ERN ReCONNET‑SLICC‑SLEuro Expert Consensus 2025: Therapeutic Management of Rare Systemic Lupus Erythematosus ManifestationsPubMed

Journal: Annals of the Rheumatic Diseases, 2025 Multipart international Delphi consensus project co‑developed by ERN ReCONNET (European Reference Network for Rare and Complex Connective‑tissue and Musculoskeletal Diseases), SLICC (Systemic Lupus International Collaborating Clinics), SLEuro (European Lupus Society)医脉通. Covers 24 rare organ‑specific SLE phenotypes, most lacking high‑level RCT evidence. All recommendations are severity‑stratified (non‑severe / severe / life‑threatening). Multidisciplinary expert voting; patient representatives included. ⚠️ Academic summary only, not clinical substitute for original article.

Keywords: rare SLE manifestations; neuropsychiatric SLE; lupus enteritis; lupus panniculitis; thrombotic microangiopathy; retinal vasculitis; Delphi consensus

Background

Main‑stream SLE guidelines focus on common organ manifestations (lupus nephritis, mucocutaneous, arthritis). Multiple rare, potentially disabling or fatal SLE phenotypes are under‑addressed in formal guidelines, evidence largely limited to case series and observational cohorts. This consensus provides pragmatic treatment algorithms for 24 rare manifestations across haematological, gastrointestinal, pulmonary, cutaneous, ocular, neurological and thrombotic domains.

Overarching General Principles

1. Distinguish true SLE‑related immune injury from antiphospholipid‑mediated thrombosis, infection, drug toxicity and comorbid conditions before escalating immunosuppression.
2. All recommendations are stratified by severity: non‑severe; severe; life‑threatening. Life‑threatening manifestations require urgent MDT (rheumatology plus relevant organ specialists).
3. Hydroxychloroquine should be maintained in nearly all patients unless contraindicated.
4. Glucocorticoids are almost always part of induction, but aim for rapid steroid‑sparing via steroid‑free maintenance regimens whenever feasible.
5. For refractory rare phenotypes: rituximab is a preferred rescue option; anifrolumab may be considered for selected cutaneous and systemic rare presentations.
6. Antiphospholipid status must be systematically assessed for every rare SLE manifestation, as management differs substantially for APS‑related complications.
7. Plasma‑exchange / intravenous immunoglobulin (IVIG) are reserved for severe/life‑threatening scenarios, not routine first‑line therapy.

Selected Core Manifestations & Consensus‑Endorsed Therapeutic Strategies

1. Cutaneous rare SLE

Lupus panniculitis (lupus profundus)

- Non‑severe: hydroxychloroquine ± low‑dose glucocorticoids; add methotrexate / mycophenolate mofetil (MMF) for partial response. - Severe, progressive disease: medium‑dose glucocorticoid, MMF or azathioprine; conditional support for anifrolumab in refractory cases医脉通.

TEN‑like acute cutaneous lupus / bullous SLE

- Severe presentation: pulse methylprednisolone + MMF; rituximab for non‑responders. IVIG for severe mucosal involvement.

2. Gastro‑intestinal rare SLE

Lupus enteritis / mesenteric vasculitis

- Non‑severe: oral glucocorticoid + MMF / azathioprine. - Severe (ischaemia‑risk, bleeding): IV methylprednisolone pulse + cyclophosphamide (Euro‑Lupus regimen). Rituximab for cyclophosphamide‑refractory cases. Rule‑out APS thrombosis before immunosuppression escalationPMC.

Lupus hepatitis (autoimmune‑type, exclude drug‑/viral‑induced)

- Mild: hydroxychloroquine + low‑dose steroids + MMF. - Severe cytolytic hepatitis: pulse steroids, cyclophosphamide or rituximab.

3. Neuro‑psychiatric SLE (rare phenotypes)

Multiple mononeuritis multiplex

- Severe: methylprednisolone pulse → oral GC 0.5‑1 mg/kg/d + cyclophosphamide induction; maintenance with MMF. - Non‑severe: medium‑dose GC + MMF / azathioprine; rituximab for refractoriness医脉通.

Lupus myelitis (transverse myelitis)

- Life‑threatening: IV methylprednisolone pulse + cyclophosphamide. Rituximab as alternative induction. Plasma‑exchange may be added for rapidly progressive disease. Long‑term maintenance MMF / azathioprine.

Cerebral vasculitis SLE

- Life‑threatening: pulse steroids + cyclophosphamide; rituximab rescue; consider plasma‑exchange. Differentiate from APS‑related cerebral thrombosis.

4. Ocular rare SLE

Retinal vasculitis / occlusive retinal vasculopathy SLE

- Severe sight‑threatening: IV methylprednisolone pulse + cyclophosphamide or rituximab. Concurrent ophthalmology MDT. Distinguish from APS‑mediated retinal thrombosis (requires anticoagulation).

Peripheral ulcerative keratitis

- Systemic immunosuppression (GC + MMF / rituximab); close ophthalmologic co‑management; rule‑out infection and vasculitis overlap.

5. Haematological‑thrombotic rare SLE

SLE‑associated thrombotic microangiopathy (TMA, exclude primary TTP)

Key distinction: SLE‑immune‑mediated TMA versus APS‑TMA. - Immune‑mediated TMA: pulse methylprednisolone + rituximab; plasma‑exchange adjunct. Cyclophosphamide alternative. - If antiphospholipid antibodies drive TMA: anticoagulation is mandatory alongside immunosuppression.

Autoimmune neutropenia severe refractory

- First‑line: GC + MMF / azathioprine. Rituximab for steroid‑dependent refractory cases. G‑CSF for symptomatic severe neutropenia with infection risk.

6. Rare pulmonary SLE

Shrinking‑lung syndrome

- Induction: medium‑high‑dose glucocorticoid + MMF / azathioprine; rituximab for refractory patients. No evidence for cyclophosphamide as routine first‑line. Physiotherapy as essential adjunct.

Rescue Therapy Hierarchy for Refractory Rare SLE Manifestations

1. Optimise baseline: confirm diagnosis, exclude infection/APS/drug injury; ensure adequate hydroxychloroquine.
2. Switch or escalate conventional synthetic immunosuppressant (MMF, azathioprine, methotrexate).
3. Rituximab (preferred biologic rescue for most severe refractory rare SLE phenotypes).
4. Anifrolumab: conditional recommendation for selected cutaneous and systemic manifestations.
5. Cyclophosphamide: reserved for life‑threatening organ damage.
6. IVIG / plasma‑exchange: adjunctive rescue for life‑threatening presentations only.

Key Diagnostic Caveats Emphasised in Consensus

1. Many “rare SLE manifestations” may be APS‑driven rather than pure SLE immune injury; treatment differs (anticoagulation mandatory for APS thrombosis).
2. Infection must be rigorously excluded before high‑dose immunosuppression for any rare severe presentation.
3. Biomarkers such as anti‑dsDNA and complement may be normal in isolated rare organ SLE manifestations.

Comparison with prior EULAR 2023 SLE recommendations

表格

Item	ERN‑ReCONNET/SLICC/SLEuro 2025 Rare‑Manifestation Consensus	EULAR 2023 SLE Recommendations
Scope	24 rare organ‑specific SLE phenotypes, severity‑stratified algorithms	Focus on common major organ manifestations (nephritis, neuropsychiatric SLE general guidance)
Rituximab positioning	Preferred rescue for most refractory rare severe SLE	Conditional for refractory major organ SLE
Anifrolumab	Conditional use for selected rare cutaneous/systemic phenotypes	Mainly addressed for mucocutaneous and arthritis
APS differentiation	Explicit, systematic requirement for every rare manifestation	Mentioned but not embedded within each organ algorithm
Plasma‑exchange / IVIG	Restricted strictly to life‑threatening rescue setting	Similar restriction, no phenotype‑specific voting

Disclaimer: this structured summary reflects the consensus framework. Clinical decisions should refer to the full‑text original publication.