Efficacy and safety of bortezomib in refractory lupus nephritis: a single-center experience

Abstract

Background and Objectives

Resistant lupus nephritis (LN) has been associated with the persistence of long-lived plasma cells. Preliminary studies identified bortezomib as a potential treatment option for patients with refractory LN. The aim of this study was to analyze the efficacy and safety of bortezomib in the treatment of severe refractory LN.

Methods

This retrospective study included 12 female patients diagnosed for the first time with class IV or IV/V LN with acute or rapidly progressive kidney injury (n = 11) and/or severe nephrotic syndrome (n = 1) who showed resistance to induction therapy with cyclophosphamide, steroids, mycophenolate, and rituximab, and were treated with either intravenous or subcutaneous bortezomib plus intravenous dexamethasone.

Results

All patients with acute or rapidly progressive kidney injury showed a significant reduction in both biochemical and immunological activity after a mean of 6 (minimum 5, maximum 7) weekly cycles of bortezomib regimen, with a significant increase in C3 levels and a significant decrease of anti-ds DNA antibody titers, Systemic Lupus Erythematosus Disease Activity Index score, serum creatinine, and proteinuria. One patient (8.3%) achieved a complete response, and 10 patients (83.4%) achieved a partial response. During follow-up, all these patients maintained partial responses under treatment with mycophenolate and low-dose glucocorticoids. The patient with refractory nephrotic syndrome showed a partial response but relapsed 11 months after the end of bortezomib treatment and was resistant to treatment. A significant decrease in serum IgG levels after initiation of bortezomib treatment was observed in all patients, five of them (41.6%) showed hypogammaglobulinemia (<500 mg/dl), but no patient suffered from opportunistic infections; in only two patients (16.6%) hypogammaglobulinemia persisted at the end of follow-up. Two patients (16.6%) suffered from sensory neuropathy, which led to bortezomib treatment discontinuation.

Conclusions

Bortezomib may be an effective option for refractory LN, but close monitoring must be performed for possible adverse events such as peripheral neuropathy and hypogammaglobulinemia.

Keywords

Lupus nephritis bortezomib refractory lupus nephritis proteasome inhibitor

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References

Weening

D'Agati

Schwartz

, et al. The classification of glomerulonephritis in systemic lupus erythematosus revisited. Kidney Int 2004; 65: 521–530.

Zimmerman

Radhakrishnan

Valeri

Appel

. Advances in the treatment of lupus nephritis. Annu Rev Med 2001; 52: 63–78.

Contreras

Pardo

Leclercq

, et al. Sequential therapies for proliferative lupus nephritis. N Engl J Med 2004; 350: 971–980.

Clark

Sontrop

. What have we learned about optimal induction therapy for lupus nephritis (III through V) from randomized, controlled trials? Clin J Am Soc Nephrol 2008; 3: 895–898.

Chan

Tang

CSO

, et al. Efficacy of mycophenolate mofetil in patients with diffuse proliferative lupus nephritis. Hong Kong–Guangzhou Nephrology Study Group. N Engl J Med 2000; 343: 1156–1162.

Sinclair

Appel

Dooley

, et al. Mycophenolate mofetil as induction and maintenance therapy for lupus nephritis: rationale and protocol for the randomized, controlled Aspreva Lupus Management Study (ALMS). Lupus 2007; 16: 972–980.

Ginzler

Dooley

Aranow

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

Cortés-Hernández

Ordi-Ros

Labrador

, et al. Predictors of poor renal outcome in patients with lupus nephritis treated with combined pulses of cyclophosphamide and methylprednisolone. Lupus 2003; 12: 287–296.

Radhakrishnan

Cattran

. The KDIGO practice guideline on glomerulonephritis: reading between the (guide)lines—application to the individual patient. Kidney Int 2012; 82: 840–856.

10.

Hahn

McMahon

Wilkinson

, et al. American College of Rheumatology guidelines for screening, treatment, and management of lupus nephritis. Arthrit Care Res (Hoboken) 2012; 64: 797–808.

11.

Rauova

Lukac

Levy

Rovensky

Shoenfeld

. High-dose intravenous immunoglobulins for lupus nephritis—a salvage immunomodulation. Lupus 2001; 10: 209–213.

12.

Smith

KGC

Jones

Burns

Jayne

DRW

. Long-term comparison of rituximab treatment for refractory systemic lupus erythematosus and vasculitis: remission, relapse, and re-treatment. Arthrit Rheum 2006; 54: 2970–2982.

13.

Chan

Tse

Tang

CSO

Lai

. Long-term outcome of patients with diffuse proliferative lupus nephritis treated with prednisolone and oral cyclophosphamide followed by azathioprine. Lupus 2005; 14: 265–272.

14.

Pons-Estel

Serrano

Plasín

Espinosa

Cervera

. Epidemiology and management of refractory lupus nephritis. Autoimmun Rev 2011; 10: 655–663.

15.

Weidenbusch

Römmele

Schröttle

Anders

. Beyond the LUNAR trial. Efficacy of rituximab in refractory lupus nephritis. Nephrol Dial Transplant 2013; 28: 106–111.

16.

Hoyer

Moser

Hauser

, et al. Short-lived plasmablasts and long-lived plasma cells contribute to chronic humoral autoimmunity in NZB/W mice. J Exp Med 2004; 199: 1577–1584.

17.

Manz

Hauser

Hiepe

Radbruch

. Maintenance of serum antibody levels. Annu Rev Immunol 2005; 23: 367–386.

18.

Neubert

Meister

Moser

, et al. The proteasome inhibitor bortezomib depletes plasma cells and protects mice with lupus-like disease from nephritis. Nat Med 2008; 14: 748–755.

19.

Lee

Kim

. Comparison of therapeutic efficacy between bortezomib and combination treatment of prednisolone and mycophenolate mofetil on nephritis in NZB/WF1 mice. Clin Exp Rheumatol 2010; 28: 393–396.

20.

Hainz

Thomas

Neubert

, et al. proteasome inhibitor bortezomib prevents lupus nephritis in the NZB/W F1 mouse model by preservation of glomerular and tubulointerstitial architecture. Nephron Exp Nephrol 2012; 120: e47–e58.

21.

Ichikawa

Conley

Muchamuel

, et al. Beneficial effect of novel proteasome inhibitors in murine lupus via dual inhibition of type I interferon and autoantibody-secreting cells. Arthrit Rheum 2012; 64: 493–503.

22.

Fröhlich

Holle

Aries

Gross

Moosig

. Successful use of bortezomib in a patient with systemic lupus erythematosus and multiple myeloma. Ann Rheum Dis 2010; 70: 1344–1345.

23.

Voll

Alexander

Peukert

, et al. SAT0203 Successful treatment of refractory SLE patients with the proteasome inhibitor bortezomib – a case series. Ann Rheum Dis 2013; 71: 540–540.

24.

Alexander

Sarfert

Klotsche

, et al. The proteasome inhibitor bortezomib depletes plasma cells and ameliorates clinical manifestations of refractory systemic lupus erythematosus. Ann Rheum Dis 2015; 74: 1474–1478.

25.

Kellum

Lameire

Aspelin

, et al. KDIGO clinical practice guideline for acute kidney injury. Kidney Int Suppl 2012; 2: 19–36.

26.

Couser

. Rapidly progressive glomerulonephritis: classification, pathogenetic mechanisms, and therapy. Am J Kidney Dis 1988; 11: 449–464.

27.

Jindal

. Management of idiopathic crescentic and diffuse proliferative glomerulonephritis: evidence-based recommendations. Kidney Int Suppl 1999; 70: S33–40.

28.

Richardson

Sonneveld

Schuster

, et al. Bortezomib or high-dose dexamethasone for relapsed multiple myeloma. N Engl J Med 2005; 352: 2487–2498.

29.

Quartuccio

Rupolo

Michieli

de Vita

. Efficacy and tolerability of repeated cycles of a once-weekly regimen of bortezomib in lupus. Rheumatology (Oxford) 2014; 53: 381–382.

30.

Gladman

Ibañez

Urowitz

. Systemic lupus erythematosus disease activity index 2000. J Rheumatol 2002; 29(2): 288–291.

31.

Cavaletti

Gilardini

Canta

, et al. Bortezomib-induced peripheral neurotoxicity: a neurophysiological and pathological study in the rat. Exp Neurol 2007; 204: 317–325.

32.

Cata

Weng

H-R

Burton

Villareal

Giralt

Dougherty

. Quantitative sensory findings in patients with bortezomib-induced pain. J Pain 2007; 8: 296–306.

33.

Palumbo

Bringhen

Ludwig

, et al. Personalized therapy in multiple myeloma according to patient age and vulnerability: a report of the European Myeloma Network (EMN). Blood 2011; 118: 4519–4529.

34.

Bringhen

Larocca

Rossi

, et al. Efficacy and safety of once-weekly bortezomib in multiple myeloma patients. Blood 2010; 116: 4745–4753.

35.

Tokuhira

Watanabe

Nemoto

, et al. Successful treatment with a modified bortezomib schedule of weekly and longer intervals for patients with refractory/resistance multiple myeloma. Leuk Res 2011; 35: 591–597.

36.

Hirai

Kadowaki

Kitawaki

, et al. Bortezomib suppresses function and survival of plasmacytoid dendritic cells by targeting intracellular trafficking of Toll-like receptors and endoplasmic reticulum homeostasis. Blood 2011; 117: 500–509.

37.

Wahren-Herlenius

Dörner

. Immunopathogenic mechanisms of systemic autoimmune disease. Lancet 2013; 382: 819–831.

38.

Aoki

Nishiyama

Imahashi

Kitamura

. Efficacy of continuous, daily, oral, ultra-low-dose 200 mg acyclovir to prevent herpes zoster events among bortezomib-treated patients: a report from retrospective study. Jpn J Clin Oncol 2011; 41: 876–881.

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