We're using cookies to give you the best experience on our site. Cookies are files stored in your browser and are used by most websites to help personalise your web experience.

By continuing to use our website without changing the settings, you're agreeing to our use of cookies.

Find out more
For more information, go to

Overview of the management of systemic lupus erythematosus

Topical Reviews front coverJohn A Reynolds, Ian N Bruce
Arthritis Research UK Epidemiology Unit, Institute of Inflammation and Repair, University of Manchester/NIHR Manchester Musculoskeletal Biomedical Research Unit, Central Manchester University Hospitals NHS Foundation Trust

Issue 2 (Topical Reviews Series 7) Spring 2013   Download pdf

  • Systemic lupus erythematosus (SLE) is a heterogeneous autoimmune disease with a broad clinical presentation
  • When assessing a patient with SLE it is important to differentiate active disease from irreversible organ damage, adverse effects of treatment and other co-morbid conditions
  • Patients with SLE have increased co-morbidities including osteoporosis, cardiovascular disease, infection risk and depression, which need to be identified and managed appropriately
  • Corticosteroids and immunosuppressant therapies are the treatments of choice for active disease, but newer biological therapies may offer improved disease control and fewer adverse effects


Systemic lupus erythematosus (SLE) is a systemic inflammatory autoimmune disease predominantly affecting women. The prevalence of lupus is estimated at 12.5–78.5 cases per 100,000 population in Europe and the USA with a female:male ratio of around 9:1.1,2 In the UK SLE is approximately 2.5 times more common in South Asian and 5–6 times more common in Afro-Caribbean individuals.3 Due to the rarity of SLE it is difficult to accurately determine the incidence, but it has been estimated to be between 2.0 and 7.6 cases per 100,000 population/year.1 The aetiology and immunopathogenesis of SLE have been extensively reviewed elsewhere.4,5 This review will focus on advances in the management of SLE in terms of both the disease itself and its associated co-morbidities.

Clinical features of SLE

SLE is one of a small number of truly multisystem disorders. The heterogeneous nature of the disease can result in delayed diagnosis and cause considerable difficulty in the design of robust clinical trials. There is no diagnostic test specific for SLE and as such the diagnosis remains a clinical one, relying on a combination of clinical and laboratory features. The 1992 Revised American College of Rheumatology (ACR) Classification Criteria, while developed to aid trial design, offer a useful aide-mémoire to the rheumatologist of some of the more common features of SLE (Table 1).6,7 Newer criteria have only recently been published but are likely to be more widely used in the future (Table 2).8

View TABLE 1: 1997 Updated American College of Rheumatology criteria for classification of systemic lupus erythematosus

View TABLE 2: Clinical and immunological criteria used in the Systemic Lupus International Collaborating Clinics (SLICC) classification system 

It is interesting to note that, in addition to differences in disease prevalence, marked ethnic variation in organ involvement has also been reported; for example, when compared to Caucasian lupus patients Afro-Caribbean patients have an increased risk of renal disease while antiphospholipid syndrome (APS) is less common.2,9

A wide spectrum of autoantibodies can be found in patients with SLE and are often associated with specific clinical features. Antinuclear antibodies (ANA) are found in 98% of SLE patients but are non-specific. The presence of anti-double-stranded DNA (dsDNA) is highly specific for SLE but they are only present in around 70% of cases.10 Other autoantibodies reported in patients with SLE include anti-Smith, anti-ribosomal P and anti-proliferating cell nuclear antigen (PCNA).11 Of all these antibodies, it is only dsDNA that has been shown to be pathogenic (for lupus nephritis)12 – the others appear to be biomarkers for the presence of an autoimmune state.

Mortality in SLE

There has been a significant reduction in mortality among lupus patients over the last 50–60 years; the 5-year survival is now estimated at around 95%.2 This does of course still mean there is an unacceptably high mortality in this condition affecting younger women. In the largest observational study to date (of c.9500 lupus patients) increased mortality was seen in female patients, particularly within the first year following diagnosis.13 This early peak in mortality, which is commonly due to lupus disease activity and infection, is followed by a second later peak chiefly due to cardiovascular disease (CVD).14

Identification of ‘high-risk’ patients

No universal prognostic factor has been identified, but some clinical features of SLE are associated with a worse prognosis. In a study by Lopez et al of 350 lupus patients, older age, higher disease activity and pre-existing organ damage were all independently associated with premature death.15 In addition, renal disease (identified either at biopsy or by measurement of serum creatinine) and thrombocytopenia are associated with increased mortality.16-18 Perhaps most importantly, it is increased lupus disease activity overall that should alert the rheumatologist to the fact that the patient is at risk of a poor outcome.17

Morbidity in SLE

The clinical course in SLE can vary markedly from relatively mild symptoms through to life-threatening multi-organ disease. A thorough assessment of lupus patients is important to clearly identify active disease and the presence of organ involvement. Disease activity scoring systems have been developed primarily for use in research studies in order to try to capture activity in this heterogeneous disease (reviewed in Griffiths et al19). Although developed for use in research studies, these scoring systems offer a useful framework for the treating physician.

Global scoring systems such as the Systemic Lupus Erythematosus Disease Activity Index (SLEDAI) provide a single total activity score, with serious manifestations (e.g. neurological disease) weighted more heavily.20 Recent updates to SLEDAI include SELENA-SLEDAI (Safety of Estrogens in Lupus Erythematosus: National Assessment-SLEDAI)21 and SLEDAI-2K, both of which aim to capture ongoing rather than just new or recurrent activity.22

The British Isles Lupus Assessment Group (BILAG) index offers a more comprehensive approach to the assessment of lupus disease activity. Rather than generating a global activity score, the BILAG-2004 index classifies activity, over a 4-week period, according to 9 different organ systems.23 Furthermore, rather than using an arbitrary definition of disease activity the benchmark is set against whether or not the signs or symptoms would prompt an escalation of therapy. It is important when using indices such as BILAG that only features due to SLE activity per se (and not damage or other conditions) are recorded.

Against a background of a cluster of negative randomised trials (see below) new scoring systems to capture therapeutic response in SLE are being developed. These response indices, analogous to an ACR or European League Against Rheumatism (EULAR) response in rheumatoid arthritis, aim to quantify changes in disease activity in clinical trials. The SLE Responder Index (SRI) comprises a reduction in SELENA-SLEDAI score of ≥4 points, no new BILAG ‘A’ or more than 1 new ‘B’ score, and no significant worsening in Physician’s Global Assessment (PGA) score.24 This composite scoring system has thus far only been used in the clinical trials of belimumab.25,26 The development of sensitive and reproducible scoring systems will be essential for the conduct of more robust clinical trials.

Clinical assessment of the lupus patient

In the assessment of symptomatic patients consideration should be given as to whether the clinical features are due to:

  • Lupus disease activity (i.e. a lupus flare)
  • Other lupus-related pathology, e.g. thrombosis or vasospasm
  • Irreversible organ damage
  • Non-lupus causes, e.g. infection, atherosclerosis, other autoimmune diseases or drug-related adverse events.

It is important to remember that other diseases (e.g. infection) can co-exist in the SLE patient and can be worsened by a lupus flare, resulting in ‘dual-pathology’. An accurate diagnosis therefore relies on interpretation of symptoms against a background of probability. For example, haematuria and proteinuria are more likely to be due to a urinary tract infection rather than lupus nephritis. Indeed, concomitant infections are one of many co-morbidities common in SLE and are discussed in detail below. The Systemic Lupus International Collaborating Clinics Damage Index (SLICC-DI) allows damage to be recorded and quantified as a score between 0 and 46.27 Unlike the measures of disease activity all damage is scored from the time of diagnosis of SLE onwards, regardless of whether or not it can be attributed to lupus.

Can a lupus flare be predicted?

SLE often follows a relapsing and remitting pattern of disease. The ability to identify those patients in whom a flare is likely allows either a proactive increase in therapy or instigation of more stringent monitoring. No single predictive marker for lupus flare has yet been identified. Perhaps the most recognised link is that between raised dsDNA titre and/or low serum complement (C3, C4 and C1q) and the development or flare of lupus nephritis.28,29 An increase in dsDNA titre, or the development of blood dyscrasia (anaemia, lymphocytopenia or thrombocytopenia) can also predict flare in lupus cohorts and has been reviewed by Bertsias et al.30 A combination of clinical (disease activity) and laboratory features (full blood count, serum complement) is therefore recommended for monitoring SLE patients, as reflected for example in the 2010 EULAR guidelines for the monitoring of lupus patients both in clinical practice and in observational studies.31

Management of lupus: no major organ involvement

The general principle of management of SLE is analogous to that of other inflammatory disorders: suppression of inflammation in an attempt to prevent organ damage. The intensity of therapy is therefore dictated by the severity and site of organ involvement, and the overall prognosis for specific organ involvement. The management of SLE is summarised in Figure 1.

Figure 1: overview of the management of systemic lupus erythematosus

Non-organ-specific symptoms in SLE are common and include marked fatigue, arthralgia, myalgia, fever, weight-loss and mood changes (often low mood and depression). These can be severe enough to significantly impair a patient’s quality of life.32 Management of these symptoms, particularly fatigue, is often challenging as the causes are multifactorial and no specific therapies exist. These symptoms will to some extent be improved by increasing overall control of the disease. Fatigue and chronic pain are therefore common in SLE, although there is evidence that the prevalence of fibromyalgia itself is lower than would be expected.33

In mild–moderate lupus, musculoskeletal and mucocutaneous features are likely to dominate the clinical picture. Common manifestations include mucosal ulceration (typically oral and nasal), scarring alopecia, non-erosive arthropathy (Jaccoud’s arthropathy) and skin rashes (malar rash, discoid lesions and other photosensitive rashes). Oral corticosteroids at low–moderate doses and antimalarial therapy are the mainstay of management of mild–moderate disease, using the lowest dose of steroids to adequately control the symptoms. Higher-dose steroids and steroid-sparing agents are used when this approach is insufficient to control the disease. In addition, steroid and antimalarial agents can be important adjuvant therapy to reduce the risk of flare in patients with more severe disease.

UV protection

Exposure to sunlight is a recognised precipitant of a lupus flare. Patients often have photosensitive rashes, or may experience a worsening of systemic symptoms in response to ultraviolet (UV) radiation. Lupus patients should be advised to avoid sitting in direct sunlight and to use physical protection from the sun (e.g. long sleeves, hats and sun-protective clothing) where appropriate. Diffusers on low-energy light bulbs and fluorescent light sources may also be of help. High-factor sunblock (ideally sun protection factor (SPF) ≥50) is also recommended and should be applied regularly. Sunlight avoidance may, however, partly contribute to the increased prevalence of vitamin D deficiency in patients with SLE.34 Although the clinical relevance of low vitamin D in SLE with regard to immunological function is currently under investigation, vitamin D deficiency is of course an established risk factor for poor bone health, including the development of osteomalacia and osteoporosis (the latter is discussed below).

Antimalarial therapy

Hydroxychloroquine (HCQ) (up to 6.5 mg/kg daily) has been shown to be very effective in the management of mucocutaneous disease, serositis and fatigue.35,36 It should be noted that prolonged use of chloroquine phosphate (but to a lesser extent HCQ) can lead to the development of retinopathy.37 In 2009 the Royal College of Ophthalmologists issued good practice guidelines for the use of antimalarial therapy by rheumatologists and dermatologists.38 In the absence of pre-existing retinal disease routine ophthalmological review is not recommended. In more refractory cases, or if ocular toxicity is a concern, mepacrine has also been used with good effect, although it can result in a dose-dependent yellow discoloration of the skin. HCQ and mepacrine can also be efficacious in combination. The therapeutic options for treatment of cutaneous lupus have been extensively reviewed by Kuhn et al.39 Importantly, HCQ use has also been associated with a reduction in overall mortality in lupus patients.40


Systemic corticosteroids remain a keystone in the management of SLE, particularly when a rapid response is desirable. The response of moderately active lupus to steroid therapy is such that if effectiveness alone were the only consideration then other agents would rarely be needed. Low doses (e.g. 5–10 mg daily) are often sufficient for mild disease, but can be increased to 0.5 mg/kg where the disease is moderately active. Corticosteroid therapy is, however, associated with significant unwanted effects and hence long-term high or moderate doses are undesirable.41 The therapeutic aim should therefore be to maximise benefit while minimising steroid-related harms. Steroid-sparing therapies such as azathioprine (AZA) can therefore be used in order to reduce the cumulative exposure to steroids. EULAR guidelines for the management of steroid therapy in rheumatic diseases were published in 2007 and cover issues such as risk stratification, monitoring and management of complications of glucocorticoids.42

Immunosuppressant agents

Azathioprine (AZA) (1–3 mg/kg) is the most commonly used steroid-sparing agent for the management of patients with SLE.43 The effective metabolism of AZA is dependent on normal thiopurine methyltransferase (TPMT) activity. Patients should therefore be screened for a homozygous deficiency of TPMT (present in 1 in 300 of the population) which results in an extremely high risk of bone marrow suppression.44 In homozygous-deficient patients AZA should be avoided. Patients with heterozygous deficiency should have their ‘target’ AZA dose adjusted downwards by approximately 50% and any further dose adjustments should be carefully monitored. In patients with inflammatory arthritis methotrexate (MTX) is often beneficial in controlling synovitis and may also reduce cutaneous disease.45 The effect of MTX on disease activity appears to be rather modest, but there is clinical trial evidence that MTX can allow more rapid and greater steroid withdrawal.46 Sulfasalazine is usually avoided in SLE due to its association with drug-induced lupus. The evidence for this association is, however, limited to case reports and has not been clearly demonstrated in larger cohorts.47

Management of lupus: major organ involvement

In patients with significant major organ involvement rapid resolution of inflammation is needed in order to prevent the development of irreversible damage. The therapeutic options include high-dose intravenous (IV) methylprednisolone, immunosuppressant therapies (including cyclophosphamide (CYC) and mycophenolate mofetil (MMF)) and biological therapies. It should however be noted that there is no clear evidence for any additional benefit of IV methylprednisolone over high-dose oral prednisolone.48 The treatment choice is dictated primarily by the site and extent of organ involvement, although other issues (e.g. gonadal function, CYC) need to be considered. Much of the evidence for the effectiveness of these therapies in SLE, particularly CYC, is derived from studies of lupus nephritis. However, CYC is also used widely for systemic features where rapid disease control is needed (e.g. vasculitis, transverse myelitis, pulmonary haemorrhage). Although a comprehensive review of the management of lupus nephritis is beyond the scope of this review an excellent summary was recently published by Houssiau.49

Mycophenolate mofetil

MMF is the pro-drug of mycophenolic acid which targets lymphocyte activation and survival by inhibiting de novo purine synthesis. As with CYC, much of the evidence base for the use of MMF in lupus is in the context of renal disease. A meta-analysis of 4 randomised controlled trials (RCTs) shows that MMF is as effective as CYC for induction of remission and is associated with fewer adverse events (gonadal failure and alopecia).50 MMF is therefore increasingly being used in preference to CYC in lupus nephritis and other major organ disease. Also MMF was superior to AZA for maintenance therapy for nephritis in the ALMS (Aspreva Lupus Management Study) trial,51 but not in the MAINTAIN (Mycophenolate Mofetil Versus Azathioprine for Maintenance Therapy of Lupus Nephritis) trial.52 These two trials differed significantly in terms of size and the racial composition of the study group. Although the positive results from these studies has led to the use of MMF for non-renal manifestations of lupus with much anecdotal success, there is relatively limited published data on its use.53

Calcineurin inhibitors

Ciclosporin A and tacrolimus have both made the transition from transplant medicine to management of lupus although they are less commonly used than the agents described above. Both ciclosporin and tacrolimus offer an adjunct therapy to MMF in systemic disease and a potential alternative for induction/maintenance therapy in lupus nephritis.54,55 Ciclosporin may be particularly attractive in lupus nephritis as it may be safer than MMF in pregnancy.56 Topical tacrolimus can also be particularly useful for the management of both subacute cutaneous lupus and discoid lupus.57


Abnormalities in B-cell activation in lupus prompted the off-licence use of B-cell-depleting therapies, most notably rituximab (RTX). RTX is a chimeric monoclonal antibody directed against CD20 which is expressed on the surface of B-cells. Treatment results in a rapid and prolonged depletion of B-cells. A recent meta-analysis of all the available open-label studies suggests that B-cell depletion occurs in around 95% of patients, with an associated improvement in disease activity.58 It was disappointing, therefore, that two RCTs failed to show any benefit. The EXPLORER (Exploratory Phase II/III SLE Evaluation of Rituximab) and the LUNAR (Lupus Nephritis Assessment with Rituximab) trials both showed no improvement with RTX when compared to the placebo arm.59,60 In both of these studies RTX was used as an adjunct to existing therapy (high doses of corticosteroids or MMF) which likely blunted any true benefit of RTX. Despite these trials RTX remains an attractive option to treat patients who have failed conventional immunosuppression, and in the UK an open-label prospective register is being established to assess safety and patterns of use of this and other biologic agents in SLE (


In 2011 belimumab (Benlysta) became the first drug for 50 years to be licensed for treatment of SLE. Belimumab is a fully-humanised monoclonal antibody which blocks the binding of the activating factor, B-lymphocyte stimulator (BLyS), to its receptor on the surface of B-cells. Two large RCTs (BLISS (Belimumab in Subjects with Systemic Lupus Erythematosus)-52 and BLISS-76) with over 1600 patients demonstrated that belimumab resulted in a modest but significant improvement in lupus disease activity when compared to adjustments of standard of care alone (as assessed using the SRI discussed above).25,26 These positive findings are encouraging, and the investigators recognised a subpopulation of patients who particularly responded to treatment (i.e. patients with increased dsDNA and low complement). Further studies are needed in order to identify those patients who are most likely to benefit, and to confirm the current safety data over a longer time period.

Management of co-morbidities in patients with SLE

The assessment and management of disease activity constitutes only part of the care of lupus patients. It is equally important to address co-morbid conditions which arise either from the lupus disease itself or as adverse effects of treatment. The 2010 EULAR guidelines for the monitoring of lupus focus on the identification of co-morbidities.31


Patients with SLE have an increased risk of osteoporosis compared to the general population. Risk factors for reduced bone mineral density (BMD) include age, low body weight, inflammatory markers (erythrocyte sedimentation rate (ESR) and C-reactive protein (CRP)) and pre-existing organ damage.61 In addition, corticosteroid doses of >7.5 mg in particular are associated with a greater risk of osteoporosis.62 Management of bone health in these patients should follow established practice for osteoporosis in other patient groups: conservative measures (including smoking cessation and exercise), optimisation of vitamin D levels (which are frequently deficient), calcium supplementation, and use of bisphosphonates.63 It is also worth noting that the FRAX tool ( which is commonly used to assess future risk of fracture is validated for patients between 40 and 90 years, and so caution should be exercised when using such a tool in younger female lupus patients.


Severe infection remains the primary cause of mortality in approximately 25% patients with SLE. Bacterial infections, particularly pneumonia, are the most common cause of hospitalisation due to infection.64 The risk of infection is increased by both disease-related factors (lung involvement, renal disease, lymphopenia, complement consumption and functional hyposplenism) and drug-related effects (cumulative steroid exposure and immunosuppressant use).64,65 The most frequently seen viral infection is herpes zoster, while S. pneumoniae, E. coli and S. aureus are the most common bacterial pathogens in this group. Hyposplenism secondary to excessive immune complex deposition results in an increased risk of infection with encapsulated organisms (e.g. S. pneumoniae, H. influenzae, S. typhi). Opportunistic infections (especially atypical tuberculosis (TB), cytomegalovirus (CMV) reactivation and Pneumocystis jirovecii) need to be considered, particularly in the lymphopenic patients.66 Infection risk can be minimised by aiming for disease remission using minimal steroid and immunosuppressive therapy. Vaccination against influenza and pneumococcal infection should also be recommended to all patients. It should be remembered, however, that live vaccines are contraindicated in patients on immunosuppressive therapy (including steroids at doses of >20 mg/day).67

Cardiovascular disease

Patients with SLE have a significantly increased risk of cardiovascular disease, around 5–6 times higher, compared to healthy controls.68 This increased risk is at least in part due to an increased prevalence of traditional cardiovascular risk factors, including smoking, hypertension, type 2 diabetes and dyslipidaemia.69,70 Guidelines for the management of these risk factors were proposed by Wajed et al.71 These offer a pragmatic ‘target-based’ approach to cardiovascular risk factor management for the clinician. It should be noted, however, that the evidence for these risk-reduction strategies is derived from their benefit in the general population; more studies are needed to demonstrate that these are beneficial in SLE.

In addition, there are lupus-specific factors that predispose these patients to premature atherosclerosis, including disease activity, renal disease and corticosteroid use.72 It is proposed, therefore, that control of inflammation, while minimising steroid exposure, may also reduce cardiovascular mortality in lupus.

Mental health

SLE has been shown to have a greater negative impact on health-related quality of life than other chronic diseases.73 The reason for this is unclear, but may be due to the systemic nature of the condition. Clear neuropsychiatric involvement is common, with a cumulative incidence of 30–40%. In 2010 EULAR guidelines for the management of neuropsychiatric lupus were published, covering the broad spectrum of disease manifestations.74 Of the quality of life assessment tools available, the LupusQoL is the most extensively validated.75 Despite the availability of these measures, there is little known about how quality of life can be improved for lupus patients. Management should therefore focus on the specific manifestations (e.g. depression, anxiety, fatigue) following conventional approaches.

Risk of thrombosis

In addition to traditional risk factors, patients with lupus have an increased risk of thromboembolic disease. Higher disease activity, lupus nephritis and hypertension may all contribute to this increased risk.76 APS is common in SLE, with clinical consequences in 10–15% of all patients.76 APS antibodies and lupus anticoagulant should be determined in all patients at baseline and following the emergence of any new risk factors for thrombosis.77 In non-pregnant patients with lupus and APS, long-term anticoagulation is required for secondary prevention of thrombosis. Assessment of thrombotic risk is also a key part of pregnancy assessment and management in SLE (see below).77,78

Premature gonadal failure

Early menopause is a common feature of SLE and other autoimmune diseases.79 Exposure to CYC may be a contributing factor in up to a half of cases.80 Distressing symptoms, including mood changes and severe flushing, are more difficult to treat in SLE due to concerns that hormone replacement therapy (HRT) may precipitate a disease flare.81 In patients with mild–moderate disease HRT increases the risk of mild–moderate flares and may also increase thrombotic risk. The effect on patients with more severe disease has not been studied. Alternative agents such as selective serotonin reuptake inhibitors (SSRIs), clonidine and topical oestrogens may be beneficial in symptom control.


Many lupus patients are women of childbearing age, which has implications for the planning and monitoring of pregnancy, disease management during pregnancy and lactation, and risk of additional complications (e.g. thrombosis, pre-eclampsia, neonatal lupus/congenital heart block). Although a comprehensive review of immunosuppressant agents in pregnancy is beyond the scope of this article it should be remembered that only corticosteroids, HCQ and AZA are considered ‘safe’ to use in pregnancy. Other agents have potential effects on fertility (e.g. CYC) or teratogenesis (e.g. CYC, MTX, MMF) and the likely risk:benefit ratio of these treatments needs to be thoroughly discussed with the patient. The management of the pregnant lupus patient has recently been reviewed in detail by Baer et al.78

Summary and future research

Despite recent advances in the treatment of SLE, morbidity and mortality remain unacceptably high. The disease is poorly understood, leading to a paucity of proven targeted therapies. Furthermore, the significant disease heterogeneity can cloud the apparent benefits of new agents in clinical trials. More research is needed into the pathogenesis of SLE in order to identify new drug targets. Trials of these new drugs will, however, only be successful if combined with more stringent and comprehensive disease outcome measures. It is highly likely that the disease that we understand as SLE comprises multiple related, but different, conditions. Identifying the exact clinical and pathological phenotype of these patients is essential in order to develop personalised treatment strategies. Until such a time, management of these patients is likely to remain as challenging as it is interesting.


    1. O’Neill S, Cervera R. Systemic lupus erythematosus. Best Pract Res Clin Rheumatol 2010 Dec;24(6):841-55.
    2. Petri M. Epidemiology of systemic lupus erythematosus. Best Pract Res Clin Rheumatol 2002 Dec;16(5):847-58.
    3. Johnson AE, Gordon C, Palmer RG, Bacon PA. The prevalence and incidence of systemic lupus erythematosus in Birmingham, England: relationship to ethnicity and country of birth. Arthritis Rheum 1995 Apr;38(4):551-8.
    4. Mok CC, Lau CS. Pathogenesis of systemic lupus erythematosus. J Clin Pathol 2003 Jul;56(7):481-90.
    5. Gualtierotti R, Biggioggero M, Penatti AE, Meroni PL. Updating on the pathogenesis of systemic lupus erythematosus. Autoimmun Rev 2010 Nov;10(1):3-7.
    6. Tan EM, Cohen AS, Fries JF et al. The 1982 revised criteria for the classification of systemic lupus erythematosus. Arthritis Rheum 1982 Nov;25(11):1271-7.
    7. Hochberg MC. Updating the American College of Rheumatology revised criteria for the classification of systemic lupus erythematosus. Arthritis Rheum 1997 Sep;40(9):1725.
    8. Petri M, Orbai AM, Alarcón GS et al. Derivation and validation of Systemic Lupus International Collaborating Clinics classification criteria for systemic lupus erythematosus. Arthritis Rheum 2012 Aug;64(8):2677-86.
    9. Molina JF, Molina J, Garcia C, Gharavi AE, Wilson WA, Espinoza LR. Ethnic differences in the clinical expression of systemic lupus erythematosus: a comparative study between African-Americans and Latin Americans. Lupus 1997 Jan;6(1):63-7.
    10. Isenberg DA, Shoenfeld Y, Walport M et al. Detection of cross-reactive anti-DNA antibody idiotypes in the serum of systemic lupus erythematosus patients and of their relatives. Arthritis Rheum 1985 Sep;28(9):999-1007.
    11. Lyons R, Narain S, Nichols C, Satoh M, Reeves WH. Effective use of autoantibody tests in the diagnosis of systemic autoimmune disease. Ann N Y Acad Sci 2005 Jun;1050:217-28.
    12. Waldman M, Madaio MP. Pathogenic autoantibodies in lupus nephritis. Lupus 2005 Jan;14(1):19-24.
    13. Bernatsky S, Boivin JF, Joseph L et al. Mortality in systemic lupus erythematosus. Arthritis Rheum 2006 Aug;54(8):2550-7.
    14. Urowitz MB, Bookman AA, Koehler BE, Gordon DA, Smythe HA, Ogryzlo MA. The bimodal mortality pattern of systemic lupus erythematosus. Am J Med 1976 Feb;60(2):221-5.
    15. Lopez R, Davidson JE, Beeby MD, Egger PJ, Isenberg DA. Lupus disease activity and the risk of subsequent organ damage and mortality in a large lupus cohort. Rheumatology (Oxford) 2012 Mar;51(3):491-8.
    16. Yap DY, Tang CS, Ma MK, Lam MF, Chan TM. Survival analysis and causes of mortality in patients with lupus nephritis. Nephrol Dial Transplant 2012 Aug;27(8):3248-54.
    17. Alarcón GS, McGwin G Jr, Bastian HM et al; LUMINA Study Group. Systemic lupus erythematosus in three ethnic groups. VII [correction of VIII]. Predictors of early mortality in the LUMINA cohort [erratum in Arthritis Rheum 2001 Jun;45(3):306]. Arthritis Rheum 2001 Apr;45(2):191-202.
    18. Kiss E, Regéczy N, Szegedi G. Systemic lupus erythematosus survival in Hungary: results from a single centre. Clin Exp Rheumatol 1999 Mar-Apr;17(2):171-7.
    19. Griffiths B, Mosca M, Gordon C. Assessment of patients with systemic lupus erythematosus and the use of lupus disease activity indices. Best Pract Res Clin Rheumatol 2005 Oct;19(5):685-708.
    20. Bombardier C, Gladman DD, Urowitz MB, Caron D, Chang CH; The Committee on Prognosis Studies in SLE. Derivation of the SLEDAI: a disease activity index for lupus patients. Arthritis Rheum 1992 Jun;35(6):630-40.
    21. Buyon JP, Petri MA, Kim MY et al. The effect of combined estrogen and progesterone hormone replacement therapy on disease activity in systemic lupus erythematosus: a randomized trial. Ann Intern Med 2005 Jun;142(12 Pt 1):953-62.
    22. Gladman DD, Ibañez D, Urowitz MB. Systemic lupus erythematosus disease activity index 2000. J Rheumatol 2002 Feb;29(2):288-91.
    23. Yee C-S, Farewell V, Isenberg DA et al. British Isles Lupus Assessment Group 2004 index is valid for assessment of disease activity in systemic lupus erythematosus. Arthritis Rheum 2007 Dec;56(12):4113-9.
    24. Furie RA, Petri MA, Wallace DJ et al. Novel evidence-based systemic lupus erythematosus responder index. Arthritis Rheum 2009 Sep;61(9):1143-51.
    25. Furie R, Petri M, Zamani O et al; BLISS-76 Study Group. A phase III, randomized, placebo-controlled study of belimumab, a monoclonal antibody that inhibits B lymphocyte stimulator, in patients with systemic lupus erythematosus. Arthritis Rheum 2011 Dec;63(12):3918-30.
    26. Navarra SV, Guzmán RM, Gallacher AE et al; BLISS-52 Study Group. Efficacy and safety of belimumab in patients with active systemic lupus erythematosus: a randomised, placebo-controlled, phase 3 trial. Lancet 2011 Feb;377(9767):721-31.
    27. Gladman DD, Goldsmith CH, Urowitz MB et al. The Systemic Lupus International Collaborating Clinics/American College of Rheumatology (SLICC/ACR) Damage Index for Systemic Lupus Erythematosus International Comparison. J Rheumatol 2000 Feb;27(2):373-6.
    28. Birmingham DJ, Irshaid F, Nagaraja HN et al. The complex nature of serum C3 and C4 as biomarkers of lupus renal flare. Lupus 2010 Oct;19(11):1272-80.
    29. Akhter E, Burlingame RW, Seaman AL, Magder L, Petri M. Anti-C1q antibodies have higher correlation with flares of lupus nephritis than other serum markers. Lupus 2011 Oct;20(12):1267-74.
    30. Bertsias G, Ioannidis JPA, 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 Feb;67(2):195-205.
    31. Mosca M, Tani C, Aringer M et al. European League Against Rheumatism recommendations for monitoring patients with systemic lupus erythematosus in clinical practice and in observational studies. Ann Rheum Dis 2010 Jul;69(7):1269-74.
    32. Mok CC, Ho LY, Cheung MY, Yu KL, To CH. Effect of disease activity and damage on quality of life in patients with systemic lupus erythematosus: a 2-year prospective study. Scand J Rheumatol 2009 Mar-Apr;38(2):121-7.
    33. Taylor J, Skan J, Erb N et al. Lupus patients with fatigueis there a link with fibromyalgia syndrome? Rheumatology (Oxford) 2000 Jun;39(6):620-3.
    34. Kamen DL, Cooper GS, Bouali H, Shaftman SR, Hollis BW, Gilkeson GS. Vitamin D deficiency in systemic lupus erythematosus. Autoimmun Rev 2006 Feb;5(2):114-7.
    35. Ruiz-Irastorza G, Ramos-Casals M, Brito-Zeron P, Khamashta MA. Clinical efficacy and side effects of antimalarials in systemic lupus erythematosus: a systematic review. Ann Rheum Dis 2010 Jan;69(1):20-8.
    36. Wallace DJ. Antimalarial agents and lupus. Rheum Dis Clin North Am 1994 Feb;20(1):243-63.
    37. Jover JA, Leon L, Pato E et al. Long-term use of antimalarial drugs in rheumatic diseases. Clin Exp Rheumatol 2012 May-Jun;30(3):380-7.
    38. Royal College of Ophthalmologists. Hydroxychloroquine and ocular toxicity: recommendations on screening. 2009 Oct. Available via:
    39. Kuhn A, Ruland V, Bonsmann G. Cutaneous lupus erythematosus: update of therapeutic options. Part I. J Am Acad Dermatol 2011 Dec;65(6):e179-e193.
    40. Alarcón GS, McGwin G, Bertoli AM et al; LUMINA Study Group. Effect of hydroxychloroquine on the survival of patients with systemic lupus erythematosus: data from LUMINA, a multiethnic US cohort (LUMINA L). Ann Rheum Dis 2007 Sep;66(9):1168-72.
    41. Saag KG, Koehnke R, Caldwell JR et al. Low dose long-term corticosteroid therapy in rheumatoid arthritis: an analysis of serious adverse events. Am J Med 1994 Feb;96(2):115-23.
    42. Hoes JN, Jacobs JW, Boers M et al. EULAR evidence-based recommendations on the management of systemic glucocorticoid therapy in rheumatic diseases. Ann Rheum Dis 2007 Dec;66(12):1560-7.
    43. Abu-Shakra M, Shoenfeld Y. Azathioprine therapy for patients with systemic lupus erythematosus. Lupus 2001 Mar;10(3):152-3.
    44. Newman WG, Payne K, Tricker K et al; TARGET study recruitment team. A pragmatic randomized controlled trial of thiopurine methyltransferase genotyping prior to azathioprine treatment: the TARGET study. Pharmacogenomics 2011 Jun;12(6):815-26.
    45. Sato EI. Methotrexate therapy in systemic lupus erythematosus. Lupus 2001 Mar;10(3):162-4.
    46. Wong JM, Esdaile JM. Methotrexate in systemic lupus erythematosus. Lupus 2005 Feb;14(2):101-5.
    47. Gordon MM, Porter DR, Capell HA. Does sulphasalazine cause drug induced systemic lupus erythematosus? No effect evident in a prospective randomised trial of 200 rheumatoid patients treated with sulphasalazine or auranofin over five years. Ann Rheum Dis 1999 May;58(5):288-90.
    48. Parker BJ, Bruce IN. High dose methylprednisolone therapy for the treatment of severe systemic lupus erythematosus. Lupus 2007 Jun;16(6):387-93.
    49. Houssiau FA. Therapy of lupus nephritis: lessons learned from clinical research and daily care of patients. Arthritis Res Ther 2012 Jan;14(1):202.
    50. Touma Z, Gladman DD, Urowitz MB, Beyene J, Uleryk EM, Shah PS. Mycophenolate mofetil for induction treatment of lupus nephritis: a systematic review and metaanalysis. J Rheumatol 2011 Jan;38(1):69-78.
    51. Dooley MA, Jayne D, Ginzler EM et al; ALMS Group. Mycophenolate versus azathioprine as maintenance therapy for lupus nephritis. N Engl J Med 2011 Nov;365(20):1886-95.
    52. Houssiau FA, D’Cruz D, Sangle S et al; MAINTAIN Nephritis Trial Group. Azathioprine versus mycophenolate mofetil for long-term immunosuppression in lupus nephritis: results from the MAINTAIN Nephritis Trial. Ann Rheum Dis 2010 Dec;69(12):2083-9.
    53. Mok CC. Mycophenolate mofetil for non-renal manifestations of systemic lupus erythematosus: a systematic review. Scand J Rheumatol 2007 Sep-Oct;36(5):329-37.
    54. Rihova Z, Vankova Z, Maixnerova D et al. Treatment of lupus nephritis with cyclosporine: an outcome analysis. Kidney Blood Press Res 2007 Apr;30(2):124-8.
    55. Lee YH, Lee HS, Choi SJ, Dai Ji J, Song GG. Efficacy and safety of tacrolimus therapy for lupus nephritis: a systematic review of clinical trials. Lupus 2011 May;20(6):636-40.
    56. Lamarque V, Leleu MF, Monka C, Krupp P. Analysis of 629 pregnancy outcomes in transplant recipients treated with Sandimmun. Transplant Proc 1997 Aug;29(5):2480.
    57. Sárdy M, Ruzicka T, Kuhn A. Topical calcineurin inhibitors in cutaneous lupus erythematosus. Arch Dermatol Res 2009 Jan;301(1):93-8.
    58. Murray E, Perry M. Off-label use of rituximab in systemic lupus erythematosus: a systematic review. Clin Rheumatol 2010 Jul;29(7):707-16.
    59. Merrill JT, Neuwelt CM, Wallace DJ et al. Efficacy and safety of rituximab in moderately-to-severely active systemic lupus erythematosus: the randomized, double-blind, phase II/III systemic lupus erythematosus evaluation of rituximab trial. Arthritis Rheum 2010 Jan;62(1):222-33.
    60. Rovin BH, Furie R, Latinis K et al. Efficacy and safety of rituximab in patients with active proliferative lupus nephritis: the Lupus Nephritis Assessment with Rituximab study. Arthritis Rheum 2012 Apr;64(4):1215-26.
    61. Sinigaglia L, Varenna M, Binelli L et al. Determinants of bone mass in systemic lupus erythematosus: a cross sectional study on premenopausal women. J Rheumatol 1999 Jun;26(6):1280-4.
    62. Bhattoa HP, Bettembuk P, Balogh A, Szegedi G, Kiss E. Bone mineral density in women with systemic lupus erythematosus. Clin Rheumatol 2002 May;21(2):135-41.
    63. Sandhu SK, Hampson G. The pathogenesis, diagnosis, investigation and management of osteoporosis. J Clin Pathol 2011 Dec;64(12):1042-50.
    64. Goldblatt F, Chambers S, Rahman A, Isenberg DA. Serious infections in British patients with systemic lupus erythematosus: hospitalisations and mortality. Lupus 2009 Jul;18(8):682-9.
    65. Ruiz-Irastorza G, Olivares N, Ruiz-Arruza I, Martinez-Berriotxoa A, Egurbide MV, Aguirre C. Predictors of major infections in systemic lupus erythematosus. Arthritis Res Ther 2009;11(4):R109.
    66. Barber C, Gold WL, Fortin PR. Infections in the lupus patient: perspectives on prevention. Curr Opin Rheumatol 2011 Jul;23(4):358-65.
    67. Millet A, Decaux O, Perlat A, Grosbois B, Jego P. Systemic lupus erythematosus and vaccination. Eur J Intern Med 2009 May;20(3):236-41.
    68. Manzi S, Meilahn EN, Rairie JE et al. Age-specific incidence rates of myocardial infarction and angina in women with systemic lupus erythematosus: comparison with the Framingham Study. Am J Epidemiol 1997 Mar;145(5):408-15.
    69. Symmons DP, Gabriel SE. Epidemiology of CVD in rheumatic disease, with a focus on RA and SLE. Nat Rev Rheumatol 2011 Jul;7(7):399-408.
    70. Bruce IN, Urowitz MB, Gladman DD, Ibañez D, Steiner G. Risk factors for coronary heart disease in women with systemic lupus erythematosus: the Toronto Risk Factor Study. Arthritis Rheum 2003 Nov;48(11):3159-67.
    71. Wajed J, Ahmad Y, Durrington PN, Bruce IN. Prevention of cardiovascular disease in systemic lupus erythematous: proposed guidelines for risk factor management. Rheumatology (Oxford) 2004 Jan;43(1):7-12.
    72. Sherer Y, Zinger H, Shoenfeld Y. Atherosclerosis in systemic lupus erythematosus. Autoimmunity 2010 Feb;43(1):98-102.
    73. Jolly M. How does quality of life of patients with systemic lupus erythematosus compare with that of other common chronic illnesses? J Rheumatol 2005 Sep;32(9):1706-8.
    74. Bertsias GK, Ioannidis JP, Aringer M et al. EULAR recommendations for the management of systemic lupus erythematosus with neuropsychiatric manifestations: report of a task force of the EULAR standing committee for clinical affairs. Ann Rheum Dis 2010 Dec;69(12):2074-82.
    75. Yazdany J. Health-related quality of life measurement in adult systemic lupus erythematosus: Lupus Quality of Life (LupusQoL), Systemic Lupus Erythematosus-Specific Quality of Life Questionnaire (SLEQOL), and Systemic Lupus Erythematosus Quality of Life Questionnaire (L-QoL). Arthritis Care Res (Hoboken) 2011 Nov;63 Suppl 11:S413-S419.
    76. Levine JS, Branch DW, Rauch J. The antiphospholipid syndrome. N Engl J Med 2002 Mar;346(10):752-63.
    77. Cohen D, Berger SP, Steup-Beekman GM, Bloemenkamp KW, Bajema IM. Diagnosis and management of the antiphospholipid syndrome. BMJ 2010 May;340:c2541.
    78. Baer AN, Witter FR, Petri M. Lupus and pregnancy. Obstet Gynecol Surv 2011 Oct;66(10):639-53.
    79. Sammaritano LR. Menopause in patients with autoimmune diseases. Autoimmun Rev 2012 May;11(6-7):A430-A436.
    80. González LA, Pons-Estel GJ, Zhang JS et al; LUMINA Study Group. Effect of age, menopause and cyclophosphamide use on damage accrual in systemic lupus erythematosus patients from LUMINA, a multiethnic US cohort (LUMINA LXIII). Lupus 2009 Feb;18(2):184-6.
    81. Lateef A, Petri M. Hormone replacement and contraceptive therapy in autoimmune diseases. J Autoimmun 2012 May;38(2-3):J170-J176.

Search arthritis information

Order our publications

Order publications from the online shop, or use the bulk order form.

Topical Reviews archives

Browse previous issues of Topical Reviews (all issues available as downloadable PDFs)

We're now

Versus Arthritis.

You're being taken through to our new website in order to finish your donation.

Thank you for your generosity.

For more information, go to
Arthritis Research UK fund research into the cause, treatment and cure of arthritis. You can support Arthritis Research UK by volunteering, donating or visiting our shops.