Guselkumab, an interleukin-23 blocker, was superior to adalimumab in treating moderate to severe psoriasis in a phase II trial. We sought to compare efficacy and safety of guselkumab with adalimumab and placebo in patients with psoriasis treated for 1 year. Patients were randomized to guselkumab 100 mg (weeks 0 and 4, then every 8 weeks; n = 329); placebo→guselkumab (weeks 0, 4, and 12 then guselkumab at weeks 16 and 20, then every 8 weeks; n = 174); or adalimumab (80 mg week 0, 40 mg week 1, then 40 mg every 2 weeks through week 47; n = 334). Physician-reported outcomes (Investigator Global Assessment, Psoriasis Area and Severity Index [PASI]), patient-reported outcomes (Dermatology Life Quality Index, Psoriasis Symptoms and Signs Diary), and safety were evaluated through week 48. Guselkumab was superior (P < .001) to placebo at week 16 (85.1% vs 6.9% [Investigator Global Assessment score of 0/1 (cleared/minimal)] and 73.3% vs 2.9% [90% or greater improvement in PASI score from baseline (PASI 90)]). Guselkumab was also superior (P < .001) to adalimumab for Investigator Global Assessment 0/1 and PASI 90 at week 16 (85.1% vs 65.9% and 73.3% vs 49.7%), week 24 (84.2% vs 61.7% and 80.2% vs 53.0%), and week 48 (80.5% vs 55.4% and 76.3% vs 47.9%). Furthermore, guselkumab significantly improved patient-reported outcomes through week 48. Adverse event rates were comparable between treatments. Analyses were limited to 48 weeks. Guselkumab demonstrated superior efficacy compared with adalimumab and was well tolerated in patients with psoriasis through 1 year.

Psoriasis is a chronic, immune-mediated, inflammatory disease that is pathogenically driven by proinflammatory cytokines. This article reviews the immunologic role of interleukin (IL)-17, the major effector cytokine in the pathogenesis of psoriatic disease, along with the rationale for targeting the IL-17 cytokine family (IL-17A, IL-17F, and IL-17 receptor A) in the treatment of psoriasis and psoriatic arthritis. Emerging evidence indicates that major sources of IL-17A in patients with psoriatic disease are mast cells, γδ T cells, αβ T cells, and innate lymphoid cells in lesional skin and synovial fluid. Within the skin and joints, IL-17A acts on cellular targets, including keratinocytes, neutrophils, endothelial cells, fibroblasts, osteoclasts, chondrocytes, and osteoblasts, to stimulate production of various antimicrobial peptides, chemokines, and proinflammatory and proliferative cytokines, which, in turn, promote tissue inflammation and bone remodeling. The critical importance of the IL-23/IL-17A axis to the pathogenesis of psoriatic disease has resulted in many new biologic treatments targeting these cytokines. These biologics dramatically improve skin and joint symptoms in patients with moderate-to-severe psoriasis and psoriatic arthritis.

Background Tralokinumab, a fully human monoclonal antibody, specifically neutralizes interleukin‐13, a key cytokine driving peripheral inflammation in atopic dermatitis (AD). In phase II studies, tralokinumab combined with topical corticosteroids provided early and sustained improvements in AD signs and symptoms. Objectives To evaluate the efficacy and safety of tralokinumab monotherapy in adults with moderate‐to‐severe AD who had an inadequate response to topical treatments. Methods In two, 52‐week, randomized, double‐blind, placebo‐controlled, phase III trials, ECZTRA 1 and ECZTRA 2, adults with moderate‐to‐severe AD were randomized (3 : 1) to subcutaneous tralokinumab 300 mg every 2 weeks (Q2W), or placebo. Primary endpoints were IGA score of 0 or 1 at week 16 and EASI 75 at week 16. Patient achieving an IGA score of 0/1 and/or EASI 75 with tralokinumab at week 16 were rerandomized to tralokinumab Q2W or every 4 weeks or placebo, for 36 weeks. Results At week 16, more patients who received tralokinumab vs. placebo achieved an IGA score of 0/1: 15·8% vs. 7·1% in ECZTRA 1 [difference (95% CI) 8·6% (4·1–13·1); P = 0·002] and 22·2% vs. 10·9% in ECZTRA 2 [11·1% (5·8–16·4); P < 0·001] and EASI 75: 25·0% vs. 12·7% [12·1% (6·5–17·7); P < 0·001] and 33·2% vs. 11·4% [21·6% (15·8–27·3); P < 0·001]. Early improvements in pruritus, sleep interference, Dermatology Life Quality Index, SCORing Atopic Dermatitis and Patient‐Oriented Eczema Measure were observed from the first postbaseline measurements. The majority of week 16 tralokinumab‐responders maintained response at week 52 with continued tralokinumab treatment without any rescue medication (including topical corticosteroids). Adverse events were reported in 76·4% and 61·5% of patients receiving tralokinumab and in 77·0% and 66·0% of patients receiving placebo in the 16‐week initial period. Conclusions Tralokinumab monotherapy was superior to placebo at 16 weeks of treatment and was well tolerated up to 52 weeks of treatment.

Importance: Atopic dermatitis (AD) is a chronic, recurrent, inflammatory skin disease with an unmet need for treatments that provide rapid and high levels of skin clearance and itch improvement.Objective: To assess the safety and efficacy of upadacitinib vs dupilumab in adults with moderate-to-severe AD.Design, Setting, and Participants: Heads Up was a 24-week, head-to-head, phase 3b, multicenter, randomized, double-blinded, double-dummy, active-controlled clinical trial comparing the safety and efficacy of upadacitinib with dupilumab among 673 adults with moderate-to-severe AD who were candidates for systemic therapy. The study was conducted from February 21, 2019, to December 9, 2020, at 129 centers located in 22 countries across Europe, North and South America, Oceania, and the Asia-Pacific region. Efficacy analyses were conducted in the intent-to-treat population.Interventions: Patients were randomized 1:1 and treated with oral upadacitinib, 30 mg once daily, or subcutaneous dupilumab, 300 mg every other week.Main Outcomes and Measures: The primary end point was achievement of 75% improvement in the Eczema Area and Severity Index (EASI75) at week 16. Secondary end points were percentage change from baseline in the Worst Pruritus Numerical Rating Scale (NRS) (weekly average), proportion of patients achieving EASI100 and EASI90 at week 16, percentage change from baseline in Worst Pruritus NRS at week 4, proportion of patients achieving EASI75 at week 2, percentage change from baseline in Worst Pruritus NRS (weekly average) at week 1, and Worst Pruritus NRS (weekly average) improvement of 4 points or more at week 16. End points at week 24 included EASI75, EASI90, EASI100, and improvement of 4 points or more in Worst Pruritus NRS from baseline (weekly average). Safety was assessed as treatment-emergent adverse events in all patients receiving 1 or more dose of either drug.Results: Of 924 patients screened, 342 (183 men [53.5%]; mean [SD] age, 36.2 [14.4] years) were randomized to receive upadacitinib and 331 were randomized to receive dupilumab (192 men [58.0%]; mean [SD] age, 36.3 [13.8] years); demographic and disease characteristics were balanced among treatment groups. At week 16, 248 patients receiving upadacitinib (72.4%) and 207 patients receiving dupilumab (62.6%) achieved EASI75 (P = .007). All ranked secondary end points also demonstrated the superiority of upadacitinib vs dupilumab, including improvement in Worst Pruritus NRS as early as week 1 (mean [SE], 32.0% [1.8%] vs 8.9% [1.8%]; P < .001), achievement of EASI75 as early as week 2 (152 [44.3%] vs 60 [18.2%]; P < .001), and achievement of EASI100 at week 16 (97 [28.4%] vs 26 [7.9%]; P < .001). Rates of serious infection, eczema herpeticum, herpes zoster, and laboratory-related adverse events were higher for patients who received upadacitinib, whereas rates of conjunctivitis and injection-site reactions were higher for patients who received dupilumab.Conclusions and Relevance: During 16 weeks of treatment, upadacitinib demonstrated superior efficacy vs dupilumab in patients with moderate-to-severe AD, with no new safety signals.Trial Registration: ClinicalTrials.gov Identifier: NCT03738397

Background Dupilumab, which blocks the shared receptor component for interleukin (IL)‐4 and IL‐13, is approved for inadequately‐controlled moderate‐to‐severe atopic dermatitis (AD) and moderate‐to‐severe eosinophilic or oral corticosteroid‐dependent asthma. AD trials reported increased conjunctivitis incidence for dupilumab vs. placebo. Objectives To further characterise conjunctivitis occurrence and risk factors in dupilumab clinical trials. Methods We evaluated randomised placebo‐controlled trials of dupilumab in AD (n=2629), asthma (n=2876), chronic rhinosinusitis with nasal polyps (CRSwNP) (n=60), and eosinophilic esophagitis (EoE) (n=47). Results In most AD trials, dupilumab‐treated patients had higher conjunctivitis incidence than placebo controls. Higher baseline AD severity and previous conjunctivitis history were associated with increased conjunctivitis incidence. Conjunctivitis was mostly mild to moderate. Most cases recovered/resolved during the treatment period; 2 patients permanently discontinued dupilumab due to conjunctivitis/keratitis. Common treatments included ophthalmic corticosteroids, antibiotics, and anti‐histamines/mast cell stabilisers. Most cases were diagnosed by investigators. In asthma and CRSwNP trials, conjunctivitis incidence was lower for both dupilumab and placebo than in AD trials; dupilumab did not increase incidence vs. placebo. In the EoE trial, no patients had conjunctivitis. Conclusions Conjunctivitis was more frequent with dupilumab treatment in most AD trials. In dupilumab trials in other type 2 diseases, incidence of conjunctivitis was overall very low, and was similar for dupilumab and placebo. In AD, conjunctivitis incidence was associated with AD severity and prior history of conjunctivitis. The aetiology and treatment of conjunctivitis in dupilumab‐treated patients require further study.