Efficacy and safety of dupilumab up to 52 weeks in adults and adolescents with eosinophilic oesophagitis (LIBERTY EoE TREET study): a multicentre, double-blind, randomised, placebo-controlled, phase 3 trial.

BACKGROUND: Long-term management options that specifically target the underlying inflammation in eosinophilic oesophagitis are needed. Dupilumab blocks the shared receptor component for interleukin (IL)-4/IL-13; we aimed to assess its long-term efficacy and safety in adults and adolescents with eosinophilic oesophagitis enrolled in part B of the LIBERTY EoE TREET study who continued to part C (part B-C). METHODS: LIBERTY EoE TREET was a three-part, double-blind, randomised, placebo-controlled, phase 3 study conducted at 65 hospitals and private clinics across ten countries in Australia, Canada, Europe, and the USA. Adults or adolescents (aged ≥12 years) with a diagnosis of eosinophilic oesophagitis by endoscopic biopsy (peak oesophageal intraepithelial eosinophil count ≥15 eosinophils per high-power field [eos/hpf]) from at least one oesophageal region despite 8 weeks of high-dose proton-pump inhibitors (PPIs) and a Dysphagia Symptom Questionnaire (DSQ) score of at least 10 at baseline were eligible. In part B, patients were randomly (1:1:1) assigned to receive subcutaneous dupilumab 300 mg either weekly or every 2 weeks or weekly placebo until week 24. Randomisation was done centrally by interactive voice response system/web response system (IVRS/IWRS) in blocks and stratified according to age (<18 years vs ≥18 years) and use of PPI at randomisation (yes vs no). Patients, study sponsors, and investigators involved in the study were masked to the randomisation outcome. Eligible patients who received placebo in part B and continued to part C were randomly assigned again (1:1) to either weekly dupilumab (placebo/weekly dupilumab group) or dupilumab every 2 weeks (placebo/dupilumab every 2 weeks), with matching placebo alternating with dupilumab doses. Patients who were randomly assigned to one of the dupilumab dose regimens in part B remained on the same regimen in part C for an additional 28 weeks (weekly dupilumab/weekly dupilumab group or dupilumab every 2 weeks/dupilumab every 2 weeks group). Treatment assignment in part C was managed by IVRS/IWRS to maintain blinding of treatment assignment in part B. The primary endpoint of this trial has been reported; here, we report the week 52 outcomes of part B-C. Efficacy and safety analyses were done in the part C safety-analysis set, which included all patients who were randomised in part B, entered part C, and received any study drug in part C. This completed trial is registered with ClinicalTrials.gov, number NCT03633617. FINDINGS: Between Aug 12, 2019, and March 11, 2021, 240 patients were randomly assigned into part B, of whom 227 (74 in placebo group, 74 in weekly dupilumab group, and 79 in dupilumab every 2 weeks group) continued into part B-C and were included in the current analysis. 37 patients switched from placebo to weekly dupilumab, and 37 from placebo to dupilumab every 2 weeks; 74 patients continued on weekly dupilumab and 79 continued on dupilumab every 2 weeks. Of the patients who entered part B-C, 75 (33%) were adolescents, 145 (64%) male, 82 (36%) female, and 206 (91%) White. At week 52, 55 (85%) patients in the weekly dupilumab/weekly dupilumab group, 25 (68%) in the placebo/weekly dupilumab group, 54 (74%) in the every 2 weeks dupilumab/every 2 weeks dupilumab group, and 23 (72%) in the placebo/every 2 weeks dupilumab group achieved a peak oesophageal intraepithelial eosinophil count of 6 eos/hpf or less. Mean percent change from part B baseline in peak eosinophil count was -95·9% (95% CI -96·9 to -94·9) in the weekly dupilumab/weekly dupilumab group, -84·2% (-98·3 to -70·2) in the placebo/weekly dupilumab group, -84·8% (-94·3 to -75·2) in the every 2 weeks dupilumab/every 2 weeks dupilumab group, and -91·2% (-95·9 to -86·5) in the placebo/every 2 weeks dupilumab group at week 52. At week 52, mean change from part B baseline in eosinophilic oesophagitis Histology Scoring System (HSS) grade score was -1·0 point (95% CI -1·1 to -0·9) in the weekly dupilumab/weekly dupilumab group and -0·9 points (-1·0 to -0·8) in the placebo/weekly dupilumab group; mean change in eosinophilic oesophagitis HSS stage score was -0·9 points (-1·0 to -0·8) in the weekly dupilumab/weekly dupilumab group and -0·9 points (-1·0 to -0·8) in the placebo/weekly dupilumab group. Similar improvements were observed in the every 2 weeks dupilumab groups. Mean absolute change from part B baseline in DSQ score was -30·3 points (95% CI -34·5 to -26·1) in the weekly dupilumab/weekly dupilumab group, -27·3 points (-32·1 to -22·4) in the placebo/weekly dupilumab group, -20·9% (-25·4 to -16·3) in the every 2 weeks dupilumab/every 2 weeks dupilumab group, and -23·7% (-29·1 to -18·3) in the placebo/every 2 weeks dupilumab group at week 52. Mean change from part B baseline in endoscopic reference score was -5·4 points (95% CI -6·1 to -4·6) in the weekly dupilumab/weekly dupilumab group, -6·1 points (-7·3 to -4·9) in the placebo/weekly dupilumab group, -5·2% (-6·0 to -4·4) in the every 2 weeks dupilumab/every 2 weeks dupilumab group, and -4·3% (-5·4 to -3·1) in the placebo/every 2 weeks dupilumab group at week 52. During part B-C, one (3%) patient in the placebo/weekly dupilumab group, one (1%) in the weekly dupilumab/weekly dupilumab group, and one (3%) in the placebo/every 2 weeks dupilumab group received rescue medication. One (3%) patient in the placebo/every 2 weeks dupilumab group and one (1%) in the dupilumab every 2 weeks/dupilumab every 2 weeks group underwent a rescue oesophageal dilation procedure. The most common treatment-emergent adverse events were injection-site reactions (ten [14%] in the weekly dupilumab/weekly dupilumab group and four [11%] in the placebo/weekly dupilumab group). INTERPRETATION: Improvements in histological, symptomatic, endoscopic, and molecular features of eosinophilic oesophagitis observed after 24 weeks of weekly dupilumab treatment were maintained or continued to improve to week 52. These findings reinforce the importance of weekly dupilumab, rather than every 2 weeks, for the improvement of symptoms in adults and adolescents with eosinophilic oesophagitis. FUNDING: Sanofi and Regeneron Pharmaceuticals Inc.

Comparison of the Inflammatory Circuits in Psoriasis Vulgaris, Non‒Pustular Palmoplantar Psoriasis, and Palmoplantar Pustular Psoriasis.

Palmoplantar pustular psoriasis (PPPP) and non‒pustular palmoplantar psoriasis (NPPP) are localized, debilitating forms of psoriasis. The inflammatory circuits involved in PPPP and NPPP are not well-understood. To compare the cellular and immunological features that differentiate PPPP and NPPP, skin biopsies were collected from a total of 30 participants with PPPP, NPPP, and psoriasis vulgaris (PV) and from 10 healthy participants. A subset consented to a second biopsy after 3 additional weeks off medication. Histologic staining of lesional and nonlesional skin showed higher neutrophil counts in PPPP than in NPPP and PV and higher CD8+ T-cell counts in NPPP. RNA sequencing and transcriptional analysis of skin biopsies showed enhanced IFN-γ pathway activation in NPPP lesions but stronger signatures of IL-17 pathway and neutrophil-related genes (e.g., IL36A) in PPPP lesional skin. Serum analysis on the Olink platform detected higher concentrations of T helper type 1, IFN-γ‒inducible chemokines in NPPP, and higher neutrophil-associated cytokines in PPPP. Taken together, this evidence suggests more pronounced T helper 1‒mediated inflammation in NPPP than in PV and PPPP and stronger neutrophil-associated activity in PPPP than in NPPP and PV. These data support targeting inflammatory pathways associated with neutrophilic inflammation (e.g., IL-36 signaling) for therapeutic development in PPPP.

Type 2 Inflammation Contributes to Skin Barrier Dysfunction in Atopic Dermatitis.

Skin barrier dysfunction, a defining feature of atopic dermatitis (AD), arises from multiple interacting systems. In AD, skin inflammation is caused by host-environment interactions involving keratinocytes as well as tissue-resident immune cells such as type 2 innate lymphoid cells, basophils, mast cells, and T helper type 2 cells, which produce type 2 cytokines, including IL-4, IL-5, IL-13, and IL-31. Type 2 inflammation broadly impacts the expression of genes relevant for barrier function, such as intracellular structural proteins, extracellular lipids, and junctional proteins, and enhances Staphylococcus aureus skin colonization. Systemic anti‒type 2 inflammation therapies may improve dysfunctional skin barrier in AD.

Dupilumab suppresses type 2 inflammatory biomarkers across multiple atopic, allergic diseases.

BACKGROUND: Type 2 inflammation is common in numerous atopic/allergic diseases and can be identified by elevated biomarker levels. Dupilumab, a fully human monoclonal antibody, blocks the shared receptor component for interleukin-4 and interleukin-13, key and central drivers of type 2 inflammation. OBJECTIVE: Assessment of dupilumab effect on type 2 inflammatory biomarkers in atopic dermatitis (AD), asthma, chronic rhinosinusitis with nasal polyps (CRSwNP) and eosinophilic esophagitis (EoE). METHODS: Data were extracted from three randomized placebo-controlled trials of dupilumab in AD (NCT02277743, N = 671; NCT02277769, N = 708; NCT02260986, N = 740); and one each in asthma (NCT02414854, N = 1902); CRSwNP (NCT02898454, N = 448); and EoE (NCT02379052, N = 47). Biomarkers assessed were serum thymus and activation-regulated chemokine (TARC), plasma eotaxin-3, serum total immunoglobulin E (IgE), serum periostin and blood eosinophil count. RESULTS: Dupilumab versus placebo significantly suppressed most type 2 inflammatory biomarker levels across all studies/indications where data were assessed. Reductions in serum TARC, plasma eotaxin-3 and serum periostin occurred rapidly, whereas reductions in serum total IgE were more gradual. Across diseases, at the end of treatment, median percentage change from baseline in TARC levels ranged from -24.8% to -88.6% (placebo +2.6% to -53.6%); -38.2% to -51.5% (placebo +8.3% to -0.16%) in eotaxin-3; -24.8% to -76.7% (placebo +8.3% to -4.4%) in total IgE; and -13.6% to -41.1% (placebo +10.1% to -6.94%) in periostin levels. Blood eosinophil responses to dupilumab varied by disease, with minimal changes in AD in the SOLO studies (median percentage change from baseline to end of treatment: 0% [95% CI: -15.8, 0]); transient increases followed by decreases to below-baseline levels in asthma (-14.6% [-20.0, -7.7]) and CRSwNP (-29.4% [-40.0, -16.3]); and significant decreases in EoE (-50.0% [-50.0, -33.3]). CONCLUSION AND CLINICAL RELEVANCE: Dupilumab reduced levels of type 2 biomarkers across clinical studies in patients with AD, asthma, CRSwNP and EoE.

A basophil-neuronal axis promotes itch.

Itch is an evolutionarily conserved sensation that facilitates expulsion of pathogens and noxious stimuli from the skin. However, in organ failure, cancer, and chronic inflammatory disorders such as atopic dermatitis (AD), itch becomes chronic, intractable, and debilitating. In addition to chronic itch, patients often experience intense acute itch exacerbations. Recent discoveries have unearthed the neuroimmune circuitry of itch, leading to the development of anti-itch treatments. However, mechanisms underlying acute itch exacerbations remain overlooked. Herein, we identify that a large proportion of patients with AD harbor allergen-specific immunoglobulin E (IgE) and exhibit a propensity for acute itch flares. In mice, while allergen-provoked acute itch is mediated by the mast cell-histamine axis in steady state, AD-associated inflammation renders this pathway dispensable. Instead, a previously unrecognized basophil-leukotriene (LT) axis emerges as critical for acute itch flares. By probing fundamental itch mechanisms, our study highlights a basophil-neuronal circuit that may underlie a variety of neuroimmune processes.

Efficacy of Dupilumab in a Phase 2 Randomized Trial of Adults With Active Eosinophilic Esophagitis.

BACKGROUND & AIMS: Eosinophilic esophagitis (EoE) is an allergen-mediated inflammatory disease with no approved treatment in the United States. Dupilumab, a VelocImmune-derived human monoclonal antibody against the interleukin (IL) 4 receptor, inhibits IL4 and IL13 signaling. Dupilumab is effective in the treatment of allergic, atopic, and type 2 diseases, so we assessed its efficacy and safety in patients with EoE. METHODS: We performed a phase 2 study of adults with active EoE (2 episodes of dysphagia/week with peak esophageal eosinophil density of 15 or more eosinophils per high-power field), from May 12, 2015, through November 9, 2016, at 14 sites. Participants were randomly assigned to groups that received weekly subcutaneous injections of dupilumab (300 mg, n = 23) or placebo (n = 24) for 12 weeks. The primary endpoint was change from baseline to week 10 in Straumann Dysphagia Instrument (SDI) patient-reported outcome (PRO) score. We also assessed histologic features of EoE (peak esophageal intraepithelial eosinophil count and EoE histologic scores), endoscopically visualized features (endoscopic reference score), esophageal distensibility, and safety. RESULTS: The mean SDI PRO score was 6.4 when the study began. In the dupilumab group, SDI PRO scores were reduced by a mean value of 3.0 at week 10 compared with a mean reduction of 1.3 in the placebo group (P = .0304). At week 12, dupilumab reduced the peak esophageal intraepithelial eosinophil count by a mean 86.8 eosinophils per high-power field (reduction of 107.1%; P < .0001 vs placebo), the EoE-histologic scoring system (HSS) severity score by 68.3% (P < .0001 vs placebo), and the endoscopic reference score by 1.6 (P = .0006 vs placebo). Dupilumab increased esophageal distensibility by 18% vs placebo (P < .0001). Higher proportions of patients in the dupilumab group developed injection-site erythema (35% vs 8% in the placebo group) and nasopharyngitis (17% vs 4% in the placebo group). CONCLUSIONS: In a phase 2 trial of patients with active EoE, dupilumab reduced dysphagia, histologic features of disease (including eosinophilic infiltration and a marker of type 2 inflammation), and abnormal endoscopic features compared with placebo. Dupilumab increased esophageal distensibility and was generally well tolerated. ClinicalTrials.gov, Number: NCT02379052.

Dupilumab reduces local type 2 pro-inflammatory biomarkers in chronic rhinosinusitis with nasal polyposis.

BACKGROUND: Chronic rhinosinusitis with nasal polyposis (CRSwNP) is a type 2-mediated inflammatory disease associated with significant clinical, social, and economic burdens and high unmet therapeutic need. Dupilumab, a fully human monoclonal antibody targeting the interleukin-4 receptor α (IL-4Rα) subunit, demonstrated efficacy and acceptable safety in CRSwNP and other type 2 diseases (eg, atopic dermatitis and asthma). We now report the local effects of dupilumab on type 2 inflammatory biomarkers in nasal secretions and nasal polyp tissues of patients with CRSwNP in a randomized, placebo-controlled, phase 2 trial (NCT01920893). METHODS: Cytokines, chemokines, and total immunoglobulin E (IgE) levels were measured using immunoassay techniques in nasal secretions and nasal polyp tissue homogenates of CRSwNP patients receiving dupilumab 300 mg or placebo weekly for 16 weeks. RESULTS: With dupilumab, type 2 biomarker concentrations decreased in nasal secretions (least squares mean area under the curve from 0 to 16 weeks for the change from baseline) vs placebo for eotaxin-3 (-30.06 vs -0.86 pg/mL; P = 0.0008) and total IgE (-7.90 vs -1.86 IU/mL; P = 0.022). Dupilumab treatment also decreased type 2 biomarker levels in nasal polyp tissues at Week 16 vs baseline for eosinophilic cationic protein (P = 0.008), eotaxin-2 (P = 0.008), eotaxin-3 (P = 0.031), pulmonary and activation-regulated chemokine (P = 0.016), IgE (P = 0.023), and IL-13 (P = 0.031). CONCLUSIONS: Dupilumab treatment reduced multiple biomarkers of type 2 inflammation in nasal secretions and polyp tissues of patients with CRSwNP, demonstrating that antagonism of IL-4Rα signaling suppresses IL-4-/IL-13-dependent processes, such as mucosal IgE formation, as well as the expression of chemokines attracting inflammatory cells to the nasal mucosa.

Dupilumab progressively improves systemic and cutaneous abnormalities in patients with atopic dermatitis.

BACKGROUND: Dupilumab is an IL-4 receptor α mAb inhibiting signaling of IL-4 and IL-13, key drivers of type 2-driven inflammation, as demonstrated by its efficacy in patients with atopic/allergic diseases. OBJECTIVE: This placebo-controlled, double-blind trial (NCT01979016) evaluated the efficacy, safety, and effects of dupilumab on molecular/cellular lesional and nonlesional skin phenotypes and systemic type 2 biomarkers of patients with moderate-to-severe atopic dermatitis (AD). METHODS: Skin biopsy specimens and blood were evaluated from 54 patients randomized 1:1 to weekly subcutaneous doses of 200 mg of dupilumab or placebo for 16 weeks. RESULTS: Dupilumab (vs placebo) significantly improved clinical signs and symptoms of AD, was well tolerated, and progressively shifted the lesional transcriptome toward a nonlesional phenotype (weeks 4-16). Mean improvements in a meta-analysis-derived AD transcriptome (genes differentially expressed between lesional and nonlesional skin) were 68.8% and 110.8% with dupilumab and -10.5% and 55.0% with placebo (weeks 4 and 16, respectively; P < .001). Dupilumab significantly reduced expression of genes involved in type 2 inflammation (IL13, IL31, CCL17, CCL18, and CCL26), epidermal hyperplasia (keratin 16 [K16] and MKi67), T cells, dendritic cells (ICOS, CD11c, and CTLA4), and TH17/TH22 activity (IL17A, IL-22, and S100As) and concurrently increased expression of epidermal differentiation, barrier, and lipid metabolism genes (filaggrin [FLG], loricrin [LOR], claudins, and ELOVL3). Dupilumab reduced lesional epidermal thickness versus placebo (week 4, P = .001; week 16, P = .0002). Improvements in clinical and histologic measures correlated significantly with modulation of gene expression. Dupilumab also significantly suppressed type 2 serum biomarkers, including CCL17, CCL18, periostin, and total and allergen-specific IgEs. CONCLUSION: Dupilumab-mediated inhibition of IL-4/IL-13 signaling through IL-4 receptor α blockade significantly and progressively improved disease activity, suppressed cellular/molecular cutaneous markers of inflammation and systemic measures of type 2 inflammation, and reversed AD-associated epidermal abnormalities.

Evaluation of Potential Disease-Mediated Drug-Drug Interaction in Patients With Moderate-to-Severe Atopic Dermatitis Receiving Dupilumab.

This open-label drug-drug interaction study assessed whether blockade by dupilumab of interleukin (IL)-4 and IL-13 signaling affects the pharmacokinetics of drugs metabolized by cytochrome P450 (CYP450) enzymes. The pharmacokinetics of five CYP450 substrates given orally (midazolam, omeprazole, S-warfarin, caffeine, and metoprolol, metabolized by CYP3A, CYP2C19, CYP2C9, CYP1A2, and CYP2D6, respectively) were evaluated before and 28 days after initiation of dupilumab treatment (subcutaneous 300 mg weekly) in 14 patients with moderate-to-severe atopic dermatitis. Dupilumab had no clinically relevant effects on the pharmacokinetics of CYP450 substrates, provided substantial clinical benefit, and was generally well tolerated. Only one serious adverse event was reported, an episode of systemic inflammatory response syndrome that resolved after treatment was discontinued. In summary, blockade of IL-4/IL-13 signaling in patients with type 2 inflammation does not appear to significantly affect CYP450 enzyme activities; the use of dupilumab in atopic dermatitis patients is unlikely to influence the pharmacokinetics of CYP450 substrates.

Sarilumab plus methotrexate suppresses circulating biomarkers of bone resorption and synovial damage in patients with rheumatoid arthritis and inadequate response to methotrexate: a biomarker study of MOBILITY.

BACKGROUND: Interleukin 6 (IL-6) signaling plays a key role in the pathophysiology of rheumatoid arthritis (RA) and is inhibited by sarilumab, a human monoclonal antibody blocking the IL-6 receptor alpha (IL-6Rα). The effects of sarilumab plus methotrexate (MTX) on serum biomarkers of joint damage and bone resorption were assessed in two independent studies (phase II (part A) and phase III (part B)) of patients with RA with a history of inadequate response to MTX from the MOBILITY study (NCT01061736). METHODS: Serum samples were analyzed at baseline and prespecified posttreatment time points. Biomarkers of tissue destruction, cartilage degradation, and synovial inflammation were measured in part A; assessment of these markers was repeated in part B and included additional analysis of biomarkers of bone formation and resorption (including soluble receptor activator of nuclear factor-kB ligand (sRANKL)). A mixed model for repeated measures was used to compare treatment effects on change in biomarkers. Additionally, changes from baseline in biomarkers were compared between American College of Rheumatology 50 % responders and nonresponders and between patients who achieved or did not achieve low disease activity (LDA), separately by treatment group, at week 24. RESULTS: In part A, sarilumab 150 and 200 mg every 2 weeks (q2w) significantly reduced biomarkers of tissue destruction, cartilage degradation, and synovial inflammation at both 2 and 12 weeks posttreatment (p < 0.05 vs placebo). These results were replicated in part B, with markers of these damaging processes reduced at weeks 2 and 24 (p < 0.05 vs placebo). Additionally, sarilumab 200 mg q2w significantly reduced both sRANKL and sRANKL/osteoprotegerin ratio at week 24 (p < 0.01 vs placebo). Trends for reduction were noted for several biomarkers in patients who achieved LDA compared with those who did not. CONCLUSIONS: Sarilumab plus MTX significantly suppressed biomarkers of bone resorption and joint damage, as compared with placebo plus MTX, in patients with RA. Additional work is needed to determine whether differences in biomarker profiles at baseline or posttreatment can identify patients who achieve improvement in disease activity. TRIAL REGISTRATION: ClinicalTrials.gov, NCT01061736 , February 2, 2010.

Effect of Subcutaneous Dupilumab on Nasal Polyp Burden in Patients With Chronic Sinusitis and Nasal Polyposis: A Randomized Clinical Trial.

IMPORTANCE: Dupilumab has demonstrated efficacy in patients with asthma and atopic dermatitis, which are both type 2 helper T-cell-mediated diseases. OBJECTIVE: To assess inhibition of interleukins 4 and 13 with dupilumab in patients with chronic sinusitis and nasal polyposis. DESIGN, SETTING, AND PARTICIPANTS: A randomized, double-blind, placebo-controlled parallel-group study conducted at 13 sites in the United States and Europe between August 2013 and August 2014 in 60 adults with chronic sinusitis and nasal polyposis refractory to intranasal corticosteroids with 16 weeks of follow-up. INTERVENTIONS: Subcutaneous dupilumab (a 600 mg loading dose followed by 300 mg weekly; n = 30) or placebo (n = 30) plus mometasone furoate nasal spray for 16 weeks. MAIN OUTCOMES AND MEASURES: Change in endoscopic nasal polyp score (range, 0-8; higher scores indicate worse status) at 16 weeks (primary end point). Secondary end points included Lund-Mackay computed tomography (CT) score (range, 0-24; higher scores indicate worse status), 22-item SinoNasal Outcome Test score (range, 0-110; higher scores indicating worse quality of life; minimal clinically important difference ≥8.90), sense of smell assessed using the University of Pennsylvania Smell Identification Test (UPSIT) score (range, 0-40; higher scores indicate better status), symptoms, and safety. RESULTS: Among the 60 patients who were randomized (mean [SD] age, 48.4 years [9.4 years]; 34 men [56.7%]; 35 with comorbid asthma), 51 completed the study. The least squares (LS) mean change in nasal polyp score was -0.3 (95% CI, -1.0 to 0.4) with placebo and -1.9 (95% CI, -2.5 to -1.2) with dupilumab (LS mean difference, -1.6 [95% CI, -2.4 to -0.7]; P < .001). The LS mean difference between the 2 groups for the Lund-Mackay CT total score was -8.8 (95% CI, -11.1 to -6.6; P < .001). Significant improvements with dupilumab were also observed for the 22-item SinoNasal Outcome Test (LS mean difference between groups, -18.1 [95% CI, -25.6 to -10.6]; P < .001) and sense of smell assessed by UPSIT (LS mean difference, 14.8 [95% CI, 10.9 to 18.7]; P < .001). The most common adverse events were nasopharyngitis (33% in the placebo group vs 47% in the dupilumab group), injection site reactions (7% vs 40%, respectively), and headache (17% vs 20%). CONCLUSIONS AND RELEVANCE: Among adults with symptomatic chronic sinusitis and nasal polyposis refractory to intranasal corticosteroids, the addition of subcutaneous dupilumab to mometasone furoate nasal spray compared with mometasone alone reduced endoscopic nasal polyp burden after 16 weeks. Further studies are needed to assess longer treatment duration, larger samples, and direct comparison with other medications. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT01920893.

Modular analysis of peripheral blood gene expression in rheumatoid arthritis captures reproducible gene expression changes in tumor necrosis factor responders.

OBJECTIVE: To establish whether the analysis of whole-blood gene expression is useful in predicting or monitoring response to anti-tumor necrosis factor (anti-TNF) therapy in patients with rheumatoid arthritis (RA). METHODS: Whole-blood RNA (using a PAXgene system to stabilize whole-blood RNA in the collection tube) was obtained at baseline and at 14 weeks from 3 independent cohorts, consisting of a combined total of 240 RA patients who were beginning therapy with anti-TNF. We used an approach to gene expression analysis that is based on modular patterns of gene expression, or modules. RESULTS: Good and moderate responders according to the European League Against Rheumatism criteria exhibited highly significant and consistent changes in multiple gene expression modules after 14 weeks of therapy, as demonstrated by hypergeometric analysis. Strikingly, nonresponders exhibited very little change in any modules, despite exposure to TNF blockade. These patterns of change were highly consistent across all 3 cohorts, indicating that immunologic changes after TNF treatment are specific to the combination of both drug exposure and responder status. In contrast, modular patterns of gene expression did not exhibit consistent differences between responders and nonresponders at baseline in the 3 study cohorts. CONCLUSION: These data provide evidence that using gene expression modules related to inflammatory disease may provide a valuable method for objective monitoring of the response of RA patients who are treated with TNF inhibitors.

Dupilumab improves the molecular signature in skin of patients with moderate-to-severe atopic dermatitis.

BACKGROUND: Severe atopic dermatitis (AD) has a high unmet need for effective and safe therapeutics. In early-phase trials, dupilumab, a fully human mAb targeting IL-4 receptor α, markedly improved disease activity, but the effect of IL-4/IL-13 blockade on AD at the molecular level has not been characterized. OBJECTIVES: We sought to evaluate dupilumab modulation of the AD molecular signature. METHODS: We performed transcriptomic analyses of pretreatment and posttreatment skin biopsy specimens from patients with moderate-to-severe AD treated weekly with 150 or 300 mg of dupilumab or placebo. RESULTS: Exacerbation of the AD transcriptome was observed in placebo-treated patients. Dupilumab improved the AD signature in a dose-dependent manner. Expression of genes upregulated in AD lesions decreased in patients treated with dupilumab by 26% (95% CI, 21% to 32%) and 65% (95% CI, 60% to 71%) for treatment with 150 and 300 mg, respectively. Genes downregulated in AD lesions increased by 21% (95% CI, 16% to 27%) and 32% (95% CI, 26% to 37%) with dupilumab (150 and 300 mg, respectively). The molecular changes paralleled improvements in clinical scores. A dupilumab treatment signature of 821 probes (>2-fold change, P < .05) significantly modulated in the 300-mg dupilumab group at week 4 compared with baseline was identified in this sample set. Significant (P < .05) decreases in mRNA expression of genes related to hyperplasia (K16 and MKI67), T cells, and dendritic cells (CD1b and CD1c) and potent inhibition of TH2-associated chemokines (CCL17, CCL18, CCL22, and CCL26) were noted without significant modulation of TH1-associated genes (IFNG). CONCLUSIONS: This is the first report showing rapid improvement of the AD molecular signature with targeted anti-IL-4 receptor α therapy. These data suggest that IL-4 and IL-13 drive a complex, TH2-centered inflammatory axis in patients with AD.