Metotrexato para el mantenimiento de la remisión de la colitis ulcerosa
Resumen
Antecedentes
El metotrexato, un antagonista del folato, es un fármaco inmunosupresor efectivo para tratar varios trastornos inflamatorios que incluyen la enfermedad de Crohn. La colitis ulcerosa, una enfermedad intestinal inflamatoria crónica, puede ser difícil de tratar. Esta revisión sistemática actualizada resume las pruebas actuales sobre el uso del metotrexato para mantener la inducción de la remisión de la colitis ulcerosa.
Objetivos
Los objetivos de esta revisión fueron evaluar la eficacia y la seguridad del metotrexato para el mantenimiento de la remisión en pacientes con colitis ulcerosa.
Métodos de búsqueda
Se realizaron búsquedas en MEDLINE, EMBASE, CENTRAL y en el registro de ensayos del Grupo Cochrane de Enfermedad Inflamatoria Intestinal y Trastornos Funcionales del Intestino (Cochrane Inflammatory Bowel Disease and Functional Bowel Disorders Group, IBD/FBD Group) desde su inicio hasta el 26 de junio de 2014. También se realizaron búsquedas de ensayos adicionales en las referencias de los estudios y en los documentos de las revisiones. Se realizaron búsquedas en los resúmenes de los principales congresos de gastroenterología para identificar investigaciones publicadas solamente en forma de resumen.
Criterios de selección
Se consideraron para inclusión los ensayos controlados aleatorios que compararon metotrexato con placebo o un comparador activo en pacientes con colitis ulcerosa inactiva.
Obtención y análisis de los datos
Dos autores de la revisión, de forma independiente, extrajeron los datos y evaluaron el riesgo de sesgo de cada estudio. El criterio de valoración primario fue la recaída clínica o endoscópica según la definición de los estudios primarios. Los criterios de valoración secundarios incluyeron frecuencia y naturaleza de los eventos adversos, cambio en la puntuación de actividad de la enfermedad y efecto economizador de esteroides. Se calculó el cociente de riesgos y el intervalo de confianza del 95% para los resultados dicotómicos. Los datos se analizaron por intención de tratar. La calidad general de las pruebas que apoyan los resultados se evaluó mediante los criterios GRADE.
Resultados principales
Tres ensayos (165 pacientes) cumplieron los criterios de inclusión. Un estudio comparó metotrexato oral (12,5 mg/semana) con placebo, otro comparó metotrexato oral (15 mg/semana) con 6‐mercaptopurina (6‐MP, 1,5 mg/kg/día) o ácido 5‐aminosalicílico (5‐ASA, 3 g/día) y el otro comparó metotrexato (15 mg/semana) en combinación con sulfasalazina (3 g/día) con sulfasalazina. El estudio controlado con placebo se calificó como de riesgo bajo de sesgo. El estudio que comparó metotrexato con 6‐MP y 5‐ASA se consideró como de alto riesgo de sesgo y el estudio que evaluó metotrexato y sulfasalazina se consideró como de riesgo incierto de sesgo para la generación de la secuencia, la ocultación de la asignación y el cegamiento. El estudio controlado con placebo no encontró diferencias estadísticamente significativas en la proporción de pacientes que mantuvieron la remisión. A los nueve meses, el 36% (5/14) de los pacientes que recibieron metotrexato mantuvieron la remisión en comparación con el 54% (10/18) de los pacientes que recibieron placebo (CR 0,64; IC del 95%: 0,28 a 1,45). Un análisis de GRADE indicó que la calidad general de las pruebas que apoyan este resultado fue baja debido a la muy reducida cantidad de datos (15 eventos). El estudio que comparó el tratamiento de combinación con la sulfasalazina no encontró diferencias estadísticamente significativas en la proporción de pacientes que mantuvieron la remisión. A los 12 meses, el 100% (14/14) de los pacientes del grupo de combinación mantuvo la remisión en comparación con el 75% (9/12) de los pacientes que recibieron sulfasalazina (CR 1,32; IC del 95%: 0,94 a 0,86). Un análisis GRADE indicó que la calidad general de las pruebas para este resultado fue muy baja debido al riesgo desconocido de sesgo y a los datos muy escasos (23 eventos). No hubo diferencias estadísticamente significativas en el mantenimiento de las tasas de remisión entre metotrexato y 6‐MP o entre metotrexato y 5‐ASA. A las 76 semanas, el 14% (1/7) de los pacientes que recibieron metotrexato mantuvieron la remisión en comparación con el 64% (7/11) de los pacientes que recibieron 6‐MP (CR 0,22; IC del 95%: 0,03 a 1,45) y el 0% (0/2) de los pacientes que recibieron 5‐ASA (CR 1,13; IC del 95%: 0,06 a 20,71). Un análisis de GRADE indicó que la calidad general de las pruebas de este resultado fue muy baja debido al riesgo alto de sesgo y a la reducida cantidad de datos. Los eventos adversos informados en estos estudios incluyeron leucopenia transitoria, migraña, náuseas y dispepsia, alopecia leve, aumento leve de los niveles de aspartato‐amino‐transferasa, absceso peritoneal, hipoalbuminemia, erupción cutánea grave y neumonía atípica
Conclusiones de los autores
Los hallazgos para los resultados de eficacia entre metotrexato y placebo, metotrexato y sulfasalazina, metotrexato y 6‐mercaptopurina, y metotrexato y ácido 5‐aminosalicílico fueron inciertos. Se desconoce si una dosis mayor o la administración parenteral del metotrexato serían eficaces para la colitis ulcerosa inactiva. Actualmente no existen pruebas que apoyen la administración de metotrexato para el mantenimiento de la remisión en la colitis ulcerosa. Se necesitan más estudios para determinar la eficacia y la seguridad del tratamiento de mantenimiento con metotrexato en pacientes con colitis ulcerosa inactiva. Se necesitan ensayos controlados aleatorios metodológicamente rigurosos a gran escala. Estos estudios deben investigar dosis mayores de metotrexato (p.ej., 15 a 25 mg/semana) y administración parenteral.
PICO
Resumen en términos sencillos
Metotrexato para mantener la colitis ulcerosa inactiva
Pregunta de la revisión
Se revisaron las pruebas de la bibliografía médica hasta el 26 de junio de 2014 acerca de los efectos y la seguridad del metotrexato para mantener la remisión en pacientes con colitis ulcerosa.
Antecedentes
¿Qué es la colitis ulcerosa?
La colitis ulcerosa es una enfermedad intestinal inflamatoria crónica caracterizada por episodios recurrentes de la enfermedad activa, que habitualmente afectan al recto o al colon, o a ambos. Los pacientes con enfermedad activa pueden presentar cólicos abdominales, urgencia para defecar y diarrea hemorrágica. Cuando los síntomas se detienen, se considera que los pacientes están en remisión.
¿Qué es metotrexato?
El metotrexato es un fármaco que reduce las respuestas inmunitarias del cuerpo y puede reducir la inflamación asociada con la colitis ulcerosa.
Características de los estudios
Los investigadores identificaron tres estudios que incluyeron un total de 165 pacientes. Un estudio (67 pacientes) comparó metotrexato oral (12,5 mg/semana) con placebo (p.ej. una pastilla de azúcar o medicina falsa); un estudio (26 pacientes) comparó metotrexato oral (15 mg/semana) y sulfasalazina (3 g/día) con sulfasalazina sola; y un estudio (72 pacientes en total; de los cuales 34 presentaban colitis ulcerosa), comparó metotrexato oral (15 mg/semana) con 6‐mercaptopurina (1,5 mg/kg/día) o ácido 5‐aminosalicílico (3 g/día). Dos estudios se consideraron de calidad muy baja y el estudio controlado con placebo se consideró de alta calidad.
Resultados clave
No hubo diferencias entre los grupos de tratamiento con metotrexato y placebo en el número de pacientes que mantuvieron la remisión a los nueve meses. Lo anterior indica que, cuando se administra a dosis baja (12,5 mg/semana), el metotrexato no mantiene la remisión en los pacientes con colitis ulcerosa inactiva. Sin embargo, este resultado es incierto debido al escaso número de pacientes que se evaluaron
No hubo diferencias entre los grupos de tratamiento de combinación (metotrexato más sulfasalazina) y de tratamiento con sulfasalazina en el número de pacientes que mantuvieron la remisión a los 12 meses. Este resultado es incierto debido al diseño deficiente del estudio y al escaso número de participantes.
El otro estudio pequeño no mostró diferencias entre el metotrexato y los otros tratamientos (6‐mercaptopurina y ácido 5‐aminosalicílico) en la proporción de participantes que pudieron mantener la remisión. Estos resultados son inciertos debido al diseño deficiente del estudio y al escaso número de participantes.
Los efectos secundarios informados en los estudios incluyeron leucopenia (una disminución en el número de leucocitos), migraña, erupción cutánea, náuseas y dispepsia (indigestión), alopecia (pérdida del cabello) leve, aumento leve de los niveles de una enzima que se encuentra en el hígado (aspartato‐amino‐transferasa), colección de pus en el tejido abdominal (absceso peritoneal), niveles anormalmente bajos de la proteína albúmina en la sangre (hipoalbuminemia) y neumonía.
Actualmente, los resultados de los ensayos médicos no apoyan la administración oral de metotrexato a dosis baja (12,5 mg a 15 mg/semana) para el mantenimiento de la remisión en pacientes con colitis ulcerosa inactiva. No se sabe si una dosis mayor de metotrexato oral, o la administración de metotrexato por una vía diferente (p.ej. por inyección), serían eficaces para el mantenimiento de la remisión en pacientes con colitis ulcerosa inactiva.
En el futuro, los investigadores deben considerar la posibilidad de organizar un estudio con un mayor número de participantes que reciban una dosis mayor de metotrexato (15 a 25 mg/semana). Los estudios futuros también deben investigar el metotrexato administrado mediante inyección. Los resultados de dichos estudios pueden resolver la incertidumbre que rodea la administración del metotrexato como tratamiento de mantenimiento en pacientes con colitis ulcerosa inactiva.
Conclusiones de los autores
Summary of findings
| Methotrexate compared to placebo for maintenance of remission in ulcerative colitis | ||||||
| Patient or population: patients with quiescent ulcerative colitis | ||||||
| Outcomes | Illustrative comparative risks* (95% CI) | Relative effect | No of Participants | Quality of the evidence | Comments | |
| Assumed risk | Corresponding risk | |||||
| Placebo | Methotrexate | |||||
| Maintenance of remission | 556 per 10001 | 356 per 1000 | RR 0.64 | 32 | ⊕⊕⊝⊝ | |
| *The basis for the assumed risk (e.g. the median control group risk across studies) is provided in footnotes. The corresponding risk (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI). | ||||||
| GRADE Working Group grades of evidence | ||||||
| 1 Control group risk comes from control arm of study | ||||||
| Methotrexate compared to 5‐ASA for maintenance of remission in ulcerative colitis | ||||||
| Patient or population: patients with quiescent ulcerative colitis | ||||||
| Outcomes | Illustrative comparative risks* (95% CI) | Relative effect | No of Participants | Quality of the evidence | Comments | |
| Assumed risk | Corresponding risk | |||||
| 5‐ASA | Methotrexate | |||||
| Maintenance of remission | 0 per 10001 | 0 per 1000 | RR 1.12 | 9 | ⊕⊝⊝⊝ | |
| *The basis for the assumed risk (e.g. the median control group risk across studies) is provided in footnotes. The corresponding risk (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI). | ||||||
| GRADE Working Group grades of evidence | ||||||
| 1 Control group risk comes from control arm of study | ||||||
| Methotrexate compared to 6‐MP for maintenance of remission in ulcerative colitis | ||||||
| Patient or population: patients with maintenance of remission in ulcerative colitis | ||||||
| Outcomes | Illustrative comparative risks* (95% CI) | Relative effect | No of Participants | Quality of the evidence | Comments | |
| Assumed risk | Corresponding risk | |||||
| 6‐MP | Methotrexate | |||||
| Maintenance of Remission | 636 per 10001 | 140 per 1000 | RR 0.22 | 18 | ⊕⊝⊝⊝ | |
| *The basis for the assumed risk (e.g. the median control group risk across studies) is provided in footnotes. The corresponding risk (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI). | ||||||
| GRADE Working Group grades of evidence | ||||||
| 1 Control group risk comes from control arm of study | ||||||
| Methorexate + SFZN compared to SFZN alone for maintenance of remission in ulcerative colitis | ||||||
| Patient or population: patients with maintenance of remission in ulcerative colitis | ||||||
| Outcomes | Illustrative comparative risks* (95% CI) | Relative effect | No of Participants | Quality of the evidence | Comments | |
| Assumed risk | Corresponding risk | |||||
| SFZN alone | Methorexate + SFZN | |||||
| Maintenance of Remission | 750 per 10001 | 990 per 1000 | RR 1.32 | 26 | ⊕⊝⊝⊝ | |
| *The basis for the assumed risk (e.g. the median control group risk across studies) is provided in footnotes. The corresponding risk (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI). | ||||||
| GRADE Working Group grades of evidence | ||||||
| 1 Control group risk comes from control arm of study | ||||||
Antecedentes
Descripción de la afección
La colitis ulcerosa es una enfermedad inflamatoria crónica del colon. Los síntomas característicos incluyen diarrea hemorrágica, retortijones abdominales y urgencia para defecar. Algunos pacientes no responden al tratamiento de primera línea que generalmente consiste en ácido 5‐aminosalicílico administrado por vía oral o tópica. Por lo tanto, se necesitan tratamientos adicionales.
Descripción de la intervención
El metotrexato, un antagonista del folato con efectos antiinflamatorios potentes, se utilizó por primera vez para el tratamiento de la artritis reumatoide en 1951 (Schnabel 1994).
De qué manera podría funcionar la intervención
Las tiopurinas, incluidas la azatioprina y la 6‐mercaptopurina, han sido los agentes inmunosupresores tradicionales de primera línea utilizados en la enfermedad de Crohn y en la colitis ulcerosa. Sin embargo, dos ensayos controlados aleatorios multicéntricos demostraron la eficacia del metotrexato parenteral para la inducción y el mantenimiento de la remisión de la enfermedad de Crohn dependiente de esteroides (Feagan 1995; Feagan 2000). En los estudios no controlados, otros investigadores han informado la eficacia de la administración subcutánea y oral del metotrexato en pacientes pediátricos con enfermedad de Crohn con intolerancia o resistentes al tratamiento con tiopurina (Turner 2007).
Por qué es importante realizar esta revisión
Aún está por definir la eficacia del metotrexato para la inducción y el mantenimiento de la remisión de la colitis ulcerosa. Una revisión Cochrane reciente encontró que el metotrexato no es efectivo en comparación con placebo o comparadores activos para la inducción de la remisión de la colitis ulcerosa(Chande 2014). El metotrexato puede ser de valor para el mantenimiento de la remisión de la colitis ulcerosa. Esta revisión sistemática es una actualización de una revisión Cochrane publicada anteriormente (El‐Matary 2009).
Objetivos
El objetivo principal fue determinar de manera sistemática la eficacia y la seguridad del metotrexato para el mantenimiento de la remisión en la colitis ulcerosa.
Métodos
Criterios de inclusión de estudios para esta revisión
Tipos de estudios
Solamente se consideraron para inclusión en esta revisión los ensayos controlados aleatorios (ECA) que compararon el metotrexato con placebo u otra intervención. No se consideraron para la inclusión los estudios de cohortes, las series de casos y los estudios con otros diseños no experimentales.
Tipos de participantes
Se consideraron para la inclusión los participantes de cualquier edad diagnosticados con colitis ulcerosa (definida por criterios clínicos y endoscópicos) que estaban en remisión (definida mediante cualquier índice de actividad) al comenzar o continuar con el metotrexato.
Tipos de intervenciones
Los estudios se consideraron si los participantes del grupo de tratamiento recibieron metotrexato por vía oral, subcutánea (SC) o intramuscular (IM) a cualquier dosis y si el grupo de comparación recibió placebo u otra intervención activa. Se permitió cualquier duración del seguimiento y cualquier cointervención (siempre que se administrara a ambos grupos).
Tipos de medida de resultado
Resultados primarios
La medida de resultado primaria fue la presencia de recaída clínica o endoscópica como la definieron los estudios primarios.
Resultados secundarios
Los resultados secundarios incluyeron:
1) Frecuencia y naturaleza de los eventos adversos;
2) Cambio en la puntuación de actividad de la enfermedad; y
3) Efecto de reducción de esteroides.
Results
Description of studies
Results of the search
The literature search conducted on 26 June 2014 identified 2770 records. Eight additional studies were identified through searching of conference abstracts. After duplicates were removed, a total of 2483 studies remained for review of titles and abstracts. Thirty‐six studies were selected for full text review (see Figure 1). Thirty‐three reports of 28 studies were excluded. Three studies met the pre‐defined inclusion criteria and were included in the review (Mate‐Jimenez 2000; Onuk 1996; Oren 1996). Two large scale studies are currently underway (NCT00498589; NCT01393405). However, the results of these studies are currently unavailable.
Study flow diagram.
Included studies
Mate‐Jimenez 2000 recruited 72 steroid‐dependent IBD patients (34 with ulcerative colitis and 38 with Crohn's disease). The trial was 106 weeks in length (30 weeks of induction phase and 76 weeks of maintenance phase). The patients were randomly assigned in a 2:2:1 ratio to receive 1.5 mg/kg/day of oral 6‐mercaptopurine (6‐MP, n = 14), 15 mg/week of oral methotrexate (n = 12) or 3 g/day of oral 5‐aminosalicylic acid (5‐ASA, n = 8).
Onuk 1996 recruited 26 patients with quiescent ulcerative colitis who were receiving maintenance therapy with sulfasalazine. Patients were randomized to receive either oral methotrexate (15 mg/week) plus oral sulfasalazine (3 g/day, n = 14) or sulfasalazine alone (n = 12) for 12 months.
Oren 1996 recruited 67 patients with active ulcerative colitis (Mayo Clinic score > 7). Concurrent use of steroids or 5‐ASA was allowed. No other immunosuppressive agent was allowed during the study or during the 3 months preceding randomization. Patients were randomly assigned to oral methotrexate 12.5 mg/week (n = 30) or placebo (n = 37) for 9 months of treatment.
Excluded studies
Reasons for exclusion are reported in the Characteristics of excluded studies table. The results of the excluded studies are described in additional Table 1.
| ID | Description | Results |
| PURSUIT‐SC induction study randomized UC patients to PBO/PBO (n=331), GLM 100mg/50mg (n=72), GLM 200mg/100mg (n=331), and GLM 400mg/200mg (n=331) at week 0 and 2. PURSUIT maintenance study enrolled 1228 patients, but only those who responded to GLM induction (n=464) were randomized (PBO, GLM 50mg or GLM 100 mg Q4W for 52 weeks) and included in the primary analysis. | During induction and maintenance, there was a positive Exposure‐Response relationship between SGC and efficacy outcomes regardless of immunomodulator (IM) use. Concomitant IM use did not appear to affect efficacy outcomes. Antibodies to GLM (ATG) incidence was lower in patients receiving IMs vs those who were not (1.5% vs 3.5%, overall 2.8%). | |
| A retrospective chart review of 38 pediatric UC patients treated with methotrexate (n=18 azathioprine unresponsiveness, n =10 azathioprine intolerance, n=4 spondyloarthropathy). Pediatric Ulcerative Colitis Activity Index (PUCAI) and use of corticosteroids were the main outcomes evaluated at baseline and at 3, 6 and 12 months. | Response or remission was achieved in 72%, 63% and 50% of patients at 3, 6 and 12 months respectively. Mean PUCAI were 49.5 ± 23.3 at baseline and 32.9 ± 21.9, 29.5 ± 21.8 and 29.4 ± 19.9 at 3, 6 and 12 months respectively (P = 0.03). 13 of the 16 patients on corticosteroids, had their steroid discontinued by 6 months. At the end of the study, 11 patients needed short course of corticosteroids for disease relapse. | |
| Open‐label 18 week study in which 19 (11 CD and 8 UC) patients with refractory IBD were given 15 mg/week methotrexate (starting at a low dose then increased gradually) | In the UC group, only 3 patients had a partial response. None of the UC patients has complete remission. However, there was a significant reduction in the daily prednisone dose. Adverse events were minor | |
| Retrospective chart review that evaluated 50 patients with UC (8 had rheumatoid arthritis as well and analyzed separately) who were intolerant or resistant to azathioprine. The mean dose of methotrexate was 19.9 mg/week for a median duration of 30 weeks and was given orally | Remission occurred in 42% of patients. Colitis remained in remission in 7/8 patients with concomitant rheumatoid arthritis. Side effects occurred in 23% but only 10% needed to stop methotrexate due to adverse effects | |
| A 20 week non‐randomized, open‐label study evaluate the effectiveness of weekly 25 mg methotrexate intramuscular injection (with 1 mg/day folic acid supplementation) in patients (n=22) with chronic active ulcerative colitis, refractory to steroids ± sulfasalazine for at least 3 months. | Fifteen patients (68%) had significant clinical improvement (Mayo Clinic score decreased from 8.2 to 4.7; P<0.001). Eleven patients achieved clinical remission (Mayo Clinic score ≤ 3), and 5/11 achieved histological remission. Under continuous sulfasalazine administration, 8/11 patients (73%) remained in remission after 6 months from cessation of methotrexate therapy. Adverse events (n=5) were not severe enough to warrant treatment interruptions. | |
| A 16 week‐randomized single‐blinded study comparing weekly SC 15 mg to 25 mg of methotrexate in 32 steroid‐dependant patients (10 with UC and 22 with CD) | Only 6 patients improved at the end of the induction period. Overall the dose escalation did not result in significant difference in treatment effect or toxicity | |
| Case series of 5 steroid‐refractory patients (3 with UC and 2 with CD) who failed methotrexate 25g/week SC for 16 weeks and had oral cyclosporine 3mg/kg/day added to methotrexate for another 16 weeks | Improvement of 3 patients with UC. One patient developed hypertension | |
| Retrospective chart review of 70 patients (48 with CD and 22 with UC) who were given methotrexate for a mean duration of 17.1 months at a mean maintenance dose of 20mg/week (oral in 62 patients and IM in 8) | Remission was achieved in 62% of patients who completed more than 3 months of treatment. The chance of maintaining remission (if treatment continues) at 12, 24 and 36 months were 90%, 73% and 51% respectively. Treatment was equally effective in UC and CD | |
| 16 week non‐randomized, open label study included 8 patients with moderate to severe refractory UC confirmed by sigmoidoscopy. They were treated with 25 mg IM MTX (and folic acid) and severity of disease was assessed by Mayo Clinic score (at recruitment, median 9, range 7‐11) | Six of eight patients completed 16 week treatment. Median Mayo Clinical score 8 (range 6‐11). One patient withdrew due to sever exacerbation and 1 withdrew because failure to improve. Treatment with 25mg MTX IM for 16 weeks was ineffective in this small group of patients with refractory UC. | |
| Retrospective study in 17 patients who were less than 16 years old and affected by steroid‐dependent or steroid‐resistant UC, They were treated with IM methotrexate (20 mg/m2/week). Clinical remission ‐ discontinuation of steroids and achievement of S0 stage of Montreal classification after 3, 6 and 12 months. endoscopic remission ‐ level 0 of Baron score at the same timing of clinical score calculation. | After 3 months, MTX induced clinical and endoscopic remission in 82% and 71% of UC patients, respectively. Of the nine UC patients continued MTX for > 3 months, 56% maintained clinical and endoscopic remission after 6 months; and 33% at 1 year. Adverse events occurred in one patient (acute pancreatitis) and led to discontinuation of treatment. | |
| Retrospective chart review that evaluated 65 patients with IBD (20 UC and 45 CD). Dose of methotrexate varied from 10‐25 mg/week | 63% achieved remission and treatment continued for a median of 11 months | |
| Retrospective chart review of 77 IBD patients (80% Crohn's disease) treated with methotrexate in eight hospitals of Madrid, Spain | Initially, 82% of patients responded (28% in remission). Forty percent of the patients lost response at a mean of 57 weeks after starting methotrexate. Adverse events included GI symptoms (n=10), myelotoxicity (n=4), and abnormal LFT (n=10), which let to withdrawal of treatments in 4 patients. | |
| Restrospective analysis of UC patients treated with infliximab (IFX, n=85), comparing duration of efficacy, and serum IFX and serum IFX and antibody‐to‐IFX (ATI) levels between those receiving IFX as monotherapy (n=46) and in combination with an immunosuppressant (n=38). | Conconmitant immunosuppressant use was associated with associated with increased duration of IFX therapy (90% vs.61% remained on therapy at 1 year, P =0.025), and less frequent ATI formation (4.5% vs. 33.3%, P=0.031). The majority of patients received purine analogues (e.g. azathioprine or mercaptopurine), only 3 out of 46 patients in the combination group received methotrexate. | |
| Pharmacogenetics study of 102 IBD patients treated with MTX and 202 patients with Crohn's disease, 205 patients with ulcerative colitis and 189 healthy volunteers to assess allele frequencies in the disease and healthy populations. Four polymorphisms (G80A in the RCF1 gene, G452T in GGH gene, and C677T and A1298C in MTHFR gene) were genotyped for genotype‐phenotype association with respect to efficacy and toxicity of MTX therapy. | No significant differences in the allele frequencies between CD, UC, and healthy controls were detected. Side effects of MTX in IBD are more likely to associate with a SNP (MTHFR 1298C) in the MTHFR gene (21% vs. 6.3%, P<0.05), but response cannot be predicted by any of the investigated SNPs. | |
| Retrospective chart review of 15 patients (13 with CD and 2 with UC) who were given 25 mg/week IM for 12 weeks followed by tapering oral dose | Symptomatic improvement occurred in 12/15 patients with reduction of prednisone dose after 3 months | |
| A multicentre, longitudinal cohort study of 1118 Crohn's disease patients (14530 patient years of follow‐up) and 1171 ulcerative colitis patients (18035 patient years of follow‐up). Patient demographics, disease characteristics according to Montreal classification, drug and surgical treatments were reviewed. Comparisons were made between 3 times periods of pre 1990, 1990‐2000, and post 2000. | In Crohn's disease cohort, cumulative probability of commencing immunomodulators was significantly reduced over the time periods (mean time to commence IM use, 15.9, 6.0 and 1.3, P<0.0001). Long‐term steroid (LTS) use (P<0.0001), surgical resection and recurrent resection (P=0.002) also decreased significantly. In ulcerative colitis cohort, time to introduction of IM significantly decreased over successive decades (P<0.0001) and was associated with significant reduction in the use of LTS (P<0.0001) and surgical resection rate (P=0.033). | |
| A retrospective study of effectiveness and safety electronic files of 543 IBD patients (58.6% UC patients) treated from 1981‐2010, of which, 48 patients were treated with methotrexate (33 CD, 14 UC, 1 undetermined) | Methotrexate was effective in 57% of patients with IBD and 27% of patients with fistulizing disease. Infection was the commonest adverse event. | |
| An open‐label observational study that recruited 21 patients with refractory IBD (14 CD and 7 UC) who were given 25 mg/week of methotrexate IM for 12 weeks | Five patients with UC had clinical improvement with successful reduction of the concurrent steroid dose. None had endoscopic healing. Complications were reported in 7 out of the 21 patients and included transient diarrhea, leucopenia, elevated AST, brittle nails and atypical pneumonitis | |
| Retrospective chart review where 86 patients (30 with UC) with refractory IBD were given 25 mg/week of parenteral methotrexate. The responders at 12 weeks were continued on oral methotrexate (7.5‐15 mg/week) | 70% of patients with UC showed some response but only 40 % continued to have response at a mean follow‐up of 59 weeks | |
| Retrospective chart review of 40 patients with UC from 8 Spanish IBD referral hospital, who received MTX for steroid dependency (70%) or steroid refractoriness (27%). Therapeutic success was defined as the absence of UC symptoms, complete steroid withdrawal and no requirement of rescue therapies within the first 6 months after starting MTX. | Forty‐five percent of patients met criteria for therapeutic success. The cumulative probability of maintaining steroid‐free clinical remission was 60%, 48%, and 35% at 6, 12, 24 months after starting MTX, respectively. Eleven patients had adverse events and 8 required MTX discontinuation. | |
| Retrospective chart review of 68 patients with IBD (45 with CD and 23 with UC) who received methotrexate because of intolerance or resistance to purine analogues. UC patients received a mean does of 23mg/week methotrexate SC. The duration of treatment was not clear | In UC group, 11 patients achieved remission and 3 had some symptomatic improvement. Adverse events developed in 26% of patients and included nausea, leucopenia, abnormal LFTs, and diarrhea | |
| Open‐label study in which 10 patients with UC‐ who were intolerant or resistant to azathioprine‐ were given methotrexate at a dose of 12.5mg/week IM | Six patients achieved complete remission and remained in remission at the end of long‐term treatment (duration was not specified). Four improved at 6 months after induction and two of them remained well | |
| Non‐randomized, open‐label study evaluating the use of methotrexate in patients with steroid dependant chronic active ulcerative colitis intolerant of thiopurines. They were treated with subcutaneous methotrexate 25 mg weekly for 12 weeks followed by oral methotrexate 15 mg/week thereafter, with standard folic acid therapy. | Six of eight patients were in clinical remission and able to fully withdraw steroid therapy. There were no relapse after a mean follow‐up period of 10 months. Two patients who failed to respond went on to receive colectomy. Methotrexate was well‐tolerated with one incidence of dose reduction due to nausea. | |
| Case series of 4 patients with UC who started on methotrexate after stopping azathioprine for various reasons. Methotrexate was given at a dose of 25 mg/week IM in 3 patients while the 4th patient had a starting dose of 15 mg which was then increased to 25 mg/week | Three patients remained in remission after 2‐3 years of treatment with methotrexate. The fourth patient had an elevated ALT concentration that lead to discontinuation of the drug | |
| Retrospective chart review of 6 patients with UC and 66 patients with CD who received methotrexate at a mean dose of 18.2 mg/week (IM in 8 patients and oral for the rest) for different indications. Fifteen patients were treated with both methotrexate and azathioprine simultaneously | All the six patients with UC completed at least 6 months of treatment. Only 3 patients had a clinical response. None of the patients with UC had adverse events while 25% of patients with CD had one or more adverse event | |
| Retrospective chart review of 131 patients with IBD (CD, n=99; UC, n=32) who were treated with MTX to examine the efficacy and safety profile of methotrexate in patients who are either intolerant or non‐responsive to AZA/MP. Clinical response (defined as steroid withdrawal, normalization of previously raised CRP or physician's clinical assessment of improvement) was assessed at 6 months. | In Crohn's disease, clinical response occurred in 18 of 29 patients (62%) refractory to AZA/MP and 42 of 70 patients (60%) intolerant to AZA/MP. In UC, clinical response occurred in 7 of 9 patients (78%) refractory to AZA/MP and 15 of 23 (65%) intolerant to thiopurines. Methotrexate was well tolerated in a majority of patients. | |
| A retrospective chart review of 93 pediatric IBD patients (75 CD, 5 UC, and 13 IC) from a single center, who received MTX treatment. Remission was defined as discontinuation of steroids and Harvey‐Bradshaw Index <4 for CD patients, PUCAI < 10 for UC or IC patients. | Among the 79 patients assessed for effectiveness of MTX, clinical remission was observed in 29, 37, 25, and 16% of CD patients (n=63) and 18, 25, 13, and 7% of patients with UC or IC (n=16), respectively, 3, 6, 12, and 24 months after initiation of MTX. Forty‐six patients (49%) experienced side effects but only 13 (14%) required discontinuation. | |
| Retrospective chart review of 104 UC patients who initiated on IFX maintenance therapy (57% on combination therapy with immunomodulator and 43% on IFX alone). Combined immunomodulator therapy included AZA, 6‐MP, or MTX. The primary outcome was occurrence of IFX discontinuation and/or colectomy. | The primary outcome occurred in 18 patients in the combination group (31%) and 18 patients in the IFX alone group (40%, P=0.31). Ten patients (17%) in the combination group and 8 patients (18%) in the IFX alone group underwent colectomy (P=0.91). Combined immunomodulator therapy was not predictive of IFX discontinuation or colectomy (HR 1.22, 95% CI 0.54‐2.76). |
Risk of bias in included studies
The risk of bias results are summarized in Figure 2. Mate‐Jimenez 2000 was an open‐label study and was rated as high risk of bias for blinding. In addition, Mate‐Jimenez 2000 did not report the methods used for randomization or allocation concealment and these items were rated as unclear risk of bias. Oren 1996 used adequate methods of randomization, blinding, and allocation concealment and was rated as low risk of bias for these items. Onuk 1996 was an abstract publication and methods used for randomization, allocation concealment and blinding were not described. These items were rated as unclear risk of bias. All three included studies were rated as low risk of bias for incomplete outcome data (Mate‐Jimenez 2000; Onuk 1996; Oren 1996). No other issues were found with the trials and they were rated as low risk of bias for the other bias item (Mate‐Jimenez 2000; Onuk 1996; Oren 1996).
Risk of bias summary: review authors' judgements about each risk of bias item for each included study.
Effects of interventions
See: Summary of findings for the main comparison Methotrexate compared to placebo for maintenance of remission in ulcerative colitis; Summary of findings 2 Methotrexate compared to 5‐ASA for maintenance of remission in ulcerative colitis; Summary of findings 3 Methotrexate compared to 6‐MP for maintenance of remission in ulcerative colitis; Summary of findings 4 Methotrexate + sulfasalazine compared to sulfasalazine
Methotrexate versus placebo
There was no statistically significant difference in the proportion of patients who maintained remission in the Oren 1996 study. Thirty‐six per cent (5/14) of methotrexate patients maintained remission compared to 54% (10/18) of placebo patients (RR 0.64; 95% CI 0.28 to 1.45; P = 0.29 ; See Figure 3). A GRADE analysis indicated that the quality of evidence is low due to very sparse data (See summary of findings Table for the main comparison ). The mean monthly steroid dose was not significantly different between the two groups. There were no statistically significant differences in the Mayo Clinic score between the two groups at baseline or during the study. Three patients were withdrawn from the study because of adverse events; two from the methotrexate group (transient leucopenia and migraine) and one from placebo group (severe rash).
Forest plot of comparison: 1 Methotrexate versus Placebo, outcome: 1.1 Maintenance of Remission.
Methotrexate versus active comparators (5‐ASA or 6‐MP)
Mate‐Jimenez 2000 looked at the efficacy of methotrexate in patients with ulcerative colitis (N = 34) for both induction of remission and maintenance of remission. Patients in remission and off steroids at the end of 30 weeks were then entered into a 76 week maintenance phase. There were no statistically significant differences in the proportion of patients who maintained remission. Only one of seven (14%) patients in the methotrexate group maintained remission at the end of study compared to 7/11 (64%) patients in 6‐MP group (RR 0.22, 95% CI 0.03 to 1.45; See Figure 4). No patients in the 5‐ASA group (0/2) maintained remission (RR 1.13, 95% CI 0.06 to 20.71, see Figure 5). However, the results of this study should be interpreted with caution due to the small sample size and poor methodological quality. GRADE analyses found the overall quality of the evidence was very low due to very sparse data and high risk of bias (see summary of findings Table 2; summary of findings Table 3). Adverse events experienced by methotrexate patients included nausea and dyspepsia, mild alopecia, mild increase in aspartate aminotransferase levels, peritoneal abscess, hypoalbuminemia, severe rash and atypical pneumonia.
Forest plot of comparison: 2 Methotrexate versus 6‐MP, outcome: 2.1 Maintenance of remission.
Forest plot of comparison: 3 Methotrexate versus 5‐ASA, outcome: 3.1 Maintenance of remission.
Methothrexate plus sulfasalazine versus sulfasalazine
Onuk 1996 studied the efficacy of methotrexate in quiescent ulcerative colitis patients receiving sulfasalazine as maintenance therapy. There was no statistically significant difference in the proportion of patients who maintained remission at 52 weeks. One hundred per cent (14/14) of patients in the combination group maintained remission compared to 75% (9/12) of patients in the sulfasalazine alone group (RR 1.32, 95% CI 0.94 to 0.86, see Figure 6). A GRADE analysis indicated that the quality of evidence is very low due to very sparse data and unknown high risk of bias (see summary of findings Table 4). Onuk 1996 reported that patient compliance with therapy was excellent and that no patients were withdrawn in either group because of drug‐related intolerance or adverse events.
Forest plot of comparison: 4 Methorexate + SFZN versus SFZN alone, outcome: 4.1 Maintenance of Remission.
Discusión
El metotrexato es un análogo del ácido dihidrofólico que inhibe la dihidrofolato reductasa y las enzimas dependientes del folato que son vitales para la síntesis de purinas y pirimidinas de novo, la formación de poliaminas y la transmetilación del ADN, el ARN, los fosfolípidos y las proteínas (Te 2000). Es interesante señalar que estos efectos se producen con altas dosis de metotrexato en lugar de dosis bajas, ya que la dosis baja de metotrexato no tiene efectos citotóxicos o antiproliferativos, pero es en cambio un inmunosupresor (Herrliger 2005; Bianchi Porro 2007).
Durante los últimos 20 años el metotrexato se ha reconocido como un fármaco antiinflamatorio potente y actualmente se utiliza en varias enfermedades inflamatorias incluida la artritis reumatoide, la psoriasis, las vasculopatías del colágeno y las enfermedades intestinales inflamatorias (Bianchi Porro 2007).
Tradicionalmente, la inducción de la remisión de la colitis ulcerosa se logra con la administración de corticosteroides o preparaciones de 5‐ASA (Schroder 2003). Estas últimas también se pueden utilizar para el mantenimiento de la remisión. Sin embargo, algunos pacientes con colitis ulcerosa pueden ser dependientes o resistentes a los esteroides, por lo que en estos casos se puede considerar el uso de inmunosupresores (Fraser 2003b). La colectomía se reserva para los pacientes que son resistentes al tratamiento médico.
La eficacia del metotrexato en el tratamiento de la enfermedad de Crohn dependiente de esteroides y resistente al tratamiento se evaluó en algunos estudios, y el metotrexato parenteral es efectivo para inducir y mantener la remisión de la enfermedad de Crohn (Feagan 1995; Feagan 2000; Turner 2007; McDonald 2014).
Por el contrario, una revisión Cochrane reciente incluyó solamente dos ensayos controlados aleatorios que examinaron la eficacia del metotrexato oral en dosis baja (12,5 a 15 mg/semanas) en pacientes con colitis ulcerosa crónica (Chande 2014). Esta revisión sistemática concluyó que el metotrexato no proporciona beneficios para inducir la remisión de la colitis ulcerosa activa. Sin embargo, la dosis y la vía de administración del metotrexato utilizadas fueron diferentes de las utilizadas frecuentemente para el tratamiento de la enfermedad de Crohn activa (25 mg/semana; Feagan 1995).
En el estudio Oren 1996 se realizó el seguimiento de los pacientes durante nueve meses. El seguimiento de los pacientes que ingresaron en la fase de remisión se realizó hasta que presentaron recurrencias. El metotrexato oral (12,5 mg/semana) no tuvo efectos beneficiosos para el mantenimiento de la remisión de la colitis ulcerosa inactiva. Los resultados del análisis GRADE indican que la calidad general de las pruebas que apoyan este resultado fue baja debido a los datos escasos. Aunque la dosis baja seleccionada que se utilizó en este estudio fue efectiva en otras enfermedades inflamatorias (artritis reumatoide), se puede argumentar que la gravedad de la inflamación es diferente en la colitis ulcerosa. El metotrexato tiene efectos antiproliferativos sólo cuando se administra en dosis altas (Herrliger 2005). Esta acción puede ser necesaria para inducir y mantener la remisión en pacientes con enfermedad inflamatoria intestinal resistente al tratamiento Feagan 2000 encontró que el metotrexato parenteral a dosis de 15 mg/semana fue efectivo para mantener la remisión en pacientes con enfermedad de Crohn que entraron en la fase de remisión después del tratamiento con metotrexato. Se desconoce si una dosis alta o la administración parenteral del metotrexato serían más efectivas para el mantenimiento de la remisión en los pacientes con colitis ulcerosa.
Los estudios más pequeños (Mate‐Jimenez 2000; Onuk 1996) evaluaron la efectividad del metotrexato en comparación con controles activos. No hubo diferencias estadísticamente significativas en las tasas de remisión clínica. Los análisis GRADE encontraron que la calidad de las pruebas fue muy baja debido a los datos escasos y al riesgo de sesgo. Por lo tanto, no es posible establecer conclusiones con respecto a la eficacia a partir de estos dos estudios.
Los eventos adversos se informaron de manera deficiente en los tres estudios incluidos y no es posible establecer conclusiones con respecto a la seguridad del tratamiento de mantenimiento con metotrexato en pacientes con colitis ulcerosa inactiva. Los eventos adversos informados en el estudio controlado con placebo incluyeron dos retiros del estudio en el grupo de metotrexato debido a leucopenia transitoria y migraña y un retiro en el grupo placebo debido a una erupción cutánea grave (Oren 1996). No se conoce si estos retiros ocurrieron durante el tratamiento de inducción o de mantenimiento. Oren 1996 no informó la proporción de pacientes que experimentaron eventos adversos o eventos adversos graves. Los eventos adversos experimentados por los pacientes que recibieron metotrexato en el estudio Mate‐Jimenez 2000 incluyeron náuseas y dispepsia, alopecia leve, aumento leve en los niveles de aspartato‐amino‐transferasa, absceso peritoneal, hipoalbuminemia, erupción cutánea grave y neumonía atípica. Mate‐Jimenez 2000 informó la proporción de pacientes que se retiraron debido a los efectos adversos, aunque no estaba claro si estos pacientes tuvieron colitis ulcerosa o enfermedad de Crohn o si los retiros ocurrieron durante las fases de inducción o de mantenimiento del estudio. Mate‐Jimenez 2000 no informó la proporción de pacientes que experimentaron eventos adversos o eventos adversos graves. Onuk 1996informó que el cumplimiento de los pacientes fue excelente y que ningún paciente se retiró debido a intolerancia o a eventos adversos relacionados con el tratamiento. El estudio Onuk 1996 no informó la proporción de pacientes que experimentaron eventos adversos o eventos adversos graves.
Study flow diagram.
Risk of bias summary: review authors' judgements about each risk of bias item for each included study.
Forest plot of comparison: 1 Methotrexate versus Placebo, outcome: 1.1 Maintenance of Remission.
Forest plot of comparison: 2 Methotrexate versus 6‐MP, outcome: 2.1 Maintenance of remission.
Forest plot of comparison: 3 Methotrexate versus 5‐ASA, outcome: 3.1 Maintenance of remission.
Forest plot of comparison: 4 Methorexate + SFZN versus SFZN alone, outcome: 4.1 Maintenance of Remission.
Comparison 1 Methotrexate versus placebo, Outcome 1 Maintenance of remission.
Comparison 2 Methotrexate versus 6‐MP, Outcome 1 Maintenance of remission.
Comparison 3 Methotrexate versus 5‐ASA, Outcome 1 Maintenance of remission.
Comparison 4 Methotrexate + sulfasalazine versus sulfasalazine, Outcome 1 Maintenance of remission.
| Methotrexate compared to placebo for maintenance of remission in ulcerative colitis | ||||||
| Patient or population: patients with quiescent ulcerative colitis | ||||||
| Outcomes | Illustrative comparative risks* (95% CI) | Relative effect | No of Participants | Quality of the evidence | Comments | |
| Assumed risk | Corresponding risk | |||||
| Placebo | Methotrexate | |||||
| Maintenance of remission | 556 per 10001 | 356 per 1000 | RR 0.64 | 32 | ⊕⊕⊝⊝ | |
| *The basis for the assumed risk (e.g. the median control group risk across studies) is provided in footnotes. The corresponding risk (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI). | ||||||
| GRADE Working Group grades of evidence | ||||||
| 1 Control group risk comes from control arm of study | ||||||
| Methotrexate compared to 5‐ASA for maintenance of remission in ulcerative colitis | ||||||
| Patient or population: patients with quiescent ulcerative colitis | ||||||
| Outcomes | Illustrative comparative risks* (95% CI) | Relative effect | No of Participants | Quality of the evidence | Comments | |
| Assumed risk | Corresponding risk | |||||
| 5‐ASA | Methotrexate | |||||
| Maintenance of remission | 0 per 10001 | 0 per 1000 | RR 1.12 | 9 | ⊕⊝⊝⊝ | |
| *The basis for the assumed risk (e.g. the median control group risk across studies) is provided in footnotes. The corresponding risk (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI). | ||||||
| GRADE Working Group grades of evidence | ||||||
| 1 Control group risk comes from control arm of study | ||||||
| Methotrexate compared to 6‐MP for maintenance of remission in ulcerative colitis | ||||||
| Patient or population: patients with maintenance of remission in ulcerative colitis | ||||||
| Outcomes | Illustrative comparative risks* (95% CI) | Relative effect | No of Participants | Quality of the evidence | Comments | |
| Assumed risk | Corresponding risk | |||||
| 6‐MP | Methotrexate | |||||
| Maintenance of Remission | 636 per 10001 | 140 per 1000 | RR 0.22 | 18 | ⊕⊝⊝⊝ | |
| *The basis for the assumed risk (e.g. the median control group risk across studies) is provided in footnotes. The corresponding risk (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI). | ||||||
| GRADE Working Group grades of evidence | ||||||
| 1 Control group risk comes from control arm of study | ||||||
| Methorexate + SFZN compared to SFZN alone for maintenance of remission in ulcerative colitis | ||||||
| Patient or population: patients with maintenance of remission in ulcerative colitis | ||||||
| Outcomes | Illustrative comparative risks* (95% CI) | Relative effect | No of Participants | Quality of the evidence | Comments | |
| Assumed risk | Corresponding risk | |||||
| SFZN alone | Methorexate + SFZN | |||||
| Maintenance of Remission | 750 per 10001 | 990 per 1000 | RR 1.32 | 26 | ⊕⊝⊝⊝ | |
| *The basis for the assumed risk (e.g. the median control group risk across studies) is provided in footnotes. The corresponding risk (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI). | ||||||
| GRADE Working Group grades of evidence | ||||||
| 1 Control group risk comes from control arm of study | ||||||
| ID | Description | Results |
| PURSUIT‐SC induction study randomized UC patients to PBO/PBO (n=331), GLM 100mg/50mg (n=72), GLM 200mg/100mg (n=331), and GLM 400mg/200mg (n=331) at week 0 and 2. PURSUIT maintenance study enrolled 1228 patients, but only those who responded to GLM induction (n=464) were randomized (PBO, GLM 50mg or GLM 100 mg Q4W for 52 weeks) and included in the primary analysis. | During induction and maintenance, there was a positive Exposure‐Response relationship between SGC and efficacy outcomes regardless of immunomodulator (IM) use. Concomitant IM use did not appear to affect efficacy outcomes. Antibodies to GLM (ATG) incidence was lower in patients receiving IMs vs those who were not (1.5% vs 3.5%, overall 2.8%). | |
| A retrospective chart review of 38 pediatric UC patients treated with methotrexate (n=18 azathioprine unresponsiveness, n =10 azathioprine intolerance, n=4 spondyloarthropathy). Pediatric Ulcerative Colitis Activity Index (PUCAI) and use of corticosteroids were the main outcomes evaluated at baseline and at 3, 6 and 12 months. | Response or remission was achieved in 72%, 63% and 50% of patients at 3, 6 and 12 months respectively. Mean PUCAI were 49.5 ± 23.3 at baseline and 32.9 ± 21.9, 29.5 ± 21.8 and 29.4 ± 19.9 at 3, 6 and 12 months respectively (P = 0.03). 13 of the 16 patients on corticosteroids, had their steroid discontinued by 6 months. At the end of the study, 11 patients needed short course of corticosteroids for disease relapse. | |
| Open‐label 18 week study in which 19 (11 CD and 8 UC) patients with refractory IBD were given 15 mg/week methotrexate (starting at a low dose then increased gradually) | In the UC group, only 3 patients had a partial response. None of the UC patients has complete remission. However, there was a significant reduction in the daily prednisone dose. Adverse events were minor | |
| Retrospective chart review that evaluated 50 patients with UC (8 had rheumatoid arthritis as well and analyzed separately) who were intolerant or resistant to azathioprine. The mean dose of methotrexate was 19.9 mg/week for a median duration of 30 weeks and was given orally | Remission occurred in 42% of patients. Colitis remained in remission in 7/8 patients with concomitant rheumatoid arthritis. Side effects occurred in 23% but only 10% needed to stop methotrexate due to adverse effects | |
| A 20 week non‐randomized, open‐label study evaluate the effectiveness of weekly 25 mg methotrexate intramuscular injection (with 1 mg/day folic acid supplementation) in patients (n=22) with chronic active ulcerative colitis, refractory to steroids ± sulfasalazine for at least 3 months. | Fifteen patients (68%) had significant clinical improvement (Mayo Clinic score decreased from 8.2 to 4.7; P<0.001). Eleven patients achieved clinical remission (Mayo Clinic score ≤ 3), and 5/11 achieved histological remission. Under continuous sulfasalazine administration, 8/11 patients (73%) remained in remission after 6 months from cessation of methotrexate therapy. Adverse events (n=5) were not severe enough to warrant treatment interruptions. | |
| A 16 week‐randomized single‐blinded study comparing weekly SC 15 mg to 25 mg of methotrexate in 32 steroid‐dependant patients (10 with UC and 22 with CD) | Only 6 patients improved at the end of the induction period. Overall the dose escalation did not result in significant difference in treatment effect or toxicity | |
| Case series of 5 steroid‐refractory patients (3 with UC and 2 with CD) who failed methotrexate 25g/week SC for 16 weeks and had oral cyclosporine 3mg/kg/day added to methotrexate for another 16 weeks | Improvement of 3 patients with UC. One patient developed hypertension | |
| Retrospective chart review of 70 patients (48 with CD and 22 with UC) who were given methotrexate for a mean duration of 17.1 months at a mean maintenance dose of 20mg/week (oral in 62 patients and IM in 8) | Remission was achieved in 62% of patients who completed more than 3 months of treatment. The chance of maintaining remission (if treatment continues) at 12, 24 and 36 months were 90%, 73% and 51% respectively. Treatment was equally effective in UC and CD | |
| 16 week non‐randomized, open label study included 8 patients with moderate to severe refractory UC confirmed by sigmoidoscopy. They were treated with 25 mg IM MTX (and folic acid) and severity of disease was assessed by Mayo Clinic score (at recruitment, median 9, range 7‐11) | Six of eight patients completed 16 week treatment. Median Mayo Clinical score 8 (range 6‐11). One patient withdrew due to sever exacerbation and 1 withdrew because failure to improve. Treatment with 25mg MTX IM for 16 weeks was ineffective in this small group of patients with refractory UC. | |
| Retrospective study in 17 patients who were less than 16 years old and affected by steroid‐dependent or steroid‐resistant UC, They were treated with IM methotrexate (20 mg/m2/week). Clinical remission ‐ discontinuation of steroids and achievement of S0 stage of Montreal classification after 3, 6 and 12 months. endoscopic remission ‐ level 0 of Baron score at the same timing of clinical score calculation. | After 3 months, MTX induced clinical and endoscopic remission in 82% and 71% of UC patients, respectively. Of the nine UC patients continued MTX for > 3 months, 56% maintained clinical and endoscopic remission after 6 months; and 33% at 1 year. Adverse events occurred in one patient (acute pancreatitis) and led to discontinuation of treatment. | |
| Retrospective chart review that evaluated 65 patients with IBD (20 UC and 45 CD). Dose of methotrexate varied from 10‐25 mg/week | 63% achieved remission and treatment continued for a median of 11 months | |
| Retrospective chart review of 77 IBD patients (80% Crohn's disease) treated with methotrexate in eight hospitals of Madrid, Spain | Initially, 82% of patients responded (28% in remission). Forty percent of the patients lost response at a mean of 57 weeks after starting methotrexate. Adverse events included GI symptoms (n=10), myelotoxicity (n=4), and abnormal LFT (n=10), which let to withdrawal of treatments in 4 patients. | |
| Restrospective analysis of UC patients treated with infliximab (IFX, n=85), comparing duration of efficacy, and serum IFX and serum IFX and antibody‐to‐IFX (ATI) levels between those receiving IFX as monotherapy (n=46) and in combination with an immunosuppressant (n=38). | Conconmitant immunosuppressant use was associated with associated with increased duration of IFX therapy (90% vs.61% remained on therapy at 1 year, P =0.025), and less frequent ATI formation (4.5% vs. 33.3%, P=0.031). The majority of patients received purine analogues (e.g. azathioprine or mercaptopurine), only 3 out of 46 patients in the combination group received methotrexate. | |
| Pharmacogenetics study of 102 IBD patients treated with MTX and 202 patients with Crohn's disease, 205 patients with ulcerative colitis and 189 healthy volunteers to assess allele frequencies in the disease and healthy populations. Four polymorphisms (G80A in the RCF1 gene, G452T in GGH gene, and C677T and A1298C in MTHFR gene) were genotyped for genotype‐phenotype association with respect to efficacy and toxicity of MTX therapy. | No significant differences in the allele frequencies between CD, UC, and healthy controls were detected. Side effects of MTX in IBD are more likely to associate with a SNP (MTHFR 1298C) in the MTHFR gene (21% vs. 6.3%, P<0.05), but response cannot be predicted by any of the investigated SNPs. | |
| Retrospective chart review of 15 patients (13 with CD and 2 with UC) who were given 25 mg/week IM for 12 weeks followed by tapering oral dose | Symptomatic improvement occurred in 12/15 patients with reduction of prednisone dose after 3 months | |
| A multicentre, longitudinal cohort study of 1118 Crohn's disease patients (14530 patient years of follow‐up) and 1171 ulcerative colitis patients (18035 patient years of follow‐up). Patient demographics, disease characteristics according to Montreal classification, drug and surgical treatments were reviewed. Comparisons were made between 3 times periods of pre 1990, 1990‐2000, and post 2000. | In Crohn's disease cohort, cumulative probability of commencing immunomodulators was significantly reduced over the time periods (mean time to commence IM use, 15.9, 6.0 and 1.3, P<0.0001). Long‐term steroid (LTS) use (P<0.0001), surgical resection and recurrent resection (P=0.002) also decreased significantly. In ulcerative colitis cohort, time to introduction of IM significantly decreased over successive decades (P<0.0001) and was associated with significant reduction in the use of LTS (P<0.0001) and surgical resection rate (P=0.033). | |
| A retrospective study of effectiveness and safety electronic files of 543 IBD patients (58.6% UC patients) treated from 1981‐2010, of which, 48 patients were treated with methotrexate (33 CD, 14 UC, 1 undetermined) | Methotrexate was effective in 57% of patients with IBD and 27% of patients with fistulizing disease. Infection was the commonest adverse event. | |
| An open‐label observational study that recruited 21 patients with refractory IBD (14 CD and 7 UC) who were given 25 mg/week of methotrexate IM for 12 weeks | Five patients with UC had clinical improvement with successful reduction of the concurrent steroid dose. None had endoscopic healing. Complications were reported in 7 out of the 21 patients and included transient diarrhea, leucopenia, elevated AST, brittle nails and atypical pneumonitis | |
| Retrospective chart review where 86 patients (30 with UC) with refractory IBD were given 25 mg/week of parenteral methotrexate. The responders at 12 weeks were continued on oral methotrexate (7.5‐15 mg/week) | 70% of patients with UC showed some response but only 40 % continued to have response at a mean follow‐up of 59 weeks | |
| Retrospective chart review of 40 patients with UC from 8 Spanish IBD referral hospital, who received MTX for steroid dependency (70%) or steroid refractoriness (27%). Therapeutic success was defined as the absence of UC symptoms, complete steroid withdrawal and no requirement of rescue therapies within the first 6 months after starting MTX. | Forty‐five percent of patients met criteria for therapeutic success. The cumulative probability of maintaining steroid‐free clinical remission was 60%, 48%, and 35% at 6, 12, 24 months after starting MTX, respectively. Eleven patients had adverse events and 8 required MTX discontinuation. | |
| Retrospective chart review of 68 patients with IBD (45 with CD and 23 with UC) who received methotrexate because of intolerance or resistance to purine analogues. UC patients received a mean does of 23mg/week methotrexate SC. The duration of treatment was not clear | In UC group, 11 patients achieved remission and 3 had some symptomatic improvement. Adverse events developed in 26% of patients and included nausea, leucopenia, abnormal LFTs, and diarrhea | |
| Open‐label study in which 10 patients with UC‐ who were intolerant or resistant to azathioprine‐ were given methotrexate at a dose of 12.5mg/week IM | Six patients achieved complete remission and remained in remission at the end of long‐term treatment (duration was not specified). Four improved at 6 months after induction and two of them remained well | |
| Non‐randomized, open‐label study evaluating the use of methotrexate in patients with steroid dependant chronic active ulcerative colitis intolerant of thiopurines. They were treated with subcutaneous methotrexate 25 mg weekly for 12 weeks followed by oral methotrexate 15 mg/week thereafter, with standard folic acid therapy. | Six of eight patients were in clinical remission and able to fully withdraw steroid therapy. There were no relapse after a mean follow‐up period of 10 months. Two patients who failed to respond went on to receive colectomy. Methotrexate was well‐tolerated with one incidence of dose reduction due to nausea. | |
| Case series of 4 patients with UC who started on methotrexate after stopping azathioprine for various reasons. Methotrexate was given at a dose of 25 mg/week IM in 3 patients while the 4th patient had a starting dose of 15 mg which was then increased to 25 mg/week | Three patients remained in remission after 2‐3 years of treatment with methotrexate. The fourth patient had an elevated ALT concentration that lead to discontinuation of the drug | |
| Retrospective chart review of 6 patients with UC and 66 patients with CD who received methotrexate at a mean dose of 18.2 mg/week (IM in 8 patients and oral for the rest) for different indications. Fifteen patients were treated with both methotrexate and azathioprine simultaneously | All the six patients with UC completed at least 6 months of treatment. Only 3 patients had a clinical response. None of the patients with UC had adverse events while 25% of patients with CD had one or more adverse event | |
| Retrospective chart review of 131 patients with IBD (CD, n=99; UC, n=32) who were treated with MTX to examine the efficacy and safety profile of methotrexate in patients who are either intolerant or non‐responsive to AZA/MP. Clinical response (defined as steroid withdrawal, normalization of previously raised CRP or physician's clinical assessment of improvement) was assessed at 6 months. | In Crohn's disease, clinical response occurred in 18 of 29 patients (62%) refractory to AZA/MP and 42 of 70 patients (60%) intolerant to AZA/MP. In UC, clinical response occurred in 7 of 9 patients (78%) refractory to AZA/MP and 15 of 23 (65%) intolerant to thiopurines. Methotrexate was well tolerated in a majority of patients. | |
| A retrospective chart review of 93 pediatric IBD patients (75 CD, 5 UC, and 13 IC) from a single center, who received MTX treatment. Remission was defined as discontinuation of steroids and Harvey‐Bradshaw Index <4 for CD patients, PUCAI < 10 for UC or IC patients. | Among the 79 patients assessed for effectiveness of MTX, clinical remission was observed in 29, 37, 25, and 16% of CD patients (n=63) and 18, 25, 13, and 7% of patients with UC or IC (n=16), respectively, 3, 6, 12, and 24 months after initiation of MTX. Forty‐six patients (49%) experienced side effects but only 13 (14%) required discontinuation. | |
| Retrospective chart review of 104 UC patients who initiated on IFX maintenance therapy (57% on combination therapy with immunomodulator and 43% on IFX alone). Combined immunomodulator therapy included AZA, 6‐MP, or MTX. The primary outcome was occurrence of IFX discontinuation and/or colectomy. | The primary outcome occurred in 18 patients in the combination group (31%) and 18 patients in the IFX alone group (40%, P=0.31). Ten patients (17%) in the combination group and 8 patients (18%) in the IFX alone group underwent colectomy (P=0.91). Combined immunomodulator therapy was not predictive of IFX discontinuation or colectomy (HR 1.22, 95% CI 0.54‐2.76). |
| Outcome or subgroup title | No. of studies | No. of participants | Statistical method | Effect size |
| 1 Maintenance of remission Show forest plot | 1 | Risk Ratio (M‐H, Fixed, 95% CI) | Totals not selected | |
| Outcome or subgroup title | No. of studies | No. of participants | Statistical method | Effect size |
| 1 Maintenance of remission Show forest plot | 1 | Risk Ratio (M‐H, Fixed, 95% CI) | Totals not selected | |
| Outcome or subgroup title | No. of studies | No. of participants | Statistical method | Effect size |
| 1 Maintenance of remission Show forest plot | 1 | Risk Ratio (M‐H, Fixed, 95% CI) | Totals not selected | |
| Outcome or subgroup title | No. of studies | No. of participants | Statistical method | Effect size |
| 1 Maintenance of remission Show forest plot | 1 | Risk Ratio (M‐H, Fixed, 95% CI) | Totals not selected | |
