Rheumatol Int (2007) 27:531–536

DOI 10.1007/s00296-006-0261-x

ORIGINAL ARTICLE

Durability of treatment with methotrexate in Venezuelan patients with rheumatoid arthritis

Gloris Sánchez · Julio S. Castro · Soham Al Snih · Luísa Pérez Blanco · María H. Esteva · Ernesto García MacGregor · Marielena González · Ysabel Granados · Francisco Marín · Alexis Rosas · Antonio Tristano · Esther Chirinos · Luís Mundaraín · Gilberto Sanoja · Guisela Zambrano-Marín · Martín A. Rodríguez

Received: 12 February 2006 / Accepted: 13 October 2006 / Published online: 11 November 2006© Springer-Verlag 2006

Abstract A multicenter, national, retrospective, andcross-sectional study of 219 hospital-based Venezuelanpatients with rheumatoid arthritis (RA) was aimed toevaluate the probability of continuity of treatment withoral methotrexate (MTX). Treatment survivaldecreased from 92% at 12 months to 42% at180 months, as assessed by life table analysis and theKaplan–Meier method. Forty-seven patients stoppedtreatment and adverse eVects (29.7%) and lack of con-tinuous access to medication (19.1%) were the mostcommon causes for withdrawal. MTX survival wasdecreased in the group with combined MTX plusleXunomide therapy, as shown by the log-rank test.Venezuelan patients with RA have a probability ofcontinuing treatment with oral MTX comparable tonon-Hispanic patient populations. However, concomi-tant use of leXunomide may increase the risk of inter-ruption of MTX treatment in this RA population.

Keywords Rheumatoid arthritis · Methotrexate · Latin America · Tolerability

Introduction

Methotrexate (MTX) is the leading DMARD for thetreatment of rheumatoid arthritis (RA). Its eYcacy hasbeen clearly demonstrated in randomized and con-trolled studies [1–7]. However, the main concern ishow long patients remain on treatment and thus howmuch joint damage can be prevented. The main reasonfor interruption of treatment with MTX is the occur-rence of adverse eVects, followed by loss of eYcacy.Nevertheless, most studies addressing this issue havebeen performed in predominantly Caucasian patientpopulations, in whom the genetic background mayinXuence treatment survival. To our understanding, nosuch studies have been carried out in Latin Americanpatients with RA. The purpose of this study was toexamine the continuity of treatment with MTX in asample of Venezuelan patients with RA and determinethe variables potentially inXuencing it.

Patients and methods

Patients and data collection

Two hundred and nineteen patients with RA from 12diVerent regional centers belonging to Centro Nacionalde Enfermedades Reumáticas, a public health organi-zation under the umbrella of the Ministry of Healthand Social Development were studied (see Appendixfor participating centers and regional distribution of

G. Sánchez · L. P. Blanco · M. H. Esteva · E. G. MacGregor · M. González · Y. Granados · F. Marín · A. Rosas · A. Tristano · E. Chirinos · L. Mundaraín · G. Sanoja · G. Zambrano-Marín · M. A. RodríguezCentro Nacional de Enfermedades Reumáticas, Ministerio de Salud, Servicio de Reumatología, Hospital Universitario de Caracas, Caracas, Venezuela

J. S. CastroInstituto de Medicina Tropical, Universidad Central de Venezuela, Apartado 2109, Caracas, Venezuela

S. A. SnihUniversity of Texas Medical Branch, Galveston, TX, USA

M. A. Rodríguez (&)Apartado 47365, Caracas 1040, Venezuelae-mail: martinalbertove@yahoo.com

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532 Rheumatol Int (2007) 27:531–536

patients). Patients were Venezuelan, as deWned bybearing maternal and paternal Hispanic surnames,traceable back to at least three generations of Venezu-elan-born ancestors. Ethnically, Venezuelans are amestizo population, deWned as a variable admixture ofSpanish, American native and African stock.

Patients were classiWed according to the AmericanCollege of Rheumatology 1987 criteria [8]. Functionalclass and anatomical stage were established using theAmerican College of Rheumatology criteria [9] andSteinbrocker classiWcation system [10], respectively.Patients were selected on the basis of past or currentuse of oral MTX and data were collected from thechart history. In order to minimize recall bias onlychart histories with uneven numbers were chosen forthe study. The following items were searched and col-lected in a standard format: age, gender, body massindex (BMI), duration of disease, duration of treat-ment with MTX, initial dose, maximal dose, concomi-tant therapy, including past or current use of otherDMARD or antiinXammatory drugs (NSAIDs), andadverse eVects. The following comorbid conditionswere also reported: obesity (BMI ¸ 30), diabetes,chronic liver disease, chronic alcoholism (abnormalsocial or psychological behavior due to sustainedalcohol abuse), chronic pulmonary disease, hypothyr-odism, hyperthyroidism, dislipidemia, hypertension,and hyperuricemia. The primary outcome measure wasduration of treatment with MTX, deWned as the timeelapsed from the moment of initiation to the momentof permanent interruption of treatment. If drug treat-ment was interrupted temporarily and then reinitiated,the case was considered as a surviving case. Data weremailed from participating centers to the pilot center atthe University Hospital in Caracas and data wereloaded in a central database. The study followed theprinciples of the Ethics Committee of our institution.

Statistical analysis

Descriptive and univariate statistics for analysis of con-tinuous variables and their association with MTX with-drawal were used. For categorical variables, contingencytables and analysis by the Fisher’s Exact test were used.Cox proportional regression analysis was used to esti-mate the hazard ratio (HR) of variables related to treat-ment survival, log rank test to compare treatmentsurvival in the group of patients receiving MTX alone orMTX plus leXunomide, and life table analysis and theKaplan–Meier method used to estimate drug survival.Survival time was deWned as the period elapsed betweenthe initiation and permanent discontinuation of treat-ment. Univariable analysis estimated the unadjusted HR

of concomitant medication on treatment survival. Multi-variable analysis estimated the adjusted HR of treat-ment survival as a function of demographics, diseaseduration, duration and dose of MTX treatment, pres-ence of a comorbid condition, adverse eVects, obesity,and concomitant treatment. The Wnal model wasobtained using forward, stepwise with inclusion criteriaof 0.1 and exit criteria of 0.05. For all analysis a two-tailed approach was used and statistical signiWcance wasassigned when type I error probability was equal to orless than 5% (P · 0.05). The STATA statistical packagewas used for analysis.

Results

Two hundred patients were females (91.3%) and 19males (8.6%). Mean age was 51.7 (range 15–84). Meanduration of disease was 7.6 years. The predominantfunctional classes were class II (48.1%) and I (28.3%),and the most common anatomical stages were II(41.1%) and III (27.9%). Eighty-eight percent ofpatients had a positive test for rheumatoid factor and24.2% showed subcutaneous nodules (Table 1).

Most common comorbid conditions were high-bloodpressure (13.6%), obesity (9.1%), hyperlipidemia(4.2%), and diabetes mellitus (4.2%). The mean totalcumulative dose of MTX was 1,364.7 § 1,364.6 mg(mean § SD). The average weekly dose was 7.5 §2.1 mg (range 5–25). One hundred eighty-seven

patients were receiving low-dose oral prednisone (·10mg daily) and 176 (80.4%) an NSAID. One hundred

eighteen patients (53.8%) were receiving treatmentwith folic acid 5 mg daily. One hundred and thirty-one

Table 1 Descriptive characteristics of the patient sample(n = 219)

Variables n (%)

Age, mean § SD 51.7 § 13.1GenderFemale 200 (91.3)Male 19 (8.6)

Disease duration (years), mean § SD 7.6 (7.9)Presence of rheumatoid factor 193 (88.1)

Functional classI 60 (28)II 102 (48)III 43 (20)IV 7 (3)

Anatomical stageI 37 (22)II 69 (41)III 47 (27)IV 15 (8)

Presence of subcutaneous nodules 53 (24.2)

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patients (59.8%) had or were receiving a concomitantDMARD, predominantly chloroquine (32.8%)(Table 2).

One hundred seventy-two patients (78.5%) werestill receiving treatment with oral MTX at the time ofthe cross-section, whereas it had been withdrawn in 47patients (21.4%). Mean age of patients who suspendedtreatment (52.3 § 13) was similar to that of the totalstudy group (51.7 § 13.1). Of the 47 patients who hadinterrupted treatment, 20 (42.5%) had received orwere receiving an additional DMARD at the time ofMTX withdrawal. Adverse eVects were observed in 95patients (43.3%), predominantly gastrointestinal symp-toms (16.8%) and elevation of serum aminotransfe-rases (7.3%) (Table 3).

Survival curves showed a steady decrease in contin-uation of treatment from 92% at 12 months of therapyto 42% at 180 months (Fig. 1). Similar results wereobserved when a minimum exposure time of 2 years onMTX was established as a cut-oV point for starting lifetable analysis (data not shown).

The reasons for interruption of MTX were adverseeVects (n = 14, 29.7%), lack of continuous access tomedication (n = 9, 19.1%), patient decision (n = 7,14.8%), lack of eYcacy as determined by attendingphysician (n = 5, 10.6%), miscellaneous causes (n = 5,10.6%), and undetermined (n = 7, 14.8%). Univariableanalysis showed a statistically signiWcant associationbetween discontinuation of treatment and living in anyof four Eastern Venezuelan states (HR = 3.63, P =0.001) (see Appendix for geographical location) andconcomitant use of leXunomide (HR = 2.88, P = 0.001)(Table 4).

The proportion of patients from eastern statesreceiving concomitant treatment with leXunomide wassigniWcantly higher than the rest of the study patientsample: 10/29 (34.4%) vs. 17/173 (9.8%) (P = 0.001,Fisher’s Exact test). Otherwise this patient subpopula-tion was comparable to the total study population inclinical and demographic variables (Data not shown).By multivariable analysis, living in an Eastern state andconcomitant treatment with leXunomide were identi-Wed as independent risk factors for discontinuation oftreatment (Table 4).

Discussion

In the current study we examined the continuity oftreatment with MTX in Venezuelan patients with RA

Table 2 Frequency of past or current use of concomitant medication (n = 219)

Drug n (%)

Any DMARD 139 (63.4)Anti-malarial 71 (32.8)Gold salts 28 (12.7)LeXunomide 27 (12.6)Azathioprine 15 (6.8)D-penicillamine 5 (2.2)Corticosteroids 187 (85.3)NSAID 176 (80.3)Folic acid 118 (53.8)

Table 3 Frequency of adverse eVects during treatment withmethotrexate (n = 219)

Adverse eVects n (%)

Gastrointestinal 37 (16.8)Nausea 31 (14.1)Abnormal liver enzymes 16 (7.3)Abdominal pain 15 (6.8)Anorexia 6 (2.7)Oral ulcers 5 (2.2)Vomiting 5 (2.2)Diarrea 5 (2.2)Stomatitis 5 (2.2)Gingivitis 1 (0.4)

Skin 9 (4.1)Pruritus 6 (2.7)Rash 3 (1.3)Bruising 2 (0.9)Alopecia 2 (0.9)Hyperpigmentation 2 (0.9)Folliculitis 1 (0.4)

Lung 6 (3.2)Cough 2 (1.3)Pneumonitis 3 (1.3)Dyspnea 1 (0.4)

Hematological 6 (3.2)Leucopenia 2 (2.7)Anemia 2 (1.8)Thrombocytopenia 1 (0.4)

Fever 2 (0.9)Miscellaneous 19 (8.6)

Fig. 1 Figure shows Kaplan–Meier survival curve for MTX treat-ment survival in patients treated with MTX alone and in patientswith MTX plus leXunomide. The diVerence between both curveswas statistically signiWcant: P = 0.009 (log-rank test)

Time (months)

0

1.00

0.75

MTX

0.50

MTX + leflunomide

0.25

0.00

50 100 150 200

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during a cumulative period of 180 months. By survivallife table analysis, less than 50% of patients were stillreceiving the drug after that time. Despite the fact thatthe occurrence of adverse eVects was the most commoncause for interruption of treatment, the only factorsthat were associated with treatment withdrawal wereliving in an state in Eastern Venezuelan and concomi-tant use of leXunomide.

Methotrexate is the leading DMARD in the treat-ment of RA. Several randomized, controlled studieshave demonstrated its therapeutic eYcacy and poten-tial for retarding joint damage [11]. Therefore, thequestion is not whether this drug is useful for diseasecontrol and damage prevention, but whether its toler-ability and eYcacy allow for its long-term use. Moststudies have been conducted in patients of Afro-American or Caucasian stock, in whom it has beenestimated that »56% of patients remain on MTX at60 months [12–15]. For example, Wolfe estimated amedian time for discontinuation of 144 months [14].It is conceivable that ethnic, as well as cultural andsocial diVerences may inXuence the survival of treat-ment with MTX in patient populations in diVerentworld regions. To our knowledge, no such data areavailable in RA patients from Latin America. Ourstudy showed a rate of 42% of patients remaining intreatment after 180 months. The same trend wasobserved when analyzing data of patients with at least2 years of disease duration, thus allowing a minimaltime of drug exposure. In most studies, the frequencyof adverse eVects can be as high as 80–90% [16–18],and their occurrence is usually the main factor inXu-encing the continuity of treatment. In the study by

Sany et al. [19], adverse eVects were seen in 37% ofpatients but in only 15% were they the cause for with-drawal. Aletaha et al. [20] showed that 42% of 593patients interrupted treatment with MTX because ofan adverse eVect. In our study 43.3% of patients hadan adverse eVect, which was the cause for treatmentinterruption in 29.4%. In general, most studies showthat major toxicity is relatively uncommon in patientstreated with MTX [17–23], and adverse eVects areusually mild and reversible. This may explain whyonly »30% of patients abandon treatment because ofan adverse eVect [21]. Another potential factor inXu-encing the rate of MTX withdrawal in our study is therelatively low-mean dose used in our patients, whichis under the current recommended guidelines [24].The time frame of the study includes many patientsthat were initially treated with tempting, certainlysuboptimal doses of MTX, and this fact may inXuencethe durability of treatment by decreasing the numberof potential responders and/or diminishing the fre-quency of dose-related side eVects.

One of the factors potentially inXuencing the dura-tion of treatment with MTX is combined therapy withadditional DMARD. Dougados et al. [25] showed nodiVerences of treatment survival during a 52-week clin-ical trial in French patients receiving MTX alone or incombination with sulphasalazine. Rau et al. [18]showed similar risk for toxicity in German patientsreceiving long-term treatment with MTX alone or incombination with gold salts. Elkayam et al. showedrates of MTX discontinuation between 52 and 63% in121 Jewish patients with RA combining MTX withgold compounds, hydroxichloroquine, sulphasalazine,

Table 4 Univariable and multivariable analysis predict-ing hazard ratios of MTX treatment survival (n = 219)

Explanatory variables Univariable Multivariable

HR (95% CI) P HR (95% CI) P

Age 0.98 (0.96–1.00) 0.22 –Gender (Female) 1.13 (0.44–0.76) 0.79 –Functional class 0.92 (0.63–1.35) 0.69 –Anatomical stage 0.95 (0.63–1.41) 0.80 –Presence of rheumatoid factor 0.66 (0.29–1.48) 0.31 –Presence of subcutaneous nodules 0.90 (0.47–1.72) 0.76 –Body mass index 1.03 (0.98–1.09) 0.18 –Presence of any comorbid condition 1.11 (0.82–1.51) 0.46 –Presence of any adverse eVect 1.46 (0.80–2.60) 0.21 –Use of any additional DMARD 0.96 (0.50–1.74) 0.91 –Corticosteroids 0.82 (0.32–2.10) 0.09 –NSAIDs 0.48 (0.22–1.05) 0.06 0.59 (0.26–1.30) 0.19Anti-malarial drugs 0.90 (0.49–1.67) 0.76 –Gold salts 0.63 (0.24–1.62) 0.33 –D-penicillamine 1.13 (0.34–3.73) 0.83 –Sulphasalazine 1.51 (0.36–6.32) 0.56 –LeXunomide 2.88 (1.49–5.45) 0.001 2.63 (1.34–5.18) 0.005Folic acid 0.59 (0.32–1.08) 0.08 0.60 (0.32–1.10) 0.10Patient from an eastern state 3.63 (1.86–7.10) 0.001 2.69 (1.27–5.69) 0.009

HR hazard ratio, CI conW-dence interval

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and minocyclin [26]. However, in a meta-analysis byMaetzel et al. [27], it was demonstrated that patientson MTX as monotherapy stayed longer in treatmentthan when MTX was associated with either gold salts,sulphasalazine or hydroxichloroquine. Our studydesign does not allow the diVerentiation between pastor current medication with additional DMARDs as ameasure of the MTX primary outcome (Table 2).Therefore, it is possible that the eVect of currentinstead of past DMARD medication may have beenunderestimated. The only concomitant DMARD asso-ciated with MTX withdrawal was leXunomide. Patientsreceiving MTX alone or MTX plus leXunomide werecomparable in various clinical and demographic vari-ables (Data not shown). However, we do not havesuYcient clinical data to establish if the subgroup ofpatients on combined therapy with leXunomide hadmore severe and active disease and thus were poten-tially more refractory to treatment. In addition, ouranalysis assumes that combined therapy occurred atthe beginning of follow-up whereas we cannot actuallypinpoint the time of initiation of combined therapy.LeXunomide is an anti-metabolite recently approveduse as a DMARD in RA that interferes with pyrimi-dine metabolism and thus selectively decreases prolif-eration rates of activated lymphocytes [28]. In turn,polyglutamates of MTX inhibit folate-dependentenzymes also involved in the synthesis of pyrimidineand purine precursors of DNA [29]. The biochemicalrationale for combination of MTX and leXunomide hasbeen previously discussed [30]. However, the associa-tion of drugs potentially targeting the same biochemi-cal end-point (namely DNA synthesis) in the same cellsubpopulation (i.e., T cells) could potentially synergizenot only in therapeutic eYcacy but also in toxicity.Limitations of our study were its retrospective designand the relatively low number of patients. On the otherhand, being a multicenter, national study, we think thatresults are generalizable to MTX treatment survival inVenezuelan patients.

In summary, treatment of RA patients with MTXhad a comparable survival in Venezuelan RA patientsas compared to RA patients of other ethnic composi-tions. The frequency of adverse eVects and their inXu-ence on MTX withdrawal was also similar. Theconcomitant use of leXunomide may be diminishing thetolerability of MTX in Venezuelan RA patients.

Acknowledgments We appreciate the critical review of manu-script by James S. Goodwin, M.D. and Sarah E. Toombs Smith,Ph.D., University of Texas, Galveston. We thank Mrs. OmairaPérez, Mayra Mayora and Cruz Milano for eYcient secretarialsupport. Supported by Grant No G-97000808, Fondo de Ciencia,Innovación y Tecnología (FONACIT).

Appendix

Table 5

References

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Table 5 Participating centers

a Cities from four Eastern states

City Center n %

Caracas Hospital Universitario 107 48.8Maracay Hospital Central 20 9.1Barcelonaa Centro Comercial Videmar 10 4.5Mérida Hospital Universitario 10 4.5Maturína Manuel Núñez Tovar 10 4.5Cumanaa Patricio Alcalá 10 4.5Maracaibo Clínica Medicina Interna 10 4.5San Cristóbal Hospital Central 10 4.5Coro Rafael Calles Sierra 9 4.1Ciudad Bolívara Ruíz y Páez 9 4.1San Fernando Pablo Acosta Ortiz 8 3.6Acarigua Hospital Jesús M. Casal 6 2.7

Total 219

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