Interventions for pityriasis rosea
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.
To assess the effects of interventions for the management of pityriasis rosea in any individual diagnosed by a medical practitioner.
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.
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 requiring withdrawal of the treatment.
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.
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 participants). 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 measured 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, moderate‐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 participants), 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).
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 investigate different dose regimens of acyclovir and the effect of antivirals on pityriasis rosea.
Jose Contreras‐Ruiz, Sandra Peternel, Carlos Jiménez Gutiérrez, Ivana Culav‐Koscak, Ludovic Reveiz, Maria de Lourdes Silbermann‐Reynoso
Plain language summary
Treatments for pityriasis rosea
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. Moreover, pityriasis rosea can cause moderate to severe itching, making effective treatment necessary.
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 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.
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 manufacturers; most studies did not report their funding sources. Disease severity was assessed by various measures, but participants were not categorised 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 improvement 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 treatment, 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.
Jose Contreras‐Ruiz, Sandra Peternel, Carlos Jiménez Gutiérrez, Ivana Culav‐Koscak, Ludovic Reveiz, Maria de Lourdes Silbermann‐Reynoso
Implications for practice
Pityriasis rosea (PR) is a self‐limiting condition, and spontaneous recovery is expected in 2 to 12 weeks without active treatment. It is unusual for the face to be affected, and many people with PR do not itch at all. The severity of itch and its effect on quality of life are not necessarily correlated with the extent of the rash. When choosing treatment options, the severity of itch, the extent and distribution of the rash, and potential adverse effects of the treatment all need to be taken into consideration. In most cases, the option of no treatment, and providing reassurance, may be a valid alternative given the benign nature of PR.
The treatments currently used for PR are for the most part not supported by well‐designed clinical trials, and many different types of treatment are used. Regarding the most commonly used treatment options in the management of people with PR, this review provides no information about which emollients or which potency topical corticosteroids might be preferred for the topical treatment of PR, and we found inadequate evidence about whether oral antihistamines or phototherapy provides any clinical benefit compared to no treatment. There is little, low‐ to moderate‐quality evidence on the favourable effects of acyclovir for the treatment of PR. However, this evidence comes from trials with different dose regimens of acyclovir; therefore, it is unclear which doses of acyclovir perform best. Since the causative agent(s) of PR have not yet been definitively identified, and the disease usually follows a benign, self‐limiting course, until sufficient evidence is obtained regarding the origin of the disease, the treatment remains symptomatic.
The current review update suggests that acyclovir probably improves the rash in PR better than placebo, vitamins, or no treatment, or when added to combined treatment regimens. However, evidence for the effect of acyclovir on itch was inconclusive. All of the trials assessing acyclovir were small, and further adequately powered studies with similar methodology are needed to corroborate these findings. The optimal dose of acyclovir remains unknown.
Regarding the use of various macrolide antibiotics, none of those reviewed (i.e. erythromycin, azithromycin, or clarithromycin) showed any conclusive beneficial effect on rash. Based on a single trial, erythromycin is probably more beneficial in reducing the severity of itching than placebo. There is probably no difference between azithromycin and placebo (or vitamins) in resolution of itch or reduction in itch score. Similarly, there is probably no difference in resolution of itch between clarithromycin and placebo.
None of the included studies in this review reported serious adverse events (based on low‐ to moderate‐quality evidence).
The single trial assessing oral clarithromycin versus placebo did not measure minor participant‐reported adverse events not requiring withdrawal of the treatment. In the other key comparisons, the rates were very low with each treatment (< 3%), and there were no significant differences between groups (low‐ to moderate‐quality evidence). Reported minor adverse events included gastrointestinal upset, mild abdominal pain, diarrhoea, and headache.
The evidence of efficacy of other treatments is insufficient to draw meaningful conclusions, but the absence of evidence of efficacy for many treatments in PR does not necessarily imply that they are not effective.
Implications for research
We recommend well‐designed, adequately powered (using a sample size calculation) randomised controlled trials to investigate treatments for PR that are commonly used by dermatologists. These interventions include topical corticosteroids versus placebo, emollients versus placebo, ultraviolet radiation, and antihistamines for people with PR who are symptomatic. Trials should adhere to the CONSORT guidelines (Schulz 2010).
We advocate that further research should be conducted to validate a set of diagnostic criteria for PR, which future clinical trials might then adopt. Pityriasis rosea may present with atypical features, and therefore the use of validated diagnostic criteria might aid in standardising the inclusion of participants in future clinical trials and allow the results to be compared. For participants with a typical PR eruption, we do not think that biopsies for confirmation are necessary. Insisting on lesional biopsy for all participants might also lead to a lower recruitment rate in randomised controlled trials and other types of research for PR, thus causing a potential threat to external validity.
As there is no universally accepted active intervention for PR, we suggest that future clinical trials for PR should include placebo as a control, rather than merely comparing several potentially active interventions against one another.
The time frame for assessing outcomes should preferably be within two weeks, as spontaneous remission cannot be excluded after two weeks. If the time frame for assessing outcomes is beyond two weeks, the study should be adequately powered to compare treatment versus placebo in order to demonstrate meaningful reductions in average time course to resolution of rash or symptoms.
None of the included studies measured our primary outcome of proportion of participants with rash improvement within two weeks as rated by the participant, but most studies measured rash improvement by a medical practitioner. However, different measures were used to assess this. Future studies should include an assessment of rash improvement measured by the participant and using a standardised outcome measure. Future trials should consult the Cochrane Skin Outcomes Set Initiative (CSG‐COUSIN) to check for any core outcome measures.
Furthermore, trials should consider always clarifying the beginning of the rash as the starting point of the disease. We advocate that, apart from baseline assessment of the extensiveness of the rash, the baseline assessment of symptoms (mainly itch) and effects on quality of life should be well documented in any future clinical trials on PR. We also advocate that validated quality of life indexes (e.g. standardised questionnaires) should be adopted as measures of this outcome. Without relevant information regarding the impact of the treatment on quality of life, complete judgement regarding the clinical importance and cost‐effectiveness of interventions is not possible due primarily to the benign and self‐limiting course of the disease.
Researchers should be alert to the fact that many people with PR have little or no itch. A diagnostic label in Latin may be given, but the condition may not bother the person at all. The potential adverse effects of any intervention should be balanced against potential benefit, if any, for this group of people.
None of the trials reported any severe side effects, and mild side effects did not differ between study groups in any of the included trials. These adverse events were measured in the short term; long‐term effects should also be taken into consideration.
As shown, there is moderate‐quality evidence for a beneficial effect of acyclovir in good or excellent rash improvement in PR (compared against placebo). Studies confirming this effect should therefore be conducted to establish whether or not this treatment could become standard of care. Since there is no ideal dose regimen of acyclovir for PR, studies evaluating different dose regimens are needed. Given the incidence of the disease, large studies evaluating dose‐response may not be possible, so even comparing dose regimens of 4 g per day to regimens of 2 g or less per day could provide a first step in clarifying whether low‐ versus high‐dose acyclovir provides a better clinical response. Since evidence suggests the implication of several members of the Herpesviridae family in PR, trials evaluating other antivirals such as valacyclovir or famciclovir could be justified, although the cost of such treatments is usually higher. Uncertainty remains about the effects of treatments that have not been appropriately assessed through controlled trials, some of which are even used as standard treatment nowadays, such as emollients, topical antihistamine creams, topical corticosteroid creams, and ultraviolet B phototherapy.