Mycophenolate Mofetil for Lupus Nephritis
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《新英格兰医药杂志》
Systemic lupus erythematosus is a chronic, life-threatening disease that predominantly affects women of childbearing age. Its pathogenesis includes autoantibody-mediated organ damage and antiphospholipid-antibody–mediated hypercoagulability. Among patients who have lupus the incidence of cardiovascular disease is 10 to 50 times as high as among age-matched control subjects. Optimal therapy for lupus would, with acceptable risk, control immune complex–mediated disease, reduce thrombotic risk, retard the progression of atherosclerosis, and reduce dependence on corticosteroids. Cyclophosphamide, which is currently the mainstay of treatment for severe lupus flares, is associated with a high rate of complications, including gonadal failure, infection, and secondary malignant disease. Physicians have long sought a satisfactory alternative to cyclophosphamide for the treatment of severe systemic lupus erythematosus.
Nephritis complicates systemic lupus in approximately 25 to 50 percent of patients and is associated with increased mortality. Controlled trials focused on proliferative nephritis have helped to establish guidelines for immunosuppressive treatment. A landmark 20-year study compared treatment with prednisone alone with prednisone plus azathioprine (Imuran), prednisone plus cyclophosphamide (Cytoxan), or prednisone plus azathioprine and cyclophosphamide.1 Although there were no differences in outcome after 5 years, after 10 and 20 years, renal survival was markedly better with any regimen containing cyclophosphamide than treatment with prednisone alone. In this study, intermittent bolus cyclophosphamide was as effective as and less toxic than daily cyclophosphamide.1 Boumpas et al.2 found that patients initially treated with monthly boluses of cyclophosphamide for six months had a much lower rate of subsequent flares if the therapy was continued every three months for a total of three years of treatment. Gourley et al.3 and Illei et al.4 found that the addition of monthly bolus methylprednisolone to monthly boluses of cyclophosphamide for lupus nephritis improved long-term renal outcomes.
To reduce the cumulative dose of cyclophosphamide and the risk of ovarian failure, regimens of lower doses of intravenous cyclophosphamide have been used,5 and sequential immunosuppressive regimens that initially use intravenous cyclophosphamide and then substitute a less toxic immunosuppressive drug have been developed. In a study by Contreras et al.,6 patients who were assigned initially to receive intravenous cyclophosphamide for six months to treat active nephritis were afterward randomly assigned to maintenance treatment with either azathioprine or mycophenolate mofetil (CellCept) or quarterly intravenous cyclophosphamide. Those assigned to azathioprine or mycophenolate mofetil had equivalent or superior disease control, with fewer adverse events, than those who received quarterly intravenous cyclophosphamide. In an open trial, suppression of ovarian function during the initial cyclophosphamide phase of sequential therapy with a gonadotropin-releasing–hormone analog was reported to reduce the risk of ovarian failure further.7
Recently, attention has been focused on mycophenolate mofetil as initial therapy for severe lupus nephritis.8,9,10 Mycophenolate mofetil is a potent and relatively well-tolerated immunosuppressive agent that inhibits the enzyme inosine monophosphate dehydrogenase, which is required for the synthesis of purines synthesis, particularly in activated lymphocytes. It has been reported to inhibit the production of antibodies in response to immunizations, inhibit vascular smooth-muscle proliferation, and retard the development of atherosclerosis associated with organ transplantation. These attributes may benefit patients with lupus who are at high risk for vascular complications.11 However, the bioavailability of mycophenolate mofetil is unpredictable, and dose adjustment becomes increasingly difficult with worsening renal failure.
In this issue of the Journal, Ginzler et al.12 report the results of a randomized, open trial that compared mycophenolate mofetil to monthly intravenous cyclophosphamide to induce remission in lupus nephritis in 140 patients. In an era of industry-sponsored clinical research, this investigator-initiated and investigator-directed clinical trial makes an important contribution to patient care. This study includes populations of patients at high risk for renal failure: 56 percent of the patients were black, a group with a disproportionately high rate of adverse outcomes in trials of treatment for lupus nephritis; and 54 percent of all patients had diffuse proliferative glomerulonephritis, the most severe histologic type. The patients generally had sufficiently well-preserved renal function for the administration of mycophenolate mofetil to be practical (mean serum creatinine, 1.07 mg per deciliter ; minimum creatinine clearance, 30 ml per minute).
This study achieved its primary end point of demonstrating the noninferiority of mycophenolate mofetil to intravenous cyclophosphamide, as assessed according to the number of patients who had complete remission of nephritis after 24 weeks of treatment. By intention-to-treat analysis, there were significantly more complete remissions in the mycophenolate mofetil group (16 patients of 71; 22.5 percent) as compared with the intravenous cyclophosphamide group (4 of 69; 5.8 percent). An additional one fourth of the patients in each of the two groups had partial remissions. More than half of the patients in the study, however, either did not achieve remission (according to rigorous criteria) or did not complete the study. At 24 weeks, the mean levels of protein excretion, serum creatinine, and serum albumin among all patients completing the study were numerically improved. This finding suggests that in the two groups some patients who did not have a response might have benefited from treatment, since untreated nephritis would be expected to worsen. Additional data with regard to long-term outcomes of the entire patient population in this study and follow-up studies would be important to inform decision making.
Additional factors that require consideration include the possibility that the renal response to intravenous cyclophosphamide, particularly resolution of proteinuria, might be more delayed than the response to mycophenolate mofetil, so that the rate of remission with intravenous cyclophosphamide would be comparatively higher after additional follow-up. Higher doses of intravenous cyclophosphamide in this study were associated with better renal responses. Some would argue that the induction of remission with monthly boluses of both cyclophosphamide and corticosteroids (my choice) is more effective than intravenous cyclophosphamide alone and should be the standard for comparison with new therapies. The requirement of a creatinine clearance greater than 30 ml per minute for study entry rules out the sickest patients — those with rapidly progressive glomerulonephritis and severe acute renal failure — who might respond more quickly to traditional therapy with intravenous cyclophosphamide and corticosteroids. In this open trial, there were a greater number of dropouts in the mycophenolate mofetil group because of concerns about lack of efficacy and a greater number of dropouts in the cyclophosphamide group because of concerns about toxic effects.
There is little doubt that mycophenolate mofetil is less toxic than cyclophosphamide, does not cause ovarian failure, and is more acceptable to patients than is cyclophosphamide. On the basis of transplantation studies, it is also possible that mycophenolate mofetil may help to retard the development of accelerated atherosclerosis, a major long-term concern among all patients with lupus and particularly among those with lupus nephritis. In one randomized trial comparing mycophenolate mofetil with intravenous cyclophosphamide for lupus nephritis, serial renal biopsies suggested both greater reduction of and improvement in histologic signs of vascular injury in the mycophenolate mofetil group.10 If mycophenolate mofetil prevents vascular damage in patients with lupus, it can be used to treat two important problems simultaneously.
How should we use mycophenolate mofetil until the results of larger follow-up clinical trials and long-term data are available? At one extreme of the clinical spectrum, mycophenolate mofetil remains inadequately tested in patients with rapidly progressive nephritis and acute renal failure; at this time, the sickest patients arguably should be treated with boluses of cyclophosphamide and corticosteroids. At the other extreme, patients with new, mild-to-moderately-severe nephritis and intact renal function, for whom fertility is a paramount concern, can reasonably start treatment with mycophenolate mofetil. For patients who occupy the middle ground, such as those with recurrent nephritis and moderate renal insufficiency, long-term studies will be critical in guiding treatment choices. It is highly likely that individual patients may respond unpredictably to one treatment or the other, and it may be necessary to change the treatment when the clinical response is inadequate. The favorable response to mycophenolate mofetil, as compared with monthly intravenous cyclophosphamide, strongly suggests that, after disease control is achieved, mycophenolate mofetil will, in most patients, prove to be superior to quarterly intravenous cyclophosphamide as a long-term treatment.
Lupus nephritis appears to respond better to immunosuppressive therapy when treatment is instituted early in the course of disease.13 I predict that wider use of mycophenolate mofetil, with its favorable side-effect profile, will be associated with earlier treatment of less advanced disease and with more favorable outcomes.
Treatment options for severe lupus will continue to increase as biologic agents are introduced, alone or in combination with immunosuppressive drugs, such as mycophenolate mofetil. Improved rates of remission and better long-term disease control among patients with lupus nephritis are realistic prospects for the near future.
Source Information
From the Division of Rheumatology, Department of Internal Medicine, University of Michigan Medical Center, Ann Arbor.
References
Steinberg AD, Steinberg SC. Long-term preservation of renal function in patients with lupus nephritis receiving treatment that includes cyclophosphamide versus those treated with prednisone only. Arthritis Rheum 1991;34:945-950.
Boumpas DT, Austin HA III, Vaughn EM, et al. Controlled trial of pulse methylprednisolone versus two regimens of pulse cyclophosphamide in severe lupus nephritis. Lancet 1992;340:741-745.
Gourley MF, Austin HA III, Scott D, et al. Methylprednisolone and cyclophosphamide, alone or in combination, in patients with lupus nephritis: a randomized, controlled trial. Ann Intern Med 1996;125:549-557.
Illei GG, Austin HA, Crane M, et al. Combination therapy with pulse cyclophosphamide plus pulse methylprednisolone improves long-term renal outcome without adding toxicity in patients with lupus nephritis. Ann Intern Med 2001;135:248-257.
Houssiau FA, Vasconcelos C, D'Cruz D, 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;46:2121-2131.
Contreras G, Pardo V, Leclercq B, et al. Sequential therapies for proliferative lupus nephritis. N Engl J Med 2004;350:971-980.
Somers EC, Marder W, Christman GM, Ognenovski V, McCune WJ. Use of a gonadotropin-releasing hormone analog for protection against premature ovarian failure during cyclophosphamide therapy in women with severe lupus. Arthritis Rheum 2005;52:2761-2767.
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.
Chan TM, Tse KC, Tang CS, Mok MY, Li FK. Long-term study of mycophenolate mofetil as continuous induction and maintenance treatment for diffuse proliferative lupus nephritis. J Am Soc Nephrol 2005;16:1076-1084.
Hu W, Liu Z, Chen H, et al. Mycophenolate mofetil vs cyclophosphamide therapy for patients with diffuse proliferative lupus nephritis. Chin Med J (Engl) 2002;115:705-709.
McCune WJ, Riskalla MM. Immunosuppressive drug therapy. In: Wallace DJ, Hahn BH, eds. Dubois' lupus erythematosus. 6th ed. Philadelphia: Lippincott Williams & Wilkins, 2002:1195-217.
Ginzler EM, Dooley MA, Aranow C, et al. Mycophenolate mofetil or intravenous cyclophosphamide for lupus nephritis. N Engl J Med 2005;353:2219-2228.
Esdaile JM, Joseph L, MacKenzie T, Kashgarian M, Hayslett JP. The benefit of early treatment with immunosuppressive drugs in lupus nephritis. J Rheumatol 1995;22:1211-1211.(W. Joseph McCune, M.D.)
Nephritis complicates systemic lupus in approximately 25 to 50 percent of patients and is associated with increased mortality. Controlled trials focused on proliferative nephritis have helped to establish guidelines for immunosuppressive treatment. A landmark 20-year study compared treatment with prednisone alone with prednisone plus azathioprine (Imuran), prednisone plus cyclophosphamide (Cytoxan), or prednisone plus azathioprine and cyclophosphamide.1 Although there were no differences in outcome after 5 years, after 10 and 20 years, renal survival was markedly better with any regimen containing cyclophosphamide than treatment with prednisone alone. In this study, intermittent bolus cyclophosphamide was as effective as and less toxic than daily cyclophosphamide.1 Boumpas et al.2 found that patients initially treated with monthly boluses of cyclophosphamide for six months had a much lower rate of subsequent flares if the therapy was continued every three months for a total of three years of treatment. Gourley et al.3 and Illei et al.4 found that the addition of monthly bolus methylprednisolone to monthly boluses of cyclophosphamide for lupus nephritis improved long-term renal outcomes.
To reduce the cumulative dose of cyclophosphamide and the risk of ovarian failure, regimens of lower doses of intravenous cyclophosphamide have been used,5 and sequential immunosuppressive regimens that initially use intravenous cyclophosphamide and then substitute a less toxic immunosuppressive drug have been developed. In a study by Contreras et al.,6 patients who were assigned initially to receive intravenous cyclophosphamide for six months to treat active nephritis were afterward randomly assigned to maintenance treatment with either azathioprine or mycophenolate mofetil (CellCept) or quarterly intravenous cyclophosphamide. Those assigned to azathioprine or mycophenolate mofetil had equivalent or superior disease control, with fewer adverse events, than those who received quarterly intravenous cyclophosphamide. In an open trial, suppression of ovarian function during the initial cyclophosphamide phase of sequential therapy with a gonadotropin-releasing–hormone analog was reported to reduce the risk of ovarian failure further.7
Recently, attention has been focused on mycophenolate mofetil as initial therapy for severe lupus nephritis.8,9,10 Mycophenolate mofetil is a potent and relatively well-tolerated immunosuppressive agent that inhibits the enzyme inosine monophosphate dehydrogenase, which is required for the synthesis of purines synthesis, particularly in activated lymphocytes. It has been reported to inhibit the production of antibodies in response to immunizations, inhibit vascular smooth-muscle proliferation, and retard the development of atherosclerosis associated with organ transplantation. These attributes may benefit patients with lupus who are at high risk for vascular complications.11 However, the bioavailability of mycophenolate mofetil is unpredictable, and dose adjustment becomes increasingly difficult with worsening renal failure.
In this issue of the Journal, Ginzler et al.12 report the results of a randomized, open trial that compared mycophenolate mofetil to monthly intravenous cyclophosphamide to induce remission in lupus nephritis in 140 patients. In an era of industry-sponsored clinical research, this investigator-initiated and investigator-directed clinical trial makes an important contribution to patient care. This study includes populations of patients at high risk for renal failure: 56 percent of the patients were black, a group with a disproportionately high rate of adverse outcomes in trials of treatment for lupus nephritis; and 54 percent of all patients had diffuse proliferative glomerulonephritis, the most severe histologic type. The patients generally had sufficiently well-preserved renal function for the administration of mycophenolate mofetil to be practical (mean serum creatinine, 1.07 mg per deciliter ; minimum creatinine clearance, 30 ml per minute).
This study achieved its primary end point of demonstrating the noninferiority of mycophenolate mofetil to intravenous cyclophosphamide, as assessed according to the number of patients who had complete remission of nephritis after 24 weeks of treatment. By intention-to-treat analysis, there were significantly more complete remissions in the mycophenolate mofetil group (16 patients of 71; 22.5 percent) as compared with the intravenous cyclophosphamide group (4 of 69; 5.8 percent). An additional one fourth of the patients in each of the two groups had partial remissions. More than half of the patients in the study, however, either did not achieve remission (according to rigorous criteria) or did not complete the study. At 24 weeks, the mean levels of protein excretion, serum creatinine, and serum albumin among all patients completing the study were numerically improved. This finding suggests that in the two groups some patients who did not have a response might have benefited from treatment, since untreated nephritis would be expected to worsen. Additional data with regard to long-term outcomes of the entire patient population in this study and follow-up studies would be important to inform decision making.
Additional factors that require consideration include the possibility that the renal response to intravenous cyclophosphamide, particularly resolution of proteinuria, might be more delayed than the response to mycophenolate mofetil, so that the rate of remission with intravenous cyclophosphamide would be comparatively higher after additional follow-up. Higher doses of intravenous cyclophosphamide in this study were associated with better renal responses. Some would argue that the induction of remission with monthly boluses of both cyclophosphamide and corticosteroids (my choice) is more effective than intravenous cyclophosphamide alone and should be the standard for comparison with new therapies. The requirement of a creatinine clearance greater than 30 ml per minute for study entry rules out the sickest patients — those with rapidly progressive glomerulonephritis and severe acute renal failure — who might respond more quickly to traditional therapy with intravenous cyclophosphamide and corticosteroids. In this open trial, there were a greater number of dropouts in the mycophenolate mofetil group because of concerns about lack of efficacy and a greater number of dropouts in the cyclophosphamide group because of concerns about toxic effects.
There is little doubt that mycophenolate mofetil is less toxic than cyclophosphamide, does not cause ovarian failure, and is more acceptable to patients than is cyclophosphamide. On the basis of transplantation studies, it is also possible that mycophenolate mofetil may help to retard the development of accelerated atherosclerosis, a major long-term concern among all patients with lupus and particularly among those with lupus nephritis. In one randomized trial comparing mycophenolate mofetil with intravenous cyclophosphamide for lupus nephritis, serial renal biopsies suggested both greater reduction of and improvement in histologic signs of vascular injury in the mycophenolate mofetil group.10 If mycophenolate mofetil prevents vascular damage in patients with lupus, it can be used to treat two important problems simultaneously.
How should we use mycophenolate mofetil until the results of larger follow-up clinical trials and long-term data are available? At one extreme of the clinical spectrum, mycophenolate mofetil remains inadequately tested in patients with rapidly progressive nephritis and acute renal failure; at this time, the sickest patients arguably should be treated with boluses of cyclophosphamide and corticosteroids. At the other extreme, patients with new, mild-to-moderately-severe nephritis and intact renal function, for whom fertility is a paramount concern, can reasonably start treatment with mycophenolate mofetil. For patients who occupy the middle ground, such as those with recurrent nephritis and moderate renal insufficiency, long-term studies will be critical in guiding treatment choices. It is highly likely that individual patients may respond unpredictably to one treatment or the other, and it may be necessary to change the treatment when the clinical response is inadequate. The favorable response to mycophenolate mofetil, as compared with monthly intravenous cyclophosphamide, strongly suggests that, after disease control is achieved, mycophenolate mofetil will, in most patients, prove to be superior to quarterly intravenous cyclophosphamide as a long-term treatment.
Lupus nephritis appears to respond better to immunosuppressive therapy when treatment is instituted early in the course of disease.13 I predict that wider use of mycophenolate mofetil, with its favorable side-effect profile, will be associated with earlier treatment of less advanced disease and with more favorable outcomes.
Treatment options for severe lupus will continue to increase as biologic agents are introduced, alone or in combination with immunosuppressive drugs, such as mycophenolate mofetil. Improved rates of remission and better long-term disease control among patients with lupus nephritis are realistic prospects for the near future.
Source Information
From the Division of Rheumatology, Department of Internal Medicine, University of Michigan Medical Center, Ann Arbor.
References
Steinberg AD, Steinberg SC. Long-term preservation of renal function in patients with lupus nephritis receiving treatment that includes cyclophosphamide versus those treated with prednisone only. Arthritis Rheum 1991;34:945-950.
Boumpas DT, Austin HA III, Vaughn EM, et al. Controlled trial of pulse methylprednisolone versus two regimens of pulse cyclophosphamide in severe lupus nephritis. Lancet 1992;340:741-745.
Gourley MF, Austin HA III, Scott D, et al. Methylprednisolone and cyclophosphamide, alone or in combination, in patients with lupus nephritis: a randomized, controlled trial. Ann Intern Med 1996;125:549-557.
Illei GG, Austin HA, Crane M, et al. Combination therapy with pulse cyclophosphamide plus pulse methylprednisolone improves long-term renal outcome without adding toxicity in patients with lupus nephritis. Ann Intern Med 2001;135:248-257.
Houssiau FA, Vasconcelos C, D'Cruz D, 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;46:2121-2131.
Contreras G, Pardo V, Leclercq B, et al. Sequential therapies for proliferative lupus nephritis. N Engl J Med 2004;350:971-980.
Somers EC, Marder W, Christman GM, Ognenovski V, McCune WJ. Use of a gonadotropin-releasing hormone analog for protection against premature ovarian failure during cyclophosphamide therapy in women with severe lupus. Arthritis Rheum 2005;52:2761-2767.
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.
Chan TM, Tse KC, Tang CS, Mok MY, Li FK. Long-term study of mycophenolate mofetil as continuous induction and maintenance treatment for diffuse proliferative lupus nephritis. J Am Soc Nephrol 2005;16:1076-1084.
Hu W, Liu Z, Chen H, et al. Mycophenolate mofetil vs cyclophosphamide therapy for patients with diffuse proliferative lupus nephritis. Chin Med J (Engl) 2002;115:705-709.
McCune WJ, Riskalla MM. Immunosuppressive drug therapy. In: Wallace DJ, Hahn BH, eds. Dubois' lupus erythematosus. 6th ed. Philadelphia: Lippincott Williams & Wilkins, 2002:1195-217.
Ginzler EM, Dooley MA, Aranow C, et al. Mycophenolate mofetil or intravenous cyclophosphamide for lupus nephritis. N Engl J Med 2005;353:2219-2228.
Esdaile JM, Joseph L, MacKenzie T, Kashgarian M, Hayslett JP. The benefit of early treatment with immunosuppressive drugs in lupus nephritis. J Rheumatol 1995;22:1211-1211.(W. Joseph McCune, M.D.)