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Current issues, treatments and clinical trials based on the presentation given to the LUPUS UK Annual Conference May 2006

Hormones and SLE
Systemic lupus erythematosus (SLE) is an autoimmune disease primarily affecting young women. There is increasing data to suggest that the sex hormone oestrogen favours the development or exacerbation of the disease, whereas androgens seem to be protective. This is reflected by the fact that SLE is 9-10x more common in women, its onset is usually after the menarche and there is a decline in disease activity with the menopause. ¹Another indicator that oestrogen is involved in the disease process is that during pregnancy SLE often flares and in women who have active disease during pregnancy the outcome for the baby is worse. Ideally all pregnancies should be planned during a period of disease quiescence which leads us to the problem of contraception in SLE.

Contraception and SLE
Recommending a contraceptive method to women with SLE is difficult. The benefits of reliable contraception in the form of the oral contraceptive pill (OCP) are that pregnancies can be planned for a time when the lupus is in remission, menstrual lupus activity can be reduced, bone protection is given and fertility is preserved. The risk of the OCP, in particular the combined OCP which contains oestrogen and progestogen, is thrombosis and lupus flares. We recommend that for women with SLE the progestogen only pill is used. Women with Hughes syndrome/Antiphospholipid syndrome should avoid the OCP all together and use intrauterine devices such as the Mirina coil.

HRT and SLE
A recent study called the SELENA study² looked at the effect of hormone replacement therapy (HRT) on women with SLE. In this study 174 women took HRT and 177 women took placebo (dummy medication). The results revealed an increase in mild/moderate flares due to the HRT, but no increase in major flares and no overall change in disease activity between the two groups. The long term use of HRT is generally declining due to the increased risk of breast cancer and also strokes and heart attacks associated with its long term use. It must be remembered that patients with SLE and Hughes syndrome are already at greater risk of strokes and heart attacks due to accelerated atherosclerosis. We would therefore only recommend the short term use of HRT for treatment of severe menopausal symptoms in women with SLE provided they did not have severe/active SLE, their blood pressure was normal and there was no history of breast/gynaecological cancer.

HRT should be avoided in antiphospholipid antibody positive women with a previous thrombosis and in women with severe migraine.

Pregnancy and SLE
Pregnancy is safe in SLE provided it is managed in a controlled way with pre-conceptual counselling to assess and minimize the risks of each pregnancy for both mother and foetus. Ideally the lupus should be in remission prior to conception as this gives the best outcome both in terms of the mothers well being and the unborn child. Other factors which make a pregnancy higher risk are kidney disease, antiphospholipid antibodies and anti-Ro/La antibodies all of which can be screened for and discussed at the pre-conceptual counseling appointment. Medications also need to be adjusted; methotrexate, cyclophosphamide, mycophenoloate mofetil and warfarin are harmful to the foetus and must be avoided/stopped during conception and pregnancy. Low dose prednisolone, hydroxychloroquine, azathioprine, cyclosporine, heparin and aspirin are relatively safe medications and can be continued during pregnancy.

The antiphospholipid syndrome (APLS) also causes problems in conception and pregnancy: APLS is associated with multiple early miscarriages and also later second trimester miscarriages. APLS can lead to intrauterine growth retardation with small for dates babies and more seriously foetal death. APLS is also associated with preeclampsia resulting in premature delivery and maternal thrombosis. The management of such pregnancies is with low dose aspirin and heparin injections.

Once pregnancy is achieved in women with SLE or APLS their care then involves a multidisciplinary team of experts including Consultant Rheumatologists, Haematologists, Obstetricians, Neonatologists and Paediatricians together with nurses and midwives to ensure a successful outcome. Women attending antenatal clinics more frequently, often require serial scans and sometimes require delivery in specialised units.

When breast feeding safe medications include; warfarin, heparin, steroids, aspirin and hydroxychloroquine.

The Heart and SLE
Women with SLE have an increased risk of heart disease and heart attacks. This is due to a process called accelerated atherosclerosis which is seen in SLE. The exact mechanism behind this process is not known but the hypothesis is that inflammation from lupus disease activity causes damage to blood vessels resulting in thickening of the blood vessels with the formation of plaques. The plaques eventually burst or rupture blocking the vessel, if the affected blood vessel is supplying the heart this results in a heart attack or if it is supplying the brain then a stroke. Accelerated atheroma has profound clinical consequences and explains the bimodal pattern of deaths seen in SLE which was first described in 1976 by Urowitz et al.³ This revealed that in patients with SLE there is an initial peak in mortality at the age 20-30 years due to lupus disease activity and infection followed by a second peak aged 40-50 years when deaths are due to heart disease and strokes (Fig 1)

Figure 1.

SLE is associated with a five fold increased risk of clinical coronary artery disease and this is accelerated in onset. Manzi et al⁴ compared 498 women with SLE with 2208 women from the Framingham Offspring study over a 13 year period and found a 50 fold increase in heart attacks in women with SLE aged 33-45 years. Strokes are reported in 2.6-20% of SLE patients and have a high rate of recurrence and result in greater mortality and morbidity than persons of a similar age and sex without SLE.⁵

Atherosclerosis and SLE
It is clear that we need to find ways to reduce the formation of atherosclerosis in SLE and there are two ways to approach this; firstly to eliminate traditional risk factors and secondly to eliminate inflammatory disease activity.

Traditional risk factors include diabetes mellitus, high cholesterol and blood pressure all of which should be checked for regularly and if present treated vigorously⁶ .All patients with SLE should stop smoking and it is also worth knowing that smoking reduces hydroxycholoroquine efficacy. Obesity must be tackled and the only effective approach is to eat less and exercise more.

Elimination of inflammatory disease activity is achieved with the use of antimalarials, corticosteroids and immunosuppression. Antimalarials such as hydroxychloroquine (HCQ), mepacrine and chloroquine are safe in long term use and can be used in combination. They are disease modifying and reduce relapse rates. The Canadian HCQ study group reports increased flares of SLE activity on stopping HCQ⁷, suggesting that these drugs should be continued in the long term. Antimalarials also improve lipid and glucose profiles and have a weak anti-thrombotic effect. HCQ does have side effects 3-5% of people develop rashes and/or diarrhoea however eye toxicity is very rare. Chloroquine is more commonly associated with eye toxicity and mepacrine can cause skin pigmentation. HCQ use has been shown to be associated with less arterial wall plaque formation⁸

Corticosteroids can suppress inflammation but at high doses increase cardiovascular risk by causing diabetes, high blood pressure, obesity and high cholesterol levels. A few studies have shown less atherosclerosis in patients receiving corticosteroids but the majority of studies have shown more⁸.

Immunosuppression with cyclophosphamide is associated with less arterial plaque formation, but no difference is seen in patients receiving azathioprine to those who are not⁸.

The MISSILE study and SLE
At St Thomas' Hospital we are conducting a unique study in an attempt to understand and find a treatment for accelerated atherosclerosis in lupus patients. The study is called the MISSILE study which stands for Mycophenolate Mofetil in SLE. Mycophenolate mofetil (MMF) is an immunosuppressant which is commonly used in SLE, for example in the treatment of kidney and skin disease. It is a well tolerated medication with few side effects the most common being diarrhoea. MMF can cause a drop in white blood cells but this is monitored for with regular blood tests and is reversible on stopping the MMF. There is evidence from animal studies that MMF reduces arterial plaque formation and we hope to show the same effect in humans.

The study aims to recruit 100 women with mild, stable SLE who are non smokers and are taking an antimalarial and/or prednisolone to control their lupus. Eligible women are then randomly allocated to a treatment group receiving MMF or a control group receiving a placebo. The medication is taken for eight weeks and then stopped.

Figure 2.

At the beginning and end of the eight weeks measurements are taken using an ultrasound probe to look at the stiffness of the arteries in the arm, this is known as flow mediated dilation (FMD). We hope to show that in the women taking MMF the arterial stiffness improves compared to those taking placebo.

Such a study obviously has major implications for the future treatment of patients with SLE as it may help establish a potential treatment for atherosclerosis and so reduce the occurrence of strokes and heart attacks in SLE. If you suffer from lupus and fit the above entry criteria and would like to find out more about this study and others being conducted at St Thomas' Hospital please do not hesitate to contact research fellow Dr Rachel Davies in writing or by leaving a message on 0207 188 7188 extension 87600 (secretaries 2).

Summary
Hormones and SLE

• Oestrogens important in development and exacerbation of SLE
• Progestogen only pill in SLE
• Avoid OCP in Hughes syndrome
• Avoid HRT in Hughes syndrome
• Pregnancy is possible but must be carefully planned

Cardiovascular disease and SLE

• Major risk factor to lupus patients
• Keep disease activity under control
• Reduce traditional risk factors
• Clinical trials to assess new therapies

References
1) Sanchez-Guerrero J et al Am J Med 2001;111:464
2) Buyon JP et al Ann Intern Med 2005;142:953
3) Urowitz M et al Am J Med 1976;60:221
4) Manzi S et al Am J Epidemiol 1997;145:408
5) Sibley JT et al J Rheumatol 1992;19:47
6) Wajed J et al Rheumatology 2004;43:7
7) Canadian HCQ study group NEJM 1991;324:150
8) Roman MJ et al NEJM 2003;349:2399

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