Christopher G. Bunick, MD, PhD, is an associate professor of dermatology at Yale University School of Medicine.

Christopher G. Bunick, MD, PhD

Boxed warnings drawn from a rheumatoid arthritis trial still shape Janus kinase (JAK) inhibitor prescribing in 

, even as long-term dermatology data show few new safety signals.

In this episode of ABCs in Dermatology, hosts Lindsay Ackerman, MD, and Chris Bunick, MD, PhD, examined how far ORAL Surveillance findings extend to JAK inhibition in atopic dermatitis.

On this episode of ABCs in Dermatology, Lindsay Ackerman, MD, and Chris Bunick, MD, PhD, talk through the safety conversation surrounding Janus kinase inhibitors and how dermatologists approach it with patients in day-to-day practice.

ABCs in Dermatology: Rethinking JAK Inhibitor Safety in Atopic Dermatitis

ORAL Surveillance randomized patients with rheumatoid arthritis aged 50 years or older with at least 1 cardiovascular risk factor to tofacitinib (Xeljanz) or a tumor necrosis factor inhibitor.

 Tofacitinib missed noninferiority for major adverse cardiovascular events (MACE; HR, 1.33; 95% CI, 0.91-1.94) and cancer (HR, 1.48; 95% CI, 1.04-2.09).

 The open-label design lacked a placebo arm, and post hoc analyses tied risk to age 65 years or older, smoking, and baseline cardiovascular burden.

Tofacitinib inhibits all 4 JAK family enzymes, whereas upadacitinib (Rinvoq) and abrocitinib (Cibinqo) selectively target JAK1, which carries IL-4 and IL-13 signaling. Concomitant methotrexate and systemic corticosteroid use in ORAL Surveillance further separates its population from typical atopic dermatitis patients.

Across 6 years of phase 3 data, adjudicated MACE rates with upadacitinib were 0.2 and less than 0.1 per 100 patient-years at 15 mg and 30 mg, respectively.

 Venous thromboembolism occurred at 0.1 per 100 patient-years with both doses, and malignancy excluding nonmelanoma skin cancer at 0.3 and 0.5.

 Herpes zoster, hepatic disorders, neutropenia, and creatine phosphokinase elevation proved dose-dependent.

In the phase 3b TRuE-AD4 trial, 241 adults with moderate disease on 10% to 20% of body surface area, after topical corticosteroid and calcineurin inhibitor failure, applied ruxolitinib cream (Opzelura) 1.5% or vehicle twice daily. At week 8, Investigator's Global Assessment success reached 61.3% vs 13.6%, with no serious treatment-related adverse events.

Plasma ruxolitinib concentrations stayed well below levels associated with JAK-mediated myelosuppression and declined between weeks 2 and 8, consistent with barrier recovery limiting absorption. Herpes zoster remains the most consistent oral JAK signal, likely reflecting interferon gamma inhibition, and recombinant zoster vaccination offers a modifiable safeguard.

Risk rises with age, so screening for clotting, cancer, cardiovascular disease, and broader clinical context helps individualize decisions. Prior thrombosis managed with anticoagulation need not exclude a patient. Retrospective database analyses warrant methodological scrutiny before shaping practice.

Collectively, the evidence suggests JAK inhibitor risk in atopic dermatitis tracks more closely with patient age and comorbidity than with drug class. Continued long-term surveillance will show whether class-wide labeling fits dermatology.

Relevant disclosures for Bunick include AbbVie, South Beach Symposium, Almirall, Apogee Therapeutics, Arcutis Biotherapeutics, Daiichi Sankyo, Eli Lilly, LEO Pharma, US, Novan, Novartis, Ortho Dermatologics, Palvella Therapeutics, Pfizer Inc., Sanofi, Sun Pharmaceutical Industries Ltd., Timber Pharmaceuticals, and UCB. Relevant disclosures for Ackerman include AbbVie, Alumis, Amgen, Arcutis, Beiersdorf, Boehringer Ingelheim, Bristol Myers Squibb, Dermavant, Galderma, L'Oréal, Novartis, Sun Pharmaceutical, and UCB.

Ytterberg SR, Bhatt DL, Mikuls TR, et al. Cardiovascular and cancer risk with tofacitinib in rheumatoid arthritis. 

Szekanecz Z, Buch MH, Charles-Schoeman C, et al. Efficacy and safety of JAK inhibitors in rheumatoid arthritis: update for the practising clinician. 

Bunick CG, Irvine AD, Silverberg JI, et al. Safety of upadacitinib in atopic dermatitis in randomized clinical trials across 6 years. 

Carrascosa JM, Prajapati VH, Hong HC, et al. Ruxolitinib cream in adults with moderate atopic dermatitis after failure of other topicals: a randomized trial. 

Podcasts

Lindsay Ackerman, MD, and Chris Bunick, MD, PhD, examine how ORAL Surveillance shaped JAK warnings and what long-term atopic dermatitis data show.

 care, and phosphodiesterase 4 (PDE4) inhibitors now offer a once-daily option capable of reaching optimal targets for skin and itch.

In this episode of ABCs in Dermatology, hosts Lindsay Ackerman, MD, and Chris Bunick, MD, PhD, examined where topical PDE4 inhibitors fit and how to measure meaningful response.

On this episode of ABCs in Dermatology, Lindsay Ackerman, MD, and Chris Bunick, MD, PhD, talk through the growing role of nonsteroidal topical therapy in eczema care and how they set treatment goals with patients.

ABCs in Dermatology: Understanding PDE4 Inhibition in Atopic Dermatitis

PDE4 hydrolyzes cyclic adenosine monophosphate (cAMP), a second messenger driving anti-inflammatory programming. Because inhibition acts upstream of the Janus kinase (JAK)-STAT pathway, it dampens Th1, Th2, Th17, and Th22 signaling. Roflumilast (Zoryve) more closely mimics cAMP than crisaborole (Eucrisa) or apremilast (Otezla), with roughly 25-fold to more than 300-fold greater in vitro potency.

In the phase 3 INTEGUMENT-1 and INTEGUMENT-2 trials, 1337 patients aged 6 years or older applied roflumilast cream 0.15% or vehicle once daily for 4 weeks.

 Validated Investigator Global Assessment success reached 32.0% vs 15.2% and 28.9% vs 12.0%, respectively, with 75.8% entering with moderate disease.

 Itch improved within 24 hours of the first application.

Application-site pain occurred in 0.9% and 2.1% of roflumilast-treated patients, and none of 47 patients who previously stopped crisaborole for stinging or burning developed application-site adverse events.

 One hypothesis attributes part of crisaborole's irritation to its boron-containing structure. Nausea affected 2.0% or fewer of treated patients,

 and moderate to severe hepatic impairment remains the key contraindication.

In the INTEGUMENT open-label extension, patients reaching clear skin switched to twice-weekly proactive application and maintained clear or almost clear skin for a median of 281 days.

 The regimen mirrors proactive corticosteroid maintenance without cumulative steroid exposure, useful on the face, eyelids, and skin folds. In children aged 2 to 5 years, roflumilast cream 0.05% likewise improved pruritus within 24 hours.

Unlike ruxolitinib cream (Opzelura), limited to short-term use on 20% or less of body surface area, roflumilast carries no duration or surface area cap. Clinicians increasingly pair it off label with biologics or oral JAK inhibitors for residual disease, often persistent itch.

Treat-to-target goals now define minimal disease activity as clear or almost clear skin plus an itch score of 0 or 1 on a 0-to-10 scale. Reduction of 4 or more points on the Worst Itch Numeric Rating Scale marks a moderate target, signaling response while deeper improvement accrues.

Collectively, once-daily topical PDE4 inhibition positions nonsteroidal therapy as a credible route to minimal disease activity in atopic dermatitis. The data reinforce corticosteroid stewardship for long-term and sensitive-site use.

Simpson EL, Eichenfield LF, Alonso-Llamazares J, et al. Roflumilast cream, 0.15%, for atopic dermatitis in adults and children: INTEGUMENT-1 and INTEGUMENT-2 randomized clinical trials. 

Simpson EL, Eichenfield LF, Papp KA, et al. Long-term safety and efficacy with roflumilast cream 0.15% in patients aged ≥6 years with atopic dermatitis: a phase 3 open-label extension trial. 

Eichenfield LF, Serrao R, Prajapati VH, et al. Efficacy and safety of once-daily roflumilast cream 0.05% in pediatric patients aged 2-5 years with mild-to-moderate atopic dermatitis (INTEGUMENT-PED): a phase 3 randomized controlled trial. 

Lindsay Ackerman, MD, and Chris Bunick, MD, PhD, discuss where topical PDE4 inhibitors fit in atopic dermatitis and how to measure skin and itch response.

ABCs in Dermatology: Topical PDE4 Inhibition in Atopic Dermatitis

Risankizumab (Skyrizi, AbbVie) maintained clear or almost clear skin in roughly 8 in 10 patients with genital 

 (PsO) and about 3 in 4 with scalp psoriasis through 52 weeks, with no new safety signals, according to Christopher G. Bunick, MD, PhD, associate professor of dermatology and of translational biomedicine at Yale School of Medicine. Bunick discussed the week-52 results of the phase 4 UnlIMMited trial (NCT05969223), which have not yet been peer-reviewed and were first presented at the EADV Symposium in Athens, Greece, May 7–9, 2026, in an interview with HCPLive at the 

2026 European Academy of Dermatology and Venereology (EADV) Congress

 in Vienna, Austria, held September 30-October 3.¹

Advances in Treating High-Impact Psoriasis from EADV 2026

UnlIMMited comprises 2 studies, Study-G in genital PsO and Study-S in scalp PsO. Patients were randomized 1:1 to risankizumab 150 mg or placebo at weeks 0 and 4, then all entered an open-label extension at week 16, receiving risankizumab 150 mg every 12 weeks through week 52.¹ At week 16, 69.1% of patients with genital PsO on risankizumab achieved a static Physician's Global Assessment-Genital (sPGA-G) score of 0 or 1 versus 13.0% with placebo (

At week 52 in Study-G, 81.5% of patients continuing risankizumab and 75.5% of those who switched from placebo had sPGA-G 0/1.¹ Dermatology Life Quality Index scores of 0 or 1 were reached by 57.4% and 50.9%, respectively, and a clinically meaningful genital itch improvement (at least a 4-point numeric rating scale gain) by 80.5% and 55.6%.¹ Minimal or no interference with sexual activity (GenPs-SFQ item 2 score of 0 or 1) was reported by 77.4% and 84.4%.¹ 

"We don't talk about this in the office with our psoriasis patients, but it's affecting their life in a tremendous way," Bunick said of sexual health.

In Study-S, scalp Investigator Global Assessment 0/1 was reached by 72.5% of continuing patients and 79.2% of switch patients at week 52, with complete clearance on the PsO Scalp Severity Index in 64.7% and 66.7%.¹ A symptom score of 0 was reported by 35.3% and 50.0%, and mean reductions in the scalp symptom score were about 7.7 and 7.5 points.¹ 

"I don't read too much into that. The point is, it's about three fourths of the patients, regardless of whether you started at the beginning or at week 16," Bunick said of the switch arm's slightly higher response. 

Adverse-event profiles were similar across both studies, and Bunick said he is not overly concerned about infections or other events that would limit long-term use of a targeted IL-23 p19 biologic.

Bunick said that for small, high-impact areas, PsO Area and Severity Index scores are less informative than IGA scores paired with patient-reported outcomes. On sequencing, he noted that the oral IL-23 receptor peptide icotrokinra and p19-specific biologics all have scalp and genital data, including 1-year icotrokinra results. He said he favors a p19 biologic in his own clinic for adherence and cited a matching-adjusted indirect comparison suggesting risankizumab outperforms icotrokinra by about 10 to 20 percentage points on most outcomes, reserving the oral option for patients with focal disease or needle fear. "In the big scheme of things, the real winner is the patient that has scalp and genital psoriasis because they now have more than ever therapies that are effective and that can be used for their high-impact sites," he said. He named how to sequence therapy in biologic-experienced patients as the biggest remaining research gap, and pointed to next-generation tyrosine kinase 2 inhibitors such as zasocitinib as data to watch.

Relevant disclosures for Bunick include AbbVie, South Beach Symposium, Almirall, Apogee Therapeutics, Arcutis Biotherapeutics, Daiichi Sankyo, Eli Lilly, LEO Pharma, US, Novan, Novartis, Ortho Dermatologics, Palvella Therapeutics, Pfizer Inc., Sanofi, Sun Pharmaceutical Industries Ltd., Timber Pharmaceuticals, and UCB.

Safety and efficacy of risankizumab in genital and scalp psoriasis in the UnlIMMited phase 4 randomized clinical trial at week 52. Presented at: European Academy of Dermatology and Venereology (EADV) Symposium; May 7-9, 2026; Athens, Greece.

Song EJ, Ehst B, Glick B, et al. Efficacy and safety of risankizumab in genital or scalp psoriasis in the UnlIMMited phase 4 randomized clinical trial at week 16. 

. 2026;16(1):293-307. doi:10.1007/s13555-025-01544-6

Videos

Chris Bunick, MD, PhD, discusses 52-week UnlIMMited data showing risankizumab sustained clearance, itch relief, and quality-of-life gains.

 (CSU) is estimated to affect up to 20% of people at some point in their lifetime, and its updated international management guidance now reflects a therapeutic landscape far broader than the omalizumab-only paradigm dermatologists have relied on for over a decade.

The hosts of ABCs in Dermatology, Lindsay Ackerman, MD, and Chris Bunick, MD, break down what's new in managing chronic hives, covering how dermatologists are approaching therapy selection today.

ABCs in Dermatology: 2026 CSU Guidelines Redefine Urticaria Treatment

, hosts Lindsay Ackerman, MD, and Chris Bunick, MD, PhD, discussed the 2025-2026 update to the international urticaria guidelines, developed with input from more than 200 experts across nearly 60 countries and over 100 dermatology and allergy/immunology societies.

The guidelines reaffirm that more than half of CSU patients have an identifiable autoimmune mechanism, divided into type 1 (auto-allergic, driven by IgE autoantibodies to self-antigens) and type 2b (autoimmune, driven by IgG antibodies that activate mast cells). Low total IgE paired with elevated IgG antibodies to thyroid peroxidase is not a validated biomarker but may signal a type 2b phenotype and predict a blunted response to omalizumab.

The guidelines now recommend baseline complete blood count, C-reactive protein or erythrocyte sedimentation rate, total IgE, and IgG anti-thyroid peroxidase testing in specialized care settings to help guide agent selection, while explicitly discouraging extensive workup in acute urticaria.

The most consequential change is structural. Where omalizumab previously stood alone as the add-on option beyond antihistamines, the guidelines now position remibrutinib and dupilumab alongside it as advanced systemic therapies for antihistamine-refractory disease, with second-generation H1 antihistamines titrated up to fourfold dosing remaining first line.

Remibrutinib, an oral Bruton tyrosine kinase (BTK) inhibitor dosed at 25 mg twice daily, and dupilumab, an IL-4 receptor alpha antagonist that reduces IL-4 and IL-13 signaling, each received conditional recommendations based on phase 3 data. In the REMIX-1 and REMIX-2 trials, remibrutinib produced significantly greater Urticaria Activity Score over 7 days (UAS7) reductions than placebo by week 12, sustained through week 24, with a favorable safety profile aside from a modest increase in petechiae.

In the LIBERTY-CSU CUPID trials, dupilumab improved UAS7 regardless of prior omalizumab exposure or response.

Bunick noted that cross-trial comparison of UAS7 curves suggested remibrutinib reaches a 15-point improvement in roughly 2 weeks, compared with approximately 10 weeks for dupilumab, consistent with BTK inhibition's more upstream mechanism in mast cells and B cells.

The guidelines also formalize outcome measures for practice, primarily UAS7, which separates skin (wheal) and itch subscores on a 0-to-42 scale, alongside the urticaria control test and disease-specific quality-of-life instruments. For patients with angioedema-predominant disease, the panel recommends checking complement C4 and C1 inhibitor levels to rule out hereditary or acquired angioedema.

Collectively, the update signals a shift from a single-agent bottleneck to individualized, mechanism-informed selection among 3 systemic options, a change both hosts characterized as likely to expand who can manage CSU beyond allergy and immunology and into broader dermatology practice.

Zuberbier T, Ansari ZA, Abdul Latiff AH, et al. The International Guideline for the Definition, Classification, Diagnosis and Management of Urticaria. Allergy. 2026;81(8):2582-2632. doi:

Maurer M, Casale TB, Saini SS, et al. Dupilumab in patients with chronic spontaneous urticaria (LIBERTY-CSU CUPID): Two randomized, double-blind, placebo-controlled, phase 3 trials. J Allergy Clin Immunol. 2024;154(1):184-194. doi:

https://doi.org/10.1016/j.jaci.2024.01.028

Metz M, Giménez-Arnau A, Hide M, et al. Remibrutinib in Chronic Spontaneous Urticaria. N Engl J Med. 2025;392(10):984-994. doi:

Giménez-Arnau AM, Szalewski R, Hide M, et al. Remibrutinib in chronic spontaneous urticaria: 52-week results from two phase 3 studies. J Allergy Clin Immunol. 2025;157(1):143-154. doi:

https://doi.org/10.1016/j.jaci.2025.09.028

Chronic spontaneous urticaria treatment now spans 3 systemic options after a major international guideline update.

Christopher G. Bunick, MD, PhD

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