Eular SLE 2023

Recommendation
EULAR recommendations for the management of
Ann Rheum Dis: first published as 10.1136/ard-2023-224762 on 12 October 2023. Downloaded from http://ard.bmj.com/ on October 14, 2023 by guest. Protected by copyright.
systemic lupus erythematosus: 2023 update
Antonis Fanouriakis ‍ ‍,1 Myrto Kostopoulou ‍ ‍,1 Jeanette Andersen,2
Martin Aringer ‍ ‍,3 Laurent Arnaud ‍ ‍,4 Sang-Cheol Bae ‍ ‍,5 John Boletis,6
Ian N Bruce,7 Ricard Cervera,8 Andrea Doria ‍ ‍,9 Thomas Dörner ‍ ‍,10
Richard A Furie ‍ ‍,11 Dafna D Gladman ‍ ‍,12 Frederic A Houssiau ‍ ‍,13
Luís Sousa Inês ‍ ‍,14 David Jayne ‍ ‍,15 Marios Kouloumas,16 László Kovács,17
Chi Chiu Mok ‍ ‍,18 Eric F Morand ‍ ‍,19 Gabriella Moroni,20 Marta Mosca,21
Johanna Mucke ‍ ‍,22 Chetan B Mukhtyar ‍ ‍,23 György Nagy ‍ ‍,24,25,26
Sandra Navarra,27 Ioannis Parodis ‍ ‍,28,29,30 José M Pego-Reigosa,31
Michelle Petri ‍ ‍,32 Bernardo A Pons-Estel,33 Matthias Schneider,22 Josef S Smolen,34
Elisabet Svenungsson ‍ ‍,28,29 Yoshiya Tanaka ‍ ‍,35 Maria G Tektonidou ‍ ‍,36
YK Onno Teng ‍ ‍,37 Angela Tincani ‍ ‍,38 Edward M Vital ‍ ‍,39
Ronald F van Vollenhoven ‍ ‍,40 Chris Wincup ‍ ‍,41 George Bertsias ‍ ‍,42
Dimitrios T Boumpas ‍ ‍1,43,44
Handling editor David S ABSTRACT be considered. Updated specific recommendations

Pisetsky Objectives To update the EULAR recommendations for are also provided for cutaneous, neuropsychiatric and
► Additional supplemental
the management of systemic lupus erythematosus (SLE) haematological disease, SLE-associated antiphospholipid
material is published online based on emerging new evidence. syndrome, kidney protection, as well as preventative
only. To view, please visit Methods An international Task Force formed the measures for infections, osteoporosis, cardiovascular
the journal online (http://dx. questions for the systematic literature reviews (January disease.
doi.org/10.1136/ard-2023-
2018–December 2022), followed by formulation and Conclusion The updated recommendations provide
224762).
finalisation of the statements after a series of meetings. consensus guidance on the management of SLE,
For numbered affiliations see A predefined voting process was applied to each combining evidence and expert opinion.
end of article. overarching principle and recommendation. Levels
of evidence and strengths of recommendation were
Correspondence to assigned, and participants finally provided their level of
Dr Dimitrios T Boumpas,
Rheumatology and Clinical
agreement with each item. INTRODUCTION
Immunology Unit, 4th Results The Task Force agreed on 5 overarching Since 2008, when the first EULAR recommen-
Department of Internal principles and 13 recommendations, concerning the dations for the management of systemic lupus
Medicine, "Attikon" University use of hydroxychloroquine (HCQ), glucocorticoids (GC), erythematosus (SLE) were published and widely
Hospital, Joint Academic
Rheumatology Program,
immunosuppressive drugs (ISDs) (including methotrexate, adopted,1 a series of specific recommendations
National and Kapodistrian mycophenolate, azathioprine, cyclophosphamide (CYC)), on disease monitoring, neuropsychiatric SLE and
University of Athens, Athens calcineurin inhibitors (CNIs, cyclosporine, tacrolimus, lupus nephritis (LN), pregnancy and women’s
12462, Greece; voclosporin) and biologics (belimumab, anifrolumab, health issues in SLE have been developed.2–5 More
b oumpasd@uoc.gr rituximab). Advice is also provided on treatment recently, updated recommendations on the manage-
Received 22 July 2023
strategies and targets of therapy, assessment of ment of general SLE and LN were published in
Accepted 18 September 2023 response, combination and sequential therapies, and 2019 and 2020, respectively, the latter jointly with
tapering of therapy. HCQ is recommended for all patients the European Renal Association/European Dialysis
with lupus at a target dose 5 mg/kg real body weight/ and Transplant Association (ERA/EDTA).
day, considering the individual’s risk for flares and Since the 2019 update, the pace of new devel-
retinal toxicity. GC are used as ’bridging therapy’ during opments in SLE has accelerated. A second biolog-
periods of disease activity; for maintenance treatment, ical drug, anifrolumab, has been approved for
© Author(s) (or their they should be minimised to equal or less than 5 mg/day the management of the disease, while the field of
employer(s)) 2023. No (prednisone equivalent) and, when possible, withdrawn. LN has also witnessed major breakthroughs; the
commercial re-use. See rights Prompt initiation of ISDs (methotrexate, azathioprine, approval of belimumab and voclosporin, a novel
and permissions. Published
by BMJ. mycophenolate) and/or biological agents (anifrolumab, calcineurin inhibitor (CNI), for patients with active
belimumab) should be considered to control the disease LN has inspired discussions on a ‘paradigm shift’ in
To cite: Fanouriakis A, and facilitate GC tapering/discontinuation. CYC and the treatment of LN, moving from the traditional
Kostopoulou M, Andersen J,
et al. Ann Rheum Dis Epub
rituximab should be considered in organ-threatening and ‘induction-maintenance’ regimen to the early use of
ahead of print: [please refractory disease, respectively. For active lupus nephritis, combination therapies.6 7 These advances created
include Day Month Year]. GC, mycophenolate or low-dose intravenous CYC are the impetus for an update of the recommendations,
doi:10.1136/ard-2023- recommended as anchor drugs, and add-on therapy with to provide guidance on an evolving landscape and
224762 belimumab or CNIs (voclosporin or tacrolimus) should capitalise on the experience gained thus far. Given
Fanouriakis A, et al. Ann Rheum Dis 2023;0:1–15. doi:10.1136/ard-2023-224762 1
Recommendation
the drug pipeline and lessons learnt regarding trial design from which panellists discussed in detail each overarching principle
previous trial failures, it is likely that new therapeutic options and recommendation and came up with the final version which
will continue to emerge, and SLE may finally enter the era of served as basis for the voting. During the third and last meeting
more frequent updates of its management recommendations, (14 May 2023), all Task Force members who were present, were
similar to other diseases.8 9 asked to vote per bullet point whether they agreed or not in
principle with the respective statement. As per the EULAR SOPs,
a recommendation was immediately accepted if more than 75%
METHODS of those present voted in favour. In cases where consensus was
Per the EULAR standard operating procedures (SOPs)10 and not met, possible causes of disagreement were discussed, amend-
the AGREE II document,11 the convenor (DTB) submitted a ments to the statements were made and a second round of voting
proposal for an update of the recommendations for the manage- requiring more than 66% agreement from participants took
ment of SLE, which was approved by the EULAR Quality of Care place. Following approval of the recommendation, every Task
Subcommittee and the EULAR Council. Following approval, a Force member provided their level of agreement (LoA) for each
Task Force was assembled to form the research questions for the statement in a scale from 0 (no agreement at all) to 10 (100%
systematic literature review (SLR), that consisted of 35 rheuma- agreement).
tologists, five nephrologists and two patient representatives (JA, Of note, the 2019 recommendations counted a total of 33
MKou), also including two methodologists (GB, CBM) and two recommendations belonging to 4 domains (goals of treatment,
fellows responsible for the SLR (AF, MK). Importantly, the Task general principles of treatment, specific manifestations and
Force also included non-European experts, four from the Amer- comorbidities). The current update aligns with the EULAR SOPs
icas (two from the USA (RF, MP), one from Canada (DDG), to include a maximum 15 bullet point statements. To this end,
one from Argentina (BAPE)), four from Asia (SCB, CCM, SVN, recommendations from the previous set were either omitted or
YT) and one from Australia (EM). EMerging EUlar NETwork merged, and new recommendations were formulated. Because
was also represented by two members (JM, CW). All members of this change from the previous update, all overarching prin-
completed a COI form. ciples and individual recommendations are hereby presented as
Before the first meeting, an outline of the proposed method- new, even for individual recommendations where the essence has
ology, a set of the main research questions and the respective remained unchanged, because a detailed description of ‘merged’,
Population, Intervention, Comparison and Outcomes (PICOs) ‘omitted’ and ‘rephrased’ statements was considered impractical.
were circulated among the panellists, who were encouraged
to comment, edit and propose additional topics for the SLR.
Through this process, it was decided that the SLRs would RESULTS
focus on five domains: (1) management of general and organ- Following the meetings mentioned above, the Task Force
specific SLE, (2) targets of treatment, (3) tapering/withdrawal formulated a final number of 5 overarching principles and 13
of treatment, (4) management of patients with SLE and anti- recommendations (table 1). The detailed results of the SLR are
phospholipid syndrome (APS), and (5) the efficacy and safety summarised in the online supplemental appendix; however,
of vaccination against herpes zoster and SARS-CoV2 viruses (a parts of the data are also presented herein, to provide an expla-
general SLR for infection prevention was not decided, as there nation of the results.
are dedicated EULAR recommendations on this topic). Sepa-
rate PICOs and search strings were developed for each domain, Overarching principles
resulting in five SLRs. The two fellows, supervised by the meth- The overarching principles contain general information on the
odologists, performed the PICO-based SLRs using two different management of SLE, reflect common sense and are not accom-
databases (PubMed and Central). Importantly, since the previous panied by a respective level of evidence. They are nevertheless
recommendations on general SLE had included papers through important to set an overall framework for the approach to a
December 2017, the current SLRs were limited to English patient with SLE and highlight the role of physician–patient
language publications published between January 2018 and interaction. The overarching principles were voted as a group of
December 2022. Pertinent articles identified by manual search principles (ie, not individually) and agreement was 100%.
within the reference list of the originally retrieved publications A. SLE requires multidisciplinary, individualised management
were also included. A risk of bias assessment was performed with patient education and shared decision-making, taking into
using the Cochrane Risk of Bias tool and Newcastle-Ottawa consideration the costs to patient and society.
scale for randomised controlled trials (RCT) and observational While rheumatologists are the specialists who should
studies, respectively. The final level of evidence and grading primarily care for patients with SLE, the multisystem nature of
of recommendations, according to the Oxford Evidence-based the disease often mandates the involvement of other disciplines
Medicine grading levels,12 considered also the body of evidence (eg, nephrologists, dermatologists etc), and treatment decisions
that had informed the 2019 EULAR recommendations.13 should be individualised considering patient preferences and
The results of the SLRs, focusing on new evidence and data patient education. Comparative costs of different treatments
quality, were presented during the first meeting (29 April 2023), should be weighed against the cost of illness and the societal
held virtually to facilitate the attendance of the international impact of SLE, in terms of social and work participation. Mean
Task Force members. The participants reviewed the evidence, (SD) LoA was 9.88 (0.40).
and an initial draft of the statements/recommendations was B. SLE disease activity should be assessed at each clinic visit (the
formulated following open deliberations. Then, suggestions frequency depending on physician’s discretion), with evaluation
and edits by all members were incorporated by the convenor, of organ damage (at least annually), using validated instruments.
methodologists and the fellows responsible for the SLR to a new Task Force members agreed on the need to formally assess
modified set of recommendations, which was again circulated lupus disease activity at each visit for the need of therapy adap-
to the panel members to propose any additional changes. To tation. The phrasing ‘frequency depending on physician’s discre-
achieve consensus, a second meeting was held (7 May 2023), in tion’ was decided following deliberations, in which it became
2 Fanouriakis A, et al. Ann Rheum Dis 2023;0:1–15. doi:10.1136/ard-2023-224762
Recommendation
Table 1 EULAR Recommendations for the management of patients with systemic lupus erythematosus—2023 update
Level of agreement
Μean (SD) % with score ≥8
Overarching principles
A. SLE requires multidisciplinary, individualised management with patient education and shared decision-making, taking into consideration the costs to patient and society. 9.88 (0.40) 100
B. SLE disease activity should be assessed at each clinic visit (the frequency depending on physician’s discretion), with evaluation of organ damage (at least annually), using validated 9.74 (0.63) 100
instruments.
C. Non-pharmacological interventions, including sun protection, smoking cessation, healthy, balanced diet, regular exercise and measures to promote bone health are important to 9.90 (0.37) 100
improve long-term outcomes
D. Pharmacological interventions are directed by patient characteristics, type and severity of organ involvement, treatment-related harms, comorbidities, risk for progressive organ 10 (0) 100
damage, and patient preferences.
E. Early SLE diagnosis (including serological assessment), regular screening for organ involvement (especially nephritis), prompt initiation of treatment aiming at remission (or low 9.81 (0.51) 100
disease activity if remission is not possible) and strict adherence to treatment are essential to prevent flares and organ damage, improve prognosis and enhance quality of life.
Recommendation/statement
1. Hydroxychloroquine is recommended for all patients (1b/A), unless contraindicated, at a target dose of 5 mg/kg real body weight/day (2b/B) but individualised based on risk for flare 9.21 (1.35) 90.4
(2b/B) and retinal toxicity.
2. Glucocorticoids, if needed, are dosed based on the type and severity of organ involvement (2b/C), and should be reduced to maintenance dose of ≤5 mg/day (prednisone equivalent) 9.57 (0.77) 97.6
(2a/B) and, when possible, withdrawn; in patients with moderate-to-severe disease, pulses of intravenous methylprednisolone (125–1000 mg/day, for 1–3 days) (3b/C) can be
considered.
3. In patients not responding to hydroxychloroquine (alone or in combination with glucocorticoids) or patients unable to reduce glucocorticoids below doses acceptable for chronic use, 9.32 (0.91) 95.2
addition of immunomodulating/immunosuppressive agents (eg, methotrexate (1b/B), azathioprine (2b/C) or mycophenolate (2a/B)) and/or biological agents (eg, belimumab (1a/A) or
anifrolumab (1a/A)) should be considered.
4. In patients with organ-threatening or life-threatening disease, intravenous cyclophosphamide (2b/C) should be considered; in refractory cases, rituximab (2b/C) may be considered. 9.38 (0.99) 95.2
5. Treatment of active skin disease should include topical agents (glucocorticoids, calcineurin inhibitors) (2b/B), antimalarials (hydroxychloroquine, chloroquine) (1a/A), and/or systemic 9.35 (1.06) 95.2
glucocorticoids (4/C) as needed, with methotrexate (1b/B), mycophenolate (4/C), anifrolumab (1a/A), or belimumab (1a/B) considered as second-line therapy.
6. In active neuropsychiatric disease attributed to SLE, glucocorticoids and immunosuppressive agents for inflammatory manifestations (1b/A) and antiplatelet agents/anticoagulants for 9.68 (0.81) 97.6
atherothrombotic/aPL-related manifestations (2b/C) should be considered.
7. For acute treatment of severe autoimmune thrombocytopenia, high-dose glucocorticoids (including pulses of intravenous methylprednisolone) (4/C), with or without intravenous 9.48 (0.86) 97.6
immunoglobulin G (4/C), and/or rituximab (2b/B), and/or high-dose intravenous cyclophosphamide (4/C), followed by maintenance therapy with rituximab (2b/B), azathioprine (2b/C),
mycophenolate (2b/C), or cyclosporine (4/C) should be considered.
8. Patients with active proliferative lupus nephritis should receive low-dose (EuroLupus) intravenous cyclophosphamide (1a/A) or mycophenolate (1a/A) and glucocorticoids (pulses of 9.36 (1.06) 92.8
intravenous methylprednisolone followed by lower oral doses); combination therapy with belimumab (either with cyclophosphamide or mycophenolate (1b/A)) or calcineurin inhibitors
(especially voclosporin or tacrolimus, combined with mycophenolate, 1b/A) should be considered.
9. Following renal response, treatment of lupus nephritis should continue for at least 3 years (2b/B); patients initially treated with mycophenolate alone or in combination with 9.56 (0.81) 95.2
belimumab or a calcineurin inhibitor should remain on these drugs (1a/A), whereas azathioprine or mycophenolate should replace cyclophosphamide for those initially treated with
cyclophosphamide alone (1a/A) or in combination with belimumab (1a/A).
10. In patients at high-risk for renal failure (defined as reduced GFR, histological presence of cellular crescents or fibrinoid necrosis, or severe interstitial inflammation), high-dose (NIH 9.57 (0.86) 95.2
regimen) intravenous cyclophosphamide (1a/A) in combination with pulse intravenous methylprednisolone, can be considered.
11. In patients with SLE achieving sustained remission, gradual tapering of treatment should be considered, with withdrawal of glucocorticoids first (2a/B). 9.89 (0.38) 100
12. SLE associated with thrombotic antiphospholipid syndrome (APS) should be managed with long-term vitamin K antagonists after the first arterial or unprovoked venous thrombotic 9.57 (0.83) 97.6
event (1b/B); low dose aspirin (75–100 mg/day) should be considered in patients with SLE without APS but with high-risk aPL profile (2a/B).
13. Immunisations for the prevention of infections (herpes zoster virus, human papillomavirus, influenza, COVID-19 and pneumococcus), management of bone health, nephroprotection 9.85 (0.36) 100
and cardiovascular risk, and screening for malignancies, should be performed (5/D).
Levels of evidence according to the Oxford Evidence-based Medicine grading levels (https://www.cebm.net/wp-content/uploads/2014/06/CEBM-Levels-of-Evidence-2.1.pdf).
aPL, antiphospholipid antibodies; GFR, glomerular filtration rate; NIH, National Institutes of Health; SLE, systemic lupus erythematosus.
clear that optimal frequency of patient visits may vary, from reader is referred there for more relevant information.16 Mean
a few days in a patient with active LN to up to 6 months in (SD) LoA was 9.90 (0.37).
patients with long-standing quiescent disease; thus, judgement D. Pharmacological interventions are directed by patient char-
of the treating physician cannot be substituted by a fixed range acteristics, type and severity of organ involvement, treatment-
of intervals. The most frequently used validated instruments related harms, comorbidities, risk for progressive organ damage
for measuring disease activity are the various versions of the and patient preferences.
SLE Disease Activity Index (SELENA-SLEDAI or SLEDAI-2K) The phenotypic heterogeneity and variable severity of organ
and the British Isles Lupus Assessment Group (BILAG). Annual involvement, as well as differential response to drugs based on
assessment of irreversible damage is important because damage patient characteristics, mandate an individualised approach.
accrual has significant prognostic value. Mean (SD) LoA for this Pharmacological treatment of lupus may range from hydroxy-
principle was 9.74 (0.63). chloroquine (HCQ) monotherapy for patients with mild skin
C. Non-pharmacological interventions, including sun protec- and/or joint symptoms, to highly potent immunosuppressive
tion, smoking cessation, healthy, balanced diet, regular exercise medications like high- dose glucocorticoids (GC) and cyclo-
and measures to promote bone health are important to improve phosphamide (CYC) in patients with organ- threatening or
long-term outcomes. life-
threatening disease. When choosing therapy, immutable
These interventions are not specific to SLE and pertain also characteristics, such as race and ethnicity, as well as socioeco-
to the general population, although patients with lupus should nomic determinants and access to different drugs should be
particularly avoid sun exposure due to the characteristic photo- taken into account. For example, black patients with LN may be
sensitivity of the disease. The importance of smoking cessation more responsive to mycophenolate than CYC.17 Patient research
should be emphasised, as smoking may also interfere with the partners in the Task Force highlighted the importance of patient
efficacy of antimalarials14 and biologics (belimumab)15 among preferences in the treatment decisions, which form the basis
its other detrimental sequelae. Importantly, a dedicated set of of shared decision-making. This principle received the highest
EULAR recommendations on non- pharmacological manage- mean LoA, mean (SD) 10 (0), indicating complete agreement of
ment of SLE and systemic sclerosis were published recently; the all individual panellists.
Recommendation
E. Early SLE diagnosis (including serological assessment), dose to within range once the patient has improved. In addition,
regular screening for organ involvement (especially nephritis), Task Force members suggested the use of monitoring HCQ blood
prompt initiation of treatment aiming at remission (or low levels to guide the optimal dose for each patient and assess for
disease activity if this is not possible), and strict adherence to possible non-adherence to therapy, based on studies suggesting
treatment are essential to prevent flares and organ damage, that HCQ whole blood levels may reflect patient adherence to
improve prognosis and enhance quality of life. treatment.26 Although a universal recommendation for HCQ
The final overarching principle highlights four pillars in blood level monitoring would be impractical, it can neverthe-
the management of SLE: (1) need for early diagnosis, because less be used to guide dosage adaptations, in settings where it
despite increased awareness in combination with the new, more is available. Finally, the use of antimalarials other than HCQ
sensitive classification criteria,18 recent studies support that was discussed mainly by non-European panellists, to address the
patients with SLE still face diagnostic delay (median 2 years issue of potential limited availability or higher cost of HCQ in
from onset of symptoms)19 20; (2) vigilant monitoring for new some countries. In such settings, chloroquine may be used as
organ involvement, mainly LN, especially during the first years an alternative, bearing in mind that it may be more toxic than
of the disease, but also thereafter. This need for increased aware- HCQ (mainly for retinal toxicity).27 Finally, quinacrine can be
ness for signs of new-onset kidney involvement was emphasised considered in patients with cutaneous manifestations and HCQ-
by several Task Force members, because LN represents a major induced retinopathy. The statement on HCQ was agreed on by
milestone in the natural history of the disease and delaying its 77.8% of participants following one round of amendments (the
diagnosis has profound prognostic repercussions; (3) pursuing a only statement where this was needed) and mean (SD) LoA was
treatment target, which should ideally be remission, as defined 9.21 (3.35).
by the recent Definition Of Remission In SLE (DORIS) criteria,21 2. Glucocorticoids, if needed, are dosed based on the type
or alternatively, a state of low disease activity, such as the Lupus and severity of organ involvement (2b/C), and should be
Low Disease Activity state (LLDAS).22 Both remission and reduced to maintenance dose of ≤5 mg/day (prednisone equiv-
LLDAS have been extensively validated and proven to reduce alent) (2a/B) and, when possible, withdrawn; in patients with
the risk for damage and other adverse outcomes in patients moderate-to-severe disease, pulses of intravenous methylpred-
with SLE (a detailed analysis of the favourable outcomes asso- nisolone (125–1000 mg per day, for 1–3 days) (3b/C) can be
ciated with remission and LLDAS is given in the online supple- considered.
mental appendix); and (4) the importance of patient adherence Minimisation of GC use, in view of their detrimental effects,
to treatment. Specific reference to the issue of adherence in the was a major theme of discussion during the Task Force meet-
overarching principles was emphasised by several panellists, ings. Numerous studies in the current SLR confirmed associa-
including the patient research partners, because medication tions of different cut-offs for daily prednisone dose with adverse
non-adherence, despite reported wide variations, is considered outcomes, most of which pointed to the threshold of 5 mg/day.
a major cause of treatment failure.23 A trusting relationship Although a controlled trial of different GC tapering regimens or
between the physician and patient forms the basis for the mini- maintenance doses is still lacking in SLE, the Task Force elected
misation of the risk of non-adherence. Mean (SD) LoA for the to lower the ‘acceptable’ threshold of daily prednisone dose for
final overarching principle was 9.81 (0.51). maintenance treatment to maximum 5 mg/day prednisone equiv-
alent, as compared with 7.5 mg/day in the 2019 recommenda-
tions. Ideally, one could envision the use of GC only as ‘bridging
Individual recommendations therapy’ in SLE, similar to rheumatoid arthritis (lowest possible
1. Hydroxychloroquine is recommended for all patients (1b/A), dose for the shortest possible period), and the complete with-
unless contraindicated, at a target dose of 5 mg/kg real body drawal of GC is the optimal target.
weight/day (2b/B), but individualised based on risk for flare Intravenous pulses of methylprednisolone (MP) of various
(2b/B) and retinal toxicity. doses (depending on disease severity and patient weight) capi-
HCQ is the mainstay of treatment for patients with SLE and talise on the immediate nongenomic effects of GC,28 and
the current SLR extended the existing body of evidence regarding may allow for a faster tapering of per os (PO) GC.29 Impor-
the multiple beneficial effects of HCQ in various aspects of the tantly, pulse IV MP has not been linked to certain established
disease. In the 2019 recommendations, emphasis was placed on GC-related harms, like avascular necrosis.30 Initial PO dose also
the specification that HCQ dose ‘should not exceed 5 mg/kg real depends on disease severity; a retrospective study in 206 patients
body weight/day’, in view of data which suggested a higher than with LN using propensity score matching found higher rates of
previously thought risk for retinal toxicity by the use of more 1-year complete response in patients who started with ≥40 mg/
sensitive screening techniques.24 A recent observational study day compared with those who started with≤30 mg/day, without
assessed the risk for flares in relation to HCQ dose during the increased risk for GC-related damage.31 A smaller study in non-
previous 6-month period and found an almost twofold risk for renal lupus had found similar reduction in disease activity at
any flare for doses ≤5 mg/kg/day (vs >5 mg/kg/day), increased to 1 year and higher risk of damage with starting dose >30 mg/day
more than sixfold for moderate or severe flares, with a threshold versus ≤30 mg/day.32 Despite these discrepancies, most panel-
dose calculated near 5 mg/kg/day.25 Until more data become lists agreed that it is the chronic exposure to GC that confers
available regarding benefit–risk relationship of different doses, the major risk, and the statement received 96.3% agreement and
it was decided that the HCQ target dose remains at 5 mg/kg/day; mean (SD) LoA was 9.57 (0.77).
however, this should be individualised based on risk for flare and 3. In patients not responding to hydroxychloroquine (alone or in
retinal toxicity, with patients at higher risk for retinal toxicity combination with glucocorticoids) or patients unable to reduce
(kidney disease, preexisting macular or retinal disease, tamox- glucocorticoids below doses acceptable for chronic use, addition
ifen use) being candidates for closer ophthalmologic follow-up. of immunomodulating/immunosuppressive agents (eg, metho-
In selected patients and circumstances (eg, moderate or severe trexate (1b/B), azathioprine (2b/C) or mycophenolate (2a/B))
disease), initial HCQ dose higher than 5 mg/kg/day (but not and/or biological agents (eg, belimumab (1a/A) or anifrolumab
exceeding 400 mg/day) may be used, followed by lowering of the (1a/A)) should be considered.
Recommendation
This statement emphasises the value of conventional and For the treatment of active skin disease in SLE, few new data
biological immunomodulatory/immunosuppressive drugs for have emerged since the 2019 recommendations, and a significant
the control of the disease and facilitation of GC tapering and body of evidence continues to originate from studies in patients
withdrawal. Since no new, high-quality data emerged in the past with cutaneous lupus erythematosus. Recommended first-line
4 years regarding conventional immunosuppressive drugs, delib- treatment (topical agents, antimalarials and/or systemic GC) has
erations regarding this statement focused on two main issues: (1) not changed in the statement. HCQ is the antimalarial of choice,
inclusion of anifrolumab, following its approval in 2021,33 34 as but chloroquine may be used in the settings discussed earlier.45
well as belimumab,35 as biological agents with proven efficacy Quinacrine (mepacrine) may also be used in cases of inadequate
in controlling disease activity, reducing flares, and allowing for response or toxic retinopathy, as add-on to HCQ or alternative
GC dose reduction. In the recommendation, there is no hier- therapy, respectively,46 but its use is limited by frequent intoler-
archy in the choice between anifrolumab and belimumab, as ance and unavailability in many countries.
the two drugs have not been compared in a head-to-head trial For the ~40% of patients not responding to first-line therapy,47
and their approval was the result of RCTs in similar extrarenal comparative studies among existing immunosuppressive drugs
SLE populations. The panel noted that there are more than 10 are lacking. Despite this paucity, recommended second-line drugs
years of real-life clinical experience with belimumab, while no have partly changed from 2019, because the Task Force decided
real-life data for anifrolumab had been published by the time to recommend drugs more familiar to rheumatologists (such as
of the SLR completion. (2) The positioning of biological agents MTX or mycophenolate, instead of dapsone or retinoids). A
in relation to conventional immunosuppressive drugs for the small retrospective study in 73 patients with refractory CLE to
treatment of SLE. For the latter point, while considerations first-line therapy found similar response rates (~65%) between
from specific countries, healthcare settings and biological reim- MTX and mycophenolate.48 Anifrolumab and belimumab have
bursement policies have to be taken into account, most panel- both shown efficacy in mucocutaneous manifestations of SLE,49 50
lists agreed that prior use of a conventional immunosuppressive although only anifrolumab has used the Cutaneous Lupus Area
drug (MTX, AZA, mycophenolate mofetil or mycophenolic acid and Severity Index in its clinical programme, whereas belimumab
(henceforth combined referred to as ‘mycophenolate’, see online has reported responses according to the general instruments
supplemental table 1 for details), leflunomide36 or others) should SLEDAI and BILAG (hence, the designation B in the Grading
not be mandatory for initiating anifrolumab or belimumab. Of of Recommendation, despite positive RCT data). Importantly,
note, this is unchanged from the 2019 recommendations. The the list of recommended drugs is indicative and other treatments
rationale driving this statement was that, despite their substan- may be considered as second-line or third-line options, including
tially higher cost, approved biological drugs have proven their dapsone, retinoids, CNI, AZA, CYC and RTX, ideally in collab-
efficacy in high-quality RCTs, while such data are lacking for oration with dermatologists experienced in the treatment of
conventional immunosuppressive drugs, which continue to be CLE. Finally, thalidomide and, more recently, lenalidomide, are
used based on rheumatologists’ long-term real-life experience. effective in various subtypes of cutaneous lupus,51 52 and lena-
This recommendation received 84.6% agreement and mean (SD) lidomide has a lower risk for polyneuropathy than thalidomide;
LoA was 9.32 (0.91). however, they should both be reserved for patients that have
4. In patients with organ-threatening or life-threatening disease, failed multiple previous agents, and with the utmost caution in
intravenous cyclophosphamide (2b/C) should be considered; in women of reproductive age. This recommendation was agreed
refractory cases, rituximab (2b/C) may be considered. on by 96.3%, mean LoA (SD) was 9.35 (1.06).
Due to its gonadal toxicity, high-dose IV CYC is reserved for 6. In active neuropsychiatric disease attributed to SLE, gluco-
severe cases of lupus, in which it may be considered owing to its corticoids and immunosuppressive agents for inflammatory
high efficacy. Rituximab (RTX) is used off-label in SLE and is manifestations (1b/A) and antiplatelet agents/anticoagulants
recommended in circumstances37 where other drugs have failed, for atherothrombotic/antiphospholipid antibodies (aPL)-related
with notable exceptions (eg, immune cytopenias, see below) manifestations (2b/C) should be considered.
where it can be used earlier. Although a universal definition of This recommendation has remained unchanged, since no new
refractory disease is lacking in SLE, it is conceived as disease not data have emerged during the last 5 years that would deem a
responding to different classes of immunosuppressive medica- modification of the recommendation appropriate.53 Approach
tions. The combination of RTX with CYC had been used in early to a patient with possible neuropsychiatric SLE should follow
studies of RTX,38 but additional benefit has not been confirmed39 the general principles as in the general population and symp-
and this combination comes at the expense of an increased risk tomatic treatment as per individual manifestation should be
for infections. Sequential strategies of RTX followed by belim- considered. Attribution of a neuropsychiatric manifestation to
umab are being explored, but more data are needed.40 41 SLE is challenginf and published attribution models may be used
Patients not responding to any of the aforementioned thera- in doubtful cases.54 55 For severe inflammatory manifestations
pies might be offered other options, such as plasma exchange,42 (eg, myelopathy, acute confusional state), potent immunosup-
haematopoietic stem cell transplantation43 or experimental pressive agents, like CYC or RTX,56 should be preferred. For the
therapies. In 2022, the use of CAR T-cells in five patients with approved biological drugs anifrolumab and belimumab, there is
severe, refractory SLE was published with encouraging results, a paucity of evidence regarding their efficacy in neuropsychiatric
yet RCTs and more long-term data are needed.44 Agreement manifestations, because patients with active, severe forms of such
for this recommendation was 100%, with mean (SD) LoA 9.38 manifestations were excluded from the RCTs of both drugs, and
(0.99). under-represented in real-life use of belimumab. Anticoagulant
5. Treatment of active skin disease should include topical agents treatment is mainly indicated in cases of cerebrovascular disease,
(glucocorticoids, calcineurin inhibitors) (2b/B), antimalarials such as ischaemic stroke associated with aPL, because its value in
(hydroxychloroquine, chloroquine) (1a/A), and/or systemic other manifestations is not clear. Agreement on this recommen-
glucocorticoids (4/C) as needed, with anifrolumab (1a/A), beli- dation was 96.3% and mean (SD) LoA was 9.68 (0.81).
mumab (1a/B), methotrexate (1b/B), or mycophenolate (4/C), 7. For acute treatment of severe autoimmune thrombocytopenia,
considered as second-line therapy. high-dose glucocorticoids (including pulses of intravenous
Recommendation
methylprednisolone) (4/C), with or without intravenous immu- kidney disease (CKD),63 (2) rates of complete response at 1–2
noglobulin G (4/C), and/or rituximab (2b/B), and/or high-dose years with SoC therapy (ie, control arms) in recent clinical trials
intravenous cyclophosphamide (4/C), followed by maintenance (including the phase 3 trials of belimumab and voclosporin,
therapy with rituximab (2b/B), azathioprine (2b/C), mycophe- respectively)64 65 are consistently low, in the range of 20%–30%,
nolate (2b/C), or cyclosporine (4/C), should be considered. and (3) both belimumab and voclosporin based on their RCTs
Similar to neuropsychiatric SLE, treatment of autoimmune have been approved for all patients with active LN, meaning
thrombocytopenia in SLE also did not witness major develop- that all patients can potentially receive them, including as first
ments since 2019; thus, the current recommendation reflects the line. Of note, in a post-hoc analysis of the BLISS-LN, belim-
principles outlined in the previous update. A platelet number umab in combination with SoC was found to reduce the risk for
of 20–30 000/mm3 is typically used as the cut-off, below which flares by 55% compared with SoC alone, and preserve glomer-
therapy is indicated. Therapy includes: (1) acute phase treat- ular filtration rate (GFR) better than SoC.66 67 To this end, the
ment with GC (including pulses of intravenous MP, followed by possibility for a universal recommendation of early combination
0.5–0.7 mg/kg/day prednisone equivalent with tapering) with or therapy aiming to increase renal response rates was intensively
without IVIG; RTX may also be used early in this setting,57 based discussed among panellists. Counterarguments included the high
also on the drug’s documented efficacy in idiopathic immune cost of these therapies and the potential of overtreating some
thrombocytopenia, (2) early use of immunosuppressive medica- patients who would respond to treatment with mycopheno-
tions as GC-sparing agents; a small retrospective study showed late or low-dose intravenous CYC alone, as well as respective
that patients with SLE with immune cytopenias who relapsed cost or risk considerations, particularly relevant for long-term
had less often received concomitant immunosuppressive agents use of a CNI. Indeed, some patients with LN present with clin-
following treatment of the initial episode.58 More importantly, ically and histologically milder disease, while others with risk
mycophenolate was shown to reduce relapse when used as first factors for progression to end-stage kidney disease; at present,
line in a RCT in patients with immune thrombocytopenia.59 it is unclear which patients will benefit more from early combi-
While a similar RCT has not been performed in SLE, this study nation therapies. Of note, recent real-life studies have reported
provided proof-of-concept for the first-line use of immunosup- higher response rates with SoC, compared with rates reported
pressive medications in immune thrombocytopenia, a practice in RCTs.68 69 Based on all the above, it was proposed that early
commonly followed by most rheumatologists . Regarding choice combination therapy ‘should be considered’ in all adult patients
of drug for maintenance therapy, there is no hierarchy between with active LN, emphasising the fact that treating physicians have
the recommended drugs, and this is left to the treating physi- the option to decide if and when combination therapy should
cian’s discretion. In cases refractory to these drugs, thrombo- be used. In the case of CNIs, combination refers to voclosporin
poietin receptor (TPO) agonists and splenectomy are options; as well as tacrolimus (TAC), since the current SLR confirmed
although the two modalities have not been formally compared the superiority of TAC+mycophenolate over SoC (mainly high-
in SLE and data mainly come from observational studies,60 it dose CYC), although based on evidence exclusively from Asian
seems reasonable to use TPO agonists prior to splenectomy, populations.70
given the possible complications and long-term sequelae of the Additional points regarding the recommendation for LN
latter. However, it should be considered that TPO agonists have warrant further clarification: first, no distinction between LN
been associated with a higher risk of thromboembolic events, histological classes is made in the recommendation. It should
therefore their use should be avoided in aPL-positive patients.61 be noted that neither belimumab nor voclosporin induced
Fostamatinib, a spleen tyrosine kinase inhibitor, is approved for higher renal response rates versus placebo in a post-hoc RCT
the treatment of chronic immune thrombocytopenia, but has not analysis of the small subgroup of patients with class V LN.66 71
been tested in SLE. Similar treatment options (excluding TPO Nevertheless, patients with pure class V were underrepresented
agonists) pertain to SLE autoimmune haemolytic anaemia. This in these trials (less than 20%), and also there were fewer flares
recommendation received 92.6% agreement and mean (SD) LoA with belimumab in the pure V subgroup. Collectively, the Task
was 9.48 (0.86). Force opined that more data are needed to decide on the optimal
8. Patients with active proliferative lupus nephritis should treatment of class V LN; to provide a succinct message, it was
receive low-dose (EuroLupus) intravenous cyclophosphamide elected that the statement considers patients with any class of
(1a/A) or mycophenolate (1a/A) and glucocorticoids (pulses of LN that needs treatment. Of note, the recommended proteinuria
intravenous methylprednisolone followed by lower oral doses); cut-off for immunosuppressive treatment in class V LN remains
combination therapy with belimumab (either with cyclophos- 1 g/day, as per the 2019 EULAR/ERA-EDTA recommendations.72
phamide or mycophenolate (1b/A)) or calcineurin inhibitors Second, the secondary analysis of the BLISS- LN trial found
(especially voclosporin or tacrolimus, combined with mycophe- that belimumab was more efficacious in patients with baseline
nolate, 1b/A) should be considered. proteinuria below 3 g/day.66 Third, voclosporin provided a rapid
The recommendation regarding treatment of active LN reduction in proteinuria, which may be preferable in patients
received the highest attention, in light of the recent approvals with a high baseline urine protein in the nephrotic range.65
of belimumab and voclosporin. Discussions revolved mainly Fourth, in AURORA-1, patients with baseline GFR<45 mL/min
around the position of these drugs in the therapeutic algorithm were excluded, thus the safety of voclosporin in patients with
of LN, that is whether they should be used upfront in an early a low baseline GFR (30–45 mL/min) is as yet unclear. The final
combination therapy with standard- of-care (SoC, low-dose decision for the treatment of active LN should depend on the
CYC62 or mycophenolate in combination with GC, see online individual patient characteristics as outlined above (histological
supplemental table 1 for usual drug doses in SLE), or whether class, baseline GFR, proteinuria), presence of extrarenal mani-
they should be reserved for non-responding or relapsing disease. festations, comorbidities, risk for toxicity, access to drugs and
In this regard, deliberations towards the formulation of this cost issues, and patient preferences. If a combination therapy is
recommendation focused on the following facts: (1) LN is by not opted for in patients with treatment-naïve LN, add-on treat-
default severe disease, accompanied by increased morbidity ment with belimumab or voclosporin should be considered in
and mortality, and leading to gradual nephron loss and chronic patients with inadequate response by 3–6 months, or those who
Recommendation
flare. In these cases, physicians should consider to acquire expert combination recently reported stable levels of GFR throughout
consultation. the 3-year period.80 This recommendation was agreed on by
Regarding dosing of GC, pulses of intravenous MP (eg, 96.4% of participants and mean (SD) LoA was 9.56 (0.81).
250–1000 mg for 1–3 days) are recommended as part of the 10. In patients at high risk for kidney failure (defined as reduced
initial (or ‘remission induction’) regimen, unless there are glomerular filtration rate, histological presence of cellular cres-
major safety concerns (eg, infection). For oral therapy, large cents or fibrinoid necrosis, or severe interstitial inflammation),
controlled trials comparing different GC regimens have not been high-dose (National Institutes of Health regimen) intravenous
performed in LN. The 2019 EULAR/ERA- EDTA recommen- cyclophosphamide (1a/A) in combination with pulse intrave-
dations endorsed a lower dose GC regimen for initial therapy nous methylprednisolone can be considered.
compared with traditional practices (starting dose 0.3–0.5 mg/ A subset of patients with LN present with baseline clinical and
kg/day and 20 mg/day for proliferative classes and class V, respec- histological characteristics associated with an adverse long-term
tively), though acknowledging that this was not based on high- prognosis. Such patients can still be treated as in recommenda-
quality data.73 In the current version of recommendations, the tion nr. 9, but it should be noted that patients with such charac-
principle for lower cumulative GC exposure was maintained. teristics are underrepresented or excluded in all recent trials in
Importantly, belimumab demonstrated superior GC- sparing LN (eg, the BLISS-LN and AURORA-1 excluded patients with
potential than SoC in the BLISS-LN study, while the AURORA GFR<30 and ≤ 45 mL/min/1.73 m2, respectively). Thus, the
study of voclosporin used significantly lower GC doses than relative efficacy of these regimens in patients at high risk for
earlier studies (20–25 mg/day starting oral prednisone rapidly kidney failure is currently unclear. A small (32 patients) post hoc
tapered to 5 mg by 12 weeks), lending further support to their analysis of the Aspreva Lupus Management Study found similar
use in LN. A recommended GC initial dose and tapering strategy response rates (proteinuria and serum creatinine) between
is shown in online supplemental table 1. The overall agreement mycophenolate and high- dose intravenous CYC.81 Thus, for
for this recommendation was 92.8%, with a mean (SD) LoA of patients presenting with impaired kidney function or histolog-
9.36 (1.06). ical evidence of crescentic glomerulonephritis and/or severe
Thrombotic microangiopathy (TMA) may be evident in up to interstitial inflammation, the traditional high-dose intravenous
20% of LN biopsies, particularly in the presence of aPL, and is CYC regimen (0.5–0.75 g/m2 monthly for 6 months) can also be
associated with an adverse impact on prognosis. Although not considered, since it is the most extensively studied therapeutic
mentioned in the statement, treatment options in TMA-LN were regimen in severe LN, in the early studies from the NIH. Impor-
discussed, even though high-quality data are lacking. In addition tantly, this recommendation received 100% agreement among
to anticoagulation therapy,74 there is emerging evidence for the Task Force members, and a mean (SD) LoA of 9.57 (0.86).
use of eculizumab, a monoclonal antibody against complement Figures 1 and 2 outline the existing treatment options for the
protein C5 which is efficacious in cases of complement-mediated management of extrarenal SLE and LN, respectively.
TMA, for patients with LN and histological evidence of TMA.75 11. In patients with SLE achieving sustained remission, gradual
9. Following renal response, treatment of LN should continue tapering of treatment should be considered, with withdrawal of
for at least 3 years (2b/B); patients initially treated with myco- glucocorticoids first (2a/B).
phenolate alone or in combination with belimumab or a calci- The possibility of tapering immunosuppressive treatment in
neurin inhibitor should remain on these drugs (1a/A), whereas patients with SLE with quiescent disease was a specific research
mycophenolate or azathioprine should replace cyclophospha- question for the SLR, and concerned GC, immunosuppressive
mide for those initially treated with cyclophosphamide alone drugs (conventional and biological), and finally, HCQ (in this
(1a/A) or in combination with belimumab (1a/A). sequence). Regarding GC, a meta- analysis calculated a 24%
Following the choice of initial treatment, renal response pooled incidence of SLE flares following GC discontinuation,
should be monitored according to the 2019 EULAR/ERA-EDTA but relative risk for major flares was not increased compared
targets (reduction in proteinuria ≥25% and 50% at 3 and 6 with patients who continued GC.82 In an investigator-initiated
months, respectively, and below 500–700 mg/day at 12 months, study from France, discontinuation of prednisone in patients
all with GFR within 10% from baseline). These therapeutic goals who had clinically quiescent disease for more than 1 year and
have now been validated.76 Provided that response is achieved, received stable 5 mg/day proved inferior to continuation of the
subsequent (or ‘maintenance’) therapy should depend on the same dose, in terms of risk of disease flares.83 Caveats of this
initial regimen. If the initial regimen included mycophenolate study were discussed between Task Force members, mainly the
(either monotherapy or in combination with belimumab or abrupt discontinuation of prednisone and the fact that biolog-
voclosporin), then the same regimen should continue for at least ical agents like belimumab were not received by any patient. It
3 years; on the other hand, if low-dose CYC had been initially was decided that these limitations, together with observational
used, alone or in combination with belimumab, it should be studies that have shown no increased risk of flares with gradual
replaced by mycophenolate or AZA while belimumab should be tapering of GC to complete withdrawal84 85 and the detrimental
continued (if used initially). effects of long-term GC use, allow for a recommendation that
Duration of immunosuppressive therapy was also intensively gradual GC tapering to discontinuation should be attempted in
discussed. Immunosuppressive treatment in LN, particularly in SLE, in line with current recommendation 2.
proliferative classes, should continue for at least 3 years.77 Of Regarding immunosuppressive agents, a second investigator-
note, in case of initial therapy with mycophenolate/CNI combi- initiated RCT (Weaning of Immunosuppression in Lupus, WIN-
nation, there is a concern regarding the duration of therapy, as LUPUS) tested whether withdrawal of mycophenolate or AZA
long-term use of ‘legacy’ CNIs (tacrolimus, cyclosporine A) has after 2–3 years of therapy in LN would be non-inferior to contin-
been associated with nephrotoxicity and GFR decline. Several uation for the occurrence of renal relapses. The study failed to
Asian RCTs have investigated CNI combination therapy as remis- show non-inferiority, as patients in the discontinuation group
sion induction, but not as a long-term maintenance therapy.78 79 had more relapses of LN and more extrarenal flares.77 On the
In this regard, it is reassuring that the long-term AURORA-2 contrary, similar to GC, uncontrolled observational studies have
study extending to 3 years use of voclosporin/mycophenolate reported successful withdrawal of immunosuppressive therapy
Recommendation
Figure 1 Treatment of non-renal systemic lupus erythematosus. Top-to bottom sequence does not imply order of preference (eg, MTX, AZA and
MMF are equal options for second-line therapy in mild disease or first-line therapy in moderate disease). *Mild disease: constitutional symptoms; mild
arthritis; rash ≤9% body surface area; platelet count (PLTs) 50–100 × 109/L; SLEDAI≤6; BILAG C or ≤1 BILAG B manifestation. *Moderate disease:
moderate–severe arthritis (‘RA-like’; rash 9%–18% BSA; PLTs 20–50×109/L; serositis; SLEDAI 7–12; ≥2 BILAG B manifestations). *Severe disease:
major organ threatening disease (cerebritis, myelitis, pneumonitis, mesenteric vasculitis); thrombocytopenia with platelets<20×109/L; TTP-like disease
or acute haemophagocytic syndrome; rash>18% BSA SLEDAI>12; ≥1 BILAG A manifestations. †Recommendation of belimumab and anifrolumab as
first-line therapy in severe disease refers to cases of extrarenal SLE with non-major organ involvement, but extensive disease from skin, joints, and
so on. The use of anifrolumab as add-on therapy in severe disease refers mainly to severe skin disease. For patients with severe neuropsychiatric
disease, anifrolumab and belimumab are not recommended. ANI, anifrolumab; aPL, antiphospholipid antbodies; APS, antiphospholipid syndrome; AZA,
azathioprine; BEL, belimumab; BILAG, British Isles Lupus Assessment Group; CNI, calcineurin inhibitor; CYC, cyclophosphamide; GC, glucocortocoids;
HCQ, hydroxychloroquine; IV, intravenous; MMF, mycophenolate mofetil; MTX, methotrexate; PO, per os; RTX, rituximab; SLEDAI, SLE Disease Activity
Index; VKA, vitamin K antagonists.
in LN. Of note, the total duration of therapy as well as of remis- Importantly, the statement on tapering treatment in quiescent
sion prior to discontinuation of immunosuppressive drugs are SLE received the highest LoA between members, 100%, and
particularly important in the LN setting86 87; patients should mean (SD) LoA 9.89 (0.38).
have received at least 3–5 years of therapy and be in remission 12. SLE associated with thrombotic antiphospholipid syndrome
for at least 2 years before withdrawal can be attempted. Prior (APS) should be managed with long-term vitamin K antagonists
to withdrawal, tapering should be undertaken very gradually. A after the first arterial or unprovoked venous thrombotic event
repeat kidney biopsy-guided decision for therapy withdrawal in (1b/B); low-dose aspirin (75–100 mg/day) should be considered
patients in clinical remission, in order to assess for residual histo- in patients with SLE/without APS with high-risk aPL profile
logical activity predictive of a subsequent flare, is supported by (2a/B).
recent observational studies and could be considered, although Patients with SLE with concomitant APS represent a chal-
this has not been formally tested in a RCT.88 89 lenging endotype of the lupus spectrum. To this end, although
Contrary to GC and immunosuppressive drugs, HCQ should EULAR has published specific recommendations for the manage-
not be discontinued in patients with SLE in the absence of ment of APS in 2019,95 it was decided that the significance of
unacceptable side- effects; in addition to its multiple benefits SLE-APS merits a specific question for the SLR. Management
including survival,90 the SLR concluded that HCQ discontinua- of definite SLE-aPL/APS should follow the same principles of
tion is associated with increased risk for flares (data from obser- therapy as primary APS, including the long-term use of vitamin
vational studies).91–93 Additionally, HCQ therapy is a protective K antagonists in patients with unprovoked venous and those
factor against disease relapse in patients discontinuing GC or with arterial thrombotic events.95 After the first RCT on novel
immunosuppressive agents.86 94 Although complete discontinua- direct oral anticoagulants (DOACs) in APS (Trial of Rivaroxaban
tion is discouraged (with the exception of adverse effects), data in AntiPhospholipid Syndrome trial), based on which the 2019
on tapering/dose reduction are equivocal91 92; thus, a decision EULAR recommendations for the management of APS recom-
for HCQ dose reduction in patients in remission should be taken mended against their use in patients with triple aPL positivity
on an individualised basis. or prior arterial thrombosis, three additional RCTs compared
Recommendation
Figure 2 Treatment of lupus nephritis. Top-to-bottom sequence does not imply order of preference (similar to figure 1). #In addition to general
protective measures, as outlined in figure 1. §BEL should always be given in combination with MMF or low-dose CYC as initial therapy, and with
MMF or AZA as maintenance therapy. ˆCNIs should be given in combination with MMF. *Particularly recommended in the presence of poor prognostic
factors: reduced eGFR, histological presence of cellular crescents or fibrinoid necrosis, or severe interstitial inflammation. ¶Extension of high-dose
CYC to subsequent phase refers to severe LN cases, in which bimonthly or quarterly CYC pulses may be given following six monthly pulses. †In
relapsing/refractory disease, especially after failure to CYC-based regimens. ACEi, angiotensin-converting enzyme inhibitors; APS, antiphospholipid
syndrome; ARB, angiotensin receptor blockers; AZA, azathioprine; BEL, belimumab; CNI, calcineurin inhibitor; CYC, cyclophosphamide; eGFR, estimated
glomerular filtration rate; GC, glucocortocoids; HCQ, hydroxychloroquine; IV, intravenous; MMF, mycophenolate mofetil; MP, methylprednisolone;
PO, per os; RTX, rituximab; SGLT2i, sodium glucose transporter 2 inhibitors; TAC, tacrolimus; Upr, urine protein; VKA, vitamin K antagonists; VOC,
voclosporin.
vitamin K antagonists versus DOACs in patients with thrombotic patients with CAPS; more recently, the complement inhibitor
APS.95 A recent meta-analysis of these trials showed that DOAC eculizumab has shown promise, especially in patients with CAPS
use was associated with increased risk of subsequent arterial with features of complement-mediated TMA (microangiopathic
thrombotic events (OR: 5.43), especially stroke (OR: 10.74), haemolytic anaemia, thrombocytopenia, acute kidney injury). 100
and the composite of arterial or venous thrombotic events (OR: The 2019 EULAR recommendations for the management of APS
4.46).96 In patients who have not experienced a thrombotic event, stated that complement inhibitors or RTX may be considered
primary prophylaxis with low-dose aspirin should be considered in refractory CAPS. Agreement for this recommendation was
in those with a high risk aPL profile, defined as lupus antico- 96.4% and mean (SD) LoA was 9.57 (0.83).
agulant positivity, or double (any combination of lupus antico- 13. Immunisations for the prevention of infections (herpes
agulant, anticardiolipin antibodies or anti-beta2glycoprotein I zoster virus, human papillomavirus, influenza, COVID-19 and
antibodies) or triple aPL (all three aPL). Apart from its other pneumococcus), management of bone health, nephroprotection
beneficial effects, HCQ has also potential antithrombotic effects and cardiovascular risk, and screening for malignancies, should
and may reduce aPL levels,97 and is particularly recommended in be performed (5/D).
patients with SLE-aPL or SLE/APS.98 99 The final recommendation is a statement regarding major
Catastrophic APS (CAPS) is a rare complication of APS, with comorbidities in SLE, reflecting expert opinion based on the
concomitant or successive thrombosis in≥3 organs. Although evidence for the general benefit of the mentioned measures. As
a detailed overview of the therapeutic options for CAPS was on APS, EULAR has issued specific recommendations regarding
outside the scope of the SLR, several Task Force members deemed vaccinations101 and cardiovascular risk management102 in
it important to cover this issue in the manuscript text. High- patients with autoimmune rheumatic diseases, including SLE,
quality studies for the treatment of CAPS in SLE are lacking. and the reader is referred to the respective manuscripts for
Precipitating conditions (eg, infections) should be aggressively further details. In view of the COVID-19 pandemic and the
sought for and treated, to minimise the risk for the develop- burden of herpes zoster in patients with lupus,103 the current
ment of CAPS. Triple therapy with full anticoagulation, high- SLR included a research question regarding the efficacy and
dose GC and plasma exchange and/or IVIG is recommended for safety of vaccines against SARS-CoV-2 and herpes zoster virus
Recommendation
patients with LN,109 and its targeting seems reasonable. A prelim-
Box 1 Future research agenda in systemic lupus
inary study of dapagliflozin in a small number of patients with
erythematosus (SLE) SLE (18 with LN) found no difference in proteinuria following
therapy.110 Until more data are available, SGLT-2 inhibitors may
Existing therapies be considered in patients with LN with reduced GFR below
⇒ Utility of measurement of drug blood levels
60–90 mL/min or proteinuria more than 0.5–1 g/day, on top of
(hydroxychloroquine, mycophenolate, etc) ACE/ARBi during the maintenance phase. The final recommen-
⇒ Randomised trials testing different initial glucocorticoid doses
dation received 92.8% agreement and mean (SD) LoA was 9.85
and different tapering regimens
(0.36).
⇒ Optimal duration of therapy and timing of
immunosuppression discontinuation (both for renal and
extrarenal disease) DISCUSSION
⇒ Value of repeat kidney biopsy prior to immunosuppression For these recommendations, we assembled a Task Force of
discontinuation world-leading experts in the field of SLE from four continents,
⇒ Value of per-protocol repeat kidney biopsy after one year of to assure the widest possible representation and broad exper-
treatment to guide further treatment tise. This is particularly important, because SLE across the world
⇒ Prediction of flare in patients who taper drugs is very different in terms of presentation and severity. To this
⇒ Prediction of flare in patients who attain the treatment target end, the current set of recommendations sought to ensure a fair
⇒ Use of statins, low-dose aspirin and other conventional balance, and guarantee equal representation of mild, moderate
therapies to prevent cardiovascular disease and severe disease, the relative frequency of which may well vary
between different countries and continents.
Pathophysiology and biomarkers A major modification to the previous sets of EULAR recom-
⇒ Pre-SLE cohort initiatives to delineate who is at risk to mendations for SLE was the reduction of the number of indi-
develop SLE and what are the sequential ‘hits’ that lead to vidual recommendations. Indeed, to align with the EULAR SOPs
disease development but also streamline and simplify the recommendations and facili-
⇒ Involvement of particular organ systems over others, tate their dissemination, the Task Force managed to condense the
multisystem versus organ-dominant disease recommendations to 13 (with 5 overarching principles). Similar
⇒ Prediction of response to specific therapies (by clinical, to the 2019 version, the first recommendations (1–4) refer to
cellular and/or molecular markers) optimal use of commonly used drugs, recommendations 5–12
⇒ Biomarkers for response to different biological drugs deal with specific organ manifestations, and the final recommen-
(pharmacogenetics, transcriptomics, etc) dation covers the issue of adjunct treatments and comorbidities.
Regarding the use of individual drugs, the emphasis on a more
Clinical trial design and new drug development restricted use of GC evolved further from the 2019 recommen-
⇒ Optimisation of clinical trial design and study endpoints to dations. Thus, GC should be used only if needed, as for mild
maximise probability of new drug approval forms of SLE HCQ alone may suffice. A maximum recom-
⇒ Handling of background medication to avoid polypharmacy mended maintenance dose of 5 mg/day prednisone equivalent is
and ‘dilution’ of positive effects of drugs under study now recommended, stricter than the 7.5 mg/day in the previous
⇒ Inclusion of organ-specific endpoints and better and more recommendations. Of note, this change did not come in view
sensitive measurements of disease activity of new high-quality data or RCTs, although we found obser-
⇒ Increase in number of adequately trained trial sites vational studies linking mean prednisone doses 5 mg/day with
(recruitment, infrastructure and training) adverse sequelae. Nevertheless, there was unanimous agreement
⇒ Academia versus industry-driven clinical trials among Task Force members that a strong recommendation for
⇒ Evaluation and standardisation of patient-reported measures a lower dose of GC should be given in view of the detrimental
of disease activity/outcomes effects of their long-term use and the approval of new agents
with GC-sparing effects.
To avoid long-term exposure to GC, early use of immunosup-
(HZV) in lupus. Both the live attenuated and the more effica- pressive drugs is recommended in SLE. The sequence between
cious recombinant zoster vaccine have been used in patients conventional and biological drugs was a matter of extensive
with SLE and, although studies are limited, they are considered debate within the Task Force. Nevertheless, in 2019, it was
safe.104 105 Similarly, several observational studies have proven already stated that add-on treatment with belimumab (then the
the immunogenicity and safety of SARS-CoV-2 vaccines, which only approved biologic) ‘should be considered in patients not
are recommended for patients with SLE.106 Prompt identifica- responding to combinations of HCQ and GC with or without
tion and management of infections/sepsis are essential in SLE, immunosuppressive agents’. Thus, it was agreed that placing
and vigilant monitoring for opportunistic infections is warranted biological drugs (now, belimumab and anifrolumab) after failure
in selected patients receiving potent immunosuppressive drugs of conventional drugs would constitute a step backwards from
(eg, high-dose GC, CYC, RTX).107 In patients with LN, adjunct 2019. To this end, the current recommendations do not require
treatment with nephroprotective agents is of utmost importance prior failure to one or more conventional drugs before initi-
to decelerate nephron loss, in combination with immunosup- ating a biological agent, although for the majority cases it may
pressive therapy. Renin–angiotensin–aldosterone blockade is be prudent to try at least one conventional immunosuppressive.
required, unless not tolerated, to control hypertension (target Since 2019, anifrolumab was approved for the treatment
level below 130/80 mm Hg).108 More recently, novel classes of of extrarenal SLE in 2021. On the other hand, there is now
agents, mainly sodium glucose transport 2 (SGLT-2) inhibitors more than 10 years real-life experience with belimumab, with
(‘flozins’), have gained attention as kidney protective drugs for results confirming good control of disease activity, reduction
any case of CKD; SGLT-2 is expressed in kidney biopsies of of flares and halting of damage accrual.111 112 The two drugs
Recommendation
have a different mechanism of action and have not been directly Task Force that the developments in the treatment of SLE will
compared. Two indirect treatment comparison studies (each continue at such pace to mandate a new update of the EULAR
supported by each one of the manufacturing companies and recommendations within the next 3 years.
using a different patient database) reported conflicting results at
low levels of evidence and high risk of bias and, therefore, cannot Author affiliations
1
be interpreted as comparative efficacy studies.113 114 Thus, with Rheumatology and Clinical Immunology Unit, "Attikon" University Hospital,
National and Kapodistrian University of Athens, Athens, Greece
current evidence, the two drugs are recommended with no hier- 2
Lupus Europe, Copenhagen, Denmark
archy between them. Of note, both drugs seem to have better 3
Division of Rheumatology, Department of Medicine III, University Medical Center &
efficacy in serologically active patients at baseline, although this Faculty of Medicine Carl Gustav Carus at the TU Dresden, Dresden, Germany
4
should not limit their use to this subset of patients.115 116 Department of Rheumatology, Hôpitaux Universitaires de Strasbourg, INSERM
Undoubtedly, the most expected outcome of the current UMR-S 1109, Centre National de Référence des Maladies Auto-immunes
Systémiques Rares (RESO), Strasbourg, France
update was the verdict regarding the positioning of belimumab 5
Department of Rheumatology, Hanyang University Hospital for Rheumatic Diseases,
and voclosporin in the treatment of LN. The rationale behind Hanyang University Institute for Rheumatology Research and Hanyang Institute of
the phrasing that early combination therapy with either beli- Bioscience and Biotechnology, Seoul, South Korea
6
mumab or a CNI ‘should be considered’ reflects the fact that Department of Nephrology and Renal Transplantation Unit, "Laiko" General
Hospital, Medical School, National and Kapodistrian University of Athens, Athens,
worldwide treatment recommendations for SLE should take into Greece
account different patient characteristics, but also variable access 7
Centre for Epidemiology Versus Arthritis, University of Manchester, Manchester,
to drugs in high-income versus low-income countries. If an early UK; National Institute for Health Research Manchester Biomedical Research Centre,
combination therapy is chosen, specific patient characteristics Manchester University Hospitals NHS Foundation Trust, Manchester Academic Health
may favour belimumab over a CNI or vice versa, for instance, Science Centre, Manchester, UK
8
Department of Autoimmune Diseases, Hospital Clinic, Barcelona, Spain
the presence of extrarenal disease activity for belimumab, or 9
Rheumatology Unit, Department of Medicine, University of Padova, Padova, Italy
nephrotic-range proteinuria for CNI. Importantly, an update of 10
Department of Rheumatology and Clinical Immunology, Charite
dedicated EULAR recommendations for the management of LN Universitätsmedizin Berlin; Deutsches Rheumaforschungszentrum, Berlin,
is currently being scheduled. Germany
11
Division of Rheumatology, Northwell Health, Great Neck, New York City, New York,
Patients with SLE experience a wide variety of symptoms,
USA
which extend beyond the classical manifestations that require 12
Lupus Program, Centre for Prognosis Studies in the Rheumatic Disease, Schroeder
immunosuppressive therapy. Indeed, symptoms such as Arthritis Institute, Krembil Research Institute, Toronto Western Hospital, University of
fatigue, non-inflammatory pain, mood disturbance and cogni- Toronto, Toronto, Ontario, Canada
13
tive dysfunction are among the ones most frequently referred Service de Rhumatologie, Cliniques Universitaires Saint-Luc and Institut de
Recherche Expérimentale et Clinique, Université catholique de Louvain, Brussels,
and valued by patients. A recently proposed system catego- Belgium
rised symptoms of SLE in two types: the typical inflammatory 14
Department of Rheumatology, Centro Hospitalar e Universitario de Coimbra,
symptoms (‘type 1’) requiring immunosuppression, and symp- Coimbra, Portugal; School of Health Sciences, Universidade da Beira Interior, Covilha,
toms such as those mentioned above (‘type 2’), which do not Portugal
15
Department of Medicine, University of Cambridge, Cambridge, UK
respond to immunosuppressive therapy, yet often dominate 16
Cyprus League Against Rheumatism, Aglantzia, Cyprus
patient-reported outcomes.117 We acknowledge that the current 17
Department of Rheumatology and Immunology, Faculty of Medicine, University of
recommendations mainly address classic inflammatory SLE Szeged, Hungary
18
manifestations, in part because the Task Force felt that the data 19
Department of Medicine, Tuen Mun Hospital, Hong Kong, China
on type 2 symptoms are not so robust to justify specific manage- Centre for Inflammatory Diseases, School of Clinical Sciences, Monash University,
Melbourne, Victoria, Australia
ment recommendations. Nevertheless, a holistic care of patients 20
Department of Biomedical Sciences Humanitas University, Nephrology and Dialysis
with SLE should value and address all symptoms mentioned by Division, IRCCS Humanitas Research Hospital, Milan, Italy
patients, both those requiring immunosuppressive therapy, as 21
Rheumatology Unit, Department of Clinical and Experimental Medicine, University
well as those in need of complimentary approaches.118 of Pisa, Pisa, Italy
22
Department of Rheumatology & Hiller Research Unit Rheumatology, UKD, Heinrich-
A crucial point pertaining to any set of management recom-
Heine University, Düsseldorf, Germany
mendations is their implementation in real-life clinical practice, 23
Vasculitis Service, Rheumatology Department, Norfolk and Norwich University
often not self-explanatory because recommendations by defi- Hospitals NHS Foundation Trust, Norwich, UK
24
nition cannot capture all aspects of everyday clinical practice. 25
Hospital of the Hospitaller Order of Saint John of God, Budapest, Hungary
To tackle this need, the EULAR SOPs suggest the definition of Department of Rheumatology and Clinical Immunology, Department of Internal
Medicine and Oncology, Semmelweis University, Budapest, Hungary
quality indicators in tabular form, at least for the most relevant 26
Heart and Vascular Center, Semmelweis University, Budapest, Hungary
recommendations, to serve as a checklist for treating physicians 27
Section of Rheumatology, Department of Medicine, University of Santo Tomas,
and facilitate rate of adherence after a reasonable period of time, Manila, Philippines
28
Importantly, following the issue of the 2019 EULAR recommen- Division of Rheumatology, Department of Medicine Solna, Karolinska Institutet,
dations for the management of SLE, such a set of quality indi- Stockholm, Sweden
29
Department of Gastroenterology, Dermatology and Rheumatology, Karolinska
cators was published,119 and subsequently tested independently University Hospital, Stockholm, Sweden
in relation to quality of life of patients.120 A similar initiative for 30
Department of Rheumatology, Faculty of Medicine and Health, Örebro University,
the current recommendations would be valuable for their wider Örebro, Sweden
31
dissemination and implementation. Rheumatology Department, Complejo Hospitalario Universitario de Vigo, IRIDIS
(Investigation in Rheumatology and Immune-Mediated Diseases) - VIGO Group,
In conclusion, the 2023 recommendations for the manage- Galicia Sur Health Research Institute, Vigo, Spain
ment of SLE provide current state- of-
the-
art guidance for 32
Division of Rheumatology, Department of Medicine, Johns Hopkins University
treating physicians around the world. Further issues for the School of Medicine, Baltimore, Maryland, USA
33
future research agenda in SLE are shown in box 1. This updated Grupo Oroño, Centro Regional de Enfermedades Autoinmunes y Reumáticas (GO-
version will inform rheumatologists and nephrologists, health CREAR), Rosario, Argentina
34
Division of Rheumatology, Department of Medicine 3, Medical University of Vienna,
professionals, patients, regulators, payers and other stakeholders Vienna, Austria
on the way modern treatment of SLE is perceived from experts 35
First Department of Internal Medicine, School of Medicine, University of
in the field spanning four continents. It is the hope of this Occupational and Environmental Health, Kitakyushu, Japan

Recommendation
36
Rheumatology Unit, First Department of Propaedeutic Internal Medicine, “Laiko” Zeneca, GSK, Janssen, Novartis, Otsuka, Roche, participation in advisory boards from
General Hospital, Medical School, National and Kapodistrian University of Athens, Astra Zeneca, GSK, Novartis, Otsuka, medical writing from Astra Zeneca, GSK. JMPR
Joint Academic Rheumatology Program, Athens, Greece reports grants from GSK, Pfizer, honoraria fees from GSK, Astra Zeneca, Lilly, support
37
Centre of Expertise for Lupus-, Vasculitis- and Complement-mediated Systemic for attending meetings from GSK, Astra Zeneca, participation in advisory boards from
autoimmune diseases, Department of Internal Medicine – section Nephrology, Leiden GSK, Otsuka, Gebro, Astra Zeneca, Boehringer-Ingelheim, MSD. BAPE reports grants
University Medical Center, Leiden, The Netherlands from Janssen, support for attending meetings from Astra Zeneca, participation in
38
Rheumatology and Clinical Immunology, Department of Clinical and Experimental advisory boards from Astra Zeneca, GSK. MS reports grants from GSK, Astra Zeneca,
Sciences, ASST Spedali Civili and University of Brescia, Brescia, Italy honoraria and/or consulting fees from Astra Zeneca, GSK, Otsuka, UCB, participation
39
Leeds Institute of Rheumatic and Musculoskeletal Medicine, University of Leeds, in advisory boards from GSK. JSS reports grants from AbbVie, Astra Zeneca, Lilly,
Leeds, UK Galapagos, royalties or licenses from Elsevier, honoraria and/or consulting fees from
40
Department of Rheumatology and Clinical Immunology, Amsterdam University AbbVie, Galapagos/Gilead, Novartis, BMS, Samsung, Sanofi, Chugai, R-Pharma,
Medical Centers, Amsterdam, The Netherlands Lilly, MSD, Janssen, participation in advisory boards from Astra Zeneca. ES reports
41
Department of Rheumatology, King’s College Hospital, London, UK stocks in Astra Zeneca. YKOT reports grants from Mitsubishi-Tanabe, Eisai, Chugai,
42
Rheumatology, Clinical Immunology and Allergy, University Hospital of Heraklion, Taisho, consulting fees from Lilly, Astra Zeneca, AbbVie, Gilead, Chugai, Boehringer-
Greece, University Hospital of Heraklion, Heraklion, Greece Ingelheim, GSK, Eisai, Taisho, BMS, Pfizer, Taiho. MGT reports grants from Genesis,
43
Laboratory of Autoimmunity and Inflammation, Biomedical Research Foundation of GSK, MSD, UCB, consulting fees from GSK, Lilly and UCB. CW reports grants from
the Academy of Athens, Athens, Greece Versus Arthritis, British Society for Rheumatology, Lupus UK, honoraria fees from
44
Joint Academic Rheumatology Program, Medical School, National and Kapodistrian UCB, support for attending meetings from AbbVie. AT reports honoraria fees from
University of Athens, Greece, Medical School, University of Cyprus, Nicosia, Cyprus UCB, GSK, participation in advisory boards from UCB, Galapagos. GB reports grants
Twitter Chetan B Mukhtyar @cmukhtyar, Edward M Vital @edvital, Chris Wincup @ from GSK, Astra Zeneca, Pfizer, honoraria and/or consulting fees from Lilly, Aenorasis,
chriswincup, George Bertsias @george_bertsias and Dimitrios T Boumpas @none Novartis, AstraZeneca, GSK, SOBI, Pfizer, participation in advisory boards from
Novartis. DTB reports unrestricted investigational grants from GSK, honoraria and/
Acknowledgements The committee wishes to acknowledge the support of the or consulting fees from GSK, Astra-Zeneca, Pfizer. The remaining authors declare no
EULAR Standing Committee on Clinical Affairs. The committee also expresses its conflict of interest.
sincere appreciation and gratitude to the EULAR Secretariat, especially Simona
Lupatin, executive assistant, and to Dora Togia for the outstanding organisation and Patient consent for publication Not applicable.
coordination. Ethics approval Not applicable.
Contributors AF and MK reviewed the literature and AF drafted the manuscript. Provenance and peer review Not commissioned; externally peer reviewed.
GB and CBM supervised the methodology. All authors edited the manuscript. DTB
Supplemental material This content has been supplied by the author(s). It
supervised the project.
has not been vetted by BMJ Publishing Group Limited (BMJ) and may not have
Funding European League against Rheumatism (project number QoC015). been peer-reviewed. Any opinions or recommendations discussed are solely those
Competing interests AF reports honoraria and/or consulting fees from Lilly, of the author(s) and are not endorsed by BMJ. BMJ disclaims all liability and
Boehringer, Novartis, Abbvie, Astra Zeneca, GSK, MSD, Pfizer, UCB, Amgen, Aenorasis, responsibility arising from any reliance placed on the content. Where the content
support for attending meetings from UCB. MK reports honoraria and/or consulting includes any translated material, BMJ does not warrant the accuracy and reliability
fees from GSK, participation in advisory boards from GSK, Astra Zeneca, Amgen. JA of the translations (including but not limited to local regulations, clinical guidelines,
reports honoraria and/or consulting fees from Novartis, Astra Zeneca, support for terminology, drug names and drug dosages), and is not responsible for any error
attending meetings from Novartis, Astra-Zeneca, participation in advisory boards and/or omissions arising from translation and adaptation or otherwise.
from Roche, Astra-Zeneca (all paid to Lupus Europe). MA reports honoraria and/
ORCID iDs
or consulting fees from AbbVie, Astra Zeneca, GSK, Otsuka, Roche, support for
Antonis Fanouriakis http://orcid.org/0000-0003-2696-031X
attending meetings from Pfizer. LA reports grants from GSK, honoraria and/or
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EFM reports grants from AbbVie, Amgen, AstraZeneca, Biogen, Bristol Myers Squibb,
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and/or consulting fees from Astra Zeneca, Eli Lilly, GSK, UCB, Janssen, participation George Bertsias http://orcid.org/0000-0001-5299-1406
in advisory boards from Idorsia. JM reports grants from GSK, honoraria and/or Dimitrios T Boumpas http://orcid.org/0000-0002-9812-4671
consulting fees from GSK, Astra Zeneca, Otsuka, BMS, participation in advisory
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Handling editor David S ABSTRACT be considered. Updated specific recommendations

Μean (SD) % with score ≥8

Fanouriakis A, et al. Ann Rheum Dis 2023;0:1–15. doi:10.1136/ard-2023-224762 11

12 Fanouriakis A, et al. Ann Rheum Dis 2023;0:1–15. doi:10.1136/ard-2023-224762

Fanouriakis A, et al. Ann Rheum Dis 2023;0:1–15. doi:10.1136/ard-2023-224762 13

14 Fanouriakis A, et al. Ann Rheum Dis 2023;0:1–15. doi:10.1136/ard-2023-224762

Fanouriakis A, et al. Ann Rheum Dis 2023;0:1–15. doi:10.1136/ard-2023-224762 15

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