2937SLEDAI<=4YesYes<=1<=7.5AllowedAllowed1 year1 year (reference <1 year) OR 0.899, p=0.877
Zen et al1717*2937SLEDAI<=4YesYes<=1<=7.5AllowedAllowed2 years2 years (reference <1 year) OR 0.279, p=0.036
Zen et al17*2937SLEDAI<=4YesYes<=1<=7.5AllowedAllowed3 years3 years (reference <1 year) OR 0.252, p=0.025
Zen et al17*2937SLEDAI<=4YesYes<=1<=7.5AllowedAllowed4 years4 years (reference <1 year) OR 0.122, p=0.001
Zen et al1717*2937SLEDAI<=4YesYes<=1<=7.5AllowedAllowed5 years≥5 years (reference <1 year) OR 0.071, p<0.001
Petri et al181356NRSLEDAI<=4YesYes<=1<=7.5AllowedAllowedNRLess than 25% RR 0.80, p=0.12, 25%–50% on remission RR 0.63, p=0.0012, 50%–75% RR 0.47, p<0.0001, >=75%, RR 0.39, p<0.0001 (reference not LLDAS)
Alarcon et al20558NRSLAM<=3NoNoNR<=7.5Not allowedAllowedNRDuration on LDAS RR: 0.1773, p<0.0001 LDAS prevented from GC-related and non-GC-related damage
Golder et al38*17072.2SLEDAI<=4YesYes<=1<=7.5AllowedAllowedNRHR 0.54, p<0.0001
Golder et al38*17072.2SLEDAI<=4YesYes<=1<=7.5AllowedAllowedNRHR 0.59, p<0.0001
Golder et al38*17072.2SLEDAI<=4YesYes<=1<=7.5AllowedAllowedNRRR 0.14 p<0.0001
Sharma et al40*20610SLEDAI<=4YesYesNR<=7.5AllowedAllowed50%HR 0.37, p<0.01 (SDI>=3)
Sharma et al40*20610SLEDAI<=4YesYesNR<=7.5AllowedAllowed30%HR 0.57, p=0.08 (SDI>=3)
Sharma et al40*20610SLEDAI<=4YesYesNR<=7.5AllowedAllowed70%HR 0.38, p<0.01 (SDI>=3)
Floris et al341161.5SLEDAI<=4YesYes<=1<=7.5AllowedAllowedNRLLDAS (not in remission) OR 0.25, p=0.049
Kang et al43*2994C-SLEDAI<=1NRNRNR5AllowedAllowedNRB=−0.033, p=0.368
Kang et al43*2994C-SLEDAI<=2NRNRNR0Not allowedallowedNRB=−0.093, p=0.390
Kang et al43*2994SLEDAI<=4YesYes<=1<=7.5AllowedAllowedNRB=−0.064, p=0.050

*If an article included more than one definition, a row per definition is included.

AM, antimalarials; C-SLEDAI, Clinical Systemic Lupus Erythematosus Disease Activity Index ; IS, immunosuppressive drug; LDA, low disease activity; LDAS, low disease activity status; LLDAS, lupus low disease activity state; ;NR, not reported; PDN, prednisone; PGA, Physician Global Assessment; SLAM, Systemic Lupus Activity Measure.

Flare

Five studies including 3033 patients evaluated longitudinally the occurrence of flares after achieving these states. Remission and LDA reduced the probability of flares in all studies included, regardless of the definition used (HR between 0.26 and 0.70 for remission and between 0.41 and 0.74 for LDA); however, the longer the duration of the state, the lower the risk. Only one study compare remission versus LDA and it did not find a statistically significant difference. These data are depicted in table 5.

Table 5

Impact of remission and LDA on flare*

Authors  Country/ region  Year of publicationPatientsFollow-up yearsRemissionImpact
Disease activity indexImmunological activityPGAPDN daily doseIS useAM useMinimal duration
Polachek et al7Canada20176204SLEDAI=0Not allowedNRNot allowedNot allowedAllowed1 yearRemission vs LDA 5% vs 4.4%, p=0.8, year 2
Mathian et al26France20194071C-SLEDAI=0AllowedNR<=5AllowedAllowedNRFor each year remission, HR 0.7, p=0.02
Golder et al27 38Asia Pacific201917072.2C-SLEDAI=0Allowed<0.50AllowedAllowedNRHR 0.39, p<0.0001 (>=50% vs<50%)
Golder et al2727Asia Pacific201917072.2C-SLEDAI=0Allowed<0.50Not allowedAllowedNRHR 0.36; p<0.0001 (>=50% vs<50%)
Golder et al27Asia Pacific201917072.2C-SLEDAI=0Allowed<0.5<=5AllowedAllowedNRHR 0.54 p<0.0001 (>=50% vs<50%)
Golder et al27Asia Pacific201917072.2C-SLEDAI=0Allowed<0.5<=5Not allowedAllowedNRHR 0.52 p<0.0001 (>=50% vs <50%)
Golder et al27Asia Pacific201917072.2C-SLEDAI=0Not allowed<0.50AllowedAllowedNRHR 0.28 p<0.0001 (>=50% vs <50%)
Golder et al27Asia Pacific201917072.2C-SLEDAI=0Not allowed<0.50Not allowedAllowedNRHR 0.26, p<0.0001(>=50% vs <50%)
Golder et al27Asia Pacific201917072.2C-SLEDAI=0Not allowed<0.5<=5AllowedAllowedNRHR 0.43, p<0.0001 (>=50% vs <50%)
Golder et al2727Asia Pacific201917072.2C-SLEDAI=0Not allowed<0.5<=5Not allowedAllowedNRHR 0.41, p<0.0001 (>=50% vs <50%)
Authors  Country/region  Year of publicationPatientsFollow-up yearsLDAImpact  
Disease activity indexExclusion of new activityMajor organ exclusionPGAPDN daily doseIS useAM useMinimal duration
Polachek et al7Canada20176204SLEDAI<=2YesNoNRNot allowedNot allowedAllowed1Remission+LDA vs active: 4.8 vs 14.6, p<0.001 (year 2), 3.7 vs 14.8, p=0.007 (year 4)
Golder et al38Asia Pacific201917072.2SLEDAI<=4YesYes<=1<=7.5AllowedAllowedAny visitHR 0.65 (any flare), p<0.0001
Golder et al38Asia Pacific201917072.2SLEDAI<=4YesYes<=1<=7.5AllowedAllowedAny visitHR 0.74 (mild-moderate flare), p<0.0001
Golder et al38Asia Pacific201917072.2SLEDAI<=4YesYes<=1<=7.5AllowedAllowedAny visitHR 0.59 (severe flare), p<0.0001
Golder et al38Asia Pacific201917072.2SLEDAI<=4YesYes<=1<=7.5AllowedAllowed50% of the follow-upHR 0.41, p<0.0001 (any flare)
Kang et al43Korea20212994C-SLEDAI<=1NRNRNR5AllowedAllowedNRB=0.419, p=0.109
Kang et al43Korea20212994C-SLEDAI<=2NRNRNR0Not allowedAllowedNRB=0.960, p=0.969
Kang et al43Korea20212994SLEDAI<=4YesYes<=1<=7.5AllowedAllowedNRB=0.090, p<0.001

*If an article included more than one definition, a row per definition is included.

AM, antimalarials; C-SLEDAI, Clinical Systemic Lupus Erythematosus Disease Activity Index; IS, immunosuppressive drug; LDA, low disease activity; NR, not reported; PDN, prednisone; PGA, Physician Global Assessment.

Health-related quality of life (HRQoL)

Ten manuscripts including 4480 patients evaluated HRQoL. Remission and LDA were associated with a better HRQoL being this impact more consistent on the physical components of HRQoL, and less so on the mental components of HRQoL. These data are depicted in tables 6 and 7.

Table 6

Impact of remission on HRQoL*

AuthorsCountry/ regionYear of publicationPatientsFollow-up yearsRemissionDomains positively associatedDomains not associated
Disease activity indexImmunological activityPGAPDN daily doseIS useAM useMinimal duration
Mok et al3Hong Kong2017769Cross-sectionalC-SLEDAI=0Allowed<0.5≤5AllowedAllowed5 yearsSF-36: >5 years vs <5 years and >5 years vs no remission role physical, vitality, social functioning, PCS >5 years vs no remission bodily pain, general health, role emotional, mental health, MCS LupusPRO: >5 years vs <5 years and >5 years vs no remission role physical, vitality, social functioning, PCS >5 years vs no remission bodily pain, general health, role emotional, mental health, MCS, remission >5 vs no remission desire/goalSF-36: >5 years vs <5 years and >5 years vs no remission symptoms, medications, procreation, physical health, emotional, HRQoL total. >5 years vs <5 years remission pain, image LupusPRO: >5 years vs <5 years and >5 years vs no remission cognition, social support, coping, satisfaction with medical care, non-HRQoL total. >5 years vs <5 years remission pain, image, remission >5 vs remission <years desire/goal
Margiotta et al29Italy2019136Cross-sectionalC-SLEDAI=0AllowedNR<=5AllowedAllowed5 yearsSF-36: >5 years vs <5 years and no remission physical functioning, role physical, bodily pain, general health and social functioningSF-36: >5 years vs <5 years and no remission vitality, role emotional, mental health
Goswami et al31India2019126Cross-sectionalC-SLEDAI=0Allowed<0.5AllowedAllowedAllowedNRSF-36: Complete remission was associated with a better PCS than clinical remission 
Poomsalood et al24Thailand2019237Cross-sectionalC-SLEDAI=0AllowedNR<=5AllowedAllowed1 yearSLEQOL: Remission vs not on remission activities, symptom, treatment, mood, self-image, total QoL univariableSLEQOL: Remission vs not on remission. Physical, remission vs LDA NS all univariable
Tsang-A-Sjoe et al15The Netherlands20191542C-SLEDAI=0Allowed<=2/10<=5AllowedAllowedNRSF-36: Remission on and off therapy and PCSSF-36: Remission on and off therapy and MCS

*If an article included more than one definition, a row per definition is included.

AM, antimalarials; C-SLEDAI, Clinical Systemic Lupus Erythematosus Disease Activity Index; HRQoL, health-related quality of life; IS, immunosuppressive drug; LDAS, low disease activity; LLDAS, lupus low disease activity state; ;MCS, Mental Component Summary; NR, not reported; PCS, Physical Component Summary; PDN, prednisone; PGA, Physician Global Assessment; SF-36, 36-Item Short Form Health Survey; SLEQOL, Systemic Lupus Erythematosus Quality of Life.

Other outcomes

Three manuscripts including 802 patients evaluated other outcomes. Being on remission and LDA was associated with a lower hospitalisation rate; LDA was associated with lower medical cost and prolonged remission with lower cardiovascular risk. These data are depicted in table 8.

Table 7

Impact of remission and LDA on HRQoL*

AuthorsCountry/regionYear of publicationPatientsFollow-up yearsLDADomains positively associatedDomains not associated
Disease activity indexExclusion of New activityMajor Organ ExclusionPGAPDN daily doseIS useAM useMinimal duration
Golder et al39APLC201717072.2SLEDAI<=4YesYes<=1<=7.5AllowedAllowedNRSF-36: PCS and MCS Multivariable role physical, bodily pain, general health, social functioning, role emotional, vitality, mental health univariableSF-36: Physical function univariable
Poomsalood et al24Thailand2019237Cross-sectionalC-SLEDAI=0AllowedNR<=5AllowedAllowed1 year1 yearSLEQOL: Physical, activities, symptom, treatment, mood, self-image, total QoL univariable, LLDAS vs no LDA b: 20.02, p=0.003 Multivariable 
Ugarte-Gil et al25USA2019472NRSLAM<=3NoNoNR<=7.5Not allowedAllowedNRSF-36: PCS, MCS, physical functioning, role physical, bodily pain, general health, social functioning, role emotional, vitality, mental health 
Ugarte-Gil et al33Peru20202432SLEDAI<=4NoNoNR<=7.5AllowedAllowedat least onceLupusQoL: Physical health, pain, planning, burden to others, emotional health, fatigueLupusQoL: Intimate relationship, body image
Louthrenoo et al42Thailand20203373.2SLEDAI<=4YesYes<=1<=7.5AllowedAllowedNRGlobal and all domains of SLEQOL, PCS and MCS SF-36 
Kang et al43Korea20212994C-SLEDAI<=1NRNRNR5AllowedAllowedNR PCS and MCS SF-36
Kang et al43Korea20212994C-SLEDAI<=2NRNRNR0Not allowedAllowedNR PCS and MCS SF-36
Kang et al43Korea20212994SLEDAI<=4YesYes<=1<=7.5AllowedAllowedNRPCS and MCS SF-36 

*If an article included more than one definition, a row per definition is included.

AM, antimalarials; HRQoL, health-related quality of life; IS, immunosuppressive drug; LDAS, low disease activity; LLDAS, lupus low disease activity state; ;MCS, Mental Component Summary; NR, not reported; PCS, Physical Component Summary; PDN, prednisone; PGA, Physician Global Assessment; SF-36, 36-Item Short Form Health Survey; SLEDAI, Systemic Lupus Erythematosus Disease Activity Index.

Table 8

Impact of remission and LDA on other outcomes*

AuthorsCountry/regionYear of publicationPatientsFollow-up yearsRemissionImpact
Disease activity indexImmunological activityPGAPDN daily doseIS useAM useMinimal duration
Reátegui-Sokolov et al28Peru2019308NRSLEDAI=0Not allowedNR≤5AllowedAllowedAt least onceOutcome: Hospitalisation HR 0.45, p=0.001
Fasano et al30Italy20192949C-SLEDAI=0AllowedNR≤5AllowedAllowed5 yearsCardiovascular event: HR 0.18, p=0.023
Authors  Country/region  Year of publicationPatientsFollow-up yearsLDA   Impact  
Disease activity indexExclusion of new activityMajor organ exclusionPGAPrednisone daily doseIS drug useAntimalarial useMinimal duration
Reátegui-Sokolov et al28Peru2019308NRSLEDAI<=4NoNoNR<=7.5AllowedAllowedAt least onceExcluding remission. Outcome: Hospitalisation HR 0.50, p=0.001
Yeo et al41Australia20202002.1SLEDAI<=4YesYes<1<=7.5AllowedAllowed50%Outcome: Direct health cost. Ratio of geometric means 0.53, p<0.001

*If an article included more than one definition, a row per definition is included.

AM, antimalarials; IS, immunosuppressive drug; LDA, low disease activity; NR, not reported; PDN, prednisone; PGA, Physician Global Assessment; SLEDAI, Systemic Lupus Erythematosus Disease Activity Index.

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.1818 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.

Data availability statement

All data relevant to the study are included in the article or uploaded as supplementary information.

Ethics statements

Patient consent for publication

Not required.

Footnote

Twitter @mugartegil, @gponsestel

Contributors All authors were involved in drafting or revising this article critically for important intellectual content, and all authors approved the final version to be published. MFU-G has full access to all of the data from the study and takes responsibility for their integrity and the accuracy of the analyses performed.

Funding The authors have not declared a specific grant for this research from any funding agency in the public, commercial or not-for-profit sectors.

Competing interests MFU-G: Grant/research support from Jannsen, Pfizer, not related to this article. CM-P declared no conflict of interest. CR-S: Grant/research support from Jannsen, not related to this article. GP-E: Grant/research support from JANSSEN and GSK; consultant of JANNSEN, GSK and SANOFI; speakers bureau: Pfizer, JANNSEN and GSK, not related to this article. RFvV: Grant/research support from AbbVie, Arthrogen, Bristol-Myers Squibb, GlaxoSmithKline, Lilly, Pfizer and UCB; consultant of AbbVie, AstraZeneca, Biotest, Bristol-Myers Squibb, Celgene, GSK, Janssen, Lilly, Medac, Merck, Novartis, Pfizer, Roche and UCB, not related to this article. GB: Grant/research support from GSK, Pfizer; consultant of Novartis, SOBI, not related to this article. GA declared no conflict of interest. BAP-E: Grant/research support from GSK, Jannsen; consultant of GSK, Janssen; speakers bureau: GSK, Janssen, not related to this article.

Provenance and peer review Not commissioned; externally peer reviewed.

Supplemental material This content has been supplied by the author(s). It has not been vetted by BMJ Publishing Group Limited (BMJ) and may not have been peer-reviewed. Any opinions or recommendations discussed are solely those of the author(s) and are not endorsed by BMJ. BMJ disclaims all liability and responsibility arising from any reliance placed on the content. Where the content includes any translated material, BMJ does not warrant the accuracy and reliability of the translations (including but not limited to local regulations, clinical guidelines, terminology, drug names and drug dosages), and is not responsible for any error and/or omissions arising from translation and adaptation or otherwise.

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© 2021 Author(s) (or their employer(s)) 2021. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ. This is an open access article distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited, appropriate credit is given, any changes made indicated, and the use is non-commercial. See:  http://creativecommons.org/licenses/by-nc/4.0/ . Notwithstanding the ProQuest Terms and Conditions, you may use this content in accordance with the terms of the License.

Abstract

Background

Remission and low disease activity (LDA) have been proposed as the treatment goals for patients with systemic lupus erythematosus (SLE). Several definitions for each have been proposed in the literature.

Objective

To assess the impact of remission/LDA according to various definitions on relevant outcomes in patients with SLE.

Methods

This systematic literature review was conducted according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses using PubMed (1946–week 2, April 2021), Cochrane library (1985–week 2, week 2, April 2021) and EMBASE (1974–week 2, April 2021). We included longitudinal and cross-sectional studies in patients with SLE reporting the impact of remission and LDA (regardless their definition) on mortality, damage accrual, flares, health-related quality of life and other outcomes (cardiovascular risk, hospitalisation and direct costs). The quality of evidence was evaluated using the Newcastle-Ottawa Scale.

Results

We identified 7497 articles; of them, 31 studies met the inclusion criteria and were evaluated. Some articles reported a positive association with survival, although this was not confirmed in all of them. Organ damage accrual was the most frequently reported outcome, and remission and LDA were reported as protective of this outcome (risk measures varying from 0.04 to 0.95 depending on the definition). Similarly, both states were associated with a lower probability of SLE flares, hospitalisations and a better health-related quality of life, in particular the physical domain.

Conclusion

Remission and LDA are associated with improvement in multiple outcomes in patients with SLE, thus reinforcing their relevance in clinical practice.

PROSPERO registration number

CRD42020162724.

Details

Title
Achieving remission or low disease activity is associated with better outcomes in patients with systemic lupus erythematosus: a systematic literature review
Author
Ugarte-Gil, Manuel Francisco 1   VIAFID ORCID Logo  ; Mendoza-Pinto, Claudia 2 ; Reátegui-Sokolova, Cristina 3   VIAFID ORCID Logo  ; Pons-Estel, Guillermo J 4 ; van Vollenhoven, Ronald F 5   VIAFID ORCID Logo  ; Bertsias, George 6 ; Alarcon, Graciela S 7 ; Pons-Estel, Bernardo A 4   VIAFID ORCID Logo 

1  Grupo Peruano de Estudio de Enfermedades Autoinmunes Sistémicas, Universidad Cientifica del Sur, Lima, Peru; Rheumatology, Hospital Nacional Guillermo Almenara Irigoyen, EsSalud, Lima, Peru 
2  Systemic Autoimmune Diseases Research Unit, Mexican Institute of Social Security, Puebla, Puebla, Mexico; Medicine School, Benemerita Universidad Autonoma de Puebla, Puebla, Puebla, Mexico 
3  Rheumatology, Hospital Nacional Guillermo Almenara Irigoyen, EsSalud, Lima, Peru; Universidad San Ignacio de Loyola, Lima, Peru 
4  Centro Regional de Enfermedades Autoinmunes y Reumáticas (GO-CREAR), Rosario, Santa Fe, Argentina 
5  Amsterdam University Medical Centers, Amsterdam, The Netherlands; Rheumatology, Amsterdam Rheumatology and Immunology Center, Amsterdam, Netherlands 
6  Medical School, University of Crete, Heraklion, Greece 
7  School of Medicine, The University of Alabama at Birmingham, Birmingham, Alabama, USA; School of Medicine, Universidad Peruana Cayetano Heredia, Lima, Peru 
Section
Epidemiology and outcomes
Publication year
2021
Publication date
2021
Publisher
BMJ Publishing Group LTD
e-ISSN
20538790
Source type
Scholarly Journal
Language of publication
English
DOI
https://doi.org/10.1136/lupus-2021-000542
ProQuest document ID
2574968519
Copyright
© 2021 Author(s) (or their employer(s)) 2021. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ. This is an open access article distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited, appropriate credit is given, any changes made indicated, and the use is non-commercial. See:  http://creativecommons.org/licenses/by-nc/4.0/ . Notwithstanding the ProQuest Terms and Conditions, you may use this content in accordance with the terms of the License.