Lisa Willcocks and Menna Clatworthy - Review Date March 2017
Systemic lupus erythematosus (SLE) is a multisystem autoimmune disease characterised by the presence of autoantibodies to a variety of self-antigens, and the formation of IgG immune complexes which become deposited in tissues. Both the severity and location of immune complex deposition can vary widely between individuals, with corresponding heterogeneity in clinical presentation. Up to half of patients with SLE will develop renal involvement (lupus nephritis), which has a variable presentation, including low grade proteinuria and haematuria, nephrosis, slowly progressive chronic kidney disease and rapidly progressive glomerulonephritis.
In the UK, systemic lupus erythematosus (SLE) has a prevalence of 10-50 per 100,000 in Caucasians, but is more common in people of Afro-Caribbean and southeast Asian ethnicities (Danchenko, Satia et al. 2006). The disease predominantly affects women under the age of 40 years (female:male ratio of 10:1).
Overt renal disease occurs in at least one-third of patients with SLE and is the most common severe manifestation. The development of nephritis is closely linked to survival and morbidity; 10–20% patients with lupus nephritis die within 10 years and a further 10–25% reach end-stage kidney disease (ESKD). However, there is considerable variation in severity, course and outcome. Lupus nephritis usually responds to corticosteroid and immunosuppressive therapy, but the toxicity of these drugs also contributes to morbidity and mortality.
The aetiology of SLE has both genetic and environmental influences (Wahren-Herlenius and Dorner 2013):
Genetic Factors: The evidence for a genetic influence on pathogenesis includes:
- 15x increased disease risk in siblings of patients with SLE
- 3% of dizygotic twins will get disease if their twin has it (concordance), whereas 30% concordance is observed in monozygotic twins
- Some racial groups have an increased frequency and severity of SLE.
In almost all cases, SLE is a polygenic disease; iea number of genes confer disease susceptibility. The genetic variants (polymorphisms) that lead to disease susceptibility are often relatively common within a population, and it is only if an individual inherits multiple susceptibility variants that they develop disease. Genes implicated in the pathogenesis of SLE predominantly have immunological functions, and include those encoding human leucocyte antigen (HLA) molecules, complement components, Fc receptors (Niederer, Clatworthy et al. 2010), Toll-like receptors (TLRs), and molecules involved in the type I interferon pathway (Rullo and Tsao 2013).
Environmental factors: A number of environmental influences have been identified which can precipitate disease in individuals with a susceptible genotype (Zandman-Goddard, Solomon et al. 2012). As noted above, SLE is more common in females than in males suggesting that hormonal factors may influence pathogenesis. Disease flares can be also be triggered by environmental stimuli such as ultraviolet light or certain drugs (Table 1). Thus, an individual may be genetically predisposed to the development of SLE but will only develop disease if they encounter a specific environmental trigger. Once initiated, other genetic, environmental, and hormonal factors act to modify the spectrum and severity of clinical manifestations.
The way in which genetic and environmental factors interact to produce disease is a subject of intense research (Choi, Kim et al. 2012). A summary of the pathogenesis of lupus nephritis is shown in Figure 1 and described in Clatworthy and Smith 2007.
Clues to the pathogenesis of the disease can be found within the clinical and pathological phenotype of patients with SLE (see clinical features). A central feature of lupus is the presence of autoantibodies, principally to nuclear components, so a key question is 'what leads to the formation of these autoantibodies?' To answer this, we have to understand a how antibodies are normally made. IgG antibodies are produced by terminally differentiated B cell (known as plasma cells). B cell activation to enable them to produce IgG antibodies requires the provision of help by a CD4 T cells which recognise the same antigen. These CD4 T cells first need to be switched-on by seeing antigen presented to them on a major histocompatibility (MHC) HLA molecule.
During B cell development, most B cells producing antibody that recognise self-antigen are eliminated, or are forced to change their antibody. Similarly, strongly autoreactive T cells are removed during their development. The fact that patients with SLE have IgG autoantibodies is indicative that some of the mechanisms used to get rid of autoreactive B and T cells are ineffective; or there is a failure of the measures used to control autoreactive cells that escape deletion. An excess of the cytokine BAFF, which supports B cell survival, may promote this process (Cancro, D'Cruz et al. 2009).
Even if these autoreactive cells are allowed to persist, they still need to encounter self-antigen. Normally, nuclear antigens are not found extracellularly, so cannot be picked up or recognised by immune cells. However, in some circumstances, nuclear antigens can be found on the surface of cells; for example, exposure of cells to UV light induces apoptosis (programmed cell death). During this process, DNA and other nuclear antigens can be found within ‘apoptoic blebs’ on the surface of cells. Thus, previously inaccessible nuclear self-antigen is internalised by immune cells (eg B cells and dendritic cells). This nuclear material is recognised by pathogen receptors (Toll-like receptors, TLR7 and 9) and other cytoplasmic receptors, which have evolved to detect microbial RNA and DNA (Migliorini and Anders 2012). This explains why some drugs, including hydralazine and procainamide, can cause SLE, because they can alter self DNA methylation or RNA structure enhancing TLR activation.
Once the self-antigen is presented to autoreactive CD4 T cells, they provide help to B cells, which in turn produce autoantibodies and immune complexes. Patients with lupus fail to clear immune complexes, which deposit in tissues, including the kidney. They also show heightened immune activation in response to deposited immune complexes, activating macrophages and neutrophils via binding to surface Fc receptors, and activating complement via the classical pathway (see figure 2a for a summary of the complement activation and figure 2b for a summary of how the location of IC deposition in the kidney determines systemic complement activation). This explains why IgG, C1q, C3, C4 and inflammatory cells are detectable in the renal biopsies of patients with lupus nephritis.
Renal disease is a one of the more serious manifestations of SLE, and forms one of the diagnostic criteria delineated by the American College of Rheumatology (Hochberg 1997). In 2012, the Systemic Lupus International Collaborating Clinics (SLICC) group proposed an updated classification system including 11 clinical and six immunological criteria (Goldblatt and O'Neill 2013). These criteria include broader definitions of the clinical abnormalities, particularly for cutaneous and neuropsychiatric lupus, and include low complement concentrations in the immunological criteria (Petri, Orbai et al. 2012) (Table 2).
Lupus nephritis is the first manifestation of disease in approximately 25% of SLE patients. In 5% of cases, renal abnormalities occur up to several years before other diagnostic criteria or serological abnormalities become apparent. Lupus nephritis may present with asymptomatic urinary abnormalities on routine testing (non-visible haematuria or proteinuria), nephrotic syndrome and/or impaired renal function. Less commonly, patients present with acute kidney injury secondary to a rapidly progressive GN, and may require renal replacement therapy. This may be accompanied by other severe manifestations, such as myocarditis or neurological involvement.
A number of factors influence the outcome of patients with lupus nephritis, and should be considered when evaluating patients during history taking and examination:
- Demography (age, sex, socio-economic status, race, duration of SLE and nephritis (if known diagnosis))
- Drug exposure (those associated with lupus (see section on aetiology), and any previous immunosuppression in patients already known to have SLE)
- Family history (rare monogenic familial cases, or history of other autoimmune diseases)
- Extra-renal organ involvement (see Table 2, including signs of anaemia, rashes (photosensitive areas), mouth ulcers, serositis (pericardial/pleural rub), murmurs (Libmann-Sachs endocarditis), joints (arthritis), neurological symptoms, splenomegaly, systemic symptoms (malaise, fevers))
- Symptoms/signs of renal impairment (high blood pressure, peripheral oedema, pulmonary oedema)
This assessment, together with the results of serological tests (see investigations) and renal biopsy, will determine the patient’s subsequent management.
Urea, electrolytes and creatinine. Lupus nephritis can lead to a decline in renal function (as evidenced by a rise in creatinine/fall in GFR).
Albumin. Some patients with lupus nephritis may have heavy proteinuria or even nephrotic syndrome. Serum albumin should be assessed.
Urine dipstick is mandatory in any patient with SLE, and may show varying degrees of blood or protein present in urine. Proteinuria should be formally quantified using a UPCR (urinary protein:creatinine ratio) or ACR (albumin:creatinine ratio). Urine microscopy may also be useful, demonstrating red cell casts in patients with an active glomerulonephritis.
Patients with SLE may have anaemia secondary to chronic disease or may have an autoimmune haemolytic anaemia. They may also have autoimmune thombocytopaenia or leucopaenia. The former is of particular relevance, since thrombocytopenia may increase the risk of bleeding following a renal biopsy. Clotting should also be assessed, particularly APTT, since a lupus anticoagulant (see immunology tests below) may interfere with the test and show a prolonged APTT, although it does not actually increase the risk of bleeding.
Erythrocyte sedimentation rate (ESR) is typically significantly elevated, whilst C-reactive protein (CRP) may be within the normal range or only mildly elevated, unless there is intercurrent infection.
Patients with SLE typically have elevated levels of IgG (hypergammaglobulinaemia), which include circulating autoantibodies. These autoantibodies lead to complement activation (via the classical pathway) which is evidenced by a reduction in serum C3, C4 and C1q. Anti-nuclear antibodies (ANA), directed against components of the cell nucleus, are present in the majority (>95%) of patients with SLE. ANA are not very specific, and may be seen other connective tissue diseases, or in more elderly patients without autoimmune disease.
Anti-double-stranded (ds)DNA antibodies and anti-Smith(Sm) antibodies are much more specific but less sensitive. Anti-phospholipid antibodies (including lupus anticoagulants, anticardiolipin antibodies and antibodies to beta2-glycoprotein I) may also be present in patients with SLE. Patients with these antibodies are at a higher risk of thrombotic renal disease – both renal artery and vein thromboses, as well as a thrombotic microangiopathy.
If the patient has an abnormal GFR or urine dipstick, an ultrasound is mandatory. This will exclude any obvious abnormality, such as cysts, masses or obstruction. It allows assessment of renal size and cortical thickness (which can provide an indication of whether there is chronic, irreversible damage) and also allows renal perfusion to be examined.
ECG (electrocardiogram) – if pericarditis is suspected. Typical changes include saddle-shaped ST elevation. If present, an echocardiogram should also be performed to exclude a significant pericardial effusion.
Renal biopsy is diagnostic and prognostic in lupus nephritis. As with all renal biopsies, useful information is provided by light microscopy, which can be supplemented by immunofluorescence and electron microscopy.
Light microscopy can demonstrate a variety of appearances, which principally result from deposited immune complexes and the inflammatory response to them. The immune complexes can be viewed as thickened glomerular capillary loops (so-called ‘wire-looping’) and may be associated with mesangial cell proliferation, expansion of the mesangial matrix and infiltration with inflammatory leucocytes (figure 3). Other pathogenic mechanisms include the infarction of glomerular segments, thrombotic microangiopathy, vasculitis and glomerular sclerosis. Extra-glomerular features of lupus nephritis include tubulo-interstitial nephritis (70% of patients), as well as thrombotic disease, seen particularly in patients with anti-phospholipid antibodies.
Immunofluorescence typically shows a ‘full house’ of immune deposits in the glomeruli and mesangium, including IgG, IgM, IgA and the complement components C3, C4, and C1q.
Electron microscopy demonstrates the sub-endothelial position of immune complexes.
The histological appearance of glomerular disease has been classified according to the pattern and extent of immune deposition and inflammation (Table 3) (Markowitz and D'Agati 2009). Transformation to a more severe or less severe histological class is well documented and may result from treatment or be part of the natural history of the disease. The activity and chronicity of lesions identified at renal biopsy are used to assess whether treatment should be intensified; and chronicity indices predict long-term renal outcomes. However, interpretation of renal biopsy is subject to observer bias and may be influenced by sample size.
Figure 3: Renal biopsy with lupus nephritis. Left panel – normal glomerulus. Middle panel – proliferative GN, with wire-looping. Right panel – immunoperoxidase staining for IgG showing deposition within glomerular capillary loops.
Treatment of lupus nephritis is governed by histological stage. Most data suggest that WHO class II lupus nephritis has a benign course, and treatment in the absence of other indications is usually not required. The outcome and treatment of class V disease (membranous) is debated, reflecting differences in the interpretation of histological criteria. The decision to treat active WHO class III and IV lupus nephritis is less controversial. The first phase of treatment (known as induction) is aimed at inducing disease remission. This is followed by a maintenance phase, aimed at preventing relapses.
This is achieved with a combination of corticosteroids and another immunosuppressive agent. Traditionally, cyclophosphamide has been used, with evidence supporting a regime of 6 fortnightly pulses of 500mg intravenously as safer, but with similar efficacy, as higher doses (Houssiau, Vasconcelos et al. 2010).
Randomised controlled trials have shown that mycophenolate mofetil (MMF) is at least as effective as pulsed intravenous cyclophosphamide when used to induce remission in lupus nephritis classes III-V, with MMF superior in non-White patients (Ginzler, Dooley et al. 2005, Appel, Contreras et al. 2009). Induction therapy generally lasts 3-6 months, although complete remission may take as long as 24 months.
Early withdrawal of immunosuppression increases relapse rate, hence MMF or azathioprine are commonly used following induction treatment to maintain remission. Recent evidence suggests that MMF is more effective at preventing relapse than azathioprine (Wofsey 2010). The optimum duration of therapy is debated; continuing treatment for a significant disease-free period, such as two years, is recommended. Ciclosporin and tacrolimus are alternative agents, particularly used in children.
Side-effects of treatment
There is a significant side-effect profile for cyclophosphamide, mycophenolate and azathioprine. Cyclophosphamide is associated with premature menopause in up to 50% of women, myelosuppression, an increased risk of severe infections and bladder malignancy. Azathioprine is associated with hypersensitivity reactions. With both azathioprine and mycophenolate the risk of myelosuppression and infection are lower than with cyclophosphamide but there is an increased risk of skin malignancy after prolonged exposure. Mycophenolate is teratogenic and should be avoided in pregnancy.
Novel immunosuppressive therapies
Treatment-related mortality and morbidity from infection are significant in SLE, as is treatment failure due to non-compliance; and other more targeted, potentially less toxic agents are undergoing clinical trials. B cells play an important role in the pathogenesis of SLE (see section on pathogenesis), and recent studies have investigated the therapeutic potential of biological agents which either deplete or block the activation of these cells. Although randomised trials have failed to convincingly demonstrate an additional benefit of rituximab (B cell-depleting, anti-CD20 chimeric monoclonal antibody) given in addition to MMF and glucocorticoids for remission induction in SLE and lupus nephritis (Furie 2009), many non-randomised studies have reported improvements in SLE refractory to standard treatment following rituximab (Ramos-Casals, Soto et al. 2009). A multicentre randomised controlled trial is planned to compare a steroid-sparing regimen of rituximab and MMF therapy with a conventional regimen of MMF and oral prednisolone in treating lupus nephritis.
Two phase III, randomized multinational studies have demonstrated efficacy and safety of belimumab, another B cell targeted monoclonal antibodies in non-renal SLE. Belimumab blocks the action of BAFF (also known as BLyS), a B cell-stimulating cytokine. In these studies, belimumab, in addition to standard care with anti-malarials, azathioprone or MMF and steroids, improved outcomes and reduced glucocorticoid doses in patients with active musculoskeletal and mucocutaneous disease (Furie, Petri et al., Navarra, Guzman et al.). This led to its approval by the FDA for treatment of lupus, the first new drug licensed for this indication in 50 years.
Autologous peripheral stem cell transplantation has been shown to be an effective treatment in small studies of patients with severe disease (including lupus nephritis) refractory to conventional treatment (Farge, Labopin et al.). However, mortality and morbidity are high, with five-year survival rates of 85%. Other potential novel therapies are reviewed in (Smith, Clatworthy et al. 2010) and (Stohl 2013)
The five-year survival in patients with SLE has increased dramatically from the 1950s, when it was approximately 40%, to more than 90% in studies beginning after 1980. Development of renal disease increases the early mortality rate in SLE. Other negative prognostic factors include cerebral involvement, low complement, older age, male gender, black ethnicity and poverty. The most important prognostic factors of renal outcome are renal histology and renal function at presentation. Following treatment, normalisation of proteinuria and the absence of relapse of nephritis are the best predictors of a good outcome (Houssiau, Vasconcelos et al. 2004).
Death within the first few years after diagnosis with SLE is usually from active disease or infection related to immunosuppression. Later on, mortality is more likely a consequence of illness sequelae, such as end stage kidney disease, or malignancies, including lymphoma and lung cancer. The risk of cardiovascular disease is greatly increased in SLE and is also a major cause of late mortality.
Pregnancy and lupus nephritis
Fertility may be impaired by SLE or its treatment and pre-existing renal impairment. Proteinuria or hypertension increase the risks of pregnancy both to the mother and foetus. Secondary anti-phospholipid syndrome occurs frequently in lupus nephritis patients and is associated with recurrent miscarriages. Lupus nephritis can relapse during pregnancy. Patients should therefore continue immunosuppression. However, mycophenolate mofetil is teratogenic, and should therefore be changed (for example to azathioprine), at least 6 weeks, prior to conception where pregnancy is planned. ACE inhibitors should also be discontinued either prior to conception or when a pregnancy is confirmed.
Anti-platelet therapy with aspirin and low molecular weight heparin are used to reduce the risk of placental failure in higher risk cases. The immediate post-partum period is associated with a high risk of relapse and a prophylactic glucocorticoid increase should be considered. Management by a specialist team before conception and during pregnancy is important in optimising foetal and renal outcomes.
- SLE is a multisystem autoimmune diseases, characterised by IgG immune complex deposition in a variety of tissues.
- The aetiology includes both genetic and environmental factors, including some drugs.
- The pathogenesis of SLE involves the abnormal presentation of nuclear self-antigen to autoreactive T cells, which in turn help autoreactive B cells to produce autoantibodies.
- Lupus nephritis is common in patients with SLE, affecting up to 50% but may be asymptomatic.
- Other clinical manifestations include photosensitivity rashes, pericarditis, a non-erosive arthritis and immune cytopaenias.
- Clinical features do not predict severity of renal biopsy findings.
- Development of lupus nephritis is a negative predictor of patient survival.
- Current treatments strategies are divided into induction and maintenance regimens. Immunosuppressive agents commonly used include corticosteroids, cyclophosphamide, mycophenolate mofetil and azathioprine.
- B cell depletion with rituximab (anti-CD20) or B cell inhibition with belimumab (anti-BAFF) may be useful where traditional immunosuppressive agents have failed.
- Treatments carry significant side-effects, particularly increasing susceptibility to infection, but have greatly improved prognosis.
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