Intervenciones para la pitiriasis rosada
Resumen
Antecedentes
La pitiriasis rosada es una erupción escamosa y pruriginosa que afecta principalmente a adultos jóvenes y se prolonga de dos a 12 semanas. No están claros los efectos de muchos de los tratamientos disponibles. Ésta es una actualización de una revisión Cochrane publicada por primera vez en 2007.
Objetivos
Evaluar los efectos de las intervenciones para el tratamiento de la pitiriasis rosada en cualquier paciente diagnosticado por un médico.
Métodos de búsqueda
Las búsquedas en las siguientes bases de datos se actualizaron hasta octubre de 2018: Registro Especializado Cochrane de Piel (Cochrane Skin Specialised Register), CENTRAL, MEDLINE, Embase y LILACS. Se realizaron búsquedas en cinco registros de ensayos. También se verificaron las listas de referencias de los estudios incluidos y excluidos, se estableció contacto con los autores de los ensayos, se examinaron los resúmenes de las principales actas de congresos de dermatología y se realizaron búsquedas en la base de datos CAB Abstracts. Se buscó información en PubMed sobre los efectos adversos hasta noviembre de 2018.
Criterios de selección
Ensayos controlados aleatorizados de intervenciones para la pitiriasis rosada. El tratamiento se podía administrar como tratamiento único o en combinación. Los comparadores elegibles fueron ningún tratamiento, placebo, vehículo solamente, otro compuesto activo o tratamiento con radiación de placebo.
Obtención y análisis de los datos
Se utilizaron los procedimientos metodológicos estándar previstos por Cochrane. Los resultados clave fueron la mejoría buena o excelente de la erupción cutánea en dos semanas, calificada por separado por el participante y el médico; los eventos adversos graves; la resolución del prurito en dos semanas (calificada por el participante); la reducción de la puntuación del prurito en dos semanas (calificada por el participante); y los eventos adversos menores informados por el participante que no requirieron el retiro del tratamiento.
Resultados principales
Se incluyeron 14 ensayos (761 participantes). En general, el riesgo de sesgo de selección fue incierto o bajo, aunque el riesgo de sesgo de realización y de informe fue alto para el 21% de los estudios.
La edad de los participantes varió de dos a 60 años y la proporción de sexos fue similar. La gravedad de la enfermedad se midió con varios índices de gravedad que los estudios incluidos no categorizaron. Se realizaron seis estudios en la India, tres en Irán, dos en Filipinas, uno en Pakistán, uno en los Estados Unidos y uno China. Los estudios incluidos se realizaron en departamentos de dermatología y en un consultorio pediátrico. La duración de los estudios varió entre cinco y 26 meses. Tres estudios fueron financiados por los fabricantes del fármaco; la mayoría de los estudios no informaron la fuente de financiación. Los estudios incluidos evaluaron antibióticos macrólidos, un agente antiviral, fototerapia, esteroides y antihistamínicos, así como medicina china.
Ninguno de los estudios midió la mejoría buena o excelente de la erupción calificada por el participante. Todos los resultados informados se evaluaron dentro de las dos semanas de tratamiento excepto los efectos adversos, que se midieron durante todo el tratamiento.
Probablemente no hay diferencias entre la claritromicina oral y el placebo en cuanto a la resolución del prurito (cociente de riesgos [CR] 0,84; intervalo de confianza [IC] del 95%: 0,47 a 1,52; un estudio, 28 participantes), ni en la mejoría de la erupción cutánea (evaluada por un médico) (CR 1,13; IC del 95%: 0,89 a 1,44; un estudio, 60 participantes). Para esta comparación no hubo eventos adversos graves (un estudio, 60 participantes), no se midieron los eventos adversos menores ni la reducción de la puntuación del prurito, y toda la evidencia fue de calidad moderada.
En comparación con placebo, la eritromicina puede dar lugar a una mejoría mayor en la erupción (calificada por el médico) (CR 4,02; IC del 95%: 0,28 a 56,61; dos estudios, 86 participantes; evidencia de calidad baja); sin embargo, el IC del 95% indica que el resultado también puede ser compatible con un efecto beneficioso de placebo, y puede haber poca o ninguna diferencia entre los tratamientos. No se midió la resolución del prurito, aunque un estudio midió la reducción de la puntuación del prurito, que probablemente es mayor con la eritromicina (DM 3,95; IC del 95%: 3,37 a 4,53; 34 participantes, evidencia de calidad moderada). En el mismo único ensayo, que fue pequeño, ninguno de los participantes presentó un evento adverso grave y no hubo diferencias claras entre los grupos en cuanto a los eventos adversos menores, incluido el malestar gastrointestinal (CR 2,00; IC: 0,20 a 20,04; evidencia de calidad moderada).
Dos ensayos compararon azitromicina oral con placebo o vitaminas. Probablemente no hay diferencias entre los grupos en cuanto a la resolución del prurito (CR 0,83; IC del 95%: 0,28 a 2,48), ni en la reducción de la puntuación del prurito (DM 0,04; IC del 95%: ‐0,35 a 0,43) (ambos resultados basados en un estudio; 70 participantes, evidencia de calidad moderada). La evidencia de calidad baja de dos estudios indica que puede no haber diferencias entre los grupos en cuanto a la mejoría de la erupción (calificada por el médico) (CR 1,02; IC del 95%: 0,52 a 2,00; 119 participantes). En estos mismos dos estudios no se informaron eventos adversos graves y no hubo diferencias claras entre los grupos en cuanto a los eventos adversos menores, específicamente el dolor abdominal leve (CR 5,82; IC del 95%: 0,72 a 47,10; evidencia de calidad moderada).
El aciclovir se comparó con placebo, vitaminas o ningún tratamiento en tres ensayos (evidencia de calidad moderada). Sobre la base de un ensayo (21 participantes), la resolución del prurito probablemente es mayor con placebo que con aciclovir (CR 0,34; IC del 95%: 0,12 a 0,94); no se midió la reducción de la puntuación del prurito. Sin embargo, probablemente hay una diferencia significativa entre los grupos en cuanto a la mejoría de la erupción (calificada por el médico) a favor del aciclovir versus todos los comparadores (CR 2,45; IC del 95%: 1,33 a 4,53; tres estudios, 141 participantes). Sobre la base de los mismos tres estudios, no hubo eventos adversos graves en ninguno de los dos grupos, y probablemente no hubo diferencias entre ellos en cuanto a los eventos adversos menores (solo un participante del grupo placebo presentó dolor abdominal y diarrea).
Un ensayo comparó el aciclovir agregado a la atención estándar (loción de calamina y cetirizina oral) versus la atención estándar sola (24 participantes). El agregado de aciclovir puede dar lugar a una mayor resolución del prurito (CR 4,50; IC del 95%: 1,22 a 16,62) y a una reducción de la puntuación del prurito (DM 1,26; IC del 95%: 0,74 a 1,78), en comparación con la atención estándar sola. No se midió la mejoría de la erupción (calificada por el médico). El ensayo no informó eventos adversos graves en ninguno de los dos grupos y puede no haber diferencias entre ellos en cuanto a los eventos adversos menores como la cefalea (CR 7,00; IC del 95%: 0,40 a 122,44) (todos los resultados se basan en evidencia de calidad baja).
Conclusiones de los autores
En comparación con placebo o ningún tratamiento, el aciclovir oral probablemente da lugar a una mejoría mayor, considerada buena o excelente, de la erupción cutánea calificada por el médico. Sin embargo, la evidencia del efecto del aciclovir sobre el prurito no fue concluyente. Se encontró evidencia de calidad baja a moderada de que la eritromicina probablemente reduce el prurito más que placebo.
Los tamaños pequeños de los estudios, la heterogeneidad y el sesgo en el cegamiento y en el informe selectivo limitaron las conclusiones. Se necesita investigación adicional que examine diferentes regímenes de dosis de aciclovir y el efecto de los antivirales sobre la pitiriasis rosada.
PICO
Resumen en términos sencillos
Tratamientos para la pitiriasis rosada
Antecedentes
La pitiriasis rosada es una erupción escamosa frecuente en adultos jóvenes. La misma da lugar a manchas con enrojecimiento y escamas seguidas por una erupción generalizada. La pitiriasis rosada generalmente se resuelve en dos a 12 semanas; sin embargo, la erupción puede parecerse a una afección cutánea contagiosa grave, lo que causa preocupación. Además, la pitiriasis rosada puede causar prurito de moderado a severo, lo que hace necesario un tratamiento efectivo.
Pregunta de la revisión
Se deseaba evaluar la efectividad y la seguridad de los tratamientos para la pitiriasis rosada. Los tratamientos elegibles fueron tópicos, sistémicos (fármacos orales o inyectables que funcionan a través de todo el cuerpo) o con luz, administrados solos o en combinación con otro tratamiento, y comparados con ningún tratamiento, placebo (un tratamiento idéntico pero inactivo), un vehículo (ingredientes inactivos que ayudan a administrar un tratamiento activo) solamente, u otro tratamiento activo. Como la recuperación espontánea suele ocurrir entre las dos y las 12 semanas en los casos de pitiriasis rosada no tratada, se consideraron los resultados informados a las dos semanas.
Características de los estudios
La evidencia está actualizada hasta octubre de 2018.
Se incluyeron 14 estudios con 761 participantes entre dos y 60 años de edad (números similares de hombres y mujeres). La mayoría de los estudios se realizaron en Asia en departamentos de dermatología y se prolongaron entre cinco y 26 meses. Tres estudios fueron financiados por los fabricantes del fármaco; la mayoría de los estudios no informaron las fuentes de financiación. La gravedad de la enfermedad se evaluó con diversas medidas, pero los participantes no se clasificaron en enfermedad leve, moderada o grave. Los tratamientos importantes evaluados por los estudios incluyeron varios antibióticos y aciclovir (un fármaco destinado a tratar las infecciones por herpes), que se compararon con placebo, ningún tratamiento o atención estándar. Los tratamientos adicionales incluyeron fototerapia, corticosteroides y antihistamínicos, así como medicina china (potenline). La mayoría de los estudios evaluaron el tratamiento utilizado durante una semana.
Todos los resultados informados se evaluaron dentro de las dos semanas de tratamiento, excepto los efectos secundarios, que se midieron durante todo el tratamiento.
Ninguno de los estudios incluidos informó sobre la calificación de la mejoría de la erupción por parte del participante. El prurito siempre fue evaluado por los participantes. La mejoría de la erupción se calificó como buena o excelente.
Probablemente no hay diferencias entre la claritromicina y el placebo para la mejoría de la erupción cutánea calificada por el médico o la resolución del prurito, y no se informaron eventos adversos graves (evidencia de calidad moderada). No se midió la reducción en la puntuación del prurito ni los efectos secundarios menores.
Del mismo modo, puede no haber diferencias en la mejoría de la erupción calificada por el médico entre la azitromicina y el placebo o las vitaminas, aunque la eritromicina puede dar lugar a una mejoría mayor de la erupción en comparación con placebo; sin embargo, los resultados muestran que puede haber efectos beneficiosos con placebo o poca o ninguna diferencia entre los tratamientos (evidencia de calidad baja para ambos resultados). Probablemente no hay diferencias entre la azitromicina y los comparadores en cuanto a la resolución del prurito o la reducción de la puntuación del prurito; no hubo diferencias claras en cuanto a los efectos secundarios menores como el dolor abdominal leve (evidencia de calidad moderada). Cuando se comparó eritromicina con placebo no se midió la resolución del prurito, aunque probablemente hay una mayor reducción en la puntuación del prurito con eritromicina. No hubo diferencias claras en la probabilidad de efectos secundarios menores, como malestar gastrointestinal, entre los grupos (evidencia de calidad moderada para ambos resultados).
Un único estudio indicó que el aciclovir probablemente es menos efectivo que placebo para lograr la resolución del prurito (aunque no se midió la reducción de la puntuación del prurito). Sin embargo, los resultados de tres estudios indican que el aciclovir probablemente es significativamente más beneficioso que placebo, ningún tratamiento o los comprimidos de vitaminas en cuanto a la mejoría de la erupción cutánea calificada por el médico. Probablemente no hay diferencias entre el aciclovir y el placebo en cuanto a la incidencia de efectos secundarios menores: un participante del grupo de placebo presentó dolor abdominal leve y diarrea (todos los resultados se basan en evidencia de calidad moderada).
Un único ensayo indicó que el aciclovir utilizado en combinación con la atención estándar (calamina [loción contra el prurito] y el antihistamínico cetirizina) puede reducir la puntuación del prurito y aumentar la resolución del prurito (evidencia de calidad baja). No se midió la mejoría de la erupción cutánea calificada por el médico. Es posible que no haya diferencias entre los grupos en cuanto a los efectos secundarios menores como el dolor de cabeza, el aumento del sueño, la enfermedad o el impacto en el gusto.
Ninguno de los estudios informó sobre eventos adversos graves (evidencia de calidad baja a moderada).
Calidad de la evidencia
La calidad de la evidencia para las comparaciones principales fue baja a moderada. Muchos de los resultados se basaron en un número pequeño de ensayos, con un número escaso de participantes. También hubo alguna variación entre los resultados de los ensayos, así como preocupación sobre el diseño de los estudios.
Conclusiones de los autores
Summary of findings
| Clarithromycin compared to placebo for pityriasis rosea | ||||||
| Patient or population: pityriasis rosea | ||||||
| Outcomes | Anticipated absolute effects* (95% CI) | Relative effect | № of participants | Quality of the evidence | Comments | |
| Risk with placebo | Risk with clarithromycin | |||||
| The proportion of participants with good or excellent rash improvement within 2 weeks, as rated by the participant | ‐ | ‐ | ‐ | ‐ | ‐ | Not measured |
| Serious adverse events, i.e. serious enough to require withdrawal of the treatment | ‐ | ‐ | Not estimable | 60 | ⊕⊕⊕⊝ | No participants in either group experienced serious adverse events. |
| The proportion of participants with resolution of itch within 2 weeks, as rated by the participant | Study population | RR 0.84 | 28 | ⊕⊕⊕⊝ | ‐ | |
| 667 per 1000 | 560 per 1000 | |||||
| Reduction in itch score within 2 weeks, as rated by the participant | ‐ | ‐ | ‐ | ‐ | ‐ | Not measured |
| The proportion of participants with good or excellent rash improvement within 2 weeks, as rated by a medical practitioner | Study population | RR 1.13 | 60 | ⊕⊕⊕⊝ | ‐ | |
| 767 per 1000 | 866 per 1000 | |||||
| Minor participant‐reported adverse events not requiring withdrawal of the treatment | ‐ | ‐ | ‐ | ‐ | ‐ | Not measured |
| *The risk in the intervention group (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). The assumed risk is calculated from the single‐study analysis or meta‐analysis, using the number of events or mean difference in the control group(s). | ||||||
| GRADE Working Group grades of evidence | ||||||
| aDowngraded by one level to moderate‐quality evidence for imprecision due to small sample size. | ||||||
| Erythromycin compared to placebo for pityriasis rosea | ||||||
| Patient or population: pityriasis rosea | ||||||
| Outcomes | Anticipated absolute effects* (95% CI) | Relative effect | № of participants | Quality of the evidence | Comments | |
| Risk with placebo | Risk with erythromycin | |||||
| The proportion of participants with good or excellent rash improvement within 2 weeks, as rated by the participant | ‐ | ‐ | ‐ | ‐ | ‐ | Not measured |
| Serious adverse events, i.e. serious enough to require withdrawal of the treatment | ‐ | ‐ | Not estimable | 34 | ⊕⊕⊕⊝ | No participants in either group experienced serious adverse events. |
| The proportion of participants with resolution of itch within 2 weeks, as rated by the participant | ‐ | ‐ | ‐ | ‐ | ‐ | Not reported |
| Reduction in itch score within 2 weeks as rated by the participant | The mean reduction in itch score within 2 weeks as rated by the participant was 1.76. | MD 3.95 higher | ‐ | 34 | ⊕⊕⊕⊝ | ‐ |
| The proportion of participants with good or excellent rash improvement within 2 weeks as rated by a medical practitioner | Study population | RR 4.02 | 86 | ⊕⊕⊝⊝ | ‐ | |
| 33 per 100 | 100 per 100 | |||||
| Minor participant‐reported adverse events not requiring withdrawal of the treatment: Gastrointestinal upset. | Study population | RR 2.00 | 34 | ⊕⊕⊕⊝ | ‐ | |
| 6 per 100 | 12 per 100 | |||||
| *The risk in the intervention group (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). The assumed risk is calculated from the single‐study analysis or meta‐analysis, using the number of events or mean difference in the control group(s). | ||||||
| GRADE Working Group grades of evidence | ||||||
| aDowngraded by one level to moderate‐quality evidence for imprecision due to small sample size. | ||||||
| Azithromycin compared to placebo or vitamins for pityriasis rosea | ||||||
| Patient or population: pityriasis rosea | ||||||
| Outcomes | Anticipated absolute effects* (95% CI) | Relative effect | № of participants | Quality of the evidence | Comments | |
| Risk with placebo or vitamins | Risk with azithromycin | |||||
| The proportion of participants with good or excellent rash improvement within 2 weeks, as rated by the participant | ‐ | ‐ | ‐ | ‐ | ‐ | Not measured |
| Serious adverse events, i.e. serious enough to require withdrawal of the treatment | ‐ | ‐ | Not estimable | 119 | ⊕⊕⊕⊝ | No participants in either group experienced serious adverse events. |
| The proportion of participants with resolution of itch within 2 weeks, as rated by the participant | Study population | RR 0.83 | 70 | ⊕⊕⊕⊝ | ‐ | |
| 171 per 1000 | 142 per 1000 | |||||
| Reduction in itch score within 2 weeks, as rated by the participant | The mean reduction in itch score within 2 weeks was 0.47. | MD 0.04 higher | ‐ | 70 | ⊕⊕⊕⊝ | ‐ |
| The proportion of participants with good or excellent rash improvement within 2 weeks as rated by a medical practitioner. | Study population | RR 1.02 (0.52 to 2.00) | 119 | ⊕⊕⊝⊝ | ‐ | |
| 441 per 1000 | 449 per 1000 | |||||
| Minor participant‐reported adverse events not requiring withdrawal of the treatment: Mild abdominal pain. | See comment | See comment | RR 5.82 | 119 | ⊕⊕⊕⊝ | No participants in the placebo group reported mild abdominal pain versus 5/60 participants in the azithromycin group. |
| *The risk in the intervention group (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI). | ||||||
| GRADE Working Group grades of evidence | ||||||
| aDowngraded by one level to moderate‐quality evidence for imprecision due to small sample size. | ||||||
| Acyclovir compared to placebo, vitamins, or no treatment for pityriasis rosea | ||||||
| Patient or population: pityriasis rosea | ||||||
| Outcomes | Anticipated absolute effects* (95% CI) | Relative effect | № of participants | Quality of the evidence | Comments | |
| Risk with placebo, vitamins, or no treatment | Risk with acyclovir | |||||
| The proportion of participants with good or excellent rash improvement within 2 weeks, as rated by the participant | ‐ | ‐ | ‐ | ‐ | ‐ | Not measured |
| Serious adverse events, i.e. serious enough to require withdrawal of the treatment | ‐ | ‐ | Not estimable | 141 | ⊕⊕⊕⊝ | No serious adverse events were reported in either group. |
| Proportion of participants with resolution of itch within 2 weeks, as rated by the participant | Study population | RR 0.34 | 21 | ⊕⊕⊕⊝ | ‐ | |
| 80 per 100 | 27 per 100 | |||||
| Reduction in itch score within 2 weeks, as rated by the participant | ‐ | ‐ | ‐ | ‐ | ‐ | Not reported |
| The proportion of participants with good or excellent rash improvement within 2 weeks, as rated by a medical practitioner | Study population | RR 2.45 | 141 | ⊕⊕⊕⊝ | ‐ | |
| 28 per 100 | 67 per 100 | |||||
| Minor participant‐reported adverse events not requiring withdrawal of the treatment | Study population | RR 0.31 | 141 | ⊕⊕⊕⊝ | 1 participant in the placebo group experienced abdominal pain and diarrhoea. No adverse events were reported with acyclovir. | |
| 7 per 100 | 2 per 100 | |||||
| *The risk in the intervention group (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). The assumed risk is calculated from the single‐study analysis or meta‐analysis, using the number of events or mean difference in the control group(s). | ||||||
| GRADE Working Group grades of evidence | ||||||
| aSingh 2016 and Ganguly 2014 utilised a dose of 800 mg 5 times per day for 7 days. Rassai 2011 utilised a dose of 400 mg 5 times per day for 7 days. | ||||||
| Acyclovir + calamine + cetirizine compared to cetirizine + calamine for pityriasis rosea | ||||||
| Patient or population: pityriasis rosea | ||||||
| Outcomes | Anticipated absolute effects* (95% CI) | Relative effect | № of participants | Quality of the evidence | Comments | |
| Risk with calamine + cetirizine | Risk with acyclovir + calamine + cetirizine | |||||
| The proportion of participants with good or excellent rash improvement within 2 weeks, as rated by the participant | ‐ | ‐ | ‐ | ‐ | ‐ | Not measured |
| Serious adverse events, i.e. serious enough to require withdrawal of the treatment | ‐ | ‐ | Not estimable | 24 | ⊕⊕⊝⊝ | No serious adverse events requiring withdrawal were reported in either group. |
| The proportion of participants with resolution of itch within 2 weeks, as rated by the participant | Study population | RR 4.50 | 24 | ⊕⊕⊝⊝ | ‐ | |
| 167 per 1000 | 750 per 1000 | |||||
| Reduction in itch score within 2 weeks, as rated by the participant | The mean reduction in itch score within 2 weeks was 0.58. | MD 1.26 higher | ‐ | 24 | ⊕⊕⊝⊝ | ‐ |
| The proportion of participants with good or excellent rash improvement within 2 weeks, as rated by a medical practitioner | ‐ | ‐ | ‐ | ‐ | ‐ | Not measuredb |
| Minor participant‐reported adverse events not requiring withdrawal of the treatment: Headache. | See comment | See comment | RR 7.00 | 24 | ⊕⊕⊝⊝ | No events in the control group versus 3/12 participants in the acyclovir group |
| *The risk in the intervention group (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI). | ||||||
| GRADE Working Group grades of evidence | ||||||
| aDowngraded by two levels to low‐quality evidence: one level for study limitations due to high risk of performance bias (participants were not blinded) and one level for imprecision. The sample size of this trial was only 24 (12 per group). | ||||||
| Acyclovir compared to erythromycin for pityriasis rosea | ||||||
| Patient or population: pityriasis rosea | ||||||
| Outcomes | Anticipated absolute effects* (95% CI) | Relative effect | № of participants | Quality of the evidence | Comments | |
| Risk with erythromycin | Risk with acyclovir | |||||
| The proportion of participants with good or excellent rash improvement within 2 weeks, as rated by the participant | ‐ | ‐ | ‐ | ‐ | ‐ | Not measured |
| Serious adverse events, i.e. serious enough to require withdrawal of the treatment | ‐ | ‐ | Not estimable | 30 | ⊕⊕⊕⊝ | All participants completed the trial and no adverse events are reported in either group. |
| The proportion of participants with resolution of itch within 2 weeks, as rated by the participant | See comment | See comment | RR 13.22 | 14 | ⊕⊕⊝⊝ | All 8 participants in the acyclovir group had resolution of itch versus zero in the erythromycin group. Hence, the assumed and corresponding risks could not be calculated. |
| Reduction in itch score within 2 weeks, as rated by the participant | ‐ | ‐ | ‐ | ‐ | ‐ | Not measured |
| The proportion of participants with good or excellent rash improvement within 2 weeks, as rated by a medical practitioner | ‐ | ‐ | Not estimable | 30 | ⊕⊕⊝⊝ | Zero events in both groups |
| Minor participant‐reported adverse events not requiring withdrawal of the treatment | ‐ | ‐ | Not estimable | 30 | ⊕⊕⊝⊝ | No participants in either group experienced adverse events. |
| *The risk in the intervention group (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI). | ||||||
| GRADE Working Group grades of evidence | ||||||
| aDowngraded by one level to moderate‐quality evidence for imprecision due to very small sample size and a small number of events in terms of response measures. | ||||||
Antecedentes
Descripción de la afección
Descripción y epidemiología
La pitiriasis rosada (PR) es una enfermedad cutánea benigna y autolimitada manchas diferenciadas de erupción cutánea en un patrón distintivo sobre el tronco y las extremidades. La pitiriasis (que significa similar al salvado) indica que hay escamas finas en las lesiones de la piel (Percival 1932). "Rosada" significa «rosa» y describe el color típico de la erupción (Percival 1932), aunque el color varía en gran medida en pacientes de diferentes razas (Ahmed 1986).
Una característica de la PR es el curso aparentemente "programado" de los eventos. Una lesión única más grande, que mide de 1 a 3 centímetros, suele preceder a la erupción generalizada en hasta dos semanas. Esta lesión inicial, también conocida como "mancha heráldica", aparece con mayor frecuencia en el tronco (Figura 1). Tiene forma ovalada, con un borde rosado, escamoso y ligeramente elevado y un centro más pálido. La mancha heráldica puede no ser identificable en muchos pacientes, por lo que su ausencia no necesariamente excluye un diagnóstico de PR.
La erupción posterior abrupta y generalizada se conoce como erupción secundaria. Las lesiones son similares a la mancha heráldica, pero más pequeñas. Su distribución suele seguir las líneas de separación de la piel, lo cual se conoce como "patrón de árbol de Navidad" (Figura 2). La erupción generalmente ocurre en el tronco y se extiende hasta la parte superior de los brazos y de los muslos, pocas veces hasta los antebrazos y las piernas. La erupción solo se extiende ocasionalmente a las palmas de las manos y las plantas de los pies, aunque la mancha heráldica a veces puede estar presente en estos sitios (Deng 2007; Robati 2009; Polat 2012; Bas 2015). El compromiso de la cara o el cuero cabelludo también es poco frecuente, aunque se ha informado con más frecuencia en pacientes de piel negra (Klauder 1924; Jacyk 1980; Amer 2007; Zawar 2010a).
Aparecerán más lesiones en las primeras dos a seis semanas. Todas las lesiones desaparecen espontáneamente sin tratamiento. La duración total de la enfermedad suele ser entre dos y 12 semanas, pero puede prolongarse hasta siete meses (Chuah 2014; Drago 2015a). Durante meses después de la recuperación aún puede observarse cierto oscurecimiento o aclaramiento de la piel afectada (Percival 1932; Amer 2007).
Se ha informado una variedad de síntomas constitucionales que preceden u ocurren de forma simultánea con el inicio de la erupción cutánea. Los mismos incluyen malestar prodrómico, pérdida del apetito, dolor de cabeza, síntomas de infección de las vías respiratorias superiores, dolor abdominal, dolor articular, inflamación de los ganglios linfáticos y fiebre leve (Percival 1932; Cheong 1989; Tay 1999; Sharma 2000; Sharma 2008; Ozyürek 2014; Drago 2015b). La erupción no es dolorosa, pero alrededor del 30% al 50% de los pacientes con PR presentará prurito de intensidad moderada a severa.
Aunque es posible observar múltiples recurrencias, la mayoría de los pacientes que presentan un episodio de PR no tendrán otro ataque (Percival 1932; Chuang 1982; Zawar 2009; Chuah 2014; Sankararaman 2014; Drago 2014a).
La pitiriasis rosada es una afección relativamente frecuente, con una incidencia aproximada del 0,5% al 2% (Zawar 2010b). Un estudio informó que por cada 100 000 personas en la comunidad, cerca de 170 tendrán PR en un año (Chuang 1982). La pitiriasis rosada se diagnostica en alrededor del 0,3% y el 1,2% de todos los pacientes atendidos por dermatólogos de todo el mundo, aunque parece ser más frecuente en varios países africanos, con tasas de incidencia anual que oscilan entre el 2,2% y el 4,8% de los pacientes dermatológicos ((Jacyk 1980; Ahmed 1986; Olumide 1987; Harman 1998; Nanda 1999; Tay 1999; Kyriakis 2006; Sharma 2008).
La incidencia de PR alcanza su punto máximo entre las edades de 15 y 30 años (Chuang 1982; Harman 1998; Sharma 2008; Zawar 2010b). La mayoría de los estudios epidemiológicos informan que las niñas y las mujeres tienen más probabilidades de presentar PR, con una proporción general de hombres a mujeres de aproximadamente 1:1,1 ‐ 1,4 (Jacyk 1980; Chuang 1982; Olumide 1987; Harman 1998; Nanda 1999; Kyriakis 2006; Ozyürek 2014). Por el contrario, la PR parece ser más frecuente en los hombres de Singapur y la India (Cheong 1989; Tay 1999; Sharma 2008).
Los datos sobre la variación estacional en la ocurrencia de la PR son contradictorios y varían entre diferentes regiones geográficas, aunque la incidencia estacional parece ser más alta durante los meses más fríos (Percival 1932; Chuang 1982; Ahmed 1986; Harman 1998; Sharma 2008). Además, se conoce que los casos de PR tienden a ocurrir en grupos (Messenger 1982; Chuh 2003a; Chuh 2005b).
Terminología
La pitiriasis rosada también se conoce con los siguientes nombres: pitiriasis rosada de Gibert, pitiriasis rosada de Vidal, pitiriasis circinata et marginata y pitiriasis maculata et circinata (Percival 1932).
Causas
Se desconoce la causa exacta de la PR. Varios hechos indican que la PR es causada por un agente infeccioso. El primero es que el curso de la enfermedad, como se mencionó anteriormente, es "programado", similar al curso de algunas erupciones virales como el sarampión o la varicela. Los síntomas constitucionales y prodrómicos que acompañan o preceden la aparición de la erupción también indican un origen infeccioso, así como los datos epidemiológicos sobre las variaciones estacionales y el hecho de que los casos ocurran en grupos. Además, la mayoría de los pacientes que han sufrido una erupción no tendrán otro ataque durante su vida.
Se han considerado numerosos agentes infecciosos como posibles causas de la PR, pero el herpesvirus humano 6 (HHV‐6) y el herpesvirus humano 7 (HHV‐7) han sido los más estudiados. Sin embargo, diferentes investigadores han informado resultados contradictorios. Hay informes positivos que apoyan el papel de uno o ambos de estos virus (Drago 1997a; Drago 1997b; Watanabe 1999; Drago 2002; Watanabe 2002, Vag 2004; Broccolo 2005; Canpolat Kirac 2009; Drago 2015b), así como muchos informes negativos (Kempf 1999; Yasukawa 1999; Yoshida 1999; Kosuge 2000; Offidani 2000; Chuh 2001; Wong 2001; Karabulut 2002; Yildirim 2004). Aunque aún es controversial, parece probable una relación causal con el HHV‐6 y el HHV‐7; y se ha indicado que la PR se asocia con la reactivación de estas infecciones (Watanabe 2002; Broccolo 2005; Drago 2009a). La evidencia ha demostrado que la PR no se asocia con el virus del herpes simple 1 y 2; el virus de Epstein‐Barr ni el citomegalovirus (Bozdag 2005; Canpolat Kirac 2009), mientras que los únicos dos estudios sobre la posible asociación con la infección por HHV‐8 han producido resultados contradictorios (Chuh 2006; Prantsidis 2009).
Algunos fármacos pueden producir una erupción cutánea como efecto secundario que puede parecerse a la PR; sin embargo, estas erupciones son de naturaleza diferente (Drago 2014b). También se ha descrito que la pitiriasis rosada y las erupciones similares a la PR ocurren después de las vacunaciones contra la viruela, la tuberculosis, el virus de la influenza H1N1; el virus del papiloma humano y otros agentes infecciosos (Chen 2011; Drago 2014c; Drago 2015c).
Impacto
Aproximadamente del 80% al 90% de los pacientes con PR presentan prurito. En un tercio a la mitad de los casos, el prurito es de intensidad moderada a severa (Percival 1932; Cheong 1989; Sharma 2008; Ozyürek 2014).
La calidad de vida de los pacientes con PR (o de los padres de niños con la enfermedad) puede verse afectada de forma significativa. Pueden experimentar ansiedad relacionada con la incertidumbre sobre la causa, la naturaleza y la posible infectividad de la erupción, así como preocupación por la apariencia física de la piel (Chuh 2003c; Chuh 2005a; Kaymak 2008). En los individuos de piel oscura, los cambios pigmentarios prominentes, especialmente cuando afectan la cara, pueden representar un problema cosmético grave.
Es probable que muchos pacientes con PR consulten a un médico de atención primaria, aunque se ha informado que los médicos de atención primaria subdiagnostican significativamente la enfermedad (Pariser 1987). La posibilidad de consultar a un médico de atención primaria y luego no recibir un diagnóstico preciso de PR podría hacer que un individuo se sienta aún más ansioso acerca de la naturaleza de la erupción y su pronóstico.
El efecto más importante, pero que se reconoció solo recientemente, de la PR es la repercusión que puede tener sobre el resultado del embarazo. Se ha informado que la PR que ocurre en mujeres embarazadas puede ir seguida de parto prematuro, hipotonía neonatal o incluso muerte fetal, con una tasa de aborto del 13% en general y de hasta el 60% si la erupción se desarrollara dentro de las primeras 15 semanas de embarazo (Drago 2008; Drago 2014d).
Descripción de la intervención
Actualmente se utilizan tratamientos tópicos y sistémicos para la pitiriasis rosada. La atención estándar actual tiene como objetivo controlar los síntomas y consiste en emolientes tópicos y lociones antipruriginosas, corticosteroides tópicos y antihistamínicos orales.
Los tratamientos tópicos comprenden principalmente emolientes y corticosteroides tópicos. El objetivo del tratamiento tópico es reducir los signos de inflamación aguda, principalmente al reducir el eritema y la descamación, y disminuir así la visibilidad de las lesiones, pero también reducir el prurito que a menudo acompaña a la erupción. Los corticosteroides tópicos y sistémicos tienen un amplio efecto antiinflamatorio no específico, por lo que se utilizan ampliamente en el tratamiento de diversas enfermedades inflamatorias de la piel. Los corticosteroides tópicos vienen en forma de crema o ungüento y se clasifican según su potencia. Los ejemplos incluyen los siguientes: propionato de clobetasol, dipropionato de betametasona, furoato de mometasona, propionato de fluticasona, valerato de betametasona, acetónido de fluocinolona y acetato de hidrocortisona. Los emolientes son la atención básica en el tratamiento de diversas formas de eccema y otras enfermedades inflamatorias de la piel y tienen como objetivo mejorar la función de barrera de la piel y reducir la sequedad y las escamas y el prurito asociados (van Zuuren 2017). A menudo se utilizan como intervención de placebo o como comparador en la evaluación de otros tratamientos tópicos en ensayos clínicos dermatológicos.
Los tratamientos sistémicos que se han probado hasta ahora incluyen fármacos para el control sintomático del prurito como los antihistamínicos orales, los corticosteroides sistémicos, la glicirricina intravenosa, los antibióticos orales del grupo de los macrólidos, el agente antiviral aciclovir y la radiación ultravioleta artificial y de la luz solar (generalmente en forma de radiación ultravioleta B de banda estrecha) (Castanedo 2003; Chuh 2007; Drago 2009b).
Los antihistamínicos orales se utilizan como tratamiento sintomático del prurito en diversos estadios de la enfermedad, independientemente de la causa. Los ejemplos incluyen los siguientes: cloropiramina, loratadina, desloratadina, cetirizina, levocetirizina, bilastina y otros. El aciclovir es un fármaco antiviral utilizado específicamente para el tratamiento de las infecciones por virus del herpes. Algunos tratamientos similares incluyen famciclovir y valaciclovir. En el contexto de la hipótesis actual sobre la etiología viral de la PR, el uso del aciclovir es un tanto polémico debido a que tiene una actividad débil contra el HHV‐6 y ninguna actividad contra el HHV‐7 en condiciones de laboratorio (Yoshida 1998). Los antibióticos macrólidos se utilizan a menudo por sus efectos antibióticos de amplio espectro en casos de infecciones bacterianas, pero también por sus efectos antiinflamatorios e inmunomoduladores no específicos. Los más frecuentes incluyen eritromicina, azitromicina y claritromicina.
La irradiación ultravioleta (generalmente administrada como fototerapia ultravioleta B de banda estrecha) se utiliza en el tratamiento de diferentes enfermedades inflamatorias de la piel como la psoriasis, el eccema atópico o el vitiligo, pero también en diversos estadios de la enfermedad acompañados de prurito (Rivard 2005).
De qué manera podría funcionar la intervención
Los corticosteroides tópicos tienen amplios efectos antiinflamatorios a través de la regulación de la expresión génica de varias citoquinas, enzimas celulares y otros elementos en las vías de señalización intracelular e intercelular. Los emolientes restauran el contenido acuoso y de lípidos de la epidermis, lo que a su vez previene la perpetuación de la inflamación de la piel y reduce la sequedad de la piel, la descamación y el prurito asociados (Rerknimitr 2017).
Los antihistamínicos son un tratamiento sistémico estándar para formas de prurito con etiología variada, causadas por enfermedades dermatológicas o no dermatológicas. Los antihistamínicos actúan al inhibir los receptores de histamina H1. El aciclovir inhibe específicamente la síntesis de ADN en los virus del herpes y puede ser efectivo en la PR debido al posible papel causal del HHV‐6 y HHV‐7 en el desarrollo de esta afección clínica. Los antibióticos macrólidos pueden ser efectivos en la PR principalmente debido a sus efectos inmunomoduladores y antiinflamatorios (Scheinfeld 2003). Se ha planteado la hipótesis de que la fototerapia ejerce su efecto antipruriginoso a través de la liberación de mediadores antipruriginosos endógenos o por un efecto directo sobre la sensibilidad de los nervios sensoriales cutáneos (Legat 2018).
Por qué es importante realizar esta revisión
La versión anterior de esta revisión no encontró evidencia adecuada de la eficacia de la mayoría de los tratamientos para la PR (Chuh 2007). Solo se encontró un posible efecto beneficioso clínico para la eritromicina oral, aunque esta evidencia provino de un único ensayo pequeño. Desde Chuh 2007, que solo incluyó tres ensayos, se han publicado varios estudios que evalúan la eficacia de varios antibióticos macrólidos, así como la del aciclovir. La presente revisión resume la evidencia existente y proporciona una conclusión actualizada sobre los tratamientos actualmente disponibles para la PR.
La pitiriasis rosada es esencialmente una enfermedad autolimitada y la erupción desaparece en su mayor parte entre las dos y las 12 semanas, con o sin tratamiento. Por lo tanto, los efectos beneficiosos asociados con el uso de cualquier intervención activa deben superar cualquier efecto adverso posible. Los efectos adversos pueden ser a corto plazo (como malestar estomacal causado por los antibióticos) o a largo plazo (como el riesgo de cáncer de piel causado por la radiación ultravioleta o los efectos de los corticosteroides sistémicos sobre los huesos). El uso de antibióticos y antivirales en teoría puede inducir resistencia a bacterias y virus, y afectar no solamente al paciente, sino también a toda la comunidad.
Hay muchas preguntas sobre el tratamiento de la PR que aún no tienen respuesta. Se desconoce si muchos de los tratamientos disponibles pueden modificar el curso de la enfermedad, aliviar el prurito o mejorar la calidad de vida. Una revisión sistemática ayudaría a determinar los tratamientos más efectivos, cuándo y para quién se deben utilizar, la duración del tratamiento, los posibles riesgos y efectos secundarios, y el nivel de aceptabilidad del tratamiento. Esta revisión también permitiría evaluar el nivel y la calidad de la evidencia actualmente disponible, e identificar áreas de incertidumbre o brechas en el conocimiento que requieren investigación adicional.
Objetivos
Evaluar los efectos de las intervenciones para el tratamiento de la pitiriasis rosada en cualquier paciente diagnosticado por un médico.
Métodos
Criterios de inclusión de estudios para esta revisión
Tipos de estudios
Todos los ensayos controlados aleatorizados (ECA) que evalúan la efectividad de las intervenciones para la pitiriasis rosada (PR).
Tipos de participantes
Cualquier paciente con un diagnóstico de PR realizado por un médico. Los estudios que solo incluyan un subconjunto de participantes relevantes se incluirán, pero se analizarán por separado.
Tipos de intervenciones
-
Tratamiento tópico
-
Emolientes
-
Cremas o ungüentos antihistamínicos
-
Cremas o ungüentos con corticosteroides
-
-
Fototerapia
-
Luz solar
-
Terapia con luz ultravioleta artificial
-
-
Tratamiento sistémico
-
Antihistamínicos orales
-
Corticosteroides orales
-
Antibióticos orales
-
Agentes antivirales orales
-
Agentes intravenosos de la medicina china
-
Las intervenciones pueden ser tratamientos únicos o combinados. Los comparadores pueden ser ningún tratamiento, placebo, vehículo solamente, otro compuesto activo o tratamiento con radiación de placebo.
Tipos de medida de resultado
Resultados primarios
-
La proporción de participantes con una mejoría buena o excelente de la erupción en un plazo de dos semanas, según la calificación del participante.
-
Eventos adversos graves, es decir, suficientemente graves para requerir el retiro del tratamiento.
Resultados secundarios
-
La proporción de participantes con resolución del prurito en un plazo de dos semanas, según la calificación del participante.
-
Reducción de la puntuación del prurito en el plazo de dos semanas, según la calificación del participante.
-
La proporción de participantes con una mejoría buena o excelente de la erupción en un plazo de dos semanas, según la calificación de un médico.
-
Mejoría de la calidad de vida según la calificación del participante, a través de cuestionarios u otros métodos.
-
Eventos adversos menores informados por los participantes, que no requirieron el retiro del tratamiento.
Momento de evaluación de los resultados
Se eligieron dos semanas como el momento de la evaluación de los resultados debido a que los pacientes sin ningún tratamiento activo suelen tener una recuperación espontánea entre las dos y las 12 semanas. Sería difícil diferenciar si cualquier mejoría después de dos semanas con un tratamiento activo se debe a la recuperación espontánea de la enfermedad o al tratamiento.
Métodos de búsqueda para la identificación de los estudios
We aimed to identify all relevant RCTs regardless of language or publication status (published, unpublished, in press, or in progress).
Búsquedas electrónicas
For this update, we revised all of our search strategies in line with current Cochrane Skin practices. Details of the previous search strategies are shown in Chuh 2007.
The Cochrane Skin Information Specialist searched the following databases up to 29 October 2018:
-
the Cochrane Skin Specialised Register using the search strategy in Appendix 1;
-
the Cochrane Central Register of Controlled Trials (CENTRAL) (2018, Issue 9), 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
-
LILACS (Latin American and Caribbean Health Science Information database, from 1982) using the strategy in Appendix 5.
Trials registers
We (JCR, SP) searched the following trials registers up to 29 October 2018 using the strategy in Appendix 6:
-
ISRCTN registry (www.isrctn.com);
-
US National Institutes of Health Ongoing Trials Register ClinicalTrials.gov (www.clinicaltrials.gov);
-
Australian New Zealand Clinical Trials Registry (www.anzctr.org.au);
-
World Health Organization International Clinical Trials Registry Platform (WHO ICTRP) (apps.who.int/trialsearch/); and
-
EU Clinical Trials Register (www.clinicaltrialsregister.eu).
Búsqueda de otros recursos
References from published studies
We checked the bibliographies of the included and excluded studies for further references to relevant RCTs.
Unpublished literature
We contacted the leading researchers identified in the trial register search in an attempt to identify relevant unpublished data. We contacted the authors of the published trials in order to obtain data on outcomes that were assessed but not reported in the published papers.
Conference proceedings
We scanned abstracts from the following major dermatology conference proceedings for further RCTs:
-
Annual Meeting of the American Academy of Dermatology (2009 to 2017);
-
Congress of the European Academy of Dermatology and Venereology (2000 to 2017);
-
World Congress of Dermatology (2011 to 2017); and
-
International Congress of Dermatology (2011 to 2017).
We searched the CAB Abstracts (Ovid) database up to November 2017 using the following text words: Pityriasis rosea, Pityriasis of Vidal, Pityriasis circinata, and Pityriasis marginata.
Adverse effects
We searched PubMed for adverse effects using the strategy in Appendix 7 up to November 2018.
Obtención y análisis de los datos
Selección de los estudios
Two review authors (JCR, CJG) independently checked the titles and abstracts identified from the searches. If it was clear to both review authors that the study did not refer to an RCT on PR, it was excluded. Any discrepancies were resolved by further analysing the full publication or by contacting study authors. We excluded quasi‐randomised trials, where allocation was by non‐random methods such as alternation or was based on characteristics such as date of birth, name, or case number.
We obtained the full texts of those studies deemed potentially relevant, and two review authors (JCR, CJG) independently assessed each study to determine whether it met the predefined selection criteria, with any differences being resolved through discussion with the review team. Review authors were not blinded as to the origin or conclusions of the article for eligibility assessment, data extraction, or quality assessment. We listed the excluded studies and the reasons for their exclusion in the Characteristics of excluded studies table.
Extracción y manejo de los datos
Two review authors (ICK and CJG) independently performed data extraction, and three other review authors (SP, JCR, LR) checked for and resolved any discrepancies between the data extraction. We obtained missing data from the trial authors where possible. We developed and piloted a data collection form to summarise the trials. Two review authors (CJG, SP) checked and entered the data into Review Manager 5 (Review Manager 2014).
Evaluación del riesgo de sesgo de los estudios incluidos
At least four review authors (CJG, LR, ICK, SP) independently assessed the risk of bias of each trial using a simple form and according to the domain‐based evaluation described in the Cochrane Handbook for Systematic Reviews of Interventions (Higgins 2011). Review authors (CJG, LR, JCR, SP, ICK) discussed any discrepancies and achieved consensus on the final assessment.
We assessed the following domains as low, high, or unclear risk of bias.
-
Generation of allocation sequence
-
Allocation concealment
-
Blinding (of participants, personnel, and outcome assessors)
-
Incomplete outcome data
-
Selective reporting
-
Other sources of bias
Generation of allocation sequence (checking for possible selection bias)
We described for each included study the method used to generate the allocation sequence in sufficient detail to permit an assessment as to whether it should produce comparable groups.
We assessed the method as:
-
low risk (any truly random process, e.g. random number table; computer random number generator); or
-
unclear risk (the trial was described as randomised, but the method used for allocation sequence generation was not described).
Allocation concealment (checking for possible selection bias)
We described for each included study the methods used to conceal the allocation sequence in sufficient detail to permit an assessment as to whether the intervention allocation could have been foreseen in advance of, or during, recruitment, or changed after assignment.
We assessed the methods as:
-
low risk (e.g. telephone or central randomisation; consecutively numbered, sealed, opaque envelopes);
-
high risk (open random allocation; unsealed or non‐opaque envelopes, alternation; date of birth); or
-
unclear risk (trial was described as randomised, but the method used to conceal the allocation was not described).
Blinding or masking (checking for possible performance and detection bias)
We described for each included study the methods used, if any, to blind study participants and personnel from the knowledge of which intervention a participant received. We judged studies as at low risk of bias if they were blinded, or if we judged that the results would not have been affected by lack of blinding. We assessed blinding separately for different outcomes or classes of outcomes.
We assessed blinding methods as:
-
low risk, high risk, or unclear risk for participants;
-
low risk, high risk, or unclear risk for personnel; and
-
low risk, high risk, or unclear risk for outcome assessors.
Incomplete outcome data (checking for possible attrition bias through withdrawals, dropouts, protocol deviations)
We assessed methods on outcome data as:
-
low risk (any one of the following): no missing outcome data; reasons for missing outcome data unlikely to be related to true outcome; missing outcome data balanced in numbers across intervention groups, with similar reasons for missing data across groups; for dichotomous outcome data, the proportions of missing outcomes compared with observed event risk was not enough to have a clinically relevant impact on the intervention effect estimate; for continuous outcome data, plausible effect size (difference in means or standardised difference in means) amongst missing outcomes was not enough to have a clinically relevant impact on observed effect size; or missing data were imputed using appropriate methods;
-
high risk (any one of the following): reason for missing outcome data was likely to be related to true outcome, with either an imbalance in numbers or reasons for missing data across intervention groups; for dichotomous outcome data, the proportion of missing outcomes compared with observed event risk was enough to induce clinically relevant bias in intervention effect estimate; for continuous outcome data, plausible effect size (difference in means or standardised difference in means) amongst missing outcomes was enough to induce clinically relevant bias in observed effect size; ‘as‐treated’ analysis done with substantial departure of the intervention received from that assigned at randomisation; or potentially inappropriate application of simple imputation; or
-
unclear risk (any one of the following): insufficient reporting of attrition/exclusions to permit a judgement of ‘low risk’ or ‘high risk’ (e.g. number randomly assigned not stated, no reasons provided for missing data); or the study did not address this outcome.
Free of other bias (bias due to problems not covered elsewhere in the table)
We described for each included study any important concerns we had about other possible sources of bias (baseline imbalance, sponsorship bias, differential verification bias, partial verification bias and incorporation bias, bias of the presentation data, etc.):
-
low risk of bias: the trial appears to be free of other components that could put it at risk of bias;
-
high risk of bias: other factors in the trial could put it at risk of bias (e.g. no sample size calculation made, academic fraud, industry involvement, extreme baseline imbalance);
-
unclear risk of bias: the trial may or may not be free of other components that could put it at risk of bias.
In addition, the quality assessment included:
-
degree of certainty that the participants have PR (e.g. whether the diagnoses were made by primary care physicians or dermatologists);
-
whether participants with drug‐induced PR‐like rashes were excluded.
We recorded the information in the Risk of bias in included studies section. We used the results of the methodological quality assessment as the basis for sensitivity analysis and not as exclusion criteria.
Medidas del efecto del tratamiento
We presented data as risk ratios (RR) with 95% confidence intervals (CIs) for dichotomous variables and according to the information provided in the trials by the authors, and as mean differences (MD) and 95% CIs for continuous variables.
Cuestiones relativas a la unidad de análisis
We did not have any unit of analysis issues. The unit of allocation and analysis was the individual participant for all included studies, and no studies were of a repeated measure, longitudinal nature, cluster trial, or cross‐over design. In the only case of a study with three groups (Lazaro‐Medina 1996), each of the three comparisons was analysed separately, and given that none of these could be pooled, we did not have to correct for omission or double‐counting of participants.
Given the nature of pityriasis rosea, we did not expect to find any within‐participant trials.
Manejo de los datos faltantes
In the case of uncertainty we contacted trial authors for clarification and to obtain missing data. When this additional information was available, it was clearly specified in the Characteristics of included studies tables.
If we identified any studies where 2×2 tables or means and standard deviations were still not available, we would use the available data such as odds ratio (OR), RR, or MD with their 95% CI.
Regarding analysis of continuous outcome data, when standard deviations were not available for changes from baseline and information was insufficient to calculate them, standard deviations were imputed as recommended in Section 16.1.3.2 of the Cochrane Handbook for Systematic Reviews of Interventions (Higgins 2011). In such cases, a correlation coefficient of 0.7 was used, alongside a sensitivity analysis using coefficients ranging from a more conservative estimate of 0.5 up to 0.8 to examine the impact of imputation on the final analysis results (Dias 2011). Use of different coefficients did not change the overall result for any of the outcomes where imputation of standard deviation was used.
Evaluación de la heterogeneidad
We investigated heterogeneity with visual examination of the forest plots. In addition, we used the Chi² test and I² statistic for testing statistical heterogeneity between studies. Only trials considered clinically and methodologically similar were pooled. We assessed the presence of statistical heterogeneity as a value of I² as per the Cochrane Handbook for Systematic Reviews of Interventions, as follows: 0% to 40%: not important; 30% to 60%: moderate heterogeneity; 50% to 90%: substantial heterogeneity; 75% to 100%: considerable heterogeneity (Higgins 2011). If heterogeneity (> 30%) existed between studies, reasons for heterogeneity were assessed by examining the characteristics of the studies, types of participants, disease severity, dosage and duration of treatment, and study quality, and subgroup analyses or sensitivity analyses were undertaken if possible (see Subgroup analysis and investigation of heterogeneity). If there was considerable heterogeneity, we downgraded the quality of the evidence using the GRADE approach (GRADE Handbook).
Evaluación de los sesgos de notificación
We described for each included study how we investigated the possibility of selective outcome reporting bias and what we found.
We assessed reporting methods using Review Manager 5 software, Review Manager 2014, per the Cochrane Handbook for Systematic Reviews of Interventions (Higgins 2011), as follows:
-
low risk (any one of the following): the study protocol is available and all of the study’s prespecified (primary and secondary) outcomes of interest in the review have been reported in the prespecified way, or the study protocol is not available, but it is clear that published reports include all expected outcomes, including those that were prespecified (convincing text of this nature may be uncommon);
-
high risk (any one of the following): not all of the study’s prespecified primary outcomes have been reported; one or more primary outcomes are reported using measurements, analysis methods, or subsets of the data (e.g. subscales) that were not prespecified; one or more reported primary outcomes were not prespecified (unless clear justification for their reporting is provided, such as an unexpected adverse effect); one or more outcomes of interest in the review are reported incompletely so that they cannot be entered into a meta‐analysis; the study report fails to include results for a key outcome that would be expected to have been reported for such a study; or
-
unclear risk: information is insufficient to permit judgement of ‘low risk’ or ‘high risk’.
If we identified selective publication in studies, we downgraded the evidence according to the GRADE criteria considering study design, study size, lag bias, search strategy, etc. (GRADE Handbook).
Síntesis de los datos
For studies with a similar type of intervention and comparator (e.g. oral antibiotics versus placebo), we performed a meta‐analysis to calculate a weighted treatment effect across trials using a random‐effects model in Review Manager 5 (Review Manager 2014). Where it was not possible to perform a meta‐analysis, we summarised the data for each trial.
We listed non‐randomised controlled studies in the Characteristics of excluded studies table; these are not discussed further.
We described studies relating to adverse effects qualitatively.
A consumer (MLS‐R) was involved throughout the review process to ensure the readability of the final review.
Análisis de subgrupos e investigación de la heterogeneidad
As stated in the protocol, parallel trials and the first phase of cross‐over trials would be analysed as separate subgroups before pooling. However, we did not identify any cross‐over trials in the previous version of this review or in this current version. We considered subgroup analyses for the following factors: age of participants (children versus adults), dosage, duration of treatment, type of treatment (topical, systemic, combination), or relapse. However, in view of the limited number of included studies covering any one specific intervention, we did not conduct any of these subgroup analyses.
Análisis de sensibilidad
We would have conducted sensitivity analyses to examine the effects of excluding studies where necessary. We planned to conduct a sensitivity analysis by removing studies at high or unclear risk of bias. We did not undertake any sensitivity analyses due to the limited number of included studies.
'Summary of findings' tables and GRADE
Assessment of the quality of the evidence using the GRADE approach
For this update we assessed the quality of the evidence using the GRADE approach, as outlined in the GRADE Handbook (GRADE Handbook). We used GRADEpro GDT to import data from Review Manager 5 in order to create a ’Summary of findings’ table (GRADEpro GDT; Review Manager 2014).
Two review authors (JCR, CJG) produced a summary of the intervention effect and a measure of quality for each of the above outcomes using GRADEpro GDT. GRADE evaluates five criteria (study limitations, consistency of effect, imprecision, indirectness, and publication bias) to assess the quality of the body of evidence for each outcome. The body of evidence is graded according to its quality as follows.
-
High: We are very confident that the true effect lies close to that of the estimate of the effect.
-
Moderate: We are moderately confident in the effect estimate: the true effect is likely to be close to the estimate of the effect, but there is a possibility that it is substantially different.
-
Low: Our confidence in the effect estimate is limited: the true effect may be substantially different from the estimate of the effect.
-
Very low: We have very little confidence in the effect estimate: the true effect is likely to be substantially different from the estimate of effect
We downgraded the evidence from high quality by one level for serious, or by two levels for very serious, factors affecting its quality. We described the rationale for downgrading in the footnotes of the respective tables. Two other review authors (SP, ICK) then reviewed the tables and criteria used to downgrade the evidence, and any discrepancies were discussed until agreement was reached.
We have presented summaries of the intervention effect and measures of quality according to the GRADE approach in the ’Summary of findings’ tables, which include the most clinically relevant comparisons, as follows.
-
Clarithromycin versus placebo
-
Erythromycin versus placebo
-
Azithromycin versus placebo (or vitamins)
-
Acyclovir versus placebo (or vitamins) or no treatment
-
Acyclovir + calamine + cetirizine versus calamine + cetirizine
-
Acyclovir versus erythromycin
The 'Summary of findings' tables include all primary outcomes (proportion of participants with good or excellent rash improvement; serious adverse events) and four secondary outcomes (proportion of participants with resolution of itch; reduction in itch score; proportion of participants with good or excellent rash improvement; and minor adverse events).
Results
Description of studies
Results of the search
This is an updated version of Chuh 2007, published in Issue 2, 2007 of the Cochrane Library. The searches of the electronic databases retrieved 56 records (Electronic searches). Our searches of other resources identified 20 additional studies that appeared to meet the inclusion criteria. We therefore had a total of 76 records, of which two references were duplicates. One further record was identified as a duplicate since the trial was published. Of the remaining 73 records, we excluded 43 records based on titles and abstracts. We obtained the full text of the remaining 30 records. We excluded a further 16 studies (see Characteristics of excluded studies). We did not identify any studies awaiting classification or any ongoing studies.
The review includes 14 studies (11 newly identified studies and three studies found in the previous review). One trial did not report outcomes at week two; therefore, although it was included in the Description of studies and 'Risk of bias' assessment, we were not able to formally add it to the analysis or derive information from it (Jairath 2015). For a further description of our screening process, see the study flow diagram (Figure 3).
Selection of studies.
Regarding adverse events, our search yielded only reports of medications that can produce "pityriasis rosea‐like" reactions and were not related to medicament toxicity when treating pityriasis rosea (PR).
Included studies
Fourteen randomised trials met the inclusion criteria of this review (Zhu 1992; Lazaro‐Medina 1996; Villarama 2002; Akhyani 2003; Amer 2006; Ehsani 2010; Rassai 2011; Ahmed 2014; Ganguly 2014; Pandhi 2014; Das 2015; Jairath 2015; Singh 2016; Sonthalia 2018). One of these studies met the inclusion criteria but did not report on outcomes at week 2 (Jairath 2015), thus it was only described since it was the only study available on the modality of ultraviolet therapy and was found to be relevant for future research.
The main characteristics of the included studies are detailed in the Characteristics of included studies table. The studies that were included in the previous review are Lazaro‐Medina 1996, Villarama 2002, and Zhu 1992. One study, Jairath 2015, was identified by a secondary search performed by one review author (JCR). Thirteen of the 14 studies have been published, whilst one study remains unpublished (Villarama 2002). The data from one study were extracted from an abstract in Chinese that was translated into English, yet we failed to obtain full text of the study from the authors, despite repeated attempts (Zhu 1992). Another trial was published in Persian, and the abstract was translated into English (Akhyani 2003). Specific questions on the methods and results of this trial were also provided from a native of Iran.
One study did not report on some of the outcomes at week 2 (Singh 2016), but the author was contacted and these data were provided. One study was missing information on pruritus, and clarification on the methods used for diagnosis and recruitment was needed; the authors were contacted and the information provided (Das 2015). Another trial was missing information on rash improvement, itch, and dropouts, but we were able to obtain this information from the authors (Pandhi 2014). One trial did not provide information on complete resolution of itch, scores on the Pityriasis Rosea Severity Score (PRSS), or standard deviations on rash improvement (Sonthalia 2018), but we were able to obtain part of this missing information from the author. Finally, two more trials had unclear information on the methodology, and the authors were contacted for clarification (Ahmed 2014; Ganguly 2014).
Design
All included studies were parallel RCTs, where each participant was randomised to the intervention or comparator group.
Setting and diagnosis
Six of the included studies were conducted in India, three in Iran, two in the Philippines, and one each in Pakistan, the USA, and China. Thirteen trials were performed in dermatology departments and one in a paediatric ward (Amer 2006). The methods of diagnosis differed slightly amongst the trials. In eight trials, the diagnosis of PR was made by one to three dermatologists (Akhyani 2003; Ehsani 2010; Ahmed 2014; Pandhi 2014; Das 2015; Jairath 2015; Singh 2016; Sonthalia 2018). In one trial dermoscopy was additionally performed (Sonthalia 2018). Five trials were conducted in dermatology departments (Zhu 1992; Lazaro‐Medina 1996; Villarama 2002; Rassai 2011; Ganguly 2014), although it was not explicitly stated whether the diagnosis of PR was made by dermatologists. In three trials the clinical diagnosis of PR was confirmed through a biopsy (Lazaro‐Medina 1996; Ganguly 2014; Jairath 2015). Paediatricians made the diagnosis in a single trial (Amer 2006). Consequently, there is a high degree of certainty for all but one trial that the participants had PR (Amer 2006). Although most trials did not specifically exclude drug‐induced PR, six trials listed prior use of drugs as exclusion criteria (Villarama 2002; Rassai 2011; Ahmed 2014; Ganguly 2014; Singh 2016; Sonthalia 2018); therefore, it can be assumed that none of these trials included participants with drug‐induced PR.
Participants
The included studies involved a total of 761 participants. The age range of participants was 2 to 60 years. Except for one study where only male patients were recruited (Amer 2006), the included studies involved both male and female participants. Three studies failed to report participant age and sex (Zhu 1992; Rassai 2011; Ganguly 2014). Of the trials that reported gender, 307 participants were male and 251 female. A detailed description of participants in each of the studies is provided in the Characteristics of included studies table. The sample sizes of the included studies ranged from 23 to 100. A total of 265 participants were included in studies that compared different macrolide antibiotics versus placebo or vitamins. Acyclovir was compared with vitamins, placebo, no treatment, or standard of care in a total sample of 188 participants (Rassai 2011; Ganguly 2014; Das 2015; Singh 2016). Erythromycin was compared with acyclovir in an additional 30 participants (Ehsani 2010). Narrowband ultraviolet B phototherapy was compared with topical emollient in 100 participants (Jairath 2015). Oral corticosteroids were compared with placebo in a study with 70 participants, Sonthalia 2018, and with antihistamines in a study with 85 participants, Lazaro‐Medina 1996. A single study with 23 participants investigated the effects of the Chinese medicine glycyrrhizin (Zhu 1992).
All trials documented the extent or severity of the rash, or both, but with diverse measures. Also, participants were not divided into categories based on disease severity. A disease‐specific severity index, the Pityriasis Rosea Severity Score (PRSS), which incorporates the extent of the disease, along with erythema, infiltration, and scaling, was used in only three studies (Pandhi 2014; Jairath 2015; Sonthalia 2018). With a theoretical maximal score of 54, baseline PRSS scores in the intervention and control groups were 25.64 ± 14.21 and 23.04 ± 15.09 in Jairath 2015; 18.06 ± 5.62 and 20.23 ± 5.16 in Pandhi 2014; and 18.51 ± 5.32 and 19.45 ± 5.88 in Sonthalia 2018. Six trials used the number of lesions as a measure of disease severity (Lazaro‐Medina 1996; Villarama 2002; Ehsani 2010; Rassai 2011; Ahmed 2014; Ganguly 2014), although most of these studies did not specify the absolute lesion count and only reported on (partial or complete) disappearance of existing lesions or the appearance of new lesions. One study used a lesional score with a theoretical maximum of 5, calculated by addition of erythema score, scaling score, and number of lesions score (Das 2015), and reported baseline values of 4.08 ± 0.79 and 4.08 ± 0.90 in the intervention and control groups, respectively. Another study used the Pityriasis Rosea Area and Severity Index (PRASI) ranging from 0 to 48 and reported baseline median scores of 3.5 and 5.4 in the intervention and control groups, respectively (Singh 2016).
Seven studies reported the presence or absence of itch at baseline. Itch accompanied the rash in the following percentages of participants: 46.7% (Ehsani 2010; Ahmed 2014), 77.8% (Singh 2016), 81.6% (Amer 2006), 83.5% (Lazaro‐Medina 1996), or all participants (Das 2015; Sonthalia 2018). Three studies assessed intensity of itch on a 0‐to‐3 scale, with comparable baseline itch severity values in the intervention and control arms: 2.17 ± 0.83 and 2.25 ± 0.75 in Das 2015; 2.00 ± 0.82 and 2.04 ± 0.82 in Jairath 2015; and 1.36 ± 1.01 and 1.15 ± 0.9 in Singh 2016. Four studies assessed itch with a visual analogue scale (VAS) ranging from 0 to 10, and baseline values in the intervention and control arms were 8.25 ± 1.06 and 8.42 ± 1.08 in Das 2015; 1.31 ± 1.02 and 1.4 ± 1.1 in Sonthalia 2018; and 1.31 ± 1.105 and 1.23 ± 1.239 in Pandhi 2014, whilst Villarama 2002 only reported on the difference in scores before and after treatment, without specifying absolute values.
Interventions
The treatments and their duration were clearly defined in all 14 included studies (see Characteristics of included studies). As most of the included studies investigated different interventions and different outcome measures, pooling of data for analysis was only feasible for a few comparisons in the 13 trials that we were able to analyse.
Four studies documented the use of medications before inclusion of participants into the study (Zhu 1992; Lazaro‐Medina 1996; Villarama 2002; Ganguly 2014). Six studies excluded patients who had taken any medication after the onset of the rash (Villarama 2002; Rassai 2011; Ahmed 2014; Ganguly 2014; Singh 2016; Sonthalia 2018). The remaining trials did not comprehensively document the use of previous medications after the appearance of rash.
Six studies analysed the use of macrolide antibiotics. In a single study that compared clarithromycin to placebo (Ahmed 2014), clarithromycin tablets were used for a week in a dose of 500 mg twice daily for adults and 250 mg twice daily for children aged 10 to 12 years. Two studies compared oral erythromycin to placebo: erythromycin was used in a daily dose of 1 g for one week, Akhyani 2003, or 250 mg for two weeks, Villarama 2002. Two studies evaluated the effects of a dose of 12 mg/kg/day of azithromycin tablets for 5 days versus placebo, Amer 2006, and vitamins, Pandhi 2014. One study compared oral erythromycin in a dose of 400 mg 4 times/day for 10 days to the antiviral agent acyclovir administered orally in a dose of 8000 mg 5 times/day for 10 days (Ehsani 2010).
Three studies compared acyclovir to placebo or no treatment (Rassai 2011; Ganguly 2014; Singh 2016). Oral acyclovir was administered in a dose of 800 mg 5 times/day, Ganguly 2014; Singh 2016, or 400 mg 5 times/day, Rassai 2011, for 7 days in adults, and in a dose of 20 mg/kg 4 times/day for 7 days in children, Ganguly 2014. One study compared acyclovir tablets in a dose of 400 mg 3 times/day for 7 days along with standard of care (calamine lotion and cetirizine 10 mg tablets once daily at bedtime) versus standard of care alone (Das 2015).
One study compared three interventions: oral antihistamine dexchlorpheniramine (4 mg 2 times/day for 2 weeks, then once a day for the following 2 weeks) versus oral corticosteroid betamethasone (500 mcg, 2 times/day for 2 weeks, then once a day for the following 2 weeks) versus combined therapy (betamethasone 250 mcg and dexchlorpheniramine 2 mg, both 2 times/day for 2 weeks, then once a day for the following 2 weeks) (Lazaro‐Medina 1996). One study compared low‐dose oral prednisolone (20 mg/day for 5 days, 15 mg/day for the next 5 days, and 10 mg/day for the last 5 days) to placebo (Sonthalia 2018).
The effects of narrowband ultraviolet B phototherapy were compared with placebo in one trial that did not report on outcomes at week 2 (Jairath 2015). Phototherapy was applied in a fixed dose of 250 mJ/cm² three times a week on non‐consecutive days for four weeks (total dose of 3 J/cm²).
One study investigated the effects of the Chinese medicine potenline (glycyrrhizin, 80 mL in 500 mL of 10% glucose intravenous solution, administered once daily) versus procaine (300 mg to 600 mg in 500 mL of 10% glucose intravenous solution, administered once daily) (Zhu 1992). The duration of treatment was unclear.
Outcomes
Objectives and outcome measures were clearly defined in 13 studies. In the study by Zhu 1992, the disappearance of symptoms and rash were assessed together. Symptoms were not specified as itch. We had to assume that symptoms were limited to itch only.
None of the included studies assessed the following participant‐reported outcomes: our primary outcome of proportion of participants with good or excellent rash improvement within two weeks, as rated by the participant, and our secondary outcome of improvement in quality of life as rated by the participant by the use of questionnaires or other methods.
Seven studies reported the proportion of participants with resolution of itch within two weeks, either in the original trial reports or upon email contact with the study authors (Lazaro‐Medina 1996; Ehsani 2010; Ahmed 2014; Pandhi 2014; Das 2015; Singh 2016; Sonthalia 2018).
Six studies assessed reduction in itch score, as rated by the participant, either on a 0‐to‐3 scale (i.e. absent, mild, moderate, severe) (Das 2015; Jairath 2015; Singh 2016), or by means of a 0‐to‐10 VAS (Villarama 2002; Pandhi 2014; Das 2015; Sonthalia 2018).
Eleven studies reported the proportion of participants with good or excellent rash improvement within two weeks, as rated by a medical practitioner. Most of these studies assessed this outcome as partial or complete response to treatment, with complete response meaning all lesions had started healing in less than two weeks without the appearance of any fresh lesion, and partial response when lesions had regressed partially, or few new lesions had appeared in two weeks, or similar. In two studies that used the PRSS as a severity index, improvement was graded as the percentage reduction as follows: good, 26% to 50%; very good, 51% to 75%; and > 75%, excellent (Pandhi 2014; Sonthalia 2018).
Twelve studies assessed adverse events. In the available translated details of Akhyani 2003 and Zhu 1992, side effects were not reported as one of the assessed outcomes. Ahmed 2014 specified upon email contact that “adverse effects were not directly asked [sic] in order to prevent disclosure of drug and placebo groups”, but that there were no serious adverse events requiring withdrawal.
Length of follow‐up
Length of follow‐up in the included studies varied from two weeks, Ganguly 2014, to as long as one year, Ehsani 2010, with one study not reporting the length of follow‐up (Zhu 1992). In four studies participants were followed up for four weeks (Amer 2006; Rassai 2011; Das 2015; Jairath 2015). In another four studies participants were followed up for six weeks (Villarama 2002; Akhyani 2003; Ahmed 2014; Pandhi 2014). In two studies participants were followed up for 12 weeks after the beginning of the treatment (Lazaro‐Medina 1996; Sonthalia 2018). In one trial participants were followed until rash resolution (approximately one month) (Singh 2016). Study duration ranged from 5 to 26 months.
Funding sources
Funding sources were not reported for the majority of the included studies (Zhu 1992; Villarama 2002; Akhyani 2003; Ehsani 2010; Rassai 2011; Ahmed 2014; Ganguly 2014; Pandhi 2014; Das 2015; Jairath 2015). One study was independently funded (Singh 2016); a pharmaceutical company provided the study medication. However, the study of Amer 2006 was supported by a grant from Pfizer Inc, and the study by Lazaro‐Medina 1996 was supported by Schering‐Plough.
Language of publication
Eleven trials were published in English (Lazaro‐Medina 1996; Amer 2006; Ehsani 2010; Rassai 2011; Ahmed 2014; Ganguly 2014; Pandhi 2014; Das 2015; Jairath 2015; Singh 2016; Sonthalia 2018); one in Persian (Akhyani 2003); and one in Chinese (Zhu 1992). One study is still unpublished, but was written in English (Villarama 2002).
Excluded studies
See Characteristics of excluded studies.
We excluded 16 studies. In the previous version of this review, 13 trials were excluded because no mention of randomisation was made. One of these studies was pseudo‐randomised because participants were assigned by alternate allocation (Sharma 2000). Three more trials were excluded from our search results because they were not randomised trials (Drago 2006; Rasi 2008; Amatya 2012). One trial stated that the participants were randomised into two groups (Amatya 2012). However, given that there was no explanation of the method of randomisation in the manuscript, we contacted the author, who stated that alternate allocation was the method used; therefore, the study was not randomised. Another study clearly stated in the methods that participants were alternately assigned (Drago 2006). Finally, the last trial is a case‐controlled, open‐label study without randomisation (Rasi 2008).
Risk of bias in included studies
'Risk of bias' assessments for each included study are provided in Characteristics of included studies and Figure 4 and Figure 5.
Risk of bias graph: review authors' judgements about each risk of bias item presented as percentages across all included studies.
Risk of bias summary: review authors' judgements about each risk of bias item for each included study.
Allocation
Random sequence generation
We assessed risk of bias arising from method of generation of the allocation sequence to be low in 10 trials (Lazaro‐Medina 1996; Villarama 2002; Rassai 2011; Ahmed 2014; Ganguly 2014; Pandhi 2014; Das 2015; Jairath 2015; Singh 2016; Sonthalia 2018). The remaining four trials were at unclear risk of bias for this domain.
Allocation concealment
We assessed risk of bias arising from method of allocation concealment to be low in seven trials (Villarama 2002; Ahmed 2014; Ganguly 2014; Pandhi 2014; Das 2015; Singh 2016; Sonthalia 2018). We judged the remaining seven trials as having an unclear risk for this domain.
Blinding
We rated risk of bias due to lack of blinding of participants and personnel as low in eight trials (Villarama 2002; Akhyani 2003; Amer 2006; Ahmed 2014; Ganguly 2014; Pandhi 2014; Singh 2016; Sonthalia 2018); unclear in three trials (Zhu 1992; Lazaro‐Medina 1996; Ehsani 2010); and high in three trials (Rassai 2011; Das 2015; Jairath 2015). Since the full text of the manuscript was not available for Zhu 1992, the information was extracted from the abstract. The authors clearly state in the abstract that this study was not blinded, but that both groups of participants received some form of intravenous therapy. Given the lack of information to determine whether or not this influenced the outcomes, we judged the risk of bias for this domain as unclear.
In nine trials, outcome assessment was clearly reported as blinded and thus detection bias was considered to be low (Villarama 2002; Akhyani 2003; Amer 2006; Ahmed 2014; Ganguly 2014; Pandhi 2014; Das 2015; Singh 2016; Sonthalia 2018). Blinding of outcome assessment was unclear in four trials (Zhu 1992; Lazaro‐Medina 1996; Ehsani 2010; Rassai 2011). We assessed one trial, Jairath 2015, as at high risk of bias because the method of blinding was not specified and in all likelihood, given the tanning effect of ultraviolet radiation, blinding would have been difficult.
Incomplete outcome data
We assessed risk of attrition bias as low in 11 trials, Zhu 1992; Villarama 2002; Akhyani 2003; Amer 2006; Ehsani 2010; Ahmed 2014; Ganguly 2014; Pandhi 2014; Das 2015; Jairath 2015; Singh 2016, and unclear in two trials, Rassai 2011; Sonthalia 2018. We judged the remaining trial, Lazaro‐Medina 1996, as at high risk of bias because multiple dropouts in a single group (group C) were evident, and no information as to the cause of the dropouts was provided.
Selective reporting
We rated risk of reporting bias as low in nine trials (Lazaro‐Medina 1996; Villarama 2002; Ehsani 2010; Rassai 2011; Ahmed 2014; Ganguly 2014; Pandhi 2014; Das 2015; Jairath 2015); unclear in two trials (Zhu 1992; Akhyani 2003); and high in three trials (Amer 2006; Singh 2016; Sonthalia 2018). Amer 2006 failed to report on pruritus and concomitant medications used, both of which were stated in the methods. Singh 2016 failed to report a secondary outcome (50% reduction in severity) and PRASI score, and in Sonthalia 2018, there were inconsistencies in the final report of results of outcomes prespecified in the original article, and upon further contact with the author, the information provided was incomplete and we received no answer to our request for clarification.
Other potential sources of bias
We rated risk of other bias as low in 12 trials (Lazaro‐Medina 1996; Villarama 2002; Amer 2006; Ehsani 2010; Rassai 2011; Ahmed 2014; Ganguly 2014; Pandhi 2014; Das 2015; Jairath 2015; Singh 2016; Sonthalia 2018), and unclear for the remaining two trials as there was insufficient information for judgement (Zhu 1992; Akhyani 2003).
Effects of interventions
See: Summary of findings for the main comparison Clarithromycin compared to placebo for pityriasis rosea; Summary of findings 2 Erythromycin compared to placebo for pityriasis rosea; Summary of findings 3 Azithromycin compared to placebo or vitamins for pityriasis rosea; Summary of findings 4 Acyclovir compared to placebo, vitamins, or no treatment for pityriasis rosea; Summary of findings 5 Acyclovir + calamine + cetirizine compared to calamine + cetirizine for pityriasis rosea; Summary of findings 6 Acyclovir compared to erythromycin for pityriasis rosea
See: summary of findings Table for the main comparison, summary of findings Table 2, summary of findings Table 3, summary of findings Table 4, summary of findings Table 5, summary of findings Table 6.
We analysed outcomes as described in the Types of outcome measures section. Each outcome was investigated for the pre‐established interventions described in the Types of interventions section. Only those outcomes for which we found suitable data are described below. None of the included studies reported on the primary outcome of proportion of participants with good or excellent rash improvement within two weeks, as rated by the participant, or the secondary outcome of improvement in quality of life measures. We meta‐analysed findings from the included studies when a drug was tested in at least two studies.
We did not perform subgroup or sensitivity analyses due to the limited number of studies identified for each specific outcome or intervention.
Comparison 1: Clarithromycin compared to placebo
We identified one study including 60 participants for this comparison (summary of findings Table for the main comparison) (Ahmed 2014). Clarithromycin was given orally in a dose of 500 mg twice daily for adults and 250 mg twice daily for children for one week. The control intervention was placebo tablets.
Primary outcome 2: Serious adverse events, i.e. serious enough to require withdrawal of the treatment
No participants from either group suffered serious adverse effects requiring withdrawal (moderate‐quality evidence).
Secondary outcome 1: The proportion of participants with resolution of itch within two weeks, as rated by the participant
The author of Ahmed 2014 was contacted and information on this outcome was provided. Each group had a total of 30 participants; however, not all participants had itch at baseline (16 in the clarithromycin group and 12 in the placebo group). No significant difference was found in the proportion of participants with resolution of itch at two weeks (9/16 versus 8/12; risk ratio (RR) 0.84, 95% confidence interval (CI) 0.47 to 1.52; moderate‐quality evidence; Analysis 1.1)
Secondary outcome 3: The proportion of participants with good or excellent rash improvement within two weeks, as rated by a medical practitioner
No significant difference was found between clarithromycin and placebo in the proportion of participants with good or excellent rash improvement (assessed as partial or complete response to treatment) at two weeks, as rated by a medical practitioner (26/30 versus 23/30; RR 1.13, 95% CI 0.89 to 1.44; moderate‐quality evidence; Analysis 1.2).
Comparison 2: Erythromycin compared to placebo
We identified two studies for this comparison (summary of findings Table 2) (Villarama 2002; Akhyani 2003). Oral erythromycin was given in a total daily dose of 1 g/day for one week, in Akhyani 2003, or two weeks, in Villarama 2002.
Primary outcome 2: Serious adverse events, i.e. serious enough to require withdrawal of the treatment
One study evaluated adverse events, and no participants from either group suffered serious adverse effects (Villarama 2002).
Secondary outcome 2: Reduction in itch score within two weeks, as rated by the participant
One trial showed that erythromycin significantly reduced itch score compared with placebo (mean difference (MD) 3.95, 95% CI 3.37 to 4.53, 34 participants; P < 0.001; moderate‐quality evidence; Analysis 2.1) (Villarama 2002).
Secondary outcome 3: The proportion of participants with good or excellent rash improvement within two weeks, as rated by a medical practitioner
For this outcome we found two relevant trials with a total of 86 participants (Villarama 2002; Akhyani 2003). The outcome was defined as partial or complete response (see Characteristics of included studies), but pooling of data was possible only for complete response, because these were the only results available regarding this outcome for one study. In the Villarama 2002 trial, with a total of 40 participants, there was a significant difference in the proportion of participants with complete cure in favour of erythromycin. Likewise, in the Akhyani 2003 study, complete cure was achieved by a higher proportion of participants in the erythromycin group. However, in the meta‐analysis, even though there were more events in the erythromycin group, the results did not show a significant difference between groups (34/43 versus 14/43; RR 4.02, 95% CI 0.28 to 56.61; I² = 86%; Analysis 2.2). We assessed the quality of the evidence as low due to the small number of participants and considerable heterogeneity amongst studies. This considerable heterogeneity may be due to the differences in the treatment duration (one week in Akhyani 2003 versus two weeks in Villarama 2002), or differences in the characteristics of participants (age, race, ethnicity).
Secondary outcome 5: Minor participant‐reported adverse events not requiring withdrawal of the treatment
In one trial (Villarama 2002), gastrointestinal upset was reported in both the erythromycin and placebo groups without any significant difference between groups (2/17 versus 1/17; RR 2.00, 95% CI 0.20 to 20.04; Analysis 2.3).
Comparison 3: Azithromycin compared to placebo (or vitamins)
Two studies were available for this comparison (summary of findings Table 3) (Amer 2006; Pandhi 2014). In both studies, azithromycin was given orally in a dose of 12 mg/kg/day for five days. The control intervention was either placebo tablets or syrup, in Amer 2006, or multivitamin tablets, in Pandhi 2014.
Primary outcome 2: Serious adverse events, i.e. serious enough to require withdrawal of the treatment
Both studies evaluated adverse events, and no participants from either group suffered serious adverse effects (moderate‐quality evidence).
Secondary outcome 1: The proportion of participants with resolution of itch within two weeks, as rated by the participant
The author of one study provided these data upon email contact (Pandhi 2014). No significant difference was found between azithromycin and placebo for this outcome (5/35 versus 6/35; RR 0.83, 95% CI 0.28 to 2.48; moderate‐quality evidence; Analysis 3.1).
Secondary outcome 2: Reduction in itch score within two weeks, as rated by the participant
In the study by Pandhi 2014, the mean itch score, evaluated by means of a VAS, significantly decreased from baseline to two weeks in each of the intervention groups (from 1.31 ± 1.10 to 0.80 ± 0.80 for azithromycin and from 1.23 ± 1.24 to 0.76 ± 0.81 for placebo). Mean decrease per group was calculated from these values, and the associated standard deviation was imputed as described above. The change in itch score was similar in both groups (0.51 ± 0.79 for azithromycin versus 0.47 ± 0.89 for placebo; MD 0.04, 95% CI −0.35 to 0.43; moderate‐quality evidence; Analysis 3.2).
Secondary outcome 3: The proportion of participants with good or excellent rash improvement within two weeks, as rated by a medical practitioner
Pooled data from two studies including a total of 119 participants showed no difference for this outcome between azithromycin and placebo (28/60 versus 26/59; RR 1.02, 95% CI 0.52 to 2.00; I² = 55%; low‐quality evidence; Analysis 3.3). The statistical heterogeneity observed may have been due to the differences between the two trials in the race/ethnicity and age of the participants, or in the duration of the disease before diagnosis (Pandhi 2014 excluded patients presenting later than two weeks, whereas Amer 2006 did not). Nevertheless, both trials showed a lack of statistically significant difference in the outcome between the intervention groups. In Amer 2006, improvement was achieved by 22/25 participants in the azithromycin group and 17/24 in the placebo group (RR 1.24, 95% CI 0.93 to 1.67), and in Pandhi 2014, this was achieved by 6/35 versus 9/35, respectively (RR 0.67, 95% CI 0.27 to 1.67).
Secondary outcome 5: Minor participant‐reported adverse events not requiring withdrawal of the treatment
Both studies reported mild abdominal pain (Amer 2006; Pandhi 2014), but the meta‐analysis did not show a significant difference between groups (119 participants; 5/60 versus 0/59; RR 5.82, 95% CI 0.72 to 47.10; I² = 0%; Analysis 3.4). No significant difference between groups was found for diarrhoea in the one trial that reported this mild adverse event (2/25 versus 0/24; RR 4.81, 95% CI 0.24 to 95.25; Analysis 3.5) (Amer 2006).
Comparison 4: Acyclovir compared to placebo (or vitamins) or no treatment
One trial compared acyclovir (400 mg 5 times/day for 1 week) against no treatment (Rassai 2011); one trial compared acyclovir (800 mg 5 times/day for 1 week) against placebo (Singh 2016); and a third trial also evaluated acyclovir 800 mg 5 times/day for 1 week but used vitamin C tablets as the control intervention (Ganguly 2014). See summary of findings Table 4. We could not analyse the effect of different dose regimens given the limited number of studies and the small sample size of the studies.
Primary outcome 2: Serious adverse events, i.e. serious enough to require withdrawal of the treatment
All three studies evaluated adverse events, and no participants from either group suffered serious adverse effects requiring withdrawal of the treatment (moderate‐quality evidence).
Secondary outcome 1: The proportion of participants with resolution of itch within two weeks, as rated by the participant
The author of one study provided information on this outcome upon email contact (Singh 2016). Three out of 11 participants in the acyclovir group and 8 out of 10 in the placebo group experienced complete resolution of itch after two weeks. This difference was significant in favour of the placebo (RR 0.34, 95% CI 0.12 to 0.94; P = 0.04; moderate‐quality evidence; Analysis 4.1)
Secondary outcome 3: The proportion of participants with good or excellent rash improvement within two weeks, as rated by a medical practitioner
Three trials assessed this outcome (Rassai 2011; Ganguly 2014; Singh 2016). One study divided the rash response into separate evaluation of erythema and scaling (Rassai 2011), and the other two studies used only a decrease or absence of erythema as a measure of response.
We performed a meta‐analysis with the data from two trials (Ganguly 2014; Singh 2016), and using only reduction in erythema as a corresponding indicator of improvement in the Rassai 2011 trial. The consumer author and the expert dermatologists authors agreed that erythema was much more important than scaling in defining improvement. The results showed a significant difference in favour of acyclovir at week 2 (48/72 versus 19/69; RR 2.45, 95% CI 1.33 to 4.53; P = 0.004; I² = 39%; moderate‐quality evidence; Analysis 4.2) (summary of findings Table 4). Singh 2016 may have been inadequately powered, had dissimilar intervention groups with regards to age, and was more strict in the definition of outcome measures (reported data only for complete cure), which could explain the moderate heterogeneity observed in the meta‐analysis.
The proportion of participants who showed a reduction in scaling of the lesions was significantly higher with acyclovir at two weeks (28/28 versus 17/26; RR 1.52, 95% CI 1.14 to 2.01; P = 0.004; Analysis 4.3) (Rassai 2011).
Secondary outcome 5: Minor participant‐reported adverse events not requiring withdrawal of the treatment
In the Singh 2016 trial, one participant in the placebo group experienced abdominal pain and diarrhoea rated as mild and not requiring treatment, whilst no side effects were detected in any of the groups in the remaining two trials. This adverse event did not reach significance (0/72 versus 1/69; RR 0.31, 95% CI 0.01 to 7.02; Analysis 4.4).
Comparison 5. Acyclovir plus calamine and cetirizine compared to calamine plus cetirizine
One trial compared the combination of acyclovir tablets (400 mg 3 times/day for 7 days), calamine lotion, and cetirizine tablets (10 mg) versus calamine lotion and cetirizine tablets alone (considered as standard of care by the trialists) (Das 2015). See summary of findings Table 5.
Primary outcome 2: Serious adverse events, i.e. serious enough to require withdrawal of the treatment
No serious adverse events requiring withdrawal were reported in either group (low‐quality evidence).
Secondary outcome 1: The proportion of participants with resolution of itch within two weeks, as rated by the participant
We contacted the author of Das 2015 who provided information on this outcome. Resolution of itch at two weeks of follow‐up was experienced by 9 out of 12 participants in the group that received acyclovir in addition to standard of care compared with only 2 out of 12 participants that received standard of care alone. This difference was significant in favour of acyclovir added to the standard of care (RR 4.50, 95% CI 1.22 to 16.62; Analysis 5.1), but we rated the quality of the evidence as low due to the small number of participants and lack of blinding (summary of findings Table 5).
Secondary outcome 2: Reduction in itch score within two weeks, as rated by the participant
In Das 2015, the mean itch score, evaluated on a scale from 0 to 10, significantly decreased from baseline to week 2 in the group receiving acyclovir plus standard of care (from 2.17 ± 0.83 to 0.33 ± 0.65), but not in the group receiving standard of care alone (from 2.25 ± 0.75 to 1.67 ± 0.98). The mean decrease per group was calculated from these values, and the associated standard deviation was imputed as described above. The mean change in itch score was significantly larger when acyclovir was added to standard of care (1.84 ± 0.60 versus 0.58 ± 0.70; MD 1.26, 95% CI 0.74 to 1.78; Analysis 5.2). As for the previous outcome, we rated the quality of the evidence as low due to the small number of participants and lack of blinding (summary of findings Table 5).
Secondary outcome 3: The proportion of participants with good or excellent rash improvement within two weeks, as rated by a medical practitioner
Das 2015 did not report on this precise outcome. However, it is worth noting that this study did evaluate participants for reduction in lesional score (a measure of rash severity), which was calculated by the addition of erythema score (0 if absent, 1 if present), scaling score (0 if absent, 1 if present), and number of lesions score (< 30 lesions given a score of 1; 30 to 100 lesions given a score of 2; and > 100 lesions given a score of 3). Similar to the above‐mentioned itch score, the mean lesional score significantly decreased from baseline to week 2 in the group receiving acyclovir plus standard of care (from 8.25 ± 1.06 to 2.17 ± 0.58), but not in the group receiving standard of care alone (from 8.42 ± 1.08 to 5.58 ± 0.51). The mean decrease per group was calculated from these values, and the associated standard deviation was imputed as described above. The mean change in lesional score was significantly greater when acyclovir was added to standard of care (6.08 ± 0.77 versus 2.84 ± 0.81; MD 3.24, 95% CI 2.61 to 3.87; Analysis 5.3). We rated the quality of the evidence as moderate due to the small number of participants.
Secondary outcome 5: Minor participant‐reported adverse events not requiring withdrawal of the treatment
No significant differences were found between groups in any of the reported adverse events in Das 2015: headache (3/12 versus 0/12; RR 7.00, 95% CI 0.40 to 122.44; Analysis 5.4); increased sleep (2/12 versus 1/12; RR 2.00, 95% CI 0.21 to 19.23; Analysis 5.5); nausea and vomiting (2/12 versus 0/12; RR 5.00, 95% CI 0.27 to 94.34; Analysis 5.6); and dysgeusia (1/12 versus 0/12; RR 3.00, 95% CI 0.13 to 67.06; Analysis 5.7). No pooling of minor side effects was possible because the authors did not specify if any of the participants experienced more than one side effect.
Comparison 6. Acyclovir compared to erythromycin
This comparison was assessed in a single trial (Ehsani 2010). Acyclovir was given in dose of 800 mg 5 times/day and erythromycin in a dose of 400 mg 4 times/day, for a total of 10 days. See summary of findings Table 6.
Primary outcome 2: Serious adverse events, i.e. serious enough to require withdrawal of the treatment.
No serious adverse events requiring withdrawal were reported in either group.
Secondary outcome 1: The proportion of participants with resolution of itch within two weeks, as rated by the participant
In a single study comparing acyclovir against erythromycin, 8/15 participants in the acyclovir group started with itch compared with 6/15 participants in the erythromycin group. Although all participants in the acyclovir group had resolution of itch compared with none of the participants in the erythromycin group, this difference did not reach statistical significance (8/8 versus 0/6; RR 13.22, 95% CI 0.91 to 192.02; Analysis 6.1). Due to the very small sample size, small number of events, and unclear risk of bias in several categories, we assessed this evidence as of low quality.
Secondary outcome 3: The proportion of participants with good or excellent rash improvement within two weeks, as rated by a medical practitioner
This outcome was assessed, but no participants in either group showed complete rash response at week 2 of follow‐up.
Secondary outcome 5: Minor participant‐reported adverse events not requiring withdrawal of the treatment
No side effects in either group are mentioned in the study.
Comparison 7: Prednisolone compared to placebo
A single trial with 70 randomised participants evaluated the comparison of low‐dose prednisolone tapered over 2 weeks versus placebo (Sonthalia 2018). Oral prednisolone was given as a single dose of 20 mg/day for 5 days, followed by 15 mg/day for the next 5 days, and 10 mg/day for the last 5 days. Concomitant symptomatic treatment with antipruritic lotion (calamine with liquid paraffin) was allowed during the study.
Primary outcome 2: Serious adverse events, i.e. serious enough to require withdrawal of the treatment
No serious adverse events requiring withdrawal were detected in either group.
Secondary outcome 1: The proportion of participants with resolution of itch within two weeks, as rated by the participant
We contacted the author of Sonthalia 2018, and information on this outcome was provided. Resolution of itch at two weeks of follow‐up was experienced by 32/34 participants in the prednisolone group and 11/34 participants in the placebo group. This difference was significant in favour of prednisolone (RR 2.91, 95% CI 1.78 to 4.76; low‐quality evidence; Analysis 7.1).
Secondary outcome 2: Reduction in itch score within two weeks, as rated by the participant
The mean itch score, evaluated on a scale from 0 to 10, significantly decreased from baseline to week 2 in each of the intervention arms (from 1.31 ± 1.02 to 0.41 ± 0.69 for prednisolone and from 1.40 ± 1.1 to 0.81 ± 0.71 for placebo). Mean decrease per group was calculated from these values, and the associated standard deviation was imputed as described above. The mean change in itch score did not differ between groups (MD 0.31, 95% CI −0.05 to 0.67; low‐quality evidence; Analysis 7.2).
Secondary outcome 3: The proportion of participants with good or excellent rash improvement within two weeks, as rated by a medical practitioner
The author of Sonthalia 2018 provided this information upon email contact. Good‐to‐excellent rash improvement at two weeks of follow‐up was noted in 34/35 participants in the prednisolone group and 21/35 participants in the placebo group. This difference was significant in favour of prednisolone (RR 1.62, 95% CI 1.23 to 2.13; low‐quality evidence; Analysis 7.3).
Secondary outcome 5: Minor participant‐reported adverse events not requiring withdrawal of the treatment
No significant differences were found between groups for any of the reported adverse events in Sonthalia 2018. In the treatment group, two participants complained of mild gastric hyperacidity (Analysis 7.4), and one participant complained of transient anxiety and palpitations (Analysis 7.5). In the placebo group, one participant complained of belching (Analysis 7.6), and another participant reported the development of a stye (Analysis 7.7).
In addition to the outcomes described, the authors of Sonthalia 2018 evaluated relapse rate at 12 weeks, detecting it in six participants (17%) in the prednisolone group and only one participant (3%) in the placebo group (RR 6.00, 95% CI 0.76 to 47.29; low‐quality evidence; Analysis 7.8).
Comparison 8. Oral dexchlorpheniramine versus oral betamethasone versus combination of oral dexchlorpheniramine and oral betamethasone
A single trial evaluated the comparison of oral dexchlorpheniramine 4 mg (alone) versus oral betamethasone 500 mcg (alone) versus a combination of oral dexchlorpheniramine 2 mg plus oral betamethasone 250 mcg (Lazaro‐Medina 1996). The study included 27 to 31 participants per group and had a high proportion of dropouts that were unbalanced between groups, along with unclear risk of bias in several other categories (see Characteristics of included studies). We therefore assessed the overall quality of the evidence for the outcomes described below for this comparison as very low.
Primary outcome 2: Serious adverse events, i.e. serious enough to require withdrawal of the treatment
Adverse events were assessed, but no serious adverse events requiring withdrawal were reported in any group.
Secondary outcome 1: The proportion of participants with resolution of itch within two weeks, as rated by the participant
No significant difference was found for this outcome when comparing oral dexchlorpheniramine versus oral betamethasone (11/25 versus 14/29; RR 0.91, 95% CI 0.51 to 1.63; Analysis 8.1) or oral dexchlorpheniramine versus a combination of oral dexchlorpheniramine and oral betamethasone (11/25 versus 9/17; RR 0.83, 95% CI 0.44 to 1.56; Analysis 9.1) or oral betamethasone versus a combination of oral dexchlorpheniramine and oral betamethasone (14/29 versus 9/17; RR 0.91, 95% CI 0.51 to 1.64; Analysis 10.1).
Secondary outcome 3: The proportion of participants with good or excellent rash improvement within two weeks, as rated by a medical practitioner
No significant difference was found for this outcome when comparing oral dexchlorpheniramine alone versus oral betamethasone alone (12/25 versus 21/29; RR 0.66, 95% CI 0.42 to 1.06; Analysis 8.2). However, a significant difference was found for this outcome favouring dexchlorpheniramine alone versus the combination of betamethasone and dexchlorpheniramine (12/25 versus 1/17; RR 8.16, 95% CI 1.17 to 57.05; P = 0.03; Analysis 9.2). A significant difference was also found favouring betamethasone alone versus betamethasone plus dexchlorpheniramine (21/29 versus 1/17; RR 12.31, 95% CI 1.81 to 83.52; P = 0.01; Analysis 10.2).
Comparison 9. Glycyrrhizin (potenline) compared to procaine
We identified one small trial for this comparison (Zhu 1992).
Secondary outcome 3: The proportion of participants with good or excellent rash improvement within two weeks, as rated by a medical practitioner
There was no significant difference between groups for this outcome (12/12 versus 8/11; RR 1.36, 95% CI 0.93 to 1.98; Analysis 11.1). Due to unclear risk of bias across different categories and very small sample size, we assessed this evidence as of very low quality.
Comparison 10. Ultraviolet light compared to emollient
One trial assessed the comparison of narrowband ultraviolet B phototherapy (fixed dose of 250 J/cm² 3 times/week for 4 weeks) with application of a topical emollient (Jairath 2015), but the outcomes were only reported at four weeks. As noted above, PR may improve after two weeks on its own, thus we excluded the trial from the analysis of efficacy outcomes.
Primary outcome 2: Serious adverse events, i.e. serious enough to require withdrawal of the treatment
No serious adverse events requiring withdrawal were reported in either group.
Secondary outcome 5: Minor participant‐reported adverse events not requiring withdrawal of the treatment
At four weeks of follow‐up, that is after completion of the treatment, the study authors noted hyperpigmentation in 62% (31/50 versus 0/50; RR 63.00, 95% CI 3.96 to 1002.01; P = 0.003; Analysis 12.1) and hypopigmentation in 16% of participants in the treatment group (8/50 versus 0/50; RR 17.00, 95% CI 1.01 to 286.82; P = 0.05; Analysis 12.2). Also, three participants in the treatment group complained of a burning sensation (3/50 versus 0/50; RR 7.00, 95% CI 0.37 to 132.10; Analysis 12.3). It is unclear whether these side effects first occurred during the treatment of after the treatment had already been completed.
Discusión
La dermatóloga francesa Camille Melchior Gibert describió por primera vez y de manera precisa la pitiriasis rosada en 1860 (Percival 1932). Se han realizado muchos ensayos para identificar la causa de la PR, aunque el número de ensayos controlados sobre su tratamiento aún es bastante pequeño. Se desconoce el número de pacientes que presentan la remisión espontánea y no buscan atención médica. Debido a que la PR es una afección bastante benigna, en algunos pacientes en los que la erupción es asintomática o no afecta la calidad de vida puede ser aceptable esperar la remisión espontánea. Desafortunadamente, los pacientes que buscan atención médica lo hacen debido a la gravedad de la erupción en sí, o debido a la incomodidad causada por el prurito. En la PR no parece haber correlación entre la extensión de la erupción, la gravedad del prurito y su impacto en la calidad de vida (Chuh 2005a). Es posible que algunos pacientes con una erupción extensa no presenten prurito.
Resumen de los resultados principales
En esta actualización de la revisión se identificaron 11 ensayos nuevos que cumplieron los criterios de inclusión. Uno de estos ensayos no logró informar de los resultados en la semana dos, por lo que no se analizó (Jairath 2015). En general, el riesgo de sesgo de selección fue incierto en aproximadamente un tercio (generación de la secuencia aleatoria) y hasta más de la mitad de los estudios (ocultación de la asignación), y bajo en el resto de los estudios. El riesgo de sesgo de realización y de informe fue alto para el 21% de los estudios. Otros juicios relacionados con el riesgo de sesgo fueron en su mayoría de bajo riesgo de sesgo.
En la presente revisión se estudiaron varias modalidades de tratamiento tópicas y sistémicas. Los tratamientos tópicos incluyeron calamina y loción emoliente. El tratamiento sistémico incluyó antibióticos orales como azitromicina, claritromicina y eritromicina; el fármaco antiviral aciclovir; los antihistamínicos orales dexclorfeniramina y cetirizina; los corticosteroides orales prednisolona y betametasona; glicirrizina y procaína administradas por vía intravenosa; y la fototerapia ultravioleta B. El agrupamiento de los datos para el análisis solo fue posible para tres comparaciones: eritromicina en comparación con placebo, azitromicina en comparación con placebo, y aciclovir en comparación con placebo, y solo para unos pocos resultados dentro de cada comparación. Los metanálisis incluyeron dos o tres ensayos como máximo.
A menos que se indicara lo contrario, todos los resultados de efectividad fueron informados por los participantes y evaluados dentro de las dos semanas de tratamiento.
La claritromicina se investigó en un único ensayo, que encontró que probablemente no tiene un efecto beneficioso adicional en comparación con placebo en cuanto al logro de la resolución del prurito o una mejoría buena o excelente de la erupción cutánea según la calificación de un médico (evidencia de calidad moderada). No se midió la reducción de la puntuación del prurito. Ver "Resumen de resultados", tabla 1.
Sobre la base del metanálisis de dos estudios, se desconoce si la eritromicina tiene un efecto beneficioso en comparación con placebo en cuanto al aumento de la proporción de participantes con una mejoría buena o excelente de la erupción cutánea (evidencia de calidad baja). Este metanálisis también tuvo una heterogeneidad considerable, posiblemente debido a las diferencias en la duración del tratamiento (una semana frente a dos semanas) o a las diferencias en las características de los participantes (edad, raza y origen étnico). No se midió la proporción de participantes con resolución del prurito, aunque la reducción de la puntuación del prurito se midió en un estudio y probablemente es mayor con eritromicina (evidencia de calidad moderada). Ver "Resumen de resultados", tabla 2.
La azitromicina probablemente no tiene efectos beneficiosos adicionales sobre la resolución del prurito o la reducción de la puntuación del prurito, en comparación con placebo (un ensayo, evidencia de calidad moderada). Además, el metanálisis de dos ensayos mostró que puede no haber diferencias entre estos tratamientos en cuanto a la proporción de participantes con una mejoría buena o excelente de la erupción cutánea, según la calificación de un médico (evidencia de calidad baja). Los datos agrupados mostraron heterogeneidad moderada, posiblemente debido a las diferencias en la raza/origen étnico y la edad de los participantes, o en la duración de la enfermedad antes del diagnóstico. Sin embargo, ambos ensayos mostraron una ausencia de diferencias entre los grupos de intervención para este resultado. Ver "Resumen de resultados", tabla 3.
Con respecto a la mejoría buena o excelente de la erupción cutánea calificada por el médico, los datos agrupados de tres ensayos mostraron que probablemente hay una mejoría mayor a favor del aciclovir en comparación con placebo, vitaminas o ningún tratamiento. Aunque los datos agrupados mostraron heterogeneidad moderada, la calidad de la evidencia se evaluó como moderada. Un ensayo pequeño indicó que la proporción de participantes con resolución del prurito probablemente es mayor con placebo que con aciclovir (evidencia de calidad moderada), aunque no se midió la reducción de la puntuación del prurito. Ver "Resumen de los hallazgos", tabla 4.
Sobre la base de un único ensayo, puede ser beneficioso agregar aciclovir a la atención estándar (loción de calamina y cetirizina oral) para reducir la gravedad del prurito y lograr su resolución (evidencia de calidad baja). En este ensayo no se midió la proporción de participantes con una mejoría buena o excelente de la erupción cutánea dentro de las dos semanas, según la calificación de un médico. Sin embargo, este estudio utilizó un sistema de puntuación para evaluar la gravedad de la erupción que incluyó la ausencia o la presencia de eritema y descamación, así como el número de lesiones, y mostró una diferencia a favor del aciclovir en cuanto a la reducción de la puntuación de la lesión de la erupción. El sistema de puntuación utilizado en este ensayo parece objetivo y los evaluadores del resultado estaban cegados (evidencia de calidad moderada); por lo tanto, estos resultados se incluyeron en las notas al pie del Resumen de los hallazgos, tabla 5.
Es importante señalar que los ensayos que compararon el aciclovir con placebo o con otras intervenciones utilizaron diferentes regímenes de dosis y diferentes intervenciones como control, lo que hizo imposible comparar diferentes dosis de aciclovir con respecto a su eficacia; sin embargo, lo anterior puede tener un impacto sobre los resultados clínicos. Ningún estudio comparó diferentes regímenes de dosis de aciclovir.
Ninguno de los estudios incluidos en esta revisión informó de efectos adversos graves. La evidencia fue de calidad baja para la comparación de aciclovir más atención estándar en comparación con atención estándar sola; fue de calidad moderada para las comparaciones claritromicina frente al placebo, eritromicina frente al placebo, azitromicina frente al placebo (o vitaminas) y aciclovir frente al placebo (o vitaminas) o ningún tratamiento.
El ensayo individual que comparó claritromicina oral frente al placebo no midió los eventos adversos menores informados por los participantes que no requirieron el retiro del tratamiento. En las otras comparaciones clave las tasas fueron muy bajas con cada tratamiento (< 3%) y no hubo diferencias significativas entre los grupos. Estos resultados se basaron principalmente en estudios individuales con un tamaño de la muestra pequeño. Los eventos adversos menores informados incluyeron malestar gastrointestinal, dolor abdominal leve, diarrea y cefalea (evidencia de calidad baja a moderada).
Ninguno de los estudios incluidos midió el resultado primario de la proporción de participantes con una mejoría buena o excelente de la erupción cutánea dentro de las dos semanas, según la calificación del participante, ni el resultado secundario de la mejoría de la calidad de vida según la calificación del participante, a través de cuestionarios u otros métodos. Aún existe incertidumbre acerca de los efectos de los tratamientos que no se han evaluado de forma adecuada mediante ensayos controlados, algunos de los cuales incluso se utilizan como tratamiento estándar en la actualidad como los emolientes, las cremas tópicas de antihistamínicos, las cremas tópicas de corticosteroides o la fototerapia ultravioleta B.
Compleción y aplicabilidad general de las pruebas
Todos excepto uno de los ensayos clínicos se realizaron en los departamentos de dermatología (uno se realizó en una sala de pediatría), donde el diagnóstico de la PR fue realizado por uno o más dermatólogos y, en algunos casos, incluso se confirmó con biopsia. Por lo tanto, existe un grado alto de certeza de que los participantes en estos ensayos efectivamente tenían PR. Anteriormente se han sugerido criterios diagnósticos de la PR (Chuh 2003b), que se validaron en pacientes chinos e indios (Chuh 2003a), aunque solo cinco ensayos mencionan específicamente el uso de estos criterios (Villarama 2002; Amer 2006; Rassai 2011; Pandhi 2014; Singh 2016).
La biopsia de las lesiones para la histopatología se realizó en todos los participantes en tres estudios (Lazaro‐Medina 1996; Ganguly 2014; Jairath 2015). Los cambios histopatológicos de las lesiones de la PR no son específicos y se pueden utilizar para corroborar el diagnóstico y excluir diagnósticos diferenciales importantes.
Aunque la edad de los participantes varió de dos a 60 años, la mayoría de los participantes en los ensayos incluidos eran adultos jóvenes que representaban de forma adecuada el grupo etario afectado con mayor frecuencia por la PR (ver tablas Características de los estudios incluidos).
Los estudios incluidos en esta revisión no cubrieron (ni evaluaron de forma adecuada) varias modalidades de tratamiento utilizadas habitualmente por los dermatólogos en la práctica para tratar la PR, como los corticosteroides tópicos de diferentes potencias, los emolientes, los antihistamínicos orales o la radiación ultravioleta (fototerapia UVB). Además, aunque esta revisión identificó alguna evidencia de calidad baja a moderada a favor del aciclovir en comparación con placebo, vitaminas, ningún tratamiento o la atención estándar, se utilizaron diferentes regímenes de dosis del fármaco en los diversos estudios pero no se compararon en ninguno. Por lo tanto, la evidencia disponible es insuficiente para permitir una conclusión sobre el régimen de dosis ideal de aciclovir en el tratamiento de la PR. Ningún estudio consideró el uso de otros antivirales como valaciclovir o famciclovir, fármacos utilizados en el tratamiento de otras infecciones herpéticas.
Ninguno de los ensayos incluidos evaluó la proporción de participantes con una mejoría de la erupción en el plazo de dos semanas, según la calificación del participante, ni la repercusión de la enfermedad sobre las medidas de la calidad de vida.
Entre los 14 estudios incluidos en esta revisión, el prurito se evaluó en nueve estudios (Lazaro‐Medina 1996; Villarama 2002; Ehsani 2010; Ahmed 2014; Pandhi 2014; Das 2015; Jairath 2015; Singh 2016; Sonthalia 2018). El estudio de Zhu 1992 agrupó los síntomas (prurito) y los signos (erupción) y los evaluó como una única medida de resultado. El resultado clave de la resolución completa del prurito en dos semanas se evaluó en siete ensayos que evaluaron azitromicina frente al placebo (Pandhi 2014), claritromicina frente al placebo (Ahmed 2014), aciclovir frente al placebo (Singh 2016), aciclovir agregado a la atención estándar frente a la atención estándar sola (Das 2015), aciclovir frente a eritromicina (Ehsani 2010), prednisolona frente al placebo (Sonthalia 2018), y dexclorfeniramina frente a betametasona frente a su combinación (Lazaro‐Medina 1996).
Seis ensayos evaluaron la reducción de las puntuaciones del prurito en la semana dos según la calificación del participante.
Con respecto al resultado de la mejoría de la erupción dentro de las dos semanas según la calificación de un médico, la mayoría de los ensayos informaron esta medida de resultado secundaria como su resultado principal, aunque utilizaron diferentes medidas para evaluarla. Hubo cierta heterogeneidad entre los estudios en cuanto a la definición de una mejoría buena o excelente de la erupción cutánea, es decir, las definiciones de respuesta completa, parcial o ninguna respuesta.
Excepto por los estudios Akhyani 2003 y Zhu 1992; para los cuales no hubo información suficiente acerca de los eventos adversos, y del estudio Ahmed 2014; en el que no se les preguntó específicamente a los participantes acerca de los efectos adversos, los estudios incluidos parecen haber evaluado de manera adecuada los eventos adversos.
Calidad de la evidencia
En general, la cantidad de ensayos comparativos de cualquier intervención para la PR es pequeña. El número de participantes en los 14 estudios incluidos en esta revisión varió de 23 a 100. El grupo de evidencia existente no permite una conclusión sólida con respecto a las principales intervenciones y resultados evaluados en la presente revisión. Se incluyeron nueve intervenciones tópicas y sistémicas diferentes en esta revisión, la mayoría de ellas basadas en un único ensayo.
El riesgo de sesgo (Figura 4 y Figura 5) fue bajo para la generación de la secuencia aleatoria en todos los ensayos excepto en cuatro, para los cuales fue incierto. La ocultación de la asignación fue incierta para siete ensayos y baja para siete ensayos. El cegamiento de los participantes y del personal se evaluó como en riesgo alto de sesgo en tres ensayos, en riesgo incierto en tres ensayos y en riesgo bajo en los ensayos restantes. El cegamiento de la evaluación de resultado se evaluó como en riesgo bajo de sesgo en nueve ensayos, en riesgo incierto en cuatro ensayos y en riesgo alto en un ensayo. El sesgo de deserción se evaluó como en riesgo bajo de sesgo en todos los ensayos, excepto en dos ensayos en los que fue incierto y en un ensayo en el que fue alto. El sesgo de informe fue bajo para la mayoría de los estudios, excepto para dos ensayos en los que fue incierto y tres ensayos en los que fue alto.
La calidad de la evidencia se evaluó como moderada o baja. La calidad de la evidencia para los resultados se disminuyó en uno o dos niveles por las siguientes razones: número pequeño de participantes en cada estudio (imprecisión), número pequeño de eventos (imprecisión), número escaso de ensayos (imprecisión), riesgo de sesgo (limitaciones del estudio) o heterogeneidad entre los estudios (inconsistencia). Las razones para disminuir la calidad de la evidencia para cada comparación y resultado se señalan en las tablas correspondientes de "Resumen de los hallazgos" (Resumen de los hallazgos, tabla 1; Resumen de los hallazgos, tabla 2; Resumen de los hallazgos, tabla 3; Resumen de los hallazgos, tabla 4; Resumen de los hallazgos, tabla 5; Resumen de los hallazgos, tabla 6).
Sesgos potenciales en el proceso de revisión
Después de realizar búsquedas exhaustivas en todas las bases de datos, registros de ensayos, actas de congresos y bibliografía pertinentes o disponibles, y después de intentar obtener ensayos clínicos publicados o no publicados de la industria farmacéutica, se realizó el proceso de recopilación y análisis de los datos. En esta versión de la revisión sistemática participaron cinco autores de la revisión que analizaron, seleccionaron y extrajeron de manera independiente los datos para su inclusión. Todos los criterios de evaluación se habían definido claramente antes del ingreso de los datos. En cada paso del proceso al menos dos autores de la revisión participaron de manera independiente, y todas las discrepancias se ponderaron y discutieron cuidadosamente hasta que se obtuvo el consenso. Por lo tanto, existe un riesgo bajo de sesgo relacionado con el proceso de búsqueda, selección de los estudios, y recolección, extracción y análisis de los datos.
Acuerdos y desacuerdos con otros estudios o revisiones
La versión original de la revisión publicada en 2007; Chuh 2007; solo incluyó tres ECA. Sobre la base de los resultados de estos ensayos, no fue posible hacer recomendación alguna con respecto a la relación coste‐efectividad de las intervenciones debido a la falta de evidencia sobre la eficacia de la mayoría de las modalidades de tratamiento. La única excepción fue la eritromicina, aunque la evidencia para este tratamiento provino de un único ensayo pequeño. Sin embargo, para el propósito de esta actualización se identificaron 11 estudios nuevos para su inclusión. A diferencia de la versión original de la revisión, esta versión actualizada encontró evidencia de que el aciclovir probablemente mejora la erupción y el prurito en la PR, a pesar de la heterogeneidad moderada de los resultados. Sin embargo, aún se necesitan ECA más grandes para confirmar estos resultados.
Otras dos revisiones sistemáticas publicadas recientemente que se centran en el aciclovir solo coinciden en parte con los resultados de esta revisión. Los autores de Chang 2019 son más positivos acerca de los efectos del aciclovir; sin embargo, dos de los estudios incluidos son ensayos no aleatorizados (Amatya 2012 y Drago 2006; ver Características de los estudios excluidos). Además, a diferencia de la presente revisión, agruparon los datos de Ehsani 2010; en el que el aciclovir se comparó con eritromicina, junto con los datos de los ensayos en los que el aciclovir se comparó con ningún tratamiento o placebo. Por otro lado, la elección de los resultados se hizo de manera tal que los datos desfavorables de Singh 2016 no se agruparon en el metanálisis. La conclusión establecida por la revisión Rodriguez‐Zuniga 2018 de que el aciclovir es superior al placebo en cuanto a la mejoría de la erupción es comparable con la de esta revisión. La diferencia principal entre estas revisiones y la revisión actual fue la inclusión de ensayos aleatorizados y cuasialeatorizados, así como la selección de varios puntos temporales para la evaluación de los resultados.
Classical pityriasis rosea. The largest lesion is the herald patch. The other lesions are the secondary eruption.
The secondary eruption in pityriasis rosea showing the 'Christmas tree pattern'.
Selection of studies.
Risk of bias graph: review authors' judgements about each risk of bias item presented as percentages across all included studies.
Risk of bias summary: review authors' judgements about each risk of bias item for each included study.
Comparison 1 Clarithromycin versus placebo, Outcome 1 The proportion of participants with resolution of itch within 2 weeks as rated by the participant.
Comparison 1 Clarithromycin versus placebo, Outcome 2 The proportion of participants with good or excellent rash improvement within 2 weeks as rated by a medical practitioner.
Comparison 2 Erythromycin versus placebo, Outcome 1 Reduction in itch score within 2 weeks as rated by the participant.
Comparison 2 Erythromycin versus placebo, Outcome 2 The proportion of participants with good or excellent rash improvement within 2 weeks as rated by a medical practitioner.
Comparison 2 Erythromycin versus placebo, Outcome 3 Minor participant‐reported adverse events not requiring withdrawal of the treatment: Gastrointestinal upset.
Comparison 3 Azithromycin versus placebo (or vitamins), Outcome 1 The proportion of participants with resolution of itch within 2 weeks as rated by the participant.
Comparison 3 Azithromycin versus placebo (or vitamins), Outcome 2 Reduction in itch score within 2 weeks as rated by the participant.
Comparison 3 Azithromycin versus placebo (or vitamins), Outcome 3 The proportion of participants with good or excellent rash improvement within 2 weeks as rated by a medical practitioner.
Comparison 3 Azithromycin versus placebo (or vitamins), Outcome 4 Minor participant‐reported adverse events not requiring withdrawal of the treatment: Stomach ache.
Comparison 3 Azithromycin versus placebo (or vitamins), Outcome 5 Minor participant‐reported adverse events not requiring withdrawal of the treatment: Diarrhoea.
Comparison 4 Acyclovir versus placebo (or vitamins) or no treatment, Outcome 1 The proportion of participants with resolution of itch within 2 weeks as rated by the participant.
Comparison 4 Acyclovir versus placebo (or vitamins) or no treatment, Outcome 2 The proportion of participants with good or excellent rash improvement within 2 weeks as rated by a medical practitioner: Rash by erythema only.
Comparison 4 Acyclovir versus placebo (or vitamins) or no treatment, Outcome 3 The proportion of participants with good or excellent rash improvement within 2 weeks as rated by a medical practitioner: Scaling only.
Comparison 4 Acyclovir versus placebo (or vitamins) or no treatment, Outcome 4 Minor participant‐reported adverse events not requiring withdrawal of the treatment.
Comparison 5 Acyclovir + calamine + cetirizine versus calamine + cetirizine, Outcome 1 The proportion of participants with resolution of itch within 2 weeks as rated by the participant.
Comparison 5 Acyclovir + calamine + cetirizine versus calamine + cetirizine, Outcome 2 Reduction in itch score within 2 weeks as rated by the participant.
Comparison 5 Acyclovir + calamine + cetirizine versus calamine + cetirizine, Outcome 3 Reduction in lesional score within 2 weeks as rated by the participant.
Comparison 5 Acyclovir + calamine + cetirizine versus calamine + cetirizine, Outcome 4 Minor participant‐reported adverse events not requiring withdrawal of the treatment: Headache.
Comparison 5 Acyclovir + calamine + cetirizine versus calamine + cetirizine, Outcome 5 Minor participant‐reported adverse events not requiring withdrawal of the treatment: Sleepiness.
Comparison 5 Acyclovir + calamine + cetirizine versus calamine + cetirizine, Outcome 6 Minor participant‐reported adverse events not requiring withdrawal of the treatment: Nausea and vomiting.
Comparison 5 Acyclovir + calamine + cetirizine versus calamine + cetirizine, Outcome 7 Minor participant‐reported adverse events not requiring withdrawal of the treatment: Dysgeusia.
Comparison 6 Acyclovir versus erythromycin, Outcome 1 The proportion of participants with resolution of itch within 2 weeks as rated by the participant.
Comparison 7 Prednisolone versus placebo, Outcome 1 The proportion of participants with resolution of itch within 2 weeks as rated by the participant.
Comparison 7 Prednisolone versus placebo, Outcome 2 Reduction in itch score within 2 weeks as rated by the participant.
Comparison 7 Prednisolone versus placebo, Outcome 3 The proportion of participants with good or excellent rash improvement within 2 weeks as rated by a medical practitioner.
Comparison 7 Prednisolone versus placebo, Outcome 4 Minor participant‐reported adverse events not requiring withdrawal of the treatment: Mild gastric hyperacidity.
Comparison 7 Prednisolone versus placebo, Outcome 5 Minor participant‐reported adverse events not requiring withdrawal of the treatment: Anxiety and palpitations.
Comparison 7 Prednisolone versus placebo, Outcome 6 Minor participant‐reported adverse events not requiring withdrawal of the treatment: Belching.
Comparison 7 Prednisolone versus placebo, Outcome 7 Minor participant‐reported adverse events not requiring withdrawal of the treatment: Stye.
Comparison 7 Prednisolone versus placebo, Outcome 8 The proportion of participants with relapse at 12 weeks.
Comparison 8 Dexchlorpheniramine versus betamethasone, Outcome 1 The proportion of participants with resolution of itch within 2 weeks as rated by the participant.
Comparison 8 Dexchlorpheniramine versus betamethasone, Outcome 2 The proportion of participants with good or excellent rash improvement within 2 weeks as rated by a medical practitioner.
Comparison 9 Dexchlorpheniramine versus dexchlorpheniramine + betamethasone, Outcome 1 The proportion of participants with resolution of itch within 2 weeks as rated by the participant.
Comparison 9 Dexchlorpheniramine versus dexchlorpheniramine + betamethasone, Outcome 2 The proportion of participants with good or excellent rash improvement within 2 weeks as rated by a medical practitioner.
Comparison 10 Betamethasone versus dexchlorpheniramine + betamethasone, Outcome 1 The proportion of participants with resolution of itch within 2 weeks as rated by the participant.
Comparison 10 Betamethasone versus dexchlorpheniramine + betamethasone, Outcome 2 The proportion of participants with good or excellent rash improvement within 2 weeks as rated by a medical practitioner.
Comparison 11 Glycyrrhizin versus procaine, Outcome 1 The proportion of participants with good or excellent rash improvement within 2 weeks as rated by a medical practitioner.
Comparison 12 Ultraviolet phototherapy versus emollient, Outcome 1 Minor participant‐reported adverse events not requiring withdrawal of the treatment: Hyperpigmentation.
Comparison 12 Ultraviolet phototherapy versus emollient, Outcome 2 Minor participant‐reported adverse events not requiring withdrawal of the treatment: Hypopigmentation.
Comparison 12 Ultraviolet phototherapy versus emollient, Outcome 3 Minor participant‐reported adverse events not requiring withdrawal of the treatment: Burning sensation.
| Clarithromycin compared to placebo for pityriasis rosea | ||||||
| Patient or population: pityriasis rosea | ||||||
| Outcomes | Anticipated absolute effects* (95% CI) | Relative effect | № of participants | Quality of the evidence | Comments | |
| Risk with placebo | Risk with clarithromycin | |||||
| The proportion of participants with good or excellent rash improvement within 2 weeks, as rated by the participant | ‐ | ‐ | ‐ | ‐ | ‐ | Not measured |
| Serious adverse events, i.e. serious enough to require withdrawal of the treatment | ‐ | ‐ | Not estimable | 60 | ⊕⊕⊕⊝ | No participants in either group experienced serious adverse events. |
| The proportion of participants with resolution of itch within 2 weeks, as rated by the participant | Study population | RR 0.84 | 28 | ⊕⊕⊕⊝ | ‐ | |
| 667 per 1000 | 560 per 1000 | |||||
| Reduction in itch score within 2 weeks, as rated by the participant | ‐ | ‐ | ‐ | ‐ | ‐ | Not measured |
| The proportion of participants with good or excellent rash improvement within 2 weeks, as rated by a medical practitioner | Study population | RR 1.13 | 60 | ⊕⊕⊕⊝ | ‐ | |
| 767 per 1000 | 866 per 1000 | |||||
| Minor participant‐reported adverse events not requiring withdrawal of the treatment | ‐ | ‐ | ‐ | ‐ | ‐ | Not measured |
| *The risk in the intervention group (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). The assumed risk is calculated from the single‐study analysis or meta‐analysis, using the number of events or mean difference in the control group(s). | ||||||
| GRADE Working Group grades of evidence | ||||||
| aDowngraded by one level to moderate‐quality evidence for imprecision due to small sample size. | ||||||
| Erythromycin compared to placebo for pityriasis rosea | ||||||
| Patient or population: pityriasis rosea | ||||||
| Outcomes | Anticipated absolute effects* (95% CI) | Relative effect | № of participants | Quality of the evidence | Comments | |
| Risk with placebo | Risk with erythromycin | |||||
| The proportion of participants with good or excellent rash improvement within 2 weeks, as rated by the participant | ‐ | ‐ | ‐ | ‐ | ‐ | Not measured |
| Serious adverse events, i.e. serious enough to require withdrawal of the treatment | ‐ | ‐ | Not estimable | 34 | ⊕⊕⊕⊝ | No participants in either group experienced serious adverse events. |
| The proportion of participants with resolution of itch within 2 weeks, as rated by the participant | ‐ | ‐ | ‐ | ‐ | ‐ | Not reported |
| Reduction in itch score within 2 weeks as rated by the participant | The mean reduction in itch score within 2 weeks as rated by the participant was 1.76. | MD 3.95 higher | ‐ | 34 | ⊕⊕⊕⊝ | ‐ |
| The proportion of participants with good or excellent rash improvement within 2 weeks as rated by a medical practitioner | Study population | RR 4.02 | 86 | ⊕⊕⊝⊝ | ‐ | |
| 33 per 100 | 100 per 100 | |||||
| Minor participant‐reported adverse events not requiring withdrawal of the treatment: Gastrointestinal upset. | Study population | RR 2.00 | 34 | ⊕⊕⊕⊝ | ‐ | |
| 6 per 100 | 12 per 100 | |||||
| *The risk in the intervention group (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). The assumed risk is calculated from the single‐study analysis or meta‐analysis, using the number of events or mean difference in the control group(s). | ||||||
| GRADE Working Group grades of evidence | ||||||
| aDowngraded by one level to moderate‐quality evidence for imprecision due to small sample size. | ||||||
| Azithromycin compared to placebo or vitamins for pityriasis rosea | ||||||
| Patient or population: pityriasis rosea | ||||||
| Outcomes | Anticipated absolute effects* (95% CI) | Relative effect | № of participants | Quality of the evidence | Comments | |
| Risk with placebo or vitamins | Risk with azithromycin | |||||
| The proportion of participants with good or excellent rash improvement within 2 weeks, as rated by the participant | ‐ | ‐ | ‐ | ‐ | ‐ | Not measured |
| Serious adverse events, i.e. serious enough to require withdrawal of the treatment | ‐ | ‐ | Not estimable | 119 | ⊕⊕⊕⊝ | No participants in either group experienced serious adverse events. |
| The proportion of participants with resolution of itch within 2 weeks, as rated by the participant | Study population | RR 0.83 | 70 | ⊕⊕⊕⊝ | ‐ | |
| 171 per 1000 | 142 per 1000 | |||||
| Reduction in itch score within 2 weeks, as rated by the participant | The mean reduction in itch score within 2 weeks was 0.47. | MD 0.04 higher | ‐ | 70 | ⊕⊕⊕⊝ | ‐ |
| The proportion of participants with good or excellent rash improvement within 2 weeks as rated by a medical practitioner. | Study population | RR 1.02 (0.52 to 2.00) | 119 | ⊕⊕⊝⊝ | ‐ | |
| 441 per 1000 | 449 per 1000 | |||||
| Minor participant‐reported adverse events not requiring withdrawal of the treatment: Mild abdominal pain. | See comment | See comment | RR 5.82 | 119 | ⊕⊕⊕⊝ | No participants in the placebo group reported mild abdominal pain versus 5/60 participants in the azithromycin group. |
| *The risk in the intervention group (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI). | ||||||
| GRADE Working Group grades of evidence | ||||||
| aDowngraded by one level to moderate‐quality evidence for imprecision due to small sample size. | ||||||
| Acyclovir compared to placebo, vitamins, or no treatment for pityriasis rosea | ||||||
| Patient or population: pityriasis rosea | ||||||
| Outcomes | Anticipated absolute effects* (95% CI) | Relative effect | № of participants | Quality of the evidence | Comments | |
| Risk with placebo, vitamins, or no treatment | Risk with acyclovir | |||||
| The proportion of participants with good or excellent rash improvement within 2 weeks, as rated by the participant | ‐ | ‐ | ‐ | ‐ | ‐ | Not measured |
| Serious adverse events, i.e. serious enough to require withdrawal of the treatment | ‐ | ‐ | Not estimable | 141 | ⊕⊕⊕⊝ | No serious adverse events were reported in either group. |
| Proportion of participants with resolution of itch within 2 weeks, as rated by the participant | Study population | RR 0.34 | 21 | ⊕⊕⊕⊝ | ‐ | |
| 80 per 100 | 27 per 100 | |||||
| Reduction in itch score within 2 weeks, as rated by the participant | ‐ | ‐ | ‐ | ‐ | ‐ | Not reported |
| The proportion of participants with good or excellent rash improvement within 2 weeks, as rated by a medical practitioner | Study population | RR 2.45 | 141 | ⊕⊕⊕⊝ | ‐ | |
| 28 per 100 | 67 per 100 | |||||
| Minor participant‐reported adverse events not requiring withdrawal of the treatment | Study population | RR 0.31 | 141 | ⊕⊕⊕⊝ | 1 participant in the placebo group experienced abdominal pain and diarrhoea. No adverse events were reported with acyclovir. | |
| 7 per 100 | 2 per 100 | |||||
| *The risk in the intervention group (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). The assumed risk is calculated from the single‐study analysis or meta‐analysis, using the number of events or mean difference in the control group(s). | ||||||
| GRADE Working Group grades of evidence | ||||||
| aSingh 2016 and Ganguly 2014 utilised a dose of 800 mg 5 times per day for 7 days. Rassai 2011 utilised a dose of 400 mg 5 times per day for 7 days. | ||||||
| Acyclovir + calamine + cetirizine compared to cetirizine + calamine for pityriasis rosea | ||||||
| Patient or population: pityriasis rosea | ||||||
| Outcomes | Anticipated absolute effects* (95% CI) | Relative effect | № of participants | Quality of the evidence | Comments | |
| Risk with calamine + cetirizine | Risk with acyclovir + calamine + cetirizine | |||||
| The proportion of participants with good or excellent rash improvement within 2 weeks, as rated by the participant | ‐ | ‐ | ‐ | ‐ | ‐ | Not measured |
| Serious adverse events, i.e. serious enough to require withdrawal of the treatment | ‐ | ‐ | Not estimable | 24 | ⊕⊕⊝⊝ | No serious adverse events requiring withdrawal were reported in either group. |
| The proportion of participants with resolution of itch within 2 weeks, as rated by the participant | Study population | RR 4.50 | 24 | ⊕⊕⊝⊝ | ‐ | |
| 167 per 1000 | 750 per 1000 | |||||
| Reduction in itch score within 2 weeks, as rated by the participant | The mean reduction in itch score within 2 weeks was 0.58. | MD 1.26 higher | ‐ | 24 | ⊕⊕⊝⊝ | ‐ |
| The proportion of participants with good or excellent rash improvement within 2 weeks, as rated by a medical practitioner | ‐ | ‐ | ‐ | ‐ | ‐ | Not measuredb |
| Minor participant‐reported adverse events not requiring withdrawal of the treatment: Headache. | See comment | See comment | RR 7.00 | 24 | ⊕⊕⊝⊝ | No events in the control group versus 3/12 participants in the acyclovir group |
| *The risk in the intervention group (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI). | ||||||
| GRADE Working Group grades of evidence | ||||||
| aDowngraded by two levels to low‐quality evidence: one level for study limitations due to high risk of performance bias (participants were not blinded) and one level for imprecision. The sample size of this trial was only 24 (12 per group). | ||||||
| Acyclovir compared to erythromycin for pityriasis rosea | ||||||
| Patient or population: pityriasis rosea | ||||||
| Outcomes | Anticipated absolute effects* (95% CI) | Relative effect | № of participants | Quality of the evidence | Comments | |
| Risk with erythromycin | Risk with acyclovir | |||||
| The proportion of participants with good or excellent rash improvement within 2 weeks, as rated by the participant | ‐ | ‐ | ‐ | ‐ | ‐ | Not measured |
| Serious adverse events, i.e. serious enough to require withdrawal of the treatment | ‐ | ‐ | Not estimable | 30 | ⊕⊕⊕⊝ | All participants completed the trial and no adverse events are reported in either group. |
| The proportion of participants with resolution of itch within 2 weeks, as rated by the participant | See comment | See comment | RR 13.22 | 14 | ⊕⊕⊝⊝ | All 8 participants in the acyclovir group had resolution of itch versus zero in the erythromycin group. Hence, the assumed and corresponding risks could not be calculated. |
| Reduction in itch score within 2 weeks, as rated by the participant | ‐ | ‐ | ‐ | ‐ | ‐ | Not measured |
| The proportion of participants with good or excellent rash improvement within 2 weeks, as rated by a medical practitioner | ‐ | ‐ | Not estimable | 30 | ⊕⊕⊝⊝ | Zero events in both groups |
| Minor participant‐reported adverse events not requiring withdrawal of the treatment | ‐ | ‐ | Not estimable | 30 | ⊕⊕⊝⊝ | No participants in either group experienced adverse events. |
| *The risk in the intervention group (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI). | ||||||
| GRADE Working Group grades of evidence | ||||||
| aDowngraded by one level to moderate‐quality evidence for imprecision due to very small sample size and a small number of events in terms of response measures. | ||||||
| Outcome or subgroup title | No. of studies | No. of participants | Statistical method | Effect size |
| 1 The proportion of participants with resolution of itch within 2 weeks as rated by the participant Show forest plot | 1 | 28 | Risk Ratio (M‐H, Random, 95% CI) | 0.84 [0.47, 1.52] |
| 2 The proportion of participants with good or excellent rash improvement within 2 weeks as rated by a medical practitioner Show forest plot | 1 | 60 | Risk Ratio (M‐H, Random, 95% CI) | 1.13 [0.89, 1.44] |
| Outcome or subgroup title | No. of studies | No. of participants | Statistical method | Effect size |
| 1 Reduction in itch score within 2 weeks as rated by the participant Show forest plot | 1 | 34 | Mean Difference (IV, Random, 95% CI) | 3.95 [3.37, 4.53] |
| 2 The proportion of participants with good or excellent rash improvement within 2 weeks as rated by a medical practitioner Show forest plot | 2 | 86 | Risk Ratio (M‐H, Random, 95% CI) | 4.02 [0.28, 56.61] |
| 3 Minor participant‐reported adverse events not requiring withdrawal of the treatment: Gastrointestinal upset Show forest plot | 1 | 34 | Risk Ratio (M‐H, Random, 95% CI) | 2.0 [0.20, 20.04] |
| Outcome or subgroup title | No. of studies | No. of participants | Statistical method | Effect size |
| 1 The proportion of participants with resolution of itch within 2 weeks as rated by the participant Show forest plot | 1 | 70 | Risk Ratio (M‐H, Random, 95% CI) | 0.83 [0.28, 2.48] |
| 2 Reduction in itch score within 2 weeks as rated by the participant Show forest plot | 1 | 70 | Mean Difference (IV, Random, 95% CI) | 0.04 [‐0.35, 0.43] |
| 3 The proportion of participants with good or excellent rash improvement within 2 weeks as rated by a medical practitioner Show forest plot | 2 | 119 | Risk Ratio (M‐H, Random, 95% CI) | 1.02 [0.52, 2.00] |
| 4 Minor participant‐reported adverse events not requiring withdrawal of the treatment: Stomach ache Show forest plot | 2 | 119 | Risk Ratio (M‐H, Random, 95% CI) | 5.82 [0.72, 47.10] |
| 5 Minor participant‐reported adverse events not requiring withdrawal of the treatment: Diarrhoea Show forest plot | 1 | 49 | Risk Ratio (M‐H, Random, 95% CI) | 4.81 [0.24, 95.25] |
| Outcome or subgroup title | No. of studies | No. of participants | Statistical method | Effect size |
| 1 The proportion of participants with resolution of itch within 2 weeks as rated by the participant Show forest plot | 1 | 21 | Risk Ratio (M‐H, Random, 95% CI) | 0.34 [0.12, 0.94] |
| 2 The proportion of participants with good or excellent rash improvement within 2 weeks as rated by a medical practitioner: Rash by erythema only Show forest plot | 3 | 141 | Risk Ratio (M‐H, Random, 95% CI) | 2.45 [1.33, 4.53] |
| 3 The proportion of participants with good or excellent rash improvement within 2 weeks as rated by a medical practitioner: Scaling only Show forest plot | 1 | 54 | Risk Ratio (M‐H, Random, 95% CI) | 1.52 [1.14, 2.01] |
| 4 Minor participant‐reported adverse events not requiring withdrawal of the treatment Show forest plot | 3 | 141 | Risk Ratio (M‐H, Random, 95% CI) | 0.31 [0.01, 7.02] |
| Outcome or subgroup title | No. of studies | No. of participants | Statistical method | Effect size |
| 1 The proportion of participants with resolution of itch within 2 weeks as rated by the participant Show forest plot | 1 | 24 | Risk Ratio (M‐H, Random, 95% CI) | 4.5 [1.22, 16.62] |
| 2 Reduction in itch score within 2 weeks as rated by the participant Show forest plot | 1 | 24 | Mean Difference (IV, Random, 95% CI) | 1.26 [0.74, 1.78] |
| 3 Reduction in lesional score within 2 weeks as rated by the participant Show forest plot | 1 | 24 | Mean Difference (IV, Random, 95% CI) | 3.24 [2.61, 3.87] |
| 4 Minor participant‐reported adverse events not requiring withdrawal of the treatment: Headache Show forest plot | 1 | 24 | Risk Ratio (M‐H, Random, 95% CI) | 7.0 [0.40, 122.44] |
| 5 Minor participant‐reported adverse events not requiring withdrawal of the treatment: Sleepiness Show forest plot | 1 | 24 | Risk Ratio (M‐H, Random, 95% CI) | 2.0 [0.21, 19.23] |
| 6 Minor participant‐reported adverse events not requiring withdrawal of the treatment: Nausea and vomiting Show forest plot | 1 | 24 | Risk Ratio (M‐H, Random, 95% CI) | 5.0 [0.27, 94.34] |
| 7 Minor participant‐reported adverse events not requiring withdrawal of the treatment: Dysgeusia Show forest plot | 1 | 24 | Risk Ratio (M‐H, Random, 95% CI) | 3.0 [0.13, 67.06] |
| Outcome or subgroup title | No. of studies | No. of participants | Statistical method | Effect size |
| 1 The proportion of participants with resolution of itch within 2 weeks as rated by the participant Show forest plot | 1 | 14 | Risk Ratio (M‐H, Random, 95% CI) | 13.22 [0.91, 192.02] |
| Outcome or subgroup title | No. of studies | No. of participants | Statistical method | Effect size |
| 1 The proportion of participants with resolution of itch within 2 weeks as rated by the participant Show forest plot | 1 | 68 | Risk Ratio (M‐H, Random, 95% CI) | 2.91 [1.78, 4.76] |
| 2 Reduction in itch score within 2 weeks as rated by the participant Show forest plot | 1 | 70 | Mean Difference (IV, Random, 95% CI) | 0.31 [‐0.05, 0.67] |
| 3 The proportion of participants with good or excellent rash improvement within 2 weeks as rated by a medical practitioner Show forest plot | 1 | 70 | Risk Ratio (M‐H, Random, 95% CI) | 1.62 [1.23, 2.13] |
| 4 Minor participant‐reported adverse events not requiring withdrawal of the treatment: Mild gastric hyperacidity Show forest plot | 1 | 70 | Risk Ratio (M‐H, Random, 95% CI) | 5.0 [0.25, 100.53] |
| 5 Minor participant‐reported adverse events not requiring withdrawal of the treatment: Anxiety and palpitations Show forest plot | 1 | 70 | Risk Ratio (M‐H, Random, 95% CI) | 3.0 [0.13, 71.22] |
| 6 Minor participant‐reported adverse events not requiring withdrawal of the treatment: Belching Show forest plot | 1 | 70 | Risk Ratio (M‐H, Random, 95% CI) | 0.33 [0.01, 7.91] |
| 7 Minor participant‐reported adverse events not requiring withdrawal of the treatment: Stye Show forest plot | 1 | 70 | Risk Ratio (M‐H, Random, 95% CI) | 0.33 [0.01, 7.91] |
| 8 The proportion of participants with relapse at 12 weeks Show forest plot | 1 | 70 | Risk Ratio (M‐H, Random, 95% CI) | 6.0 [0.76, 47.29] |
| Outcome or subgroup title | No. of studies | No. of participants | Statistical method | Effect size |
| 1 The proportion of participants with resolution of itch within 2 weeks as rated by the participant Show forest plot | 1 | 54 | Risk Ratio (M‐H, Random, 95% CI) | 0.91 [0.51, 1.63] |
| 2 The proportion of participants with good or excellent rash improvement within 2 weeks as rated by a medical practitioner Show forest plot | 1 | 54 | Risk Ratio (M‐H, Random, 95% CI) | 0.66 [0.42, 1.06] |
| Outcome or subgroup title | No. of studies | No. of participants | Statistical method | Effect size |
| 1 The proportion of participants with resolution of itch within 2 weeks as rated by the participant Show forest plot | 1 | 42 | Risk Ratio (M‐H, Random, 95% CI) | 0.83 [0.44, 1.56] |
| 2 The proportion of participants with good or excellent rash improvement within 2 weeks as rated by a medical practitioner Show forest plot | 1 | 42 | Risk Ratio (M‐H, Random, 95% CI) | 8.16 [1.17, 57.05] |
| Outcome or subgroup title | No. of studies | No. of participants | Statistical method | Effect size |
| 1 The proportion of participants with resolution of itch within 2 weeks as rated by the participant Show forest plot | 1 | 46 | Risk Ratio (M‐H, Random, 95% CI) | 0.91 [0.51, 1.64] |
| 2 The proportion of participants with good or excellent rash improvement within 2 weeks as rated by a medical practitioner Show forest plot | 1 | 46 | Risk Ratio (M‐H, Random, 95% CI) | 12.31 [1.81, 83.52] |
| Outcome or subgroup title | No. of studies | No. of participants | Statistical method | Effect size |
| 1 The proportion of participants with good or excellent rash improvement within 2 weeks as rated by a medical practitioner Show forest plot | 1 | 23 | Risk Ratio (M‐H, Random, 95% CI) | 1.36 [0.93, 1.98] |
| Outcome or subgroup title | No. of studies | No. of participants | Statistical method | Effect size |
| 1 Minor participant‐reported adverse events not requiring withdrawal of the treatment: Hyperpigmentation Show forest plot | 1 | 100 | Risk Ratio (M‐H, Random, 95% CI) | 63.00 [3.96, 1002.01] |
| 2 Minor participant‐reported adverse events not requiring withdrawal of the treatment: Hypopigmentation Show forest plot | 1 | 100 | Risk Ratio (M‐H, Random, 95% CI) | 17.0 [1.01, 286.82] |
| 3 Minor participant‐reported adverse events not requiring withdrawal of the treatment: Burning sensation Show forest plot | 1 | 100 | Risk Ratio (M‐H, Random, 95% CI) | 7.0 [0.37, 132.10] |
