Back to the Basic Science: Why PDE-4?
In a live panel at the Elevate-Derm RAPIDS Conference in Fort Lauderdale, Buchi Neita, PA-C, and Shanna Miranti, PA-C, asked Dr. Jason Hawkes to walk the audience through the origins of PDE-4 inhibition and why it earned a place in dermatology. Hawkes explained that phosphodiesterase is a large family — about 10 or 11 members —, but PDE-4 stood out because it tends to be more restricted to immune cells, making it an obvious target for shutting off a pathway that drives immune-cell activation in inflammatory conditions.
Hawkes offered a mental shortcut for anyone who spent residency agonizing over whether cyclic AMP goes up or down: skip it. Instead, he frames PDE-4 as an activator of NF-kappa-B, a broadly pro-inflammatory pathway. Because NF-kappa-B is so nonspecific — comparable in reach to the TNF pathway — systemic PDE-4 inhibition touches TH1, TH2, and TH17 all at once. That breadth, he noted, is exactly why a systemic agent viewed as 'very safe' can still have a wide impact on the immune response, and why topical PDE-4 inhibition can work across multiple inflammatory conditions rather than just one type.
The Topical Niche: Steroid Stewardship and Simpler Regimens
Miranti raised the field-wide push to move away from topical steroids, and Hawkes was direct: across the board, topical steroids are inappropriately used — thrown at patients while joints and BSA get ignored — partly because the system pressures clinicians to hand over a big tub and get people out the door. He tied the emerging concept of 'topical steroid stewardship' to using steroids more thoughtfully and stopping when they aren't working.
The practical advantage of topical PDE-4s, he said, is that they simplify complex steroid regimens. Instead of juggling hydrocortisone for the face, triamcinolone for the body, and clobetasol or betamethasone for hands and feet, clinicians can use one agent anywhere — face, genitals, under the breasts, axilla, abdomen — without worrying about long-term steroid side effects. He singled out scalp psoriasis and seborrheic dermatitis, conditions that can mimic each other, as areas where having a single once-daily therapy makes a real difference. Hawkes also flagged real-world lifestyle friction: many female patients simply don't wash their hair often, so a foam vehicle beats a shampoo for adherence.
Neita added a science point the panel agreed was underappreciated: topical PDE-4 inhibitors are not all created equal. She noted three different binding sites — the glutamine, metal ion, and hydrogen/water binding sites — and that the molecule's fit correlates with efficacy, with topical roflumilast generally outperforming topical crisaborole. Hawkes drew the parallel to TIK2 inhibitors: later-generation agents hit the target better, stay on it longer, and avoid the stinging and burning that plagued earlier options.
Oral Apremilast: A Real but Limited Role
Miranti asked how nervous the hosts were to ask whether Hawkes reaches for apremilast. He was characteristically blunt: apremilast might work for other conditions, but the problem is it doesn’t really hit any of those pathways well. In psoriasis specifically, with roughly 14 medications now setting a very high bar for skin clearance, he doesn't feel the drug is needed.
Where he sees potential is in mixed inflammatory states without approved therapies — using the broader 'shotgun' effect rather than a sniper approach — and possibly as an adjunct rather than a monotherapy. He gave hidradenitis suppurativa as an example, where existing therapies get decent but incomplete control and an added mechanism might help. But he was honest that in every space where apremilast has been tested it hasn't been a slam dunk; he's never seen it turn off joint disease in a patient already on a targeted therapy, and it disappointed him for palmoplantar pustulosis. He also cautioned that small molecules don't hold their targets well, and that this class faces stiff competition from JAK inhibitors, whose broader mechanism reaches conditions lacking approved therapies.
Safety, Setting Expectations, and Future Directions
On safety, Hawkes pushed back on the myth that topical PDE-4s cause the GI side effects of the orals through systemic absorption. He reminded listeners that clinical-trial adverse events are reported by FDA requirement without needing a proven cause-and-effect — a patient who gets COVID or a headache on therapy still shows up in the label — so much of what appears in prescribing information deserves clinical skepticism. The topicals, in his view, simply aren't producing systemic side effects.
For expectation-setting, Hawkes said steroids are 'home runs initially' — fast and effective — while nonsteroidal topicals work more gradually. But he rarely meets patients who love their steroids; most want off them. The easy sell is a once-daily agent that can't be overused, won't thin the skin, and can go anywhere on the body. A newer value proposition, seen in both the aryl hydrocarbon receptor and PDE-4 space, is prolonged clearance that may let patients use therapy intermittently — a few times a week — lowering overall treatment burden.
The panel closed with speculative territory. On combining GLP-1s with apremilast for obese, milder psoriasis patients, Hawkes said the weight data are hit-or-miss with only modest metabolic benefit, and he wouldn't pull a well-controlled apremilast patient off a working regimen. On vitiligo and repigmentation — prompted by Miranti's case of dramatic improvement in a seborrheic/psoriasis overlap patient — he grounded the discussion in basic science: vitiligo is likely driven predominantly by TH1/interferon inflammation, so PDE-4's partial TH1 coverage might help post-inflammatory hypopigmentation more readily than vitiligo. He also noted that even with strong immunosuppression, vitiligo patients mostly repigment in sun-exposed areas, suggesting UV and pigmentation are linked. His bottom line throughout: bring the science, and let good data decide where each mechanism belongs.