Mycophenolate mofetil therapy for lupus nephritis refractory to intravenous cyclophosphamide

Mycophenolate Mofetil Therapy for Lupus Nephritis Refractory to Intravenous Cyclophosphamide Daniel Glicklich, MD, and Anjali Acharya, MD ● Intravenous (IV) cyclophosphamide has been the treatment of choice for diffuse proliferative glomerulonephritis (DPGN) in patients with systemic lupus erythematosus (SLE). However, there is little guidance in the medical literature about what to do when this therapy fails. Mycophenolate mofetil (MMF), a new immunosuppressive agent, has been used successfully in patients with solid organ transplants and rheumatoid arthritis. We report two patients with diffuse proliferative glomerulonephritis who responded favorably to MMF therapy after IV cyclophosphamide failed. r 1998 by the National Kidney Foundation, Inc. INDEX WORDS: Lupus nephritis; cyclophosphamide; mycophenolate mofetil.

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YCLOPHOSPHAMIDE intravenous (IV) bolus therapy has generally been considered the treatment of choice for diffuse proliferative glomerulonephritis (DPGN) in patients with systemic lupus erythematosus (SLE).1-3 However, treatment failure with IV cyclophosphamide and oral steroids has recently been well described, especially in black patients.4 There is little guidance in the medical literature about what to do when this therapy fails.5 A new immunosuppressive agent, mycophenolate mofetil (MMF), has recently been shown to delay renal damage and prolong life in a murine lupus model.6 This drug blocks the proliferation of activated B cells and T cells and downregulates the expression of adhesion molecules. In humans, MMF has been used widely with solid organ transplantations to prevent or reverse acute rejection.7,8 It has also been used successfully to treat patients with rheumatoid arthritis whose disease was refractory to a variety of other drugs.9 There have been preliminary reports of patients with SLE glomerular diseases or with vasculitis who responded to MMF.10-12 We describe our experience with MMF treatment in two patients with DPGN that was refractory to both IV cyclophosphamide (patients 1 and 2) and cyclosporine (patient 1).

From the Renal Division, Department of Medicine, Montefiore Medical Center of the Albert Einstein College of Medicine, Bronx, NY. Received November 24, 1997; accepted in revised form April 3, 1998. Address reprint requests to Daniel Glicklich, MD, Renal Division, Montefiore Medical Center, 111 East 210th St, Bronx, NY 10467-2490.

r 1998 by the National Kidney Foundation, Inc. 0272-6386/98/3202-0020$3.00/0 318

CASE REPORTS

Case 1 A 47-year-old black woman born in Jamaica was diagnosed with SLE in August 1989 when she presented with fever, arthralgia, anemia, and nephrotic syndrome associated with a positive antinuclear antibody 1:320, an elevated anti-dsDNA antibody level of 1,212 IU/mL, and hypocomplementemia. Her serum creatinine level was 0.8 mg/dL. A renal biopsy showed mesangial cell proliferation on light microscopy and extensive subendothelial deposits on electron microscopy. After therapy with prednisone (60 mg/d) was started, all systemic symptoms of lupus resolved and proteinuria decreased from 7 g/24 hr to 1 g/24 hr, but serological abnormalities did not change. She experienced a possible allergic reaction to azathioprine; therefore, weekly methotrexate was added in April 1990 as a steroid-sparing agent. Over the next 12 months, as the methotrexate dose was increased to 12.5 mg/wk, the serum creatinine level was stable but proteinuria persisted, hematuria developed, CH50 level was low (⬍55 U/mL), and anti-DNA antibody levels were high (⬎1,000 IU/mL). IV cyclophosphamide and oral methylprednisolone (40 mg/d) were started in April 1991. She received six monthly doses of cyclophosphamide (1 g/m2) and then six additional doses (0.6 g/m2) over an 18-month period. The dose of cyclophosphamide was adjusted to maintain a nadir white blood cell (WBC) count greater than 2,000/µL. Her serum creatinine level was 0.8 to 1.1 mg/dL, but 2⫹ proteinuria, hypocomplementemia, and elevated anti-DNA antibody titers persisted (Table 1). Cyclophosphamide therapy was discontinued for 8 months after the patient developed lower extremity cellulitis and then staphylococcal line sepsis. Monthly cyclophosphamide (0.5 g/m2) was resumed in November 1993 when serum creatinine levels increased to 1.3 mg/dL, urine protein excretion was 2 g/24 hr, and anti-DNA antibody titer was greater than 2,000 IU/mL. A total of 19.5 g of cyclophosphamide was administered from April 1991 through November 1994. Three 1-g boluses of IV methylprednisolone were administered in August 1994 when the serum creatinine level increased to 1.7 mg/dL. By January 1995, blood pressure had increased to 210/110 mm Hg, serum creatinine level was 2.0 mg/dL, and urine protein excretion was 7.5 g/24 hr. Urinalysis showed 10 to 20 red blood cells (RBCs) and 10 to 15 WBCs per highpower field. Total hemolytic complement decreased to 75

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Table 1. Case 1: Clinical Response to Sequential Immunosuppressive Treatments

Date

IV Cyclophosphamide (total g)

Methylprednisolone (mg/d)

Scr (mg/dL)

Uprot/Cr Ratio

U/A (RBC HPF)

CH50 (U/mL)

Anti-DNA Ab (IU/mL)

6/91 6/92 3/93 12/93 6/94 11/94

1.5 8.5 10.5 11.5 14.5 19.5

40 20 20 16 16 32

0.8 0.8 1.1 1.3 1.6 1.8

0.8 0.3 — 2.0 — 6.2

15 5 15 10 — 20

⬍55 ⬍55 70 ⬍55 — 78

1,230 1,739 940 944 — ⬎2,000

40 32 16 16 32 16

2.0 1.9 2.0 1.9 2.3 2.5

6.2 2.2 1.0 1.1 0.3 3.3

— 10 5 10 0 15

75 101 227 249 213 120

1,513 537 550 376 412 381

8 8 8 6 6 4 4 4

2.9 2.3 2.3 2.3 2.5 2.6 2.3 2.3

2.5 0.8 0.2 0.1 0.1 0.1 0.1 0.1

10 2 — 0 0 0 0 0

120 ⬎250 ⬎250 ⬎250 190 215 219 —

— 180 209 116 187 ⬍100 165 —

Cyclosporine (mg/d)

12/94 3/95 6/95 9/95 1/96 3/96

200 200 200 200 250 250 Mycophenolate Mofetil (mg/d)

4/96 8/96 12/96 4/97 7/97 10/97 1/98 3/98

1,000 1,000 1,500 1,000 1,000 500 500 0

Abbreviations: Scr, serum creatinine; Uprot/Cr, urine protein-creatine ratio; U/A, urinalysis; HPF, high-power field; Ab, antibodies.

U/mL and anti-DNA antibody titer was 1,513 IU/mL. She underwent an open biopsy in March 1995 that showed 75 glomeruli, 20% sclerosed and the rest with DPGN. The activity index was 10 and the chronicity index was 5. Immunofluorescence was positive for immunoglobulin A (IgA), IgG, and C3. Electron microscopy showed extensive subendothelial and subepithelial deposits. Cyclosporine (4 mg/kg daily) and methylprednisolone (20 mg twice daily) were started. Cyclosporine doses were adjusted to maintain 12-hour plasma trough levels at 100 to 200 mg/dL. There was initial clinical improvement with stabilization of serum creatinine levels, decreases in proteinuria and anti-DNA antibody titer, and an increase in CH50 to normal levels (Table 1). However, by April 1996, the serum creatinine level was 2.5 mg/dL, urine protein-creatinine ratio was 3.3, urinalysis showed occasional RBC casts and 25 RBCs per high-power field, and CH50 had decreased. Cyclosporine therapy was stopped and MMF (500 mg twice daily) was started. On this new regimen, the patient’s hematuria resolved, urine protein excretion decreased to low levels, and CH50 and anti-DNA antibody levels normalized. Her blood pressure has been well controlled. Serum creatinine levels have remained stable for 24 months (Table 1). On two occasions, when MMF was increased to 750 mg twice daily, the patient experienced severe nausea, vomiting, and diarrhea that resolved when the drug was temporarily discon-

tinued. MMF was recently discontinued and the patient is being closely observed.

Case 2 A 38-year-old black man born in the Virgin Islands was diagnosed with SLE in 1984, when he presented with discoid lupus, fever, arthralgia, and positive antinuclear antibody 1:160. In 1987, he developed a seizure disorder believed to be secondary to lupus cerebritis that responded to high-dose methylprednisolone and phenytoin therapy. In 1990, hypertension, proteinuria, and microscopic proteinuria were first noted. In January 1991, the serum creatinine level was 1.0 mg/dL, CH50 level was less than 55 U/mL, and anti-DNA antibody titer was 959 IU/mL. A renal biopsy showed DPGN. The activity index was 10 and the chronicity index was 1. IV cyclophosphamide was administered at 0.5 g/m2 per month for six doses, then 0.5 g/m2 every 3 months for an additional 12 doses. The cyclophosphamide dose was limited by the nadir WBC count. In October 1995, the serum creatinine level was 1.5 mg/dL and urinalysis showed 1⫹ protein and 0 to 5 RBCs per high-power field. He was lost to follow-up until April 1996, when he presented with hypertension of 180/100 mm Hg, nephrotic syndrome, creatinine level elevated to 2.1 mg/dL, and anti-DNA antibody level of 1,100 IU/mL. A second renal biopsy showed DPGN with

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minimal sclerotic changes. The activity index was 12 and the chronicity index was 2. Monthly 0.5-g/m2 IV cyclophosphamide infusions were resumed and oral methylprednisolone (32 mg twice daily) was administered. Over the next 5 months, his creatinine level increased to 2.9 mg/dL, urine protein decreased from 7 to 2 g/24 hr, and anti-DNA antibody titer returned to normal. A total of 24 g of IV cyclophosphamide was administered. In September 1996, he was admitted to the hospital for seizures. Blood pressure was 190/110 mm Hg, serum creatinine level was 3.8 mg/dL, urine protein-creatinine ratio was 13, and the urinalysis showed many RBCs, occasional RBC casts, and 30 WBCs per high-power field. The initial serum phenytoin level was low and the neurological workup was inconclusive. Serum creatine phosphokinase levels were not markedly elevated. The CH50 level was decreased (70 U/mL), but the anti-DNA antibody titer was normal. Three 1-g boluses of IV methylprednisolone were administered, along with clonidine (0.3 mg three times daily), Procardia XL (120 mg/d), and phenytoin daily. Over the next 10 days, his urine output decreased to the oliguric range and serum creatinine levels increased to 8.6 mg/dL, requiring two hemodialysis treatments. A third renal biopsy was performed, which showed 20 glomeruli, four totally sclerosed and the rest with diffuse proliferative changes. Fifty percent of the glomeruli had cellular crescents. The activity index was 12 and the chronicity index was 6. MMF (1,000 mg twice daily) was started on October 4, 1996. There was rapid improvement in renal function. Serum creatinine level was 2.9 mg/dL, the urine protein-creatinine ratio was 5.3, and urinalysis showed 5 to 10 RBCs per high-power field on November 10, 1996, when the patient was hospitalized for fever. He was found to have staphylococcal pneumonia with bacteremia, fungal esophagitis, and pancytopenia, with a hematocrit of 18%, WBC count of 2,400/µL, and platelet count of 114,000/µL. MMF was discontinued. Methylprednisolone (40 mg twice daily) was begun. He responded well to IV antibiotics. After 4 weeks, methylprednisolone was tapered slowly to 8 mg daily. At last follow-up in February 1998, his creatinine level was 3.9 mg/dL and slowly increasing, urine protein-creatinine ratio was 2.4, and his urinalysis showed no cells. Serum complement levels and anti-DNA antibody levels were normal. The patient has been reluctant to resume immunosuppressive therapy. He received only 1 month of MMF therapy.

DISCUSSION

We have described two patients with diffuse proliferative lupus nephritis who had active disease despite prolonged courses of IV cyclophosphamide, bolus IV methylprednisolone, and, in one case, cyclosporine. Their renal disease responded dramatically to the initiation of MMF therapy. The first patient had resolution of nephrotic-range proteinuria and hematuria, normalization of serum complement and anti-DNA antibody levels, and stable serum creatinine levels

for 24 months. To our knowledge, this is the longest reported follow-up of a patient with lupus nephritis receiving MMF therapy. She responded to dosages of MMF (500 to 1,000 mg daily) that would be considered subtherapeutic in renal transplantation patients who are generally prescribed 2,000 mg/d. Initially concerned about possible inadequate therapy, we increased the patient’s dose to 1,500 mg/d on two occasions, only to provoke significant gastrointestinal side effects. The optimal dose and duration of MMF to treat lupus nephritis is unknown, but may be considerably less than that described for renal transplantation patients. Others have reported the efficacy of reduced-dose MMF in short-term studies of patients with lupus nephritis.11 Because there have been no clinical signs of active renal disease for more than 1 year, we have elected recently to stop MMF therapy and to follow the patient closely. Our second patient illustrates the potential danger of overtreatment with MMF. After five monthly infusions of IV cyclophosphamide, he presented with rapidly progressive glomerulonephritis that failed to respond to 3 g of IV methylprednisolone. After MMF 2,000 mg/d was begun, there was a striking improvement in renal function and decrease in proteinuria. However, after only one month of MMF, he developed staphylococcal sepsis and pancytopenia. His renal function stabilized after a course of oral methylprednisolone. Thus, both cyclophosphamide and MMF share the potential for severe immunosuppression and life-threatening infections. In our patient, a deleterious cumulative effect of both drugs may have been responsible. Several limitations of our case reports should be mentioned. No follow-up biopsies were performed after initiation of MMF therapy to assess changes in activity and chronicity indices. Although cumulative doses of cyclophosphamide were significant, the dosing used in our patients was generally less than that recommended in the National Institutes of Health protocol.1 Over time, both of our patients have had deterioration of baseline renal function. At least theoretically, MMF is less broadly immunosuppressive than cyclophosphamide. MMF inhibits inosine 5’-monophosphate dehydrogenase, which is the rate-limiting enzyme in

MYCOPHENOLATE MOFETIL IN LUPUS NEPHRITIS

de novo synthesis of guanosine triphosphate (GTP). Activated B and T lymphocytes are dependent on de novo synthesis of purines, whereas other cells can use a purine salvage pathway. MMF has a selective antiproliferative effect on lymphocytes that is reversible. It blocks antibody formation and the generation of cytotoxic T cells. By depleting GTP, which is required for transfer of mannose and fucose to glycoproteins, MMF downregulates the expression of adhesion molecules. In experimental models, it also inhibits proliferation of vascular smooth muscle cells.13 Studies at the National Institutes of Health have shown that immunosuppressive therapy is clearly superior to prednisone therapy alone in preserving renal function in patients with lupus nephritis,1,3 but the best immunosuppressive regimen has not yet been defined. After 16 years of follow-up, there was no difference in outcome between IV cyclophosphamide and oral cyclophosphamide alone or in combination with azathioprine.2 In lupus patients with DPGN, IV cyclophosphamide with relatively low-dose oral prednisone has become the standard therapy.5 However, the optimal intensity and duration of IV cyclophosphamide therapy is uncertain. In one study, a long course of IV therapy in patients with DPGN did not reduce the risk for doubling serum creatinine levels compared with those treated with a short induction course of IV cyclophosphamide, yet patients receiving a short course of therapy had a greater risk of relapse of lupus nephritis when induction therapy was not followed by maintenance therapy with oral cytotoxic agents.14 Not all patients do well with cyclophosphamide, and there seems to be a clear racial difference in response to treatment of DPGN. Black patients had a worse 5-year renal outcome than nonblacks with IV cyclophosphamide.4 We believe that the time has come to consider newer immunosuppressive agents that are not as broadly cytotoxic as cyclophosphamide and azathioprine for the treatment of lupus nephritis. MMF, with its more specific action against activated B and T cells, may be a valuable adjunct in the treatment of lupus patients not responding to standard therapy. The need for multicenter, prospective, randomized, controlled trials comparing MMF with standard therapies in lupus nephri-

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tis and other glomerular diseases has recently been emphasized.12,15 For example, in lupus patients with DPGN, such a study might involve an induction phase with standard monthly IV cyclophosphamide, 1 g/m2 for 6 months. This would be followed by randomization to receive either standard maintenance IV cyclophosphamide, 0.5 to 1.0 g/m2 every 3 months for an additional 24 months, or oral MMF, up to 2 g/d for 24 months. We plan to enroll patients onto such a study in the near future. REFERENCES 1. Austin HA, Klippel JH, Balow JE, Le Riche NGH, Steinberg AD, Plotz PH, Decker JL: Therapy of lupus nephritis-controlled trial of prednisone and cytotoxic drugs. N Engl J Med 314:614-619, 1986 2. 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 alone. Arthritis Rheum 34:945-949, 1991 3. Gourley MF, Austin HA, Scott D, Yarboro CH, Vaughn EM, Muir J, Boumpas DT, Klippel JH, Balow JE, Steinberg AD: Methylprednisolone and cyclophosphamide, alone or in combination in patients with lupus nephritis. Ann Intern Med 125:549-557, 1996 4. Dooley MA, Hogan S, Jennette C, Falk R: Cyclophosphamide therapy for lupus nephritis: Poor renal survival in black Americans. Kidney Int 51:1188-1195, 1997 5. Berden JHM: Lupus nephritis. Kidney Int 52:538-558, 1997 6. Corna D, Morigi M, Facchinetti D, Bertani T, Zoja C, Remuzzi G: Mycophenolate mofetil limits renal damage and prolongs life in murine lupus autoimmune disease. Kidney Int 51:1583-1589, 1997 7. Sollinger HW: Mycophenolate mofetil for the prevention of acute rejection in primary cadaveric renal allograft recipients. Transplantation 60:225-232, 1995 8. Danovitch G: Mycophenolate mofetil for the treatment of refractory acute cellular renal transplant rejection. Transplantation 61:722-729, 1996 9. Goldblum R: Therapy of rheumatoid arthritis with mycophenolate mofetil. Clin Exp Rheumatol 11:5117-5119, 1993 10. Hebert LA, Cosio FG, Bay WH, Hernandez R, Lautman J: Mycophenolate mofetil therapy of systemic lupus erythematosus and ANCA vasculitis. J Am Soc Nephrol 8:87A, 1997 (abstr) 11. Nachman PH, Dooley MA, Hogan SL, Aiello JR, Jennette JC, Falk RJ: Mycophenolate mofetil therapy in patients with cyclophosphamide-resistant or relapsing diffuse proliferative lupus nephritis. J Am Soc Nephrol 8:94A, 1997 (abstr) 12. Briggs WA, Choi MJ, Scheel PJ: Successful mycophenolate mofetil treatment of glomerular disease. Am J Kidney Dis 31:213-217, 1998 13. Raisanen-Sokolowski A, Vuoristo P, Myllarnierni M,

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Yilmaz S, Kallio E, Hayry P: Mycophenolate mofetil inhibits inflammation and smooth muscle cell proliferation in rat aortic allografts. Transplant Immunol 3:342-352, 1995 14. Boumpas DT, Austin HA, Vaughn EM, Klippel JH, Steinberg AD, Yarboro CH, Balow JE: Controlled trial of

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pulse methylprednisolone versus two regimens of pulse cyclophosphamide in severe lupus nephritis. Lancet 340:741745, 1992 15. Kiberd B, MacDonald A: Mycophenolate and glomerular disease. Am J Kidney Dis 31:364-365, 1998