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Boscia G, Spataro F, Desantis V, Solimando AG, Vacca A, Ria R, Savastano A. Ocular Side Effects of Dupilumab: A Comprehensive Overview of the Literature. J Clin Med 2025; 14:2487. [PMID: 40217936 PMCID: PMC11989250 DOI: 10.3390/jcm14072487] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/09/2025] [Revised: 04/02/2025] [Accepted: 04/03/2025] [Indexed: 04/14/2025] Open
Abstract
Dupilumab, a monoclonal antibody targeting the interleukin (IL)-4 receptor alpha subunit and IL-13, has markedly advanced the treatment of atopic conditions such as dermatitis, asthma, and chronic rhinosinusitis. However, its expanding use has brought increased attention to a range of ocular adverse events-conjunctivitis, blepharitis, keratitis, corneal ulcers, and cicatricial conjunctivitis-that remain underrecognized and frequently underestimated in clinical practice. These manifestations often emerge in patients with atopic dermatitis and display varying severity, posing diagnostic and therapeutic challenges. Rather than isolated phenomena, these effects appear to stem from a complex interplay of goblet cell depletion, mucin deficiency, immune dysregulation, and microbiome alterations, including Demodex proliferation. Current management strategies remain largely empirical, lacking standardized protocols, and are often guided by anecdotal evidence. In this review, we critically appraise the existing literature, synthesize emerging pathogenic hypotheses, and highlight the unmet clinical need for evidence-based treatment algorithms. We advocate for a multidisciplinary approach and future research aimed at elucidating mechanisms, refining risk stratification, and minimizing ocular toxicity without compromising the therapeutic benefits of dupilumab. Furthermore, we intend to provide a more practical and straightforward resource for the reader based on the current literature on approaching the topic.
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Affiliation(s)
- Giacomo Boscia
- Department of Translational Biomedicine Neuroscience, University of Bari “Aldo Moro”, 70121 Bari, Italy
| | - Federico Spataro
- Guido Baccelli Unit of Internal Medicine, Department of Precision and Regenerative Medicine and Ionian Area (DiMePRe-J), University of Bari Aldo Moro, 70124 Bari, Italy
| | - Vanessa Desantis
- Section of Pharmacology, Department of Precision and Regenerative Medicine and Ionian Area (DiMePRe-J), School of Medicine, University of Bari Aldo Moro, 70124 Bari, Italy;
| | - Antonio Giovanni Solimando
- Guido Baccelli Unit of Internal Medicine, Department of Precision and Regenerative Medicine and Ionian Area (DiMePRe-J), School of Medicine, University of Bari Aldo Moro, 70124 Bari, Italy; (A.G.S.); (A.V.); (R.R.)
| | - Angelo Vacca
- Guido Baccelli Unit of Internal Medicine, Department of Precision and Regenerative Medicine and Ionian Area (DiMePRe-J), School of Medicine, University of Bari Aldo Moro, 70124 Bari, Italy; (A.G.S.); (A.V.); (R.R.)
| | - Roberto Ria
- Guido Baccelli Unit of Internal Medicine, Department of Precision and Regenerative Medicine and Ionian Area (DiMePRe-J), School of Medicine, University of Bari Aldo Moro, 70124 Bari, Italy; (A.G.S.); (A.V.); (R.R.)
| | - Alfonso Savastano
- School of Medicine, Libera Università Mediterranea Degennaro, 70010 Casamassima, Italy;
- Ospedale Generale Regionale F. Miulli, 70021 Acquaviva delle Fonti, Italy
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Abdel-Mageed HM. Atopic dermatitis: a comprehensive updated review of this intriguing disease with futuristic insights. Inflammopharmacology 2025; 33:1161-1187. [PMID: 39918744 PMCID: PMC11914373 DOI: 10.1007/s10787-025-01642-z] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/18/2024] [Accepted: 01/10/2025] [Indexed: 03/19/2025]
Abstract
Atopic dermatitis (AD) is a paradigmatic prevalent, long-lasting, and inflammatory skin condition with a diverse range of clinical manifestations. The etiology and clinical symptoms of AD are influenced by complex pathophysiological processes, which involve a strong genetic component, epidermal dysfunction, and immunological dysregulation, and a strong influence of other physiological and environmental factors. The FDA has approved targeted and well-tolerated immunomodulators including biologics like dupilumab and crisaborole, and small molecules such as baricitinib, as novel therapies for AD. They effectively treat AD but are too expensive for most patients. The review provides an update on the state of knowledge of AD pathogenesis, discusses the available diagnostic and scoring indices, and provides a scientific foundation for treatment methods for AD. This review also presents data on clinical efficacy of innovative treatments' considering recent guidelines, emphasizing the newest medications and ongoing trials. Finally, the new implication of artificial intelligence (AI) in AD management is explored, where AI can speed up diagnosis and therapy. The PubMed, Google Scholar, and ScienceDirect databases were used for this review.
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Affiliation(s)
- Heidi M Abdel-Mageed
- Molecular Biology Department, National Research Centre, El Behoth St, Dokki, Giza, Egypt.
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3
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Silverberg JI, Bieber T, Paller AS, Beck L, Kamata M, Puig L, Wiseman M, Ezzedine K, Irvine AD, Foley P, Del Rosso J, Gold LS, Johansson E, Dossenbach M, Gallo G, Akmaz B, Casillas M, Karlsson A, Curteis T, Chovatiya R. Lebrikizumab vs Other Systemic Monotherapies for Moderate-to-Severe Atopic Dermatitis: Network Meta-analysis of Efficacy. Dermatol Ther (Heidelb) 2025; 15:615-633. [PMID: 39953372 PMCID: PMC11909319 DOI: 10.1007/s13555-025-01357-7] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/13/2024] [Accepted: 02/03/2025] [Indexed: 02/17/2025] Open
Abstract
INTRODUCTION A systematic literature review and network meta-analysis (NMA) were conducted to compare the short-term efficacy of lebrikizumab to other biologic and Janus kinase (JAK) inhibitor monotherapies approved for moderate-to-severe atopic dermatitis in adults and adolescents. METHODS The NMA included randomized, double-blind, placebo-controlled monotherapy phase 2 and 3 trials of biologics (lebrikizumab 250 mg every 2 weeks [Q2W], dupilumab 300 mg Q2W, and tralokinumab 300 mg Q2W) and JAK inhibitors (abrocitinib 100/200 mg daily, baricitinib 2/4 mg daily, and upadacitinib 15/30 mg daily) at approved doses. Efficacy outcomes included the proportions of patients achieving Eczema Area and Severity Index (EASI) improvement, an Investigator Global Assessment of 0 or 1 (IGA 0/1), and a ≥ 4-point improvement in pruritus/itch numeric rating scale score at 12 weeks (abrocitinib) or 16 weeks (other treatments). Itch was also assessed at week 4. A Bayesian NMA employing baseline risk-adjusted random effects models was used to estimate treatment differences. RESULTS Twenty-two monotherapy studies involving 8531 patients were included in the NMA. By week 12/16, lebrikizumab had superior odds of achieving IGA 0/1 and itch improvement compared to baricitinib and tralokinumab; similar odds to dupilumab, abrocitinib, and upadacitinib 15 mg; and inferior odds to upadacitinib 30 mg. Additionally, lebrikizumab had a higher probability of improving EASI than baricitinib 2 mg; similar probability to baricitinib 4 mg, tralokinumab, dupilumab, abrocitinib, and upadacitinib 15 mg; and lower probability than upadacitinib 30 mg daily. At week 4, lebrikizumab had superior odds of improving itch compared to tralokinumab; similar odds to baricitinib, dupilumab, and abrocitinib 100 mg; and inferior odds to abrocitinib 200 mg and upadacitinib. CONCLUSION Among biologics, lebrikizumab was comparable to dupilumab and superior to tralokinumab in improving response rates at week 16. Upadacitinib 30 mg was the only JAK inhibitor with superior response rates compared to lebrikizumab.
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Affiliation(s)
- Jonathan I Silverberg
- Department of Dermatology, The George Washington University School of Medicine and Health Sciences, Washington, USA.
| | - Thomas Bieber
- Medicine Campus Davos, Davos, Switzerland
- Department of Dermatology, University Hospital, Zurich, Switzerland
| | - Amy S Paller
- Department of Dermatology, Northwestern University Feinberg School of Medicine, Chicago, USA
| | - Lisa Beck
- University of Rochester Medical Center, Rochester, USA
| | - Masahiro Kamata
- Department of Dermatology, Teikyo University School of Medicine, Tokyo, Japan
| | - Luis Puig
- Department of Dermatology, Hospital de la Santa Creu i Sant Pau, Barcelona, Spain
| | - Marni Wiseman
- Department of Dermatology, University of Manitoba, Winnipeg, Canada
- SKiNWise Dermatology, Winnipeg, Canada
| | | | - Alan D Irvine
- Department of Clinical Medicine, Trinity College, Dublin, Ireland
| | - Peter Foley
- Skin Health Institute, Carlton, VIC, Australia
| | | | | | | | | | - Gaia Gallo
- Eli Lilly and Company, Indianapolis, USA
| | | | | | | | | | - Raj Chovatiya
- Rosalind Franklin University Chicago Medical School, North Chicago, USA
- The Center for Medical Dermatology + Immunology Research, Chicago, USA
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Katoh N, Tanaka A, Takahashi H, Shimizu R, Kataoka Y, Torisu-Itakura H, Morisaki Y, Igawa K. Efficacy and safety of lebrikizumab combined with topical corticosteroids in Japanese patients with moderate-to-severe atopic dermatitis: a phase 3, double-blind, placebo-controlled, randomized clinical trial (ADhere-J). Curr Med Res Opin 2025; 41:1-12. [PMID: 39625230 DOI: 10.1080/03007995.2024.2436982] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/17/2024] [Revised: 11/28/2024] [Accepted: 11/28/2024] [Indexed: 12/14/2024]
Abstract
OBJECTIVE To evaluate efficacy and safety of lebrikizumab combined with topical corticosteroids (TCS) in Japanese patients with moderate-to-severe atopic dermatitis (AD). METHODS Phase 3, randomized, double-blind, placebo-controlled study (ADhere-J; NCT04760314) conducted at 37 centers in Japan (March 2021-February 2023), comprising 16-week induction (reported herein) and 52-week maintenance periods. Overall, 286 patients aged ≥12 years and ≥40 kg were randomized (interactive web response system) to subcutaneous placebo, lebrikizumab 250 mg every 4 weeks (Q4W), or lebrikizumab 250 mg every 2 weeks (Q2W) with TCS (82, 81, and 123 patients, respectively). Coprimary endpoints were proportions of patients achieving (1) Investigator's Global Assessment score of 0 or 1 (IGA [0,1]) with ≥2-point improvement from baseline, and (2) ≥75% improvement from baseline in Eczema Area and Severity Index (EASI 75) at week 16. RESULTS At week 16, compared with placebo, a significantly greater proportion of the lebrikizumab Q4W and Q2W groups achieved IGA (0,1) (6.1% vs. 29.1% and 33.4%, respectively; both p < 0.001) and EASI 75 (13.4% vs. 47.2% and 51.2%, respectively; both p < 0.001). Serious adverse events (AEs) occurred in 2.4%, 0%, and 0.8% of placebo, lebrikizumab Q4W and Q2W groups, respectively. Common treatment-emergent AEs, including pyrexia (placebo: 15.9%; lebrikizumab Q4W/Q2W: 18.5%/20.3%), conjunctivitis allergic (placebo: 4.9%; lebrikizumab Q4W/Q2W: 12.3%/17.1%), and conjunctivitis (placebo: 2.4%; lebrikizumab Q4W/Q2W: 6.2%/9.8%), were more frequent with lebrikizumab; most were mild or moderate. CONCLUSION Consistent with global data, lebrikizumab demonstrated clinical improvements with a positive benefit-risk profile in Japanese adults and adolescents with moderate-to-severe AD through 16 weeks.
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Affiliation(s)
- Norito Katoh
- North Campus, Kyoto Prefectural University of Medicine, Kyoto, Japan
| | - Akio Tanaka
- Department of Dermatology, Graduate School of Biomedical and Health Sciences, Hiroshima University, Hiroshima, Japan
| | | | | | - Yoko Kataoka
- Department of Dermatology, Osaka Habikino Medical Center, Osaka, Japan
| | | | | | - Ken Igawa
- Department of Dermatology, Dokkyo Medical University, Tochigi, Japan
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Musa M, Bale BI, Suleman A, Aluyi-Osa G, Chukwuyem E, D’Esposito F, Gagliano C, Longo A, Russo A, Zeppieri M. Possible viral agents to consider in the differential diagnosis of blepharoconjunctivitis. World J Virol 2024; 13:97867. [PMID: 39722756 PMCID: PMC11551683 DOI: 10.5501/wjv.v13.i4.97867] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/11/2024] [Revised: 08/20/2024] [Accepted: 08/27/2024] [Indexed: 10/18/2024] Open
Abstract
BACKGROUND Blepharoconjunctivitis poses a diagnostic challenge due to its diverse etiology, including viral infections. Blepharoconjunctivits can be acute or chronic, self-limiting, or needing medical therapy. AIM To review possible viral agents crucial for accurate differential diagnosis in cases of blepharoconjunctivitis. METHODS The PubMed database was searched for records relating to viral blepharoconjunctivitis. The search string generated was "("virally"[All Fields] OR "virals"[All Fields] OR "virology"[MeSH Terms] OR "virology"[All Fields] OR "viral"[All Fields]) AND "Blepharoconjunctivitis"[All Fields]". RESULTS A total of 24 publications were generated from the search string. Reference lists from each relevant article were also searched for more information and included in this review. Viral etiologies such as adenovirus, herpes simplex virus (HSV), varicella-zoster virus (VZV), and Epstein-Barr virus (EBV) are frequently implicated. Adenoviral infections manifest with follicular conjunctivitis and preauricular lymphadenopathy, often presenting as epidemic keratoconjunctivitis. HSV and VZV infections can result in herpetic keratitis and may exhibit characteristic dendritic corneal ulcers. EBV, although less common, can cause unilateral or bilateral follicular conjunctivitis, particularly in immunocompromised individuals. Other potential viral agents, such as enteroviruses and molluscum contagiosum virus, should also be considered, especially in pediatric cases. CONCLUSION Prompt recognition of these viral etiologies is essential for appropriate management and prevention of complications. Thus, a thorough understanding of the clinical presentation, epidemiology, and diagnostic modalities is crucial for accurate identification and management of viral blepharoconjunctivitis.
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Affiliation(s)
- Mutali Musa
- Department of Optometry, University of Benin, Benin 300283, Nigeria
- Department of Ophthalmology, Africa Eye Laser Centre Ltd, Benin 300105, Nigeria
- Department of Ophthalmology, Centre for Sight Africa Ltd, Nkpor 434212, Nigeria
| | | | - Ayuba Suleman
- Department of Ophthalmology, Africa Eye Laser Centre Ltd, Benin 300105, Nigeria
| | - Gladness Aluyi-Osa
- Department of Ophthalmology, Africa Eye Laser Centre Ltd, Benin 300105, Nigeria
| | - Ekele Chukwuyem
- Department of Ophthalmology, Centre for Sight Africa Ltd, Nkpor 434212, Nigeria
| | - Fabiana D’Esposito
- Imperial College Ophthalmic Research Group Unit, Imperial College, London NW1 5QH, United Kingdom
- GENOFTA srl, Via A. Balsamo, 93, Naples 80065, Italy
| | - Caterina Gagliano
- Department of Medicine and Surgery, University of Enna "Kore", Catania 94100, Italy
- Eye Clinic, Catania University San Marco Hospital, Catania 95121, Italy
| | - Antonio Longo
- Department of Ophthalmology, University Hospital of Catania, Catania 95123, Italy
| | - Andrea Russo
- Department of Ophthalmology, University Hospital of Catania, Catania 95123, Italy
| | - Marco Zeppieri
- Department of Ophthalmology, University Hospital of Udine, Udine 33100, Italy
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Chomistek AK, Franklin JM, Sobel RE, Marcus AF, Sinnott SJ, Ezzy SM, Gately RV, Green J, Howell A, Sultan I, Akpek EK, Wang FT. Development and Validation of Claims-Based Algorithms for Conjunctivitis and Keratitis. Pharmacoepidemiol Drug Saf 2024; 33:e70052. [PMID: 39533508 DOI: 10.1002/pds.70052] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/06/2024] [Revised: 10/04/2024] [Accepted: 10/21/2024] [Indexed: 11/16/2024]
Abstract
BACKGROUND Ocular surface disorders have been reported among patients with various medical conditions, including atopic dermatitis (AD). Nonetheless, validated algorithms to identify conjunctivitis and keratitis in claims data are lacking. OBJECTIVE Develop validated, claims-based algorithms for conjunctivitis and keratitis among patients with AD using medical records. METHODS Patients with AD were identified in a claims database between March 2017 and November 2019. Among these patients, candidate algorithms were developed that included diagnosis codes for conjunctivitis or keratitis, alone and in combination with ophthalmic treatments. Among patients who met ≥ 1 candidate algorithms, a subset was randomly selected for medical record review. Additionally, records from a random sample of patients with AD were reviewed to assess sensitivity. Overall, 341 records were sought and 262 adjudicated by an expert ophthalmologist. The positive predictive value (PPV) of each algorithm was calculated and compared to a pre-specified threshold of ≥ 70%. RESULTS For conjunctivitis, the final algorithm was ≥ 1 conjunctivitis diagnosis (PPV = 81%, 95% confidence interval [CI]: 73%-87%). For keratitis, the final algorithm combined the following 2 candidate algorithms: ≥ 1 keratitis diagnosis and ≥ 1 dispensing of a topical antibiotic or antibiotic-steroid combination (PPV = 91%); and ≥ 1 keratitis diagnosis and ≥ 1 dispensing of an ophthalmic corticosteroid, topical immune-modulator, or topical NSAID (PPV = 68%) for an overall PPV of 80% (95% CI: 55%-93%). CONCLUSION The first claims-based algorithms to identify conjunctivitis and keratitis among AD patients were developed and validated. They are available for use in future studies, particularly to better understand conjunctivitis and keratitis occurrence among patients with AD.
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Affiliation(s)
| | | | - Rachel E Sobel
- Regeneron Pharmaceuticals Inc., Tarrytown, New York, USA
| | | | | | | | | | | | - Ashley Howell
- Regeneron Pharmaceuticals Inc., Tarrytown, New York, USA
| | | | - Esen K Akpek
- Johns Hopkins University, Baltimore, Maryland, USA
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Lopez-Bernal T, Mazaira Fernández M, Vargas-Machuca Salido I, Aranegui B. Corneal Transplant Rejection and Alopecia Areata Universalis in a Patient With Severe Atopic Dermatitis on Dupilumab. ACTAS DERMO-SIFILIOGRAFICAS 2024; 115:933-934. [PMID: 38159837 DOI: 10.1016/j.ad.2023.02.039] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/27/2022] [Revised: 02/06/2023] [Accepted: 02/25/2023] [Indexed: 01/03/2024] Open
Affiliation(s)
- T Lopez-Bernal
- Servicio de Dermatología, Hospital Universitario Infanta Cristina, Parla, Madrid, Spain.
| | - M Mazaira Fernández
- Servicio de Dermatología, Hospital Universitario Infanta Cristina, Parla, Madrid, Spain
| | | | - B Aranegui
- Servicio de Dermatología, Hospital Universitario Infanta Cristina, Parla, Madrid, Spain
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Lopez-Bernal T, Mazaira Fernández M, Vargas-Machuca Salido I, Aranegui B. Corneal Transplant Rejection and Alopecia Areata Universalis in a Patient With Severe Atopic Dermatitis on Dupilumab. ACTAS DERMO-SIFILIOGRAFICAS 2024; 115:T933-T934. [PMID: 38925452 DOI: 10.1016/j.ad.2024.06.004] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/27/2022] [Revised: 02/06/2023] [Accepted: 02/25/2023] [Indexed: 06/28/2024] Open
Affiliation(s)
- T Lopez-Bernal
- Servicio de Dermatología, Hospital Universitario Infanta Cristina, Parla, Madrid, España.
| | - M Mazaira Fernández
- Servicio de Dermatología, Hospital Universitario Infanta Cristina, Parla, Madrid, España
| | | | - B Aranegui
- Servicio de Dermatología, Hospital Universitario Infanta Cristina, Parla, Madrid, España
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Sroka-Tomaszewska J, Bulińska B, Wilkowska A, Nowicki RJ, Trzeciak M. Dupilumab for the treatment of moderate and severe atopic dermatitis: real-life experience. Postepy Dermatol Alergol 2023; 40:747-752. [PMID: 38282886 PMCID: PMC10809831 DOI: 10.5114/ada.2023.133818] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/26/2023] [Accepted: 07/07/2023] [Indexed: 01/30/2024] Open
Abstract
Introduction Atopic dermatitis is a relapsing, chronic, inflammatory dermatosis. So far, treatment options for more severe forms of the disease have been limited. The prospect has changed with the advent of biological drug registrations. Dupilumab is a monoclonal antibody targeting the a subunit of the IL-4 receptor and is responsible for blocking the signalling of interleukin (IL) 4 (IL-4) and IL-13. Clinical trials conducted for over 10 years have confirmed the efficacy and safety of dupilumab's treatment for atopic dermatitis. Aim Evaluating the efficacy of dupilumab treatment in patients with moderate and severe atopic dermatitis in real life. Material and methods We retrospectively evaluated medical records of patients treated with dupilumab for atopic dermatitis at the Department of Dermatology, Venereology and Allergology in Gdansk. Results Ten patients in total were studied. They received dupilumab with standard dosing. The mean percentage reduction in SCORAD score was 52.16% in 8 weeks. Dupilumab was generally well tolerated and did not cause serious side effects. The most common adverse event was conjunctivitis. Conclusions Dupilumab is an effective disease-modifying drug for patients with moderate to severe atopic dermatitis. The effects of treatment in real life are consistent with those demonstrated in clinical trials.
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Affiliation(s)
- Jowita Sroka-Tomaszewska
- Department of Dermatology, Venereology and Allergology, Faculty of Medicine, Medical University of Gdansk, Gdansk, Poland
| | - Barabara Bulińska
- Department of Dermatology, Venereology and Allergology, Faculty of Medicine, Medical University of Gdansk, Gdansk, Poland
| | - Aleksandra Wilkowska
- Department of Dermatology, Venereology and Allergology, Faculty of Medicine, Medical University of Gdansk, Gdansk, Poland
| | - Roman J Nowicki
- Department of Dermatology, Venereology and Allergology, Faculty of Medicine, Medical University of Gdansk, Gdansk, Poland
| | - Magdalena Trzeciak
- Department of Dermatology, Venereology and Allergology, Faculty of Medicine, Medical University of Gdansk, Gdansk, Poland
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Ghosh D, Mersha TB. Atopic dermatitis and ocular allergy: common mechanisms and uncommon questions. Curr Opin Allergy Clin Immunol 2023; 23:383-389. [PMID: 37527055 PMCID: PMC10528981 DOI: 10.1097/aci.0000000000000931] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 08/03/2023]
Abstract
PURPOSE OF REVIEW Atopic dermatitis (AD) and ocular allergy aka allergic eye disease (AED) are two common conditions that often coexist in patients. However, molecular connections between these two conditions are incompletely understood. While common etiologic components including Th2 immune signaling have been suggested for AD and AED, the mechanism how current Th2-targetd therapies (dupilumab, tralokinumab) for AD can augment conjunctivitis is not well understood. RECENT FINDINGS Differentially regulated genes and pathways relevant for AD disease manifestation are known. In contrast, similar information is not yet available for AED, which could be largely addressed by emerging noninvasive ocular sampling techniques. Emerging evidence indicated a reduction in goblet cell number and mucin production in a subpopulation of AD patients with AD leading to adverse ocular outcomes, while other potential mechanisms could also be involved. Involvement of particular barrier function protein(s) in AED needs further investigation. SUMMARY Modern cytokine-targeted therapies for AD showed elevated risk for developing conjunctivitis. Recently developed noninvasive sampling techniques should be leveraged to identify AD endotypes associated with AED and with dupilumab-associated ocular outcomes.
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Affiliation(s)
- Debajyoti Ghosh
- Division of Immunology, Allergy & Rheumatology, Department of Internal Medicine, University of Cincinnati, Cincinnati, OH, USA
| | - Tesfaye B. Mersha
- Division of Asthma Research, Department of Pediatrics, Cincinnati Children’s Hospital Medical Center, University of Cincinnati, Cincinnati, OH, USA
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Hardison SA, Senior BA. The argument against the use of dupilumab in patients with limited polyp burden in chronic rhinosinusitis with nasal polyposis (CRSwNP). J Otolaryngol Head Neck Surg 2023; 52:64. [PMID: 37759322 PMCID: PMC10537999 DOI: 10.1186/s40463-023-00668-z] [Citation(s) in RCA: 7] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/29/2023] [Accepted: 09/07/2023] [Indexed: 09/29/2023] Open
Abstract
Dupilumab and other biologics have revolutionized the management of recalcitrant polyps in patients with chronic rhinosinusitis with nasal polyposis (CRSwNP). Despite strong evidence for the efficacy of dupilumab in treating polyps, factors such as cost and uncertain efficacy over surgery have limited its use to patients who have failed the use of topical nasal steroids and initial surgical management. Likewise, the use of this drug is often directed towards patients with greater polyp burdens. Recent studies, however, have investigated the use of dupilumab and other biologics in expanded patient populations, including those with limited polyp burden. The overall trend in the literature suggests a future move towards the use of biologics as first-line therapy for all patients with CRSwNP. The arguments against widespread, routine use of dupilumab and biologics in all patients with CRSwNP are threefold. First, endoscopic sinus surgery has been found to provide similar symptomatic benefit to dupilumab in the treatment of these patient populations. The surgical improvement of patients' sinonasal anatomy offers a rapid elimination of sources of ongoing inflammation that contribute to long-term polyp formation and symptoms. Medical non-compliance in this specific patient population is known to be an issue, with surgery offering a much greater long-term prospect of symptomatic relief in non-compliant patients. The second concern revolves around the potential for side effects of dupilumab and other biologics. Initial studies have shown an acceptable safety profile, but trials assessing the use of dupilumab for a separate indication revealed a higher rate of conjunctivitis. Long-term safety data is limited for biologics, and we must be prepared for the possibility of severe, unanticipated adverse events in the future. Our third and most profound concern is the significant cost of dupilumab. This medication is enormously expensive, and all current literature suggests that treatment would need to be life-long to remain effective. Studies comparing endoscopic sinus surgery to various biologics, including dupilumab, have shown comparable overall quality of life metrics with biologics, all while delivering considerably higher anticipated lifetime costs. As our knowledge progresses regarding the efficacy of dupilumab and other biologics in a variety of clinic situations, it is important to understand the context in which these advances are being made. While dupilumab and other biologics offer undeniable efficacy in the treatment of chronic rhinosinusitis with nasal polyposis which has failed to respond to standard therapies, we argue that biologics remain only a component of effective management in this patient population. Endoscopic sinus surgery and topical nasal steroids offer equal efficacy and substantially lower costs than biologics, and these factors should be considered when selecting treatment options for patients.
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Affiliation(s)
- Scott A Hardison
- Department of Otolaryngology/Head and Neck Surgery, The University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.
- Division of Rhinology, Allergy and Endoscopic Skull Base Surgery, The University of North Carolina at Chapel Hill, 101 Manning Drive, Chapel Hill, NC, 27599-7070, USA.
| | - Brent A Senior
- Department of Otolaryngology/Head and Neck Surgery, The University of North Carolina at Chapel Hill, Chapel Hill, NC, USA
- Division of Rhinology, Allergy and Endoscopic Skull Base Surgery, The University of North Carolina at Chapel Hill, 101 Manning Drive, Chapel Hill, NC, 27599-7070, USA
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Gelato F, Mastorino L, Quaglino P, Cavaliere G, Ortoncelli M, Ribero S. Ocular Adverse Events in Patients With Atopic Dermatitis Treated With Upadacitinib: A Real-Life Experience. Dermatitis 2023; 34:445-447. [PMID: 36917522 DOI: 10.1089/derm.2022.0063] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/28/2023]
Abstract
Background: Dupilumab, an interleukin (IL)-4 receptor-α inhibitor that blocks IL-4 and IL-13 signaling pathways, is an effective and well-tolerated therapy for moderate-to-severe atopic dermatitis (AD). However, an increased incidence of dupilumab-associated conjunctivitis has been reported in patients treated with dupilumab. In contrast, upadacitinib, a selective Janus kinase 1 inhibitor, is reported to have lower incidence of conjunctivitis than dupilumab. Objective: The aim of this retrospective study was to investigate ocular adverse events in adult patients with moderate-to-severe AD treated with upadacitinib after discontinuing treatment with dupilumab. Methods: In total, 33 patients were examined at the start of treatment with upadacitinib after discontinuation of dupilumab, then again after 4 weeks and every 12 weeks up to a maximum of 72 weeks. Results: Among the patients in the study, 14 had developed dupilumab-associated conjunctivitis during dupilumab treatment and had complete resolution of ocular symptoms after the switch to upadacitinib within the 1-month follow-up visit. In addition, only 1 patient treated with upadacitinib developed an episode of conjunctivitis. This condition was of mild severity and it spontaneously resolved quickly. Interestingly, this patient had no history of dupilumab-associated conjunctivitis. Conclusions: All patients who developed dupilumab-associated conjunctivitis experienced complete remission on upadacitinib and only 3% of the patients in our sample developed conjunctivitis after the start of treatment with upadacitinib. In light of this, upadacitinib appears to be a prudent and safe treatment option for AD patients with uncontrolled ocular symptoms associated with dupilumab therapy.
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Affiliation(s)
- Federica Gelato
- From the *Dermatology Clinic, Department of Medical Sciences, University of Turin, Turin, Italy
| | - Luca Mastorino
- From the *Dermatology Clinic, Department of Medical Sciences, University of Turin, Turin, Italy
| | - Pietro Quaglino
- From the *Dermatology Clinic, Department of Medical Sciences, University of Turin, Turin, Italy
| | - Giovanni Cavaliere
- From the *Dermatology Clinic, Department of Medical Sciences, University of Turin, Turin, Italy
| | - Michela Ortoncelli
- From the *Dermatology Clinic, Department of Medical Sciences, University of Turin, Turin, Italy
| | - Simone Ribero
- From the *Dermatology Clinic, Department of Medical Sciences, University of Turin, Turin, Italy
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13
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Bernardo D, Bieber T, Torres T. Lebrikizumab for the Treatment of Moderate-to-Severe Atopic Dermatitis. Am J Clin Dermatol 2023; 24:753-764. [PMID: 37266844 PMCID: PMC10460333 DOI: 10.1007/s40257-023-00793-5] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 05/11/2023] [Indexed: 06/03/2023]
Abstract
Atopic dermatitis (AD) is a common, heterogeneous, inflammatory skin disorder characterized by chronic or relapsing eczematous lesions with intense pruritus and discomfort. Affected patients often experience significant impairment in their quality of life, and the treatment of moderate-to-severe AD forms remains challenging. In the past few decades, increasing knowledge on the AD pathogenesis has driven the development of novel targeted therapies. Interleukin (IL)-13 plays a central and pleiotropic role in AD pathogenesis, contributing directly or indirectly to epidermal barrier disfunction, type-2 inflammation, dysbiosis, fibrosis, and itch response. For this reason, agents selectively targeting IL-13, such as lebrikizumab, emerged as a potential therapy for AD. This article reviews the current evidence about lebrikizumab in the management of AD. The phase II and phase III trials seem to corroborate efficacy of lebrikizumab in the treatment of moderate-to-severe AD, as shown by significant improvement of Eczema Area and Severity Index, body surface area, and pruritus scores. Also, lebrikizumab demonstrated favorable safety and tolerability profiles, with the majority of patients experiencing no significant adverse events. Lebrikizumab seems to be a promising emerging targeted biological agent for patients with moderate-to-severe AD. More data on the long-term efficacy and safety, head-to-head comparisons with other agents, and real-world evidence will help to clarify its place in therapy in AD.
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Affiliation(s)
- Diana Bernardo
- Department of Dermatology, Centro Hospitalar Universitário de Sto António, Porto, Portugal
| | - Thomas Bieber
- Department of Dermatology and Allergy, University Hospital, Bonn Germany and Christine Kühne-Center for Allergy Research and Education, Davos, Switzerland
| | - Tiago Torres
- Department of Dermatology, Centro Hospitalar Universitário de Sto António, Porto, Portugal.
- Instituto de Ciências Biomédicas Abel Salazar, University of Porto, Porto, Portugal.
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14
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Lytvyn Y, Gooderham M. Targeting Interleukin 13 for the Treatment of Atopic Dermatitis. Pharmaceutics 2023; 15:568. [PMID: 36839890 PMCID: PMC9966769 DOI: 10.3390/pharmaceutics15020568] [Citation(s) in RCA: 13] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/23/2022] [Revised: 01/24/2023] [Accepted: 02/06/2023] [Indexed: 02/10/2023] Open
Abstract
Atopic dermatitis (AD) is a common chronic inflammatory skin condition that has a significant impact on a patient's quality of life and requires ongoing management. Conventional topical and systemic therapies do not target specific components of AD pathogenesis and, therefore, have limited efficacy and may be associated with long-term toxicity. Thus, AD management is challenging, with a significant proportion of patients not achieving clear skin or a reduction in pruritus. There remains a large unmet need for effective therapeutic strategies with favorable safety profiles that can be used long-term in patients with refractory AD. The emergence of targeted biological and small molecule therapies has effectively broadened available treatment options for moderate-to-severe AD. Most recently, interleukin 13 (IL-13) inhibitors were shown to be efficacious and well-tolerated, with tralokinumab already approved for use in this patient population. It is important for dermatologists to be aware of the evidence behind this emerging class of biologic agents to guide treatment choices and improve outcomes in patients with AD. The main objective of this paper is to review the current literature regarding the efficacy and safety of current and emerging anti-IL-13 monoclonal antibodies, including tralokinumab, lebrikizumab, cendakimab, and eblasakimab, for the treatment of moderate-to-severe AD.
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Affiliation(s)
- Yuliya Lytvyn
- Temerty Faculty of Medicine, University of Toronto, Toronto, ON M5S 1A1, Canada
| | - Melinda Gooderham
- SKiN Centre for Dermatology, Peterborough, ON K9J 5K2, Canada
- Probity Medical Research, Waterloo, ON N2J 1C4, Canada
- Department of Family Medicine, Queen’s University, Kingston, ON K7L 3N6, Canada
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15
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Felfeli T, Georgakopoulos JR, Jo CE, Mimouni M, Piguet V, Drucker AM, Yeung J, Chan CC. Prevalence and Characteristics of Dupilumab-Induced Ocular Surface Disease in Adults With Atopic Dermatitis. Cornea 2022; 41:1242-1247. [PMID: 34843182 DOI: 10.1097/ico.0000000000002866] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/05/2021] [Accepted: 07/16/2021] [Indexed: 11/27/2022]
Abstract
PURPOSE Dupilumab-induced ocular surface disease (DIOSD) is a common reaction among patients treated for atopic dermatitis. This study aimed to identify the clinical characteristics, associated risk factors, treatment strategies, and long-term outcomes of DIOSD. METHODS We conducted a multicenter retrospective cohort study of consecutive adult outpatients treated with dupilumab for moderate-to-severe atopic dermatitis from 2017 through 2021 at 2 tertiary care centers. We used stepwise multivariable logistic regression to assess the association between patient characteristics and development of DIOSD. RESULTS Among 210 patients treated with dupilumab, 37% (n = 78) developed DIOSD over the 52-week follow-up period. Vision-threatening complications including corneal scarring and cicatricial ectropion were noted in 1% (n = 3) of patients. Clinical features were blepharoconjunctivitis (68%, n = 53), burning/stinging/dryness (14%, n = 29), epiphora (13%, n = 10), pruritus (13%, n = 10), blurred vision (3%, n = 2), and photophobia (1%, n = 1). DIOSD was associated with a history of asthma (odds ratio: 2.94, 95% confidence interval: 1.26-6.87, P = 0.01) and a family history of atopic dermatitis (odds ratio: 2.58, 95% confidence interval: 1.08-6.17, P = 0.03). Interventions were initiated for 63% of patients with DIOSD, with artificial tears (56%) and corticosteroid drops (29%) most commonly used. Dupilumab was discontinued because of DIOSD in 4% of patients. CONCLUSIONS DIOSD is a common adverse event that is usually mild but may lead to treatment interruption and vision-threatening complications. A personal history of asthma and family history of atopic dermatitis may be associated with a higher risk of developing DIOSD.
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Affiliation(s)
- Tina Felfeli
- Department of Ophthalmology and Vision Sciences, University of Toronto, ON, Canada
- Institute of Health Policy, Management and Evaluation, Dalla Lana School of Public Health, University of Toronto, ON, Canada
| | | | - Christine E Jo
- Faculty of Medicine, University of Ottawa, Ottawa, ON, Canada
| | - Michael Mimouni
- Department of Ophthalmology, Toronto Western Hospital, University Health Network, ON, Canada
| | - Vincent Piguet
- Division of Dermatology, Department of Medicine, University of Toronto, ON, Canada
- Division of Dermatology, Department of Medicine, and Women's College Research Institute, Women's College Hospital, Toronto, ON, Canada
| | - Aaron M Drucker
- Institute of Health Policy, Management and Evaluation, Dalla Lana School of Public Health, University of Toronto, ON, Canada
- Division of Dermatology, Department of Medicine, University of Toronto, ON, Canada
- Division of Dermatology, Department of Medicine, and Women's College Research Institute, Women's College Hospital, Toronto, ON, Canada
| | - Jensen Yeung
- Division of Dermatology, Department of Medicine, University of Toronto, ON, Canada
- Division of Dermatology, Department of Medicine, and Women's College Research Institute, Women's College Hospital, Toronto, ON, Canada
- Sunnybrook Health Sciences Centre, Toronto, ON, Canada
- Probity Medical Research Inc., Waterloo, ON, Canada; and
| | - Clara C Chan
- Department of Ophthalmology and Vision Sciences, University of Toronto, ON, Canada
- Department of Ophthalmology, Toronto Western Hospital, University Health Network, ON, Canada
- Department of Ophthalmology, St. Michael's Hospital, Unity Health Toronto, ON, Canada
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16
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Blauvelt A, Boguniewicz M, Brunner PM, Luna PC, Biswas P, DiBonaventura M, Farooqui SA, Rojo R, Cameron MC. Abrocitinib monotherapy in Investigator's Global Assessment nonresponders: improvement in signs and symptoms of atopic dermatitis and quality of life. J DERMATOL TREAT 2022; 33:2605-2613. [PMID: 35763326 DOI: 10.1080/09546634.2022.2059053] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/17/2022]
Abstract
BACKGROUND Abrocitinib, a once-daily, oral Janus kinase 1 selective inhibitor, was shown to be an effective treatment for moderate-to-severe atopic dermatitis in phase 2 b/3 monotherapy trials. METHODS These analyses included data for Investigator's Global Assessment responder (clear [0] or almost clear [1] with ≥2-grade improvement) and nonresponder patients with moderate-to-severe atopic dermatitis who received abrocitinib (200 mg or 100 mg) or placebo in three abrocitinib monotherapy trials (phase 2 b, NCT02780167; two phase 3, NCT03349060/JADE MONO-1 and NCT03575871/JADE MONO-2). Outcomes measuring skin clearance, itch, and quality of life were evaluated. RESULTS Both nonresponders (n = 548) and responders (n = 260) treated with abrocitinib had rapid and clinically meaningful improvement in skin clearance, itch, and quality of life compared with placebo. CONCLUSION Patients with moderate-to-severe atopic dermatitis treated with abrocitinib who did not achieve an Investigator's Global Assessment 0/1 response at week 12 still experienced rapid, clinically meaningful improvements across several other validated measures of efficacy and quality of life. CLINICALTRIALS.GOV NCT02780167, NCT03349060, NCT03575871.
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Affiliation(s)
- Andrew Blauvelt
- Department of Dermatology, Oregon Medical Research Center, Portland, OR, USA
| | - Mark Boguniewicz
- Division of Allergy and Immunology, Department of Pediatrics, National Jewish Health and University of Colorado School of Medicine, Denver, CO, USA
| | - Patrick M Brunner
- Department of Dermatology, Medical University of Vienna, Vienna, Austria, and Department of Dermatology, Icahn School of Medicine at Mount Sinai, New York, NY, USA
| | - Paula C Luna
- Dermatology Department, Hospital Alemán, Buenos Aires, Argentina
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17
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Neagu N, Dianzani C, Avallone G, Dell'Aquila C, Morariu SH, Zalaudek I, Conforti C. Dupilumab ocular side effects in patients with atopic dermatitis: a systematic review. J Eur Acad Dermatol Venereol 2022; 36:820-835. [PMID: 35122335 DOI: 10.1111/jdv.17981] [Citation(s) in RCA: 26] [Impact Index Per Article: 8.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/03/2021] [Accepted: 01/05/2022] [Indexed: 11/29/2022]
Abstract
Atopic dermatitis (AD) is a chronic, inflammatory skin disorder that most frequently occurs in children, but it can also affect adults. Even though most AD cases can be managed with topical treatments, moderate-to-severe forms require systemic therapies. Dupilumab is the first human monoclonal antibody approved for the treatment of AD. Its action is through IL-4 receptor alpha subunit inhibition, thus blocking IL-4 and IL-13 signaling pathways. It has been shown to be an effective, well tolerated therapy for AD, as well as for asthma, chronic rhinosinusitis with nasal polyposis (CRSwNP) and eosinophilic esophagitis (EoE). However, an increasing incidence of Dupilumab-induced ocular surface disease (DIOSD) has been reported in patients treated with Dupilumab, as compared to placebo. The aim of this study was to summarize scientific data regarding DIOSD in AD patients treated with Dupilumab. A search of PubMed and clinicaltrials.gov databases was performed. There was no limit to study design. All AD cases were moderate-to-severe. DIOSD was either dermatologist-, allergist-, or ophtalmologist-assessed. Evidence shows that DIOSD occurs most frequently in patients with atopic dermatitis and not in other skin conditions, neither in patients with asthma, CRSwNP, nor EoE who are on Dupilumab treatment. Further studies are warranted in order to establish a causal relationship between Dupilumab and ocular surface disease. Nevertheless, ophtalmological evaluations prior to Dupilumab initiation can benefit AD patients with previous ocular pathology or current ocular symptomatology. Also, patch testing for ocular allergic contact dermatitis might be advantageous in patients with a history of allergic conjunctivitis. Furthermore, TARC, IgE and circulating eosinophils levels might be important biomarkers for a baseline assessment of future candidates to Dupilumab treatment. However, TARC measurements should be resumed for research purposes only.
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Affiliation(s)
- N Neagu
- State Clinic of Dermatology, Mureș County Hospital, Tîrgu Mureș, Romania
| | - C Dianzani
- Plastic and Reconstructive Surgery Unit, Medico University of Rome, Campus Bio, Rome, Italy
| | - G Avallone
- Medical Sciences Department, Section of Dermatology, University of Turin, Turin, Italy
| | - C Dell'Aquila
- Department of Medical, Surgical Sciences and Health, Eye Clinic, University of Trieste, Trieste, Italy
| | - S-H Morariu
- State Clinic of Dermatology, Mureș County Hospital, Tîrgu Mureș, Romania
| | - I Zalaudek
- Dermatology Clinic, Maggiore Hospital of Trieste, Trieste, Italy
| | - C Conforti
- Dermatology Clinic, Maggiore Hospital of Trieste, Trieste, Italy
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18
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Doan S, Arnould L, Febvay C, Fournié P, Gueudry J, Labalette P, Ouilhon C, Tran THC, Vabres B, Barbarot S, Bouaziz JD, Du-Thanh A, Jachiet M, Seneschal J, Soria A, Staumont-Sallé D, Baudouin C, Mortemousque B. Blépharo-conjonctivites sous dupilumab : recommandations du groupe CEDRE. Dermatite atopique, conjonctivites et dupilumab : quelle prise en charge ? J Fr Ophtalmol 2022; 45:277-287. [DOI: 10.1016/j.jfo.2021.12.007] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/05/2021] [Accepted: 12/20/2021] [Indexed: 11/17/2022]
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19
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Kamata M, Tada Y. A Literature Review of Real-World Effectiveness and Safety of Dupilumab for Atopic Dermatitis. JID INNOVATIONS 2021; 1:100042. [PMID: 34909737 PMCID: PMC8659403 DOI: 10.1016/j.xjidi.2021.100042] [Citation(s) in RCA: 45] [Impact Index Per Article: 11.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/27/2021] [Revised: 07/01/2021] [Accepted: 07/14/2021] [Indexed: 02/08/2023] Open
Abstract
Atopic dermatitis (AD) is a chronic inflammatory skin disease with pruritus, characterized by recurrent eczema with exacerbations and remissions. AD impairs patients’ QOL and places a heavy burden on patients. Recently, dupilumab, an anti–IL-4Rα antibody, was approved for the treatment of patients with moderate-to-severe AD who are refractory to topical agents and/or conventional systemic therapy. Clinical trials of dupilumab for AD demonstrated high efficacy and tolerable safety profiles. Furthermore, real-world evidence of dupilumab for AD is accumulating. Most of these data show favorable effectiveness and safety profile; however, they also clarified issues, including conjunctivitis and facial redness. There are still a certain number of patients with significant failure. In this article, we review real-world evidence of dupilumab for AD, identify concerns specific to dupilumab, and discuss unmet needs and issues to be addressed in the future.
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Key Words
- AA, alopecia areata
- AD, atopic dermatitis
- CsA, cyclosporin A
- EASI, Eczema Area and Severity Index
- HSV, herpes simplex virus
- IGA, Investigator’s Global Assessment
- LDH, lactate dehydrogenase
- TCS, topical corticosteroid
- Th, T helper type
- q2w, every other week
- qw, weekly
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Affiliation(s)
- Masahiro Kamata
- Department of Dermatology, Teikyo University School of Medicine, Tokyo, Japan
| | - Yayoi Tada
- Department of Dermatology, Teikyo University School of Medicine, Tokyo, Japan
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20
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Lai B, Phan K, Lewis N, Shumack S. A rare case of vernal keratoconjunctivitis in a patient with atopic dermatitis treated with tralokinumab. J Eur Acad Dermatol Venereol 2021; 36:e343-e345. [PMID: 34807480 DOI: 10.1111/jdv.17824] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/26/2021] [Revised: 11/03/2021] [Accepted: 11/17/2021] [Indexed: 12/14/2022]
Affiliation(s)
- B Lai
- St George Dermatology and Skin Cancer Centre, Kogarah, NSW, Australia
| | - K Phan
- St George Dermatology and Skin Cancer Centre, Kogarah, NSW, Australia
| | - N Lewis
- Department of Ophthalmology, Royal North Shore Hospital, St Leonards, NSW, Australia.,University of Sydney Medical School, Sydney, NSW, Australia
| | - S Shumack
- St George Dermatology and Skin Cancer Centre, Kogarah, NSW, Australia.,University of Sydney Medical School, Sydney, NSW, Australia.,Department of Dermatology, Royal North Shore Hospital, St Leonards, NSW, Australia
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21
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Zengarini C, Roda M, Schiavi C, Bruni F, Bardazzi F, Bellusci C, Raone B. Successful treatment of severe recalcitrant Vernal keratoconjunctivitis and atopic dermatitis associated with elevated IgE levels with omalizumab: a case report. Clin Exp Dermatol 2021; 47:604-606. [PMID: 34731495 DOI: 10.1111/ced.15000] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/25/2021] [Accepted: 11/01/2021] [Indexed: 11/28/2022]
Abstract
Atopic Dermatitis (AD) is a chronic inflammatory skin condition, defined as extrinsic when associated with elevated serum IgE levels and sensitization to various allergens1 . It is linked to multiple allergic disorders; among them, Vernal keratoconjunctivitis (VKC) is one of the worst affecting the eyes, which may lead to corneal scarring and vision loss if not treated properly.
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Affiliation(s)
- C Zengarini
- Dermatology Unit, IRCCS of Policlinico Sant'Orsola Hospital, Bologna, Italy.,Department of Experimental, Diagnostic and Specialty Medicine (DIMES), University of Bologna, Bologna, Italy
| | - M Roda
- Department of Experimental, Diagnostic and Specialty Medicine (DIMES), University of Bologna, Bologna, Italy.,Ophthalmology Unit, IRCCS of Policlinico Sant'Orsola Hospital, Bologna, Italy
| | - C Schiavi
- Department of Experimental, Diagnostic and Specialty Medicine (DIMES), University of Bologna, Bologna, Italy.,Ophthalmology Unit, IRCCS of Policlinico Sant'Orsola Hospital, Bologna, Italy
| | - F Bruni
- Dermatology Unit, IRCCS of Policlinico Sant'Orsola Hospital, Bologna, Italy.,Department of Experimental, Diagnostic and Specialty Medicine (DIMES), University of Bologna, Bologna, Italy
| | - F Bardazzi
- Dermatology Unit, IRCCS of Policlinico Sant'Orsola Hospital, Bologna, Italy.,Department of Experimental, Diagnostic and Specialty Medicine (DIMES), University of Bologna, Bologna, Italy
| | - C Bellusci
- Department of Experimental, Diagnostic and Specialty Medicine (DIMES), University of Bologna, Bologna, Italy.,Ophthalmology Unit, IRCCS of Policlinico Sant'Orsola Hospital, Bologna, Italy
| | - B Raone
- Dermatology Unit, IRCCS of Policlinico Sant'Orsola Hospital, Bologna, Italy.,Department of Experimental, Diagnostic and Specialty Medicine (DIMES), University of Bologna, Bologna, Italy
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22
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Wang EQ, Le V, Winton JA, Tripathy S, Raje S, Wang L, Dowty ME, Malhotra BK. Effects of Renal Impairment on the Pharmacokinetics of Abrocitinib and Its Metabolites. J Clin Pharmacol 2021; 62:505-519. [PMID: 34637151 PMCID: PMC9303631 DOI: 10.1002/jcph.1980] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/03/2021] [Accepted: 09/30/2021] [Indexed: 11/11/2022]
Abstract
Abrocitinib, an oral once‐daily Janus kinase 1 selective inhibitor, is under development for the treatment of atopic dermatitis. This phase 1, nonrandomized, open‐label, single‐dose study (NCT03660241) investigated the effect of renal impairment on the pharmacokinetics, safety, and tolerability of abrocitinib and its metabolites following a 200‐mg oral dose. Twenty‐three subjects with varying degrees of renal function (normal, moderate, and severe impairment) were enrolled. Active moiety exposures were calculated as the sum of unbound exposures for abrocitinib and its active metabolites. For abrocitinib, the adjusted geometric mean ratios (GMRs; %) for area under the concentration‐time curve from time 0 extrapolated to infinite time and maximum plasma concentration were 182.91 (90% confidence interval [CI], 117.09‐285.71) and 138.49 (90% CI, 93.74‐204.61), respectively, for subjects with moderate renal impairment vs normal renal function; corresponding GMRs were 121.32 (90% CI, 68.32‐215.41) and 99.11 (90% CI, 57.30‐171.43) for subjects with severe impairment vs normal renal function. Metabolite exposures generally increased in subjects with renal impairment. The GMRs of unbound area under the concentration‐time curve from time 0 extrapolated to infinite time and maximum plasma concentration of active moiety were 210.20 (90% CI, 154.60‐285.80) and 133.87 (90% CI, 102.45‐174.92), respectively, for subjects with moderate renal impairment vs normal renal function. Corresponding values were 290.68 (90% CI, 217.39‐388.69) and 129.49 (90% CI, 92.86‐180.57) for subjects with severe renal impairment vs normal renal function. Abrocitinib was generally safe and well tolerated. Both moderate and severe renal impairment led to higher exposure to abrocitinib active moiety, suggesting that abrocitinib dose should be reduced by half for patients with moderate or severe renal impairment. ClinicalTrials.gov identifier: NCT03660241
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Affiliation(s)
- Ellen Q Wang
- Clinical Pharmacology, Pfizer Inc., New York, NY
| | | | | | | | - Sangeeta Raje
- Clinical Pharmacology, Global Product Development, Pfizer Inc., Collegeville, PA
| | | | - Martin E Dowty
- Pharmacokinetics, Metabolism, and Dynamics, Medicine Design, Pfizer Inc., Cambridge, MA
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23
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Wollenberg A, Beck LA, de Bruin Weller M, Simpson EL, Imafuku S, Boguniewicz M, Zachariae R, Olsen CK, Thyssen JP. Conjunctivitis in adult patients with moderate-to-severe atopic dermatitis: results from five tralokinumab clinical trials. Br J Dermatol 2021; 186:453-465. [PMID: 34637142 DOI: 10.1111/bjd.20810] [Citation(s) in RCA: 43] [Impact Index Per Article: 10.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 10/07/2021] [Indexed: 11/30/2022]
Abstract
BACKGROUND Tralokinumab, a fully human immunoglobulin G4 monoclonal antibody that specifically binds to the interleukin-13 cytokine with high affinity, effectively reduces moderate-to-severe atopic dermatitis when given every 2 weeks. The incidence of conjunctivitis is elevated compared to placebo, but severity and etiology have not been examined. OBJECTIVE To analyze conjunctivitis data recorded in five randomized, placebo-controlled trials of tralokinumab in adult patients with moderate-to-severe atopic dermatitis. METHODS Overall, 2285 adults with atopic dermatitis were studied up to 16 weeks. Cochran-Mantel-Haenszel weights were applied to calculate adjusted adverse-event incidences. RESULTS Incidence of conjunctivitis was higher (7.5%) with tralokinumab compared to placebo (3.2%). Most events were mild or moderate in severity and 78.6% and 73.9% of events resolved during the trial in the tralokinumab and placebo groups, respectively. Two (1.4%) events led to permanent discontinuation of tralokinumab. An increased incidence of conjunctivitis, regardless of treatment group, was associated with more severe baseline atopic dermatitis, and history of allergic conjunctivitis/atopic keratoconjunctivitis, as well as the number of atopic comorbidities. Limitation This analysis reports events up to Week 16 only, with limited confirmation of conjunctivitis and its etiology by an ophthalmologist and insufficient reporting of ophthalmic treatments. CONCLUSIONS Treatment with tralokinumab was associated with increased incidence of conjunctivitis compared to placebo, but these cases were mostly mild and transient.
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Affiliation(s)
- A Wollenberg
- Klinikum der Universität München, Klinik und Poliklinik für Dermatologie und Allergologie, Munich, Germany
| | - L A Beck
- Department of Dermatology, Medicine and Pathology, University of Rochester Medical Center, Rochester, NY, USA
| | - M de Bruin Weller
- Department of Dermatology and Allergology, University Medical Center Utrecht, Utrecht, the Netherlands
| | - E L Simpson
- Department of Dermatology, Oregon Health & Science University, Portland, OR, USA
| | - S Imafuku
- Department of Dermatology, Fukuoka University, Faculty of Medicine, Fukuoka, Japan
| | - M Boguniewicz
- Division of Allergy-Immunology, Department of Pediatrics, National Jewish Health, Denver, CO, USA
| | | | | | - J P Thyssen
- Department of Dermatology and Venereology, Bispebjerg Hospital, University of Copenhagen, Copenhagen, Denmark
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Ocular surface disorders associated with the use of dupilumab based on WHO VigiBase. Sci Rep 2021; 11:14293. [PMID: 34253801 PMCID: PMC8275737 DOI: 10.1038/s41598-021-93750-3] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/22/2020] [Accepted: 06/29/2021] [Indexed: 11/09/2022] Open
Abstract
Dupilumab is a dual inhibitor of interleukin-4 and interleukin-13 and is mainly used to treat moderate-to-severe atopic dermatitis. Post-marketing safety data related to dupilumab have been accumulated, and it has been found that ocular surface diseases are closely associated with dupilumab treatment. The aim of this study was to detect dupilumab-related signals and to determine the safety characteristics of dupilumab with respect to eye disorders using real-world big data. Data on dupilumab use until December 29, 2019 were collected. The data were mined by calculating three indices: proportional reporting ratios, reporting odds ratios, and information components. The detected signals were classified using the primary system organ class in MedDRA terminology. Among 21,161,249 reports for all drugs, 20,548 reports were recorded for dupilumab. A total of 246 signals in the preferred terms were detected for dupilumab. Among the 246 positive signals obtained, 61 signals were related to eye disorders, which accounted for the largest percentage (24.8%), and 38 signals were anatomically related to the ocular surface. Dupilumab may cause extensive eye disorders; however, the underlying mechanisms and risk factors remain unclear. Our findings may facilitate broad safety screening of dupilumab-related eye disorders using real-world big data.
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Gonçalves F, Freitas E, Torres T. Selective IL-13 inhibitors for the treatment of atopic dermatitis. Drugs Context 2021; 10:dic-2021-1-7. [PMID: 33889195 PMCID: PMC8015935 DOI: 10.7573/dic.2021-1-7] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/26/2021] [Accepted: 02/26/2021] [Indexed: 12/19/2022] Open
Abstract
Background Atopic dermatitis (AD) is one of the most common chronic inflammatory skin diseases worldwide. AD pathogenesis is multifactorial, involving environmental and genetic factors. IL-13 stands out as one of the main cytokines in the pathophysiology of AD. Currently, dupilumab, which targets both IL-4 and IL-13 signalling, is the only biologic agent approved for the treatment of moderate-to-severe AD. New targeted biologic therapies are being developed, such as lebrikizumab and tralokinumab, two selective IL-13 inhibitors. This article reviews the role of IL-13 in AD and the most recent data on lebrikizumab and tralokinumab. Methods A narrative review of the literature was written after retrieving relevant articles in the PubMed database (up until December 2020) using the following keywords present in the title, abstract or body: atopic dermatitis; interleukin 13; IL-13; tralokinumab; lebrikizumab, biologic therapy. Discussion A phase IIb trial showed that all three dosing regimens evaluated (lebrikizumab 125 mg every 4 weeks (Q4W), 250 mg Q4W or 250 mg every 2 weeks) achieved rapid and dose-dependent efficacy concerning the signs and symptoms of AD, with a statistically significant improvement, at week 16. Tralokinumab was studied in three phase III clinical trials and reached its primary endpoints at week 16 (ECZTRA 1 and 2 in monotherapy and ECZTRA 3 with concomitant topical corticosteroids), with response maintained over time. Both lebrikizumab and tralokinumab exhibited good safety profiles in AD trials, with adverse effects usually being comparable between the control and treatment groups. Conclusion The evidence supports the hypothesis that selective antagonism of IL-13 is sufficient to control AD, providing an improvement in the patient’s quality of life. Therefore, the development of lebrikizumab and tralokinumab represents a new and exciting phase in the management of AD.
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Affiliation(s)
- Francisca Gonçalves
- Instituto de Ciências Biomédicas Abel Salazar, University of Porto, Porto, Portugal
| | - Egídio Freitas
- Department of Dermatology, Centro Hospitalar do Porto, Porto, Portugal
| | - Tiago Torres
- Instituto de Ciências Biomédicas Abel Salazar, University of Porto, Porto, Portugal.,Department of Dermatology, Centro Hospitalar do Porto, Porto, Portugal.,Dermatology Research Unit, Centro Hospitalar do Porto, Porto, Portugal
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Joshi TP, Anvari S, Gupta MR, Davis CM, Hajjar J. Case Report: Dupilumab Successfully Controls Severe Eczema in a Child With Elevated IgE Levels and Recurrent Skin Infections. Front Pediatr 2021; 9:646997. [PMID: 34660469 PMCID: PMC8511520 DOI: 10.3389/fped.2021.646997] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/28/2020] [Accepted: 08/31/2021] [Indexed: 11/26/2022] Open
Abstract
The efficacy of dupilumab in pediatric patients with severe eczema presenting in the setting of elevated immunoglobulin E (IgE) levels and recurrent bacterial skin infections is not well-understood. Here we present the case of a child with elevated IgE levels in whom dupilumab treatment led to remarkable control of his eczema and recurrent skin infections. We also review the use of dupilumab in other patients with molecularly proven cases of hyper IgE (HIGE) syndrome. Our case supports the notion that dupilumab may have a seminal application in treating severe eczema that occurs in the setting of elevated IgE levels and recurrent bacterial skin infections.
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Affiliation(s)
- Tejas P Joshi
- Baylor College of Medicine, Houston, TX, United States
| | - Sara Anvari
- Department of Pediatrics, Baylor College of Medicine, Houston, TX, United States
| | - Meera R Gupta
- Department of Pediatrics, Baylor College of Medicine, Houston, TX, United States
| | - Carla M Davis
- Department of Pediatrics, Baylor College of Medicine, Houston, TX, United States.,Wiliam T Shearer Center for Human Immunobiology, Texas Children's Hospital, Houston, TX, United States
| | - Joud Hajjar
- Department of Pediatrics, Baylor College of Medicine, Houston, TX, United States.,Wiliam T Shearer Center for Human Immunobiology, Texas Children's Hospital, Houston, TX, United States
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