The present case is of a 79-year-old woman with metastatic cholangiocarcinoma who developed painful, reticulated lower extremity ulcers shortly after initiating pemigatinib therapy. Clinical, laboratory, and imaging findings supported the diagnosis of iatrogenic calciphylaxis, a rare but potentially life-threatening adverse effect of fibroblast growth factor receptor (FGFR) inhibitors. Prompt recognition and discontinuation of pemigatinib along with initiation of intravenous sodium thiosulfate and supportive wound care led to significant clinical improvement and normalization of phosphate levels. Given the increasing use of FGFR inhibitors and the rarity of this cutaneous complication, we believe this case is educational and timely.
Background : Atopic hand and foot dermatitis (AHFD) is a common, recalcitrant, and debilitating manifestation of atopic dermatitis (AD) driven by type 2 inflammation, including overexpression of interleukin-13, with pruritus and pain as primary symptoms. Despite substantial impact on quality of life (QoL) and work productivity, systemic treatment options for AHFD remain limited. Objectives : To evaluate efficacy and safety of lebrikizumab, a selective interleukin-13-inhibitor, as monotherapy in adults and adolescents with moderate-to-severe AHFD. Methods: ADtouch (NCT06921759) was a multi-center, randomized, double-blind, placebo-controlled, parallel-group phase 3b trial evaluating lebrikizumab versus placebo in adults (≥18 years) and adolescents (≥12 to <18 years, ≥40kg total body weight) with moderate-to-severe AHFD. Eligible patients had AHFD ≥1 year in at least 2 of 4 anatomical areas (left hand/right hand/left foot/right foot) at screening and baseline; a documented history of AD not limited to hands and feet; a Hand Foot Investigator’s Global Assessment (HF-IGA) score of moderate (3) or severe (4) at screening and baseline; a HF-Peak Pruritus Numeric Rating Scale (NRS) score ≥4; and inadequate response to topical therapies. Patients were randomized 1:1 to subcutaneous lebrikizumab (500mg loading doses at baseline and week 2, then 250mg every 2 weeks to week 16) or placebo. The primary endpoint was HF-IGA 0/1 with ≥2-point improvement from baseline at week 16. Secondary endpoints evaluated safety, pruritus, pain, disease activity, QoL, and Atopic Hand Dermatitis Clearance Satisfaction (AHDCS), a novel single-item patient-reported scale. Results reflect the primary outcome database lock, which included all data through Week 16. Results: Participants (N=221) were randomized to lebrikizumab (n=110) or placebo (n=111). Baseline disease characteristics were comparable between groups, including HF-IGA (severe: 27.3% vs 27.9%), HF-Peak Pruritus NRS (mean: 7.2 in each arm) and HF-Peak Pain NRS (mean: 6.2 in each arm). All primary and key secondary endpoints achieved statistical significance. More participants in the lebrikizumab group achieved HF-IGA 0/1 with ≥2-point improvement vs placebo at week 16 (53.3% vs. 27.2%; p<0.001). A higher proportion of lebrikizumab vs placebo-treated participants achieved HF-IGA 0/1 with ≥2-point improvement at week 2 (7.8% vs 0.9%; nominal p<0.05) and week 4 (16.9% vs 5.6%; p=0.008). At weeks 2, 4, and 16, HF-Peak Pruritus NRS ≥4-point improvements were higher with lebrikizumab (15.8%; 27.3%; 57.1%) than with placebo (0.9%; 7.9%; 19.0%; all p<0.001). HF-Peak Pain NRS ≥4-point improvements were higher for lebrikizumab vs placebo at week 16 (59.1% vs 18.8%; p<0.001). Among participants who were not satisfied at baseline on AHDCS, more lebrikizumab than placebo-treated participants were "satisfied" or "very satisfied" with hand dermatitis clearance at week 16 (76.7% vs 39.6%; p<0.001). Treatment-emergent adverse events (TEAEs) were reported in 41.8% of patients receiving lebrikizumab and 39.6% of patients receiving placebo; no severe TEAEs and no serious AEs were reported, and treatment discontinuations due to AEs were infrequent in lebrikizumab (0.9%) and placebo groups (2.7%). Conclusion: Lebrikizumab monotherapy achieved clinically meaningful and statistically significant improvements over placebo in atopic hand and foot dermatitis skin clearance, pruritus, pain, and patient satisfaction. Safety findings were consistent with the established lebrikizumab profile.
Introduction & Objectives While phase 3 studies established the safety and efficacy of upadacitinib (UPA), an oral JAK inhibitor, for treatment of atopic dermatitis (AD) in adults and adolescents,1-3 it is important to evaluate its safety, efficacy, and optimal dosing in the younger pediatric population. START UP is an ongoing open-label, efficacy-assessor-blinded, phase 3 study comparing UPA to dupilumab in children from 2 to < 12 years of age for the treatment of moderate to severe AD. Materials & Methods START UP (NCT06461897) is comprised of a 35-day screening period, an open-label treatment period (week 0 to 160; assessor-blinded up to week 16) and a follow-up period. Eligible patients are 2 to < 12 years of age with moderate to severe AD. In one cohort, patients with inadequate response (IR) to systemic therapy or intolerance of topical corticosteroids and/or topical calcineurin inhibitors or dupilumab-exposed patients without IR will be randomized 3:1:1 to receive an adult equivalent weight-based dose of UPA 15mg, an adult equivalent weight-based dose of UPA 7.5mg, or a label-indicated dose of dupilumab. In the second cohort, patients with IR or intolerance of dupilumab (dupilumab-IR) or for whom dupilumab is medically inadvisable will be treated with an adult equivalent weight-based dose of UPA 15mg. UPA will be administered as an oral solution twice a day (BID) or, for patients ≥ 30kg, as an oral tablet once daily (QD). Patients will be followed for 30 days after the last dose of UPA and for 12 weeks after the last dose of dupilumab. In countries other than the USA, the primary efficacy objective is to assess the proportion of patients achieving ≥75% improvement in Eczema Area and Severity Index (EASI-75) at week 16 in patients treated with UPA 15mg compared with those treated with dupilumab. In the USA and China, the primary, descriptive efficacy objective is to assess the proportion of patients achieving validated Investigator Global Assessment scale for Atopic Dermatitis (vIGA-AD) 0 or 1 with a reduction from baseline of ≥ 2 points at week 16 in each treatment group, with dupilumab as the reference arm for UPA 15mg. From Week 20 to Week 40, patients not achieving EASI-75 will be eligible for dose escalation: those on UPA 7.5 mg may increase to UPA 15 mg, with further escalation to UPA 30 mg if EASI-75 is still not achieved; patients on UPA 15 mg may escalate directly to UPA 30 mg. At week 52, a dose reduction will be mandatory for patients who achieve EASI-90 with UPA 15mg or UPA 30mg. No dose changes will be permitted with dupilumab. Safety will be assessed throughout the study. Results Recruitment and follow-up for the START-UP study are ongoing. Conclusion The ongoing START UP study will compare the efficacy and safety of UPA to dupilumab in children aged 2 to < 12 years with moderate to severe AD, evaluate UPA in dupilumab-IR or dupilumab medically inadvisable patients, and assess dose optimization.
Introduction: In the maintenance periods of ADvocate1 and ADvocate2, efficacy was consistent between the every 2 weeks and every 4 weeks (Q4W) maintenance dosing regimens, and a high proportion of Week 16 responders in the lebrikizumab withdrawal arm exhibited durable efficacy, suggesting less frequent dosing could maintain effectiveness in atopic dermatitis (AD). An extension to the ADjoin long-term study (ADjoin extension) subsequently evaluated the Q8W interval as a maintenance regimen. In the overall ADjoin extension population, Q8W has been reported to provide clinical responses consistent with Q4W dosing. As approximately 10% of adolescents have AD, this analysis describes whether adolescents in the ADjoin extension had a durable response over 32 weeks of Q4W or Q8W dosing. Methods: ADjoin extension was a 32-week study that enrolled patients with AD who had completed the 100-week long-term ADjoin study (NCT04392154) after participation in the parent studies. Key eligibility criteria included being adults or adolescents (≥12–<18 years at parent study baseline; weight ≥40 kg) and moderate-to-severe AD for ≥1 year at parent study entry. At ADjoin extension baseline, patients were re-randomized to receive open label lebrikizumab 250 mg Q4W or Q8W. The two primary endpoints were percentages of patients achieving ≥75% improvement (from parent study baseline) in Eczema Area and Severity Index (EASI 75) and Investigator’s Global Assessment score of 0/1 (IGA 0,1) at Week 32. Proportion of patients requiring concomitant treatment for AD was also reported. In this post-hoc analysis, a combined non-responder imputation and multiple imputation method was used for intercurrent events and missing data. Efficacy outcomes were summarized descriptively within each maintenance regimen. Results: Overall, 40 adolescent patients (Q4W, N=22; Q8W, N=18) enrolled in the 32-week extension. At extension baseline, 86.4% and 83.3% of Q4W and Q8W patients had an EASI 75 and 68.2% and 66.7% had an IGA (0,1), respectively. In both arms, mean response rates remained high through extension Week 32: percentages of patients (95% confidence interval) who met an EASI 75 were 81.8% (65.7%-97.9%) and 70.9% (49.4%-92.4%) in the Q4W and Q8W groups, respectively; 68.2% (48.7%-87.6%) and 63.1% (40.2%-86.0%) met an IGA (0,1). Six (27.3%) Q4W and seven (38.9%) Q8W patients required concomitant AD treatment. Conclusions: Lebrikizumab dosed every 4 or 8 weeks as maintenance provides durable response in adolescent patients with moderate to severe AD. The availability of Q4W and Q8W maintenance regimens for lebrikizumab provide clinicians with greater flexibility to individualize treatment for adolescents
