Demystifying Phosphorylation and the JAK-STAT Pathway
Fresh off the stage at the 2026 Elevate-Derm RAPIDS Conference, immunodermatology speaker Dr. Diego Ruiz Dasilva sat down with NP Victoria Garcia-Alvea to unpack a term clinicians toss around without always defining: phosphorylation. As Dr. Ruiz Dasilva explained, phosphorylation is simply a way to activate a protein — adding a phosphorus group flips the switch so the protein can carry out the next step in an assembly line of cellular machinery, whether that end goal is inflammation, activating a cell to kill a microbe, or making a red blood cell.
Why does this matter for JAK inhibitors? Because, as he put it, the JAK inhibitor sits in the ATP-binding site of the JAK protein, so the protein cannot be phosphorylated. Without that phosphorylation step, the entire downstream cascade cannot proceed. For APPs who hear 'JAK-STAT' and 'phosphorylation' in a lecture, that mental picture — an assembly line that stalls when the switch can't be flipped — makes the mechanism click.
The Castle Advanced Atopic Dermatitis (AD) Test: Matching Patients to Mechanism
One of the most practical pearls of the conversation was the Castle Advanced AD test, which Dr. Ruiz Dasilva described as 'hot off the press' with a recently published validation study in the JAAD. The test profiles 487 genes across roughly 12 inflammatory pathways and uses a neural network algorithm to sort patients into categories — for example, a TH2 profile versus a JAK-inhibitor-responder profile. Collection is non-invasive: he compared it to a KOH, taking a fine scraping of scale with the dull side of a curette, with results back in about two weeks.
The validation data he described were striking. Patients flagged as JAK-inhibitor responders who received a biologic essentially didn't get completely clear, rarely hit EASI 90, and didn't reach optimal itch improvement — but when given a JAK inhibitor, they achieved strong rates across those metrics. TH2-profile patients, by contrast, responded equally well to either a biologic or a JAK, presumably because their disease was more IL-13 driven.
In practice, Dr. Ruiz Dasilva said he reaches for the test in most patients for whom he's choosing an advanced systemic — those suffering enough, with enough BSA, or highly motivated. He may skip it when comorbidities have already steered the drug choice, such as reaching for dupilumab in a patient with asthma or upadacitinib in a patient with concurrent psoriatic or rheumatoid arthritis. He noted the test can be used in patients already on a systemic that's working inadequately, and that if it says 'JAK,' clinicians shouldn't waste time cycling through more biologics. He believes it can be used in patients 12 and older, though he flagged he'd want to double-check that age cutoff. As for cost: no patient is paying out of pocket right now, and some insurers are covering it while others are still figuring out what it is.
Screening Before a JAK: What Gives Him Pause
When starting a JAK inhibitor, Dr. Ruiz Dasilva keeps his baseline history simple: has the patient ever had a heart attack, stroke, blood clot, or cancer? A clean 'no' makes the decision easy. A 'yes' means digging into nuance. A provoked clot 20 years ago after a long flight or after surgery doesn't worry him; a family history of clots plus a personal clot suggests a genetic basis and warrants pause. Prostate cancer a decade ago is different from stage IV melanoma treated with immunotherapy last year.
He also weighs overall health and patient engagement—if someone isn’t doing what their doctor asks (statin, exercise, limiting drinking, smoking, and fast food), he may pause to focus on their broader health first. Garcia-Alvea and Dr. Ruiz Dasilva agreed on looping in other specialists. He said he'll reach out to oncology, rheumatology, PCPs, or cardiology, and noted a telling shortcut: if a patient no longer sees their hematologist or oncologist, that discharge itself often signals they're now low risk. He also warned APPs that other specialists frequently defer back to dermatology, sometimes saying they've never heard of these drugs as risky.
Off-Label Frontiers: HS, Granulomatous Disease, and Intralesional JAKs
Asked what excites him most, Dr. Ruiz Dasilva pointed first to hidradenitis suppurativa, predicting maybe two oral JAKs could be approved within the next year or two for a disorder he called deeply debilitating. As a self-described pruritus expert, he's drawn to HS less for itch and more for the permanent scarring, tunneling, and functional impairment patients endure.
Further out — possibly never formally approved — he's treated granulomatous disorders off-label with JAK inhibitors, including sarcoidosis, granuloma annulare, and necrobiosis lipoidica (NLD). His confidence came from basic science: these diseases run through interferon gamma, a key inflammatory cytokine blocked by JAK1-selective drugs. Many of these patients were also intensely itchy, so he framed early attempts as improving itch — and then the GA and sarcoid actually improved, serving as proof of concept. Topical JAKs also work well, he said, limited mainly by how hard it is to cover generalized disease.
Finally, Dr. Ruiz Dasilva said he does expect intralesional JAKs eventually. He cited his colleague Dr. Leo Wang, an MD-PhD at Penn studying this for alopecia, whose work he understands is progressing positively — a potential game changer for localized skin disease.