Systemic Lupus Erythematosus

Overview

Systemic lupus erythematosus (SLE) is a multisystem autoimmune disease of unknown aetiology that can present at any age. SLE is prone to relapses and remissions and can result in morbidity due to flares of disease activity and accumulating damage over time, along with an increased risk of premature death due to infection or cardiovascular disease.

Lupus erythematosus describes the typical rash seen in SLE. The “systemic” part indicates the potential for multi-organ involvement.

Antiphospholipid syndrome can happen secondary to SLE, which carries an increased risk of venous thromboembolism.

Pathophysiology

SLE is thought to be a type III hypersensitivity reaction where impaired clearance of dead cells and failure of processes giving immune tolerance to nuclear antigens may lead to the development of antibodies against double-stranded DNA and nuclear proteins.

Epidemiology

• Affects 1/1000 of the UK population
• More common in women than men
• More common in people of African-Caribbean descent

Risk Factors

• Female sex
• Age >30yrs
• African-Caribbean descent
• Certain drugs can cause drug-induced lupus, whose symptoms resolve upon withdrawal of the offending drug:
  • Procainamide
  • Hydralazine
  • Minocycline
  • Terbinafine
  • Sulfasalazine
  • Isoniazid
  • Phenytoin
  • Carbamazepine
• Family history
• Smoking

Associations

• Antiphospholipid syndrome
• Overlap syndromes
  • Some patients do not have pure SLE but overlapping features with other rheumatological conditions e.g. rheumatoid arthritis/scleroderma/polymyositis/Sjögren’s syndrome
• Other autoimmune diseases e.g. thyroiditis
• Drug allergy
• Increased infection risk
• Atherosclerosis/hypertension/dyslipidaemia/diabetes/osteoporosis
• Malignancies – non-Hodgkin’s lymphoma

Presentation

SLE presents with varied and non-specific symptoms:

• General symptoms:
  • Fever
  • Fatigue
  • Lymphadenopathy
  • Mouth ulcers
• Skin and hair:
  • Malar (butterfly) rash over the cheeks and bridge of the nose, sparing the nasolabial folds
  • Photosensitive rash
    • Sun exposure usually exacerbates skin manifestations of SLE
  • Discoid rashes: erythematous raised patches that are scaly and well-demarcated.
    • These tend to present in sun-exposed areas. 
  • Mild Raynaud’s phenomenon
  • Livedo reticularis
  • Alopecia – typically diffuse or patchy and non-scarring
  • Vasculitic rashes
• Musculoskeletal symptoms:
  • Joint and muscle pains, often with early morning stiffness
    • Joint swelling is unusual
  • Arthritis can be present, which is similar to rheumatoid arthritis but is usually non-erosive
    • Monoarthritis of a large joint in a patient with SLE is unusual and should prompt investigation for another cause e.g. infection/avascular necrosis.
• Pulmonary symptoms:
  • Pleurisy
  • Fibrosing alveolitis
  • Patients with secondary antiphospholipid syndrome are at an increased risk of a pulmonary embolism
• Cardiovascular symptoms:
  • Pericarditis
  • Hypertension
  • Myocarditis
• Renal symptoms:
  • Asymptomatic nephritis – proteinuria, haematuria, hypertension or raised serum urea or creatinine
  • Glomerulonephritis – diffuse proliferative glomerulonephritis or membranous glomerulonephritis
    • Blood pressure and urinalysis looking for proteinuria and haematuria should be routinely performed
• Neuropsychiatric symptoms:
  • Anxiety
  • Depression
  • Psychosis
  • Seizures
  • Strokes secondary to vasculitis or thrombosis associated with secondary antiphospholipid syndrome

Signs on Examination

• Features mentioned above
• Butterfly rash
• Discoid skin rashes
• Alopecia
• Fever
• Lymphadenopathy
• MSK symptoms mentioned above

Differential Diagnoses

Rheumatoid arthritis (RA)

• RA is erosive, SLE is not
• Mouth ulcers, photosensitivity, and a malar rash are not present in RA

Antiphospholipid syndrome

• Recurrent venous or arterial thrombosis
• Recurrent foetal loss
• Antiphospholipid antibodies present

Systemic sclerosis (SSc)

• The main presenting complaint in SSc is hardened, sclerotic skin
• Raynaud’s in systemic sclerosis is more likely to ulcerate
• Systemic sclerosis has sclerodactyly and calcinosis

Mixed connective tissue disease (MCTD)

• There may be overlapping symptoms of SLE, systemic sclerosis, and myositis
• May be difficult to distinguish clinically
• Autoantibodies specific to SLE tend to be absent

Haematological malignancy

• Bone marrow/imaging/histology distinguishes diagnosis
• Autoantibodies negative

Investigations

Overview

• Autoantibodies:
  • Anti-nuclear antibodies (ANA) – present in 95% of patients with SLE
    • High sensitivity but not very specific as many rheumatological conditions also have ANA present
  • Anti-double-stranded DNA (anti-dsDNA)
    • High specificity (>99%) but less sensitive
  • Other specific autoantibodies include:
    • Anti-Smith, anti-Ro (SS-A), and anti-La (SS-B)
• Monitoring disease activity:
  • Erythrocyte sedimentation rate (ESR) is used
  • C-reactive protein (CRP) may be normal during active disease
    • If CRP is raised, this may indicate an underlying infection
  • Complement levels
    • C3 and C4 may be low in active disease

Other investigations in all patients suspected to have SLE:

• Full blood count (FBC):
  • May show anaemia/leukopenia/thrombocytopenia
• Activated partial thromboplastin time (APTT):
  • Prolonged if patients have antiphospholipid syndrome
• Urea and electrolytes (U&Es):
  • Identifies renal manifestations
• Urinalysis:
  • Identifies renal manifestations, which may show:
    • Haematuria
    • Casts
    • Proteinuria

Other investigations relevant to presentation:

• Chest x-ray for patients with cardiopulmonary symptoms, which may show:
  • Pleural effusions
  • Infiltrates
  • Cardiomegaly
• ECG for patients with cardiopulmonary symptoms
  • Excludes other causes of chest pain
• Antiphospholipid antibodies:
  • In patients with a history of venous thromboembolism, recurrent miscarriages, or prolonged APTT

Sensitivity vs. specificity

SNOUT SPIN can be used when interpreting SLE serology as a general rule of thumb:

• SNOUT
  • SeNsitive: positive test not very useful, but negative useful, good to rule disease OUT
• SPIN
  • SPecific: positive test very useful, but negative result not very useful, good to rule disease IN

Diagnosis

SLE is diagnosed based on clinical criteria and the presence of its autoantibodies:

• The American College of Rheumatology Classification system may be used which involves using set factors
• The Systemic Lupus International Collaborating Clinic Index 2012 (SLICC) may also be used

Management

Management of SLE varies significantly, the following notes are a general rule of thumb.

• Effective sunscreen use and avoiding excess sun exposure
• NSAIDs for musculoskeletal pain and headaches:
  • Options are naproxen, or celecoxib if patients have a high risk of GIT ulcers and have a low cardiovascular risk
  • Consider gastroprotection if considering long-term use 

If simple analgesia and NSAIDs fail to control symptoms of disease, further options are considered depending on the systems involved:

• Hydroxychloroquine is the initial treatment of choice
• If there’s further involvement of internal organs or hydroxychloroquine is insufficient, prednisolone, cyclophosphamide, azathioprine, and many other drug options are considered.

Monitoring

• Disease activity is measured using ESR
• If a patient has a presumed flare of symptoms, it is essential to exclude infection and comorbidity first
• Patients with lupus nephritis should have their renal function monitored through renal biopsy, kidney, functional tests, and urinalysis. 

Patient Advice

• Patients should avoid excessive sun exposure and use effective sun screen
• Patients should be aware that some drugs can exacerbate SLE
• Patients should have smoking cessation help and aim to stop
• Oestrogen-containing hormonal contraception can worsen SLE, but the lowest dose can cautiously be used if there are no contraindications and no anticardiolipin antibodies present
• Fertility is normal and pregnancy is safe in stable/mild SLE
• If SLE is severe, pregnancy should be delayed until the disease is better controlled:
  • Morbidity is common in pregnancy and SLE, especially if the patient has antiphospholipid antibodies
  • Complications can include:
    • Recurrent miscarriage
    • Pre-eclampsia
    • Intrauterine growth restriction
    • Preterm delivery
    • Increased risk of thrombosis throughout, especially post-partum
  • Pre-existing renal disease may worsen pregnancy and hypertension might be difficult to control
  • The risks of pregnancy are greatly increased if lupus nephritis, hypertension, and active disease are present at the time of conception

Complications

• Anaemia of chronic disease
  • Improves with control of disease activity
• Lupus nephritis – a type of rapidly-progressing glomerulonephritis that may result in end-stage renal disease:
  • Treatment involves immunosuppression with glucocorticoids and cyclophosphamide/mycophenolate
• Raynaud’s phenomenon
• Pericarditis
• Myocarditis
• Infection due to immunosuppression
• Miscarriages
• Pulmonary hypertension
• Lupus pneumonitis
• Venous thromboembolism
• Malignancy
• Thrombocytopenia
• Corticosteroid-related complications
• NSAID-related complications

Prognosis

• Life expectancy is 25 years lower than the average
• Around 1/3 develop lupus nephritis and are at risk of end-stage renal disease