Lupus nephritis: treatment with mycophenolate mofetil

12 downloads 0 Views 79KB Size Report
Jan 6, 2004 - months; mean duration of nephritis 57 months; nine with focal proliferative glomerulonephritis, three with diffuse proliferative glomerulonephritis ...
Rheumatology 2004;43:377–380 Advance Access publication 6 January 2004

doi:10.1093/rheumatology/keh012

Lupus nephritis: treatment with mycophenolate mofetil P. P. Kapitsinou, J. N. Boletis1, F. N. Skopouli2, K. A. Boki and H. M. Moutsopoulos Objective. To evaluate the safety and efficacy of mycophenolate mofetil (MMF) treatment in patients with lupus nephritis. Methods. Eighteen patients with biopsy-proven lupus nephritis (17 females, one male; mean age 31.6 yr; mean lupus duration 92 months; mean duration of nephritis 57 months; nine with focal proliferative glomerulonephritis, three with diffuse proliferative glomerulonephritis, six with membranous nephropathy) were included. With five exceptions, all patients had been treated previously with cyclophosphamide and were selected because of either toxicity or inadequate clinical response to treatment. MMF was given at 2 g daily in combination with steroids for up to 31months (mean 15.3 months). The side-effects of MMF were recorded and efficacy was assessed as the renal function profile. Results. Complete remission was observed in 10/18 patients and another 4/18 went into partial remission. Both creatinine clearance and proteinuria were significantly improved during MMF treatment in patients with the proliferative forms of nephritis. MMF demonstrated a steroid-sparing effect in the whole population. Treatment failure was recorded in 4/18 patients, all with membranous nephropathy. Two patients developed gastrointestinal complaints and infectious meningitis occurred in one patient. Conclusion. MMF appears to be an efficacious and safe treatment in patients with proliferative forms of lupus nephritis who do not respond to or cannot tolerate conventional treatment. The efficacy of MMF in lupus membranous nephropathy remains unclear. KEY WORDS: Mycophenolate mofetil, Lupus nephritis, Proliferative nephritis, Lupus membranous nephropathy, Immunosuppression.

Cyclophosphamide (CYC) intravenous bolus therapy has generally been considered the treatment of choice for the diffuse proliferative glomerulonephritis (DPGN) in patients with systemic lupus erythematosus [1, 2, 3]. However, the increased risk of marrow suppression, infertility and malignancy needs to be carefully weighed against improvement in renal outcome [4, 5]. Mycophenolate mofetil (MMF) is widely used in solid organ transplantation and it reduces the rate of acute rejection following renal transplantation [6]. It has also been used to treat patients with other immune-mediated disorders such as immunoglobulin A nephropathy, small-vessel vasculitides and psoriasis. MMF has been demonstrated to be effective in mouse models of lupus nephritis [7, 8]. There is limited clinical experience of the use of MMF in patients with lupus nephritis [9–12]. In a recent randomized controlled trial in patients with DPGN, MMF has been shown to be as effective as CYC [12]. However, at the longer follow-up, patients treated with MMF developed a significantly higher incidence of relapse compared with patients who received CYC, even though renal function remained similar in the two groups [13]. Furthermore, the role of MMF in lupus membranous nephropathy is unclear because of the lack of prospective data. We describe our experience of the use of MMF in 20 patients with lupus nephritis, six of whom had lupus membranous nephropathy.

Patients and methods In this retrospective study, 20 patients with lupus nephritis were treated with MMF at the dose of 1 g twice a day in combination

with steroids. Thirteen out of 18 patients had been treated previously with CYC and steroids and were selected for MMF treatment because of prior therapy-related toxicity in 10 of them, and the remaining three had failed to respond. In addition, five patients received MMF as first-line treatment. Eleven out of 18 patients were on antihypertensive therapy with ACE inhibitors or -blockers at the time MMF was introduced. All patients had systemic lupus erythematosus according to the criteria of the American Rheumatism Association, including at least one biopsy revealing lesions consistent with lupus nephritis. The medical records of the patients were reviewed and their clinical course and laboratory profile, which included routine blood and urine biochemical tests, were assessed during the follow-up. Creatinine clearance was calculated using the Cockroft–Gault formula. Observation onset was defined as the time that MMF was introduced for each patient. Follow-up was censored on 31 November 2001. Renal biopsy files were also reviewed and histopathological changes had been classified according to the WHO classification of 1982. In addition, the activity index and chronicity index, where applicable, were recorded. For patients with two or more renal biopsies (eight patients), the most recent one was considered. Complete remission was defined as proteinuria less than 0.5 g/24 h, with normal urinary sediment and normal values for both serum creatinine and creatinine clearance. Partial remission was defined as either a reduction of more than 30% in proteinuria or proteinuria less than 2 g/24 h in a previously nephrotic patient with normal urinary sediment and stable renal function.

Department of Pathophysiology, Medical School, University of Athens, 1Department of Nephrology, Laikon General Hospital and 2Euroclinic of Athens, Athens, Greece. Submitted 14 April 2003; revised version accepted 24 July 2003. Correspondence to: H. M. Moutsopoulos, Department of Pathophysiology, School of Medicine, National University of Athens, 75 Mikras Asias Street, 11527 Athens, Greece. E-mail: [email protected] 377 Rheumatology Vol. 43 No. 3 ß British Society for Rheumatology 2004; all rights reserved

P. P. Kapitsinou et al.

378

Treatment failure was defined as no remission at the end of follow-up. Comparison of laboratory characteristics was performed using the Wilcoxon signed rank test. McNemar’s test was used for comparisons of dichotomous variables before and after treatment (P < 0.05 was considered significant). The patients’ written consent to participation in the study was obtained according to the Declaration of Helsinki, and the design of the study conformed to standards currently applied in Greece.

Results Regarding renal histology, nine patients had focal proliferative glomerulonephritis, three had diffuse proliferative glomerulonephritis and six had membranous nephropathy. Superimposed proliferative changes were noted in three patients with membranous nephropathy (Vc, one patient; Vd, two patients), whereas the remaining three had pure membranous nephropathy (Va, one patient; Vb, two patients). The mean values of the activity and chronicity indexes were 4.9 and 2.4 respectively. In view of the apparent diversity in the renal histology, our study population was divided into two groups: group A consisted of patients whose specimens showed either diffuse or focal proliferative changes (12 patients), and patients with membranous glomerulonephritis constituted group B (six patients). The baseline characteristics of the patients in the two groups were similar (Table 1A). Disease duration and the time from renal biopsy to MMF onset tended to be longer in group B than in group A, although the difference was not statistically significant. Renal function was preserved in both groups. Four patients had nephrotic syndrome at baseline, two of whom had membranous nephropathy. Complete remission was observed in 10/18 patients (56%) and partial remission in another 4/18 (22%). Treatment failure was recorded in four of the 18 patients, all with membranous nephropathy. Mean proteinuria decreased significantly in group A

after 3 months of treatment (P ¼ 0.008) and it remained significantly lower at 12 months (P ¼ 0.004) (Fig. 1 and Table 1B). Mean creatinine clearance was also significantly lower than the baseline value after 12 months of therapy in group A (P ¼ 0.012). In group B, mean proteinuria decreased from 1.9 to 1 g/day (not significant) and mean creatinine clearance did not change significantly. In group A, of the 11 patients with active urinary sediment at the beginning, ten had normal urinary sediment at 12 months (P ¼ 0.002), whereas in group B two patients still had active urinary sediment at 12 months. Mean systolic and diastolic blood pressures remained stable during treatment with MMF. All of the patients were on steroids at the time of MMF initiation, and no increase was made in the prescribed dose of steroids. During the follow-up, the steroid dose could be reduced in 14/18 patients. The mean dose of steroids used in combination with MMF was reduced from 15  13 mg/day at the beginning to 7  5 mg/day at the end of follow-up. Two patients developed gastrointestinal intolerance which necessitated a reduction of the MMF dose to 1.5 g/day in one patient and transient discontinuation in the other. Pneumococcal meningitis occurred in one patient, who died from respiratory failure due to diaphragm myositis 1 yr later, while in partial remission.

TABLE 1A. Demographic characteristics of the patients in group A (patients with proliferative lupus nephritis) and in group B (patients with lupus membranous nephropathy) at baseline and at 12 months

Variable

Group A (n ¼ 12)

Group B (n ¼ 6)

Sex (M, F) Age (yr) Duration of lupus (months) Duration of nephritis (months) Time from renal biopsy (months) Duration of treatment with MMF (months)

1, 11 30  13 69  70 48  48 22  23 15.6  5.1

0, 6 36  16 137  109 75  73 43  48 14.8  8.5

FIG. 1. Proteinuria in patients with proliferative forms of lupus nephritis (group A, solid line) or with membranous nephropathy (group B, broken line).

TABLE 1B. Laboratory values of patients in groups A and in B at baseline and at 12 months Group A Variable

Baseline

12 months

Serum creatinine (mol/l) Calculated creatinine clearance (ml/s) Proteinuria (g/24 h) Active urinary sediment

106  44

89  28

1.29  0.48

1.45  0.45

2.9  5.6

0.3  0.2

11/12

1/12

Group B D/R (95% CI)

1.19 (0.91 to 1.78) 0.89 (0.57 to 1.09) 2.6 (20.5 to 0.3)

P

Baseline

12 months

0.013

80  18

90  23

0.012

1.40  0.35

1.23  0.33

0.004

1.9  1.4

1.0  1.0

0.002

4/6

2/6

D/R (95% CI) 0.89 (0.47 to 1.22) 1.14 (0.81 to 2.08) 0.9 (3.0 to 1.5)

P n.s. n.s. n.s. n.s.

CI, confidence interval; D/R, difference ratio (for serum creatinine and creatinine clearance, the ratio of the baseline value to the value at 12 months is given; for proteinuria the difference between the values at baseline and 12 months is given).

MMF and lupus nephritis

In view of the toxicity related to CYC therapy, the need for alternative therapeutic approaches for the treatment of proliferative lupus nephritis is widely acknowledged. Newer treatment strategies include novel forms and combinations of chemotherapeutic agents, attempts to achieve immunological reconstitution using near-ablative chemotherapy (with or without stem-cell rescue), and the use of monoclonal antibodies to block interaction between T and B cells [14]. Mycophenolate acid, the active metabolite of MMF, is a more specific immunosuppressive than CYC. The preferential antiproliferative effects of MMF on lymphocytes and kidney mesangial cells, combined with its inhibitory action on cell adhesion molecules and the migration of inflammatory cells, may provide an additional clinical benefit in the treatment of lupus nephritis [15] A number of uncontrolled studies have been conducted to assess the efficacy and toxicity of MMF in the treatment of lupus nephritis, and the evidence to date was recently reviewed by Mok et al. [15]. These authors highlighted the methodological limitations of these studies, which are shared to some extent by the present study. A heterogeneous group of patients was included; data on renal histological characteristics and damage after MMF treatment were not available; both steroid and MMF were administered (and in the absence of a control population steroid might also have contributed in part to the improvement in renal parameters); and the contribution of previous immunosuppression cannot be excluded. Controlled trials of MMF in lupus nephritis are few, and some are now in progress. In a recent randomized controlled study, the combination of MMF and prednisolone was demonstrated to be as effective as a regimen of CYC and prednisolone followed by azathioprine and prednisolone [12]. Nevertheless, this study involved only a small cohort of patients and the follow-up was too short to address the efficacy of MMF in the long-term preservation of renal function compared with the established therapeutic treatments. On the other hand, the therapeutic role of MMF in lupus membranous nephropathy remains unclear, as there are only 13 cases reported in the literature so far, of whom six are children. Because experience with the use of MMF in lupus nephritis is still preliminary, we add our observations on 18 patients with lupus nephritis treated with MMF. Complete or partial remission was observed in 14 patients. In terms of renal histology, while all patients with proliferative forms of lupus nephritis had either complete or partial remission, four out of six patients with membranous glomerulonephritis failed to respond. Given the relatively short follow-up (mean 15.3 months) and the small numbers treated, our observations regarding this relatively uncommon form of lupus nephritis need cautious interpretation. The coexistence of proliferative changes in three of the four nonresponders may partially explain this finding. Pasquali et al. [16] have shown that among patients with lupus membranous nephropathy, those with more proliferative change on renal biopsy, were more likely to have persistent non-nephrotic proteinuria, and were less likely to have complete resolution of proteinuria. Furthermore, the frequently reported transformation of diffuse proliferative glomerulonephritis by treatment into the membranous form may represent the residuum that aggressive therapy is unable to reverse [17]. In a recently published report, Najafi et al. [18] have highlighted the relatively malignant nature of complex membranous forms of lupus glomerulonephritis. On the other hand, two out of three patients with pure membranous nephropathy had complete remission, whereas the remaining patient failed to respond after having been treated for 9 months. Thus, in our study population patients with pure membranous nephropathy tended to have a better response to MMF treatment compared with patients with complex membranous nephropathy. There was a statistically significant improvement in mean creatinine clearance and proteinuria for patients with proliferative

nephritis during treatment with MMF. Proteinuria also decreased in patients with membranous nephritis, although the decrease was not statistically significant. Drugs like ACE inhibitors and statins also affect proteinuria but none of these medications was introduced in any patient during the study period. Interestingly, MMF has been shown to reduce proteinuria without changing serum creatinine in patients with idiopathic membranous nephropathy [19, 20]. Given the lack of formal studies of MMF in lupus membranous glomerulonephritis, this observation is noteworthy because one might look to idiopathic membranous glomerulonephritis as a model for the former one (lupus membranous nephropathy). The steroid dose could be reduced in 14 of the 18 patients administered steroid at the time of introduction of MMF. With regard to side-effects, gastrointestinal intolerance developed in two of our patients and resolved on dose reduction and transient discontinuation of MMF. Pneumococcal meningitis occurred in one patient during lupus flare. Treatment with MMF was withdrawn and reintroduced after patient recovery. Gastrointestinal complaints such as diarrhoea, vomiting and nausea appear to be the most frequently reported side-effects in published retrospective studies [10, 11]. In the controlled study by Chan et al. [12], infection was the most common adverse event, but it was mild and insignificant in all cases. Thus, adverse events associated with the use of MMF in lupus nephritis are infrequent and relatively mild compared with those reported in transplant recipients. This is possibly due to a lower intensity of immunosuppression. The present report is not intended to definitively address the many critical issues of the role of MMF in the treatment of lupus nephritis. However, our study does indicate that MMF is a safe and probably efficacious treatment in patients with proliferative forms of lupus nephritis who do not respond or cannot tolerate conventional treatment. We suggest that further prospective controlled trials are warranted to compare the long-term efficacy and safety of MMF with those of established treatments. Inclusion of patients with lupus membranous nephropathy and accurate histopathological stratification of renal biopsies would be helpful in order to clarify the role of MMF in this infrequent type of lupus nephritis [18]. The authors have declared no conflicts of interest.

Rheumatology

Discussion

379

Key messages MMF appears to be a safe and efficacious alternative treatment in proliferative lupus nephritis, whereas its efficacy in lupus membranous nephropathy remains unclear.

References 1. Donadio JV Jr, Holley KE, Ferguson RH, Ilstrup DM. Treatment of diffuse proliferative lupus nephritis with prednisone and combined prednisone and cyclophosphamide. N Engl J Med 1978;229:1151–5. 2. Boumpas DT, Austin HA 3rd, Vaughn EM et al. Controlled trial of pulse methylprednisolone versus two regimens of pulse cyclophosphamide in severe lupus nephritis. Lancet 1992;340:741–5. 3. Ioannidis JP, Boki KA, Katsorida ME et al. Remission, relapse, and re-remission of proliferative lupus nephritis treated with cyclophosphamide. Kidney Int 2000;57:258–64. 4. Katsifis GE, Tzioufas AG, Vlachoyiannopoulos PG, Voulgarelis M, Moutsopoulos HM, Ioannidis JP. Risk of myelotoxicity with intravenous cyclophosphamide in patients with systemic lupus erythematosus. Rheumatology 2002;41:780–6.

380

P. P. Kapitsinou et al.

5. Ioannidis JP, Katsifis GE, Tzioufas AG, Moutsopoulos HM. Predictors of sustained amenorrhea from pulsed intravenous cyclophosphamide in premenopausal women with systemic lupus erythematosus. J Rheumatol 2002;29:2129–35. 6. Mathew TH for the Tricontinental Mycophenolate Mofetil Renal Transplantation Study Group. A blinded, long-term, randomized multicenter study of mycophenolate mofetil in cadaveric renal transplantation. Results at three years. Transplantation 1998;65:1450–4. 7. 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 1997;51:1583–9. 8. Van Bruggen MC, Walgreen B, Rijge TP, Berden JH. Attenuation of murine lupus nephritis by mycophenolate mofetil. J Am Soc Nephrol 1998;9:1407–15. 9. Briggs WA, Choi MJ, Scheel PJ Jr. Successful mycophenolate mofetil treatment of glomerular disease. Am J Kidney Dis 1998;31: 213–7. 10. Dooley MA, Cosio FG, Nachman PH et al. Mycophenolate mofetil therapy in lupus nephritis: clinical observations. J Am Soc Nephrol 1999;10:833–9. 11. Kingdon EJ, McLean AG, Psimenou E et al. The safety and efficacy of MMF in lupus nephritis: a pilot study. Lupus 2001;10:606–11. 12. Chan TM, Li FK, Tang CS et al. Efficacy of mycophenolate mofetil in patients with diffuse proliferative lupus nephritis.

13.

14. 15. 16.

17.

18.

19. 20.

Hong Kong-Guangzhou Nephrology Study Group. N Engl J Med 2000;343:1156–62. Chan TM, Wong RWS, Lau CS et al. Prolonged follow-up of patients with diffuse proliferative lupus nephritis treated with prednisolone and mycophenolate mofetil. J Am Soc Nephrol 2001;12:1010A. Balow JE, Boumpas DT, Austin HA 3rd. New prospects for treatment of lupus nephritis. Semin Nephrol 2000;20:32–9. Mok CC, Lai KN. Mycophenolate mofetil in lupus glomerulonephritis. Am J Kidney Dis 2002;40:447–57. Pasquali S, Banfi G, Zucchelli A, Moroni G, Ponticelli C, Zucchelli P. Lupus membranous nephropathy: long-term outcome. Clin Nephrol 1993;39:175–82. Donadio JV Jr. Treatment of membranous nephropathy in systemic lupus erythematosus. Nephrol Dial Transplant 1992;7(Suppl. 1): 97–104. Najafi CC, Korbet SM, Lewis EJ, Schwartz MM, Reichlin M, Evans J. The Lupus Nephritis Collaborative Study Group. Significance of histologic patterns of glomerular injury upon long-term prognosis in severe lupus glomerulonephritis. Kidney Int 2001;59:2156–63. Choi MJ, Eustace JA, Gimenez LF et al. Mycophenolate mofetil treatment for primary glomerular diseases. Kidney Int 2002;61:1098–114. Miller G, Zimmerman R 3rd, Radhakrishnan J, Appel G. Use of mycophenolate mofetil in resistant membranous nephropathy. Am J Kidney Dis 2000;36:250–6.