Systemic Lupus Erythematosus (SLE)

A multisystem, autoimmune conditions characterised by an autoantibody response to nuclear (ANA) and other cellular antigens, and by a broad spectrum of clinical presentations encompassing almost all organs.

Background/Epidemiology

• Lupus erythematosus describes the typical rash seen in SLE, whilst many patients also have systemic features
• Prevalence may be as high as 50/100,000 and the incidence is rising (currently 2-8/100,000)
• Age of onset varies between 16-55 (most commonly early adulthood)
• Female:Male ratio is 9:1
  • NB Males tend to present older, with less photosensitivity but more serositis (see below)
• More common in Chinese, Southeast Asian and Afro-Caribbean compared to white European

Aetiology and Risk factors

•  Genetics/Familial
  • Siblings of an individual with SLE are ~30× more likely to develop the disease and around 8% of individuals with SLE have an affected first degree relative
  • As with many other autoimmune diseases, an HLA allele (in SLE it is HLA-DRB1*3, DRB*2 and DRB*4) has been associated
  • Other genes, e.g. those encoding for complement C4 (C4A null allele), as well as a number of others involved in the inflammatory process
• Environmental
  • Viruses
    • Epstein-Barr virus (EBV)
      • May reside in, or interact with, B cells and promote interferon α production by dendritic cells
  • Drugs
    • Drug induced lupus erythematosus can be caused by a number of drugs/drug types including antiarrhythmics, antibiotics (isoniazid), hydralazine, procainamide, anticonvulsants, antipsychotics (chlorpromazine), statins, biologics, chemotherapy agents, atenolol… etc
      • NB May be associated with HLA-DR4
      • Cutaneous and pulmonary features are usually more common than renal/CNS
      • Autoantibodies – homogeneous anti nuclear antibodies
      • Usually remits on stopping the drug

Pathogenesis

• The exact event that triggers the pathogenesis is unknown.

1. Increased amounts of apoptosis-related nucleic acids stimulate production of IFNα
2. This promotes autoimmunity by breaking self-tolerance through activation of antigen-presenting cells (in particular HLA-DLRB)
3. Immune complexes are formed and continue to drive the inflammatory response

see http://www.eular.org/myUploadData/files/sample%20chapter20_mod%2017.pdf for in detail.

Presentation

• SLE is a remitting/relapsing disease.  It is also often called the ‘immitator’, because many of its signs/symptoms are, alone, characteristic of other diseases.
• Common presenting symptoms and signs
  • Rash/cutaneous symptoms
    • Malar rash– erythema over the cheeks and nasal bridge (sparing the nasolabial folds- cf dermatomyositis).  Can last days/weeks.  Usually painless/non-itchy but can be either.
    • Photosensitivity- Either acute or chronic.  Eruption/rash usually lasts 2 days and is commonly macular.
    • Discoid lupus- a plaque-like rash often characteristically oval and occuring on sun-exposed sites and are usually chronic.  It is thought that the presence of a discoid lupus suggests milder, less systemic disease
  • Constitutional symptoms
    • Fever is common
    • Malaise/fatigue (often severe)
  • Joint/Muscles
    • Non-erosive arthritis involving 2 or more peripheral joints- typically affecting the small joints of the hands
    • Arthralgia is the most common symptom at onset
    • Tenosynovitis- achilles tendonitis and tendon ruptures are not uncommon
• Other features
  • Renal
    • Kidney is the most commonly affected visceral organ, with clinical manifestations occuring in around 40-70% of patients, caused by immune-complex deposition in the glomeruli
    • Glomerular nephritis is usually asymptomatic but can be detected on urinalysis (see below)
  • Other cutaneous features
    • Raynaud’s phenomenon (occurs in ~60%)
    • Erythema nodosum (panniculitis)
    • Oral Ulcers
    • Patchy, non-scarring alopecia
  • Neuropsychiatric
    • SLE can affect both the CNS and PNS
      • The American College of Rheumatology have classified 19 different neuropsychiatric syndromes of SLE, which include acute confusional state (similar to delirium); acute inflammatory demyelinating polyradiculopathy; anxiety disorder; aseptic meningitis; autonomic dysfunction; cerebrovascular disease; cognitive dysfunction, demyelinating syndrome; headache; mononeuropathy; mood disorders; choreal; MG; myelopathy; cranial neuropathy; plexopathy; polyneuropathy and…
      • Psychosis; Seizures- these are included in the diagnostic criteria for SLE
  • Pulmonary
    • Pleural serositis is a relatively common feature in SLE patients (pleuritic pain/rub)
    • More rarely, patients can be at higher risk of pulmonary embolism (particularly if associated with antiphospholipid syndrome), fibrosing alveolitis, alveolar haemorrhage (more common than with other connective tissue diseases), pulmonary infections; pleural effusion, lupus pneumonitis, shrinking lung syndrome
  • Cardiovascular
    • Chest pain may occur as a result of pericarditis
    • Patients are generally at increased risk of atherosclerosis and cardiovascular events (particularly coronary heart disease and hypertension)
  • GI
    • Abdominal pain occurs in around 30%
    • Hepato/Splenomegaly

Investigations

• FBC and ESR
  • Mild normochromic normocytic anaemia is common
  • ESR is often raised (CRP can be normal)
  • Leukopenia/thrombocytopenia may be present but are often side effects of treatment rather than true features
• U&Es and LFTs
  • Both liver and (especially) kidney function can be affected by SLE and should be monitored regularly (they are not particularly diagnostic- but are important to measure extent/severity of disease)
• Serology
  • Antinuclear antibodies (ANA)
    • Good for screening (95% sensitivity)- i.e. if negative it is unlikely to be SLE but if positive, it is not specific for SLE
  • Anti-double-stranded-DNA (Anti-dsDNA)
    • More specific but sensitivity only 70%
    • Most commonly used to confirm SLE
  • Anti-Smith (anti-Sm) is the most specific test but only has a 30% sensitivity
• Investigations of symptoms
  • ECG for chest pain
  • Urinalysis should be evaluated for haematuria, proteinuria
  • Serum creatinine may be useful in evaluating muscle pains (SLE can cause myositis)
  • Tissue biopsies can only really be useful in assessing severity and so should only be done if necessary- kidney biopsies are fairly common to help differentiate kidney injury due to lupus and that due to another cause

Management

No organ involvement (I.e. constitutional, dermatological and musculoskeletal symptoms)

• For mild-moderate disease, musculo-skeletal symptoms may be treated with NSAIDs/simple analgesia.  UV protection should also be recommended where appropriate (SPF>50)
  • hydrochloroquine is used first line for mild disease and is particularly useful for rashes, joint/muscle symptoms and malaise, although it may take several weeks to work (also beware re ocular toxicity- retinopathy)
  • corticosteroid treatment is also commonly used and has a much quicker onset
    • use lowest dose possible (start 5mg daily)
  • Depending on control/severity, steroid-sparing (immunosuppressive) agents e.g. azathioprine may be used to reduce the steroid dose (NB before starting AZA- check for normal metabolism of AZA with TPMT assay)
• Monitoring
  • ESR/PV (NOT CRP- can be normal with active disease)
  • Complement C3/4- classically low with active disease
  • Anti dsDNA titres

Major Organ Involvement/ Acute Flare

• Lupus nephritis
  • An acute diagnosis of lupus nephritis usually requires a period of intense immunosuppressive treatment with IV Mycophenolate mofetil (MMF) or IV Cyclophosphamide (The former is considered more popular than the latter due to less side effects)
• Neuropsychiatric lupus
  • Usually IV methyprednisolone +/- IV Cyclophosphamide

Co-morbidities

• Osteoporosis
• Infections
• Cardiovascular disease

Lupus in pregnancy

• Corticosteroids, HCQ and AZA are ‘safe’ to use in pregnancy- others are potentially teratogenic and could also effect fertility- so discussions should be made with any woman of child-bearing age
• The contraceptive pill should be safe but (oestrogen hormones) can exacerbate SLE
• Pregnant women with SLE are at increased risk of early loss of pregnancy, pre-eclampsia, IUGR, preterm delivery and DVT.
  • Women with SLE are also more likely to have anti-phospholipid syndrome and may require LMW-heparin/low-dose aspirin if there is a history of APS and miscarriage