Dermatologists are increasingly turning to advanced treatments for atopic dermatitis, but the lack of predictive biomarkers is forcing many patients into a trial-and-error cycle with costly therapies. This gap in precision medicine means that even as new therapies emerge, clinicians often lack the tools to determine which patients will respond best to specific drugs. The challenge is particularly acute in a disease as heterogeneous as atopic dermatitis, where underlying inflammatory pathways can vary significantly from one individual to another. While interleukin-4 (IL-4), IL-13, and IL-31 inhibitors, along with oral Janus kinase (JAK) inhibitors, offer targeted mechanisms of action, their selection is still largely based on observable characteristics rather than molecular profiling. This uncertainty prolongs the diagnostic journey for patients, many of whom endure persistent symptoms while handling high-cost treatments with no guarantee of success.
Biologic cycling leaves patients in limbo
In a recent discussion, dermatologist Angela Lamb described how clinicians select therapies based on patient phenotype, age restrictions, and whether symptoms are itch-dominant or cover large areas of the body. The decision-making process often begins with an assessment of disease severity. Age also plays a critical role, as some medications are approved only for adults, while others have pediatric indications with specific dosing requirements. However, these clinical parameters provide only indirect clues about the underlying immunologic drivers of a patient’s disease.
Lamb called this “biologic cycling,” a pattern driven by the absence of objective data to guide initial treatment. The process typically unfolds in stages: a patient begins with one biologic, often chosen based on insurance coverage or familiarity, and if the response is inadequate, the clinician switches to an alternative with a different mechanism of action. This sequential approach can lead to prolonged periods of uncontrolled inflammation, as each trial requires time to assess efficacy. The delays are compounded by the need to evaluate whether a treatment is working.
Patients may try multiple expensive drugs before finding one that works, if they find one at all. The financial burden of this process is substantial, with some biologics costing tens of thousands of dollars per year. Even with insurance coverage, patients often face high out-of-pocket expenses, including copays, deductibles, and prior authorization requirements that can delay access to medications. Beyond the direct costs, the indirect toll is equally significant. Children with uncontrolled atopic dermatitis frequently miss school due to flare-ups or doctor’s appointments, while adults may struggle with presenteeism—showing up to work but performing below their potential due to fatigue, pain, or distraction from symptoms. The psychological impact is also profound, as chronic itching and visible lesions can lead to anxiety, depression, and social withdrawal, further diminishing quality of life.
The consequences extend beyond individual suffering. The systemic costs add up—insurers cover drugs that may not be effective, while patients endure prolonged discomfort. From a healthcare economics perspective, the inefficiency of biologic cycling drives up overall spending without necessarily improving outcomes. Insurers may initially deny coverage for newer or more expensive therapies, only to approve them later after cheaper options have failed, resulting in higher cumulative costs. Additionally, patients who do not achieve stable disease control are more likely to require emergency department visits or hospitalizations for complications such as skin infections or eczema herpeticum, further straining healthcare resources. Some never achieve stable control of their condition, cycling through treatments indefinitely or discontinuing therapy altogether due to frustration or financial exhaustion.
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Atopic dermatitis affects roughly 20% of children and 10% of adults worldwide, though severity varies. The disease exists on a spectrum, with some patients experiencing mild, intermittent symptoms that respond well to topical therapies, while others suffer from severe, treatment-resistant inflammation. For those with moderate-to-severe cases, biologics and JAK inhibitors have become standard options, but the lack of precision tools means many patients spend years searching for the right fit. The heterogeneity of atopic dermatitis is a key obstacle—while some patients exhibit a Th2-dominant immune response driven by IL-4 and IL-13, others may have contributions from Th17, Th22, or other pathways. Without biomarkers to distinguish these subtypes, clinicians are left to make educated guesses, often relying on trial and error to identify the most effective therapy.
Head-to-head data shifts the conversation
The LEVEL UP study, a head-to-head trial comparing the JAK1 inhibitor upadacitinib to dupilumab, offered new clarity. The randomized, double-blind design enrolled patients with moderate-to-severe atopic dermatitis who had an inadequate response to topical therapies. The results demonstrated that upadacitinib, at both 15 mg and 30 mg doses, achieved statistically significant higher rates of skin clearance and itch reduction compared to dupilumab across key measures.
Lamb noted the data has already changed how she talks to payers, who often push back on newer, more expensive therapies. Prior to the LEVEL UP study, insurers frequently required patients to fail dupilumab before approving upadacitinib, citing its higher cost and lack of comparative data. The trial’s findings provided evidence that upadacitinib could deliver superior outcomes in certain patient populations, giving clinicians a stronger basis to advocate for its use earlier in the treatment algorithm. The data also helped reframe conversations about cost-effectiveness, as earlier use of a more effective therapy could potentially reduce long-term expenses by minimizing the need for additional treatments, hospitalizations, or emergency care.
Still, the study doesn’t solve the broader issue: without biomarkers, clinicians are still guessing at the best first-line treatment. While the LEVEL UP results provide valuable comparative data, they do not address the fundamental question of which patients are most likely to respond to JAK inhibition versus IL-4/IL-13 blockade. The trial’s population was broad, encompassing a range of disease severities and phenotypes, but it did not identify specific subgroups that derived greater benefit from one drug over the other. This limitation shows the need for predictive tools that can stratify patients based on their underlying inflammatory pathways. Until such biomarkers are validated and integrated into clinical practice, dermatologists will continue to rely on indirect indicators, such as prior treatment history or phenotypic characteristics, to guide therapy selection.
For now, the field is caught between rapid innovation and persistent gaps in understanding. New biologics and JAK inhibitors continue to enter the market, each targeting different components of the immune response. These agents expand the therapeutic arsenal but also complicate decision-making, as clinicians must weigh their unique mechanisms of action, safety profiles, and efficacy data. Meanwhile, topical JAK inhibitors offer alternatives for patients with localized disease or those who prefer non-systemic options. However, the proliferation of choices does not inherently solve the problem of biologic cycling—it merely increases the number of options patients may try before finding an effective match. The hope remains that future research will uncover reliable biomarkers, enabling a shift from reactive to predictive medicine.
