Lindsay Ackerman, MD, FAAD, is a board-certified dermatologist in Phoenix, Arizona, and founder of Medical Dermatology Specialists, now part of US Dermatology Partners. She created 

, a multimedia educational nonprofit network built to educate how the skin reveals deeper truths of human health, and co-hosts HCPLive’s ABCs in Dermatology podcast. She is clinical faculty at the University of Arizona College of Medicine – Phoenix and has been an AAD delegate to the AMA since 2005.

Lindsay S. Ackerman, MD, FAAD

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

 (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.

 (EPP) remains among dermatology's most under-recognized diagnoses, often mistaken for solar urticaria or polymorphic light eruption for years before clinicians identify its hallmark feature: severe burning pain after sun exposure with little or no visible skin change.

, hosts Lindsay Ackerman, MD, and Christopher Bunick, MD, PhD, spoke with Angelika Erwin, MD, PhD, founder and director of the Porphyria Center at Cleveland Clinic, about diagnosing and managing EPP and its X-linked counterpart, XLP.

On this episode of ABCs in Dermatology, Angelika Erwin, MD, PhD, founder and director of the Porphyria Center at Cleveland Clinic, joins hosts Lindsay Ackerman, MD, and Christopher Bunick, MD, PhD, to discuss a rare, often-missed photosensitivity disorder and how care for it is evolving.

ABCs in Dermatology: Updates in Erythropoietic Protoporphyria Management for 2026

EPP results from ferrochelatase deficiency, causing free protoporphyrin IX to accumulate in red blood cells, plasma, and skin. Pain typically strikes within minutes of sun exposure, most often on the backs of the hands, and can precede any visible finding. Onset usually occurs between ages 1 and 4, and diagnosis is frequently delayed for years because symptoms resolve before a clinician examines the skin. About 5% of patients develop protoporphyric hepatopathy, which in rare cases progresses to fulminant liver failure requiring transplantation paired with bone marrow transplant, since liver transplant alone is not curative.

Erwin outlined a diagnostic pathway starting with plasma total porphyrins, available through standard commercial labs, followed by erythrocyte protoporphyrin testing at specialized centers such as Mayo Clinic or ARUP to distinguish EPP from XLP based on the ratio of free to zinc-bound protoporphyrin. Urine porphyrins remain normal in both conditions and should not be used for screening. Genetic testing targets the FECH gene in EPP, an autosomal recessive condition typically involving a common low-expression allele paired with a disease-causing mutation, and the ALAS2 gene on the X chromosome in XLP.

Before afamelanotide's 2019 approval, management relied on physical sun avoidance, zinc oxide and titanium dioxide sunscreens, and UV-filtering window films, with limited benefit from oral beta-carotene. Afamelanotide, a subcutaneous implant given every 60 days, increased pain-free sun exposure by a mean of 69 hours over 6 months versus placebo in the US phase 3 trial

, though it is not approved in pediatric patients. Bitopertin, an oral glycine transporter 1 inhibitor now in phase 3 testing, reduces porphyrin production upstream in the heme biosynthetic pathway and has shown promise in patients as young as 12 years in earlier trials

Erwin also pointed to earlier-stage candidates, including an ABCG2 inhibitor, ex vivo FECH gene replacement, mRNA-based delivery, and dersimelagon, an oral melanocortin receptor agonist in phase 3 testing. She emphasized that suspected EPP warrants erythrocyte protoporphyrin or plasma porphyrin testing rather than urine studies, and that confirmed cases require coordinated monitoring of liver function and vitamin D levels alongside referral to a specialized porphyria center.

Langendonk JG, Balwani M, Anderson KE, et al. Afamelanotide for erythropoietic protoporphyria. N Engl J Med. 2015;373(1):48-59. doi:

Yeung AK, Bonkovsky HL, Balwani M, et al. Bitopertin shows efficacy in patients with erythropoietic protoporphyria: results from the randomized, double-blind, placebo-controlled AURORA trial. J Am Acad Dermatol. 2025. doi:

Erythropoietic protoporphyria and X-linked protoporphyria present in early childhood with rapid-onset, severe phototoxic burning pain and minimal visible erythema, leading to frequent misdiagnosis and prolonged diagnostic delay. Pathobiology centers on excess protoporphyrin IX from ferrochelatase deficiency (EPP) or ALAS2 gain-of-function (XLP), with rare but serious protoporphyric hepatopathy. Diagnosis hinges on plasma porphyrins and specialized erythrocyte protoporphyrin fractionation, not urine testing. Management has shifted from strict photoprotection to melanocortin-based and heme-pathway–targeted therapies.

Angelika Erwin, MD, PhD, joins the podcast to discuss diagnosing and managing EPP and XLP on ABCs in Dermatology.

Lindsay S. Ackerman, MD, FAAD

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