Anti IL-5 Research Articles

Efficacy and Safety of Biologic Therapies for Treatment of Psoriasis: A Systematic Review and Observational Meta-Analysis

Abstract Background Psoriasis is a chronic, systemic, immune-mediated inflammatory skin disease of unknown etiology, however, several cytokines were reported to share in the pathogenesis of psoriasis as IL-12, IL- 23 and TNF-α. Biologics targeting these cytokines showed effective results in treatment of psoriasis patients. However, long term efficacy and tolerability of these agents is still questionable. Objective To compare the efficacy and safety of anti-TNF alpha, anti IL12/23, anti IL17, anti IL23 in moderate to severe psoriasis over long periods of treatment in order to complete the efficacy and safety profile of biologic therapies. Patients and Methods We searched ClinicalTrials.gov register (www.clinicaltrials.gov) up to July 2022 with the following search terms: psoriasis AND one by one each biologic therapy name listed in types of interventions. Results Regarding rate of PASI 75 at year 1, IL-12/23 inhibitors have a greater probability of achieving a PASI 75 response than anti-TNF alpha, with the pooled PASI 75 estimate at 84% and 76.18%, respectively. While, regarding rate of PASI 75 at year 2, 3, 4 and 5, there are no studies that assess the PASI 75 at year 2 or more for anti-TNF. The PASI 75 at years 2, 3, and 5 for IL- 12/23 inhibitors appeared to be stable at about 80 %, while it reached 91% at year 4. Rate of serious infections was 2.9% and 2.4% with anti-TNF alpha and IL-12/23 inhibitors respectively. There was showing no significant difference in the risk of serious infection between the two classes. In the current study, the rate of malignancy showed no-significant difference in psoriatic patients as patients receiving anti-TNF-alpha had 3.7% rate while in patients receiving IL 12/23 inhibitors the rate was 3.9%. Data Sources Medline databases (PubMed, Medscape, ScienceDirect. EMF-Portal) and all materials available in the Internet till 2023. Conclusion In the current meta-analysis we compare the efficacy and safety of anti-TNF alpha and anti IL12/23 in moderate to severe psoriasis over long periods of treatment in order to complete the efficacy and safety profile of biologic therapies. IL-12/23 inhibitors have a greater probability of achieving a PASI 75 response than anti-TNF alpha. There was no significant difference in the risk of serious infection or rate of malignancy between the two classes. Moreover, there was insignificant risk of MACEs with IL12/23 inhibitors and a slight increased risk with anti-TNF alpha. There was significant rate of common adverse events in patients receiving anti-TNF-alpha compared to patients receiving IL 12/23 inhibitors.

Anti–IL-4R versus anti–IL-5/5R after anti–IL-5/5R failure in asthma: An emulated target trial

BackgroundSwitching biologics is now common practice in severe eosinophilic asthma. After insufficient response to anti-interleukin 5 or 5 receptor (anti-IL-5/5R), the optimal switch between an anti-IL-4R monoclonal antibody (mAb) (inter-class) or another anti-IL-5/5R drug (intra-class) remains unknown. ObjectiveWe compared the effectiveness of these two strategies on asthma control in patients with severe eosinophilic asthma and insufficient response to an anti-IL-5/5R mAb. MethodsWe emulated a target randomized trial using observational data from the RAMSES Cohort. Eligible patients were switched to an anti-IL-4R mAb or another anti-IL-5/5R drug after insufficient response to an anti-IL-5/5R mAb. The primary outcome was the change in Asthma Control Test (ACT) score at 6 months. ResultsAmong the 2046 patients in the cohort, 151 were included in the study: 103 switched to an anti-IL-4R mAb and 48 to another anti-IL-5/5R. At 6 months, the difference in ACT score improvement was not statistically significant (mean difference groups, 0.82 [-0.47,2.10], p=0.213). The inter-class group exhibited greater cumulative reduction in oral corticosteroids dose (Pinter-intra -1.05g [-1.76, -0.34], p=0.041). The inter-class group had a better effect, although not significantly, on reducing exacerbations (Δinter-intra -0.37 [-0.77, 0.02], p=0.124) and increasing lung function (FEV1) (126.8 ml [-12.7, 266.4], p=0.124). ConclusionAfter anti-IL-5/5R mAb insufficient response, switching to dupilumab demonstrated similar improvement in ACT scores compared to intra-class switching. However, it appeared more effective in reducing oral corticosteroid use. Larger studies are warranted to confirm these results.

Faecal microbiota study reveals specific dysbiosis in spondyloarthritis according to subtype, disease activity and treatment

To compare the diversity and composition of the gastrointestinal microbiome of patients with SpA. MiSeq sequencing of the V3-V4 region of the 16S ribosomal RNA gene was performed on DNA isolated from stool. Patients with concurrent SpA and IBD were excluded. Differences were assessed for richness and diversity indices by QIIME 2™. Differences between means >0,2% with a p-value<0,05 were assumed significant. Institutional Ethics Committee endorsement. 69 individuals included, 49 with SpA (ankylosing spondylitis-AS 72,9%, psoriatic arthritis-PsA 18,8%, reactive arthritis-ReA 8,3%) 5 positive controls-dysbiosis and 15 controls-eubiosis. Conventional treatment in 42,9%, anti-IL-17 16,3% and anti-TNF 40,8%. By subtype, statistically significant differences in favour of AS were found for the diversity indices. AS vs PsA there was a difference in favour of AS for Clostridium clostridioforme (p=0,002), Gemmiger formicilis (p=0,009), Roseburia inulivorans (p=0,008) and Lachnospira pectinoschiza. AS vs ReA there was a difference in favour of AS for L. pectinoschiza (p=0,009), Ruminococcus callidus (p=0.006), Clostridium ruminantium (p=0.031); G. formicilis (p=0,034). Diversity and richness showed differences in patients with high activity for Simpson's and Pielou's indices. In high activity, lower enrichment of Bacteroides eggerthii (p= 0,0003), C. ruminantium (p= 0,026) and Alistipes putredinis (p=0,035) was found. The number of ASV was higher in the anti-IL-17 vs conventional group (p=0.025) and a trend between anti-IL-17 vs anti-TNF (p=0.09). In anti-TNF there was a lower proportion for C. clostridioforme (p=0.023), G. formicilis (p=0.030) and R. callidus (p= 0.003). In anti IL-17, Alistipes indistinctus (p= 0.012) was decreased. There are differences in microbial diversity for SpA subtypes. The level of disease activity is plausible to influence the composition of the faecal microbiota. Anti-TNFα treatment may influence the microbiome environment favouring restoration of the gut microbiota, while anti-IL-17 may maintain an inflammatory environment.

Опыт применения генно-инженерных биологических препаратов при тяжелой бронхиальной астме в Республике Саха (Якутия)

In the Republic of Sakha (Yakutia), from 2001 to 2020, the incidence of asthma is increasing from 4.1 per 1000 population to 12.5 per 1000 population. Considering that currently one of the most effective modern methods of treating severe asthma is genetic engineering biological therapy, research on biologically active medications, as well as the lack of research on this problem in the Yakut population, our work seems relevant. The purpose of this study was to evaluate the effectiveness of treatment with genetic engineering biological drugs (GEBD) in patients with severe asthma in the Yakut population. The study included 17 patients suffering from severe asthma. In 5 patients with severe asthma, the effectiveness of the following GEBD was assessed: anti IL-4, IL-13 drug, in 6 patients – anti IL-5 drug, in 6 patients – anti IgE drug. The effectiveness of treatment was assessed using the ACQ-5 symptom control test, the number of exacerbations over the previous 12 months of asthma therapy, IgE levels, the absolute number of eosinophils, indicators of external respiratory function, and the need of patients for additional asthma therapy. Before initiation, 8 (47.10%) patients had exacerbations and sought medical help; 2 patients were hospitalized in the pulmonology department; after 6 and 12 months, no exacerbations or hospitalizations in specialized hospitals were registered. When using a GEBD for 12 months, the need for inhaled corticosteroids decreased in micrograms/day. Thus, treatment of severe asthma in the Yakut population with GEBD makes it possible to achieve control over its symptoms, reduce the risk of severe exacerbations and the number of hospitalizations, and prevent side effects from high doses of standard therapy.

Impact of pre-biologic impairment on meeting domain-specific biologic responder definitions in patients with severe asthma

BackgroundThere is little agreement on clinically useful criteria for identifying real-world responders to biologic treatments for asthma. ObjectiveTo investigate the impact of pre-biologic impairment on meeting domain-specific biologic responder definitions in adults with severe asthma. MethodsThis was a longitudinal, cohort study across 22 countries participating in the International Severe Asthma Registry (https://isaregistries.org/) between May 2017 and January 2023. Change in 4 asthma domains (exacerbation rate, asthma control, long-term oral corticosteroid [LTOCS] dose, and lung function) was assessed from biologic initiation to 1 year post-treatment (minimum 24 weeks). Pre- to post-biologic changes for responders and nonresponders were described along a categorical gradient for each domain derived from pre-biologic distributions (exacerbation rate: 0 to 6+/y; asthma control: well controlled to uncontrolled; LTOCS: 0 to >30 mg/d; percent-predicted forced expiratory volume in 1 second [ppFEV1]: <50% to ≥80%). ResultsPercentage of biologic responders (ie, those with a category improvement pre- to post-biologic) varied by domain and increased with greater pre-biologic impairment, increasing from 70.2% to 90.0% for exacerbation rate, 46.3% to 52.3% for asthma control, 31.1% to 58.5% for LTOCS daily dose, and 35.8% to 50.6% for ppFEV1. The proportion of patients having improvement post-biologic tended to be greater for anti–IL-5/5R compared with for anti-IgE for exacerbation, asthma control, and ppFEV1 domains, irrespective of pre-biologic impairment. ConclusionOur results provide realistic outcome-specific post-biologic expectations for both physicians and patients, will be foundational to inform future work on a multidimensional approach to define and assess biologic responders and response, and may enhance appropriate patient selection for biologic therapies. Trial RegistrationThe ISAR database has ethical approval from the Anonymous Data Ethics Protocols and Transparency (ADEPT) committee (ADEPT0218) and is registered with the European Union Electronic Register of Post-Authorization studies (ENCEPP/DSPP/23720). The study was designed, implemented, and reported in compliance with the European Network Centres for Pharmacoepidemiology and Pharmacovigilance (ENCEPP) Code of Conduct (EUPAS38288) and with all applicable local and international laws and regulation, and registered with ENCEPP (https://www.encepp.eu/encepp/viewResource.htm?id=38289). Governance was provided by ADEPT (registration number: ADEPT1220).

Biologics in allergic rhinitis.

This paper aims to review biologics in allergic rhinitis (AR). Biologic agents of Omalizumab, Dupilumab, Mepolizumab, Reslizumab, and Benralizumab are reviewed in detail. The search is performed in "Pubmed," "Google," Google Scholar" and EBSCO Academic Search Ultimate (EKUAL) database of Kırıkkale University Library from 2021 to 2000, and randomized and/or placebo-controlled studies, review papers, meta-analysis, and reports are taken into consideration. The search was performed with the keywords of "allergic rhinitis," "biologics," "biologic agents," "Omalizumab," "Dupilumab," "Mepolizumab," "Reslizumab," "Benralizumab," "Anti IgE," "Anti-IL-4/IL-13", "Anti IL-5". Search is also performed in the "U.S. Food and Drug Administration" (FDA) and "European Medicines Agency" (EMA) web systems. Biological agents such as monoclonal antibodies (MAb) in treatment are called biological therapy or biotherapy. Omalizumab is a humanized Anti-IgE monoclonal antibody. Omalizumab treatment improved the Daily Nasal Rescue Medication Score (DNSSS) and decreased the use of antiallergic drugs in seasonal and perennial AR and rhino-conjunctivitis. Omalizumab is also used in specific immunotherapy patients with allergic rhinitis and reduced allergic reactions associated with allergen immunotherapy, such as anaphylaxis. Dupilumab is an Anti-IL-4/IL-13 biologic agent. Dupilumab treatment significantly improved sino-nasal Outcome Test (SNOT-22) total scores in perennial allergic rhinitis. Anti-IL-5 monoclonal antibodies of Mepolizumab, Reslizumab Benralizumab reduce the number of eosinophils in the blood and tissue, corticosteroid addiction and asthma attacks are reduced, and their use in the treatment of severe eosinophilic asthma has been approved. Biologics, especially Omalizumab, and Dupilumab, may be used more in allergic rhinitis.

Effectiveness of Dupilumab in the Treatment of Adult and Older Adult Patients with Severe, Uncontrolled CRSwNP.

Chronic rhinosinusitis with nasal polyps (CRSwNP) is a multifactorial disease that significantly impacts patients' quality of life. New therapeutic strategies and in particular biologic treatments are now available for these patients. It has been demonstrated that Dupilumab (an anti IL-4/IL-13 biologic drug) is effective in reducing the size of nasal polyps and in improving patients' symptoms and thus, quality of life. No real-world studies examining Dupilamab's efficacy in the elderly with respect to other adult age groups have as yet been carried out. The aim of this multicentric study was to evaluate Dupilumab's efficacy in young-middle adults as opposed to an older adult population affected by severe, uncontrolled CRSwNP. Of the 96 patients included in the study, 22 were 65 years old or older. Significant improvements were observed in all the parameters considered in both age groups after treatment was begun (T0 mean values for SNOT-22 = 58.5 ± 20.3, VAS NO = 7.6 ± 2.2, VAS smell = 8.6 ± 2.1, NPS = 5.6 ± 1.4, PNIF = 101.6 ± 59.4, S'S = 5.1 ± 3.1), T4 mean values for SNOT-22 = 15.1 ± 12.7, VAS NO = 1.7 ± 1.8, VAS smell = 2.4 ± 3, NPS = 1.7 ± 1.7, PNIF = 162.4 ± 43.2, S'S = 10.4 ± 3.7) (p < 0.0001). No differences in the variables considered were observed between the two age groups during the study, with the exception of the Peak Nasal Inspiratory Flow (PNIF), which was marginally higher; this was also the case according to multivariate analyses (p = 0.008) in the young-middle adult group with respect to the elderly one (p = 0.07). At multivariate analyses, asthma and the female sex negatively influenced the PNIF values (p = 0.001 and p = 0.012, respectively). Age negatively influenced the Visual Analog Scale (VAS) for nasal obstruction (p = 0.0032) and Endoscopic Sinus Surgery (ESS) negatively influenced the patents' olfactory performance (p = 0.028) to the same degree in both groups. Dupilumab was found to be effective to the same degree in both age groups. It can be considered a safe and reliable option for the treatment of elderly patients with severe, uncontrolled CRSwNP.

Severe asthma clinical remission after biologic treatment with anti-IL4/IL13: A real-life experience

IntroductionDupilumab, a fully human anti-interleukin-4/interleukin-13 monoclonal antibody, has shown efficacy in many aspects of Type-2 severe asthma management. Currently, we lack real-life studies addressing the achievment of clinical remission in patients treated with this biologic. Materials and methodsWe performed a prospective study enrolling 18 patients with severe asthma treated with Dupilumab. We assessed main clinical, functional and biological severe asthma features at baseline (T0) and after a 1-year course of treatment (T12). Clinical remission was defined at T12 in patients without asthma exacerbations, no oral corticosteroid (OCS) use, ACT ≥ 20 and FEV1 improvement ≥ 100 ml from baseline. ResultsAmong total population, 38.9% of patients achieved clinical remission at T12. Anti IL-4/IL-13 treatment significantly reduced asthma exacerbations and OCS use in the overall cohort, with a more pronounced ACT improvement in the remission group. Patients achieving clinical remission went through a step down of the inhalation therapy, suspending long-acting anti-muscarinics administration at T12. ConclusionsTreatment with anti-IL4/IL13 can induce clinical remission in patients with T2 severe asthma.

Tralokinumab shows clinical improvement in patients with prurigo nodularis-like phenotype atopic dermatitis: A multicenter, prospective, open-label case series study

There are several phenotypes of atopic dermatitis (AD). 1 Girolomoni G. de Bruin-Weller M. Aoki V. et al. Nomenclature and clinical phenotypes of atopic dermatitis. Ther Adv Chronic Dis. 2021; 2620406223211002979 Google Scholar The prurigo nodularis (PN)-like phenotype occurs in nearly one-half of the patients with AD. 1 Girolomoni G. de Bruin-Weller M. Aoki V. et al. Nomenclature and clinical phenotypes of atopic dermatitis. Ther Adv Chronic Dis. 2021; 2620406223211002979 Google Scholar In all AD phenotypes, chronic itch usually leads to an itch-scratch cycle with the development of secondary lesions. These include, in the PN-like phenotype, excoriated hyperkeratotic, intensely itchy papules and nodules in areas accessible to scratch. 1 Girolomoni G. de Bruin-Weller M. Aoki V. et al. Nomenclature and clinical phenotypes of atopic dermatitis. Ther Adv Chronic Dis. 2021; 2620406223211002979 Google Scholar An emergent role of the type 2 cytokines, including interleukin (IL) 4, IL-13, IL-31, and IL-5, has been suggested in the pathogenesis underlying AD itch. IL-13 is a potent enhancer of the neuronal response to different itch stimuli. 2 Miron Y. Miller P.E. Hughes C. et al. Mechanistic insights into the antipruritic effects of lebrikizumab, an anti–IL-13 mAb. J Allergy Clin Immunol. 2022; 150: 690-700 Abstract Full Text Full Text PDF PubMed Scopus (9) Google Scholar Tralokinumab, a fully human IgG4 monoclonal antibody neutralizing IL-13, is a novel treatment that has demonstrated safety and efficacy in clinical trials in treating adult patients with moderate-to-severe AD. 3 Wollenberg A. Blauvelt A. Guttman-Yassky E. et al. Tralokinumab for moderate-to-severe atopic dermatitis: results from two 52-week, randomized, double-blind, multicentre, placebo-controlled phase III trials (ECZTRA 1 and ECZTRA 2). Br J Dermatol. 2021; 184: 437-449 Crossref PubMed Scopus (170) Google Scholar In our open-label, retrospective case series study, tralokinumab improved clinical manifestations in 2 patients presenting with PN-like phenotype. 4 Pezzolo E. Naldi L. Tralokinumab in the treatment of resistant atopic dermatitis: an open-label, retrospective case series study. J Eur Acad Dermatol Venereol. 2023; 37: e644-e645 Crossref Scopus (2) Google Scholar Therefore, we prospectively investigated tralokinumab efficacy and safety in treating for at least 16 weeks, 17 adult patients with moderate-to-severe PN-like phenotype AD at 5 dermatology tertiary referral centers, from July 2021 to November 2022. Patients were eligible for treatment with tralokinumab after failing the first-line approved biologic treatment dupilumab, without achieving eczema area and severity index (EASI)-50 after 16 weeks of treatment. Written informed consent was obtained for each patient. At baseline, patients (mean age, 60.75 years; 76.5% women) presented moderate-to-severe PN-like phenotype AD and with means (ranges) EASI of 27.2 (16-45), Investigator Global Assessment (IGA) of 3.7 (3-4), numeric rating scale (NRS)-itch of 9.8 (8-10), NRS-sleeplessness of 8.9 (6-10), and dermatology life and quality index (DLQI) of 16.3 (14-24). Seventy percent of patients used concomitant topical corticosteroids at baseline. Patients reached EASI-50 within 4 weeks, EASI-75 within 12 weeks, and EASI-90 within 32 weeks (mean EASI reduction from 27.2-1.7, P <.001) (Fig 1). The mean NRS-itch and sleeplessness and DLQI values significantly decreased as early as week 4 (P <.001) and progressively reduced after 16-week continuous treatment. Tralokinumab resulted in complete or almost complete clinical remission (IGA 0 or 1) in 76% (13/17) of patients, in 47% (8/17) within week 12, in 23% within week 32, and 6% within week 64, and an at least 2-grade IGA reduction in the others (24%) (Fig 2). Both patients with 16-weeks treatment observation (8/17) and patients with 32 or 64 weeks of continuous treatment (9/17) maintained clinical efficacy without reporting any serious adverse effect. 5 Licata G, Tancredi V, Pezzolo E, et al. Efficacy and safeness of tralokinumab in patients with atopic dermatitis who developed conjunctivitis under dupilumab: a case series. J Eur Acad Dermatol Venereol. Published online April 5, 2023. https://doi.org/10.1111/jdv.19108 Google Scholar Mild conjunctivitis represented the main adverse effect (12%), followed by injection-site reaction, localized urticaria, and mild herpetic stomatitis. Fig 2Atopic dermatitis severity assessed by the Investigator Global Assessment score at different times. IGA, Investigator Global Assessment. View Large Image Figure Viewer Download Hi-res image

Dupilumab as Adjunct Treatment for Persistent Food Allergy in Adulthood

Atopic disease affects both immunocompetent and immunodeficient patients. Known risk factors for atopic disease, such as atopic dermatitis (AD) and IgE mediated food allergy, include impaired skin integrity, Th2 predominance, and altered T-regulatory activity. Food allergies in particular can be life-threatening and there is no known cure, although immunomodulatory (anti IL-4Rα/IL-13, anti IL-5, and anti IgE) trials for food allergy are underway. The allergen-specific IgE levels and skin prick tests of atopic dermatitis patients often decrease while on dupilumab (anti IL-4Rα/IL-13) therapy but the question remains: does dupilumab improve or eliminate food allergy? One case report has reported success with dupilumab in an adult woman. Here we describe the de-labeling of several allergenic foods in an adult patient being treated for AD with dupilumab.A 29-year-old man presented to our allergy clinic with a history of severe AD and multiple food allergies. His eczema had been recalcitrant to high-dose topical steroids, BB-UVB phototherapy, cyclosporine, methotrexate, and both intramuscular and intralesional Kenalog (ILK). He finally improved on weekly dupilumab dosing and did not have adverse effects from dupilumab therapy. His food allergies posed significant morbidity with multiple reactions requiring epinephrine as well as ongoing anxiety regarding cross-contact. His history is notable for childhood reactions to peanut, tree nuts, fish, and shellfish, with concordantly elevated skin prick and specific IgE levels. After dupilumab therapy, these reactions decreased, leading to a risk/benefit discussion and agreement to perform physician-guided oral food challenges in an effort to broaden his diet (Figure 1). The majority of challenges were passed and the patient has maintained those foods in his diet (Figure 2). In addition, the patient reports substantial improvement in his anxiety at work as well as in social interactions. In this case, dupilumab as an immodulatory agent for AD offered the additional benefit of decreasing morbidity from food allergies. Given the persistence of food allergy, further research into adjunctive therapeutic options is vital to improving patient quality of life. Unlike other therapies like JAKinhibitors and systemic steroids used for atopic dermatitis, anti-IL-4Rα/IL-13 therapy is not immunosuppressive and has a favorable side-effect profile for patients. [Display omitted] [Display omitted]

593 Inverse psoriasis involvement in moderate to severe psoriatic patients: A comparison between anti IL23 and anti IL17

593 Inverse psoriasis involvement in moderate to severe psoriatic patients: A comparison between anti IL23 and anti IL17

Upper airway disease diagnosis as a predictive biomarker of therapeutic response to biologics in severe asthma.

Asthma is a heterogeneous disease sharing airway instability but with different biology, risk factors, and response-to-therapy patterns. Biologics have revolutionized the one-size-fits-to-all approach to personalized medicine in severe asthma (SA), which relies on the identification of biomarkers that define distinct endotypes. Thus, blood eosinophils and, to some extent, exhaled nitric oxide (FeNO) can predict the response to approved anti-type 2 (T2) biologics (anti-IgE, anti-IL-5, and anti-IL-4R alpha), whereas age at onset and comorbidities such as anxiety/depression, obesity, reflux, and upper airway disease (UAD) also influence therapeutic responses in SA. In this article, focusing on the predictive value of biomarkers for the therapeutic response to biologics in SA, we first summarize the level of prediction achieved by T2 biomarkers (blood eosinophils, FeNO) and then review whether data support the predictive value of upper airway diagnosis on such outcomes. Post hoc analysis of most studies with T2 biologics suggests that chronic rhinosinusitis with nasal polyps (CRSwNP) and, to a lower extent, allergic rhinitis may help in predicting clinical response. Considering that T2 biologics are now also approved for the treatment of severe CRSwNP, diagnosis of upper airway disease is a key step in determining eligibility for such therapy.

CARD14 Missense Variant Underlying CARD14-Associated Papulosquamous Eruption with Beneficial Response to Secukinumab

CARD14-associated papulosquamous eruption is an autosomal dominant genodermatosis characterized by early-onset, generalized erythematous patches and plaques with prominent scales, mostly with facial involvement. Heterozygous gain-of-function variants in the CARD14 gene have been reported to be causative for this entity. The pathogenesis mainly involves the IL-23‒IL-17 inflammatory circuit, yet the efficacy of anti‒IL-17 treatment remained less examined. In this study, we report one previously unidentified variant underlying the CARD14-associated papulosquamous eruption and showed its gain-of-function property. Furthermore, we present the beneficial effect of anti‒IL-17A treatment in our patient.

Allergic bronchopulmonary aspergillosis in identical twins: Effectiveness of dupilumab

Allergic bronchopulmonary aspergillosis in identical twins: Effectiveness of dupilumab

Skin Related Paradoxical Adverse Events (Mainly Psoriasis) During Il-17 Blockage: A Systematic Review

Background: Paradoxical Adverse Events (PAEs) during biological therapy are characterized by the onset of a new inflammatory disease or by the exacerbation of the preexisting condition (with a different morphology or localization) while treating the patient with a class-agent proven efficacious for both conditions. They can be divided in two subgroups: “true PAE” characterized by the previously proven efficacy of the biological agent for the PAE and “borderline PAE” defined by the development of an inflammatory condition where the biological agent has not a proven efficacy. Methods: systematic search of English databases in order to identify true and borderline-skin PAE under anti IL-17 therapy. Results: We retrieved 58 patients affected by skin-PAE during anti-IL-17 therapy, 40 cases classified as True-PAE and 18 as Borderline-PAE., with a mean age of onset of 51 years. Secukinumab was the most frequent agent associated to skin-PAE and mean onset of the skin-PAE was 18 weeks. Conclusion: True-skin-PAE occur during anti Il-17 therapy, the underlaying immunological mechanism is not yet known, but pustular variants of psoriasis seem to be more prevalent; withdrawal of the anti-IL-17 therapy has been mainly performed and other therapies such as antiIL-23 biologics seem to control both the underlying disease and the true-skin-PAE. Further studies are needed in order to better understand the immunological mechanism involved.

Spondyloarthritides: Theories and beyond.

Spondyloarthritides (SpA) are a family of interrelated rheumatic disorders with a typical disease onset ranging from childhood to middle age. If left untreated, they lead to a severe decrease in patients' quality of life. A succesfull treatment strategy starts with an accurate diagnosis which is achieved through careful analysis of medical symptoms. Classification criterias are used to this process and are updated on a regular basis. Although there is a lack of definite knowledge on the disease etiology of SpA, several studies have paved the way for understanding plausible risk factors and developing treatment strategies. The significant increase of HLA-B27 positivity in SpA patients makes it a strong candidate as a predisposing factor and several theories have been proposed to explain HLA-B27 driven disease progression. However, the presence of HLA-B27 negative patients underlines the presence of additional risk factors. The current treatment options for SpAs are Non-Steroidal Anti-Inflammatory Drugs (NSAIDs), TNF inhibitors (TNFis), Disease-Modifying Anti-Rheumatic Drugs (DMARDs) and physiotherapy yet there are ongoing clinical trials. Anti IL17 drugs and targeted synthetic DMARDs such as JAK inhibitors are also emerging as treatment alternatives. This review discusses the current diagnosis criteria, treatment options and gives an overview of the previous findings and theories to clarify the possible contributors to SpA pathogenesis with a focus on Ankylosing Spondylitis (AS) and enthesitis-related arthritis (ERA).

PROLONGED BLOOD HYPEREOSINOPHILIA AND EOSINOPHILIC ENTEROCOLITIS FROM PINWORM INFECTION ASSOCIATED WITH IGA AND IGE DEFICIENCY

<h3>Introduction</h3> Pinworm (<i>Enterobius vermicularis</i>) infection is generally considered a benign infection without systemic symptoms. However, severe infections can cause gastrointestinal inflammation, blood eosinophilia and systemic symptoms. What factors contribute to severe disease remains unclear. We present a case of pinworm infection causing prolonged blood hypereosinophilia and eosinophilic enterocolitis in a patient with severe combined IgA and IgE deficiency. <h3>Case Description</h3> A 16-year-old, non-atopic female presented at age 10 with intermittent low-grade fevers, abdominal pain and blood eosinophilia (AEC 3100 cells/mcL). Etiology was undetermined. As her abdominal pain continued, she was diagnosed with IBS; her blood hypereosinophilia persisted and remained unexplained. At age 15, she developed recurrent episodes of abdominal pain, non-bloody watery diarrhea and intermittent emesis. Evaluation revealed severe blood eosinophilia (AEC 6200 cells/mcL), elevated fecal calprotectin (95 mcg/gm) and gastrointestinal (esophagus, stomach, small and large intestine) eosinophilic inflammation. Direct endoscopic visualization, stool and serology testing for parasites were negative. Immunologic evaluation revealed mildly decreased IgG (621 mg/dL), undetectable IgE, low IgA (14.5 mg/dL) and normal IgM. Eosinophilia etiology remained undetermined; she was diagnosed with hypereosinophilic syndrome and treated with mepolizumab (anti–IL-5), which improved her blood eosinophilia but not her symptoms. Repeat EGD/colonoscopy (after 6 months) showed improved gastrointestinal eosinophilia but was notable for direct visualization of pinworms. Mepolizumab was discontinued. Albendazole completely resolved her symptoms; blood eosinophilia and IgG normalized, but IgA and IgE remained undetectable. <h3>Discussion</h3> Pinworms can cause persistent gastrointestinal disease and severe blood hypereosinophilia. We postulate that mucosal immunodeficiency secondary to IgA and IgE deficiency contributed to this presentation.

Peribronchial Inflammation Resulting from Regulatory T Cell Deficiency Damages the Respiratory Epithelium and Disturbs Barrier Function.

Regulatory T cells (Tregs) that express the transcription factor Foxp3 have a critical role in limiting inflammatory processes and tissue damage. Whether Tregs are functional in maintaining epithelial barriers and in control of tight junction expression has not yet been explored. In this study, we investigated the effect of Treg deficiency on the airway epithelial barrier in an experimental murine model in which diphtheria toxin was repeatedly injected in Foxp3-diphtheria toxin receptor (DTR) mice to deplete Tregs. This resulted in spontaneous peribronchial inflammation and led to a systemic and local increase of IL-4, IL-5, CCL3, IFN-γ, and IL-10 and a local (lung) increase of IL-6 and IL-33 and decreased amphiregulin levels. Moreover, Treg depletion increased airway permeability and decreased epithelial tight junction (protein and mRNA) expression. CTLA4-Ig treatment of Treg-depleted mice almost completely prevented barrier dysfunction together with suppression of lung inflammation and cytokine secretion. Treatment with anti-IL-4 partly reversed the effects of Treg depletion on tight junction expression, whereas neutralization of IL-6 of IFN-γ had either no effect or only a limited effect. We conclude that Tregs are essential to protect the epithelial barrier at the level of tight junctions by restricting spontaneous T cell activation and uncontrolled secretion of cytokines, in particular IL-4, in the bronchi.

Eosinophilia Induced by Blocking the IL-4/IL-13 Pathway: Potential Mechanisms and Clinical Outcomes.

Five biological drugs are currently marketed for treatment of uncontrolled severe asthma. They all block type 2 inflammatory pathways by targeting IgE (omalizumab), the IL-5 pathway (mepolizumab, reslizumab, benralizumab), or the IL-4/IL-13 pathway (dupilumab). Hypereosinophilia has been observed in 4%-25% of patients treated with dupilumab and is transient in most cases, although there have been reports of persistent cases of symptomatic hypereosinophilia consistent with eosinophilic granulomatosis with polyangiitis (EGPA), eosinophilic pneumonia, eosinophilic vasculitis, and sudden worsening of asthma symptoms. Cases of EGPA have been reported with all biologics, including anti-IL-5 agents, and with leukotriene receptor antagonists in publications or in the EudraVigilance database. In many cases, EGPA appears during tapering of systemic corticosteroids or after switching from an anti-IL-5 biologic to dupilumab, suggesting that systemic corticosteroids or the anti-IL-5 agent were masking vasculitis. This review investigates plausible mechanisms of dupilumab-induced hypereosinophilia and review cases of symptomatic hypereosinophilia associated with dupilumab. Blockade of the IL-4/IL-13 pathway reduces eosinophil migration and accumulation of blood by inhibiting eotaxin-3, VCAM-1, and TARC without simultaneously inhibiting eosinophilopoiesis in bone marrow. When choosing the optimal biologic, it seems necessary to consider the presence of hypereosinophilia (>1500/μL), in which case an anti-IL-5/IL-5R agent is preferable. Furthermore, when switching from an anti-IL-5/5R to an anti-IL-4/13R agent, blood eosinophils and clinical progress should be closely monitored. Nevertheless, dual therapy with anti-IL-5/5R and anti-IL4/IL-13R agents may be needed for optimal control, since both the IL-5 and the IL-4/IL-13 pathways can simultaneously contribute to airway inflammation. This approach can prevent the development of EGPA and other types of symptomatic hypereosinophilia while maintaining control of nasal polyposis. In the near future, it will be possible to use a new generation of biological therapies for the treatment of severe asthma. These act at a higher level of the inflammatory cascade, as is the case of the antialarmins tezepelumab and itepekimab.

Immunological Effects of Anti‒IL-17/12/23 Therapy in Patients with Psoriasis Complicated by Candida Infections

Biologics that block the T helper (Th) 17 pathway are very effective in the treatment of psoriasis and other inflammatory diseases. However, IL-17 is also crucial for antifungal host defense, and clinical trial data suggest an increase in the incidence of Candida infections during IL-17 inhibitor (IL-17i) therapy. We investigated the innate and adaptive immune responses of patients with psoriasis with a history of skin and/or mucosal candidiasis during IL-17i or IL-12/23 inhibitor therapy, comparing those responses with those of healthy controls. Patients with psoriasis with IL-17i showed significantly lower CD4+Th1-like (CCR6‒CXCR3+CCR4‒) and Th1 Th17-like (CD4+CCR6+CXCR3+CCR4‒) cell percentages. Patient cells stimulated with Candida albicans produced significantly lower IL-6 in the IL-12/23 inhibitor group and IL-1β in the IL-17i group, whereas the release of TNF-α and ROS was similar between patients and controls. IFN-γ and IL-10 production in response to several stimuli after 7 days was particularly decreased in patients receiving IL-17i therapy. Finally, after stimulation with the polarizing cytokines IL-1β and IL-23, the Th17 cytokine response was significantly lower in the IL-17i patient group. These innate and adaptive immune response defects can diminish antifungal host immune response and thereby increase susceptibility to candidiasis in patients treated with IL-17i or IL-12/23 inhibitor.