Department of Rheumatology, St George's Healthcare NHS Trust, Blackshaw Road, London SW17 0QT, UK
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Abstract |
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Methods. Twenty patients with active RA received leflunomide 100 mg for 3 days followed by 20 mg daily for 32 weeks. At week 2 all patients started infliximab 3 mg/kg, and received a further four infusions at weeks 4, 8, 16 and 24.
Results. Adverse events led to 11 patients being withdrawn before the end of the study. The commonest adverse event was pruritis associated with an eczematous rash. Other serious reactions included infliximab infusion reactions in four patients and StevensJohnson syndrome in one. There was no relationship between the serum concentration of A77 1726, the active metabolite of leflunomide, and adverse events. The mean Disease Activity Score (DAS28) fell from 7.18 at week 0 to 5.18 (P<0.0001, paired t-test) at week 4 and remained between 3.85 and 4.85 up to week 32. In those patients remaining on treatment, more than 80% achieved an ACR20 response from week 8 to week 28, and up to 46% achieved an ACR70 response.
Conclusion. Infliximab plus leflunomide combination therapy appears to be highly efficacious in the treatment of adult RA. However, widespread use may be limited by adverse events, which were common and in some cases severe.
KEY WORDS: Rheumatoid arthritis, Infliximab, Leflunomide, Treatment, Anti-TNF- therapy.
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Introduction |
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Although etanercept may be prescribed on its own, infliximab may only be used in combination with MTX. The rationale for choosing MTX as the anchor drug appears to be based on its efficacy, cost and widespread use as a single agent in RA treatment rather than any specific therapeutic synergism between MTX and inhibitors of TNF- [5]. Indeed, in the published study which addresses this, synergy was only found between MTX and low-dose infliximab (1 mg/kg) and not with higher doses (3 or 10 mg/kg) of infliximab [1]. In the same study, MTX was found to have immunosuppressive properties in markedly reducing the incidence of human anti-chimeric antibodies. This study has not been repeated, and it remains unclear whether this reduction in the immunogenicity of infliximab has any clinical relevance in terms of improved tolerability or increased duration of response to infliximab, though this is widely assumed to be the case.
Although the mechanisms of action of MTX are not well defined, decreased production of intra-articular macrophage-derived interleukin (IL)-1 and IL-6 is recognized [6]. This effect of MTX becomes redundant if MTX is used in combination with anti-TNF- agents, because inhibition of TNF-
has been shown to have down-regulatory effects on other macrophage-derived cytokines, including IL-1 and IL-6 [7]. With regard to the mechanism of action, disease-modifying anti-rheumatic drugs (DMARD) that principally target T cells might be better placed to act in synergism with anti-TNF-
agents. In the non-biological domain, both cyclosporin A and leflunomide would be appropriate candidates. Cyclosporin A is limited by its toxicity and is expensive. Leflunomide inhibits de novo pyrimidine synthesis by selective inhibition of dihydro-orotate dehydrogenase. T cells predominantly synthesize pyrimidines by this pathway and are particularly sensitive to the effects of leflunomide [8, 9]. Leflunomide is less expensive than cyclosporin A and has better overall safety and tolerability [1013].
We conducted an open-label pilot study of treatment with infliximab plus leflunomide to assess the safety and efficacy of this combination in adult patients with active RA.
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Patients and methods |
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The median age was 55 yr (range 3873 yr) and 18 patients were female. The median duration of RA was 10 yr (range 431 yr), the disease was erosive in all patients, 17 were positive for rheumatoid factor and 12 were positive for antinuclear antibodies (ANA). All patients had been treated previously with DMARDs (median 4 different drugs, range 28 different drugs), of whom nine had been intolerant of MTX. At enrolment, 14 patients were taking NSAIDs, 15 were on low-dose prednisolone (median dose 7.5 mg, range 515 mg) and all patients were on a DMARD (12 on MTX, four on cyclosporin A, two on sulphasalazine, two on leflunomide, two on hydroxychloroquine, one on gold, one on azathioprine), taken as monotherapy by 17 and in combination by three patients.
At enrolment, DMARDs were stopped, oral prednisolone was reduced to 7.5 mg in those taking higher doses (n=7), and NSAIDs (non-steroidal anti-inflammatory drugs) were continued. Four weeks later (week 0), patients received leflunomide 100 mg for 3 days followed by 20 mg daily, apart from the two patients already taking leflunomide, who continued with 20 mg daily. Two weeks after starting leflunomide (week 2), all patients received infliximab 3 mg/kg intravenously and this was repeated at weeks 4, 8, 16 and 24 such that each patient received a total of five infusions.
Adverse event enquiry and disease activity parameters were collected every 2 weeks to week 12 then every 4 weeks to week 32. The Disease Activity Score (DAS28) was the primary outcome measure of efficacy and the ACR20, 50 and 70 response rates were calculated at each time point as secondary measures of efficacy.
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Results |
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Skin
A total of 14 patients (70%) experienced skin reactions, characterized by varying degrees of local or generalized pruritis, and rash. In most cases the rash consisted of intensely pruritic eczematous patches with excoriations (Fig. 2). In some cases there were also areas of confluent erythematous macules with lichenoid features and pruritis. In seven patients (35%) the skin reaction was severe, with pruritis requiring immediate cessation of treatment in two cases. In the remaining five cases the dose of leflunomide was reduced to 10 mg daily. This resulted in resolution of symptoms in two cases but minimal impact on symptoms in the others. In these three patients, pruritis and rash persisted despite a further reduction of leflunomide to 5 mg. Ultimately leflunomide was stopped, metabolism accelerated with cholestyramine, and infliximab infusions discontinued. Subsequently skin symptoms resolved slowly, taking up to 12 weeks to disappear. Pruritis was not eased with a variety of antihistamine treatments, although hydroxyzine was helpful in one patient.
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Infusion reactions
Four patients experienced mild anaphylactic reactions during infliximab infusions, characterized by sudden facial erythema, cough, light-headedness and hypotension. This occurred with the first, second, third and fifth infusions. In each case infliximab was discontinued immediately, the patient was laid flat and oxygen was given, and the reaction resolved within a few minutes. One patient was rechallenged 2 weeks later with infliximab given at half speed, and initial intravenous chlorpheniramine. There was no immediate reaction but pruritis and rash became much worse in the next 2 weeks, requiring the patient to be withdrawn from the trial. Two other patients had also had adverse skin events prior to infusion reactions, but the fourth patient had had no adverse event of any kind until the reaction to the third infusion.
Diarrhoea
Six patients reported diarrhoea, which occurred and resolved within the first 8 weeks in all cases. In one patient the diarrhoea returned at week 21 and was the reason for withdrawal from the trial. Extensive investigations failed to find a cause, symptoms resolved within 1 month of stopping both infliximab and leflunomide, and the patient subsequently received infliximab and methotrexate without recurrence.
Elevated liver enzymes
An elevation in serum alanine transaminase (ALT) to >2.5 times the upper limit of normal was detected in three patients. The level returned to normal following a dose reduction of leflunomide to 10 mg. In each case leflunomide was increased again to 20 mg, resulting in a second reversible increase in ALT in one of the patients.
Hypertension
Four patients developed hypertension during the study (>160/90 mmHg) and in a further two patients pre-existing mild hypertension was exacerbated; in all cases the hypertension occurred between weeks 10 and 16. In five patients the hypertension was persistent and required treatment. One patient refused treatment and remained hypertensive throughout the trial; the remaining four patients all responded to antihypertensive drugs.
Mucositis
Nasal and oral mucosal ulceration occurred in three patients, in two of whom it occurred at the same time as pruritis and rash. Two of the three patients had had a similar reaction to methotrexate previously, and in one of these patients StevensJohnson syndrome developed at week 7. All three patients were treated with topical steroid and a reduction in the dose of leflunomide. One patient recovered and continued in the trial on 10 mg leflunomide but subsequently developed transient recurrent mucosal ulceration. In the other two cases leflunomide was discontinued, metabolism enhanced with cholestyramine and infliximab stopped. Both patients recovered fully.
Infections
Six patients reported infectious symptoms (one sinusitis and five respiratory infections). Antibiotics were given to four patients and in two the next infliximab infusion was delayed by a week. Although respiratory symptoms resolved after antibiotics in all patients, ongoing lethargy and a persistently elevated ESR in one case prompted further investigations. This revealed pulmonary cavitation, and culture of aspirated purulent fluid led to the growth of pseudomonas species. Prolonged incubation did not result in the growth of mycobacterial species. This patient died as a result of haemodynamic compromise following a large upper gastrointestinal bleed whilst recovering from these investigations.
Autoantibodies and A77 1726 concentration
Seventeen patients were positive for rheumatoid factor at entry to the study and 14 were still positive at the end of the study. None of the three patients who were seronegative at entry to the study became seropositive.
Eight patients were ANA-negative at entry to the study and five of these had become ANA-positive by the end of the study; all were negative for double-stranded DNA (dsDNA) antibodies.
Twelve patients were ANA-positive at entry to the study, of whom nine were dsDNA-negative. In nine patients, the type of ANA remained unchanged at the end of the study, two patients who were ANA-positive, dsDNA-negative became ANA-negative and one patient changed from ANA-positive, dsDNA-positive to ANA-positive, dsDNA-negative.
Serum was collected from all patients at weeks 0, 2, 4, 8, 16, 24 and 32 and stored at -70°C. The serum concentration of A77 1726, the active metabolite of leflunomide, was measured by Aventis Pharma (West Malling, Kent, UK). The concentrations obtained were well within the limits observed in adult RA patients receiving steady-state leflunomide 20 mg daily. In particular, changes in the A77 1726 concentration were not related to the emergence of adverse events.
Efficacy
All patients reported improvement in symptoms and function, in some cases 2 weeks after the first infliximab infusion. No patient was withdrawn from the study because of its lack of efficacy, but eight patients required either an intra-articular (n=7) or an intramuscular (n=2) injection of steroid at some stage in the study.
Fifteen patients were taking low-dose prednisolone (7.5 mg or less) at entry to the study, of whom seven had been reduced from a steady state of between 9 and 15 mg to 7.5 mg during the 4-week washout period. In 11 patients an attempt was made to reduce the prednisolone dose further from week 8 onwards. In nine patients this was successful, with a final dose of 5 mg in four cases, 2.5 mg in one case, 1.25 mg in two cases and complete cessation of prednisolone in two cases.
DAS28 composite score
The mean DAS28 score at the start of leflunomide therapy (week 0) was 7.18, scores for all patients lying above 5.1 (range 5.59-8.44), an accepted threshold that indicates highly active disease [14]. There was a very significant fall in DAS28 4 weeks later (mean 5.18, P<0.0001, paired t-test). From week 8 to week 32, the mean DAS28 score fell further and remained between 3.85 and 4.85 (P<0.0001, paired t-test, all time points compared with week 0) (Fig. 3).
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ACR composite score
Of those patients remaining on treatment, >80% achieved an ACR20 response from week 8 to week 28, including 100% at weeks 12 and 16. An ACR50 response was achieved in >40% of patients between weeks 8 and 28, including >80% at weeks 16 and 20. An ACR70 response was achieved in up to 46% of patients at week 20 (Fig. 4).
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Post-trial treatment
At the end of the study, the eight patients who remained in the trial continued on infliximab and leflunomide combination therapy. Amongst the 11 patients who were withdrawn, five have been treated with infliximab and methotrexate and two with etanercept, without adverse events.
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Discussion |
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The most frequent adverse event was pruritis with an eczematous rash, occurring in 70% of the group, sufficiently severe to require a reduction in medication or withdrawal from the study in 35% of the group. It is likely that the combination of infliximab and leflunomide was responsible for this adverse event, rather than either agent alone, as no clear pattern of toxicity was observed. For example, a role for infliximab is suggested in three patients in whom successive infusions appeared to exacerbate both pruritis and rash, and in one other patient in whom skin symptoms resolved after stopping infliximab, with continuation of leflunomide. In contrast, a role for leflunomide is suggested in two patients, in whom skin symptoms improved following a dose reduction of leflunomide, with no change in infliximab infusions. Furthermore, in three patients, although skin symptoms did not improve following a reduction in the dose of leflunomide, they did resolve once both agents had been discontinued and did not return when infliximab was subsequently restarted with MTX.
A total of 564 reports of rash have been received by Schering Plough (August 2001) out of an estimated 120 000 world-wide recipients of infliximab, giving a reported incidence of 0.47%. In the 3 mg/kg 8-weekly infusion arm of the phase III infliximab+MTX study, rash was reported in 6% of 89 patients [3]; similarly, the incidence of skin reactions following leflunomide treatment is low, occurring in 24 and 10% of patients in phase III trials [11, 12]. In comparison, the incidence of skin reactions encountered in this trial (70%) is excessive. Serum concentrations of the active leflunomide metabolite A77 1726 did not indicate that the drug combination used had resulted in toxic levels of leflunomide. The mechanism of this adverse event remains unclear but seems to be a result of an undefined interaction between the two agents.
Other adverse events were encountered in this trial, some more frequently than expected with either agent. In particular, infliximab infusion reactions occurred in four of the patients (20%), whereas the infliximab summary of the product characteristics indicates reactions in up to 8% during the first infusion and a diminishing frequency with subsequent infusions. Diarrhoea, elevated liver enzymes, hypertension and mucositis have all been reported with leflunomide and, more rarely, with infliximab. Phase III studies of leflunomide and the 3 mg/kg 8-weekly infusion arm of the phase III infliximab + MTX combination study report diarrhoea in 1733 and 8% of patients respectively [11, 12, 3], raised transaminases in 15% [12], hypertension in 611 and 6% [11, 12, 3] and mucositis in 6 and 4% [12, 3]. The incidence of the same adverse effects in this study is comparable or higher (30, 15, 30 and 15% respectively), though the small numbers make a firm comparison of these figures difficult.
StevensJohnson syndrome has been reported in one other patient receiving leflunomide and in no patients receiving infliximab. The patient affected in this trial had had previous mucositis with methotrexate and subsequently developed a rash with sulphasalazine, indicating particular sensitivity to DMARDs in this case.
Infections are well recognized following anti-TNF- therapy. Upper respiratory infections were reported at 30 weeks in 33% of 89 patients in the 3 mg/kg 8-weekly infusion arm of the phase III infliximab + MTX combination study [3]; similarly, they occurred in 30% of patients in this study and responded promptly to antibiotic treatment. It is noteworthy that in the patient who died, invasive investigations had been prompted by the known association of reactivated tuberculosis with anti-TNF-
therapy. It is not likely that the upper gastrointestinal bleed in this patient was directly related to infliximab plus leflunomide therapy, but the stress associated with invasive tests may have increased the risk of the gastrointestinal bleed.
It is hard to draw any firm conclusions regarding the efficacy of this combination given the open-label nature of this trial and the high number of adverse events. The mean DAS28 score fell highly significantly at all time points from week 4, but did not fall below 3.2, the accepted threshold for low disease activity [14]. This may reflect the long-standing resistant nature of RA in this study group. However, the ACR data are remarkable, with a maximum of 100% of the patients who remained on therapy achieving an ACR20 response, and 46% of patients achieving an ACR70 response for periods of the study. If these figures were reproduced in a blinded setting they would represent a significant improvement on the efficacy achieved with infliximab and MTX, for which, at 6 months and 1 year, maximum ACR20 and ACR70 responses are 5042% and 810% respectively [3, 15]. It is particularly noteworthy that such high response rates were achieved in the face of a multitude of adverse events and the long-standing DMARD-resistant nature of RA in the study population. Whether this lends support to the original hypothesis that the combination of infliximab with an anti-T-cell agent may be more efficacious than infliximab and methotrexate remains speculative but intriguing.
The tendency for both the DAS and the ACR responses to worsen towards the end of the study (Figs 3 and 4
) is likely to be related to two factors. First, many of the patients voluntarily chose to remain on lower doses of prednisolone despite a slight relapse in disease activity. Secondly, there was considerable anxiety amongst the patients regarding infliximab therapy at the end of the trial. In particular, the patient global scores and tender joint counts were higher at the final, week 32 assessment, at which time the next infliximab infusion was due, but not available due to lack of funding.
In summary, this open-label study of infliximab plus leflunomide combination therapy in DMARD-resistant active RA has revealed a high frequency of adverse events, sufficiently severe to cause premature withdrawal from the study in 55% of the patients. Despite this, the efficacy data indicate that a substantial improvement in RA disease activity may be achieved with this combination. This lends encouragement to the quest to find a well-tolerated anti-TNF-/DMARD combination that achieves sufficiently high response rates to justify the widespread application of anti-TNF-
therapy to patients with RA.
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Acknowledgments |
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Notes |
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References |
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