Multitarget therapy of tacrolimus, mycophenolate mofetil and steroids achieved a 45.9% complete remission rate in induction treatment of lupus nephritis. This study assessed the efficacy of continuing multitarget therapy versus switching to azathioprine as maintenance treatment over 18 months. The cumulative renal relapse rate was lower in the multitarget group at 5.47% compared to 7.62% in the azathioprine group. More patients in the multitarget group maintained complete remission during maintenance treatment with no significant differences in safety profiles between the groups.

1. Multitarget Therapy for Maintenance
Treatment of Lupus Nephritis
Maj. Chaken Maniyan M.D.
Fellow nephrology
Phramongkutklao Hospital

2. Introduction
§ Treatment of lupus nephritis two phases:
§ Induction therapy
§ reverse immune processes and disease remission
§ high doses of immunosuppressant over short
period of time.
§ Maintenance treatment
§ ensure a durable response and prevent recurrences

3. Introduction
§ Induction treatment of LN with multitarget therapy (tacrolimus
and mycophenolate mofetil [MMF] combined with steroid for 24
weeks achieved a complete remission rate of 45.9%,
§ Efficacy of maintenance treatment with multitarget therapy in
patients with LN remains unclear.
§ We continued to treat patients in remission with a multitarget
maintenance treatment for an additional 18 months to assess the
efficacy of multitarget therapy for LN.

6. Study Design
§ This study was a continuation of induction-phase study
§ Continued multitarget therapy as a maintenance and did not
rerandomize patients before maintenance treatment.
§ This study was a prospective, open label, multicenter study
that compared efficacy and safety of multitarget therapy
with AZA treatment in patients who had responded to
induction therapy.

7. Study Participants
§ Patients with LN ages 18–65 years old who had
responded (CR or PR) to multitarget therapy or
IVCY during 24-week induction treatment were
recruited.

8. Exclusion criteria
§ Not achieve CR or PR at the end of the 24-week
induction phase,
§ Liver dysfunction
§ WBC < 3000/mm3
§ Chronic infections

9. Immunosuppressive Treatment
and Study Schedule
§ Patients who treated multitarget therapy during induction phase continued to multitarget therapy
§ Patients who treated IVCY induction were switched to AZA as a maintenance treatment.
§ Multitarget group continued to receive
§ MMF (0.75 g/d for 6 months and then tapered to 0.5 g/d for another 12 months) and
§ FK506 (3 mg/d for 6 months and then tapered to 2 mg/d for another 12 months)
§ AZA group were orally administered AZA (2 MKD for 18 months).
§ Oral prednisone to both groups at a dose of 10 mg/d

10. Immunosuppressive Treatment
and Study Schedule
§ Patients who treated multitarget therapy during induction phase continued to multitarget therapy
§ Patients who treated IVCY induction were switched to AZA as a maintenance treatment.
§ Multitarget group continued to receive
§ MMF (0.75 g/d for 6 months and then tapered to 0.5 g/d for another 12 months) and
§ FK506 (3 mg/d for 6 months and then tapered to 2 mg/d for another 12 months)
§ AZA group were orally administered AZA (2 MKD for 18 months).
§ Oral prednisone to both groups at a dose of 10 mg/d
§ Patients were prohibited from methotrexate, leflunomide, antimalarials, NSAIDs
§ Any drugs that affected blood concentrations of FK506 (e.g., macrolides, estradiol, rifampicin,
phenobarbital, carbamazepine, and fluconazole) were avoided.

11. Outcomes and Efficacy Assessment
§ Primary end point : cumulative rate of renal relapse at 18 months
§ Secondary end points
§ Rate of extrarenal relapse
§ Time to relapse
§ Rate of renal end point events (ESRD, doubling of SCr or a 30% reduction
in eGFR)
§ CR status at 6, 12, and 18 months during the maintenance treatment phase;
§ Changes in proteinuria, albumin, SCr, eGFR, immunologic indices
(antibodies, C3, and C4), and SLEDAI scores from baseline to month 18

12. Outcomes and Efficacy Assessment
§ Complete remission was defined as
§ 24-hour urinary protein excretion <0.4 g,
§ absence of active urine sediments, a serum albumin level >3.5 g/dL,
and a normal SCr level.
§ Partial remission was defined as a
§ >50% reduction in proteinuria and urine protein level < 3.5 g/24 h
§ Serum albumin level >3 g/dL
§ Normal or <25% increase in SCr level from baseline

13. Outcomes and Efficacy Assessment
§ Renal relapse was defined by presence of any
§ Persistent proteinuria >1.0 g/24 h after CR
§ Increase of >2.0 g/24 h after PR
§ Increase in SCr levels defined as > 50% increase in
SCr level compared with baseline
§ 30% increase in SCr compared with abnormal level
at baseline with increased hematuria

14. Study flow

15. Demographics and baseline characteristics

16. Probability of patients without renal relapse
during maintenance treatment

17. Patients in each group maintained CR status
during maintenance treatment

18. Changes in SCr levels and eGFR during the
maintenance treatment

19. Changes in proteinuria during the
maintenance treatment

20. Changes in serum C3 levels during the
maintenance treatment

21. Changes in SLEDAI during the
maintenance treatment

22. Cumulative probability of achieving CR

23. Adverse events during
maintenance treatments

24. Discussion
§ Relapse rate of patients with LN treated with multitarget therapy
was 5.47%, not significant compared with AZA (7.62%)
§ Lower relapse rate observed in this trial
§ In this study, 59.5 % of patients in multitarget group achieved CR
before maintenance study, whereas in Aspreva Lupus Management
Study (ALMS), rate of CR at end of induction therapy was 10%
§ Higher CR rate might explain why our studies showed lower
relapse rates during the maintenance treatment.

25. Discussion
§ Long term prognosis of patients with LN is determined by remission is achieved.
§ 10 yr renal survival rate in patients who achieved CR was 94%, whereas it was 45% in
patients with PR
§ According to ALMS, 62 % of patients in MMF group and 59.5% in AZA group achieved
CR during maintenance therapy
§ Notably, the CR rates were 59.5% in the multitarget group and 44.4% in the AZA
group at baseline; however, the CR rates increased to 78.3% and 78.0%, respectively, in
these groups at 18 months.
§ This catchup phenomenon was observed in the AZA arm, and it strengthens the value of
using AZA as a maintenance therapy.

26. Discussion
§ Incidence rates of overall adverse events = 16.4% in multitarget group and 44.4% in AZA
group.
§ Esp. liver dysfunction and leucopenia
§ 1.7% of patients in multitarget group withdrew from study due to adverse events, whereas
8.9% of patients in the AZA group withdrew from the study due to adverse events.
§ In Symphony Study of KT revealed that use of low-dose FK506, MMF, and prednisone for 3
years, with a trough FK506 con- centration of 3–7 ng/ml, had no effect on patients’ eGFRs
§ In this study, during 18-month maintenance treatment, the SCr levels and eGFR remained
stable in the multitarget and AZA groups, with no significant difference between two groups.

27. Limitations
§ Patients who did not respond to induction therapy
were not recruited;
§ Conducted only in a Chinese population.
§ A randomized, controlled trial is needed to further
evaluate the efficacy and safety of multitarget therapy as
a maintenance treatment for patients with LN.