Systemic lupus erythematosus

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162 Systemic lupus erythematosus

Instruction

Examine this patient’s face (usually a young woman).

Salient features

Examination

Fig. 162.2 Oral mucosal ulcerations: generally painless and can present on other cutaneous tissues.

(With permission from Powers 2008.)

Note: SLE principally affects skin, joints, kidney and serosal membranes.

Diagnosis

This patient has a butterfly rash of the face with telangiectasia (lesion) caused by systemic lupus erythematosus (aetiology) and has renal failure, probably caused by lupus nephritis as evidenced by the haemodialysis catheter (functional status).

Advanced-level questions

What is the histology of the skin rash in systemic lupus erythematosus?

• Liquefactive degeneration of the basal layer of the epidermis together with oedema at the dermoepidermal junction. Immunofluorescence microscopy shows deposition of immunoglobulin and complement along the dermoepidermal junction.

• Oedema of the dermis accompanied by infiltrates of perivascular mononuclear cells.

• Vasculitis with fibrinoid necrosis of the vessels.

What are the skin manifestations of systemic lupus erythematosus?

Butterfly rash, periungal erythema, nailfold telangiectasia, alopecia, livedo reticularis, hyperpigmentation, urticaria, purpura, scarring eruption of discoid lupus.

What are the criteria for diagnosis of systemic lupus erythematosus?

Any four of the following 11 criteria are required to make a diagnosis:

Note: American Rheumatic Association criteria are intended to provide a degree of diagnostic certainty primarily for research purposes. It is often possible to be reasonably confident about a diagnosis of SLE on less-strict clinical grounds. A diagnosis of SLE is usually made when patients have three or four typical manifestations, such as a characteristic skin rash, thrombocytopenia, serositis or nephritis and ANA. Polyarthritis and dermatitis are the most common manifestations. It should be noted that antibodies to double-stranded DNA and the so-called Smith antigen (Sm) are virtually diagnostic of SLE.

What do you know about systemic lupus erythematosus in older patients?

The initial presentation of idiopathic SLE usually occurs between the first and fourth decades of life. However, about 10% may first occur in patients >60 years of age. Patients with SLE after the age of 50 years less often present with malar rash, arthritis and nephritis.

Diagnosis of SLE in older patients must be one of exclusion. The frequency of low titres on ANA tests increases with advancing age, and a positive test may be associated with malignant disease or chronic infection.

What do you know about drug-induced lupus erythematosus?

• Procainamide is responsible for the majority of the cases. Other causes include hydralazine, quinidine, isoniazid.

• Drugs causing lupus-like syndrome do not seem to aggravate primary SLE.

• Patients with drug-induced lupus usually present with skin and joint manifestations.

• Although multiple organs are affected, nephritis and CNS features are not ordinarily present.

• Anti-histone antibodies are characteristic of drug-induced lupus but are not specific for this syndrome; anti-native DNA is almost never detected.

• Clinical manifestations and many laboratory features return to normal after the offending drug is withdrawn.

How useful is the detection of anti-nuclear antibodies in the diagnosis of systemic lupus erythematosus?

The detection of ANA is a sensitive screening test for SLE. Since ANA occurs in 95% of the patients, it is hard to be certain of the diagnosis in their absence. The degree of positivity is diagnostically important. Serum dilutions below which normal serum may be positive for these antibodies vary in different laboratories. Titres that are less than two times higher than the normal limit in any laboratory ought to be viewed sceptically. The positive predictive value of the test increases with higher titres.

What are the patterns of lupus nephritis?

The WHO’s morphological classification of lupus nephritis describes five patterns:

• Normal by light, electron and immunofluoroscence microscopy (rare)

• Mesangial lupus glomerulonephritis

• Focal proliferative glomerulonephritis

• Diffuse proliferative glomerulonephritis

• Membranous glomerulonephritis.

Note: None of these patterns is specific for lupus.

How would you manage a patient with systemic lupus erythematosus?

• Avoidance of sunlight provocation. In Britain, patients should avoid being outside from 11 am to 3 pm from March to September and should wear protective clothing, including hats; patients should holiday in temperate latitudes or during the winter. In addition, sun block creams such as titanium dioxide (rather than barrier cream) are essential

• Avoidance of drug provocation: penicillin, sulphonamides

• Encourage the patient to join the Lupus Society

• Educate the patient that no therapy is curative and that medical treatment is largely empirical, selected on the basis of specific manifestations:

Disease manifestation	Treatment
Serological abnormalities and minor cytopenia unaccompanied by symptoms	No treatment
Rash and mild systemic symptoms	Antimalarial drugs
Mild or moderate arthritis, fever, pleuropericarditis	NSAIDs or low-dose prednisolone
Malaise, weight loss and lymphadenopathy	Low-dose steroids
High fever, active inflammatory glomerulonephritis, severe thrombocytopenia, severe haemolytic anaemia and most neurological disturbances	High-dose prednisolone (>60 mg per day for 4–6 weeks)
Rapidly progressive renal disease	Intravenous administration of bolus doses of 1000 mg methylprednisolone
Lupus nephritis with high histological activity score	Oral or intravenous cyclophosphamide or mycophenolate mofetil with high-dose steroids (N Engl J Med 2000;343:1156–62)
Thromboembolism with antiphospholipid antibody	Long-term anticoagulation
Severe disease	Experimental treatments

Experimental treatments include apharesis, intravenous gammaglobulin, ciclosporin, immunoadsorption, photochemotherapy, nodal irradiation, various monoclonal antibodies and autologous haemopoietic stem-cell infusion (Lancet 2000;356:701–7).

What are the common causes of death in systemic lupus erythematosus?

The most common causes of death are renal failure and intercurrent infections followed by diffuse CNS disease.

What do you know about the pathogenesis of systemic lupus erythematosus?

• Pathogenic autoantibodies are the primary cause of tissue damage in patients with lupus including:

• anti-double-stranded DNA, anti-nucleosome and anti–α-actinin antibodies contribute to lupus nephritis (anti-double-stranded DNA antibodies also occur, however, in 23–64% of patients with type 1 autoimmune hepatitis, depending on the assay used)

• anti-Ro antibodies, anti-La antibodies, or both in pregnancy confers a 1–2% risk of fetal heart block

• antibodies against the N-methyl-d-aspartate (NMDA) receptor may be important in CNS lupus (NMDA is an excitatory amino acid released by neurons)

• anti-Ro and anti-nucleosome antibodies may play a role in cutaneous lupus.

• autoantibody-mediated destruction of red cells is important in the haemolytic anaemia that can occur in patients with lupus

• anti-platelet antibodies are important in the pathogenesis of thrombocytopenia that can occur in patients with lupus

• T lymphocyte help is critical in the pathogenesis of lupus. The effect on the T cell depends on the interaction between molecules on the surface of the cell with the antigen presented on the surface of the antigen-presenting cell.

• B cells acting as an antigen-presenting cells also interact with T cells, costimulation requiring interaction between CD40 and the CD40 ligand. The interaction stimulates the T cell to produce cytokines, some of which act on the B cell to promote antibody formation, to stimulate cell division, to switch antibody production from IgM to IgG, and to promote changes in the secreted antibody so that it binds more strongly to the driving antigen. (Note: CD20 and CD22 are present on B cells and interleukin-10 is produced by B cells).

• Plasmacytoid dendritic cells (producing interferon) have been found in the inflamed skin of lupus. They can internalize immune complexes in SLE, which, in turn, triggers the cells to secrete interferon-α through activation of toll-like receptor (TLR).

Promising therapies base on these pathlogical changes include:

• rituximab: antibody against CD20 on the surface of all mature B cells; non-specific

• abetimus sodium: depletes only B lymphocytes that produce anti-double-stranded DNA antibodies and forms complexes with anti-double-stranded DNA antibodies, which can then be cleared from the circulation; more specific.

Further reading

Cervaera R, the European Working Party on SLE. Systemic lupus erythematosus: clinical and immunologic patterns of disease expression in a cohort of 1000 patients. Medicine. 1993;72:113.

Hay EM, Snaith ML. Systemic lupus erythematosus and lupus-like syndromes. BMJ. 1995;310:1257-1261.

Mills JA. Systemic lupus erythematosus. N Engl J Med. 1994;330:187.

Tan EM, Cohen AS, Fries JF, et al. The 1982 criteria for classification of SLE. Arthritis Rheum. 1982;25:1271.

Ferdinand von Hebra (1816–1880) from Vienna described an eruption that occurs ‘mainly on the face, on the cheeks and nose in a distribution not dissimilar to a butterfly’ in 1845.

Pierre Louis Alphée Cazenave (1795–1877) from Paris first used the term lupus érythémateux in 1851.

Sir William Osler (1849–1919) first described the systemic manifestations of SLE under the name exudative erythema between 1895 and 1904.

RRA Coombs (1921–2006), Professor of Immunology at Cambridge, is reported to have said ‘red blood cells were primarily designed by God as tools for the immunologist and only secondarily as carriers of haemoglobin’.

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