Rheumatology Advance Access originally published online on July 15, 2008
Rheumatology 2008 47(9):1430-1431; doi:10.1093/rheumatology/ken240
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LETTERS TO THE EDITOR |
Tolerability of methotrexate and leflunomide combination therapy for inflammatory arthritis in routine clinical practice: results of a four-centre study
1St George's Healthcare NHS Trust, London, 2West Suffolk Hospital, Bury St Edmonds, 3Great Western Hospital, Swindon and 4Epsom and St Helier NHS Trust, Epsom, UK
Correspondence to: A. Kaul, Department of Rheumatology, Royal Free Hospital, Pond Street, London NW3 2QG, UK. E-mail: arvind.kaul{at}royalfree.nhs.uk
SIR, Combination DMARD therapy is increasingly used for the treatment of inflammatory arthritis because monotherapy often does not produce remission [1]. The contrasting modes of action of MTX and LEF make them attractive candidates for use in combination [2] with the potential to provide additive or synergistic actions, perhaps without the need for expensive biologic agents [3].
Although combination DMARDs in early RA confer long-term structural advantages [4,5], meta-analysis of clinical trial data shows that combination therapies convey a small increased risk of toxicity [6]. Furthermore, the summary of product characteristics (SmPC) for LEF discourages co-prescription with other hepatotoxic drugs including MTX (Sanofi-Aventis, personal communication). Despite this, anecdotal experience suggests that MTX and LEF are often used in combination for the treatment of inflammatory arthritis. The aim of this study was to determine the tolerability of this combination in routine clinical practice at four UK centres.
We conducted a case note review of 108 adult patients (32 males, 76 females, mean age 54.6 yrs, range 20–84 yrs) identified from clinic letters or departmental databases treated at four UK centres. Inclusion criteria were a diagnosis of inflammatory arthritis, treatment with MTX/LEF combination therapy for at least 6 months and no other DMARDs or biologic therapies except steroids. All demographic, diagnostic and outcome data were collected by the treating rheumatologists and nurse practitioners at each centre.
Of the 108 patient records that were reviewed (86 RA, 11 PsA, 2 AS, 9 undifferentiated inflammatory arthritis), 55 (51%) were still on combination therapy (mean duration on therapy 32.8 months, median 24.5 months, range 6–67 months) while 53 patients (49%) had discontinued therapy (mean time to discontinuation 10.9 months, median 7.3 months, range 1–45 months).
In patients who discontinued the combination (n = 53), the commonest reasons for stopping were GI-related, particularly nausea, vomiting and diarrhoea (28.8%), deranged Liver Function Tests (11.5%), lack of efficacy (11.5%), combined factors (23.0%) and haematological problems (pancytopenia) in one patient (1.9%). Other complications included rash (9.6%), mouth ulcers (1.9%), alopecia, hypertension, facilitating conception and undefined malaise (combined incidence 11.5%) with no reports of serious infections causing discontinuation. One patient died 3 months after starting combination therapy for reasons unrelated to therapy.
A LEF loading dose (100 mg LEF on two or three consecutive days followed by standard dose) was given to 28 (53.8%) of the eventual discontinuations and 23 (41.1%) of those who were still on therapy. In those who stopped the combination, mean time to discontinuation was longer if patients were given a loading dose (14.7 months vs 5.83 months).
Kaplan–Meier analysis (Fig. 1) to determine expectation for staying on combination therapy (‘survival’) showed that after 36 months, 50% of patients are still on therapy.
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This is the largest study of the tolerability of MTX/LEF combination therapy during routine care outside a clinical trial setting. Tolerability was good with only one serious adverse reaction (pancytopenia). Most withdrawals were due to minor reversible events consistent with other studies [2, 7–9], with no evidence for serious hepatotoxicity, despite explicit warnings in the LEF SmPC.
In our study, the incidence of discontinuation due to adverse events was 44%. This is more than the 12% reported in a clinical trial of RA patients (MTX/LEF vs MTX/placebo) followed for 24 weeks [8] or the 15% reported in a Belgian study of 60 RA patients (MTX/LEF vs LEF alone) in routine care [9]. The discordant results may reflect methodological differences or confounders (co-therapy, access to specialist advice during adverse events). No serious infections were reported in our or other studies.
Lack of efficacy was a reason for stopping therapy in 11.5% of the discontinuations in our study. This represents 5.5% of the entire cohort vs 6.9% reported in a clinical trial setting [8] and 18.3% in the Belgian study [9], implying good efficacy. The discrepancies between studies may reflect different thresholds used to define lack of efficacy. In our study, the decision to withdraw the combination for inefficacy was left to the treating rheumatologist. Standardized measures (e.g. DAS28) in future studies would provide more objective results.
Kaplan–Meier analysis showed that the most rapid decline in ‘survival’ on combination therapy occurs within the first 10 months. At 36 months, 50% of patients are still on therapy, results similar to the Belgian study that showed 62% of patients still receiving LEF at 30 months [9].
Anecdotal concerns about toxicity and clinical trial evidence [10] have limited the use of LEF loading doses. Our results suggest that LEF loading doses were associated with prolonged survival on the combination rather than discontinuation, perhaps because of exclusion of patients felt to be less likely to tolerate the combination.
Overall, our findings show that MTX/LEF combination therapy is well tolerated by most patients. While adverse events lead to withdrawal in some patients, these are rarely serious.
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Acknowledgements |
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We would like to thank Dr Alex Keough for assistance with data collection at St George's Healthcare NHS Trust and Dr Richard Morris, Department of Population Sciences, Royal Free and University College Hospitals Medical School for help with statistical analysis.
Disclosure statement: P.D.W.K. has received departmental support from Sanofi-Aventis. All other authors have declared no conflicts of interest.
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