Estudo clinico, randômico e duplo cego do uso do metotrexato em pacientes com lúpus eritematoso sistêmico
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1997
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Carneiro, José Ronaldo Matos [UNIFESP]
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Sato, Emilia Inoue [UNIFESP]
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Dissertação de mestrado
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Abstract
Embora o MTX venha sendo utilizado ha quase duas decadas com bastante frequencia em doencas reumaticas, particularmente na AR, existem poucas referencias na literatura quanto ao seu em LES, nao havendo ate o momento nenhum estudo, controlado e randomico. O presente trabalho teve por objetivos avaliar a capacidade do MTX em controlar atividade da doenca, reduzir a necessidade de corticoesteroides e estudar a tolerabilidade ao MTX em pacientes com LES. Participaram do estudo pacientes com LES, segundo criterios classificatorios do CAR, com doenca ativa, em uso de prednisona  0,5 mg/kg/dia sem uso de imunossupressores, aumento recente de corticoesteroides, comprometimento com risco de vida ou perda recente de funcao renal, e sem contra-indicacoes ao uso do MTX. O estudo foi duplo cego, randomico, controlado e comparou a eficacia do MTX a do PL. Entraram para o estudo 41 pacientes, dos quais 37 terminaram seguimento de 6 meses. Trinta e cinco eram do sexo feminino, 19 de cor branca, com idade variando de 16 a 49 anos (media de 31,2 anos). O tempo medio de doenca foi de 82,5 meses e variou de seis meses a 201 meses. Aleatoriamente, 20 pacientes receberam MTX na dose de 15mg/semana para os que pesassem ate 50kg e 20mg/semana para os com mais de 50kg de peso corporeo. Vinte e um pacientes receberam igual numero de capsulas de placebo. A dose de prednisona foi mantida, umentada ou reduzida a partir de um mes, de acordo com a evolucao clinica e laboratorial. Avaliacao clinica e laboratorial foram realizadas a intervalos mensais, ou a intervalos menores, quando necessario. A dose de prednisona, o escore do SLEDAI e a avaliacao da dor articular (escala analogica), hemograma, VHS, urina, creatinina, CH50 e anti-DNAn foram anotados a cada visita. Foi considerado melhora clinica quando o escore do SLEDAI, ao final do estudo, foi 50% menor que o inicial com diferenca minima de 3 pontos, e considerado significante quando a dose final de prednisona foi pelo menos 50% menor em relacao a inicial, sem haver exacerbacao da doenca. Os testes de Friedman, Mann-Withney e qui quadrado foram utilizados para a analise estatistica, sendo fixado em 0,05 o nivel de rejeicao da hipotese de nulidade. Os grupos foram homogeneos e comparaveis no inicio do estudo quanto as condicoes socio economicas, sexo, idade, escores do SLEDAI, dose media de prednisona, nota da escala analogica visual de dor e manifestacoes clinicas. Dois pacientes do grupo PL foram retirados do estudo por apresentarem piora significativa da doenca necessitando internacao hospitalar. Duas pacientes do grupo MTX tambem foram retiradas do estudo por terem apresentado efeitos colaterais e/ou complicacoes (tuberculose pulmonar em um caso e dispepsia intensa e lesoes cutaneas que foram atribuidas ao MTX em outro caso). Ao final do ensaio observou-se que 16 pacientes do grupo PL e apenas um do grupo MTX apresentavam manifestacoes articulares (p<0,001). A analise dos valores da escala analogica de dor mostrou que os valores do grupo PL foram significantemente maiores do que os do grupo MTX a partir do primeiro mes. Dezesseis pacientes do grupo PL e tres do MTX apresentavam lesoes cutaneas ao termino do trabalho (p<0,001). Nao houve diferenca significante entre os grupos MTX e PL quanto a presenca de proteinuria, hematuria, vasculites de polpas digitais e comprometimento hematologico. Ao final do estudo, quatro pacientes do grupo MTX e onze do PL apresentavam hipocomplementemia (CH50 <130U) (p<0,001) Com relacao aos escores do SLEDAI, comparando-se os dois grupos observou-se pelo teste de Mann-Whitney que os valores do SLEDAI do grupo PL foram significantemente maiores do que os do grupo MTX a partir do terceiro mes. Com relacao a dose de prednisona 13 pacientes do grupo MTX e apenas um do grupo PL conseguiram reduzir a dose ao longo do estudo (p < 0,001). O teste de Mann-Whitney mostrou que as medias das doses de prednisona foram significantementemenores no grupo MTX quando comparado ao grupo PL. Durante o estudo, no grupo MTX foram observados efeitos colaterais em 14/20 pacientes (70%). Doze pacientes apresentaram 60 episodios de efeitos adversos leves, sendo 29 clinicos e 31 laboratoriais. A sindrome dispeptica foi observada em 13,3% dos episodios, e, aumentos da AST e ALT, foram responsaveis, respectivamente, por 16,6% e 13,3% dos episodios de efeitos colaterais. No grupo PL foram observados sintomas gastrintestinais leves em 14,3% dos pacientes. Nosso trabalho permite concluir que o MTX foi eficaz no controle da atividade cutanea e articular de pacientes com LES e permitiu a reducao da dose de prednisona. Na dose de 15 a 20 mg/semanais, por 6 meses apresentou efeitos colaterais leves e frequentes, nao necessitando a suspensao da droga na maioria dos casos
Although MTX has been used for more than two decades in the treatment of rheumatic diseases, specially rheumatoid arthritis, few references about the use of MTX in SLE patients are found in the literature, none of which is a randomized, controlled clinical trial. The aim of the present study was to evaluate the ability of MTX to control SLE disease activity and to reduce corticosteroid requirement, as well as to study the side effects of MTX in these patients. The study was designed as a controlled, double blind, randomized trial to compare the efficacy of MTX and placebo (PL). SLE patients (fulfilling ACR criteria) with active disease, prednisone dose 0,5 mg/kg/day, no immunossupressive drugs, no recent increase of corticosteroid, and no contraindication to MTX use were randomly allocated to receive MTX or PL. Forty-one patients entered the trial and 37 completed the 6 months of study. Thirty-five were female, 19 white color, and the age ranged from 16 to 49 years old (median of 31.2 y.o). The mean disease duration was 82.5 months, ranging from 6 to 201 months. Twenty patients received MTX (15 mg/week for patients weighing up to 50 kg and 20 mg/week for patients weighing more than 50 kg). Twenty-one patients received an equivalent number of placebo capsules. The prednisone dose was maintained, increased or reduced after the first month of study, according the clinical and laboratory evaluation. Clinical and laboratory evaluation was performed monthly or at shorter intervals when necessary. Prednisone dose, SLEDAI score, evaluation of articular pain (analogic scale), hemogram, erythrocyte sedimentation rate, serum creatinin, urinalysis, total serum complement, and anti-DNA antibodies determination were registered at each evaluation. Clinical improvement was defined by a 50% drop in the final SLEDAI score relative to the initial score, without flare. Relevant reduction of prednisone dose was defined by a minimum 50% decrease in prednisone requirement, without flare. Friedman, Mann-Whitney and Qui-square tests were used for statistical analysis, fixing at 0.05 the level of rejection of null hypothesis. Both groups were homogeneous and comparable at the beginning of study concerning socio-economic status, age, sex, SLEDAI score, mean prednisone dose, mean pain visual analogic scale, and clinical involvement. Two patients from PL group dropped out due severe flare of disease. Two patients from MTX group dropped out due to side effects (pulmonary tuberculosis and dyspepsia and cutaneous lesions attributed to MTX). Thirty-seven patients (18 MTX and 19 PL) concluded the study. At end of study 16 patients from PL group and only one patient from MTX group presented articular complaints (p<0.001). Pain analogic scale scores were significantly higher in the PL group than the MTX group from the first month of study on. Sixteen patients in PL group and three patients in MTX presented cutaneous lesions after 6 months of treatment (p<0.001). No significant difference was observed between MTX and PL group concerning the presence of proteinuria, hematuria, digital vasculitis, and hematological involvement. At the end of the study four patients in MTX group and eleven PL group presented hypocomplementemia (CH50 <130U) ( p<0.001). Friedman variance analysis showed significant decrease in SLEDAI scores from the first month on in the MTX group, while in PL group the scores of months 0, 1, 5, and 6 were significantly higher than those in months 2, 3, and 4. When both groups were compared by the Mann-Whitney test, SLEDAI scores in PL group were significantly higher than those in MTX group from the third month on. Thirty patient in MTX group and only one in PL group allowed prednisone dose decrease along the study (p<0.001 ). The Mann-Whitney test showed that the prednisone dose was significantly lower at months 5 and 6 in the MTX group when compared to PL group. Fourteen patients in the MTX group (70%) presented side effects, two of whom droped out. Twelve patients presented 60 side effects episodes along the study, being 29 clinically evident and 31 only detected by laboratory tests. Dyspeptic syndrome occurred in 13.3% of side effects episodes; AST and ALT elevation were detected in 16.6% and 13.3% of side effect episodes, respectively. In PL group mild gastrointestinal complaints occurred in 14,3% of patients. Our study allowed to conclude that MTX was efficient in controlling cutaneous and articular activity in patients with SLE and allowed prednisone dose reduction. At doses of 15 to 20 mg/week for 6 months MTX presented frequent but mild side effects, which did not result in drug discontinuation in the majority of patients.
Although MTX has been used for more than two decades in the treatment of rheumatic diseases, specially rheumatoid arthritis, few references about the use of MTX in SLE patients are found in the literature, none of which is a randomized, controlled clinical trial. The aim of the present study was to evaluate the ability of MTX to control SLE disease activity and to reduce corticosteroid requirement, as well as to study the side effects of MTX in these patients. The study was designed as a controlled, double blind, randomized trial to compare the efficacy of MTX and placebo (PL). SLE patients (fulfilling ACR criteria) with active disease, prednisone dose 0,5 mg/kg/day, no immunossupressive drugs, no recent increase of corticosteroid, and no contraindication to MTX use were randomly allocated to receive MTX or PL. Forty-one patients entered the trial and 37 completed the 6 months of study. Thirty-five were female, 19 white color, and the age ranged from 16 to 49 years old (median of 31.2 y.o). The mean disease duration was 82.5 months, ranging from 6 to 201 months. Twenty patients received MTX (15 mg/week for patients weighing up to 50 kg and 20 mg/week for patients weighing more than 50 kg). Twenty-one patients received an equivalent number of placebo capsules. The prednisone dose was maintained, increased or reduced after the first month of study, according the clinical and laboratory evaluation. Clinical and laboratory evaluation was performed monthly or at shorter intervals when necessary. Prednisone dose, SLEDAI score, evaluation of articular pain (analogic scale), hemogram, erythrocyte sedimentation rate, serum creatinin, urinalysis, total serum complement, and anti-DNA antibodies determination were registered at each evaluation. Clinical improvement was defined by a 50% drop in the final SLEDAI score relative to the initial score, without flare. Relevant reduction of prednisone dose was defined by a minimum 50% decrease in prednisone requirement, without flare. Friedman, Mann-Whitney and Qui-square tests were used for statistical analysis, fixing at 0.05 the level of rejection of null hypothesis. Both groups were homogeneous and comparable at the beginning of study concerning socio-economic status, age, sex, SLEDAI score, mean prednisone dose, mean pain visual analogic scale, and clinical involvement. Two patients from PL group dropped out due severe flare of disease. Two patients from MTX group dropped out due to side effects (pulmonary tuberculosis and dyspepsia and cutaneous lesions attributed to MTX). Thirty-seven patients (18 MTX and 19 PL) concluded the study. At end of study 16 patients from PL group and only one patient from MTX group presented articular complaints (p<0.001). Pain analogic scale scores were significantly higher in the PL group than the MTX group from the first month of study on. Sixteen patients in PL group and three patients in MTX presented cutaneous lesions after 6 months of treatment (p<0.001). No significant difference was observed between MTX and PL group concerning the presence of proteinuria, hematuria, digital vasculitis, and hematological involvement. At the end of the study four patients in MTX group and eleven PL group presented hypocomplementemia (CH50 <130U) ( p<0.001). Friedman variance analysis showed significant decrease in SLEDAI scores from the first month on in the MTX group, while in PL group the scores of months 0, 1, 5, and 6 were significantly higher than those in months 2, 3, and 4. When both groups were compared by the Mann-Whitney test, SLEDAI scores in PL group were significantly higher than those in MTX group from the third month on. Thirty patient in MTX group and only one in PL group allowed prednisone dose decrease along the study (p<0.001 ). The Mann-Whitney test showed that the prednisone dose was significantly lower at months 5 and 6 in the MTX group when compared to PL group. Fourteen patients in the MTX group (70%) presented side effects, two of whom droped out. Twelve patients presented 60 side effects episodes along the study, being 29 clinically evident and 31 only detected by laboratory tests. Dyspeptic syndrome occurred in 13.3% of side effects episodes; AST and ALT elevation were detected in 16.6% and 13.3% of side effect episodes, respectively. In PL group mild gastrointestinal complaints occurred in 14,3% of patients. Our study allowed to conclude that MTX was efficient in controlling cutaneous and articular activity in patients with SLE and allowed prednisone dose reduction. At doses of 15 to 20 mg/week for 6 months MTX presented frequent but mild side effects, which did not result in drug discontinuation in the majority of patients.
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CARNEIRO, José Ronaldo Matos. Estudo clinico, randômico e duplo cego do uso do metotrexato em pacientes com lúpus eritematoso sistêmico.1997. Dissertação (Mestrado em Ciências) - Escola Paulista de Medicina, Universidade Federal de São Paulo (UNIFESP), São Paulo, 1997.