The British Society for Rheumatology guideline for the management of systemic lupus erythematosus in adults:
Executive Summary
Caroline Gordon Maame-Boatemaa Amissah-Arthur Mary Gayed Sue Brown Ian N. Bruce David D’Cruz Benjamin Empson Bridget Griffiths David Jayne Munther Khamashta et al
Rheumatology, kex291, doi.org/10.1093/rheumatolog...
Published: 06 October 2017
Scope and purpose of the guideline
Need for the guideline
SLE (or lupus) is a complex, multi-system autoimmune disease that affects nearly 1 in 1000 people in the UK [1]. Despite improvement in survival over the last 40 years, lupus patients still die on average 25 years earlier than the mean for women and men in the UK [2].
NICE has accredited the process used by the BSR to produce its guidance on the management of systemic lupus erythematosus in adults. Accreditation is valid for 5 years from 10 June 2013. More information on accreditation can be viewed at nice.org.uk/accreditation. For full details on our accreditation visit: nice.org.uk/accreditation.
General recommendations for the management of lupus have not been published since 2008, although European and USA guidelines for LN management were published in 2012 [3–5]. As the disease causes significant morbidity and mortality, and can be associated with the rapid accumulation of damage if not promptly diagnosed, regularly monitored and appropriately treated, an up-to-date guideline, consistent with current National Health Service (NHS) practice, is warranted to help improve the outcome of this disease.
Objectives of the guideline
To provide comprehensive recommendations, covering the diagnosis, assessment, monitoring and treatment of mild, moderate and severe active lupus disease based on a literature review (to June 2015) for non-renal lupus, supplemented as necessary by UK expert opinion and consensus agreement, and that do not imply a legal obligation. We also provide a summary of and our strength of agreement (SOA) with the EULAR and European Renal Association–European Dialysis and Transplant Association (EULAR/ERA-EDTA) recommendations for LN [4] in the full guideline [6].
Target audience
The guidelines have been developed by a multidisciplinary group established by the British Society for Rheumatology (BSR) and consisting of academic and NHS consultants in rheumatology and nephrology, rheumatology trainees, a general practitioner, a clinical nurse specialist, a patient representative and a lay member. The target audience for the guideline includes rheumatologists and other clinicians who care for lupus patients, such as nephrologists, immunologists, dermatologists, emergency medicine practitioners, general practitioners, trainees, clinical nurse specialists and other allied health professionals.
Areas that the guideline does not cover
This guideline does not cover the evidence for topical or systemic therapy for isolated cutaneous lupus, or paediatric lupus. Detailed dosing regimens are beyond the scope of this document. The management of the complications of lupus (including chronic fatigue, thrombosis, cardiovascular risk, osteoporosis, infection and cancer risk) are not discussed in detail and should be managed as for patients with similar risk factors according to relevant national and international guidelines.
Key recommendations from the guideline
The guideline was developed according to the BSR Protocol for Guidelines. The Scottish Intercollegiate Guidelines Network (SIGN) methodology [7] was used to determine the levels of evidence (LOEs) and grades of recommendations (GORs) for each statement, and these are shown in brackets below (LOE/GOR). For each recommendation, the strength of agreement (SOA) of the group was sought on a scale of 1 (no agreement) to 10 (complete agreement). The mean percentage agreement was calculated and is shown after each recommendation. Treatment strategies are summarized in Table 1. The smallest effective dose of CS should be used. More detailed comments about the recommendations, the supporting evidence and cautions are provided in the full guideline, available at Rheumatology Online. NICE guidance for use of belimumab in active autoantibody-positive SLE in adults has been published (nice.org.uk/guidance/TA397). Reimbursement for rituximab is limited to the NHS England 2013 Interim Clinical Commissioning Policy statement for rituximab in adult SLE patients (england.nhs.uk/wp-content/u....
SLE is a multisystem autoimmune disorder. The diagnosis requires a combination of clinical features and the presence of at least one relevant immunological abnormality. If there is a clinical suspicion of lupus, blood tests (including serological marker tests) should be checked (LOE 2 ++, GOR B, SOA 98%).
ANA are present in ∼95% of SLE patients. If the test is negative, there is a low clinical probability of the patient having SLE. A positive ANA test occurs in ∼5% of the adult population, and alone it has poor diagnostic value in the absence of clinical features of autoimmune rheumatic disease (2 ++/B, SOA 96%).
The presence of anti-dsDNA antibodies (2 ++/B), low complement levels (2 ++/C) or anti-Smith (Sm) antibodies (2+/C) are highly predictive of a diagnosis of SLE in patients with relevant clinical features. Anti-Ro,/La and anti-RNP antibodies are less-specific markers of SLE (2+/C) as they are found in other autoimmune rheumatic disorders as well as SLE (2+/C) (SOA 95%).
aPLs should be tested in all lupus patients at baseline, especially in those with an adverse pregnancy history or arterial/venous thrombotic events (2 ++/B). Confirmatory tests for APS are positive LA, aCL (IgG, IgM) and/or anti-beta-2 glycoprotein-1 (IgG, IgM) on two occasions at least 12 weeks apart (2 ++/B) (SOA 97%).
Assessment of SLE patients
Clinical manifestations in SLE patients may be due to disease activity, damage, drug toxicity or the presence of co-morbidity. In the case of disease activity, it is important to ascertain whether this is due to active inflammation or thrombosis, as this will define treatment strategies (LOE 2 ++, GOR B, SOA 97%).
Clinical assessment of a lupus patient should include a thorough history and review of systems, full clinical examination and monitoring of vital signs, urinalysis, laboratory tests, assessment of health status and quality of life, and measurement of disease activity and damage using standardized SLE assessment tools (2 ++/B). Imaging (4/D), renal (2 ++/B) and other biopsies (4/D) should be performed where indicated (SOA 100%).
Disease activity is categorized into mild, moderate and severe, with the occurrence of flares (2+/C). Mild disease activity is clinically stable with no life-threatening organ involvement, mainly manifestings as arthritis, mucocutaneous lesions and mild pleuritis. Patients with moderate disease activity have more serious manifestations, and severe disease activity is defined as organ- or life-threatening (4/D) (SOA 93%).
Monitoring of SLE
Patients with lupus should be monitored on a regular basis for disease manifestations, drug toxicity and co-morbidities (LOE 2 ++, GOR B, SOA 99%).
Those with active disease should be reviewed at least every 1–3 months (2+, C/D), with blood pressure (1+/A), urinalysis (1+/A), renal function (1+/A), anti-dsDNA antibodies (2 ++/B), complement levels (2+/C), CRP (2+/C), full blood count (3/C), and liver function tests (4/D) forming part of the assessment, and further tests as necessary (4/D). Patients with stable low disease activity or in remission can be monitored less frequently, for example, 6–12 monthly (4/D) (SOA 99%).
The presence of aPLs is associated with thrombotic events, damage, and adverse outcomes in pregnancy (2 ++/B). If previously negative, they should be re-evaluated prior to pregnancy or surgery, or in the presence of a new severe manifestation or vascular event (4/D) (SOA 96%).
Anti-Ro and anti-La antibodies are associated with neonatal lupus (including congenital heart block) and should be checked prior to pregnancy (1+/A) (SOA 100%).
Patients with lupus are at increased risk of co-morbidities, such as atherosclerotic disease, osteoporosis, avascular necrosis, malignancy and infection (2+/C). Management of modifiable risk factors, including hypertension, dyslipidaemia, diabetes, high BMI and smoking, should be reviewed at baseline and at least annually (4/D) (SOA 98%).
Immunosuppressive therapy may lead to toxicities. Close monitoring of drugs by regular laboratory tests and clinical assessment should be performed in accordance with drug monitoring guidelines (4/D) (SOA 98%).
Management of mild SLE
Treatments to be considered for the management of mild non–organ-threatening disease include the disease-modifying drugs HCQ (1 ++/A) and MTX (1+/A), and short courses of NSAIDs (3/D) for symptomatic control. These drugs allow for the avoidance of or dose reduction of CSs (SOA 94%).
Prednisolone treatment at a low dose of ⩽7.5 mg/day may be required for maintenance therapy (2+/C). Topical preparations may be used for cutaneous manifestations, and IA injections for arthritis (4/D) (SOA 93%).
High–Sun Protection Factor (SPF) UV-A and UV-B sunscreen are important in the management and prevention of UV radiation–induced skin lesions (2 ++/B). Patients must also be advised about sun avoidance and the use of protective clothing (4/D) (SOA 97%).
Management of moderate SLE
The management of moderate SLE involves higher doses of prednisolone (up to 0.5 mg/kg/day) (2+/C), or the use of i.m. (4/D) or i.v. doses of methylprednisolone (2+/C). Immunosuppressive agents are often required to control active disease and are steroid-sparing agents (2+/C). They can also reduce the risk of long-term damage accrual (4/D) (SOA 98%).
MTX (1+/A), AZA (2+/C), MMF (2 ++/B), ciclosporin (2+/C) and other calcineurin inhibitors (3/D) should be considered in cases of arthritis, cutaneous disease, serositis, vasculitis or cytopaenias if HCQ is insufficient (SOA 97%).
For refractory cases, belimumab (1+/B) or rituximab (2+/C) may be considered (SOA 98%).
Management of severe SLE
Patients who present with severe SLE, including renal and neuropsychiatric manifestations, need thorough investigation to exclude other aetiologies, including infection (4/D). Treatment depends on the underlying aetiology (inflammatory and/or thrombotic), and patients should be treated accordingly with immunosuppression and/or anticoagulation, respectively (4/D) (SOA 98%).
Immunosuppressive regimens for severe active SLE involve i.v. methylprednisolone (2+/C) or high-dose oral prednisolone (up to 1 mg/kg/day) (4/D) to induce remission, either on their own or more often as part of a treatment protocol with another immunosuppressive drug (4/D) (SOA 98%).
MMF or CYC are used for most cases of LN and for refractory severe non-renal disease (2 ++/B) (SOA 98%).
Biologic therapies belimumab (1+/B) or rituximab (2+/C) may be considered, on a case-by-case basis, where patients have failed to respond to other immunosuppressive drugs, due to inefficacy or intolerance (SOA 98%).
IVIG (2-/D) and plasmapheresis (3/D) may be considered in patients with refractory cytopaenias, thrombotic thrombocytopaenic purpura (1+/B), rapidly deteriorating acute confusional state and the catastrophic variant of APS (SOA 93%).
Funding: No specific funding was received from any funding bodies in the public, commercial or not-for-profit sectors to carry out the work described in these guidelines.
Disclosure statement: D.D.’C. has undertaken consultancies and received honoraria from GlaxoSmithKline/Human Genome Sciences and Roche, has been a member of the speakers’ bureau for GlaxoSmithKline/Human Genome Sciences, Union Chimique Belge (UCB) and Eli Lilly and has received research grant support from Aspreva/Vifor Pharma. C.G. has undertaken consultancies and received honoraria from Bristol-Myers Squibb, Eli-Lilly, GlaxoSmithKline, MedImmune, Merck Serono, Parexel, Roche and UCB, has been a member of the speakers’ bureau for GlaxoSmithKline, UCB and Lilly and has received research grant support from Aspreva/Vifor Pharma in the past and UCB currently. Y.N. has received funding to attend scientific meetings and received honoraria from UCB and GlaxoSmithKline. P.N. has received funding to attend scientific meetings and received honoraria from UCB. I.N.B. has undertaken consultancies and received honoraria from Astra-Zeneca, GlaxoSmithKline, MedImmune, Merck Serono, Pfizer, Roche and UCB, has been a member of the speakers’ bureau for GlaxoSmithKline, UCB and Pfizer and has received research grant income from Genzyme Sanofi, GlaxoSmithKline, UCB and Roche. B.G. has received honoraria from Pfizer. M.K. has received funding to attend scientific meetings and honoraria from AstraZeneca, MedImmune, GlaxoSmithKline, INOVA Diagnostics and UCB. S.B. has received honoraria from Actelion INB to attend scientific meetings, has undertaken consultancies and received honoraria from AstraZeneca, GlaxoSmithKline, MedImmune, Merck Serono, Pfizer, Roche and UCB and has been a member of the speakers’ bureau for GlaxoSmithKline, UCB and Pfizer. M.G. has received funding to support scientific meetings from Roche, Abbvie and Bristol-Myers Squibb. D.J. has received research grants, honoraria and consulting fees from Roche/Genentech, consulting fees from Boehringer Ingelheim, Chemocentryx, GlaxoSmithKline and Medimmune and is a Board member of Aurinia Pharmaceuticals. D.I. has consulted for Merck Serono, Eli Lilly, Celegene, UCB, XTLBio, Anthera and Baxalta; the honoraria received have been passed on to a local arthritis charity. L.L. has received research funding in grants/in kind from Roche and Genentech, has acted as an advisor to Genentech, Medimmune and Rigel and has received honoraria/travel grants from Genentech, Roche and UCB. K.S. received funding to attend a scientific meeting from Daiichi Sankyo. All other authors have declared no conflicts of interest.
References
1Rees F, Doherty M, Grainge M et al. The incidence and prevalence of systemic lupus erythematosus in the UK, 1999–2012. Ann Rheum Dis 2016;75:136–41.
2Yee CS, Su L, Toescu V et al. Birmingham SLE cohort: outcomes of a large inception cohort followed for up to 21 years. Rheumatology 2015;54:836–43.
3Bertsias G, Ioannidis JP, Boletis J et al. EULAR recommendations for the management of systemic lupus erythematosus. Report of a Task Force of the EULAR Standing Committee for International Clinical Studies Including Therapeutics. Ann Rheum Dis 2008;67:195–205.
4Bertsias GK, Tektonidou M, Amoura Z et al. Joint European League Against Rheumatism and European Renal Association–European Dialysis and Transplant Association (EULAR/ERA-EDTA) recommendations for the management of adult and paediatric lupus nephritis. Ann Rheum Dis 2012;71:1771–82.
5Hahn BH, McMahon MA, Wilkinson A et al. American College of Rheumatology guidelines for screening, treatment, and management of lupus nephritis. Arthritis Care Res 2012;64:797–808.
6Gordon C, Amissah-Arthur MB, Gayed M et al. The British Society for Rheumatology guideline for the management of systemic lupus erythematosus in adults. Rheumatol 2017; doi: 10.1093/rheumatology/kex286.
7Harbour R, Miller J. A new system for grading recommendations in evidence based guidelines. BMJ 2001;323(7308):334–6.
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© The Author 2017. Published by Oxford University Press on behalf of the British Society for Rheumatology. All rights reserved.
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