Switching Treatment Between Mycophenolate Mofetil and Azathioprine in Lupus Patients: Indications and Outcomes

Arthritis Care & Research Vol. 66, No. 12, December 2014, pp 1905 1909 DOI 10.1002/acr.22364 2014, American College of Rheumatology ORIGINAL ARTICLE Switching Treatment Between Mycophenolate Mofetil and Azathioprine in Lupus Patients: Indications and Outcomes HESHAM AL MAIMOUNI, DAFNA D. GLADMAN, DOMINIQUE IBAÑEZ, AND MURRAY B. UROWITZ Objective. To determine the reasons for changing treatment from mycophenolate mofetil (MMF) to azathioprine (AZA) or vice versa in lupus patients and to evaluate the effect of the change. Methods. Lupus patients were identified from the University of Toronto Lupus Clinic database. Global disease activity in the 6 months prior to the change in therapy and 6 months after the change was calculated. The reasons for changing therapy were identified. Results. One hundred eight switches occurred among 92 lupus patients: 89 switches from AZA to MMF and 19 from MMF to AZA. There was significant improvement in disease activity in the 6 months after drug switching compared to the 6 months prior to the switch when the reason was a drug failure. There was no statistically significant deterioration in disease activity in the 6 months after drug switching when the reason for the switch was a side effect, pregnancy, renal transplant, or financial. In the 19 patients who switched because of side effects, 15 (79%) had resolution of the side effects. Conclusion. Switching from AZA to MMF is most often due to AZA failure, whereas switching from MMF to AZA is mostly due to side effects and pregnancy. When the reason for the switch was drug failure, improvement in disease activity occurred and there was a reduction of steroid dose after 6 months. When the reason for switching was something other than drug failure, there was no deterioration in global disease activity. Switching for side effects usually resulted in elimination of the side effect. INTRODUCTION Disease activity is one of the important predictors of subsequent organ damage and mortality in lupus (1). However, the optimal choice for long-term immunosuppression to reduce or prevent relapses of systemic lupus erythematosus (SLE) is unknown. Standard immunosuppressive therapies for SLE have been used to treat lupus manifestations and as steroid-sparing agents. Lack of therapeutic efficacy may arise in different ways: intolerance of the standard therapy due to side effects, inability to induce remission, or disease relapse during therapy or following The Lupus Clinic is supported by the Smythe Foundation and the University Health Network. Hesham Al Maimouni, MD, Dafna D. Gladman, MD, FRCPC, Dominique Ibañez, MSc, Murray B. Urowitz, MD, FRCPC: University of Toronto Lupus Clinic, Centre for Prognosis Studies in the Rheumatic Diseases, Toronto Western Hospital, Toronto, Ontario, Canada. Address correspondence to Murray B. Urowitz, MD, FRCPC, University of Toronto Lupus Clinic, Centre for Prognosis Studies in the Rheumatic Diseases, Toronto Western Hospital, 399 Bathurst Street, 1E-410B, Toronto, Ontario, M5T 2S8, Canada. E-mail: m.urowitz@utoronto.ca. Submitted for publication February 13, 2014; accepted in revised form April 29, 2014. withdrawal of therapy (2). Previously, maintenance regimens consisted primarily of a combination of cyclophosphamide or azathioprine (AZA) and glucocorticoids (3). National Institutes of Health studies have established that long-term treatment with cyclophosphamide in patients with proliferative lupus nephritis beyond the induction phase enhanced renal survival. Unfortunately, such regimens have substantial toxicity in terms of risk of infections, infertility, and the long-term risk of bladder or other tumors (4 7). Currently, the 2 most common regimens for maintenance therapy in lupus nephritis are AZA and mycophenolate mofetil (MMF) (8). There has been controversy regarding the superiority of MMF over AZA as maintenance therapy. The Aspreva Lupus Management Study (ALMS) demonstrated the superiority of MMF over AZA as maintenance therapy after successful induction therapy both in time to treatment failure and time to renal flare and rescue therapy (9). In contrast, the Mycophenolate Mofetil versus Azathioprine for Maintenance Therapy of Lupus Nephritis (MAINTAIN) trial demonstrated equivalence with similar flare rates in MMF versus AZA (19% versus 25%) (10). This has been supported by a meta-analysis of randomized controlled trials (RCTs) suggesting that MMF offers a similar prognosis to AZA for maintenance therapy, while 1905

1906 Al Maimouni et al Significance & Innovations Switching from azathioprine (AZA) to mycophenolate mofetil (MMF) in patients with systemic lupus erythematosus is most often due to AZA failure, whereas switching from MMF to AZA is mostly due to side effects and pregnancy. When the reason for the switch was drug failure, improvement in disease activity occurred and a reduction in steroid dose was seen after 6 months. When the reason for switching was something other than drug failure, there was no deterioration in the adjusted mean Systemic Lupus Erythematosus Disease Activity Index score. Switching for side effects usually resulted in elimination of the side effect. MMF appears safer than AZA in the treatment of lupus nephritis (11). At present, there are no guidelines for the duration of treatment beyond 3 years, so continuing therapy for longer time periods should be individualized (8). In particular, any change in treatment can result in flares in previously stable disease. Moreover, with the possible superiority of MMF over AZA, one might expect a disease flare when MMF is replaced by AZA. The purpose of this study was to determine the reasons for and to evaluate the effect of switching treatment between MMF and AZA in patients with lupus. PATIENTS AND METHODS Patients from the University of Toronto Lupus Clinic were studied. All consecutive patients seen in the clinic between 2001 and 2012 were included. We used that start date because that is when MMF became available for our patients. Patients with SLE ( 4 American College of Rheumatology [ACR] criteria or 3 ACR criteria plus a typical histologic lesion of SLE on renal or skin biopsy) have been followed prospectively at the University of Toronto Lupus Clinic (12,13). Collection and storage of data at the lupus clinic were conducted in accordance with the Declaration of Helsinki and approved by the Research Ethics Board of the University Health Network. Signed informed consent was obtained from all patients at the lupus clinic. Patients attended the lupus clinic at 2 6-month intervals regardless of the state of activity of their lupus. The standard protocol included a complete history, physical examination, and laboratory evaluation. Disease activity was measured at each visit by the Systemic Lupus Erythematosus Disease Activity Index 2000 (SLEDAI-2K) in a 30-day window, a valid measure of disease activity in SLE (14 16). We selected patients in whom treatment was changed from MMF to AZA or vice versa within a 6-month interval, and were evaluated 6 months before and 6 months after the switch. Our first aim was to identify the reasons for changing treatment from MMF to AZA or vice versa (drug failure, side effect, pregnancy, financial, or other). Flares were determined by the development of a new score for a particular system on the SLEDAI-2K. Our second aim was to determine whether switching between medications improved the disease activity in the drug failure groups and whether disease activity stabilized or deteriorated in the other groups (side effect, pregnancy, financial, or other) by calculating the global disease activity in the 6 months prior to the change in therapy and 6 months after the change using the adjusted mean SLEDAI (AMS), a validated measure of disease activity over time (17). The AMS was compared in the 6 months prior to and after the switch using generalized estimating equations, adjusting for repeated measures. RESULTS Between 2001 and 2012, a total of 463 patients were receiving AZA and 16% switched after a mean SD period of 4.0 4.3 years. During the same period, a total of 315 patients were receiving MMF and 6.0% switched after a mean SD period of 1.7 1.6 years. Comparing patients who switched with those who did not, there were more whites among those who did not switch from AZA, but there was no difference among patients who switched or did not while taking MMF. Overall, 92 patients fulfilled the inclusion criteria for a total of 108 switches: 80 patients had 1 switch, 8 patients had 2 switches, and 4 patients had 3 switches. The majority of the 92 patients were women (n 82 [89.1%]). The patients ethnic distribution was white (n 40 [43.5%]), African American (n 25 [27.2%]), Asian (n 10 [10.9%]), and other (n 17 [18.5%]). Mean SD age at SLE diagnosis was 25.9 10.4 years, mean SD disease duration at the time of the switch was 9.5 11.9 years, and mean SD SLEDAI-2K score at the time of the switch was 10.5 6.5 (Table 1). There were no differences in sex, race, age at diagnosis, disease duration, or SLEDAI-2K score between patients who switched from MMF to AZA and those who switched from AZA to MMF (Table 2). Reasons for switch from AZA to MMF. There were 89 switches from AZA to MMF. Drug failure was the reason for the switch in 76 (85.4%), leading to flares in a number of organ systems. Therefore, renal flare occurred in 42 Table 1. Characteristics of the 92 patients at entry to the study* Value (n 92) Female sex, no. (%) 82 (89.1) White, no. (%) 40 (43.5) Age at diagnosis, years 25.9 10.4 Disease duration, years 9.5 11.9 SLEDAI-2K score 10.5 6.5 * Values are the mean SD unless indicated otherwise. SLEDAI- 2K Systemic Lupus Erythematosus Disease Activity Index 2000.

Changing Treatment Between MMF and AZA in Lupus Patients 1907 Table 2. Characteristics evaluated to compare patients who switched from AZA to MMF with patients who switched from MMF to AZA* AZA 3 MMF (n 89) MMF 3 AZA (n 19) P Female sex, no. (%) 80 (89.9) 18 (94.7) 1.00 White, no. (%) 39 (43.8) 8 (42.1) 1.00 Age at diagnosis, years 25.3 10.2 25.4 10.6 0.95 Disease duration, years 10.6 7.6 8.0 6.8 0.18 SLEDAI-2K score 10.3 6.5 9.2 6.2 0.47 * Values are the mean SD unless indicated otherwise. AZA azathioprine; MMF mycophenolate mofetil; SLEDAI-2K Systemic Lupus Erythematosus Disease Activity Index 2000. (55.3%), systemic flare in 12 (15.8%), central nervous system flare in 5 (6.6%), musculoskeletal flare in 4 (5.3%), vasculitis flare in 3 (3.9%), serositis flare in 3 (3.9%), hematologic flare in 3 (3.9%), skin flare in 2 (2.6%), myositis flare in 1 (1.3%), and interstitial lung disease flare in 1 (1.3%). All patients were taking steroids at the time of switch when the reason was a drug failure, with the mean AZA dosage of 2 mg/kg/day 6 months before the switch and the mean MMF dosage of 2,000 mg/day 6 months after the switch. Side effects were the reason for the switch in 11 (12.4%): 5 (45.5%) had impairment of liver enzymes, 3 (27.3%) had leukopenia, 2 (18.2%) had gastrointestinal intolerance, and 1 (9.1%) had warts. In 9 (81.8%) of the 11 patients, the side effect was eliminated, and in 2 (18.2%) it persisted after drug switching. Renal transplant was the reason for the switch in 2 (2.2%). Reasons for switch from MMF to AZA. There were 19 switches from MMF to AZA. Drug failure was the reason for the switch in 3 (15.8%): renal flare in 1 (33.3%) and systemic flare in 2 (66.7%). Side effects were the reason for the switch in 8 (42.1%): 5 (62.5%) had gastrointestinal intolerance, 1 (12.5%) had leukopenia, 1 (12.5%) had skin rash, and 1 (12.5%) had fatigue with decreased libido. In 6 (75%) of the 8 patients, the side effect was eliminated, and in 2 (25%) it persisted after drug switching. Wish to conceive was the reason for the switch in 7 (36.8%) and financial issues in 1 (5.3%) (Figure 1). Effect of switch. There was a statistically significant improvement in AMS in the 6 months after drug switching compared to the 6 months prior to the switch in the total group when the reason was a drug failure (mean SD 11.2 6.1 versus 9.1 5.7; P 0.0001). The improvement in the laboratory component was most significant (P 0.0006) and the clinical component showed only a trend (P 0.08) (Table 3). Switching treatment because of drug failure resulted in a significant reduction in the steroid dose 6 months after drug switching compared to the dose at the time of switch (mean SD 24.9 14.6 mg versus 18.3 11.7 mg; P 0.0002). There was no statistically significant deterioration in the AMS or its clinical and laboratory components in 6 months after drug switching in the total group when the reason for the switch was a side effect, pregnancy, renal transplant, or financial (mean SD 6.7 4.6 versus 5.9 4.6; P 0.33). In the 19 patients who switched because of side effects, 15 (79%) had resolution of the side effects, and in 4 (21%) the side effects persisted after drug switching. DISCUSSION Our study demonstrated that switching from AZA to MMF is most often due to AZA failure, particularly with respect to renal disease. When the reason for the switch was drug failure, improvement in disease activity occurred and there was a reduction in steroid dose after 6 months. The improvement in the laboratory component was most significant (P 0.0006) and the clinical component showed only a trend (P 0.08). In 2002, Karim et al studied 21 patients with lupus, most of whom had previously been treated with courses of cyclophosphamide and AZA or methotrexate. Indications for treatment with MMF included worsening renal involvement and uncontrolled disease activity. In their report, MMF therapy resulted in decreased proteinuria, as assessed by the SLEDAI (P 0.027), and reduced disease activity (P 0.0001) with a significant reduction in steroid dose (P 0.0001). Unlike our study, anti double-stranded DNA antibodies and complement levels were not significantly affected (2). Maintenance therapy with MMF and AZA in patients with lupus nephritis has been compared in 2 large RCTs (18). The MAINTAIN trial in European patients who received treatment with MMF (19%) or AZA (25%) found no difference in renal flares over a 4-year followup period following induction with intravenous cyclophosphamide and steroids according to the Euro-Lupus Nephritis Trial protocol in both groups (10). The ALMS maintenance trial randomized 227 patients to receive MMF or AZA after initial renal response in the induction trial (9). Over a 3-year followup period, they found fewer treatment failures in the MMF group (doubling of serum creatinine, renal failure, and death) and demonstrated a longer time to Figure 1. Reason for switches. MMF mycophenolate mofetil; AZA azathioprine.

1908 Al Maimouni et al Table 3. Improvement in AMS clinical and laboratory measures in the 6 months after drug switching compared to the 6 months prior to the switch in the total group when the reason was drug failure or something other than drug failure* Drug failure (n 79) Other (n 29) First drug Second drug P First drug Second drug P AMS 11.19 6.05 9.06 5.65 0.0001 6.74 4.62 5.93 4.58 0.33 CNS 0.45 1.63 0.41 1.64 0.84 0 0 0 0 N/A Vasculitis 0.20 1.09 0.05 0.45 0.26 0.28 1.49 0 0 0.33 Musculoskeletal 0.31 1.00 0.15 0.77 0.06 0.07 0.37 0.17 0.53 0.43 Renal 6.16 5.54 5.38 4.91 0.07 3.47 3.77 3.13 4.36 0.62 Skin 0.78 1.24 0.61 1.02 0.17 0.55 1.09 0.50 1.05 0.72 Serositis 0.12 0.51 0.08 0.37 0.36 0 0 0 0 N/A Immunologic 3.05 1.35 2.34 1.49 0.0001 2.20 1.59 2.07 1.62 0.52 Fever 0.03 0.17 0.006.06 0.21 0.07 1.62 0.02 0.09 0.26 Hematologic 0.09 0.26 0.04 0.18 0.06 0.10 0.28 0.05 0.20 0.08 AMS, clinical 1.90 3.07 1.30 2.12 0.08 0.97 2.21 0.68 1.16 0.36 AMS, laboratory 9.30 5.96 7.75 5.53 0.0006 5.78 3.80 5.25 4.54 0.48 DNA, no. (%) abnormal 59 (74.7) 53 (67.1) 0.08 15 (51.7) 16 (55.2) 0.32 C3, no. (%) abnormal 68 (86.1) 47 (59.5) 0.000 19 (65.5) 17 (58.6) 0.41 C4, no. (%) abnormal 38 (48.1) 19 (24.1) 0.0001 8 (27.6) 8 (27.6) 1.00 Steroid dose, mg 24.9 14.6 18.3 11.7 0.0002 16.0 12.5 11.4 5.9 0.01 * Values are the mean SD unless indicated otherwise. AMS adjusted mean Systemic Lupus Erythematosus Disease Activity Index score; CNS central nervous system; N/A not applicable. rescue therapy and time to renal flare. The results favored MMF regardless of patient demographics, geography, or induction therapy. These trials have resulted in AZA or MMF being the recommended first-line lupus nephritis maintenance therapies (8,19). Feng et al conducted a meta-analysis of RCTs assessing the prognosis and safety of MMF versus AZA used as maintenance therapy for lupus nephritis (11). They identified 4 RCT studies, including the ALMS and the MAINTAIN studies, and more than 300 patients, and there was no statistically significant difference in mortality (relative risk [RR] 0.96 [95% confidence interval (95% CI) 0.28 3.26], P 0.95), doubling serum creatinine (RR 0.52 [95% CI 0.21 1.26], P 0.15), and end-stage renal failure (RR 0.45 [95% CI 0.13 1.57], P 0.21). Although patients in the MMF group tended to have lower risks of relapse, it did not reach statistical significance (RR 0.70 [95% CI 0.49 1.00], P 0.05). In our report, switching between MMF and AZA for side effects usually resulted in elimination of the side effect. There were more patients who had gastrointestinal intolerance (5 [62.5%] of 8 from MMF) and more patients who had impairment of liver enzymes (5 [45.5%] of 11 from AZA). Side effects persisted in 4 patients, 2 from the AZA and 2 from MMF. It is not clear if these were drug-related effects, disease activity related, or other. In our report, we did not include those in whom side effects were treated with dose adjustment. In the ALMS maintenance trial (9), adverse events, most commonly gastrointestinal disorders and minor infections, occurred in approximately 95% of the patients in both groups (P 0.68). Serious adverse events developed in 33.3% of patients in the AZA group and in 23.5% of those in the MMF group (P 0.11), and the withdrawal rate due to adverse events was higher with AZA than with MMF (39.6% versus 25.2%; P 0.02). In the MAINTAIN trial (10), adverse events did not differ between the 2 groups except for cytopenias, which were statistically more frequent in the AZA group (P 0.03), but only 1 patient dropped out. In the meta-analysis conducted by Feng et al, MMF was associated with a significantly lower incidence of leukopenia and amenorrhea (11). Perhaps the most considerable difference between the 2 trials concerns the demographics of the study populations. ALMS was an international trial that enrolled a significant proportion of nonwhite patients, with one-third of all patients identified as Hispanic ethnicity, whereas the MAINTAIN trial was a European trial predominantly comprised of whites (79%). In lupus nephritis outcomes, the prognostic importance of race and ethnicity has been well demonstrated (20,21). Therefore, the superiority of MMF detected may be partially explained by the higher-risk population enrolled in the ALMS trial. In the metaanalysis conducted by Feng et al, although patients in the MMF group tended to have lower risks of relapse, it did not reach statistical significance (RR 0.70 [95% CI 0.49 1.00], P 0.05) (11). In our report, we had a variety of ethnic and racial groups, with 43.5% white, 27.2% African American, 10.9% Asian, and 18.5% other. In our report, when AZA was used to replace MMF, often due to pregnancy, there was no statistically significant deterioration in the AMS. This is consistent with a study performed by Fischer-Betz et al, who reviewed medical records of women with lupus nephritis counseled for pregnancy wish. Women receiving therapy with either MMF or AZA (control group), with inactive lupus and quiescent lupus nephritis (serum creatinine 1.5 mg/dl, proteinuria 1 gm/24 hours, and inactive sediment for the preceding 6 months), were eligible for this study. They identified 54 women (23 received MMF [group 1] and 31

Changing Treatment Between MMF and AZA in Lupus Patients 1909 received AZA [group 2]). MMF dose was tapered and changed subsequently to AZA, which was maintained throughout pregnancy. Three patients (13%) in group 1 versus none in group 2 developed a renal flare 36 months after changing from MMF to AZA (P 0.14) before pregnancy ensued. Risk for adverse outcome within 48 pregnancies (preterm delivery 20.5%, preeclampsia 9%) increased with every milligram of prednisone dose (odds ratio [OR] 2.03) and every single unit of SLEDAI score (OR 3.92). Renal flares developed postpartum in 2 women. No patients developed worsening of renal function (22). Limitations of our research include the small number of patients who switched from MMF to AZA in the drug failure group. We did not compare patients who switched from AZA to MMF with patients who continued on AZA without switching. The strength of our research is the prospective followup after switching medications, which enabled us to use disease activity indices and a variety of ethnic and racial groups. In summary, switching from AZA to MMF is most often due to AZA failure, whereas switching from MMF to AZA is mostly due to side effects and wish to conceive. When the reason for the switch was drug failure, improvement in disease activity occurred and a reduction in steroid dose was seen after 6 months. When the reason for switching was something other than drug failure, there was no deterioration in the AMS. Switching for side effects usually resulted in elimination of the side effect. AUTHOR CONTRIBUTIONS All authors were involved in drafting the article or revising it critically for important intellectual content, and all authors approved the final version to be published. Dr. Urowitz had full access to all of the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis. Study conception and design. Al Maimouni, Gladman, Ibañez, Urowitz. Acquisition of data. Al Maimouni, Gladman, Urowitz. Analysis and interpretation of data. Gladman, Ibañez, Urowitz. REFERENCES 1. Lopez R, Davidson JE, Beeby MD, Egger PJ, Isenberg DA. Lupus disease activity and the risk of subsequent organ damage and mortality in a large lupus cohort. Rheumatology (Oxford) 2012;51:491 8. 2. Karim MY, Alba P, Cuadrado MJ, Abbs IC, D Cruz DP, Khamashta MA, et al. Mycophenolate mofetil for systemic lupus erythematosus refractory to other immunosuppressive agents. Rheumatology (Oxford) 2002;41:876 82. 3. Hogan J, Appel GB. Update on the treatment of lupus nephritis. Curr Opin Nephrol Hypertens 2013;22:224 30. 4. Gourley MF, Austin HA III, Scott D, Yarboro CH, Vaughan EM, Muir J, et al. 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