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Systemic lupus erythematosus is an autoimmune disease that may affect many organs, especially the skin, musculoskeletal, vascular and renal systems. It occurs predominantly in women of childbearing age, but also affects people in their sixth decade or older. In these patients, female predominance is less marked and renal disease less common.

The natural history of the disease has changed over the past 20-30 years; survival rates have increased from 50% at five years in the 1950s to 80%-90% at 10 years in the 1990s. The explanations for this improvement include earlier diagnosis, recognition of milder disease, advances in medical therapy, and better supportive care, including renal replacement therapy. Despite these advances, the standardised mortality ratio for lupus remains at 3. Morbidity and mortality rates are bimodal, with early events related to disease activity or infection and later events often due to premature vascular disease such as stroke and myocardial ischaemia.

Currently, minor manifestations of systemic lupus erythematosus (cutaneous, musculoskeletal, fatigue) are managed with non-steroidal anti-inflammatory drugs (NSAIDs), antimalarial drugs (particularly hydroxychloroquine) and low-dose corticosteroids. The selective COX-2 inhibitors, celecoxib (a sulfonamide) and rofecoxib, are now available in Australia. With their lower gastrointestinal toxicity, they represent a significant advance. Patients with lupus, however, have a high prevalence of sulfonamide allergy (20% in some studies) and 30%-50% have antiphospholipid antibodies, which are associated with arteriovenous thrombosis and miscarriages (the antiphospholipid syndrome). Case reports of thrombotic events in patients with antiphospholipid antibodies taking COX-2 inhibitors necessitate judicious use of these drugs until further data are available.¹

Hydroxychloroquine should no longer be restricted to those with minor disease. Data from the Canadian Hydroxychloroquine Study Group suggest that taking hydroxychloroquine causes a reduction in flares and a lower risk of organ-threatening dissemination.² An ability to lower blood glucose and cholesterol levels, combined with an antiplatelet effect, makes this drug an attractive therapeutic option for all patients with lupus. The risk of retinal toxicity with hydroxychloroquine may have been overstated in the past, and the Royal College of Ophthalmologists, London, recommends routine ophthalmic screening in adults only if the dosage of hydroxychloroquine is greater than 6.5 mg/kg lean body weight per day, if there is impaired renal or hepatic function, if visual symptoms develop, or if the duration of therapy extends beyond five years.³ Patients refractory to hydroxychloroquine may show improvement with chloroquine, although with chloroquine the risk of retinal toxicity is greater. Treatment-resistant cutaneous lupus has been treated with thalidomide, with improvement in up to 84% of patients.⁴ However, its use will remain limited because of the risk of fetal abnormalities and the high rate of neuropathy.

There is increasing concern about the long term use of steroids, including low-dose therapy, in patients with lupus. With time, musculoskeletal damage, including avascular necrosis and osteoporosis, heads the organ damage list. Petri has shown that avascular necrosis is strongly associated with the highest prednisolone dose used and osteoporosis with the cumulative dose. She has also shown that an increase in prednisolone dose is associated with an aggravation of cardiovascular risk factors. If the prednisolone dose is increased by 10 mg, the average weight gain is 2 kg, and increases in serum cholesterol level and mean arterial blood pressure occur.⁵

The management of major organ involvement (eg, renal, neuropsychiatric) necessitates combining steroids and immunosuppressants such as cyclophosphamide and azathioprine, and, more recently, cyclosporin A and mycophenolate mofetil. Intermittent monthly pulses of intravenous cyclophosphamide is the standard treatment for diffuse proliferative nephritis and results in a significant improvement in outcome compared with steroid use alone. The appropriate treatment for other classes of lupus nephritis has not been subject to the same level of scrutiny, and uncertainty exists as to what is the optimum management of membranous nephropathy.

Although successful in the management of lupus nephritis, high-dose pulse cyclophosphamide (0.75-1.0 g/m ² monthly) and steroids have been associated with significant toxicity, including premature ovarian failure in 55% and infection in 29% of patients.⁶ Understandably, fertile women are reticent to accept such therapy and alternatives need to be considered. In retrospective studies, a short, low-dose cyclophosphamide regimen followed by azathioprine has been found to be a successful combination, with reduced incidence of ovarian failure and infection.⁷ A European prospective study comparing high- and low-dose cyclophosphamide for treating lupus nephritis has now completed recruitment; initial short-term remission rates are comparable in both groups.⁸ In small series, mycophenolate mofetil has been found to be effective, including in some patients who have shown resistance to cyclophosphamide. Chan et al found mycophenolate to be equal in efficacy to oral cyclophosphamide in patients with diffuse proliferative lupus nephritis.⁹ Long term data (at least five years' follow-up) will be necessary to determine the incidence of relapse and complications. Cyclosporin has been shown to reduce proteinuria in patients with membranous and diffuse proliferative nephropathy. However, concern continues about nephrotoxicity and relapse on ceasing to take the drug. Cyclophosphamide combined with plasmapheresis has not been shown to provide additional benefit compared with cyclophosphamide alone, and its use is now limited to patients who develop a thrombotic thrombocytopenic purpura-like illness or who have very treatment-resistant disease.¹⁰

There is growing interest in the use of immunoablation and stem-cell transplantation in a variety of autoimmune disorders. Autologous stem-cell grafting is feasible in systemic lupus erythematosus and anecdotal reports of success exist. The appropriate timing of stem-cell transplantation, however, remains difficult. Ideally, transplantation should occur in patients who have shown resistance to standard therapy, but before they develop significant irreversible damage. At this stage, the prognostic markers are not sufficiently refined to allow early identification of patients likely to fail immunosuppressive therapy.¹¹

Increased understanding of the pathogenesis of systemic lupus erythematosus has led to the development of numerous novel therapeutic agents. Several of these are in phase II and phase III studies and show promise. However, manipulating the immune system is not without risk, and the expense, particularly of biological agents, will initially limit availability to those with severe disease. While we eagerly await the arrival of such agents, the care of lupus patients in the early years of the 21st century involves innovative approaches with available agents, as well as recognising and aggressively treating the risk factors for premature vascular disease.

Timothy R Godfrey
Rheumatologist, Rheumatology Unit
The Alfred and St Vincent's Hospitals, Melbourne, VIC

Peter F J Ryan
Clinical Associate Professor of Medicine; and Head
Rheumatology Unit, Alfred Health Care Group, Melbourne, VIC

1. Gupta S, McCune WJ, Kaplan M, et al. Thrombosis and ischaemia in patients with systemic lupus erythematosus treated with celecoxib: a series of two cases. Arthritis Rheum 1999, 9(Suppl): S149.
2. Tsakonas E, Joseph L, Esdaile JM, et al. A long term study of hydroxychloroquine withdrawal on exacerbations in systemic lupus erythematosus. The Canadian Hydroxychloroquine Study Group. Lupus 1998; 7: 80-85.
3. Royal College of Ophthalmologists. Ocular toxicity and hydroxychloroquine: guidelines for screening. London: RCO, 1998.
4. Ordi-Ros J, Cortes F, Cucurull, Mauri M, et al. Thalidomide in the treatment of cutaneous lupus refractory to conventional therapy. J Rheumatol 2000; 27: 1429-1433.
5. Petri M. Hopkins Lupus Cohort 1999 Update. Rheum Dis Clinics 2000; 26: 199-213.
6. Gourley MF, Austin III HA, Scott D, et al. Methylprednisolone and cyclophosphamide, alone or in combination, in patients with lupus nephritis. Ann Intern Med 1996; 125: 549-557.
7. Martin-Suarez I, D'Cruz D, Mansoor M, et al. Immunosuppressive treatment in severe connective tissue diseases: effects of low dose intravenous cyclophosphamide. Ann Rheum Dis 1997; 56: 481-487.
8. Houssiau F, Vasconcelos C, Abramovicz D, et al. The Euro-Lupus Nephritis Trial: comparison between a low dose and a high dose cyclophosphamide regimen. Ann Rheum Dis 1999 (EULAR abstracts): 116.
9. Chan TM, Li FK, Tang CS, et al. Efficacy of mycophenolate mofetil in patients with diffuse proliferative lupus nephritis. N Engl J Med 2000; 343: 1156-1162.
10. Schroeder J, Schwab U, Zeuner R, et al. Plasmapheresis and subsequent pulse cyclophosphamide in severe SLE: preliminary results of the LPSG Trial. Arthritis Rheum 1997, 40(Suppl): S325.
11. Formiga F, Moga I, Pac M, et al. High disease activity at baseline does not prevent a remission in patients with systemic lupus erythematosus. Rheumatology 1999; 38: 724-727.

©MJA 2001
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