Systemic lupus erythematosus
CLINICAL SCIENCE
Management of systemic lupus erythematosus: a
Ann Rheum Dis: first published as 10.1136/ard-2023-225319 on 22 May 2024. Downloaded from http://ard.bmj.com/ on June 4, 2024 by guest. Protected by copyright.
systematic literature review informing the 2023
update of the EULAR recommendations
Myrto Kostopoulou ,1 Chetan B Mukhtyar ,2 George Bertsias ,3,4
Dimitrios T Boumpas ,1,5 Antonis Fanouriakis 1
Handling editor Kimme L ABSTRACT
Hyrich Objectives To analyse the new evidence (2018–2022) WHAT IS ALREADY KNOWN ON THIS TOPIC
for the management of systemic lupus erythematosus ⇒ Since the 2019 European League Against
► Additional supplemental
material is published online (SLE) to inform the 2023 update of the European League Rheumatism (EULAR) recommendations for the
only. To view, please visit the Against Rheumatism (EULAR) recommendations. management of systemic lupus erythematosus
journal online (https://d oi.org/ Methods Systematic literature reviews were performed (SLE), several studies have been published
10.1136/ard-2023-225319). providing data on alternative therapeutic
in the Medline and the Cochrane Library databases
For numbered affiliations see capturing publications from 1 January 2018 through 31 options and treatment targets. A systematic
end of article. December 2022, according to the EULAR standardised literature review (SLR) focusing on recent
operating procedures. The research questions focused advances was performed to inform the 2023
Correspondence to on five different domains, namely the benefit/harm of update of EULAR recommendations for the
Dr Antonis Fanouriakis, SLE treatments, the benefits from the attainment of management of SLE.
Rheumatology and Clinical
remission/low disease activity, the risk/benefit from
Immunology Unit, "Attikon"
University Hospital, National treatment tapering/withdrawal, the management of WHAT THIS STUDY ADDS
and Kapodistrian University of SLE with antiphospholipid syndrome and the safety of ⇒ In extrarenal disease, anifrolumab and
Athens School of Medicine, immunisations against varicella zoster virus and SARS- belimumab were superior to standard of
Athens, Greece; CoV2 infection. A Population, Intervention, Comparison
a fanour@med.u oa.gr
care treatment in a number of high-quality
and Outcome framework was used to develop search randomised controlled trials.
Received 27 November 2023 strings for each research topic. ⇒ High-quality evidence points towards better
Accepted 10 May 2024 Results We identified 439 relevant articles, the efficacy of combination treatments with
majority being observational studies of low or moderate belimumab or voclosporin compared with
quality. High-quality randomised controlled trials standard of care in patients with lupus
(RCTs) documented the efficacy of the type 1 interferon nephritis.
receptor inhibitor, anifrolumab, in non-renal SLE, ⇒ Both remission and low disease activity have
and belimumab and voclosporin, a novel calcineurin been associated with lower risk of adverse
inhibitor, in lupus nephritis (LN), when compared with outcomes in observational studies.
standard of care. For the treatment of specific organ ⇒ Although treatment discontinuation increases
manifestations outside LN, a lack of high-quality the risk of flares, successful glucocorticoid
data was documented. Multiple observational studies withdrawal was accomplished in patients with
confirmed the beneficial effects of attaining clinical SLE in remission in several cohort studies.
remission or low disease activity, reducing the risk for
multiple adverse outcomes. Two randomised trials with HOW THIS STUDY MIGHT AFFECT RESEARCH,
some concerns regarding risk of bias found higher rates PRACTICE OR POLICY
of relapse in patients who discontinued glucocorticoids ⇒ This SLR provided a systematic update of
(GC) or immunosuppressants in SLE and LN, respectively, current evidence regarding the management of
yet observational cohort studies suggest that treatment patients with SLE, to inform the 2023 update of
withdrawal might be feasible in a subset of patients. the EULAR recommendations.
Conclusion Anifrolumab and belimumab achieve
“© European Alliance of better disease control than standard of care in extrarenal
Associations for Rheumatology, SLE, while combination therapies with belimumab
EULAR 2024. Re-use permitted phenotype, the variable severity of involvement
and voclosporin attained higher response rates in
under CC BY-NC-ND. No even within the same organ manifestation, and
commercial re-use. No
high-quality RCTs in LN. Remission and low disease
the different efficacy of drugs in different patient
derivatives. See rights and activity are associated with favourable long-term
subgroups and disease manifestations.1 Patients with
permissions. Published by BMJ outcomes. In patients achieving these targets, GC and
on behalf of EULAR.” SLE will frequently require multiple drugs during
immunosuppressive therapy may gradually be tapered.
the course of their disease to achieve and maintain
To cite: Kostopoulou M, Cite Now
sufficient control. To this end, it is important that
Mukhtyar CB, Bertsias G,
et al. Ann Rheum Dis Epub
recent years have witnessed significant progress
ahead of print: [please in the form of introduction of new drugs to treat
include Day Month Year]. INTRODUCTION the disease. Anifrolumab, an anti-type 1 interferon
doi:10.1136/ard-2023- Management of systemic lupus erythematosus (SLE) receptor inhibitor, was approved in 2021 for the
225319 is challenging, owing to the heterogeneity of disease treatment of moderate-to-severe extrarenal SLE.2 3
Kostopoulou M, et al. Ann Rheum Dis 2024;0:1–13. doi:10.1136/ard-2023-225319 1
, Systemic lupus erythematosus
Belimumab and voclosporin (a novel calcineurin inhibitor (CNI)) publications, were also included. For each research question,
were also approved by the European Medicines Agency in 2021 a predefined extraction form was used to capture the popula-
Ann Rheum Dis: first published as 10.1136/ard-2023-225319 on 22 May 2024. Downloaded from http://ard.bmj.com/ on June 4, 2024 by guest. Protected by copyright.
and 2022, respectively, for the treatment of lupus nephritis (LN), tion set, all relevant interventions, their duration of use, route
a cardinal manifestation of the disease affecting up to 40%–50% of administration, dosage, follow- up time and the respective
of patients, with significant impact on morbidity and survival.4 5 effect estimates, including incidence rate, mean difference, risk
These important advances provided the ground for an update difference, correlation coefficient, odds ratio (OR) and relative
of the European League Against Rheumatism (EULAR) recom- risk. For each research question, results were synthesised and
mendations for the management of SLE, which was published presented according to the interventions used and the respective
recently.6 To this end, we performed structured systematic liter- outcomes.
ature reviews (SLRs), aiming to update the evidence for the effi- Risk of bias (RoB) was assessed using the revised Cochrane
cacy and safety of different therapies, as well as try to define Risk of Bias Assessment Tool for RCTs (ROB V.2), the Newcastle-
the optimal therapy of different organ manifestations of the Ottawa scale for observational studies, and the AMSTAR V.2
disease. The results of these SLRs were presented to the Task tool for meta-analyses (online supplemental file 3). In case of
Force members during dedicated meetings to form the current disagreements, these were internally discussed until achieve-
evidence base, on which the formulation of the current recom- ment of consensus, and one methodologist was involved when
mendations was based. The current manuscript presents in detail deemed necessary. A Preferred Reporting Items for Systematic
the results of these SLRs. Reviews and Meta-Analyses checklist was completed and has
been submitted along with the manuscript.
METHODS
RESULTS
We followed the standardised operating procedures for the devel-
We screened a total of 10 889 articles, of which 578 were
opment of EULAR-endorsed recommendations and employed
selected for full-text review, and 439 were finally included for
the Appraisal of Guidelines Research and Evaluation instrument.
data extraction (see figure 1 for a detailed flow diagram of the
Following assembly of the Task Force, the convenor (DTB), one
selection process). The results below are presented in terms
methodologist (GB), one co- methodologist (CBM), and two
of general efficacy of drugs in SLE, followed by treatment of
fellows responsible for the SLR (AF and MK) created an outline
specific manifestations, with a focus on LN.
of the proposed methodology, as well as the main research ques-
tions in the form of Population, Intervention, Comparison and
Outcomes (PICOs), which were circulated among Task Force Efficacy and safety of hydroxychloroquine (HCQ) in SLE
members. A Delphi-based methodology within the Task Force Between January 2018 and December 2022, a total of 39 studies
finally identified five research questions: (1) management of (all observational) evaluated and confirmed the association of
general and organ- specific SLE (divided in six subquestions HCQ with various favourable outcomes (online supplemental
regarding drug efficacy and safety in patients with active SLE, file 4, table S4.1). A total of 10 studies reported a negative asso-
active mucocutaneous, musculoskeletal, haematological, neuro- ciation between HCQ use and mortality in SLE; a meta-analysis
psychiatric and kidney involvement, respectively), (2) targets of of 21 studies (26 037 patients) found a pooled HR 0.46 for
treatment, (3) management of patients with SLE and antiphos- death in patients with SLE receiving HCQ (consistent results in
pholipid syndrome, (4) tapering/withdrawal of treatment in SLE all geographic regions).8 Fewer (or individual) studies showed
and (5) efficacy and safety of vaccination against varicella zoster a positive effect of HCQ on various outcomes (reduced rate
virus (VZV) reactivation and SARS-CoV2 infection (a generic of disease flares, thrombosis, osteonecrosis, infections, among
SLR for infection risk and prevention in SLE was not performed, others). Regarding safety of HCQ, the focus was on retinal
because there are specific EULAR recommendations on this toxicity.9 10 The current SLRs identified 10 studies (mostly of
topic).7 Separate search strings were developed for each PICO poor or fair quality) (table 1); two retrospective cohort studies of
(1–5), resulting in five separate SLRs (the six subquestions of good quality (ie, lower RoB) reported retinopathy rates of 0.8%
PICO 1 (PICO 1a–f) were examined with a single search string) and 4.3%, respectively. Longer duration of HCQ intake and a
(online supplemental file 1 and 2, tables S1.1–S1.10). higher cumulative dose were confirmed as risk factors for retinal
Under the supervision of the methodologists, AF and MK toxicity. Regarding other safety issues, a concern for corrected
performed the SLRs independently in two different databases QT (QTc) prolongation was raised when HCQ was used during
(MEDLINE through PubMed and the Cochrane Library), with the early phases of the COVID-19 pandemic; however, a total
additional inclusion of Lancet Rheumatology (due to non- of six studies found no clinically relevant QTc prolongation with
inclusion of the latter in PubMed). Since this was an update of HCQ use.
the 2019 recommendations on general SLE, the current SLRs The recommended dose of 5 mg/kg in the 2023 recommen-
evaluated all English language publications published between dations was based on (1) an observational study of good quality,
January 2018 and December 2022. All study designs were which calculated the threshold for an increased risk of flares
included (meta-analyses, randomised controlled trials (RCTs), near 5 mg/kg/day of HCQ dose,11 (2) older evidence of good
quasi-RCTs, cohort studies, case–control studies, cross–sectional quality, suggesting that risk of toxicity is low for doses below 5
studies) while narrative reviews, case series, case reports, confer- mg/kg real body weight10 and (3) indirect evidence for a slightly
ence abstracts, animal studies, trials in non-English language, increased risk of flares in patients who taper HCQ versus those
trials with population<20 and trials on paediatric populations who continue (see below, Safety of treatment tapering in SLE).
were excluded. In case a study was captured as an original publi-
cation and was also included in a meta-analysis, then only the Efficacy and safety of glucocorticoids (GC) in SLE
meta-analysis data were used, to avoid duplicating the evidence Although GC are widely used in SLE, high- quality RCTs
from that particular study. Eligible studies were reviewed for assessing the efficacy of different schemes and tapering strate-
snowball references and relevant articles, identified by manual gies are still lacking. A single, retrospective study of good quality
search within the reference list of the originally retrieved in 206 patients with LN found higher rates of 1-year complete
2 Kostopoulou M, et al. Ann Rheum Dis 2024;0:1–13. doi:10.1136/ard-2023-225319
