Efficacy and safety of multitarget therapy with cyclophosphamide and tacrolimus for lupus nephritis: a prospective,single-arm,single-centre,open label pilot study in Japan

Abstract

Background

Pulsed cyclophosphamide or mycophenolate mofetil for lupus nephritis has limited efficacy. We previously reported a case of mixed-class IV + V lupus nephritis successfully treated with cyclophosphamide and tacrolimus. This study assessed the efficacy and safety of multitarget therapy with cyclophosphamide and tacrolimus for the treatment of lupus nephritis.

Methods

In a prospective, single-arm, open label pilot study, we recruited 15 patients aged 18–64 years with active lupus nephritis who met the American College of Rheumatology criteria for a diagnosis of systemic lupus erythematosus (1997). The treatment protocol was a starting dose of prednisolone of 0.6−1.0 mg/kg/day for 2 weeks and then tapered to a maintenance dose, intravenous cyclophosphamide (500 mg biweekly for 3 months) and tacrolimus (3.0 mg/day). Tacrolimus was continued as maintenance therapy. Complete remission was defined as a spot urine protein/creatinine ratio of < 0.5 g/gCr with no active urine casts and a serum creatinine level that was either normal or within 30% of a previously abnormal baseline level. We retrospectively compared results for the study patients with those of 18 historical controls conventionally treated with cyclophosphamide and prednisolone.

Results

At baseline, the mean patient age was 41.5 ± 14.6 years (male:female ratio 2:13), urine protein/creatinine ratio 3.9 ± 2.3 g/gCr and serum creatinine 84.6 ± 34.6 µmol/L. Lupus nephritis classifications included classes IV (n = 8), III + V (n = 1), IV + V (n = 5) and unclassified (n = 1). Eleven patients completed the treatment protocol and four withdrew. At 6 months, 12 of 15 (80.0%) had achieved complete remission using intention-to-treat analysis, significantly more than historical controls (seven of 18 patients, 38.9%). A transient increase in serum creatinine and gastric symptoms occurred in three cases. One patient withdrew due to cytomegalovirus antigenemia and severe diabetes, and one patient died of thrombotic microangiopathy.

Conclusions

Multitarget therapy with cyclophosphamide and tacrolimus can be a therapeutic option for lupus nephritis.

Clinical trials registration

Combination therapy of tacrolimus and intravenous cyclophosphamide for remission induction of lupus nephritis, UMIN: 000004893, URL: https://upload.umin.ac.jp/cgi-open-bin/ctr/ctr.cgi?function=brows&action=brows&type=summary&recptno=R000005830&language=E. Date of registration: 18 January 2011.

Keywords

Cyclophosphamide lupus nephritis multitarget therapy mycophenolate mofetil tacrolimus

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References

Appel

Contreras

Dooley

et al.

Mycophenolate mofetil versus cyclophosphamide for induction treatment of lupus nephritis. J Am Soc Nephrol 2009; 20: 1103–1112.

Ginzler

Dooley

Aranow

et al.

Mycophenolate mofetil or intravenous cyclophosphamide for lupus nephritis. N Engl J Med 2005; 353: 2219–2228.

Peng

et al.

A prospective multicentre study of mycophenolate mofetil combined with prednisolone as induction therapy in 213 patients with active lupus nephritis. Lupus 2008; 17: 622–629.

Ren

Zhang

et al.

Mycophenolate mofetil or tacrolimus compared with intravenous cyclophosphamide in the induction treatment for active lupus nephritis. Nephrol Dial Transplant 2012; 27: 1467–1472.

Mok

Lau

Wong

. Risk factors for ovarian failure in patients with systemic lupus erythematosus receiving cyclophosphamide therapy. Arthritis Rheum 1998; 41: 831–837.

Plotz

Klippel

Decker

et al.

Bladder complications in patients receiving cyclophosphamide for systemic lupus erythematosus or rheumatoid arthritis. Ann Intern Med 1979; 91: 221–223.

Tessier-Cloutier

Clarke

Ramsey-Goldman

Gordon

Hansen

Bernatsky

. Systemic lupus erythematosus and malignancies: a review article. Rheum Dis Clin North Am 2014; 40: 497–506; viii.

BaO

Liu

Z-H

Xie

H-L

W-X

Zhang

H-T

L-S

. Successful treatment of class V+IV lupus nephritis with multitarget therapy. J Am Soc Nephrol 2008; 19: 2001–2010.

Liu

Zhang

Liu

et al.

Multitarget therapy for induction treatment of lupus nephritis: a randomized trial. Ann Intern Med 2015; 162: 18–26.

10.

Ikeuchi

Hiromura

Takahashi

et al.

Efficacy and safety of multi-target therapy using a combination of tacrolimus, mycophenolate mofetil and a steroid in patients with active lupus nephritis. Mod Rheumatol 2014; 24: 618–625.

11.

Tanaka

Aizawa

Watanabe

Oki

Tsuruga

Imaizumi

. Efficacy of mizoribine-tacrolimus-based induction therapy for pediatric lupus nephritis. Lupus 2014; 23: 813–818.

12.

Nomura

Shimizu

Kishimoto

et al.

Efficacy and safety of multitarget therapy with mizoribine and tacrolimus for systemic lupus erythematosus with or without active nephritis. Lupus 2012; 21: 1444–1449.

13.

Kagawa

Hiromasa

Hara

et al.

Mizoribine, tacrolimus, and corticosteroid combination therapy successfully induces remission in patients with lupus nephritis. Clin Exp Nephrol 2012; 16: 760–766.

14.

Lanata

Mahmood

Fine

Petri

. Combination therapy of mycophenolate mofetil and tacrolimus in lupus nephritis. Lupus 2010; 19: 935–940.

15.

Mok

. Combined low-dose mycophenolate mofetil and tacrolimus for lupus nephritis with suboptimal response to standard therapy: a 12-month prospective study. Lupus 2013; 22: 1135–1141.

16.

Cortes-Hernandez

Torres-Salido

Medrano

Tarres

Ordi-Ros

. Long-term outcomes – mycophenolate mofetil treatment for lupus nephritis with addition of tacrolimus for resistant cases. Nephrol Dial Transplant 2010; 25: 3939–3948.

17.

Condon

Ashby

Pepper

et al.

Prospective observational single-centre cohort study to evaluate the effectiveness of treating lupus nephritis with rituximab and mycophenolate mofetil but no oral steroids. Ann Rheum Dis 2013; 72: 1280–1286.

18.

Parikh

Rovin

. Current and emerging therapies for lupus nephritis. J Am Soc Nephrol 2016; 27: 2929–2939.

19.

Yasuda

Atsumi

Shimamura

et al.

Surveillance for the use of mycophenolate mofetil for adult patients with lupus nephritis in Japan. Mod Rheumatol 2015; 25: 854–857.

20.

Nishi

Kameda

Ogawa

et al.

Efficacy of weekly mizoribine pulse therapy in refractory lupus nephritis. Mod Rheumatol 2013; 23: 97–103.

21.

Boumpas

Austin

Vaughn

et al.

Controlled trial of pulse methylprednisolone versus two regimens of pulse cyclophosphamide in severe lupus nephritis. Lancet (London, England) 1992; 340: 741–745.

22.

Bertsias

Tektonidou

Amoura

et al.

Joint European League Against Rheumatism and European Renal Association–European Dialysis and Transplant Association (EULAR/ERA–EDTA) recommendations for the management of adult and paediatric lupus nephritis. Ann Rheum Dis 2012; 71: 1771–1782.

23.

Kurasawa

Nagasawa

Nishi

et al.

Successful treatment of class IV+V lupus nephritis with combination therapy of high-dose corticosteroids, tacrolimus and intravenous cyclophosphamide. Intern Med 2013; 52: 1125–1130.

24.

Hochberg

. Updating the American College of Rheumatology revised criteria for the classification of systemic lupus erythematosus. Arthritis Rheum 1997; 40: 1725.

25.

Houssiau

Vasconcelos

D'Cruz

et al.

Immunosuppressive therapy in lupus nephritis: the Euro-Lupus Nephritis Trial, a randomized trial of low-dose versus high-dose intravenous cyclophosphamide. Arthritis Rheum 2002; 46: 2121–2131.

26.

Bombardier

Gladman

Urowitz

Caron

Chang

. Derivation of the SLEDAI. A disease activity index for lupus patients. The Committee on Prognosis Studies in SLE. Arthritis Rheum 1992; 35: 630–640.

27.

Weening

D'Agati

Schwartz

et al.

The classification of glomerulonephritis in systemic lupus erythematosus revisited. J Am Soc Nephrol 2004; 15: 241–250.

28.

Austin

Muenz

Joyce

et al.

Prognostic factors in lupus nephritis. Contribution of renal histologic data. Am J Med 1983; 75: 382–391.

29.

Mok

. Con: Cyclophosphamide for the treatment of lupus nephritis. Nephrol Dial Transplant 2016; 31: 1053–1057.

30.

Somers

Marder

Christman

Ognenovski

McCune

. Use of a gonadotropin-releasing hormone analog for protection against premature ovarian failure during cyclophosphamide therapy in women with severe lupus. Arthritis Rheum 2005; 52: 2761–2767.

31.

Blumenfeld

Mischari

Schultz

Boulman

Balbir-Gurman

. Gonadotropin releasing hormone agonists may minimize cyclophosphamide associated gonadotoxicity in SLE and autoimmune diseases. Semin Arthritis Rheum 2011; 41: 346–352.

32.

Helfrich

Banner

Steen

Medsger

. Normotensive renal failure in systemic sclerosis. Arthritis Rheum 1989; 32: 1128–1134.

33.

Pham

Peng

Wilkinson

et al.

Cyclosporine and tacrolimus-associated thrombotic microangiopathy. Am J Kidney Dis 2000; 36: 844–850.

34.

Isenberg

Appel

Contreras

et al.

Influence of race/ethnicity on response to lupus nephritis treatment: the ALMS study. Rheumatology (Oxford) 2010; 49: 128–140.

35.

Szeto

C-C

Kwan

BC-H

Lai

FM-M

et al.

Tacrolimus for the treatment of systemic lupus erythematosus with pure class V nephritis. Rheumatology (Oxford) 2008; 47: 1678–1681.

36.

Tedeschi

Arnaud

Hie

Mathian

Amoura

. Successful treatment of combined proliferative and membranous lupus nephritis using a full corticosteroid-free regimen. Ann Rheum Dis 2014; 73: 474–475.

37.

Tanaka

Takeuchi

Miyasaka

et al.

Efficacy and safety of rituximab in Japanese patients with systemic lupus erythematosus and lupus nephritis who are refractory to conventional therapy. Mod Rheumatol 2016; 26: 80–86.

38.

Moroni

Raffiotta

Trezzi

et al.

Rituximab vs mycophenolate and vs cyclophosphamide pulses for induction therapy of active lupus nephritis: a clinical observational study. Rheumatology (Oxford) 2014; 53: 1570–1577.

39.

Chen

S-Y

Choi

C-B

et al.

Glucocorticoid use in patients with systemic lupus erythematosus: association between dose and health care utilization and costs. Arthritis Care Res (Hoboken) 2015; 67: 1086–1094.

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