Leukotriene receptor antagonists for eczema

Summary of findings for the main comparison. Montelukast versus placebo for eczema

Montelukast compared with placebo for eczema
Patient or population: eczema Setting: 2 studies were conducted in 2 centres each; setting of remaining study is unknown Intervention: montelukast Comparison: placebo
Outcomes	*Illustrative comparative risks (95% CI)**		Relative effect (95% CI)	No. of participants (studies)	Quality of the evidence (GRADE)	Comments
	Assumed risk	Corresponding risk
	Placebo	Montelukast
Change (improvement) in disease severity (4 to 8 weeks) SMD (modified EASI score and SASSAD)	The mean improvement score ranged across placebo group from 0.68 to 1.9.	The mean improvement in the intervention group was 0.29 higher (0.23 lower to 0.81 higher).	‐	131 (3 RCTs)	⊕⊕⊝⊝ LOW ¹
Effect of long‐term control (> 3 months)	See comment	See comment	‐	‐	‐	Not measured, as longest follow‐up was only 8 weeks
Adverse effects (4 to 8 weeks)	See comment	See comment	‐	131 (3 RCTs)	⊕⊕⊝⊝ LOW ¹	2 adverse events were reported (1 episode of septicaemia and 1 dizzy spell in the montelukast group) out of 29 participants (Friedmann 2007). No adverse effects were observed in the other 2 studies (Nettis 2002; Veien 2005), but Nettis 2002 reported an equivalent dropout rate in both montelukast and placebo groups due to aggravation of eczema or loss to follow‐up.
Requirement for corticosteroid (steroid‐sparing effect)	See comment	See comment	‐	58 (1 RCT)	⊕⊕⊝⊝ LOW ¹	The frequency of topical corticosteroids use was not significantly different between montelukast and placebo treatments using a 5‐point scale (Friedmann 2007).
Reduction of pruritus (score range 0 to 10; higher score means better improvement)	The mean change in improvement of pruritus score from baseline was 0.8 in the placebo group.	The mean change in improvement of pruritus score from baseline was 0.7 lower in the montelukast group.	‐	58 (1 RCT)	⊕⊕⊝⊝ LOW ¹	The study authors assessed this difference as non‐significant (but no P value or standard deviations provided) (Friedmann 2007).
Improvement in quality of life	See comment	See comment	‐	‐	‐	No studies evaluated quality of life.
Need for emollient use	See comment	See comment	‐	‐	‐	No studies evaluated emollient requirement.
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). CI: confidence interval; EASI: Eczema Area and Severity Index; RCT: randomised controlled trial; SASSAD: Six‐Area, Six‐Sign Atopic Dermatitis; SMD: standardised mean difference
GRADE Working Group grades of evidence High quality: Further research is very unlikely to change our confidence in the estimate of effect. Moderate quality: Further research is likely to have an important impact on our confidence in the estimate of effect and may change the estimate. Low quality: Further research is very likely to have an important impact on our confidence in the estimate of effect and is likely to change the estimate. Very low quality: We are very uncertain about the estimate.
¹We downgraded by two levels, one level due to imprecision because the total number of participants included in all studies was insufficient; and one level due to indirectness because the studies only included adults with moderate‐to‐severe eczema, with no evidence from those with mild eczema or paediatric patients.

Summary of findings 2. Montelukast versus conventional treatment for eczema

Montelukast compared with conventional treatment for eczema
Patient or population: eczema Setting: 1 study was conducted in a single centre; the setting of the other study is unknown Intervention: montelukast Comparison: conventional treatment (topical corticosteroid and oral antihistamine +/‐ oral antibiotics)
Outcomes	*Illustrative comparative risks (95% CI)**		Relative effect (95% CI)	No. of participants (studies)	Quality of the evidence (GRADE)	Comments
	Assumed risk	Corresponding risk
	Conventional treatment	Montelukast
Change (improvement) in disease severity (4 weeks) SCORAD score	The mean improvement in severity score was 4.73.	The mean improvement in severity score in the intervention group was 10.57 units greater (4.58 greater to 16.56 greater).	‐	31 (1 RCT)	⊕⊝⊝⊝ VERY LOW ¹	Another study with 32 participants reported no significant difference in SCORAD between the montelukast (mean improvement = 25.2 points) and conventional treatment (mean improvement = 23.9) (6 weeks follow‐up) groups (Capella 2001), but the authors did not provide the statistical values needed to calculate standard deviation, thus we could not pool these data.
Effect of long‐term control (> 3 months)	See comment	See comment	‐	‐	‐	Not measured, as longest follow‐up was only 6 weeks
Adverse effects (4 to 6 weeks)	See comment	See comment	‐	63 (2 RCTs)	⊕⊕⊝⊝ LOW ²	2 studies reported no adverse effects (Capella 2001; Rahman 2006).
Requirement for corticosteroid (steroid‐sparing effect)	See comment	See comment	‐	‐	‐	Not evaluated in either study
Reduction of pruritus	See comment	See comment	‐	‐	‐	Not evaluated in either study
Improvement in quality of life	See comment	See comment	‐	‐	‐	Not evaluated in either study
Need for emollient use	See comment	See comment	‐	‐	‐	Not evaluated in either study
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). CI: confidence interval; RCT: randomised controlled trial; SCORAD: SCORing of Atopic Dermatitis
GRADE Working Group grades of evidence High quality: Further research is very unlikely to change our confidence in the estimate of effect. Moderate quality: Further research is likely to have an important impact on our confidence in the estimate of effect and may change the estimate. Low quality: Further research is very likely to have an important impact on our confidence in the estimate of effect and is likely to change the estimate. Very low quality: We are very uncertain about the estimate.
¹We downgraded by three levels: one level due to imprecision because the total number of participants included in the study was insufficient; a second level due to indirectness because the study only included adults with moderate‐to‐severe eczema, with no evidence from those with mild eczema or paediatric patients; and a third level due to risk of bias because the outcome assessors were not blinded. ²We downgraded by two levels: one level due to imprecision because the total number of participants included in the studies was insufficient; and one level due to indirectness because the studies only included adults with moderate‐to‐severe eczema, with no evidence from those with mild eczema or paediatric patients.

Antecedentes

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Descripción de la afección

El eccema, también conocido como “eccema atópico” o “dermatitis”, es una afección inflamatoria común, crónica y recurrente de la piel (Johansson 2004). El eccema causa piel seca y picor, que tienden a presentar exacerbaciones intermitentes, debido a varios factores internos y externos (Ring 2012).

El eccema a menudo ocurre en familias con enfermedades atópicas incluido el asma, la rinitis alérgica/fiebre del heno (y alergia a los alimentos) y el eccema atópico. Estas enfermedades comparten una patogenia común y con frecuencia están presentes juntas en el mismo individuo y familia. La palabra “atopia” se refiere a la tendencia genética a producir anticuerpos de inmunoglobulina E (IgE) en respuesta a cantidades pequeñas de proteínas ambientales comunes como el polen, los ácaros del polvo doméstico y los alérgenos alimentarios (Stone 2002; Thomsen 2015). Alrededor del 30% de los pacientes con eccema desarrollan asma, y un 35% desarrolla rinitis alérgica(Luoma 1983). Sin embargo, se sabe que la atopia no ocurre de forma concurrente en todos los pacientes con eccema atópico. En vista de lo anterior, ha habido propuestas para usar el término “eccema” para definir a los pacientes con y sin atopia. Por lo tanto, de acuerdo con la “nomenclatura revisada para la alergia para uso global” (Johansson 2004) y al igual que en otras revisiones Cochrane que evalúan los tratamientos para el eccema (van Zuuren 2017), se ha usado el término “eccema” en toda la revisión.

El eccema se presenta en la niñez en la mayoría de los casos. Alrededor del 65% de los niños con eccema son afectados a los 18 meses de edad. Algunos de estos casos se resuelven en la primera infancia y en la adultez un 60% se ha resuelto(Spergel 2010). Aunque la prevalencia es inferior en los adultos, para los que presentan la afección, a menudo es más grave y de naturaleza crónica (Katsarou 2011). El síntoma más angustiante es la picor, que causa daño en la piel y a la vez más picor (es decir el ciclo de prurito‐rascado), lo cual da lugar a los signos visibles del eccema (Yarbrough 2013). La repercusión en la calidad de vida puede ser considerable, en especial en los casos graves. El eccema puede reducir la asistencia a la escuela o al trabajo (Holm 2006) y puede dar lugar a perturbaciones del sueño para la persona afectada y su familia(Moore 2006; Reid 1995).

El eccema es una enfermedad multifactorial, con factores genéticos y ambientales que contribuyen a grados variables en diferentes individuos y poblaciones (Thomsen 2007). Es una afección crónica, de manera que el tratamiento efectivo incluye el reconocimiento de los factores desencadenantes, la reducción de los alérgenos e irritantes y la aplicación frecuente de emolientes (Akdis 2006). Además, a veces se requieren corticosteroides tópicos e inhibidores de la calcineurina(Eichenfield 2014).

Los estudios de prevalencia global indican que el eccema es generalizado en todo el mundo, en países de ingresos bajos, medios y altos y la investigación reciente muestra que la prevalencia del eccema se está elevando(Odhiambo 2009). El eccema afecta las actividades diarias y la calidad de vida y también consume una parte significativa de tiempo y financiación en la atención primaria y secundaria(Gupta 2004). Los padres de los niños que sufren eccema, los adultos con eccema y los médicos por igual agradecerían la existencia de otros tratamientos tópicos para el eccema tanto durante las fases de mantenimiento como de brote. Debido a las inquietudes en cuanto a los efectos secundarios locales con el uso de corticosteroides tópicos, hay un impulso particularmente fuerte para encontrar otros tratamientos para las exacerbaciones del eccema (Guttman‐Yassky 2013).

Descripción de la intervención

Durante una exacerbación del eccema, la base del tratamiento es la aplicación diaria de corticosteroides tópicos de potencia variada según la gravedad del brote y el sitio afectado (Eichenfield 2014a; Ring 2012). Debido a los efectos secundarios no deseados como el adelgazamiento de la piel, los médicos prescriben por lo general corticosteroides tópicos a la menor potencia efectiva durante periodos cortos, con frecuencia no más de 14 días(NICE 2007). Si los corticosteroides tópicos solos no son efectivos, los médicos a veces no tienen ninguna alternativa sino ascender en la escalera de tratamiento a los corticosteroides orales durante los períodos de brotes graves(Ring 2012a).

Existen otros tratamientos tópicos además de los corticosteroides, como los inhibidores de la calcineurina tópicos, pimecrolimús y tacrolimús, aunque no se ha observado que alguno sea superior y cada tratamiento tiene su propio perfil de efectos secundarios que restringe su uso(Ashcroft 2007). Los pacientes con eccema y los cuidadores de los niños con eccema intentan cumplir con esquemas complejos del tratamiento tópico y la aplicación de emolientes, aunque a menudo encuentran difícil adherirse a dichos tratamientos cuando se combinan con las exigencias diarias (Bass 2015).

Los pacientes con eccema grave que no responden al tratamiento tópico requieren tratamientos sistémicos, como corticosteroides, antihistamínicos, antibióticos, ciclosporina, azatioprina, micofenolato mofetilo, metotrexato y leflunomida; productos biológicos; y fototerapia (Simon 2011).

Los corticosteroides tópicos son el tratamiento de primera línea para las exacerbaciones del eccema (Eichenfield 2014a; Ring 2012). Sin embargo, los pacientes, las familias y los profesionales sanitarios tratan de limitar su uso debido a los efectos secundarios no deseados potenciales o el temor generalizado a los corticosteroides (corticofobia)(Artik 2003). En muchos casos, las inquietudes en cuanto a la posibilidad de efectos secundarios a menudo dan lugar a una subutilización de los corticosteroides tópicos, lo cual resulta en un control deficiente del eccema (Arkwright 2013). Los corticosteroides tópicos son categorizados en cuanto a su potencia: leves, moderados, potentes, o muy potentes(Ring 2012). El efecto secundario principal del adelgazamiento de la piel se observa con frecuencia después de la aplicación de preparados muy potentes, en especial en áreas sensibles de la piel (p.ej. eccema facial o genital), durante períodos prolongados, como es necesario a veces en los casos de eccema grave (Callen 2007). Los corticosteroides sistémicos pueden usarse para el tratamiento de los casos graves de eccema y suelen ser prescritos para un tratamiento de corta duración, debido a que el uso a largo plazo puede tener numerosos efectos secundarios, incluidos los trastornos metabólicos, del sistema nervioso central, musculoesqueléticos, cutáneos y oftálmicos y la supresión del sistema inmunitario(Sidbury 2014). La administración sistémica de esteroides mejora la aparición clínica de lesiones y alivia los síntomas, aunque la enfermedad presenta recurrencias rápidamente una vez que se interrumpe la medicación (Sidbury 2014). Por lo tanto, se agradecería la existencia de otros tratamientos sin efectos secundarios de este tipo.

Los leucotrienos son una clase de mediadores inflamatorios derivados del ácido araquidónico a través de la vía 5‐lipoxigenasa (Iversen 1994). La administración de antagonistas de los receptores de leucotrienos (ARLT) como una medicación antiinflamatoria para tratar con éxito el asma se ha confirmado ampliamente en la bibliografía(Bisgaard 2005; Robertson 2007). Los dos ARLT prescritos más ampliamente son el montelukast (comercializado como Singulair) y el zafirlukast (comercializado como Accolate) (Asthma Canada 2018). La Food and Drug Administration de EE.UU. y las organizaciones de salud pública en otros países han aprobado la prescripción del ARLT montelukast para el tratamiento preventivo a largo plazo en los niños pequeños con asma (Papadopoulos 2012). Normalmente prescrito en forma oral, en la actualidad se cree que la administración de ARLT es segura tanto en adultos como en los niños (Chauhan 2012). Las guías globales sobre el asma recomiendan los ARLT para los niños de hasta cinco años de edad (GINA 2014). Aunque los ARLT no son superiores a los corticosteroides como monoterapia para el asma (Chauhan 2012), tienen una función como agente de reducción de la dosis de corticosteroides en el asma crónica (Joos 2008). En cuanto al asma agudo, no existe evidencia que apoye el uso de ARLT orales en adultos y niños(Watts 2012). Los corticosteroides tópicos son centrales en el tratamiento del eccema, al igual que los corticosteroides inhalados lo son para el asma (Darsow 2005). Según lo que se conoce, los ARLT no son prescritos de forma sistemática para el eccema. Sin embargo, es posible que los ARLT puedan tener una función en el tratamiento del eccema al igual que la tienen en el asma, en particular debido a su potencial como agente de reducción de la dosis de esteroides.

Debido a su función en la prevención a largo plazo en el asma así como su perfil de seguridad en los estudios del asma, es posible que los ARLT puedan tener una función similar en el eccema. Muchos pacientes con eccema encuentran que la aplicación de los tratamientos tópicos disponibles en la actualidad puede tomar mucho tiempo y ser inconveniente. Los agentes orales alternativos disponibles para los pacientes con eccema están restringidos al uso a corto plazo (prednisolona) o presentan problemas de seguridad significativos (p.ej. ciclosporina, metotrexato y otros agentes sistémicos). Por lo tanto, vale la pena examinar los antagonistas de los receptores de leucotrienos, que pueden ser administrados por vía oral y quizás presentar un perfil de seguridad aceptable. La investigación disponible hasta la fecha ha revelado resultados contradictorios y existe alguna controversia en cuanto a la eficacia de los ARLT en el eccema. Se decidió realizar esta revisión para considerar estas dudas.

De qué manera podría funcionar la intervención

Un estudio, Adamek‐Guzik 2002; observó que el nivel de leucotrieno urinario aumentó durante las exacerbaciones del eccema en adultos y que no hubo diferencias en los niveles del leucotrieno urinario entre los controles saludables no eccematosos y los participantes con eccema durante las fases de remisión. Por lo tanto, sería razonable suponer que la producción de leucotrieno puede correlacionarse con la inflamación de la piel durante los brotes de eccema. Además, un estudio, Oymar 2005; observó un mayor nivel de leucotrieno urinario E4 en los niños con eccema grave. Este hecho sugiere que en realidad puede haber una relación entre el grado o la gravedad de la inflamación de la piel y la producción de leucotrieno. Esta evidencia impulsó la idea de que el bloqueo de la producción de leucotrienos con ARLT puede ayudar a reducir la inflamación de la piel y por lo tanto los ARLT pueden ser efectivos para tratar el eccema. Los antagonistas de los receptores de leucotrienos podrían tener un efecto de reducción de la dosis de corticosteroides que sería beneficioso en el eccema (Sher 2012).

Por qué es importante realizar esta revisión

El eccema es una enfermedad común global de la piel tratada por médicos de atención primaria, dermatólogos y pediatras. Los pacientes y los cuidadores a menudo tienen un deseo fuerte de encontrar alternativas a los corticosteroides. Si se observa que son efectivos y seguros, los ARLT son candidatos a la inclusión en los procedimientos de tratamiento del eccema debido a que podrían reducir la administración de corticosteroides tópicos. Los estudios anteriores de los ARLT para el eccema han revelado resultados contradictorios. Esta revisión sistemática procuró aportar evidencia acerca de la efectividad de los ARLT en el eccema y examinar el perfil de seguridad de los ARLT en los pacientes con eccema.

Los planes para esta revisión se publicaron como un protocolo de “Antagonistas de los receptores de leucotrienos para el eccema atópico” (Futamura 2014).

Objetivos

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Evaluar los posibles efectos beneficiosos y perjudiciales de los antagonistas de los receptores de leucotrienos para el eccema.

Métodos

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Criterios de inclusión de estudios para esta revisión

Tipos de estudios

Se incluyeron todos los ensayos controlados aleatorios publicados y no publicados. Se incluyeron ensayos informados sólo como resúmenes cuando había información suficiente disponible para evaluar la metodología y el riesgo de sesgo.

No se incluyeron ensayos cruzados ni cuasialeatorios.

Tipos de participantes

Se incluyó a adultos y niños con eccema establecido. El diagnóstico por un médico del eccema fue obligatorio. Se incluyeron todos los contextos de ensayo, y no se restringió la inclusión de acuerdo a la edad, el origen étnico ni el sexo de los participantes, ni según la gravedad del eccema.

Tipos de intervenciones

Las intervenciones incluyeron tratamiento con ARLT sistémicos (orales o intravenosos) solos o en combinación con otros tratamientos (tópicos o sistémicos) en la fase aguda o crónica (mantenimiento) del eccema en comparación con otros tratamientos solos o placebo. Otros tratamientos incluyeron todos los tratamientos tópicos o sistémicos, incluidos los corticosteroides, los inhibidores de la calcineurina tópicos, inmunomoduladores y medicación alternativa.

Se excluyeron los ensayos que comparaban otras intervenciones con la misma dosis de ARLT entre los grupos, es decir, un ensayo que evalúa grupos con ARLT y tratamiento A versus ARLT y tratamiento B. Dichos ensayos no examinan los efectos de los ARLT sino que en cambio evalúan la eficacia de otros tratamientos.

Tipos de medida de resultado

Se examinaron los resultados primarios y secundarios enumerados más abajo. Los resultados se dividieron en los efectos a corto plazo, que se definieron como menos de tres meses y a largo plazo, que se definieron como a los tres meses o más.

Resultados primarios

Cambio en la gravedad de la enfermedad evaluada con el índice de gravedad SCORAD (SCORing of Atopic Dermatitis), EASI (Eczema Area and Severity Index), la puntuación de la gravedad SASSAD (Six Area, Six Sign Atopic Dermatitis), IGA Investigator's Global Assessment), o cualquier sistema de calificación validado para el eccema a corto y a largo plazo. Una reducción de la puntuación mediante estos sistemas validados de calificación se equipara a una mejoría en el eccema del participante.
Efecto del control a largo plazo, como el tiempo hasta la recurrencia del “brote” en la fase de mantenimiento (sin brotes).
Todos los eventos adversos, incluidas las reacciones alérgicas y la repercusión sobre la calidad de vida y la piel.

Resultados secundarios

Necesidad de cualquier corticosteroide tópico o sistémico, es decir los ARLT permiten la disminución o minimización de la dosis de corticosteroides necesarios, por lo tanto se evitan algunos de los efectos secundarios indeseables de los corticosteroides.
Reducción del prurito.
Mejoría en la calidad de vida con cualquier sistema de calificación validado.
Necesidad de uso de emolientes.

Tabla de "Resumen de resultados"

Se incluyeron dos tablas de “Resumen de los resultados” en las cuales se resumieron los hallazgos para los resultados primarios y secundarios para las comparaciones más importantes. Se utilizaron los criterios GRADE para evaluar la calidad de la evidencia en los estudios incluidos para cada resultado, lo cual se resumió en las tablas de “Resumen de resultados”. Las evaluaciones con criterios GRADE se basaron en cinco dominios: limitaciones de los estudios (riesgo de sesgo), inconsistencia de los resultados, falta de direccionalidad de la evidencia, imprecisión y sesgo de publicación. La evidencia pudo ser disminuida para estos dominios de alta a moderada, baja, o muy baja (Schünemann 2013).

Métodos de búsqueda para la identificación de los estudios

We aimed to identify all relevant randomised controlled trials regardless of language or publication status (published, unpublished, in press, or in progress).

Búsquedas electrónicas

The Cochrane Skin Information Specialist searched the following databases up to 7 September 2017 using strategies based on the draft strategy for MEDLINE in our published protocol (Futamura 2014):

the Cochrane Skin Specialised Register using the strategy in Appendix 1;
the Cochrane Central Register of Controlled Trials (CENTRAL) (2017, Issue 8), in the Cochrane Library using the strategy in Appendix 2;
MEDLINE via Ovid (from 1946) using the strategy in Appendix 3;
Embase via Ovid (from 1974) using the strategy in Appendix 4; and
the Global Resource for EczemA Trials (GREAT) (Centre of Evidence Based Dermatology (www.greatdatabase.org.uk)) using the strategy in Appendix 5.

We (the review author team) searched the following database up to 7 September 2017:

ISI Web of Science (from 1945) using the strategy in Appendix 6.

Trial registries

We (the review author team) searched the following trial registries to 7 September 2017 using the terms 'atopic eczema (dermatitis)', 'leukotriene', 'montelukast', 'zafirlukast', 'zileuton', and 'pranlukast':

the ISRCTN registry (www.isrctn.com);
ClinicalTrials.gov (www.clinicaltrials.gov);
the Australian New Zealand Clinical Trials Registry (www.anzctr.org.au);
the World Health Organization International Clinical Trials Registry Platform (www.who.int/trialsearch); and
the EU Clinical Trials Register (www.clinicaltrialsregister.eu/).

Búsqueda de otros recursos

References from included studies

We checked the bibliographies of the included studies for further references to relevant trials.

Adverse effects

Although we did not perform an adverse events search, we assessed all effects of LTRA reported in the treatment trials identified by our search, including any reported adverse effects or events. We acknowledge that these studies were not specifically designed to identify adverse effects, but we felt it would be useful to include these data as it is highly relevant to clinical decision‐making.

Obtención y análisis de los datos

Some parts of the Methods section of this review use text that was originally published in the Cochrane Handbook for Systematic Reviews of Interventions (Higgins 2011), or have been taken from a standard template used by the Cochrane Pregnancy and Childbirth Review Group.

Selección de los estudios

Two review authors (MF and LF) independently selected the trials according to the inclusion criteria. Any differences of opinion were resolved through discussion by consulting a third review author (RM) if required.

Extracción y manejo de los datos

We designed a data extraction form. Two review authors (MF and LF) independently extracted the data from eligible studies using the agreed‐upon form. We sought to record the study design, characteristics of participants, and types of interventions and doses of treatment used in each study. We also recorded the demographics of participants, results according to our outcome measures, and adverse effects. We further recorded methods of randomisation, treatment concealment, etc. to enable a 'Risk of bias' assessment for each study. Any discrepancies were resolved through discussion or by consulting a third review author (RM) if required. We entered data into Review Manager 5 and checked the data entry for accuracy. When any information was unclear, we attempted to contact the authors of the original reports to ask them to provide further details. Data expressed in figures without actual numbers were extracted using WebPlotDigitizer software (WebPlotDigitizer).

Evaluación del riesgo de sesgo de los estudios incluidos

Two review authors (MF and RK) independently assessed the risk of bias for eligible studies, which we summarised in the 'Risk of bias' table for each included study in Characteristics of included studies. Assessment of the risk of bias included evaluation of the following components for each included trial, using the criteria outlined in the Cochrane Handbook for Systematic Reviews of Interventions (Higgins 2011). We planned to resolve any disagreements by discussion or by involving a third review author.

1. Random sequence generation (checking for possible selection bias)

For each included study, we described the method used to generate the allocation sequence in sufficient detail to allow an assessment of whether it should produce comparable groups.
We assessed the methods as low risk of bias (e.g. referring to a random number table or computer random number generator); high risk of bias (e.g. sequence generated by date of birth or admission); or unclear risk of bias.
We only included randomised controlled trials.

2. Allocation concealment (checking for possible selection bias)

For each included study, we described the method used to conceal allocation to intervention prior to assignment and assessed whether intervention allocation could have been foreseen in advance of or during recruitment or changed after assignment.
We assessed the methods as low risk of bias (e.g. telephone or central randomisation; consecutively numbered, sealed, opaque envelopes); high risk of bias (e.g. open random allocation; unsealed or non‐opaque envelopes); or unclear risk of bias.

3. Blinding of participants, personnel (checking for possible performance bias), and outcome assessment (checking for possible detection bias)

For each included study, we described the methods used, if any, to blind study participants, personnel, and outcome assessors from knowledge of which intervention a participant had received. We considered studies to be at low risk of bias if they were blinded or if we judged that the lack of blinding would be unlikely to affect results. We considered studies to be at high risk of bias if they were not blinded or if we judged that the lack of blinding would be likely to affect results.
We assessed the methods as low risk of bias (e.g. both participants and outcome assessors were blinded); high risk of bias (e.g. neither were blinded); or unclear risk of bias for participants, personnel, and assessors.

4. Incomplete outcome data (checking for possible attrition bias due to the amount, nature, and handling of incomplete outcome data)

For each included study, we described the completeness of data, including attrition and exclusions from the analysis. We assessed risk of bias of incomplete outcome data with the overall level of missing data. We stated whether the study reported attrition and exclusions, the numbers included in the analysis at each stage (compared with the total number of randomised participants), and the reasons for attrition or exclusion where disclosed, as well as whether missing data were balanced across groups. Where studies reported sufficient information or the trial authors could supply it, we included missing data in our analyses
We assessed methods as low risk of bias (e.g. no missing outcome data; missing outcome data balanced across groups); high risk of bias (e.g. numbers or reasons for missing data imbalanced across groups; 'as treated' analysis done with substantial departure of intervention received from that assigned at randomisation); or unclear risk of bias.

5. Selective reporting (checking for reporting bias)

For each included study, we described how we investigated the possibility of selective outcome reporting bias and what we found.
We assessed the methods as low risk of bias (where it was clear that all of the study's prespecified outcomes and all expected outcomes of interest to the review had been reported); high risk of bias (where not all of the study's prespecified outcomes were reported; one or more reported primary outcomes were not prespecified; outcomes of interest were reported incompletely and so could not be used; study failed to include results of a key outcome that would have been expected to have been reported); or unclear risk of bias.

6. Other bias (checking for bias due to problems not covered by items one to five above)

For each included study, we described any important concerns we had about other possible sources of bias.
We assessed whether each study was free of other problems that could put it at risk of bias, classifying each study as at low, high, or unclear risk of other bias.

7. Overall risk of bias

We made explicit judgements as to whether studies were at high risk of bias, according to the criteria provided in the Cochrane Handbook for Systematic Reviews of Interventions (Higgins 2011). We assessed the overall risk of bias as low when all domains were classified as low risk; unclear when at least one domain was classified as unclear risk; and high when at least one domain was judged as high risk. With reference to items one to six above, we assessed the likely magnitude and direction of the bias and whether we considered that it was likely to impact on the findings. We planned to explore the impact of the level of bias by undertaking sensitivity analyses (see Sensitivity analysis).
We considered trials that were classified as being at low risk of bias in all of the above domains as trials at low risk of bias. We considered trials to be at unclear risk of bias when at least one of the domains was at unclear risk of bias and none of the domains was at high risk of bias, and trials to be at high risk of bias when at least one of the domains was at high risk of bias.

Medidas del efecto del tratamiento

For dichotomous data, we planned to calculate and present results as summary risk ratios (RR) with 95% confidence intervals (CI).

For continuous data, we calculated mean differences (MD) except where continuous outcomes were reported in different units, in which case we calculated a standardised mean difference (SMD). Where studies measured continuous outcomes with different scales and provided commonly used measures of effect, such as standard deviation or standard error, we calculated SMDs with 95% CIs from individual studies.

Cuestiones relativas a la unidad de análisis

We included both individual‐ and cluster‐randomised controlled trials. In the event that we included trials with multiple arms, we included the comparisons considered relevant to the review as two‐arm comparisons, with adjustment to avoid double‐counting where appropriate. We analysed the data of the cluster‐randomised trial using the methods described in Section 16.3 of the Cochrane Handbook for Systematic Reviews of Interventions if we found such data at the selection stage.

Manejo de los datos faltantes

For included studies, we noted levels of attrition. We planned to explore the impact of including studies with high levels of missing data on the overall assessment of treatment effect by undertaking sensitivity analysis.

For all outcomes, we carried out analyses on an intention‐to‐treat basis to the greatest degree possible, that is we attempted to include all participants randomised to each group in the analyses, and we analysed all participants in the group to which they were allocated, regardless of whether or not they received the allocated intervention.

For dichotomous data, we assumed the missing values to have a poor outcome. For continuous data, we considered imputing the mean change from baseline and corresponding standard deviation or, where applicable, the after‐value scores.

We contacted the original authors of all studies to enquire if they had any missing data that they did not report in the trial (Table 1). In cases where outcome data were not available, we carried out an available‐case analysis.

Evaluación de la heterogeneidad

We evaluated the clinical implications of treatment effects differing between trials. We assessed statistical heterogeneity using the I² statistic. When the I² statistic for each primary outcome was greater than 80%, we did not undertake meta‐analysis, but applied a narrative approach instead. When the I² statistic for each primary outcome was between 50% and 80%, then significant heterogeneity was present, which we planned to explore by looking for differences in participants and treatment factors.

Evaluación de los sesgos de notificación

We planned to assess reporting bias if more than 10 studies were suitable for inclusion in the meta‐analysis, and draw funnel plots for the primary outcomes using the log of effect measure and standard errors for individual studies. Additionally, for continuous outcomes, we planned to use the original linear regression test proposed by Egger (Egger 1997). We planned to perform a linear regression of the intervention effect estimates on their standard errors, weighting by 1/(variance of the intervention effect estimate). For dichotomous outcomes, we planned to use the modified regression test proposed by Harbord (Harbord 2006). If asymmetry was detected in any of these tests or was suggested by a visual assessment, we planned to perform exploratory analyses to investigate it.

Síntesis de los datos

We carried out statistical analysis using Review Manager 5 software. We used random‐effects meta‐analysis to produce an overall summary. We planned to treat the random‐effects summary as the average range of possible treatment effects, and we discussed the clinical implications of treatment effects differing between trials.

Análisis de subgrupos e investigación de la heterogeneidad

If we identified substantial heterogeneity, we planned to investigate it using subgroup analyses and sensitivity analyses. We planned to consider whether an overall summary was meaningful, and if it was, we would use random‐effects analysis to produce it.

We planned to carry out the following subgroup analyses:

age of participants: children (16 years old or under) versus adults; and
drug preparation, route of administration, dose, duration, frequency, who delivers it to participants, and whether deliverers need to be trained.

We planned to use the following outcomes in subgroup analysis:

change in disease severity;
effect of long‐term control; and
adverse events.

We were unable to carry out the planned subgroup analysis to evaluate differences in participants and treatment factors due to insufficient data.

Análisis de sensibilidad

We were unable to perform a sensitivity analysis due to insufficient data. In future updates we may be able to conduct sensitivity analysis to assess the effect of studies at high risk of bias on the results

Results

Description of studies

We have included all of the primary and secondary outcomes in summary of findings Table for the main comparison and summary of findings Table 2.

Results of the search

The searches of the six databases (see Electronic searches) retrieved 158 records after removal of duplicates. Our searches of the trial registries did not produce any further results. We reviewed the references of the included studies but did not identify any additional suitable studies. Of the 158 records, we excluded 137 after analysing their titles and abstracts. We obtained the full text of the remaining 21 records. We excluded 14 studies that did not meet the inclusion criteria after full‐text screening (see Characteristics of excluded studies). We included five studies in the review (see Characteristics of included studies), and assessed two studies as awaiting classification (see Characteristics of studies awaiting classification). The screening process is further described in the study flow diagram (Figure 1).

Figure 1

Study flow diagram.

Included studies

Five studies (involving a total of 202 participants) met the inclusion criteria of this review and are summarised in the Characteristics of included studies tables.

Design

Three studies were double‐blind trials (Friedmann 2007; Nettis 2002; Veien 2005); one was single‐blind (Capella 2001); and one was an open‐label trial (Rahman 2006). All five trials included individually randomised participants.

Sample sizes

The sample sizes for the five studies ranged from 20 to 60 participants.

Setting

Two studies were two‐centre trials (Friedmann 2007; Veien 2005), and one study was conducted in a single centre (Rahman 2006). The other two studies did not report information about setting. Studies were conducted in Italy (two studies), the United Kingdom, Bangladesh, and Denmark.

Participants

Participants of one study included children aged six years and above (Rahman 2006). The remaining studies did not include children; the age range in these studies was from 16 to 70 years. One study included only men (Nettis 2002), with the remaining studies including both genders. Study participants were diagnosed with moderate‐to‐severe eczema in four studies (Capella 2001; Nettis 2002; Rahman 2006; Veien 2005), and only moderate eczema in one study (Friedmann 2007). With regard to coexisting asthma, one study reported that 15 of 32 participants had allergic asthma (Capella 2001).

Interventions

All studies used montelukast 10 mg for adults (age 14 years and above) or 5 mg for children (age 6 years to 14 years) in tablet form taken orally as the LTRA intervention; three studies compared this with placebo (Friedmann 2007; Nettis 2002; Veien 2005), and two studies compared this with conventional treatment (Capella 2001; Rahman 2006). Conventional treatment included oral antihistamine and topical corticosteroid in both Capella 2001 and Rahman 2006, but Capella 2001 also included oral antibiotics (clarithromycin) in the conventional treatment arm. Two of the three studies using a placebo tablet did not allow participants in either arm to use topical corticosteroids.

The intervention periods varied: 4 weeks in 2 studies (Rahman 2006; Veien 2005), 6 weeks in 2 studies (Capella 2001; Nettis 2002), and 8 weeks in 1 study (Friedmann 2007).

Outcomes

All studies assessed disease severity using validated scores such as SCORAD, EASI, or SASSAD. The outcomes and type of data collected in the included studies are provided in Table 2.

See: Summary of findings for the main comparison Montelukast versus placebo for eczema; Summary of findings 2 Montelukast versus conventional treatment for eczema

Table 2. Summary of study design and outcomes provided for included studies

Study	Comparison	Observation	Scale	Data
Capella 2001	Conventional treatment	6 weeks	SCORAD	n, median, mean, range
Nettis 2002	Placebo	6 weeks	SCORAD	n, F value, P value
Friedmann 2007	Placebo	8 weeks	SASSAD	n, Δmean, ΔSD, 95% CI, P value
Rahman 2006	Conventional treatment	4 weeks	SCORAD	n, mean, SD, P value
Veien 2005	Placebo	4 weeks	modified EASI	n, mean, P value

CI: confidence interval; EASI: Eczema Area and Severity Index; SASSAD: Six‐Area, Six‐Sign Atopic Dermatitis; SCORAD: SCORing of Atopic Dermatitis; SD: standard deviation

The outcome measures varied: for example, different scoring systems were used, and these were analysed using varied measures of effect, which effectively precluded their quantitative comparison. We sought further details of the five included studies from the study contact authors (see Table 1), but unfortunately we were unable to obtain additional data beyond those reported in the published papers either because the author(s) did not reply or because they did not possess additional data. We extracted data from the figure in Nettis 2002 using WebPlotDigitizer software (WebPlotDigitizer). We performed analyses using available data from the included studies and estimated values using data from relevant studies where possible.

Excluded studies

We excluded 14 studies from our search that did not meet our inclusion criteria (see Characteristics of excluded studies). Three of these were reviews, and we checked their references for reports of any other relevant studies. One was not a comparative study, and one was not a randomised controlled trial. One study included participants with other atopic diseases, and as we were unable to separate out the specific effects of LTRA on eczema, we excluded the study. Seven studies were cross‐over trials, and a further reference was related to one of the cross‐over trials.

Studies awaiting classification

Two studies were published as conference abstracts (Craig 2002; Melamed 2010). We attempted to contact the authors, but to date we have not received any reply (see details in Characteristics of studies awaiting classification).

Risk of bias in included studies

The 'Risk of bias' assessment is summarised in Figure 2.

Figure 2

Risk of bias summary: review authors' judgements regarding the level of risk of bias for each type of bias for all included studies.

All but one study, Nettis 2002, were published as full papers after the CONSORT statement became well recognised (CONSORT 2010). However, most studies did not adequately elaborate on their methodology (Characteristics of included studies).

Allocation

Random sequence generation

We assessed four studies that inadequately described their method of randomisation as at unclear risk of bias (Capella 2001; Nettis 2002; Rahman 2006; Veien 2005). Friedmann 2007 used computer‐generated randomised sequence; we judged this study to be at low risk of bias for this domain.

Allocation concealment

We considered Capella 2001, Nettis 2002, Rahman 2006, and Veien 2005 to be at unclear risk of bias as they did not describe their method of allocation concealment. Friedmann 2007 used containers labelled with sequential participant numbers; we judged this study to be at low risk of bias for allocation concealment.

Blinding

Overall, the included studies made efforts to blind participants. We acknowledge that the risk of performance bias is potentially higher in studies comparing LTRA to conventional therapies without placebo, due to the drug delivery mode (e.g. topical versus oral). We have explored how authors attempted to overcome this. Capella 2001 tried to minimise outwardly appreciable differences between treatments: the treatment group received oral montelukast, a placebo tablet, and a topical placebo gel, while the control group received an oral antibiotic, oral antihistamine, and topical corticosteroid ointment. However, as this was a single‐blind randomised controlled trial where outcome assessors were not blinded, we therefore considered the study to be at high risk of bias. Friedmann 2007 supplied montelukast and placebo tablets in containers labelled with sequential participant numbers. They blinded treatment allocation to participants and investigators throughout the trial, which we judged to be at low risk of bias for this domain. In the Veien 2005 study, placebo tablets were also used, and the code was not broken until all statistical calculations had been performed, but the method of blinding were not described. We therefore judged this study to be at unclear risk of bias.

Nettis 2002 was a double‐blind study, but the method of blinding was not described, and therefore the risk of bias was unclear. Rahman 2006 was an open‐label study, which we judged as at high risk of bias.

Incomplete outcome data

In three studies, all participants completed the trial (Capella 2001; Nettis 2002; Rahman 2006). The remaining two studies performed intention‐to‐treat analysis. Two participants in Friedmann 2007 and six in Veien 2005 dropped out after randomisation. We therefore judged all studies as at low risk of bias for this domain.

Selective reporting

We judged all trials to be at low risk of bias, as the authors reported on all their planned outcomes.

Other potential sources of bias

We considered Friedmann 2007 and Veien 2005 as at unclear risk of bias because they were funded or supported by the company that sells montelukast.

We did not draw funnel plots to assess reporting bias because the review included only five studies.

Overall risk of bias

We judged three studies as at unclear risk of bias (Friedmann 2007; Nettis 2002; Veien 2005), and two studies as at high risk of bias (Capella 2001; Rahman 2006).

Effects of interventions

Three studies compared montelukast with placebo (Friedmann 2007; Nettis 2002; Veien 2005), and two compared montelukast with conventional treatments (Capella 2001; Rahman 2006). We have therefore divided the effects, data and analyses into 'versus placebo' (Analysis 1.1, Analysis 1.2; Analysis 1.3, summary of findings Table for the main comparison) and 'versus conventional treatment' (Analysis 2.1, Analysis 2.3, summary of findings Table 2) for each outcome, where available.

1. Montelukast versus placebo

i) Primary outcome 1: change in disease severity in the short term and long term

All three studies for the comparison montelukast versus placebo assessed this outcome, for 4 weeks in Veien 2005, 6 weeks in Nettis 2002, and 8 weeks in Friedmann 2007.

Veien 2005 reported using the modified EASI (Eczema Area and Severity Index) score, which they calculated as the sum of the pruritus scores (0 to 3) and the EASI score. The modified EASI decreased from 8.9 to 6.8 in the montelukast group (n = 25) and from 9.5 to 7.6 in the placebo group (n = 28) (no standard deviations (SDs) provided). The difference between the groups was not significant (P = 0.46, confidence interval not stated) (Analysis 1.1).

Nettis 2002 showed a 20% reduction of SCORAD (SCORing of Atopic Dermatitis) scores after six weeks of treatment with montelukast (n = 10), which was a significant decrease compared with placebo (n = 10) (P = 0.021, confidence interval not stated). No raw data were provided (Analysis 1.1). We extracted data from the figure provided in the text using WebPlotDigitizer software (WebPlotDigitizer), which showed that mean scores changed from 56.07 to 45.81 in the montelukast group and 60.85 to 60.17 in the placebo group after six weeks.

Friedmann 2007 evaluated the effect of montelukast on disease severity with SASSAD (Six Area, Six Sign Atopic Dermatitis) and IGA (Investigator's Global Assessment). They found no significant difference between mean SASSAD score changes in the montelukast group (mean ± SD; 1.41 ± 12.2, n = 29) and the placebo group (1.76 ± 12.2, n = 29) (mean difference 0.35, 95% confidence interval (CI) ‐5.93 to 6.63) (Analysis 1.1).

Although these studies met our inclusion criteria, they only addressed a restricted version of our review questions in terms of the population, outcomes, and comparators used. We therefore downgraded this evidence due to indirectness as participants all had moderate‐to‐severe eczema with no mild cases or paediatric participants. We also downgraded evidence due to imprecision related to the small sample size: the three relevant studies only included a total of 139 participants.

We were able to pool data from the three included studies, involving 131 participants. Participants were treated with either montelukast or placebo (Analysis 1.2, Figure 3). There was no significant difference in improvement in disease severity for montelukast versus placebo (standardised mean difference 0.29, 95% CI ‐0.23 to 0.81). The I² statistic was 51%, which corresponds to a moderate amount of heterogeneity (Figure 3). Even if we had based our conclusions on data from two studies, Friedmann 2007; Veien 2005, without using the extracted data from the figure (Nettis 2002), the overall result would not have substantially changed.

Figure 3

Forest plot of comparison: 1 Montelukast versus placebo, outcome: 1.2 Improvement in disease severity.

ii) Primary outcome 2: effect of long‐term control

We defined three months or more as long term. We found no data evaluating this outcome, as the longest included study was of only eight weeks' duration.

iii) Primary outcome 3: adverse events

All three studies reported on this outcome (total of 131 followed participants). We judged the quality of evidence for the outcome adverse events as low, downgrading due to imprecision (small sample size and low event rate) and indirectness because only participants with moderate‐to‐severe eczema were included. Additionally, these were treatment studies, and as such not specifically designed to detect this outcome.

Friedmann 2007 reported one serious adverse event of septicaemia and one dizzy spell in 29 participants in the montelukast group, both of which resulted in withdrawal from the study (Analysis 1.3). Although the authors did not comment on whether these effects were thought to be related to the treatment, it seems unlikely that septicaemia was treatment‐related. The authors reported that one participant withdrew due to worsening of eczema in the placebo group. Other adverse events of a fairly mild nature like respiratory tract infections, headache, flares of eczema, and mild gastrointestinal disturbances were observed and according to the authors were "fairly evenly distributed between montelukast and placebo groups".

No adverse effects were observed in the 35 participants who received montelukast and the 38 who received placebo in the other two studies (Nettis 2002; Veien 2005). Veien 2005 reported a dropout rate of six participants: four in the montelukast group and two in the placebo group. This was due to aggravation of eczema or loss to follow‐up. The authors reported that there was no significant difference between groups in terms of dropout rate (Chi² test for contingency tables, P = 0.62). All participants in the Nettis 2002 study completed the study.

iv) Secondary outcome 1: requirement for any topical or systemic corticosteroids

None of the three studies permitted use of systemic corticosteroids during their trials.

Among these studies where topical corticosteroids were not part of the control arm (i.e. where montelukast was compared to placebo), Friedmann 2007 only permitted the use of topical corticosteroids as needed. Friedmann 2007 evaluated the frequency of topical corticosteroid use with a 5‐point scale ("twice daily", "once daily", "alternative days", "occasionally", and "none"), but did not evaluate the amount of steroid used. The frequency of topical corticosteroid usage did not reveal any steroid‐sparing effect (n = 58) (Table 3).

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Table 3. Topical corticosteroid usage in Friedmann 2007

	‐2 weeks	0 week	4 weeks	8 weeks
Montelukast
Twice daily	8	6	9	7
Once daily	11	10	7	5
Alternative day	5	7	6	9
Occasional	4	6	6	3
None	2	1	1	2
Placebo
Twice daily	8	8	5	4
Once daily	9	10	11	9
Alternative day	6	8	7	5
Occasional	4	4	6	7
None	3	0	0	1

The number of participants using topical corticosteroid according to frequency of use at each assessment point of the study. The data were extracted from Figure 2 of the publication, using WebPlotDigitizer software (WebPlotDigitizer).

The other two studies (Nettis 2002 and Veien 2005 involving 79 randomised participants) did not permit the use of topical corticosteroids; therefore, neither study was designed to detect steroid‐sparing capacity.

We judged the quality of evidence as low, downgrading due to imprecision and indirectness because the outcome was assessed in only one study (Friedmann 2007), which included only 58 evaluable participants who were all adults with moderate‐to‐severe eczema.

v) Secondary outcome 2: reduction of pruritus and undesirable skin conditions

Only one study involving 58 participants evaluated pruritus score separately to disease severity (Friedmann 2007). The other studies used SCORAD or EASI, which included pruritus scores as one of their outcomes; however, no other study reported a pruritus score independently in their results.

In Friedmann 2007, mean pruritus score at baseline (using a visual analogue scale, range 0 to 10) was 5.8 in the montelukast group (n = 29) and 5.7 in the placebo group (n = 29). The response to treatment was reported as mean improvement in pruritis score, and an improvement of 0.1 was seen in the treatment group and 0.8 in the placebo group. The mean difference was 0.7 (placebo superior to montelukast) on the visual analogue scale. The authors assessed this difference as non‐significant (but provided no P value or SDs).

Veien 2005 included a modified EASI, which was calculated by adding the traditional EASI score to a pruritis score, measured using a 10‐centimetre 0‐to‐3 visual analogue scale. The primary endpoint was the modified EASI, and the secondary endpoint was the "pruritis score during the trial as a percentage of the baseline value". However, the authors did not provide data from the pruritis score independent of the EASI; therefore, we could not pool these data with those of Friedmann 2007.

Nettis 2002 reported a combined score of daytime pruritis and sleep loss, which was not statistically significant between the two treatments (F‐test = 0.08, P = 0.92), nor was it significant for either group before and after treatment (F‐test = 1.95, P = 0.18). The authors describe recording these "subjective criteria" separate to the SCORAD but do not elucidate on the scoring system. As no actual data (other than graphical representation), mean values, or SDs were provided, we could not further analyse this finding.

We judged the quality of this evidence as low, downgrading due to imprecision and indirectness because Friedmann 2007 included only 58 evaluable participants, who were all adults with moderate‐to‐severe eczema.

vi) Secondary outcome 3: improvement in quality of life

No studies specifically used this outcome measure.

A global assessment scale provided by participants provides some information related to quality of life. One study (involving 58 evaluable participants) reported a participant‐assessed measure of treatment success (Friedmann 2007), which was defined as "better" or "markedly improved" on a seven‐point scale. Out of 29 participants in the montelukast group, six reported success; in the placebo group 10 out of 29 participants reported success. There was no significant difference between groups. Mean sleep disturbance scores are also relevant to this outcome: the mean improvement using a visual analogue scale (range 0 to 10) was 1.0 in the treatment group and 1.6 in the placebo group. Again, there was no significant difference between groups.

Nettis 2002 reported a combined score of daytime pruritis and sleep loss, but the difference between the two treatments was not statistically significant (F‐test = 0.08, P = 0.92), nor was it significant for either group before and after treatment (F‐test = 1.95, P = 0.18). The authors describe recording these "subjective criteria" separate to the SCORAD but do not elucidate on the scoring system. As no actual data (other than graphical representation), mean values, or SDs were provided, we could not further analyse this finding.

vii) Secondary outcome 4: need for emollient use

Liberal emollient use was permitted in both treatment arms in all three studies (Friedmann 2007; Nettis 2002; Veien 2005, involving 139 randomised participants). None of the studies evaluated the amount or frequency of emollient use.

2. Montelukast versus conventional treatment

i) Primary outcome 1: change in disease severity in the short term and long term

Two of the five included studies used this comparison (involving 63 participants). Treatment with montelukast was compared with conventional treatment for four weeks in the Rahman 2006 study and six weeks in the Capella 2001 study (Analysis 2.1).

Rahman 2006 showed that the SCORAD score (mean ± SD) decreased for the montelukast group from 52.70 ± 15.95 to 37.41 ± 6.04 at 4 weeks (P = 0.003), but the score only changed from 53.31 ± 15.17 to 48.58 ± 14.37 (P = 0.088) in the conventional treatment group. The mean difference in improvement in disease severity between groups was 10.57 (95% CI 4.58 to 16.56, P < 0.001, n = 31), in favour of the montelukast group (Analysis 2.2, Figure 4).

Figure 4

Forest plot of comparison: 2 Montelukast versus conventional treatment, outcome: 2.2 Improvement in disease severity.

Capella 2001 reported a significant improvement of disease severity measured using SCORAD (i.e. a decrease in score) in both the montelukast group (the mean reduced from 49.1 at baseline to 23.9 after 6 weeks) and the conventional treatment group (from 48.2 at baseline to 24.3 at 6 weeks). However, there was no significant difference in medians of SCORAD variations between the montelukast and conventional treatment groups (Mann‐Whitney, P < 0.05). No standard deviation was provided; therefore, we were unable to pool the data from this study with that of Rahman 2006 without having to make serious assumptions about the exact P value and true standard deviation.

We judged the quality of evidence for this outcome as very low, downgrading due to risk of bias, indirectness, and imprecision because outcome assessors were not blinded, and the sample size of each study was small. In addition, participants in these studies only had moderate‐to‐severe eczema; mild cases were not included.

ii) Primary outcome 2: effect of long‐term control

We defined three months or more as long term. We found no data evaluating this outcome, as the longest included study was of only six weeks' duration.

iii) Primary outcome 3: adverse events

Both studies reported on this outcome. We judged the quality of evidence on adverse events as low, downgrading due to imprecision and indirectness because only 63 participants were evaluated, and only participants with moderate‐to‐severe eczema were included. Additionally, these were treatment studies, and as such not specifically designed to detect this outcome.

Neither of the studies reported any adverse effects in the montelukast group (32 participants) (Capella 2001; Rahman 2006) (Analysis 2.3). Capella 2001 commented that no side effects were reported by participants or observed by the authors in the montelukast or control group. Rahman 2006 only commented about the montelukast group, reporting that montelukast was "excellently tolerated".

iv) Secondary outcome 1: requirement for any topical or systemic corticosteroids

Neither study permitted use of systemic corticosteroids during their trials.

Both studies compared montelukast with conventional treatments that included topical corticosteroids (Capella 2001 and Rahman 2006, a total of 63 out of 202 participants). These studies were therefore not designed to detect steroid‐sparing capacity.

v) Secondary outcome 2: reduction of pruritus and undesirable skin conditions

No studies evaluated the effect of montelukast on reduction of pruritus or on undesirable skin conditions compared with conventional treatment.

Although they reported no specific data, Capella 2001 did mention that "according to patients' impressions, pruritis was the most influenced SCORAD item by both montelukast and conventional groups, immediately followed by sleep loss and inflammatory signs". This study found no significant difference in SCORAD scores before and after treatment between treatment groups, but as the authors did not provide further data on this specific measure, we were unable to use this information in our analyses.

Interestingly, Rahman 2006 also reported that "according to patients' impressions, pruritis was the most influenced SCORAD item... followed by sleep loss and inflammatory signs", but did not provide any specific data to support this or enable further analysis. The authors of this study reported that the overall SCORAD was significantly improved after four weeks in the montelukast group but not in the group received conventional treatment, and there was a significant difference between montelukast and control groups at four weeks (P = 0.001).

vi) Secondary outcome 3: improvement in quality of life

No studies specifically used this outcome measure.

However, sleep disturbance is one of the most important parameters when assessing quality of life. Although they reported no specific data, Capella 2001 did mention that "according to patients' impressions, pruritis was the most influenced SCORAD item by both M (montelukast) and C (conventional) groups, immediately followed by sleep loss...". This study found no significant difference in SCORAD scores before and after treatment between treatment groups, but did not provide further data on this specific measure.

Rahman 2006 also reported that "according to patients' impression pruritis was the most influenced SCORAD item followed by sleep loss and inflammatory signs", but did not provide any specific data to support this or enable further analysis. The authors of this study reported that the overall SCORAD was significantly improved after four weeks in the montelukast group but not in the group received conventional treatment, and there was a significant difference between montelukast and control groups at four weeks (P = 0.001).

vii) Secondary outcome 4: need for emollient use

In one study, emollient use was included in the conventional treatment arm, which was compared with montelukast (Capella 2001). Rahman 2006 did not provide details of emollient use. Neither study evaluated the amount or frequency of emollient use.

Discusión

disponible en

Resumen de los resultados principales

Basado en la evidencia de cinco estudios que incluyen a un total de 202 participantes que contribuyeron con datos a los objetivos de la revisión, se encontró que la repercusión de los ARLT en el eccema es incierta. Estos resultados se demuestran de forma cuantitativa en las tablas de “Resumen de resultados” (Tabla 1 Resumen de resultados; Tabla 2 Resumen de resultados).

Todos los ensayos fueron de duración a corto plazo (cuatro a ocho semanas) y evaluaron el eccema moderado a grave, de manera que los efectos de los ARLT en los casos más leves del eccema siguen siendo inciertos. Los resultados informados se midieron al final del tratamiento. Ninguno de los estudios incluidos evaluó la necesidad de uso de emolientes ni la mejoría en la calidad de vida. Los cinco estudios usaron montelukast; por lo tanto, no fue posible establecer ninguna conclusión acerca de otros ARLT. Dos de los cinco estudios incluidos tenían vínculos de financiación con el fabricante del fármaco. Se excluyeron varios estudios que consideraban el efecto del montelukast debido a que tenían un diseño cruzado, que era un criterio de exclusión de esta revisión.

Los agentes orales alternativos usados en el eccema tienen perfiles de seguridad significativos, y los agentes tópicos a menudo no son bien tolerados, lo cual da lugar a un cumplimiento deficiente, de manera que era particularmente relevante realizar una revisión de los efectos adversos del montelukast. De acuerdo a los objetivos, se examinó el número de efectos adversos informados en los cinco estudios incluidos. Todos los estudios informaron de forma explícita los efectos adversos (lo cual dio lugar a un total de 101 participantes que recibieron montelukast).

Montelukast versus placebo

(ver Resumen de resultados tabla 1.)

Con respecto al cambio en la gravedad de la enfermedad, no se halló evidencia de una diferencia entre el montelukast (10 mg) y el placebo en cuanto a la mejoría media (3 estudios, n = 131), la reducción del prurito (1 estudio, n = 58) o la administración de corticosteroides tópicos (un estudio, n = 58). La calidad de esta evidencia se calificó como baja.

En los tres estudios (131 participantes) de esta comparación, sólo hubo dos efectos adversos informados (septicemia y mareos) que dieron lugar al retiro (ambos ocurrieron en el mismo estudio). El más grave de estos efectos adversos, un "episodio septicémico breve", no es un efecto secundario reconocido del montelukast, y parece improbable que hubiese estado relacionado con el tratamiento. Los efectos adversos leves como las infecciones de las vías respiratorias, la cefalea y los trastornos gastrointestinales leves se informaron de manera bastante equitativa en ambos grupos de intervención. Por lo tanto, no se encontró evidencia de que el tratamiento con montelukast diera lugar a más eventos adversos que el placebo. Sin embargo, las restricciones como el número de participantes y las características de los participantes dieron lugar a la disminución de la evidencia sobre los efectos adversos, a baja calidad, lo cual significa que sólo existe una confianza limitada en esta conclusión.

Montelukast versus tratamiento convencional

(Ver "Resumen de resultados", tabla 2.)

Los dos estudios de esta comparación informaron que ninguno de los participantes experimentó efectos adversos; estos estudios no informaron la reducción del prurito ni el uso de corticosteroides tópicos.

Aunque el montelukast mejoró la gravedad de la enfermedad en comparación con el tratamiento convencional en un estudio (n = 31), otros estudios no revelaron ninguna diferencia clara (n = 32); sin embargo, no existe seguridad acerca de estos resultados debido a que la calidad de la evidencia fue muy baja.

En términos generales, hubo una falta de estudios que buscaran responder a las preguntas de la revisión y, por lo tanto, los números de participantes incluidos en esta revisión fueron relativamente bajos. No hubo ningún estudio que explorara la repercusión a más largo plazo del montelukast y, por lo tanto, no fue posible establecer conclusiones acerca de la función del montelukast en el tratamiento de mantenimiento para el eccema.

Se esperaba poder realizar el análisis de subgrupos de los efectos de los ARLT en los niños versus adultos, aunque sólo uno de los cinco estudios incluidos reclutó tanto a adultos como a niños como participantes (Rahman 2006). En consecuencia, es difícil formular observaciones sobre la función de los ARLT en la población pediátrica. La evidencia adicional sobre la población pediátrica sería útil debido a que es probable que este grupo se beneficie más con los agentes de reducción de la dosis de esteroides, debido a que los niños tienen más eccema y pueden potencialmente recibir tratamientos más prolongados con esteroides y por lo tanto presentan más efectos secundarios durante la vida causados por los esteroides.

En términos generales, los estudios que cumplieron con los criterios de inclusión fueron insuficientes para permitir proporcionar un metanálisis sólido o conclusiones consistentes. La mayoría de los estudios incluidos no logró informar de manera adecuada sobre los métodos de asignación y cegamiento, lo cual impide la clasificación apropiada del sesgo. Del mismo modo que con otra investigación sobre los tratamientos del eccema, el período de estudio fue por unanimidad a corto plazo, lo cual impide formular observaciones sobre la función de los ARLT en el mantenimiento a largo plazo (una faceta del eccema que es muy importante para muchos pacientes con eccema).

Compleción y aplicabilidad general de las pruebas

En términos generales, los objetivos de esta revisión no se consideraron de forma completa, en consecuencia la validez externa es débil. Hubo una falta general de evidencia que cumpliera con los criterios de inclusión; se necesitaban más ensayos controlados aleatorios para evaluar si los ARLT presentan la misma efectividad que los tratamientos convencionales, o si al menos son significativamente mejores que el placebo. Sin embargo, todos los estudios informaron de forma específica los efectos adversos de los ARLT.

Los estudios usaron medidas de resultado variadas y no siempre proporcionaron medidas del efecto utilizadas con frecuencia, como la desviación estándar o el error estándar, por lo cual no fue posible combinar los resultados al grado que se habría deseado para proporcionar un cociente de riesgos. Se estableció contacto con los autores de algunos estudios incluidos y excluidos para solicitar más información, aunque lamentablemente no se recibieron respuestas positivas para ayudar a la causa. También hubo una falta de evidencia explícita para permitir un análisis minucioso de los resultados secundarios (capacidad de reducción de la dosis de corticosteroides, calidad de vida y uso de emolientes). Además, la mayoría de los participantes del estudio eran adultos, y un estudio sólo incluyó a hombres de 18 a 28 años de edad, lo cual da lugar a que los resultados sean potencialmente menos generalizables a todos los individuos con eccema.

No se encontraron estudios que evaluaran el efecto sobre el control a largo plazo. Los períodos de tratamiento para los cinco estudios fueron relativamente cortos (cuatro a ocho semanas) debido a que el eccema es una afección crónica. En esta revisión no se identificaron estudios con una duración más larga del tratamiento y del seguimiento.

La fisiopatología del eccema es compleja: hay factores genéticos y ambientales que contribuyen a diferentes grados en diferentes poblaciones. Si se tiene en cuenta este hecho, los ARLT en realidad pueden ser beneficiosos sólo en un subgrupo de pacientes con eccema, en los que el proceso patógeno fundamental es diferente a la mayoría. De todas formas, los ARLT pueden ser completamente inefectivos en el eccema en general. Podría valer la pena la evaluación del subgrupo de pacientes con eccema y asma, debido a que este fenotipo quizá tenga teóricamente una mejor respuesta al montelukast que los pacientes con eccema solo. Sólo uno de los estudios incluidos seleccionó a participantes con eccema y con asma (Capella 2001), aunque no fue posible realizar análisis de sensibilidad en este subgrupo.

Se debieron excluir algunos estudios debido a que incluían a participantes con "afecciones atópicas" en lugar de especificar qué resultados se relacionaban con los pacientes con eccema versus asma. Se excluyeron los ensayos cruzados (cross‐over) debido a que no fue posible excluir el efecto de "resaca" de los ARLT después del período de lavado; debido a la variabilidad natural de la gravedad del eccema, se cree que este diseño de estudio fue menos fiable que los ensayos controlados aleatorios.

También hay inquietudes en cuanto a la elección del comparador en los estudios que utilizaron el "tratamiento convencional"(Capella 2001; Rahman 2006). En un estudio se usaron antibióticos orales (Capella 2001), que no es el tratamiento estándar del eccema a menos que presente una infección aguda. El otro estudio usó un corticosteroide tópico muy leve, que puede haber sido inadecuado para la gravedad del eccema en el grupo (Rahman 2006).

A falta de investigación adicional, es poco probable que los resultados de esta revisión cambien la práctica clínica actual; por el momento, las guías internacionales actuales no recomiendan los ARLT para el eccema debido a la evidencia insuficiente (Ver Acuerdos y desacuerdos con otros estudios o revisiones).

Calidad de la evidencia

Se incluyeron sólo cinco estudios con un total de 202 participantes en esta revisión y la mayoría de los estudios carecieron de información suficientemente detallada para permitir un metanálisis. En consecuencia, el cúmulo de evidencia no permite una conclusión consistente con respecto al efecto de los ARLT en el eccema y sus efectos adversos en este grupo de pacientes.

Las limitaciones graves incluyeron que todos los estudios sólo seleccionaron a pacientes con eccema moderado a grave y que cada resultado se evaluó con un tamaño de muestra pequeño. En consecuencia, se disminuyeron todos los resultados debido a la imprecisión y la falta de direccionalidad de la evidencia, y la calidad de la evidencia se consideró baja para todos los resultados en la comparación del montelukast versus placebo. Para la comparación del montelukast versus tratamiento convencional, la evidencia sobre los efectos adversos también se consideró de baja calidad por las razones expresadas anteriormente, aunque el resultado primario del cambio en la gravedad de la enfermedad se calificó como de muy baja calidad debido a que no se realizó el cegamiento de los evaluadores de resultado, lo cual causó la disminución adicional por las limitaciones del estudio (ver Tabla 1 Resumen de resultados; Tabla 2 Resumen de resultados).

Aunque sólo se disminuyó un resultado debido a las limitaciones de los estudios, hubo dudas metodológicas adicionales con respecto a la asignación y el cegamiento. Hubo incertidumbre en cuanto a cómo los participantes fueron asignados a los grupos en cuatro de los cinco estudios, lo cual da lugar a que la formulación de observaciones sobre el sesgo general sea desafiante. Solo tres estudios fueron doble ciego; en consecuencia, se concuerda con la observación en Friedmann 2007 que declara que "Debido a la variabilidad natural del eccema con el transcurso del tiempo y la naturaleza subjetiva de la afección, los estudios no controlados y sin ocultación deben interpretarse con cuidado" y se cree que la misma es muy relevante para la revisión. Además, algunos informes de los estudios omitieron los datos numéricos, lo cual dio lugar a que el agrupamiento de los estudio suponga un reto.

Sesgos potenciales en el proceso de revisión

Se realizaron búsquedas y nuevas búsquedas en la bibliografía varias veces para evitar la omisión de estudios. Dos autores de la revisión filtraron los estudios para evitar cualquier sesgo. Se solicitó a un tercero que tradujera cualquier estudio publicado en idiomas diferentes al hablado por los autores de la revisión. No fue posible incluir dos estudios publicados como resúmenes de congresos debido a la ausencia de información sobre los métodos, a pesar de establecer contacto con los autores para solicitar más información. La anterior fue una restricción fuera del control de la revisión. Se intentó realizar una búsqueda exhaustiva de estudios, aunque el hecho de que dos estudios, Craig 2002; Melamed 2010; todavía no se hayan incorporado es una posible fuente de sesgo. Se intentó establecer contacto con los autores de todos los estudios incluidos para obtener más información, pero no se proporcionó ninguna. (Tabla 1). La manera en que se llevó a cabo la correspondencia con los autores de los estudios estuvo limitada al correo electrónico en todos los casos. Debido a que no fue posible realizar un metanálisis estadístico completo (debido a la falta de medidas de resultado equivalentes y los grupos variados de participantes), cualquier conclusión establecida se basa en la interpretación de los estudios por parte de los autores de la revisión. Sin embargo, debido a que los resultados eran contradictorios y la evidencia de baja calidad, no se estableció ninguna conclusión consistente, de manera que es poco probable que esta limitación del proceso de revisión haya introducido un sesgo significativo. También se debió depender del software WebPlotDigitizer para extraer los datos que no habían sido proporcionados en un formato utilizable en un estudio (Nettis 2002; WebPlotDigitizer).

Acuerdos y desacuerdos con otros estudios o revisiones

Los estudios incluidos parecen coincidir con otras revisiones sistemáticas recientes y guías en la bibliografía. En el Reino Unido, los ARLT no son parte del enfoque escalonado al tratamiento del eccema en los niños de hasta 12 años de edad (NICE 2007). El European Dermatology Forum, cuya revisión sistemática informó las guías para el tratamiento del eccema (Ring 2012), declaró que "en la actualidad no hay suficiente evidencia de ECA (ensayo controlado aleatorio) para apoyar el uso seguro de los antagonistas de los receptores de leucotrienos en el tratamiento del picor del EA (eccema atópico)". De igual manera, las guías de las revisiones sistemáticas estadounidenses recientes sobre el tratamiento del eccema declaran que "hay datos limitados sobre los inhibidores de leucotrieno. Por lo tanto, es difícil determinar la eficacia relativa de las opciones disponibles" (Sidbury 2014). En Japón, las guías de las revisiones sistemáticas no incluyen datos sobre los ARLT (Katayama 2014). Otra revisión sistemática encontró, como esta revisión, que los "resultados de estos ensayos son inconsistentes" (Roekevish 2014).

Entre las publicaciones recientes no basadas en la metodología de las revisiones sistemáticas, las conclusiones han sido más positivas a favor de los ARLT. Por ejemplo, una búsqueda de sesiones bibliográficas basada en un subconjunto pediátrico estableció la conclusión de que el "montelukast puede reducir de forma significativa la gravedad de la dermatitis atópica, aunque con menos efecto sobre el grado de la enfermedad" (Holme 2013). Los autores formularon observaciones en cuanto a que puede haber "subgrupos dentro de la población que responden mejor al tratamiento con montelukast" y por lo tanto un "ensayo de un mes de duración es razonable". Se necesitan más datos de ensayos que cubran a la población pediátrica para respaldar estas afirmaciones.

Los efectos adversos potenciales de los ARLT detallados por los fabricantes y en otra bibliografía extensiva sobre el asma incluyen trastornos gastrointestinales, cefalea, reacciones de hipersensibilidad, somnolencia y efectos neurosiquiátricos incluida la posibilidad de cambios del estado de ánimo e ideación suicida. De acuerdo con otra bibliografía, esta revisión halló que la tasa de efectos adversos informados con montelukast puede ser baja (2 incidentes adversos a partir de 101 participantes, que dieron lugar al retiro del estudio).

Figure 1

Study flow diagram.

Figure 2

Risk of bias summary: review authors' judgements regarding the level of risk of bias for each type of bias for all included studies.

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Figure 3

Forest plot of comparison: 1 Montelukast versus placebo, outcome: 1.2 Improvement in disease severity.

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Figure 4

Forest plot of comparison: 2 Montelukast versus conventional treatment, outcome: 2.2 Improvement in disease severity.

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Study
Friedmann 2007	The montelukast effect on disease severity with SASSAD and IGA. They found no significant difference between mean score changes in the montelukast group (mean ± SD; 1.41 ± 12.2) and the placebo group (1.76 ± 12.2)
Nettis 2002	A 20% reduction of SCORAD scores after 6 weeks of treatment with montelukast, and this was a significant decrease compared with placebo (P = 0.021)
Veien 2005	The modified EASI score, the sum of EASI score and the pruritus scores (0 ‐ 3), decreased from 8.9 to 6.8 in the montelukast group and from 9.5 to 7.6 in the placebo group. The difference between the groups was not significant (P = 0.46)

Analysis 1.1

Comparison 1 Montelukast versus placebo, Outcome 1 Improvement in disease severity (narrative table).

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Analysis 1.2

Comparison 1 Montelukast versus placebo, Outcome 2 Improvement in disease severity.


Study
Friedmann 2007	1 serious adverse event of septicaemia and 1 dizzy spell in 29 participants of the montelukast group. 1 worsening of eczema causing withdrawal of the trial in the placebo group. Other adverse events of a fairly mild nature like respiratory tract infections, headache, flares of eczema and mild gastrointestinal disturbances were observed and they were "fairly evenly distributed between montelukast and placebo groups" according to the authors.
Nettis 2002	No adverse effects were observed.
Veien 2005	No adverse effects were observed.

Analysis 1.3

Comparison 1 Montelukast versus placebo, Outcome 3 Adverse effects (narrative table).


Study
Capella 2001	A significant improvement of SCORAD score both in the montelukast group (mean: from 49.1 to 23.9) and the conventional treatment group (from 48.2 to 24.3). There was no significant difference between the groups.
Rahman 2006	Montelukast significantly improved the SCORAD score compared with conventional treatment (P = 0.001). In the montelukast group, the score (mean ± SD) decreased from 52.70 ± 15.95 to 37.41 ± 6.04 (P = 0.003); otherwise the score changed from 53.31 ± 15.17 to 48.58 ± 14.37 (P=0.088) in the conventional group.

Analysis 2.1

Comparison 2 Montelukast versus conventional treatment, Outcome 1 Improvement in disease severity (narrative table).

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Analysis 2.2

Comparison 2 Montelukast versus conventional treatment, Outcome 2 Improvement in disease severity.


Study
Capella 2001	No adverse effects were observed.
Rahman 2006	No adverse effects were observed.

Analysis 2.3

Comparison 2 Montelukast versus conventional treatment, Outcome 3 Adverse effects (narrative table).

Summary of findings for the main comparison. Montelukast versus placebo for eczema

Montelukast compared with placebo for eczema
Patient or population: eczema Setting: 2 studies were conducted in 2 centres each; setting of remaining study is unknown Intervention: montelukast Comparison: placebo
Outcomes	*Illustrative comparative risks (95% CI)**		Relative effect (95% CI)	No. of participants (studies)	Quality of the evidence (GRADE)	Comments
	Assumed risk	Corresponding risk
	Placebo	Montelukast
Change (improvement) in disease severity (4 to 8 weeks) SMD (modified EASI score and SASSAD)	The mean improvement score ranged across placebo group from 0.68 to 1.9.	The mean improvement in the intervention group was 0.29 higher (0.23 lower to 0.81 higher).	‐	131 (3 RCTs)	⊕⊕⊝⊝ LOW ¹
Effect of long‐term control (> 3 months)	See comment	See comment	‐	‐	‐	Not measured, as longest follow‐up was only 8 weeks
Adverse effects (4 to 8 weeks)	See comment	See comment	‐	131 (3 RCTs)	⊕⊕⊝⊝ LOW ¹	2 adverse events were reported (1 episode of septicaemia and 1 dizzy spell in the montelukast group) out of 29 participants (Friedmann 2007). No adverse effects were observed in the other 2 studies (Nettis 2002; Veien 2005), but Nettis 2002 reported an equivalent dropout rate in both montelukast and placebo groups due to aggravation of eczema or loss to follow‐up.
Requirement for corticosteroid (steroid‐sparing effect)	See comment	See comment	‐	58 (1 RCT)	⊕⊕⊝⊝ LOW ¹	The frequency of topical corticosteroids use was not significantly different between montelukast and placebo treatments using a 5‐point scale (Friedmann 2007).
Reduction of pruritus (score range 0 to 10; higher score means better improvement)	The mean change in improvement of pruritus score from baseline was 0.8 in the placebo group.	The mean change in improvement of pruritus score from baseline was 0.7 lower in the montelukast group.	‐	58 (1 RCT)	⊕⊕⊝⊝ LOW ¹	The study authors assessed this difference as non‐significant (but no P value or standard deviations provided) (Friedmann 2007).
Improvement in quality of life	See comment	See comment	‐	‐	‐	No studies evaluated quality of life.
Need for emollient use	See comment	See comment	‐	‐	‐	No studies evaluated emollient requirement.
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). CI: confidence interval; EASI: Eczema Area and Severity Index; RCT: randomised controlled trial; SASSAD: Six‐Area, Six‐Sign Atopic Dermatitis; SMD: standardised mean difference
GRADE Working Group grades of evidence High quality: Further research is very unlikely to change our confidence in the estimate of effect. Moderate quality: Further research is likely to have an important impact on our confidence in the estimate of effect and may change the estimate. Low quality: Further research is very likely to have an important impact on our confidence in the estimate of effect and is likely to change the estimate. Very low quality: We are very uncertain about the estimate.
¹We downgraded by two levels, one level due to imprecision because the total number of participants included in all studies was insufficient; and one level due to indirectness because the studies only included adults with moderate‐to‐severe eczema, with no evidence from those with mild eczema or paediatric patients.

Summary of findings for the main comparison. Montelukast versus placebo for eczema

Summary of findings 2. Montelukast versus conventional treatment for eczema

Montelukast compared with conventional treatment for eczema
Patient or population: eczema Setting: 1 study was conducted in a single centre; the setting of the other study is unknown Intervention: montelukast Comparison: conventional treatment (topical corticosteroid and oral antihistamine +/‐ oral antibiotics)
Outcomes	*Illustrative comparative risks (95% CI)**		Relative effect (95% CI)	No. of participants (studies)	Quality of the evidence (GRADE)	Comments
	Assumed risk	Corresponding risk
	Conventional treatment	Montelukast
Change (improvement) in disease severity (4 weeks) SCORAD score	The mean improvement in severity score was 4.73.	The mean improvement in severity score in the intervention group was 10.57 units greater (4.58 greater to 16.56 greater).	‐	31 (1 RCT)	⊕⊝⊝⊝ VERY LOW ¹	Another study with 32 participants reported no significant difference in SCORAD between the montelukast (mean improvement = 25.2 points) and conventional treatment (mean improvement = 23.9) (6 weeks follow‐up) groups (Capella 2001), but the authors did not provide the statistical values needed to calculate standard deviation, thus we could not pool these data.
Effect of long‐term control (> 3 months)	See comment	See comment	‐	‐	‐	Not measured, as longest follow‐up was only 6 weeks
Adverse effects (4 to 6 weeks)	See comment	See comment	‐	63 (2 RCTs)	⊕⊕⊝⊝ LOW ²	2 studies reported no adverse effects (Capella 2001; Rahman 2006).
Requirement for corticosteroid (steroid‐sparing effect)	See comment	See comment	‐	‐	‐	Not evaluated in either study
Reduction of pruritus	See comment	See comment	‐	‐	‐	Not evaluated in either study
Improvement in quality of life	See comment	See comment	‐	‐	‐	Not evaluated in either study
Need for emollient use	See comment	See comment	‐	‐	‐	Not evaluated in either study
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). CI: confidence interval; RCT: randomised controlled trial; SCORAD: SCORing of Atopic Dermatitis
GRADE Working Group grades of evidence High quality: Further research is very unlikely to change our confidence in the estimate of effect. Moderate quality: Further research is likely to have an important impact on our confidence in the estimate of effect and may change the estimate. Low quality: Further research is very likely to have an important impact on our confidence in the estimate of effect and is likely to change the estimate. Very low quality: We are very uncertain about the estimate.
¹We downgraded by three levels: one level due to imprecision because the total number of participants included in the study was insufficient; a second level due to indirectness because the study only included adults with moderate‐to‐severe eczema, with no evidence from those with mild eczema or paediatric patients; and a third level due to risk of bias because the outcome assessors were not blinded. ²We downgraded by two levels: one level due to imprecision because the total number of participants included in the studies was insufficient; and one level due to indirectness because the studies only included adults with moderate‐to‐severe eczema, with no evidence from those with mild eczema or paediatric patients.

Summary of findings 2. Montelukast versus conventional treatment for eczema

Table 1. Contact history for data collection

Study	Author contacted	Question posed	Reply	Date contact letter was sent	Date reply was received
Craig 2002	Craig TJ	We asked whether the conference abstract had subsequently been published as a full article. Additionally, we requested missing data to complete our extraction form.	The author did not have any data and proposed that we seek the data on the clinical trials website. We could not find any additional data.	9 July 2015	26 October 2015
Melamed 2010	Melamed IR and Heffron MG	We asked whether the conference abstract had subsequently been published as a full article. Additionally, we requested missing data to complete our extraction form.	No reply	9 July 2015	‐
Capella 2001	Capella GL	We requested additional analytical data for each group and full data on the eczema severity scores to provide missing outcome measures for the meta‐analysis.	The author could not add anything to the data in the article.	27 October 2015	29 October 2015
Nettis 2002	Nettis E	We requested additional analytical data for each group and full data on the eczema severity scores to provide missing outcome measures for the meta‐analysis.	The author no longer had the original data from the trial. No one in the Danish branch of MSD could provide further information about the trial.	27 October 2015	28 October 2015; 24 November 2015
Friedmann 2007	Friedmann P and Berth‐Jones J	We requested additional analytical data for each group and full data on the eczema severity scores to provide missing outcome measures for the meta‐analysis.	No reply	27 October 2015	‐
Rahman 2006	Rahman ML	We requested additional analytical data for each group and full data on the eczema severity scores to provide missing outcome measures for the meta‐analysis.	Invalid email address	27 October 2015	‐
Veien 2005	Veien NK	We requested additional analytical data for each group and full data on the eczema severity scores to provide missing outcome measures for the meta‐analysis.	No reply	27 October 2015	‐

Table 1. Contact history for data collection

Table 2. Summary of study design and outcomes provided for included studies

Study	Comparison	Observation	Scale	Data
Capella 2001	Conventional treatment	6 weeks	SCORAD	n, median, mean, range
Nettis 2002	Placebo	6 weeks	SCORAD	n, F value, P value
Friedmann 2007	Placebo	8 weeks	SASSAD	n, Δmean, ΔSD, 95% CI, P value
Rahman 2006	Conventional treatment	4 weeks	SCORAD	n, mean, SD, P value
Veien 2005	Placebo	4 weeks	modified EASI	n, mean, P value
CI: confidence interval; EASI: Eczema Area and Severity Index; SASSAD: Six‐Area, Six‐Sign Atopic Dermatitis; SCORAD: SCORing of Atopic Dermatitis; SD: standard deviation

Table 2. Summary of study design and outcomes provided for included studies

Table 3. Topical corticosteroid usage in Friedmann 2007

	‐2 weeks	0 week	4 weeks	8 weeks
Montelukast
Twice daily	8	6	9	7
Once daily	11	10	7	5
Alternative day	5	7	6	9
Occasional	4	6	6	3
None	2	1	1	2
Placebo
Twice daily	8	8	5	4
Once daily	9	10	11	9
Alternative day	6	8	7	5
Occasional	4	4	6	7
None	3	0	0	1
The number of participants using topical corticosteroid according to frequency of use at each assessment point of the study. The data were extracted from Figure 2 of the publication, using WebPlotDigitizer software (WebPlotDigitizer).

Table 3. Topical corticosteroid usage in Friedmann 2007

Comparison 1. Montelukast versus placebo

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 Improvement in disease severity (narrative table) Show forest plot			Other data	No numeric data

2 Improvement in disease severity Show forest plot	3	131	Std. Mean Difference (Random, 95% CI)	0.29 [‐0.23, 0.81]

3 Adverse effects (narrative table) Show forest plot			Other data	No numeric data

Comparison 1. Montelukast versus placebo

Comparison 2. Montelukast versus conventional treatment

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 Improvement in disease severity (narrative table) Show forest plot			Other data	No numeric data

2 Improvement in disease severity Show forest plot	1	31	Mean Difference (IV, Random, 95% CI)	10.57 [4.58, 16.56]

3 Adverse effects (narrative table) Show forest plot			Other data	No numeric data

Comparison 2. Montelukast versus conventional treatment