The British Society for Rheumatology Guideline for the Management of Systemic Lupus Erythematosus in Adults

Caroline Gordon; Maame-Boatemaa Amissah-Arthur; Mary Gayed; Sue Brown; Ian N. Bruce; David D'Cruz; Benjamin Empson; Bridget Griffiths; David Jayne; Munther Khamashta; Liz Lightstone; Peter Norton; Yvonne Norton; Karen Schreiber; David Isenberg

Disclosures

Rheumatology. 2018;57(1):e1-e45.

Scope and Purpose of the Guideline

Background

SLE (or lupus for short) is a multisystem, autoimmune disease, involving complex pathogenetic mechanisms that can present at any age. It most commonly presents in women in the reproductive age group, although lupus is increasingly recognized after the age of 40 years, particularly in Europeans.^[1–3] Lupus affected nearly 1 in 1000 of the population in the UK in 2012^[4] and was most frequently observed in people of African-Caribbean and South Asian descent.^[4–6] The age-standardized incidence in the UK according to the Clinical Practice Research Datalink is 8.3/100 000/year for females and 1.4/100 000/year for males,^[4] and the highest incidence rates are seen in those of African-Caribbean descent: 31.4/100 000/year, compared with 6.7/100 000/year for those of white European descent. The mean age at diagnosis is 48.9 years,^[4] but it is lower in those of African ancestry in the UK^[4–6] and North America.^[2,7]

The disease is prone to relapses and remissions, resulting in considerable morbidity due to flares of disease activity and accumulated damage, and an increased risk of premature death, mostly due to infection or cardiovascular disease.^[2,8–14] Death from active lupus is rare in the UK;^[15,16] however, a 10% mortality over 20 years and a mean age of death of 53.7 years was recently reported.^[16] About one-third of SLE patients in the UK develop LN.^[16–18] Patients of African ancestry tend to present young with LN in the UK, as in the USA and elsewhere,^[2,17,19] and are at considerable risk of developing end-stage renal disease (ESRD) and of dying prematurely. In another UK cohort, ESRD occurred in 20% of LN patients within 10 years of diagnosis, and the mean age at death in LN patients was 40.3 years, with an average of 7.5 years between development of LN and death.^[18]

The mainstay of therapy for active lupus until recently has been NSAIDs, CSs, antimalarials such as HCQ, and immunosuppressants such as AZA and CYC, although only prednisolone and HCQ are licensed for lupus.^[8,20] With the exception of LN, there were relatively few trials until the last 15 years, and in 2011, belimumab became the first drug to be licensed for the treatment of active lupus for over 50 years.^[20] New therapies that will reduce the need for CSs to control lupus activity and to reduce the development of damage and infection are needed to improve outcome.^{[10–12,16,21]} In the meantime it is important to manage patients optimally with the treatment strategies that are available.

Need for the Guideline

Despite some improvement in survival data over the last 40 years,^[2,13] lupus patients still die on average 25 years earlier than the mean for women and men in the UK.^[16] The disease can present with slowly or rapidly progressive active disease at any age and can be associated with the rapid accumulation of damage if not promptly diagnosed, appropriately treated and regularly monitored.^{[2,8,14,19,20]} An up-to-date comprehensive guideline to optimize these aspects of management that is consistent with current evidence and National Health Service (NHS) practice is warranted to improve the outcome of this variable and potentially life-threatening disease that causes considerable morbidity. There have been no previous UK-based guidelines for lupus. The European (EULAR) recommendations for the management of lupus in general were not very detailed and were published in 2008,^[22] although more specific recommendations were published for neuropsychiatric lupus in 2010,^[23] and joint EULAR and European Renal Association–European Dialysis and Transplant Association (EULAR/ERA-EDTA) recommendations for LN were published in 2012,^[24] as well as ACR guidelines for the management of LN in 2012.^[25]

Objectives of the Guideline

The aim of this guideline was to produce recommendations for the management of adult lupus patients in the UK that cover the diagnosis, assessment and monitoring of lupus and the treatment of mild, moderate and severe active lupus disease, but which do not imply a legal obligation. The resulting recommendations are based on an extensive review of the literature up to June 2015 to produce evidence-based guidelines, particularly for the treatment of non-renal lupus, supplemented as necessary by expert opinion and consensus agreement (Table 1 and Table 2). The guideline development group recommended that patients with LN are managed according to the EULAR/ERA-EDTA recommendations for LN^[24] and provide their strengths of agreement (SOAs) with a summary of the most important items in those recommendations (Table 3).

Target Population, Target Audience and Stakeholder Involvement

The guidelines address the management of adult patients only and have been developed by a multidisciplinary guideline development group set up by the British Society for Rheumatology (BSR) and led by C.G., consisting of academic (C.G., I.N.B., D.D.C., M.K., D.I.) and NHS consultants in rheumatology (M.A., B.G.) and nephrology (D.J., L.L.), rheumatology trainees (M.G., K.S.), a GP (B.E.), a clinical nurse specialist (S.B.), a patient representative (Y.N.) and a lay member (P.N.). All participants declared any conflicts of interest and these are listed at the end of this article. The target audience includes rheumatologists and other clinicians such as nephrologists, immunologists and dermatologists, trainees in these specialties and emergency medicine, GPs, clinical nurse specialists and other allied health professionals involved in the care of adult lupus patients. Opinions of other key stakeholders such as other consultant members of the BSR, additional trainees, podiatrists, nurse specialists and representatives of Lupus UK were sought during the preparation of these guidelines.

Areas That the Guideline Does not Cover

This guideline does not cover the evidence for topical or systemic therapy for isolated cutaneous lupus, nor does it discuss paediatric lupus, as there is relatively little literature on paediatric lupus. As the disease tends to come on after puberty, most of the recommendations are likely to be appropriate for children/adolescents, with suitable dose modifications. We provide only summary advice about the use of drugs in the management of pregnant lupus patients, and refer to the extensive review of drugs used in pregnancy and breast-feeding that have been recently published.^[239,240] The management of complications of lupus, including chronic fatigue, cardiovascular risk, osteoporosis, infection and cancer risk are not discussed in detail, as these issues should be managed as for other patients with similar risk factors according to national and international guidelines. Management of thrombosis will depend on whether or not the criteria for APS are met.^[241]

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17

Next Section

Table 1. Levels of evidence and grades of recommendation for diagnosis, assessment and monitoring of non-renal SLE
Statement/item	Number of studies	Overall SIGN level of evidence	Grade of recommendation	Selected references covering items discussed in text
Diagnosis from clinical and serological features
Prognostic value of:
Clinical features ANA Anti-dsDNA antibodies Low C3/C4 levels Anti-Ro/La antibodies aPLs	29 8 17 13 4 12	2 ++ 2 ++ 2 ++ 2 + 2 + 2 ++	B B B C C B	[7, 10, 26–35] [26–29, 34, 36–38] [26–29, 37, 39, 40] [27, 41–46] [10, 27–29, 37] [26, 27, 29, 47]
Assessment and monitoring of SLE disease activity and damage
Clinical flare	6	2+	C	[48, 49]
Good diagnostic utility of:
clinical and laboratory monitoring anti-dsDNA and C3/C4 levels aPL repeat anti-Ro/La for neonatal lupus	28 14 – 6	2 ++ 2 ++ – 1+	B B D A	[11, 16, 21, 32, 50–57] [40, 43, 44, 46, 49, 58–60, 61–63] [47] [64, 65]
CRP low or normal unless infection	4	2+=	B	[66–69]
ESR correlates with active lupus	2	2+	C	[69, 70]
Prognostic value of lupus disease activity and damage indices	>60	2 ++	B	Reviewed in [12, 71] [11, 14–16, 32, 72, 73]
Monitoring and treating cardiovascular risk factors in SLE patients	6	2+	C	Reviewed in [22, 71, 74–76]
Frequency of monitoring SLE:
For active disease, every 1–3 months after diagnosis or flare Low/no disease activity, stable treatment: 6- to 12-monthly	2 –	2+ –	C D	[72, 77] Expert opinion
Monitoring for drug toxicity/levels	2	2+	C	[78, 79]

SIGN: Scottish Intercollegiate Guidelines Network

Table 2. Levels of evidence and grades of recommendation for medications used in the treatment of non-renal SLE
Treatment (recommended target dosage)	Main uses (unless contra-indications)	Total number of papers	Overall SIGN level of evidence	Grade of recommendation	Comments: including number of reports and references for RCTs, cohort studies and systematic reviews/meta-analyses (SRs)
Antimalarials: HCQ ⩽6.5 mg/kg/day	Mild lupus, prevent flare in all patients, prevent damage, steroid-sparing	45	1 ++	A	7 RCTs [80–86]; 36 cohort studies [87–120]; 2 SRs [121, 122]
MTX ⩽25 mg/week	Mild and moderate lupus, prevent flare, steroid sparing	12	1+	A	2 blind, 1 open-label RCTs [123–125]; 5 cohort studies [126–130]; 2 case series [131, 132]; 2 SRs [133, 319]
NSAIDs	Symptom control in mild non-renal lupus only	1	3	D	1 SR covers case series/reports [134]
Sunscreen (high-SPF UV-A and UV-B)	Prevents UV-induced rashes and other manifestations	7	2 ++	B	1 blind RCT [135]; 5 cohort studies [136–140]; 1 case series [141]
Low-dose oral prednisolone (⩽7.5 mg)	Mild lupus and to prevent flares	0	4	D	Expert opinion
Higher doses of oral prednisolone ⩽0.5 mg/kg/day	Moderate lupus and prevention of flares	0 2	4 2+	D C	To prevent flare: 1 blind RCT [46] and 1 open-label RCT [60]
I.m. triamcinolone	Moderate lupus	1	2+	C	1 open-label RCT [142]
I.m. methylprednisolone (80–120 mg)	Moderate lupus	0	4	D	Expert opinion
I.v. methylprednisolone (100–250 mg)	Moderate lupus	1	2+	C/D	1 blind RCT for 100 mg vs 1000 mg [143]
I.v. methylprednisolone (500 mg–1 g) × 1–3 pulses	Moderate and severe lupus	6	2+	C	2 small blind RCTs [143, 144]; 1 open-label trial [145]; 3 cohort studies [146–148]
AZA (if TPMT normal) 2–3 mg/kg/day	Moderate lupus, prevent flare, steroid sparing	10	2+	C	4 open-label RCTs [149–152]; 5 cohort studies [153–157]; 1 case series [158]
MMF 2–3 g/day	Moderate/severe lupus, prevent flare, steroid-sparing	13	2 ++	B	3 open-label RCTs [159–161]; 7 cohort studies [162–168]; 1 case series [169]; 2 SRs [133, 170]
Mycophenolic acid/sodium 1.44–2.16 g/day	For patients intolerant of MMF	2	3	D	1 open-label RCT [171]; 1 cohort study [172]
Ciclosporin ⩽2.5 mg/kg/day	Moderate/severe lupus including cytopenias, prevent flare, steroid-sparing	11	2+	C	2 open-label RCTs [152, 173]; 8 cohort studies [174–181]; 1 SR [133]
Tacrolimus 1–3 mg/day (assess drug levels)	Moderate/severe lupus, steroid-sparing	3	3	D	2 cohort studies [182, 183]; 1 SR [133]
LEF (20 mg/day)	Moderate lupus without subacute rash	3	3	D	1 small blind RCT [184]; 1 cohort study [185]; 1 SR [133]
CYC (see text for dosing)	Severe lupus, including NPSLE, prevent flare, steroid-sparing	30	2 ++	B	4 open-label RCTs [186–189]; 25 cohort studies covered by 1 SR [133]
Rituximab 1000 mg × 2	Refractory severe and moderate lupus; steroid-sparing	33	2+	C	1 blind RCT [190, 191]; 3 open-label RCTs [192–194]; 24 cohort studies [195–198 not in SRs]; 2 case series [194, 199]; 2 SRs, including 1 meta-analysis [200, 201]; 1 SR with 26 extra case reports/series [202]
Belimumab 10 mg/kg/4 weeks	Refractory moderate/severe lupus; prevent flare and steroid-sparing (not NPSLE)	5	1+	B	2 phase III blind RCTs [203, 204]; 1 phase II blind RCT [205]; post hoc combined analysis [206]; 1 open-label extension [207, 208]; 1 meta-analysis [209]
IVIG (see text)	Refractory severe lupus (including catastrophic APS)	19	2−	D	Rarely indicated: 3 open-label trials [210–212]; 10 cohort studies [213–222]; 4 case series [223–226]; 2 SRs with 1 meta-analysis [227, 228]
Plasmapharesis	TTP; refractory severe SLE	10	2 ++ for TTP; 3 otherwise	B for TTP; D otherwise	Rarely indicated: 9 cohort/case series [229–237]; 1SR [238]

TPMT: thiopurine S-methyltransferase (see text); TTP: thrombocytopaenic purpura.

Table 3. Strength of agreement of authors with the main EULAR/ERA-EDTA recommendations for the management of LN
Management of SLE patients with renal involvement	SOA^a
Assessment of renal involvement
1. Indications for first renal biopsy in SLE	97
Any sign of renal involvement—in particular, urinary findings such as reproducible proteinuria ⩾0.5 g/24 h, especially with glomerular haematuria and/or cellular casts—should be an indication for renal biopsy. Renal biopsy is indispensable since, in most cases, clinical, serologic and laboratory tests cannot accurately predict renal biopsy findings.	97
2. Pathological assessment of kidney biopsy	98
The use of the International Society of Nephrology/Renal Pathology Society (ISN/RPS) 2003 classification system is recommended, with assessment not only of active and chronic glomerular and tubulointerstitial changes, but also of vascular lesions associated with aPLs/APS.	98
Treatment of renal involvement
3. Indications and goals of immunosuppressive treatment in LN	98
3.1 Initiation of immunosuppressive treatment should be guided by a diagnostic renal biopsy. Immunosuppressive agents are recommended in class III_A or III_A/C (±V) and IV_A or IV_A/C (±V) nephritis, and also in pure class V nephritis if proteinuria exceeds 1 g/24 h despite the optimal use of renin–angiotensin–aldosterone system blockers.	98
3.2 The ultimate goals of treatment in LN are long-term preservation of renal function, prevention of disease flares, avoidance of treatment-related harms and improved quality of life and survival. Treatment should aim for complete renal response with UPCR <50 mg/mol and normal or near-normal (within 10% of normal GFR if previously abnormal) renal function. Partial renal response, defined as ⩾ 50% reduction in proteinuria to subnephrotic levels and normal or near-normal renal function, should be achieved preferably by 6 months but no later than 12 months following initiation of treatment.	98
4. Treatment of adult LN—initial treatment
4.1 For patients with class III_A or III_A/C (±V) and class IV_A or IV_A/C (±V) LN, mycophenolic acid (MPA) (MMF target dose: 3 g/day for 6 months, or MPA sodium at equivalent dose) or low-dose i.v. CYC (total dose 3 g over 3 months), in combination with glucocorticoids, are recommended as initial treatment as they have the best efficacy/toxicity ratio.	93
4.2 In patients with adverse prognostic factors (acute deterioration in renal function, substantial cellular crescents and/or fibrinoid necrosis), similar regimens may be used, but CYC can also be prescribed monthly at higher doses (0.75–1 g/m²) for 6 months or orally (2–2.5 mg/kg/day) for 3 months.	92
4.3 To increase efficacy and reduce cumulative glucocorticoid doses, treatment regimens should be combined initially with three consecutive pulses of i.v. methylprednisolone 500–750 mg, followed by oral prednisone 0.5 mg/kg/day for 4 weeks, reducing to ⩽ 10 mg/day by 4–6 months	98
4.4 In pure class V nephritis with nephrotic-range proteinuria, MPA (MMF target dose 3 g/day for 6 months) in combination with oral prednisone (0.5 mg/kg/day) may be used as initial treatment based on better efficacy/toxicity ratio. CYC or calcineurin inhibitors (ciclosporin, tacrolimus) or rituximab are recommended as alternative options or for non-responders.	95
4.5 AZA (2 mg/kg/day) may be considered as an alternative to MPA or CYC in selected patients without adverse prognostic factors (as defined 4.2), or when these drugs are contraindicated, not tolerated or unavailable. AZA use is associated with a higher flare risk.	96
Subsequent treatment
4.6 In patients improving after initial treatment, subsequent immunosuppression is recommended with either MPA at lower doses (initial target MMF dose 2 g/day) or AZA (2 mg/kg/day) for at least 3 years, in combination with low-dose prednisone (5–7.5 mg/day). Gradual drug withdrawal, glucocorticoids first, can then be attempted.	97
4.7 Patients who responded to initial treatment with MPA should remain on MPA unless pregnancy is contemplated, in which case they should switch to AZA at least 3 months prior to conception.	98
4.8 Calcineurin inhibitors can be considered in pure class V nephritis.	93
Refractory disease
4.9 For patients who fail treatment with MPA or CYC, either because of lack of effect (as defined above) or due to adverse events, we recommend that the treatment is switched from MPA to CYC, or CYC to MPA, or that rituximab be given.	95
5. Adjunct treatment in patients with LN
5.1 Angiotensin-converting enzyme inhibitors or angiotensin receptor blockers are indicated for patients with proteinuria (UPCR >50 mg/mmol) or hypertension.	98
6. Management of end-stage renal disease in LN
6.1 All methods of renal replacement treatment can be used in lupus patients, but there may be increased risk of infections in peritoneal dialysis patients still on immunosuppressive agents, and vascular access thrombosis in patients with aPLs.	98
6.2 Transplantation should be performed when lupus activity has been absent, or at a low level, for at least 3–6 months, with superior results obtained with living donor and pre-emptive transplantation. aPLs should be sought during transplant preparation because they are associated with an increased risk of vascular events in the transplanted kidney.	96
7. APS-associated nephropathy in SLE
7.1 In patients with lupus and APS-associated nephropathy (APSN), HCQ and/or antiplatelet/anticoagulant treatment should be considered.	91

^aReproduced from Bertsias 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 71: 771–82. Copyright 2012, with permission from BMJ Publishing Group Ltd [24]. Numbers are mean (s.d.) and median (IQR) agreement level among authors. A score of 10 represents the highest SOA. GFR: glomerular filtration rate; SOA: strength of agreement; UPCR: urine protein:creatinine ratio.

Table 4. The ACR criteria for classification of SLE ^a
Criterion	Definition
Malar rash	Fixed erythema, flat or raised, over the malar eminences, tending to spare the nasolabial folds
Discoid rash	Erythematous raised patches with adherent keratotic scaling and follicular plugging; atrophic scarring may occur in older lesions
Photosensitivity	Skin rash as a result of unusual reaction to sunlight, by patient history or physician observation
Oral ulcers	Oral or nasopharyngeal ulceration, usually painless, observed by a physician
Arthritis	Non-erosive arthritis involving two or more peripheral joints, characterized by tenderness, swelling or effusion
Serositis	Pleuritis: convincing history of pleuritic pain or rub heard by a physician or evidence of pleural effusion OR Pericarditis: documented by ECG or rub or evidence of pericardial effusion
Renal disorder	Persistent proteinuria >0.5 g/day or > 3+ if quantitation not performed OR
Renal disorder	Cellular casts: may be red cell, haemoglobin, granular, tubular or mixed
Neurologic disorder	Seizures: in the absence of offending drugs or known metabolic derangements; e.g. uremia, ketoacidosis or electrolyte imbalance OR
Neurologic disorder	Psychosis: in the absence of offending drugs or known metabolic derangements, e.g. uremia, ketoacidosis or electrolyte imbalance
Haematologic disorder	Haemolytic anaemia with reticulocytosis OR
	Leukopenia <4000/mm³ total on two or more occasions OR
	Lymphopenia <1500/mm³ on two or more occasions OR
	Thrombocytopenia <100 000/mm³ in the absence of offending drugs
Immunologic disorder	Anti-DNA: antibody to native DNA in abnormal titre OR
	Anti-Sm: presence of antibody to Sm nuclear antigen OR
	Positive finding of aPLs on: an abnormal serum level of IgG or IgM aCL; a positive test result for LA using a standard method, or; a false positive test result for at least 6 months confirmed by Treponema pallidum immobilization or the fluorescent treponemal antibody absorption test
ANA	An abnormal titre of ANA by immunofluorescence, or an equivalent assay at any point in time and in the absence of drugs known to be associated with drug-induced lupus syndrome

^aThe proposed classification is based on 11 criteria. For the purpose of identifying patients in clinical studies, a person shall be said to have SLE if any 4 or more of the 11 criteria are present, serially or simultaneously, during any interval of observation. Adapted from Tan EM et al. The 1982 revised criteria for the classification of systemic lupus erythematosus. Arthritis Rheum 25:1271–7, copyright 1982 [255]; and Hochberg MC. Updating the American College of Rheumatology revised criteria for the classification of systemic lupus erythematosus. Arthritis Rheum 40:1725, copyright 1997 [256], with permission from John Wiley & Sons. Anti-Sm: anti-Smith antibody.

Table 5. Clinical and Immunologic Criteria Used in the SLICC Classification Criteria for SLE ^a
Clinical Criteria
Acute cutaneous lupus including:
lupus malar rash (do not count if malar discoid), bullous lupus, toxic epidermal necrolysis variant of SLE, maculopapular lupus rash, photosensitive lupus rash, (in the absence of dermatomyositis), or subacute cutaneous lupus, nonindurated psoriaform and/or annular polycyclic lesions that resolve without scarring, although occasionally with postinflammatory dyspigmentation or telangiectasias)
Chronic cutaneous lupus including:
classical discoid rash, localized (above the neck), generalized (above and below the neck), hypertrophic, (verrucous) lupus, lupus panniculitis (profundus), mucosal lupus, lupus erythematosus tumidus, chilblains lupus, discoid lupus/lichen planus overlap
Oral ulcers:
Palate, buccal, tongue, or nasal ulcers (in the absence of other causes, such as vasculitis, Behcet's disease, infection (herpes viruses), inflammatory bowel disease, reactive arthritis, acidic foods)
Nonscarring alopecia:
diffuse thinning or hair fragility with visible broken hairs (in the absence of other causes such as alopecia areata, drugs, iron deficiency and androgenic alopecia)
Synovitis involving two or more joints:
characterized by swelling or effusion or tenderness in 2 or more joints and thirty minutes or more of morning stiffness .
Serositis:
typical pleurisy for > 1 day or pleural effusions or pleural rub or typical pericardial pain (pain with recumbency improved by sitting forward) for > 1 day or pericardial effusion or pericardial rub or pericarditis by EKG (in the absence of other causes, such as infection, uremia, and Dressler's pericarditis)
Renal:
Urine protein:creatinine ratio (or 24 hr urine protein) representing 500 mg of protein/24 hr or red blood cell casts
Neurologic:
seizures, psychosis, mononeuritis multiplex (in the absence of other known causes such as primary vasculitis), myelitis, peripheral or cranial neuropathy (in the absence of other known causes such as primary vasculitis, infection, and diabetes mellitus), acute confusional state (in the absence of other causes, including toxic-metabolic, uremia, drugs)
Hemolytic anemia
Leukopenia: < 4000/mm³ at least once (in the absence of other known causes such as Felty's, drugs, portal hypertension)
OR
Lymphopenia: < 1000/mm³ at least once (in the absence of other known causes such as corticosteroids, drugs and infection)
Thrombocytopenia: <100,000/mm³ at least once (in the absence of other known causes such as drugs, portal hypertension, TTP)
Immunologic Criteria
ANA level above laboratory reference range
Anti-dsDNA antibody level above laboratory reference range (or > 2 fold the laboratory reference range if tested by ELISA)
Anti-Sm
Antiphospholipid antibody:
any of the following: lupus anticoagulant, false-positive rapid plasma regain (RPR), medium or high titer, nticardiolipin antibody level (IgG, IgM or IgA), anti-β₂ glycoprotein I (IgG, IgM or IgA)
Low complement:
low C3, low C4, low CH50
Direct Coombs' test (in the absence of hemolytic anemia)

^aPatients can be classified as having SLE if they satisfy four of the clinical and immunological criteria, including at least one clinical criterion and one immunologic criterion, OR if they have biopsy-proven nephritis compatible with SLE in the presence of ANAs or anti-dsDNA antibodies. Reproduced from Petri M et al. Derivation and validation of the Systemic Lupus International Collaborating Clinics classification criteria for systemic lupus erythematosus. Arthritis Rheum 64:2677–86. Copyright 2012. With permission from John Wiley & Sons [258]. TTP: thrombocytopaenic purpura; anti-Sm: anti-Smith antibodies.

Table 6. Assessment and monitoring of SLE in lupus patients
Item	Initial assessment	Assessment (active disease)	Monitoring (stable disease)	Pregnancy
		Patients with active disease should be reviewed at least every 1–3 months	Patients with stable/low disease activity should be reviewed every 6–12 months	Pregnancy counselling and follow-up
History and examination
Detailed history	X	focused history	focused history	obstetric history
Clinical examination	X	X	X^a	X
Vital signs (Blood pressure, heart rate, weight)	X	X	X	X
Drug review including vaccination status	X	X	X	X
Bloods
Full blood count	X	X	X	X
Other tests for anaemia	X^a	X^a	X^a	X^a
Renal function	X	X	X	X
Bone profile	X	X^a	X^a	X
Liver function tests	X	X^a	X^a	X
Creatine kinase	X	X^a	X^a	X^a
CRP	X	X^a	X^a	X^a
Vitamin D3	X	X^a	Annually	X
Thyroid function	X	X^a	X^a	X
Immunology
ANA	X	–	–	X^a
Anti-dsDNA titre, C3/C4 level	X	X	X	X
aPL (LA, aCL, anti-beta2-glycoptroteinI)	X	X^a	X^a	Repeat if negative in the past
Anti-Ro/La, anti-RNP and anti-Sm antibodies	X	–	–	Repeat if negative in the past
Immunoglobulins	X	X^a	Annually^a	X^a
Direct Coombs' test	X	X^a	X^a	X^a
Urine
Urinalysis (screen for proteinuria, haematuria, leucocyturia and nitrites to exclude infection)	X	X	X	X
Urine random protein:creatinine ratio Or 24-h urine collection for protein	X^a	X^a	X^a	X^a
Urine microscopy (and culture)	X^a	X^a	X^a	X^a
Other investigations
Microbiology (other)	X^a	X^a	X^a	X^a
Biopsy (e.g. skin, kidney)	X^a	X^a	X^a	X^b
Lung function tests	X^a	X^a	X^a	X^a
Neurophysiology	X^a	X^a	X^a	X^a
ECG	X	X^a	X^a	X^a
Imaging
Chest X-ray	X	X^a	X^a	X^b
Other imaging (US, CT, MRI)	X^a	X^a	X^a	X^b
Modifiable cardiovascular risk factors
Hypertension	X	X^a	Annually	X
Dyslipidaemia	X	X^a	Annually	X^a
Diabetes mellitus	X	X^a	Annually	X
High BMI	X	X^a	Annually	X
Smoking	X	X^a	Annually	X
Disease activity and damage scores
BILAG (BILAG 2004 index) or	X	X^a	Annually	BILAG2004P^c
SLEDAI (SLEDAI–2K or SELENA SLEDAI)	X	X^a	Annually	SLEPDAI^d
SLICC/ACR Damage Index	X	X^a	Annually	X
Quality of life questionnaires
Short-form 36 or LupusQoL	X	X^a	Annually	X^a

^aWhen indicated;
^bwhen indicated and benefit > risks;
^cBILAG2004 pregnancy version;
^dSLEDAI pregnancy version. Anti-Sm antibodies: anti-Smith antibodies.

Table 7. SLE treatment strategies for examples of mild, moderate and severe lupus
Item	Mild activity/flare BILAG C scores or single B score; SLEDAI <6	Moderate activity/flare BILAG 2 or more systems with B scores, SLEDAI 6–12	Severe activity/flare (non-renal) BILAG 1 or more A scores; SLEDAI >12
Typical manifestations attributed to lupus	Fatigue, malar rash, diffuse alopecia, mouth ulcers, arthralgia, myalgia, platelets 50–149 × 10⁹/l	Fever, lupus-related rash up to 2/9 body surface area, cutaneous vasculitis, alopecia with scalp inflammation, arthritis, pleurisy, pericarditis, hepatitis, platelets 25–49 × 10⁹/l	Rash involving >2/9 body surface area, myositis, severe pleurisy and/or pericarditis with effusion, ascites, enteritis, myelopathy, psychosis, acute confusion, optic neuritis, platelets <25 × 10⁹/l
Initial typical drugs and target doses if no contra-indications	CSs^a: topical preferred or oral prednisolone ⩽20 mg daily for 1–2 weeks or I.m. or IA methyl-prednisolone 80–120 mg and HCQ ⩽6.5 mg/kg/day and/or MTX 7.5–15 mg/week and/or NSAIDs (for days to few weeks only)	Prednisolone^a ⩽0.5 mg/day or i.v. methyl-prednisolone ⩽250 mg × 1–3 or i.m. methyl-prednisolone 80–120 mg and AZA 1.5–2.0 mg/kg/day or MTX 10–25 mg/week or MMF 2–3 g/day or ciclosporin ⩽2.0 mg/kg/day and HCQ ⩽6.5 mg/kg/day	Prednisolone^a ⩽0.5 mg/day and/or i.v. methyl-prednisolone 500 mg × 1–3 or prednisolone ⩽0.75–1 mg/kg/day and AZA 2–3 mg/kg/day or MMF 2–3 g/day or CYC i.v. or ciclosporin ⩽2.5 mg/kg/day and HCQ ⩽6.5mg/kg/day
Aiming for typical maintenance drugs/doses providing no contra-indications	Prednisolone^a ⩽ 7.5 mg/day and HCQ 200 mg/day and/or MTX 10 mg/week	Prednisolone^a ⩽7.5 mg/day and AZA 50–100 mg/day or MTX 10 mg/week or MMF 1 g/day or ciclosporin 50–100 mg/day and HCQ 200 mg/day;	Prednisolone^a ⩽7.5 mg/day and MMF 1.0–1.5 g/day or AZA 50–100 mg/day or ciclosporin 50–100 mg/day and HCQ 200 mg/day;
	Aim to reduce and stop drugs except HCQ eventually when in stable remission	Aim to reduce and stop drugs except HCQ eventually when in stable remission	Aim to reduce and stop drugs except HCQ eventually when in stable remission

^aThe lowest effective dose of prednisolone or other CSs should be used at all times.

Table 8. Research priorities to improve the management of lupus patients
Analysis of the BILAG Biologics Register data is needed to assess the efficacy and safety of using rituximab for treating refractory lupus disease, administered according to the NHS England Interim Clinical Commissioning Policy Statement.
Analysis of the BILAG Biologics Register should also provide some data on the use of MMF in non-renal lupus patients; this is needed to support data from previous renal trials.
More research into stratified and personalised medicine and the cost-effectiveness of immunosuppressive drugs in lupus patients is warranted to help identify which drug will be most suitable for an individual.
Trials of immunosuppressive regimens and biologic therapies that will significantly reduce the need for CSs are needed in renal and non-renal lupus patients.
The cost-effectiveness and value of monitoring drug levels in order to improve adherence/compliance with drug therapy and improve the outcome in terms of reduced disease activity, damage and steroid usage should be investigated (e.g. for HCQ, MMF).
The role of IVIG and plasma exchange in the management of lupus patients requires further evaluation.
More data are required on the long-term outcome for children born to mothers with lupus who were exposed to drugs used pre-conception, while pregnant and/or while breast-feeding.

NHS: National Health Service.

Supplementary Table S1. Search terms used in PubMed and Cochrane Database of Systematic Reviews for the literature review
	Topic	Search terms used in addition to SLE OR Systemic Lupus Erythematosus OR Lupus
Diagnosis and background	Clinical	Diagnosis Clinical manifestations/Manifestations Clinical features Presentation Classification
	Serologic	Immunology/Immunological Antibody/auto-antibody/serological Anti-nuclear antibodies, ANA, anti-dsDNA, anti-Ro, anti-Sm, C3, C4, anti-phospholipid, antiphospholipid, anti-cardiolipin, anticardiolipin, lupus anticoagulant
	Lupus manifestations including differences between lupus in males and females	SLE activity Disease Damage Mortality Presentation Outcome ACR classification criteria Malar rash Discoid Rash Photosensitivity Oral Ulcers Nonerosive arthritis Pleuritis OR Pericarditis Proteinuria OR Cellular casts Neuropsychiatric Haemolytic anaemia OR Leucopenia/Leukopenia OR Lymphopenia OR Thrombocytopenia anti-double stranded DNA OR anti-Sm OR antiphospholipid antibodies OR anti-phospholipid antibodies OR ANA +/- gender differences +/- male/men/man
For assessment and monitoring	Lupus features	All above items AND Assess/assessment Activity/disease activity/BILAG/SLEDAI Monitoring Damage/SLICC Prognosis Quality indicators Recommendations
	Neuro-psychiatric disease	Neuropsychiatric AND Prevalence Risk factors Screening Diagnosis Monitoring Prevention Prognosis
	Malignancy	Cancer OR Malignancy AND Mortality Lymphoma HPV OR cervical dysplasia OR cervical Lung Prostate Endometrial Ovarian Screen
	Infection	Infection Risk AND/OR Death Antibiotic prophylaxis vaccin* Bacteria* Infections CMV HPV Varicella Zoster virus Hepatitis B AND C Hepatitis vaccin* Pneumocystis jiroveci TB OR Tuberculosis
Treatment	Hydroxychloroquine/chloroquine/mepacrine Methotrexate NSAIDs Sunscreen/sunblock Prednisolone/prednisone/methylprednisolone/methylprednisone/triamcinolone/corticosteroid* Azathioprine Ciclosporin/cyclosporine/cyclosporin/cyclosporine/tacrolimus Mycophenolate mofetil/mycophenolic acid Leflunomide Rituximab Belimumab Intra-venous immunoglobulin/intravenous immunoglobulin/IVIG Plasma exchange/plasmapharesis	Treatment or therapy or trial or study or management) AND Therapy NAME AND/OR Mild or Moderate or Severe Activity or damage or flare BILAG or SLEDAI or ECLAM or SLAM or disease activity index Efficacy or safety or outcome Non-renal Constitutional Rash or mucocutaneous or dermatol* Vasculitis Arthritis or musculoskeletal Cardiac or respiratory or cardio-respiratory or gastro-intestinal Neuro-psychiatric or neuro*

Supplementary Table S2. SIGN revised grading system for recommendations in evidence based guidelines
SIGN Levels of evidence	SIGN Grades of recommendations
1++ High quality meta-analyses, systematic reviews of RCTs, or RCTs with a very low risk of bias 1+ Well conducted meta-analyses, systematic reviews of RCTs, or RCTs with a low risk of bias 1− Meta-analyses, systematic reviews or RCTs, or RCTs with a high risk of bias 2++ High quality systematic reviews of case-control or cohort studies or High quality case-control or cohort studies with a very low risk of confounding, bias, or chance and a high probability that the relationship is causal 2+ Well conducted case-control or cohort studies with a low risk of confounding, bias, or chance and a moderate probability that the relationship is causal 2− Case-control or cohort studies with a high risk of confounding, bias, or chance and a significant risk that the relationship is not causal 3 Non-analytic studies, e.g. case reports, case series 4Expert opinion	A At least one meta-analysis, systematic review, or RCT rated as 1++ and directly applicable to the target population or a systematic review of RCTs or a body of evidence consisting principally of studies rated as 1+ directly applicable to the target population and demonstrating overall consistency of results B A body of evidence including studies rated as 2++ directly applicable to the target population and demonstrating overall consistency of results or Extrapolated evidence from studies rated as 1++ or 1+ C A body of evidence including studies rated as 2+ directly applicable to the target population and demonstrating overall consistency of results or Extrapolated evidence from studies rated as 2++ DEvidence level 3 or 4 or Extrapolated evidence from studies rated as 2+

Reproduced from A new system for grading recommendations in evidence based guidelines, Harbour R, Miller J, 323, 334–6, 2001 with permission from BMJ Publishing Group Ltd [1].

Supplementary Table S3. Cumulative incidence of SLE manifestations in lupus cohorts
Cumulative % incidence of SLE manifestations in lupus cohorts
Author Year Reference	Worral 1990 (2)	Pons Estel 2004 (3)	Font 2004 (4)	Cervera 2009 (5)	Lim 2014 (6)	Isenberg 2010 (7)
Number of patients in cohort studied	(n=100)	(n=1214)	(n=600)	(n=1000)	(n=1156)	(n=500)
Constitutional Fever Weight Loss Lymphadenopathy	- - -	57 27 15	42 - 1	17 - -	- - -	- - -
Cutaneous Alopecia Oral/nasal ulcers Photosensitivity Malar rash Discoid rash Subacute cutaneous Raynaud's phenomenon	27 36 48 90^a 90^a - -	58 42 56 61 12 3 28	18 30 41 54 6 8 22	- 13 23 31 8 - 16	- 22 26 32 23 - -	- 26 35 62^a 62^a - -
Musculoskeletal Arthralgia/Arthritis Myalgia/myositis	94 -	93 18	83 7	48^b 4	67^b -	94 -
Cardiorespiratory Pericarditis Pleurisy Pneumonitis Myocarditis Endocarditis	57^a 57^a - - -	17 22 2 3 3	28^a 28^a 4 2 8	16^a 16^a - - -	43^a 43^a - - -	43^a 43^a - - -
Neurological Seizures Psychosis Chorea Transverse myelitis Organic brain syndrome	45^c 45^c 45^c 45^c 45^c	8 4 0.4 0.6 2	12^a 12^a 0.5 - -	19^a 19^a - - -	14^a 14^a - - -	21^c 21^c 21^c - -
Renal Proteinuria/sediment Nephrotic Syndrome ESRD	29 - -	46 7 2	34 - -	28 - -	34 - 7	31 - -
Gastrointestinal Ascites Liver	- -	1 -	- 0.3	- -	- -	- -
Haematological Haemolytic anaemia Leucopenia Lymphopenia Thrombocytopenia Thrombosis	- 57 81 21 -	12 42 59 19 6	8 66 82 31 7	5 - - 13 9	- 75^a 75^a - -	- - - - -
Serological ANA Anti-dsDNA Anti-Smith Anticardiolipin IgG/IgM Lupus anticoagulant Anti-Ro Anti-RNP Rheumatoid factor Low C3 Low C4	99 55 - 34 19 - - 27 - -	98 71 48 51/39 30 49 51 - 49 54	99 90 13 - 15 23 - 12 31 38	- - 10 - - 25 13 18 - -	82^d 64^e 64^e 64^e - - - - - -	95 64 13 21/9 14 37 27 25 44 -

^acombined incidence for items with same value. ^bconfirmed arthritis only (usually non-erosive). ^call neurological features associated with lupus combined. ^dpossible failure of ascertainment but patients met ⩾4 ACR criteria. ^ecombined as met ACR criteria for immunological involvement. - not reported.

Authors and Disclosures

Caroline Gordon^1,2,3, Maame-Boatemaa Amissah-Arthur¹, Mary Gayed^1,3, Sue Brown⁴, Ian N. Bruce^5,6, David D'Cruz⁷, Benjamin Empson⁸, Bridget Griffiths⁹, David Jayne^10,11, Munther Khamashta^12,13, Liz Lightstone¹⁴, Peter Norton¹⁵, Yvonne Norton¹⁵, Karen Schreiber¹³ and David Isenberg¹⁶ for the British Society for Rheumatology Standards, Audit and Guidelines Working Group

¹Rheumatology Research Group, Institute of Inflammation and Ageing, College of Medical and Dental Sciences, University of Birmingham, ²Rheumatology Department, City Hospital, Sandwell and West Birmingham Hospitals NHS Trust, ³Rheumatology Department, University Hospitals Birmingham NHS Foundation Trust, Birmingham, ⁴Royal National Hospital for Rheumatic Diseases, Bath, ⁵Arthritis Research UK Centre for Epidemiology, Centre for Musculoskeletal Research, Institute for Inflammation and Repair, University of Manchester, Manchester Academic Health Sciences Centre, ⁶The Kellgren Centre for Rheumatology, NIHR Manchester Musculoskeletal Biomedical Research Unit, Central Manchester University Hospitals NHS Foundation Trust, Manchester, ⁷Louise Coote Lupus Unit, Guy's Hospital, London, ⁸Laurie Pike Health Centre, Modality Partnership, Birmingham, ⁹Department of Rheumatology, Freeman Hospital, Newcastle upon Tyne, ¹⁰Department of Medicine, University of Cambridge, ¹¹Lupus and Vasculitis Unit, Addenbrooke's Hospital, Cambridge, ¹²Lupus Research Unit, The Rayne Institute, St Thomas' Hospital, ¹³Division of Women's Health, King's College London, ¹⁴Section of Renal Medicine and Vascular Inflammation, Division of Immunology and Inflammation, Department of Medicine, Imperial College London, London, ¹⁵LUPUS UK, Romford, Essex and ¹⁶Centre for Rheumatology, University College London, London, UK

Correspondence to
Caroline Gordon, Rheumatology Research Group, Institute of Inflammation and Ageing, University of Birmingham Research Laboratories, New Queen Elizabeth Hospital, Mindelsohn Way, Edgbaston, Birmingham B15 2WB, UK. E-mail: p.c.gordon@bham.ac.uk

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 AstraZeneca, 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.