Systemic lupus erythematosus

Systemic lupus erythematosus (SLE) is a complex autoimmune disease with multisystem involvement. Although abnormalities in almost every aspect of the immune system have been found, the key defect is thought to result from a loss of self-tolerance to auto-antigens.

Epidemiology

There is a strong female predilection in adults, with women affected 9-13 times more than males. In children, this ratio is reversed, and males are affected two to three times more often.

While it can affect any age group, the peak age at onset around the 2^nd to 4^th decades, with 65% tend to presentof patients presenting between the ageages of 16 and 65--i years (i.e., during during childbearing years). The disease is sometimes classified according to early and late onset groups ^8,9.

Prevalence varies according to ethnicity with ratios as high as 1:500 to 1:1000 in Afro-Caribbeans and indigenous Australians, down to 1:2000 in Caucasians^14-17.

Recent advances in diagnosis and treatment strategies has resulted in a survival improvement from 5 year survival at 40-50% in the 1950s up to a 10 year survival now estimated at 80-90%. Nevertheless, patients with SLE have a standardized mortality ratio of 3. Early deaths in disease course are usually due to active disease and immunosuppression while late deaths tend to arise from coronary atherosclerosis and SLE or treatment complications (e.g., chronic kidney disease and end-stage renal failure) ¹⁸. 

The disease is sometimes classified according to early and late onset groups ^8,9.

Pathology

SLE can affect multiple components of the immune system, including the complement system, T-suppressor cells, and cytokine production. Emerging evidence has demonstrated a key player in the generation of autoantigens in SLE is the increase in generation (i.e., increased apoptosis) and/or decrease in clearance of apoptotic cell materials (i.e., decreased phagocytosis)¹³. It can result in a generation of autoantibodies, which can circulate for many years prior to the development of clinical SLE. The disease tends to have a relapsing and remitting course.

SLE has a myriad of clinical features and radiographic presentations that are discussed under individual subtopics:

• CNS manifestations of systemic lupus erythematosus (CNS lupus): neuropsychiatric events can occur in ~45% (range 14-75%) of cases ^6,10
• renal manifestations of systemic lupus erythematosus
• gastrointestinal manifestations of systemic lupus erythematosus: there may be GI involvement in ~20% of cases ⁵
• thoracic manifestations of systemic lupus erythematosus
• cardiovascular manifestations of systemic lupus erythematosus
• musculoskeletal manifestations of systemic lupus erythematosus

Genetic factors

Though pathogenesis is complex and not yet completely understood, there is a known genetic predisposition with multiple twin studies demonstrating higher concordance in monozygotic twins ¹⁹. Susceptibility likely results from a combination of multiple genetic and epigenetic aberrations with over 60 risk loci identified. Changes in gene expression contributing to SLE can be due to any and all of: sequence mutation, DNA methylation, histone modification, miRNAs and lncRNAs ^20,21.

Environmental factors

UV light (increased keratinocyte apoptosis), infection (via molecular mimicry and bacterial CpG motifs), smoking (OR 1.56 in current smokers, 1.23 in ex-smokers), environmental pollutants (silica) and intestinal dysbiosis are all known risk factors for SLE. 

A number of culprit drugs have been involved in the development of drug-induced lupus which is a similar but separate disease entity characterised by generation of anti-dsDNA and anti-histone antibodies and a more protracted disease course resolving with withdrawal of the causative medicine. Drugs include chlorpromazine, diltiazem, hydralazine, IFN-alpha, isoniazid, methyldopa, minocycline, penicillamine, procainamide, quinidine. 

TNF inhibitors can similarly induce autoantibodies in up to 70-80% of patients but rarely causes clinical lupus. 

Markers

Almost all patients with SLE have a positive ANA (NPV >99%). Approximately 85% (range 70-98%) of patients test positive for anti-dsDNA antibodies ¹¹, which can also be used to monitor disease activity. ~20% of Caucasians and ~35% of Asians/blacks test positive for anti-Smith antibodies ¹² which are highly specific for SLE and tend to indicate a more serious disease course with renal and CNS involvement. Other antibodies include anti-Ro (neonatal lupus, subacute cutaneous lupus, Sjogren's), anti-La (neonatal lupus, Sjogren's), anti-U1RNP (myositis, Raynaud's), anti-ribosomal p (neuropsychiatric manifestations). Low complement C3 and C4 levels are often seen. 

Diagnosis

The diagnosis of SLE made be if four of eleven ACR (American College of Rheumatology) criteria are present, either serially or simultaneously ². These criteria were initially published in 1982 but have been revised in 1997.

ACR criteria:

• malar rash: fixed, flat or raised, occurs over malar eminences and tends to spare the nasolabial folds.
• discoid rash: erythematous raised patches with adherent keratotic scaling and follicular plugging
• photosensitivity
• oral ulcers
• non-erosive arthritis: where there is involvement of two or more peripheral joints with tenderness, swelling or joint effusions; can occur in ~80% of cases ¹
• pleuritis and/or pericarditis: present in ~35% (range 17-50%) of cases ¹
• proteinuria: >0.5 grams/day
• haematological abnormality
  • haemolytic anaemia or
  • leukopenia: <4000/mm³ on more than two occasions
  • lymphopenia: <1500/mm³ on more than two occasions
  • thrombocytopenia: <100,000/mm³ without any precipitant medications
• neuropsychiatric manifestations
  • seizures or psychotic events in the absence of any underlying precipitating drugs or metabolic abnormalities
• immune abnormality on serology
  • anti-DNA antibodies or
  • anti-Sm antibodies or
  • antiphospholipid antibodies (requires certain criteria)
    • 27-42% of SLE patient can have the antiphospholipid antibody syndrome ¹
• positive antinuclear antibodies