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5. Tatham AS1, Shewry PR. Allergens to wheat and related cereals. Clin Exp Allergy. 2008;38:1712-26.
6. Ototake Y, Inomata N, Sano S, Takahashi S, Aihara M. A case of an anaphylactic reaction due to oats in granola. Allergol Int. 2015;64:386-7.
Manuscript received October 14, 2019; accepted for publication January 7, 2020.
Margarita Tomas Pérez Department of Allergy Hospital La Paz Paseo de la Castellana, 261 28046 Madrid, Spain E-mail: margui.tomas@gmail.com
Dupilumab-Associated Conjunctivitis in Patients With Atopic Dermatitis: A Multicenter Real-Life Experience
Nettis E1, Bonzano L2, Patella V3, Detoraki A4, Trerotoli P5, Lombardo C6, on behalf of the Italian DADReL study group#
1Allergist and Dermatologist Department of Emergency and
Organ Transplantation, School and Chair of Allergology and Clinical Immunology, University of Bari - Aldo Moro, Bari, Italy
2Dermatology Unit, Surgical, Medical and Dental Department
of Morphological Sciences related to Transplant, Oncology and Regenerative Medicine, University of Modena and Reggio Emilia, Modena, Italy
3Division of Allergy and Clinical Immunology, Department of
Medicine ASL Salerno, "Santa Maria della Speranza" Hospital, Battipaglia, Salerno, Italy
4Department of Internal Medicine and Clinical Pathology, Azienda
Ospedaliera Universitaria Federico II, Naples, Italy
5Department of Biomedical Science and Human Oncology,
University of Bari - Aldo Moro, Bari, Italy
6Division of Dermatology "U.O. Multizonale APSS", Santa Chiara
Hospital, Trento, Italy
J Investig Allergol Clin Immunol 2020; Vol. 30(3): 201-204 doi: 10.18176/jiaci.0481
Key words: Atopic dermatitis. Conjunctivitis. Dupilumab. Palabras clave: Dermatitis atópica. Conjuntivitis. Dupilumab.
Dupilumab was recently approved for the treatment of adults with moderate-to-severe atopic dermatitis (AD), for which current treatment options are limited [1]. Dupilumab binds to the IL-4Rα subunit and blocks the signaling of IL-4 and IL-13, thereby inhibiting the release of proinflammatory cytokines, chemokines, and IgE [2,3]. Although generally well-tolerated, high rates of unspecified conjunctivitis have been reported in patients on dupilumab [2-4].
This multicenter prospective observational study involved 15 secondary care centers as a task force for the Italian Society of Allergy, Asthma, and Clinical Immunology. The aim was to investigate the baseline factors associated with the incidence of dupilumab-induced conjunctivitis. Ninety-six patients with severe AD—defined as an Eczema Area and Severity Index (EASI) score ≥24—and with inadequate response to/ intolerance of cyclosporin A (CsA), or medically classified as unsuitable for CsA treatment, were enrolled and treated with a 600-mg loading dose and subsequent biweekly 300-mg injections of dupilumab for 16 weeks. During treatment, the investigators diagnosed, reported, and determined the severity and type of conjunctivitis (conjunctivitis; conjunctivitis, bacterial; conjunctivitis, viral; conjunctivitis, allergic; and #The members of the Italian DADReL (Dupilumab Atopic Dermatitis in Real Life) Study Group are listed in the Acknowledgments
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atopic keratoconjunctivitis [Medical Dictionary for Regulatory Activities preferred terms]) at baseline and at weeks 4, 8, 12, and 16. All patients with moderate-to-severe conjunctivitis were referred to an ophthalmologist.
The study protocol was approved by the principal ethics committee, and informed consent was obtained from all patients. To assess the risk of baseline characteristics being associated with a conjunctivitis event, a Cox regression time-to-event analysis was performed. Baseline factors were evaluated individually and in a multivariable model, including age class (≤33 years vs >33 years) and sex. These factors were as follows: clinical scores (EASI, classified as above vs below the 75th percentile; Dermatology Life Quality Index [DLQI], classified as a small effect on quality of life [QoL] below 6, moderate effect on QoL up to 10, very large effect on QoL up to 20 and more than 20; Scoring Atopic Dermatitis [SCORAD], classified as above or below the 75th percentile; Patient-Oriented Eczema Measure [POEM], classified as mild when lower than 8, moderate up to 16, severe up to 24, and very severe more than 24; numerical rating scale [NRS] for sleep and NRS for pruritus, both classified as below and above the 75th percentile), IgE levels (classified as normal up to 100, from 100 to the 75th percentile, below the 75th percentile), eosinophil counts (classified as below or above 350), and family history of allergic conjunctivitis and history of conjunctivitis (both classified as present or not present). A stepwise selection procedure was used to improve the model fit and select variables associated with moderate-to-severe conjunctivitis events; a P value ≤.05 entry model was applied. The final model was adjusted for age class, sex, IgE (≤3637 vs >3637), and history of conjunctivitis. The goodness of fit was evaluated using R2 and the C-index according to Pencina and D’Agostino [5].
Among the 96 patients invited to participate, 24 were diagnosed with conjunctivitis at baseline and were removed from the analysis. Among the remaining 72 patients, 29 (40.3%) were diagnosed with dupilumab-associated conjunctivitis during follow-up. This was mild in 18 patients (62%), moderate in 8 (27.6%), and severe in 3 (10.3%). Mean time to the first dupilumab-associated conjunctival event was 12 weeks (standard error, 0.58).
Cases were managed with topical therapy, as previously described [6]. In 19 cases (65.5%), conjunctivitis had resolved or was resolving by the end of week 16. Nine cases (31%) had not resolved, and 1 case (3.4%) had resolved with sequelae. Dupilumab was discontinued in 1 patient owing to bilateral conjunctivitis and cicatricial ectropion (Table).
The factors that were significantly associated with dupilumab-induced conjunctivitis in the univariable analysis (Supplementary Table) included family history of allergic conjunctivitis (HR, 2.77; 95%CI, 1.05-7.29), history of conjunctivitis (HR, 21.31; 95%CI, 5.03-90.26), presence of other atopic conditions (HR, 2.51; 95%CI, 1.21-5.24), SCORAD score (>76.6 vs <76.6; HR, 2.29; 95%CI, 1.04-5.05), baseline IgE levels (>3637 vs ≤100; HR, 3.15; 95%CI, 1.2-8.26), and baseline blood eosinophil counts (>350 vs ≤350; HR, 3.99; 95%CI, 1.71-9.29). In the stepwise selection procedure for the multivariable regression, all predictors were removed except history of conjunctivitis; HR and 95%CI remained unchanged, R2 was 0.39, and the C-index was 0.53.
Dupilumab-associated conjunctivitis was recently reported in up to 50% of AD patients undergoing treatment [5]. The predictors of its incidence are not well known. Over a 16-week observational period, the current study reports a prospectively registered incidence of conjunctivitis in 40.3% of patients without conjunctivitis at baseline. Cases were mostly mild-or-moderate (90%) and had resolved/were resolving in the case of patients continuing treatment. The risk factors for dupilimuab-associated conjunctivitis in previous studies are severe AD [2,3,6], prior history of conjunctivitis [3,7], atopic AD phenotype [4,7], and high baseline IgE levels and eosinophil counts [3] .
The current study reinforces the role of these risk factors in the development of dupilumab-associated conjunctivitis and highlights their value for clinical practice. After accounting for any simultaneous effects of risk factors, the main predictor for the development of dupilumab-associated conjunctivitis was a history of conjunctivitis.
The cause of dupilumab-associated conjunctivitis is still unclear [4,8]. Patients with AD have a greater prevalence of ocular comorbidities than the general population [9], and administration of dupilumab for asthma or nasal polyposis
aThe incidence was calculated among the 72 patients who were not diagnosed with conjunctivitis at baseline. bConjunctivitis in which the etiology remained unspecified.
Table. Summary of Conjunctivitis Events at Initiation of Treatment and During the Treatment Period in 96 Patients
Conjunctivitis Incidence of Conjunctivitis Prevalence of Conjunctivitis at Initiation During Treatment With During Treatment With
of Dupilumab Dupilumaba Dupilumab
(n=24) (n=29) (n=53)
Conjunctivitis event, No. (%) 24 (25.0%) 29 (40.3%) 53 (55.2%)
Conjunctivitisb 3 (3.2%) 22 (30.6%) 25 (26.0%) Allergic conjunctivitis 17 (17.7%) 2 (2.8%) 19 (19.8%) Atopic keratoconjunctivitis 4 (4.1%) 3 (4.2%) 7 (7.3%) Bacterial conjunctivitis 0 (0%) 1 (1.4%) 1 (1.0%) Viral conjunctivitis 0 (0%) 1 (1.4%) 1 (1.0 %) 202
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has not been associated with higher rates of conjunctivitis [4]. Some authors hypothesize that both dupilumab- and AD-related mechanisms may be involved and that ocular or immune differences between patients with AD and other type 2 diseases might be considered [3]. Others have suggested that an increased eosinophil count after drug administration, which plays a part in the development of allergic eye disorders, could increase the risk of dupilumab-induced conjunctivitis [4,9]. Recent papers hypothesize that the IL-13 and/or IL-4 blocking effect might lead to reduction of goblet cells and mucin production in a subpopulation of AD patients that may potentially result in irritative conjunctivitis [10,11]. This fact was confirmed when dupilumab was withdrawn [12]. The use of artificial tears during treatment with dupilumab might reduce the incidence of conjunctivitis/keratitis [6,13].
While limited by its relatively small sample size, short follow-up, and a lack of a control group, our study shows that patients with moderate-to-severe AD and a history of conjunctivitis seem to be at greater risk of developing dupilumab-associated conjunctivitis. Identifying associated risk factors at baseline may help to predict the onset of conjunctivitis during treatment with dupilumab. We recommend artificial tears in patients with AD treated with dupilumab to reduce the incidence of conjunctivitis and keratitis.
Acknowledgments
Italian DADReL (Dupilumab Atopic Dermatitis in Real Life) Study Group
Alessandrini G1, Bonifazi E2, Brancaccio R3, Calogiuri G4, Caruso C5, Castellana C6, Congedo M7, Damiani A8, De Feo G9, De Pasquale T10, De Paulis A3, Di Gioacchino M11, Di Leo E12, D’Ippolito G13, Gaeta F5, Gatta A11, Guanti MB14, Guerriero S15, Leto Barone ME16, Macchia L17, Paladini A18, Pannofino A19, Parronchi P20, Pellacani G14, Pucci S10, Rossi D21, Rossi O22, Salvati L20, Spadaro G3, Tagliavanti MR23, Triggiani M9, Vena GA24
1Dermatology and Venereology Private Practice, Gallipoli, Lecce,
Italy; 2Dermatology and Venereology Private Practice Bari,
Italy; 3Department of Internal Medicine and Clinical Pathology,
Azienda Ospedaliera Universitaria Federico II, Naples, Italy;
4Pneumology Department, Sacro Cuore Hospital, Gallipoli,
Lecce, Italy; 5Allergy Unit, Fondazione Policlinico A. Gemelli,
IRCSS, Rome; 6Dermatology and Venereology Private Practice,
Bari, Italy; 7Dermatology Unit, “Vito Fazzi” Hospital, Lecce,
Italy; 8Dermatology and Venereology Private Practice, Bisceglie,
Italy; 9Division of Allergy and Clinical Immunology, University of
Salerno, Salerno, Italy; 10Division of Allergy, Civitanova Marche
Hospital, Civitanova Marche, Italy; 11Department of Medicine and
Science of Ageing, Specialization School of Allergy and Clinical Immunology, G. D'Annunzio University, Chieti, Italy; 12Section
of Allergy and Clinical Immunology, Unit of Internal Medicine, “F. Miulli” Hospital, Acquaviva delle Fonti, Italy; 13Section of
Allergy and Clinical Immunology, Francavilla Fontana Hospital, Brindisi, Italy; 14Dermatology Unit, Surgical, Medical and Dental
Department of Morphological Sciences related to Transplant, Oncology and Regenerative Medicine, University of Modena and Reggio Emilia, Modena, Italy; 15Department of Ophthalmology
and Otolaryngology, University of Bari, Italy; 16Dipartimento
Biomedico di Medicina Interna e Specialistica, Università degli Studi di Palermo, Scuola di Medicina e Chirurgia, Palermo, Italy;
17Department of Emergency and Organ Transplantation, School
and Chair of Allergology and Clinical Immunology, University of Bari - Aldo Moro, Bari, Italy; 18“A. Perrino” Hospital, Brindisi,
Italy; 19Allergology and Immunology Clinic, Operative Unit of
Medicine, Policoro Hospital, Policoro, Matera, Italy.; 20Department
of Clinical and Experimental Medicine, Unit of Internal Medicine, University of Florence, Florence, Italy; 21Dermatology and
Venereology Private Practice Bari, Italy; 22Immunoallergology
Unit, Careggi University Hospital, Florence, Italy; 23Dermatology
and Venereology Private Practice Bari, Italy; 24Dermatology and
Venereology Private Practice Bari, Barletta, Italy Funding
The authors declare that no funding was received for the present study.
Conflicts of Interest
The authors declare that they have no conflicts of interests. References
1. Sastre J, Dávila I. Dupilumab: A New Paradigm for the Treatment of Allergic Diseases. J Investig Allergol Clin Immunol. 2018;28(3):139-50.
2. Wollenberg A, Ariens L, Thurau S, van Luijk C, Seegräber M, de Bruin-Weller M. Conjunctivitis occurring in atopic dermatitis patients treated with dupilumab-clinical characteristics and treatment. J Allergy Clin Immunol Pract. 2018;6(5):1778-80. 3. Akinlade B, Guttman-Yassky E, de Bruin-Weller M, Simpson
EL, Blauvelt A, Cork MJ, et al. Conjunctivitis in dupilumab clinical trials. Br J Dermatol. 2019;181(3):459-73.
4. Treister AD, Kraff-Cooper C, Lio PA. Risk factors for dupilumab-associated conjunctivitis in patients with atopic dermatitis. JAMA Dermatol. 2018;154:1208-11.
5. Pencina MJ and D’Agostino RB. Overall C as a measure of discrimination in survival analysis: model specific population value and confidence interval estimation. Statistics in Medicine. 2004,23:2109-23.
6. Rial MJ, Barroso B, Rodríguez-Bermejo C, Sastre J. Letter regarding “Conjunctivitis occurring in atopic dermatitis patients treated with dupilumab—clinical characteristics and treatment”. J Allergy Clin Immunol Pract. 2019;7:853. 7. Simpson EL, Akinlade B, Ardeleanu M. Two Phase 3 Trials of
Dupilumab versus Placebo in Atopic Dermatitis. N Engl J Med. 2017;376(11):1090-1.
8. Nettis E, Guerriero S, Masciopinto L, Di Leo E, Macchia L. Dupilumab-induced bilateral cicatricial ectropion in real-life. J Allergy Clin Immunol Pract. 2019 Nov 12. pii: S2213-2198(19)30906-7.
9. Thyssen JP, Toft PB, Halling-Overgaard AS, Gislason GH, Skov L, Egeberg A. Incidence, prevalence, and risk of selected ocular disease in adults with atopic dermatitis. J Am Acad Dermatol. 2017;77(2):280-6.e1.
10. Bakker DS, Ariens LFM, Luijk C, van der Schaft J, Thijs JL, Schuttelaar MLA, et al. Goblet cell scarcity and conjunctival 203
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Manuscript received December 23, 2019; accepted for publication January 7, 2020.
Laura Bonzano Dermatology Unit, Surgical, Medical and Dental Department
of Morphological Sciences related to Transplant, Oncology and Regenerative Medicine, University of Modena and Reggio Emilia Largo del Pozzo, 71 41125 Modena, Italy E-mail: laurabonzano83@gmail.com inflammation during treatment with dupilumab in patients with atopic dermatitis. Br Dermatol. 2019;180:1248-9. 11. Waldman RA, DeWane ME, Sloan SB. Does interleukin-4
inhibition play a role in dupilumab-associated conjunctivitis? Br J Dermatol. 2020;182(1):251.
12. Voorberg AN, den Dunnen WFA, Wijdh RHJ, de Bruin-Weller MS, Schuttelaar MLA. Recurrence of conjunctival goblet cells after discontinuation of dupilumab in a patient with dupilumab-related conjunctivitis. J Eur Acad Dermatol Venereol. 2020;34(2):e64-6.
13. Armario-Hita JC, Pereyra-Rodriguez J, Silvestre JF, Ruiz-Villaverde R, Valero A, Izu-Belloso R, et al. Treatment of moderate-to-severe atopic dermatitis with dupilumab in real clinical practice: a multicentre, retrospective case series. Br J Dermatol. 2019;181(5):1072-4.
Occupational Rhinoconjunctivitis Induced by Unusual Allergens of Carrot
Sánchez-Guerrero IM1, Nieto A1, Meseguer J1, Navarro M1, López Sáez MP1, Magdalena MK1, Sánchez Pérez M1, Pineda F2, López Sánchez JD1
1Allergy Service, Hospital Clínico Universitario Virgen de la
Arrixaca, Murcia, Spain
2Application Laboratory, Diater, Madrid, Spain
J Investig Allergol Clin Immunol 2020; Vol. 30(3): 204-206 doi: 10.18176/jiaci.0482
Key words: Carrot allergy. Occupational rhinoconjunctivitis. Immunoblotting. Allergens.
Palabras clave: Alergia a zanahoria. Rinoconjuntivitis ocupacional. Immunoblotting. Alérgenos.
Daucus carota L. (carrot) is a vegetable that belongs to the
Umbelliferae (Apiaceae) family. It is frequently implicated in food allergy and oral allergy syndrome, usually in association with other foods. Thus, hypersensitivity to carrot is commonly associated with allergy to Apiaceae species and sensitization to birch and mugwort pollens [1,2]. In southern Spain, allergy to Artemisia vulgaris is quite frequent, in contrast to allergy to Betula verrucosa. Nevertheless, few cases of rhinitis and asthma induced by carrot allergy have been reported [3,4]. We investigated the allergens involved in a case of occupational rhinoconjunctivitis induced by carrot.
A 38-year-old male cook diagnosed with allergic rhinitis and asthma due to mite and pollen had been treated successfully with subcutaneous immunotherapy. For the previous 3 years, the patient had developed facial contact urticaria, sneezing, rhinorrhea, and conjunctivitis within a few minutes of handling or cutting raw carrots, although he had previously tolerated both raw and cooked intake.
A skin prick test (SPT) was performed with a set of airborne and commercial food allergens, as well as native fresh foods. The result was positive (average wheal diameter ≥3 mm) to house dust mite, cat, dog, and pollens (grasses, Salsola, and
Olea) and negative to Artemisia species and birch pollens,
lipid transfer protein (LTP), profilin, and commercial extract of carrot. Native fresh food SPT was positive to carrot (peel and pulp) and celery and negative to parsley, anise, and dill. A rubbing test with fresh carrot was also negative.
Levels of specific IgE (sIgE) were determined using the ImmunoCap system (Thermo Fisher Scientific). A positive sIgE result (>0.35 kUA/L) was recorded for rPhl p 1 (0.44 kUA/L), nOle e 1 (10.10 kUA/L), nSal k 1 (61.60 kUA/L),
Artemisia vulgaris (10.80 kUA/L), carrot (12.80 kUA/L), and celery (12.20 kUA/L). sIgE was negative for LTP (rPru p 3) and profilin (rPhl p 12).
A causal relationship between exposure to an occupational agent and rhinitis can only be established with certainty by means of specific nasal provocation testing. When this is 204
