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
Arthritis pattern tends to be less symmetrical
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
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.
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.
Although the presence of ANA is common, the presence of dsDNA and Smith antibodies are not.
May be asymptomatic
Although the presence of ANA is common, the presence of dsDNA and Smith antibodies are not.
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.
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
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
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
Typically no systemic manifestations (e.g., rash) unless co-exists with SLE
Diagnosis is typically clinical
Auto-antibodies will be negative
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