current treatment strategies in anca-positive renal vasculitis

Nephrol Dial Transplant (2003) 18 [Suppl 5]: v2–v4

DOI: 10.1093/ndt/gfg1032

Current treatment strategies in ANCA-positive renal

vasculitis—lessons from European randomized trials

V. Tesar, Z. Rıhova, E. Jancova, R. Rysava and M. Merta

First Medical Department, First Medical Faculty, Charles University, Prague, Czech Republic

Abstract

Antineutrophil cytoplasmic antibody (ANCA)-positive renal vasculitis is the most common cause ofrapidly progressive (crescentic) glomerulonephritis.Its life-threatening natural course may be modifiedsubstantially by current treatment modalities. TheEuropean Vasculitis Study Group (EUVAS) developeda subclassification of ANCA-positive vasculitidesbased on the disease severity at presentation, andhave organized (so far) two waves of clinical trials.The first wave of randomized clinical trials had the aimof optimizing the existing therapeutic regimens; thesecond wave concentrated on testing some newertherapeutic approaches. Here, the design and availableresults of the first wave and the design of some secondwave trials are reviewed briefly. The potential of thenew targeted approaches (e.g. anti-tumour necrosisfactor therapy) is also briefly mentioned.

Keywords: anti-neutrophil cytoplasmic antibodies;treatment; vasculitis

Introduction

Pauci-immune rapidly progressive (crescentic) glomer-ulonephritides commonly are accompanied by thepresence of antineutrophil cytoplasmic antibodies(ANCAs) directed toward several epitopes of azuro-philic neutrophil granules. The most common types ofANCA are antibodies directed against proteinase-3(PR3) and myeloperoxidase (MPO).

ANCA-positive (or ANCA-associated) vasculitidescan be subclassified based on different criteria: from aclinical point of view, we can define Wegener’s granu-lomatosis, microscopic polyangiitis, Churg–Strauss

syndrome and isolated pauci-immune necrotizing/crescenting glomerulonephritis. Based on the subtypeof ANCA, we can differentiate between anti-PR3 andanti-MPO diseases [1]. These classifications are clearlyoverlapping: patients with Wegener’s granulomatosisusually have anti-PR3 antibodies, while anti-MPOantibodies are more common in microscopic poly-angiitis (micro-PAN). Some renal features are typicalof these different categories. Wegener’s granulomatosisand anti-PR3 disease may present with more activerenal disease (necrosis, epithelial crescents, acute orrapidly progressive renal failure) with a better chance ofimproving renal function, but with higher risk ofrelapses. Micro-PAN and anti-MPO disease may becharacterized more frequently by a more indolent renaldisease with less active and more chronic changes(fibrous crescents, glomerulosclerosis, interstitial fibro-sis) in the renal biopsy at presentation and with a lowerchance of improving renal function. Micro-PAN isusually associated with lower risk of relapses.

Classification of ANCA-positive vasculitides basedon disease severity

The European Vasculitis Study Group (EUVAS) wascreated gradually during the first half of the 1990s,starting with the investigation of the diagnostic roleof ANCA, followed by the standardization of ANCAtesting, histological assesment and the classification ofANCA-positive vasculitis. It was assumed that despitetheir different clinicopathological characteristics,ANCA-positive vasculitides could be studied together,and a new classification of ANCA-positive vasculi-tides, based on the severity of the disease, wasintroduced [2]. Pauci-immune small vessel vasculitideswere subclassified as follows: (i) localized vasculitis(with serum creatinine <120 mmol/l, no constitutionalsymptoms, no threat to any vital organ function andpositive or negative ANCA); (ii) early systemicvasculitis (with serum creatinine <120 mmol/l andconstitutional symptoms, no threat to any vital organ

Correspondence and offprint requests to: Vladimır Tesar, MD, PhD,First Medical Department, First Medical Faculty, CharlesUniversity, U nemocnice 2, Praha 2, 128 08, Czech Republic.E-mail: [email protected]

� 2003 European Renal Association–European Dialysis and Transplant Association

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function and positive or negative ANCA); (iii) gen-eralized vasculitis (with serum creatinine <500 mmol/land constitutional symptoms, dysfunction of any vitalorgan and positive ANCA); (iv) severe renal vasculitis(with serum creatinine >500 mmol/l, constitutionalsymptoms and positive ANCA); and (v) refractoryvasculitis (any serum creatinine, constitutional symp-toms, threatened function of any vital organ andpositive or negative ANCA). Daily oral cyclophos-phamide for 1 year in combination with a taperingdose of oral prednisolone was considered as astandard therapeutic regimen [3].

Lessons from clinical trials organized by EUVAS

In the so-called first wave of randomized clinical trialsaimed at optimizing existing therapeutic regimens, themost important studies compared the effect ofmethotrexate and cyclophosphamide on the remissionrate in early systemic vasculitis (NORAM trial), theeffect of short-term vs long-term treatment withcyclophosphamide (and early or later switch toazathioprine) on the relapse rate (CYCAZAREMtrial) in generalized vasculitis, and finally, the effect ofplasma exchange, or pulsed methylprednisolone asadd-on therapy on renal survival in severe renalvasculitis (MEPEX trial).

In the CYCAZAREM trial, all patients were treatedwith oral cyclophosphamide for 3–6 months (untilremission) and were then randomized either to switchto azathioprine or to undergo prolonged treatment withcyclophosphamide for 1 year and followed for 18months. Remission rate (93%) and relapse rate (16%altogether, 19% in patients with Wegener’s granulo-matosis and 8% in patients with microscopic poly-angiitis) were the same in both arms of the trial, with anon-significant trend to more frequent severe adverseevents during remission in patients on prolongedtreatment with cyclophosphamide [4]. Therefore, inpatients with generalized vasculitis (with impaired renalfunction, but without overt renal failure), the earlyswitch to azathioprine seems to be as safe andcomparably effective as prolonged treatment withcyclophosphamide.

In the MEPEX trial, the patients were randomized toadjunctive therapy with either seven plasma exchangetreatments (each 60ml/kg) or three pulses of intrave-nous methylprednisolone (each 15mg/kg). The 3months follow-up data have been published recently[5]. Although the mortality in both trial arms was thesame (16%), renal survival was much better in patientstreated with plasma exchange. Only 14.8% of patientstreated by plasma exchange remained dialysis depen-dent compared with 36.5% of patients treated bypulsed methylprednisolone. These data confirmed themeta-analysis of several smaller studies [4] and stronglysuggest that plasma exchange should be used as anadjunctive treatment in patients with ANCA-positiverenal vasculitis with acute renal failure.

The NORAM trial compared treatment either withoral cyclophosphamide (2mg/kg/day) or with oralmethotrexate (15–25mg weekly) with a similarlytapering dose of prednisolone for 1 year and follow-up of 18 months. According to preliminary data [6],the remission rates were similar in both trial arms (atthe end of 6 months, 83% vs 84% for methotrexateand cyclophosphamide, respectively), but the relapserate was higher (69% vs 42%) in patients treated withmethotrexate. The final evaluation should include theanalysis of the adverse event rate which is not yetavailable. A high relapse rate in both arms suggeststhat even in patients with early systemic vasculitis,immunosuppression should be prolonged beyond1 year.

Second wave randomized controlled trials wereaimed at testing newer approaches. Pulsed cyclo-phosphamide was compared with oral continuouscyclophosphamide in patients with generalized vascu-litis (the primary end-point is the disease-free period;the CYCLOPS trial), nasal mupirocin ointment iscompared with placebo in patients with Wegener’sgranulomatosis in stable remission (the end-point isthe relapse rate; the MUPIBAC trial) and prolongedtreatment with azathioprine and prednisolone (4years) is compared with shorter treatment (2 years,the end-point is the relapse rate; the REMAIN trial).

Patient recruitment for the CYCLOPS trial isalmost finished. Our centre recruited for this trial 28patients with newly diagnosed, biopsy-proven, ANCA-associated renal vasculitis (generalized vasculitis withserum creatinine <500 mmol/l). Currently, 18 patientshave completed the trial. Seven of them wererandomized to the pulse arm (10 pulses of cyclophos-phamide 15mg/kg i.v. during 6 months) and 11patients were treated with oral cyclophosphamide(2mg/kg/day for months 0–3 and 1.5mg/kg/day formonths 3–6). Non-fatal adverse events (mostly infec-tions) were frequent in both arms of the trial (45%). Themortality was relatively high and tended to be higher inpatients treated with oral cyclophosphamide (1/7 vs4/11), mostly due to infectious complications. All otherpatients with the exception of one in the oral arm wentinto remission, and only one relapse was documented inthe pulsed arm. These data are in keeping with therecently published meta-analysis [7] demonstrating alower cumulative dose of cyclophosphamide (17 g vs34 g), a higher remission rate (93% vs 77%), a lowerinfection rate (39% vs 58%), but also a higher relapserate (42% vs 29%) in patients treated with pulsed(compared with oral continuous) cyclophosphamide.The final results of the CYCLOPS trial should help us todefine newer recommendations concerning the role ofcyclophosphamide treatment in generalized ANCA-positive vasculitis.

Newer therapeutic approaches

Newer immunosuppressive drugs currently are beingtested in patients with ANCA-positive vasculitis. Based

Current treatment strategies in ANCA-positive renal vasculitis v3


on a small pilot study with mycophenolate mofetil [8],EUVAS recently launched the IMPROVE trialcomparing mycophenolate and azathioprine as a main-tenance therapy in patients in remission. Anti-tumournecrosis factor (TNF) strategies (anti-TNF antibodyinfliximab and humanized soluble TNF receptoretanercept) hopefully may also improve further theoutcome and the quality of life in patients with ANCA-positive vasculitis (Wegener’s granulomatosis [9]).

Based on the experience from these Europeanrandomized trials, the treatment of ANCA-positivevasculitides should be tailored according to thedisease severity at presentation. Current therapywith cyclophosphamide is quite effective, but hasrelatively high short- and long-term toxicity. Thesearch for therapeutic modalities which are at least aseffective but less toxic is therefore warranted.

References

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2. Jayne D. Update on the European Vasculitis Study Grouptrials. Curr Opin Rheumatol 2001; 13: 48–55

3. Hoffman GS, Kerr GS, Leavitt RY et al. Wegenergranulomatosis: an analysis of 158 patients. Ann Intern Med1992; 116: 488–498

4. Jayne D. Conventional treatment and outcome of Wegener’sgranulomatosis and microscopic polyangiitis. Cleveland Clin JMed 2002; 69 [Suppl 2]: 110–115

5. Gaskin G, Jayne D. Adjunctive plasma exchange is superior tomethylprednisolone in acute renal failure due to ANCA-associated glomerulonephritis. J Am Soc Nephrol 2002; 13[Suppl S]: 2A–3A

6. De Groot K, Rasmussen N, Cohen Tervaert JW, Jayne DRW.Randomized trial of cyclophosphamide versus methotrexate forinduction of remission in ‘non-renal’ ANCA-associatedvasculitis. Cleveland Clin J Med 2002; 69 [Suppl 2]: 116

7. De Groot K, Adu D, Savage C. The value of pulsecyclophosphamide in ANCA-associated vasculitis: meta-analysis and critical review. Nephrol Dial Transplant 2001; 16:2018–2027

8. Nowack R, Gobel U, Klooker P et al. Mycophenolate mofetilfor maintenance therapy of Wegener’s granulomatosis andmicroscopic polyangiitis: a pilot study in 11 patients with renalinvolvement. J Am Soc Nephrol 1999; 10: 1965–1971

9. Stone J, Uhlfelder M, Hellmann D et al. Etanercept withconventional treatment in Wegener’s granulomatosis: a sixmonth open-label trial to evaluate safety. Arthritis Rheum 2001;44: 1149–1154

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current treatment strategies in anca-positive renal vasculitis

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