The exact mechanism of action of roflumilast is still to be elucidated (figure 2). Roflumilast and its active metabolite, roflumilast N-oxide, are PDE4 inhibitors (PDE4i), which happen to be the main enzymes involved in the metabolism of cyclic adenosine monophosphate (cAMP) found in lung tissue, skin, heart, kidneys, GI tract, and nervous system.28 At cellular level, PDE4 turns cAMP into adenosine monophosphate (AMP), thereby terminating the cellular messaging started by cAMP.29 Roflumilast blocks the effect of PDE4, thus leading to the accumulation of cAMP in target cells, and increasing the signaling mediated by this molecule. This results in the inhibition of chemotaxis, reduction of inflammatory infiltration, decreased release of inflammatory and cytotoxic mediators, and an overal reduction of inflammation.30 In dermatology, PDE4 is present in epidermal keratinocytes, neutrophils, Langerhans cells, and T lymphocytes.31 Additionally, high levels of PDE4 have been found in peripheral blood mononuclear cells of patients with psoriasis, along with changes to ATP signaling.32 The effectiveness of roflumilast is based on the inhibition of multiple inflammatory pathways, acting at epidermal level in keratinocytes and Langerhans cells, and dermal level in neutrophils, T lymphocytes, and macrophages.30,33 In atopic dermatitis, the hyperactivation of PDE4 induces an inflammatory response with polarization towards the Th2 pathway.31,33 Specifically, cAMP has immunosuppressive and anti-inflammatory properties, which are mostly mediated by the nuclear factor-κB, which is key for the activity of multiple cytokines, including tumor necrosis factor-alpha (TNF-α) and interleukins (IL) 1, 2, 8, 12, 18, 23, 27, or 36.34,35 The multiple PDE4-mediate signaling pathways suggest that its blockade may be useful to trest various dermatoses, such as hidradenitis suppurativa, recurrent aphthous stomatitis, or lichen planus.3

Figure 2.

Mechanism of action of roflumilast. Phosphodiesterase inhibitors lead to an accumulation of intracellular cAMP by interfering with its degradation. The increased intracellular concentration of cAMP results in the inhibition of chemotaxis, reduced inflammatory cell infiltration, and decreased release of inflammatory and cytotoxic mediators, thereby reducing inflammation.

5’-AMP, 5’-adenylic acid; AC, adenylate cyclase; ATF, activating transcription factor 1; ATP, adenosine triphosphate; Bcl-6, B-cell lymphoma protein 6; c-AMP, cyclic adenosine monophosphate; CREB, cAMP responsive element; Egr-1, early growth response protein 1; Elk-1, E-26-like protein 1; ERK, extracellular signal-regulated kinase; GP, G protein; GPCR, G protein-coupled receptors; IKKbeta, inhibitor of nuclear factor kappa-B kinase subunit beta; IPDE-4, inhibitor of phosphodiesterase type 4; MAPK, mitogen-activated protein kinases; NFKB, nuclear factor KB; PDE4, phosphodiesterase type 4; PDE4i, phosphodiesterase type 4 inhibitor; PKA, protein kinase A; Raf, rapidly accelerated fibrosarcoma protein kinases; RTK, receptor tyrosine kinases.34

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Overall, roflumilast is well-tolerated and has an excellent safety profile24 (table 3). In clinical trials (CT) on roflumilast to treat COPD and chronic bronchitis, the most common adverse event (AE) reported were diarrhea (8% to 9%), weight loss (6% to 12%), and nausea (5%). The incidence of nasopharyngitis (5% to 8%) and upper respiratory tract infections (4%) has been reported. However, these data are similar to those from the placebo group. AEs were mainly reported within the first weeks of treatment and were mostly self-limiting.28 A meta-analysis reported a higher rate of AEs in the roflumilast 500μg/day group vs placebo.36 A total of 15% discontinued treatment due to AEs (compared to 9% from the placebo group). The most common reasons for drug discontinuation were diarrhea and nausea.28 These initial analyses also reported higher rates of acute pancreatitis, psychiatric symptoms, and even prostate, lung, and colorectal cancer.37 However, these initial findings could not be confirmed later, and roflumilast has even been proposed as an adjuvant therapy to treat various neoplasms, such as lung cancer or diffuse large B-cell lymphoma.38,39

Regarding weight loss, its incidence was nearly double (67.4% vs 37.7%) in the roflumilast group, and weight loss turned out to be significant (> 10% compared to baseline in 7.1% of the treatment group vs 1.9% of the control group).37 This significant weight loss was associated with an improved glycemic metabolic profile and constitutes a potential therapeutic approach for the management of obesity, insulin resistance, and metabolic syndrome.40,41 The psychiatric symptoms included in the initial studies were anxiety, depression, and insomnia.28 However, subsequent studies have confirmed that this risk is minimal, and in fact, roflumilast could be a promising drug to treat cognitive impairment, Alzheimer's disease, or schizophrenia.8,10,42 Finally, the increased incidence of atrial fibrillation in patients on oral roflumilast has been a matter of discussion due to its higher incidence rate in the oral roflumilast group (n=24) compared to the placebo group (n=9) in pre-commercialization trials. However, this has not been confirmed in the routine clinical practice. Additionally, the results of 24-hour Holter EKG monitoring in 55 patients showed no inter-gropu differences regarding heart rate or the occurrence of arrhythmias.43

Long-term safety data with PDE4i, specifically roflumilast, are equally favorable, with no new AEs or cumulative AEs being reported.44,45 AEs have not been described either in diseases in which this drug is commonly used, such as COPD.46 Currently, there is an ongoing clinical trial to assess the long-term safety profile of oral roflumilast to treat COPD.47

The safety profile of topical roflumilast cream is also favorable, with exceptionally rare serious AE being reported due to its minimal absorption (bioavailability of 1% to 2%). The most common AEs reported include diarrhea (3% to 4%) and headache (2% to 4%), followed by insomnia, nausea, itching, or discomfort at the application site.7,27

The use of oral roflumilast has been approved by the FDA (unlike the EMA) for the topical treatment of plaque psoriasis and mild-to-moderate seborrheic dermatitis.6,7,27 The first report on roflumilast in the management of plaque psoriasis dates back to 2017 when Michels et al.48 described a case of psoriasis and concomitant COPD in which skin lesions improved while lung disease was being treated with oral roflumilast. In 2020, Papp et al.49 reported the first stage I/IIa clinical trial (CT). This trial confirmed that a response was achieved when plaque psoriasis was treated with 0.5% and 0.15% topical roflumilast cream, which was superior compared to the administration of placebo. The DERMIS-1 and DERMIS-2 trials27 led to the FDA approval of 0.3% topical roflumilast to treat plaque psoriasis, with 42.4% of cases achieving the Investigator's Global Assessment Scale (IGA) endpoint of complete clearance or improved IGA ≥ 2 points compared to baseline vs 6.1% of the patients from the control group (DERMIS-1), and 37.5% achieving the IGA endpoint compared to 6.9% from the control group (DERMIS-2). The safety profile was favorable in both studies, being GI discomfort the most common AE of all.77 Recently, 2 stage IIb50 and stage III6 trials have been published confirming the efficacy profile of 0.3% topical roflumilast to treat pruritus, nocturnal rest, and scalp involvement, respectively (table 4).

The FDA approval of topical roflumilast to treat seborrheic dermatitis was granted back in April 2023, following the publication of the results from a multicenter, placebo-controlled stage IIa CT on the efficacy and safety profile of 0.3% roflumilast in 226 patients with a >3-month history of seborrheic dermatitis and IGA scores ≥ 3 (≥ moderate) with involvement of <20% of the body surface area, including the scalp, face, trunk, and intertriginous areas.7 The trial achieved the target IGA (≥ 2-point clearance from baseline) in 73.8% of the patients on roflumilast, compared to 40.9% of the patients from the control group (P <.001). The difference was significant from the 2nd week of treatment. No higher rate of AEs was ever reported in the roflumilast group compared to the control one.

The medical literature available includes various trials (most of them small series of cases or initial CT) on the off-label use of roflumilast in dermatology (table 5). Specifically, we found 4 clinical trials on the use of topical roflumilast. Regarding atopic dermatitis, one stage IIa CT (n=40) failed to achieve its proposed endpoints with 0.5% topical roflumilast being compared to placebo at 16 weeks. The primary endpoint of this trial was to determine the number of patients who achieved a reduction of, at least, 75% in the Hand Eczema Severity Index (HECSI75) after treatment with roflumilast topical cream.51 Another randomized stage IIa clinical trial (n=136) showed an improved Eczema Area and Severity Index (EASI) score at 12 weeks with 0.15% topical roflumilast (superior to that obtained with the 0.05% concentration and placebo). However, these results did not reach statistical significance.52 Two currently ongoing clinical trials on the effects of topical roflumilast to treat chronic hand eczema,53 and papulopustular rosacea.54 The CT on chronic hand eczema (n=230) is stage IIa trial on the efficacy and safety profile of topical roflumilast cream at 0.3% vs 0.1% vs placebo. The trial will be assessed at week 12. The CT on papulopustular rosacea (n=40) has already been completed and is currently pending publication. It evaluates the efficacy profile of 0.5% topical roflumilast vs placebo. Recently, a preclinical trial found higher levels of PDE4 in the skin of patients with vitiligo. After the application of topical roflumilast, the PDE4 levels dropped, and skin lesions improved partially.55

Regarding the off-label use of oral roflumilast, we found 4 trials on the off-labe use of roflumilast to treat psoriasis (table 5). Gyldenløve et al. have recently reported the efficacy of 500μg/day of oral roflumilast to treat plaque psoriasis in a stage III CT (n=46) vs placebo, with 35% of the intervention group achieving PASI 75 vs 13% of the placebo group (P=.014) at week 12. Mostly mild AEs were reported.45 Recently, the same group published the results of oral roflumilast in the first patient with refractory plaque psoriasis in whom this drug was ever prescribed, a 48-year-old man.56 They later reported on the long-term disease progression (18 months) of this individual.57 Recently, its utility has also been described in another clinical case: a 59-year-old man who was simultaneously being treated for COPD and psoriasis.48 In both cases, roflumilast was used at a dose of 500μg/day, with no significant adverse events being reported. Aside from psoriasis, the scientific medical literature currently available includes 5 articles on oral roflumilast in dermatological disease (table 5): 1 case series and 4 isolated clinical cases, most of them reported by the same health care center in Denmark. Ring et al. described 1 case of refractory hidradenitis suppurativa with axillary involvement, failed adalimumab and infliximab, and good clinical response to roflumilast at 12 weeks, with associated weight loss.58 Gyldenløve et al. reported 2 cases of recurrent oral aphthosis treated with oral roflumilast 500μg/day, showing proper and rapid responses within 2 to 3 weeks and maintained responses after 3 months of treatment.59 Similarly, they also described 1 case of nummular eczema with failed multiple treatments that, somehow, achieved an early and sustained response to oral roflumilast, without visible adverse events being reported.60 There was also 1 case of erosive oral lichen planus refractory to first-line therapies and on systemic corticosteroids. Oral roflumilast allowed for down-titration of prednisone to 2.5mg/day at 3 months.61 A Spanish group recently reported 1 case of refractory Behçet's disease successfully treated with roflumilast 250μg/day, without significant adverse events being reported.62 Finally, a stage IV clinical trial (n=40) currently in the recruitment stage is evaluating oral roflumilast at a dose of 500μg/day vs placebo to treat chronic hand eczema.63

Given its mechanism of action, which is similar to that of apremilast and the possibility of elevated PDE4 levels, multiple dermatoses in which this drug has been used off-label could potentially benefit from oral or topical roflumilast (table 6). Among these we find primarily autoimmune dermatoses like vitiligo or alopecia areata,3 erythematosquamous diseases similar to psoriasis such as pityriasis rubra pilaris,64 or Sneddon-Wilkinson syndrome,65 blistering diseases such as vulgar pemphigus or acquired epidermolysis bullosa,3 genodermatoses such as familial benign pemphigus (Hailey-Hailey disease),66 or ichthyosis.3 Other diseases where apremilast could also be useful include hidradenitis suppurativa,67 cutaneous lichen planus,68 or other lichenoid and interface dermatitis,69 cutaneous lupus erythematosus70, or cutaneous sarcoidosis.71 Its potential application in morphea, a relatively common disease where PDE4i have shown to reduce dermal fibrosis is of special interest. In fact, good results have been reported with apremilast to treat this entity.72–74