Superficial Conjunctival Cells from Dupilumab-treated Atopic Dermatitis Patients with Ocular Adverse Events Display a Transcriptomic Psoriasis Signature.

Dupilumab has demonstrated efficacy in the treatment of atopic dermatitis (AD). However, a subset of patients experiences ocular adverse events (OAE), including conjunctivitis and dry eye syndrome, the pathological mechanisms of which are still unknown. In a bicentric study, we used DNA microarray analysis to compare the transcriptome of AD patient conjunctival cells collected by impression cytology before (M0) and 4 months after (M4) initiating dupilumab treatment. Thirty-six patients were included and divided in two groups according to their ophthalmological status at M4: 12 with OAE (OAE+) and 24 without (OAE-). The analysis revealed 52 differentially expressed genes (DEG) between OAE+ and OAE- patients at M0, and 113 at M4. Ingenuity Pathway Analysis enrichment revealed a psoriasis signature in OAE+ patients, both before and after OAE outcomes. Additionally, we noticed the overexpression of several genes involved in keratinocyte differentiation, particularly encoding cornified envelope components. Among the 16 DEG selected for real-time RT-PCR validation, 9 were confirmed as upregulated at M4 in OAE+ vs OAE- patients, validating the psoriasis signature, while MUC-7 was downregulated. In conclusion, these results suggest that a conjunctival transcriptomic profile predisposes some AD patients to develop OAE upon dupilumab treatment.

Current goals of NSAID-ERD management: patient-centered approaches involving NSAID desensitization with and without biologics.

Classic approach of non-steroidal anti-inflammatory drugs (NSAIDs) - exacerbated respiratory disease (NSAID-ERD) includes pharmaceutical and surgical treatments, as well as avoidance of COX-1-inhibitor NSAIDs. The introduction of biologics in the treatment of severe asthma and chronic rhinosinusitis with nasal polyps (CRSwNP) represents an alternative therapeutic approach to the classical aspirin therapy after desensitization (ATAD) in some regions, and with convincing results. However, their use is limited due to approval and/or high-cost restrictions. NSAID-ERD is a mainly type 2 (T2) and highly eosinophilic disease, and monoclonal antibodies targeting IgE or interleukins (IL)-5, IL-4, and IL-13 have been shown to be effective for both severe asthma and severe CRSwNP. So far, dupilumab demonstrated greater efficacy in NSAID-ERD than in aspirin-tolerant patients with regards to several clinical outcomes. Patients with NSAID-ERD respond very rapidly to omalizumab also, with reduction in the release of prostaglandin D2 and cysteinyl leukotrienes. Patients favored biologic treatment over ATAD in multiple retrospective analyses, which must be acknowledged when choosing one or the other option. While this review will summarize ATAD in general, it will more prominently focus on when ATAD should be considered, even when T2 biologics are available. Additionally, there are conflicting studies as to whether patients on a T2 biologic become desensitized to NSAIDs, as omalizumab proved to restore tolerance to aspirin in only two thirds of patients. This goal of NSAIDs tolerance should be considered as part of disease control future approaches, representing one of many aspects in a patient-centered care approach.

Correlation of sino-nasal outcome test and nasal polyp score in dupilumab-treated chronic rhinosinusitis with nasal polyps.

BACKGROUND: The alignment between objective scores and patient-reported outcome measures (PROMs) is underexplored. This study aimed to assess changes in Nasal Polyp Score (NPS) and Sino-Nasal Outcome Test (SNOT) scores in chronic rhinosinusitis with nasal polyps (CRSwNP) patients undergoing dupilumab treatment and explore correlations between these scores. METHODS: CRSwNP patients received dupilumab therapy for six months. SNOT-20 German Adapted Version (GAV)/SNOT-22 scores were assessed weekly, and NPS was measured at baseline and after one, three, and six months. Correlations were analyzed using Spearman's rank correlation and regression analysis. RESULTS: 69 patients were included. After one, three and six months of dupilumab therapy, SNOT and NPS scores improved significantly. Correlation analysis of SNOT and NPS showed significant correlations only within the nasal subscores, along with a weak trend for SNOT-20. Absolute changes over time lacked significance. However, correlation analysis revealed significant associations between relative changes in SNOT score and NPS, irrespective of timing, and when stratified by baseline NPS of 8, 6, and 4 (r = -0.54, p = 0.01; r = -0.44, p < 0.001; r = -0.7, p < 0.001). This was supported by linear regression modeling, suggesting potential predictive capability of NPS reduction on relative SNOT score improvement. CONCLUSION: Dupilumab therapy significantly improved subjective and objective CRSwNP scores, exhibiting weak correlations in absolute values for nasal subscores. Furthermore, evidence indicated a correlation between relative changes in SNOT score and NPS, substantiated by predictive capability. This might be due to subjective perception variability, highlighting the suitability of relative change correlation analysis.

Impact of Overweight on Response to Dupilumab Treatment in Chronic Rhinosinusitis with Nasal Polyps.

Chronic rhinosinusitis with nasal polyps (CRSwNP) significantly impacts quality of life and often presents therapeutic challenges, with biologics like dupilumab showing promise in managing severe, uncontrolled cases. The aim of this study was to assess the influence of overweight on the effectiveness of dupilumab in patients with uncontrolled CRSwNP. This retrospective study analyzed treatment outcomes of 75 CRSwNP patients receiving dupilumab, categorizing them into underweight/normal-weight (BMI ≤ 24.9 kg/m2) and overweight/obese (BMI ≥ 25 kg/m2) groups. Outcome measures included changes in nasal polyp score (NPS) and sinonasal outcome test (SNOT-22) scores. Results demonstrated that the underweight/normal-weight group experienced significantly greater improvements in NPS and a higher rate of total NPS improvement compared to the overweight/obese group. While SNOT-22 scores improved in both groups, no significant differences were observed. Among patients with comorbid asthma, the underweight/normal-weight subgroup also showed significantly better outcomes, including greater reductions in both NPS and SNOT-22 scores. Multiple regression analysis identified BMI as an independent prognostic factor for NPS outcomes. The findings suggest that overweight/obesity adversely affects the response to dupilumab in CRSwNP, emphasizing the need for personalized treatment strategies considering BMI.

Predicting dupilumab effectiveness with Type-2 biomarkers: A real-world study of severe asthma.

BACKGROUND: The therapeutic effectiveness of dupilumab for severe asthma in real-world settings is yet to be prospectively investigated across multiple institutions, and uncertainties persist regarding predictive factors for its effectiveness. We aimed to assess the effectiveness of dupilumab and identify predictors of its effectiveness in real-world settings using two type-2 biomarkers: FeNO concentration and blood eosinophil count. METHODS: This prospective multicenter study included 103 patients with severe asthma. Exacerbations and respiratory functions were monitored for 24 weeks. Asthma control was evaluated using the Asthma Control Questionnaire-5. Clinical symptoms and their impact on cough and sputum were assessed using the Cough and Sputum Assessment Questionnaire (CASA-Q). Subgroup analyses of type-2 biomarkers were conducted based on FeNO levels and blood eosinophil counts at baseline. RESULTS: Treatment with dupilumab led to a reduction in exacerbations and enhancement in asthma control, FEV1, and CASA-Q scores. FEV1 improvement was correlated with enhancement in the sputum domain of the CASA-Q. Patients exhibiting elevated FeNO levels and blood eosinophil counts demonstrated more significant enhancements in FEV1. CASA-Q sputum domain scores were significantly higher in the group with elevated eosinophil counts. Regression analysis revealed that FeNO levels and blood eosinophil counts are significant predictors of FEV1 improvement, with blood eosinophil counts also predicting sputum improvement in patients treated with dupilumab. CONCLUSIONS: Type-2 biomarkers may act as indicators of improvement in FEV1 and sputum outcomes among patients with severe asthma undergoing dupilumab treatment in real-world settings.

Successful Co-administration of Dupilumab and Anti-tuberculosis Drugs in a Severely Uncontrolled Asthma Patient With Pulmonary Tuberculosis.

The co-occurrence of active tuberculosis (TB) in patients with moderate to severe asthma presents unique therapeutic challenges, particularly with the advent of biologics like dupilumab, which targets the interleukin-4 (IL-4) and interleukin-13 (IL-13) pathways in asthma treatment. Despite the general safety of biologics, concerns about immunosuppression and susceptibility to infections like TB persist. This case report discusses a male with severe, uncontrolled type 2 allergic asthma, who experienced multiple exacerbations despite maximal bronchodilator therapy and then concomitantly developed pulmonary TB. This case demonstrates a potential clinical scenario for co-administering dupilumab with anti-TB treatment, suggesting a beneficial approach for similar clinical scenarios and contributing to the literature on this topic.

Successful treatment of the dupilumab-induced psoriatic dermatitis/arthritis and atopic dermatitis with a JAK inhibitor: A case report and literature review.

Dupilumab-induced psoriatic dermatitis and arthritis in a patient with atopic dermatitis were effectively managed with upadacitinib, highlighting the use of Janus kinase inhibitors as a possible treatment for biologic therapy side effects.

Resolution of Molluscum Contagiosum After Discontinuation of Topical Corticosteroids During Dupilumab Therapy for Atopic Dermatitis: A Case Report.

A 35-year-old male patient with atopic dermatitis (AD) was referred to our department for exacerbated AD lesions. His sudden discontinuation of topical corticosteroid had induced erythroderma on his face, extremities, and trunk. Additionally, he presented small multiple whitish papules, mainly on the trunk and thighs, diagnosed as molluscum contagiosum (MC). Dupilumab was initiated in combination with a topical corticosteroid (0.05% betamethasone butyrate propionate). After four weeks, the AD symptoms substantially improved, while MC showed no changes. After 11 weeks of dupilumab therapy, he abruptly stopped topical corticosteroid treatment, and the MC lesions completely resolved in two weeks.

Pustular Psoriasis Induced by Dupilumab: A Case Report.

Atopic dermatitis (AD) and psoriasis (Pso) are both recurrent inflammatory diseases. Recently, it has been reported that a small number of AD patients experience immune drift after receiving dupilumab treatment, leading to a transition from eczema-like lesions to psoriasis-like lesions. Here, we report a case of pustular psoriasis caused by dupilumab treatment for atopic dermatitis. This case underscores the diagnostic challenges associated with immune drift related to biological agents while also highlighting the shortened time frame for immune drift onset compared to previous reports.

Association Between Smell Loss, Disease Burden, and Dupilumab Efficacy in Chronic Rhinosinusitis with Nasal Polyps.

OBJECTIVE: To evaluate the association between smell loss and other aspects of disease, and evaluate dupilumab efficacy in patients with severe chronic rhinosinusitis with nasal polyps (CRSwNP) and moderate or severe smell loss. METHODS: This post-hoc analysis of the SINUS-24/52 studies (NCT02912468/NCT02898454) analyzed nasal polyp score (NPS, 0-8), nasal congestion/obstruction (NC, 0-3), Lund-Mackay CT-scan score (LMK-CT, 0-24), rhinosinusitis severity visual analog scale (RS-VAS, 0-10), and 22-item Sinonasal Outcome Test (SNOT-22, 0-110) according to baseline monthly average patient-reported loss of smell scores (LoS, 0-3) of >1 to 2 (moderate) or >2 to 3 (severe) in patients randomized to dupilumab 300 mg or placebo every 2 weeks. RESULTS: Of 724 patients randomized, baseline LoS was severe in 601 (83%) and moderate in 106 (15%). At baseline, severe versus moderate LoS was associated with 1-point greater severity of NC (odds ratio [OR] 6.01 [95% confidence interval, (CI) 3.95, 9.15]), 5-point greater severity of LMK-CT (OR 2.19 [1.69, 2.85]), and 8.9-point greater severity of SNOT-22 (OR 1.35 [1.20, 1.49]). At Week 24, least squares mean differences (95% CI) dupilumab versus placebo in change from baseline were: NPS -1.90 (-2.56, -1.25) and -1.95 (-2.20, -1.70) in the moderate and severe baseline LoS subgroups, respectively; NC -.35 (-.64, -.06) and -1.00 (-1.13, -.87); LMK-CT -6.30 (-7.88, -4.72) and -6.22 (-6.82, -5.63); RS-VAS -1.18 (-2.20, -.16) and -3.47 (-3.90, -3.03); and SNOT-22 -7.52 (-14.55, -.48) and -21.72 (-24.63, -18.82); all nominal P < .05 versus placebo. Improvements with dupilumab in NC, RS-VAS, and SNOT-22 were statistically greater in patients with severe versus moderate baseline LoS. CONCLUSION: Significant smell impairment in severe CRSwNP is associated with significant disease (NC, RS-VAS, LMK), health-related quality of life impairment (SNOT-22), asthma, and non-steroidal anti-inflammatory drug-exacerbated respiratory disease. Dupilumab significantly improved NPS, NC, LMK-CT, RS-VAS, and SNOT-22 in subjects with moderate and severe baseline smell loss.

Possibility of maintaining remission with topical therapy alone after withdrawal of dupilumab in Japanese patients with atopic dermatitis and their characteristics in the real world.

Psossibility and appropriate timing of discontinuation of dupilumab for atopic dermatitis (AD) remain unclear. We explored the possibility of patients, who could maintain remission with topical therapy alone after withdrawing dupilumab in the real world. Furthermore, we identified their characteristics. All adult AD patients who initiated dupilumab from June 2018 to July 2022 and were treated with dupilumab for more than 3 months at our hospital were included in this study. The observation period was from June 2018 to July 2023. In 138 patients, 58 (42.0%) discontinued dupilumab at least once. Among them, 18 (13.0%) discontinued dupilumab but reinitiated dupilumab later due to exacerbation. Only seven patients (5.1%) could maintain remission with topical therapy alone after discontinuation of dupilumab, with characteristics of lower POEM, VAS of pruritus, serum levels of TARC and LDH, and neutrophil counts at baseline, and those of longer duration of dupilumab until its discontinuation (24.0 ± 13.3 vs. 12.8 ± 7.3 months) and lower EASI and affected BSA at the discontinuation of dupilumab. In 118 patients treated with dupilumab for at least 1 year, 38 patients (32.2%) discontinued at least once. Only four patients (3.4%) could maintain remission with topical therapy alone after discontinuation of dupilumab, with characteristics of lower POEM at baseline and lower EASI at the discontinuation of dupilumab. In conclusion, maintaining remission after withdrawing dupilumab is challenging. Discontinuation of dupilumab may be considered in patients with low baseline POEM, after more than 2 years of dupilumab treatment, with a substantial decrease in EASI.

Dupilumab and House Dust Mite Immunotherapy in Patients with Atopic Dermatitis: A Preliminary Study.

BACKGROUND: Severe atopic dermatitis (AD) is a complex disease requiring systemic treatment. This study aimed to assess the effectiveness of combined therapy consisting of dupilumab and sublingual dust mite allergen immunotherapy (SLIT-HDM) in patients with severe AD and HDM allergies. METHODS: Patients diagnosed with severe AD were included in this randomised, placebo-controlled, double-blind 12-month trial; they received SLIT for HDMs and/or dupilumab for 12 months and were compared with patients on cyclosporine. The primary outcomes for the treatment arms were changes in the Eczema Area and Severity Index (EASI), body surface area (%BSA), and Investigator Global Assessment (IsGA) over 12 months. The secondary outcomes were the proportion of patients who achieved IsGA success and reduced medication scores. RESULTS: Significant improvements were observed in all analysed groups after 12 months of therapy based on the EASI, %BSA, and IsGA. However, the most substantial changes were observed in the groups treated with dupilumab or a combination of SLIT-HDM and dupilumab. Additionally, the proportion of patients who achieved an IsGA reduction was significantly greater in the group receiving combination therapy than in the other groups (9/14 [64% of the group receiving SLIT-HDM] vs. 11/14 [73% of the group receiving dupilumab] vs. 15/17 [88% of the group receiving dupilumab and SLIT-HDM] vs. 7/13 [53% of the group receiving cyclosporine]) (p < 0.05). CONCLUSIONS: In patients with severe AD and HDM allergies, combination treatment with dupilumab and allergen immunotherapy for HDMs may increase the therapeutic benefit over treatment with these methods separately.

CERS1 is a Biomarker of Staphylococcus aureus Abundance and Atopic Dermatitis Severity.

BACKGROUND: Atopic dermatitis (AD) is an inflammatory skin condition characterized by widely variable cutaneous Staphylococcus aureus abundance that contributes to disease severity and rapidly responds to type 2 immune blockade (i.e., dupilumab). The molecular mechanisms regulating S. aureus levels between AD subjects remain poorly understood. OBJECTIVE: To investigate host genes that may be predictive of S. aureus abundance and correspond with AD severity. METHODS: Data derived from the NIH/NIAID-funded (NCT03389893 [ADRN-09]) randomized, double-blind, and placebo-controlled multicenter study of dupilumab in adults (n=71 subjects) with moderate-severe AD. Bulk RNA-sequencing of skin biopsies (n=57 lesional, 55 non-lesional) was compared to epidermal S. aureus abundance, lipidomics, and AD clinical measures. RESULTS: S. aureus abundance and ceramide synthase 1 (CERS1) expression positively correlated at baseline across both non-lesional (r=0.29, p=0.030) and lesional (r=0.41, p=0.0015) skin. Lesional CERS1 expression also positively correlated with AD severity (i.e., SCORing AD [SCORAD] r=0.44, p=0.0006) and skin barrier dysfunction (transepidermal water loss area under the curve [TEWL AUC] r=0.31, p=0.025) at baseline. CERS1 expression (forms C18:0-sphingolipids) was negatively associated with elongation of very long chain fatty acids (ELOVL6; C16:0→C18:0) expression and corresponded with a shorter chain length sphingolipid composition. Dupilumab rapidly reduced CERS1 expression (day 7) and ablated the relationship with S. aureus abundance and ELOVL6 expression by day 21. CONCLUSION: CERS1 is a unique molecular biomarker of S. aureus abundance and AD severity that may contribute to dysfunctional skin barrier and shorter chain sphingolipid composition through fatty acid sequestration as a maladaptive compensatory response to reduced ELOVL6.

'Efficacy of biologics in NSAID-ERD: United airways from the nose to the bronchi'.

NSAID-exacerbated respiratory disease (NSAID-ERD), the clinical triad of severe chronic rhinosinusitis with nasal polyps (CRSwNP), asthma, and respiratory reactions to cyclooxygenase 1 inhibitors, is often challenging to manage, with many patients failing first line therapies for CRSwNP and asthma. There are now six biologic mediations approved for asthma and/or severe CRSwNP: omalizumab, mepolizumab, reslizumab, benralizumab, dupilumab and tezepelumab. With the availability of respiratory biologic treatment for both asthma and CRSwNP, clinicians now have a multitude of additional management options for patients with NSAID-ERD. Herein we will review the currently available clinical trial and real-world evidence for biologic efficacy and safety patients with NSAID-ERD, discuss the mechanisms of biologic therapy specific to NSAID-ERD, and review evidence regarding the use of biologic therapy versus endoscopic sinus surgery therapy for CRSwNP and NSAID-ERD. We will propose a management approach for choosing biologic therapy or endoscopic sinus surgery with aspirin therapy after desensitization for patients with NSAID-ERD.

Mild and symptom-free months in patients with chronic rhinosinusitis with nasal polyps treated with dupilumab.

BACKGROUND: Commonly reported outcomes of clinical trials in chronic rhinosinusitis with nasal polyps (CRSwNP) may have limited relatability for patients. OBJECTIVE: To enhance the patient relatability of outcomes in dupilumab clinical trials for CRSwNP, daily symptom scores were used to determine new patient­centered endpoints: mild-to-no-symptom months (MSM) and symptom-free months (SFM). METHODS: Post hoc analysis of patients receiving dupilumab 300 mg or placebo every 2 weeks for 24 weeks (SINUS-24 study; NCT02912468) or 52 weeks (SINUS­52; NCT02898454). Patients recorded symptom severity scores daily for each of nasal congestion, loss of smell, and anterior and posterior rhinorrhea on a scale of 0-3 (0 = no symptoms; 1 = mild; 2 = moderate; 3 = severe). We assessed the proportions of patients reporting only mild or no symptoms (MSM) or no symptoms (SFM) throughout the 28­day periods prior to randomization, Week 24 (pooled studies), and Week 52 (SINUS­52). RESULTS: Significantly more dupilumab­treated than placebo-treated patients achieved MSM for all four symptoms (Week 24: 31.0% vs 4.4%; OR 12.9 [6.4, 25.8]; Week 52: 38.3% vs 2.6%; OR 15.6 [5.9, 41.0]; both P < .0001). Additionally, significantly more dupilumab-treated than placebo­treated patients achieved SFM for at least one of the four symptoms (Week 24: 35.4% vs 10.8%; odds ratio [OR] 4.9 [95% confidence interval 3.1, 7.8]; Week 52: 50.0% vs 9.2%; OR 9.1 [4.6, 17.9]; both P < .0001). CONCLUSION: One-third of patients with severe CRSwNP treated with dupilumab achieved MSM for all four cardinal symptoms (nasal congestion, loss of smell, and anterior and posterior rhinorrhea). Moreover, half of patients achieved SFM for at least one of the four symptoms. These results support the benefit of dupilumab in improving patient­centered outcomes.

Update on the pharmacological treatment of chronic obstructive pulmonary disease.

INTRODUCTION: Chronic obstructive pulmonary disease (COPD) is a common syndrome associated with smoking and environmental exposures coupled with genetic susceptibility. Recent major advancements in the treatment of COPD patients have become available. AREAS COVERED: New data on the role of classic bronchodilators, including short-acting and long-acting beta2-agonists and anti-muscarinic antagonists, in the treatment of COPD patients are discussed. Data promoting a more targeted approach to inhaled and systemic corticosteroid use in COPD are reviewed. Phosphodiesterase (PDE) inhibitors, including the recently approved PDE 3/4 inhibitor inhaled ensifentrine, are noted. Selective use of antibiotics can play a role in complex COPD patients. COPD patients with evidence of asthma-COPD overlap syndrome and type-two lymphocytic inflammatory-mediated airway constriction appear to respond to biologics, particularly the anti-IL-4/IL-3 antagonist monoclonal antibody, dupilumab. EXPERT OPINION: New therapeutic options have made the approach and treatment of the COPD patient much more complicated. These options tend to be very expensive. Attention to identifying the endotype and phenotype will help direct the pharmacotherapy.