Alizadeh Aghdam, Mehran

Assil, Salma

Kentie, Petra A.

Knulst, Andre C.

Luijf, Teddy

Meertens, Michelle A.J.

Röckmann, Heike

Soegiharto, Reineke

van Doorn, Martijn B.A.

van Lindonk, Esmee A.M.

Utrecht University Repository

Clinical CommunicationsAge and fast initial response predictomalizumab retreatment in chronicurticariaMichelle A.J. Meertens, MDa, Teddy Luijf, MDa,*,Esmee A.M. van Lindonk, BScb,*,Reineke Soegiharto, MDa, Salma Assil, MDb,Mehran Alizadeh Aghdam, MDa, Petra A. Kentie, NPa,Andre C. Knulst, MD, PhDa,Martijn B.A. van Doorn, MD, PhDb,**, andHeike Röckmann, MD, PhDa,**Clinical Implications355We found that omalizumab can be discontinued to revealdisease remission and avoid drug exposure in patients withchronic urticaria. Higher age and fast initial responsepredict the need for retreatment and can be used to counselpatients in clinical practice.Omalizumab, a monoclonal anti-IgE antibody, is an effectiveand safe add-on treatment in patients with chronic spontaneousurticaria (CSU) with insufficient response to a 4-fold dose ofsecond-generation antihistamines.1 In daily practice, omalizumabtreatment protocols differ between centers and countries withregard to dose escalation, prolongation of dosing intervals, andstopping criteria. Little is known about the treatment-free in-tervals after discontinuation of omalizumab when the disease iswell controlled and the determinants that predict the need torestart treatment.The objectives of our study were (1) to analyze the treatment-free period after discontinuation of omalizumab and identifypredictors for retreatment and (2) to compare treatment effec-tiveness and treatment intervals between the first and secondtreatment episode.Data concerning patient and treatment characteristics of allpatients with chronic urticaria (CU; including all subtypes: CSU,angioedema, and chronic inducible urticaria) on omalizumabtreatment (February 2012 to May 2021) in 2 Dutch universitycenters (University Medical Center Utrecht [UMCU] andErasmus Medical Center [EMC] Rotterdam) were collected.According to the International and Dutch guidelines,1,2 all pa-tients showed insufficient response to high-dose antihistaminesand were initially treated with omalizumab 300 mg every 4weeks. After 3 (EMC Rotterdam) and 6 (UMCU) administra-tions, respectively, treatment intervals in patients with well-controlled disease (Urticaria Activity Score [UAS7] 6 orUrticaria Control Test [UCT] 12) were gradually increasedwithin 1 week. Treatment was discontinued in symptom-freepatients with an 8-week treatment interval or in patients withinsufficient response or side effects.3 Patients with relapse ofsymptoms could restart omalizumab with the steady-state inter-val of the first treatment period, which was subsequently grad-ually prolonged. The steady-state interval was defined as the6longest well-controlled (UCT 12 or UAS 6) treatment in-terval achieved on at least 2 consecutive administrations.3,4To eliminate potential bias due to a too short treatment period,patients with a follow-up period of 14.5 months after the initialstart of omalizumab were excluded. Patients with a follow-upperiod of 6 months after the start of the second treatmentperiod were excluded from comparative analyses of effectivenessand steady-state interval between treatment episodes.We identified 633 patients with CU who had received omali-zumab treatment. A total of 142 patients were excluded (treatment14.5 months) and 492 patients (mean age 41 years; 71% female)were included. At data lock, 204 patients (41.5%) were continu-ously treated. A total of 288 patients (58.5%) discontinued oma-lizumab after the first treatment period, of whom 116 (40.3%)restarted omalizumab treatment with a median treatment-freeperiod of 4.4 months (minimum-maximum: 1.8-54.5 months).Patient and treatment characteristics were comparable betweenthe 2 centers and other daily practice populations (Table E1,available in this article’s Online Repository at www.jaci-inpractice.org).5 The treatment-free period after discontinuation of the firsttreatment period was analyzed by survival analysis. The 1-, 2-, 4-,and 7-year treatment-free survival rates were 66%, 58%, 54%,and 52%, respectively (Figure 1). By Cox regression multivariateanalysis, higher age and fast initial treatment response (UAS7 6or UCT 12 within 1 month of treatment) were identified aspredictors for a shorter treatment-free period (Figure 2). Of pa-tients who restarted, total percentages of patients who achievedcomplete, good, partial, or poor response did not differ signifi-cantly between the 2 treatment episodes (Table E2, available inthis article’s Online Repository at www.jaci-inpractice.org). Themajority of patients (88.1%) achieved equal or better effectivenessin the second treatment episode. Of patients with a good orcomplete response in the first treatment period, 90.1% againachieved a good or complete response. Of patients with an initialpartial or poor response (n ¼ 16), 44 % (n ¼ 7) achieved a goodor complete response in the second treatment period. Only 8patients (7.9%) achieved a worse response during the secondtreatment episode (Table E2, available in this article’s OnlineRepository at www.jaci-inpractice.org). The mean steady-statetreatment interval in the second treatment period was signifi-cantly longer (8.1 weeks) compared with the first period (7 weeks;P ¼ .002). A total of 88.2% of patients (n ¼ 82) showed an equalor longer steady-state interval in the second treatment periodcompared with the first.In this study, we display the omalizumab-free survival ratesafter 1 to 7 years and show that only few patients need to restartomalizumab after a 1-year treatment-free period. A recent studyby Di Bona et al6 (n¼137) also demonstrated long-termremission after discontinuation of omalizumab treatment inapproximately 50% of patients with a follow-up period of up to4 years. In this study, age above 60 years, high wheal score, andlonger treatment duration were independent predictors for dis-ease relapse after omalizumab treatment discontinuation.We also found higher age as an independent predictor for oma-lizumab retreatment, which might be explained by immunose-nescence mechanisms, needing further investigation. In addition,we identified fast treatment response as an independent predictor forFIGURE 1. Treatment-free survival after discontinuation of the first omalizumab treatment period. Kaplan-Meier curve representingtreatment-free period survival, analyzing the time between the last administration of the first treatment period and the first administrationof the second treatment period.FIGURE 2. Predictors of time to restart after discontinuation of the first omalizumab (OMA) treatment period. (A) Characteristics thatwere deemed relevant were analyzed in a univariate Cox regression analysis. Candidate predictors with a P value of .2 (marked in bold)were used in the multivariate Cox regression analysis with backward selection. (B) Determinants with a P value of <.05 were consideredstatistically significant and were identified as independent predictors of time to restart . CI, Confidence interval; CindU, chronic inducibleurticaria; UAS7, Urticaria Activity Score.J ALLERGY CLIN IMMUNOL PRACTVOLUME 11, NUMBER 11CLINICAL COMMUNICATIONS 3557omalizumab retreatment. Patients with a fast response, according toour treatment algorithm, will quickly initiate interval prolongationwith subsequent early discontinuation, potentially leaving less timefor “true” disease remission and therefore have a higher chance ofrelapse. This theory might be supported by the finding that withinpatients who discontinued omalizumab due to well-controlled dis-ease, the treatment duration was shorter in patients who restarted(median 12 months) than in patients who did not restart omalizu-mab (median 14 months) (strong trend; P ¼ .053). Our findingssuggest that some delay in discontinuation in patients with a fastresponse might be reasonable.Our data also show that omalizumab is equally or moreeffective in a second treatment period compared with the firstperiod in the majority of patients with equal or longer dosingintervals, on population and individual level. A few smallstudies have compared the effectiveness of the first and secondomalizumab treatment episodes and showed comparable per-centages of patients with a good or complete response.5In conclusion, these data provide important real-world prac-tice information demonstrating that omalizumab can beeffectively discontinued to reveal disease remission and avoidunnecessary drug exposure. In addition, we found higher age anda fast initial treatment response to be important determinants forthe need to restart omalizumab treatment. These findings are ofgreat value for patient counseling when discontinuing omalizu-mab in clinical practice.aUrticaria Centre of Excellence and Reference (UCARE), Department ofDermatology/Allergology, University Medical Center Utrecht, Utrecht University,Utrecht, the NetherlandsbUrticaria Centre of Excellence and Reference (UCARE), Department ofDermatology, Erasmus Medical Center Rotterdam, Rotterdam, the Netherlands*These authors contributed equally to this work.**These authors contributed equally to this work.No funding was received for this work.Conflicts of interest: M. B. A. van Doorn has acted as a clinical investigator and/orreceived consulting fees or honorarium from Novartis, Abbvie, Pfizer, Leopharma,Sanofi, Lilly, Janssen, Celgene, and Third Harmonic; and has received a grant andpayment for lectures including service on speakers’ bureaus and advisory boardsfrom Novartis, Sanofi-Genzyme, and Janssen, outside the submitted work. A. C.Knulst is a member of the advisory board of Novartis and has received a healthJ ALLERGY CLIN IMMUNOL PRACTNOVEMBER 20233558 CLINICAL COMMUNICATIONScare innovation grant from Novartis and Pharming, to institution. H. Röckmann isa member of the national and international advisory board of Novartis, and hasreceived consulting fees or honorarium from Novartis and Sanofi and financialresearch support from Novartis and Pharming; all to institution. The rest of theauthors declare that they have no relevant conflicts of interest.Received for publication April 1, 2023; revised July 10, 2023; accepted forpublication July 17, 2023.Available online July 28, 2023.Corresponding author: Heike Röckmann, MD, PhD, Department of Dermatology,University Medical Centre Utrecht, Heidelberglaan 100, PO box 85500, 3584 CXUtrecht, the Netherlands. E-mail: h.rockmann@umcutrecht.nl.2213-2198 2023 The Authors. Published by Elsevier Inc. on behalf of the American Academyof Allergy, Asthma & Immunology. This is an open access article under the CC BYlicense (http://creativecommons.org/licenses/by/4.0/).https://doi.org/10.1016/j.jaip.2023.07.030REFERENCES1. Zuberbier T, Abdul Latiff AH, Abuzakouk M, Aquilina S, Asero R, Baker D,et al. The international EAACI/GA2LEN/EuroGuiDerm/APAAACI guideline forthe definition, classification, diagnosis, and management of urticaria. Allergy2022;77:734-66.2. Knulst AC, Nieuwhof C, Stadermann M, Tupker RA, van Doorn MBA,Franken SM, et al. Multidisciplinaire evidence based richtlijn: chronische spontaneurticaria [in Dutch]; 2015. Nederlandse Vereniging voor Dermatologie en Vene-reologie. Accessed December 20, 2022. https://www.alii.care//engine/download/blob/alii/470/2019/41/2017-11-28-Chronische-spontane-urticaria.pdf?app¼alii&class¼74&id¼2216&field¼4703. Niemeyer-van der Kolk T, van Maaren MS, van Doorn MBA. Personalizedomalizumab treatment improves clinical benefit in patients with chronic spon-taneous urticaria. J Allergy Clin Immunol 2018;142:1992-4.4. Aghdam MA, Pieterse RH, Kentie PA, Rijken F, Knulst AC, Röckmann H.Effective omalizumab interval prolongation in the treatment of chronic urticaria.J Allergy Clin Immunol Pract 2020;8:3667-3668.e1.5. Tonacci A, Nettis E, Asero R, Rossi O, Tontini C, Gangemi S. Omalizumabretreatment in patients with chronic spontaneous urticaria: a systematic review ofpublished evidence. Eur Ann Allergy Clin Immunol 2020;52:100-3.6. Di Bona D, Nettis E, Bilancia M, Ridolo E, Minenna E, Nizi MC, et al. Durationof chronic spontaneous urticaria remission after omalizumab discontinuation:a long-term observational study. J Allergy Clin Immunol Pract 2021;9:2482-2485.e2.J ALLERGY CLIN IMMUNOL PRACTVOLUME 11, NUMBER 11CLINICAL COMMUNICATIONS 3558.e1ONLINE REPOSITORYTABLE E1. Characteristics and disease activity of patients with CUCharacteristic Total (N [ 492) CT* (N [ 204)Stop-NR†(N [ 172)Restart-E1z(N [ 116)Restart-E2x(N [ 116)P valueS-NR/restart-E1Female, n (%) 355 (72.2) 148 (72.5) 124 (71.6) 83 (73.3) n.a. .920Age at start treatment (y)(mean  SD)42.1  15.7 42.3  14.7 39.6  15.9 45.5  16.4 n.a. .003**CU duration (y), n (%) n.a. .044**<1 70 (14.2) 23 (11.3) 29 (16.9) 18 (15.5)1-2 88 (17.9) 37 (18.1) 36 (20.9) 15 (12.9)2-5 98 (19.9) 45 (22.1) 29 (16.9) 24 (20.7)>5 146 (29.7) 64 (31.4) 44 (25.6) 37 (31.9)Subtype CU, n (%) n.a. .029**CSU-wheals 416 (84.6) 166 (81.4) 149 (86.6) 101 (87.1)CSU-AE 40 (8.1) 17 (8.3) 10 (5.8) 13 (11.2)CindU 36 (7.3) 31 (10.3) 13 (7.6) 2 (1.7)UAS7T-Baseline|| 27 (0-42);M{: 16727 (0-42);M: 7425 (0-42);M: 5429.6 (0-42);M: 3923.6 (0-42);M: 68.040**UCTT-Baseline|| 4 (0-16);M: 1384 (0-16);M: 484 (0-16);M: 565 (0-16);M: 344 (0-16);M: 59.663Treatment response#, n (%)Complete 56 (55.4) 49 (48.5) n.a.Good 28 (27.7) 31 (30.7) n.a.Partial 7 (6.9) 11 (10.9) n.a.Poor 9 (8.6) 7 (6.9) n.a.Missing 1 (1.0) 3 (3.0) n.a.CindU, Chronic inducible urticaria; CSU-AE, chronic spontaneous urticaria angioedema; CU, chronic urticaria; n.a., not applicable; SD, standard deviation; UAS7, UrticariaActivity Score; UCT, urticaria control test.*CT: continuous treatment of omalizumab.†Stop-NR: patients stopped omalizumab and did not restart.zRestart-E1: first episode of omalizumab treatment for restart patients.xRestart-E1: second episode of omalizumab treatment for restart patients.||T-baseline: start of omalizumab.{M: number of missing values.#Comparison of response between the first and second treatment period on group level (Wilcoxon signed-rank test) (P value ¼ .331).**Significant difference between S-NR and restart-E1 (P < .05).TABLE E2. Response in the first and second omalizumab treat-ment episodeFirst treatment episodeSecond treatment episodeComplete Good Partial Poor TotalComplete 36 15 2 1 56Good 9 13 3 2 28Partial 2 2 3 0 7Poor 2 1 2 4 9Total 49 31 11 7Patients with restart omalizumab and follow-up of >6 months after the start of thesecond treatment period are analyzed (n ¼ 100).Complete response ¼ Urticaria Activity Score [UAS7] 0 at end; good response ¼0 < UAS7  6 at end; partial response¼ UAS7 reduction 10; and poor response¼UAS7 reduction <10.Comparison of response between the first and second treatment period on patientlevel: k: 0.295.

Age and fast initial response predict omalizumab retreatment in chronic urticaria

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Age and fast initial response predict omalizumab retreatment in chronic urticaria

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