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Specialist Registrar in Rheumatology
Campaign Professor of Rheumatology
Systemic lupus erythematosus (SLE) is an autoimmune rheumatic disorder that can affect any organ or system. Its prevalence varies according to ethnic group: from about 35
(Caucasian) to 200 (Afro-Caribbean) per 100,000 population. SLE usually develops between the ages of 15 and 45 years and has a female-to-male ratio of 9:1. The disease tends to follow a more aggressive course in those of Afro-Caribbean origin.
Immune complexes and autoantibodies, notably anti-dsDNA antibodies, are the hallmark of SLE. They are generated through breakdown of selftolerance, the immune system’s ability to distinguish self from foreign antigens. Several mechanisms for this have been proposed, including abnormalities of antigen-presenting cells, B cells, T cells, NK cells and programmed cell death (apoptosis). Deposition or local formation of immune complexes in skin, kidney, brain and other organs results in the recruitment of inflammatory cells, complement activation and tissue damage, with the subsequent release of more self antigens, thereby perpetuating the cycle of autoantibody and immune complex formation. Autoantibodies, particularly those specific for dsDNA, are thought to have a direct pathogenic effect, particularly in lupus nephritis.
SLE can cause life-threatening organ damage, and it is for this reason that patients should be monitored regularly at an outpatient clinic. In the early stages of the disease patients may complain of rather vague flu-like symptoms or worsening myalgia/arthralgia. Serological tests help to identify a true flare; in particular, rising dsDNA antibody titres and falling C3 complement levels are markers of increased activity.
Hypertension, blood in the urine and worsening renal function in an appropriate clinical context are highly suggestive of lupus nephritis. Cerebral lupus is a major diagnostic problem and can present with any neuropsychiatric syndrome. It is estimated to affect 14–75% of patients and in extreme cases causes cerebrovascular accidents and status epilepticus, which require sedation and intubation.
Current drug practice in Europe
Arthralgia, myalgia and rashes are features of mild SLE that often respond to treatment with nonsteroidal anti-inflammatory drugs (NSAIDs) and antimalarial agents such as hydroxychloroquine. The usual dosage of hydroxychloroquine is 400mg/day. Retinal damage is an extremely rare complication, and whether an annual ophthalmological review is really needed is controversial. Sun block and topical steroids are used to treat skin lesions.
In moderate disease, corticosteroids are often used, together with NSAIDs or hydroxychloroquine, and provide an effective way of gaining rapid disease control. Corticosteroids are given either as an intramuscular (IM) injection (ie, depomedrone 120mg) or as oral prednisolone. IM depots can provide symptom relief for several months before gradually wearing off. The severity of symptoms dictates oral administration of prednisolone, and it is usually in the range of 10–40mg per day. Side-effects of corticosteroids include: infection, fluid retention, hypertension, hypercholesterolaemia, hirsutism, diabetes and, rarely, at higher doses acute psychosis. Long-term use predisposes to osteoporosis, and it is therefore essential to reduce and stop prednisolone as soon as possible. Regular DEXA scans (every one to two years) are strongly advised. Some patients remain steroid-dependent, and osteoprotection with daily calcium and vitamin D supplements is recommended. A bisphosphonate should be added if there is evidence of bone mineral loss on DEXA scan.
Azathioprine is used in those patients requiring stronger immunosuppression, usually starting at a dose of 50mg/day, and gradually increasing over a period of several weeks to 2–3mg/kg body weight per day. Sideeffects include bone marrow suppression and hepatotoxicity. Regular blood tests are mandatory (see Table 1). Azathioprine is potentiated by allopurinol, and the combination can cause severe bone marrow suppression. Where there is no alternative to this combination, the dose of azathioprine should be reduced by at least 50%, with close monitoring of full blood count.
Methylprednisolone and cyclophosphamide are the treatments of choice for severely active SLE. Methylprednisolone at a dose of 1g IV per day is given for three days. The widely used US National Institute of Health (NIH) guideline recommends cyclophosphamide 1g/m(2) monthly for six months, followed by three-monthly pulses for two years, notably for patients with lupus nephritis. There are, however, a number of ongoing studies exploring the possibility of using lower doses. Haemorrhagic cystitis is a particular risk with cyclophosphamide and is minimised by prehydration and the use of mesna. There is also an age-related risk of infertility, particularly in those over 30 years, and patients should receive counselling for germ cell preservation.
A number of other secondline drug therapies are available. Mycophenolate mofetil, initially used in transplantation, is well tolerated and increasingly used to treat lupus nephritis. Methotrexate has a role in treating severe arthritis and polyserositis but requires regular blood test monitoring. Ciclosporin can provide reasonable disease control but is associated with side-effects, such as hypertrichosis, gumhyperplasia and nephrotoxicity. There is also a need for drug level monitoring. Oral dapsone is reserved for resistant cutaneous lesions due to its associated risk of haemolytic anaemia.
SLE is associated with a number of linked syndromes, for which specific drug therapies have been developed: Raynaud’s syndrome affects 20–30% of patients and in severe cases causes digital ischaemia and infarction. Calcium channel blockers such as nifedipine act on arteriolar smooth muscle to cause vasodilation and are the mainstay of treatment. Severe Raynaud’s is treated with IV iloprost, often for five consecutive days. Side-effects include facial flushing and headaches. Human calcitonin gene-related peptide 1 has been used with success in selected patients.(1)
Secondary antiphospholipid syndrome affects approximately 10% of SLE patients and predisposes to thrombotic events, livedo reticularis, headache, epilepsy and recurrent first-trimester miscarriage. Those with thrombosis require anticoagulation with warfarin, aiming for an INR of 3–3.5.
A variety of other autoimmune diseases, including Sjögren’s syndrome, hypothyroidism and myositis, may develop in patients with SLE. About 30% of patients with SLE suffer a second, third or even fourth autoimmune condition.
Pregnancy in SLE is associated with an increased risk of pre-eclampsia, intrauterine growth retardation and premature labour. Flares of SLE may occur at any time, but whether they are more likely to occur in pregnancy is controversial. It is recommended that NSAIDs be avoided in the last few weeks of pregnancy. Corticosteroids are not teratogenic and may be used. When stronger immunosuppression is required, azathioprine is considered to be safest. Cyclophosphamide is teratogenic and should be avoided.
Drugs in development and research into the disease
New biological agents targeting B cells and cytokines such as IL-10 are currently undergoing clinical trials.
B-lymphocyte depletion using anti-CD20 monoclonal antibody (rituximab) has recently been assessed in an open study of six patients.(2) This study of patients with active disease who had failed conventional therapy used two 500mg pulses of rituximab in combination with two fortnightly 750mg pulses of cyclophosphamide plus 30 or 60mg oral prednisolone per day for five days. One patient was lost to followup. The remaining patients showed improvements in serological markers and British Isles Lupus Assessment Group (BILAG) scores (a comprehensive tool for assessing disease activity) at six months. Two patients relapsed at seven and eight months and were retreated. A further two patients were well enough not to require any immunosuppression at 18 and 16 months. No significant infusion-related adverse effects were observed. Several episodes of respiratory tract infection and gastroenteritis were reported. These were either self-limiting or responded to conventional antibiotic treatment. The study concluded that there was sufficient evidence to justify a formal controlled trial to assess safety and efficacy of B-cell depletion further.
A selective B-cell immunomodulator, LPJ 394, which induces B-cell anergy by interacting with the B-cell receptor, has recently been used in a clinical trial and showed a 40% reduction in anti-dsDNA antibodies.(3) A multicentre trial is ongoing in the USA at present.
A murine monoclonal antibody directed against IL-10 has been used in an open-ended clinical trial of six patients with SLE.(4) The SLE Disease Activity Index (SLEDAI) score (a global disease activity scoring system) decreased from a mean of 8.83 before treatment to a mean of 1.33 at six months, indicating that the disease had become inactive. However, one of the patients failed to respond, and four required existing drug modification at the end of the second month. In addition, all patients developed antibodies against the murine monoclonal antibody. It is therefore not possible to administer this antibody repeatedly. One possible solution is to develop adjuvant therapies to minimise the development of antibodies to the murine components of biological agent. Another, which is currently in development, is to make “humanised” biological agents that are less immunogenic.
As in patients with rheumatoid arthritis, biological therapies are opening up new lines of treatment for patients with resistant SLE. However, these agents are expensive and, if proven to be efficacious in large-scale trials, will undoubtedly put a strain on already limited healthcare resources. As with infliximab, the anti-TNF antibody used in rheumatoid arthritis and Crohn’s disease, a scoring system will probably need to be developed to identify patients who are most likely to benefit from treatment. Costeffectiveness will need to be evaluated and measures taken to identify the best drug combinations.