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Roflumilast in seborrheic dermatitis: Review
*Corresponding author: Prathyusha Songa, Department of Dermatology, Dr. Nimmy’s Skin Clinic, Secunderabad, India. doctor.songa.prathyusha@gmail.com
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Received: ,
Accepted: ,
How to cite this article: Songa P, Bhatnagar A, Dias F, Oberoi B. Roflumilast in seborrheic dermatitis: Review. J Compr Dermatol. 2025;1:2. doi: 10.25259/JCD_13_2024
Abstract
Seborrheic dermatitis (SD) is a chronic skin condition that can significantly impact patients’ quality of life. While topical antifungals and corticosteroids are often used, they frequently provide only a partial response or may lead to side effects with long-term use. The objective of our study was to evaluate the efficacy and safety of topical phosphodiesterase-4 inhibitor (0.3% roflumilast foam [ROF]) in the treatment of SD. We conducted a comprehensive literature search in PubMed, Embase, Scopus, and Cochrane databases until May 2024. Our inclusion criteria were randomized, non-randomized, and open-label trials that compared ROF with a control; patients with SD treated with ROF; and reported relevant outcomes. We excluded studies with overlapping populations. The risk of bias was assessed using Cochrane’s guidelines. R programming was used to evaluate the risk ratio using a random-effects model and assess heterogeneity. Our analysis included three studies comprising a total of 1083 patients. The pooled results at week 4 showed that 53.64% (95% CI, 30.25%–77.03%; p = 0.88; I2 = 98%) of patients in the ROF group achieved Investigator Global Assessment success, and 53.91% (95% CI, 47.40%–60.43%; p = 0.55; I2 = 72%) achieved Worst Itch Numeric Rating Scale success. Furthermore, a subgroup analysis of randomized controlled trials (RCTs) was performed, which reduced the heterogeneity and demonstrated the significant efficacy of ROF in the treatment of SD. The key limitations of our study were the short follow-up period and the high degree of heterogeneity in our pooled analysis. We concluded that ROF shows promise for the treatment of SD, but further RCTs with extended follow-up periods are needed to fully evaluate its efficacy. This review was prospectively registered on PROSPERO (ID-CRD42024546079) and was conducted without any funding support.
Keywords
Keywords
Dermatitis
General dermatology
Phosphodiesterase inhibitors
Roflumilast
Seborrheic dermatitis
INTRODUCTION
Seborrheic Dermatitis (SD) is a common chronic skin condition which has an estimated overall global prevalence of over 5%, and it is even more common in specific populations, such as those with neurological, psychiatric, and immunodeficiency diseases.1,2 The cardinal features of SD include erythema, scaling, itching, and dyspigmentation, which can cause cosmetic concerns, physical discomfort, and significant psychosocial morbidity in the form of anxiety and distress.3 Thus, SD can negatively impact the quality of life.4,5
Among the repertoire of pharmacotherapy currently available for moderate to severe SD, topical antifungals (to reduce the proliferation of the yeast, Malassezia species) and corticosteroids (to suppress inflammation) are the mainstay of the approved standard of care.6,7 Nevertheless, these therapeutic options are often short-term solutions. Additionally, patients who take these medications for an extended period of time report unfavorable side effects from the treatment, including local pain, irritability, itching, acne, skin atrophy, telangiectasia, rosacea, and ocular toxicity. All of these side effects have the potential to worsen the already-existing disease burden.
Furthermore, SD affects both hair-bearing and non-hair-bearing body areas such as the scalp, face, ears, neck, trunk, axilla, and groin. However, unfortunately, currently there is no single formulation that is both clinically effective and cosmetically acceptable for all body areas. The increased cost burden of concurrently maintaining multiple formulations for different body areas deters patients from adhering to the recommended long-term treatment strategies. This highlights the unmet medical needs of SD patients, which are caused by the lack of a single topical medication that maximizes cost-effectiveness, minimizes adverse pharmacologic effects, and is suitable for both hairy and non-hairy body areas.
While roflumilast, a phosphodiesterase 4 (PDE4) inhibitor, has been showing promising results in the treatment of other inflammatory dermatoses such as psoriasis and eczema, its potential benefits as a treatment for SD remain unclear.8–11 Thus, in order to evaluate the efficacy and safety of the novel topical, ROF 0.3%, in patients with SD, we performed a systematic review and meta-analysis of studies evaluating this treatment for this specific population.
OBJECTIVES
To perform a systematic review and meta-analysis of the efficacy and safety of novel topical ROF in patients diagnosed with SD.
MATERIAL AND METHODS
Eligibility criteria
Inclusion criteria—(1) randomized controlled trials (RCTs), non-randomized controlled trials (NRCTs), that compared ROF with a control group, and open-label trials (OLTs); (2) evaluating patients diagnosed with SD; (3) treated with ROF once daily; and (4) reporting any outcomes of interest. We excluded studies with overlapping samples from populations.
Information sources
Databases including PubMed, Cochrane, Embase, and Scopus were comprehensively and systematically searched for studies meeting the eligibility criteria and published from inception until May 12th, 2024.
Search strategy
The search strategy was as follows: (“seborrheic dermatitis” OR “dermatitis seborrheica” OR “seborrheic dermatitides” OR “seborrheic eczema” OR “seborrheic psoriasis” OR seborrhea OR dandruff) AND (roflumilast OR Daxas OR Daliresp OR Zoryve OR “phosphodiesterase 4 inhibitor” OR “PDE4 inhibitor”).
Selection process
Zotero was used as the reference manager tool to delete duplicates. In addition, the references of relevant articles, reviews, and included studies were analyzed for other eligible studies.
Data collection process
The qualified studies were listed, outlining details of the intervention, study methodology, participant demographics, and recorded results. These details were assessed against our established criteria to confirm their significance for our intended analyses.
Two authors independently extracted data of predetermined baseline characteristics and outcomes and compared their findings.
Data items
Investigator Global Assessment (IGA) score, Worst Itch Numeric Rating Scale (WI-NRS) score, overall assessment of erythema score, and overall assessment of scaling score were the efficacy outcomes evaluated. Under these scores, the data of the primary studies, which was provided as percentages of patients achieving significant improvement, were labelled and evaluated as the number of patients achieving IGA success, WI-NRS success, erythema success, and scaling success, respectively.
Study risk of bias assessment
Cochrane risk of bias the RoB 2 tool was used to assess the quality of individual RCTs and RoB 1 for OLT by two independent authors. Each trial received a score of high, low, or unclear risk of bias in five domains: randomization process, deviations from the intended interventions, missing outcomes, measurement of the outcome, and selection of reported results. Finally, the RCTs were labeled with very low, low, moderate, or high risk based on the scores in all domains. The layout was produced by Robvis.
Effect measures, end points and subgroup analysis
We employed risk ratio (RR) to assess IGA, WI-NRS, erythema and scaling success. Meta-analysis of proportions was used for the OLT. First, a single-arm meta-analysis of the efficacy outcomes at week 4 was performed using only the ROF arm of all the included studies. Second, we performed a subgroup analysis of the efficacy outcomes of only the RCTs at weeks 2, 4, and 8, comparing the ROF group with the control group. The overall treatment-related adverse events (trAEs) outcome was evaluated as a safety outcome separately.
Synthesis methods
Based on eligibility criteria, three studies (2 RCTs and 1 OLT) were ultimately involving a total of 1083 patients, of whom 858 (80%) patients received ROF and 20% received the control. To ensure that the units used in the studies were consistent, data conversions were done. Tables and figures were created as visual aids to help explain these findings. Forest plots were employed to depict the impact magnitudes and confidence intervals for each research study. A summary table presents the key characteristics and conclusions of the included research.
The analyses were conducted utilizing R Studio for the 4.4.0 version of R programming. A random-effects model was used to address potential variability among studies and adhere to PRISMA 2020 recommendations. We used the inverse variance method and untransformed proportions for our analysis. Statistical diversity was evaluated utilizing the I2 metric, where values exceeding 50% signify significant variability. Additionally, the chi-square test (Cochran’s Q test) was carried out to appraise heterogeneity. The individual research findings were combined with study attributes to provide information on each variable of interest.
The review has been registered with the registration number CRD42024546079 on PROSPERO and is available for access on its official site. No modifications to the information were given during registration or in the protocol.
RESULTS
Study selection
The initial search yielded 95 articles Supplementary Figure 1. After eliminating 41 duplicates and 31 ineligible studies, 23 articles remained for full review. Among these, 3 were only abstracts, and 1 reported on a similar population. Of the remaining articles, 16 did not meet our inclusion criteria. Ultimately, 3 studies were included in the analysis, comprising a total of 683 patients from 2 RCTs and 400 patients from 1 OLT. A total of 858 (80%) patients received ROF. We also reviewed studies demonstrating the pharmacology of PDE4 inhibitors in various inflammatory dermatoses.12–14
Supplementary Figure 1:
Supplementary Figure 1:PRISMA flow diagram of study screening and selection..
Study characteristics
The average age of the included studies Zirwas et al., Blauvelt et al., and Alexis et al., was approximately 43–45 years, and there was a fairly even distribution of gender across the studies.15-17 White individuals made up about 77%–80% of the sample group. The average affected Body Surface Area was approximately 3%–3.6%. The mean scores on the WI-NRS varied between 4.7 and 5.8. The follow-up duration differed, lasting 8 weeks for the Zirwas and Blauvelt studies and 52 weeks for Alexis’s study [Table 1].15-17
| Zirwas et al.15 | Blauvelt et al.16 | Alexis et al.17 | ||||
|---|---|---|---|---|---|---|
| Study design | RCT | RCT | Observational - single arm | |||
| Intervention/control | ROF (N = 154) | VF (N = 72) | ROF (N = 304) | VF (N = 153) | ROF (N = 400) | |
| Age, mean (SD), years | 45.3 (17.0) | 44.2 (16.3) | 43.2 (16.8) | 41.8 (17.5) | 43.3 (16.4) | |
| Gender, N (%) | ||||||
| Male | 76 (49.4) | 40 (55.6) | 153 (50.3) | 75 (49.0) | 197 (49.3) | |
| Female | 78 (50.6) | 32 (44.4) | 151 (49.7) | 78 (51.0) | 203 (50.8) | |
| Ethnicity, N (%) | ||||||
| Hispanic or Latino | 29 (18.8) | 16 (22.2) | 69 (22.7) | 28 (18.3) | 115 (28.8) | |
| Not Hispanic or Latino | 125 (81.2) | 56 (77.8) | 235 (77.3) | 125 (81.7) | 283 (70.8) | |
| Race, N (%) | ||||||
| American Indian or Alaskan Native | 1 (0.6) | 0 | 4 (1.3) | 0 | 0 | |
| Asian | 7 (4.5) | 1 (1.4) | 18 (5.9) | 10 (6.5) | 17 (4.3) | |
| African American | 17 (11.0) | 6 (8.3) | 36 (11.8) | 15 (9.8) | 51 (12.8) | |
| Native Hawaiian or Other Pacific Islander | 0 | 0 | 0 | 1 (0.7) | 1 (0.3) | |
| White | 123 (79.9) | 62 (86.1) | 234 (77.0) | 122 (79.7) | 319 (79.8) | |
| Other | 1 (0.6) | 2 (2.8) | 11 (3.6) | 4 (2.6) | 6 (1.5) | |
| >1 race | 5 (3.2) | 1 (1.4) | 1 (0.3) | 1 (0.7) | 3 (0.8) | |
| BSA affected, mean (SD), % | 3.3 (2.51) | 3.0 (2.11) | 2.89 (2.03) | 2.98 (2.57) | 3.6 (3.1) | |
| WI-NRS | ||||||
| Mean (SD) | 5.8 (2.7) | 5.7 (2.3) | 5.1 (2.34) | 4.7 (2.29) | 5.7 (2.6) | |
| Median | 6.0 | 6.0 | 5.3 | 5.0 | N/A | |
| Patients with baseline score ≥4, N (%) | 125 (81.2) | 59 (81.9) | 206 (67.8) | 98 (64.1) | 316 (75.7) | |
| Follow-up (weeks) | 8 | 8 | 52 | |||
ROF: Roflumilast foam, 0.3%; VF: Vehicle foam; BSA: Body surface area; WI-NRS: Worst itch numeric rating scale, RCT: Randomized controlled trial. N: Number of patients, SD: Standard deviation.
Results of all individual studies
Zirwas et al. found that ROF demonstrated superior IGA success rates compared to vehicle foam (VF) at week 2 (33.5% vs. 14.4%), week 4 (56.4% vs. 28.2%), and week 8 (73.3% vs. 40.5%).15 These differences were statistically significant with p-values ranging from 0.003 to less than 0.001. Blauvelt et al.16 discovered that ROF showed superior rates of IGA success at 2 weeks (43.0% compared to 25.7%), 4 weeks (73.1% compared to 47.1%), and 8 weeks (50.6% compared to 27.7%). These variances were statistically significant with p-values below 0.001 for all comparisons, while Alexis’s study reported an IGA success rate of 55.7% for ROF at week 8.16 The studies are systematically summarized in Table 2.
| Sr. no. | Study | Country | Study design | Outcomes | Key findings | Risk of bias |
|---|---|---|---|---|---|---|
| 1 | Zirwas et al.15 | US and Canada | RCT | IGA success, WI-NRS, erythema success, scaling success, TEAE, and ADRs. | At week 8, 104 (73.8%) roflumilast-treated patients achieved IGA success compared with 27 (40.9%) in the vehicle group (p < 0.001). Roflumilast-treated patients had statistically significantly higher rates of IGA success vs. vehicle at week 2, the first time point assessed. Mean (SD) reductions (improvements) on the WI-NRS at week 8 were 59.3% (52.5%) vs. 36.6% (42.2%) in the roflumilast and vehicle groups, respectively (p < 0.001). Roflumilast was well tolerated, with the rate of adverse events similar to that of the vehicle foam. | Low |
| 2 | Blauvelt et al.16 | US and Canada | RCT | IGA success, WI-NRS, erythema success, scaling success, TEAE, and ADRs. | 79.5% of roflumilast-treated and 58.0% of vehicle-treated patients met the primary endpoint (p < 0.001). | Low |
| 3 | Alexis et al.17 | US and Canada | Single arm trial | IGA success, WI-NRS, erythema success, scaling success, TEAE, and ADRs. | In this long-term safety trial, ROF 0.3% demonstrated favorable safety and tolerability and effectively maintained improvements in IGA and WI-NRS in patients with SD. The local tolerability profile as assessed by both patients and investigators was favorable and consistent with the phase 2a study. Most patients with hypo- or hyperpigmentation experienced full resolution. Once-daily treatment with ROF 0.3% resulted in durable improvement on efficacy endpoints. These data support further investigation of ROF 0.3% as a nonsteroidal, once-daily topical treatment option for SD with a mechanism of action that supports acute and chronic use across affected areas, including the face and scalp. | Moderate |
IGA: Investigator global assessment, TEAE: Treatment-emergent adverse event, WI-NRS: Worst itch numeric rating scale, ADR: Adverse drug reactions, SD: Standard deviation, ROF: Roflumilast foam, RCT: Randomized controlled trial.
Limitations of included studies
The study by Zirwas et al. included a total sample size of 226 participants.15 The study conducted by Alexis et al. employed an OLT design, which may introduce potential performance bias.17 Additionally, the follow-up duration in the studies by Zirwas et al. and Blauvelt et al. was limited to only 8 weeks, in contrast to the 52-week follow-up period reported in the study by Alexis et al.15-17
Results of syntheses
Pooled analysis of the ROF group—The pooled analysis of the efficacy and safety outcomes of the ROF group at week 4 revealed that the proportion of patients achieving IGA success was 64% (95% CI, 30.25%–77.03%; p = 0.88; I2 = 98%) [Figure 1]; WI-NRS success was 53.91% (95% CI, 47.40%–60.43%; p = 0.55; I2 = 72%) [Figure 1]; erythema success was 35.66% (95% CI, 26.78%–44.54%; p = 0.21; I2 = 87%) [Figure 1]; an overall scaling success was 39.09% (95% CI, 27.83%–50.36%; p = 0.03; I2 = 93%) [Figure 1]; and an overall trAEs incidence rate of 3.32% (95% CI, 1.26%–5.37%; p = 0.02; I2 = 65%) [Figure 1]. The high heterogeneity of the pooled analysis was addressed with subgroup analysis of the RCTs comparing the ROF group with the control group.
- Pooled analysis. IGA: Investigator global assessment; WI-NRS: Worst itch numeric rating acale; ROF: Roflumilast foam; CI: Confidence interval; RCT: Randomized controlled trial.
Subgroup analysis of RCTs
At week 2, roflumilast was statistically more efficacious regarding the IGA success (RR 1.79; 95% CI, 1.37–2.34; I2 = 0%, p < 0.001), WI-NRS success (RR 2.20; 95% CI, 1.63–2.97; I2 = 0%, p < 0.001), erythema success (RR 2.34; 95% CI, 1.19–4.62; I2 = 44%, p = 0.014), and scaling success (RR 2.04; 95% CI, 1.41–2.93; I2 = 0%; p < 0.001).
At week 4, roflumilast also showed better results for the IGA success (RR 1.41; 95% CI 1.05–1.88; I2 = 44%; p = 0.020) [Figure 2], WI-NRS success (RR 1.77; 95% CI, 1.41–2.21; I2 = 0%; p < 0.001) [Figure 2], erythema success (RR 2.28; 95% CI 1.19–4.35; I2 = 66%; p = 0.013) [Figure 2], and scaling success (RR 2.22; 95% CI, 1.69–2.90; I2 = 0%; p < 0.001) [Figure 2].
- Subgroup analysis of RCTs. RCT: Randomized controlled trial.
At week 8, there was a significant increase in the proportion of subjects who achieved an IGA success (RR 1.82; 95% CI, 1.49–2.23; I2 = 0%; p < 0.001). The WI-NRS success was significant in the group treated with roflumilast (RR 1.63, 95% CI, 1.37–1.96; I2 = 0%; p < 0.001), as was the erythema success (RR 1.87; 95% CI 1.50–2.33; I2 = 0%; p < 0.001) and scaling success (RR 1.72; 95% CI, 1.36–2.16; I2 = 17%; p < 0.001).
Overall, trAEs amongst the RCTs revealed RR 1.14 (95% CI, 0.84–1.55; I2 = 0%; p = 0.4063) [Figure 2]. The summary of results is presented in Table 3.
| Pooled analysis | |||||||
|---|---|---|---|---|---|---|---|
| Sr. no. | Outcome | Proportion (95% CI) | Heterogeneity | Subgroup differences | Number of participants (number of studies) | Comment | |
| 1 | IGA score 0 at week 4 | 53.64 (20.25, 77.03) |
Tau2 = 0.0418; Chi2 = 85.00; df = 2 (p < 0.01); I2 = 98% | Chi2 = 0.02; df = 1 (p = 0.88) |
858 (2 RCTs and 1 NRCT)15–17 | Figure 1 | |
| 2 | WI-NRS 0 at week 4 | 53.91 (47.40, 60.43) |
Tau2 = 0.0024; Chi2 = 7.14; df = 2 (p = 0.03); I2 = 72% | Chi2 = 0.35; df = 1 (p = 0.55) |
858 (2 RCTs and 1 NRCT)15–17 | Figure 1 | |
| 3 | Erythema score 0 at week 4 | 35.66 (26.78, 44.54) |
Tau2 = 0.0053; Chi2 = 15.79; df = 2 (p < 0.01); I2 = 87% | Chi2 = 1.58; df = 1 (p = 0.21) |
858 (2 RCTs and 1 NRCT)15–17 | Figure 1 | |
| 4 | Scaling 0 at week 4 | 39.09 (27.83, 50.36) |
Tau2 = 0.0090; Chi2 = 27.53; df = 2 (p < 0.01); I2 = 93% | Chi2 = 4.80; df = 1 (p = 0.03) |
858 (2 RCTs and 1 NRCT)15–17 | Figure 1 | |
| 5 | Treatment-related ADRs | 26.70 (20.53, 32.86) | Tau2 = 0.0022; Chi2 = 8.96; df = 2 (p = 0.01); I2 = 78% | Chi2 = 8.90; df = 1 (p < 0.01) |
858 (2 RCTs and 1 NRCT)15–17 | Figure 1 | |
| 6 | Any TEAE | 3.32 (1.26, 5.37) | Tau2 = 0.0002; Chi2 = 5.72; df = 2 (p = 0.06); I2 = 65% | Chi2 = 5.49; df = 1 (p = 0.02) |
858 (2 RCTs and 1 NRCT)15–17 | Figure 1 | |
| Meta-analysis of RCTs | |||||||
| Sr. No. | Outcome | Risk in ROF group (0.3%) | Risk in vehicle foam group | Relative risk (95% CI) | Heterogeneity | Test for overall effect | Number of participants (number of studies) |
| 7 | IGA success at week 2 | 182/458 | 50/225 | 1.79 (1.37, 2.34) | Tau2 = 0; Chi2 = 0.93; df = 1 (p = 0.33); I2 = 0% |
Z = 4.24 (p < 0.001) |
683 (2 RCTs)15,16 |
| 8 | IGA success at week 4 | 271/458 | 92/225 | 1.41 (1.05, 1.88) | Tau2 = 0.0227; Chi2 = 1.78; df = 1 (p = 0.18); I2 = 44% | Z = 2.32 (p < 0.020) |
683 (2 RCTs)15,16 |
| 9 | IGA success at week 8 | 267/458 | 71/225 | 1.82 (1.49, 2.23) | Tau2 = 0; Chi2 = 0.00; df = 1 (p = 0.96); I2 = 0% |
Z = 5.78 (p < 0.001) |
683 (2 RCTs)15,16 |
| 10 | WI-NRS success at week 2 | 181/458 | 40/225 | 2.20 (1.63, 2.97) | Tau2 = 0; Chi2 = 0.09; df = 1 (p = 0.77); I2 = 0% |
Z = 5.14 (p < 0.001) |
683 (2 RCTs)15,16 |
| 11 | WI-NRS success at week 4 | 235/458 | 65/225 | 1.77 (1.41, 2.21) | Tau2 = 0; Chi2 = 0.92; df = 1 (p = 0.34); I2 = 0% |
Z = 4.98 (p < 0.001) |
683 (2 RCTs)15,16 |
| 12 | WI-NRS success at week 8 | 290/458 | 87/225 | 1.63 (1.37, 1.96) | Tau2 = 0; Chi2 = 0.95; df = 1 (p = 0.33); I2 = 0% |
Z = 5.38 (p < 0.001) |
683 (2 RCTs)15,16 |
| 13 | Erythema success at week 2 | 104/458 | 23/225 | 2.34 (1.19, 4.62) | Tau2 = 0.1218; Chi2 = 1.80; df = 1 (p = 0.18); I2 = 44% | Z = 2.45 (p = 0.013) |
683 (2 RCTs)15,16 |
| 14 | Erythema success at week 4 | 190/458 | 46/225 | 2.28 (1.19, 4.35) | Tau2 = 0.1526; Chi2 = 2.95; df = 1 (p = 0.09); I2 = 66% | Z = 2.50 (p = 0.013) | 683 (2 RCTs)15,16 |
| 15 | Erythema success at week 8 | 244/458 | 64/225 | 1.87 (1.50, 2.33) | Tau2 = 0; Chi2 = 0.32; df = 1 (p = 0.57); I2 = 0% |
Z = 5.53 (p < 0.001) |
683 (2 RCTs)15,16 |
| 16 | Scaling success at week 2 | 125/458 | 30/225 | 2.04 (1.41, 2.93) | Tau2 = 0; Chi2 = 0.20; df = 1 (p = 0.65); I2 = 0% |
Z = 3.82 (p < 0.001) |
683 (2 RCTs)15,16 |
| 17 | Scaling success at week 4 | 214/458 | 48/225 | 2.22 (1.69, 2.90) | Tau2 = 0; Chi2 = 0.33; df = 1 (p = 0.57); I2 = 0% |
Z = 5.76 (p < 0.001) |
683 (2 RCTs)15, 16 |
| 18 | Scaling success at week 8 | 263/458 | 75/225 | 1.72 (1.36, 2.16) | Tau2 = 0.0058; Chi2 = 1.21; df = 1 (p = 0.27); I2 = 17% | Z = 4.58 (p < 0.001) |
683 (2 RCTs)15,16 |
IGA: Investigator global assessment; WI-NRS = Worst itch numeric rating scale; ROF: Roflumilast foam; CI: Confidence interval; RCT = Randomized controlled trial.
Quality and evidence assessment
The risk of bias appraisal of each study was observed across all five domains, including bias related to randomization, deviations from the intended intervention, missing outcome data, and selection of reported results. The 2 RCTs were deemed as having a low risk of bias across all domains. The 1 OLT was deemed as having a moderate risk in measurement of outcomes and selection of reported results Supplementary Figure 2.
Supplementary Figure 2:
Supplementary Figure 2:Risk of bias in studies.
DISCUSSION
In this systematic review and meta-analysis, including three studies (2 RCTs and 1 OLT) comprising 1083 patients, the PDE4 inhibitor, the efficacy and safety of the ROF was evaluated in patients with SD. The main findings were as follows: ROF was associated with (i) a significant reduction in IGA; (ii) an increase in the proportion of patients achieving WI-NRS success; (iii) a significant reduction in erythema and scaling; and (iv) no significant trAEs compared with the control group. To the best of our knowledge, this is the first meta-analysis assessing the efficacy and safety of topical ROF in SD, and it was found that topical ROF shows promise for SD treatment.
When evaluating the therapeutic landscape of SD, it is important to consider the limitations of current standard treatments. Topical antifungals, such as ketoconazole and ciclopirox, primarily target the Malassezia spp. implicated in SD pathogenesis but often require prolonged use and may be less effective in reducing inflammation. Topical corticosteroids, while effective in controlling inflammation and erythema, are associated with potential adverse effects such as cutaneous atrophy, telangiectasia, tachyphylaxis, and rebound flares, especially with long-term use. Moreover, these agents are not always suitable for use on sensitive areas such as the face or intertriginous zones.6,7
Currently, PDE4 inhibitors are indicated as monotherapy or adjunctive therapy in the treatment of various inflammatory conditions.8–11 Apremilast, an oral PDE4 inhibitor, is approved for psoriasis and psoriatic arthritis but is associated with systemic adverse effects including gastrointestinal disturbances (nausea, vomiting, and diarrhea), headache, nasopharyngitis, and weight loss, which may limit its long-term tolerability in dermatologic use. Crisaborole, a topical PDE4 inhibitor approved for atopic dermatitis, has a favorable safety profile, with mild application site reactions being the most commonly reported adverse effect. Orismilast and mufemilast are newer PDE4 inhibitors currently under investigation, with emerging data suggesting improved selectivity and tolerability profiles. Compared to these agents, roflumilast exhibits a higher lipophilicity (logP 4.6) and molecular weight (403.2 g/mol), properties that may enhance its dermal retention and potency when used topically.12 ROF inhibits PDE4, which leads to an increase in the intracellular cyclic adenosine monophosphate (cAMP), a crucial second messenger that plays an important role in inflammation and keratinocyte proliferation and differentiation. Elevated intracellular cAMP is linked to the suppression of inflammation and epidermal cell proliferation, thereby subsequently aiding in the restoration of the disrupted skin barrier and resolution of other signs and symptoms of SD.13,14
Roflumilast is available in oral tablets, powder, topical cream, and foam formulations. ROF is a 65% water-based emollient foam containing 0.3% roflumilast as the active ingredient. The formulation includes an emollient that aids in skin barrier restoration and a mild emulsifier that maintains the integrity of the skin barrier. The foam’s propellant evaporates quickly upon application, enhancing its cosmetic acceptability. Additionally, this foam formulation is suitable for both hairy and non-hairy areas of the body. It is free from fragrances and common irritants such as polyethylene glycol and has an added advantage of a convenient once-daily dose. Consequently, ROF provides a better safety and tolerability profile.15–17
Considering the chronic and relapsing nature of SD, short-term clinical trials may be insufficient to comprehensively assess the long-term efficacy and safety of emerging therapeutic agents such as roflumilast. The 52-week follow-up in the study by Alexis et al. provides important evidence supporting the sustained clinical benefit and favorable tolerability profile of ROF 0.3% over an extended period.17 These findings highlight its potential as a viable long-term treatment option for SD. However, further large-scale, long-duration studies in diverse patient populations are needed to validate these results and enhance their generalizability.
The results of our meta-analysis demonstrated superior efficacy and profiles of topical ROF in SD, in concordance with other reviews of Polo et al.,8 Fan et al., and narratives in the literature available on PDE4 inhibitors.18–20
CONCLUSION
Our meta-analysis provides the best evidence-based information accessible for the practicing clinicians that topical ROF has potential therapeutic benefits as a non-steroid topical agent in the treatment of patients with SD due to its favorable efficacy and safety profiles. To supplement the current evidence, a second meta-analysis of the tolerability outcomes of ROF in various inflammatory conditions involving more RCTs might be beneficial. The limitations of our meta-analysis are (i) the short follow-up period for a chronic illness like SD, and (ii) the high heterogeneity in our pooled analysis. To address the high heterogeneity of the single-arm pooled analysis, a subgroup analysis of only the RCTs was performed, which revealed no heterogeneity.
Our systematic review and meta-analysis suggest that ROF may be an effective alternative and/or adjunct therapy to the currently approved pharmacotherapy options in SD. However, larger, well-designed trials with longer follow-up periods and direct comparison with the other currently available topical agents are required to validate our findings and to further establish its therapeutic benefits in SD.
Author contribution
PS and AB: Conceptualized the study; PS, FD, and BO: Contributed to literature review and manuscript; AB: Conducted statistical analysis. All authors approved the final version.
Ethical approval
Institutional Review Board approval is not required.
Declaration of patients consent
Patient’s consent not required as patients identity is not disclosed or compromised.
Financial support and sponsorship
Nil.
Conflicts of interest
There are no conflicts of interest.
Use of artificial intelligence (AI)-assisted technology for manuscript preparation
The authors confirm that there was no use of artificial intelligence (AI)-assisted technology for assisting in the writing or editing of the manuscript and no images were manipulated using AI.
REFERENCES
- The global prevalence of seborrheic dermatitis: A Systematic Review and Meta-Analysis. JAMA Dermatol. 2024;160:846-55.
- [CrossRef] [PubMed] [PubMed Central] [Google Scholar]
- An overview of the diagnosis and management of seborrheic dermatitis. Clin Cosmet Investig Dermatol. 2022;15:1537-48.
- [CrossRef] [PubMed] [PubMed Central] [Google Scholar]
- Unmet needs for patients with seborrheic dermatitis. J Am Acad Dermatol. 2024;90:597-60.
- [CrossRef] [PubMed] [Google Scholar]
- National quality of life in dermatology group. Quality of life in patients suffering from seborrheic dermatitis: Influence of age, gender and education level. Mycoses. 2009;52:357-63.
- [Google Scholar]
- Seborrheic dermatitis in older adults: Pathogenesis and treatment options. Drugs Aging. 2022;39:315-21.
- [CrossRef] [PubMed] [Google Scholar]
- Seborrheic Dermatitis—Looking beyond malassezia. Exp Dermatol. 2019;28:991-1001.
- [CrossRef] [PubMed] [Google Scholar]
- Topical and oral roflumilast in dermatology: A narrative review. Actas Dermosifiliogr. 2024;115:265-79.
- [CrossRef] [PubMed] [Google Scholar]
- A randomized, controlled pilot study of oral roflumilast compared with intramuscular methotrexate for plaque and scalp psoriasis. J Am Acad Dermatol. 2024;90:1063-5.
- [CrossRef] [PubMed] [Google Scholar]
- Severe and Therapeutic challenging oral erosive lichen planus treated with oral roflumilast. Clin Exp Dermatol. 2023;48:556-7.
- [CrossRef] [PubMed] [Google Scholar]
- Rapid clearing of refractory nummular dermatitis with oral roflumilast therapy. J Eur Acad Dermatol Venereol. 2022;36:765-6.
- [CrossRef] [PubMed] [Google Scholar]
- Phosphodiesterase-4 inhibition in the management of psoriasis. Pharmaceutics. 2023;16:23.
- [CrossRef] [PubMed] [PubMed Central] [Google Scholar]
- Roflumilast analogs with improved metabolic stability, plasma protein binding, and pharmacokinetic profile. Drug Test Anal. 2019;11:886-97.
- [CrossRef] [PubMed] [Google Scholar]
- Roflumilast prevents lymphotoxin α (TNF-β)-Induced inflammation activation and degradation of type 2 collagen in chondrocytes. Inflamm Res. 2020;69:1191-9.
- [CrossRef] [PubMed] [Google Scholar]
- Efficacy of roflumilast foam, 0.3%, In patients with seborrheic dermatitis: A double-blind, vehicle-controlled phase 2a randomized clinical trial. JAMA Dermatol. 2023;159:613-20.
- [CrossRef] [PubMed] [PubMed Central] [Google Scholar]
- Roflumilast foam 0.3% For adolescent and adult patients with seborrheic dermatitis: A randomized, double-blinded, vehicle-controlled, phase 3 trial. J Am Acad Dermatol. 2024;90:986-93.
- [CrossRef] [PubMed] [Google Scholar]
- Long-term safety and efficacy of roflumilast foam. European academy of dermatology and venereology congress 2022 [Last accessed 15 May 2025].
- [CrossRef] [PubMed] [Google Scholar]
- PDE4 Inhibitors: Potential protective effects in inflammation and vascular diseases. Front Pharmacol. 2024;15:1407871.
- [CrossRef] [PubMed] [PubMed Central] [Google Scholar]
- Noncorticosteroid topical therapies for the treatment of plaque psoriasis: a narrative review. J Pharm Technol. 2023;39:247-55.
- [Google Scholar]
- Topical roflumilast for the treatment of psoriasis. Expert Rev Clin Immunol. 2023;19:1053-62.
- [CrossRef] [PubMed] [Google Scholar]