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Mepolizumab targets multiple immune cells in aspirin-exacerbated respiratory disease

Kathleen M. Buchheit, MD, Erin Lewis, BA, Deborah Gakpo, BA, Jonathan Hacker, BA, Aaqib Sohail, PhD, Faith Taliaferro, BS, Evans Berreondo Giron, Chelsea Asare, Marko Vukovic, BS, Jillian C. Bensko, PA-C, Daniel F. Dwyer, PhD,a Alex K. Shalek, PhD, Jose Ordovas-Montanes, PhD, and Tanya M. Laidlaw, MD Boston and Cambridge, Mass PMID: 34144111

To identify the mechanisms by which anti-IL-5 treatment improves respiratory inflammation in AERD, we studied 18 patients with AERD on mepolizumab for severe eosinophilic asthma compared to 18 matched control patients with AERD not on mepolizumab. Subjects with AERD treated with mepolizumab, had decreased production of inflammatory eicosanoids, and upregulation of nasal epithelial cell transcripts involved in tight junction pathways and cilium organization, compared to AERD patients not treated with mepolizumab. These effects of mepolizumab are likely due to decreased signaling of IL-5 on local respiratory tissue eosinophils, basophils, mast cells, and epithelial cells – all of which have functional IL-5Rα. We determined that the mechanism by which IL-5 inhibition provides therapeutic benefit in respiratory inflammation is not due exclusively to anti-eosinophil effects.

Efficacy of dupilumab in patients with aspirin-exacerbated respiratory disease and previous inadequate response to anti-IL-5 or anti-IL-5Rα in a real-world setting

Bavaro N, Gakpo D, Mittal A, Bensko JC, Laidlaw TM, Buchheit KM. Efficacy of dupilumab in patients with aspirin-exacerbated respiratory disease and previous inadequate response to anti-IL-5 or anti-IL-5Rα in a real-world setting. J Allergy Clin Immunol Pract. 2021 Feb 22:S2213-2198(21)00200-2. doi: 10.1016/j.jaip.2021.02.020. Epub ahead of print. PMID: 33631410.

In recent years, biologics have become a more common treatment option for patients with aspirin-exacerbated respiratory disease (AERD).  Respiratory biologic medications targeting interleukin (IL)-4Ra, IL-5, IL-5Ra, and IgE are approved for severe asthma and have recently been approved or being studied for CRSwNP. Treatment with biologic medications targeting type 2 cytokines and cytokine receptors is an attractive option for treating AERD, but data guiding selection of the appropriate agent are limited. In this study, we examined 41 patients who were treated with mepolizumab, reslizumab, or benralizumab. 27 of the 41 patients transitioned to dupilumab for inadequately controlled symptoms while 14 remained on mepolizumab.

For the 27 who switched to dupilumab, their SNOT-22 and ACT scores, and the FEV1% predicted did not improve while they were on the anti-IL-5/IL-5Ra biologic. However, there was significant improvement in symptoms scores and lung function, and reduction in asthma exacerbations while on dupilumab. For the 14 patients that remained on mepolizumab, they saw a significant improvement in total SNOT-22 and ACT scores but not in lung function. Of note, the only difference between the two groups was the baseline IgE level, which may serve as a useful biomarker for biologic selection in AERD patients. Although the study is limited by the retrospective nature of the data, it highlights the need for head-to-head, prospective studies aimed at understanding identifying responder endotypes to guide selection of appropriate biologic therapy.

Aspirin-Exacerbated Respiratory Disease: Association Between Patient-Reported Sinus and Asthma Morbidity

Bergmark RW, Palumbo M, Rahman S, Maurer R, Dominas C, Roditi R, Bhattacharyya N, Maxfield A, Buchheit KM, Laidlaw TM. Aspirin-Exacerbated Respiratory Disease: Association Between Patient-Reported Sinus and Asthma Morbidity. J Allergy Clin Immunol Pract. 2020 Dec 8:S2213-2198(20)31278-2. doi: 10.1016/j.jaip.2020.11.051. Epub ahead of print. PMID: 33307278.

This study looked to establish and understand the connection between pulmonary and sinonasal symptoms in aspirin-exacerbated respiratory disease (AERD). To better understand the connection, the investigators reviewed the Sino-Nasal Outcomes Test (SNOT) 22-item and Asthma Control Test (ACT) scores, and percent predicted FEV1 (FEV1% predicted) from 1065 AERD Registry participants. The SNOT-22 was used as the predictor variable while ACT score and FEV1% predicted served as primary outcomes.  Any ten-point increase in SNOT-22 was associated with a 0.87-point decrease in ACT and a 0.75% decrease in FEV1%. Any one-point increase in ACT was associated with a 1.0% increase in FEV1% This study also demonstrates an association between subjective and objective measures of asthma severity.

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Impact of reported NSAID “allergies” on opioid use disorder in back pain

Li L, Chang Y, Song S, Losina E, Costenbader KH, Laidlaw TM. Impact of reported NSAID “allergies” on opioid use disorder in back pain. J Allergy Clin Immunol. 2020 Sep 9:S0091-6749(20)31236-7. doi: 10.1016/j.jaci.2020.08.025. Epub ahead of print. PMID: 32916184; PMCID: PMC7995999.

Li et al. investigated the clinical impact of reported nonsteroidal anti-inflammatory drug (NSAID) allergy on opioid use disorder (OUD) in patients with chronic back pain. NSAIDs are commonly prescribed for treatment of acute and chronic pain, but their therapeutic use is limited by reported allergies. Allergy overreporting and lack of further investigation can lead to unnecessary avoidance of NSAIDs and increased utilization of alternative analgesics, including opioids, to manage pain. The investigators looked at over 47,000 patients with chronic back pain of whom over 3,600 (7.7%) had an NSAID allergy listed in their health record. They found that patients with chronic back pain and self-reported NSAID allergies are at increased risk of being prescribed opioids and developing OUD. Patients with chronic back pain and NSAID allergies should be referred to allergy specialists for potential allergy delabeling in order to minimize unnecessary opioid prescribing and to reduce the risk of OUD.

IL-5Rα marks nasal polyp IgG4- and IgE-expressing cells in aspirin-exacerbated respiratory disease

Buchheit KM, Dwyer DF, Ordovas-Montanes J, Katz HR, Lewis E, Vukovic M, Lai J, Bankova LG, Bhattacharyya N, Shalek AK, Barrett NA, Boyce JA, Laidlaw TM. IL-5Rα marks nasal polyp IgG4- and IgE-expressing cells in aspirin-exacerbated respiratory disease. J Allergy Clin Immunol. 2020 June;145(6):1574-1584. PubMed PMID: 32199912. PubMed Central PMCID: PMC7282948.

This study showed that sinus tissue IgE and IgG4 levels were elevated in patients with AERD compared to controls and that subjects with AERD whose nasal polyps recurred rapidly had higher IgE levels than did subjects with AERD, with slower polyp regrowth. Single-cell RNA sequencing revealed increased IL5RA, IGHG4, and IGHE in antibody-expressing cells from patients with AERD compared to those from NSAID-tolerant patients with CRSwNP, and there were more IL-5Rα+plasma cells in the polyp tissue from AERD than in polyp tissue from CRSwNP. IL-5 stimulation of plasma cells in vitro induced changes in a distinct set of transcripts. These findings suggest a role for IL-5Rα+ antibody-expressing cells in facilitating local antibody production and severe nasal polyps in AERD.

Unique Effect of Aspirin Therapy on Biomarkers in Aspirin-exacerbated Respiratory Disease. A Prospective Trial

Cahill KN, Cui J, Kothari P, Murphy K, Raby BA, Singer J, Israel E, Boyce JA, Laidlaw TM. Unique Effect of Aspirin Therapy on Biomarkers in Aspirin-exacerbated Respiratory Disease. A Prospective Trial. Am J Resp Crit Care Med 2019 Sept;200(6):704-711. PMID:30978291

These analyses revealed that 8 weeks of treatment with high-dose aspirin therapy decreased nasal symptoms and urinary prostaglandin E metabolite and increased urinary leukotriene E4 levels in subjects with AERD, but not in those with aspirin-tolerant asthma. Only in subjects with AERD, exhaled nitric oxide, plasma tryptase, and blood eosinophil and basophil counts increased on aspirin. These findings show that high-dose aspirin therapy for 8 weeks paradoxically increases markers of type 2 inflammation in AERD, despite reducing nasal symptoms. This effect of aspirin is unique to AERD and not observed in subjects with aspirin-tolerant asthma.

Dupilumab improves nasal polyp burden and asthma control in patients with CRSwNP and AERD

Laidlaw TM, Mullol J, Fan C, Zhang D, Amin N, Khan A, Chao J, Mannent LP. Dupilumab improves nasal polyp burden and asthma control in patients with CRSwNP and AERD. J Allergy Clin Immunol Pract. 2019 Sept;7(7):2462-2465. PMID:30954643

In this analysis of Phase 2 data of the efficacy of dupilumab in treating patients with CRSwNP, we found that in the subgroup of patients with CRSwNP and comorbid AERD, dupilumab significantly improved CRSwNP disease outcomes, along with asthma control and lung function. In some cases, the dupilumab-induced improvement in outcomes was greater in the patients with AERD than it was in the aspirin-tolerant CRSwNP patients.

Sinus surgery improves lower respiratory tract reactivity during aspirin desensitization for AERD

Huang GX, Palumbo ML, Singer JI, Cahill KN, Laidlaw TM. Sinus surgery improves lower respiratory tract reactivity during aspirin desensitization for AERD. J Allergy Clin Immunol Pract. 2019. May-Jun;77(5):1647-1649. PMID:30877073

This retrospective clinical study found that for patients with AERD, when a recent endoscopic sinus surgery precedes aspirin challenge or aspirin desensitization, less aspirin-induced lower airway reactivity and improved safety are observed.

Plasma tryptase elevation during aspirin-induced reactions in aspirin-exacerbated respiratory disease

Cahill KN, Murphy K, Singer J, Israel E, Boyce JA, Laidlaw TM. Plasma tryptase elevation during aspirin-induced reactions in aspirin-exacerbated respiratory disease (AERD). J Allergy Clin Immunol. 2019 Feb;143(2):799-803.e2. PMID: 30339852

This study of patients with AERD found that an elevation of plasma tryptase during aspirin-induced respiratory reactions occurs in 50% of reactions despite CysLT1R antagonist prophylaxis and identifies lung function decline and extra-respiratory symptoms in AERD.

Dietary Fatty Acid Modification for the Treatment of Aspirin-Exacerbated Respiratory Disease: A Prospective Pilot Trial

Schneider TR, Johns CB, Palumbo ML, Murphy KC, Cahill KN, Laidlaw TM. Dietary Fatty Acid Modification for the Treatment of Aspirin-Exacerbated Respiratory Disease: A Prospective Pilot Trial. J Allergy Clin Immunol Pract. 2018 May-June;6(3)825-31. PMID:29133219

We followed 10 patients with AERD who completed a 2-week strict dietary intervention that aimed to reduce dietary omega-6 fatty acid consumption to less than 4 grams per day and increase omega-3 intake to more than 3 grams per day. We noted that the dietary change induced a significant decrease in urinary levels of leukotriene E4 and prostaglandin D2 metabolites, and also improved patient symptoms, with a 15-point reduction in the SNOT-22 score and an 0.27-point improvement in the Asthma Control Questionnaire. Therefore we concluded that a high omega-3/low omega-6 diet may be an appropriate adjunct treatment option for patients with AERD.

Allergic inflammatory memory in human respiratory epithelial progenitor cells

Ordovas-Montanes J, Dwyer DF, Nyquist SK, Buchheit KM, Vukovic M, Deb C, Wadsworth MH, Hughes TK, Kazer SW, Yoshimoto E, Cahill KN, Bhattacharyya N, Katz HR, Laidlaw TM, Boyce JA, Barrett NA, Shalek AK. Allergic inflammatory memory in human respiratory epithelial progenitor cells. Nature. 2018. Aug;560(7720):649-54. PMID: 30135581

By profiling human surgical nasal polyp and sinusitis samples, we determined that cultured basal cells retain intrinsic memory of IL-4/IL-13 exposure. Overall this study found that reduced epithelial diversity stemming from functional shifts in basal cells is a key characteristic of type 2 immune-mediated barrier tissue dysfunction. Our results demonstrate that epithelial stem cells may contribute to the persistence of human disease by serving as repositories for allergic memories.

Dexpramipexole depletes blood and tissue eosinophils in nasal polyps with no change in polyp size

Laidlaw TM, Prussin C, Panettieri RA, Lee S, Ferguson BJ, Adappa ND, Lane AP, Palumbo ML, Sullivan M, Archibald D, Dworetzky SI, Hebrank GT, Bozik ME. Dexpramipexole effectively lowers blood and tissue eosinophils in subjects with chronic rhinosinusitis with nasal polyps. Laryngoscope. 2019 Feb;129(2)E61-E66. PMID:30284267

This was an open-label study of 16 subjects with CRSwNP, peripheral eosinophilia, and histologic finding of eosinophilic inflammation within their nasal polyp tissue, who were treated for 6 months with the novel eosinophil-lowering agent, dexpramipexole. After 6 months of dexpramipexole, which was quite well tolerated, there was a 94% reduction in blood eosinophils, and a 97% reduction in nasal polyp tissue eosinophils. However, neither the total polyp score, nor any other clinical endpoints significantly improved. This “negative” study has in fact had a dramatic effect on the previous dogma in the field, which suggested that the respiratory tissue eosinophils were a driving cause of patient polyp burden and symptoms. Instead, we found that despite the near-elimination of polyp eosinophils, there was no improvement in symptoms or polyp burden noted.

A trial of type 12 purinergic (P2Y 12) receptor inhibition with prasugrel identifies a potentially distinct endotype of patients with aspirin-exacerbated respiratory disease

Laidlaw TM, Cahill KN, Cardet JC, Murphy K, Cui J, Dioneda B, Kothari P, Raby B, Israel E, Boyce JA. A randomized-controlled trial of P2Y12 receptor inhibition with prasugrel identifies a distinct platelet-dependent and mast cell-independent endotype of patients with aspirin-exacerbated respiratory disease. J Allergy Clin Immunol. 2019 Jan;143(1):316-324. PMID: 29890239

In this trial, 40 patients with AERD completed a 10-week, double-blind, placebo-controlled crossover trial of prasugrel, and then underwent oral aspirin challenges after 4 weeks of prasugrel and after 4 weeks of placebo. Prasugrel did not significantly change the severity of aspirin-induced reactions or the provocative dose of aspirin. However, 5 subjects (responders) reacted to aspirin while receiving placebo but did not have any reaction to aspirin challenge after the prasugrel arm. Those 5 patients did not have significant aspirin-induced increases in urinary leukotriene E4, prostaglandin D2 metabolite, or thromboxane B2 levels; and did not display increases in serum tryptase levels during aspirin reactions on the placebo arm, all of which were observed in the nonresponders. Therefore, in a small subset of patients with AERD, P2Y12 receptor antagonism with prasugrel completely inhibited all aspirin-induced reaction symptoms, suggesting a contribution from P2Y12 receptor signaling in this subset.

KIT Inhibition by Imatinib in Patients with Severe Refractory Asthma

Cahill KN, Katz HR, Cui J, Lai J, Kazani S, Crosby-Thompson A, Garofolo D, Castro M, Jarjour N, DiMango E, Erzurum S, Trevor JL, Shenoy K, Chinchilli VM, Wechsler ME, Laidlaw TM, Boyce JA, Israel, E. KIT Inhibition by Imatinib in Patients with Severe Refractory Asthma. N Engl J Med. 2017, 376(20):1911-20. PMID:28514613

In a randomized, placebo-controlled, 24-week trial of imatinib in patients with poorly controlled severe asthma who had airway hyperresponsiveness despite receiving maximal medical therapy, imatinib decreased airway hyperresponsiveness, mast-cell counts, and tryptase release. These results suggest that KIT-dependent processes and mast cells contribute to the pathobiologic basis of severe asthma.

Thymic stromal lymphopoietin controls prostaglandin D2 generation in patients with aspirin-exacerbated respiratory disease

Buchheit KM, Cahill KN, Katz HR, Murphy KC, Feng C, Lee-Sarwar K, Lai J, Bhattacharyya N, Israel E, Boyce JA, and Laidlaw TM. Thymic stromal lymphopoietin controls prostaglandin D2 generation in aspirin-exacerbated respiratory disease. J Allergy Clin Immunol. 2016 May:137(5):1566-1576. PMID:26691435

This translational study found that urinary levels of a prostaglandin D2 metabolite (uPGD-M) were 2-fold higher in patients with AERD relative to those in aspirin-tolerant subjects and increased further during aspirin-induced reactions. Peak uPGD-M levels during aspirin reactions correlated with reductions in blood eosinophil counts and lung function and increases in nasal congestion. Nasal polyp mast cells expressed high levels of PGD2 synthase, which was correlated with nasal polyp TSLP mRNA expression. Levels of the active form of TSLP were increased in nasal polyps from patients with AERD, and recombinant TSLP induced PGD2 generation by cultured human mast cells. These findings suggested that mast cell-derived PGD2 is a major effector of type 2 immune responses driven by TSLP and that dysregulation of this innate system contributes significantly to the pathophysiology of AERD.

Prostaglandin D₂: a dominant mediator of aspirin-exacerbated respiratory disease

Cahill KN, Bensko JC, Boyce JA, Laidlaw TM. Prostaglandin D2: A dominant mediator of aspirin exacerbated respiratory disease. J Allergy Clin Immunol. 2015; 135(1):245-252. PMID:25218285

This observational study stratified 29 patients with AERD into those who tolerated aspirin desensitization and those who did not. Urine was analyzed for eicosanoid metabolites at baseline, during aspirin reactions, and during high-dose aspirin therapy. Blood was analyzed for cell differentials at baseline and during aspirin therapy. We found that failure to tolerate aspirin desensitization, and the development of severe extrapulmonary symptoms during the aspirin-induced reactions in AERD, is associated with prostaglandin D2 overproduction.

Cysteinyl leukotriene overproduction in aspirin-exacerbated respiratory disease is driven by platelet-adherent leukocytes

Laidlaw TM, Kidder MS, Bhattacharyya N, Xing W, Shen S, Milne GL, Castells MC, Chhay H, Boyce JA. Cysteinyl leukotriene overproduction in aspirin exacerbated respiratory disease is driven by platelet-adherent leukocytes. Blood. 2012; 119(16):3790-8. PMID:22262771

This study found that nasal polyps from subjects with AERD contained many extravascular platelets that colocalized with leukocytes, and the percentages of circulating neutrophils, eosinophils, and monocytes with adherent platelets were higher in the blood of subjects with AERD than in aspirin-tolerant controls. Platelet-adherent subsets of leukocytes had higher expression of several adhesion markers than did platelet nonadherent subsets. Adherent platelets contributed much of the LTC4 synthase activity of peripheral blood granulocytes, and urinary LTE4 levels correlated with percentages of circulating platelet-adherent granulocytes. Because platelet adherence to leukocytes allows for augmented transcellular conversion of leukotrienes, a disturbance in platelet-leukocyte interactions may be partly responsible for the overproduction of cysteinyl leukotrienes that characterize AERD.

Characterization of a novel human mast cell line that responds to stem cell factor and expresses functional FcεRI

Laidlaw TM, Steinke JW, Tiñana AM, Feng C, Xing W, Lam BK, Paruchuri S, Boyce JA, Borish L. Characterization of a novel human mast cell line that responds to stem cell factor and expresses functional FcεRI. J Allergy Clin Immunol. 2011; 127:815-22. PMID:21281958

This work characterized a human MC line, termed “LUVA cells” that arose spontaneously from a culture of nontransformed hematopoietic progenitor cells. LUVA cells are an immortalized human MC line that can be maintained without stem cell factor and display high levels of normally signaling c-kit and FcεRI, and may be valuable for future functional human MC studies.

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