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Interventions for pityriasis rosea (Review)
Contreras-Ruiz J, Peternel S, Jiménez Gutiérrez C, Culav-Koscak I, Reveiz L, Silbermann-Reynoso
MDL
Contreras-RuizJ, PeternelS, Jiménez GutiérrezC, Culav-KoscakI, ReveizL, Silbermann-ReynosoMDL.
Interventions for pityriasis rosea.
Cochrane Database of Systematic Reviews 2019, Issue 10. Art. No.: CD005068.
DOI: 10.1002/14651858.CD005068.pub3.
www.cochranelibrary.com
Interventions for pityriasis rosea (Review)
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T A B L E O F C O N T E N T S
HEADER......................................................................................................................................................................................................... 1
ABSTRACT..................................................................................................................................................................................................... 1
PLAIN LANGUAGE SUMMARY....................................................................................................................................................................... 2
SUMMARY OF FINDINGS.............................................................................................................................................................................. 4
BACKGROUND.............................................................................................................................................................................................. 13
Figure 1.................................................................................................................................................................................................. 13
Figure 2.................................................................................................................................................................................................. 15
OBJECTIVES.................................................................................................................................................................................................. 17
METHODS..................................................................................................................................................................................................... 17
RESULTS........................................................................................................................................................................................................ 21
Figure 3.................................................................................................................................................................................................. 22
Figure 4.................................................................................................................................................................................................. 25
Figure 5.................................................................................................................................................................................................. 26
DISCUSSION.................................................................................................................................................................................................. 32
AUTHORS' CONCLUSIONS........................................................................................................................................................................... 34
ACKNOWLEDGEMENTS................................................................................................................................................................................ 36
REFERENCES................................................................................................................................................................................................ 37
CHARACTERISTICS OF STUDIES.................................................................................................................................................................. 42
DATA AND ANALYSES.................................................................................................................................................................................... 67
Analysis 1.1. Comparison 1 Clarithromycin versus placebo, Outcome 1 The proportion of participants with resolution of itch
within 2 weeks as rated by the participant.........................................................................................................................................
67
Analysis 1.2. Comparison 1 Clarithromycin versus placebo, Outcome 2 The proportion of participants with good or excellent
rash improvement within 2 weeks as rated by a medical practitioner.............................................................................................
68
Analysis 2.1. Comparison 2 Erythromycin versus placebo, Outcome 1 Reduction in itch score within 2 weeks as rated by the
participant.............................................................................................................................................................................................
68
Analysis 2.2. Comparison 2 Erythromycin versus placebo, Outcome 2 The proportion of participants with good or excellent rash
improvement within 2 weeks as rated by a medical practitioner.....................................................................................................
68
Analysis 2.3. Comparison 2 Erythromycin versus placebo, Outcome 3 Minor participant-reported adverse events not requiring
withdrawal of the treatment: Gastrointestinal upset.........................................................................................................................
69
Analysis 3.1. Comparison 3 Azithromycin versus placebo (or vitamins), Outcome 1 The proportion of participants with
resolution of itch within 2 weeks as rated by the participant...........................................................................................................
70
Analysis 3.2. Comparison 3 Azithromycin versus placebo (or vitamins), Outcome 2 Reduction in itch score within 2 weeks as
rated by the participant.......................................................................................................................................................................
70
Analysis 3.3. Comparison 3 Azithromycin versus placebo (or vitamins), Outcome 3 The proportion of participants with good or
excellent rash improvement within 2 weeks as rated by a medical practitioner..............................................................................
70
Analysis 3.4. Comparison 3 Azithromycin versus placebo (or vitamins), Outcome 4 Minor participant-reported adverse events
not requiring withdrawal of the treatment: Stomach ache...............................................................................................................
70
Analysis 3.5. Comparison 3 Azithromycin versus placebo (or vitamins), Outcome 5 Minor participant-reported adverse events
not requiring withdrawal of the treatment: Diarrhoea......................................................................................................................
71
Analysis 4.1. Comparison 4 Acyclovir versus placebo (or vitamins) or no treatment, Outcome 1 The proportion of participants
with resolution of itch within 2 weeks as rated by the participant...................................................................................................
72
Analysis 4.2. Comparison 4 Acyclovir versus placebo (or vitamins) or no treatment, Outcome 2 The proportion of participants
with good or excellent rash improvement within 2 weeks as rated by a medical practitioner: Rash by erythema only.................
72
Analysis 4.3. Comparison 4 Acyclovir versus placebo (or vitamins) or no treatment, Outcome 3 The proportion of participants
with good or excellent rash improvement within 2 weeks as rated by a medical practitioner: Scaling only..................................
72
Analysis 4.4. Comparison 4 Acyclovir versus placebo (or vitamins) or no treatment, Outcome 4 Minor participant-reported
adverse events not requiring withdrawal of the treatment...............................................................................................................
73
Analysis 5.1. Comparison 5 Acyclovir + calamine + cetirizine versus calamine + cetirizine, Outcome 1 The proportion of
participants with resolution of itch within 2 weeks as rated by the participant..............................................................................
73
Analysis 5.2. Comparison 5 Acyclovir + calamine + cetirizine versus calamine + cetirizine, Outcome 2 Reduction in itch score
within 2 weeks as rated by the participant.........................................................................................................................................
74
Analysis 5.3. Comparison 5 Acyclovir + calamine + cetirizine versus calamine + cetirizine, Outcome 3 Reduction in lesional score
within 2 weeks as rated by the participant.........................................................................................................................................
74
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Analysis 5.4. Comparison 5 Acyclovir + calamine + cetirizine versus calamine + cetirizine, Outcome 4 Minor participant-reported
adverse events not requiring withdrawal of the treatment: Headache............................................................................................
74
Analysis 5.5. Comparison 5 Acyclovir + calamine + cetirizine versus calamine + cetirizine, Outcome 5 Minor participant-reported
adverse events not requiring withdrawal of the treatment: Sleepiness...........................................................................................
75
Analysis 5.6. Comparison 5 Acyclovir + calamine + cetirizine versus calamine + cetirizine, Outcome 6 Minor participant-reported
adverse events not requiring withdrawal of the treatment: Nausea and vomiting..........................................................................
75
Analysis 5.7. Comparison 5 Acyclovir + calamine + cetirizine versus calamine + cetirizine, Outcome 7 Minor participant-reported
adverse events not requiring withdrawal of the treatment: Dysgeusia............................................................................................
75
Analysis 6.1. Comparison 6 Acyclovir versus erythromycin, Outcome 1 The proportion of participants with resolution of itch
within 2 weeks as rated by the participant.........................................................................................................................................
76
Analysis 7.1. Comparison 7 Prednisolone versus placebo, Outcome 1 The proportion of participants with resolution of itch
within 2 weeks as rated by the participant.........................................................................................................................................
77
Analysis 7.2. Comparison 7 Prednisolone versus placebo, Outcome 2 Reduction in itch score within 2 weeks as rated by the
participant.............................................................................................................................................................................................
77
Analysis 7.3. Comparison 7 Prednisolone versus placebo, Outcome 3 The proportion of participants with good or excellent rash
improvement within 2 weeks as rated by a medical practitioner.....................................................................................................
77
Analysis 7.4. Comparison 7 Prednisolone versus placebo, Outcome 4 Minor participant-reported adverse events not requiring
withdrawal of the treatment: Mild gastric hyperacidity.....................................................................................................................
77
Analysis 7.5. Comparison 7 Prednisolone versus placebo, Outcome 5 Minor participant-reported adverse events not requiring
withdrawal of the treatment: Anxiety and palpitations.....................................................................................................................
78
Analysis 7.6. Comparison 7 Prednisolone versus placebo, Outcome 6 Minor participant-reported adverse events not requiring
withdrawal of the treatment: Belching...............................................................................................................................................
78
Analysis 7.7. Comparison 7 Prednisolone versus placebo, Outcome 7 Minor participant-reported adverse events not requiring
withdrawal of the treatment: Stye.......................................................................................................................................................
78
Analysis 7.8. Comparison 7 Prednisolone versus placebo, Outcome 8 The proportion of participants with relapse at 12 weeks..... 79
Analysis 8.1. Comparison 8 Dexchlorpheniramine versus betamethasone, Outcome 1 The proportion of participants with
resolution of itch within 2 weeks as rated by the participant...........................................................................................................
79
Analysis 8.2. Comparison 8 Dexchlorpheniramine versus betamethasone, Outcome 2 The proportion of participants with good
or excellent rash improvement within 2 weeks as rated by a medical practitioner.........................................................................
79
Analysis 9.1. Comparison 9 Dexchlorpheniramine versus dexchlorpheniramine + betamethasone, Outcome 1 The proportion
of participants with resolution of itch within 2 weeks as rated by the participant..........................................................................
80
Analysis 9.2. Comparison 9 Dexchlorpheniramine versus dexchlorpheniramine + betamethasone, Outcome 2 The proportion
of participants with good or excellent rash improvement within 2 weeks as rated by a medical practitioner................................
80
Analysis 10.1. Comparison 10 Betamethasone versus dexchlorpheniramine + betamethasone, Outcome 1 The proportion of
participants with resolution of itch within 2 weeks as rated by the participant..............................................................................
81
Analysis 10.2. Comparison 10 Betamethasone versus dexchlorpheniramine + betamethasone, Outcome 2 The proportion of
participants with good or excellent rash improvement within 2 weeks as rated by a medical practitioner....................................
81
Analysis 11.1. Comparison 11 Glycyrrhizin versus procaine, Outcome 1 The proportion of participants with good or excellent
rash improvement within 2 weeks as rated by a medical practitioner.............................................................................................
82
Analysis 12.1. Comparison 12 Ultraviolet phototherapy versus emollient, Outcome 1 Minor participant-reported adverse events
not requiring withdrawal of the treatment: Hyperpigmentation......................................................................................................
82
Analysis 12.2. Comparison 12 Ultraviolet phototherapy versus emollient, Outcome 2 Minor participant-reported adverse events
not requiring withdrawal of the treatment: Hypopigmentation........................................................................................................
83
Analysis 12.3. Comparison 12 Ultraviolet phototherapy versus emollient, Outcome 3 Minor participant-reported adverse events
not requiring withdrawal of the treatment: Burning sensation.........................................................................................................
83
APPENDICES................................................................................................................................................................................................. 83
WHAT'S NEW................................................................................................................................................................................................. 85
HISTORY........................................................................................................................................................................................................ 85
CONTRIBUTIONS OF AUTHORS................................................................................................................................................................... 85
DECLARATIONS OF INTEREST..................................................................................................................................................................... 86
SOURCES OF SUPPORT............................................................................................................................................................................... 86
DIFFERENCES BETWEEN PROTOCOL AND REVIEW.................................................................................................................................... 86
INDEX TERMS............................................................................................................................................................................................... 87
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[Intervention Review]
Interventions for pityriasis rosea
Jose Contreras-Ruiz1a, Sandra Peternel2,3b, Carlos Jiménez Gutiérrez4, Ivana Culav-Koscak5, Ludovic Reveiz6, Maria de Lourdes
Silbermann-Reynoso7
1Department of Dermatology, Hospital General Dr. Manuel Gea González, Mexico City, Mexico. 2Department of Dermatovenereology,
Clinical Hospital Center Rijeka, Rijeka, Croatia. 3University of Rijeka, Faculty of Medicine, Rijeka, Croatia. 4Adscrito Unidad de Investigación
Traslacional, Universidad Tecnologica de México-Laureate International Universities, México.DF, Mexico. 5Department of Dermatology
and Venereology, General hospital "Dr. Ivo Pedisic", Sisak, Croatia. 6Free time independent Cochrane reviewer, Potomac, MD, USA. 7c/o
Cochrane Skin Group, The University of Nottingham, Nottingham, UK
aJoint first author. bJoint first author
Contact address: Jose Contreras-Ruiz, Department of Dermatology, Hospital General Dr. Manuel Gea González, Puente de Piedra 150-T1-
C111. Col. Toriello Guerra, Mexico City, 14050, Mexico. contruiz@gmail.com.
Editorial group: Cochrane Skin Group
Publication status and date: New search for studies and content updated (conclusions changed), published in Issue 10, 2019.
Citation: Contreras-RuizJ, PeternelS, Jiménez GutiérrezC, Culav-KoscakI, ReveizL, Silbermann-ReynosoMDL. Interventions for
pityriasis rosea. Cochrane Database of Systematic Reviews 2019, Issue 10. Art. No.: CD005068. DOI: 10.1002/14651858.CD005068.pub3.
Copyright © 2019 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
A B S T R A C T
Background
Pityriasis rosea is a scaly, itchy rash that mainly affects young adults and lasts for 2 to 12 weeks. The effects of many available treatments
are uncertain. This is an update of a Cochrane Review first published in 2007.
Objectives
To assess the effects of interventions for the management of pityriasis rosea in any individual diagnosed by a medical practitioner.
Search methods
We updated our searches of the following databases to October 2018: the Cochrane Skin Specialised Register, CENTRAL, MEDLINE, Embase,
and LILACS. We searched five trials registers. We also checked the reference lists of included and excluded studies, contacted trial authors,
scanned the abstracts from major dermatology conference proceedings, and searched the CAB Abstracts database. We searched PubMed
for adverse effects to November 2018.
Selection criteria
Randomised controlled trials of interventions in pityriasis rosea. Treatment could be given in a single therapy or in combination. Eligible
comparators were no treatment, placebo, vehicle only, another active compound, or placebo radiation treatment.
Data collection and analysis
We used standard methodological procedures expected by the Cochrane. Our key outcomes were good or excellent rash improvement
within two weeks, rated separately by the participant and medical practitioner; serious adverse events; resolution of itch within two weeks
(participant-rated); reduction in itch score within two weeks (participant-rated); and minor participant-reported adverse events not re-
quiring withdrawal of the treatment.
Main results
We included 14 trials (761 participants). In general, risk of selection bias was unclear or low, but risk of performance bias and reporting
bias was high for 21% of the studies.
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Participant age ranged from 2 to 60 years, and sex ratio was similar. Disease severity was measured by various severity indices, which the
included studies did not categorise. Six studies were conducted in India, three in Iran, two in the Philippines, and one each in Pakistan, the
USA, and China. The included studies were conducted in dermatology departments and a paediatric clinic. Study duration ranged from 5
to 26 months. Three studies were funded by drug manufacturers; most studies did not report their funding source. The included studies
assessed macrolide antibiotics, an antiviral agent, phototherapy, steroids and antihistamine, and Chinese medicine.
None of the studies measured participant-rated good or excellent rash improvement. All reported outcomes were assessed within two
weeks of treatment, except for adverse effects, which were measured throughout treatment.
There is probably no difference between oral clarithromycin and placebo in itch resolution (risk ratio (RR) 0.84, 95% confidence interval
(CI) 0.47 to 1.52; 1 study, 28 participants) or rash improvement (medical practitioner-rated) (RR 1.13, 95% CI 0.89 to 1.44; 1 study, 60 par-
ticipants). For this comparison, there were no serious adverse events (1 study, 60 participants); minor adverse events and reduction in itch
score were not measured; and all evidence was of moderate quality.
When compared with placebo, erythromycin may lead to increased rash improvement (medical practitioner-rated) (RR 4.02, 95% CI 0.28
to 56.61; 2 studies, 86 participants, low-quality evidence); however, the 95% CI indicates that the result may also be compatible with a
benefit of placebo, and there may be little or no difference between treatments. Itch resolution was not measured, but one study mea-
sured reduction in itch score, which is probably larger with erythromycin (MD 3.95, 95% CI 3.37 to 4.53; 34 participants, moderate-quality
evidence). In the same single, small trial, none of the participants had a serious adverse event, and there was no clear difference between
groups in minor adverse events, which included gastrointestinal upset (RR 2.00, CI 0.20 to 20.04; moderate-quality evidence).
Two trials compared oral azithromycin to placebo or vitamins. There is probably no difference between groups in itch resolution (RR 0.83,
95% CI 0.28 to 2.48) or reduction in itch score (MD 0.04, 95% CI −0.35 to 0.43) (both outcomes based on one study; 70 participants, moder-
ate-quality evidence). Low-quality evidence from two studies indicates there may be no difference between groups in rash improvement
(medical practitioner-rated) (RR 1.02, 95% CI 0.52 to 2.00; 119 participants). In these same two studies, no serious adverse events were
reported, and there was no clear difference between groups in minor adverse events, specifically mild abdominal pain (RR 5.82, 95% CI
0.72 to 47.10; moderate-quality evidence).
Acyclovir was compared to placebo, vitamins, or no treatment in three trials (all moderate-quality evidence). Based on one trial (21 par-
ticipants), itch resolution is probably higher with placebo than with acyclovir (RR 0.34, 95% CI 0.12 to 0.94); reduction in itch score was
not measured. However, there is probably a significant difference between groups in rash improvement (medical practitioner-rated) in
favour of acyclovir versus all comparators (RR 2.45, 95% CI 1.33 to 4.53; 3 studies, 141 participants). Based on the same three studies, there
were no serious adverse events in either group, and there was probably no difference between groups in minor adverse events (only one
participant in the placebo group experienced abdominal pain and diarrhoea).
One trial compared acyclovir added to standard care (calamine lotion and oral cetirizine) versus standard care alone (24 participants).
The addition of acyclovir may lead to increased itch resolution (RR 4.50, 95% CI 1.22 to 16.62) and reduction in itch score (MD 1.26, 95%
CI 0.74 to 1.78) compared to standard care alone. Rash improvement (medical practitioner-rated) was not measured. The trial reported
no serious adverse events in either group, and there may be no difference between groups in minor adverse events, such as headache (RR
7.00, 95% CI 0.40 to 122.44) (all results based on low-quality evidence).
Authors' conclusions
When compared with placebo or no treatment, oral acyclovir probably leads to increased good or excellent, medical practitioner-rated
rash improvement. However, evidence for the effect of acyclovir on itch was inconclusive. We found low- to moderate-quality evidence
that erythromycin probably reduces itch more than placebo.
Small study sizes, heterogeneity, and bias in blinding and selective reporting limited our conclusions. Further research is needed to inves-
tigate different dose regimens of acyclovir and the effect of antivirals on pityriasis rosea.
P L A I N L A N G U A G E S U M M A R Y
Treatments for pityriasis rosea
Background
Pityriasis rosea is a common scaly rash prevalent in young adults. A patch of redness and scales is followed by widespread rash. Pityriasis
rosea usually resolves within 2 to 12 weeks; however, the rash can resemble a serious contagious skin condition, causing concern. More-
over, pityriasis rosea can cause moderate to severe itching, making effective treatment necessary.
Review question
We wanted to evaluate the effectiveness and safety of treatments for pityriasis rosea. Eligible treatments were topical, systemic (oral or
injected medicines that work throughout the entire body), or light therapy, given alone or in combination with another treatment, and
compared against no treatment, placebo (an identical but inactive treatment), vehicle (inactive ingredients that help deliver an active
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treatment) only, or another active treatment. As spontaneous recovery usually occurs between 2 and 12 weeks in cases of untreated
pityriasis rosea, we considered outcomes reported at two weeks.
Study characteristics
The evidence is current to October 2018.
We included 14 studies with a total of 761 participants aged between 2 and 60 years (similar numbers of males and females). Most studies
were conducted in Asia in dermatology departments and lasted between 5 to 26 months. Three studies were funded by drug manufactur-
ers; most studies did not report their funding sources. Disease severity was assessed by various measures, but participants were not cate-
gorised into mild, moderate, or severe disease. Important treatments assessed by the studies included various antibiotics and acyclovir (a
drug meant to treat herpes infections), which were compared to placebo, no treatment, or standard care. Additional treatments included
phototherapy, corticosteroids and antihistamine, and Chinese medicine (potenline). Most studies assessed treatment used for one week.
All reported outcomes were assessed within two weeks of treatment, except for side effects, which were measured throughout treatment.
None of the included studies reported on the participant's rating of rash improvement. Itch was always participant-assessed. Rash im-
provement was rated as good or excellent.
There is probably no difference between clarithromycin and placebo in medical practitioner-rated rash improvement or itch resolution,
and no serious adverse events were reported (all moderate-quality evidence). Reduction in itch score and minor side effects were not
measured.
Similarly, there may be no difference in medical practitioner-rated rash improvement between azithromycin and placebo or vitamins, but
erythromycin may lead to increased rash improvement when compared to placebo; however, the results show there may be a benefit with
placebo or little or no difference between treatments (low-quality evidence for both outcomes). There is probably no difference between
azithromycin and comparators in itch resolution or reduction in itch score; there was no clear difference in minor side effects, such as
mild abdominal pain (both moderate-quality evidence). When comparing erythromycin to placebo, itch resolution was not measured, but
there is probably a greater reduction in itch score with erythromycin. There was no clear difference in the likelihood of minor side effects,
such as gastrointestinal upset, between groups (moderate-quality evidence for both outcomes).
A single study suggested that acyclovir is probably less effective than placebo in achieving itch resolution (but itch score reduction was not
measured). However, results from three studies indicate that acyclovir is probably significantly more beneficial than placebo, no treat-
ment, or vitamin tablets in medical practitioner-rated rash improvement. There is probably no difference between acyclovir and placebo
in the incidence of minor side effects: one participant in the placebo group experienced mild abdominal pain and diarrhoea (all outcomes
based on moderate-quality evidence).
A single trial indicated that acyclovir used in combination with standard care (calamine (anti-itch lotion) and the antihistamine cetirizine)
may reduce itch score and increase itch resolution (low-quality evidence). Medical practitioner-rated rash improvement was not measured.
There may be no difference between groups in minor side effects, such as headache, increased sleep, sickness, and impact on taste.
None of the studies reported serious adverse events (low- to moderate-quality evidence).
Quality of the evidence
The quality of the evidence for the main comparisons was low to moderate. Many of the results were based on a small number of trials,
with a low number of participants. There was also some variation amongst the trial results and concerns over study design.
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S U M M A R Y O F F I N D I N G S
Summary of findings for the main comparison. Clarithromycin compared to placebo for pityriasis rosea
Clarithromycin compared to placebo for pityriasis rosea
Patient or population: pityriasis rosea
Setting: outpatient dermatology clinic
Intervention: clarithromycin
Comparison: placebo
Anticipated absolute effects*
(95% CI)
Outcomes
Risk with
placebo
Risk with
clar-
ithromycin
Relative ef-
fect
(95% CI)
№ of partici-
pants
(studies)
Quality of the
evidence
(GRADE)
Comments
The proportion of participants with good or excellent rash im-
provement within 2 weeks, as rated by the participant
- - - - - Not measured
Serious adverse events, i.e. serious enough to require withdrawal
of the treatment
- - Not estimable 60
(1 RCT)
⊕⊕⊕⊝
Moderate a
No partici-
pants in ei-
ther group ex-
perienced se-
rious adverse
events.
Study populationThe proportion of participants with resolution of itch within 2
weeks, as rated by the participant
667 per 1000 560 per 1000
(313 to 1000)
RR 0.84
(0.47 to 1.52)
28
(1 RCT)
⊕⊕⊕⊝
Moderate a
-
Reduction in itch score within 2 weeks, as rated by the participant - - - - - Not measured
Study populationThe proportion of participants with good or excellent rash im-
provement within 2 weeks, as rated by a medical practitioner
767 per 1000 866 per 1000
(682 to 1000)
RR 1.13
(0.89 to 1.44)
60
(1 RCT)
⊕⊕⊕⊝
Moderate a
-
Minor participant-reported adverse events not requiring withdraw-
al of the treatment
- - - - - Not measured
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*The risk in the intervention group (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and
its 95% CI). The assumed risk is calculated from the single-study analysis or meta-analysis, using the number of events or mean difference in the control group(s).
CI: confidence interval; RCT: randomised controlled trial; RR: risk ratio
GRADE Working Group grades of evidence
High quality: We are very confident that the true effect lies close to that of the estimate of the effect.
Moderate quality: We are moderately confident in the effect estimate: the true effect is likely to be close to the estimate of the effect, but there is a possibility that it is sub-
stantially different.
Low quality: Our confidence in the effect estimate is limited: the true effect may be substantially different from the estimate of the effect.
Very low quality: We have very little confidence in the effect estimate: the true effect is likely to be substantially different from the estimate of effect.
aDowngraded by one level to moderate-quality evidence for imprecision due to small sample size.
Summary of findings 2. Erythromycin compared to placebo for pityriasis rosea
Erythromycin compared to placebo for pityriasis rosea
Patient or population: pityriasis rosea
Setting: outpatient dermatology clinic
Intervention: erythromycin
Comparison: placebo
Anticipated absolute effects*
(95% CI)
Outcomes
Risk with
placebo
Risk
with ery-
thromycin
Relative ef-
fect
(95% CI)
№ of partici-
pants
(studies)
Quality of the
evidence
(GRADE)
Comments
The proportion of participants with good or excellent rash im-
provement within 2 weeks, as rated by the participant
- - - - - Not measured
Serious adverse events, i.e. serious enough to require withdrawal
of the treatment
- - Not estimable 34
(1 RCT)
⊕⊕⊕⊝
Moderate a
No partici-
pants in ei-
ther group ex-
perienced se-
rious adverse
events.
The proportion of participants with resolution of itch within 2
weeks, as rated by the participant
- - - - - Not reported
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Reduction in itch score within 2 weeks as rated by the participant
Assessed with: visual analogue scale
Scale from: 0 to 10 (higher score = worse itch)
The mean re-
duction in itch
score within 2
weeks as rated
by the partici-
pant was 1.76.
MD 3.95 high-
er
(3.37 higher to
4.53 higher)
- 34
(1 RCT)
⊕⊕⊕⊝
Moderate a
-
Study populationThe proportion of participants with good or excellent rash im-
provement within 2 weeks as rated by a medical practitioner
Assessed with: complete cure 33 per 100 100 per 100
(9 to 100)
RR 4.02
(0.28 to 56.61)
86
(2 RCTs)
⊕⊕⊝⊝
Low b
-
Study populationMinor participant-reported adverse events not requiring with-
drawal of the treatment: Gastrointestinal upset.
Assessed with: presence or absence of the side effect 6 per 100 12 per 100
(1 to 100)
RR 2.00
(0.20 to 20.04)
34
(1 RCT)
⊕⊕⊕⊝
Moderate a
-
*The risk in the intervention group (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and
its 95% CI). The assumed risk is calculated from the single-study analysis or meta-analysis, using the number of events or mean difference in the control group(s).
CI: confidence interval; MD: mean difference; RCT: randomised controlled trial; RR: risk ratio
GRADE Working Group grades of evidence
High quality: We are very confident that the true effect lies close to that of the estimate of the effect.
Moderate quality: We are moderately confident in the effect estimate: the true effect is likely to be close to the estimate of the effect, but there is a possibility that it is sub-
stantially different.
Low quality: Our confidence in the effect estimate is limited: the true effect may be substantially different from the estimate of the effect.
Very low quality: We have very little confidence in the effect estimate: the true effect is likely to be substantially different from the estimate of effect.
aDowngraded by one level to moderate-quality evidence for imprecision due to small sample size.
bDowngraded by two levels to low-quality evidence: one level for imprecision due to small sample size and one level for inconsistency due to heterogeneity amongst studies.
Summary of findings 3. Azithromycin compared to placebo or vitamins for pityriasis rosea
Azithromycin compared to placebo or vitamins for pityriasis rosea
Patient or population: pityriasis rosea
Setting: outpatient dermatology and paediatric clinics
Intervention: azithromycin
Comparison: placebo or vitamins
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Anticipated absolute effects*
(95% CI)
Outcomes
Risk with
placebo or vi-
tamins
Risk with
azithromycin
Relative ef-
fect
(95% CI)
№ of partici-
pants
(studies)
Quality of the
evidence
(GRADE)
Comments
The proportion of participants with good or excellent rash im-
provement within 2 weeks, as rated by the participant
- - - - - Not measured
Serious adverse events, i.e. serious enough to require with-
drawal of the treatment
- - Not estimable 119
(2 RCTs)
⊕⊕⊕⊝
Moderate a
No participants in
either group expe-
rienced serious ad-
verse events.
Study populationThe proportion of participants with resolution of itch within 2
weeks, as rated by the participant
171 per 1000 142 per 1000
(48 to 425)
RR 0.83
(0.28 to 2.48)
70
(1 RCT)
⊕⊕⊕⊝
Moderate a
-
Reduction in itch score within 2 weeks, as rated by the partic-
ipant
Assessed with: visual analogue scale
Scale from: 0 to 10 (higher score = worse itch)
The mean re-
duction in itch
score within
2 weeks was
0.47.
MD 0.04 high-
er
(0.35 lower to
0.43 higher)
- 70
(1 RCT)
⊕⊕⊕⊝
Moderate a
-
Study populationThe proportion of participants with good or excellent rash im-
provement within 2 weeks as rated by a medical practitioner.
Assessed with: complete or partial resolution, no response 441 per 1000 449 per 1000
(229 to 881)
RR 1.02 (0.52
to 2.00)
119
(2 RCTs)
⊕⊕⊝⊝
Lowb
-
Minor participant-reported adverse events not requiring
withdrawal of the treatment: Mild abdominal pain.
Assessed with: presence or absence of the side effect
See comment See comment RR 5.82
(0.72 to 47.10)
119
(2 RCTs)
⊕⊕⊕⊝
Moderate a
No participants
in the placebo
group reported
mild abdominal
pain versus 5/60
participants in
the azithromycin
group.
*The risk in the intervention group (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and
its 95% CI).
CI: confidence interval; MD: mean difference; RCT: randomised controlled trial; RR: risk ratio
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GRADE Working Group grades of evidence
High quality: We are very confident that the true effect lies close to that of the estimate of the effect.
Moderate quality: We are moderately confident in the effect estimate: the true effect is likely to be close to the estimate of the effect, but there is a possibility that it is sub-
stantially different.
Low quality: Our confidence in the effect estimate is limited: the true effect may be substantially different from the estimate of the effect.
Very low quality: We have very little confidence in the effect estimate: the true effect is likely to be substantially different from the estimate of effect.
aDowngraded by one level to moderate-quality evidence for imprecision due to small sample size.
bDowngraded by two levels to low-quality evidence: one level for imprecision due to small sample size, and a further level for study limitations due to high risk of reporting
bias in one study (Amer 2006). It was stated that the presence of pruritus was measured at baseline and at each follow-up, but this information was not included in the results.
There was also no report on concomitant treatment used, although this was stated to have been recorded at each follow-up. Also, random sequence generation and allocation
concealment were unclear.
Summary of findings 4. Acyclovir compared to placebo, vitamins, or no treatment for pityriasis rosea
Acyclovir compared to placebo, vitamins, or no treatment for pityriasis rosea
Patient or population: pityriasis rosea
Setting: outpatient dermatology clinic
Intervention: acyclovir
Comparison: placebo, vitamins, or no treatment
Anticipated absolute effects*
(95% CI)
Outcomes
Risk with
placebo, vit-
amins, or no
treatment
Risk with
acyclovir
Relative ef-
fect
(95% CI)
№ of partici-
pants
(studies)
Quality of the
evidence
(GRADE)
Comments
The proportion of participants with good or excellent rash
improvement within 2 weeks, as rated by the participant
- - - - - Not measured
Serious adverse events, i.e. serious enough to require
withdrawal of the treatment
Assessed with: presence or absence
- - Not estimable 141
(3 RCTs) a
⊕⊕⊕⊝
Moderate b
No serious adverse
events were reported
in either group.
Study populationProportion of participants with resolution of itch within 2
weeks, as rated by the participant
80 per 100 27 per 100
(10 to 75)
RR 0.34
(0.12 to 0.94)
21
(1 RCT) c
⊕⊕⊕⊝
Moderate b
-
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Reduction in itch score within 2 weeks, as rated by the
participant
- - - - - Not reported
Study populationThe proportion of participants with good or excellent rash
improvement within 2 weeks, as rated by a medical prac-
titioner
Assessed with: decrease or absence of erythema
28 per 100 67 per 100
(37 to 100)
RR 2.45
(1.33 to 4.53)
141
(3 RCTs) a
⊕⊕⊕⊝
Moderate d
-
Study populationMinor participant-reported adverse events not requiring
withdrawal of the treatment
7 per 100 2 per 100
(0 to 54)
RR 0.31
(0.01 to 7.02)
141
(3 RCTs) a
⊕⊕⊕⊝
Moderate b
1 participant in the
placebo group experi-
enced abdominal pain
and diarrhoea. No ad-
verse events were re-
ported with acyclovir.
*The risk in the intervention group (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and
its 95% CI). The assumed risk is calculated from the single-study analysis or meta-analysis, using the number of events or mean difference in the control group(s).
CI: confidence interval; RCT: randomised controlled trial; RR: risk ratio
GRADE Working Group grades of evidence
High quality: We are very confident that the true effect lies close to that of the estimate of the effect.
Moderate quality: We are moderately confident in the effect estimate: the true effect is likely to be close to the estimate of the effect, but there is a possibility that it is sub-
stantially different.
Low quality: Our confidence in the effect estimate is limited: the true effect may be substantially different from the estimate of the effect.
Very low quality: We have very little confidence in the effect estimate: the true effect is likely to be substantially different from the estimate of effect.
aSingh 2016 and Ganguly 2014 utilised a dose of 800 mg 5 times per day for 7 days. Rassai 2011 utilised a dose of 400 mg 5 times per day for 7 days.
bDowngraded by one level to moderate-quality evidence for imprecision due to small sample size.
cSingh 2016 utilised a dose of 800 mg 5 times per day for 7 days.
dDowngraded by one level to moderate-quality evidence due to study limitations, as one of the trials had a high risk of performance bias and unclear risk of selection bias
(allocation concealment), detection bias, and attrition bias (10 dropouts with unknown numbers and reasons per group) (Rassai 2011).
Summary of findings 5. Acyclovir + calamine + cetirizine compared to calamine + cetirizine for pityriasis rosea
Acyclovir + calamine + cetirizine compared to cetirizine + calamine for pityriasis rosea
Patient or population: pityriasis rosea
Setting: outpatient dermatology clinic
Intervention: acyclovir + calamine + cetirizine
Comparison: calamine + cetirizine
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Anticipated absolute effects*
(95% CI)
Outcomes
Risk with
calamine +
cetirizine
Risk with
acyclovir +
calamine +
cetirizine
Relative ef-
fect
(95% CI)
№ of partici-
pants
(studies)
Quality of the
evidence
(GRADE)
Comments
The proportion of participants with good or excellent rash im-
provement within 2 weeks, as rated by the participant
- - - - - Not measured
Serious adverse events, i.e. serious enough to require with-
drawal of the treatment
Assessed with: presence or absence
- - Not estimable 24
(1 RCT)
⊕⊕⊝⊝
Low a
No serious adverse
events requiring
withdrawal were
reported in either
group.
Study populationThe proportion of participants with resolution of itch within 2
weeks, as rated by the participant
Follow-up: 2 weeks 167 per 1000 750 per 1000
(203 to 1000)
RR 4.50
(1.22 to 16.62)
24
(1 RCT)
⊕⊕⊝⊝
Low a
-
Reduction in itch score within 2 weeks, as rated by the partic-
ipant
Assessed with: visual analogue scale
Scale from: 0 to 10 (higher score = worse itch)
The mean re-
duction in itch
score within
2 weeks was
0.58.
MD 1.26 high-
er
(0.74 higher to
1.78 higher)
- 24
(1 RCT)
⊕⊕⊝⊝
Low a
-
The proportion of participants with good or excellent rash im-
provement within 2 weeks, as rated by a medical practitioner
-----Not measuredb
Minor participant-reported adverse events not requiring
withdrawal of the treatment: Headache.
Assessed with: presence or absence
See comment See comment RR 7.00
(0.40 to
122.44)
24
(1 RCT)
⊕⊕⊝⊝
Low a
No events in the
control group ver-
sus 3/12 partici-
pants in the acy-
clovir group
*The risk in the intervention group (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and
its 95% CI).
CI: confidence interval; MD: mean difference; RCT: randomised controlled trial; RR: risk ratio
GRADE Working Group grades of evidence
High quality: We are very confident that the true effect lies close to that of the estimate of the effect.
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Moderate quality: We are moderately confident in the effect estimate: the true effect is likely to be close to the estimate of the effect, but there is a possibility that it is sub-
stantially different.
Low quality: Our confidence in the effect estimate is limited: the true effect may be substantially different from the estimate of the effect.
Very low quality: We have very little confidence in the effect estimate: the true effect is likely to be substantially different from the estimate of effect.
aDowngraded by two levels to low-quality evidence: one level for study limitations due to high risk of performance bias (participants were not blinded) and one level for impre-
cision. The sample size of this trial was only 24 (12 per group).
bThis study did not report on this precise outcome. However, it did evaluate participants for reduction in lesional score (a measure of rash severity), which was calculated by
addition of erythema score (0 if absent, 1 if present), scaling score (0 if absent, 1 if present), and number of lesions score (< 30 lesions was given a score of 1, 30 to 100 lesions a
score of 2, and > 100 lesions a score of 3). The mean change in lesional score was significantly larger when acyclovir was added to the standard of care (6.08 ± 0.69 versus 2.84 ±
0.74; MD 3.24, 95% CI 2.67 to 3.81; Analysis 5.3). Downgraded by one level to moderate-quality evidence for imprecision; outcome assessors were blinded.
Summary of findings 6. Acyclovir compared to erythromycin for pityriasis rosea
Acyclovir compared to erythromycin for pityriasis rosea
Patient or population: pityriasis rosea
Setting: outpatient dermatology clinic
Intervention: acyclovir
Comparison: erythromycin
Anticipated absolute effects*
(95% CI)
Outcomes
Risk
with ery-
thromycin
Risk with
acyclovir
Relative ef-
fect
(95% CI)
№ of partici-
pants
(studies)
Quality of the
evidence
(GRADE)
Comments
The proportion of participants with
good or excellent rash improve-
ment within 2 weeks, as rated by
the participant
- - - - - Not measured
Serious adverse events, i.e. serious
enough to require withdrawal of
the treatment
- - Not estimable 30
(1 RCT)
⊕⊕⊕⊝
Moderate a
All participants completed the trial and no
adverse events are reported in either group.
The proportion of participants with
resolution of itch within 2 weeks,
as rated by the participant
See comment See comment RR 13.22
(0.91 to
192.02)
14
(1 RCT)
⊕⊕⊝⊝
Low b
All 8 participants in the acyclovir group had
resolution of itch versus zero in the ery-
thromycin group. Hence, the assumed and
corresponding risks could not be calculated.
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Reduction in itch score within 2
weeks, as rated by the participant
- - - - - Not measured
The proportion of participants with
good or excellent rash improve-
ment within 2 weeks, as rated by a
medical practitioner
Assessed with: complete response
- - Not estimable 30
(1 RCT)
⊕⊕⊝⊝
Low b
Zero events in both groups
Minor participant-reported adverse
events not requiring withdrawal of
the treatment
- - Not estimable 30
(1 RCT)
⊕⊕⊝⊝
Lowb
No participants in either group experienced
adverse events.
*The risk in the intervention group (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and
its 95% CI).
CI: confidence interval; RCT: randomised controlled trial; RR: risk ratio
GRADE Working Group grades of evidence
High quality: We are very confident that the true effect lies close to that of the estimate of the effect.
Moderate quality: We are moderately confident in the effect estimate: the true effect is likely to be close to the estimate of the effect, but there is a possibility that it is sub-
stantially different.
Low quality: Our confidence in the effect estimate is limited: the true effect may be substantially different from the estimate of the effect.
Very low quality: We have very little confidence in the effect estimate: the true effect is likely to be substantially different from the estimate of effect.
aDowngraded by one level to moderate-quality evidence for imprecision due to very small sample size and a small number of events in terms of response measures.
bDowngraded by two levels to low-quality evidence: one level for imprecision due to very small sample size and a small number of events in terms of response measures and one
level for study limitations (unclear risk of selection bias, performance bias, and detection bias), as this trial does not specify randomisation methods, and very little information
is provided on blinding of participants and outcome assessors.
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B A C K G R O U N D
Description of the condition
Description and epidemiology
Pityriasis rosea (PR) is a benign, self-limited skin disease charac-
terised by the sudden appearance of multiple, discrete patches of
skin rash in a distinctive pattern over the trunk and limbs. 'Pityri-
asis' (meaning bran-like) indicates that there are fine scales in the
skin lesions (Percival 1932). 'Rosea' means rose-like and describes
the typical colour of the rash (Percival 1932), although the colour
varies to a wide extent in people of different races (Ahmed 1986).
A characteristic of PR is the apparently 'programmed' course of
events. A single larger lesion, measuring about 1 to 3 centimetres,
usually precedes the widespread rash for up to two weeks. This ini-
tial lesion, also known as the 'herald patch', most commonly ap-
pears on the trunk (Figure 1). It is oval-shaped, with a rose, scaly,
slightly elevated border and paler centre. The herald patch may not
be identifiable in many people, thus its absence does not necessar-
ily exclude a diagnosis of PR.
Figure 1. Classical pityriasis rosea. The largest lesion is the herald patch. The other lesions are the secondary
eruption.
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The subsequent, abrupt, generalised eruption is known as the sec-
ondary eruption. Lesions are similar to the herald patch but small-
er. Their distribution commonly follows the skin cleavage lines in
what is referred to as the 'Christmas tree pattern' (Figure 2). The
rash usually occurs on the trunk and extends to the upper arms
and upper thighs, rarely to the forearms and legs. The eruption on-
ly occasionally spreads to the palms and soles, although the her-
ald patch can sometimes present at these sites (Deng 2007; Robati
2009; Polat 2012; Bas 2015). Involvement of the face or scalp is also
rare but has been reported, more frequently in people with black
skin (Klauder 1924; Jacyk 1980; Amer 2007; Zawar 2010a).
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Figure 2. The secondary eruption in pityriasis rosea showing the 'Christmas tree pattern'.
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More lesions will appear in the first two to six weeks. All lesions will
then disappear spontaneously without treatment. The entire dis-
ease duration is usually between 2 and 12 weeks, but it may last for
as long as 7 months (Chuah 2014; Drago 2015a). Some darkening or
lightening of the affected skin can remain for months after recovery
(Percival 1932; Amer 2007).
A variety of constitutional symptoms have been reported as pre-
ceding or occurring simultaneously with the onset of skin erup-
tion. These include prodromal malaise, loss of appetite, headache,
symptoms of upper respiratory tract infection, abdominal pain,
joint pain, swelling of lymph nodes, and mild fever (Percival 1932;
Cheong 1989; Tay 1999; Sharma 2000; Sharma 2008; Ozyürek 2014;
Drago 2015b). The rash is not painful, but about 30% to 50% of peo-
ple with PR will experience itching of moderate to severe intensity.
Whilst multiple recurrences are possible, most individuals who ex-
perience an episode of PR will not have another attack (Percival
1932; Chuang 1982; Zawar 2009; Chuah 2014; Sankararaman 2014;
Drago 2014a).
Pityriasis rosea is a relatively common condition with an approx-
imate incidence of 0.5% to 2% (Zawar 2010b). One study report-
ed that for every 100,000 people in the community, about 170 will
have PR in any one year (Chuang 1982). Pityriasis rosea is diag-
nosed in about 0.3% to 1.2% of all patients seen by dermatologists
worldwide, although it seems to occur more frequently in several
African countries, with annual incidence rates ranging from 2.2%
up to 4.8% of dermatological patients (Jacyk 1980; Ahmed 1986;
Olumide 1987; Harman 1998; Nanda 1999; Tay 1999; Kyriakis 2006;
Sharma 2008).
The incidence of PR peaks between the ages of 15 and 30 years
(Chuang 1982; Harman 1998; Sharma 2008; Zawar 2010b). Most epi-
demiological studies report that girls and women are more likely
to experience PR, with the overall male to female ratio of about
1:1.1-1.4 (Jacyk 1980; Chuang 1982; Olumide 1987; Harman 1998;
Nanda 1999; Kyriakis 2006; Ozyürek 2014). In contrast, PR seems to
occur more frequently in men in Singapore and India (Cheong 1989;
Tay 1999; Sharma 2008).
The data on seasonal variation in occurrence of PR is conflicting
and varies between different geographical regions, but seasonal
incidence seems to be highest during the colder months (Percival
1932; Chuang 1982; Ahmed 1986; Harman 1998; Sharma 2008). Fur-
thermore, it is known that cases of PR tend to occur in clusters (Mes-
senger 1982; Chuh 2003a; Chuh 2005b).
Terminology
Pityriasis rosea is also known by the following names: pityriasis
rosea of Gibert, pityriasis rosea of Vidal, pityriasis circinata et mar-
ginata, and pityriasis maculata et circinata (Percival 1932).
Causes
The exact cause of PR is unknown. Several facts suggest that PR is
caused by an infectious agent. The first is that the disease course, as
mentioned above, is 'programmed', similar to the course of some
viral rashes such as measles or chickenpox. The constitutional, pro-
dromal symptoms that accompany or precede the onset of rash al-
so suggest an infectious origin, as well as the epidemiological da-
ta on seasonal variations and case clustering. Furthermore, most
people who have suffered from the eruption will not have another
attack during their lifetime.
Numerous infectious agents have been considered as possible
causes of PR, but the human herpesvirus 6 (HHV-6) and human her-
pesvirus 7 (HHV-7) have been studied most extensively. However,
different investigators have reported conflicting results. There are
positive reports supporting the role of one or both of these viruses
(Drago 1997a; Drago 1997b; Watanabe 1999; Drago 2002; Watanabe
2002, Vag 2004; Broccolo 2005; Canpolat Kirac 2009; Drago 2015b),
as well as many negative reports (Kempf 1999; Yasukawa 1999;
Yoshida 1999; Kosuge 2000; Offidani 2000; Chuh 2001; Wong 2001;
Karabulut 2002; Yildirim 2004). Whilst still controversial, a causative
relationship with HHV-6 and HHV-7 seems likely, and it has been
suggested that PR is associated with the reactivation of these infec-
tions (Watanabe 2002; Broccolo 2005; Drago 2009a). Evidence has
shown that PR is not associated with herpes simplex virus 1 and
2, Epstein–Barr virus, or cytomegalovirus (Bozdag 2005; Canpolat
Kirac 2009), whereas the only two studies on the possible associ-
ation with HHV-8 infection have yielded conflicting results (Chuh
2006; Prantsidis 2009).
Some drugs can produce a skin rash as a side effect that can re-
semble PR; however, these rashes are different in nature (Drago
2014b). Pityriasis rosea and PR-like eruptions have also been de-
scribed as occurring after vaccinations against smallpox, tubercu-
losis, H1N1 influenza virus, human papillomaviruses, and other in-
fectious agents (Chen 2011; Drago 2014c; Drago 2015c).
Impact
About 80% to 90% of people with PR experience itching. In one-
third to one-half of cases, itching is of moderate to severe intensity
(Percival 1932; Cheong 1989; Sharma 2008; Ozyürek 2014).
The quality of life of people with PR (or parents of children with the
disease) may be significantly affected. They may experience anxi-
ety related to uncertainties about the cause, nature, and possible
infectivity of the eruption, as well as concern regarding physical
appearance of the skin (Chuh 2003c; Chuh 2005a; Kaymak 2008).
In dark-skinned individuals, prominent pigmentary changes, espe-
cially when involving the face, may represent a serious cosmetic
problem.
It is likely that many people with PR will consult a primary care
physician, but primary care physicians have been reported to sig-
nificantly underdiagnose the disease (Pariser 1987). Consulting a
primary care physician and then not receiving a precise diagnosis of
PR could potentially make an individual even more anxious about
the nature of the eruption and its prognosis.
The most important, although only recently recognised, effect of
PR is the impact it may have on the outcome of pregnancy. It has
been reported that PR occurring in pregnant women may be fol-
lowed by premature delivery, neonatal hypotonia, or even foetal
death, with an abortion rate of 13% overall and up to about 60% if
the rash developed within first 15 weeks of pregnancy (Drago 2008;
Drago 2014d).
Description of the intervention
Both topical and systemic treatments are currently used to treat
pityriasis rosea. Current standard of care is aimed at controlling
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symptoms and consists of topical emollients and antipruritic lo-
tions, topical corticosteroids, and oral antihistamines.
Topical treatments mainly comprise emollients and topical corti-
costeroids. The aim of topical treatment is to reduce the signs of
acute inflammation, primarily by reducing the erythema and scal-
ing thus to decrease the visibility of the lesions, but also to reduce
the pruritus that often accompanies the rash. Corticosteroids, both
topical and systemic, have a broad, non-specific anti-inflammato-
ry effect and are therefore widely used in the treatment of various
inflammatory skin diseases. Topical corticosteroids come in the
form of a cream or an ointment, and are ranked based on their po-
tency. Examples include the following: clobetasol propionate, be-
tamethasone dipropionate, mometasone furoate, fluticasone pro-
pionate, betamethasone valerate, fluocinolone acetonide, and hy-
drocortisone acetate. Emollients are basic care in the management
of various forms of eczema and other inflammatory skin diseases
and are aimed at improving the skin barrier function and reducing
dryness and the associated scaling and pruritus (van Zuuren 2017).
They are often used as a placebo intervention or comparator in the
evaluation of other topical treatments in dermatological clinical tri-
als.
Systemic treatments that have been tried thus far include medica-
tions for symptomatic control of itch such as oral antihistamines,
systemic corticosteroids, intravenous glycyrrhizin, oral antibiotics
of the macrolide group, the antiviral agent acyclovir, and sunlight
and artificial ultraviolet radiation (usually as narrowband ultravio-
let B) (Castanedo 2003; Chuh 2007; Drago 2009b).
Oral antihistamines are used as symptomatic treatment of pruri-
tus in various disease states, regardless of the cause. Examples in-
clude the following: chloropyramine, loratadine, desloratadine, ce-
tirizine, levocetirizine, bilastine, and others. Acyclovir is an antiviral
drug specifically used for the treatment of infections with herpes
viruses. Similar treatments include famciclovir and valacyclovir. In
the context of the current hypothesis on the viral aetiology of PR,
the use of acyclovir is somewhat controversial because it has weak
activity against HHV-6 and no activity against HHV-7 in laborato-
ry conditions (Yoshida 1998). Macrolide antibiotics are often used
for their broad-spectrum antibiotic effects in cases of bacterial in-
fections, but also due to their non-specific anti-inflammatory and
immunomodulatory effects. The most common ones include ery-
thromycin, azithromycin, and clarithromycin.
Ultraviolet irradiation (usually delivered as narrow-band ultravio-
let B phototherapy) is used in the treatment of various inflamma-
tory skin diseases such as psoriasis, atopic eczema, or vitiligo, but
also in various disease states accompanied by itch (Rivard 2005).
How the intervention might work
Topical corticosteroids have broad anti-inflammatory effects
through the regulation of gene expression of various cytokines, cel-
lular enzymes, and other elements in the intra- and intercellular sig-
nalling pathways. Emollients restore the epidermal aqueous and
lipid content, which in turn prevents perpetuation of skin inflam-
mation and reduces skin dryness, scaling, and the associated itch
(Rerknimitr 2017).
Antihistamines are standard systemic treatment of aetiologically
varying forms of pruritus, caused by dermatological or non-derma-
tological diseases. Antihistamines work by inhibiting H1 histamine
receptors. Acyclovir specifically inhibits DNA synthesis in herpes
viruses and may be effective in PR due to the possible causative
role of HHV-6 and HHV-7 in the development of this clinical enti-
ty. Macrolide antibiotics may be effective in PR primarily due to
their immunomodulatory and anti-inflammatory effects (Schein-
feld 2003). It has been hypothesised that phototherapy exerts its
antipruritic effect through release of endogenous antipruritic me-
diators or by direct effect on the sensitivity of cutaneous sensory
nerves (Legat 2018).
Why it is important to do this review
The previous version of this review found inadequate evidence for
the efficacy of most treatments for PR (Chuh 2007). Potential clini-
cal benefit was shown only for oral erythromycin, but this evidence
came from a single, small trial. Since Chuh 2007, which included
only three trials, several studies evaluating the efficacy of various
macrolide antibiotics as well as that of acyclovir have been pub-
lished. The current review summarises the existing evidence and
provides an updated conclusion on the currently available treat-
ments for PR.
Pityriasis rosea is essentially a self-limiting disease, and the rash
disappears for the most part at 2 to 12 weeks, with or without treat-
ment. The benefits associated with the use of any active interven-
tion should therefore outweigh any potential adverse effects. Ad-
verse effects may be short term (such as stomach upsets caused by
antibiotics) or long term (such as the risk of skin cancer caused by
ultraviolet radiation, or the effects of systemic corticosteroids on
bones). The use of antibiotics and antivirals may theoretically in-
duce resistance to bacteria and viruses, thus affecting not only the
individual but also the community as a whole.
There are many questions regarding the treatment of PR that do not
have answers. It is unknown whether many of the available treat-
ments can modify the disease course, relieve itch, or improve qual-
ity of life. A systematic review would help determine the most ef-
fective therapies, when and for whom they should be used, the du-
ration of treatment, possible risks and side effects, and the level of
treatment acceptability. This review would also enable an assess-
ment of the level and quality of the currently available evidence,
and identify areas of uncertainty or gaps in knowledge that require
further research.
O B J E C T I V E S
To assess the effects of interventions for the management of pityr-
iasis rosea in any individual diagnosed by a medical practitioner.
M E T H O D S
Criteria for considering studies for this review
Types of studies
All randomised controlled trials (RCTs) that evaluate the effective-
ness of interventions for pityriasis rosea (PR).
Types of participants
Any individual who has been diagnosed with PR by a medical prac-
titioner. Studies including only a subset of relevant participants will
be included but analysed separately.
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Types of interventions
•Topical therapy
*Emollients
*Antihistamine creams or ointments
*Corticosteroid creams or ointments
•Light therapy
*Sunlight
*Artificial ultraviolet light therapy
•Systemic therapy
*Oral antihistamines
*Oral corticosteroids
*Oral antibiotics
*Oral antiviral agents
*Intravenous Chinese medicine agents
The interventions may be either single or combination therapy. The
comparators may be no treatment, placebo, vehicle only, another
active compound, or placebo radiation treatment.
Types of outcome measures
Primary outcomes
•The proportion of participants with good or excellent rash im-
provement within two weeks, as rated by the participant.
•Serious adverse events, i.e. serious enough to require withdraw-
al of the treatment.
Secondary outcomes
•The proportion of participants with resolution of itch within two
weeks, as rated by the participant.
•Reduction in itch score within two weeks, as rated by the partic-
ipant.
•The proportion of participants with good or excellent rash im-
provement within two weeks, as rated by a medical practitioner.
•Improvement in quality of life as rated by the participant by the
use of questionnaires or other methods.
•Minor participant-reported adverse events not requiring with-
drawal of the treatment.
Timing of outcome assessment
We chose 2 weeks as the timing of the outcome assessment, as peo-
ple without any active treatment usually have spontaneous recov-
ery between 2 and 12 weeks. Any improvement after two weeks
with active treatment would be difficult to differentiate whether
the improvement is due to spontaneous recovery from the disease
or to the 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
For this update, we revised all of our search strategies in line with
current Cochrane Skin practices. Details of the previous search
strategies are shown in Chuh 2007.
The Cochrane Skin Information Specialist searched the following
databases up to 29 October 2018:
•the Cochrane Skin Specialised Register using the search strategy
in Appendix 1;
•the Cochrane Central Register of Controlled Trials (CENTRAL)
(2018, Issue 9), in the Cochrane Library using the strategy in Ap-
pendix 2;
•MEDLINE via Ovid (from 1946) using the strategy in Appendix 3;
•Embase via Ovid (from 1974) using the strategy in Appendix 4;
and
•LILACS (Latin American and Caribbean Health Science Informa-
tion database, from 1982) using the strategy in Appendix 5.
Trials registers
We (JCR, SP) searched the following trials registers up to 29 October
2018 using the strategy in Appendix 6:
•ISRCTN registry (www.isrctn.com);
•US National Institutes of Health Ongoing Trials Register Clinical-
Trials.gov (www.clinicaltrials.gov);
•Australian New Zealand Clinical Trials Registry (www.anzc-
tr.org.au);
•World Health Organization International Clinical Trials Registry
Platform (WHO ICTRP) (apps.who.int/trialsearch/); and
•EU Clinical Trials Register (www.clinicaltrialsregister.eu).
Searching other resources
References from published studies
We checked the bibliographies of the included and excluded stud-
ies for further references to relevant RCTs.
Unpublished literature
We contacted the leading researchers identified in the trial regis-
ter search in an attempt to identify relevant unpublished data. We
contacted the authors of the published trials in order to obtain data
on outcomes that were assessed but not reported in the published
papers.
Conference proceedings
We scanned abstracts from the following major dermatology con-
ference proceedings for further RCTs:
•Annual Meeting of the American Academy of Dermatology (2009
to 2017);
•Congress of the European Academy of Dermatology and Venere-
ology (2000 to 2017);
•World Congress of Dermatology (2011 to 2017); and
•International Congress of Dermatology (2011 to 2017).
We searched the CAB Abstracts (Ovid) database up to November
2017 using the following text words: Pityriasis rosea, Pityriasis of Vi-
dal, Pityriasis circinata, and Pityriasis marginata.
Adverse eects
We searched PubMed for adverse effects using the strategy in Ap-
pendix 7 up to November 2018.
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Data collection and analysis
Selection of studies
Two review authors (JCR, CJG) independently checked the titles
and abstracts identified from the searches. If it was clear to both
review authors that the study did not refer to an RCT on PR, it was
excluded. Any discrepancies were resolved by further analysing the
full publication or by contacting study authors. We excluded qua-
si-randomised trials, where allocation was by non-random meth-
ods such as alternation or was based on characteristics such as date
of birth, name, or case number.
We obtained the full texts of those studies deemed potentially rel-
evant, and two review authors (JCR, CJG) independently assessed
each study to determine whether it met the predefined selection
criteria, with any differences being resolved through discussion
with the review team. Review authors were not blinded as to the
origin or conclusions of the article for eligibility assessment, data
extraction, or quality assessment. We listed the excluded studies
and the reasons for their exclusion in the Characteristics of exclud-
ed studies table.
Data extraction and management
Two review authors (ICK and CJG) independently performed data
extraction, and three other review authors (SP, JCR, LR) checked for
and resolved any discrepancies between the data extraction. We
obtained missing data from the trial authors where possible. We
developed and piloted a data collection form to summarise the tri-
als. Two review authors (CJG, SP) checked and entered the data in-
to Review Manager 5 (Review Manager 2014).
Assessment of risk of bias in included studies
At least four review authors (CJG, LR, ICK, SP) independently as-
sessed the risk of bias of each trial using a simple form and ac-
cording to the domain-based evaluation described in the Cochrane
Handbook for Systematic Reviews of Interventions (Higgins 2011).
Review authors (CJG, LR, JCR, SP, ICK) discussed any discrepancies
and achieved consensus on the final assessment.
We assessed the following domains as low, high, or unclear risk of
bias.
•Generation of allocation sequence
•Allocation concealment
•Blinding (of participants, personnel, and outcome assessors)
•Incomplete outcome data
•Selective reporting
•Other sources of bias
Generation of allocation sequence (checking for possible
selection bias)
We described for each included study the method used to generate
the allocation sequence in sufficient detail to permit an assessment
as to whether it should produce comparable groups.
We assessed the method as:
•low risk (any truly random process, e.g. random number table;
computer random number generator); or
•unclear risk (the trial was described as randomised, but the
method used for allocation sequence generation was not de-
scribed).
Allocation concealment (checking for possible selection bias)
We described for each included study the methods used to conceal
the allocation sequence in sufficient detail to permit an assessment
as to whether the intervention allocation could have been foreseen
in advance of, or during, recruitment, or changed after assignment.
We assessed the methods as:
•low risk (e.g. telephone or central randomisation; consecutively
numbered, sealed, opaque envelopes);
•high risk (open random allocation; unsealed or non-opaque en-
velopes, alternation; date of birth); or
•unclear risk (trial was described as randomised, but the method
used to conceal the allocation was not described).
Blinding or masking (checking for possible performance and
detection bias)
We described for each included study the methods used, if any,
to blind study participants and personnel from the knowledge of
which intervention a participant received. We judged studies as at
low risk of bias if they were blinded, or if we judged that the re-
sults would not have been affected by lack of blinding. We assessed
blinding separately for different outcomes or classes of outcomes.
We assessed blinding methods as:
•low risk, high risk, or unclear risk for participants;
•low risk, high risk, or unclear risk for personnel; and
•low risk, high risk, or unclear risk for outcome assessors.
Incomplete outcome data (checking for possible attrition bias
through withdrawals, dropouts, protocol deviations)
We assessed methods on outcome data as:
•low risk (any one of the following): no missing outcome da-
ta; reasons for missing outcome data unlikely to be related
to true outcome; missing outcome data balanced in numbers
across intervention groups, with similar reasons for missing da-
ta across groups; for dichotomous outcome data, the propor-
tions of missing outcomes compared with observed event risk
was not enough to have a clinically relevant impact on the in-
tervention effect estimate; for continuous outcome data, plau-
sible effect size (difference in means or standardised difference
in means) amongst missing outcomes was not enough to have
a clinically relevant impact on observed effect size; or missing
data were imputed using appropriate methods;
•high risk (any one of the following): reason for missing outcome
data was likely to be related to true outcome, with either an
imbalance in numbers or reasons for missing data across inter-
vention groups; for dichotomous outcome data, the proportion
of missing outcomes compared with observed event risk was
enough to induce clinically relevant bias in intervention effect
estimate; for continuous outcome data, plausible effect size (dif-
ference in means or standardised difference in means) amongst
missing outcomes was enough to induce clinically relevant bias
in observed effect size; ‘as-treated’ analysis done with substan-
tial departure of the intervention received from that assigned at
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randomisation; or potentially inappropriate application of sim-
ple imputation; or
•unclear risk (any one of the following): insufficient reporting of
attrition/exclusions to permit a judgement of ‘low risk’ or ‘high
risk’ (e.g. number randomly assigned not stated, no reasons pro-
vided for missing data); or the study did not address this out-
come.
Free of other bias (bias due to problems not covered elsewhere
in the table)
We described for each included study any important concerns
we had about other possible sources of bias (baseline imbalance,
sponsorship bias, differential verification bias, partial verification
bias and incorporation bias, bias of the presentation data, etc.):
•low risk of bias: the trial appears to be free of other components
that could put it at risk of bias;
•high risk of bias: other factors in the trial could put it at risk of
bias (e.g. no sample size calculation made, academic fraud, in-
dustry involvement, extreme baseline imbalance);
•unclear risk of bias: the trial may or may not be free of other com-
ponents that could put it at risk of bias.
In addition, the quality assessment included:
•degree of certainty that the participants have PR (e.g. whether
the diagnoses were made by primary care physicians or derma-
tologists);
•whether participants with drug-induced PR-like rashes were ex-
cluded.
We recorded the information in the Risk of bias in included studies
section. We used the results of the methodological quality assess-
ment as the basis for sensitivity analysis and not as exclusion crite-
ria.
Measures of treatment eect
We presented data as risk ratios (RR) with 95% confidence intervals
(CIs) for dichotomous variables and according to the information
provided in the trials by the authors, and as mean differences (MD)
and 95% CIs for continuous variables.
Unit of analysis issues
We did not have any unit of analysis issues. The unit of allocation
and analysis was the individual participant for all included stud-
ies, and no studies were of a repeated measure, longitudinal na-
ture, cluster trial, or cross-over design. In the only case of a study
with three groups (Lazaro-Medina 1996), each of the three compar-
isons was analysed separately, and given that none of these could
be pooled, we did not have to correct for omission or double-count-
ing of participants.
Given the nature of pityriasis rosea, we did not expect to find any
within-participant trials.
Dealing with missing data
In the case of uncertainty we contacted trial authors for clarifica-
tion and to obtain missing data. When this additional information
was available, it was clearly specified in the Characteristics of in-
cluded studies tables.
If we identified any studies where 2×2 tables or means and standard
deviations were still not available, we would use the available data
such as odds ratio (OR), RR, or MD with their 95% CI.
Regarding analysis of continuous outcome data, when standard
deviations were not available for changes from baseline and in-
formation was insufficient to calculate them, standard deviations
were imputed as recommended in Section 16.1.3.2 of the Cochrane
Handbook for Systematic Reviews of Interventions (Higgins 2011). In
such cases, a correlation coefficient of 0.7 was used, alongside a
sensitivity analysis using coefficients ranging from a more conserv-
ative estimate of 0.5 up to 0.8 to examine the impact of imputation
on the final analysis results (Dias 2011). Use of different coefficients
did not change the overall result for any of the outcomes where im-
putation of standard deviation was used.
Assessment of heterogeneity
We investigated heterogeneity with visual examination of the for-
est plots. In addition, we used the Chi test and I statistic for testing
statistical heterogeneity between studies. Only trials considered
clinically and methodologically similar were pooled. We assessed
the presence of statistical heterogeneity as a value of I as per the
Cochrane Handbook for Systematic Reviews of Interventions, as fol-
lows: 0% to 40%: not important; 30% to 60%: moderate hetero-
geneity; 50% to 90%: substantial heterogeneity; 75% to 100%: con-
siderable heterogeneity (Higgins 2011). If heterogeneity (> 30%) ex-
isted between studies, reasons for heterogeneity were assessed by
examining the characteristics of the studies, types of participants,
disease severity, dosage and duration of treatment, and study qual-
ity, and subgroup analyses or sensitivity analyses were undertaken
if possible (see Subgroup analysis and investigation of heterogene-
ity). If there was considerable heterogeneity, we downgraded the
quality of the evidence using the GRADE approach (GRADE Hand-
book).
Assessment of reporting biases
We described for each included study how we investigated the pos-
sibility of selective outcome reporting bias and what we found.
We assessed reporting methods using Review Manager 5 software,
Review Manager 2014, per the Cochrane Handbook for Systematic
Reviews of Interventions (Higgins 2011), as follows:
•low risk (any one of the following): the study protocol is available
and all of the study’s prespecified (primary and secondary) out-
comes of interest in the review have been reported in the pre-
specified way, or the study protocol is not available, but it is clear
that published reports include all expected outcomes, including
those that were prespecified (convincing text of this nature may
be uncommon);
•high risk (any one of the following): not all of the study’s pre-
specified primary outcomes have been reported; one or more
primary outcomes are reported using measurements, analysis
methods, or subsets of the data (e.g. subscales) that were not
prespecified; one or more reported primary outcomes were not
prespecified (unless clear justification for their reporting is pro-
vided, such as an unexpected adverse effect); one or more out-
comes of interest in the review are reported incompletely so that
they cannot be entered into a meta-analysis; the study report
fails to include results for a key outcome that would be expected
to have been reported for such a study; or
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•unclear risk: information is insufficient to permit judgement of
‘low risk’ or ‘high risk’.
If we identified selective publication in studies, we downgraded the
evidence according to the GRADE criteria considering study design,
study size, lag bias, search strategy, etc. (GRADE Handbook).
Data synthesis
For studies with a similar type of intervention and comparator (e.g.
oral antibiotics versus placebo), we performed a meta-analysis to
calculate a weighted treatment effect across trials using a ran-
dom-effects model in Review Manager 5 (Review Manager 2014).
Where it was not possible to perform a meta-analysis, we sum-
marised the data for each trial.
We listed non-randomised controlled studies in the Characteristics
of excluded studies table; these are not discussed further.
We described studies relating to adverse effects qualitatively.
A consumer (MLS-R) was involved throughout the review process to
ensure the readability of the final review.
Subgroup analysis and investigation of heterogeneity
As stated in the protocol, parallel trials and the first phase of cross-
over trials would be analysed as separate subgroups before pool-
ing. However, we did not identify any cross-over trials in the pre-
vious version of this review or in this current version. We consid-
ered subgroup analyses for the following factors: age of partici-
pants (children versus adults), dosage, duration of treatment, type
of treatment (topical, systemic, combination), or relapse. Howev-
er, in view of the limited number of included studies covering any
one specific intervention, we did not conduct any of these subgroup
analyses.
Sensitivity analysis
We would have conducted sensitivity analyses to examine the ef-
fects of excluding studies where necessary. We planned to conduct
a sensitivity analysis by removing studies at high or unclear risk of
bias. We did not undertake any sensitivity analyses due to the lim-
ited number of included studies.
'Summary of findings' tables and GRADE
Assessment of the quality of the evidence using the GRADE approach
For this update we assessed the quality of the evidence using
the GRADE approach, as outlined in the GRADE Handbook (GRADE
Handbook). We used GRADEpro GDT to import data from Review
Manager 5 in order to create a ’Summary of findings’ table (GRADE-
pro GDT; Review Manager 2014).
Two review authors (JCR, CJG) produced a summary of the inter-
vention effect and a measure of quality for each of the above out-
comes using GRADEpro GDT. GRADE evaluates five criteria (study
limitations, consistency of effect, imprecision, indirectness, and
publication bias) to assess the quality of the body of evidence for
each outcome. The body of evidence is graded according to its qual-
ity as follows.
•High: We are very confident that the true effect lies close to that
of the estimate of the effect.
•Moderate: We are moderately confident in the effect estimate:
the true effect is likely to be close to the estimate of the effect,
but there is a possibility that it is substantially different.
•Low: Our confidence in the effect estimate is limited: the true
effect may be substantially different from the estimate of the ef-
fect.
•Very low: We have very little confidence in the effect estimate:
the true effect is likely to be substantially different from the es-
timate of effect
We downgraded the evidence from high quality by one level for se-
rious, or by two levels for very serious, factors affecting its quality.
We described the rationale for downgrading in the footnotes of the
respective tables. Two other review authors (SP, ICK) then reviewed
the tables and criteria used to downgrade the evidence, and any
discrepancies were discussed until agreement was reached.
We have presented summaries of the intervention effect and mea-
sures of quality according to the GRADE approach in the ’Summary
of findings’ tables, which include the most clinically relevant com-
parisons, as follows.
•Clarithromycin versus placebo
•Erythromycin versus placebo
•Azithromycin versus placebo (or vitamins)
•Acyclovir versus placebo (or vitamins) or no treatment
•Acyclovir + calamine + cetirizine versus calamine + cetirizine
•Acyclovir versus erythromycin
The 'Summary of findings' tables include all primary outcomes
(proportion of participants with good or excellent rash improve-
ment; serious adverse events) and four secondary outcomes (pro-
portion of participants with resolution of itch; reduction in itch
score; proportion of participants with good or excellent rash im-
provement; and minor adverse events).
R E S U L T S
Description of studies
Results of the search
This is an updated version of Chuh 2007, published in Issue 2, 2007
of the Cochrane Library. The searches of the electronic databases
retrieved 56 records (Electronic searches). Our searches of other re-
sources identified 20 additional studies that appeared to meet the
inclusion criteria. We therefore had a total of 76 records, of which
two references were duplicates. One further record was identified
as a duplicate since the trial was published. Of the remaining 73
records, we excluded 43 records based on titles and abstracts. We
obtained the full text of the remaining 30 records. We excluded a
further 16 studies (see Characteristics of excluded studies). We did
not identify any studies awaiting classification or any ongoing stud-
ies.
The review includes 14 studies (11 newly identified studies and
three studies found in the previous review). One trial did not report
outcomes at week two; therefore, although it was included in the
Description of studies and 'Risk of bias' assessment, we were not
able to formally add it to the analysis or derive information from it
(Jairath 2015). For a further description of our screening process,
see the study flow diagram (Figure 3).
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Figure 3. Selection of studies.
Regarding adverse events, our search yielded only reports of med-
ications that can produce "pityriasis rosea-like" reactions and were
not related to medicament toxicity when treating pityriasis rosea
(PR).
Included studies
Fourteen randomised trials met the inclusion criteria of this re-
view (Zhu 1992; Lazaro-Medina 1996; Villarama 2002; Akhyani 2003;
Amer 2006; Ehsani 2010; Rassai 2011; Ahmed 2014; Ganguly 2014;
Pandhi 2014; Das 2015; Jairath 2015; Singh 2016; Sonthalia 2018).
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One of these studies met the inclusion criteria but did not report on
outcomes at week 2 (Jairath 2015), thus it was only described since
it was the only study available on the modality of ultraviolet thera-
py and was found to be relevant for future research.
The main characteristics of the included studies are detailed in the
Characteristics of included studies table. The studies that were in-
cluded in the previous review are Lazaro-Medina 1996, Villarama
2002, and Zhu 1992. One study, Jairath 2015, was identified by a
secondary search performed by one review author (JCR). Thirteen
of the 14 studies have been published, whilst one study remains un-
published (Villarama 2002). The data from one study were extract-
ed from an abstract in Chinese that was translated into English, yet
we failed to obtain full text of the study from the authors, despite
repeated attempts (Zhu 1992). Another trial was published in Per-
sian, and the abstract was translated into English (Akhyani 2003).
Specific questions on the methods and results of this trial were also
provided from a native of Iran.
One study did not report on some of the outcomes at week 2 (Singh
2016), but the author was contacted and these data were provided.
One study was missing information on pruritus, and clarification on
the methods used for diagnosis and recruitment was needed; the
authors were contacted and the information provided (Das 2015).
Another trial was missing information on rash improvement, itch,
and dropouts, but we were able to obtain this information from
the authors (Pandhi 2014). One trial did not provide information on
complete resolution of itch, scores on the Pityriasis Rosea Severi-
ty Score (PRSS), or standard deviations on rash improvement (Son-
thalia 2018), but we were able to obtain part of this missing infor-
mation from the author. Finally, two more trials had unclear infor-
mation on the methodology, and the authors were contacted for
clarification (Ahmed 2014; Ganguly 2014).
Design
All included studies were parallel RCTs, where each participant was
randomised to the intervention or comparator group.
Setting and diagnosis
Six of the included studies were conducted in India, three in Iran,
two in the Philippines, and one each in Pakistan, the USA, and Chi-
na. Thirteen trials were performed in dermatology departments
and one in a paediatric ward (Amer 2006). The methods of diagno-
sis differed slightly amongst the trials. In eight trials, the diagno-
sis of PR was made by one to three dermatologists (Akhyani 2003;
Ehsani 2010; Ahmed 2014; Pandhi 2014; Das 2015; Jairath 2015;
Singh 2016; Sonthalia 2018). In one trial dermoscopy was addition-
ally performed (Sonthalia 2018). Five trials were conducted in der-
matology departments (Zhu 1992; Lazaro-Medina 1996; Villarama
2002; Rassai 2011; Ganguly 2014), although it was not explicitly
stated whether the diagnosis of PR was made by dermatologists.
In three trials the clinical diagnosis of PR was confirmed through
a biopsy (Lazaro-Medina 1996; Ganguly 2014; Jairath 2015). Pae-
diatricians made the diagnosis in a single trial (Amer 2006). Con-
sequently, there is a high degree of certainty for all but one trial
that the participants had PR (Amer 2006). Although most trials did
not specifically exclude drug-induced PR, six trials listed prior use
of drugs as exclusion criteria (Villarama 2002; Rassai 2011; Ahmed
2014; Ganguly 2014; Singh 2016; Sonthalia 2018); therefore, it can
be assumed that none of these trials included participants with
drug-induced PR.
Participants
The included studies involved a total of 761 participants. The age
range of participants was 2 to 60 years. Except for one study where
only male patients were recruited (Amer 2006), the included stud-
ies involved both male and female participants. Three studies failed
to report participant age and sex (Zhu 1992; Rassai 2011; Gangu-
ly 2014). Of the trials that reported gender, 307 participants were
male and 251 female. A detailed description of participants in each
of the studies is provided in the Characteristics of included studies
table. The sample sizes of the included studies ranged from 23 to
100. A total of 265 participants were included in studies that com-
pared different macrolide antibiotics versus placebo or vitamins.
Acyclovir was compared with vitamins, placebo, no treatment, or
standard of care in a total sample of 188 participants (Rassai 2011;
Ganguly 2014; Das 2015; Singh 2016). Erythromycin was compared
with acyclovir in an additional 30 participants (Ehsani 2010). Nar-
rowband ultraviolet B phototherapy was compared with topical
emollient in 100 participants (Jairath 2015). Oral corticosteroids
were compared with placebo in a study with 70 participants, Son-
thalia 2018, and with antihistamines in a study with 85 participants,
Lazaro-Medina 1996. A single study with 23 participants investigat-
ed the effects of the Chinese medicine glycyrrhizin (Zhu 1992).
All trials documented the extent or severity of the rash, or both, but
with diverse measures. Also, participants were not divided into cat-
egories based on disease severity. A disease-specific severity index,
the Pityriasis Rosea Severity Score (PRSS), which incorporates the
extent of the disease, along with erythema, infiltration, and scal-
ing, was used in only three studies (Pandhi 2014; Jairath 2015; Son-
thalia 2018). With a theoretical maximal score of 54, baseline PRSS
scores in the intervention and control groups were 25.64 ± 14.21
and 23.04 ± 15.09 in Jairath 2015; 18.06 ± 5.62 and 20.23 ± 5.16 in
Pandhi 2014; and 18.51 ± 5.32 and 19.45 ± 5.88 in Sonthalia 2018.
Six trials used the number of lesions as a measure of disease sever-
ity (Lazaro-Medina 1996; Villarama 2002; Ehsani 2010; Rassai 2011;
Ahmed 2014; Ganguly 2014), although most of these studies did not
specify the absolute lesion count and only reported on (partial or
complete) disappearance of existing lesions or the appearance of
new lesions. One study used a lesional score with a theoretical max-
imum of 5, calculated by addition of erythema score, scaling score,
and number of lesions score (Das 2015), and reported baseline val-
ues of 4.08 ± 0.79 and 4.08 ± 0.90 in the intervention and control
groups, respectively. Another study used the Pityriasis Rosea Area
and Severity Index (PRASI) ranging from 0 to 48 and reported base-
line median scores of 3.5 and 5.4 in the intervention and control
groups, respectively (Singh 2016).
Seven studies reported the presence or absence of itch at baseline.
Itch accompanied the rash in the following percentages of partici-
pants: 46.7% (Ehsani 2010; Ahmed 2014), 77.8% (Singh 2016), 81.6%
(Amer 2006), 83.5% (Lazaro-Medina 1996), or all participants (Das
2015; Sonthalia 2018). Three studies assessed intensity of itch on a
0-to-3 scale, with comparable baseline itch severity values in the in-
tervention and control arms: 2.17 ± 0.83 and 2.25 ± 0.75 in Das 2015;
2.00 ± 0.82 and 2.04 ± 0.82 in Jairath 2015; and 1.36 ± 1.01 and 1.15 ±
0.9 in Singh 2016. Four studies assessed itch with a visual analogue
scale (VAS) ranging from 0 to 10, and baseline values in the inter-
vention and control arms were 8.25 ± 1.06 and 8.42 ± 1.08 in Das
2015; 1.31 ± 1.02 and 1.4 ± 1.1 in Sonthalia 2018; and 1.31 ± 1.105
and 1.23 ± 1.239 in Pandhi 2014, whilst Villarama 2002 only report-
ed on the difference in scores before and after treatment, without
specifying absolute values.
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Interventions
The treatments and their duration were clearly defined in all 14 in-
cluded studies (see Characteristics of included studies). As most of
the included studies investigated different interventions and differ-
ent outcome measures, pooling of data for analysis was only fea-
sible for a few comparisons in the 13 trials that we were able to
analyse.
Four studies documented the use of medications before inclusion
of participants into the study (Zhu 1992; Lazaro-Medina 1996; Vil-
larama 2002; Ganguly 2014). Six studies excluded patients who had
taken any medication after the onset of the rash (Villarama 2002;
Rassai 2011; Ahmed 2014; Ganguly 2014; Singh 2016; Sonthalia
2018). The remaining trials did not comprehensively document the
use of previous medications after the appearance of rash.
Six studies analysed the use of macrolide antibiotics. In a single
study that compared clarithromycin to placebo (Ahmed 2014), clar-
ithromycin tablets were used for a week in a dose of 500 mg twice
daily for adults and 250 mg twice daily for children aged 10 to 12
years. Two studies compared oral erythromycin to placebo: ery-
thromycin was used in a daily dose of 1 g for one week, Akhyani
2003, or 250 mg for two weeks, Villarama 2002. Two studies evalu-
ated the effects of a dose of 12 mg/kg/day of azithromycin tablets
for 5 days versus placebo, Amer 2006, and vitamins, Pandhi 2014.
One study compared oral erythromycin in a dose of 400 mg 4 times/
day for 10 days to the antiviral agent acyclovir administered orally
in a dose of 8000 mg 5 times/day for 10 days (Ehsani 2010).
Three studies compared acyclovir to placebo or no treatment (Ras-
sai 2011; Ganguly 2014; Singh 2016). Oral acyclovir was adminis-
tered in a dose of 800 mg 5 times/day, Ganguly 2014; Singh 2016,
or 400 mg 5 times/day, Rassai 2011, for 7 days in adults, and in a
dose of 20 mg/kg 4 times/day for 7 days in children, Ganguly 2014.
One study compared acyclovir tablets in a dose of 400 mg 3 times/
day for 7 days along with standard of care (calamine lotion and cet-
irizine 10 mg tablets once daily at bedtime) versus standard of care
alone (Das 2015).
One study compared three interventions: oral antihistamine dex-
chlorpheniramine (4 mg 2 times/day for 2 weeks, then once a day
for the following 2 weeks) versus oral corticosteroid betametha-
sone (500 mcg, 2 times/day for 2 weeks, then once a day for the
following 2 weeks) versus combined therapy (betamethasone 250
mcg and dexchlorpheniramine 2 mg, both 2 times/day for 2 weeks,
then once a day for the following 2 weeks) (Lazaro-Medina 1996).
One study compared low-dose oral prednisolone (20 mg/day for 5
days, 15 mg/day for the next 5 days, and 10 mg/day for the last 5
days) to placebo (Sonthalia 2018).
The effects of narrowband ultraviolet B phototherapy were com-
pared with placebo in one trial that did not report on outcomes at
week 2 (Jairath 2015). Phototherapy was applied in a fixed dose of
250 mJ/cm three times a week on non-consecutive days for four
weeks (total dose of 3 J/cm).
One study investigated the effects of the Chinese medicine poten-
line (glycyrrhizin, 80 mL in 500 mL of 10% glucose intravenous so-
lution, administered once daily) versus procaine (300 mg to 600 mg
in 500 mL of 10% glucose intravenous solution, administered once
daily) (Zhu 1992). The duration of treatment was unclear.
Outcomes
Objectives and outcome measures were clearly defined in 13 stud-
ies. In the study by Zhu 1992, the disappearance of symptoms and
rash were assessed together. Symptoms were not specified as itch.
We had to assume that symptoms were limited to itch only.
None of the included studies assessed the following participant-re-
ported outcomes: our primary outcome of proportion of partici-
pants with good or excellent rash improvement within two weeks,
as rated by the participant, and our secondary outcome of improve-
ment in quality of life as rated by the participant by the use of ques-
tionnaires or other methods.
Seven studies reported the proportion of participants with resolu-
tion of itch within two weeks, either in the original trial reports or
upon email contact with the study authors (Lazaro-Medina 1996;
Ehsani 2010; Ahmed 2014; Pandhi 2014; Das 2015; Singh 2016; Son-
thalia 2018).
Six studies assessed reduction in itch score, as rated by the partic-
ipant, either on a 0-to-3 scale (i.e. absent, mild, moderate, severe)
(Das 2015; Jairath 2015; Singh 2016), or by means of a 0-to-10 VAS
(Villarama 2002; Pandhi 2014; Das 2015; Sonthalia 2018).
Eleven studies reported the proportion of participants with good or
excellent rash improvement within two weeks, as rated by a med-
ical practitioner. Most of these studies assessed this outcome as
partial or complete response to treatment, with complete response
meaning all lesions had started healing in less than two weeks with-
out the appearance of any fresh lesion, and partial response when
lesions had regressed partially, or few new lesions had appeared in
two weeks, or similar. In two studies that used the PRSS as a sever-
ity index, improvement was graded as the percentage reduction as
follows: good, 26% to 50%; very good, 51% to 75%; and > 75%, ex-
cellent (Pandhi 2014; Sonthalia 2018).
Twelve studies assessed adverse events. In the available translated
details of Akhyani 2003 and Zhu 1992, side effects were not reported
as one of the assessed outcomes. Ahmed 2014 specified upon email
contact that “adverse effects were not directly asked [sic] in order
to prevent disclosure of drug and placebo groups”, but that there
were no serious adverse events requiring withdrawal.
Length of follow-up
Length of follow-up in the included studies varied from two weeks,
Ganguly 2014, to as long as one year, Ehsani 2010, with one study
not reporting the length of follow-up (Zhu 1992). In four studies par-
ticipants were followed up for four weeks (Amer 2006; Rassai 2011;
Das 2015; Jairath 2015). In another four studies participants were
followed up for six weeks (Villarama 2002; Akhyani 2003; Ahmed
2014; Pandhi 2014). In two studies participants were followed up
for 12 weeks after the beginning of the treatment (Lazaro-Medina
1996; Sonthalia 2018). In one trial participants were followed until
rash resolution (approximately one month) (Singh 2016). Study du-
ration ranged from 5 to 26 months.
Funding sources
Funding sources were not reported for the majority of the includ-
ed studies (Zhu 1992; Villarama 2002; Akhyani 2003; Ehsani 2010;
Rassai 2011; Ahmed 2014; Ganguly 2014; Pandhi 2014; Das 2015;
Jairath 2015). One study was independently funded (Singh 2016);
a pharmaceutical company provided the study medication. How-
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ever, the study of Amer 2006 was supported by a grant from Pfizer
Inc, and the study by Lazaro-Medina 1996 was supported by Scher-
ing-Plough.
Language of publication
Eleven trials were published in English (Lazaro-Medina 1996; Amer
2006; Ehsani 2010; Rassai 2011; Ahmed 2014; Ganguly 2014; Pandhi
2014; Das 2015; Jairath 2015; Singh 2016; Sonthalia 2018); one in
Persian (Akhyani 2003); and one in Chinese (Zhu 1992). One study
is still unpublished, but was written in English (Villarama 2002).
Excluded studies
See Characteristics of excluded studies.
We excluded 16 studies. In the previous version of this review, 13
trials were excluded because no mention of randomisation was
made. One of these studies was pseudo-randomised because par-
ticipants were assigned by alternate allocation (Sharma 2000).
Three more trials were excluded from our search results because
they were not randomised trials (Drago 2006; Rasi 2008; Amatya
2012). One trial stated that the participants were randomised into
two groups (Amatya 2012). However, given that there was no ex-
planation of the method of randomisation in the manuscript, we
contacted the author, who stated that alternate allocation was the
method used; therefore, the study was not randomised. Another
study clearly stated in the methods that participants were alter-
nately assigned (Drago 2006). Finally, the last trial is a case-con-
trolled, open-label study without randomisation (Rasi 2008).
Risk of bias in included studies
'Risk of bias' assessments for each included study are provided in
Characteristics of included studies and Figure 4 and Figure 5.
Figure 4. Risk of bias graph: review authors' judgements about each risk of bias item presented as percentages
across all included studies.
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Figure 5. Risk of bias summary: review authors' judgements about each risk of bias item for each included study.
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Figure 5. (Continued)
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Allocation
Random sequence generation
We assessed risk of bias arising from method of generation of the
allocation sequence to be low in 10 trials (Lazaro-Medina 1996; Vil-
larama 2002; Rassai 2011; Ahmed 2014; Ganguly 2014; Pandhi 2014;
Das 2015; Jairath 2015; Singh 2016; Sonthalia 2018). The remaining
four trials were at unclear risk of bias for this domain.
Allocation concealment
We assessed risk of bias arising from method of allocation conceal-
ment to be low in seven trials (Villarama 2002; Ahmed 2014; Gan-
guly 2014; Pandhi 2014; Das 2015; Singh 2016; Sonthalia 2018). We
judged the remaining seven trials as having an unclear risk for this
domain.
Blinding
We rated risk of bias due to lack of blinding of participants and per-
sonnel as low in eight trials (Villarama 2002; Akhyani 2003; Amer
2006; Ahmed 2014; Ganguly 2014; Pandhi 2014; Singh 2016; Son-
thalia 2018); unclear in three trials (Zhu 1992; Lazaro-Medina 1996;
Ehsani 2010); and high in three trials (Rassai 2011; Das 2015; Jairath
2015). Since the full text of the manuscript was not available for Zhu
1992, the information was extracted from the abstract. The authors
clearly state in the abstract that this study was not blinded, but
that both groups of participants received some form of intravenous
therapy. Given the lack of information to determine whether or not
this influenced the outcomes, we judged the risk of bias for this do-
main as unclear.
In nine trials, outcome assessment was clearly reported as blind-
ed and thus detection bias was considered to be low (Villarama
2002; Akhyani 2003; Amer 2006; Ahmed 2014; Ganguly 2014; Pand-
hi 2014; Das 2015; Singh 2016; Sonthalia 2018). Blinding of out-
come assessment was unclear in four trials (Zhu 1992; Lazaro-Med-
ina 1996; Ehsani 2010; Rassai 2011). We assessed one trial, Jairath
2015, as at high risk of bias because the method of blinding was not
specified and in all likelihood, given the tanning effect of ultraviolet
radiation, blinding would have been difficult.
Incomplete outcome data
We assessed risk of attrition bias as low in 11 trials, Zhu 1992; Vil-
larama 2002; Akhyani 2003; Amer 2006; Ehsani 2010; Ahmed 2014;
Ganguly 2014; Pandhi 2014; Das 2015; Jairath 2015; Singh 2016, and
unclear in two trials, Rassai 2011; Sonthalia 2018. We judged the re-
maining trial, Lazaro-Medina 1996, as at high risk of bias because
multiple dropouts in a single group (group C) were evident, and no
information as to the cause of the dropouts was provided.
Selective reporting
We rated risk of reporting bias as low in nine trials (Lazaro-Medina
1996; Villarama 2002; Ehsani 2010; Rassai 2011; Ahmed 2014; Gan-
guly 2014; Pandhi 2014; Das 2015; Jairath 2015); unclear in two tri-
als (Zhu 1992; Akhyani 2003); and high in three trials (Amer 2006;
Singh 2016; Sonthalia 2018). Amer 2006 failed to report on pruri-
tus and concomitant medications used, both of which were stated
in the methods. Singh 2016 failed to report a secondary outcome
(50% reduction in severity) and PRASI score, and in Sonthalia 2018,
there were inconsistencies in the final report of results of outcomes
prespecified in the original article, and upon further contact with
the author, the information provided was incomplete and we re-
ceived no answer to our request for clarification.
Other potential sources of bias
We rated risk of other bias as low in 12 trials (Lazaro-Medina 1996;
Villarama 2002; Amer 2006; Ehsani 2010; Rassai 2011; Ahmed 2014;
Ganguly 2014; Pandhi 2014; Das 2015; Jairath 2015; Singh 2016;
Sonthalia 2018), and unclear for the remaining two trials as there
was insufficient information for judgement (Zhu 1992; Akhyani
2003).
Eects of interventions
See: Summary of findings for the main comparison Clar-
ithromycin compared to placebo for pityriasis rosea; Summary of
findings 2 Erythromycin compared to placebo for pityriasis rosea;
Summary of findings 3 Azithromycin compared to placebo or vit-
amins for pityriasis rosea; Summary of findings 4 Acyclovir com-
pared to placebo, vitamins, or no treatment for pityriasis rosea;
Summary of findings 5 Acyclovir + calamine + cetirizine compared
to calamine + cetirizine for pityriasis rosea; Summary of findings 6
Acyclovir compared to erythromycin for pityriasis rosea
See: Summary of findings for the main comparison, Summary of
findings 2, Summary of findings 3, Summary of findings 4, Summa-
ry of findings 5, Summary of findings 6.
We analysed outcomes as described in the Types of outcome mea-
sures section. Each outcome was investigated for the pre-estab-
lished interventions described in the Types of interventions sec-
tion. Only those outcomes for which we found suitable data are de-
scribed below. None of the included studies reported on the pri-
mary outcome of proportion of participants with good or excellent
rash improvement within two weeks, as rated by the participant, or
the secondary outcome of improvement in quality of life measures.
We meta-analysed findings from the included studies when a drug
was tested in at least two studies.
We did not perform subgroup or sensitivity analyses due to the lim-
ited number of studies identified for each specific outcome or in-
tervention.
Comparison 1: Clarithromycin compared to placebo
We identified one study including 60 participants for this compari-
son (Summary of findings for the main comparison) (Ahmed 2014).
Clarithromycin was given orally in a dose of 500 mg twice daily for
adults and 250 mg twice daily for children for one week. The control
intervention was placebo tablets.
Primary outcome 2: Serious adverse events, i.e. serious enough
to require withdrawal of the treatment
No participants from either group suffered serious adverse effects
requiring withdrawal (moderate-quality evidence).
Secondary outcome 1: The proportion of participants with
resolution of itch within two weeks, as rated by the participant
The author of Ahmed 2014 was contacted and information on this
outcome was provided. Each group had a total of 30 participants;
however, not all participants had itch at baseline (16 in the clar-
ithromycin group and 12 in the placebo group). No significant dif-
ference was found in the proportion of participants with resolution
of itch at two weeks (9/16 versus 8/12; risk ratio (RR) 0.84, 95% con-
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