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Remission of Severe Relapsing or Persistent Lupus Nephritis Using Mycophenolate Mofetil
Archives of Medical Research 37 (2006) 68–73
ORIGINAL ARTICLE
Remission of Severe Relapsing or Persistent Lupus Nephritis Using Mycophenolate Mofetil Luis Felipe Flores-Sua´rez Department of Immunology and Rheumatology, Instituto Nacional de Ciencias Me´dicas y Nutricio´n, Mexico City, Mexico Received for publication October 5, 2004; accepted April 8, 2005 (ARCMED-D-04-00105).
Background. The therapy of severe lupus nephritis (LN) consists of high-dose steroids and immunosuppressive agents, usually cyclophosphamide. Although effective in up to 90% of cases, this approach leads to undesirable complications in many cases. In recent years, mycophenolate mofetil (MMF), an immunosuppressive drug used in transplantation regimes, seems to be effective in selected cases of lupus nephritis. Methods. In this report we present the results using MMF in seven cases of LN. MMF stabilized renal function, controlled extrarenal disease activity and led to less steroid dosing. Results. Three patients achieved complete remission, two partial remissions and two failed, although these two patients were the ones with the highest chronicity indices in the renal biopsies. However, they were able to maintain stable renal function for more than one year with tolerable side effects. In two more patients the latter were mild and did not require either hospitalization or intense therapy. Conclusions. MMF can be an option for selected cases with severe relapsing or persistent LN and can lead to induction of remission. This observation needs to be expanded. Larger randomized controlled studies are needed to evaluate its indication in earlier cases as induction of de novo disease and/or effective remission maintenance. 쑖 2006 IMSS. Published by Elsevier Inc. Key Words: Lupus nephritis, Renal function, Cyclophosphamide, Mycophenolate mofetil.
Introduction The therapy of severe lupus nephritis (LN), mainly that of proliferative glomerulonephritis or membranous glomerulonephritis with proliferative changes (classes IV or Vb of the WHO), usually consists of high-dose prednisone and cyclophosphamide as immunosuppressive drugs. The therapeutic protocol developed more than 20 years ago at the National Institutes of Health (NIH, Bethesda, MD) is the most usual one employed in this type of nephritis (1). However, some patients have persistent activity or after a period of remission they have relapsing disease, which leads them to receive additional courses of the same drugs. Although the efficacy of this scheme as compared to high-dose steroids is proven, the toxicity due to this therapy is high
Address reprint requests to: Luis Felipe Flores-Sua´rez, Department of Immunology and Rheumatology, Instituto Nacional de Ciencias Me´dicas y Nutricio´n, Vasco de Quiroga 15 Col. Seccio´n XVI, Tlalpan C.P. 14000, Mexico, D.F., Me´xico; E-mail: [email protected]
0188-4409/06 $–see front matter. Copyright d o i : 10 .1 0 1 6/ j.ar c med .2 0 05 .0 4 .0 1 1
and morbidity and mortality account for permanent damage or even death (2). Mycophenolate mofetil, an inhibitor of the de novo pathway of purine synthesis in lymphocytes (3), is a useful immunosuppressive that has broadened its indications from preventing transplant rejection (4) to its use in several autoimmune diseases including lupus nephritis (5). The actions of this drug are multiple and include selective depletion of both T and B lymphocytes, reduced expression of adhesion molecules, diminished expression of inducible nitric oxide synthase and reduced proliferation of mesangial cells (6,7). In the first randomized study comparing it to cyclophosphamide as inductor of remission, the efficacy of MMF was comparable to the one using oral CYC, as well as the relapse rate, but with less toxicity when using MMF (8). An interim follow-up report, however, showed that MMF patients tended to relapse later at a higher rate than those treated with the usual scheme (9). In this report, we present the first cases treated in our center with MMF as reinduction therapy in persistent or relapsing
쑖 2006 IMSS. Published by Elsevier Inc.
MMF in Mexican Mestizo Patients with Severe Lupus Nephritis
cases of LN. We also report on their follow-up after they stopped MMF due to inability to continue due to cost. As far as we know, this is the first formal report using MMF for LN in Latin America. Our population is comparable in terms of disease behavior to Afro-Americans, a subset of patients who are prone to a less favorable course. Therefore, we believe that this communication is especially interesting for Latin American centers that treat lupus patients.
69
avoiding potential gonadal toxicity due to CYC. He had experienced lung hemorrhage for 6 months previously attributed to severe SLE activity and was being treated favorably for a suspected type III LN. All patients were followed regarding clinical disease activity (either renal or extrarenal) using the SLEDAI-2K score, a recent refinement of the original SLEDAI (11), laboratory parameters of renal function (serum creatinine, creatinine clearance calculated using 24-h urine collection to determine glomerular filtration rate in mL/min and corrected to body surface, 24-h protein urinary excretion, urinary protein/urinary creatinine ratio), lupus activity markers (serum C3 and C4, lymphopenia) and presence of adverse effects including MMF peripheral blood toxicity (hemoglobin, cytopenias) and infections, as well as prednisone dose decrease. Once patients accepted to receive MMF they stopped other immunosuppressives for 5 days, basal clinical and laboratory evaluations were performed, and they started on MMF as follows: for patients with CrCl ⬎60 mL/min/1.73 m2 body surface, 500 mg PO qd for 3 days with 500 mg increments every 3 days up to a total dose of 1 g bid. For those patients with CrCl between 30 and 60 mL/min/1.73 m2 body surface the maximum dose given was 1.5 g daily and for those with CrCl ⬍30 mL/min/1.73 m2 body surface 1 g in two divided doses. Prednisone was prescribed according to disease severity at the beginning of MMF with a mean dose of 31 ⫾ 21.5 mg qd. During the first 2 months patients were followed with complete blood count (CBC) every 2 weeks, then at monthly intervals. A complete clinical and laboratory evaluation was performed at least every 3 months, except for Farr or ELISA assays, which was hampered by the impossibility of some patients to pay the costs and were therefore not included in the remission definitions (see below). After stopping MMF the choice of further immunosuppressive was selected according to the disease status. Data from their latest visit (either on or off MMF) are presented. The clinical and laboratory parameters at the beginning and end of the MMF therapy were compared
Materials and Methods From May 2000 to February 2002, seven Mexican mestizo LN patients presenting with relapsing or persistent LN (except for one patient, see below) in spite of adequate therapy or due to serious side effects with azathioprin or CYC (either oral or IV) were offered MMF as induction or reinduction therapy. All fulfilled the American College of Rheumatology (ACR) criteria for systemic lupus erythematosus (SLE) (10). The characteristics of the patients are summarized in Table 1. The majority of patients had biopsy-proven lupus glomerulonephritis: one class IIIC, three class IV and one class V of the WHO. As seen, three had diffuse proliferative LN which is the most serious lupus nephritis lesion with a poorer long-term prognosis. Two patients had no biopsy done, one due to thrombocytopenia and one due to refusal. On clinical grounds they were suspected to have membranous LN (type V) and focal segmental LN (type III). Patients who were offered MMF had either developed a flare of LN activity under other immunosuppressives (relapse), were still active under adequate therapy (persistence), and/or had serious side effects, except for patient 6 (see below). Three of the patients (1, 2 and 4) had prior bone marrow toxicity due to the other immunosuppressive schemes, one had severe viral and bacterial infections under her previous therapy (patient 4) and another was switched to MMF due to failure of oral CYC in achieving remission and also hemorrhagic cystitis (patient 5). The sixth patient decided to switch to MMF due to procreation desire,
Table 1. Patient characteristics at the time of MMF initiation Patient number
Age at MMF start
Gender
WHO classificationa
Activity/chronicity indices in biopsy
Disease status at MMF startb
1 2 3 4
23 22 32 40
F F F F
IV (V) V IV
12/2 NA NA 5/3
Relapse (7 mo) Persistent (5 mo) Relapse (10 mo) Persistent (66 mo)
5 6 7
51 27 43
F M F
IV (III) IIIC
4/1 NA NA
Persistent (31 mo) De novo Persistent (48 mo)
a
Previous treatment and side effects AZA/CYC (bone marrow toxicity) AZA (bone marrow toxicity) CYC AZA/CYC (bone marrow toxicity and serious infections) AZA/CYC (hemorrhagic cystitits) AZA/CYC AZA (did not accept IV-CYC at start)
Numbers in parentheses indicate that patients were categorized to have this type of lupus nephritis on clinical grounds; no biopsy was available (see text). Numbers in parentheses indicate time of evolution of relapsing or persistent disease when MMF was started. MMF, mycophenolate mofetil; WHO, World Health Organization; AZA, azathioprin; CYC, cyclophosphamide; NA, not applicable.
b
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Flores-Sua´rez / Archives of Medical Research 37 (2006) 68–73
according to the following definitions: complete remission (CR): serum creatinine not ⬎15% as compared to that at start of therapy with MMF (basal value), creatinine clearance not ⬍15% of basal, proteinuria ⬍300 mg/day, prednisone dose ⬍10 mg qd, no extrarenal symptoms of lupus and inactive urine sediment (less than six red blood cells/HPF, no granular casts). Partial remission (PR): serum creatinine and creatinine clearance stabilization, proteinuria between 300 and 2900 mg/day and no extrarenal symptoms of lupus. These definitions are more stringent than those proposed by Boumpas et al. (12). Failure was defined as neither achievement of complete or partial remission, development of serious side effects that precluded treatment or renal function deterioration. All adverse effects to therapy or presence of infections were recorded. Comparisons were made between the time of initiation of MMF and the last follow-up under treatment with this drug. Descriptive statistics of continuous variables was used to state mean, standard deviation, median and range and analyzed with two-tailed Wilcoxon rank sum test for nonparametric variables. McNemar chi-square test was used for comparisons between categorical variables. A p value ⬍0.05 was considered significant. Results Patient’s demographic characteristics at the beginning of treatment are shown in Table 1. There were six females and one male, with a mean age at the inclusion of this study of 34 ⫾ 11 years. Two patients did not have biopsy performed due to the above-mentioned reasons. Two patients had relapsing disease after being inactive, four had persistent disease in spite of adequate treatment and patient 6 had de novo renal disease. The mean time of disease evolution at the start of MMF was 82.7 ⫾ 63.7 months with an interval of 8–183 months. Mean follow-up of the group until last censored patient under treatment with MMF was 26 ⫾ 13 months (range: 12–45 months). The main results are shown in Table 2. Others, like serological tests, were not available for all but they are mentioned in the text. SLEDAI-2K was significantly decreased (p ⫽ 0.018). This reflects that extrarenal involvement was controlled with MMF. Those patients with final high scores in the SLEDAI-2K were those who either failed treatment or did not achieve complete remission, with the scoring being related to renal indices (active urine sediment or proteinuria above 0.5 g/day). In general, a decrease in serum creatinine and improvement of CrCl were seen although this was not significant. As for daily protein loss and the urinary protein/ urinary creatinine ratio, both decreased substantially with MMF, reaching p values of 0.018. None of the serological parameters were different at the end of the MMF treatment period except for a rising C4 level and a reduction of Farr assay levels in all three who had it measured. In antiDNA antibodies measurement by ELISA, a reduction was
seen in one of six, whereas in two it remained negative, in one it was decreased but did not become negative, and in the other two, levels increased although clinical CR was achieved (patients 2 and 6) (data not shown). There were no significant effects on blood cell counts. Mean prednisone dose at 12 months of therapy with MMF was significantly lowered (p ⫽ 0.027), but as patient number 4 who had prednisone increased to 50 mg qd in comparison to the dose at the time MMF was begun (40 mg qd) due to failure, this difference was lost at the end of total follow-up, although a trend towards decrease in the mean dose was observed (p ⫽ 0.07). The final renal outcome was the following: there were three CR (patients 1, 2 and 6), two PR (patients 3 and 5) and two failures (patients 4 and 7), although they reached criteria for PR at some point in their evolution. Case 1 is remarkable as she was in predialytic condition with severe hematological activity when MMF was started and she has remained in CR with a CrCl of 47 mL/min/1.73 m2 body surface and no proteinuria, being the patient with the longest duration of MMF therapy. As can be seen, those patients who were able to maintain MMF for more than 18 months are the patients who had a better outcome except for patient number 4, who only went into a brief period of partial remission but at the end was considered as a failure. Both patients who received MMF for ⬍18 months had an unfavorable outcome. Patient number 5 achieved partial remission at the end of MMF, but 5 months after its suspension she needed two immunosuppressive agents for severe nephrotic syndrome, in spite of which she deteriorated and rapidly developed progressive glomerulonephritis unresponsive to therapy with high-dose corticosteroids and IV-CYC. She died 25 months after stopping MMF from rapidly progressive glomerulonephritis and acute pulmonary edema. Patient number 7, who at the start of MMF had lost, in 1 month, 40% of renal function and had active urine sediment in the frame of a class IIIC lesion, achieved partial remission for a short period under MMF, but had to discontinue treatment due to its high cost. She was switched to IV-CYC but relapsed and went into non-dialysis-dependent chronic renal failure and severe hypertension in spite of treatment with five drugs. Only patient number 6 is still on MMF and remains in CR with MMF 500 mg daily as maintenance drug. Adverse effects during therapy are shown in Table 3. They included two herpes zoster infections, neither requiring hospitalization. The first patient continued taking MMF and herpes lesions were already established when she reported them. She did not require systemic therapy and no dose reduction was needed. In the second patient, MMF was temporally suspended for 1 week. Two patients developed diarrhea. In the first patient it happened twice. At the first episode, MMF was reduced from 500 mg tid to 500 mg bid, thereafter was increased again, but at the second episode it was temporarily withheld for 3 days and restarted at a lower dose with no further symptoms. She continued taking
Table 2. Follow-up time under MMF therapy, baseline and end parameter comparisons and final renal outcome of each patient
Starting/Final serum creatinine (mg/dL)
1
16/0
4.4/1.85
2 3 4
14/2 6/4 8/4
0.4/0.6 1/0.8 1.9/5
5
6/4
6 7
12/0 12/4
Patient number
Starting/ Final CrCl (mL/min/1.73 sqm body surface)
Starting/ Final daily proteinuria (g/day)b
Starting/Final PrU/CrU ratiob
Follow-up time under MMF
Disease evolution after MMF completion
2.43/0
5.39/0
45
CR (16;12)c
Improved
107.6/153 101.7/92 34.5/12.7
1.3/0.21 7.25/0.8 10.8/4
2.4/0.17 4.5/0.79 11.9/4.45
19 39 21
CR (11;7)c PR (11) F
Stable Stable Went onto ESRD
0.8/0.8
95.6/87.6
2.82/1.48
3.03/1.73
12
PR (7)
Developed nephrotic syndrome 5 months after stopping MMF
0.95/0.95 1.3/1.1
130.6/104 41/83.5
0.84/0.3 12.4/7.36
0.47/0.21 10.3/6.16
33 13
CR (4;2)c F
Stable Stable
8/47
Therapy received at end of MMF AZA 50/75 mg on alternate days MTX ⫹ OH-CLQ AZA Initially high OCS; stopped after ESRD developed until no treatment left Initially AZA; then AZA ⫹ PO-CYC; finally IV-CYC and high OCS Still on maintenance MMF IV-CYC plus OCS
Renal outcome at last visit Stable renal function Normal renal function Normal renal function On CAPD; awaits renal transplant
Died due to RPGN in ESRD and acute pulmonary edema Normal renal function Developed chronic renal failure
p ⫽ 0.018; bp ⫽ 0.018 for both parameters; remainder shown in table not significant; cfirst number in parentheses indicates time in months when patients achieved CR; second number time when PR was achieved. CR, complete remission; PR, partial remission; F, failure; ESRD, end stage renal disease; MTX, methotrexate; OH-CLQ, hydroxychloroquine; AZA, azathioprin; MMF, mycophenolate mofetil; IV-CYC, intravenous cyclophosphamide pulses; PO-CYC, daily oral cyclophosphamide; OCS, oral corticosteroids; CAPD, continuous ambulatory peritoneal dialysis.
a
MMF in Mexican Mestizo Patients with Severe Lupus Nephritis
Starting/Final SLEDAI-2K scoresa
Outcome at end of MMF (time of either CR or PR achievement in months)
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Flores-Sua´rez / Archives of Medical Research 37 (2006) 68–73
72
Table 3. Adverse effects while on MMF therapy
Patient number
Gastrointestinal
1
Diarrhea (twice)
4 7
None Diarrhea and moderate abdominal pain
Months of therapy with MMF 1 and 10
1
Due modification
Infections
Dose reduction on first episode, Herpes zoster temporal suspension on second Herpes zoster Transient dose reduction None
500 mg bid until she completed 1 year of therapy. Thereafter, the dose could be gradually decreased until she took 500 mg qd during the last 10 months of the 45 she received MMF. In the second patient, diarrhea was accompanied by mild abdominal pain that resolved with dosage lowering. Later it was given at the initial dose without complaints. Discussion In recent years, the awareness that CYC therapy for LN can be very toxic (2) has led to the search for different treatment options, both for induction of remission and its maintenance. MMF is a prodrug that after conversion to the active compound, mycophenolic acid, exerts different actions leading to improvement of renal function both in animal models and patients. In a study of MMF as induction drug, patients who received it for 6 months at a maximal dose of 2 g qd had a similar outcome in terms of complete and partial remission achieved and renal function parameters to those treated with PO-CYC for 6 months who were then switched to AZA. The MMF arm had a dose decrease after 6 months to an average of 1 g qd and then also switched to AZA (8). On an interim analysis at 2-year follow-up, patients who had received MMF tended to relapse more than those who were treated with CYC and then AZA (9). Recently, however, it has been shown that certain patients treated according to the NIH protocol (1) can develop renal flares and some even progress to ESRD. In this study, the majority of patients received azathioprin as remission therapy but renal flares could not be prevented in all (13). Moreover, about 10% of patients treated under the NIH protocol are not able to achieve remission, and this was the case in two of our previously CYC-treated patients. In two others there were relapses of the disease after successful initial response to CYC, which could not reinduce the patients into remission on a second occasion. In this pilot observation, improvement in renal function was seen in two patients, stabilization was achieved and maintained in four and only one patient had persistent decline in CrCl. The most dramatic effect was seen in terms of proteinuria and all patients showed decrease in the PrU/CrU ratio. Other parameters were not significantly affected after MMF treatment. In terms of control of extrarenal symptoms, MMF proved to be useful and this reflects in the SLEDAI2K score and also the steady reduction of prednisone in all
Months of therapy with MMF
Due modification
5.5
None necessary
2
Temporal suspension
patients, leading to its suspension in five of the seven patients. In the two patients who finally failed, renal function stabilization and a brief partial remission period was observed at some point during their treatment. These patients had the highest chronicity indices and scarring histopathologic features in their kidney biopsies. The adverse effects that occurred were indeed few and mild and not severe enough to modify treatment. In the only study comparing CYC and MMF for induction of remission, Chan et al. switched patients under MMF after 1 year to azathioprin. Patients who received MMF had equal outcomes in terms of renal function to those who received CYC, with less side effects (8), although in the 2-year interim analysis, MMF patients seemed to have relapsed more (9). Compared to azathioprin, MMF seems to be more effective in maintaining remission after IV-CYC as shown recently by the group at the University of Miami (14). It is worth mentioning that, in this study, “Hispanics” were included. However, most were from Cuban origin. There are profound differences with the Mexican mestizos. In the former there is considerable African background with little input from the native Indian population, whereas in the latter, the background from the native indigenous population was considerable after the Spanish conquest in the 16th century, making the Mexican mestizo population unique with respect to the genetic and ethnic characteristics, which are very different from other so-called Hispanic groups. The evidence presented up to now suggests that MMF could be preferable in some cases to CYC as induction therapy, and this concept has support by some (15). However, the only way to answer this question would be through a large multinational ransomized trial with patients from different ethnic backgrounds. There is only one multicentric study published in abstract form that favors MMF as induction treatment option (16). In conclusion, although MMF has been available for several years for treatment of LN, there has not been a formal follow-up study done in Latin American patients to evaluate its efficacy. We have seen a favorable response to MMF treatment in inducing remission in persistent or severe relapsing disease with good tolerance. Patients maintained their renal function, there was a decrease in proteinuria and extrarenal manifestations of the disease were controlled. These results have encouraged us to perform an open-label study comparing IV-CYC and MMF in cases as the ones presented here, which is in progress and close to completion.
MMF in Mexican Mestizo Patients with Severe Lupus Nephritis
Acknowledgments The author wants to thank Isabel Balderas, M.D. for her collaboration in the initial phase of the study. The author is also deeply indebted to Antonio Villa, M.D. for help with the statistical analysis, Roche Mexico, especially through Ms. Jaqueline Haces and Noe´ Soria, M.D. The Women’s Volunteer Committee from the Instituto Nacional de Ciencias Me´dicas y Nutricio´n provided the MMF to the patients.
References 1. Austin HA III, 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 1986;614–619. 2. Kang I, Park SH. Infectious complications in SLE after immunosuppressive therapies. Curr Opin Rheumatol 2003;15:528–534. 3. Fulton B, Markham A. Mycophenolate mofetil. A review of its pharmacodynamic and pharmacokinetic properties and clinical efficacy in renal transplantation. Drugs 1996;51:278–298. 4. The Tricontinental Mycphenolate Mofetil Renal Transplantation Study Group. A blinded, randomized clinical trial of mycophenolate mofetil for the prevention of acute rejection in cadaveric renal transplantation. Transplantation 1996;61:1029–1037. 5. Mok CC, Lai KN. Mycophenolate mofetil in lupus glomerulonephritis. Am J Kidney Dis 2002;40:447–457. 6. Allison AC, Eugui EM. Mycophenolate mofetil and its mechanisms of action. Immunopharmacology 2000;47:85–118. 7. Lui SL, Tsang R, Wong D, Chan KW, Chan TM, Fung PC, Lai KN. Effect of mycophenolate mofetil on severity of nephritis and nitric oxide production in lupus-prone MRL/lpr mice. Lupus 2002;11:411–418.
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8. Chan TM, Li FK, Tang CSO, Wong RWS, Fang GX, Ji YL, Lu CS, Wong AKM, Tong MKL, Chan KW, Lai KN for the Hong KongGuangzhou Nephrology Study Group. Efficacy of mycophenolate mofetil in patients with diffuse proliferative lupus nephritis. N Engl J Med 2000;343:1156–1162. 9. Chan TM, Wong WS, Lau CS, Tsang EWK, Ji YL, Mok MY, Tong MKL, Wong AKM, Lai KN. Prolonged follow-up of patients with diffuse proliferative lupus nephritis (DPLN) treated with prednisolone and mycophenolate mofetil (MMF) (abstract). J Am Soc Nephrol 2001; 12:195A. 10. Tan EM, Cohen AS, Fries JF, Masi AT, McShane DJ, Rothfield NF, Schaller JG, Talal N, Winchester RJ. The 1982 revised criteria for the classification of systemic lupus erythematosus. Arthritis Rheum 1982;25:1271–1277. 11. Gladman DD, Iban˜ez D, Urowitz MB. Systemic lupus erythematosus disease activity index 2000. J Rheumatol 2002;29:288–291. 12. Boumpas DT, Balow JE. Outcome criteria for lupus nephritis trials: a critical overview. Lupus 1998;7:622–629. 13. Mok CC, Ying KY, Tang S, Leung CY, Lee KW, Ng WL, Wong RWS, Lau CS. Predictors and outcome of renal flares after successful cyclophosphamide treatment for diffuse proliferative lupus glomerulonephritis. Arthritis Rheum 2004;50:2259–2268. 14. Contreras G, Pardo V, Leclerq B, Lenz O, Tozman E, O’Nan P, Roth D. Sequential therapies for proliferative lupus nephritis. N Engl J Med 2004;350:971–980. 15. Karim Y, D’Cruz DP. The NIH pulse cyclophosphamide regime: the end of an era? Lupus 2004;13:1–3. 16. Ginzler EM, Aranow C, Buyon J, Dooley MA, Merrill JT, Petri M, Appel G, Gilkeson G, Wallace D, Weisman M. A multicenter study of mycophenolate mofetil (MMF) vs. intravenous cyclophosphamide (IVC) as induction therapy for severe lupus nephritis (LN): preliminary results. Arthritis Rheum 2003;48:S647.
ORIGINAL ARTICLE
Remission of Severe Relapsing or Persistent Lupus Nephritis Using Mycophenolate Mofetil Luis Felipe Flores-Sua´rez Department of Immunology and Rheumatology, Instituto Nacional de Ciencias Me´dicas y Nutricio´n, Mexico City, Mexico Received for publication October 5, 2004; accepted April 8, 2005 (ARCMED-D-04-00105).
Background. The therapy of severe lupus nephritis (LN) consists of high-dose steroids and immunosuppressive agents, usually cyclophosphamide. Although effective in up to 90% of cases, this approach leads to undesirable complications in many cases. In recent years, mycophenolate mofetil (MMF), an immunosuppressive drug used in transplantation regimes, seems to be effective in selected cases of lupus nephritis. Methods. In this report we present the results using MMF in seven cases of LN. MMF stabilized renal function, controlled extrarenal disease activity and led to less steroid dosing. Results. Three patients achieved complete remission, two partial remissions and two failed, although these two patients were the ones with the highest chronicity indices in the renal biopsies. However, they were able to maintain stable renal function for more than one year with tolerable side effects. In two more patients the latter were mild and did not require either hospitalization or intense therapy. Conclusions. MMF can be an option for selected cases with severe relapsing or persistent LN and can lead to induction of remission. This observation needs to be expanded. Larger randomized controlled studies are needed to evaluate its indication in earlier cases as induction of de novo disease and/or effective remission maintenance. 쑖 2006 IMSS. Published by Elsevier Inc. Key Words: Lupus nephritis, Renal function, Cyclophosphamide, Mycophenolate mofetil.
Introduction The therapy of severe lupus nephritis (LN), mainly that of proliferative glomerulonephritis or membranous glomerulonephritis with proliferative changes (classes IV or Vb of the WHO), usually consists of high-dose prednisone and cyclophosphamide as immunosuppressive drugs. The therapeutic protocol developed more than 20 years ago at the National Institutes of Health (NIH, Bethesda, MD) is the most usual one employed in this type of nephritis (1). However, some patients have persistent activity or after a period of remission they have relapsing disease, which leads them to receive additional courses of the same drugs. Although the efficacy of this scheme as compared to high-dose steroids is proven, the toxicity due to this therapy is high
Address reprint requests to: Luis Felipe Flores-Sua´rez, Department of Immunology and Rheumatology, Instituto Nacional de Ciencias Me´dicas y Nutricio´n, Vasco de Quiroga 15 Col. Seccio´n XVI, Tlalpan C.P. 14000, Mexico, D.F., Me´xico; E-mail: [email protected]
0188-4409/06 $–see front matter. Copyright d o i : 10 .1 0 1 6/ j.ar c med .2 0 05 .0 4 .0 1 1
and morbidity and mortality account for permanent damage or even death (2). Mycophenolate mofetil, an inhibitor of the de novo pathway of purine synthesis in lymphocytes (3), is a useful immunosuppressive that has broadened its indications from preventing transplant rejection (4) to its use in several autoimmune diseases including lupus nephritis (5). The actions of this drug are multiple and include selective depletion of both T and B lymphocytes, reduced expression of adhesion molecules, diminished expression of inducible nitric oxide synthase and reduced proliferation of mesangial cells (6,7). In the first randomized study comparing it to cyclophosphamide as inductor of remission, the efficacy of MMF was comparable to the one using oral CYC, as well as the relapse rate, but with less toxicity when using MMF (8). An interim follow-up report, however, showed that MMF patients tended to relapse later at a higher rate than those treated with the usual scheme (9). In this report, we present the first cases treated in our center with MMF as reinduction therapy in persistent or relapsing
쑖 2006 IMSS. Published by Elsevier Inc.
MMF in Mexican Mestizo Patients with Severe Lupus Nephritis
cases of LN. We also report on their follow-up after they stopped MMF due to inability to continue due to cost. As far as we know, this is the first formal report using MMF for LN in Latin America. Our population is comparable in terms of disease behavior to Afro-Americans, a subset of patients who are prone to a less favorable course. Therefore, we believe that this communication is especially interesting for Latin American centers that treat lupus patients.
69
avoiding potential gonadal toxicity due to CYC. He had experienced lung hemorrhage for 6 months previously attributed to severe SLE activity and was being treated favorably for a suspected type III LN. All patients were followed regarding clinical disease activity (either renal or extrarenal) using the SLEDAI-2K score, a recent refinement of the original SLEDAI (11), laboratory parameters of renal function (serum creatinine, creatinine clearance calculated using 24-h urine collection to determine glomerular filtration rate in mL/min and corrected to body surface, 24-h protein urinary excretion, urinary protein/urinary creatinine ratio), lupus activity markers (serum C3 and C4, lymphopenia) and presence of adverse effects including MMF peripheral blood toxicity (hemoglobin, cytopenias) and infections, as well as prednisone dose decrease. Once patients accepted to receive MMF they stopped other immunosuppressives for 5 days, basal clinical and laboratory evaluations were performed, and they started on MMF as follows: for patients with CrCl ⬎60 mL/min/1.73 m2 body surface, 500 mg PO qd for 3 days with 500 mg increments every 3 days up to a total dose of 1 g bid. For those patients with CrCl between 30 and 60 mL/min/1.73 m2 body surface the maximum dose given was 1.5 g daily and for those with CrCl ⬍30 mL/min/1.73 m2 body surface 1 g in two divided doses. Prednisone was prescribed according to disease severity at the beginning of MMF with a mean dose of 31 ⫾ 21.5 mg qd. During the first 2 months patients were followed with complete blood count (CBC) every 2 weeks, then at monthly intervals. A complete clinical and laboratory evaluation was performed at least every 3 months, except for Farr or ELISA assays, which was hampered by the impossibility of some patients to pay the costs and were therefore not included in the remission definitions (see below). After stopping MMF the choice of further immunosuppressive was selected according to the disease status. Data from their latest visit (either on or off MMF) are presented. The clinical and laboratory parameters at the beginning and end of the MMF therapy were compared
Materials and Methods From May 2000 to February 2002, seven Mexican mestizo LN patients presenting with relapsing or persistent LN (except for one patient, see below) in spite of adequate therapy or due to serious side effects with azathioprin or CYC (either oral or IV) were offered MMF as induction or reinduction therapy. All fulfilled the American College of Rheumatology (ACR) criteria for systemic lupus erythematosus (SLE) (10). The characteristics of the patients are summarized in Table 1. The majority of patients had biopsy-proven lupus glomerulonephritis: one class IIIC, three class IV and one class V of the WHO. As seen, three had diffuse proliferative LN which is the most serious lupus nephritis lesion with a poorer long-term prognosis. Two patients had no biopsy done, one due to thrombocytopenia and one due to refusal. On clinical grounds they were suspected to have membranous LN (type V) and focal segmental LN (type III). Patients who were offered MMF had either developed a flare of LN activity under other immunosuppressives (relapse), were still active under adequate therapy (persistence), and/or had serious side effects, except for patient 6 (see below). Three of the patients (1, 2 and 4) had prior bone marrow toxicity due to the other immunosuppressive schemes, one had severe viral and bacterial infections under her previous therapy (patient 4) and another was switched to MMF due to failure of oral CYC in achieving remission and also hemorrhagic cystitis (patient 5). The sixth patient decided to switch to MMF due to procreation desire,
Table 1. Patient characteristics at the time of MMF initiation Patient number
Age at MMF start
Gender
WHO classificationa
Activity/chronicity indices in biopsy
Disease status at MMF startb
1 2 3 4
23 22 32 40
F F F F
IV (V) V IV
12/2 NA NA 5/3
Relapse (7 mo) Persistent (5 mo) Relapse (10 mo) Persistent (66 mo)
5 6 7
51 27 43
F M F
IV (III) IIIC
4/1 NA NA
Persistent (31 mo) De novo Persistent (48 mo)
a
Previous treatment and side effects AZA/CYC (bone marrow toxicity) AZA (bone marrow toxicity) CYC AZA/CYC (bone marrow toxicity and serious infections) AZA/CYC (hemorrhagic cystitits) AZA/CYC AZA (did not accept IV-CYC at start)
Numbers in parentheses indicate that patients were categorized to have this type of lupus nephritis on clinical grounds; no biopsy was available (see text). Numbers in parentheses indicate time of evolution of relapsing or persistent disease when MMF was started. MMF, mycophenolate mofetil; WHO, World Health Organization; AZA, azathioprin; CYC, cyclophosphamide; NA, not applicable.
b
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according to the following definitions: complete remission (CR): serum creatinine not ⬎15% as compared to that at start of therapy with MMF (basal value), creatinine clearance not ⬍15% of basal, proteinuria ⬍300 mg/day, prednisone dose ⬍10 mg qd, no extrarenal symptoms of lupus and inactive urine sediment (less than six red blood cells/HPF, no granular casts). Partial remission (PR): serum creatinine and creatinine clearance stabilization, proteinuria between 300 and 2900 mg/day and no extrarenal symptoms of lupus. These definitions are more stringent than those proposed by Boumpas et al. (12). Failure was defined as neither achievement of complete or partial remission, development of serious side effects that precluded treatment or renal function deterioration. All adverse effects to therapy or presence of infections were recorded. Comparisons were made between the time of initiation of MMF and the last follow-up under treatment with this drug. Descriptive statistics of continuous variables was used to state mean, standard deviation, median and range and analyzed with two-tailed Wilcoxon rank sum test for nonparametric variables. McNemar chi-square test was used for comparisons between categorical variables. A p value ⬍0.05 was considered significant. Results Patient’s demographic characteristics at the beginning of treatment are shown in Table 1. There were six females and one male, with a mean age at the inclusion of this study of 34 ⫾ 11 years. Two patients did not have biopsy performed due to the above-mentioned reasons. Two patients had relapsing disease after being inactive, four had persistent disease in spite of adequate treatment and patient 6 had de novo renal disease. The mean time of disease evolution at the start of MMF was 82.7 ⫾ 63.7 months with an interval of 8–183 months. Mean follow-up of the group until last censored patient under treatment with MMF was 26 ⫾ 13 months (range: 12–45 months). The main results are shown in Table 2. Others, like serological tests, were not available for all but they are mentioned in the text. SLEDAI-2K was significantly decreased (p ⫽ 0.018). This reflects that extrarenal involvement was controlled with MMF. Those patients with final high scores in the SLEDAI-2K were those who either failed treatment or did not achieve complete remission, with the scoring being related to renal indices (active urine sediment or proteinuria above 0.5 g/day). In general, a decrease in serum creatinine and improvement of CrCl were seen although this was not significant. As for daily protein loss and the urinary protein/ urinary creatinine ratio, both decreased substantially with MMF, reaching p values of 0.018. None of the serological parameters were different at the end of the MMF treatment period except for a rising C4 level and a reduction of Farr assay levels in all three who had it measured. In antiDNA antibodies measurement by ELISA, a reduction was
seen in one of six, whereas in two it remained negative, in one it was decreased but did not become negative, and in the other two, levels increased although clinical CR was achieved (patients 2 and 6) (data not shown). There were no significant effects on blood cell counts. Mean prednisone dose at 12 months of therapy with MMF was significantly lowered (p ⫽ 0.027), but as patient number 4 who had prednisone increased to 50 mg qd in comparison to the dose at the time MMF was begun (40 mg qd) due to failure, this difference was lost at the end of total follow-up, although a trend towards decrease in the mean dose was observed (p ⫽ 0.07). The final renal outcome was the following: there were three CR (patients 1, 2 and 6), two PR (patients 3 and 5) and two failures (patients 4 and 7), although they reached criteria for PR at some point in their evolution. Case 1 is remarkable as she was in predialytic condition with severe hematological activity when MMF was started and she has remained in CR with a CrCl of 47 mL/min/1.73 m2 body surface and no proteinuria, being the patient with the longest duration of MMF therapy. As can be seen, those patients who were able to maintain MMF for more than 18 months are the patients who had a better outcome except for patient number 4, who only went into a brief period of partial remission but at the end was considered as a failure. Both patients who received MMF for ⬍18 months had an unfavorable outcome. Patient number 5 achieved partial remission at the end of MMF, but 5 months after its suspension she needed two immunosuppressive agents for severe nephrotic syndrome, in spite of which she deteriorated and rapidly developed progressive glomerulonephritis unresponsive to therapy with high-dose corticosteroids and IV-CYC. She died 25 months after stopping MMF from rapidly progressive glomerulonephritis and acute pulmonary edema. Patient number 7, who at the start of MMF had lost, in 1 month, 40% of renal function and had active urine sediment in the frame of a class IIIC lesion, achieved partial remission for a short period under MMF, but had to discontinue treatment due to its high cost. She was switched to IV-CYC but relapsed and went into non-dialysis-dependent chronic renal failure and severe hypertension in spite of treatment with five drugs. Only patient number 6 is still on MMF and remains in CR with MMF 500 mg daily as maintenance drug. Adverse effects during therapy are shown in Table 3. They included two herpes zoster infections, neither requiring hospitalization. The first patient continued taking MMF and herpes lesions were already established when she reported them. She did not require systemic therapy and no dose reduction was needed. In the second patient, MMF was temporally suspended for 1 week. Two patients developed diarrhea. In the first patient it happened twice. At the first episode, MMF was reduced from 500 mg tid to 500 mg bid, thereafter was increased again, but at the second episode it was temporarily withheld for 3 days and restarted at a lower dose with no further symptoms. She continued taking
Table 2. Follow-up time under MMF therapy, baseline and end parameter comparisons and final renal outcome of each patient
Starting/Final serum creatinine (mg/dL)
1
16/0
4.4/1.85
2 3 4
14/2 6/4 8/4
0.4/0.6 1/0.8 1.9/5
5
6/4
6 7
12/0 12/4
Patient number
Starting/ Final CrCl (mL/min/1.73 sqm body surface)
Starting/ Final daily proteinuria (g/day)b
Starting/Final PrU/CrU ratiob
Follow-up time under MMF
Disease evolution after MMF completion
2.43/0
5.39/0
45
CR (16;12)c
Improved
107.6/153 101.7/92 34.5/12.7
1.3/0.21 7.25/0.8 10.8/4
2.4/0.17 4.5/0.79 11.9/4.45
19 39 21
CR (11;7)c PR (11) F
Stable Stable Went onto ESRD
0.8/0.8
95.6/87.6
2.82/1.48
3.03/1.73
12
PR (7)
Developed nephrotic syndrome 5 months after stopping MMF
0.95/0.95 1.3/1.1
130.6/104 41/83.5
0.84/0.3 12.4/7.36
0.47/0.21 10.3/6.16
33 13
CR (4;2)c F
Stable Stable
8/47
Therapy received at end of MMF AZA 50/75 mg on alternate days MTX ⫹ OH-CLQ AZA Initially high OCS; stopped after ESRD developed until no treatment left Initially AZA; then AZA ⫹ PO-CYC; finally IV-CYC and high OCS Still on maintenance MMF IV-CYC plus OCS
Renal outcome at last visit Stable renal function Normal renal function Normal renal function On CAPD; awaits renal transplant
Died due to RPGN in ESRD and acute pulmonary edema Normal renal function Developed chronic renal failure
p ⫽ 0.018; bp ⫽ 0.018 for both parameters; remainder shown in table not significant; cfirst number in parentheses indicates time in months when patients achieved CR; second number time when PR was achieved. CR, complete remission; PR, partial remission; F, failure; ESRD, end stage renal disease; MTX, methotrexate; OH-CLQ, hydroxychloroquine; AZA, azathioprin; MMF, mycophenolate mofetil; IV-CYC, intravenous cyclophosphamide pulses; PO-CYC, daily oral cyclophosphamide; OCS, oral corticosteroids; CAPD, continuous ambulatory peritoneal dialysis.
a
MMF in Mexican Mestizo Patients with Severe Lupus Nephritis
Starting/Final SLEDAI-2K scoresa
Outcome at end of MMF (time of either CR or PR achievement in months)
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Table 3. Adverse effects while on MMF therapy
Patient number
Gastrointestinal
1
Diarrhea (twice)
4 7
None Diarrhea and moderate abdominal pain
Months of therapy with MMF 1 and 10
1
Due modification
Infections
Dose reduction on first episode, Herpes zoster temporal suspension on second Herpes zoster Transient dose reduction None
500 mg bid until she completed 1 year of therapy. Thereafter, the dose could be gradually decreased until she took 500 mg qd during the last 10 months of the 45 she received MMF. In the second patient, diarrhea was accompanied by mild abdominal pain that resolved with dosage lowering. Later it was given at the initial dose without complaints. Discussion In recent years, the awareness that CYC therapy for LN can be very toxic (2) has led to the search for different treatment options, both for induction of remission and its maintenance. MMF is a prodrug that after conversion to the active compound, mycophenolic acid, exerts different actions leading to improvement of renal function both in animal models and patients. In a study of MMF as induction drug, patients who received it for 6 months at a maximal dose of 2 g qd had a similar outcome in terms of complete and partial remission achieved and renal function parameters to those treated with PO-CYC for 6 months who were then switched to AZA. The MMF arm had a dose decrease after 6 months to an average of 1 g qd and then also switched to AZA (8). On an interim analysis at 2-year follow-up, patients who had received MMF tended to relapse more than those who were treated with CYC and then AZA (9). Recently, however, it has been shown that certain patients treated according to the NIH protocol (1) can develop renal flares and some even progress to ESRD. In this study, the majority of patients received azathioprin as remission therapy but renal flares could not be prevented in all (13). Moreover, about 10% of patients treated under the NIH protocol are not able to achieve remission, and this was the case in two of our previously CYC-treated patients. In two others there were relapses of the disease after successful initial response to CYC, which could not reinduce the patients into remission on a second occasion. In this pilot observation, improvement in renal function was seen in two patients, stabilization was achieved and maintained in four and only one patient had persistent decline in CrCl. The most dramatic effect was seen in terms of proteinuria and all patients showed decrease in the PrU/CrU ratio. Other parameters were not significantly affected after MMF treatment. In terms of control of extrarenal symptoms, MMF proved to be useful and this reflects in the SLEDAI2K score and also the steady reduction of prednisone in all
Months of therapy with MMF
Due modification
5.5
None necessary
2
Temporal suspension
patients, leading to its suspension in five of the seven patients. In the two patients who finally failed, renal function stabilization and a brief partial remission period was observed at some point during their treatment. These patients had the highest chronicity indices and scarring histopathologic features in their kidney biopsies. The adverse effects that occurred were indeed few and mild and not severe enough to modify treatment. In the only study comparing CYC and MMF for induction of remission, Chan et al. switched patients under MMF after 1 year to azathioprin. Patients who received MMF had equal outcomes in terms of renal function to those who received CYC, with less side effects (8), although in the 2-year interim analysis, MMF patients seemed to have relapsed more (9). Compared to azathioprin, MMF seems to be more effective in maintaining remission after IV-CYC as shown recently by the group at the University of Miami (14). It is worth mentioning that, in this study, “Hispanics” were included. However, most were from Cuban origin. There are profound differences with the Mexican mestizos. In the former there is considerable African background with little input from the native Indian population, whereas in the latter, the background from the native indigenous population was considerable after the Spanish conquest in the 16th century, making the Mexican mestizo population unique with respect to the genetic and ethnic characteristics, which are very different from other so-called Hispanic groups. The evidence presented up to now suggests that MMF could be preferable in some cases to CYC as induction therapy, and this concept has support by some (15). However, the only way to answer this question would be through a large multinational ransomized trial with patients from different ethnic backgrounds. There is only one multicentric study published in abstract form that favors MMF as induction treatment option (16). In conclusion, although MMF has been available for several years for treatment of LN, there has not been a formal follow-up study done in Latin American patients to evaluate its efficacy. We have seen a favorable response to MMF treatment in inducing remission in persistent or severe relapsing disease with good tolerance. Patients maintained their renal function, there was a decrease in proteinuria and extrarenal manifestations of the disease were controlled. These results have encouraged us to perform an open-label study comparing IV-CYC and MMF in cases as the ones presented here, which is in progress and close to completion.
MMF in Mexican Mestizo Patients with Severe Lupus Nephritis
Acknowledgments The author wants to thank Isabel Balderas, M.D. for her collaboration in the initial phase of the study. The author is also deeply indebted to Antonio Villa, M.D. for help with the statistical analysis, Roche Mexico, especially through Ms. Jaqueline Haces and Noe´ Soria, M.D. The Women’s Volunteer Committee from the Instituto Nacional de Ciencias Me´dicas y Nutricio´n provided the MMF to the patients.
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