Intervenciones antiestreptocócicas para la psoriasis guttata y en placas crónica
Resumen
Antecedentes
La psoriasis es una enfermedad crónica de la piel que afecta a cerca de un 2% de la población general. La psoriasis en placas es la forma más común: por lo general, se presenta en forma de placas rojas y elevadas en la piel inflamada, cubiertas por escamas blanco‐plateadas. Las placas a menudo se presentan en forma de un patrón simétrico. La psoriasis guttata es una forma particular de psoriasis con lesiones eritematoescamosas pequeñas y diseminadas. Se presume que la infección estreptocócica es un factor desencadenante para la aparición de la psoriasis guttata y la exacerbación de la psoriasis en placas crónica. La anterior revisión Cochrane sobre este tema se publicó en 2000; requirió una actualización porque sigue en uso el tratamiento antiestreptocócico para la psoriasis, especialmente para la forma aguda de psoriasis guttata.
Objetivos
Evaluar la repercusión de las intervenciones antiestreptocócicas para la psoriasis guttata y crónica en placas.
Métodos de búsqueda
Se hicieron búsquedas en el registro especializado del Grupo Cochrane de Piel (Cochrane Skin Specialised Register), Cochrane Register of Studies Online, CENTRAL, MEDLINE, Embase, LILACS, y en cinco registros de ensayos (enero 2019). Se verificaron las listas de referencias de los estudios incluidos y excluidos y se realizaron búsquedas en las actas de congresos de la American Academy of Dermatology, Society for Investigative Dermatology, y en la European Academy of Dermatology and Venereology.
Criterios de selección
Se consideraron los ensayos controlados aleatorios (ECA) que evaluaran las intervenciones antiestreptocócicas (amigdalectomía o tratamiento con antibióticos sistémicos) en pacientes con diagnóstico de psoriasis guttata aguda y en placas crónica en comparación con un placebo, ninguna intervención o entre sí.
Obtención y análisis de los datos
Se utilizaron los procedimientos metodológicos estándar previstos por la Colaboración Cochrane. Las medidas de resultado primarias fueron: 1) tiempo hasta la resolución; ausencia o casi ausencia de lesiones de piel (Physician Global Assessment [PGA] 0 o 1; o Psoriasis Area and Severity Index [PASI] 90 o 100); 2) proporción de participantes con efectos adversos y efectos adversos graves. Los resultados secundarios fueron: 1) la proporción de participantes que logran la ausencia o casi ausencia de lesiones de la piel; 2) la proporción de participantes que logró un PASI 75 o una PGA 1 a 2; 3) el riesgo de presentar al menos una recaída en el seguimiento a largo plazo. La evaluación a corto plazo se definió como el período de ocho semanas del comienzo del tratamiento; se consideró largo plazo el período de al menos un año después del comienzo del tratamiento.
Resultados principales
Se incluyeron cinco ensayos (162 participantes asignados al azar); tres se realizaron en un departamento de dermatología del hospital. Un estudio declaró financiación por parte de una empresa farmacéutica. Las edades de los participantes variaron de 12 a 77 años; Sólo dos participantes eran menores de 15 años. La media de la puntuación PASI al inicio varió de 5,7 (leve) a 23 (severa) en cuatro estudios. De 162 participantes, 23 tuvieron un cultivo de hisopado faríngeo positivo para Streptococcus. No se realizó un metanálisis debido a la heterogeneidad de las intervenciones y las características de los participantes.
Ninguno de los ensayos midió el resultado primario de eficacia (tiempo hasta la resolución) ni el resultado secundario (riesgo de presentar al menos una recaída en el seguimiento a largo plazo).
Se calificó la calidad de los resultados como evidencia de muy baja calidad, debido al alto riesgo de sesgo (falta de cegamiento de los participantes y los cuidadores, y alto riesgo de sesgo de informe de resultados) y la imprecisión (datos de un único estudio con un número de eventos reducido). En consecuencia, hay muy poca seguridad acerca de los resultados presentados.
Psoriasis guttata
Un ensayo de tres brazos (N = 43) evaluó la penicilina (50 000 unidades internacionales [UI]/kg/día en tres dosis) versus eritromicina (250 mg cuatro veces por día)versus ningún tratamiento (tratamiento durante 14 días, con seguimiento de seis semanas desde el comienzo del tratamiento). No se midieron los eventos adversos ni la proporción de participantes que logró la ausencia o la casi ausencia de lesiones de piel.
Un ensayo (N = 20) evaluó la penicilina (1,6 MU [millones de unidades] por vía intramuscular una vez al día) versus ningún tratamiento (seis semanas de tratamiento, con seguimiento de ocho semanas desde el comienzo del tratamiento). En el seguimiento de seis semanas (corto plazo), no se observaron eventos adversos en ninguno de los grupos, y no hubo diferencias estadísticamente significativas entre los dos grupos en la proporción de participantes con ausencia o casi ausencia de lesiones de la piel (cociente de riesgos [CR] 2,00; intervalo de confianza [IC] del 95%: 0,68 a 5,85).
Un ensayo (N = 20) evaluó la rifampicina (300 mg dos veces al día) versus placebo (duración del tratamiento 14 días; seguimiento de seis semanas desde el comienzo del tratamiento); no se midió ninguno de los resultados de la revisión.
Estos ensayos no midieron la proporción de participantes que lograron un PASI de 75 o una PGA de 1 a 2.
Psoriasis en placas crónica
Un ensayo (N = 50) evaluó el tratamiento con azitromicina a largo plazo (dosis diaria de 500 mg) versus vitamina C. Los eventos adversos se informaron en el grupo de azitromicina (10 de cada 30 pacientes presentaron náuseas y molestias abdominales leves), pero no en el grupo de vitamina C. No se midió la proporción de participantes que logró la ausencia o casi ausencia de lesiones de la piel. En el grupo de azitromicina, 18/30 versus 0/20 participantes del grupo de vitamina C lograron un PASI de 75 al finalizar las 48 semanas de tratamiento (CR 25,06; IC del 95%: 1,60 a 393,59).
Un ensayo (N = 29) evaluó la amigdalectomía versus ningún tratamiento, con un seguimiento de 24 meses después de la cirugía. Un participante del grupo de amigdalectomía presentó hemorragia leve. En el seguimiento de ocho semanas, 1/15 del grupo de amigdalectomía y 0/14 del grupo de ningún tratamiento alcanzó un PASI de 90; y 3/15 participantes en el grupo de amigdalectomía y 0/14 en el grupo de ningún tratamiento logró un PASI de 75 (CR 6,56; IC del 95%: 0,37 a 116,7).
Conclusiones de los autores
Se encontraron sólo cinco ensayos (N = 162), que evaluaron los efectos de cinco comparaciones (tratamiento con antibióticos sistémicos [penicilina, azitromicina] o amigdalectomía). Dos comparaciones (eritromicina en comparación con ningún tratamiento y rifampicina en comparación con placebo) no midieron ninguno de los resultados de interés. La evidencia para los resultados medidos fue de muy baja calidad. Por lo tanto, se desconoce la eficacia y la seguridad de las intervenciones antiestreptocócicas para la psoriasis guttata y la psoriasis en placas crónica.
El riesgo de sesgo en los ensayos incluidos fue poco claro o alto y estos incluyeron sólo un número pequeño de participantes no representativos, con medición limitada de los resultados de interés. Los estudios no permitieron la investigación sobre la influencia de la infección estreptocócica, y no se evaluó una intervención clave (amoxicilina).
Se necesitan ensayos adicionales que evalúen la eficacia y la tolerancia de la penicilina V o la amoxicilina en niños y adultos jóvenes con psoriasis guttata.
PICO
Resumen en términos sencillos
¿El tratamiento de la faringitis estreptocócica mejora la psoriasis?
Pregunta de la revisión
Se buscó determinar la efectividad y la seguridad de los tratamientos para las infecciones causadas por la bacteria Streptococcus en comparación con ningún tratamiento, el placebo (un tratamiento idéntico pero inactivo) o entre sí, en pacientes con psoriasis guttata aguda o en placas crónica.
Antecedentes
La psoriasis en placas crónica es una afección a largo plazo que causa parches de piel enrojecida y cubierta con escamas (las llamadas placas); es la forma más frecuente de psoriasis y es más común en adultos.
La psoriasis guttata se caracteriza por lesiones más pequeñas y es más frecuente en niños y jóvenes. Algunos estudios han indicado que la psoriasis guttata se presenta en menos de un 30% de pacientes con psoriasis.
Se desconoce la causa, aunque la infección estreptocócica puede desencadenar la psoriasis guttata o las exacerbaciones de la psoriasis en placas crónica.
La amigdalectomía puede prevenir o reducir la gravedad de las infecciones de garganta y limitar el reservorio del Streptococcus. Los antibióticos actúan al destruir las bacterias que parecen desencadenar la psoriasis.
Características de los estudios
La evidencia está actualizada hasta enero de 2019.
Se incluyeron cinco estudios (162 participantes); tres se realizaron en los departamentos de dermatología del hospital. Los participantes tenían entre 12 y 77 años de edad (100 hombres; 62 mujeres). Un estudio fue financiado por una compañía farmacéutica. La gravedad de la afección varió de leve a severa. Se hallaron Streptococcus en la faringe de un 14% de pacientes.
Se clasificaron los resultados medidos dentro de las ocho semanas del comienzo del tratamiento como de corto plazo, y los medidos al menos un año después del comienzo del tratamiento como de largo plazo. Todos los ensayos de antibióticos en pacientes con psoriasis guttata fueron a corto plazo; el ensayo de antibióticos para la psoriasis en placas crónica duró 48 semanas.
Tres estudios incorporaron a participantes con psoriasis guttata, y evaluaron los efectos a corto plazo de los antibióticos: penicilina (20 participantes) o eritromicina en comparación con ningún tratamiento (43 participantes), y rifampicina en comparación con un placebo (20 participantes).
Dos estudios incorporaron a participantes con psoriasis en placas crónica. Un estudio evaluó la azitromicina (antibiótico) versus la vitamina C a las 48 semanas (50 participantes); uno evaluó la amigdalectomía versus ninguna intervención a las ocho semanas y a los 24 meses (29 participantes).
Resultados clave
Estos resultados están apoyados por evidencia de muy baja calidad, por lo que no hay seguridad acerca de su exactitud. Cada resultado se basa en un solo estudio.
Ningún estudio midió el resultado principal de interés, el tiempo hasta que la piel esté libre (o casi libre) de lesiones ni el riesgo de recaída por lo menos una vez durante el seguimiento a largo plazo.
No se observaron efectos secundarios cuando la penicilina se comparó con ningún tratamiento en pacientes con psoriasis guttata. Los efectos secundarios no se midieron para las comparaciones de rifampicina versus placebo ni para eritromicina versus ningún tratamiento.
En los participantes con psoriasis en placas crónica, un ensayo evaluó la azitromicina versus vitamina C, y diez participantes del grupo de azitromicina presentaron náuseas o molestias gástricas leves. Un ensayo sobre amigdalectomía versus ningún tratamiento informó de un caso de hemorragia leve en el grupo de amigdalectomía.
Dos estudios en participantes con psoriasis en placas crónica midieron la cantidad de participantes que lograban una reducción de un 75% en el Psoriasis Area and Severity Index (PASI 75). En uno, 18 de 30 participantes del grupo de azitromicina lograron un PASI de 75 versus ninguno en el grupo de vitamina C. En el otro, 3 de 15 en el grupo de amigdalectomía alcanzaron un PASI 75 versus ninguno del grupo de ningún tratamiento. Este resultado no se evaluó en los ensayos de psoriasis guttata.
No se sabe si la cantidad de participantes con psoriasis guttata que logró la ausencia o casi ausencia de lesiones de la piel difiere de los que recibieron penicilina y de los que no recibieron ningún tratamiento. Sólo un participante con psoriasis en placas crónica logró la piel casi limpia en el grupo de amigdalectomía en comparación con ninguno del grupo de ningún tratamiento. Los otros tres ensayos no midieron este resultado.
Calidad de la evidencia
No se evaluaron muchos de los resultados principales. Los resultados que se evaluaron estaban basados en evidencia de muy baja calidad, por lo que no hay mucha seguridad sobre su exactitud. Los estudios fueron muy pequeños, y tuvieron un alto riesgo de sesgo porque los participantes y los evaluadores del ensayo sabían la asignación de los tratamientos. Se necesitan más estudios para verificar si el tratamiento con antibióticos para la infección estreptocócicaacorta la duración de la psoriasis guttata aguda e impide que ésta se cronifique (psoriasis en placas crónica).
Authors' conclusions
Summary of findings
| Penicillin compared to no treatment for guttate psoriasis | ||||||
| Patient or population: guttate psoriasis Setting: inpatients in department of dermatology | ||||||
| Outcomes | Anticipated absolute effects* (95% CI) | Relative effect | № of participants | Certainty of the evidence | Comments | |
| Risk with no treatment | Risk with Penicillin | |||||
| Time‐to‐resolution: achieving PASI 90 to 100 or PGA 0 to 1 | ‐ | ‐ | ‐ | ‐ | ‐ | Not measured |
| Proportion of participants with adverse events and severe adverse events | See comment | See comment | ‐ | 20 (1 RCT) | ⊕⊝⊝⊝ | It was specified that no adverse events were observed in either group. |
| Proportion of participants achieving clear or almost clear skin (PASI 90 to 100 or PGA 0 to 1) | 300 per 1000 | 600 per 1000 (204 to 1000) | RR 2.00 (0.68 to 5.85) | 20 | ⊕⊝⊝⊝ | Study authors state that no difference was observed between baseline and 6 weeks for psoriasis severity (PASI). |
| Proportion of participants achieving PASI 75 or PGA 1 to 2 | ‐ | ‐ | ‐ | ‐ | ‐ | Not measured in either trial. PASI assessment results were only presented as mean PASI at 6 weeks. No difference was observed between the two groups in either trial. |
| Risk of having at least one relapse at long‐term follow‐up | ‐ | ‐ | ‐ | ‐ | ‐ | No long‐term follow‐up |
| *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 | ||||||
| 1Downgraded by three levels to very low certainty. Evidence was downgraded by two levels due to risk of bias. The study was at high risk of bias as the study was not blinded. The study was at unclear risk of bias for selective outcome reporting (no primary outcome stated). Evidence was downgraded further by one level due to imprecision: the study included few participants (N = 20). 2Downgraded by three levels to very low certainty. Evidence was downgraded by two levels due to risk of bias. The study was at high risk of bias as the study was not blinded and clinical assessment of psoriasis severity was subjective. The study was at unclear risk of bias for selective outcome reporting (no primary outcome stated). Evidence was downgraded further by one level due to imprecision: the study included few participants (N = 20). | ||||||
| Erythromycin compared to no treatment for guttate psoriasis | ||||||
| Patient or population: guttate psoriasis Setting: inpatients in department of dermatology | ||||||
| Outcomes | Anticipated absolute effects* (95% CI) | Relative effect | № of participants | Certainty of the evidence | Comments | |
| Risk with no treatment | Risk with erythromycin | |||||
| Time‐to‐resolution: achieving PASI 90 to 100 or PGA 0 to 1 | ‐ | ‐ | ‐ | ‐ | ‐ | Not measured |
| Proportion of participants with adverse events and severe adverse events | ‐ | ‐ | ‐ | ‐ | ‐ | Not measured |
| Proportion of participants achieving clear or almost clear skin (PASI 90 to 100 or PGA 0 to 1) | ‐ | ‐ | ‐ | ‐ | ‐ | Not measured |
| Proportion of participants achieving PASI 75 or PGA 1 to 2 | ‐ | ‐ | ‐ | ‐ | ‐ | Not measured Results were only reported as mean PASI at baseline and at 6 weeks. No difference was found between groups for mean PASI at 6 weeks. |
| Risk of having at least one relapse at long‐term follow‐up | ‐ | ‐ | ‐ | ‐ | ‐ | 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). | ||||||
| GRADE Working Group grades of evidence | ||||||
| Azithromycin compared to vitamin C for chronic plaque psoriasis | ||||||
| Patient or population: chronic plaque psoriasis Intervention: azithromycin | ||||||
| Outcomes | Anticipated absolute effects* (95% CI) | Relative effect | № of participants | Certainty of the evidence | Comments | |
| Risk with vitamin C | Risk with azithromycin | |||||
| Time‐to‐resolution: achieving PASI 90 to 100 or PGA 0 to 1 | ‐ | ‐ | ‐ | ‐ | ‐ | Not measured |
| Proportion of participants with adverse events and severe adverse events Follow‐up: 48 weeks | See comment | See comment | ‐ | 50 | ‐ | Nausea and mild abdominal upset were reported in 10/30 in the azithromycin group. There was no mention of the presence or absence of adverse events in the Vitamin C group. |
| Proportion of participants achieving clear or almost clear skin (PASI 90 to 100 or PGA 0 to 1) | ‐ | ‐ | ‐ | ‐ | ‐ | Not measured |
| Proportion of participants achieving PASI 75 or PGA 1 to 2 | See comment | See comment | RR 25.06 (1.60 to 393.59) | 50 | ⊕⊝⊝⊝ | 18/30 participants in the azithromycin group versus 0/20 in the vitamin C group. |
| Risk of having at least one relapse at long‐term follow‐up | ‐ | ‐ | ‐ | ‐ | ‐ | 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). | ||||||
| GRADE Working Group grades of evidence | ||||||
| 1Downgraded by three levels to very low certainty: 2 levels due to unclear risk of bias for selective reporting (any primary outcome was specified) and high risk of bias for incomplete outcome data, and a further one level due to imprecision (one small study, wide confidence interval) | ||||||
| Rifampicin compared to placebo for guttate psoriasis | ||||||
| Patient or population: guttate psoriasis Setting: not reported | ||||||
| Outcomes | Anticipated absolute effects* (95% CI) | Relative effect | № of participants | Certainty of the evidence | Comments | |
| Risk with placebo | Risk with rifampicin | |||||
| Time‐to‐resolution: achieving PASI 90 to 100 or PGA 0 to 1 | ‐ | ‐ | ‐ | ‐ | ‐ | Not measured |
| Proportion of participants with adverse events and severe adverse events | ‐ | ‐ | ‐ | ‐ | ‐ | Not measured |
| Proportion of participants achieving clear or almost clear skin (PASI 90 to 100 or PGA 0 to 1) | ‐ | ‐ | ‐ | ‐ | ‐ | Not measured However, no change in psoriasis severity was observed in any group at 14 days and 6 weeks. |
| Proportion of participants achieving PASI 75 or PGA 1 to 2 | ‐ | ‐ | ‐ | ‐ | ‐ | Not measured |
| Risk of having at least one relapse at long‐term follow‐up | ‐ | ‐ | ‐ | ‐ | ‐ | 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). | ||||||
| GRADE Working Group grades of evidence | ||||||
| Tonsillectomy compared to no intervention for guttate or chronic plaque psoriasis | ||||||
| Patient or population: chronic plaque psoriasis Setting: not reported | ||||||
| Outcomes | Anticipated absolute effects* (95% CI) | Relative effect | № of participants | Certainty of the evidence | Comments | |
| Risk with no intervention | Risk with tonsillectomy | |||||
| Time‐to‐resolution: achieving PASI 90 to 100 or PGA 0 to 1 | ‐ | ‐ | ‐ | ‐ | ‐ | Not measured |
| Proportion of participants with adverse events and severe adverse events | See comment | See comment | RR 2.81 (0.12 to 63.83) | 29 | ⊕⊝⊝⊝ | One participant had minor bleeding in the tonsillectomy group. No adverse events in the no treatment group. |
| Proportion of participants achieving clear or almost clear skin (PASI 90 to 100 or PGA 0 to 1) | See comment | See comment | RR 2.81 (0.12 to 63.83) | 29 | ⊕⊝⊝⊝ | No events in the control group. |
| Proportion of participants achieving PASI 75 or PGA 1 to 2 | See comment | See comment | RR 6.56 (0.37 to 116.7) | 29 | ⊕⊝⊝⊝ | No events in the control group. |
| Risk of having at least one relapse at long‐term follow‐up | ‐ | ‐ | ‐ | ‐ | ‐ | 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). | ||||||
| GRADE Working Group grades of evidence | ||||||
| 1Downgraded by three levels to very low certainty: two levels due to risk of bias (participant and caregiver were not blinded; subjective outcome) and one further level due to imprecision (only one study, small number of participants) | ||||||
Background
For an explanation of terms we used in this review, please see Table 1.
| Term | Explanation |
| Acute pharyngitis | Inflammation of the mucous membrane of the pharynx; sore throat |
| Adenotonsillectomy | Surgical removing of tonsils and adenoids |
| Anaphylactic shock | Allergic reaction characterised by swelling, collapse, and respiratory distress |
| Antistreptolysin O titre | Blood test to measure antibodies against streptolysin O, a substance produced by group A Streptococcus bacteria |
| Beta‐haemolytic streptococcus | Pathogenic Streptococci, anaerobic bacteria, gram positive, often arranged in a chain |
| Chronic tonsillitis | Constant or recurrent infection of tonsils |
| Cytokines | Broad category of small proteins that are important in cell signalling. They are released by cells, and affect the behaviour of other cells and sometimes the releasing cell itself |
| Cutaneous lymphocyte–associated antigen (CLA) | The CLA is a fucose‐containing carbohydrate that is attached to P‐selectin glycoprotein ligand‐1 on T cells. CLA is expressed on the surface of most T cells recovered from skin, and on about 5% to 10% of circulating CD8+ T cells |
| Dendritic cells | A subtype of white blood cells |
| Epidermal | Related to the outer layer of the skin |
| Epidermal hyperplasia | Abnormal increase in the number of normal cells in the epidermis of the skin, which increases its volume |
| Erythematous | Redness of the skin |
| Erythematosquamous | Redness and covered with scales |
| Hyperkeratosis | Thickening of the cornea |
| Histological | Related to the examination of a piece of tissue, with a microscope |
| Homozygous | Having identical pairs of genes for any given pair of hereditary characteristics |
| Heterozygous | Having dissimilar pairs of genes for any given pair of hereditary characteristics |
| Interleukin 17 (IL‐17) | A pro‐inflammatory cytokine |
| Immune‐mediated disease | Group of conditions or diseases that lack a definitive etiology, but that are characterised by common inflammatory pathways leading to inflammation, and which may result from, or be triggered by, a dysregulation of the normal immune response |
| Keratinocytes | The most important cell type in the epidermis, the most superficial layer of the skin |
| Macrolide antibiotics | A specific family of antibiotics |
| Neutrophils | A subtype of white blood cells |
| Psoriasis Area Severity Index (PASI) | Index used to express the severity of psoriasis. It combines the severity (erythema or redness, induration, and desquamation) and percentage of the affected area |
| Physician Global Assessment (PGA) | Average assessment of all psoriatic lesions based on erythema (redness), scale, and induration |
| Pathogens | Micro‐organisms responsible for infection (such as virus or bacteria) |
| Pathophysiology, physiopathological | Convergence of pathology with physiology. Pathophysiology seeks to explain the physiological processes or mechanisms whereby a condition develops and progresses |
| Ribonucleic acid (RNA) | Polymeric molecule. It is involved in a range of biological roles in coding, decoding, regulation, and expression of genes |
| Serology/serologic | Refers to the diagnostic identification of antibodies in the serum |
| Stevens‐Johnson syndrome | Allergic reaction to a drug characterised by mucous membrane and skin epidermal necrolysis and involving less than 10% of the entire body surface |
| Toxic epidermal necrolysis | Allergic reaction to a drug characterised by mucous membrane and skin epidermal necrolysis and involving more than 30% of the entire body surface |
| T lymphocytes, T cells | A subtype of a white blood cell |
Description of the condition
Psoriasis is a common, chronic inflammatory disorder that primarily affects the skin, and sometimes the joints. Guttate psoriasis is a particular form of psoriasis, characterised by a distinct clinical presentation with widespread small (0.5 to 1.5 cm) erythematosquamous lesions, located mainly on the trunk. It has an acute onset and a possibility of spontaneous resolution. Plaque psoriasis is the most common form of psoriasis. It typically appears as raised and well‐demarcated red areas of inflamed skin covered with silvery white scales; it often shows a symmetrical distribution on the body. Antibiotics or tonsillectomy have been proposed as treatments for guttate psoriasis or flares of chronic plaque psoriasis; these treatments were introduced on the basis of the suspected relationship between infections with beta‐haemolytic Streptococci (which can cause a throat infection, and more rarely perianal Streptococcal dermatitis) and acute manifestations of psoriasis (Telfer 1992).
Epidemiology
Psoriasis affects approximately two per cent of the general population, with equal distribution between the sexes (Parisi 2013). There are several forms of psoriasis, and different clinical presentations can be observed in the same person, either simultaneously or over time. Among these, chronic plaque psoriasis (psoriasis vulgaris) accounts for 90% of cases (Griffiths 2007). The prevalence of guttate psoriasis has not been clearly reported, but several studies cite a prevalence of less than 30% among people with psoriasis (Kundakci 2002; Kwon 2012; Rigopoulos 2010; Valenzuela 2011).
Clinical presentation and natural history
Chronic plaque psoriasis presents as erythematous plaques, which have a precise outline. They have a scaly surface. The plaques are usually located on the elbows, the knees, and the scalp, but the nails, hands, feet, and trunk are also frequently affected sites. Plaque size can vary from a minimal area to coverage of the entire body (Wolff 2009). Plaque psoriasis is a chronic disease with severity fluctuation over time. It is more common in adults than in children, with an increasing incidence with age up to around 40 years, and a second peak at around 50 to 59 years (Parisi 2013).
Guttate psoriasis is an eruptive form of psoriasis, with small lesions and a greater tendency toward spontaneous resolution. It typically appears in young adults and children with no previous history of psoriasis, where it is referred to as 'acute guttate psoriasis' (Mercy 2013). Sometimes, it occurs in people who already have chronic plaque psoriasis, where it is called a 'guttate flare of chronic psoriasis' (Chalmers 2001). Although guttate psoriasis is usually considered a form of psoriasis with a better prognosis, few studies have evaluated its long‐term clinical course.
Based on limited data, guttate psoriasis is considered a form that resolves spontaneously after a few months (Ko 2010), from which one‐ to two‐thirds of participants will subsequently develop a form of chronic plaque psoriasis (Ko 2010; Martin 1996; Williams 1976). There is little information on the rate at which people develop a chronic form of psoriasis after experiencing a first episode of acute guttate psoriasis. Rates of chronic plaque psoriasis after a first episode of guttate psoriasis vary in different studies: Martin 1996 found 33% of people developed it within 10 years after a first episode of guttate psoriasis; Ko 2010 found 36% developed chronic plaque psoriasis within six years; and Williams 1976 found 68% developed chronic plaque psoriasis within one year. The risk of recurrence of guttate psoriasis after a first resolved episode is also unknown. Mean time to disease clearance was 3.9 ± 2.4 months (Ko 2010).
The diagnosis of cutaneous psoriasis is clinical. A skin biopsy can be used to confirm the diagnosis in difficult cases.
Pathophysiology
The pathogenesis of psoriasis is still not fully known. An inflammatory immune response involving T lymphocytes, dendritic cells, neutrophils, and keratinocytes leads to a rapid turnover of skin renewal and histological inflammatory infiltrate, characteristic of psoriasis (Newman 2008).
Psoriasis occurs in people with a genetic predisposition (Elder 2010). Factors that can exacerbate it include skin trauma, smoking, alcohol, emotional stress, or drugs (Berth‐Jones 2005). Pathogens, notably beta‐haemolytic Streptococci, are considered to be triggering factors (Picciani 2013). A nested case‐control study on a database from the United Kingdom examined exposure to systemic antibacterial prescriptions and infections within two years prior to a diagnosis of psoriasis in children with newly diagnosed psoriasis (N = 845) compared with age‐ and sex‐matched controls (N = 8450). Infections of skin (adjusted odds ratio (aOR) 1.5, 95% confidence interval (CI) 1.2 to 1.7) and other sites (aOR 1.3, 95% CI 1.1 to 1.6) were associated with newly diagnosed psoriasis in children (Horton 2016). The link between acute guttate psoriasis and flares of chronic plaque psoriasis and Streptococcal infection is suspected but not proven.
Infections with beta‐haemolytic Streptococci, which can cause a throat infection, and more rarely, perianal Streptococcal dermatitis (Ledoux 2009), may lead to acute guttate psoriasis, and are also suspected to cause flares of chronic plaque psoriasis (Gudjonsson 2003). (Where we refer to Streptococcal or Streptococcus in this section, we specifically mean beta‐haemolytic Streptococci.) In one study, streptococci were isolated from the throats of 97% of people with guttate psoriasis (Tervaert 1970), while in two earlier studies, serologic evidence of recent Streptococcal infection was found in 56% and 85% of people (Norrlind 1955; Whyte 1964). In a prospective study, 58% of people with acute guttate psoriasis versus 26% of people with guttate exacerbations of chronic psoriasis had serologic evidence for recent Streptococcal infection (Telfer 1992). A relationship between Streptococci and chronic plaque psoriasis was also proposed in a prospective study, in which people with psoriasis reported a sore throat 10 times more often than controls in the same household, and Streptococcal throat infections could cause exacerbation of chronic plaque psoriasis (Gudjonsson 2003). However, as serological evidence is no longer considered a relevant test, the strength of the conclusions of these studies became weaker (Shulman 2012). In addition to these studies that highlighted an association without established causality, in vitro studies put forward the superantigen theory to explain the interaction between psoriasis and infection (Abe 1991; Kotzin 1993; Leung 1995; Valdimarsson 1997). Some bacteria are superantigens, which means that they are able to trigger multiple immune reactions, leading to the stimulation of different T cells and activation of cytokines (Kotzin 1993). A recent study showed the direct involvement of Streptococcal infection in pathological mechanisms of psoriasis, such as interleukin 17 (IL‐17) production and epidermal cell activation: Streptococcal throat extracts (isolated from the throats of participants with psoriatic), added to the cultures of epidermal cells, which were obtained by skin biopsy of psoriatic lesions, led to the activation of circulating psoriatic cutaneous lymphocyte–associated antigen memory T cells (Ferran 2013).
Description of the intervention
Antistreptococcal interventions include tonsillectomy or antibiotic treatment. These antistreptococcal treatments are not recommended in current guidelines; however, these guidelines addressed only chronic plaque psoriasis in adulthood, except the NICE guideline, in which phototherapy is recommended for acute guttate psoriasis (NICE 2017).
Tonsillectomy
Tonsillectomy is a surgical procedure during which the tonsils are removed; it is carried out under general anaesthesia. Recurrent acute pharyngitis and chronic tonsillitis are the most common reasons for tonsillectomy in adults. A Cochrane Review showed a modest benefit of tonsillectomy or adenotonsillectomy in the treatment of recurrent acute tonsillitis in children (Burton 2009). Most published studies refer to a paediatric population, and the small amount of information available about adult sore throat and the effect of tonsillectomy suggests that surgery is beneficial, but the evidence for this is not robust (Laing 1991; Paradise 1984; SIGN 2010). Tonsillectomy is associated with morbidity that includes possible hospitalisation, the risk of anaesthesia, and prolonged throat pain; there are also financial costs to consider (SIGN 2010). Bleeding during or after surgery is not uncommon, and there may be other complications (Baugh 2011).
Antibiotics
Antibiotics are recommended for acute sore throat, or for those with chronic recurrent sore throat. Treatment for people with Group A Streptococcal (GAS) pharyngitis, recommended by the Infectious Diseases Society of America (IDSA), is 10 days of: phenoxymethylpenicillin (penicillin V) 250 mg four times daily or 500 mg twice daily; or amoxicillin 50 mg/kg once daily (maximum of 1000 mg) or 25 mg/kg (maximum of 500 mg) twice daily (Shulman 2012; Tanz 2007).
For the treatment of GAS, few antibiotic regimens have been evaluated prospectively in randomised controlled trials, and in the literature, there are a few studies about the eradication of Streptococcal transmission (Shulman 2012). The most common adverse effects of antibiotics are gastrointestinal disorders. However, rare serious adverse effects, which are sometimes life‐threatening, such as a bacterial overgrowth (pseudomembranous colitis by overgrowth of Clostridium difficile bacteria) or allergic reactions (anaphylactic shock, Stevens‐Johnson syndrome, or toxic epidermal necrolysis), are also described. At the population level, the use of antibiotics must be limited because of the emergence of bacterial resistance to antibiotics (Baugh 2011; Burton 2009; Shulman 2012; SIGN 2010).
Treatments recommended for chronic plaque psoriasis are topical therapy (topical corticosteroids or vitamin D analogues, or both), phototherapy, and systemic therapy (non‐biological or biological). In current practice, some physicians prescribe antibiotics for acute guttate psoriasis in a context of pre‐existing or concomitant infection, mainly pharyngitis, as first‐line treatment, or in addition to recommended treatments. However, surveys carried out in different countries, and studies of the prescribing patterns of dermatologists, general practitioners, or paediatricians for children with psoriasis, did not mention the use of antibiotic therapy (Augustin 2013; De Jager 2009; Mahe 2018; Vogel 2012).
How the intervention might work
It is thought that by eradicating Streptococcus, antistreptococcal interventions will stop the superantigen activity of Streptoccocus, which is suspected of triggering the immune reactions responsible for psoriasis, and so may improve or clear an acute flare of guttate psoriasis, and decrease or inhibit flares of chronic plaque psoriasis.
Removing the tonsils, which are a site of Streptococcus infection and a Streptococcus reservoir, may prevent throat infections, reduce the severity of throat infections, or limit the Streptococcus reservoir (Burton 2009).
Why it is important to do this review
Despite the fact that guidelines on psoriasis no longer recommend the use of antistreptococcal interventions (SIGN 2010), antibiotics continue to be perceived as a good treatment option, especially for the acute form of guttate psoriasis. This is because epidemiological and in vitro studies report arguments in favour of a link between psoriasis flare and Streptococcal infection. As the previous Cochrane Review is old, it is important to conduct a new assessment of the available evidence on the efficacy and safety of antistreptococcal interventions (Owen 2000). We chose to do this by drafting a new protocol because we changed the objectives and outcomes of the original review (Dupire 2015).
Objectives
To assess the effects of antistreptococcal interventions for guttate and chronic plaque psoriasis.
Methods
Criteria for considering studies for this review
Types of studies
We included randomised controlled trials (RCTs), including multi‐arm trials.
Types of participants
We included participants with clinically diagnosed acute guttate or chronic plaque psoriasis. In cases where studies only include a subset of relevant participants, we only included the study if the characteristics of participants and results were provided separately, or could be obtained through contact with authors.
Types of interventions
We considered any antistreptococcal antibiotic therapies, or tonsillectomy compared with placebo or no intervention, or comparisons between each other.
Types of outcome measures
Primary outcomes
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Time to resolution (time between inclusion and resolution), where resolution was defined as participants achieving clear or almost clear skin (Physician Global Assessment (PGA) 0 or 1; or Psoriasis Area and Severity Index (PASI) 90, which refers to at least 90% reduction, or PASI 100, which refers to 100% reduction in the PASI score)
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Proportion of participants with adverse effects, and severe adverse effects
Secondary outcomes
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Proportion of participants achieving clear or almost clear skin (PGA 0 or 1 or PASI 90 or 100)
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Proportion of participants achieving PASI 75 or PGA 1 to 2
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Risk of having at least one relapse at long‐term follow‐up.
Timing of outcomes
By short‐term, we mean within eight weeks of the start of treatment, and by long‐term, we mean at least one year after the start of treatment.
Search methods for identification of studies
We aimed to identify all relevant RCTs, regardless of language or publication status (published, unpublished, in press, or in progress).
Electronic searches
The Cochrane Skin Information Specialist searched the following databases up to 23 January 2019, using strategies based on the draft strategy for MEDLINE in our published protocol (Dupire 2015):
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the Cochrane Skin Specialised Register, using the search strategy in Appendix 1;
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the Cochrane Infectious Diseases Specialised Register and the Cochrane Sexually Transmitted Infections Specialised Register via the Cochrane Register of Studies Online (CRSO), using the strategy in Appendix 2;
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the Cochrane Central Register of Controlled Trials (CENTRAL) 2019, Issue 1, in the Cochrane Library, using the strategy in Appendix 3;
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MEDLINE Ovid (from 1946), using the strategy in Appendix 4;
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Embase Ovid (from 1974), using the strategy in Appendix 5; and
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LILACS (Latin American and Caribbean Health Science Information database, from 1982), using the strategy in Appendix 6.
Trials registers
We searched the following trials registers, up to 24 January 2019, with the search term 'psoriasis':
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the ISRCTN registry (www.isrctn.com);
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ClinicalTrials.gov (www.clinicaltrials.gov);
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the Australian New Zealand Clinical Trials Registry (www.anzctr.org.au);
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the World Health Organization International Clinical Trials Registry Platform (ICTRP (apps.who.int/trialsearch/)); and
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the EU Clinical Trials Register (www.clinicaltrialsregister.eu).
Searching other resources
References from included studies
We checked the bibliographies of included and excluded studies for further references to relevant trials.
Contacting prominent authors in the field
We attempted to contact authors of included trials, in order to identify additional published or unpublished data.
Handsearching
We searched the following conference proceedings for years not included in the Cochrane Skin Specialised Register:
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American Academy of Dermatology (AAD) for 2008 and 2009, and from 2012 to 2016;
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Society for Investigative Dermatology (SID) from 2008 to 2016; and
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European Academy of Dermatology and Venereology (EADV) from 2008 to 2014.
Adverse effects
We did not perform a separate search for adverse effects of the target intervention. However, we examined data on adverse effects from the included studies we identified.
Data collection and analysis
We included 'Summary of findings' tables in our review for all comparisons, which we created with GRADEpro GDT software (GRADEpro GDT). In these, we summarised all of our primary and secondary outcomes (see section 12.2 of the Cochrane Handbook for Systematic Reviews of Interventions (Higgins 2011)).
Some parts of the methods section of this review uses text that was originally published in another Cochrane protocol (Le Cleach 2011).
Selection of studies
Two review authors (GD and CD) independently examined each title and abstract to exclude obviously irrelevant reports; they then independently examined the full text of potentially relevant articles to determine eligibility. These review authors discussed any disagreements with a third author (LLC) to reach consensus. We contacted study authors for clarification when necessary. We listed excluded studies, and document the primary reason for exclusion.
Data extraction and management
Two review authors (GD and CD) independently extracted the data from published and unpublished reports, using a standardised form. The team piloted this data extraction form on a set of included trials. A third author (LLC) was involved to resolve any disagreements on data extraction between the two review authors. We extracted from each included trial: study design, inclusion and exclusion criteria, baseline characteristics of the total number of participants randomised to each intervention, description of interventions and outcomes. We extracted these data to populate the 'Characteristics of included studies' tables. One review author (GD) checked and entered data into Review Manager 5 computer software (Review Manager 2014). We contacted the authors of the studies to provide missing data when required.
Assessment of risk of bias in included studies
Two review authors (GD and CD) independently used Cochrane's 'Risk of bias' tool to assess the risk of bias of each of our included studies. They discussed disagreements with a third author (LLC) to reach consensus. We determined the risk of bias as 'low', 'high', or 'unclear' for each of the following domains, according to the general principles in section 8.4 of the Cochrane Handbook for Systematic Reviews of Interventions (Higgins 2011):
Selection bias
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Was the allocation sequence adequately generated? We considered randomisation adequate if the allocation sequence was generated from a table of random numbers or by computer. We considered it inadequate if sequences could be related to prognosis. We considered it unclear if it was stated that the trial was randomised, but the method was not described.
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Was allocation adequately concealed? We deemed allocation concealment adequate if the report stated that it was undertaken by means of sequentially pre‐numbered, sealed, opaque envelopes, or by a centralised system. We considered a double‐blind double‐dummy process at low risk of bias, even if the method of allocation concealment was not described.
Performance and detection bias
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Was knowledge of the allocated intervention adequately prevented during the study? We evaluated the risk of bias separately for personnel and participants, outcome assessors, and each outcome. In trials that compared pharmaceutical interventions (antibiotics) with placebo, if the presentation of the interventions was the same, we considered the blinding adequate, even in cases where there was no precise description of the blinding procedure.
Attrition bias
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Were incomplete outcome data adequately addressed? We examined if there was an imbalance across intervention groups in numbers or reasons for missing data, the types of measures undertaken to handle missing data, and whether the analysis was carried out on an intention‐to‐treat basis. We assessed the use of strategies to handle missing data.
Reporting bias
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Are reports of the study free of suggestion of selective outcome reporting? We evaluated whether each outcome was measured, analysed, and reported. We compared outcomes specified in study protocols (if available e.g. on trial registers), and in the methods sections, with outcomes presented in the results.
Other bias
We did not fulfil the 'other risk of bias' item, as we did not highlight particular circumstances leading to other risks of bias from particular trial designs, contamination between the experimental and control groups, or particular clinical settings.
Measures of treatment effect
For each pair‐wise comparison and each dichotomous outcome, we used risk ratios (RR) with 95% confidence intervals (CI) as a measure of treatment effect.
For time‐to‐event outcomes, we had planned to combine estimates of log hazard ratios and standard errors obtained from results of Cox proportional hazards regression models, using the generic inverse‐variance method; however, no time‐to‐event outcomes were available in the included trials.
Unit of analysis issues
The primary unit of analysis was the participant. We included only the first phase of cross‐over studies because of the risk of carry‐over bias and the unpredictable evolution of psoriasis, which may have an effect in subsequent phases.
Dealing with missing data
We extracted the number of randomised and analysed participants from each included trial. We requested missing data from trial authors or sponsors, by email. For missing data, we used simple imputation methods. We assumed that all missing data were either events or non‐events (Higgins 2011).
Assessment of heterogeneity
We had planned to assess statistical heterogeneity by visual inspection of the forest plots and by calculating I² statistics. We had planned to interpret the I² statistic value according to the following thresholds (section 9.5.2 of the Cochrane Handbook for Systematic Reviews of Interventions (Higgins 2011)):
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0% to 40% might not be important;
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30% to 60% may represent moderate heterogeneity;
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50% to 90% may represent substantial heterogeneity; and
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75% to 100% represents considerable heterogeneity
Assessment of reporting biases
To address publication bias, we had planned to draw contour‐enhanced funnel plots for each meta‐analysis if 10 or more studies had contributed data to our outcomes (Egger 1997). We did not draw funnel plots because of the insufficient number of included studies.
Data synthesis
We had planned to undertake meta‐analyses only if we judged participants, interventions, comparisons, and outcomes to be sufficiently similar. In cases of heterogeneity, we had planned to use a random‐effects meta‐analysis to combine studies. In cases of multi‐arm trials, we had planned to combine groups to create a single pair‐wise comparison. We had not planned to combine studies in a meta‐analysis if the value of the I² statistic exceeded 75%, because this represents considerable heterogeneity. It was not possible to combine any data because of the small number of trials, and the absence of multiple trials comparing the same intervention and measuring our planned outcomes.
Subgroup analysis and investigation of heterogeneity
We had planned to investigate the influence of the presence, absence, or unknown status of an active Streptococcal infection at the time of treatment onset, via subgroup analyses. According to the IDSA guidelines, cultures or rapid antigen detection tests (RADT) are recommended rather than antibody titers that only become positive several weeks after the end of infection. We considered the results of these tests for subgroup analyses (Shulman 2012).
We also planned to investigate the following two characteristics:
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guttate versus plaque psoriasis
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tonsillectomy versus antibiotic therapy.
In the absence of meta‐analyses, we did not carry out any subgroup analyses.
Sensitivity analysis
For studies at higher risk of bias, we had planned to conduct sensitivity analyses. We had planned to perform sensitivity analysis to assess how sensitive the results were to reasonable changes in the assumptions we may have made with regard to missing data. In the absence of meta‐analysis, we did not carry out any sensitivity analyses.
Results
Description of studies
Results of the search
The searches of the electronic databases retrieved 414 records. The searches of other sources (e.g. handsearching conference proceedings, the Federal Drug Administration (FDA) reviews and the World Heatlh Organization (WHO) International Clinical Trials Registry Platform) identified one additional trial. After duplicate records were removed, we had 413 records.
We excluded 389 records based on titles and abstracts. We examined the full text of the remaining 24 citations. We excluded 13 studies reported in 16 papers; one was excluded based on the abstract as no full text could be obtained; see Characteristics of excluded studies (Masood 1997). We did not identify any relevant ongoing studies. We classified one study as awaiting classification; see Characteristics of studies awaiting classification. We included five trials, reported in seven papers; see Characteristics of included studies.
For a further description of our screening process, see the study flow diagram (Figure 1).
Flow diagram describing the searches and screening of studies
We obtained additional information via email for one trial (Thorleifsdottir 2012).
Included studies
We included five studies, involving 162 randomised participants; see the 'Characteristics of included studies' tables.
Trial design
All of the trials were parallel‐arm trials: four trials assessed two arms and one trial included three arms (Dogan 2008). Three were single‐centre trials (Caca‐Biljanovska 2002; Dogan 2008; Thorleifsdottir 2012), one was a multicentric trial (two centres (Saxena 2010)), and the information was not reported in one (Vincent 1992). Trials were carried out in Turkey (Dogan 2008), the Republic of Macedonia (Caca‐Biljanovska 2002), Iceland (Thorleifsdottir 2012), India (Saxena 2010), and for one, the information was not provided (Vincent 1992). Total duration of follow‐up was six weeks (Dogan 2008; Vincent 1992) to eight weeks (Caca‐Biljanovska 2002), for the three trials assessing guttate psoriasis; and 48 weeks (Saxena 2010) to two years (Thorleifsdottir 2012), for two trials assessing chronic plaque psoriasis.
One trial declared pharmaceuticals funding (Vincent 1992), one institutional funding (Thorleifsdottir 2012), one no funding (Saxena 2010); there was no information about funding for the other two trials. The setting described in three trials was a dermatology hospital department (Caca‐Biljanovska 2002; Dogan 2008; Saxena 2010); the setting of the other two trials was not reported.
Participants
The mean number of participants randomised per trial was 32 (minimum 20 to maximum 50). A total of 92 participants were included in intervention arms, and 70 in placebo or no treatment arms.
Participants' age varied from 12 to 77 years.
In total, 62 participants were female and 100 were male; one trial included only men (Dogan 2008).
In three trials, all participants had guttate psoriasis (Caca‐Biljanovska 2002; Dogan 2008; Vincent 1992); in two trials, all participants had chronic plaque psoriasis (Saxena 2010; Thorleifsdottir 2012).
Mean Psoriasis Area and Severity Index (PASI) score at baseline was 5.7, 10.6, 11.9, and 23 in Caca‐Biljanovska 2002; Dogan 2008; Saxena 2010; Thorleifsdottir 2012, respectively, corresponding to mild, moderate, and severe psoriasis. The PASI score was not provided in Vincent 1992.
Four trials took throat swabs (Caca‐Biljanovska 2002; Dogan 2008; Saxena 2010; Vincent 1992). All cultures of nose and throat swabs were negative in Caca‐Biljanovska 2002; 8/43 (17%) were positive for β‐haemolytic streptococcus in Dogan 2008, 1/20 participants were positive for β‐haemolytic Streptococcal in Vincent 1992, and 14/29 were positive for streptococcus in Thorleifsdottir 2012 (additional information provided by the author by email). In one trial, the authors reported the results of the throat swab culture as equivocal (Saxena 2010).
Interventions
Systemic antibiotic therapy
Four trials assessed systemic antibiotic therapy; penicillin (1.6 MU (million units) given intermuscularly (IM) once a day for six weeks was compared to no treatment (Caca‐Biljanovska 2002), oral azithromycin (500 mg daily dose, given orally for four days with a gap of 10 days, repeated 24 times) was compared to vitamin C (Saxena 2010), and oral rifampicin (300 mg twice daily given for 14 days) was compared to placebo (Vincent 1992). Oral erythromycin (250 mg four times a day) was compared to oral phenoxymethylpenicillin (50,000 IU/kg/d in three doses), and to no treatment for 14 days (Dogan 2008).
All of the participants in two trials received a co‐intervention, namely topical betamethasone dipropionate 0.05% cream and phototherapy in Caca‐Biljanovska 2002, and penicillin V or erythromycin 250 mg four times a day for 14 days in Vincent 1992.
The total duration of each trial was as follows: 8 weeks (Caca‐Biljanovska 2002), 48 weeks (Saxena 2010), and 6 weeks (Dogan 2008; Vincent 1992).
Tonsillectomy
Tonsillectomy was compared to no intervention in one two‐year long trial (Thorleifsdottir 2012). Topical or systemic psoriasis treatment was allowed, if needed by the participant.
Outcomes
Our primary outcome, time‐to‐achieve clear or almost clear status, was not reported in any included study. Adverse events were not reported in two trials (Dogan 2008; Vincent 1992), reported in only one group in another (Saxena 2010), and obtained through email contact with the author for one trial (Thorleifsdottir 2012); see Table 2 for details on study author contact.
| Author | Date contacted | Reply |
| Dr Dogan | 6 October 2012; 17 October 2012 | No answer |
| Dr Saxena | 29 March 2016; 18 April 2016 | No answer |
| Dr V’lckova‐Laskoska | 29 March 2016; 18 April 2016 | No answer |
| Dr Vladimarsson | 29 March 2016; 18 April 2016; 21 April 2016 | 1. Did you have primary or secondary outcomes?
2. Could you give me more information concerning the results?
3. Did you have patients with secondary effects ?
4. Concerning the relapse of participants:
4. How did you perform the sequence generation (table, computer)? 5. How did you perform the allocation concealment? Reply:
6. What was the setting of the study ?
7. Did you perform throat swab before/during your study? If yes, what was the result?
8. Concerning the proportion of participants having at least one relapse at long‐term follow‐up (at least one year after the start of treatment) after randomisation: did you follow the control group or only the tonsillectomy Group?
|
| Dr Vincent | No email address found | ‐ |
Concerning our secondary outcomes, two of the five included trials reported the proportion of participants achieving clear or almost clear skin (Physician Global Assessment (PGA) 0 or 1, or PASI 90 or 100 (Caca‐Biljanovska 2002; Thorleifsdottir 2012)), and the proportion of participants achieving PASI 75 or PGA 1 to 2 (Saxena 2010; Thorleifsdottir 2012). One reported partially on the risk of having at least one relapse at long‐term follow‐up (Thorleifsdottir 2012).
The primary outcome chosen by the study authors was not stated in four of the five trials, and was uncertain in one trial. One trial provided no information in the main publication, but we were able to obtain more information by contacting the study author, and by reading a secondary report on the study. The study author stated that the primary outcome was a reduction in the PASI score, with a coinciding decrease in the blood frequency of T lymphocytes, which recognise auto‐antigens in the skin. However, in a secondary publication, the authors stated that the primary endpoints were defined as clinically significant changes in HRQoL (health‐related quality of life), assessed by the Psoriasis Disability Index (PDI) and the Psoriasis Life Stress Inventory (PLSI), at 12 and 24 months (Thorleifsdottir 2012).
PASI was assessed in all trials, reported as the decrease of mean PASI scores from baseline in each group, or rate of PASI reduction, or rate of participants achieving PASI 75. Physician clinical assessment was assessed on a scale from 0 to 4, or 0 to 5 in two trials. No numerical results for efficacy assessment were available for one trial (Vincent 1992), and were presented only in figures, with no numerical data, for another (Thorleifsdottir 2012).
Excluded studies
Reasons for exclusion were described in the 'Characteristics of excluded studies' tables. We excluded 16 reports corresponding to 13 studies, for one of which, we were unable to obtain more than an abstract. The main reason for exclusion was absence of randomisation, which was true in seven of the excluded studies.
Studies awaiting classification
One study, registered in clinicaltrials.gov in 2007, comparing bicillin L‐A to placebo in participants with chronic plaque psoriasis, was terminated in 2015 because there were "not enough enrollees to obtain". We were not able to find a report of the results or to contact the lead author, so we considered it to be awaiting classification (NCT00427609).
Ongoing study
We found no ongoing studies.
Risk of bias in included studies
We summarised 'Risk of bias' assessments in Figure 2 and Figure 3. All trials were at high risk of bias in at least two domains. Figure 2 presents our judgements about each risk of bias item, presented as percentages across all included studies. Figure 3 presents each risk of bias item for each included study.
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
Randomisation was never described as centralised. The report for three trials did not contain the description of the process of allocation sequence generation, and we considered them at unclear risk of bias for generation of sequence generation. In Saxena 2010, there was an important difference in PASI evaluation scores at baseline between groups that could be interpreted as a failure of the randomisation process. Sequence generation was reported, and was adequate for two others (Caca‐Biljanovska 2002; Thorleifsdottir 2012).
Allocation concealment
Methods to guarantee allocation concealment were not reported in any of the five trials. Thus, we considered all trials at unclear risk of bias for allocation concealment.
Blinding
Performance bias
In four trials, participants and caregivers were presented as not blinded, and we considered them at high risk of bias. One trial was described as single blind, however, they did not clearly explain who was supposed to be blind, the participant or the assessor, and the comparator was not a real placebo, but a vitamin C tablet, so we considered it was at unclear risk of bias for performance bias (Saxena 2010).
Detection bias
As all outcomes are subjective, absence of blinding was considered to be a high risk of bias. For two trials, the assessor was not blinded, and we considered them at high risk of detection bias (Caca‐Biljanovska 2002; Vincent 1992). In two trials, the assessor was described as blinded; however as participants were not blinded, and no information was provided regarding specific measures undertaken to avoid communication on treatment between assessor, caregiver, and participants, we considered these trials at unclear risk of detection bias. We only considered one trial at low risk (Thorleifsdottir 2012).
Incomplete outcome data
We considered this item at unclear risk of bias for three trials, as no information on the number of withdrawals or the methods used to manage missing data was provided (Caca‐Biljanovska 2002; Dogan 2008; Vincent 1992). We considered Saxena 2010 at high risk of bias, as an intention‐to‐treat analysis was not performed, and there was an unbalanced number of withdrawal between the two groups. One trial specified that no participant withdrew, and we considered it at low risk (Thorleifsdottir 2012).
Selective reporting
None of the included trials were registered in a trial registry. Four trials did not state the primary outcome. Among these, one did not report all the outcomes described in the methods section, and we considered it at high risk of bias for selective outcome reporting (Vincent 1992). We considered the three others at unclear risk of bias. For one study, the primary outcome was not stated in the main publication, and the primary outcome stated by the author in an email and the secondary publication were different, so we rated this trial at high risk of bias (Thorleifsdottir 2012).
Other potential sources of bias
None identified.
Effects of interventions
See: Summary of findings for the main comparison Penicillin compared to no treatment for guttate psoriasis; Summary of findings 2 Erythromycin compared to no treatment for guttate psoriasis; Summary of findings 3 Azithromycin compared to vitamin C for chronic plaque psoriasis; Summary of findings 4 Rifampicin compared to placebo for guttate psoriasis; Summary of findings 5 Tonsillectomy compared to no intervention for chronic plaque psoriasis
We could not pool any data in this review because of heterogeneity of:
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intervention: different class of antibiotics: penicillin (Caca‐Biljanovska 2002; Dogan 2008), macrolides – erythromycin (Dogan 2008), and azithromycin (Saxena 2010), and rifampicin Vincent 1992); or surgery (Thorleifsdottir 2012);
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comparator: no treatment (Caca‐Biljanovska 2002; Dogan 2008; Thorleifsdottir 2012;), vitamin C (Saxena 2010), or placebo (Vincent 1992); and
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participants: plaques psoriasis (Saxena 2010; Thorleifsdottir 2012), or guttate psoriasis (Caca‐Biljanovska 2002; Dogan 2008; Vincent 1992).
(1) Penicillin versus no treatment
(summary of findings Table for the main comparison)
Two trials compared penicillin (penicillin 1.6 MU (million units) intramuscularly once daily for 14 days (Caca‐Biljanovska 2002), and oral benzathine phenoxymethylpenicillin (penicillin V) 50,000 UI/kg/d for 14 days (Dogan 2008)) to no treatment in guttate psoriasis.
In Caca‐Biljanovska 2002, participants of both groups received a co‐intervention of ultraviolet B (UVB) and betamethasone.
Primary outcomes
1. Time‐to‐resolution (time between inclusion and resolution), where resolution was defined as participants achieving clear or almost clear skin (Physician Global Assessment (PGA) 0 or 1, or Psoriasis Area and Severity Index (PASI) 90 or 100)
This outcome was not reported.
2. Proportion of participants with adverse effects and severe adverse effects
In one trial, no adverse events were observed in either group (Caca‐Biljanovska 2002).
In the other trial, adverse events were not reported (Dogan 2008).
Secondary outcomes
1. Proportion of participants achieving clear or almost clear skin (PGA 0 or 1 or PASI 90 or 100)
In Caca‐Biljanovska 2002, there were six events of clearance in the penicillin group, and three events in the no treatment group at six weeks. There was no statistically significant difference between the two groups (relative risk (RR) 2.00, 95% confidence interval (CI) 0.68 to 5.85; 20 participants; Analysis 1.1).
The proportion of participants achieving clear or almost clear skin was not reported in the other trial (Dogan 2008). No difference was observed for mean PASI score between baseline and six weeks in each group (Dogan 2008).
2. Proportion of participants achieving PASI 75 or PGA 1 to 2
Results were reported as mean PASI score at baseline and at six weeks in both trials, and not as proportion of participants achieving PASI 75 or PGA 1 to 2. No difference was found between groups for mean PASI at six weeks in both trials (Caca‐Biljanovska 2002; Dogan 2008).
3. Risk of having at least one relapse at long‐term follow‐up
Long‐term follow‐up was not reported.
(2) Erythromycin versus no treatment
One trial compared oral erythromycin 1 g per day for 14 days to no treatment, in guttate psoriasis (Dogan 2008)
Primary outcomes
1. Time‐to‐resolution (time between inclusion and resolution), where resolution was defined as participants achieving clear or almost clear skin (Physician Global Assessment (PGA) 0 or 1, or Psoriasis Area and Severity Index (PASI) 90 or 100)
This outcome was not reported.
2. Proportion of participants with adverse effects and severe adverse effects
Adverse events were not reported.
Secondary outcomes
1. Proportion of participants achieving clear or almost clear skin (PGA 0 or 1, or PASI 90 or 100)
This outcome was not reported.
2. Proportion of participants achieving PASI 75 or PGA 1 to 2
Results were reported as a mean PASI score at baseline and at six weeks, and not as proportion of participants achieving PASI 75 or PGA 1 to 2. No difference was found between groups for mean PASI at six weeks (Dogan 2008).
3. Risk of having at least one relapse at long‐term follow‐up
Long‐term follow‐up was not reported.
(3) Azithromycin versus vitamin C
One trial compared oral azithromycin 500 mg/d for four consecutive days every 14 days over 48 weeks in participants with chronic plaque psoriasis (Saxena 2010).
Primary outcomes
1. Time‐to‐resolution (time between inclusion and resolution), where resolution was defined as participants achieving clear or almost clear skin (Physician Global Assessment (PGA) 0 or 1, or Psoriasis Area and Severity Index (PASI) 90 or 100)
This outcome was not reported.
2. Proportion of participants with adverse effects and severe adverse effects
Adverse events (nausea and mild abdominal upset) were reported in 10/30 in the azithromycin group. There was no mention of the presence or absence of adverse events in the Vitamin C group.
Secondary outcomes
1. Proportion of participants achieving clear or almost clear skin (PGA 0 or 1 or PASI 90 or 100)
This outcome was not reported.
2. Proportion of participants achieving PASI 75 or PGA 1 to 2
At 48 weeks, 60% (18/30) of participants in the azithromycin group versus 0/20 in the vitamin C group reached PASI 75 (RR 25.06, 95% CI 1.60 to 393.59; 50 participants; Analysis 2.1).
3. Risk of having at least one relapse at long‐term follow‐up
This outcome was not reported.
(4) Rifampicin versus placebo
One trial compared oral rifampicin 600 mg/d versus placebo for five days in participants with guttate psoriasis (Vincent 1992). participants of both groups received oral penicillin V 50,000 IU/kg/d or oral erythromycin 1 g/d for 14 days as a co‐intervention.
Primary outcomes
1. Time‐to‐resolution (time between inclusion and resolution), where resolution was defined as participants achieving clear or almost clear skin (Physician Global Assessment (PGA) 0 or 1, or Psoriasis Area and Severity Index (PASI) 90 or 100)
This outcome was not reported.
2. Proportion of participants with adverse effects and severe adverse effects
Adverse events were not reported.
Secondary outcomes
1. Proportion of participants achieving clear or almost clear skin (PGA 0 or 1 or PASI 90 or 100)
This outcome was not reported. However, no change in psoriasis severity was observed in either group at 14 days and six weeks.
2. Proportion of participants achieving PASI 75 or PGA 1 to 2
This outcome was not reported.
3. Risk of having at least one relapse at long‐term follow‐up
Long‐term follow‐up was not reported.
(5) Penicillin versus erythromycin
One trial compared oral benzathine phenoxymethylpenicillin (penicillin V) 50,000 IU/kg/d to oral erythromycin 1 gr/d for 14 days in guttate psoriasis (Dogan 2008).
Primary outcomes
1. Time‐to‐resolution (time between inclusion and resolution), where resolution was defined as participants achieving clear or almost clear skin (Physician Global Assessment (PGA) 0 or 1, or Psoriasis Area and Severity Index (PASI) 90 or 100)
This outcome was not reported.
2. Proportion of participants with adverse effects and severe adverse effects
Adverse events were not reported.
Secondary outcomes
1. Proportion of participants achieving clear or almost clear skin (PGA 0 or 1 or PASI 90 or 100)
This outcome was not reported.
2. Proportion of participants achieving PASI 75 or PGA 1 to 2
Results were reported as mean PASI scores at baseline and at six weeks, and not as the proportion of participants achieving PASI 75 or PGA 1 to 2. No difference was found between groups for mean PASI at six weeks (Dogan 2008).
3. Risk of having at least one relapse at long‐term follow‐up
Long‐term follow‐up was not reported.
(6) Tonsillectomy versus no treatment
One trial compared tonsillectomy to no treatment in participants with chronic plaque psoriasis (Thorleifsdottir 2012). Other treatments (topical or systemic) for psoriasis were allowed during the trial.
Primary outcomes
1. Time‐to‐resolution (time between inclusion and resolution) where resolution was defined as participants achieving clear or almost clear skin (Physician Global Assessment (PGA) 0 or 1 or Psoriasis Area and Severity Index (PASI) 90 or 100)
This outcome was not reported.
2. Proportion of participants with adverse effects and severe adverse effects
One participant had an adverse event (minor bleeding) in the tonsillectomy group (RR 2.81, 95% CI 0.12 to 63.83; 29 participants; Analysis 3.1).
Secondary outcomes
1. Proportion of participants achieving clear or almost clear skin (PGA 0 or 1 or PASI 90 or 100)
In the tonsillectomy arm, 1/15 (7%) participants achieved PASI 90 after eight weeks; there were none in the no intervention arm (RR 2.81, 95% CI 0.12 to 63.83; 29 participants; Analysis 3.2).
2. Proportion of participants achieving PASI 75 or PGA 1 to 2
Three of fifteen (20%) participants in the tonsillectomy group, and none in the no treatment group achieved PASI 75 after eight weeks (RR 6.56, 95% CI 0.37 to 116.70; 29 participants; Analysis 3.3).
3. Risk of having at least one relapse at long‐term follow‐up
Authors reported that five participants in the tonsillectomy arm had a recurrence of psoriasis lesions in the winter, without providing any more precise information.
Discussion
Summary of main results
We included five trials: four assessed antibiotic treatment (penicillin, a macrolide (either erythromycin or azithromycin), or rifampicin). Three examined participants with guttate psoriasis (summary of findings Table for the main comparison; summary of findings Table 2; summary of findings Table 4); and one included participants with chronic plaque psoriasis (summary of findings Table 3). One trial assessed the effects of tonsillectomy in participants with chronic plaque psoriasis (summary of findings Table 5).
We performed no meta‐analyses due to heterogeneity of participants' characteristics (guttate or plaque psoriasis) and interventions. No studies reported our efficacy primary outcome of time‐to‐resolution (time between inclusion and resolution), where resolution was defined as participants achieving clear or almost clear skin (Physician Global Assessment (PGA) 0 or 1, or Psoriasis Area and Severity Index (PASI) 90 or 100. None of the studies measured the risk of having at least one relapse at long‐term follow‐up, either.
We rated the certainty of evidence as very low for all reported outcomes, because the five included trials were at high risk of bias, the results were imprecise, and the trials involved a small number of participants, with almost no children. Therefore, we are uncertain of the accuracy of the results that we report, and the efficacy and safety of antistreptococcal interventions.
Adverse events were not measured in the two trials that compared rifampicin against placebo, and erythromycin or penicillin against no treatment. In the three remaining trials, adverse events were reported in those taking azithromycin (nausea and mild abdominal upset), but there was no information provided about adverse events in those given vitamin C (50 participants randomised, measured at 48 weeks); there was only one minor adverse event (minor bleeding) reported in participants who had a tonsillectomy, and none reported in those given no treatment (29 participants randomised, measured at eight weeks); and in the trial comparing penicillin with no treatment, no adverse events were seen in either group (20 participants randomised, measured at six weeks).
The proportion of participants achieving clear or almost clear skin (Physician Global Assessment (PGA) 0 or 1, or Psoriasis Area and Severity Index (PASI) 90 or 100) was only reported in one trial on guttate psoriasis, in which penicillin was compared to no treatment (20 participants randomised). We are uncertain if the number of participants with guttate psoriasis achieving clear or almost clear skin differed between groups at six weeks. Similarly, PASI 90 was measured in only one chronic plaque psoriasis trial, which compared tonsillectomy with no intervention (29 participants randomised): only one participant in the tonsillectomy group achieved PASI 90, measured after eight weeks. Three trials, which compared rifampicin with placebo, erythromycin or penicillin with no treatment, and azithromycin with vitamin C, did not measure this outcome.
The proportion of participants achieving PASI 75 or PGA 1 to 2 was not measured in any guttate psoriasis trial, so there were no results for rifampicin versus placebo, and penicillin or erythromycin versus no treatment. However, the number of participants reaching PASI 75 was measured in both chronic plaque psoriasis trials. PASI 75 was achieved at 48 weeks in just over half of the participants (18/30) in the azithromycin group versus none in the group taking vitamin C (50 participants randomised). Three out of 15 participants in the tonsillectomy group achieved PASI 75 compared with none in the no treatment group after eight weeks (29 participants randomised).
Overall completeness and applicability of evidence
The evidence is incomplete for antistreptococcal interventions for guttate psoriasis. We found three trials assessing systemic antibiotic treatment in 83 participants with guttate psoriasis.
The objective of treatment is to shorten the time‐to‐resolution of guttate psoriasis, and to reduce the number of people with long‐term chronic plaque psoriasis. Thus, we considered time‐to‐resolution as a primary outcome of interest for efficacy, where resolution was defined as participants achieving clear or almost clear skin within eight weeks of the start of treatment. This outcome was not assessed or reported in the three guttate psoriasis trials. We also considered the risk of having at least one relapse at long‐term follow‐up as an outcome of interest. It was not reported in any of the three trials, which lasted only six to eight weeks. Adverse events were not reported at all in two trials, and very briefly described in the third.
The evidence is also incomplete for antistreptococcal interventions for chronic plaque psoriasis. We found two trials involving 79 participants; one assessed long‐term antibiotic treatment (azithromycin for 48 weeks from baseline), and one trial assessed the effects of tonsillectomy. They did not report on time‐to‐resolution, or risk of at least one relapse at long‐term follow‐up. One trial reported on adverse events in the treated group only, the other trial very briefly described adverse events.
The mean age of the participants was 26 years (a minimum age of 12 years to a maximum of 77 years); only two participants were under 15 years old, yet guttate psoriasis is described as more frequent in children and young adults (Mercy 2013). The included population was heterogeneous in term of severity; participants had mild to severe psoriasis, as attested by baseline PASI scores.
More men than women were included (100 men/62 women). Future trials should try to recruit equally from both sexes, since the burden of psoriasis is shared roughly equally by both sexes (GHDx 2018).
The link between proven infection and effect of antistreptococcal treatment was something we hoped to investigate via subgroup analyses, regarding the presence, absence, or unknown status of active Streptococcal infection at the time of treatment onset, but it was not possible, due to our inability to meta‐analyse. However, we noted that in the three trials concerning guttate psoriasis, only 10% of the participants were found to have a positive throat swab culture. The baseline results for culture of swab were reported as equivocal in one trial on chronic plaque psoriasis, and only half of participants in both groups were colonised by Streptococci in the other. In total, Streptococcus bacteria were found in the throats of only 23 people (about 14%).
The choice of antibiotic is questionable, as two comparisons assessed penicillin, and two comparisons assessed rifampicin and erythromycin, while current guidelines recommend using penicillin V or amoxicillin to treat Streptococcal pharyngitis (Shulman 2012). Amoxicillin was not assessed by any of the included studies.
Quality of the evidence
The results for all outcomes measured in this review were based on very low‐certainty evidence.
We downgraded the evidence, and rated it as very low for the three comparisons reporting at least one of our outcomes. There was a high or unclear risk of bias in the included studies for:
-
blinding of participants, caregivers, or assessors;
-
selective outcome reporting (no primary outcome specified);
-
incomplete outcome data.
We also downgraded the evidence for imprecision for all comparisons, because the included studies had a small number of participants, which resulted in wide confidence intervals.
The small number of included studies and heterogeneity of participants and interventions did not allow assessment of publication bias, or meta‐analysis.
Potential biases in the review process
We attempted to conduct a comprehensive search for studies, but we did not succeed in obtaining results of a study comparing Bicillin LA to placebo, which was registered in 2007, and listed as terminated because there were not enough enrollees to obtain a valid conclusion (NCT00427609). When there were missing data from results, or information that prevented us from assessing risk of bias, we contacted the authors of those trials to request additional information; however, we did not receive any reply from several trialists.
We found a trial comparing a topical antibiotic (polymyxin B) to vehicle in plaque psoriasis (Stutz 1996). We decided not to include this study, because it was not in line with the physiopathological hypothesis linking infection and psoriasis. As finding a trial assessing a topical antibiotic was not anticipated, the protocol did not specify initially that only systemic antibiotics were considered. We added this point in the section Differences between protocol and review.
Agreements and disagreements with other studies or reviews
The previous version of this Cochrane Review assessed the same question, concluding that no evidence was available about the efficacy of antistreptococcal intervention in cutaneous psoriasis (Owen 2000). They included only one trial, which was also included in this review (Vincent 1992). We included four additional trials, published after 2000. Our conclusion was different from the conclusion of the systematic review Rachakonda 2015, which concluded that "tonsillectomy may be a potential option for people with recalcitrant psoriasis associated with episodes of tonsillitis". Rachakonda 2015 considered including all types of study designs (clinical cases to randomised controlled trials) that assessed the efficacy of tonsillectomy, and included one randomised controlled trial, also included in our review (Thorleifsdottir 2012); one retrospective study; four prospective observational studies; seven case reports; and seven case series. They did not perform a formal assessment of risk of bias.
The antibiotics assessed by the studies in our review are not in accordance with national recommendations (Shulman 2012). Furthermore, the indication for tonsillectomy does not aline with current guidelines that do not recommend tonsillectomy solely to reduce the frequency of Group A Streptococcal pharyngitis (Shulman 2012).
Flow diagram describing the searches and screening 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 Penicillin versus no treatment in guttate psoriasis, Outcome 1 Proportion of participants achieving clear or almost clear skin (PASI 90 or 100 or PGA 0 or 1).
Comparison 2 Oral azithromycin versus vitamin C in chronic plaque psoriasis, Outcome 1 Proportion of participants achieving PASI 75 or PGA 1 to 2.
Comparison 3 Tonsillectomy versus no intervention in chronic plaque psoriasis, Outcome 1 Number of participants with adverse events or severe adverse events.
Comparison 3 Tonsillectomy versus no intervention in chronic plaque psoriasis, Outcome 2 Proportion of participants achieving clear or almost clear skin (PASI 90 or 100 or PGA 0 or 1).
Comparison 3 Tonsillectomy versus no intervention in chronic plaque psoriasis, Outcome 3 Proportion of participants achieving PASI 75 or PGA 1 to 2.
| Penicillin compared to no treatment for guttate psoriasis | ||||||
| Patient or population: guttate psoriasis Setting: inpatients in department of dermatology | ||||||
| Outcomes | Anticipated absolute effects* (95% CI) | Relative effect | № of participants | Certainty of the evidence | Comments | |
| Risk with no treatment | Risk with Penicillin | |||||
| Time‐to‐resolution: achieving PASI 90 to 100 or PGA 0 to 1 | ‐ | ‐ | ‐ | ‐ | ‐ | Not measured |
| Proportion of participants with adverse events and severe adverse events | See comment | See comment | ‐ | 20 (1 RCT) | ⊕⊝⊝⊝ | It was specified that no adverse events were observed in either group. |
| Proportion of participants achieving clear or almost clear skin (PASI 90 to 100 or PGA 0 to 1) | 300 per 1000 | 600 per 1000 (204 to 1000) | RR 2.00 (0.68 to 5.85) | 20 | ⊕⊝⊝⊝ | Study authors state that no difference was observed between baseline and 6 weeks for psoriasis severity (PASI). |
| Proportion of participants achieving PASI 75 or PGA 1 to 2 | ‐ | ‐ | ‐ | ‐ | ‐ | Not measured in either trial. PASI assessment results were only presented as mean PASI at 6 weeks. No difference was observed between the two groups in either trial. |
| Risk of having at least one relapse at long‐term follow‐up | ‐ | ‐ | ‐ | ‐ | ‐ | No long‐term follow‐up |
| *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 | ||||||
| 1Downgraded by three levels to very low certainty. Evidence was downgraded by two levels due to risk of bias. The study was at high risk of bias as the study was not blinded. The study was at unclear risk of bias for selective outcome reporting (no primary outcome stated). Evidence was downgraded further by one level due to imprecision: the study included few participants (N = 20). 2Downgraded by three levels to very low certainty. Evidence was downgraded by two levels due to risk of bias. The study was at high risk of bias as the study was not blinded and clinical assessment of psoriasis severity was subjective. The study was at unclear risk of bias for selective outcome reporting (no primary outcome stated). Evidence was downgraded further by one level due to imprecision: the study included few participants (N = 20). | ||||||
| Erythromycin compared to no treatment for guttate psoriasis | ||||||
| Patient or population: guttate psoriasis Setting: inpatients in department of dermatology | ||||||
| Outcomes | Anticipated absolute effects* (95% CI) | Relative effect | № of participants | Certainty of the evidence | Comments | |
| Risk with no treatment | Risk with erythromycin | |||||
| Time‐to‐resolution: achieving PASI 90 to 100 or PGA 0 to 1 | ‐ | ‐ | ‐ | ‐ | ‐ | Not measured |
| Proportion of participants with adverse events and severe adverse events | ‐ | ‐ | ‐ | ‐ | ‐ | Not measured |
| Proportion of participants achieving clear or almost clear skin (PASI 90 to 100 or PGA 0 to 1) | ‐ | ‐ | ‐ | ‐ | ‐ | Not measured |
| Proportion of participants achieving PASI 75 or PGA 1 to 2 | ‐ | ‐ | ‐ | ‐ | ‐ | Not measured Results were only reported as mean PASI at baseline and at 6 weeks. No difference was found between groups for mean PASI at 6 weeks. |
| Risk of having at least one relapse at long‐term follow‐up | ‐ | ‐ | ‐ | ‐ | ‐ | 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). | ||||||
| GRADE Working Group grades of evidence | ||||||
| Azithromycin compared to vitamin C for chronic plaque psoriasis | ||||||
| Patient or population: chronic plaque psoriasis Intervention: azithromycin | ||||||
| Outcomes | Anticipated absolute effects* (95% CI) | Relative effect | № of participants | Certainty of the evidence | Comments | |
| Risk with vitamin C | Risk with azithromycin | |||||
| Time‐to‐resolution: achieving PASI 90 to 100 or PGA 0 to 1 | ‐ | ‐ | ‐ | ‐ | ‐ | Not measured |
| Proportion of participants with adverse events and severe adverse events Follow‐up: 48 weeks | See comment | See comment | ‐ | 50 | ‐ | Nausea and mild abdominal upset were reported in 10/30 in the azithromycin group. There was no mention of the presence or absence of adverse events in the Vitamin C group. |
| Proportion of participants achieving clear or almost clear skin (PASI 90 to 100 or PGA 0 to 1) | ‐ | ‐ | ‐ | ‐ | ‐ | Not measured |
| Proportion of participants achieving PASI 75 or PGA 1 to 2 | See comment | See comment | RR 25.06 (1.60 to 393.59) | 50 | ⊕⊝⊝⊝ | 18/30 participants in the azithromycin group versus 0/20 in the vitamin C group. |
| Risk of having at least one relapse at long‐term follow‐up | ‐ | ‐ | ‐ | ‐ | ‐ | 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). | ||||||
| GRADE Working Group grades of evidence | ||||||
| 1Downgraded by three levels to very low certainty: 2 levels due to unclear risk of bias for selective reporting (any primary outcome was specified) and high risk of bias for incomplete outcome data, and a further one level due to imprecision (one small study, wide confidence interval) | ||||||
| Rifampicin compared to placebo for guttate psoriasis | ||||||
| Patient or population: guttate psoriasis Setting: not reported | ||||||
| Outcomes | Anticipated absolute effects* (95% CI) | Relative effect | № of participants | Certainty of the evidence | Comments | |
| Risk with placebo | Risk with rifampicin | |||||
| Time‐to‐resolution: achieving PASI 90 to 100 or PGA 0 to 1 | ‐ | ‐ | ‐ | ‐ | ‐ | Not measured |
| Proportion of participants with adverse events and severe adverse events | ‐ | ‐ | ‐ | ‐ | ‐ | Not measured |
| Proportion of participants achieving clear or almost clear skin (PASI 90 to 100 or PGA 0 to 1) | ‐ | ‐ | ‐ | ‐ | ‐ | Not measured However, no change in psoriasis severity was observed in any group at 14 days and 6 weeks. |
| Proportion of participants achieving PASI 75 or PGA 1 to 2 | ‐ | ‐ | ‐ | ‐ | ‐ | Not measured |
| Risk of having at least one relapse at long‐term follow‐up | ‐ | ‐ | ‐ | ‐ | ‐ | 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). | ||||||
| GRADE Working Group grades of evidence | ||||||
| Tonsillectomy compared to no intervention for guttate or chronic plaque psoriasis | ||||||
| Patient or population: chronic plaque psoriasis Setting: not reported | ||||||
| Outcomes | Anticipated absolute effects* (95% CI) | Relative effect | № of participants | Certainty of the evidence | Comments | |
| Risk with no intervention | Risk with tonsillectomy | |||||
| Time‐to‐resolution: achieving PASI 90 to 100 or PGA 0 to 1 | ‐ | ‐ | ‐ | ‐ | ‐ | Not measured |
| Proportion of participants with adverse events and severe adverse events | See comment | See comment | RR 2.81 (0.12 to 63.83) | 29 | ⊕⊝⊝⊝ | One participant had minor bleeding in the tonsillectomy group. No adverse events in the no treatment group. |
| Proportion of participants achieving clear or almost clear skin (PASI 90 to 100 or PGA 0 to 1) | See comment | See comment | RR 2.81 (0.12 to 63.83) | 29 | ⊕⊝⊝⊝ | No events in the control group. |
| Proportion of participants achieving PASI 75 or PGA 1 to 2 | See comment | See comment | RR 6.56 (0.37 to 116.7) | 29 | ⊕⊝⊝⊝ | No events in the control group. |
| Risk of having at least one relapse at long‐term follow‐up | ‐ | ‐ | ‐ | ‐ | ‐ | 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). | ||||||
| GRADE Working Group grades of evidence | ||||||
| 1Downgraded by three levels to very low certainty: two levels due to risk of bias (participant and caregiver were not blinded; subjective outcome) and one further level due to imprecision (only one study, small number of participants) | ||||||
| Term | Explanation |
| Acute pharyngitis | Inflammation of the mucous membrane of the pharynx; sore throat |
| Adenotonsillectomy | Surgical removing of tonsils and adenoids |
| Anaphylactic shock | Allergic reaction characterised by swelling, collapse, and respiratory distress |
| Antistreptolysin O titre | Blood test to measure antibodies against streptolysin O, a substance produced by group A Streptococcus bacteria |
| Beta‐haemolytic streptococcus | Pathogenic Streptococci, anaerobic bacteria, gram positive, often arranged in a chain |
| Chronic tonsillitis | Constant or recurrent infection of tonsils |
| Cytokines | Broad category of small proteins that are important in cell signalling. They are released by cells, and affect the behaviour of other cells and sometimes the releasing cell itself |
| Cutaneous lymphocyte–associated antigen (CLA) | The CLA is a fucose‐containing carbohydrate that is attached to P‐selectin glycoprotein ligand‐1 on T cells. CLA is expressed on the surface of most T cells recovered from skin, and on about 5% to 10% of circulating CD8+ T cells |
| Dendritic cells | A subtype of white blood cells |
| Epidermal | Related to the outer layer of the skin |
| Epidermal hyperplasia | Abnormal increase in the number of normal cells in the epidermis of the skin, which increases its volume |
| Erythematous | Redness of the skin |
| Erythematosquamous | Redness and covered with scales |
| Hyperkeratosis | Thickening of the cornea |
| Histological | Related to the examination of a piece of tissue, with a microscope |
| Homozygous | Having identical pairs of genes for any given pair of hereditary characteristics |
| Heterozygous | Having dissimilar pairs of genes for any given pair of hereditary characteristics |
| Interleukin 17 (IL‐17) | A pro‐inflammatory cytokine |
| Immune‐mediated disease | Group of conditions or diseases that lack a definitive etiology, but that are characterised by common inflammatory pathways leading to inflammation, and which may result from, or be triggered by, a dysregulation of the normal immune response |
| Keratinocytes | The most important cell type in the epidermis, the most superficial layer of the skin |
| Macrolide antibiotics | A specific family of antibiotics |
| Neutrophils | A subtype of white blood cells |
| Psoriasis Area Severity Index (PASI) | Index used to express the severity of psoriasis. It combines the severity (erythema or redness, induration, and desquamation) and percentage of the affected area |
| Physician Global Assessment (PGA) | Average assessment of all psoriatic lesions based on erythema (redness), scale, and induration |
| Pathogens | Micro‐organisms responsible for infection (such as virus or bacteria) |
| Pathophysiology, physiopathological | Convergence of pathology with physiology. Pathophysiology seeks to explain the physiological processes or mechanisms whereby a condition develops and progresses |
| Ribonucleic acid (RNA) | Polymeric molecule. It is involved in a range of biological roles in coding, decoding, regulation, and expression of genes |
| Serology/serologic | Refers to the diagnostic identification of antibodies in the serum |
| Stevens‐Johnson syndrome | Allergic reaction to a drug characterised by mucous membrane and skin epidermal necrolysis and involving less than 10% of the entire body surface |
| Toxic epidermal necrolysis | Allergic reaction to a drug characterised by mucous membrane and skin epidermal necrolysis and involving more than 30% of the entire body surface |
| T lymphocytes, T cells | A subtype of a white blood cell |
| Author | Date contacted | Reply |
| Dr Dogan | 6 October 2012; 17 October 2012 | No answer |
| Dr Saxena | 29 March 2016; 18 April 2016 | No answer |
| Dr V’lckova‐Laskoska | 29 March 2016; 18 April 2016 | No answer |
| Dr Vladimarsson | 29 March 2016; 18 April 2016; 21 April 2016 | 1. Did you have primary or secondary outcomes?
2. Could you give me more information concerning the results?
3. Did you have patients with secondary effects ?
4. Concerning the relapse of participants:
4. How did you perform the sequence generation (table, computer)? 5. How did you perform the allocation concealment? Reply:
6. What was the setting of the study ?
7. Did you perform throat swab before/during your study? If yes, what was the result?
8. Concerning the proportion of participants having at least one relapse at long‐term follow‐up (at least one year after the start of treatment) after randomisation: did you follow the control group or only the tonsillectomy Group?
|
| Dr Vincent | No email address found | ‐ |
| Outcome or subgroup title | No. of studies | No. of participants | Statistical method | Effect size |
| 1 Proportion of participants achieving clear or almost clear skin (PASI 90 or 100 or PGA 0 or 1) Show forest plot | 1 | 20 | Risk Ratio (M‐H, Random, 95% CI) | 2.0 [0.68, 5.85] |
| Outcome or subgroup title | No. of studies | No. of participants | Statistical method | Effect size |
| 1 Proportion of participants achieving PASI 75 or PGA 1 to 2 Show forest plot | 1 | 50 | Risk Ratio (M‐H, Random, 95% CI) | 25.06 [1.60, 393.59] |
| Outcome or subgroup title | No. of studies | No. of participants | Statistical method | Effect size |
| 1 Number of participants with adverse events or severe adverse events Show forest plot | 1 | 29 | Risk Ratio (IV, Random, 95% CI) | 2.81 [0.12, 63.83] |
| 2 Proportion of participants achieving clear or almost clear skin (PASI 90 or 100 or PGA 0 or 1) Show forest plot | 1 | 29 | Risk Ratio (IV, Random, 95% CI) | 2.81 [0.12, 63.83] |
| 3 Proportion of participants achieving PASI 75 or PGA 1 to 2 Show forest plot | 1 | 29 | Risk Ratio (IV, Random, 95% CI) | 6.56 [0.37, 116.70] |
