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Managing the Complications of Lupus and its Treatments

Studies have shown that damage as a result of the disease occurs in many body systems. Common sites of damage include the musculoskeletal system, renal and cardiovascular systems. This article attempts to give an overview of the problems encountered but is not comprehensive and ignores certain important areas such as nervous system disease.

Musculoskeletal system damage
About 30% of patients with SLE will develop some hand deformity, this often takes the form of a so-called 'Jacoud's' arthropathy where the fingers seem to drift over to the little finger side of the hand. Function is often surprisingly good despite this and in contrast to rheumatoid arthritis it rarely results in erosive damage visible on x-ray.

Tendon ruptures can occur and are most common in the infrapatellar tendon (just below the knee cap) and in the Achilles tendon (between the calf and the heel). They often present acutely, particularly at times of high disease activity or following the use of high dose steroids.

Some patients can develop muscle wasting and weakness, usually as a result of long-term steroid use but occasionally as a consequence of the development of autoimmune myositis (muscle inflammation) which can accompany SLE.

Avascular necrosis is a condition where the blood supply to a joint is interrupted and results in collapse of part of the bony structure of the joint. It is commonest in the hip joint but can also occur elsewhere and on occasions is severe enough to warrant joint replacement.

Another important complication of long term disease is osteoporosis or bone thinning. This affects up to 40% of lupus patients and studies suggest that the risk of sustaining a fracture is increased 5 fold compared to healthy people of the same age. There are a number of factors contributing to osteoporosis including steroids, early menopause and relative immobility. Prevention is better than cure with regard to osteoporosis and steps should be taken to minimise bone loss. Firstly everyone should be encouraged to take regular weight bearing exercise - for most people walking is the best option. Secondly it is vital to maximise your calcium and vitamin D intake. Aim for 1000mg calcium per day either by improving your diet or using supplements as necessary. Many of the supplements contain vitamin D but there are also good quantities in cod liver oil. The other good source of vitamin D, sunlight, is obviously problematic in lupus sufferers. Aiming to reduce the prednisolone dosage by the use of alternative immunosuppressants is something that most doctors and patients will already be trying to do. A DEXA scan can detect osteoporosis in its early stages and may be worth considering if you have taken high dose steroids for any length of time; it is also sometimes helpful in monitoring progress but has its limitations in that scanning too frequently will fail to pick up significant changes. If bone density is low or falling then it may be necessary to start treatment with a bisphosphonate. These are a group of drugs which slow bone loss, strengthen bone and reduce the risk of fracture. Examples include alendronate or residronate.

Cardiovascular disease
Hypertension (high blood pressure) is common in patients with SLE and may be a consequence of renal disease, drug treatment or 'essential' (where it occurs without any specific cause). Untreated hypertension increases the risk of developing heart disease or stroke and should therefore be treated effectively. The usual blood pressure lowering drugs are used.

Heart disease is more common than expected in patients with lupus and affects up to 10% of patients. Overall it is a factor in 30% of deaths in patients with lupus. Studies suggest that women aged 35-44 years with SLE are 50 times more likely to have a myocardial infarction (heart attack) than healthy women of the same age and that those aged 45-64 years are 4 times more likely. The average age of development of heart disease in women with SLE is between 48 and 49 years - much lower than normal. The risk factors for developing heart disease can be split into those which affect the population in general (eg smoking, obesity) and those specific to SLE. Lupus itself can damage blood vessel walls encouraging formation of atheroma which 'furs up' the artery and reduces blood flow. As with osteoporosis the message is that prevention is the key. Risk factors should be addressed eg stopping smoking, losing weight. High blood pressure should be lowered and any other contributory factors (such as the anti-phospholipid antibodies which cause 'sticky blood') treated.

Thromboembolic disease and miscarriage
Patients with SLE are susceptible to clots. One important factor in their development is the presence of anti-phospholipid antibodies where patients' blood contains a factor which makes it 'sticky'. These antibodies can cause a multitude of symptoms including clots, migraines and recurrent miscarriage. Treatment with blood thinning agents such as aspirin and warfarin have been very successful in some patients. Other factors such as immobility and intercurrent disease can contribute to clotting risk. Pregnancy in patients with lupus is more hazardous than in normal healthy women but making sure that the disease is as well controlled as possible prior to conception improves the outlook for a successful pregnancy. Most patients are advised to continue their steroids and immunosuppressive agents throughout pregnancy and are seen frequently to assess the baby's growth and the mother's health. The presence of anti-Ro and/or anti-La antibodies in the mother can be associated with particular problems in the baby. These antibodies are small enough to cross the placenta and enter the unborn baby's circulation. In the majority of pregnancies this does not cause any harm but in about 5% of cases problems occur. Two main problems are seen in the newborn. Firstly the rash of neonatal lupus is seen in about 5% of cases. It usually appears at about 6 weeks of age and lasts about 17 weeks before fading spontaneously. In most cases the rash clears completely but a few children are left with areas of depigmentation or telangiectasia (red spots). Secondly the child can be born with congenital heart block (CHB). This is rare, occurring in less than 2% of pregnancies in women with anti-Ro or anti-La antibodies and may be detected during pregnancy by ultrasound scanning from about 16 weeks of pregnancy. It is slightly commoner in female children and if the mother has had a previous child with CHB then the risk of a subsequent pregnancy being affected goes up to 12%. In general women with anti-Ro or anti-La antibodies should be offered fetal cardiology scans at about 18 and 32 weeks of pregnancy. These are similar to, but more detailed than, the normal ultrasound scans done during pregnancy. If CHB is detected then delivery should be in a centre with paediatric cardiology support available.

Renal involvement
Between 22 and 41% of patients with SLE will develop renal (kidney) disease at some point. The five year survival rates for those developing renal disease have improved to 95% and hence many patients are surviving with a degree of renal impairment. Studies suggest that cyclophosphamide is still the most effective treatment in the acute phase followed by azathioprine, mycophenolate or cyclosporine in the maintenance phase. There is no doubt that early detection and treatment of renal inolvement improves the outcome and at-risk patients should have their urine checked regularly. Some patients are left with a degree of renal damage but fortunately few require dialysis or transplant. Renal disease can lead to high blood pressure, anaemia and electrolyte (salt) imbalance all of which require appropriate treatment. It is also a factor in the development of osteoporosis and heart disease.

Skin disease
Skin disease is common in SLE and causes a wide variety of lesions some of which can cause scarring and chronic skin damage. Subacute lupus is usually highly sun-sensitive and non-scarring whereas discoid lupus is usually less sun-sensitive but can scar. In general all patients with lupus should avoid sun exposure by wearing appropriate clothing and applying high factor sunscreens active against both UVA and UVB. Topical steroids and oral antimalarials are the mainstay of treatment for skin disease but there has been some success with newer agents such as topical tacrolimus and retinoids. Treatment should always aim to prevent scarring where possible but if scarring does occur then camouflage techniques may be helpful and training in these may be available via the local branch of the Red Cross.

Infection
More than 50% of lupus patients will suffer an episode of serious infection during the course of their illness, with infection accounting for more than 20% of deaths and up to 20% of hospitalisations of lupus patients. Infection can mimic a lupus flare and it is important that expert advice is sought if there is any doubt. Infection can affect virtually any part of the body including skin, bladder, joints, brain, lungs and blood. Prevention with appropriate vaccination and prophylactic antibiotics is sometimes possible and prompt treatment can be life saving.

Malignancy
Until recently there was conflicting evidence about the risk of malignancy in patients with SLE. A recent multinational study seems to have resolved this issue. It has shown an increased risk of mainly lymphoma, and to a lesser extent of haematological cancers, in patients with SLE. This increased risk is seen early in the course of the disease and does not seem related to drug use.

Drug side effects
The careful use of steroids and immunosuppressive drugs over the last 20 years has undoubtedly been the main reason for the improved prognosis of patients with SLE. Unfortunately the drugs themselves are not without problems and potential side effects. Steroids have multiple effects on the bodily systems - they increase cholesterol levels, accelerate bone loss, waste muscles, stimulate the appetite, suppress growth in children and are associated with complications such as avascular necrosis and increased risk of infection. Yet for many patients with SLE they are essential. The message is always to aim to take the lowest possible dose that keeps you well. This can often be achieved by the addition of other immunosuppressive drugs.

The most commonly used alternative immunosuppressant is azathioprine. Azathioprine can be associated with liver and bone marrow toxicity and therefore requires monitoring with regular blood tests. Some people have an inherited defect in the enzyme system which metabolises azathioprine and in cases of particular concern it is possible to measure levels of the enzyme (thiopurine methytransferase or TPMT) prior to starting treatment. If patients fail to tolerate azathioprine an alternative is mycophenolate. This has a lower risk of liver toxicity but an increased risk of infection and of lowering the white cell count.

Cyclophosphamide is used predominantly for patients with renal or central nervous system disease. It can induce infertility and premature menopause. There have been fewer side effects documented when the drug is given as intravenous pulses rather than orally. Where preservation of fertility is particularly important there is some evidence that suppressing hormonal activity during cyclophosphamide treatment reduces ovarian damage. Cyclophosphamide can irritate the lining of the bladder causing a condition known as haemorrhagic cystitis. The risk of this can be reduced by maintaining a high fluid throughput during treatment and by the use of a drug known as Mesna which acts by binding to acrolein, the irritant metabolite.

Conclusion
As the management and survival of patients with SLE improves there is an increasing need to manage the complications of long term disease and the consequences of chronic drug usage.

Our grateful thanks to Dr. Price for producing her National Conference address in print so swiftly!

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