Guidelines

Introduction

The most up to date guidelines for the treatment of systemic lupus erythematosus (SLE) were published by the European League Against Rheumatism (EULAR) in 2019. This document is an update to a set of recommendations first released by the EULAR in 2008, which was followed in the succeeding decade by specific recommendations on restricted topics, including disease/response monitoring, individual manifestations (e.g., lupus nephritis), and pregnancy and female reproductive health. Advances in the management of SLE achieved in the period -2018 prompted the EULAR to update their general SLE guidelines. The American College of Rheumatology (ACR) is currently working on an SLE guideline project, with an estimated release date of early 2025.

The 2019 EULAR guidelines consist of 33 specific recommendations or statements, informed by four overarching principles:

• SLE is a multisystem disease—occasionally limited to one or few organs—diagnosed on clinical grounds in the presence of characteristic serological abnormalities
• SLE care is multidisciplinary, based on a shared patient-physician decision and should consider individual, medical and societal costs
• Treatment of organ-threatening/life-threatening SLE includes an initial period of high-intensity immunosuppressive therapy to control disease activity, followed by a longer period of less intensive therapy to consolidate response and prevent relapses
• Treatment goals include long-term patient survival, prevention of organ damage and optimization of health-related quality of life

The task force in charge of the guidelines formulated the recommendations on the basis of available evidence, assigning each recommendation a level of evidence (LoE) ranking (according to the Oxford Centre for Evidence-Based Medicine 2011 Levels of Evidence) and a strength of recommendation grade (according to the GRADE [Grading of Recommendations, Assessment, Development and Evaluations] framework). The LoEs and grades are presented in Table 9.1. Individual recommendations are organized into four groups: 1) Goals of treatment; 2) Treatment of SLE; 3) Specific manifestations; and 4) Comorbidities. The recommendations are presented in the sections below.

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Goals of Treatment

The “Goals of treatment” group includes two recommendations concerning the target goals of treatment and the general pharmacological approach to achieving those goals.

• Treatment in SLE should aim at remission or low disease activity (LoE 2b, Grade B) and prevention of flares (LoE 2b, Grade B) in all organs, maintained with the lowest possible dose of glucocorticoids
• Flares of SLE can be treated according to the severity of organ(s) involvement by adjusting ongoing therapies (glucocorticoids, immunomodulating agents) to higher doses, switching, or adding new therapies (LoE 2b, Grade C)

Treatment of SLE

The “Treatment of SLE” group contains 11 recommendations on the use of specific pharmacological agents or groups of agents, including hydroxychloroquine (2 recommendations), glucocorticoids (4 recommendations), immunosuppressive drugs (3 recommendations) and biologic agents (2 recommendations).

• Hydroxychloroquine (HCQ):
  • HCQ is recommended for all patients with SLE (LoE 1b, Grade A), unless contraindicated, at a dose not exceeding 5 mg/kg/real body weight (LoE 3b, Grade C)
  • In the absence of risk factors for retinal toxicity, ophthalmological screening (by visual fields examination and/or spectral domain-optical coherence tomography) should be performed at baseline, after 5 years, and yearly thereafter (LoE 2b, Grade B)
• Glucocorticoids (GC):
  • GC can be used at doses and route of administration that depend on the type and severity of organ involvement (LoE 2b, Grade C)
  • Pulses of intravenous methylprednisolone (usually 250-1000 mg per day, for 1-3 days) provide immediate therapeutic effect and enable the use of lower starting dose of oral GC (LoE 3b, Grade C)
  • For chronic maintenance treatment, GC should be minimized to less than 7.5 mg/day (prednisone equivalent) (LoE 1b, Grade B) and, when possible, withdrawn
  • Prompt initiation of immunomodulatory agents can expedite the tapering/discontinuation of GC (LoE 2b, Grade B).
• Immunosuppressive therapies:
  • In patients not responding to HCQ (alone or in combination with GC) or patients unable to reduce GC below doses acceptable for chronic use, addition of immunomodulating/immunosuppressive agents such as methotrexate, (LoE 1b, Grade B) azathioprine (LoE 2b, Grade C), or mycophenolate (LoE 2a, Grade B) should be considered
  • Immunomodulating/immunosuppressive agents can be included in the initial therapy in cases of organ-threatening disease (LoE 2b, Grade C)
  • Cyclophosphamide can be used for severe organ-threatening or life-threatening SLE as well as ‘rescue’ therapy in patients not responding to other immunosuppressive agents (LoE 2b, Grade C)
• Biologics:
  • In patients with inadequate response to standard-of-care (combinations of HCQ and GC with or without immunosuppressive agents), defined as residual disease activity not allowing tapering of glucocorticoids and/or frequent relapses, add-on treatment with belimumab should be considered (LoE 1a, Grade A)
  • In organ-threatening disease refractory or with intolerance/contraindications to standard immunosuppressive agents, rituximab can be considered (LoE 2b, Grade C)

Specific Manifestations

The “Specific manifestations” group includes 13 recommendations on the management of organ-/tissue-specific manifestations of SLE, including cutaneous (2 recommendations), neuropsychiatric (2 recommendations), hematological (3 recommendations) and renal (6 recommendations).

• Skin disease:
  • First-line treatment of skin disease in SLE includes topical agents (GC, calcineurin inhibitors) (LoE 2b, Grade B), antimalarials (HCQ, quinacrine) (LoE 1a, Grade A) and/or systemic GC (LoE 4, Grade C)
  • In non-responsive cases or cases requiring high-dose GC, methotrexate (LoE 3a, Grade B), retinoids (LoE 4, Grade C), dapsone (LoE 4, Grade C), or mycophenolate (LoE 4, Grade C) can be added
• Neuropsychiatric disease:
  • Attribution to SLE—as opposed to non-SLE—related neuropsychiatric manifestations, is essential and can be facilitated by neuroimaging, investigation of cerebrospinal fluid, consideration of risk factors (type and timing of the manifestation in relation to the onset of lupus, patient age, non-neurological lupus activity, presence of aPL) and exclusion of confounding factors (LoE 2b, Grade C)
  • Treatment of SLE-related neuropsychiatric disease includes glucocorticoids/immunosuppressive agents for manifestations considered to reflect an inflammatory process (LoE 1b, Grade A) and antiplatelet/anticoagulants for atherothrombotic/aPL-related manifestations (LoE 2b, Grade C)
• Hematological disease:
  • Acute treatment of lupus thrombocytopenia includes high-dose GC (including pulses of intravenous methylprednisolone) (LoE 4, Grade C) and/or intravenous immunoglobulin G (LoE 4, Grade C)
  • For maintenance of response, immunosuppressive/GC-sparing agents such as mycophenolate (LoE 2b, Grade C), azathioprine (LoE 2b, Grade C), or cyclosporine (LoE 4, Grade C) can be used
  • Refractory cases can be treated with rituximab (LoE 3a, Grade C) or cyclophosphamide (LoE 4, Grade C)
• Renal disease:
  • Early recognition of signs of renal involvement and—when present—performance of a diagnostic renal biopsy are essential to ensure optimal outcomes (LoE 2b, Grade B)
  • Mycophenolate (LoE 1a, Grade A) or low-dose intravenous cyclophosphamide (LoE 2a, Grade B) are recommended as initial (induction) treatment, as they have the best efficacy/toxicity ratio
  • In patients at high risk for renal failure (reduced glomerular filtration rate [GFR], histological presence of fibrous crescents or fibrinoid necrosis, or tubular atrophy/interstitial fibrosis), similar regimens may be considered but high-dose intravenous cyclophosphamide can also be used (LoE 1b, Grade A)
  • For maintenance therapy, mycophenolate (LoE 1a, Grade A) or azathioprine (LoE 1a, Grade A) should be used
  • In cases with stable/improved renal function but incomplete renal response (persistent proteinuria >0.8-1 g/24 hours after at least 1 year of immunosuppressive treatment), repeat biopsy can distinguish chronic from active kidney lesions (LoE 4, Grade C)
  • Mycophenolate may be combined with low dose of a calcineurin inhibitor in severe nephrotic syndrome (LoE 2b, Grade C) or incomplete renal response (LoE 4, Grade C), in the absence of uncontrolled hypertension, high chronicity index at kidney biopsy and/or reduced GFR

Comorbidities

The final recommendation group, “Comorbidities,” contains 7 recommendations on the prevention and management of three comorbidities commonly associated with SLE, including antiphospholipid syndrome (3 recommendations), infections (2 recommendations) and cardiovascular disease (2 recommendations).

• Antiphospholipid syndrome:
  • All patients with SLE should be screened at diagnosis for anti-phospholipid antibodies (aPLs) (LoE 1a, Grade A)
  • Patients with SLE with high-risk aPL profile (persistently positive medium/high titers or multiple positivity) may receive primary prophylaxis with antiplatelet agents (LoE 2a, Grade C), especially if other atherosclerotic/thrombophilic factors are present, after balancing the bleeding hazard
  • For secondary prevention (thrombosis, pregnancy complication/loss), the therapeutic approach should be the same as for primary antiphospholipid syndrome (LoE 1b, Grade B)
• Infectious diseases:
  • Patients with SLE should be assessed for general and disease-related risk factors for infections, such as advanced age/frailty (LoE –, Grade D), diabetes mellitus (LoE –, Grade D), renal involvement (LoE 2b, Grade B), immunosuppressive/biological therapy (LoE 1b-2b, Grade B-C) and use of GC (LoE 1a, Grade A)
  • General preventative measures (including immunizations) and early recognition and treatment of infection/sepsis are recommended (LoE –, Grade D)
• Cardiovascular disease:
  • Patients with SLE should undergo regular assessment for traditional (LoE 1b, Grade B-C) and disease-related risk factors for cardiovascular disease, including persistently active disease (LoE 1b, Grade B), increased disease duration (LoE 1b, Grade A), medium/high titers of aPLs (LoE 1b, Grade A), renal involvement (LoE 1b, Grade B) (especially, persistent proteinuria and/or GFR <60 mL/min) and chronic use of GC (LoE 1b, Grade B)
  • Based on their individual cardiovascular risk profile, patients with SLE may be candidates for preventative strategies as in the general population, including low-dose aspirin (LoE 2b, Grade D) and/or lipid-lowering agents (LoE 2b, Grade D)