Angioedema and prescribing of omalizumab for chronic urticaria in countries with limited financial resources
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Bibliographic record
Abstract
Urticaria comprises a spectrum of conditions characterized by the appearance of itchy wheals. If the symptoms recur for longer than 6 weeks (average duration is 5–7 years), the condition falls within the definition of chronic urticaria.1Zuberbier T. Aberer W. Asero R. et al.The EAACI/GA(2)LEN/EDF/WAO guideline for the definition, classification, diagnosis and management of urticaria.Allergy. Jul 2018; 73: 1393-1414Crossref PubMed Scopus (622) Google Scholar In more than half of the cases of chronic urticaria (CU), the wheals are accompanied by swelling of the deeper cutaneous and subcutaneous tissues referred to as angioedema, which can persist for several days.2Metz M. Maurer M. Rupatadine for the treatment of allergic rhinitis and urticaria.Expert Rev Clin Immunol. Jan 2011; 7: 15-20Crossref PubMed Scopus (22) Google Scholar Angioedema often develops in the face, lips and oral cavity. In around 10% of affected patients, angioedema occurs in the absence wheals. In this case, hereditary angioedema and other forms of bradykinin mediated angioedema have to be ruled out, as the two conditions have very different pathogenic mechanisms and associated risks.3Maurer M. Magerl M. Ansotegui I. et al.The international WAO/EAACI guideline for the management of hereditary angioedema-The 2017 revision and update.Allergy. Aug 2018; 73: 1575-1596Crossref PubMed Scopus (250) Google Scholar When determining the diagnosis and management of CU, wheals and angioedema are generally viewed together: disease severity is established on the basis of subjective and objective indicators, treatment starts with the licensed doses of H1-antihistamines, which may be subsequently increased up to 4 times.4Popov T.A. Challenges in the management of chronic urticaria.World Allergy Organ J. Mar 2011; 4: 28-31Abstract Full Text Full Text PDF Scopus (2) Google Scholar Patients with severe CU, who do not respond to off-label high doses of second generation H1-antihistamines pose serious problems to the treating physicians.1Zuberbier T. Aberer W. Asero R. et al.The EAACI/GA(2)LEN/EDF/WAO guideline for the definition, classification, diagnosis and management of urticaria.Allergy. Jul 2018; 73: 1393-1414Crossref PubMed Scopus (622) Google Scholar Omalizumab (anti-IgE) has been proven to substantially increase the success rate of treatment in such antihistamine non-responsive cases.1Zuberbier T. Aberer W. Asero R. et al.The EAACI/GA(2)LEN/EDF/WAO guideline for the definition, classification, diagnosis and management of urticaria.Allergy. Jul 2018; 73: 1393-1414Crossref PubMed Scopus (622) Google Scholar,5Mlynek A. Zalewska-Janowska A. Martus P. Staubach P. Zuberbier T. Maurer M. How to assess disease activity in patients with chronic urticaria?.Allergy. Jun 2008; 63: 777-780Crossref PubMed Scopus (265) Google Scholar Omalizumab sequesters IgE, the classical antibody associated with allergic diseases and asthma. In so doing so, omalizumab cuts short multiple mast cell activation mechanisms, suppresses the release of mediators, including histamine, and prevents pathological symptoms.6Kaplan A.P. Popov T.A. Biologic agents and the therapy of chronic spontaneous urticaria.Curr Opin Allergy Clin Immunol. 2014; 14: 347-353Crossref PubMed Scopus (9) Google Scholar Omalizumab, thus, represents a treatment option with societal benefit with the cost of the product itself being counterbalanced by the effect on indirect (productivity) costs.7Graham J. McBride D. Stull D. et al.Cost utility of omalizumab compared with standard of care for the treatment of chronic spontaneous urticaria.PharmacoEconomics. Aug 2016; 34: 815-827Crossref PubMed Scopus (15) Google Scholar Omalizumab is approved for the treatment of antihistamine-resistant chronic spontaneous urticaria (CSU) in over 80 countries around the world and is licensed by the European Medicines Agency of the European Union and the Food and Drug Administration of the USA. However, if reimbursement is not provided by the healthcare systems in the countries where it is licensed, its accessibility for treatment is precluded by its relatively high cost. An argument of the health authorities to keep it off reimbursement lists is that CU is not a fatal disease and the regulators in countries with limited financial resources do not attach to omalizumab enough weight to override the reimbursement threshold. However, the presence of angioedema imparts to CU a higher level of importance, as the general public perceives the condition as life threatening.1Zuberbier T. Aberer W. Asero R. et al.The EAACI/GA(2)LEN/EDF/WAO guideline for the definition, classification, diagnosis and management of urticaria.Allergy. Jul 2018; 73: 1393-1414Crossref PubMed Scopus (622) Google Scholar The very first episode of facial edema and sense of swelling in the oral cavity and the throat triggers an existential fear of suffocation in patients with CU. The dramatically altered psycho-emotional state of those affected is conveyed to the emergency medical staff: high doses of parenteral corticosteroids are applied and often hospitalization is proposed. The patients become convinced that they have had a close encounter with death, and the horror of future similar episodes is seeded in them. In most cases, systemic corticosteroids are prescribed,8Broder M.S. Raimundo K. Antonova E. Chang E. Resource use and costs in an insured population of patients with chronic idiopathic/spontaneous urticaria.Am J Clin Dermatol. Aug 2015; 16: 313-321Crossref PubMed Scopus (35) Google Scholar and attempts to discontinue them are usually followed by the resurgence of CU/angioedema symptoms, thereby initiating a vicious circle of chronicity. Based on our clinical experience, the real risk for patients with chronic urticaria associated angioedema is addiction to systemic corticosteroids and the ensuing side effects that can trigger other chronic diseases (e.g. osteoporosis, diabetes, arterial hypertension, ulcer, obesity) and disturb the overall hormonal balance (particularly unwanted for female patients).9Oray M. Abu Samra K. Ebrahimiadib N. Meese H. Foster C.S. Long-term side effects of glucocorticoids.Expert Opin Drug Saf. 2016; 15: 457-465Crossref PubMed Scopus (186) Google Scholar As in asthma,10Canonica G.W. Colombo G.L. Bruno G.M. et al.Shadow cost of oral corticosteroids-related adverse events: a pharmacoeconomic evaluation applied to real-life data from the Severe Asthma Network in Italy (SANI) registry.World Allergy Organ J. 2019; 12 (100007)Abstract Full Text Full Text PDF Scopus (39) Google Scholar the shadow cost of oral corticosteroid-related adverse events is likely to have a significant unwanted economic impact on society and health insurance systems (Fig. 1). While omalizumab, like other biologics, may appear relatively expensive, the arguments for its reimbursement for the treatment of CU are several. First, angioedema occurs frequently in patients with CU, one report indicating an incidence of up to 71%.11Maurer M. Abuzakouk M. Berard F. et al.The burden of chronic spontaneous urticaria is substantial: real-world evidence from ASSURE-CSU.Allergy. Dec 2017; 72: 2005-2016Crossref PubMed Scopus (98) Google Scholar Second, angioedema is commonly underdiagnosed,12Sussman G. Abuzakouk M. Berard F. et al.Angioedema in chronic spontaneous urticaria is underdiagnosed and has a substantial impact: analyses from ASSURE-CSU.Allergy. Aug 2018; 73: 1724-1734Crossref PubMed Scopus (33) Google Scholar and it may happen at any time during the course of the disease. Third, in CU patients with angioedema, angioedema episodes are frequent. In a recent study on 91 CU patients with angioedema, 60% of patients had angioedema weekly.13Staubach P. Metz M. Chapman-Rothe N. et al.Effect of omalizumab on angioedema in H1 -antihistamine-resistant chronic spontaneous urticaria patients: results from X-ACT, a randomized controlled trial.Allergy. Aug 2016; 71: 1135-1144Crossref PubMed Scopus (80) Google Scholar Fourth, 9 of 10 patients experience angioedema of the lips and more than half report angioedema of the tongue, the mouth and upper airways.13Staubach P. Metz M. Chapman-Rothe N. et al.Effect of omalizumab on angioedema in H1 -antihistamine-resistant chronic spontaneous urticaria patients: results from X-ACT, a randomized controlled trial.Allergy. Aug 2016; 71: 1135-1144Crossref PubMed Scopus (80) Google Scholar Fifth, in 45% of patients, the duration of angioedema is more than 24 hours. Sixth, in a study of 665 patients with CU, the severity of angioedema was assessed as moderate or severe in 78% of patients.14Kolkhir P. Church M.K. Weller K. Metz M. Schmetzer O. Maurer M. Autoimmune chronic spontaneous urticaria: what we know and what we do not know.J Allergy Clin Immunol. Jun 2017; 139: 1772-1781 e1771Abstract Full Text Full Text PDF PubMed Scopus (138) Google Scholar Seventh, omalizumab has been shown to decrease systemic corticosteroid use in most CU cases in 1 retrospective study15Labrador-Horrillo M. Valero A. Velasco M. et al.Efficacy of omalizumab in chronic spontaneous urticaria refractory to conventional therapy: analysis of 110 patients in real-life practice.Expert Opin Biol Ther. Sep 2013; 13: 1225-1228Crossref PubMed Scopus (63) Google Scholar and to have steroid sparing effect in a case report16Gatta A. Della Valle L. Farinelli A. Cavallucci E. Paganelli R. Di Gioacchino M. Omalizumab in chronic spontaneous urticaria: steroid sparing effect.J Dermatol Treat. 2018; 29: 6-9Crossref PubMed Scopus (2) Google Scholar: thus, it may reduce the possibility of corticosteroid-related adverse events. Finally, and perhaps most importantly, angioedema markedly impairs quality of life, even in patients with low wheal scores, and often leads to social isolation.11Maurer M. Abuzakouk M. Berard F. et al.The burden of chronic spontaneous urticaria is substantial: real-world evidence from ASSURE-CSU.Allergy. Dec 2017; 72: 2005-2016Crossref PubMed Scopus (98) Google Scholar,17Weldon D.R. Quality of life in patients with urticaria.Allergy Asthma Proc. Mar-Apr 2006; 27: 96-99PubMed Google Scholar Although omalizumab provides an effective treatment for CU patients with angioedema, it is all too often not available to them because of the failure of health authorities to reimburse it.1Zuberbier T. Aberer W. Asero R. et al.The EAACI/GA(2)LEN/EDF/WAO guideline for the definition, classification, diagnosis and management of urticaria.Allergy. Jul 2018; 73: 1393-1414Crossref PubMed Scopus (622) Google Scholar,13Staubach P. Metz M. Chapman-Rothe N. et al.Effect of omalizumab on angioedema in H1 -antihistamine-resistant chronic spontaneous urticaria patients: results from X-ACT, a randomized controlled trial.Allergy. Aug 2016; 71: 1135-1144Crossref PubMed Scopus (80) Google Scholar,18Maurer M. Raap U. Staubach P. et al.Antihistamine-resistant chronic spontaneous urticaria: 1-year data from the AWARE study.Clin Exp Allergy. 2019; 49 (Epub 2018 Dec 7): 655-662Crossref PubMed Scopus (22) Google Scholar,19Maurer M. Rosen K. Hsieh H.J. et al.Omalizumab for the treatment of chronic idiopathic or spontaneous urticaria.N Engl J Med. Mar 7 2013; 368: 924-935Crossref PubMed Scopus (630) Google Scholar All authors have reviewed and approved of the final manuscript. No actual work with human subjects or animals had been conducted in relation to this letter-to-editor. None of the authors has any competing interests. The authors wish to thank Ms. Beate Schinzel for her secretarial assistance.
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Full frame distilled prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. Learned from the 10,348 direct Codex labels and 10,348 direct Gemma labels. Candidate is the union of thresholded teacher heads; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels or direct frontier model labels.
Codex and Gemma teacher scores by category
| Category | Codex | Gemma |
|---|---|---|
| Metaresearch | 0.000 | 0.000 |
| Meta-epidemiology (narrow) | 0.000 | 0.000 |
| Meta-epidemiology (broad) | 0.000 | 0.000 |
| Bibliometrics | 0.000 | 0.001 |
| Science and technology studies | 0.000 | 0.000 |
| Scholarly communication | 0.000 | 0.000 |
| Open science | 0.000 | 0.000 |
| Research integrity | 0.000 | 0.000 |
| Insufficient payload (model declined to judge) | 0.000 | 0.000 |
Machine scores (provisional)
The two teacher heads of the student model, read on this work. A score orders the frame for review; it never asserts a category, and the validation status ships verbatim with every row.
Baseline scores from an immature model (maturity gate not passed, 7 training rounds). Scores rank; they never assert a category.
score_only:v0-immature-baseline · verbatim from the scoring run: score_only means the number may rank works, and no category label ships from it