Roflumilast in Dermatology: A Newer Phosphodiesterase-4 Inhibitor

Introduction

Roflumilast is a potent and selective inhibitor of phosphodiesterase-4 inhibitor.[1] It has already been in use for treating COPD exacerbations for a few years.[2] In recent years, after the success of apremilast in the treatment of multiple inflammatory skin conditions, roflumilast has been tried in various clinical trials and got FDA approval in a topical formulation for the treatment of psoriasis and seborrheic dermatitis.[3,4] There is a lack of options among non-steroidal topical formulations for treating inflammatory skin conditions; thus, attention has been turned towards a molecule such as roflumilast, which is the need of the hour. In this article, we will look at the various skin conditions where roflumilast is available as a treatment option.

Psoriasis

Psoriatic skin has elevated levels of phosphodiesterase-4 (PDE-4) that lead to decreased levels of cyclic 3’,5’-adenosine monophosphate and subsequently higher levels of pro-inflammatory cytokine levels such as IL-17, IL-23, IFN-γ, and TNF-α.[3] Roflumilast is approximately 25–300 times more potent than apremilast and crisaborole and has a much greater affinity to block PDE-4.[5] Topical roflumilast 0.3% cream was approved by the US FDA for the treatment of plaque psoriasis in July 2022.[6] Roflumilast can be safely applied to intertriginous areas, and it is approved for use in children (≥12 years).[3] The drug is advised for once daily application owing to its longer half-life, which is approximately 4 days.[7] When compared to oral dosage, topical roflumilast 0.3% was found to be in much higher concentrations in the epidermis.[8] The most common treatment-emergent adverse effects were headache and diarrhoea but were seen at a much lower rate in comparison to oral dosage.[2] Other rare adverse effects reported were nausea, headache, and pain at the application site.[9] Response was noted as early as 4 weeks, and symptomatic relief was noted by 2 weeks.[3] However, oral roflumilast in the dosage of 500 μg once daily has shown efficacy in the treatment of moderate-to-severe psoriasis.[8]

Seborrheic Dermatitis

Roflumilast in 0.3% foam formulation was US FDA-approved for the treatment of seborrheic dermatitis in April 2023.[10] This foam formulation has shown minimal adverse effects as it is attributed to the use of a ceramide-based vehicle rather than propylene glycol.[4] On the contrary, crisaborole (another PDE-4 inhibitor), which has been recently approved for use in mild-to-moderate atopic dermatitis, has a major limitation in the form of application site pain, burning, and stinging sensation; thus, topical roflumilast cream can be a good alternative in atopic dermatitis in near future.[11,12] In addition, roflumilast inhibits yeast PDE activity, thus acting as an antifungal agent.[11]

In Other Skin Conditions

A successful use of oral roflumilast in treating a recalcitrant case of oral lichen planus has been reported.[13] However, clinical trials are required for further confirmation. The use of oral roflumilast has shown rapid improvement in a case of idiopathic aphthous ulcers with minimal side effects.[14] Similarly, oral roflumilast therapy was used successfully for treating a case of refractory nummular dermatitis.[15] In Table 1, we have tabulated the various clinical trials on the off-label use of roflumilast in dermatology. Apart from these, some clinical trials are going on to evaluate the safety and efficacy of roflumilast in chronic hand eczema and rosacea. Roflumilast can also potentially be useful for the treatment of alopecia areata and vitiligo due to the same mechanism of action as that of apremilast.[16] Figure 1 demonstrates the different pathways involved where roflumilast acts as an anti-inflammatory agent.[16]

Table 1.

Clinical trials on the off-label use of roflumilast in dermatology

Dermatoses	Study	Type of Study	Study end-points	Results
Hidradenitis suppurativa	Ring et al.,[17] 2022	Case report	Assess the response to oral roflumilast in a patient with severe axillary HS on failed adalimumab and infliximab therapy	Adequate response with fewer lesions reported, and no notable adverse events at 3 months; associated with a 9-kg weight loss
Recurrent oral aphthosis	Gyldenløve et al.,[14] 2022	Case series	Assess the response to oral roflumilast in two patients with recurrent oral aphthosis who did not meet Behçet’s disease criteria	Complete lesion resolution occurred early (2–3 weeks) and was sustained after 3 months of treatment; good safety profile
Behçet’s disease	Peñuelas et al.,[18] 2023	Case report	Assess the response to oral roflumilast 250 µg/day in a patient with refractory Behçet’s disease	Favourable response to roflumilast therapy without noticeable adverse events
Nummular eczema	Gyldenløve et al.,[15] 2022	Case report	Assess the response to oral roflumilast 500 µg/day in a 69-year-old patient with nummular eczema refractory to topical steroids, UVB, methotrexate, and azathioprine	Early response (2 weeks) and complete lesion clearance after 3 months of treatment; good safety profile
Erosive lichen planus	Fage et al.,[13] 2023	Case report	Assess the response to oral roflumilast in a patient with erosive oral lichen planus refractory to topical and oral steroids, methotrexate, cyclosporine, azathioprine, apremilast, and adalimumab	Substantial resolution of lesions after 3 months of treatment, initially concomitant with descending prednisone (7.5 mg to 2.5 mg after 3 months on roflumilast)
Atopic dermatitis	Gooderham et al.,[19] 2023	Stage IIa clinical trial	Assess the efficacy and safety profile of 0.15% topical roflumilast vs 0.05% topical roflumilast vs placebo to treat atopic dermatitis	A decrease in EASI of 6.4 points in the 0.15% roflumilast group, 6 points in the 0.05% roflumilast group, and 4.8 points in the control group, without statistical significance; good safety profile

Figure 1.

Different pathways involved where roflumilast acts as an anti-inflammatory agent

Roflumilast is a newer drug with a favourable safety profile. It is a cost-effective drug when compared to other commonly used immunosuppressive agents such as cyclosporine and injectable methotrexate.[16] The oral formulation is available in the Indian market, but the topical formulation is not yet available, which is a major limitation. Currently, roflumilast is FDA-approved only for psoriasis and seborrheic dermatitis, but it has a much wider potential to be used for the treatment of other dermatoses. In Table 2, we have included the various skin conditions where roflumilast has been tried with the level of evidence and strength of recommendation mentioned for each condition. Roflumilast in both topical and oral formulations will be a good armamentarium for a dermatologist in the near future.

Table 2.

Various off-label indications with the level of evidence and strength of recommendation of roflumilast

Treatment option	Indication	Level of evidence	Strength of recommendation
Topical 0.3% cream	Chronic plaque psoriasis	Level 1	Strong
Oral 500 mg OD tablet	Moderate to severe plaque psoriasis	Level 2a	Strong
0.3% foam formulation	Seborrheic dermatitis	Level 2a	Strong
Oral 500 mg OD tablet	Hidradenitis suppurativa	Level 5	Weak
Oral 500 mg OD tablet	Recurrent oral aphthosis	Level 4	Weak
Oral 250 mg/day	Behcet’s disease	Level 5	Weak
Oral 500 mg/day	Nummular eczema	Level 5	Weak
Oral 500 mg/day	Erosive lichen planus	Level 5	Weak
Topical 0.15% cream vs 0.05% cream	Atopic dermatitis	Level 2a	Strong

Conflicts of interest

There are no conflicts of interest.

Funding Statement

Nil.