BMJ  2005;330:377-378 (19 February), doi:10.1136/bmj.330.7488.377

Editorial

The treatment of lupus nephritis

New and more conservative approaches in treatment are a major advance

For 30 years the US National Institutes of Health have dominated the treatment of lupus nephritis with controlled trials of monthly high dose intravenous pulse cyclophosphamide, now the standard treatment for nephritis and severe lupus. However, adverse effects such as ovarian failure and infections are significant with prolonged treatment.¹ As most lupus patients are women of childbearing age, this price has been high and patients and clinicians are questioning this protocol. Recent studies offer two different approaches that may be as effective and better tolerated.

The use of low dose cyclophosphamide, pioneered at St Thomas' Hospital, London, was recently compared with the US regimen in a European study.^{2 3} There were similar improvements in renal variables in proliferative lupus nephritis with both regimens but with a tendency to lower toxicity in the group receiving cyclophosphamide at low dosages. This probably reflects the shorter exposure to cyclophosphamide (three months v 1 year) and the early switch to azathioprine though longer term follow-up is needed. Similar results were shown in the European systemic vasculitis study, reflecting the trend towards shorter induction periods with cyclophosphamide.⁴

A different approach with mycophenolate mofetil is being widely studied. A randomised trial of mycophenolate mofetil versus oral cyclophosphamide in lupus nephritis⁵ was followed by case series, showing that it is well tolerated. A randomised trial in lupus nephritis showed advantages in efficacy and toxicity for azathioprine and mycophenolate mofetil over the National Institutes of Health's cyclophosphamide regimen as maintenance treatment.⁶ A further abstract shows that mycophenolate mofetil is as useful as the National Institutes of Health's regimen in induction but with less toxicity.⁷ These findings are prompting industry sponsored studies aimed at licensing mycophenolate mofetil for both induction and maintenance treatment. The National Institutes of Health's prolonged cyclophosphamide regimen has been useful, but its use may be drawing to a close.

Intravenous immunoglobulin is widely used in immunoglobulin deficiencies, Guillain-Barré syndrome, Kawasaki's disease, and systemic vasculitis. Numerous reports describe its use especially in patients with severe lupus complicated by sepsis, in whom it can be life saving. Although theoretical risks of infection (for example, with prion transmission) exist, these remain low compared with its efficacy. Randomised studies of intravenous immunoglobulin in lupus do not exist and it remains expensive.

A more targeted approach was pioneered by the team at University College Hospital London, who first used the B cell depleting anti-CD20 monoclonal antibody rituximab in rheumatoid arthritis. Some 20 lupus patients have now been treated, and the results are remarkable. Following two infusions of rituximab and intravenous cyclophosphamide, prolonged remissions have resulted in patients previously unresponsive to other treatments.⁸

Probably the most challenging aspect of lupus is central nervous system involvement. Recently, many central nervous system manifestations have been associated with antiphospholipid antibodies and this has altered our approach. For example, strokes, seizures, headache, and cognitive dysfunction, once thought to be due to inflammatory disease in lupus, are now clearly associated with the antiphospholipid (Hughes) syndrome.^{9 w1 w2} In patients with lupus who are positive for antiphospholipid antibodies, anticoagulation rather than immunosuppression needs to be considered. A difficult area is the overlap with multiple sclerosis. Demyelinating syndromes, although rare in lupus, may be associated with antiphospholipid antibodies. Similar appearances owing to antiphospholipid antibodies on magnetic resonance imaging may be impossible to distinguish from multiple sclerosis, leading to diagnostic confusion and uncertainty over treatment.^{10 w3} Preliminary reports indicate benefit from anticoagulation.

The ramifications of antiphospholipid antibodies extend beyond the nervous system. For example, hypertension is a common complication of lupus nephritis, predictive of renal impairment. Recent studies show that stenosis of the renal artery and thrombotic microangiopathy associated with antiphospholipid antibodies may contribute to the development of hypertension and renal impairment in the context of lupus nephritis. This has led to the concept that anticoagulation may improve blood pressure control and prevent irreversible renal damage.^{11 w4}

Women with lupus, especially with previous nephritis, were strongly advised to avoid pregnancy. This advice has changed dramatically, with the development of multidisciplinary clinics for lupus in pregnancy. Lupus nephritis considerably increases pregnancy related maternal and fetal morbidity risks but these risks can now be managed, providing the nephritis is quiescent at conception.¹²

Lupus was once considered a rare disease for which high dose corticosteroids were the only treatment. Arguably, a major advance in treatment has come from the widespread acceptance of a more conservative approach to treatment—especially with lower doses of corticosteroids. Clinicians in many specialties need to consider how best to manage patients with lupus, given the recent advances in treatment.

Lupus Research Unit, Rayne Institute, St Thomas' Hospital, London SE1 7EH (david.d'cruz{at}kcl.ac.uk)

Lupus Research Unit, Rayne Institute, St Thomas' Hospital, London SE1 7EH

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Additional references w1-w4 are on bmj.com

Competing interests: DDC and GRVH are participating in clinical trials of mycophenolate mofetil in lupus and are on the advisory board of Aspreva Pharmaceuticals.

References

1. Raptopoulou A, Sidiropoulos P, Boumpas D. Ovarian failure and strategies for fertility preservation in patients with systemic lupus erythematosus. Lupus 2004;13: 887-90.[Free Full Text]
2. D'Cruz D, Cuadrado MJ, Mujic F, Tungekar MF, Taub N, Lloyd M, Khamashta MA, Hughes GRV. Immunosuppressive therapy in lupus nephritis. Clin Exp Rheumatol 1997;15: 275-82.[ISI][Medline]
3. Houssiau FA, Vasconcelos C, D'Cruz D, Sebastiani GD, Garrido Ed Ede R, Danieli MG, et al. Immunosuppressive therapy in lupus nephritis: the Euro-lupus nephritis trial, a randomized trial of low-dose versus high-dose intravenous cyclophosphamide. Arthritis Rheum 2002;46: 2121-31.[CrossRef][ISI][Medline]
4. Jayne D, Rasmussen N, Andrassy K, Bacon P, Tervaert JW, Dadoniene J, et al. European Vasculitis Study Group. A randomized trial of maintenance therapy for vasculitis associated with antineutrophil cytoplasmic autoantibodies. N Engl J Med 2003;349: 36-44.[Abstract/Free Full Text]
5. Chan TM, Li FK, Tang CS, Wong RW, Fang GX, Ji YL, et al. Efficacy of mycophenolate mofetil in patients with diffuse proliferative lupus nephritis. Hong Kong-Guangzhou Nephrology Study Group. N Engl J Med 2000;343: 1156-62.[Abstract/Free Full Text]
6. Contreras G, Pardo V, Leclercq B, Lenz O, Tozman E, O'Nan P, et al. Sequential therapies for proliferative lupus nephritis. N Engl J Med 2004;350: 971-80.[Abstract/Free Full Text]
7. Ginzler E, Aranow C, Buyon J, Dooley MA, Merrill JT, Petri M, et al. A multicenter study of mycophenolate mofetil vs intravenous cyclophosphamide as induction therapy for severe lupus nephritis: preliminary results. Arthritis Rheum 2003;48(suppl): s647.
8. Leandro MJ, Edwards JC, Cambridge G, Ehrenstein MR, Isenberg DA. An open study of B lymphocyte depletion in systemic lupus erythematosus. Arthritis Rheum 2002;46: 2673-7.[CrossRef][ISI][Medline]
9. Sanna G, Bertolaccini ML, Cuadrado MJ, Laing H, Khamashta MA, Mathieu A, et al. Neuropsychiatric manifestations in systemic lupus erythematosus: prevalence and association with antiphospholipid antibodies. J Rheumatol 2003;30: 985-92.[ISI][Medline]
10. Cuadrado MJ, Khamashta MA, Ballesteros A, Godfrey T, Simon MJ, Hughes GR. Can neurologic manifestations of Hughes (antiphospholipid) syndrome be distinguished from multiple sclerosis? Analysis of 27 patients and review of the literature. Medicine (Baltimore). 2000;79: 57-68.[CrossRef][Medline]
11. Sangle SR, D'Cruz DP, Jan W, Karim MY, Khamashta MA, Abbs IC, et al. Renal artery stenosis in the antiphospholipid (Hughes) syndrome and hypertension. Ann Rheum Dis 2003;62: 999-1002.[Abstract/Free Full Text]
12. Moroni G, Ponticelli C. The risk of pregnancy in patients with lupus nephritis. J Nephrol 2003;16: 161-7.[ISI][Medline]

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