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