University Medical Centre St Radboud, Nijmegen, The Netherlands.
Correspondence to: M. Flendrie, Department of Rheumatology, University Medical Centre St Radboud, P.O. Box 9101, Postal code 6500 HB, Nijmegen, The Netherlands. E-mail: m.flendrie{at}reuma.umcn.nl
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Abstract |
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Methods. RA patients starting infliximab therapy were prospectively followed from January 2000. Every 3 months data were collected regarding disease activity (DAS28), adverse events and treatment changes. In the primary analyses all patients were classified into a leflunomide group (LEF group) if they had used leflunomide during infliximab therapy or within 6 months prior to starting infliximab therapy, the latter because of the long half-life of leflunomide. All other patients were considered as controls (non-LEF group). Secondary drug survival analyses were performed with the LEF group consisting only of patients on active leflunomide at the start of infliximab (active LEF group).
Results. A total of 162 RA patients started infliximab therapy (57 in the LEF group, 105 in the non-LEF group). No statistically significant differences in baseline characteristics were observed between the groups. Maximum follow-up time was 46 months for both groups. No differences in drug survival, disease activity or adverse events were observed between the groups. In both groups an increase in patients positive for antinuclear antibodies (ANA) was seen. ANA positivity at start did not predict DAS28 or the occurrence of adverse events. Secondary drug survival analyses showed no differences between the active LEF group and the non-LEF group.
Conclusion. The results indicate that the administration of infliximab after or simultaneously with leflunomide is safe and efficacious in RA patients.
KEY WORDS: Rheumatoid arthritis, Therapy, Infliximab, Leflunomide, Non-standard abbreviations: LEF = leflunomide, AE = adverse event, pt = patients
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Introduction |
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Leflunomide is a relatively new DMARD, which has proven efficacy and safety in randomized controlled trials in RA [2, 3]. It is an isoxazole derivate and its active metabolite inhibits de novo pyrimidine synthesis, resulting in inhibition of T-cell proliferation. Leflunomide has a long elimination half-life of 15 to 18 days.
The development of anti-rheumatic drugs has shifted from empirically based strategies towards drugs specifically designed to target critical elements in the inflammatory process in RA. An important cytokine in RA is tumour necrosis factor alpha (TNF) [4]. Inhibition of TNF
by monoclonal antibodies or by soluble receptors has proved to be a major advance in the treatment of RA. Two monoclonal anti-TNF
antibodies (infliximab and adalimumab) and one soluble receptor (etanercept) have proved to be efficacious in clinical trials and are currently being used in clinical practice [57].
Combining two or more DMARDs can enhance efficacy by either additive or synergistic effects, without a decrease in tolerability [8]. Although infliximab has proved to be efficacious as monotherapy in RA [9, 10], combining infliximab with concomitant methotrexate resulted in a sustained therapeutic response at lower infliximab doses, compared with both drugs administered as monotherapy [10]. Furthermore, the incidence of antibodies to infliximab was reduced when infliximab was administered with concomitant methotrexate, which might explain the apparent synergy between infliximab and methotrexate. In patients with Crohn's disease the development of anti-infliximab antibodies has been shown to be associated with a reduction in the duration of response and with a higher risk of infusion reactions. In addition to this, concomitant immunosuppressive treatment was associated with a reduction in antibody titres [11].
The results of Maini et al. [10] provided the rationale for the combination of infliximab and methotrexate, which has further been evaluated in clinical trials and is now the recommended strategy for infliximab therapy in RA [5, 12]. However, not all patients tolerate or respond to methotrexate, which warrants research into the combination of infliximab with other DMARDs like leflunomide.
At present three studies have been published investigating the combination of infliximab and leflunomide in RA [1315]. All three studies report the combination to be efficacious. A marked reduction of disease activity in RA patients was reported in two studies, one 32-week open-label prospective study and one retrospective study, both with a small number of patients. However, in two studies with small patient numbers approximately half of the patients in both studies were withdrawn from therapy due to adverse events, which were in some cases severe [13, 15]. Another retrospective study in 88 RA patients showed the combination to be efficacious and well tolerated over an average of 6.6 months [14]. The reported studies lack a control group, have a limited follow-up time and two of them are retrospective. In this prospective cohort study we investigated the efficacy and safety of infliximab in RA patients with previous and concomitant use of leflunomide over a longer period and compared it with the combination of infliximab with other DMARDs.
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Patients and methods |
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Treatment
Infliximab was administered intravenously and was started according to a standard dosing regimen with a dosage of 3 mg/kg, which was rounded off to a multiple of 100 mg and was administered at the start of treatment, weeks 2, 6 (loading dose phase) and every 8 weeks thereafter. After the loading dose phase the dose or interval in individual patients could be adjusted if the response was insufficient. Guidelines for maximum infliximab dose per interval corresponded with 10 mg/kg every 8 weeks. Guidelines at the treatment centre recommended infliximab to be administered in combination with methotrexate, in accordance with general recommendations [12]. If methotrexate was ineffective or not tolerated the choice of concomitant DMARD treatment was made by the treating physician.
Evaluations
At the start of infliximab therapy the following patient characteristics were collected: age, gender, weight, duration of RA, rheumatoid factor (RF) (considered positive if RF >10 IU/ml; by enzyme-linked immunosorbent assay), antinuclear antibody (ANA; by immunofluorescence on Hep-2 cells). Previously and currently used DMARDs were recorded, as well as orally administered corticosteroids. Patients were assessed every 3 months. Assessments consisted of joint evaluations (28 joint counts for tenderness and swelling), erythrocyte sedimentation rate (ESR; Westergren method) and a patient assessment of disease activity on a visual analogue scale (VAS). Furthermore, at every visit the dosage and interval of infliximab, changes in concomitant DMARDs and systemic corticosteroids, and adverse events were recorded. ANA was measured at baseline and once a year thereafter.
Adverse events were defined as any new medical condition or worsening of a pre-existing medical condition occurring during or after treatment with infliximab and were recorded by the rheumatologist if they were considered clinically important. They were divided into minor and major events. Major events were defined as those events for which intravenous therapy or hospitalization was necessary.
In cases where infliximab therapy was discontinued the reason for discontinuation was recorded and follow-up was continued. Reasons for discontinuation were classified as discontinuation due to inefficacy, adverse events or other reasons.
Disease activity was assessed using the DAS28, a composite index consisting of 28 joint counts for tender and swollen joints, the ESR and the VAS for disease activity [17, 18]. Response to treatment was evaluated using the European League Against Rheumatism (EULAR) response criteria, based on the DAS28 [19].
Statistical analysis
Patients were classified into two groups. They were classified into the leflunomide group (LEF group) if they were using leflunomide during infliximab treatment or if they had used leflunomide within the last 6 months prior to starting infliximab therapy, the latter because of the long half-life of leflunomide. All other patients were considered in the control group (non-LEF group). These groups were compared for baseline characteristics, drug survival, adverse events, reason for discontinuation, DAS28 over time and ANA status. Secondary analyses were performed with the LEF group consisting only of patients on active leflunomide therapy at the start of infliximab (active LEF group). All other patients were considered as controls. Baseline characteristics were compared and drug survival analyses were repeated. Furthermore, patients on infliximab monotherapy were compared with patients on infliximabDMARD combinations for differences in baseline characteristics, adverse events and ANA status.
Differences in baseline characteristics between groups were compared by 2 tests for dichotomous variables and Student's t-tests for continuous variables. Life table analysis was performed to compare drug survival on infliximab between groups with 1 January 2004 as the date of censoring. Separate drug survival analyses were performed for inefficacy and for adverse events as reasons for discontinuation. To correct for possible differences in baseline characteristics between the groups Cox regression analysis was used. In addition, the same analyses were repeated for the active LEF group.
Adverse events and reasons for discontinuing infliximab therapy were compared between the treatment groups. The DAS28 over time was compared between groups by longitudinal regression analysis using generalized estimating equations (GEE). Differences in baseline characteristics between the groups were corrected for. The exchangeable correlation structure was used and the identity link function and the Gaussian variance model were applied. Percentages of response were calculated for the groups at 3, 6, 12, 18 and 24 months.
Differences between groups in ANA status at start and during follow-up were compared by 2 tests. Relative risks of developing adverse events over the first year of follow-up were calculated for ANA-positive patients at baseline as opposed to ANA-negative patients at baseline for both treatment groups, and for conversion to ANA positivity as opposed to patients who remained ANA negative during infliximab therapy for both treatment groups. The DAS28 over time was compared overall between patients who were ANA positive and ANA negative at the start of infliximab using GEE with the exchangeable correlation structure. Analyses were performed using SAS statistical software (version 8.0, SAS Institute Inc., USA), and SPSS statistical software (version 11.0, SPSS Inc., USA).
Ethical approval was obtained from the Ethical Committee of the University Medical Centre St Radboud for the observational study. Patient informed consent was obtained verbally; no written informed consent was required.
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Results |
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The median duration of leflunomide treatment was 11 months (range 066 months) with a median dose of 20 mg/day (range 1030 mg/day). In the 33 patients who used leflunomide during infliximab therapy 12 (36%) stopped leflunomide during infliximab therapy (five for inefficacy and seven for adverse events) and three (9%) stopped leflunomide after infliximab therapy was discontinued (three adverse events). The median duration of leflunomide treatment during infliximab was 9 months (range 232 months).
In the non-LEF group 22 patients used infliximab as monotherapy. Concomitantly used DMARDs were methotrexate (n = 62), sulphasalazine (n = 19) and azathioprine (n = 12), hydroxychloroquine (n = 1) and parenteral gold (n = 1). Oral corticosteroids were used by four patients (18%) on infliximab monotherapy and by 23 patients (24%) on infliximab and concomitant DMARDs in the non-LEF group.
Infliximab therapy
Mean infliximab dose at the start of therapy was 253 mg in the LEF group and 257 mg in the non-LEF group. After 6 months of infliximab therapy two dosage increases and no interval reductions were seen in the LEF group, compared with seven dosage increases and four interval reductions in the non-LEF group. After 12 months of therapy 12 dosage increases and one interval reduction were seen in the LEF group, compared with 10 dosage increases and five interval reductions in the non-LEF group. Mean doses at 6 and 12 months were 262 mg and 317 mg every 8 weeks in the LEF group, and were 268 and 300 mg every 8 weeks in the non-LEF group. Patients body weight did not differ between the two groups.
Drug survival
Maximum follow-up time was 46 months in both groups. No difference in survival on drug was found between the two groups, as shown in Fig. 1A. Median survival time was 23 months in the LEF group and 25 months in the non-LEF group. After correction for differences in baseline variables also no differences in drug survival were seen. In separate drug survival analyses no differences between the two groups could be shown for discontinuation of infliximab therapy due to inefficacy and due to adverse events (Figs. 1B and 1C). In secondary analyses drug survival was compared between patients on active leflunomide treatment at the start of infliximab (active LEF group) and controls. No significant differences between the two groups were found, also after correction for differences in baseline characteristics.
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The most frequent minor adverse events reported in both groups were infections, infusion reactions, allergic reactions and dermatological conditions. A systemic lupus erythematosus (SLE)-like syndrome was reported in three patients in the LEF group only (two major adverse events). One |major and five minor neurological events were reported, all in the non-LEF group. They included headache (n = 2), one radicular syndrome (major adverse event), one peripheral nerve palsy, one optic neuritis and one demyelinating disease. The latter presented with peripheral nerve palsy and white matter lesions.
Anti-nuclear antibodies
ANA status at the start of infliximab therapy was available for 51 patients (90%) in the LEF group and 100 patients (95%) in the non-LEF group. ANA status during follow-up was available for 46 patients (81%) in the LEF group and for 79 patients (75%) in the non-LEF group. In the LEF group 24 patients (47%) were ANA positive at start and in the non-LEF group 38 patients (38%) were ANA positive at start of infliximab therapy.
Of the patients who were ANA negative at the start 70% in the LEF group and 65% in the non-LEF group converted to ANA positivity during infliximab therapy. Of these patients 70 and 82% respectively remained ANA positive throughout infliximab therapy in the LEF group and non-LEF group respectively. Of the patients who were ANA positive at the start 4% in the LEF group and 11% in the non-LEF group converted to ANA negative. The differences between the two groups in number of ANA-positive patients at the start and during follow-up were not statistically significant (P = 0.29, respectively P = 0.18).
Overall, no differences in DAS28 over time were found between patients who were ANA positive and ANA negative at the start. The estimated relative risks for ANA positivity at baseline of developing adverse events over the first year of follow-up were calculated and are shown in Fig. 4. For both treatment groups ANA positivity at baseline did not increase or decrease the risk for adverse events.
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Infliximab monotherapy
A total of 33 out of 162 patients started infliximab without concomitant treatment with DMARDs, equally distributed between the LEF group and the non-LEF group (see results, DMARD treatment). No statistically significant differences were found in baseline characteristics, except for the mean prior number of DMARDs [4.7 (S.D. = 1.7) in patients on monotherapy versus 3.9 (S.D. = 17) in patients on concomitant DMARDs, P = 0.03].
Forty-one adverse events (six major adverse events, were recorded in 20 of 33 patients (61%) on monotherapy, compared with 130 (15 major) in 73 of 129 (57%) patients on concomitant treatment with DMARDs. No statistically significant differences were found in the number of patients experiencing adverse events (P = 0.67) or in the number of adverse events per patient (P = 0.56). ANA conversion from negative to positive occurred in 77% of the patients on monotherapy and in 60% of the patients on concomitant treatment with DMARDs (P = 0.22). Conversion from positive to negative occurred in 9% of the patients on monotherapy and in 8% of the patients on concomitant DMARDs (P = 0.96).
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Discussion |
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We investigated the clinical consequences, in terms of survival on drug, efficacy and safety, of a possible interaction between infliximab and leflunomide. An interaction can take place in the period of active use of both drugs in combination, as well as during the elimination phase after withdrawal of one of the drugs. The active metabolite of leflunomide (A771726) has a relative long half-life of 15 to 18 days in RA patients [2], which results from low hepatic clearance and enterohepatic cycling. The standard deviation is 9 days (in a group of RA patients who received 25 mg/day in a phase II study) [20], indicating large differences in the duration of the elimination phase between individuals. In our analysis we included patients who stopped leflunomide in the 6 months prior to the start of infliximab into the LEF group in the study. Six months is approximately 10 times the mean half-life of A771726, after which only 0.1% of the original plasma concentration is present. To investigate the effect of the chosen group definition on the results a second analysis was performed including only patients who used leflunomide during infliximab therapy in the leflunomide group.
In this study the two treatment groups showed no statistically significant differences in baseline characteristics, although patients in the LEF group were more often RF positive and had used more DMARDs before starting infliximab therapy, both indicating a more severe course of the disease. Dose or interval changes had been applied more frequently in the LEF group in the first year of follow-up, which supports the possibility that the LEF group consisted of patients with a more severe form of RA. Despite these differences the survival on drug was comparable between both groups, with a median survival time of approximately 2 yr. Also, in the secondary analyses drug survival was comparable between groups.
The disease activity was comparable between the groups. In both groups the mean DAS28 showed a marked decrease after onset of infliximab therapy, which then remained more or less stable over the course of follow-up. Also, the response percentages observed were comparable for both groups. Both treatment groups showed variation in response over time, but overall no consequent pattern was seen.
The effects on disease activity in the LEF group are similar to the effects of a 32-week open-label study with 20 RA patients [15]. All patients first started on leflunomide and shortly thereafter on infliximab. At start these patients had a very high disease activity, probably due to a washout period. The mean DAS28 dropped from 7.18 at the start to 5.18 at week 4 and remained between 3.85 and 4.85 throughout the study.
In a retrospective multicentre study with 88 RA patients who had received leflunomide in combination with infliximab, Hansen et al. [14] also showed a marked decrease in disease activity parameters. Most patients had used leflunomide for several months before starting infliximab, as in our study. The authors did not present response measures because the data set was incomplete.
The reasons for discontinuation of infliximab reported in the present study were more often adverse events than inefficacy. These findings are in line with previous reports, although drug survival rates differ. Kiely et al. [15] reported 12 of 20 patients to have stopped combination therapy before 32 weeks because of adverse events, which consisted of skin reactions, infusion reactions, respiratory infections, diarrhoea, elevated liver enzymes, hypertension and mucosal ulceration, and were in some cases severe. Godinho et al. [13] retrospectively assessed the safety of the combination of leflunomide and infliximab in 17 RA patients. Adverse events were reported in 13 (76%) patients. Eight patients (47%) stopped the combination therapy because they experienced adverse events before the fifth infusion. The adverse events that led to discontinuation included heart failure, hypertension with thoracic pain, eczematous patches and neutropenia. In all three patients with neutropenia white cell counts returned to normal after stopping leflunomide.
The retrospective data collection in one study and the small number of patients in both previous studies makes interpretation difficult. Furthermore, in the study by Kiely et al. [15] patients started both drugs within a short period of time. This could have contributed to the high number of adverse events, compared with the present study in which most patients had started leflunomide in the months or years before infliximab. They either tolerated the drug or had stopped using it in the 6 months prior to start of infliximab. It must be noted that in the present study adverse events were only reported if they were considered as clinically important by the treating rheumatologist.
In the study by Hansen et al. [14] 88 patients received infliximab in combination with leflunomide over an average of 6.6 months. Ten patients (11%) had discontinued infliximab therapy during the follow-up period, six (7%) because of adverse events. These findings are more in line with the survival rates in the present study than the studies reported above. In the present study 16% had discontinued infliximab after 7 months, as shown in Fig. 1A.
Major and minor adverse events were reported in equal percentages of patients in the two treatment groups, but the number of adverse events per patient was slightly higher in the LEF group. The most common minor adverse events were skin reactions, infusion reactions and infections and were reported slightly more frequently in the LEF group. To our knowledge most adverse events in the present study have been reported previously during infliximab therapy [5, 10], with the exception of diabetes mellitus and gingival hyperplasia.
ANA are commonly found in RA patients and an increase in ANA-positive patients during infliximab treatment has been observed [13, 15, 2123]. In previous reports no association of ANA has been found with the rate of discontinuation [21], the occurrence of adverse events [13] or loss of efficacy of infliximab [23].
In the present study no differences in DAS28 over time were found between patients who were ANA positive and ANA negative at the start of infliximab. Also, ANA positivity at baseline and conversion to ANA positivity during infliximab treatment were not associated with an increased risk for adverse events in either treatment group. For ANA conversion patient numbers were small and interpretation needs to be made with caution.
Combining DMARDs and biological therapies could increase treatment options and enhance treatment effect in clinical practice. The combination of infliximab with DMARDs other than methotrexate is of special interest, firstly because infliximab is an important new therapeutic option in RA treatment and secondly because monotherapy is not widely accepted as an option because of the possible problem of immunogenicity. Thirdly, not all patients tolerate or respond to methotrexate, which is the only DMARD investigated in combination with infliximab in randomized controlled trials.
The present study shows that previous or concomitant treatment with leflunomide does not decrease the efficacy of infliximab therapy in RA patients. Furthermore, the safety data presented in this study are reassuring and show previous or concomitant treatment with leflunomide in combination with infliximab to be safe and well tolerated. The results indicate that infliximab is safe and efficacious after previous treatment with leflunomide and that the combination of infliximab and leflunomide is a valuable therapeutic option in RA.
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The authors have declared no conflicts of interest.
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References |
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