Systemic lupus erythematosus Larissa Lisnevskaia, Grainne Murphy, David Isenberg Lancet 2014; 384: 1878–88 Published Online May 30, 2014 S0140-6736(14)60128-8 Oshawa Clinic, Oshawa, ON, Canada (L Lisnevskaia MD); and Centre for Rheumatology, Department of Medicine, University College London Hospital, London, UK (G Murphy PhD, Prof D Isenberg MD) Correspondence to: Prof David Isenberg, Centre for Rheumatology, Department of Medicine, University College London Hospital, The Rayne Building, Room 424, 5 University Street, London WC1E 6JF, UK [email protected]

Systemic lupus erythematosus is a remarkable and challenging disorder. Its diversity of clinical features is matched by the complexity of the factors (genetic, hormonal, and environmental) that cause it, and the array of autoantibodies with which it is associated. In this Seminar we reflect on changes in its classification criteria; consider aspects of its more serious clinical expression; and provide a brief review of its aetiopathogenesis, major complications, coping strategies, and conventional treatment. Increased understanding of the cells and molecules involved in the development of the diseases has encouraged the identification of new, better targeted biological approaches to its treatment. The precise role of these newer therapies remains to be established.

Introduction Systemic lupus erythematosus is a challenging disease to assess and manage. The progress in our understanding of its aetiopathogenesis is notable. In this Seminar we provide an update on its clinical presentations and conventional management. We also review some of the many studies published in the past decade that used biological drugs, the development of which has been based on improved understanding of the causes of this disease. However, success in treatment of systemic lupus erythematosus with biological strategies is less impressive than that for rheumatoid arthritis. This difference is attributable to the complexity of the disorder and the likely diverse mechanisms that contribute to its clinical expression. This extra challenge makes the work of scientists, who seek to understand the disease better, and clinicians treating patients with lupus, more demanding.

Epidemiology The incidence and prevalence of systemic lupus erythematosus seems to be increasing, probably because of both the identification of milder cases and improved survival. In 2007, a review outlined the geographical variability in disease incidence and prevalence. In the US population, the all race incidence was 5·1 per 100 000 per year and the prevalence was 52·2 per 100 000, with comparative figures of 3·8 and 26·2 in the UK, and 2·9 and 28·4 in Japan, respectively.1 These figures are substantially higher in some ethnic populations, notably in individuals of African-American

Search strategy and selection criteria We searched PubMed (January, 2009, to September, 2013) and Summon Search (January, 2009, to September, 2013) databases with the terms “systemic lupus erythematosus” and “lupus” in combination with the terms “epidemiology”, “classification”, “cardiovascular risk”, “lupus nephritis”, “CNS lupus”, “antiphospholipid syndrome”, “pregnancy”, “pathogenesis”, “presentation”, and “management”, with no language restrictions. We also searched the references of articles identified by this strategy and selected those that were relevant.


or African-Caribbean descent. Systemic lupus erythematosus affects women of childbearing age, with a male-to-female ratio of about 9:1 commonly reported. This female predominance is less striking in the juvenile and elderly populations with ratios of 2–6:1 and 3–8:1, respectively, in these age groups. This difference is largely thought to reflect the effect of female sex hormones on aspects of the immune system. In view of the relative rarity of systemic lupus erythematosus in men and in juvenile patients, investigators of many studies in the past 20 years have considered whether this disease has a particular clinical or serological profile in these patients. Although findings from the Euro-lupus project—a prospective cohort study of 1000 patients with lupus followed up from 1991— showed a higher rate of serositis and lower rate of arthritis in men than in women, a review2 of nearly 500 patients followed up for 30 years showed very few differences between sexes. In children, however, consistent evidence suggests a significantly higher risk of lupus nephritis, and perhaps greater mortality, than in patients who develop disease as adults. These findings draw attention to the need for close monitoring and more intensive therapy, particularly with reference to the risk of lupus nephritis, for these patients, who are susceptible to greater damage accrual as a result of aggressive inflammatory disease. The Euro-lupus project has offered some valuable insights into the epidemiology and clinical manifestations of systemic lupus erythematosus.3 Nearly half (48%) of patients presented with arthritis and a third had a malar rash. Active nephropathy was detected in 28% of patients. The presence of antidouble-stranded DNA antibodies was a predictor of nephritis (relative risk 1·79) and haemolytic anaemia (2·49), and lupus anticoagulant predicted clinical antiphospholipid syndrome (1·2–1·53). The 10 year survival was 92%, which is significantly better than mortality rates reported earlier in the 20th century. The activity of disease and infections (28·9% each) were major causes of mortality during the first 5 years of follow-up. Thrombosis (26·1%) was the most common cause of death during the last 5 years of the study. The mortality risk has decreased substantially over past decades. In a cohort of 1241 patients with lupus from a clinic in Toronto, the standardised mortality ratio Vol 384 November 22, 2014


changed from 12·60 in the 1970s, to 3·46 in the past decade.4 Despite the improved mortality rate, patients with systemic lupus erythematosus have a higher mortality risk than that of the general population, particularly in patients with a younger age at disease onset.5 Furthermore, in developed countries with high gross domestic product, survival is much higher because of better access to health care, educational level, physician availability, and treatment compliance.6 Clearly the outcome for systemic lupus erythematosus depends on more than just the development of new drugs. Furthermore, in some countries the funding for such drugs is not available. Some differences in outcome are evident in terms of ethnic origin. In the Lupus cohort at University College Hospital, London, UK, black patients with renal disease were far more likely to go into renal failure than were white patients,7 with the reasons almost certainly nothing to do with economics since health care is free at the point of entry in the UK’s National Health Service. In similar studies in the USA economic and genetic factors have been hard to disentangle.

Revised classification criteria Since the publication of the last Seminar on systemic lupus erythematosus in The Lancet in 2007,1 a major development has been the publication of the Systemic Lupus International Collaborating Clinics (SLICC) classification criteria in 2012.8 This classification attempted to rationalise the clinical criteria and provided a modest expansion in recognised laboratory abnormalities (panel 1). Biopsy-proven nephritis compatible with systemic lupus erythematosus in the presence of antinuclear or antidouble-stranded DNA antibodies in the absence of other lupus features is regarded as sufficient for a patient to be diagnosed as having lupus. The symptoms and laboratory abnormalities are cumulative and need not to be present concurrently.

Pathogenesis Systemic lupus erythematosus is a multifactorial disease with evidence of genetic susceptibility, environmental effects, and disturbances in both innate and adaptive immunity manifest by disturbances in apoptotic cell clearance, cytokines, B-cell immunity, and T-cell signalling. Although a detailed review of the pathogenesis of lupus has been published,9 we briefly summarise some noteworthy developments. Deficiencies in components of the complement cascade are well known to predispose to the development of systemic lupus erythematosus. However, more than 28 other disease susceptibility loci have now been confirmed.10 Some of the strongest associated risk loci identified through genome-wide association studies are ITGAM, FcγR, PRDM1-ATG5, and TNFAIP3. Whether these loci will help to identify additional inflammatory pathways implicated in the disorder that will translate into novel therapeutic targets is unknown. Vol 384 November 22, 2014

Lupus is strongly associated with defects in apoptotic clearance.11 The initiating events are likely to vary, but the consequent excessive apoptotic debris has an important pathogenic effect. Early apoptotic cells express so-called eat-me signals—ie, cell-surface proteins such as phophatidylserine that prompt circulating immune cells to engulf these cells. They also express so-called find-me signals to attract macrophages and dendritic cells. Failure of phagocytes to remove apoptotic material efficiently Panel 1: Clinical and immunological criteria used in the Systemic Lupus International Collaborating Clinics (SLICC) classification system* Clinical criteria 1 Acute cutaneous lupus, including lupus malar rash, bullous lupus, toxic epidermal necrolysis variant of systemic lupus erythematosus, maculopapular lupus rash, photosensitive lupus rash, or subacute cutaneous lupus (psoriaform or annular polycyclic lesions, or both) 2 Chronic cutaneous lupus, including classic discoid rash (localised and generalised), hypertrophic lupus, lupus panniculitis, mucosal lupus, lupus erythematosus tumidus, chilblains lupus, and discoid lupus/lichen planus overlap 3 Oral ulcers or nasal ulcers 4 Non-scarring alopecia 5 Synovitis involving two or more joints and at least 30 min of morning stiffness 6 Serositis 7 Renal (urine protein-to-creatinine ratio [or 24 h urine protein]) representing 500 mg protein per 24 h or red blood cell casts 8 Neurological: seizures, psychosis, mononeuritis multiplex, myelitis, peripheral and cranial neuropathy, acute confusional state 9 Haemolytic anaemia 10 Leukopenia (7·5 mg in BLISS-52, and 44–48% in BLISS-76) and some also took other immunosuppressive drugs. The success of belimumab encourages other studies of molecules that block B-cell activating factors. Atacicept is another agent that blocks the interaction between BLyS and APRIL (a proliferation-inducing ligand) and their receptors. APRIL has a function similar to BLyS.77 Atacicept is a recombinant receptor-Ig fusion protein that binds to BLyS and APRIL. It suppresses the differentiation and survival of antibody-producing B cells. Atacicept with mycophenolate mofetil was used in a trial of lupus nephritis that was stopped after the enrolment of six patients because of serious infections. Detailed analysis of these infections proved them to be mainly due to hypogammaglobulinaemia induced by mycophenolate mofetil before atacicept had been given. The efficacy of atacicept was not assessed.78 The preliminary results of a major trial in non-renal lupus have indicated that atacicept might be effective at prevention of disease flare.79 The full results are awaited. CD22 is a B-lymphocyte-specific transmembrane sialoglycoprotein. It is present in highest concentration on the surface of mature IgM+/IgD+ B cells and is absent on memory and plasma cells.80 CD22 functions through the B-cell receptor (BCR) complex by phosphorylation of three tyrosine-based inhibitory motifs on its intracellular part. Phosphorylation initiates the recruitment of the tyrosine phosphotase 1 molecules that inhibit BCR signalling. Epratuzumab is a humanised anti-CD22 IgG1 monoclonal antibody. Treatment with epratuzumab causes a decrease in the peripheral B lymphocyte count in patients with lupus. An initial open-label clinical trial of epratuzumab in 14 patients with moderately active systemic lupus erythematosus, which was undertaken in 2008, showed that epratuzumab was well tolerated and improved BILAG scores by more than 50% in 77% of patients at 6 weeks, and in all patients at some point during the study period.81 A phase IIb study of epratuzumab in 227 patients with moderate to severe lupus showed that patients had a symptom reduction or absence of active disease within specific body systems, especially cardiorespiratory or neuropsychiatric systems.82 Vol 384 November 22, 2014

Panel 4: Biological treatments available or potentially available for the treatment of systemic lupus erythematosus Targeting B cells • • • •

B-cell depleting therapy: rituximab B-cell modulating therapy: epratuzumab Inhibition of B-cell survival: belimumab, atacicept Other potential B-cell (plasma cell) targeting strategies: bortezomib

Targeting T cells •

Inhibition of T-cell function: abatacept, ruplizumab, toralizumab, lupuzor

Interleukin 6 •


Tumour necrosis factor α inhibitors • •

Infliximab Etanercept

Type I interferon inhibitors • •

Sifalimumab Rontalizumab

Complement inhibitors •


T cells have also been suggested as a therapeutic target in systemic lupus erythematosus. Abatacept is a biological drug that blocks T-cell costimulation. It is a fusion protein consisting of the T-lymphocyte-associated antigen-4 (CTLA-4) and modified Fc portion of human immunoglobulin.83 To be activated T lymphocytes require two signals: the antigen-specific signal 1 and costimulatory signal 2. CTLA-4 plays a part in the inhibition of costimulation; through its engagement with CD80/86, it causes inhibition of T-cell activation. In a double-blind, placebo-controlled trial of abatacept in patients with nonlife-threatening lupus,84 118 patients were studied. The primary endpoint was the proportion of new flares after tapering of the steroid dose. The study did not meet the primary endpoint, but treatment differences were evident in patients with polyarthritic symptoms in post-hoc analyses.84 19·4% of patients in the study were negative for antinuclear and double-stranded DNA antibodies, which is substantially higher than in lupus cohorts in general. Sifalimumab, a human anti-interferon α monoclonal antibody, binds and neutralises most interferon α subtypes. It prevents signalling through the type 1 interferon receptor. Two randomised, double-blind studies85,86 showed its safety, and results support the continued clinical development of strategies targeting interferon α for treatment of systemic lupus erythematosus. Other antiinterferon α  molecules that have been going through testing in phase 2 studies are rontalizumab, AGS-009, MEDI-546, and interferon-α kinoid.87 Panel 4 summarises biological agents already available or potentially available for use for the treatment of systemic lupus erythematosus. 1885


Coping with the disease and quality of life Non-pharmacological management of systemic lupus erythematosus is also important. The psychological effects of lupus include depression, fatigue, psychological distress, and difficulties with emotion-oriented coping.88 A study of 120 patients with this disorder showed that treatment of depression, and consideration of stress and insomnia, reduced fatigue.88 Of 154 Australian and UK patients with lupus, 26% were clinically depressed.89 Depression and insufficient suitable coping mechanisms and support impair the ability to manage chronic disease effectively. Some studies indicate dissatisfaction with social support, notably poor understanding and unsatisfactory contacts with the doctor or little information about the disorder.90 Ideally, patients with lupus should be assessed regularly for depression, and medical intervention and referral to psychology services should be available. Connecting the patient with support groups or societies available locally can relieve the frustration of searching unreliable internet sources A supervised cardiovascular training programme in patients with lupus substantially improves exercise tolerance, aerobic capacity, depression, and quality of life. A study of 60 patients who participated in a training protocol on a treadmill showed that the training group had a significant improvement in their aerobic capacity, as measured by the anaerobic threshold, and improvements in depression and quality-of-life scales.91 Supervised physical exercise also improves endothelial function and aerobic capacity without worsening of the disease activity in patients with systemic lupus erythematosus.92

Conclusion Understanding of the pathogenesis of lupus is clearly growing. Encouragingly, this knowledge is being applied in clinical practice with improvements in classification, a better appreciation of lupus features and complications, and the development of new drugs. There is better understanding of the importance of other aspects of lupus management such as quality of life, mental health, prevention of complications such as atherosclerosis, and pregnancy morbidity, and they play an important part in day-to-day practice. Despite the complexity and diversity of the disease there is hope for these patients. New promising agents targeting its different mechanisms are already used or in development. Contributors LL cowrote the first draft of this Seminar with GM, did much of the original literature search, and approved the responses to reviewers written by GM and DI. GM cowrote the first draft of this Seminar with LL, and modified some of the panels and table. DI set out the original plan for the Seminar, had a major contribution to redrafting the original version, and took responsibility for answering the reviewers’ comments. Declaration of interests DI has undertaken consulting work for several pharmaceutical companies including Eli Lilly, Merck Serono, GlaxoSmithKline, and UCB Pharma. The support offered is made available to a local arthritis charity. LL and GM declare that they have no competing interests.


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Systemic lupus erythematosus.

Systemic lupus erythematosus is a remarkable and challenging disorder. Its diversity of clinical features is matched by the complexity of the factors ...
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