Systemic lupus erythematosus (SLE) is a multisystem autoimmune disease with variable presentation, course and prognosis.
Recommendations for its management, endorsed by the European League Against Rheumatism (EULAR), were first published in 2008. Due to the emergence of new data on treatment strategies and goals of treatment, an update of these recommendations was deemed appropriate. This involved a multidisciplinary task force and was based on combination of evidence base (in the form of a systematic literature review, period 01/2007-12/2017, to address 15 different research questions) and expert opinion.1
General principles and choice of drugs
Treatment in SLE should aim at remission or at least low disease activity in all organ systems, and prevention of flares. The latter can be treated according to the severity of organ involvement, either by adjusting current therapies to higher doses or switching to alternative drugs.
Hydroxychloroquine (HCQ) is recommended for all patients with SLE, in the absence of contraindications, at a dose not exceeding 5mg/kg real body weight. Ophthalmological screening for retinal toxicity should be performed at baseline, after 5 years and yearly thereafter, by means of optical coherence tomography, 10-2 visual fields, or both (fundoscopy may be sufficient only for the baseline examination).
Glucocorticoid (GC) dose for chronic treatment should be minimised to less than 7.5mg/d prednisone equivalent or, when possible, withdrawn. To this end, use of pulse intravenous methylprednisolone may allow for a lower starting dose of oral GC, whereas early initiation of immunosuppressive (IS) drugs may assist in tapering and ultimately discontinuing GC.
Methotrexate (MTX), azathioprine (AZA), mycophenolate mofetil (MMF), or belimumab should be considered in patients not responding to HCQ in combination with GC, or in patients unable to reduce GC below 7.5-10 mg/d. Cyclophosphamide (CYC) should be reserved for organ- or life-threatening disease, and as a rescue therapy in refractory non-major organ manifestations.
Regarding biologic agents, belimumab should be considered in extrarenal disease with inadequate control to standard of care (combination of HCQ with GC with or without IS agents), frequent flares, and/or inability to taper GC. Patients with refractory cutaneous and musculoskeletal manifestations who are serologically active may respond better to the drug. In organ-threatening disease refractory or contraindicated to standard immunosuppressive agents (including CYC), rituximab (RTX) can be considered, despite its off-label status.
Individual manifestations of SLE
For skin manifestations of SLE, effective protection from ultraviolet exposure with sunscreens and smoking cessation are strongly recommended. First-line treatment includes topical agents (GC, calcineurin inhibitors) and antimalarials, with or without systemic GC. In non-responding cases, MTX, retinoids, dapsone, or MMF can be added.
Attribution of neuropsychiatric manifestations to SLE requires a multidisciplinary approach to rule out mimics (infections, malignancy and others). Neuroimaging, cerebrospinal fluid analysis, consideration of risk factors (type and timing of the manifestation in relation to the onset of lupus, patient age, non-neurological disease activity, presence of antiphospholipid antibodies (aPL)) are essential in the diagnostic process.
Treatment of SLE-related neuropsychiatric disease includes GC and IS agents for a presumed inflammatory process (for example, psychosis, myelopathy, acute confusional state) and antiplatelet/anticoagulants for atherothrombotic/aPL-related manifestations, especially stroke. Targeted symptomatic therapy is indicated according to the type of manifestation (for example, antipsychotics for psychosis, anxiolytics for anxiety disorders).
Haematological disorders needing IS treatment are thrombocytopenia and autoimmune haemolytic anaemia. Lupus thrombocytopenia warrants therapy for platelet counts <20-30000/mm³. First-line treatment consists of high dose GC (including pulses of intravenous methylprednisolone) with or without intravenous immunoglobulin (IVIG). For the sustainment of response, MMF, AZA or cyclosporine can be used. In refractory cases, RTX or CYC should be considered. The same general principles apply for the treatment of autoimmune haemolytic anaemia.
Vigilance for early recognition of signs of kidney involvement and performance of kidney biopsy for the diagnosis of lupus nephritis (LN) are essential to ensure better outcomes. For initial (“induction”) treatment, MMF and low-dose CYC (Euro-Lupus regimen) are recommended, as they have the best efficacy/toxicity ratio.
In severe forms of LN, associated with increased risk of progression into end-stage kidney disease (reduced glomerular filtration rate, histological presence of fibrous crescents or fibrinoid necrosis, or tubular atrophy/interstitial fibrosis), high-dose intravenous CYC can also be considered. For subsequent (“maintenance”) therapy, MMF or AZA should be used, the former being associated with fewer relapses. MMF may be combined with low dose of a calcineurin inhibitor (especially tacrolimus) in class V LN, podocytopathy or in proliferative disease with refractory nephrotic syndrome.
In cases with incomplete renal response (persistent proteinuria> 0.8-1gr/24h after at least one year of IS treatment) or nephritic flares, repeat biopsy can distinguish chronic from active lesions or a possible histologic transition, respectively.
SLE comorbidities
All patients with SLE should be screened for aPL at diagnosis. Patients with SLE and high-risk aPL profile (persistently positive medium/high titres or multiple positivity), should receive primary prophylaxis with antiplatelet agents, especially if additional atherosclerotic/thrombophilic factors are present. For secondary prevention, treatment should not differ from the treatment of primary antiphospholipid syndrome (APS).2
Increased risk of infection in SLE is attributed to both disease-related and treatment-related factors. High-dose GC therapy, CYC, MMF and RTX are related with an increased risk of infection, as is the case with high disease activity, severe leukopenia and kidney involvement. General preventive measures, including vaccinations, and early recognition and treatment of infection are recommended.
SLE is an independent risk factor for cardiovascular disease (CVD) and patients should undergo regular assessment for traditional and disease-related risk factors such as persistent disease activity, history of LN, presence of aPL and use of GC. Lupus patients may be candidates for CVD-preventive strategies, including lipid-lowering agents and low-dose aspirin, based on individual risk stratifications and calculation of the 10-year cardiovascular risk.
Authors
Sofia Koutsoviti MD
Antonis Fanouriakis MD, PhD
Department of Rheumatology, “Asklepieion” General Hospital, Athens, Greece
References
- Fanouriakis A et al. 2019 update of the EULAR recommendations for the management of systemic lupus erythematosus Ann Rheum Dis 2019;78:736-45.
- Tektonidou M et al. EULAR recommendations for the management of antiphospholipid syndrome in adults. Ann Rheum Dis 2019;78:1296-30.
