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J Am Soc Nephrol 10: 833–839, 1999 Mycophenolate Mofetil Therapy in Nephritis: Clinical Observations

MARY ANNE DOOLEY,* FERNANDO G. COSIO,† PATRICK H. NACHMAN,* MICHAEL E. FALKENHAIN,† SUSAN L. HOGAN,* RONALD J. FALK, * and LEE A. HEBERT† *Department of Medicine, The University of North Carolina, Chapel Hill, North Carolina; and †Department of Internal Medicine, The Ohio State University, Columbus, Ohio.

Abstract. Controlled clinical trials in renal transplantation have elevated anti-double-stranded DNA levels at baseline demonstrated that mycophenolate mofetil is well tolerated and improved in some, but not all, patients. The mean initial dose has lower renal transplant rejection rates than of MMF was 0.92 g/d (range, 0.5 to 2 g/d). The mean duration regimens. This study reports on the clinical experiences at two of therapy was 12.9 mo (range, 3 to 24 mo). Adverse events institutions with mycophenolate mofetil (MMF) for severe included herpes simplex stomatitis associated with severe leu- lupus nephritis. Twelve patients with relapsing or resistant kopenia (n ϭ 1), asymptomatic leukopenia (n ϭ 2), nausea/ nephritis previously treated with therapy diarrhea (n ϭ 2), thinning of scalp hair (n ϭ 1), pancreatitis and one patient who refused cyclophosphamide as initial ther- (n ϭ 1), and pneumonia without leukopenia (n ϭ 1). Recur- apy for diffuse proliferative nephritis but accepted MMF were rence of the pancreatitis led to discontinuation of MMF in this included. During combined MMF/prednisone therapy, serum patient; all other adverse events resolved with dose reduction. creatinine values remained normal or declined from elevated It is concluded that MMF is well tolerated and has possible values: mean change in serum creatinine was Ϫ0.26 Ϯ 0.46 efficacy in controlling major renal manifestations of systemic ␮M/L, P ϭ 0.039. significantly decreased: mean lupus erythematosus. Controlled clinical trials are needed to change in urine protein-to-creatinine ratios was Ϫ2.53 Ϯ 3.76, define the role of MMF in the management of lupus nephritis. P ϭ 0.039. Decreased serum complement component C3 and

Systemic lupus erythematosus (SLE) is a multisystem inflam- monophosphate dehydrogenase, a critical, rate-limiting en- matory disorder characterized by abnormalities in T and zyme in the de novo synthesis of purines (9). Because lym- function and frequent renal involvement. The treatment of phocytes require a fully functioning de novo pathway for patients with SLE who have severe glomerulonephritis remains purine synthesis and proliferation, MMF functions as a rela- controversial. Clinical trials of intermittent intravenous cyclo- tively selective antimetabolite. MMF exerts a fivefold more phosphamide therapy demonstrate greater long-term renal, but potent inhibition of the inducible isoform of inosine mono- not overall, survival compared with therapy (1– phosphate dehydrogenase expressed in stimulated 4). Longer duration of cyclophosphamide therapy is associated compared with the isoform constitutively expressed in resting with fewer relapses of nephritis and better renal outcome (4). cells (10). In vitro, MMF blocks proliferation of both B and T However, a significant proportion of patients with proliferative cells, inhibits antibody formation and the generation of cyto- lupus nephritis demonstrates poor renal response to intermit- toxic T cells, and decreases the expression of adhesion mole- tent intravenous cyclophosphamide (CyP) therapy (5,6). The cules on lymphocytes impairing their ability to bind to endo- optimal therapy for patients with CyP-resistant or relapsing thelial cells (11–13). In a murine model of lupus nephritis, lupus nephritis remains unclear. Increased exposure to CyP is MMF therapy prolongs overall survival and delays the onset associated with increased risk of infection, infertility, and and severity of nephritis (14). Historical data on the effective- long-term risks of malignancy (7). ness of MPA as a single agent in the treatment of psoriasis (15) Mycophenolate mofetil (MMF) is hydrolyzed to mycophe- and small pilot studies suggest that MMF therapy is beneficial nolic acid (MPA), the active immunosuppressant compound in patients with other autoimmune disorders, including rheu- (8). MPA is a reversible inhibitor of the enzyme inosine matoid arthritis, autoimmune hemolytic anemia, antineutrophil cytoplasmic antibody-associated vasculitis, and IgA nephrop- Received June 23, 1998. Accepted October 20, 1998. athy (16–18). A recent study of MMF in glomerular disease Correspondence to Dr. Lee A. Hebert, The Ohio State University, 1654 Upham included successful short-term treatment of two patients with Dr, Room N210, Columbus, OH 43210. Phone: 614-293-4997; Fax: 614-293- 3073; E-mail: [email protected] lupus nephritis (19). Herein, we report a clinical series of 13 patients treated with MMF for severe lupus nephritis at two 1046-6673/1004-0833$03.00/0 Journal of the American Society of academic centers, the University of North Carolina at Chapel Copyright © 1999 by the American Society of Nephrology Hill (UNC) and Ohio State University (OSU). 834 Journal of the American Society of Nephrology J Am Soc Nephrol 10: 833–839, 1999

Materials and Methods Therapy Patient Selection MMF doses were chosen arbitrarily. The starting dose for MMF was 0.5 to 2 g/d. The MMF dose was increased to maximum doses of Patients in these studies had SLE with documentation of at least 1.0 to 2.5 g/d with the goal to suppress renal sediment activity and four criteria from the 1982 revised American College of Rheumatol- improve serum creatinine, unless gastrointestinal or hematologic tox- ogy criteria for classification of SLE (20). Twelve patients were icity developed. offered MMF therapy for resistant or relapsing lupus nephritis; patient Prednisone therapy varied with SLE activity. Four patients received 13 received MMF after he and his parents refused initial CyP therapy pulse intravenous methylprednisolone at 7 mg/kg per d for 3 d: three for diffuse proliferative lupus nephritis. All but patient 13 had previ- for rapidly increasing serum creatinine and/or proteinuria and active ously received one or more courses of oral or intravenous cyclophos- urinary sediment and one with severe arthralgias, rash, and polyser- phamide therapy, and many had also received previous courses of ositis without rapidly declining renal function. In the remaining pa- azathioprine (AZA) or methotrexate therapy (Table 1). With the tients, prednisone doses remained lower (5 to 40 mg per day) when exception of patient 13, patients were offered MMF therapy in an MMF therapy was begun. attempt to avoid further CyP therapy and with the hope that MMF Agents to control BP included diuretics, angiotensin-converting would be more effective than AZA in treating active lupus nephritis. enzyme inhibitors (ACE), calcium channel blockers, angiotensin re- Patients 1 to 6 had undergone renal at varying points to define ceptor blockers (ARB), and beta blockers as prescribed by the treating lupus nephritis before initial CyP therapy. Patients 7 to 13 had physician. Those patients receiving ACE, calcium channel blockers, undergone repeat for recurrent nephritis before consid- or ARB did not have their doses changed during MMF therapy. ering further immunosuppressant therapy and were required to dem- onstrate active diffuse proliferative glomerulonephritis (DPGN; World Health Organization [WHO] class IV). Nine patients had a Statistical Analyses history of SLE-DPGN previously treated with and CyP All mean values are shown Ϯ 1SDandP values Ͻ 0.05 are for at least 6 mo before repeat biopsy. Four patients had received two considered statistically significant. Changes in laboratory values from prior courses of CyP. Four patients had declining renal function while baseline to last follow-up were compared using a nonparametric test receiving CyP and two had relapsing nephritis after attaining remis- for paired data. sion with CyP. Each patient was informed that the use of MMF (CellCept®, Roche Laboratories, Nutley, NJ) represented a new application of MMF in Results treating human diseases. The patients were offered MMF therapy as Baseline Clinical Parameters an alternative to further cyclophosphamide therapy for nephritis as an Table 1 displays the baseline clinical characteristics of the FDA-approved drug for a nonapproved indication. study patients. The patients included four men and nine women

Table 1. Demographic and baseline clinical characteristics of the study patientsa

Renal Biopsy Previous Therapyf Patient- Age SLEc Centerb (yr) Gender Race (yr) Classd Year Organse CyP AZA MTX

01-OSU 48 M W 9 V 1994 K 12/26 18/54 0 02-OSU 25 F W 4 IV 1996 K,J,S 8/18 19/70 0 03-OSU 48 F W 7 IV 1990 K,J 3/9 0 0 04-OSU 40 F W 15 IV 1988 K,J 2/9 48/72 72/2.3 05-OSU 36 F B 18 IV 1994 K 6/15 60/90 12/0.3 06-OSU 46 F B 17 IV 1996 K 10/16g 0 3/0.2 07-UNC 35 F H 2.5 IV 1996 K 6/8.2g 00 08-UNC 31 F B 5 IV 1996 K 26/16.8g 6/18 0 09-UNC 24 F W 11 IV 1997 K 48/19.4g 00 10-UNC 42 F W 20 IV 1997 K 10/9 12/36 0 11-UNC 37 M W 8 IV 1996 K 18/6.7g 0 4/0.2 12-UNC 25 M B 4 IV 1996 K 30/21.2g 00 13-UNC 16 M W 3 IV 1996 K,J,S,H 0 0 0

a W, white; B, black; H, Hispanic; SLE, systemic lupus erythematosus; CyP, cyclophosphamide; AZA, azathioprine; MTX, methotrexate; MMF, mycophenolate mofetil. b Patients were followed through either Ohio State University (OSU) or The University of North Carolina (UNC). c Years since diagnosis of SLE. d World Health Organization (WHO) classification. Patients 1 to 6 had dominant renal manifestations with renal biopsy in the past; patients 7 to 13 underwent renal biopsy before MMF therapy. e involvement at the start of MMF therapy: K, ; J, joint; S, skin; H, hematologic. f Given in months/total dose (g). g Intravenous CyP. J Am Soc Nephrol 10: 833–839, 1999 MMF Therapy in Lupus Nephritis 835 with average age 34.8 (range, 16 to 48 yr old). The racial creatitis. Mean serum creatinine significantly declined from distribution included one Hispanic, four black, and eight white 149.0 Ϯ 88.5 at entry to 123.2 Ϯ 62.4 ␮M/L at last follow-up; patients. The mean duration of SLE was 9.5 yr (range, 2.5 to 20 mean change in serum creatinine was Ϫ0.26 Ϯ 0.46; P ϭ yr). Nine patients had active renal disease as the sole manifes- 0.039. Excluding patient 9 from analysis, urine protein-to- tation of lupus activity at entry. Renal pathology had demon- creatinine ratios showed a mean change of Ϫ3.31 Ϯ 2.62 P ϭ strated WHO class IV in all but patient 1, who manifested 0.012 and serum creatinine showed a mean change of Ϫ0.34 Ϯ WHO class V nephritis. 0.37, P ϭ 0.012. Serum C3 level increased in four patients with hypocomple- Therapy mentemia at entry, but decreased from normal values in patient Table 2 shows the MMF and prednisone therapy used during 9 after discontinuation of MMF therapy. Serum anti-double- this study. The mean duration of therapy was 12.9 mo (range, stranded DNA levels fell in four of the six patients who 3 to 24 mo). During follow-up, the MMF dose tended to initially had high anti-double-stranded DNA levels. Not shown decrease either in response to MMF side effects or to determine is that abnormal urine sediments (hematuria and/or urinary whether SLE remission could be maintained at a lower dose of cellular casts) were present at baseline in all 13 patients. At last MMF. The prednisone dose tapering schedule during MMF testing, the abnormal urine sediments have reverted to normal therapy varied by practitioner, but generally occurred at the in six of 13 patients. rate of 10 mg each 2 to 4 wk after the first month until a maintenance dose of 5 to 10 mg of prednisone was reached. Toxicity Two patients discontinued prednisone therapy during treatment White blood cell counts were measured at 1, 2, and 4 wk with MMF. after the start of MMF therapy and then at least 4 to 8 wk thereafter. Patients 4 and 6 became leukopenic. The white Renal Outcomes count returned to normal with reduction in the MMF dose. Table 3 shows the renal and serologic parameters at baseline However, the leukopenia in patient 6 was severe and was and at most recent testing. Mean duration of follow-up was associated with severe herpes simplex stomatitis. She had 13.2 mo (range, 3 to 24). Proteinuria significantly decreased received MMF 1.5 g/d for 2 mo by the time the severe leuko- from a mean protein-to-creatinine ratio (P/C) at entry of 5.45 Ϯ penia occurred. She is now receiving 1 g/d MMF and main- 3.37 to 2.92 Ϯ 2.52; the mean change in P/C ratios was taining a normal white count. Patient 13, with long-standing Ϫ2.53 Ϯ 3.76; P ϭ 0.039. As can be seen in Figure 1, immune-mediated leukopenia, had an increase in white blood proteinuria declined during MMF therapy in 10 patients. Seven cell counts while receiving MMF. Patient 4 experienced no- of the 10 patients with nephrotic-range proteinuria at baseline ticeable scalp hair loss. The MMF dose was decreased in showed decreased urine protein-to-creatinine ratios of less than response to these complaints. Three patients developed mild 3.5 at last follow-up. As shown in Figure 2, serum creatinine gastrointestinal symptoms of nausea and/or diarrhea. The either remained stable or improved in all patients with the symptoms disappeared with a reduction in the MMF dose. exception of patient 9, who discontinued therapy due to pan- Patient 8 developed severe nausea, vomiting, and diarrhea

Table 2. Dose information on individual patients

Initial Current Duration of Total Initial Dose Current Duration of Dose Dose Dose Dose a Patient MMF MMF MMF MMF Prednisone Prednisone Prednisone (g/d) (g/d) (mo) (g) (mg/qd) (mg/qd) (mo)

01 1.0 1.0 14 344 5 5 14 02 1.0 2.0 24 1149 30 2.5 24 03 2.0 1.0 10 327 60 5 10 04 1.0 0.25 16 220 40 7.5 16 05 1.0 1.0 7 205 15 15 7 06 1.5 1.0 8 210 20 10 8 07 1.0 1.0 21 1470 10 0 15 08 0.5 0.25 19 240 Pulseb 419 09 0.5 0.0 7 100 15 5 7 10 0.5 2.0 12 505 15 10 12 11 0.5 1.0 12 348 30 4 12 12 0.5 1.5 13 550 Pulse 0 9 13 0.5 1.0 3 60 Pulse 20 3

a Duration of prednisone ϭ duration of prednisone since institution of MMF. b Pulse ϭ 7 mg/kg per d times3dofintravenous methylprednisolone. 836 Journal of the American Society of Nephrology J Am Soc Nephrol 10: 833–839, 1999

Table 3. Laboratory values at the start of MMF therapy (baseline) and at last follow-upa

Baseline Months Change Serum Last Serum Baseline C3 Last C3 Baseline Last anti- Patient in P/C Creatinine c c Follow-Up Creatinine ␮ b (g/L) (g/L) anti-DNA DNA Ratio (␮mol/L)b ( mol/L)

01 15 ϩ0.7 97 97 1.2 1.1 ND ND 02 24 Ϫ5.9 80 71 0.1 0.7 Neg ND 03 10 Ϫ3.6 150 106 0.6 1.1 189 35 04 16 Ϫ3.99 80 71 0.6 1.0 ND Neg 05 7 Ϫ0.8 97 71 0.7 0.8 1:80 ND 06 8 Ϫ6.0 274 195 ND 2.0 Neg ND 07 21 Ϫ2.9 115 71 1.0 1.3 1:10 Neg 08 18 Ϫ2.6 354 239 1.4 1.2 1:10 1:10 09 13 ϩ6.8 133 195 1.3 0.8 Neg Neg 10 12 0 124 97 ND ND ND ND 11 12 Ϫ2.6 106 97 0.8 1.0 Neg Neg 12 3 Ϫ8.5 256 212 ND 0.9 1:320 Neg 13 13 Ϫ3.6 71 80 0.7 1.0 1:40 1:80

a P/C, protein-to-creatinine; ND, not done; Neg, negative. b Serum creatinine in mg/dl ϭ ␮mol/L Ϭ 88.4. c Serum complement, C3 in mg/dl ϭ g/L Ϭ 0.01. d Farr assay with normal Ͻ50. All other tests at OSU performed using a crithidia assay with normal as negative. At UNC, an enzyme- linked immunoabsorbant assay was used with negative as normal.

Figure 1. Urine protein-to-creatinine ratio at baseline and at last follow-up for individual patients. The dotted line indicates the patient (patient 9) who discontinued therapy with mycophenolate mofetil (MMF) because of pancreatitis. associated with volume depletion requiring withholding ther- therapy remain the mainstay of therapy with improved renal apy and reinstitution at lower dose. At MMF doses of 0.5 g/d, survival at the cost of long-term adverse events, including patient 9 developed pancreatitis (abdominal discomfort, weight increased risk of infection, infertility, avascular necrosis, os- loss, and elevated serum amylase and lipase) that recurred on teoporosis, and long-term risks of malignancy (7). MMF was rechallenge with MMF. Abdominal ultrasound remained nor- recently approved for clinical use on the basis of three large mal, and no long-term sequelae have been noted at 6 mo since prospective controlled double-blind trials in renal transplanta- MMF was discontinued. tion (21–23). In those trials, MMF (2 or 3 g daily) was shown to be superior to azathioprine (1 to 2 mg/kg daily) or placebo Discussion in preventing renal allograft rejection. With most immunosup- The treatment of patients with severe lupus nephritis remains pressive agents, increasing the degree of controversial. Corticosteroids and intermittent intravenous CyP increases the likelihood of side effects of immunosuppression, J Am Soc Nephrol 10: 833–839, 1999 MMF Therapy in Lupus Nephritis 837

Figure 2. Serum creatinine (␮mol/L) at baseline and at last follow-up for individual patients. The dotted line indicates the patient (patient 9) who discontinued therapy with MMF because of pancreatitis. including infection and bone marrow suppression. However, ment in serum creatinine levels and proteinuria over a mean experience from controlled clinical trials in renal transplanta- duration of therapy of 12.9 mo (range, 3 to 24 mo). With one tion shows that MMF may be an exception to this generaliza- exception, our patients tolerated MMF without adverse events tion because the MMF-treated patients were able to achieve a requiring discontinuation of the drug. Serologic measures of greater degree of immunosuppression (less renal transplant disease activity improved in some, but not all, patients. To rejection) yet suffered little increase in the incidence of infec- date, two patients were able to discontinue prednisone therapy tion or bone marrow suppression (24). Tissue-invasive cyto- and remain on MMF as a single agent for nephritis. Long-term megalovirus infection was increased among patients receiving follow-up of all patients continues. 3 g daily (21–23). In these multidrug immunosuppressive Many of our study patients manifested predictors of adverse regimens, lymphoproliferative disease including lymphoma renal outcome of lupus nephritis at the start of MMF therapy, developed in three patients receiving MMF compared with including elevated serum creatinine, heavy proteinuria, WHO zero in the azathioprine group (21) and in four receiving MMF class IV renal pathology, history of recurrent flares of nephritis compared with one in the azathioprine group (23). Use of (28), and black race (5,6). The improvement in proteinuria MMF as a single agent may have less risk of malignancy and observed in our patients during MMF therapy could not be infection. Long-term therapy of 85 patients with psoriasis for attributed to changes in antihypertensive therapy, which was up to 13 yr with , the parent compound of unchanged during this period. MMF, demonstrated no increased cancer rate (15). Therapy of Our results suggest that the doses of MMF usually used in using MMF as a single agent in more than management of renal transplant patients (2 to 3 g/d) may not be 600 patients demonstrated primarily gastrointestinal side ef- needed in lupus patients. MMF dosages in the range of 0.5 to fects similar to those observed in our patients (nausea, vomit- 1.5 g/d may be sufficient into treat lupus nephritis. At these ing, diarrhea). No clinically significant hematologic, hepatic, lower doses, MMF was generally well tolerated. The predom- or nephrotoxic toxicity has been noted (16). Data presented in inant manifestations were gastrointestinal toxicity observed abstract form reporting efficacy and toxicity in more than 350 even in those receiving low-dose MMF. MMF is tightly protein patients with RA show similar adverse events (25). bound, and patients with nephrotic syndrome and decreased Recently, MMF therapy in a murine model of lupus has been serum albumin may have increased unbound fraction (29). shown to improve survival and decrease renal disease with Substantial thinning of scalp hair was seen in one patient, marked reduction in autoantibody formation (14). Similar re- which reversed with a reduction in MMF dose. The only sults are reported in abstract form in other murine strains with serious toxicity noted in this study was one patient who devel- lupus-like disease, although improved renal and pro- oped severe neutropenia complicated by herpes simplex sto- teinuria were not uniformly associated with changes in sero- matitis, which was reversible. One patient was hospitalized for logic markers of lupus activity (26,27). The single previous pneumonia during MMF therapy without leukopenia. report of MMF therapy in human lupus nephritis notes im- There are important limitations to studies such as this in provement in two patients with proliferative nephritis at 2 and which patients serve as their own controls, particularly if 3 mo of therapy (19). The present study examines the outcomes patients chosen for study are manifesting a relapse (e.g., in- of 13 patients receiving combined MMF/prednisone therapy crease in proteinuria). Under those circumstances, a decrease in for severe lupus nephritis. We observed significant improve- proteinuria during an experimental treatment may not represent 838 Journal of the American Society of Nephrology J Am Soc Nephrol 10: 833–839, 1999 improvement in the underlying disease process. Rather, it may Lockshin MD: Systemic lupus erythematosus: Emerging con- represent proteinuria spontaneously “regressing” to its average cepts. Part I. Renal, neuropsychiatric, cardiovascular, pulmo- value (regression to the mean). However, it is unlikely that nary, and hematologic disease. Ann Intern Med 122: 940–950, regression to the mean can explain the improvement observed 1995 during MMF therapy in our patients. Regression to the mean is 8. Morris RE, Hoyt EG, Murphy MP: Mycophenolic acid morpho- most relevant to conditions that have a relatively high rate of linoethylester (RS-61433) is a new immunosuppressant that pre- vents and halts heart allograft rejection by selective inhibition of spontaneous remission, e.g., idiopathic membranous nephrop- T- and B-cell purine synthesis. Transplant Proc 22: 1659–1662, athy. However, it is very unusual for patients with severe lupus 1990 nephritis to show spontaneous improvement in proteinuria and 9. Eugui EM, Almquist S, Muller CD, Allison AC: renal function, particularly large improvement over a short selective cytostatic and immunosuppressive effects of mycophe- period of time as we observed in most of our patients. Thus, the nolic acid in vitro: Role of deoxyguanosine nucleotide depletion. improvement observed during MMF and prednisone therapy Scan J Immunol 33: 161–173, 1991 was likely the result of that treatment. Nevertheless, the above 10. Carr SF, Papp E, Wu JC, Natsumeda Y: Characterization of interpretation is a hypothesis that must be tested in controlled, human type I and type II IMP dehydrogenases. J Biol Chem 268: prospective, randomized trials. We suggest that the results of 27286–27290, 1993 the present study provide strong justification for considering 11. Allison AC, Eugui EM, Sollinger HW: Mycophenolate mofetil MMF therapy for testing in such trials. We suggest further that (RS-61443): Mechanism of action and effects in transplantation. the results of the present study should prove useful in trial Transplant Rev 7: 129–139, 1993 design by providing objective data regarding sample size cal- 12. Allison AC: Preferential suppression of lymphocyte proliferation culation, doses of MMF, and the side effects likely to be by mycophenolic acid and predicted long-term effects of myco- phenolate mofetil in transplantation. Transplant Proc 26: 3205– encountered in patients with lupus nephritis. 3210, 1994 13. Allison AC, Kowalski WJ, Muller CJ, Waters RV, Eugui EM: Mycophenolic acid and brequinar, inhibitors of purine and py- Acknowledgments rimidine synthesis, block the glycosylation of adhesion mole- This work was supported in part by National Institutes of Health cules. Transplant Proc 25[Suppl 2]: 67–70, 1993 Grants MO1-RR00034 and DK49339. We gratefully acknowledge the 14. Corna D, Morigi M, Faccinetti D, Bertani T, Zoja C, Remuzzi G: help of the following physicians whose patients participated in this Mycophenolate mofetil limits renal damage and prolongs life in clinical series: Dr. William H. Bay (The Ohio State University); Dr. murine lupus . Kidney Int 51: 1583–1589, Raul Hernandez, Jr (Zanesville, OH); Dr. Jeffrey Lautman (Euclid, 1997 OH); Dr. Robert Lockridge (Lynchburg, VA); Dr. Matthew 15. Epinette WW, Parker C, Jones L, Greist MC: Mycophenolic acid Godlewski (Parkersburg, WV); and Dr. Brad H. Rovin (The Ohio for psoriasis: A review of pharmacology, long term efficacy, and State University). safety. J Am Acad Dermatol 17: 962–971, 1987 16. Goldblum R: Therapy of rheumatoid arthritis with mycopheno- late mofetil. Clin Exp Rheumatol 11[Suppl]: S117–S119, 1993 References 17. Zimmer-Molsberger B, Knauf W, Eckhard T: Mycophenolate mofetil for severe autoimmune hemolytic anemia. Lancet 350: 1. Austin HA, Klippel, JH, Balow JE, le Riche NGH, Steinberg 1003–1004, 1997 AD, Plotz PH, Decker JL: Therapy of lupus nephritis: Controlled 18. Nowack R, Birck R, van der Woude FJ: Mycophenolate mofetil trial of prednisone and cytotoxic drugs. N Engl J Med 314: 614–619, 1986 for systemic vasculitis and IgA nephropathy [Letter]. Lancet 349: 2. Valeri A, Radhakrishnan J, Estes D, D’Agati V, Kopelman R, 774, 1997 Pernis A, Flis R, Pirani C, Appel GB: Intravenous pulse cyclo- 19. Briggs WA, Choi MJ, Scheel PJ: Successful treatment of glo- phosphamide treatment of severe lupus nephritis: A prospective merular disease with mycophenolate mofetil. Am J Kidney Dis five-year study. Clin Nephrol 42: 71–78, 1994 31: 213–217, 1998 3. Lehman TJ, Sherry DD, Wagner-Weiner L, McCurdy DK, Em- 20. Tan EM, Cohen AS, Fries J: The 1982 revised criteria for the ery HM, Magilavy DB: Intermittent intravenous cyclophospha- classification of systemic lupus erythematosus. Arthritis Rheum mide therapy for lupus nephritis. J Pediatr 114: 1055–1060, 25: 1271–1277, 1982 1989 21. Sollinger HW, for the U.S. Renal Transplant Mycophenolate 4. Boumpas DT, Austin HA, Vaughn EM, Klippel JH, Steinberg Mofetil Study Group: Mycophenolate mofetil for the prevention AD, Yarboro CH, Balow JE: Controlled trial of pulse methyl- of acute rejection in primary cadaveric renal allograft recipients. versus two regimens of pulse cyclophosphamide in Transplantation 60: 225–232, 1995 severe lupus nephritis. Lancet 340: 741–745, 1992 22. European Mycophenolate Mofetil Cooperative Study Group: 5. Austin AH 3rd, Boumpas DT, Vaughan EM, Balow JE: High- Placebo-controlled study of mycophenolate mofetil combined risk features of lupus nephritis: Importance of race and clinical with cyclosporin and for prevention of acute and histological factors in 166 patients. Nephrol Dial Transplant rejection. Lancet 345: 1321–1325, 1995 19: 1670–1678, 1995 23. Tricontinental Mycophenolate Mofetil Renal Transplantation 6. Dooley MA, Hogan S, Jennette CJ, Falk RJ: Cyclophosphamide Study Group: A blinded, randomized clinical trial of myco- therapy for lupus nephritis: Poor renal survival in black Ameri- phenolate mofetil for the prevention of acute rejection in cans. Kidney Int 51: 1188–1195, 1997 cadaveric renal transplantation Transplantation 61: 7. Boumpas DT, Austin HA, Fessler BJ, Balow JE, Klippel JH, 1029–1037, 1996 J Am Soc Nephrol 10: 833–839, 1999 MMF Therapy in Lupus Nephritis 839

24. Halloran P, Mathew T, Tomlanovich S, Groth C, Hooftman L, 27. Mieke CJ, Walgreen B, Rijke TPM, Berden JHM: Mycopheno- Barker C: Mycophenolate mofetil in renal allograft recipients. late mofetil delays lupus nephritis MRL/lpr mice [Abstract]. Transplantation 63: 39–47, 1997 J Am Soc Nephrol 8: 468A, 1997 25. Franklin CM, Goldblum R, Robinson C, Chiang Y: Dose-rang- 28. Moroni, G, Quaglini, S, Maccario, M, Banfi, G, Ponticelli, C: ing, placebo-controlled trial of mycophenolate mofetil (MYC) in “Nephritic flares” are predictors of bad long-term renal outcome refractory rheumatoid arthritis (RA) [Abstract]. Arthritis Rheum in lupus nephritis. Kidney Int 50: 2047–2053, 1996 11[Suppl]: S57, 1993 29. Allison AC, Almquist SJ, Muller CD, Nowak I, Shaw LM: 26. McMurray RW, Elbourne KB, Lal S: Mycophenolate mofetil Mycophenolic acid binding to human serum albumen: Charac- prevents lupus nephritis and mortality in the female B/W mouse terization and relation to pharmacodynamics. Clin Chem 41: model of SLE [Abstract]. Arthritis Rheum 9(Suppl): S324, 1997 1011–1017, 1995

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