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
- antinuclear antibodies, dsDNA, Smith antigen
- 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
- antiphospholipid antibodies
- Coombs test
- For RBC surface-bound auto-antibodies
- positive
- 24-hour urine collection for protein or spot urine for protein/creatinine ratio
- complement levels
- creatine phosphokinase
- plain x-rays of affected joint(s)
- inflammation, non-erosive arthritis
- renal ultrasound
- to exclude other causes of renal impairment
- chest CT
- pulmonary function tests
- pleural aspiration
- brain MRI
- 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
Managementa) 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) surgicalPrognosis- 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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