Introduction
Psoriasis is a chronic, immune-mediated inflammatory disease characterized by recurrent cutaneous inflammation, keratinocyte hyperproliferation, and the development of well-demarcated erythematous plaques with variable scaling. Although its clinical expression is predominantly cutaneous, psoriasis is increasingly understood as a systemic inflammatory disorder rather than an isolated dermatosis. The population affected is substantial.
Analysis of Global Burden of Disease 2021 data estimated that the number of people living with psoriasis worldwide increased from approximately 23.1 million in 1990 to nearly 43.0 million in 2021, while incident cases rose from 2.85 million to 5.10 million over the same period.1 This growing burden, combined with the chronic and relapsing nature of the disease, means that many patients require treatment and surveillance over decades rather than during isolated episodes of activity.2
The consequences extend well beyond visible plaques. Persistent pruritus, scaling, discomfort, and lesions affecting visible or functionally sensitive sites can interfere with sleep, work, interpersonal relationships, and daily activities; equally important, psoriasis carries a considerable psychological burden. Depression is consistently more frequent among affected individuals, particularly in patients with greater disease severity, and frequently coexists with impaired quality of life.3 Psoriasis is also associated with psoriatic arthritis and a range of cardiometabolic and inflammatory comorbidities, reinforcing the need for effective disease control rather than treatment directed solely at cosmetic improvement.1,3 Against this background, therapies for limited plaque psoriasis must satisfy a deceptively difficult set of requirements: they should work rapidly, remain tolerable during repeated use, be convenient enough to encourage adherence, and ideally remain affordable when prolonged treatment is required.
For patients with mild-to-moderate or localized disease, topical treatment remains a central component of management.4 Topical corticosteroids are among the most established options because they suppress cutaneous inflammation and can produce relatively rapid clinical improvement; however, continuous or inappropriate use is constrained by local and, less commonly, systemic adverse effects, while treatment complexity and dissatisfaction with topical formulations may undermine adherence.5 These limitations have sustained interest in combination regimens capable of improving efficacy without simply escalating corticosteroid potency or exposure. Such strategies have a sound biological basis. Contemporary understanding of psoriasis centers on an inflammatory network involving dendritic cells, T-helper 17 cells, keratinocytes, and particularly the interleukin-23/interleukin-17 axis.6 At the intracellular level, cyclic adenosine monophosphate (cAMP)-dependent signaling also influences inflammatory cytokine production, and the clinical success of phosphodiesterase 4 (PDE4) inhibition in psoriasis has renewed interest in therapeutic approaches that modulate this pathway.7
Caffeine is a methylxanthine with established cutaneous penetration and several pharmacological actions that make its topical use biologically plausible.8 At sufficiently high local concentrations, inhibition of phosphodiesterase activity may increase intracellular cAMP, providing one possible link between caffeine and inflammatory regulation; adenosine-receptor antagonism and antioxidant effects represent additional mechanisms, although their contribution within psoriatic lesions remains uncertain.7,8 Clinical evidence is notably sparse. In a randomized, double-blind, placebo-controlled right-left comparison involving 39 patients with stable plaque psoriasis, Vali et al evaluated topical 10% caffeine for eight weeks and reported a greater reduction in the Psoriasis Area and Severity Index (PASI) than with placebo at the final assessment.9 That study provided an important proof of concept, but caffeine was tested as monotherapy against placebo. Whether a lower concentration of caffeine can enhance the therapeutic effect of an established topical corticosteroid has remained largely unexplored.
Fluocinolone acetonide 0.025% is an established topical corticosteroid with anti-inflammatory activity in localized plaque psoriasis. In a clinical study comparing blue-light therapy with fluocinolone acetonide 0.025% ointment, improvement was observed with fluocinolone treatment over four weeks.10 Nevertheless, corticosteroid monotherapy may not provide adequate disease control in all patients, and prolonged corticosteroid exposure is constrained by the potential for local adverse effects. Adding a nonsteroidal adjunct such as caffeine could therefore be clinically useful if it enhances short-term efficacy without requiring an increase in corticosteroid potency or dose.
At the same time, incorporation of caffeine into a corticosteroid cream could theoretically alter formulation stability, drug release, cutaneous penetration, or local tolerability; these considerations warrant evaluation when interpreting a compounded combination preparation.
The present randomized, double-blind clinical trial was therefore designed to compare topical 5% caffeine combined with fluocinolone acetonide 0.025% cream (FAC) with FAC alone in patients with chronic plaque psoriasis. The principal objective was to determine whether the addition of caffeine produced a greater reduction in psoriasis severity, assessed serially using PASI during four weeks of treatment. By testing caffeine as an adjunct rather than as a substitute for corticosteroid therapy, this study addresses a clinically distinct question that has not been adequately examined in previous human trials.
The findings may provide preliminary evidence for a simple, inexpensive combination strategy while also defining the rationale for larger trials with longer follow-up and broader efficacy and safety outcomes.
Material and Methods
Study Design and Setting
This randomized, parallel-group, double-blind clinical trial was conducted at the dermatology outpatient clinic of Sina Hospital, Tabriz University of Medical Sciences, Tabriz, Iran. The trial compared topical 5% caffeine added to FAC with FAC alone in patients with chronic plaque psoriasis. Participant recruitment was conducted from November 22, 2023, to March 20, 2024, and each participant was followed for 4 weeks after treatment initiation.
No post-treatment follow-up was performed after completion of the 4-week treatment period.
The trial was prospectively registered in the Iranian Registry of Clinical Trials on October 28, 2023 (IRCT20091012002581N10; https://irct.ir/trial/73367), before the prespecified recruitment start date. The manuscript was prepared in accordance with the CONSORT 2025 recommendations for reporting randomized trials.11 The study protocol was approved by the Ethics Committee of Tabriz University of Medical Sciences on August 7, 2023 (IR.TBZMED.REC.1402.342). Before enrollment, the study procedures, potential benefits, and possible treatment-related risks were explained to all participants or, when applicable, their legal guardians, and written informed consent was obtained.
Participant information was kept confidential and coded for analysis. The study was conducted in accordance with the principles of the Declaration of Helsinki.
Participants and Eligibility Criteria
Patients presenting consecutively to the dermatology outpatient clinic with clinically typical chronic plaque psoriasis were screened for eligibility. The diagnosis was confirmed clinically by dermatologists before enrollment. Eligible participants were 7 to 70 years of age, had chronic plaque psoriasis, had no history of immunosuppression or iatrogenic immune suppression, had not received psoriasis-directed medication or other therapeutic interventions during the two weeks preceding enrollment, had no known allergy to caffeine, and, where applicable, were neither pregnant nor breastfeeding.
Written consent to participate was mandatory.
Participants were excluded or discontinued if they developed hypersensitivity during treatment, including vesicular eruption, clinically important erythema, or pruritus attributable to the study preparation; experienced clinically meaningful worsening of psoriasis; developed joint involvement requiring systemic treatment; became pregnant; or withdrew consent.
At baseline, demographic and clinical characteristics were recorded using the study data-collection form. These included age, sex, duration of psoriasis since the first appearance of lesions, previous treatment history, family history of psoriasis, relevant systemic disease, and anatomical distribution of lesions.
Sample Size
The sample size was determined a priori using G*Power version 3.1 (Heinrich Heine University, Düsseldorf, Germany), with the between-group difference in reduction of the PASI at the end of the 4-week treatment period defined as the primary efficacy outcome. The effect-size estimate was informed by the randomized clinical trial of Singh et al, in which an adjunctive topical regimen produced a 46.4-percentage-point greater reduction in PASI at week 4 than topical corticosteroid monotherapy (95% CI, 28.9% to 63.8%).12 To avoid overestimating the expected treatment effect, the lower bound of the reported 95% confidence interval was used for sample-size planning. Based on the reported group sizes and variability, this corresponded to a standardized effect size of approximately Cohen’s d=0.92.
Assuming a two-sided α of 0.05, statistical power of 80%, and equal 1:1 allocation, an independent-samples t-test required 20 participants per treatment group, yielding a minimum total sample size of 40 participants.
Randomization, Allocation Concealment, and Blinding
After baseline assessment and confirmation of eligibility, participants were randomized in a 1:1 ratio to the intervention or control group. Allocation was implemented using sequentially prepared sealed envelopes corresponding to groups A and B, with 20 allocations assigned to each group. The envelope was selected after enrollment by a nurse who was unaware of treatment identity.
The allocation remained concealed until baseline procedures had been completed.
Participants, treating investigators, and the data analyst were masked to treatment allocation. The study preparations were dispensed in identical containers bearing coded labels so that the treatment identity could not be inferred from packaging. The treating physician therefore assessed clinical outcomes without knowledge of the assigned preparation.
The code linking study labels to treatment groups was maintained separately from the clinical assessment records.
At completion of follow-up, blinding was evaluated in a subset of 20 randomly selected participants and assessors using a standardized treatment-guess questionnaire. The questionnaire asked respondents to indicate which treatment they believed had been administered.
Study Interventions
Participants assigned to the intervention arm received topical 5% caffeine combined with FAC. Pharmaceutical-grade caffeine powder (C8H10N4O2; Aarri Co., India; purity ≥98%) was incorporated into commercially manufactured FAC (Emad Darman Pars Co., Iran) using its hydrophilic cream base. Compounding was performed under pharmacist supervision to obtain a uniform caffeine concentration of 5% throughout the preparation.
Stability of the compounded preparation was assessed by high-performance liquid chromatography at preparation and after 15 and 30 days of storage at 25°C and 60% relative humidity. The assay was used to confirm preservation of caffeine content throughout the intended treatment period. No separate quantitative assay of fluocinolone acetonide concentration or dedicated assessment of drug-release characteristics was performed.
Participants in the control arm received FAC without added caffeine. Both preparations were transferred into identical 70 mL tubes bearing coded labels to preserve masking. Study creams were dispensed at treatment initiation and again at the second weekly assessment, consistent with the registered protocol.
Beginning at week 0, participants applied the assigned preparation once daily in the evening for four consecutive weeks. Approximately 2 mg/cm2 of cream was applied to affected psoriatic areas, with sufficient cream distributed to cover the involved lesion surface completely. Participants were instructed to use only the allocated study preparation on the assessed lesions during the intervention period.
Treatment Adherence
Adherence was monitored throughout follow-up using participant treatment diaries and weekly weighing of returned study tubes. Participants recorded each application in the diary, while changes in tube weight provided an additional objective estimate of topical treatment use. Adherence of at least 80% of prescribed applications was considered adequate for inclusion in the per-protocol analysis.
Treatment adherence was reviewed at each scheduled follow-up visit.
Clinical Assessments and Outcomes
The principal clinical efficacy outcome was change in the PASI from baseline during the four-week treatment period. PASI was the only physician-assessed psoriasis severity measure collected in this trial; Investigator Global Assessment (IGA) and target-lesion PASI were not obtained. PASI assessments were performed before treatment and at weekly intervals during weeks 1, 2, 3, and 4 by a blinded physician.
PASI was scored according to its established methodology.13 Four anatomical regions were assessed: the head, upper extremities, trunk, and lower extremities, weighted as 10%, 20%, 30%, and 40% of total body surface area, respectively. Within each region, erythema, induration, and scaling were each graded from 0 to 4. The extent of involvement was graded from 0 to 6, corresponding to no involvement, <10%, 10% to 29%, 30% to 49%, 50% to 69%, 70% to 89%, and 90% to 100% involvement.
Regional severity and area scores were combined using the conventional PASI weighting system, producing a total score ranging from 0 to 72.
The primary efficacy assessment was the magnitude of PASI reduction during treatment, particularly the change from baseline to week 4. Complete clinical clearance was defined a priori as a PASI score of 0 at the week-4 final assessment. Exploratory subgroup analyses of week-4 complete clearance were performed according to age, sex, and duration of psoriasis, in accordance with the prespecified study objectives.
Because the study was not powered to evaluate treatment-effect heterogeneity across subgroups, these analyses were considered exploratory. Treatment response was also examined in relation to age, sex, and duration of psoriasis, in accordance with the prespecified thesis objectives.
Safety Assessment
Safety was evaluated throughout the four-week treatment period. Participants recorded symptoms and potential adverse events (AEs) in structured diaries, and clinicians actively asked about AEs at each follow-up visit. Events were classified by severity as mild when self-limiting and requiring no specific intervention, moderate when requiring clinical intervention, or severe when necessitating discontinuation of the study treatment.
The relationship between an AE and study treatment was assessed using the World Health Organization-Uppsala Monitoring Centre (WHO-UMC) causality system.14 Causality categories were classified as certain, probable/likely, possible, unlikely, conditional/unclassified, or unassessable/unclassifiable. These are the official WHO-UMC categories, replacing the nonstandard terms contained in the draft text. Any serious adverse event (SAE) was to be reported to the study safety oversight body within 24 hours of recognition and managed according to institutional procedures.
Statistical Analysis
Statistical analyses were performed using IBM SPSS Statistics version 22. The normality of continuous variables was assessed using the Shapiro–Wilk test, and the distributions of the PASI data were consistent with the assumption of normality. Continuous variables were therefore summarized as mean and standard deviation.
Baseline continuous variables and between-group PASI values were compared using independent-samples t-tests. Changes in PASI from baseline were evaluated within treatment groups using paired-samples t-tests, while between-group differences in the magnitude of PASI reduction were assessed using independent-samples t-tests. Ordinal variables were analyzed using ordinal regression, as specified in the original statistical analysis plan.
Categorical outcomes, including complete clearance, were compared using the chi-square test or Fisher’s exact test when expected cell counts were small. All tests were two-sided, and statistical significance was defined as P<0.05. The primary analysis retained participants according to their randomized treatment assignment when outcome data were available, while the prespecified per-protocol analysis required treatment adherence of at least 80%.
Results
Participant Characteristics
The analysis included 40 patients with chronic plaque psoriasis, with 20 participants assigned to each treatment group. Participant allocation, follow-up, and analysis are summarized in Figure 1. Baseline demographic and disease characteristics are presented in Table 1.
No statistically significant between-group differences were detected in the reported baseline characteristics (all P>0.05).Table 1Baseline Demographic and Clinical Characteristics of the Study ParticipantsCharacteristic5% Caffeine + FAC (n = 20)FAC Alone (n = 20)P valueAge, years39.60 ± 9.0240.95 ± 16.660.752Sex0.327 Male9 (45.0%)6 (30.0) Female11 (55.0%)14 (70.0)Duration of psoriasis0.134 <1 year9 (45.0%)11 (55.0%) 1–2 years7 (35.0%)9 (45.0%) >2 years4 (20.0%)0 (0.0%)Family history of psoriasis9 (45.0%)7 (35.0%)0.519Anatomical distribution Trunk11 (55.0%)7 (35.0%)0.204 Upper extremities19 (95.0%)18 (90.0%)1.000 Lower extremities15 (75.0%)18 (90.0%)0.407Notes: Data are presented as mean ± SD or n (%), as appropriate. A participant could have psoriasis involvement at more than one anatomical site; therefore, percentages for anatomical distribution do not sum to 100%. Age was compared using an independent-samples t-test.
Categorical variables were compared using the chi-square test or Fisher’s exact test, as appropriate. An exact test was used for psoriasis duration because of small expected cell counts. A two-sided P<0.05 was considered statistically significant.Abbreviations: FAC, fluocinolone acetonide 0.025% cream; SD, standard deviation.Figure 1CONSORT-style flow diagram of patient enrollment, allocation, follow-up, and analysis.The flowchart outlines the process of patient enrollment, allocation, follow-up and analysis in a study involving 40 participants.
Enrollment begins with assessing eligibility for 40 individuals, with none excluded. Randomization allocates 20 participants to the control group and 20 to the intervention group. Both groups received their allocated interventions, with none failing to receive them.
During follow-up, no participants were lost or discontinued the intervention in either group. In the analysis phase, all 20 participants from each group were analyzed, with none excluded from the analysis.A flowchart of patient enrollment, allocation, follow-up and analysis for a study with 40 participants.Abbreviation: FAC, fluocinolone acetonide 0.025% cream.
PASI Scores During Treatment
Mean PASI scores were similar between groups at baseline (3.41 ± 1.86 vs 3.79 ± 1.51; P=0.484) but were significantly lower in the 5% caffeine plus FAC group at every post-treatment assessment. By week 4, mean PASI had decreased to 0.39 ± 0.17 in the intervention group compared with 2.29 ± 1.31 in the FAC-alone group (P=0.001). The longitudinal pattern is shown in Figure 2, and detailed PASI values and changes from baseline are presented in Table 2.Table 2Psoriasis Area and Severity Index Scores and Changes from Baseline During TreatmentOutcome5% Caffeine + FAC (n = 20)FAC Alone (n = 20)P valuePASI score Baseline3.41 ± 1.863.79 ± 1.510.484 Week 11.62 ± 0.402.89 ± 1.470.020 Week 20.92 ± 0.272.48 ± 1.390.001 Week 30.55 ± 0.232.38 ± 1.280.001 Week 40.39 ± 0.172.29 ± 1.310.001Reduction in PASI from baseline Week 11.78 ± 1.200.90 ± 0.670.007 Week 22.48 ± 1.371.30 ± 1.020.004 Week 32.85 ± 1.311.40 ± 1.00<0.001 Week 43.01 ± 1.481.49 ± 1.01<0.001Notes: Data are presented as mean ± SD.
For absolute PASI scores, p values represent between-group comparisons at each assessment, as reported in the thesis. For changes from baseline, P values represent between-group comparisons of the magnitude of PASI reduction using independent-samples t-tests.Abbreviations: FAC, fluocinolone acetonide 0.025% cream; PASI, Psoriasis Area and Severity Index; SD, standard deviation.Figure 2Changes in mean Psoriasis Area and Severity Index scores during the 4-week treatment period.A line graph showing mean Psoriasis Area and Severity Index scores across study visits for two groups.Note: Mean PASI scores are shown for patients receiving 5% caffeine plus FAC and those receiving FAC alone. Error bars represent standard deviations.
P values represent between-group comparisons at each assessment.Abbreviations: FAC, fluocinolone acetonide 0.025% cream; PASI, Psoriasis Area and Severity Index; SD, standard deviation.
Complete Clearance and Safety
At week 4, complete clearance (PASI=0) occurred in 14 of 20 participants (70%) in the 5% caffeine plus FAC group and 1 of 20 (5%) in the FAC-alone group (P=0.001). Treatment escalation and safety outcomes are summarized in Table 3.Table 3Complete Clearance, Treatment Escalation, and Adverse Events at the End of Follow-upOutcome5% Caffeine + FAC (n = 20)FAC Alone (n = 20)p valueComplete clearance, PASI = 014 (70.0%)1 (5.0%)0.001Escalation to systemic treatment because of disease progression0 (0.0%)1 (5.0%)NRAny reported adverse event0 (0.0%)0 (0.0%)NRNotes: Data are presented as n (%). Complete clearance was defined as a PASI score of 0 at the final assessment.
One patient in the FAC-alone group required conversion from topical to systemic treatment because of progression of psoriatic lesions at the final visit. No adverse events were reported in either group during the study period. Statistical comparisons were not reported in the thesis for treatment escalation or adverse events and therefore are indicated as NR rather than being calculated retrospectively.Abbreviations: FAC, fluocinolone acetonide 0.025% cream; NR, not reported; PASI, Psoriasis Area and Severity Index.
Exploratory Subgroup Analysis of Week-4 Complete Clearance
Within the intervention group, exploratory analyses of week-4 complete clearance showed differences across age categories (P=0.021). Among the 14 participants who achieved complete clearance, 7 (50.0%) were aged 38–50 years, 5 (35.7%) were aged 25–37 years, and 1 (7.1%) each were aged 12–24 and 50–60 years. Complete clearance also differed according to sex (P=0.024), with 10 of the 14 complete responders (71.4%) being female and 4 (28.6%) male.
These subgroup findings should be interpreted cautiously because of the small numbers and were considered hypothesis-generating rather than confirmatory.
Discussion
The present randomized clinical trial showed that adding topical 5% caffeine to FAC produced a greater short-term improvement in chronic plaque psoriasis than FAC alone. Although PASI decreased in both treatment groups, separation between the groups was already evident at the first post-treatment assessment and persisted throughout the 4-week treatment period. Complete clearance was also substantially more frequent with the caffeine-containing formulation, whereas only 1 patient receiving FAC alone achieved PASI 0.
No adverse events were reported in either group during follow-up. These findings suggest that topical caffeine may have value as an adjunct to corticosteroid therapy rather than merely as an alternative topical agent.
Topical therapy remains central to the management of limited and mild-to-moderate plaque psoriasis, and corticosteroids continue to be among the most frequently used treatments because of their anti-inflammatory efficacy and relatively rapid onset of action.4,5 Their clinical usefulness, however, is tempered by concerns regarding prolonged or inappropriate exposure, including cutaneous atrophy and other local adverse effects, as well as the practical problem of maintaining adherence to chronic topical regimens. Contemporary reviews therefore emphasize strategies that improve topical efficacy while limiting unnecessary corticosteroid exposure, including rational combination therapy and incorporation of nonsteroidal agents.4,5 In this context, the present findings are clinically relevant because caffeine was evaluated as an adjunct to an active corticosteroid comparator. The improvement observed in the FAC-alone group confirms that the comparator itself was therapeutically active, while the larger reduction in PASI in the combination arm suggests additional activity associated with the caffeine-containing formulation.
Direct clinical evidence regarding topical caffeine in psoriasis remains remarkably sparse, which is precisely why the present trial is potentially useful. The principal human study remains the randomized, double-blind, right-left comparison by Vali et al, in which 39 patients with stable plaque psoriasis applied 10% caffeine to one side and placebo to the contralateral side three times daily for 8 weeks. PASI reductions favored caffeine throughout follow-up, although statistical significance was reached at week 8, and mild pruritus was the only reported adverse effect.9 The direction of those findings is consistent with the present study, but several distinctions deserve emphasis.
Vali et al studied caffeine against placebo, whereas the current trial examined whether caffeine could add to an established corticosteroid regimen. The caffeine concentration was also lower in the present study, 5% rather than 10%, and treatment lasted 4 rather than 8 weeks. The earlier separation between groups observed in our study may therefore reflect the combined anti-inflammatory effects of FAC and the adjunctive preparation rather than a more rapid intrinsic effect of caffeine itself.
Differences in baseline disease severity, formulation, dosing schedule, and study design also prevent direct comparison of treatment magnitude.
Evidence supporting FAC as an active topical comparator is also available. Memarzadeh et al compared blue-light therapy with fluocinolone 0.025% ointment in patients with localized plaque psoriasis and reported improvement with both interventions over a 4-week treatment period. Their study used a localized lesion-severity assessment rather than the whole-body outcome structure employed here, but it reinforces the established clinical activity of fluocinolone 0.025% in localized plaque disease.10 The present trial addresses a different question.
Rather than determining whether FAC is effective, the results indicate that clinical improvement may be increased when 5% caffeine is incorporated into the corticosteroid preparation. This distinction is important because an active-comparator trial imposes a more clinically informative test than comparison with vehicle alone: any observed difference represents potential incremental benefit over an existing treatment.
The biological rationale for such an adjunctive effect is plausible, although it should not be overstated. Psoriasis is now understood as an immune-mediated disorder sustained by reciprocal signaling between innate and adaptive immune cells and keratinocytes, with the interleukin-23/interleukin-17 axis occupying a central position in the inflammatory network.6 Numerous intracellular signaling mechanisms contribute to this process. Caffeine is a methylxanthine with several pharmacological actions, including antagonism of adenosine receptors and, at sufficiently high concentrations, inhibition of phosphodiesterase activity; antioxidant and other cutaneous effects have also been described.8 These properties provide a mechanistic basis for investigating caffeine in inflammatory skin disorders, but the present trial did not measure intracellular cAMP, phosphodiesterase activity, cytokines, oxidative-stress biomarkers, or tissue caffeine concentrations.
The greater clinical response observed with the combination therefore cannot establish which, if any, of these pathways mediated the treatment effect.
The phosphodiesterase-cAMP pathway is nevertheless particularly relevant because it now has strong clinical validation in psoriasis. PDE4 hydrolyzes cAMP, and selective PDE4 inhibition increases intracellular cAMP signaling while modulating production of inflammatory mediators.7 This therapeutic concept is no longer merely theoretical. In the large Phase 3 DERMIS-1 and DERMIS-2 randomized trials, topical roflumilast 0.3%, a selective PDE4 inhibitor, produced substantially higher Investigator Global Assessment success and PASI responses than vehicle in patients with plaque psoriasis.15 A subsequent systematic review and meta-analysis of randomized trials likewise supported the efficacy and generally favorable tolerability of topical roflumilast.16 These observations strengthen the broader biological premise that manipulating phosphodiesterase-cAMP signaling can improve psoriatic inflammation.
They do not, however, prove that caffeine acts as a selective PDE4 inhibitor in psoriatic skin. Caffeine has broader pharmacological activity and considerably lower phosphodiesterase selectivity than roflumilast. Accordingly, the roflumilast literature should be regarded as mechanistic support for the pathway, not as direct evidence that the treatment effect in our trial arose through the same molecular mechanism.
Another potential contributor to the observed clinical response is the vasoactive effect of caffeine. Caffeine can antagonize vascular adenosine receptors and thereby promote vasoconstriction, although its net vascular effects are depended on tissue and concentration because it can also influence cAMP- and nitric oxide-mediated pathways.17 In psoriatic plaques, local vasoconstriction could theoretically reduce the erythema component of the PASI score and therefore contribute to the apparent clinical improvement. However, cutaneous blood flow, vascular reactivity, and individual PASI components were not assessed separately in the present study.
A contribution from local vasoconstriction therefore cannot be excluded, but the current data do not allow its effect to be distinguished from anti-inflammatory or other local pharmacological actions of caffeine.
The magnitude of complete clearance observed in the intervention group is notable, but it also requires careful clinical framing. Participants entered the study with relatively low mean baseline PASI scores, and consequently the absolute amount of disease that needed to resolve for an individual to reach PASI 0 was smaller than would be expected in trials enrolling patients with more extensive or severe psoriasis. For this reason, the 70% complete-clearance rate should not be directly compared with clearance proportions reported in trials of moderate-to-severe psoriasis or with studies using endpoints such as PASI 75, PASI 90, or an Investigator Global Assessment of clear or almost clear.
Modern topical psoriasis trials illustrate just how strongly response estimates depend on entry severity, anatomical involvement, treatment duration, and endpoint definition. For example, the DERMIS trials evaluated substantially larger populations for 8 weeks and used a composite Investigator Global Assessment endpoint, while contemporary reviews of topical therapy encompass heterogeneous outcome definitions across corticosteroids, vitamin D analogues, tapinarof, roflumilast, and combination preparations.5,15 The present clearance result should therefore be understood within this trial’s population and endpoint rather than used to claim superiority over unrelated topical treatments.
Another relevant observation is the temporal consistency of the treatment difference. Mean PASI decreased progressively in both groups, but the caffeine-containing regimen remained more favorable at each post-baseline assessment. This pattern is more informative than an isolated difference at the final visit because it indicates that the treatment-group separation was sustained across serial assessments.
An important limitation is the absence of post-treatment follow-up. Participants were observed only during the 4-week treatment period, and no assessments were performed after treatment discontinuation. Consequently, the present study cannot determine whether the observed improvement was sustained, how rapidly lesions recurred, whether a rebound phenomenon occurred after treatment withdrawal, or whether repeated treatment courses would maintain efficacy.
Longer post-treatment observation will be essential in future trials to assess durability of response and recurrence after discontinuation. Current discussions of topical psoriasis management increasingly emphasize not only induction of clearance but also maintenance, tolerability, simplicity of application, and long-term adherence.5 The logical next question is therefore not merely whether the combination can improve lesions rapidly, but whether that advantage persists after treatment and whether adjunctive caffeine can reduce the amount or duration of corticosteroid exposure required for disease control.
Short-term tolerability was favorable in the present trial because no adverse events were reported during treatment. This finding is encouraging but should be interpreted according to the exposure available to detect harm. Only 20 participants received the caffeine-containing preparation, and follow-up lasted 4 weeks.
Such a sample can identify common, immediate intolerance but cannot reliably exclude uncommon reactions or adverse effects associated with repeated and prolonged application. The mild itching reported with 10% caffeine by Vali et al9 suggests that local tolerability may also depend on formulation or concentration. More generally, the increasing availability of nonsteroidal topical therapies has shifted attention toward treatments that combine efficacy with long-term usability, particularly because chronic exposure to topical corticosteroids can be limited by local adverse effects.4,5,16 Larger and longer studies of caffeine-containing corticosteroid formulations should therefore include structured assessment of application-site reactions, skin atrophy, tolerability, treatment adherence, and cumulative corticosteroid exposure rather than relying solely on short-term efficacy.
The age- and sex-related differences in complete clearance reported in the exploratory subgroup analyses should be interpreted with considerably greater restraint than the primary treatment comparison. The intervention group contained only 20 participants, and stratifying that sample across several age and sex categories resulted in very small cell sizes. The trial was not powered to test treatment-effect heterogeneity, and no biological measurements were available to explain demographic differences in response.
These observations are therefore hypothesis-generating and should not be used to select patients for treatment. Confirmation would require substantially larger samples with prespecified interaction analyses rather than within-group comparisons across small subcategories.
The study has several limitations. Most importantly, the sample size was small and recruitment was confined to a single center, limiting both statistical precision and external generalizability. Follow-up was restricted to the 4-week treatment period, with no post-treatment assessment after discontinuation.
Therefore, durability of clearance, time to recurrence, possible rebound after treatment withdrawal, and longer-term efficacy and safety could not be evaluated. Disease severity at baseline was relatively low, which should be considered when interpreting the high proportion achieving PASI 0 and may limit extrapolation to patients with more extensive psoriasis. The absence of a caffeine-only arm prevents separation of the independent therapeutic effect of caffeine from any pharmacological or formulation-related interaction between caffeine and FAC.
PASI was the sole physician-assessed efficacy measure. Because the study population had relatively low baseline disease severity, PASI may have been less sensitive to small or localized changes than measures such as the IGA or target-lesion PASI. These alternative severity assessments were not collected.
Patient-reported outcomes such as pruritus, treatment satisfaction, and dermatology-specific quality of life were also not incorporated, despite their importance in contemporary assessment of psoriasis treatment. No biochemical or pharmacokinetic endpoints were collected, so the proposed contribution of phosphodiesterase-cAMP signaling remains mechanistic speculation rather than an experimentally demonstrated pathway in this trial. Although the compounded preparation was assessed for preservation of caffeine content during the treatment period, the study did not include a separate quantitative stability assay for fluocinolone acetonide or evaluate whether caffeine altered corticosteroid release or cutaneous penetration.
Therefore, a formulation-related interaction between caffeine and FAC cannot be excluded and should be examined in future pharmaceutical and pharmacokinetic studies. Finally, exploratory demographic subgroup analyses were based on small numbers and require independent confirmation. Future multicenter randomized trials should enroll larger and more diverse populations, extend both treatment and post-treatment observation, incorporate patient-reported and quality-of-life outcomes, and evaluate whether the combination permits reduction in corticosteroid exposure while maintaining disease control.
Mechanistic studies assessing cutaneous caffeine penetration, local cAMP signaling, and inflammatory biomarkers would also clarify whether the clinical benefit observed here reflects a pharmacologically specific adjunctive effect or another property of the combined formulation.
Conclusion
Topical 5% caffeine combined with FAC produced greater short-term improvement in chronic plaque psoriasis than FAC alone over 4 weeks, with a more pronounced reduction in PASI scores and a higher rate of complete clearance. No adverse events were reported during the treatment period. These findings suggest that caffeine may serve as a useful adjunct to topical corticosteroid therapy in plaque psoriasis.
Given the small, single-center sample and short duration of follow-up, however, the results should be considered preliminary. Larger multicenter randomized trials with longer follow-up are needed to confirm efficacy, characterize long-term safety, and determine whether the combination can provide sustained disease control or reduce cumulative corticosteroid exposure.