Mapping the Future of Immunodermatology: JAK Inhibitors, Genetic Profiling, and the Next Frontier

From the mechanisms of cellular machinery to the cutting edge of personalized medicine, immunodermatology is advancing rapidly.

In a recent episode of the 2026 Rapids Special Conference Coverage SkinSync podcast, host Victoria Garcia-Albea, NP, sat down with Dr. Diego DaSilva following his lectures on advanced systemics. They dove deep into what "phosphorylation" actually means in practice, a groundbreaking new genetic test for atopic dermatitis (AD), safety screening protocols, and the off-label future of JAK inhibitors.

Here are the key takeaways from their conversation.

1. Demystifying Cellular Machinery: What is Phosphorylation?

In dermatology, providers frequently discuss the JAK-STAT pathway and "phosphorylation," but the term is often used without a clear explanation of its mechanism.

Dr. DaSilva breaks it down simply:

"Phosphorylation is essentially a way to activate a protein. By adding that phosphorus, it’s activated and goes on to do the next step in this assembly line machinery."

Whether the end goal is to trigger inflammation, activate a cell to kill a microbe, or produce red blood cells, it all hinges on this single chemical event. Without it, the inflammatory cascade grinds to a halt.

How JAK Inhibitors Intervene

JAK inhibitors work by sitting directly in the ATP-binding site of the JAK protein. Because the drug blocks this site, the protein cannot be phosphorylated. No phosphorylation means no signal cascade, effectively shutting down the downstream inflammation.

2. Personalizing AD Treatment: The Castle Advanced AD Test

One of the most exciting updates in personalized dermatology is the validation of the non-invasive Castle Advanced AD test (recently published in the Journal of the American Academy of Dermatology).

Leveraging extensive genetic profiling experience, this test evaluates 487 genes across roughly 12 different inflammatory pathways. Using a neural network algorithm, it categorizes atopic dermatitis patients based on their specific inflammatory gene profile into two main buckets:

• TH2 Profile
• JAK Inhibitor Responder Profile

Clinical Outcomes & Validation

Prospective validation data revealed a stark contrast in how these groups respond to different advanced systemics over three months:

Practice Integration: How to Use It

• The Procedure: It is completely non-invasive—similar to a KOH prep. Providers use the dull side of a curette to scrape a small amount of scale gently. Results return in about two weeks.
• Patient Selection: Dr. DaSilva uses this test for most patients who are candidates for advanced systemic therapy. Exceptions include patients with clear comorbidities that dictate the drug choice (e.g., choosing dupilumab for a patient with co-existing severe asthma, or upadacitinib for someone with concurrent psoriatic arthritis).
• Inadequate Responders: The test is highly valuable for patients already on systemic therapy who are not responding adequately. If a patient is failing an IL-13 inhibitor but the test reveals they are a JAK responder, it gives the clinician the confidence to immediately pivot to a JAK inhibitor rather than cycling through another biologic.
• Age Limit & Cost: The test is validated for ages 12 and older. Currently, insurance coverage varies, but patients are not being balance-billed or paying out of pocket.

3. Screening Protocols: Overcoming the "Pause" Factors

When initiating a patient on an oral JAK inhibitor, Dr. DaSilva keeps his initial screening history incredibly straightforward by asking about a history of four key events:

1. Heart Attack
2. Stroke
3. Blood Clot (DVT/PE)
4. Cancer

A "yes" to any of these is not an automatic contraindication, but rather a prompt to dig into the nuances:

• Provoked vs. Unprovoked Clots: A blood clot experienced 20 years ago following a long-haul flight or a major surgery is less concerning than a patient with a strong family history of hypercoagulability and recurrent unprovoked clots.
• Oncology History: A history of prostate cancer treated successfully 10 years ago carries a very different risk profile than a patient who was on active immunotherapy for stage IV melanoma just last year.
• Overall Lifestyle Compliance: Dr. DaSilva notes that overall cardiovascular health matters. If a patient is a "vascular path" and refuses to take their prescribed statins, modify their diet, limit smoking, or exercise, it causes a pause to address overall health first.

Interdisciplinary Tip: When consulting with a patient’s specialist (oncology, cardiology, or rheumatology), do not be surprised if they defer back to you. Because these targeted systemics are unique to dermatology and rheumatology, many outside providers are not yet familiar with their specific safety profiles.

4. Off-Label and Future Horizons: From HS to Granulomatous Diseases

The therapeutic pipeline for JAK inhibitors is expanding rapidly beyond atopic dermatitis and alopecia areata.

The Imminent Pipeline: Hidradenitis Suppurativa (HS)

We are likely to see up to two oral JAK inhibitors approved for HS within the next year or two. For a disease characterized by painful tunneling, scarring, and profound functional impairment, this will be a massive milestone for patient quality of life.

The Orphan & Granulomatous Diseases

Dr. DaSilva has successfully utilized off-label oral and topical JAK inhibitors to treat rare, interferon-gamma-driven conditions, including:

• Sarcoidosis
• Generalized Granuloma Annulare (GA)
• Necrobiosis Lipoidica (NLD)

The biological rationale stems from basic science: these conditions involve interferon-gamma, a class of inflammatory cytokines that is blocked by selective JAK-1 inhibitors. In many cases, treating the severe pruritus associated with these orphan diseases led to the secondary finding that the underlying granulomatous lesions also cleared completely.

Is Intralesional JAK Delivery Next?

While oral and topical JAKs are widely used, localized skin diseases could benefit immensely from intralesional delivery. Because current formulations do not suspend easily for injection, it hasn't been clinically viable. However, Dr. DaSilva highlighted ongoing MD/PhD research at the University of Pennsylvania (such as Dr. Leo Wang's work on alopecia) that is making significant progress toward the development of intralesional JAK inhibitors. This development would be an absolute game-changer for localized dermatologic therapy.

Listen to the entire podcast on Apple Podcasts or Spotify