New advances in the treatment of Lupus and the Antiphospholipid (Hughes) Syndrome
David DCruz MD, FRCP,
Consultant Rheumatologist,
St Thomas Hospital, London
Lupus (SLE - Systemic Lupus Erythematosus) is a disease with a wide spectrum of manifestations.
Treatment is twofold:
1) to get the underlying disease under control
2) to prevent flare-ups of the disease in the future
The medications available are in general very effective at treating lupus and preventing complications. However, this list of drugs is relatively limited. The mainstay of treatment for relatively mildly- affected patients is antimalarial therapy, usually with Hydroxychloroquine (Plaquenil). Mepacrine is a useful additional antimalarial. For more severe lupus, steroids such as Prednisolone are very effective. Although the list of side-effects is fearsome, these can be minimised by using small doses. The immunosuppressive drugs include Azathioprine, Methotrexate and Cyclophosphamide. There have been a number of treatment advances in the last few years that are worth a brief mention.
Antimalarials
Although this class of drugs has been around for more than one hundred years, we are learning more about them all the time. It is now quite clear that Hydroxychloroquine is relatively safe for long-term use in lupus and has clearly been shown to prevent flare-ups. The classical study showing this was by the Canadian Hydroxychloroquine Study Group and published in a major medical journal, The New England Journal of Medicine, in 1991.
More recently, it has been appreciated that Hydroxychloroquine has many other beneficial effects that can partly counteract the side-effects of steroids. For example, Hydroxychloroquine can improve high blood sugar levels, can slightly lower cholesterol levels and also acts to thin the blood slightly in those patients with a clotting tendency. It does not replace Aspirin or Warfarin though. Furthermore, the risk of side effects in the eye is extremely low when compared to the much older drug Chloroquine.
Cyclophosphamide
Cyclophosphamide has been the mainstay for patients with severe lupus, especially where there is kidney inflammation (nephritis). For many years doctors have used the high dose monthly intravenous pulse regimen pioneered at the National Institutes of Health in the USA. While there is no doubt that this is very effective, there are significant side effects such as reduced fertility and infections. Over the last 15 years, St Thomas has been pioneering the use of much lower doses of intravenous Cyclophosphamide. A large trial across Europe due to be published soon has clearly shown that these lower doses of Cyclophosphamide given fortnightly are as effective as the older high dose monthly treatment. There were also fewer side effects with the lower doses. The publication of this trial we hope will encourage a move to this lower dose regimen which, importantly, has a very low risk to fertility.
Methotrexate
Methotrexate is very widely used in rheumatology for the treatment of Rheumatoid Arthritis. It is only given once a week and it has been very effective in the treatment of lupus patients, especially where arthritis has been a major feature. As with Cyclophosphamide and Azathioprine, regular blood monitoring is always needed.
Mycophenolate Mofetil
Mycophenolate (MMF) is being increasingly used in lupus patients where other drugs have failed or have caused side effects. At St Thomas Hospital we have approximately 40 patients taking MMF with excellent results. We have used MMF mainly in patients with very severe lupus, especially with kidney disease, The vast majority of these patients are now doing well and we will shortly be publishing our experience with this drug. MMF, like many of our current drugs, was first used in the transplant world and, using slightly smaller doses, we can keep the side effects to a minimum. As always though, regular monitoring, including blood tests, is important.
Two new studies with MMF are planned. The first, MAINTAIN, will study patients with new kidney involvement. In this trial all patients will receive our standard low dose pulse Cyclophosphamide treatment. When this three-month course has been completed, patients will receive either Azathioprine (the standard treatment) or MMF and these two drugs will be compared for effectiveness and side effects. This study has now started at St Thomas Hospital and five other centres in Europe.
The other study, PRISM, will directly compare the older high-dose monthly pulse Cyclophosphamide regimen with MMF in new patients with lupus kidney disease. This study has not yet started.
Overall, MMF is a very promising (but extremely expensive!) new treatment.
Leflunomide
This is a relatively new treatment for Rheumatoid Arthritis. So far its use in lupus has been rather limited and side effects such as tummy and liver upsets are rather common. Leflunomide is still being investigated in lupus.
Statins One of the major advances in recent years has been the realisation that lupus increases the risk of hardening of the arteries, resulting in strokes and heart attacks. There is a world-wide effort to learn more about this complication of lupus and its treatment. At present the advice remains standard: keep your weight down, eat a healthy diet, exercise regularly, stop smoking and consume alcohol only in moderation. If you are on steroids, regular checks of blood pressure and urine tests for sugar are necessary. Statins are a class of drugs that powerfully reduce cholesterol levels. There is a growing appreciation though that statins may be a weak yet useful drug for treating lupus as well as cholesterol and we are planning laboratory experiments in the Lupus Research Unit to explore these potential effects.
Stem cell transplantation
This is a fairly radical treatment that has many risks. At the moment it is reserved only for patients with very dangerous disease that is failing to respond to everything else.
Intravenous immunoglobulin
Lupus is caused by an overactive immune system that results in antibodies that cause the symptoms of lupus. Healthy individuals make antibodies normally that can counteract lupus antibodies. Intravenous immunoglobulin (IVIG) utilises this effect by pooling purified antibodies from thousands of blood donor samples and giving it to lupus patients. There have been a number of very successful reports of IVIG and at St Thomas we have found it to be exceptionally useful in very sick patients who have lupus complicated by infection. In this context IVIG has been life-saving. Once again though, this is a very expensive treatment that is useful in selected lupus patients.
B-Cell depletion (Rituximab)
Some years ago, Professor Edwards at University College Hospital, London, showed that eliminating B cells (which are the antibody producing cells), using an antibody against B cells called Rituximab, was very helpful in Rheumatoid Arthritis. Their team and others are now exploring Rituximab in lupus patients. Studies are at a very early stage but look promising. Rituximab is not widely used at the moment and awaits further larger studies, but seems to have few major side-effects.
DHEA (Prasterone)
Patients in the USA will be very familiar with DHEA, which is available over the counter there. A large study showed some weak benefit of DHEA in patients with mild lupus but, interestingly, the patients who received the dummy drug (placebo) also had some benefit. DHEA is not licensed in the UK.
Heparin
One of the major problems in lupus is headache. Indeed many patients are familiar with the term lupus headache. Recently at St Thomas, Dr Hughes wondered whether the sticky blood (antiphospholipid) syndrome may be the cause of these headaches. We have treated a small number of patients with a brief (2 week) course of a blood thinning injection, heparin, with very promising results. Dr Maria Cuadrado in our unit is still recruiting patients into this study of heparin and headache.
Warfarin vs. Aspirin
About 30% of lupus patients will have antiphospholipid (sticky blood) antibodies but only about 10% will have complications from these antibodies, such as blood clots or pregnancy losses. That leaves 20% of lupus patients who have antibodies but no problems. At present we offer all such patients low dose Aspirin but this may well not be enough to prevent blood clots. A large study being co-ordinated in the UK by Dr Maria Cuadrado and Dr Munther Khamashta here at St Thomas is looking for such patients who have lupus (but no blood clots), and sticky blood antibodies. In this study we will be comparing the standard dose of Aspirin 75 mg daily against Aspirin 75 mg together with low dose Warfarin - a blood thinning tablet. We aim to recruit 1000 patients over the next three years across Europe - quite a tall order!
LJP
LJP stands for La Jolla Pharmaceuticals, an American pharmaceutical company. They are developing an injection that neutralises the B-cells that produce lupus antibodies. So far, this study has recruited several hundred patients in the USA and Europe and the injection is fairly well tolerated. The major difficulty though is that the injection has to be given every week and this has limited the study to patients who are able to attend so frequently. Nevertheless, the theory behind the drug is very exciting - truly 21st century medicine!
Cyclosporin
Cyclosporin is another drug that has been borrowed from the transplant world. Its use in lupus has been limited by side effects such as high blood pressure and reduced kidney function. However, an ongoing study co-ordinated by Dr Bridget Griffiths in Newcastle is comparing Azathioprine with low dose Cyclosporin in patients with mild to moderately active lupus whose disease is not being controlled on steroids alone. The results of this study should be available next year.
Thalidomide
Those of you with long memories will recall the disastrous effects of Thalidomide in the l950s and l960s with severe birth defects in babies born to mothers taking this drug during pregnancy. In the last few years though this drug has had a renaissance on account of its effects on the immune system. It has been shown to be very helpful in patients with leprosy, HIV/AIDS and cancers such as myeloma. Over the last few years several hospitals, including St Thomas, have been using Thalidomide carefully in patients with severe skin lupus, with very good results. The major side-effects however, have been nerve damage leading to numbness and, in some patients, this has been permanent. It may be that very small doses of this drug might still be useful and could avoid this serious side-effect.
Fatigue
One of the most debilitating aspects of lupus, even when in remission, is severe fatigue. Our studies, co-ordinated by Dr Colin Tench who was a research fellow with me at St Bartholomews and The Royal London Hospital, has shown that small amounts of regular exercise clearly help fatigue without exacerbating lupus. Dr Tench and I will be writing a much fuller article on this for a future edition of News & Views. Suffice it to say that 20 minutes of exercise three times a week, sufficient to raise your pulse rate, may be very beneficial.
Summary
Treatment options are increasing rapidly and this is a very exciting time for lupus patients and their physicians. There is intense research into new treatments going on and if lupus patients wish to enrol in studies on-going at St Thomas, then do not hesitate to contact us. Do, however, get the permission of your physician first.
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