Behind The Medical Headlines

Lupus

• Dr H Sadik, Research Fellow, Academic Rheumatology Unit, University Hospital Aintree, Liverpool, UK
• Dr R Moots, Professor of Rheumatology, School of Clinical Sciences, University of Liverpool, Liverpool, UK

Summary

Lupus is an inflammatory disease caused by disordered functioning of the immune system and can affect only the skin or, more seriously, many internal organs. In this article, requested by a visitor to the BTMH site, Dr H Sadik and Dr R Moots provide an overview of the diagnosis and management of this serious disease.

Declaration of interests: No conflict of interests declared.

What is Systemic Lupus Erythematosis?

Systemic Lupus Erythematosis is a multi-system autoimmune inflammatory condition that affects women nearly ten times more often than men and is associated with significant morbidity and mortality. Systemic Lupus Erythematosis can be sub-divided into the form that only affects skin (discoid lupus) or the more serious systemic form (SLE). The prevalence of SLE is variable, depending upon geography and race.^{1 2} It is more common in Blacks² and people of Asian origin³ and has a prevalence of approximately 20 per 100,000 in European Whites.^{4 5 6} The pathological processes underlying this condition are not fully known. However, it appears to arise from a dysregulation of the immune system, particularly in cells that make antibodies (B cells). Although there is a genetic pre-disposition to SLE (with higher concordance rates in identical than in non-identical twins), the details are unclear.⁷

Drugs

Drugs may sometimes precipitate SLE. This should always be considered in patients on drug therapy, as stopping the causative drug results in resolution of the SLE. Drugs causing SLE include isoniazide, procainamide, hydralazine, minocycline, penicillamine and anticonvulsants.

Diagnosis

Immunological abnormalities are typical of SLE. Some 95% of patients with SLE have antinuclear antibodies (ANA) in the blood and the absence of this antibody should lead to particular care in diagnosis. Antinuclear antibodies are, however, non-specific and anti-DNA, and anti-SM antibodies are much more specific. However, there is no specific laboratory test and the diagnosis is based on clinical and laboratory parameters using the American College of Rheumatology criteria (table 1).

Table 1 Criteria in the diagnosis of SLE⁸

Malar rash	fixed red ‘butterfly’ rash over the cheeks
Discoid rash	erythematous areas of skin associated with scaling and plugging of the hair follicles
Photosensitivity	rash resulting from exposure to sunlight
Mucosal ulcers	oral and nasal mucosal ulcerations
Serositis	pleuritis or pericarditis
Arthritis	or arthralgia
Renal disorders	usually detected by routine blood and urine analysis
Neurological disorder	seizures or psychosis
Haematological disorder	haemolytic anaemia, leucopoenia, lymphopenia or thrombocytopenia
Immunologic disorder	tests for lupus erythematosus (LE) cells, anti-DNA and anti-SM antibodies , or false positive VDRL syphilis test for at least 6 months
Anti-Nuclear Antibody (ANA blood test)	when found in the blood and the patient is not taking drugs, it is known to cause a positive test for lupus in most cases, but is not necessarily conclusive

(Note: four or more criteria, simultaneously or sequentially, are needed to diagnose SLE.)

Treatment

The aim of treatment in SLE is to suppress the underlying inflammatory process, minimising symptoms and maximising function and quality of life. Where possible, this should be achieved without causing unacceptable side effects. Corticosteroids, for example, are highly effective in suppressing the inflammation of SLE, but often at the high price of unacceptable side effects if in high dose and for a prolonged time. Treatment is tailored to individual patients, and depends upon the organ(s) involved. We will therefore look at treatment in parallel with a brief discussion of clinical features and organ involvement of SLE.

Skin involvement

One of the best-known features of this condition, the red scaly rash (which has led to the term ‘lupus’ meaning wolf), occurs in areas exposed to sunlight. This is typically on the front of the face in a butterfly distribution that bridges the nose, and around the neck, wrist and hands. Conservative treatment, including avoiding sunlight, using high-factor sun screen and camouflage for the rash may be all that is needed for some individuals. Topical corticosteroids and oral hydroxychloroquine may also be effective, as may topical tacrolimus or pimecrolimus.⁹ Alopecia can occur in a patchy distribution or, rarely, completely and, when present, can be particularly worrying to patients.

Joints

Joint disease is common, usually causing pain and stiffness. Rarely, it causes a deforming clinical picture similar to rheumatoid arthritis (RA), but, in contrast to RA, SLE does not cause joint erosions. Arthralgia (often with associated myalgia and fatigue) may often be controlled with anti-malarial drugs such as hydroxychloroquine, or non-steroidal anti-inflammatory drugs (NSAIDs) without recourse to corticosteroids, but the latter may often be required.

Raynaud’s phenomenon

As with other connective tissue diseases, Raynaud’s phenomenon (a temporary disruption of blood flow to extremities provoked by temperature change or emotion) may be caused by SLE. While sometimes the first presentation of lupus, more often than not it develops after the disease has become established. Simple measures, such as wearing gloves and long-sleeved clothes, avoiding vasoconstrictors such as beta-blockers, and stopping smoking, are important, and may be all that is needed. In more severe cases, pharmacological intervention with drugs such as calcium channel blockers, ACE inhibitors, nitrates or paroxetine can be helpful. In situations of critical ischaemia, the more potent vasodilators such as intravenous prostacyclin (iloprost) are needed.¹⁰

Renal disease

Renal involvement develops in up to 30% of patients with SLE. Although often mild, it can lead to a progressive and rapid nephritis and renal failure and is a worrying feature. Often, it is picked up during routine follow-up by finding blood and/or protein on urine dipstick tests. However, it can also present acutely with malignant hypertension or rapidly progressing renal failure. It is therefore important to screen for renal disease in patients with SLE at each clinic visit with urinalysis and blood pressure measurement. In addition, at least on an annual basis, more detailed tests of kidney function, such as 24-hour creatinine clearance and protein excretion, are required as well.

Treatment of renal disease in lupus depends upon extent and severity and is best managed in collaboration with nephrologists. Mild renal involvement may not require special treatment. The more severe forms need urgent treatment with potent immuno-suppressive agents such as cyclophosphamide, mycophenalate mofetil and methyl prednisolone.⁹ Non-responders to cyclophosphamide may have clinically significant responses to rituximab, a monoclonal antibody that depletes CD20 cells.¹¹ Unfortunately, some patients with SLE still go on to end-stage renal disease requiring dialysis and, potentially, renal transplantation.

Nervous system

Involvement of the central nervous system (CNS) can occur at a variety of levels. Cerebral vasculitis is an especially unpleasant and life-threatening complication, requiring urgent investigation with magnetic resonance imaging (MRI) and treatment with high-dose immunosuppressive drugs (usually combination intravenous cyclophosphamide and methylprednisolone). Milder forms of CNS involvement may present with psychiatric complaints ranging from depression to psychosis. Any patient with SLE and a significant change of mood or mental state may need urgent investigation for potential cerebral involvement. If diagnosed and treated effectively, the outcome can be good. Depression and migraine can affect up to 30% of patients with lupus and there may be a role for anti-depressant and anti-psychotic agents¹² alongside therapy to treat the underlying inflammatory problem.

Lung disease

Inflammatory lung disease may be found in SLE, leading to pulmonary fibrosis and, sometimes, respiratory failure. Regular pulmonary function tests, paying particular attention to lung volumes, gas transfer and FEV1/FVC ratio should be undertaken at regular intervals supported, where relevant, with chest radiography and high-resolution CT scanning of the lungs to detect active inflammation. Inflammatory lung disease, if clinically significant and active, requires treatment with high-dose immunosuppressive drugs such as cyclophosphamide and methylprednisolone. Systemic Lupus Erythematosis is also associated with a serositis (pericarditis and pleurisy), causing breathlessness and chest pains. Pericarditis, when present, can be detected with echo-cardiography and may require treatment with anti-inflammatory drugs and corticosteroids and possibly paracentesis for an effusion. Pulmonary hypertension is a rare complication and may be treated with bosentan, sildenafil or prostocyclin analogues.⁹

Haematological abnormalities

Active SLE is often associated with a reduction of the red blood cells, while blood cells or platelets in the blood, and sometimes all three (pancytopaenia), anti-phospholipid antibodies and the SLE anti-coagulant (which cause thrombo-embolic disease, such as deep vein thombosis, pulmonary emboli and miscarriages). Up to two thirds of patients with SLE have anti-phospholipid antibodies in the blood.

Anti-phospholipid antibodies

There is still debate as to how best to manage patients who have anti-phospholipid antibodies in the blood, but without clinical symptoms. The role of aspirin in prophylaxis, for example, is debated. What is agreed, however, is that patients who smoke should stop and overweight patients should lose weight, to reduce the risk of thrombosis. Patients who have suffered a thombotic event need anti-coagulation with warfarin (INR ratio running between 2–3 in relatively low risk patients, and 3–4.5 in higher risk individuals). Catastrophic anti-phospholipid antibody syndrome occurs in approximately 1% of patients with such antibodies. This is associated with a high mortality and needs urgent treatment with steroids, plasma exchange and immunoglobulins.¹³

Pregnancy in SLE

As SLE is most common in women of childbearing age, pregnancy in patients with SLE is a major issue. The disease may have adverse effects on the baby (e.g. a tendency to miscarriage or preclampsia at later stages) and the mother (e.g. aggravation of pulmonary hypertension or severe flare-ups of SLE). Management of pregnancy in SLE is highly specialised and should be undertaken by a rheumatologist with an interest in SLE and an obstetrician who specialises in medical disorders. In such situations, the outcome can be good. The most important thing is to plan pregnancy, aiming for conception at a time of low disease activity when the outcome for mother and baby is likely to be best.

Cardiovascular disease

Systemic Lupus Erythematosis is a significant risk factor for cardiovascular disease,¹⁴ with a 5–6 times greater increase risk of a cardiovascular event – particularly in young women, where the excess risk may be more than 50 times. Various factors may contribute, including the chronic inflammation of SLE, corticosteroids and associated hypercholoresteralemia. Other as yet unidentified factors may also contribute.¹⁵ Pericarditis, referred to above, can also occur.

Monitoring disease

Given the multi-system nature of, and wide spectrum of activity in, SLE, it is important to monitor affected patients closely. One of the best measures for monitoring general disease activity is the erythrocyte sedimentation rate (ESR), which tends to rise in parallel with disease activity (whereas the acute phase protein CRP is more likely to rise when a complication, such as an infection, has occured). Other tests that may reflect disease activity in SLE include C3, a complement component, which tends to fall during inflammatory episodes. It is also important to monitor for sub-clinical organ involvement in the kidneys and the lungs as described above.

References

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