Systemic lupus erythematosus

01Definition and overview

Systemic lupus erythematosus (SLE) is a chronic, relapsing autoimmune disease marked by autoantibodies against nuclear antigens, above all double-stranded DNA and nucleoproteins, and by inflammation that can reach almost any organ. Its course runs in flares and remissions, and every patient has their own pattern: one has only rashes and joint pains for decades, another presents with nephritis or seizures.

Lupus comes in several forms:

• systemic lupus, the subject here;
• cutaneous lupus without systemic disease, such as discoid lupus, of which only a minority goes on to SLE;
• drug-induced lupus, a milder illness that settles when the drug is stopped;
• neonatal lupus, in babies of mothers with anti-Ro antibodies.

It overlaps with the other connective tissue diseases (systemic sclerosis, myositis, Sjögren syndrome) and often comes with antiphospholipid antibodies, sometimes with the full antiphospholipid syndrome.

02Etiology and pathophysiology

Who gets it

• Genes: a sibling has a risk many times that of the general population, and identical twins are concordant in about a quarter of cases. More than a hundred risk loci are known, among them HLA-DR2 and DR3 and genes of interferon signalling and of B and T cells. Inherited deficiency of the early complement components C1q, C4 and C2 is rare but carries the highest risk of all: about 9 in 10 people without C1q develop lupus.
• Sex: oestrogen and genes of the X chromosome. The receptor TLR7, which senses RNA, escapes X inactivation in some cells; men with Klinefelter syndrome (XXY) have a risk close to that of women.
• Environment: ultraviolet light, which triggers flares and rashes; Epstein–Barr virus; smoking; silica.
• Drugs: they cause drug-induced lupus, described below.

How lupus begins

1. 1

   Debris from dying cells

   Cells dying by apoptosis expose nuclear material (DNA, histones, Ro and other ribonucleoproteins) in blebs on their surface. Normally phagocytes clear them quickly, helped by C1q. In lupus clearance is slow, so the material lingers and is presented to the immune system.
2. 2

   Loss of tolerance

   Self-reactive B cells escape control, helped by T cells and by high levels of the survival factor BLyS (BAFF). They make antibodies against nuclear antigens, often years before the first symptom: in stored blood, ANA appeared on average more than three years before diagnosis.
3. 3

   Type I interferon

   Immune complexes carrying DNA and RNA are taken up by plasmacytoid dendritic cells, whose endosomal receptors TLR7 and TLR9 sense the nucleic acid and release floods of type I interferon. Interferon activates more B cells and antigen-presenting cells, a loop that sustains the disease. Most adults with SLE have a high interferon gene signature in their blood.
4. 4

   Tissue damage

   Immune complexes deposit in glomeruli, skin and serosa, or form there, and activate complement; neutrophils and macrophages enter, and the tissue is inflamed. Some antibodies act directly: against red cells, platelets and lymphocytes, causing cytopenias, and anti-Ro against the fetal conduction tissue.

This is a type III hypersensitivity disease, with a share of type II damage. Complement is consumed in active disease, so C3 and C4 fall. Small vessel vasculitis, thrombosis from antiphospholipid antibodies and accelerated atherosclerosis add vascular injury.

Drug-induced lupus

Drugs can provoke a lupus-like illness, usually after months or years of use:

Terbinafine, proton pump inhibitors, thiazides and calcium channel blockers more often cause a drug-induced subacute cutaneous lupus with anti-Ro antibodies, and immune checkpoint inhibitors can trigger lupus-like disease.

03Clinical features

General symptoms are common: fatigue, which may persist when the disease is quiet, fever, weight loss and lymphadenopathy.

Organ by organ

Lupus nephritis

Renal involvement decides much of the prognosis. A kidney biopsy classifies it by the ISN/RPS scheme (2003, revised in 2018, when the active and chronic labels were replaced by activity and chronicity indices):

Classes III and IV, with or without V, are the proliferative, aggressive forms. Tubulointerstitial inflammation and thrombotic microangiopathy from antiphospholipid antibodies can sit alongside. The class can change between biopsies.

Judging activity and damage

Activity and damage are scored separately: activity with the SLEDAI-2K or the BILAG index, permanent damage with the SLICC/ACR damage index. Damage builds from the disease and from steroids: osteonecrosis, cataract, osteoporosis, diabetes, kidney failure and cardiovascular events.

04Diagnosis and management

Tests

• ANA by indirect immunofluorescence on HEp-2 cells: positive in nearly all patients, but also at low titre in many healthy people, so a positive ANA alone does not make the diagnosis. Once positive, it is not repeated.
• Anti-dsDNA: in about 60 to 70 per cent over the course of the disease, and specific; high levels go with nephritis and its rise often precedes a flare.
• Anti-Sm: highly specific, in about 1 in 5 European patients and more in people of African and Asian descent. Anti-Ro, anti-La and anti-U1-RNP are common but not specific; anti-histone points to drug-induced lupus; antiphospholipid antibodies (lupus anticoagulant, anticardiolipin, anti-β2-glycoprotein I) are found in about a third.
• C3 and C4: low in active disease, especially nephritis, from consumption. A persistently low C4 can also be inherited.
• Blood count, with a film and a direct antiglobulin test; renal function, albumin.
• ESR and CRP: the ESR rises with activity, but the CRP usually stays normal or modestly raised. A high CRP in lupus means infection until proven otherwise, unless there is serositis or synovitis.
• Urine: dipstick, microscopy for dysmorphic red cells and casts, and the protein to creatinine ratio.
• Biopsy where needed: kidney, skin (immunoglobulin and complement along the dermoepidermal junction).
• Imaging as the organs need: echocardiography, chest CT, brain MRI; lumbar puncture to exclude infection in neuropsychiatric disease.

Classification: the 2019 EULAR/ACR criteria

The criteria are for classifying patients in studies, not a checklist that must be met for a diagnosis, but they teach what counts. The entry criterion is an ANA of 1 in 80 or more on HEp-2 cells, or an equivalent positive test, at least once. Then each domain counts its highest item, items need not occur together, an item counts only if nothing more likely explains it, and at least one clinical item is needed:

A total of 10 or more classifies SLE. In the validation cohort they were 96 per cent sensitive and 93 per cent specific. Class III or IV nephritis on biopsy with a positive ANA is enough on its own.

the entry criterion, on HEp-2 cells

1:80ANA titrethe entry criterion, on HEp-2 cells

to classify SLE, with one clinical item

10pointsto classify SLE, with one clinical item

the most hydroxychloroquine, by real body weight

5mg/kg a daythe most hydroxychloroquine, by real body weight

the long-term ceiling, or stop

5mg prednisolonethe long-term ceiling, or stop

Treatment: the principles

The aim is remission, or at least low disease activity, with the least steroid, while preventing damage and the complications of treatment. Lupus is managed by a rheumatologist with nephrologists, dermatologists and others as the organs require, and the patient is taught sun protection, the signs of a flare and of infection.

• Hydroxychloroquine for every patient unless contraindicated, at no more than 5 mg/kg of real body weight a day, usually up to 400 mg, less when the eGFR is below 30. It reduces flares, damage, thrombosis and death. Retinal toxicity is dose-dependent and silent until late, so the retina is examined at baseline and yearly after five years of use, earlier with risk factors such as a high dose or kidney disease.
• Glucocorticoids as a bridge: intravenous methylprednisolone pulses (usually 250 to 1000 mg a day for one to three days) for organ-threatening disease, which allow a lower oral starting dose, then a taper. For maintenance, prednisolone is cut to 5 mg a day or less and stopped where possible, because steroid damage accrues with dose and time.
• Immunosuppressants, started early when the disease does not settle on hydroxychloroquine or steroids cannot be tapered: methotrexate (joints and skin), azathioprine (compatible with pregnancy) or mycophenolate (kidney and most organ disease); calcineurin inhibitors (tacrolimus, ciclosporin, voclosporin) in nephritis.
• Biologics, added to control persistent activity and to spare steroids: belimumab, an antibody against BLyS, and anifrolumab, an antibody against the type I interferon receptor, given intravenously every four weeks or, since December 2025 in the EU, as a weekly injection under the skin. Anifrolumab raises the risk of herpes zoster and was not tested in active severe nephritis or neuropsychiatric lupus.
• Cyclophosphamide for organ-threatening disease, mainly nephritis, neuropsychiatric lupus and vasculitis; the low-dose Euro-Lupus regimen of 500 mg intravenously every two weeks for six doses has largely replaced high monthly doses, sparing fertility. Rituximab, which depletes B cells, is used off-label for refractory disease.
• Symptoms: NSAIDs briefly for joint and serosal pain, with care for the kidneys; topical steroids or calcineurin inhibitors for the skin.

Treatment by organ

Lupus nephritis

Nephritis of classes III and IV, with or without V, and active class V with significant proteinuria, need immunosuppression; classes I and II need treatment of any extrarenal lupus and kidney protection (unless nephrotic, a lupus podocytopathy treated with steroids like minimal change disease), and class VI needs preparation for kidney replacement. The guidance of 2024 to 2025, from KDIGO, EULAR and the ACR, agrees on the backbone:

1. 1

   Induction

   Methylprednisolone pulses, then oral prednisolone (0.3 to 0.7 mg/kg a day in European recommendations; no more than about 0.5 to 0.6 mg/kg and at most 40 mg a day in American and KDIGO guidance) tapered to 5 mg a day or less by 4 to 6 months. With an anchor drug, mycophenolate (2 to 3 g a day of mycophenolate mofetil) or low-dose intravenous cyclophosphamide.
2. 2

   Combination from the start

   European recommendations (2025) favour adding a third drug for active nephritis, especially with poor prognostic features, keeping a single anchor drug as an alternative for lower-risk patients: belimumab with mycophenolate or cyclophosphamide; a calcineurin inhibitor, voclosporin or tacrolimus, with mycophenolate, suited to heavy proteinuria when the eGFR is above about 45; or obinutuzumab, an anti-CD20 antibody, with mycophenolate, licensed in the EU since December 2025 for active class III or IV nephritis, with or without class V. KDIGO 2024, written before obinutuzumab's trial was published, accepts mycophenolate or cyclophosphamide alone as well as the belimumab and calcineurin inhibitor combinations, and keeps anti-CD20 drugs for disease that persists.
3. 3

   Response

   Complete response is a urine protein to creatinine ratio below about 50 mg/mmol (0.5 g/g) with stable kidney function, aimed for within 12 months; partial response is a fall of at least half, to below 3 g/g (about 300 mg/mmol), by 6 to 12 months. European recommendations add milestones: proteinuria down by a quarter at 3 months, by half at 6 months, and below about 0.7 g/g (70 mg/mmol) at 12 months. Failure to respond prompts a check of adherence, a repeat biopsy and a switch or escalation, with rituximab or obinutuzumab among the options.
4. 4

   Maintenance

   Immunosuppression continues for at least three years after response, usually with mycophenolate (or azathioprine, if pregnancy is planned), the add-on drug where it was used, hydroxychloroquine and the least steroid.

Every patient also gets kidney protection: blood pressure below 130/80 mmHg, an ACE inhibitor or angiotensin receptor blocker for proteinuria, statins as needed, and an SGLT2 inhibitor considered when proteinuria persists 6 to 12 months into treatment.

Pregnancy

Fertility is usually normal, but pregnancy carries more flares, pre-eclampsia, miscarriage, preterm birth and growth restriction, above all with active nephritis or antiphospholipid antibodies. So:

• pregnancy is planned for when the disease has been quiet for at least six months;
• mycophenolate, cyclophosphamide and methotrexate harm the fetus and are stopped before conception: mycophenolate at least six weeks before, methotrexate one to three months before; hydroxychloroquine, azathioprine, tacrolimus, ciclosporin and low-dose prednisolone continue;
• low-dose aspirin from before 16 weeks lowers the risk of pre-eclampsia, and heparin is added in antiphospholipid syndrome;
• with anti-Ro or anti-La antibodies, about 2 per cent of babies develop congenital heart block, which is permanent and often needs a pacemaker, and about 1 in 6 after an affected sibling. The fetal heart is watched by echocardiography from about 16 to 26 weeks, and hydroxychloroquine roughly halves the recurrence. Neonatal lupus can also cause a transient rash, cytopenias and hepatitis;
• oestrogen-containing contraception is avoided in active disease and with antiphospholipid antibodies.

Long-term care

• Cardiovascular risk: risk factors are treated actively, with blood pressure below 130/80 mmHg and lipids managed as in the general population, which underestimates lupus patients' risk. Disease control and less steroid lower the risk too.
• Infection: vaccination against influenza, pneumococcus, COVID-19 and herpes zoster (with the non-live vaccine), and HPV; live vaccines avoided on immunosuppression; prophylaxis against Pneumocystis on high-dose steroids with other immunosuppressants.
• Bone: calcium, vitamin D (sunscreen-wearing patients run low), bone density and treatment as needed on steroids.
• Cancer screening, especially of the cervix, and sun protection.

05Epidemiology

SLE affects about 5 people per 100,000 a year and about 40 to 50 per 100,000 in all, on a global estimate, with very wide variation between regions and groups. About nine in ten patients are women, and onset peaks in the childbearing years. It is commoner and more severe in people of African, Afro-Caribbean, Asian and Hispanic descent, who also have more nephritis: among Afro-Caribbean women in the UK it is as common as about 1 in 250. Lupus starting in childhood or after 50 is less common; late-onset lupus is milder, with a lower female excess. Childhood lupus is more often severe and renal.

06Prognosis

Survival has risen greatly, to about 90 per cent at ten years, but death rates remain two to three times those of people of the same age. Mortality is bimodal: early deaths come from active disease, especially nephritis and neuropsychiatric lupus, and from infection; late deaths from atherosclerosis, with myocardial infarction and stroke, and from damage. Young women with lupus have many times the expected risk of myocardial infarction. Lymphoma and some other cancers are commoner.

A worse outlook comes with nephritis (especially class IV and a high chronicity index), early damage, neuropsychiatric disease, antiphospholipid antibodies, male sex, African descent, low income, and poor adherence. In older series about a quarter of patients with overt nephritis reached kidney failure within ten years. In high-income countries the five-year risk fell to about 1 in 10 by the mid-1990s and has changed little since; class IV carries the highest risk. Persistent proteinuria, a low eGFR and hypertension at diagnosis and repeated flares still predict it. Patients who reach it do well with dialysis and transplantation, and nephritis rarely recurs in the graft.

Patients are followed for life: activity, damage and adverse effects at each visit, with urine, blood count, renal function, anti-dsDNA and complement every few months, and yearly checks of cardiovascular risk, bone and, on hydroxychloroquine, the eyes. Many reach lasting remission, and some can eventually taper their treatment, but a flare can come at any time.