Endotypes Still Don't Pick the Drug: What Guides Inflammatory Skin Care

Upadacitinib 30 mg beat every other atopic dermatitis treatment on five of six patient-relevant outcomes — and caused 108 extra adverse events per 1000 patients. That trade-off, drawn from a network meta-analysis of 149 trials and 28,686 patients, captures the state of precision dermatology in 2025: we can rank drugs by mechanism, but no biomarker yet tells you which patient should get which one.

A new review across atopic dermatitis, psoriasis, and hidradenitis suppurativa asks whether molecular endotypes can guide prescribing. The short answer: not yet. Endotypes currently guide drug development far more than they guide the prescription pad.

Atopic dermatitis: rich biology, no biomarker strategy

The old extrinsic-versus-intrinsic split — extrinsic disease, marked by elevated IgE, accounts for roughly 80% of cases — now looks simplistic. Current classifications span Th1, Th2, and Th17/Th22 immune endotypes, filaggrin mutations, age at onset, ethnicity, and Staphylococcus aureus colonization. The patterns shift. With age, cutaneous Th2/Th22 activity falls while Th1/Th17 rises. Asian patients show psoriasis-like features with greater Th17 polarization; African American patients show predominant Th2/Th22 activity. Children skew Th2-heavy with normal filaggrin expression, so adult data may not transfer.

Data-driven clustering deepens the picture. Serum biomarkers identify four adult and four pediatric clusters, with only one overlapping. A skin transcriptomic analysis found an IL-1 family subtype, including IL-36, tied to more severe disease and heavier S aureus colonization. Yet clinicians have no strategy for selecting treatment by phenotype or endotype, the review authors note. Prescribing still runs on severity.

Some signals exist. Thymus and activation-regulated chemokine correlates with clinical severity, and elevated IL-13 predicts response to dupilumab. But levels fluctuate, testing can be costly, and no one has proven endotypes stay stable over time.

Targeted trials have delivered mixed verdicts. Secukinumab and risankizumab failed in AD. Mepolizumab cut eosinophils without cutting severity. Nemolizumab relieved pruritus without moving clinical scores. Even dupilumab, a validated Th2 target, achieves EASI-75 in only 44%–65% of patients and EASI-90 in 30%–51%.

The meta-analysis, with searches updated through November 2022 covering 75 interventions, ranked upadacitinib 15 mg (EASI difference −11.43) and dupilumab (−10.72) behind the 30 mg dose (−13.99). Dupilumab, lebrikizumab, and tralokinumab offered intermediate efficacy with favorable safety — dupilumab showed no adverse-event difference from placebo.

Two class-wide signals matter. Conjunctivitis rates run similar across all three IL-13-targeting agents (ORs 2.88, 2.58, and 2.46), pointing to IL-13 blockade as the cause. High-dose JAK inhibitors raise cutaneous viral infections (OR 2.81 with abrocitinib 200 mg; 2.58 with upadacitinib 30 mg). Long-term JAK safety remains open, given the ORAL tofacitinib study's cardiovascular and cancer signals in rheumatoid arthritis. The biologic-versus-JAK choice is, the authors say, a value-based decision: maximal symptom control or maximal certainty of safety.

Psoriasis: rankings exist, but patient preference decides

The Cochrane meta-analysis behind the adapted EuroGuiDerm guideline shows anti-IL-17 agents outperforming everything else on PASI 90. Top performers versus placebo: infliximab (RR 49.16), bimekizumab (RR 27.86), ixekizumab (RR 27.35), risankizumab (RR 26.16). Yet the guideline authors themselves concede they cannot differentiate recommendation levels on efficacy and safety — trials ran 8–24 weeks, some used non-EMA doses, and serious adverse events rested on few cases.

Safety separates classes. Bimekizumab caused candidiasis in 21.2% of patients versus 4.6% with secukinumab; Crohn's patients were excluded from phase 3, and chronic inflammatory bowel disease is a relative contraindication. Deucravacitinib, the selective TYK2 inhibitor, brings upper respiratory infections, herpes simplex, oral ulcers, folliculitis, acne, and possible creatine kinase elevation — with unknown long-term risk.

Newcomer icotrokinra, an oral peptide selectively binding the IL-23 receptor, outperformed both placebo and deucravacitinib in the phase 3 ICONIC-ADVANCE 1 and 2 trials (774 and 731 adults). Adverse events through week 16: 48% with icotrokinra 200 mg daily versus 57% with placebo; by week 24, 57% versus 65% with deucravacitinib. Caveats are real — data cover only 24 weeks of 3-year trials, no head-to-head against injectable biologics, and sponsor employees sat among the authors.

Hidradenitis suppurativa: comorbidities, not biomarkers

The 2025 European S2k guidelines strongly recommend adalimumab, secukinumab, or bimekizumab as first biologic after conventional systemic therapy fails. The guidelines split inflammatory from non-inflammatory disease — the latter routed to surgery by Hurley stage — but admit clinical predictors and biomarkers for choosing between drugs are lacking. Bimekizumab caused oral candidiasis in 10% and 13% of patients and new inflammatory bowel disease in under 1%, prompting a "may be considered" recommendation for IBD screening before initiation.

What does this change for prescribers?

Little, at the level of the individual patient — and that's the honest takeaway. Severity, comorbidity, safety, and patient preference still drive selection across all three diseases. Until longitudinal studies prove endotype stability and trials stratify by biomarker, pathway knowledge refines what's on the shelf, not who gets it.