Systemic lupus erythematosus

01OverviewDefinition, clinical context and the essential points that orientate the chapter.

Systemic lupus erythematosus is a relapsing-remitting autoimmune disease with wide variation between patients and over time. The diagnostic task is pattern recognition: inflammatory manifestations in several systems, supported by immunology and after credible mimics are excluded. Classification criteria help organise evidence but were designed for research and do not substitute for clinical diagnosis. Record which manifestations are active, previous severe organ disease and irreversible damage because each has different treatment implications.

Mucocutaneous and musculoskeletal disease are common, but kidneys, blood cells, nervous system, lungs, heart and blood vessels determine much of the serious risk. Inflammatory arthritis is usually non-erosive, although deforming Jaccoud arthropathy can develop. Renal disease may be asymptomatic. A disproportionately raised CRP often prompts a search for infection, yet bacterial infection can occur with any marker pattern and serositis or arthritis can raise CRP. Do not use one laboratory rule to separate flare from infection.

Hydroxychloroquine is background treatment for most patients because it reduces disease activity and flares and has favourable reproductive compatibility. Beyond it, select therapy by organ: methotrexate or azathioprine may support persistent skin or joint disease; belimumab or anifrolumab may be considered for eligible active non-renal disease; lupus nephritis and other major-organ manifestations follow specialist combination pathways. Glucocorticoid is a rapidly acting bridge or rescue component, not a harmless long-term default.

Life-course care includes sun protection, smoking cessation, vaccination, cardiovascular and bone risk management, cervical screening where appropriate, contraception and pregnancy planning, mental health and work support. Review infection before immunosuppression and avoid live vaccines during relevant therapy. Patients need a written route for fever, urinary change, breathlessness, neurological symptoms and pregnancy because disease status can change between scheduled appointments.

Key points

Suspect SLE when inflammatory joint disease, photosensitive or subacute cutaneous rash, oral or nasal ulcers, alopecia, serositis, cytopenia, renal abnormality or neurological disease occur in a coherent multisystem pattern.
ANA is a sensitive entry test but is not specific and must not be used as a population screen for non-specific fatigue or pain; a negative result makes ordinary SLE less likely but does not replace specialist judgement.
When the phenotype supports lupus, define anti-dsDNA, anti-Sm, C3 and C4, FBC, renal and liver function, urinalysis and quantitative protein, and test antiphospholipid, anti-Ro and anti-La antibodies for their distinct consequences.
At every review, check blood pressure, urine, creatinine, blood count, symptoms and treatment adherence; clinically silent nephritis is missed if urine is tested only after oedema appears.
Continue hydroxychloroquine for most people unless contraindicated, using no more than 5 mg/kg actual body weight daily and arranging retinal monitoring according to dose, duration and kidney risk.
Match immunosuppression to the organ and severity: topical measures or steroid-sparing conventional therapy may control skin and joints, whereas renal, neurological, pulmonary or haematological disease needs rapid specialist combination treatment.
A rise in anti-dsDNA or fall in complement can support activity but neither alone proves a flare or justifies treatment escalation; integrate examination, organ measures, infection assessment and trend.
Plan pregnancy while disease is quiet on compatible medicines; continue hydroxychloroquine, identify antiphospholipid and anti-Ro or anti-La antibodies, and replace methotrexate, mycophenolate or cyclophosphamide before conception under specialist care.
Avoid using long-term oral glucocorticoid as maintenance by default; cumulative exposure drives infection, diabetes, cataract, cardiovascular disease, avascular necrosis and osteoporosis.
Distinguish reversible inflammatory activity from accumulated damage, infection, fibromyalgia and medicine toxicity before increasing immunosuppression.

02AetiologyUnderlying causes, associations and risk factors, with why each one matters.

Polygenic immune susceptibility

HLA-region variants, complement deficiencies and numerous immune-regulatory alleles lower the threshold for loss of self-tolerance; no single result confirms ordinary polygenic lupus.

Hormonal and demographic influences

Disease is much more frequent in women of reproductive age, while ancestry influences prevalence, organ pattern and severity through interacting genetic and social determinants.

Environmental and medicine triggers

Ultraviolet light, smoking, infections and selected medicines can expose nuclear antigens or alter immune signalling, provoking onset or flares in a susceptible person.

03PathophysiologyThe causal sequence from the underlying abnormality to symptoms and harm.

1
Loss of nuclear self-tolerance
Impaired clearance of apoptotic material exposes DNA, RNA and associated proteins, allowing autoreactive B and T cells to persist and generate antinuclear antibodies.
2
Interferon and B-cell amplification
Nucleic-acid sensing activates type-I interferon pathways and B-cell survival signals, sustaining autoantibody production and inflammatory-cell recruitment across multiple tissues.
3
Immune-complex tissue injury
Autoantibody-antigen complexes deposit in glomeruli, skin, joints and vessels, activate complement and recruit inflammatory cells; falling complement can accompany active consumption.
4
Thrombotic and treatment-related damage
Antiphospholipid antibodies may drive thrombosis independently of immune-complex activity, while infection, corticosteroids and irreversible scarring add damage not corrected by more immunosuppression.

04Clinical features and red flagsSymptoms, examination findings, patterns of presentation and time-critical warnings.

Mucocutaneous pattern

Photosensitive acute or subacute cutaneous eruption, discoid lesions, painless oral or nasal ulcers and non-scarring alopecia support lupus when objectively documented.

Inflammatory joint and serosal disease

Symmetrical inflammatory arthralgia or synovitis, pleuritic pain and pericarditic symptoms are frequent, but infection and thrombosis remain important alternatives.

Renal warning patternRed flag

Hypertension, proteinuria, dysmorphic haematuria, casts or creatinine change may be the only evidence of nephritis and requires urgent combined review.

Blood-cell involvement

Autoimmune haemolysis, leukopenia, lymphopenia or thrombocytopenia can reflect active lupus, infection, hypersplenism, malignancy or treatment toxicity.

Neuropsychiatric diseaseRed flag

Seizure, psychosis, cognitive change, headache, neuropathy or stroke requires cause-specific investigation because lupus, APS, infection and metabolic disease overlap.

Raynaud and vascular phenotype

Raynaud phenomenon, livedo, ulcers or thrombosis should prompt vascular examination and antiphospholipid assessment rather than being assumed to be immune-complex activity.

Red flags requiring action

Fever with hypotension, neutropenia, immunosuppression or a focal source requires immediate sepsis assessment even when lupus activity is also plausible.
Haemoptysis, falling haemoglobin and new diffuse infiltrates may indicate pulmonary haemorrhage and need emergency respiratory, renal and rheumatology care.
New proteinuria, glomerular haematuria, casts, hypertension or rising creatinine requires urgent lupus-nephritis assessment rather than routine follow-up.
Seizure, psychosis, transverse myelitis, mononeuritis multiplex or focal deficit requires urgent neurological investigation for inflammatory, thrombotic, infectious and metabolic causes.
Chest pain, troponin rise, arrhythmia, heart failure or tamponade physiology requires acute cardiac assessment rather than attribution to benign serositis.

05InvestigationsWhat to request, why it matters and how to interpret it.

Investigation order

Read from the initial assessment onwards. Tests may run in parallel in urgent care; first-line, preferred, confirmatory, definitive and gold-standard labels appear only when the chapter explicitly states them.

01
ANA by validated assayFirst step
Why
Support diagnostic assessment when the clinical pre-test probability is meaningful.
Interpretation and limitations
A positive ANA is common outside SLE and its titre and pattern need context; repeated ANA titres do not monitor activity.
02
Anti-dsDNA, anti-Sm, C3 and C4
Why
Add diagnostic specificity and provide activity trends alongside organ assessment.
Interpretation and limitations
Anti-Sm is specific but insensitive; rising dsDNA and falling complement can accompany flare, yet normal values do not exclude active organ disease.
03
FBC, film, reticulocytes, LDH and haptoglobin
Why
Characterise cytopenia and identify immune haemolysis, microangiopathy, infection or medicine toxicity.
Interpretation and limitations
Interpret cell-line trends and film urgently; schistocytes with thrombocytopenia and organ injury suggests a thrombotic microangiopathy rather than routine flare.
04
Creatinine, blood pressure, urinalysis, ACR or PCR
Why
Screen repeatedly for clinically silent renal involvement and quantify a new abnormality.
Interpretation and limitations
Protein, glomerular blood, casts or declining eGFR requires urgent nephrology-rheumatology assessment; serology cannot determine histological class.
05
Antiphospholipid antibody panel
Why
Define thrombotic and pregnancy risk when SLE is diagnosed or the clinical history suggests APS.
Interpretation and limitations
Test lupus anticoagulant, anticardiolipin and anti-beta2-glycoprotein-I; persistence at least twelve weeks apart and clinical context determine APS significance.
06
Targeted organ imaging, fluid sampling or biopsy
Why
Confirm the threatened-organ mechanism and exclude infection, thrombosis, malignancy or irreversible damage.
Interpretation and limitations
Choose echocardiography, CT, MRI, lumbar puncture, skin or kidney biopsy according to the presentation; do not apply a blanket investigation panel.

06Differential diagnosisRealistic alternatives and the features that help distinguish them.

Infection

Fever, cytopenia, raised inflammatory markers and organ dysfunction may reflect bacterial, viral or opportunistic infection; immunosuppression can mute localising signs and CRP patterns are not definitive.

Other connective-tissue disease

Raynaud phenomenon, sicca, myositis or sclerodactyly may indicate Sjogren syndrome, systemic sclerosis, inflammatory myopathy, mixed or overlapping connective-tissue disease.

Drug-induced lupus

A temporal medicine relationship, arthralgia and serositis with antihistone antibodies may suggest drug-induced disease; renal and central nervous system disease are less typical.

Malignancy or haematological disease

Lymphadenopathy, weight loss, cytopenia, thrombosis or paraprotein findings require evaluation for lymphoma, leukaemia, plasma-cell disease or another haematological process.

07ManagementImmediate care, first-line treatment, alternatives and escalation.

01First assessmentBuild a clinical and organ mapFirst stepMultisystem inflammatory features raise a credible suspicion of systemic lupus erythematosus.

1Document chronology, objective skin and joint findings, serosal, neurological, renal, obstetric and thrombotic history, medicines, infections and family history.
2Request ANA with FBC, renal and liver profile, ESR or CRP, blood pressure and urine assessment; add specific antibodies and complements when the phenotype remains compatible.
3Refer to rheumatology, urgently when an organ is threatened, while directing acute kidney, neurological, cardiac, pulmonary, thrombotic or infection care in parallel.

02Preferred background treatmentUse hydroxychloroquine with preventionPreferredSLE is confirmed and no contraindication prevents antimalarial treatment.

1Record actual body weight, eGFR, interacting medicines, ocular history and baseline examination requirements before selecting a dose no higher than 5 mg/kg/day.
2Combine treatment with UV avoidance, smoking cessation, immunisation, cardiovascular and bone protection, reproductive planning and clear flare or infection advice.
3Assess adherence and toxicity at review; a low drug exposure from missed doses should not be mislabelled refractory disease.

03Escalation by organTreat the mechanism and severityEscalationActive disease persists or a major organ is involved despite background care.

1Exclude infection, thrombosis, toxicity and fixed damage, then define severity with organ-specific measures and tissue diagnosis where it will change treatment.
2Use the least cumulative glucocorticoid compatible with control and introduce the appropriate conventional, biologic or organ-specific steroid-sparing treatment early.
3EscalationSet response, taper and failure criteria before treatment; escalate renal, neuropsychiatric, pulmonary, cardiac or severe haematological disease through a multidisciplinary service.

04Pregnancy pathwayEnter pregnancy with quiet diseasePregnancy is planned, possible or newly confirmed in a person with SLE.

1Review activity, damage, renal function, urine protein, blood pressure, anti-Ro, anti-La and antiphospholipid antibodies with rheumatology and maternal medicine.
2AlternativeContinue compatible control, including hydroxychloroquine, and replace teratogenic or fetotoxic medicines early enough to demonstrate stability on the alternative.
3Agree aspirin or anticoagulation only for the relevant pre-eclampsia or APS indication and arrange maternal, placental and fetal surveillance matched to antibody and organ risk.

Key medicines and prescribing safety5 treatments · regimens, roles and cautions

Background treatment for most patients, reducing activity and flares and supporting safer glucocorticoid reduction.

Hydroxychloroquine

Usually 200–400 mg orally once daily with food, using the lowest effective dose and not exceeding 5 mg/kg actual body weight per day; reduce exposure when kidney function or other toxicity risk requires it.

Avoid in established maculopathy, review QT-prolonging combinations, cardiomyopathy, hypoglycaemia and renal impairment, and arrange retinal monitoring after five years or after one year when high risk. It is compatible with pregnancy and breastfeeding under BSR guidance.

Steroid-sparing treatment for selected skin, joint, haematological or organ disease and a pregnancy-compatible alternative in suitable patients.

Azathioprine

Specialist oral dosing is commonly started at 25–50 mg daily and increased toward 1–2 mg/kg/day according to TPMT status, response and blood monitoring.

Check TPMT, FBC, liver and renal function and infection status; allopurinol or febuxostat interactions require expert dose adjustment or avoidance. Monitor cytopenia, hepatitis and pancreatitis. BSR regards doses no greater than 2 mg/kg/day as compatible with pregnancy.

Conventional steroid-sparing treatment when inflammatory skin or musculoskeletal activity remains troublesome.

Methotrexate with folic acid

For persistent non-renal skin or joint disease, specialist treatment commonly starts at 7.5–15 mg orally or subcutaneously once weekly with folic acid at least 5 mg on a different day, titrating to response.

Never dose daily. Monitor FBC, liver and renal function; avoid trimethoprim or co-trimoxazole, significant liver disease and serious infection. Stop at least one month before maternal conception and do not use during pregnancy.

B-cell survival-factor inhibition for selected active autoantibody-positive SLE despite standard treatment, including compatible renal pathways where commissioned.

Belimumab

Licensed adult regimens are 200 mg subcutaneously once weekly or 10 mg/kg by intravenous infusion on days 0, 14 and 28 and then every 28 days, under specialist eligibility and monitoring.

Screen infection and vaccination status, monitor infusion or injection reactions, mood and suicidality, and coordinate use in pregnancy or breastfeeding with specialists because evidence is more limited than for established conventional medicines.

Provides rapid anti-inflammatory control while definitive organ-specific and steroid-sparing therapy takes effect.

Prednisolone

Dose is severity-dependent: use a short low dose for minor inflammatory disease or specialist high-dose and intravenous methylprednisolone rescue for organ-threatening disease, with a documented taper and maintenance target.

Obtain cultures when infection is possible, use gastric and bone protection when indicated, monitor glucose, blood pressure, mood and eyes, and avoid abrupt cessation after sustained use. Minimise cumulative exposure because damage is dose-related.

08ComplicationsImportant consequences, why they occur and why they matter clinically.

Renal and cardiopulmonary injury

Nephritis, pulmonary haemorrhage, interstitial lung disease, pulmonary hypertension, myocarditis and accelerated atherosclerosis can produce irreversible organ loss or death.

Neurological and haematological disease

Inflammatory, thrombotic and antibody-mediated mechanisms can cause seizures, psychosis, neuropathy, stroke, immune haemolysis or severe thrombocytopenia.

Infection and medicine toxicity

Disease-related immune dysfunction combines with glucocorticoids and immunosuppressants to increase serious infection, malignancy, metabolic, skeletal, reproductive and organ-specific toxicity.

Pregnancy and fetal risk

Active disease, nephritis and antiphospholipid antibodies increase maternal and placental complications; anti-Ro or anti-La antibodies confer fetal conduction and neonatal-lupus risk.

09Monitoring and follow-upTreatment response, safety checks and longer-term review.

At each review record symptoms, examination, disease activity, irreversible damage, adherence, infection and adverse effects rather than relying on serology alone.
Measure blood pressure, urinalysis, quantitative protein when abnormal, creatinine and FBC regularly; increase frequency after any renal or haematological change.
Trend anti-dsDNA and C3 or C4 where they have been informative, but treat the patient and organ rather than an isolated laboratory result.
Follow medicine-specific FBC, liver, renal, retinal and infection schedules and confirm vaccinations before major immunosuppression where timing permits.
Review cardiovascular risk, smoking, lipid profile, diabetes, bone health, vitamin D, cervical screening, mental health, fatigue and participation at least annually.
Revisit contraception and pregnancy intentions before every teratogenic prescription and after disease or relationship circumstances change.

10Special situationsVariants, exceptions and circumstances that change the usual approach.

ANA establishes probability, not activity

ANA positivity supports entry into a diagnostic assessment but repeat titre does not tell whether kidneys, brain or joints are inflamed.

CRP has no absolute rule

A high CRP should intensify infection assessment, but lupus serositis and synovitis can raise it and infection may occur without a dramatic rise.

Damage can mimic activity

Avascular necrosis, osteoarthritis, neuropathic pain, scarring and fibromyalgia cause symptoms that will not improve with added immunosuppression.

Urine is a vital sign

Regular urinalysis and protein quantification identify renal disease before oedema or a large creatinine rise develops.

Antibody results carry different jobs

Anti-dsDNA may track activity, anti-Sm adds specificity, anti-Ro affects fetal planning and antiphospholipid antibodies redirect thrombosis prevention.

11Common pitfallsFrequent interpretation and management errors.

01
Ordering ANA for isolated fatigue or widespread pain without a compatible inflammatory phenotype, then labelling an incidental positive result as lupus.
02
Escalating immunosuppression for fever before cultures and infection assessment in an immunosuppressed patient.
03
Using complement or anti-dsDNA change alone to diagnose a clinical flare or determine its organ.
04
Failing to screen urine and blood pressure because the patient has no oedema or renal symptoms.
05
Continuing oral glucocorticoids indefinitely without a steroid-sparing plan and explicit damage surveillance.
06
Allowing pregnancy to begin on mycophenolate, methotrexate or cyclophosphamide because reproductive intentions were not revisited.