Department of Rheumatology, University of Schleswig-Holstein, Campus Luebeck, Rheumaklinik Bad Bramstedt GmbH, Bad Bramstedt, Germany.
Correspondence to: E. Reinhold-Keller, Poliklinik für Rheumatologie des Universitätsklinikums Schleswig-Holstein, Campus Luebeck, Rheumaklinik Bad Bramstedt GmbH, Oskar-Alexander-Strasse 26, D-24576 Bad Bramstedt, Germany. E-mail: RKeller{at}rheuma-zentrum.de
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Abstract |
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Methods. This was a Phase II, single-centre, open-label clinical investigation of patients with generalized WG treated with leflunomide after the induction of complete (n = 4) or partial (n = 16) remission by cyclophosphamide/prednisolone combination therapy. Leflunomide treatment was initiated at 20 mg/day and increased to 30 mg/day after 12 weeks and, in patients with partial remission, to 40 mg/day after 24 weeks. Concomitant low-dose prednisolone (10 mg/day) was allowed during the study. In addition to the frequency of relapse, treatment efficacy was assessed by the standard measures of disease activity/extent.
Results. A total of 20 patients were enrolled in the trial. During a treatment period of up to 2.5 yr (median 1.75 yr, range 12.5 yr), one patient had a major relapse and required retreatment with cyclophosphamide/prednisolone. Eight patients had minor relapses that were successfully treated by dose increases to 40 mg/day leflunomide. Disease activity remained unchanged for the duration of the study. The most frequently reported adverse events were mild respiratory infection (40%), arthralgia (35%) and hypertension (35%); dry skin, nail disorder and diarrhoea were each reported by 30% of patients. Despite the aggressive pretreatment with cyclophosphamide, adverse events with leflunomide treatment at the higher dose (3040 mg/day) were comparable with those seen with the standard dose (20 mg/day) for rheumatoid arthritis patients.
Conclusion. Leflunomide appears to be safe and well tolerated for the maintenance of complete or partial remission of WG. The results of this pilot study encourage further controlled trials comparing leflunomide with alternative remission maintenance therapies.
KEY WORDS: Wegener's granulomatosis, Leflunomide, Prednisolone, Remission, Maintenance therapy.
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Introduction |
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Leflunomide is a new disease-modifying anti-rheumatic drug (DMARD) which is approved for the treatment of rheumatoid arthritis (RA). It targets activated T-cells and other immunocompetent cells [5] and thus may prove to be another therapeutic option for the maintenance of remission in WG [8]. The present trial is a pilot study of the safety and efficacy of leflunomide for the treatment of patients with WG in partial or complete remission.
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Patients and methods |
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Study design
This was a single-centre, open-label trial. The study started directly after induction therapy with cyclophosphamide and prednisolone. There was a 1-week screening phase followed by a 52-week treatment period. Patients discontinuing treatment for any reason during the initial 52-week period were observed for an additional 8-week period.
The doses of leflunomide used were higher than those recommended for the treatment of RA because of the severity of disease in these patients. All patients received a leflunomide loading dose of 100 mg/day for 3 days, followed by 20 mg/day for up to 12 weeks. After 12 weeks of treatment, the leflunomide dose was increased by repeating the 100 mg/day loading dose for 2 days, followed by a dose of 30 mg/day. After 24 weeks of treatment, if the patient had not achieved complete remission compared with the first interdisciplinary efficacy assessment [2, 11], the leflunomide dose was increased again, to 40 mg/day. Patients who benefited from leflunomide treatment were given the option of continuing therapy for up to two additional years. Dose reduction was not permitted. In the case of an adverse event necessitating dose reduction, the patient had to be withdrawn from the study and a cholestyramine washout procedure was applied. Concomitant low-dose prednisolone (10 mg/day) was permitted during the study; in the absence of disease activity it was tapered by 2.5 mg every month until it reached 5 mg and was tapered thereafter by 1 mg/month.
The protocol was conducted in accordance with the principles of the good clinical practice guidelines of the European Community and the Declaration of Helsinki. The study was also carried out in keeping with local legal requirements. All patients gave written informed consent to participation in the study.
Efficacy outcomes
The primary efficacy outcome was the frequency of major/minor relapses. Further efficacy outcomes were the evaluation of disease activity using the Disease Extent Index (DEI) [12], the Birmingham Vasculitis Activity Score (BVAS) (first version) [13] and the cytoplasmic antineutrophil cytoplasmic antibody (cANCA) titre [14]. The initial study end-point was defined as 52 weeks, but patients could stay on treatment if it was successful, and assessments were then continued to the last visit. The DEI gives the equivalent of organ involvement attributable to active disease in WG [12], whereas the BVAS considers clinical features and laboratory data to give a measure of vasculitis activity [13]. A major relapse was defined as life- or organ-threatening disease activity requiring cessation of leflunomide and reinstitution of cyclophosphamide. Such manifestations included acute renal failure, acute pulmonary haemorrhage and heart or central nervous system conditions. A minor relapse was defined as an increase in WG activity without life- or organ-threatening manifestations treated with an increase in the leflunomide dose prior to the 12- and 24-week time-points specified in the protocol and/or an increase in the prednisolone dose. All patients who received at least one dose of study medication and who had any follow-up data were analysed, and missing post-baseline data were replaced using the last observation carried forward method.
Secondary efficacy outcomes included patient self-assessment of disease activity, the Medical Outcomes Survey Short Form-36 (SF-36) (36 questions concerning physical, emotional and mental functionality, pain and social handicap) [15, 16] and levels of acute-phase reactants, specifically the Westergren erythrocyte sedimentation rate (ESR) and C-reactive protein (CRP) concentration.
Safety outcomes
Patient-reported adverse events were recorded at each visit and were assessed according to body system and the relationship to study medication. Laboratory safety data included haematology measures (full blood count), extended blood chemistry measures (creatinine, liver enzymes) and urinalysis.
Statistical analysis
In general, continuous data are described using summary statistics, and categorical data are described using absolute and relative frequencies. Because this was an uncontrolled pilot study, data were analysed descriptively. Summary statistics were calculated for the DEI, BVAS, cANCA titres, ESR and CRP in terms of changes from baseline and mean values at each time-point.
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Results |
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In general, mean total SF-36 scores did not vary over time. The mean total SF-36 score was 2.8 at baseline (range 2.03.5) and was still 2.8 (range 1.93.5) at the study end-point, indicating that patient functional ability was maintained over the course of leflunomide treatment.
The traditional measures of the acute-phase response are ESR and CRP levels. The mean ESR increased slightly, from 29.1 (range 6.094.0) mm/1st h at baseline to 35.9 (8.080.0) mm/1st h at the study end-point. This change equated to a mean increase of 6.9 mm/1st h with a range of 6.220.0 mm/1st h. Mean (range) CRP level was 0.7 (0.52.2) mg/dl at baseline and 1.1 (0.54.1) mg/dl at the end-point, indicating that there was no remarkable change in CRP during the investigation. Concomitant prednisolone could be tapered from the median (range) of 4.5 (010) to 1 (010) mg/day.
Safety outcomes
All 20 patients were included in the safety analysis. Only one patient was non-compliant with the study medication (<80% study medication). Table 2 summarizes adverse events possibly related to study medication. All 20 patients reported at least one adverse event during the treatment period. A total of 166 adverse events were reported, with an average of 8.3 adverse events per patient.
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Four of the seven patients reporting hypertension as an adverse event also suffered from hypertension as a concomitant, pre-existing disease, and two of these patients had pre-existing renal disorders (kidney failure and kidney cyst). Hypertension was newly observed in three patients during the study. Nine patients (45%) experienced adverse events that were judged by the study investigators to be causally related to the study medication: hypertension in three patients, and diarrhoea, nausea and alopecia in two patients each.
There were no cases of leucopenia reported in any patients. Furthermore, abnormal elevations in liver enzymes were not observed in any patients.
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Discussion |
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Twenty patients participated in this single-centre, open-label, pilot investigation of WG remission maintenance therapy using daily leflunomide (30 mg/40 mg) and low-dose prednisolone. Over a treatment period of up to 2.5 yr, only one patient suffered from a major relapse that required the reinstatement of cyclophosphamide therapy. Minor relapses were reported in eight patients, and in the majority of cases these minor events occurred after 1 yr of remission maintenance with leflunomide. All patients with minor relapses were successfully treated with an increase in leflunomide dose to 40 mg/day, four of these patients also requiring a transient increase in the prednisolone dose. Mean DEI and BVAS were maintained from baseline to the study end-point, indicating the maintenance of disease activity. Furthermore, concomitant prednisolone treatment was reduced in four patients and unchanged in 12 patients, and overall the median dose of prednisolone was reduced from 4.5 mg daily at the start of the study to 1 mg daily at the study end-point. Only one patient experienced a drug-related adverse event requiring discontinuation of the study medication.
The present open-label investigation was designed primarily to assess the safety of leflunomide treatment in daily doses of up to 40 mg for the maintenance of remission in WG patients, and secondarily to assess treatment efficacy. Therefore, comparative assessments of leflunomide treatment and alternative remission maintenance therapies can only be qualitative. In a comparable open-label investigation of remission maintenance in 31 WG patients treated with low-dose methotrexate following remission induction with cyclophosphamide and prednisolone, five of the 31 patients (16%) suffered disease relapse after a median period of 13 months and a median of 8 months to discontinuation of steroids [3]. This compares with a median time to discontinuation of prednisolone of 12 months in the present study. In a further large cohort consisting of 71 WG patients in remission treated with low-dose methotrexate maintenance therapy, 26 patients (37%) suffered a relapse over a similar observation period; 18 of these relapses were classified as major relapses, 16 of them with serious renal involvement [4]. In a study of nine patients with WG and two patients with microscopic polyangiitis treated with mycophenolate mofetil for the maintenance of remission, one relapse occurred during the 1-yr treatment period. The number of adverse events was high; they included two cases of leucopenia, two respiratory infections and one report of cytomegalovirus colitis [17].
The preliminary results of the first prospective, randomized controlled study from the European Vasculitis Study Group CYCAZAREM (Cyclophosphamide vs. Azathioprine as Maintenance of Remission) revealed a relapse rate of 17% with cyclophosphamide and 16% with azathioprine [18]. However, the follow-up period of this study was only 18 months from diagnosis [18]. Consistent with the present study, most relapses occurred at least 1 yr after initiation of the remission regimen.
Trimethoprimsulphamethoxazole has also been evaluated as an alternative remission maintenance therapy [19, 20]. In a placebo-controlled trial, trimethoprimsulphamethoxazole reduced the incidence of WG disease relapse: 82% of trimethoprimsulphamethoxazole-treated patients remained in remission over 24 months of therapy compared with 60% of placebo-treated patients [19]. However, results of a subsequent non-placebo-controlled study [20] revealed higher relapse rates with trimethoprimsulphamethoxazole monotherapy than with placebo for the maintenance of remission in WG.
The present study suggests that leflunomide combined with low-dose prednisolone is at least comparable to methotrexate combined with prednisolone for the maintenance of remission of WG induced by cyclophosphamide/prednisolone; however, a randomized trial comparing the two treatments will provide a more valid assessment of efficacy. Such a prospective, randomized, controlled, multicentre study comparing methotrexate with leflunomide for the maintenance of remission in WG has recently been initiated in Germany.
Leflunomide has potential advantages over methotrexate in maintaining remission in WG patients with renal insufficiency, due to leflunomide's lack of accumulation with decreased renal function. An important advantage of leflunomide compared with all other drugs is the absence of complications in patients with leucopenia. In the present study, no induction or worsening of pre-existing leucopenia was encountered during the study period, even with the higher dose of 40 mg leflunomide per day, especially in comparison with a comparable group of WG patients treated with methotrexate for the maintenance of remission, in which 15% of transient leucopenias were reported [21]. In fact, the safety profile of leflunomide at the higher than normal dosing regimen for WG was comparable to that found in clinical trials of leflunomide therapy for the treatment of RA.
In the present study, liver function tests for all WG patients were within normal ranges. This is in contrast to previous clinical trials of leflunomide for RA, in which mild, reversible, elevated liver enzyme levels were reported as a drug-related effect [2224]. A recent statement by the European Agency for the Evaluation of Medicinal Products (EMEA) reported nine cases of fatal liver failure in RA patients treated with leflunomide to date; however, many of these patients were receiving concomitant medications and correct monitoring procedures may not have been adhered to [25]. With regular monitoring, the use of leflunomide for the treatment of RA is associated with a low rate of liver toxicity, even in combination with other DMARDs, such as methotrexate [26]. In the present study, non-steroidal anti-inflammatory agents, which are potentially hepatotoxic, were not among the concomitant medications, and this may explain the absence of reports of abnormal liver function.
In summary, this is the first report of the use of maintenance leflunomide treatment for WG in patients with complete or partial remission induced by cyclophosphamide and prednisolone. Such cytostatic therapy could potentially compromise the haematological system even after it has been discontinued, yet despite aggressive pretreatment and the higher than usual leflunomide dose, the safety profile of leflunomide was not different from the known safety profile of leflunomide in RA. Leflunomide appears to sustain WG disease in complete or partial remission safely and effectively for up to 2.5 yr, with remission maintained in the majority of patients. These results indicate the viability of further controlled investigations of the efficacy of leflunomide for the maintenance of remission in WG patients, such as the multicentre study recently initiated in Germany comparing the effects of methotrexate with those of leflunomide in the maintenance of remission in WG.
The authors have declared no conflicts of interest.
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Acknowledgments |
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References |
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