Review

ERN ReCONNET–SLICC–SLEuro expert consensus on the

therapeutic management of rare systemic lupus
erythematosus manifestations
Laurent Arnaud, Guillermo Ruiz-Irastorza, Cynthia Aranow, Sasha Bernatsky, Maria Dall’Era, Olufemi Adelowo, Sang-Cheol Bae, Lorenzo Beretta,
Eloisa Bonfa, Ricard Cervera, François Chasset, Ann E Clarke, Nathalie Costedoat-Chalumeau, Andrea Doria, Gerard Espinosa, Antonis Fanouriakis,
Micaela Fredi, Mariele Gatto, Dafna D Gladman, José A Gomez-Puerta, Murat Inanç, Luís S Ines, David Isenberg, Shinji Izuka, Nikita Khmelinskii,
Alexandra Legge, Carla Macieira, Odirlei Andre Monticielo, Eric F Morand, Roberto Muñoz-Louis, Ivan Padjen, Michelle Petri, Matteo Piga,
Bernardo A Pons-Estel, Giuseppe A Ramirez, Rosalind Ramsey-Goldman, Christophe Richez, Savino Sciascia, Carlos Enrique Toro-Gutierrez,
Ronald F Van Vollenhoven, Edward M Vital, Maria Gerosa, Zahi Touma, Marta Mosca, Chiara Tani, for the European Reference Network on Rare
and Complex Connective Tissue and Musculoskeletal Diseases, the Systemic Lupus Erythematosus International Collaborating Clinics group, and
the European Lupus Society rare systemic lupus erythematosus taskforce member panel*

Existing guidelines for systemic lupus erythematosus (SLE) predominantly focus on common and major organ Lancet Rheumatol 2025
involvements. An international taskforce involving experts from three SLE expert groups (ie, the European Reference Published Online
Network on Rare and Complex Connective Tissue and Musculoskeletal Diseases, the Systemic Lupus Erythematosus May 23, 2025
https://doi.org/10.1016/
International Collaborating Clinics group, and the European Lupus Society) was established. A total of 119 participants
S2665-9913(25)00063-3
contributed to the development of consensus therapeutic strategies for 24 rare SLE manifestations, using a multistep
*Members of the European
process. For SLE enteritis and pancreatitis, experts recommended hydroxychloroquine, glucocorticoids, and Reference Network on Rare and
cyclophosphamide or mycophenolate mofetil. Rare lung conditions such as pneumonitis were also managed with Complex Connective Tissue and
cyclophosphamide if severe or with mycophenolate mofetil if not severe. SLE for myocarditis with hydroxychloroquine, Musculoskeletal Diseases, the
Systemic Lupus Erythematosus
gluco­corticoids, and cyclophosphamide or mycophenolate mofetil, are recommended based on severity. For CNS
International Collaborating
manifestations, hydroxychloroquine, glucocorticoids, and cyclophosphamide or mycophenolate mofetil were Clinics group, and the European
common choices for treatment. For rare skin manifestations, the preferred strategy was a combination of Lupus Society rare systemic
hydroxychloroquine and glucocorticoids with anifrolumab or mycophenolate mofetil. This expert-based consensus lupus erythematosus taskforce
are listed in the appendix
provides a valuable framework for guiding therapeutic decisions where the available recommendations might be
(pp 29–31)
insufficient or inapplicable.
Department of Rheumatology,
National Reference Center for
Introduction dependent on variable methodologies or single reports, Autoimmune Diseases (RESO),
Systemic lupus erythematosus (SLE) is a systemic and were instrumental in shaping our under­standing of INSERM UMR-S 1109,
Strasbourg, France
autoimmune disease characterised by considerable the scarce evidence available. Since this systematic
(Prof L Arnaud MD PhD);
clinical heterogeneity ranging from mild articular or review, no other additional consensus document or high- Biobizkaia Health Research
cutaneous manifestations to potentially life-threatening level evidence has been published in the field of rare SLE Institute, University of the
systemic complications.1 Although several international manifestations. Altogether, these findings underscored Basque Country, Barakaldo,
Spain
guidelines exist for the therapeutic management of the crucial need for a comple­mentary methodology, such
(Prof G Ruiz-Irastorza MD PhD);
SLE,2,3 their focus is mainly on major organ involvement as expert consensus, to develop meaningful Department of Medicine and of
and more common disease manifestations. A major gap recommendations where evidence alone is insufficient. Molecular Medicine at the
remains in the therapeutic management of the rare With this global and collective expertise of three SLE Feinstein Institute for Medical
Research, Hofstra School of
manifestations of SLE.4,5 Due to their rarity and the networks, we developed expert consensus strategies for Medicine, New York, NY, USA
general lack of evidence-based data on how to treat them, the therapeutic management of rare SLE manifestations. (Prof C Aranow MD PhD);
these rare SLE manifestations pose unique treatment This international collaboration provides guidance to Department of rheumatology,
challenges.6 improve the care and outcomes for these challenging Centre for Health Outcomes
Research and Division of
Our objective was to establish an international features of SLE. Clinical Epidemiology at the
consensus on therapeutic strategies for rare SLE Research Institute of the
manifestations. To achieve this, we brought together Methods MUHC, Montreal, QC, Canada
three international networks: the European Reference Participants (Prof S Bernatsky MD PhD);
Division of Rheumatology,
Network on Rare and Complex Connective Tissue and This ad hoc taskforce was headed by a convenor (LA) an University of California,
Musculoskeletal Diseases (ERN ReCONNET), the international steering committee of eight SLE experts San Francisco, CA, USA
Systemic Lupus International Collaborating Clinics (LA, GR-I, CA, SB, MD’E, ZT, MM, and CT) while the (Prof M Dall’Era MD);
(SLICC) group and the European Lupus Society (SLEuro) working group included members of three international Rheumatology Unit,
Department of Medicine Lagos
expert Group. The question of rare SLE manifestations SLE networks: the ERN ReCONNET (LA, GR-I, LB, RC, State University Teaching
was systematically reviewed within the ReCONNET AD, MF, NK, CM, OAM, GAR, CR, SS, MGe, MM, and Hospital, Lagos, Nigeria
network.5 The findings from this systematic review CT, via its SLE disease group), the SLICC group (LA, (Prof O Adelowo MD MACR);
highlighted the major gaps in high-quality evidence GR-I, SB, MD’E, S-CB, EB, AEC, NC-C, AD, DDG, MI, Department of Rheumatology,
Hanyang University Hospital
regarding rare SLE manifestations, with many findings DI, AL, MPe, BAP-E, RR-G, RFVV, and MM), and

www.thelancet.com/rheumatology Published online May 23, 2025 https://doi.org/10.1016/S2665-9913(25)00063-3 1

 Review

for Rheumatic Diseases, SLEuro (LA, NC-C, AD, MGa, LSI, and EMV). Most those reported during step 1; and during step 3,
Hanyang University Institute participants were rheumatologists, but the taskforce participants who had previously encountered one or
for Rheumatology Research
and Hanyang Institute of
also included participants from internal medicine, more of the included rare mani­festations were asked to
Bioscience and Biotechnology, nephrology, and dermatology. Experts in these networks submit therapeutic strategy proposals for these
Seoul, South Korea are renowned for their expertise and active participation manifestations using a systematic template. During
(Prof S-C Bae MD PhD); Referral in patient cohorts, ensuring that the suggested strategies step 4, participants were invited to review and rank the
Center for Systemic
Autoimmune Diseases
are based on real-life clinical experiences. Additionally, most relevant therapeutic strategies, for each rare
Fondazione IRCCS Ca’ Granda a select number of additional experts from diverse manifestation, according to severity.
Ospedale Maggiore Policlinico geographical origins (eg, OA from Africa, FC
di Milano, Milan, Italy [dermatology expert] from Europe, SI from Asia, OAM Statistical analysis
(L Beretta MD); Rheumatology
Division, Hospital das Clinicas
and CET-G from Latin America, and RM-L from the Descriptive statistics, including the number and
HCFMUSP, Faculdade de Carribean), and backgrounds were invited to join the percentage of responders, and median (IQR) values
Medicina, Universidade de Sao taskforce as a way to further enhance the diversity, were assessed. Interaction with participants was by
Paulo, Sao Paulo, Brazil generalisability, and applicability of the therapeutic email and using the Limesurvey online survey tool. For
(Prof E Bonfa MD PhD);
Department of Rheumatology,
strategies across different health-care settings and each rare manifestation, participants were asked to rate
Hospital Clínic, Universitat de populations, thereby strengthening the overall validity on a 0–10 scale the confidence that they had picked the
Barcelona, Barcelona, Catalonia, and relevance of the consensus statement. Each best therapeutic strategy for this manifestation.
Spain (Prof R Cervera MD PhD,
member of the taskforce provided informed consent Confidence of the selected option(s) was calculated
G Espinosa MD PhD,
J A Gomez-Puerta MD PhD); before participating in the study. taking into account only those who had participated in
Institut d’Investigacions the ranking for each manifestation. Statistical analysis
Biomèdiques August Pi i Sunyer Overview of the multistep expert-based consensus was performed using JMP v13.0 software (SAS Institute,
(IDIBAPS), Barcelona, Catalonia,
process USA).
Spain (Prof R Cervera, G Espinosa,
J A Gomez-Puerta); Sorbonne This taskforce consensus on therapeutic strategies for
Université, Faculté de rare SLE manifestations was achieved by a four-step Results
médecine, Assistance Publique- process (appendix pp 2–4). Briefly, during step 1, A total of 119 participants (55 [46%] women and 64 [54%]
Hôpitaux de Paris (AP-HP),
participants were asked to list rare SLE manifestations men) were involved in various steps of this taskforce. Of
Service de Dermatologie et
Allergologie, Hôpital Tenon, for potential inclusion; during step 2, participants were these participants, 61 were ERN ReCONNET members,
and CIMI, INSERM U1135 Paris, asked to select rare manifestations to be included from 33 were from SLICC, 11 from SLEuro and 22 from other
France (F Chasset MD PhD); backgrounds included for diversity of expertise (total
Division of Rheumatology,
>100% as some participants belong to multiple groups).
Cumming School of Medicine, Step 1
University of Calgary, Calgary, 658 proposals for rare SLE manifestations During step 1, 77 experts contributed by submitting a
submitted* by 77 participants
AB, Canada (A E Clarke MD MSc); total of 658 proposals for rare SLE manifestations
Service de Médecine Interne, (figure 1). Following removal of duplicates and arbitration
Centre de Référence des
Maladies Auto-immunes et 613 proposals excluded by the steering committee, 45 unique rare SLE
Auto-inflammatoires 518 duplicates manifestations were selected to be voted upon during
59 non-specific manifestations or concepts
Systémiques Rares d’Ile-de-
25 other diseases (eg, APS) or overlaps
phase 2 (appendix pp 6–18).
France, de l’Est et de l’Ouest, 8 non-rare manifestations During step 2, 86 participants were selected and
Hôpital Cochin, AP-HP and 2 neonatal lupus
INSERM, Équipe ECAMO, CRESS
21 (47%) of the 45 manifestations (figure 1, appendix p 5)
1 side-effect of treatment
(Centre of Research in were included in the following steps. Following additional
Epidemiology and Statistics), discussions with the steering committee, the lupus
UMR 1153, Université Paris Step 2
45 rare SLE manifestations assessed for vasculitis category was split into skin, CNS, and systemic
Cité, Paris, France inclusion by 86 participants
(Prof N Costedoat-Chalumeau
lupus vasculitis. Similarly, lupus neuropathy was split
MD PhD); Rheumatology Unit, into lupus polyneuropathy, demyelinating neuropathy,
Department of Medicine,
21 rare SLE manifestations included in
mononeuritis multiplex, and autonomic neuropathy
University of Padua, Padua, the consensus subcategories.
Italy (Prof A Doria MD);
Rheumatology and Clinical
For step 3, a total of 234 potential therapeutic strategies
Immunology, Attikon Step 3 were submitted by 64 participants for the rare SLE
234 potential therapeutic strategies
University Hospital, National
submitted by 64 participants
manifestations selected during step 2 (figure 1). This step
Kapodistrian University of yielded 152 unique therapeutic strategies after removal of
Athens Medical School, Athens,
Greece (Prof A Fanouriakis PhD);
duplicates (appendix pp 6–18). The number of strategies
Step 4
Rheumatology and Clinical Ranking of the most relevant therapeutic submitted ranged from one for autonomic neuropathy to
strategies by 101 participants
Immunology Unit, ASST 16 for macrophage activation syndrome. The median
Spedali Civili of Brescia and
confidence level of experts that they had submitted the
Department of Clinical and Figure 1: Flow chart of the consensus process
Experimental Sciences, best strategy for treating each of these rare SLE
The four steps of the expert consensus for rare SLE manifestations and the
University of Brescia, Brescia, corresponding number of participants and manifestations at each stage.
manifestations was 8 (IQR 7–9) on the 0–10 scale.
Italy (M Fredi MD PhD); APS=antiphospholipid syndrome. SLE=systemic lupus erythematosus. During step 4, 101 participants ranked up to
Academic Rheumatology *Including duplicates. five therapeutic strategies from those submitted during

2 www.thelancet.com/rheumatology Published online May 23, 2025 https://doi.org/10.1016/S2665-9913(25)00063-3

 Review

Strategies for severe presentation of each manifestation Strategies for non-severe presentation of each
manifestation
Best suggested strategy* Number of Best suggested strategy* Number of
voters ranking voters ranking
this strategy this strategy
as first step as first step
(n/n, %) (n/n, %)
Aplastic anaemia (myelofibrosis)
Ranking among seven strategies; participants: severe mPred then Pred (0·5–1 mg/kg/day, if possible 30/78 (38%) mPred then Pred (0·5–1 mg/kg/day, if 15/31 (48%)
(n=78), non-severe (n=31); confidence: 5 (range 3–7) tapered over 6 months) plus RTX (with or possible tapered over 6 months) plus
without MMF) MMF
Interstitial lung disease (NSIP)
Ranking among seven strategies; participants: severe With or without mPred plus Pred 34/83 (41%) With or without mPred plus Pred 48/58 (83%)
(n=83), non-severe (n=58); confidence: 7 (range 6–8) (0·5–1 mg/kg/day, if possible tapered over a (0·5–1 mg/kg/day, if possible tapered over
maximum of 6 months) plus MMF a maximum of 6 months) and MMF
Libman–sacks
Ranking among four strategies; participants: severe (n=82), Pred (40–60 mg/day) with MMF plus 26/82 (32%) Low-dose aspirin (valvular thickening) or 22/45 (49%)
non-severe (n=45); confidence: 7 (range 5–8) anticoagulation (warfarin) anticoagulation (valve nodule or
vegetation)
Lupus enteritis
Ranking among four strategies; participants: severe (n=85), mPred then Pred (0·5 mg/kg/day, if possible 34/85 (40%) Pred (0·5–1 mg/kg/day) plus MMF 27/37 (73%)
non-severe (n=37); confidence: 7 (range 5–8) tapered over 6 months to 5 mg/day) with CYC 2–3 g/day
(EuroLupus) then MMF
Lupus meningitis
Ranking among four strategies; participants: severe (n=83), mPred then Pred (0·25–0·5 mg/kg/day if possible 27/83 (33%) mPred with Pred (0·5–1 mg/kg/day) plus 19/30 (63%)
non-severe (n=30); confidence: 6 (range 5–8) tapered to ≤5 mg/day) plus CYC (EuroLupus) then MMF (or AZA)
maintenance with MMF or AZA
Lupus pancreatitis
Ranking among four strategies; participants: severe (n=79), With or without mPred then Pred 33/79 (42%) With or without mPred plus Pred 24/38 (63%)
non-severe (n=38); confidence: 5 (range 3–7) (0·25–0·5 mg/kg/day, tapered) plus CYC (0·5–1 mg/kg/day, tapered) and MMF
(Eurolupus) then maintenance with MMF or AZA
Lupus panniculitis
Ranking among 12 strategies; participants: severe (n=80), With or without mPred with Pred 17/80 (21%) Pred (0·25–0·5 mg/kg/day) with MTX 16/52 (31%)
non-severe (n=52); confidence: 6 (range 5–7·75) (0·25–0·5 mg/kg/day) plus anifrolumab (with or
without MTX, MMF, or AZA)
Lupus pneumonitis (acute)
Ranking among six strategies; participants: severe (n=82), mPred then Pred (1 mg/kg/day, if possible tapered 28/82 (34%) mPred with Pred (0·5–1 mg/kg/day) plus 27/32 (84%)
non-severe (n=32); confidence: 7 (range 5–8) over a maximum of 6 months) plus CYC MMF or AZA
(EuroLupus) then maintenance with MMF or AZA
Lupus psychosis
Ranking among eight strategies; participants: severe (n=84), With or without mPred plus Pred (0·5–1 mg/kg) 17/84 (20%) mPred with Pred (0·5–1 mg/kg)† 7/31 (23%)
non-severe (n=31); confidence: 7 (range 5–8) and CYC (NIH)† or with or without mPred plus
Pred (0·5–1 mg/kg) and CYC (EuroLupus) then
MMF or AZA
Skin vasculitis
Ranking among 13 strategies; participants: severe (n=81), With or without mPred plus Pred 15/81 (19%) With or without mPred plus Pred 17/55 (31%)
non-severe (n=55); confidence: 7 (range 6–8) (0·5–1 mg/kg/day) and MMF (0·25–0·5 mg/kg/day)
CNS vasculitis
Ranking among six strategies; participants: severe (n=85), mPred then Pred (0·5–1 mg/kg/day if possible 39/85 (46%) mPred then Pred (0·5–1 mg/kg/day if 7/22 (32%)
non-severe (n=22); confidence: 7 (range 5–8) tapered over a maximum of 6 months) with CYC possible tapered over a maximum of
(NIH) 6 months) plus MMF (or AZA)
Systemic lupus vasculitis
Ranking among six strategies; participants: severe (n=84), mPred then Pred (0·5–1 mg/kg/day if possible 29/84 (35%) mPred then Pred (0·5–1 mg/kg/day if 17/27 (63%)
non-severe (n=27); confidence: 6 (range 5–8) tapered over a maximum of 6 months) with CYC possible tapered over a maximum of
(NIH) 6 months) plus MMF (or AZA)
Retinal vasculitis
Ranking among three strategies; participants: severe (n=79), mPred then Pred (0·5–1 mg/kg/day if possible 42/79 (53%) mPred then Pred (0·5–1 mg/kg/day if 19/28 (68%)
non-severe (n=28); confidence: 6 (range 5–8) tapered over a maximum of 6 months) with CYC possible tapered over a maximum of
(EuroLupus) then MMF 6 months) plus MMF
Macrophage activation syndrome
Ranking among 16 strategies; participants: severe (n=82), mPred with Pred (0·5–1 mg/kg/day) and anakinra 16/82 (20%) mPred with Pred (0·5–1 mg/kg/day) plus 7/26 (27%)
non-severe (n=26); confidence: 6 (range 5–7) plus cyclosporine or tacrolimus MMF
(Table continues on next page)

www.thelancet.com/rheumatology Published online May 23, 2025 https://doi.org/10.1016/S2665-9913(25)00063-3 3

 Review

Strategies for severe presentation of each manifestation Strategies for non-severe presentation of each
manifestation
Best suggested strategy* Number of Best suggested strategy* Number of
voters ranking voters ranking
this strategy this strategy
as first step as first step
(n/n, %) (n/n, %)
(Continued from previous page)
Transverse myelitis
Ranking among eight strategies; participants: severe (n=81), mPred then Pred (0·5–1 mg/kg/day if possible 17/81 (21%) mPred then Pred (0·5–1 mg/kg/day if 7/20 (35%)
non-severe (n=20); confidence: 6 (range 5–8) tapered over 12 months) plus RTX then possible tapered over 12 months) plus
maintenance with MMF RTX then maintenance with MMF
Lupus myocarditis
Ranking among ten strategies; participants: severe (n=84), mPred then Pred (1 mg/kg, if possible tapered 28/84 (33%) Pred (0·5 mg/kg, if possible tapered over a 18/31 (58%)
non-severe (n=31); confidence: 7 (range 6–8) over a maximum of 6 months) plus CYC maximum of 6 months) plus MMF
(EuroLupus) then maintenance with MMF
Organic brain syndrome
Ranking among four strategies; participants: severe (n=81), mPred then Pred (0·5–1 mg/kg/day, if possible 31/81 (38%) mPred then pred (0·5–1 mg/kg/day) plus 14/24 (58%)
non-severe (n=24); confidence: 6 (range 4–7) tapered over a maximum of 6 months) plus CYC MMF (or AZA)
intravenously (EuroLupus) then maintenance
with MMF
Pulmonary arterial hypertension
Ranking among four strategies; participants: severe (n=82), With or without mPred then Pred 40/82 (49%) With or without mPred then Pred 25/33 (76%)
non-severe (n=33); confidence: 7 (range 5–8) (0·5–1 mg/kg/day, if possible tapered over a (0·5–1 mg/kg/day, if possible tapered over
maximum of 6 months) plus MMF and addition a maximum of 6 months) plus MMF with
of pulmonary arterial hypertension-specific drugs, addition of pulmonary arterial
as indicated hypertension-specific drugs, as indicated
Seizures
Ranking among four strategies; participants: severe (n=80), With or without mPred plus Pred 52/80 (65%) With or without mPred plus Pred 15/24 (63%)
non-severe (n=24); confidence: 7 (range 5–8) (0·5–1 mg/kg/day, tapered) and CYC (EuroLupus) (0·5–1 mg/kg/day, tapered) and MMF (or
then maintenance with MMF (or AZA) with anti- AZA) with anti-seizure medications
seizure medications
Shrinking lung syndrome
Ranking among four strategies; participants: severe (n=78), With or without mPred then Pred (1 mg/kg/day, if 38/78 (49%) Pred (0·5 mg/kg/day, tapered) plus MMF 22/35 (63%)
non-severe (n=35); confidence: 5 (range 3–7) possible tapered over 4–6 months) plus CYC (or AZA)
(Eurolupus) then MMF (or AZA)
Demyelinating neuropathy
Ranking among five strategies; participants: severe (n=79), mPred with or without Pred (0·5–1 mg/kg/day) 29/79 (37%) mPred with or without Pred 9/19 (47%)
non-severe (n=19); confidence: 6 (range 3–7) plus IVIG monthly for 6 months then progressive (0·5–1 mg/kg/day) plus IVIG monthly for
spacing of infusion to discontinuation (if 6 months then progressive spacing of
possible) infusion, to discontinuation (if possible)
Polyneuropathy
Ranking among three strategies; participants: severe (n=75), mPred then Pred (1 mg/kg/day, if possible tapered 32/75 (43%) mPred then Pred (1 mg/kg/day, if possible 12/30 (40%)
non-severe (n=30); confidence: 6 (range 4–7) over a maximum of 6 months) plus RTX tapered over a maximum of 6 months)
Mononeuropathy multiplex
Ranking among five strategies; participants: severe (n=83), mPred then Pred (0·5–1 mg/kg/day) plus CYC 39/83 (47%) mPred then Pred (0·5–1 mg/kg/day) plus 11/23 (48%)
non-severe (n=23); confidence: 6 (range 5–8) (EuroLupus) then maintenance with MMF MMF
Thrombotic microangiopathy
Ranking among five strategies; participants: severe (n=83), Plasma exchange with or without mPred then 30/83 (36%) Plasma exchange plus mPred then Pred 8/19 (42%)
non-severe (n=19); confidence: 6 (range 5–7) Pred (1 mg/kg) plus RTX with or without MMF (0·5–1 mg/kg/day, if possible tapered to
plus Caplacizumab (if TTP-like) or RTX (or CYC or the minimum effective dose over
MMF) and Eculizumab (if atypical HUS or 12 months) and MMF
complement mediated)

Participants were able to distinguish between severe and non-severe presentation of each manifestation, if they deemed this was appropriate. Confidence refers to whether the best strategy had been selected
and was assessed by participants on a 0–10 scale. AZA=azathioprine. CYC=cyclophosphamide. EuroLupus=using the EuroLupus regimen. HUS=haemolytic and uraemic syndrome. IVIG=intravenous
immunoglobulin. MMF=mycophenolate mofetil. mPred=methylprednisolone infusion. MTX=methotrexate. NIH=using the National Institutes of Health regimen. NSIP=non-specific interstitial pneumonia.
Pred=prednisone (or prednisolone). RTX=rituximab. TTP=thrombotic thrombocytopenic purpura. *Hydroxychloroquine should be added as background treatment to all these strategies, unless contraindicated.
†In combination with anti-psychotic therapy, as ordered by psychiatrist.

Table: Most common therapeutic strategies selected by participants for each rare SLE manifestation, by severity

4 www.thelancet.com/rheumatology Published online May 23, 2025 https://doi.org/10.1016/S2665-9913(25)00063-3

 Review

Centre, Department of Clinical

and Biological Sciences
(Prof M Gatto MD PhD),
Lupus meningitis
University Center of Excellence
mPred with Pred (0·5–1 mg/kg/day) plus MMF Presence of severity criteria? mPred then Pred (0·25–0·5 mg/kg/day) plus on Nephrologic, Rheumatologic
(or AZA) Mostly reported as always severe, in particular if: CYC (EuroLupus) then or AZA and Rare Diseases (ERK-Net,
Severe symptoms ERN-Reconnect and RITA-ERN
No Encephalitis Yes Member) with Nephrology and
Poor response to treatment Dialysis Unit and Center of
Extent or severity of changes on imaging Immuno-Rheumatology and
Deterioration of general condition
Rare Diseases (CMID),
Coordinating Center of the
Lupus psychosis Interregional Network for Rare
Diseases of Piedmont and
mPred with Pred (0·5–1 mg/kg) Presence of severity criteria? mPred with or without Pred (0·5–1 mg/kg) plus Aosta Valley, San Giovanni
Usually reported as severe, in particular if: CYC (NIH) Bosco Hub Hospital and
Threat to patient safety
Department of Clinical and
No Requiring hospitalisation Yes
Concomitant organic brain injury Biological Sciences, University
Delusion preventing compliance of Turin, Turin, Italy
Catatonia (Prof S Sciascia MD PhD);
Schroeder Arthritis Institute,
Krembil Research Institute,
Organic brain syndrome
University of Toronto, Toronto,
mPred then pred (0·5–1 mg/kg/day) plus Presence of severity criteria? mPred then Pred (0·5–1 mg/kg/day) plus CYC ON, Canada
MMF (or AZA) Usually reported as severe, in particular if: intravenously (EuroLupus) then MMF (Prof D D Gladman MD,
No Alteration of consciousness Yes Z Touma MD PhD); Toronto
Focal neurological deficits Lupus Clinic, Toronto Western
Requiring hospitalisation Hospital, Toronto, ON, Canada
(Prof D D Gladman); Division of
Seizures Rheumatology, Department of
Internal Medicine, Istanbul
mPred with or without Pred (0·5–1 mg/kg/day) Presence of severity criteria? mPred with or without Pred (0·5–1 mg/kg/day) Faculty of Medicine, Istanbul
plus MMF (or AZA) and anti-seizure Refractory treatment plus CYC (EuroLupus) then (or AZA) and University, Istanbul, Türkiye
medications No Grand mal Yes anti-seizure medications (Prof M Inanç MD);
Requiring hospitalisation or ICU admission Rheumatology Department,
Evidence of brain injury
ULS Coimbra, Coimbra
University Hospital, Coimbra,
CNS vasculitis Portugal (Prof L S Ines MD PhD);
The Department for Ageing
mPred then Pred (0·5–1 mg/kg/day) plus Presence of severity criteria? mPred then Pred (0·5–1 mg/kg/day) plus CYC Rheumatology and
MMF (or AZA) Usually reported as severe, in particular if: (NIH) Regenerative Medicine,
No Complicated with seizure, coma, Yes Division of Medicine, University
catatonia, and severe neurological deficit
College London, London, UK
Rapidly worsening of symptoms or MRI lesions
(Prof D Isenberg MD FAMS);
Department of Allergy and
Transverse myelitis Rheumatology, Graduate
School of Medicine, University
mPred then Pred (0·5–1 mg/kg/day) plus Presence of severity criteria? mPred then Pred (0·5–1 mg/kg/day) with RTX of Tokyo, Tokyo, Japan
RTX then MMF Usually reported as severe, in particular if: then MMF (S Izuka MD); Rheumatology
No Motor deficiency Yes
Department, ULS Santa Maria,
Concern about bladder or bowel dysfunction
Not responsive to initial steroid treatment Hospital de Santa Maria, CAML,
Lisbon, Portugal
(N Khmelinskii MD MSc,
Demyelinating neuropathy C Macieira MD); Division of
Rheumatology, Department of
mPred with or without Pred (0·5–1 mg/kg/day) Presence of severity criteria? mPred with or without Pred (0·5–1 mg/kg/day)
Medicine, Dalhousie University,
plus IVIG monthly for 6 months then spacing No Severe motor deficit (eg, inability to walk) Yes plus IVIG monthly for 6 months then spacing of
of infusion, to discontinuation (if possible) Multiple nerve territories infusion, to discontinuation (if possible) Halifax, NS, Canada
(A Legge MD); Division of
Rheumatology, Department of
Polyneuropathy Internal Medicine, Hospital de
Clínicas de Porto Alegre,
mPred then Pred (1 mg/kg/day) Presence of severity criteria? mPred then Pred (1 mg/kg/day) with RTX
No Yes Universidade Federal do Rio
Severe (sensory) motor deficit
Grande do Sul, Porto Alegre,
Brazil
Mononeuropathy multiplex (Prof O A Monticielo MD PhD);
Monash Health and
mPred then Pred (0·5–1 mg/kg/day) plus MMF Presence of severity criteria? mPred then Pred (0·5–1 mg/kg/day) plus CYC
Department of Rheumatology,
No Usually reported as severe, in particular if: Yes (EuroLupus) then MMF
Monash University, Melbourne,
Presence (and severity) of motor deficit
Australia (Prof E F Morand MD);
Hospital Docente Padre Billini,
Rheumatology Service
(Figure 2 continues on next page)

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 Review

Reumatología e Investigación Thrombotic microangiopathy

Clínica (RIC), Santo Domingo,
Dominican Republic Plasma exchange with mPred then Pred Presence of severity criteria? Plasma exchange with mPred then Pred
(R Muñoz-Louis MD MSc); (0·5–1 mg/kg/day) plus MMF Usually reported as severe, in particular if: (1 mg/kg) plus RTX with or without MMF plus
School of Medicine, University No Organ dysfunction (in particular, severity Yes caplacizumab (if TTP-like) or RTX (or CYC or
of Zagreb, Zagreb, Croatia of neurological or renal involvement) MMF) with eculizumab (if atypical HUS or
complement mediated)
(Prof I Padjen MD PhD); Division
of Clinical Immunology and
Rheumatology, Referral Centre Lupus pancreatitis
for SLE and Related Disorders,
Department of Internal mPred with or without Pred (0·5–1 mg/kg/day) Presence of severity criteria? mPred with or without Pred
Medicine, University Hospital plus MMF Severity of symptoms (0·25–0·5 mg/kg/day) plus CYC (EuroLupus)
Centre Zagreb, Zagreb, Croatia Markedly elevated serum amylase or lipase then MMF or AZA
Other organ failure and hypotension
(Prof I Padjen); Johns Hopkins
Extent and severity in CT scan
University School of Medicine, No Yes
Necrotising pancreatitis
Baltimore, MD, USA Pancreatic insufficiency
(Prof M Petri MD MPH); Anticipated prolonged parenteral nutrition
Rheumatology Unit, AOU Requiring hospitalisation
Cagliari, Department of Medical High Ranson score
Science and Public Health,
University of Cagliari, Cagliari,
Lupus enteritis
Italy (Prof M Piga MD); Regional
Center for Autoimmune and Pred (0·5–1 mg/kg) with MMF (2–3 g/day) Presence of severity criteria? mPred then Pred (0·5 mg/kg/day) plus CYC
Rheumatic Diseases (CREAR), Digestive perforation or ischaemia (EuroLupus) then MMF
Rosario, Argentina Digestive haemorrhage
(B A Pons-Estel MD); IRCCS Severity of symptoms, generalised oedema,
Ospedale San Raffaele, Unit of weight loss, and inability to eat
No Yes
Sepsis due to bacteria translocation
Immunology, Rheumatology,
Extent and severity at imaging
Allergy and Rare Diseases and
Severe hypoalbuminemia (eg, <20 g/L) or severe
Università Vita-Salute San dehydration or ion abnormalities
Raffaele, Milan, Italy Requiring hospitalisation
(G A Ramirez MD PhD); Feinberg
School of Medicine,
Northwestern University, Figure 2: Preferred strategy according to the presence of severity criteria
Chicago, IL, USA The most preferred strategy for each rare SLE manifestation, according to the presence of severity criteria is shown.
(Prof R Ramsey-Goldman MD The colors of the boxes are the related to the organ-domain: blue for neurological involvement, orange for digestive involvement, and grey for renal involvement.
DrPH); Department of AZA=azathioprine. CYC=cyclophosphamide. EuroLupus=EuroLupus regimen. HUS=haemolytic and uraemic syndrome. ICU=intensive care unit. IVIG=intravenous
Rheumatology, Centre de immunoglobulin. MMF=mycophenolate mofetil. mPred=methylprednisolone infusion. MTX=methotrexate. NIH=National Institutes of Health regimen.
Référence des Maladies Auto- Pred=prednisone (or prednisolone). RTX=rituximab. TTP=thrombotic thrombocytopenic purpura.
immunes Systémiques Rares
RESO, Hôpital Pellegrin, and step 3 for each rare SLE manifestation, from best to In all the submitted therapeutic strategies, hydroxy­
University Bordeaux, CNRS,
ImmunoConcEpT, UMR 5164,
worst. The three most common therapeutic strategies chloroquine was proposed as background therapy in
Bordeaux, France selected by participants were extracted (the most combination with glucocorticoid therapy and con­
(Prof C Richez MD PhD); common therapeutic strategy is shown in the table, ventional synthetic or biological immunosuppressives,
Reference Center in figures 2 and 3, and the in the appendix pp 19–24), for as it is the mainstay of SLE treatment and recommended
Osteoporosis and
Rheumatology Pontificia
severe and non-severe manifestations separately, when in all patients unless contraindicated.2
Javeriana University, Cali, deemed appropriate. The personal experience of In detail, for each rare SLE manifestation, the total
Colombia participants regarding the management of these rare number of strategies voted upon, the number of
(Prof C E Toro-Gutierrez MD MSc); SLE manifestations was captured by their estimated total participants (ie, reported for severe and non-severe
Amsterdam UMC, Amsterdam,
Netherlands (Prof
number of patients with SLE seen throughout their presentation, separately), and the ranking of the
R F Van Vollenhoven MD PhD); career (appendix p 25). three most common therapeutic strategies selected by
National Institute for Health participants, according to severity, are shown in the table.
and Care Research Leeds Consensus on therapeutic strategies for rare SLE A summary of criteria for severity are shown in the
Biomedical Research Centre,
University of Leeds, Leeds, UK
manifestations appendix (pp 26–28) and figures 2 and 3.
(E M Vital MD PhD); Department Overall, 81 (80%) of 101 participants used no methyl­
of Rheumatology and Medical prednisolone infusions for treating non-severe SLE Aplastic anaemia: myelofibrosis
Science, Rheumatology Clinic, manifestations. Of the 20 participants who did use The preferred therapeutic strategy for severe aplastic
ASST-G.Pini-CTO, Milan, Italy
(M Gerosa MD PhD);
methyl­prednisolone, eight (40%) used 125 mg or seven anaemia (78 participants) was a combination of
Department of Clinical and (25%) used 250 mg, typically for 3 days (n=14, 70%). hydroxychloroquine and methyl­prednisolone infusions
Experimental Medicine, When treating severe SLE manifestations, all 101 experts followed by oral glucocorticoids (0·5–1 mg/kg/day, if
University of Pisa, Pisa, Italy
used methylprednisolone infusions with 50 (50%) possible tapered over 6 months) plus rituximab (and
(Prof M Mosca MD,
C Tani MD PhD) using 500 mg or 26 (26%) using 1000 mg, less optional myco­phenolate mofetil). The preferred strategy
commonly 17 (17%) using 250 mg, five (5%) using indicated for severe aplastic anaemia was selected by 30
750 mg or three (3%) using 125 mg, typically for 3 days (38%) of 78 and by 15 (48%) of 31 for non-severe aplastic
(n=97, 96%). anaemia. 30 (39%) participants felt that aplastic anaemia

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 Review

might occasionally not be severe and preferred a Rare cardiac and cardiovascular manifestations: Correspondence to:
combination of hydroxychloroquine and methyl­ Libman–Sacks endocarditis, pulmonary arterial Prof Laurent Arnaud,
Department of Rheumatology,
prednisolone infusions followed by oral glucocorticoids hypertension, and lupus myocarditis National Reference Center for
(0·5–1 mg/kg/day, if possible tapered over 6 months) The preferred therapeutic strategy for Libman–Sacks Autoimmune Diseases (RESO),
plus myco­phenolate mofetil. endocarditis (82 participants) was a combination of INSERM UMR-S 1109,
hydroxy­ chloroquine plus oral gluco­
corticoids 67000 Strasbourg, France
laurent.arnaud@chru-
Rare gastrointestinal manifestations: lupus enteritis (40–60 mg/day) with mycophenolate mofetil and strasbourg.fr
and lupus pancreatitis anticoagulation (warfarin). Also, 45 (55%) parti­cipants
See Online for appendix
The preferred therapeutic strategy for severe lupus felt that Libman–Sacks endocarditis might occasionally
For Limesurvey see https://
enteritis (85 participants) and lupus pancreatitis not be severe and preferred a combination of www.limesurvey.org/
(79 participants) was a combination of hydroxychloroquine hydroxychloroquine plus low-dose aspirin (in case of
and methyl­prednisolone infusions followed by oral gluco­ valvular thickening) or anticoagulation (for valve nodule
corticoids (0·25–0·5 mg/kg/day, then tapered) plus or vegetation).
intravenous cyclophosphamide (EuroLupus protocol—ie, For pulmonary arterial hypertension (82 participants),
a fixed dose of 500 mg cyclophosphamide administered the preferred therapeutic strategy proposed was a com­
every 2 weeks for a total of six doses),7 then mycophenolate bin­ation of hydroxychloroquine and (optional)
mofetil (or azathioprine in the case of pancreatitis) for methyl­­­­­­­­pred­nisolone infusions followed by oral
maintenance. Also, 37 (44%) of 85 partici­pants felt that glucocorticoids (0·5–1 mg/kg/day, if possible tapered
lupus enteritis might occasionally not be severe and over a maximum of 6 months) plus mycophenolate
preferred a combination of hydroxy­chloroquine plus oral mofetil and pulmonary arterial hyper­ tension-specific
gluco­corticoids (0·5–1 mg/kg) plus mycophenolate mofetil drugs, as indicated. Also, 33 (40%) of 82 participants
2–3 g/day. 38 (48%) of 79 participants felt that lupus thought that pulmonary arterial hypertension could be
pancreatitis might occasionally not be severe and preferred non-severe, of whom 25 (76%) of 33 recommended the
a combin­ ation of hydroxychloroquine and (optional) same therapeutic strategy as used in severe cases.
methyl­­prednisolone infusions, followed by oral The preferred therapeutic strategy for lupus myocarditis
glucocorticoids (0·5–1 mg/kg/day, tapered) plus (84 participants) was a combination of hydroxy­
mycophenolate mofetil. chloroquine and methylprednisolone infusions followed
by oral glucocorticoids (1 mg/kg, if possible tapered over
Rare lung manifestations: lupus pneumonitis, shrinking a maximum of 6 months) plus intravenous cyclophos­
lung syndrome, and interstitial lung disease phamide (EuroLupus protocol) then main­tenance with
(non-specific interstitial pneumonia) mycophenolate mofetil. Also, 31 (37%) participants
The preferred therapeutic strategy for severe lupus thought that lupus myocarditis was a non-severe
pneumonitis (82 participants) and shrinking lung manifestation and 18 (55%) of 33 preferred a combination
syndrome (78 participants) was a combination of of hydroxy­ chloroquine with oral glucocorticoids
hydroxy­chloroquine and methylprednisolone infusions (0·5 mg/kg, if possible tapered over a maximum of
(optional for shrinking lung), followed by oral 6 months) plus mycophenolate mofetil.
glucocorticoids (1 mg/kg/day, if possible tapered over a
maximum of 6 months) plus intravenous cyclo­ phos­ Rare cutaneous manifestations: lupus panniculitis and
phamide (EuroLupus protocol) and then by main­tenance skin vasculitis
with mycophenolate mofetil (or azathioprine). Also, The preferred therapeutic strategy for both lupus
32 (39%) of 82 (severe lupus pneumonitis) and 35 (45%) panniculitis (80 participants) and skin vasculitis
of 78 (shrinking lung syn­drome) participants, felt that (81 participants) was a combination of hydroxy­
lupus pneumonitis and shrinking lung might occa­ chloroquine and (optional) methylprednisolone infusions
sionally not be severe and preferred a combination of followed by oral glucocorticoids (0·25–0·5 mg/kg/day for
hydroxy­chloroquine and methyl­prednisolone infusions lupus panniculitis and 0·5–1 mg/kg/day for skin
(in lupus pneumonitis) or oral glucocorticoids vasculitis).
(0·5 mg/kg/day) followed by tapering plus In combination with glucocorticoids, anifrolumab (and
mycophenolate mofetil (or azathioprine). optional methotrexate or mycophenolate mofetil or
For severe interstitial lung disease, the preferred azathioprine) was proposed for lupus panniculitis
therapeutic strategy (83 participants) was a combination whereas mycophenolate mofetil was suggested for skin
of hydroxychloroquine and (optional) methyl­ vasculitis. Also, 52 (65%) participants felt that panniculitis
prednisolone infusions followed by oral glucocorticoids might occasionally not be severe and preferred a
(0·5–1·0 mg/kg/day, if possible tapered over a maximum combination of hydroxychloroquine, oral glucocorticoids
of 6 months) plus myco­phenolate mofetil. Also, 58 (70%) (0·25–0·5 mg/kg/day), and methotrexate. Of note,
of 83 participants felt that interstitial lung disease might 55 (68%) participants felt that skin vasculitis might
occasionally not be severe, but nevertheless, mainly occasionally not be severe and preferred a combination of
recommended the same therapeutic strategy. hydroxychloroquine and (optional) methyl­prednisolone

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 Review

Pulmonary arterial hypertension

mPred with or without Pred (0·5–1 mg/kg/day) Presence of severity criteria? mPred with or without Pred (0·5–1 mg/Kg/day)
with addition of pulmonary arterial UIP pattern (vs NSIP) plus MMF
hypertension-specific drugs, as indicated Rapidly progressive interstitial lung disease
plus MMF High-resolution CT extent ≥20%
Forced vital capacity ≤50–70% predicted
No Diffusing capacity for carbon monoxide ≤70% or Yes
decline ≥10% at 6 months
Severe hypoxia (eg, pO2 <60 mm Hg)
Effect on patient’s functional status
Requiring hospitalisation

Lupus pneumonitis (acute)

mPred with Pred (0·5–1 mg/kg/day) plus MMF Presence of severity criteria? mPred then Pred (1 mg/kg/day) with CYC
or AZA Usually reported as severe, in particular if: (EuroLupus) then MMF or AZA
Hypoxaemia (eg, pO2 <60 mm Hg)
Respiratory failure
No Yes
Need for invasive ventilation
Rapidly progressive interstitial lung disease
Extension ≥20% on high-resolution CT
Requiring hospitalisation or ICU

Shrinking lung syndrome

Pred (0·5 mg/kg/day) with MMF (or AZA) Presence of severity criteria? mPred with or without Pred (1 mg/kg/day) with
Respiratory insufficiency CYC (EuroLupus) then MMF (or AZA)
Oxygen requirement
No Effect on patient daily activities Yes
ICU admission
Forced vital capacity ≤50–70% predicted
Rapid decline in pulmonary function

Macrophage activation syndrome

mPred with Pred (0·5–1 mg/kg/day) plus MMF Presence of severity criteria? mPred with Pred (0·5–1 mg/kg/day) plus
Usually reported as severe, in particular if: anakinra and cyclosporine or tacrolimus
Symptoms (eg, fever and haemodynamic
No instability) Yes
Laboratory abnormalities (eg, anaemia,
thrombocytopenia, and increased liver enzymes)
Organ dysfunction

Aplastic anaemia (myelofibrosis)

mPred then Pred (0·5–1 mg/kg/day) with MMF Presence of severity criteria? mPred then Pred (0·5–1 mg/kg/day) plus RTX
Severity of cytopenia (with or without MMF)
Complications due to cytopenia (eg, angina or
No Yes
NSTEMI, fever, bleeding, or infection)
Transfusions or growth factor dependency
Requiring hospitalisation

Libman sacks

Low-dose aspirin (valvular thickening) Presence of severity criteria? Pred (40–60 mg/day) with MMF plus
or anticoagulation (valve nodule or vegetation) Severe valve dysfunction anticoagulation (warfarin)
Heart failure
No Evidence of embolic disease Yes
Presence of vegetation and vegetation instability
as assessed by the cardiologist
Requiring hospitalisation

Pulmonary arterial hypertension

mPred with or without Pred (0·5–1 mg/kg/day) Presence of severity criteria? mPred with or without Pred (0·5–1 mg/kg/day)
with addition of pulmonary arterial Clinical symptoms with addition of pulmonary arterial
No Yes
hypertesion-specific drugs, as indicated plus Rapid progression hypertension-specific drugs, as indicated plus
MMF Markedly raised pulmonary arterial hypertension MMF

(Figure 3 continues on next page)

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 Review

Lupus myocarditis

Pred (0·5 mg/kg) with MMF Presence of severity criteria? mPred then Pred (1 mg/kg) with CYC
Cardiac failure or reduction of ventricular filling (EuroLupus) then MMF
volume
No Yes
Kinetic alteration on echocardiography
Arrhythmia or conduction abnormalities
Diffuse myocardial MRI oedema

Skin vasculitis

mPred with or without Pred Presence of severity criteria? mPred with or without Pred (1 mg/kg/day) with
(0·25–0·5 mg/kg/day) Severe pain, skin ulceration, or necrosis CYC (EuroLupus) then MMF (or AZA)
Extension of involvement (ie, >9–18% BSA)
Digital ischaemia or gangrene with high risk of
No tissue loss or necrosis Yes
Disfiguring lesions
Inability to walk
Refractory to first-line treatment
Requiring hospitalisation

Lupus panniculitis

Pred (0·25–0·5 mg/kg/day) with MTX Presence of severity criteria? mPred with or without Pred
High number of lesions (0·25–0·5 mg/kg/day) plus anifrolumab (with or
Ulcerations and necrosis without MTX, MMF, or AZA)
Extent of lesions (eg, >9% BSA)
No Severe symptoms (eg, severe pain) Yes
Facial involvement
High scarring risk
Refractory to first-line treatment
Requiring hospitalisation

Systemic lupus vasculitis

mPred then Pred (0·5–1 mg/kg/day) with MMF Presence of severity criteria? mPred then Pred (0·5–1 mg/kg/day) with CYC
(or AZA) Usually reported as severe, in particular if: (NIH)
Life-threatening or organ-threatening disease
No Yes
CNS vasculitis
Multiple mononeuritis
Requiring hospitalisation

Retinal vasculitis

mPred then Pred (0·5–1 mg/kg/day) with MMF Presence of severity criteria? mPred then Pred (0·5–1 mg/kg/day) with CYC
Usually reported as severe, in particular if: (EuroLupus) then MMF
No Visual impairment or risk of visual loss Yes
Severity of lesions (eg, retinal necrosis,
detachment, and haemorrhage)
Bilateral involvement

Figure 3: Preferred strategy according to the presence of severity criteria

The most preferred strategy for each rare systemic lupus erythematosus manifestation, according to the presence of severity criteria is shown. The colors of the
boxes are related to the organ-domain: green for lung involvement, grey for hematological involvement, yellow for cardiological involvement, light purple for
skin involvement, and light green for vasculitis involvement. AZA=azathioprine. CYC=cyclophosphamide. EuroLupus=EuroLupus regimen. BSA=body surface
area. HUS=haemolytic and uraemic syndrome. ICU=intensive care unit. MMF=mycophenolate mofetil. mPred=methylprednisolone infusion.
MTX=methotrexate. NIH=National Institutes of Health regimen. Pred=prednisone (or prednisolone). NSIP=non-specific interstitial pneumonia. NSTEMI=non-
ST-segment elevation myocardial infarction. pO2=partial pressure oxygen. RTX=rituximab. TTP=thrombotic thrombocytopenic purpura. UIP=usual interstitial
pneumonia.

infusions followed by oral glucocorticoids CNS and systemic vasculitis

(0·25–0·5 mg/kg/day). The preferred therapeutic strategy for CNS vasculitis
It is important to highlight the tendency to clinically (85 participants) and systemic (lupus) vasculitis
overestimate the prevalence of SLE-related cutaneous (84 participants) was the same, comprising a combination
vasculitis in patients with digital involvement, in which of hydroxychloroquine and methyl­prednisolone infusions
lesions are frequently violaceous or purpuric.8 Moreover, followed by oral glucocorticoids (0·5–1 mg/kg/day if
a recent study found that SLE-related cutaneous vasculitis possible tapered over a maximum of 6 months) and
is rare and that other causes of vasculitis should be ruled intravenous cyclophosphamide (National Institutes of
out before considering this diagnosis.9 Health [NIH] protocol).10 Most participants (22 for CNS

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 Review

and 27 for systemic vasculitis) felt that they are not always preferred a combination of antipsychotic therapy (as
severe manifestations of SLE and preferred a combination ordered by a psychiatrist) combined with hydroxy­
of hydroxychloroquine and methyl­prednisolone infusions chloroquine and (optional) methylprednisolone
followed by oral glucocorticoids (0·5–1 mg/kg/day, if infusions, followed by oral glucocorticoids (0·5–1 mg/kg).
possible tapered over a maximum of 6 months) and
mycophenolate mofetil (or azathioprine). Rare focal CNS manifestations: myelitis and seizures
The preferred therapeutic strategies for myelitis
Retinal vasculitis (81 participants) were either a combination of
The preferred therapeutic strategy for retinal vasculitis hydroxychloroquine and methylprednisolone infusions
(79 participants) was a combination of hydroxychloroquine followed by oral glucocorticoids (0·5–1 mg/kg/day if
and methylprednisolone infusions followed by oral possible tapered over 12 months) and rituximab plus
glucocorticoids (0·5–1 mg/kg/day if possible tapered mycophenolate mofetil, or a combination of hydroxy­
over a maximum of 6 months) and intravenous cyclo­ chloroquine and methylprednisolone infusions followed
phosphamide (EuroLupus protocol), then mycophenolate by oral glucocorticoids (0·5–1 mg/kg/day if possible
mofetil for maintenance. Also, 28 (35%) participants felt tapered over a maximum of 6 months) and cyclo­
that retinal vasculitis might occasionally not be severe phosphamide (NIH regimen). Of note, a few participants
and preferred a combination of hydroxy­chloroquine and (n=20, 25%) felt that myelitis might not always be
methylprednisolone infusions followed by oral severe, but recommended the same main therapeutic
glucocorticoids (0·5–1 mg/kg/day if possible tapered strategy.
over a maximum of 6 months) and mycophenolate The preferred therapeutic strategy for seizures
mofetil. (80 participants) attributed to active neuropsychiatric
lupus and necessitating treatment was a combination of
Macrophage activation syndrome hydroxy­chloroquine and (optional) methylprednisolone
The preferred therapeutic strategy for macrophage infusions followed by oral glucocorticoids
activation syndrome (82 participants) was a combination (0·5–1 mg/kg/day, tapered) and intravenous cyclophos­
of hydroxychloroquine and methyl­ pred­
nisolone phamide (EuroLupus protocol), then maintenance with
infusions followed by oral glucocorticoids mycophenolate mofetil (or azathioprine) plus anti-
(0·5–1 mg/kg/day) and anakinra plus cyclosporine or seizure medications. Also, 33 (41%) participants felt that
tacrolimus. Also, 26 (32%) participants felt that seizures might occasionally not be severe and preferred
macrophage activation syndrome might occasionally not using a combination of hydroxychloroquine and
be severe and preferred a combination of hydroxy­ (optional) methylprednisolone infusions followed by oral
chloroquine and methyl­prednisolone infusions followed glucocorticoids (0·5–1 mg/kg/day, tapered) plus
by oral glucocorticoids (0·5–1 mg/kg/day) and myco­ mycophenolate mofetil (or azathioprine) and anti-seizure
phenolate mofetil. medications.

Rare diffuse CNS manifestations: organic brain Rare peripheral nervous system manifestations:
syndrome, lupus psychosis, and lupus meningitis demyelinating neuropathy, lupus polyneuropathy, and
The preferred therapeutic strategy for organic brain mononeuropathy multiplex
syndrome (81 participants), lupus psychosis 79 participants thought that demyelinating neuropathy is
(84 participants), and lupus meningitis (83 participants) usually a severe manifestation and 29 (37%) of them
was a combination of hydroxychloroquine and methyl­ preferred the treatment strategy of a combination of
prednisolone infusions (optional in psychosis) followed hydroxychloroquine and methyl­prednisolone infusions
by oral glucocorticoids (0·25–1 mg/kg/day, if possible followed by oral glucocorticoids (0·5–1 mg/kg/day) and
tapered over a maximum of 6 months) and intravenous monthly intravenous immuno­ globulin (for 6 months)
cyclophosphamide (EuroLupus protocol), then main­ with progressive spacing of infusion to discontinuation
tenance with mycophenolate mofetil indicated in organic (if possible). 19 participants felt that demyelinating
brain syndrome and mycophenolate mofetil or neuropathy is occasionally a non-severe manifestation
azathioprine indicated in meningitis; a background and nine (47%) of them prioritised the same treatment
therapy with antipsychotic drugs as ordered by strategy as for severe.
psychiatrist is also indicated in lupus psychosis. A few For polyneuropathy, 75 participants thought that this
participants (n=24, 30%) felt that organic brain syndrome was a severe manifestation and 32 (43%) preferred a
and lupus meningitis might occasionally not be severe treatment strategy of a combination of hydroxy­
and preferred a combination of hydroxy­chloroquine and chloroquine and methyl­prednisolone infusions followed
methylprednisolone infusions followed by oral gluco­ by oral glucocorticoids (1 mg/kg/day, if possible tapered
corticoids (0·5–1 mg/kg/day) and myco­phenolate mofetil over a maximum of 6 months) and rituximab.
(or azathioprine ). Also, 31 (37%) participants felt that 30 participants thought that polyneuropathy is
lupus psychosis might occasionally not be severe and occasionally a non-severe manifestation and 12 (40%) of

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 Review

them preferred a combination of hydroxychloroquine strategies, yielding a final consensus of a total of 24 rare
and methylprednisolone infusions followed by oral SLE manifestations, according to severity.2
glucocorticoids (1 mg/kg/day, if possible tapered over a Due to the general absence of high-quality evidence,
maximum of 6 months). largely attributable to the rarity of the aforementioned
83 participants thought that mononeuropathy SLE manifestations, the therapeutic strategies described
multiplex is usually a severe manifestation and preferred herein are primarily based on expert opinion and clinical
a treatment strategy of a combination of hydroxy­ experience. This expert-based approach compensates for
chloroquine and methyl­prednisolone infusions followed the scarcity of robust clinical trial data, ensuring that the
by oral gluco­ corticoids (0·5–1 mg/kg/day) and intra­ consensus statements are grounded in the practical
venous cyclo­­phosphamide (EuroLupus protocol), then insights and consensus of leading specialists in the field.
main­tenance with myco­phenolate mofetil. 23 participants Importantly, all therapeutic strategies submitted by the
thought that mononeuropathy multiplex was occasionally participants have been successfully tested and judged to
a non-severe manifestation and 11 (48%) of them be efficacious, further reinforcing the credibility and
preferred a combination of hydroxychloroquine and relevance of the consensus.
methyl­prednisolone infusions followed by oral gluco­ We provide the three most voted for strategies for each
corticoids (0·5–1 mg/kg/day) and mycophenolate manifestation, acknowledging that other alternative
mofetil. strategies might exist. Clinical judgment should always
be applied when selecting these strategies considering
Thrombotic microangiopathy that these manifestations often do not occur in isolation.
83 participants thought that thrombotic microangiopathy The ultimate selection of treatment should consider all
is usually a severe manifestation with 30 (36%) of them active clinical features and the patient’s personal context,
preferring a treatment strategy of a common initial including potential contraindications. With these
treatment with a combination of plasma exchange and parameters, the analysis of the data collected in this
hydroxychloroquine plus (optional) methylprednisolone project revealed some important aspects about the
infusions, followed by oral glucocorticoids (1 mg/kg). current therapeutic approach to rare disease mani­
Then, the association of rituximab (with or without festations and offered interesting insights.
mycophenolate mofetil) plus caplacizumab in case of Looking at the results globally, the combination of
thrombotic thrombo­cyto­penic purpura-like presentation. methylprednisolone and cyclophosphamide was the
Alternatively, rituximab (or intravenous cyclo­ preferred initial option in most clinical scenarios of
phosphamide or mycophenolate mofetil) and eculizumab severe SLE manifestations. Of note, the use of rituximab
can be used if atypical haemolytic uraemic syndrome or was uncommon, at least within the most voted initial
complement-mediated thrombotic microangiopathy. regimens. On the other hand, methylprednisolone
19 participants felt that thrombotic micro­angiopathy pulses have not been used by 80% of participants for
might occasionally be a non-severe manifestation and non-severe SLE manifestations. The recent description
eight (42%) of them preferred a treatment strategy of of higher remission rates and oral glucocorticoid-
plasma exchange, hydroxy­ chloroquine and methyl­ sparing effects with the use of methylprednisolone
prednisolone infusions followed by oral glucocorticoids pulses also in patients with moderate lupus activity11
(0·5–1 mg/kg/day, if possible tapered to the minimum might increase its use for milder SLE symptoms in the
effective dosage over 12 months) and mycophenolate coming future. Of note, one barrier to use of intravenous
mofetil. pulse glucocorticoids could be difficulties relating to
access in the outpatient setting. The issue of
Discussion glucocorticoid dosing is also worth discussing.
The therapeutic management of rare SLE manifestations Regarding methylprednisolone, 500 mg/day for
presents unique challenges as these manifestations are 3 consecutive days was the chosen option by more than
typically not reported in clinical trials or in half of the panel, with 1000 mg/day ranking second with
recommendations available to date.4,5 The ERN 25% of the votes despite data showing that the use of
ReCONNET, SLICC group, and SLEuro consensus for higher doses is associated with more infectious
rare SLE manifestations aimed to provide clinicians with complications, whereas lower doses could be just as
an expert-based framework. The development of effective.12 The EuroLupus regime for cyclophosphamide
therapeutic strategies involved several key steps. First, a was preferred over the higher-dose NIH regimen,
panel of international SLE experts convened to identify possibly mirroring the recommendations for patients
rare SLE manifestations with a survey after which a with lupus nephritis.2 Lastly, the most voted options
prioritisation exercise was conducted whereby the experts included initial doses of oral prednisone between
voted on which manifestations should be included. 0·5–1 mg/kg/day, without specified tapering schemes,
Subsequently, therapeutic strategies used by the generally recommended to be reduced or withdrawn at
participants for managing these rare manifestations 6 months if possible. Although some proposed schemes
were gathered. Lastly, the panel was asked to rank these incorporated rapid tapering to a target of 5 mg/day

www.thelancet.com/rheumatology Published online May 23, 2025 https://doi.org/10.1016/S2665-9913(25)00063-3 11

 Review

within 12 weeks, similar to recent schedules for lupus contraindications, past or concomitant medications, or
nephritis,13 the scheme of high initial doses with patient preferences.1
tapering according to clinical response has been Supportive and accompanying therapy should go hand
consolidated by use for many decades. However, there is in hand with immunological therapy in some mani­
a growing tendency to start with lower initial doses and festations (eg, psychosis and pulmonary arterial
to speed up the reduction of prednisone to maintenance hyper­ tension); this aspect emerges clearly in the
doses of 5 mg/day and lower, with the aim of preventing proposed strategies and underscores the importance of
glucocorticoid-related side-effects;2 therefore, this the multidisciplinary approach.20
should always be considered when treating individual Study limitations include the fact that not all taskforce
patients with severe and rare SLE manifestations. members participated at each step, but all were invited
Importantly, more recent biologics (eg, belimumab and and received multiple recall emails. Nevertheless, the
anifrolumab) are scarcely considered in these total number of participating experts and their
manifestations. The recent introduction of anifrolumab geographical diversity, including participants from
in the treatment armamentarium could be a possible Africa, South America, and the Asia-Pacific region
explanation for its minimalm use; geographical ensured a broad coverage of diverse medical practices.
disparities in access to biologics could be the cause for Most participants in the taskforce were rheumatologists,
the minimal representation of belimumab and but we also included internal medicine, nephrology, and
anifrolumab in the proposed strategies.14 Of note, dermatology colleagues to ensure diversity. Multi­
anifrolumab has been proposed as the first choice disciplinary discussion with colleagues from end-organ
strategy in lupus panniculitis, possibly driven by some specialties outside the field of rheumatology is clearly
successful experiences reported in the literature.15–17 Of crucial in the management of these rare SLE
course, the limited representation of biologics in these manifestations. Such collaborations are essential for
strategies represents an unmet need and should be enhancing the accuracy of diagnosis, the effectiveness of
considered a stimulus for future research and real-life treatment strategies, and the overall quality of patient
studies evaluating the use of these drugs, even in rarer care.12 Also, the taskforce focused on the most relevant
SLE manifestations that are invariably underrepresented rare SLE manifestations, as ranked by taskforce
in clinical trials.18 members, while other rare manifestations might be
The potential treatment strategies for skin vasculitis interesting to consider in future work. Furthermore,
did not include biologics, such as belimumab and given the rarity of these manifestations and the absence
rituximab, as no treatment with a biologic was submitted of high-level evidence for treatment, the consensus
during step 3 for this manifestation. Current strategies reached is mostly expert-based and there was no
can evolve with the approval of new medications for SLE involvement of people with lived experience at any stage.
and when recently available biologics are more broadly Of note, all therapeutic strategies should be interpreted
used in real-life settings.19 in the more general context of treatment accessibility, as
Regarding Libman–Sacks endocarditis, the preferred not all recommended therapeutic strategies are fully
strategy when severe was a combination of hydroxy­ available in all world regions. It is important to note that
chloroquine and oral glucocorticoids (40–60 mg/day) to date, no universal recommendation for SLE exists,
with mycophenolate mofetil and anticoagulation including for common manifestations.
(warfarin). However, in many cases, Libman–Sacks Lastly, we believe this Review is a good starting point for
endo­ carditis is attributed to the presence of expanding research on the topic of rare SLE manifestations
antiphospholipid antibodies, and in the absence of active where there is still little evidence. To fill the current
SLE features, the main strategy selected for non-severe knowledge gap, the taskforce strongly believes we should
endocarditis (a combination of hydroxychloroquine, encourage additional studies on rare manifestations,
low-dose aspirin in case of valvular thickening, or survey the medication availability in different countries to
anticoagulation for valve nodule or vegetation) might be treat rare disease manifestations, and eventually compare
preferable. treatment strategies in different countries.
In most cases, these rare SLE manifestations were
perceived as severe, necessitating aggressive immuno­ Conclusion
suppressive interventions. However, some participants In conclusion, the therapeutic management of rare SLE
reported having encountered milder forms, which might manifestations remains a complex and underexplored
require a less intensive treatment approach. A list of area, often absent from existing clinical trials and
severity criteria (appendix pp 26–28), as suggested by guidelines. The consensus efforts of ERN ReCONNET,
taskforce participants, is provided to help guide the the SLICC group, and SLEuro represent a considerable
appropriate level of treatment. Regardless, clinical advancement in this field, offering clinicians expert-
judgment remains crucial as the systemic nature of SLE based strategies tailored to the severity of 24 distinct rare
might necessitate adjustments to the therapeutic strategy manifestations of SLE. This work provides a valuable
based on other manifestations, comorbidities, framework for guiding therapeutic decisions where the

12 www.thelancet.com/rheumatology Published online May 23, 2025 https://doi.org/10.1016/S2665-9913(25)00063-3

 Review

writing, or educational events from AbbVie, AstraZeneca, Celltrion, GSK,

Search strategy and selection criteria Janssen, and UCB. EFM received research funding or consulting fees
from AbbVie, Amgen, AstraZeneca, Biogen, Bristol Myers Squibb,
This consensus was based on the previous literature review
Dragonfly, Lilly, EMD Serono, Galapagos, Genentech, GSK, Janssen,
conducted by the European Reference Network on Rare and Novartis, Remegen, Takeda, and UCB. MM received consultant or
Complex Connective Tissue and Musculoskeletal Diseases5 speaker fees from AstraZeneca, GSK, AbbVie, Alpine, Biogen, Bristol
complemented by an additional search of PubMed with the Myers Squibb, Lilly, UCB, Otsuka, and Idorsia. IP received speakers fees
from AbbVie, AstraZeneca, Boehringer-Ingelheim, Lilly, Novartis, and
terms “rare manifestations” and “lupus” from 2022, until
Pfizer. MPi received lecture and consultancy fees from AstraZeneca,
January 2025. Only papers published in English were GSK, Otsuka, and Roche. BAP-E received consultant fees from Alpine,
reviewed. The final reference list was generated on the basis AstraZeneca, GSK, Janssen, and Werfen. GAR received honoraria for
of originality and relevance to the broad scope of this work. advisory boards or invited talks from Amgen, AstraZeneca, GSK, and
Vifor. RR-G received consultant fees from Biogen, Bristol Myers Squibb,
Cabaletta, Exagen Diagnostics, and Ampel Solutions. CR received
consultant fees from AbbVie, AstraZeneca, Biogen, Bristol Myers Squibb,
available recommendations might be insufficient or GSK, Lilly, Novartis, and Pfizer. CET-G received speaker fees from
inapplicable. Further research and ongoing updates of AbbVie, Bristol Myers Squibb, AstraZeneca, Boehringer-Ingelheim,
Janssen, Novartis, Pharmalab, Pfizer, Roche, and UCB. RFVV received
these consensus statements will be essential to refine institutional research support from Bristol Myers Squibb; support for
and expand the treatment options available for these educational programmes from Alfasigma, AstraZeneca, Galapagos,
challenging presentations of SLE. Ultimately, this Merck Sharp Dhome, Novartis, Pfizer, Roche, Sanofi, and UCB; and
consensus serves as a crucial step toward improving consultancy or speaker fees from AbbVie, AstraZeneca, Biogen, Bristol
Myers Squibb, Galapagos, GSK, Janssen, Pfizer, RemeGen, and UCB.
global outcomes for patients with rare and severe SLE EMV received consultant fees from AbbVie, Alpine, AstraZeneca,
manifestations. Aurinia, Bristol Myers Squibb, Pfizer, Merck, Roche, Novartis, UCB, and
Contributors Otsuka. S-CB received funding from the Basic Science Research Program
LA, ZT, SB, CA, MD’E, and GR-I made substantial contributions to the via the National Research Foundation of Korea funded by the Ministry of
conception and design of the study. LA, ZT, SB, CA, MD’E, and GR-I Education (NRF-2021R1A6A1A03038899). EB received a researcher
drafted the article and all authors revisited it critically for important support grant from Conselho Nacional de Desenvolvimento Científico e
intellectual content. All authors contributed to acquisition and Tecnológico (#305242/2019–9). GR-I was supported by the Department of
interpretation of data, gave their final approval of the version to be Education of the Basque Government (research grant IT 1512-22). ZT is
submitted, and had the final responsibility for the decision to submit for supported by the Department of Medicine, University of Toronto and
publication. holds the Dr Murray B Urowitz Chair in Lupus Research at the
University Health Network. OA, LB, DDG, MI, SI, AL, CM, RM-L, MPe,
Declaration of interests SS, MGe, SB, and CT declare no competing interests.
CA received consultant fees from Bristol Myers Squibb, Kezar, Merck,
GSK, and Synthekine. LA received consultant fees from AbbVie, Acknowledgments
AstraZeneca, Alpine, Biogen, Bristol Myers Squibb, Boehringer- We thank Katia Baumgaertner for her invaluable role in the preparation
Ingelheim, Chugaï, GSK, Grifols, Janssen, Kezar, LFB, Lilly, Medac, of the manuscript. This work was promoted in the framework of the
Merck, Novartis, Pfizer, Roche, and UCB. RC received consultant or European Reference Network on Rare and Complex Connective Tissue
advisor fees from AstraZeneca, Celgene, GSK, Janssen, Lilly, Pfizer, UCB, and Musculoskeletal Diseases (ERN ReCONNET). ERN ReCONNET is
Rubió, Werfen, Alpine, and Thermo-Fisher. FC received grant or research one of the 24 ERNs approved by the ERN Board of Member States.
support from AstraZeneca, Bristol Myers Squibb, and GSK; participated ReCONNET-CROSSADAPT was approved by the steering committee of
in an advisory board related to sytemic lupus erthematosous for the ERN ReCONNET. The ERNs are funded by the EU. This
AstraZeneca, GSK, Celgene, Merck, Horizon Therapeutics, and publication was supported by the ERN ReCONNET grant agreement
Principabio, and received speaker fees and honoraria from AstraZeneca, 101157143.
GSK, and Bristol Myers Squibb related to sytemic lupus erthematosous. Reference
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14 www.thelancet.com/rheumatology Published online May 23, 2025 https://doi.org/10.1016/S2665-9913(25)00063-3