Upadacitinib for refractory prurigo nodularis: a two-centre real-world cohort using step-up dosing

Technical Summary: Upadacitinib for Refractory Prurigo Nodularis

Problem Statement
Prurigo nodularis (PN) is a chronic inflammatory and neuroimmune skin disease characterized by intensely pruritic nodules and a persistent itch-scratch cycle, significantly impairing quality of life and sleep. While targeted biologic therapies (dupilumab and nemolizumab) have been established for moderate-to-severe PN, access remains limited in certain healthcare systems due to reimbursement constraints. Although Janus kinase (JAK) inhibitors have shown promise in PN, real-world data regarding their effectiveness and safety, particularly in biologic-naïve patients without atopic dermatitis, remain limited. Furthermore, existing literature often relies on small, uncontrolled studies with heterogeneous outcomes and limited long-term safety data.

Methodology
This study presents a retrospective, two-centre real-world cohort analysis conducted between January 2024 and December 2025 at dermatology outpatient clinics in Istanbul, Turkey.

• Population: The study included 20 adults (mean age 54.1 years; 85% female) with moderate-to-severe PN (defined as ≥20 nodules). All patients were biologic-naïve, had no history of atopic dermatitis, and had demonstrated an inadequate response to at least one conventional treatment (e.g., corticosteroids, phototherapy, pregabalin).
• Intervention: Patients were treated off-label with oral upadacitinib, a selective JAK1 inhibitor. A response-guided "step-up" dosing strategy was employed:
  • All patients initiated therapy at 15 mg daily.
  • Dose escalation to 30 mg daily occurred only if the Worst Itch Numeric Rating Scale (WI-NRS) score had not decreased by ≥4 points after a minimum of 12 weeks on the 15 mg dose.
• Outcome Measures: Efficacy was assessed via changes in WI-NRS and Peak Pruritus Numerical Rating Scale (PP-NRS) from baseline to the last documented visit. A reduction of ≥4 points was considered a clinically meaningful response, and a score of 0 indicated complete itch resolution. Safety was monitored through adverse event reporting and laboratory abnormalities.
• Statistical Analysis: Continuous variables were compared using the Wilcoxon signed-rank test. Exploratory comparisons between patients remaining on 15 mg and those requiring escalation to 30 mg utilized the Mann-Whitney U test and Fisher's exact test. No multivariable models were fitted due to the small sample size.

Key Results

• Efficacy: Over a median treatment duration of 6.6 months (range 6–18 months), upadacitinib demonstrated marked efficacy.
  • Mean WI-NRS decreased significantly from 9.25 at baseline to 0.65 at the last visit (p < 0.001).
  • 100% of patients (20/20) achieved a clinically meaningful WI-NRS reduction of ≥4 points.
  • 70% of patients (14/20) achieved complete itch resolution (WI-NRS = 0).
  • Mean PP-NRS decreased from 9.05 to 0.95 (p < 0.001), with 95% of patients achieving a ≥4-point reduction and 50% achieving PP-NRS = 0.
• Dosing Strategy:
  • 55% of patients (11/20) maintained adequate control on the 15 mg dose.
  • 45% of patients (9/20) required escalation to 30 mg due to inadequate response at 12 weeks.
  • Notably, all patients who required escalation eventually met the ≥4-point response criterion by the final visit, with 7 of these 9 achieving itch-free status.
• Safety: The treatment was well-tolerated. Four patients (20%) experienced non-serious adverse events (three cases of acneiform eruption, two cases of gastrointestinal intolerance; one patient had both). No serious adverse events, herpes zoster, venous thromboembolism, or malignancies were recorded. No patients discontinued treatment due to adverse events.
• Exploratory Findings: Patients requiring dose escalation were significantly older (58.9 vs. 50.2 years; p=0.044) and more likely to have diabetes or cardiovascular disease (100% vs. 45%; p=0.014). They also presented with a higher baseline nodule burden (>100 nodules in 89% vs. 18%; p=0.005). Baseline itch intensity was similar between the two groups.

Significance and Claims
The authors claim that this study provides valuable real-world evidence supporting the use of upadacitinib for refractory PN in biologic-naïve patients without atopic dermatitis. Key contributions include:

1. Validation of Efficacy: The study confirms that JAK1 inhibition can provide substantial symptom control, with 70% of patients achieving complete itch resolution in a real-world setting.
2. Dosing Framework: The paper introduces and validates a practical, response-guided step-up dosing strategy (15 mg to 30 mg). This approach allowed 55% of patients to remain on the lower, potentially safer dose, while ensuring that non-responders were escalated to achieve therapeutic goals.
3. Alternative Therapy: In settings where approved biologic therapies are inaccessible or unreimbursed, upadacitinib may serve as a useful oral alternative.
4. Safety Context: Despite a cohort with high cardiometabolic comorbidity (55% diabetes, 30% cardiovascular disease), no serious adverse events were observed, though the authors caution that the sample size and follow-up duration are insufficient to establish long-term safety profiles.

Limitations
The authors explicitly acknowledge several limitations: the study is retrospective, uncontrolled, and small (n=20); outcomes were assessed at variable time points rather than fixed intervals; and the dose-escalation analysis was exploratory and underpowered for multivariable modeling. Consequently, the authors conclude that while the results are promising, larger controlled studies with standardized outcomes and longer safety follow-up are necessary.