J Am Soc Nephrol 10: 1965 1971, 1999 Mycophenolate Mofetil for Maintenance Therapy of Wegener s Granulomatosis and Microscopic Polyangiitis: A Pilot Study in 11 Patients with Renal Involvement RAINER NOWACK,* URSULA GÖBEL, PIETER KLOOKER, OLAF HERGESELL, KONRAD ANDRASSY, and FOKKO J. VAN DER WOUDE* *5th Medical Clinic (Nephrology, Endocrinology), University-Clinic Mannheim, Faculty of Clinical Medicine of the University of Heidelberg, Mannheim, Germany; Medical Clinic (Nephrology, Hypertension), Faculty of Clinical Medicine of the Humboldt University Berlin, Campus Buch, Berlin, Germany; Klinikum der Stadt Ludwigshafen, Medizinische Klinik A, Ludwigshafen, Germany; and Department of Nephrology, Ludolf- Krehl-Klinik, University of Heidelberg, Heidelberg, Germany. Abstract. Successful maintenance therapy with mycophenolate mofetil (MMF) 2 g/d and low-dose oral corticosteroids (OCS) over a period of 15 mo was given to patients with Wegener s granulomatosis (WG) (n 9) and microscopic polyangiitis (MPA) (n 2). All patients had severe generalized disease with pauci-immune necrotizing glomerulonephritis and received standard induction therapy with oral cyclophosphamide and OCS for a mean of 14 wk until remission was achieved. Of 11 patients, only one WG patient relapsed in the 14th month of maintenance therapy. Maintenance therapy with MMF was able to further reduce grumbling disease activity as measured by the Birmingham vasculitis activity score (BVAS2) and proteinuria that were still present by the end of induction therapy. OCS could be reduced to a median daily dose of 5 mg and discontinued in three patients. Possible drug-related adverse effects were transient and included abdominal pain, respiratory infection, diarrhea, leukopenia, and a cytomegalovirus-colitis in one patient that was successfully treated with ganciclovir. It is concluded that MMF in combination with low-dose OCS is well tolerated and effective for maintenance therapy of WG and MPA. Long-term treatment with MMF in these diseases is attractive because of its low toxicity. MMF will have to be studied further and compared with cyclophosphamide or azathioprine maintenance therapy in randomized trials. Wegener s granulomatosis (WG) and microscopic polyangiitis (MPA) are systemic vasculitides with small to medium vessel involvement. Together with idiopathic pauci-immune necrotizing glomerulonephritis (NCGN), which is considered a renal limited variant of MPA, they are the most common cause of rapidly progressive glomerulonephritis. These entities are frequently associated with antineutrophil cytoplasmic autoantibodies (ANCA), and are therefore categorized together as ANCA-associated systemic vasculitides (AASV) (1). Despite some differences in clinical presentation and prognosis between them, AASV are treated following a common therapeutic concept. Untreated generalized WG has a poor prognosis with a mortality of 80% within the first year after diagnosis (2). The disease became treatable only when alkylating agents were Received November 16, 1998. Accepted March 6, 1999. Correspondence to Dr. Rainer Nowack, 5th Medical Clinic (Nephrology, Endocrinology), University-Clinic Mannheim, Theodor-Kutzer-Ufer 1-3, 68167 Mannheim, Germany. Phone: 49 621 383 3521; Fax: 49 621 383 2049; E-mail: rnowack@rumms.uni-mannheim.de 1046-6673/1009-1965 Journal of the American Society of Nephrology Copyright 1999 by the American Society of Nephrology combined with corticosteroids (3,4). The combination of oral cyclophosphamide (CYC) in a dose of 2 mg/kg per d with oral corticosteroids (OCS) in a starting dose of 1 mg/kg per d became the standard treatment of WG from the 1970s onward (5,6). To stabilize remission and prevent relapses, CYC is usually maintained together with tapered OCS for up to 12 mo or longer after induction of remission. Together with the amount of CYC that will be administered for treatment of relapses, this policy results in a high cumulative dosage of CYC and increases drug-related toxicity. Serious CYC-related long-term complications have been identified by retrospective analyses of AASV patients (7 9). The increased risk for malignancies, e.g., 30-fold for bladder carcinoma and 10-fold for lymphomas, is the most serious complication of CYC treatment and will certainly contribute to the still-reduced life expectancy of WG patients (10). This dilemma has stimulated the search for less toxic but equally effective drugs to replace CYC for treatment of AASV (11,12). Mycophenolate mofetil (MMF) is a strong immunosuppressive drug with rather low toxicity due to its lymphocyteselective mode of action (13). Mycophenolic acid, the active metabolite of MMF, reversibly inhibits inosin-monophosphatedehydrogenase, a key enzyme of de novo purine synthesis
1966 Journal of the American Society of Nephrology J Am Soc Nephrol 10: 1965 1971, 1999 (14,15). Lymphocytic proliferation and function relies almost exclusively on de novo purine synthesis, whereas most other cells can also use the salvage pathway. MMF has been approved for prophylaxis and treatment of renal transplant rejection (16 20), for which it proved to be superior over azathioprine (AZA) (16,20). Encouraged by a preliminary experience with MMF in four AASV patients (21), this pilot study with MMF for maintenance therapy of AASV in patients with generalized disease was performed. Materials and Methods Patients Newly detected or untreated patients with AASV (WG, MPA, and NCGN) of both genders between the ages 18 to 75 yr were eligible for the study. Consecutive patients fulfilling the inclusion criteria were approached until 11 patients had been recruited. Diagnosis had to be based on clinical presentation, serology, and/or histology. Renal involvement by AASV and/or severe involvement of other organs was required. Exclusion criteria were: pregnancy and lactation, mental retardation, major psychiatric illnesses, malignancies, active virus hepatitis, HIV infection, drug abuse, other multisystem disease, active peptic ulcer disease, severe gastrointestinal disease with malabsorption, noncompliance, and inadequate contraception. Protocol and Treatment This study was a prospective open-label study conducted in four nephrology departments in Germany. The study was carried out in accordance with the guidelines proposed in the Declaration of Helsinki. All patients gave written informed consent before inclusion and were insured for the time of the study. Ethical approval was obtained in each participating center. Reliability of the data in the record books was checked throughout the study by a professional monitoring company (SKM Oncology Research, Wiesbaden, Germany). After diagnosis all patients received standard induction therapy (2 mg/kg per d CYC and 1 mg/kg per d OCS) for at least 3 mo or longer until remission was achieved. Deviations from the protocol, e.g., intravenous pulses of CYC or corticosteroids or plasma exchange, were allowed after discussion with the principal investigator. For maintenance therapy, patients were switched from CYC to MMF 2 g/d, which was maintained until the study end. For further reduction of OCS, a guideline was provided aiming at a daily dosage of not more than 7.5 mg/d by the end of the study. No other immunosuppressive or cytotoxic therapy was allowed. Patients of both genders were advised to perform effective contraception for the time of the study and for an additional 3 mo after discontinuation of therapy. At entry the following data were obtained: hemoglobin, white blood cell count, platelets, erythrocyte sedimentation rate, serum creatinine, C-reactive protein (CRP), aspartate aminotransferase/alanine aminotransferase, alkaline phosphatase, albumin, glucose, ANCA, anti-pr3, anti-myeloperoxidase (MPO), anti-glomerular basement membrane antibodies, antinuclear antibody, rheumatoid factor, cryoglobulins, hepatitis B antigen, hepatitis C antibody, HIV, C3, C4, GFR by creatinine clearance, and proteinuria. On follow-up, hemoglobin, white blood cell count, platelets, ESR, serum creatinine, CRP, aspartate aminotransferase/alanine aminotransferase, alkaline phosphatase, and albumin were monitored monthly, and ANCA, anti- PR3, anti-mpo, GFR by creatinine clearance, and proteinuria were monitored every three months. For measuring disease activity, clinical judgment was further affirmed by calculation of the Birmingham vasculitis activity score (BVAS) (22,23). BVAS is calculated from symptoms and signs attributable to AASV in nine separate organ systems that are weighed according to their relative contribution on mortality and morbidity of AASV. BVAS1 reflects acute activity and is calculated from new or deteriorated symptoms and signs of disease activity within the previous month; BAVS2 for grumbling or persistent disease activity is calculated from items recorded to be present, but neither new nor worse. Organ damage attributable to ASSV was scored by the vasculitis damage index (VDI) (24) at diagnosis and by the end of induction therapy and by the end of maintenance therapy. To count for VDI, the signs or symptoms had to be present for at least 3 mo. Within this trial, the scores were used for monitoring the patients and not for decisionmaking. The decisions on remission and relapse were based on the clinical judgment of the participating physicians, but in reasonable agreement with the scores. For remission, new or deteriorated disease activity had to be absent (BVAS1 0), but signs of grumbling disease activity, e.g., persistent proteinuria, were allowed to be present (BVAS2 0). For relapses, the recurrence or first appearance of major organ involvement by AASV severe enough to switch to induction treatment was required (BVAS1 0). These definitions of remission and relapse were adopted from the criteria used within the therapeutic trials of the European vasculitis study group (12). Results Eleven consecutive patients with newly diagnosed and untreated AASV (WG, n 9) and MPA, n 2) were recruited for the study (Table 1). Their median age was 58 yr (range, 19 to 70) and they had active generalized disease (Table 1) with biopsy-proven pauci-immune necrotizing glomerulonephritis and a high median BVAS1 score of 24 (range, 10 to 34). At diagnosis, renal failure (serum creatinine 150 mol/l) was present in 6 of 11 patients (Table 2), and in patients 1, 5, and 11 segmental glomerular crescents were found histologically. Patients 1 through 5, 7, and 11 presented with pulmonary infiltrates unresponsive to antibiotics; in patient 3, artificial respiration had to be performed for 4 d because of respiratory failure. CRP was elevated to a median of 12 mg/dl (range, 3 to 45), and the median hemoglobin was reduced to 9.5 g/dl (range, 7.3 to 13). All patients with WG were positive for C-ANCA with anti-pr3 antibody and patients with MPA for P-ANCA with anti-mpo antibody, respectively. Standard induction therapy was given for a mean of 14 (range, 9 to 19) wk, in which a mean cumulative CYC dosage of 11.9 g (4.3 to 18) was reached (Table 3). Modifications of the standard induction therapy included additional plasma exchange or intravenous pulses of CYC or methylprednisolone (Table 3). In one patient, the induction therapy was switched to MMF after 9 wk because of persistent severe CYC-associated leukopenia. When remission was achieved and medication was switched to maintenance therapy, new or deteriorated disease activity was absent in all patients (BAVS1 0), but grumbling disease activity of variable degree was still present, as indicated by a median BVAS2 of 5 (range, 0 to 11). The CRP had fallen to a median of 4 (range, 0 to 10). In 10 of the 11 patients, permanent organ damage attributable to AASV was present at remission as indicated by a median VDI of 2 (range, 0 to 5). Renal
J Am Soc Nephrol 10: 1965 1971, 1999 MMF in Systemic Vasculitis 1967 Table 1. Diagnosis, age, gender, ANCA status, and organ involvement by AASV at time of diagnosis a Patient Diagnosis Age (yr) Gender ANCA K A B L E EY S P GI C H 1 MPA 70 F P-ANCA X X X X X 2 WG 29 F C-ANCA X X X X X X 3 MPA 57 F P-ANCA X X X X 4 WG 50 F C-ANCA X X X X X X X X X 5 WG 50 M C-ANCA X X X X X 6 WG 62 M C-ANCA X X 7 WG 64 M C-ANCA X X X X X X 8 WG 55 M C-ANCA X X X 9 WG 65 F C-ANCA X X X X X 10 WG 58 M C-ANCA X X X X X X X X 11 WG 67 F C-ANCA X X X X a ANCA, antineutrophil cytoplasmic autoantibodies; AASV, ANCA-associated systemic vasculitis; K, nephritic sediment, new rise in creatinine, rapidly progressive glomerulonephritis/other; A, arthralgia/myalgia, arthritis; B, temperature 38.5 C, loss of body weight 5 kg, night sweats; L, infiltrate, nodule, pleurisy, hemoptysis, other; E, nose, sinusitis, retrobulbar granuloma, ear, hearing impairment; EY, red eye, retinal changes, visual impairment, S, purpura, ulcerations, gangrene, other; P (NS), peripheral neuropathy sensory, peripheral neuropathy motor; GI, gastrointestinal involvement; C (NS), pathologic magnetic resonance imaging/cerebrospinal fluid symptomatic; H, myocarditis, pericarditis, coronaritis; P-ANCA, perinuclear ANCA; C-ANCA, cytoplasmic ANCA; MPA, microscopic polyangiitis; WG, Wegener s granulomatosis. function could be preserved in all patients; at remission, the serum creatinine had fallen below 150 mol/l in all but one of the six patients with renal failure (Table 2). During maintenance therapy, no further decline of renal function occurred. In patient 1, renal function recovered only partially, and the serum creatinine stabilized between 170 and 190 mol/l until the end of the trial. After switching from CYC to MMF 2 g/d, all but one patient remained in stable remission for 15 mo (BVAS 0). The relapse occurred in patient 4 in the 14th month of maintenance therapy with recurrence of peripheral neuropathy, arthralgias, and constitutional symptoms (increase of BVAS1 score to 12). This patient with a high initial BVAS1 score of 34 had needed a prolonged course of induction therapy (18 wk) and had considerable, although declining, grumbling disease activity throughout maintenance treatment. BVAS2 further decreased during maintenance therapy in all patients and became negative in 6 of 11 patients. Proteinuria gradually declined during remission treatment from a median of 0.5 g/d (range, 0.08 to 2.8) to a median of 0.2 g/d (range, 0.03 to 1.4) in all patients, and fell below 0.5 g/d in all except three patients (Table 2). OCS could be reduced step by step as indicated in the guidelines, and a median daily dosage of 5 mg was reached by the end of the study. In three patients, OCS were discontinued several months before the end of the study (Figure 1). ANCA titers became negative in 6 of 11 patients by the end of the induction therapy, and two additional patients became negative during remission therapy. Three patients remained ANCApositive throughout the study period. The patient with relapse was among those who became ANCA-negative early during induction therapy, but had an elevation of ANCA prior to and at clinical relapse. A few adverse effects, probably drug-related, were observed during remission therapy, including abdominal pain (n 3), diarrhea (n 2), respiratory infection (n 2), and leukopenia ( 3000/ l) (n 2). Leukopenia occurred in the second and third month of treatment with MMF and was reversible with dosage reduction to 1 g/d. The reduced dose was subsequently maintained until the end of the study. In one patient, MMF was stopped in the 14th month of treatment when a cytomegalovirus-colitis was diagnosed histologically. The patient remained in remission with low-dose OCS, and the colitis was successfully treated with ganciclovir. Discussion In this prospective pilot study of patients with WG and MPA, maintenance of remission for 15 mo was achieved with a combination of MMF and low-dose OCS. Only 1 of 11 recruited patients relapsed and the medication was generally well tolerated. The standard treatment of active AASV is a combination of oral CYC (2 mg/kg per d) and OCS (starting dose, 1 mg/kg per d), which leads to high remission rates and effective prevention of relapses, but carries the risk of serious acute and long-term adverse effects (7 9). How these complications of AASV therapy can be avoided is currently unsolved. Strategies aim at reducing the total dosage and/or treatment time of CYC or replacing the drug from the beginning of treatment by a less toxic but still effective drug. The total dose of CYC can be significantly reduced by giving the drug as monthly intravenous pulses instead of daily oral therapy. Protocols using intravenous pulses of CYC were indeed associated with fewer and less serious adverse effects (25 29). However, although the remission rates of intravenous pulse and daily oral therapy are about the same, intravenous protocols were shown to be less effective (30,31)
1968 Journal of the American Society of Nephrology J Am Soc Nephrol 10: 1965 1971, 1999 Table 2. Serum creatinine, creatinine clearance, and proteinuria at entry, remission, and end of the study Study Phase and Patient No. Serum Creatinine ( mol/l) Creatinine Clearance (ml/min per 1.73 m 2 ) Proteinuria (g/d) Entry 1 839 7 0.8 2 145 50 1.2 3 300 10 0.5 4 70 110 0.8 5 415 13 0.4 6 141 81 0.7 7 221 23 1.1 8 79 76 0.6 9 145 43 1.0 10 282 12 1.8 11 335 11 0.7 Remission 1 176 35 2.80 2 88 96 2.20 3 89 72 0.08 4 79 100 0.50 5 70 68 0.50 6 114 115 0.40 7 132 72 1.40 8 79 120 0.50 9 141 60 0.50 10 142 39 1.30 11 149 80 0.50 End of study 1 176 46 0.3 2 87 93 0.6 3 88 71 0.2 4 71 123 0.1 5 73 98 0.2 6 97 91 0.6 7 106 110 0.4 8 70 119 0.03 9 150 41 0.2 10 133 67 1.4 11 124 91 0.1 for prevention of relapses in WG patients. In contrast, when mixed populations of WG and MPA patients (26 28) and patients with panarteritis nodosa or Churg-Strauss syndrome (28,32) were studied, both treatment modalities were equivalent also for prevention of relapses. It remains therefore controversial whether giving less CYC by intravenous pulse protocols can be recommended for all patients with AASV. Administration of methotrexate (MTX) instead of CYC from the beginning of treatment led to promising results in patients with limited WG (33,34). However, in patients with renal failure, such as in this pilot study, MTX cannot be given. AZA, when given for active AASV, was not effective (6,8). In limited WG, the antibiotic trimethoprim-sulfamethoxazol may induce remission and it may also be used as an additional drug for prevention of relapses during maintenance treatment (35 37). The most widely used strategy to reduce the toxic burden of CYC is to limit the administration to the period of active disease (induction therapy) and then switch to a less toxic drug for maintenance therapy. Discontinuation of CYC at the time of remission without introduction of another immunosuppressant proved not to be safe, since it resulted in many early relapses (5). Instead of CYC, MTX was given for maintenance treatment of limited WG with good success (38), and AZA is currently investigated in a randomized controlled trial comparing it with CYC (12). The new immunosuppressant MMF is currently studied in patients with different autoimmune diseases. In this pilot study, a low relapse rate of less than 10% within 15 mo of treatment with MMF and low-dose OCS was achieved in patients with WG and MPA. This relapse rate, which is lower than in previous treatment studies of AASV, is encouraging, but should be interpreted with caution for several reasons. A relapse rate between 25 and 45% was published for the longer observation time of 3 to 5 yr after diagnosis of AASV (6,8) and can therefore not directly be compared with the results of this pilot study with a much shorter observation time. The median time to relapse was found to be as long as 27 mo (range, 2 to 168 mo) in a Swedish series of WG and MPA patients (8). Whether relapses occurring later than 15 mo after remission will be prevented by treatment with MMF and OCS is unknown. Other factors that hamper the direct comparibility of outcomes between this study and published retrospective and prospective studies are differences in mixture of patient s diagnosis, severity of disease, and length and protocol of induction therapy. Finally, no common definition of relapse was applied. Maintenance immunosuppression means prolonged exposure to the side effects of the drug used, and a favorable side effect profile is therefore even more warranted than for drugs used for induction treatment. The low incidence of short-term adverse effects of MMF in this study is therefore as important as the demonstration of efficacy. A cytomegalovirus-colitis in one patient was the most serious complication. Since OCS could be reduced to less than 7.5 mg/d and even discontinued in some patients, this regimen may also help to avoid OCS-related side effects in AASV patients. CYC-induced myelosuppression is not a rare problem in old patients with AASV. In this respect, the observation is certainly of interest that MMF could replace CYC already during induction treatment in one old patient with severe CYC-induced leukopenia. Although MMF itself may cause leukopenia, this patient could safely be treated with MMF without the need to increase the OCS dosage. Besides short-term tolerability of MMF, the long-term safety of the drug will be crucial for the future of MMF-containing regimens in AASV. Thus far, long-term safety data from other studies look promising. The overall frequency of malignancies in the transplant studies in which MMF was combined with other immunosuppressive drugs was as low as 1%. In patients treated for rheumatoid arthritis, no malignancies occurred (39).
J Am Soc Nephrol 10: 1965 1971, 1999 MMF in Systemic Vasculitis 1969 Table 3. Duration of induction therapy, cumulative CYC dosage, and modifications of treatment a Patient Diagnosis Induction Therapy (weeks) Cumulative CYC Dosage (g) Modification of Treatment 1 MPA 9 4.3 2 WG 14 9.8 5 plasma exchange 3 MPA 17 6.8 5 plasma exchange 4 WG 18 11.2 5 WG 12 12.6 6 WG 13 15.9 4 1 g CYC intravenously 7 WG 16 18 2 0.75 g CYC intravenously 2 250 mg MeP intravenously 8 WG 19 16.6 1 1.5 g CYC intravenously 9 WG 12 8.3 10 WG 12 12.6 11 WG 12 15.4 a CYC, cyclophosphamide; MeP, methylprednisolone. Other abbreviations as in Table 1. Figure 1. Daily dosages of oral corticosteroids (OCS) during maintenance therapy. In three patients, OCS were discontinued before the study end. Important data on long-term safety came from the experience in psoriasis patients with mycophenolic acid, the active compound of MMF, in the 1970s. The safety data of 85 patients who were treated with mycophenolic acid for up to 13 yr in comparatively high dosage (maximum dose of 7.4 g/d) showed no increased malignancy rate (40,41). In conclusion, this pilot study shows that MMF is not only well tolerated but also effective in WG and MPA patients to maintain remission. Replacement of CYC in maintenance therapy of these diseases would be of great benefit, and therefore randomized trials comparing the efficacy of MMF with that of CYC should be started. References 1. Jennette JC, Falk RJ, Andrassy K, Bacon PA, Churg J, Gross WL, Hagen EC, Hoffman GS, Hunder GG, Kallenberg CG: Nomenclature of systemic vasculitides: Proposal of an international consensus conference. Arthritis Rheum 39: 189 195, 1994 2. Walton EW: Giant cell granuloma of the respiratory tract (Wegener s granulomatosis). Br Med J 2: 265 270, 1958 3. Hollander D, Manning RT: The use of alkylating agents in the treatment of Wegener s granulomatosis. Ann Intern Med 67: 393 398, 1967 4. Novack SN, Pearson CM: Cyclophosphamide therapy in Wegener s granulomatosis. N Engl J Med 284: 938 942, 1971 5. Fauci AS, Katz P, Haynes BF, Wolff SM: Cyclophosphamide therapy of severe systemic necrotizing vasculitis. N Engl J Med 301: 235 238, 1979 6. Fauci AS, Haynes BF, Katz P, Wolff SM: Wegener s granulomatosis: Prospective clinical and therapeutic experience with 85 patients for 21 years. Ann Intern Med 98: 76 85, 1983 7. Hoffman GS, Kerr GS, Leavitt RY, Hallahan CW, Lebovics RS, Travis WD, Rottem M, Fauci AS: Wegener granulomatosis: An analysis of 158 patients. Ann Intern Med 116: 488 498, 1992 8. Westman KWA, Bygren PG, Olsson H, Ranstam J, Wieslander J: Relapse rate, renal survival, and cancer morbidity in patients
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J Am Soc Nephrol 10: 1965 1971, 1999 MMF in Systemic Vasculitis 1971 five patients with generalized Wegener s granulomatosis: Methotrexate versus trimethoprim/sulfamethoxazole. Arthritis Rheum 39: 2052 2061, 1996 39. Mycophenolate Mofetil (RS-61443-000), Investigational brochure, Palo Alto, CA, Roche Bioscience, 7th Ed., 1996 40. Jones EL, Frost P, Epinette WW, Gomez E: Mycophenolic acid: An evaluation of long-term safety. In: Psoriasis: Proceedings of the Second International Symposium 1976, edited by Farber EM, New York, NY, 1977 41. Epinette WW, Parker CM, Jones EL, Greist MC: Mycophenolic acid for psoriasis: A review of pharmacology, long-term efficacy, and safety. J Am Acad Dermatol 17: 962 971, 1987 This article can be accessed in its entirety on the Internet at http://www.lww.com/jasn along with related UpToDate topics.