Chronic Itch in 2026: Targeting Th2, IL-31, BTK, and Beyond
Gil Yosipovitch, MD, delivered a comprehensive and mechanistic update on chronic itch during his Masterclasses in Dermatology session, “Itch Happens: New Insights, New Treatments,” reframing pruritus as a neuro-immune disorder involving the skin, peripheral nerves, spinal cord, and brain.
“Th2 immunity is a major driver of chronic pruritus,” Dr Yosipovitch emphasized. Cytokines, such as IL-4, IL-13, and IL-31, sensitize sensory nerves, contributing to neural amplification and central sensitization. Chronic itch becomes a “neural sensitization phenomenon,” perpetuated beyond the initial inflammatory trigger.
Biologics targeting type 2 inflammation demonstrate significant anti-pruritic effects. Dupilumab, approved for atopic dermatitis (AD), prurigo nodularis (PN), bullous pemphigoid, and chronic spontaneous urticaria (CSU), reduces itch severity across multiple indications. Lebrikizumab and tralokinumab (IL-13 inhibitors) show meaningful improvements in pruritus Numeric Rating Scale (NRS) scores in moderate-to-severe AD.
Nemolizumab, an anti–IL-31 receptor antibody, is emerging as a “pan-pruritic therapy targeting the final common neuronal pathway.” In PN, nemolizumab demonstrated rapid itch reduction by day 2, with ≥4-point pruritus NRS improvement in 41% at week 4 vs 7.7% with placebo in OLYMPIA-2. Long-term extension data through 100 weeks showed sustained benefit.
Oral JAK inhibitors provide rapid itch control by inhibiting downstream cytokine signaling. Upadacitinib and abrocitinib offer once-daily options for moderate-to-severe AD, while topical ruxolitinib and delgocitinib address localized inflammation-associated itch. In PN, povorcitinib demonstrated significant ≥4-point pruritus NRS responses at week 16 in phase 2 data.
Mast cell–directed therapy represents another frontier. Remibrutinib, a highly selective BTK inhibitor, showed rapid itch relief within 2 to 4 hours in CSU, with significant Worst Itch NRS reduction by say 1 in the REMIX 1 and 2 phase 3 trials. This positions BTK inhibition as a promising oral strategy for mast cell–mediated itch.
Neuromodulators retain an important role. Kappa opioid receptor (KOR) agonists such as difelikefalin are approved for chronic kidney disease-associated pruritus in hemodialysis patients. Off-label butorphanol nasal spray (KOR agonist, mu-opioid receptor antagonist) has demonstrated benefit in intractable itch conditions, including PN and cholestatic pruritus. Gabapentinoids and mirtazapine remain options for neuropathic or nocturnal itch.
Dr Yosipovitch concluded with practical selection pearls: infants with type 2 inflammation may favor dupilumab; monthly dosing preferences may steer toward lebrikizumab; itch-dominant PN may benefit from nemolizumab; rapid flare control may warrant JAK inhibitors; mast cell–driven CSU may respond to remibrutinib.
For more meeting coverage, visit the Masterclasses in Dermatology newsroom.
Reference
Yosipovitch G. Itch happens: new insights, new treatments. Presented at: Masterclasses in Dermatology; February 19–22, 2026; Sarasota, FL.
