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Systemic lupus erythematosus

Definition
  • Chronic multi-system disorder
  • Most commonly affects women during their reproductive years
  • Characterised by the presence of anti-nuclear antibodies
  • In addition to constitutional symptoms, it most frequently involves the skin and joints
  • Serositis, nephritis, haematological cytopenias, and neurological manifestations may occur
Differential diagnosis
  • Rheumatoid arthritis (RA)
    • Arthritis pattern tends to be less symmetrical
  • Antiphospholipid syndrome
    • Characterised by the occurrence of venous or arterial thrombosis or recurrent fetal loss in the presence of antiphospholipid antibodies
    • These antibodies may also be positive in SLE
  • Systemic sclerosis
    • Raynaud's phenomenon is present in almost all patients with systemic sclerosis, being the initial symptom in about 70% of patients
    • Patients with SLE often have Raynaud's phenomenon as well, but these tend not to ulcerate compared to patients with systemic sclerosis.
    • Patients with systemic sclerosis have characteristic sclerodactyly and calcinosis, not present in SLE
    • Auto-antibodies
      • Positive anti-centromere antibodies (limited cutaneous systemic sclerosis)
      • Anti-topoisomerase 1 (Scl-70) antibodies (diffuse cutaneous systemic sclerosis)
  • Mixed connective tissue disease (MCTD)
    • MCTD is characterised by a combination of manifestations similar to those in SLE, systemic sclerosis, and myositis
    • Difficult to differentiate clinically.
    • Auto-antibodies: positive anti-RNP antibodies are specific to MCTD.
    • Patients with MCTD tend to lack other antibodies such as anti-Sm, anti-Ro, anti-La, and anti-dsDNA.
  • Adult Still's disease
    • A variant of juvenile rheumatoid arthritis
    • Characterised by seronegative chronic polyarthritis in association with a systemic inflammatory illness
      • Manifests as symptoms similar to those of SLE
    • The fever in adult Still's disease usually occurs once or twice daily with marked temperature elevation and normal temperature in between.
    • The rash is often only seen during febrile periods and is a salmon-coloured macular or maculopapular non-pruritic lesion
    • Elevated ferritin has been reported in most patients
    • Joint symptoms are similar to RA and joint erosions and fusion on x-ray may occur, unlike in SLE.
  • Lyme disease
    • History of possible erythema migrans or exposure to ticks.
    • Lyme-specific IgM and IgG are positive.
    • Although the presence of ANA is common, the presence of dsDNA and Smith antibodies are not.
  • HIV
    • Although the presence of ANA is common, the presence of dsDNA and Smith antibodies are not.
  • CMV
    • May be asymptomatic
    • Although the presence of ANA is common, the presence of dsDNA and Smith antibodies are not.
  • Infectious mononucleosis
    • Positive agglutination test, for example, monospot.
    • Although the presence of ANA is common, the presence of dsDNA and Smith antibodies are not.
  • Haematological malignancy
    • SLE may be difficult to distinguish clinically from haematological malignancy.
    • Bone marrow, other histology or imaging tests may distinguish the diagnosis.
    • Auto-antibodies will be negative.
  • Glomerulonephritis
    • Difficult to differentiate clinically if no other symptoms or signs associated with SLE are present
      • For example, Raynaud's, rash
    • Antibodies for dsDNA may be positive if SLE is the cause
    • Renal biopsy may aid in diagnosis
  • Chronic fatigue syndrome
    • No other signs that are typically associated with SLE (e.g., Raynaud's, rash) will be present
    • Auto-antibodies will be negative
  • Generalised tonic-clonic seizures
    • May be difficult to differentiate clinically as seizures can be a feature of SLE
      • However, no other signs that are typically associated with SLE (e.g., Raynaud's, rash) will be present.
    • EEG will demonstrate epileptiform activity
    • Brain MRI may demonstrate a lesion
    • Auto-antibodies will be negative in epilepsy
  • Fibromyalgia
    • Poorly localised symmetrical musculoskeletal pain with no diurnal variation
    • Poorly responsive to analgesics/non-steroidal anti-inflammatory drugs (NSAIDs)
    • May co-exist with SLE
    • Positive typical tender points
    • Diagnosis is typically clinical
    • Auto-antibodies will be negative
  • Depression
    • Typically no systemic manifestations (e.g., rash) unless co-exists with SLE
    • Diagnosis is typically clinical
    • Auto-antibodies will be negative
  • Septic arthritis
    • May be difficult to differentiate clinically if patient presents with monoarthritis and no other features of SLE
    • Joint aspiration or synovial biopsy yields positive culture
Epidemiology
  • Most studies report an increasing incidence
  • Disease occurs most frequently between the ages of 15 and 45 years
    • 12 times more common in females than in males
  • In those aged >45 years, the female-to-male ratio is 2:1
  • In the UK, the estimated prevalence is 28 per 100,000
  • Studies show a racial gradient in the occurrence and severity of SLE
    • 21 per 100,000 in white people
    • 47 per 100,000 in people of Asian descent
    • 112 per 100,000 in those of African descent
      • cf reduced CD44 expression => reduced apoptotic clearance
Aetiology
  • As with many other autoimmune diseases, the aetiology of SLE is not known
  • The interaction of an environmental agent in a genetically susceptible host is thought to be fundamental
  • The strong female preponderance also suggests a role for hormonal factors
  • Genetic factors
    • Familial aggregation and higher-than-expected rates of concordance in twin studies
    • SLE is more common in those with complement deficiency
      • Especially C2-deficient homozygotes and C4 heterozygotes
    • Associations with genes in the histocompatibility region (6p21.33; 6p21.32)
    • ssociation with polymorphisms of integrin alpha M (ITGAM)
      • May explain the impaired clearance of immune complexes and vasculopathy characteristic of SLE
    • Association with interferon regulatory factor 5 (IRF5) gene polymorphisms
      • Confirmation of the fundamental role of interferon production in SLE
  • Environmental factors
    • The association may be non-infectious or infectious
    • The strongest non-infectious causative agents are drugs
      • Procainamide
      • Minocycline
      • Terbinafine
      • Sulfasalazine
      • Isoniazid
      • Phenytoin
      • Carbamazepine
    • Hypotheses that have suggested a role for Epstein-Barr virus are based on serological findings
      • Potentially down-regulates phagocytic activity in monocytes + macrophages
    • Role of endogenous retroviruses has been speculated because of their increased expression in murine lupus
Clinical features
  • Malar (butterfly) rash
    • Most commonly erythema over the cheeks and bridge of nose, sparing the nasolabial folds
    • Photosensitive rash
    • Can be painful and pruritic and usually lasts a few days, healing without scarring
  • Discoid rash
    • Erythematous raised patches with adherent keratotic scaling and follicular plugging
    • Atrophic scarring may occur in older lesions
  • Fatigue
    • A common complaint in patients with SLE, occurring in 80% to 100% of patients
    • Absence of other symptoms suggestive of SLE excludes the diagnosis
    • The occurrence of fatigue is often independent of signs and symptoms in other systems
  • Weight loss
    • Often parallels the course of the illness
  • Fever 
    • Is seen in >50% of patients at onset
    • No specific pattern is characteristic
    • Evidence has shown that an elevated CRP is suggestive of infection rather than underlying disease
      • Fever in patients with pre-existing SLE treated with immunosuppressive therapy should lead to a diligent search for opportunistic infection
  • Oral ulcers
    • Occur in 12% to 45% of patients
    • Typically painless but prolonged and recurrent
  • Alopecia
    • Hair thinning and patchy alopecia are an understandable concern in young women with SLE
    • Parallel the systemic disease course
    • Usually non-scarring
    • Areas of scarring alopecia are more characteristic of chronic discoid lupus
  • Arthralgia/arthritis
    • Arthralgia is common in SLE
    • Inflammatory joint symptoms occur in >50% of patients
    • The arthritis can be similar to rheumatoid arthritis, although classically non-erosive
    • Monoarthritis of a large joint is unusual in a patient with SLE and should initially prompt the search for another cause such as infection or avascular necrosis
  • Fibromyalgia
    • Poorly localised symmetrical musculoskeletal pain with no diurnal variation
    • Poorly responsive to analgesics/non-steroidal anti-inflammatory drugs (NSAIDs) suggests co-existing fibromyalgia
      • Typical tender points should be checked for
  • Raynaud's phenomenon
    • Colour changes of the digits induced by cold or emotion
    • Typical triphasic colour change from white to blue to red in fingers and/or toes
    • Invariably bilateral and occurs in as many as 50% of patients at disease onset, although often predating other features of SLE
    • It is often less severe than that seen in systemic sclerosis
    • Raynaud's phenomenon leading to ulceration is unusual and should prompt consideration of other causes
  • Chest pain and shortness of breath
    • Pleuritis is more common than pericarditis and peritonitis is rare
      • Pleuritis can be either unilateral or bilateral
    • In a minority, pleural effusions can co-exist
    • Other cardiovascular manifestations include myocarditis, endocarditis, and premature atheromatous coronary artery disease
  • Hypertension
    • May occur as part of cardiopulmonary manifestations
    • Renal involvement is usually subclinical and usually develops in the first few years of illness
    • Hypertension may be one of the first signs of lupus nephritis
    • Blood pressure and urinalysis looking for proteinuria and haematuria should be routinely performed
  • Signs of nephrosis (e.g., oedema)
    • Renal involvement is usually subclinical and usually develops in the first few years of illness
    • Blood pressure and urinalysis looking for proteinuria and haematuria should be routinely performed
  • Lymphadenopathy
    • Peripheral lymphadenopathy is more often regional than generalised
    • The nodes are usually non-tender, vary in size from shotty to 3 to 4 cm and often are in the cervical and axillary regions
    • Hilar lymphadenopathy is uncommon
    • Patients with lymphadenopathy are more likely to have constitutional manifestations
    • Lymphoma and infectious mononucleosis should be excluded
    • Histology of lymph node biopsies in SLE frequently shows reactive hyperplasia
  • Venous or arterial thrombosis
    • The presence of antiphospholipid antibodies increases the risk of venous or arterial thromboses
  • Abdominal pain, vomiting, or diarrhoea
    • Occurs as part of gastrointestinal manifestation of SLE
    • Caused by lupus peritonitis or mesenteric artery occlusion
Pathophysiology
  • It is primarily an antigen-driven immune-mediated disease characterised by high affinity IgG antibodies to double-stranded (ds) DNA as well as nuclear proteins
  • Tolerance to self antigens in the B-cell pool is maintained by several mechanisms, one of which is via regulatory and helper T cells
    • Several mechanisms have been proposed, by which T-cell dysregulation of B cells may arise, resulting in autoimmunity
  • "Abrogation of central tolerance"
  • This understanding has resulted in consideration of novel therapies being tested, such as rituximab, epratuzumab, and belimumab
  • One attractive but unconfirmed hypothesis is that persistently high levels of exposure to endogenous nuclear material in SLE may arise from apoptotic cells
    • If not cleared, may result in the persistence of nuclear and cytoplasmic material
      • i.e. progression to "late apoptotic cells"
    • These potentially can be modified to antigens, provoking an immune response
    • It has been proposed that in some patients with SLE, mechanisms for clearance of apoptotic cells are impaired
      • Reduced CD44 expression
      • Downregulation of complement and CRP
Investigations
  • FBC and differential
    • anaemia, leukopenia, thrombocytopenia; rarely pancytopenia
  • activated PTT
    • may be prolonged in patients with antiphospholipid antibodies
  • urea and electrolytes
    • elevated urea and creatinine
  • ESR and CRP
    • elevated (non-specific)
  • antinuclear antibodies, dsDNA, Smith antigen
    • positive
  • urinalysis
    • haematuria, casts (red cell, granular, tubular, or mixed) or proteinuria
  • chest x-ray
    • pleural effusion, infiltrates, cardiomegaly
  • ECG
    • may exclude other causes of chest pain
  • blood and urine cultures
    • may exclude infection
  • antiphospholipid antibodies
    • positive
  • Coombs test 
    • For RBC surface-bound auto-antibodies
    • positive
  • 24-hour urine collection for protein or spot urine for protein/creatinine ratio
    • proteinuria
  • complement levels
    • complement consumption
  • creatine phosphokinase
    • may be elevated
  • plain x-rays of affected joint(s)
    • inflammation, non-erosive arthritis
  • renal ultrasound
    • to exclude other causes of renal impairment
  • chest CT
    • lung fibrosis, effusions
  • pulmonary function tests
    • restrictive pattern
  • pleural aspiration
    • exudate
  • brain MRI
    • white matter changes
  • echocardiography
    • pericarditis, pericardial effusion, pulmonary hypertension
  • skin biopsy
    • immune deposits at the dermal-epidermal junction on immunofluorescence or non-specific inflammation
  • renal biopsy
    • immune deposits, mesangial hypercellularity; focal, segmental, or global glomerulonephritis
  • TSH
    • normal level usually excludes hypothyroidism
Management

a) conservative
  • Lifestyle changes
    • Dietary advice, smoking cessation, sun protection, and exercise
    • Sunscreens >SPF 15
  • Supportive treatment
    • Hypromellose eye drops are recommended for dry eyes
    • A thorough oral care regime to prevent ulcers
    • Artificial saliva preparations may be required for those with dry mouth
    • Lidocaine ointment may be beneficial for the management of pain secondary to major oral aphthae
b) medical
  • NSAIDS
    • Naproxen is preferred to ibuprofen due to the rare occurrence of aseptic meningitis in this patient group with ibuprofen
    • If long-term therapy is indicated, Helicobacter pylori eradication should be considered as well as the need for gastroprotection
  • Hydroxychloroquine
    • Used when NSAIDs ineffective, but 3 to 4 months required to take effect
    • May also be used as first-line therapy to prevent flares, though evidence is limited
  • Corticosteroids
    • Used when NSAIDs and hydroxychloroquine are inadequate
  • Methotrexate + folinic acid
    • Addition of methotrexate can be helpful in reducing concomitant corticosteroid dose
    • Folinic acid is given to counteract the folate-antagonist action of methotrexate
  • Cyclophosphamide
    • Intravenous pulse therapy
    • Given with mesna (uroprotective agent) and adequate intravenous fluid therapy (approximately 2.5-3 L/day) to reduce risk of haemorrhagic cystitis
    • White cell count should be measured at 10 to 14 days after therapy
  • Azathioprine maintenance regimen
    • Thiopurine methyltransferase (TPMT) is the main enzyme responsible for inactivating toxic products of azathioprine metabolism
    • Increased risk of pancytopenia in patients with low functional TPMT levels; 1 in 300 people
    • TPMT levels should be checked prior to commencing therapy
  • Mycophenolate
    • Has fewer adverse effects than cyclophosphamide
  • Plasmapheresis
    • Adjunctive therapy if there are clinical or investigatory findings of cerebral vasculitis
    • Data from large randomised trials are lacking
    • The aim is to remove circulating auto-antibodies
    • May be useful in the setting of antiphospholipid antibodies
  • CNS pharmacotherapy
    • Antidepressants, anticonvulsants, antipsychotics, or antimigraine therapies should be prescribed on the advice of relevant specialist on an individual patient basis
c) surgical
  • n/a
Prognosis
  • Mortality
    • Life span in SLE has improved significantly
      • 5-year survival 95% and 10-year survival 92%
    • Early mortality is related to active disease (primarily renal and CNS), thrombosis, and infection
    • Later deaths are due to infection and premature atherosclerotic vascular disease
      • It is yet to be clarified whether this is iatrogenic or due to the underlying disease process
  • Mucocutaneous disease
    • Outcome is determined by the number and severity of systemic complications
    • 20% of patients with chronic discoid lupus develop systemic disease, usually of the non-organ-threatening variety
    • Smoking is known to exacerbate skin disease
  • Musculoskeletal disease
    • Tenosynovitis may result in tendon ruptures or, less frequently, Jaccoud's arthritis
    • Correctable ulnar deviation and joint subluxations in the hands in the absence of radiological damage is characteristic
  • Serositis
    • Persistent exudative pleural and pericardial effusions can arise
    • Outcome is a function of the local effects of their occurrence
  • Renal disease
    • Outcome is determined by the renal histological International Society of Nephrology/Renal Pathology Society (ISN/RPS) grade and severity index as well as the extent of renal impairment
    • Combined treatment with corticosteroids and cyclophosphamide to induce remission and substitution with azathioprine has improved outcome
      • Other therapeutic strategies to minimise iatrogenic complications are being developed
    • Improvements in renal replacement therapy have resulted in commensurate improvements in those who progress to end-stage renal disease
  • CNS disease
    • The presence of CNS manifestations is associated with poorer outcomes, but the site and extent of damage has to be taken into consideration
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