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Insights and advances in chronic urticaria: a Canadian perspective Sussman, Gordon; Hébert, Jacques; Gulliver, Wayne; Lynde, Charles; Waserman, Susan; Kanani, Amin; Ben-Shoshan, Moshe; Horemans, Spencer; Barron, Carly; Betschel, Stephen; Yang, William H; Dutz, Jan; Shear, Neil; Lacuesta, Gina; Vadas, Peter; Kobayashi, Kenneth; Lima, Hermenio; Simons, F E R Feb 11, 2015

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REVIEWInsights and advances in car, Stephen Betschel , William H Yang , Jan Dutz ,asstealibnodotigeling to the cerebrum and is associated with significant induces remission in H1-antihistamine-resistant CSUALLERGY, ASTHMA & CLINICAL IMMUNOLOGYSussman et al. Allergy, Asthma & Clinical Immunology  (2015) 11:7 DOI 10.1186/s13223-015-0072-2further classified as spontaneous, i.e. chronic spontan-eous urticaria (CSU), or inducible by physical stimuli1University of Toronto, Medicine, Toronto, ON, CanadaFull list of author information is available at the end of the articlemorbidity [1-3].In this review, we provide an update on clinically rele-vant advances in the classification, investigations, andmanagement of chronic urticaria that have occurred inthe past few years (see list of key points for insights andadvances).and is used as third-line treatment for this indication.ReviewDefinitions, classification, and epidemiologyAcute urticaria, defined as hives lasting less than 6 weeks,can occur spontaneously, or be associated with acuteviral infections or allergic reactions to foods, medica-tions, or insect stings or bites. Chronic urticaria, definedas hives occurring intermittently for at least 6 weeks, is* Correspondence: gsussman@rogers.comfrom mediator-induced sensory nerve impulses travel-OmalizumabIntroductionUrticaria is characterized by wheals of various sizes sur-rounded by flares (erythema). Mast cells play a centralrole in the pathophysiology. Their activation throughimmunologic or non-immunologic processes induces de-granulation that results in release of potent preformedinflammatory mediators such as histamine, and newly-synthesized mediators such as leukotrienes and prosta-glandins. The main biologic effects of these mediatorsare pruritus, increased vascular permeability, and tis-sue edema. Pruritus, the primary symptom, resultsList of key points for insights and advances The term chronic spontaneous urticaria (CSU)replaces the term chronic idiopathic urticaria (CIU). Second-generation non-impairing non-sedatingH1-antihistamines are recommended for first-linetreatment of CSU. Up-dosing with second-generation non-impairingnon-sedating H1-antihistamines (to 2, 3, or 4 timesthe licensed dose) is recommended as second-linetreatment in CSU. Omalizumab (anti-IgE antibody) effectively and safelya Canadian perspectiveGordon Sussman1*, Jacques Hébert2, Wayne Gulliver3, ChMoshe Ben-Shoshan6, Spencer Horemans1, Carly Barron1Neil Shear1, Gina Lacuesta8, Peter Vadas1, Kenneth KobayAbstractIn the past few years there have been significant advancereview, we aim to update physicians about clinically relevanof chronic urticaria that have occurred in recent years. Thesand classify urticaria. We also detail the development and vthe impairment on quality-of-life and the morbidity causedof chronic urticaria now focuses on evidence-based use ofin standard doses and if this is not effective, in up to 4-foldomalizumab treatment has emerged as an effective, safe opKeywords: Chronic urticaria, Diagnosis, Classification, Mana© 2015 Sussman et al.; licensee BioMed CentrCommons Attribution License (http://creativecreproduction in any medium, provided the orDedication waiver (http://creativecommons.orunless otherwise stated.hi7, Hermenio Lima4 and F Estelle R Simons9which have changed the face of chronic urticaria. In thisadvances in the classification, diagnosis and managementinclude clarification of the terminology used to describedation of instruments to assess urticaria and understandy this disease. Additionally, the approach to managementn-impairing, non-sedating H1-antihistamines given initiallyses. For urticaria refractory to H1-antihistamines,on.ment, Immunology, Antihistamines, Up-dosing,Open Accesshronic urticaria:les Lynde1, Susan Waserman4, Amin Kanani5,1 7 5al. This is an Open Access article distributed under the terms of the Creativeommons.org/licenses/by/4.0), which permits unrestricted use, distribution, andiginal work is properly credited. The Creative Commons Public Domaing/publicdomain/zero/1.0/) applies to the data made available in this article,(Figure 1, Table 1). Spontaneous lesions are not indu-cible. The prevalence of CSU is 0.5% to 1% in the gen-eral population. It occurs most commonly in women,and has a peak age of onset between 20 and 40 years.There is associated angioedema, defined as asymmetricnon-dependent swelling of sub-mucosal tissues, in 33%-66% of patients with CSU [1-3] (Figure 2).Etiology and pathogenesisSpontaneous implies an endogenous cause; therefore, itis not surprising that in most patients with CSU, an ex-ternal trigger such as an allergen cannot be identified[1,2]. Approximately 45% of patients have an auto-immune component associated with antibodies to theIgE receptor alpha subunit or to IgE itself on mast cellsurfaces. Also, approximately 25% of CSU patients haveassociated thyroid auto-antibodies; however, in CSU,these antibodies do not correlate with altered thyroidfunction [1-3].Patients with CSU can have high levels of anxiety. Psy-chiatric co-morbidities including mood, anxiety, andpersonality disorders have been reported [4]. These co-morbidities are often major contributors to quality of lifeimpairment [5]. It has been suggested that psychosocialfactors may play a role in the pathogenesis of CSU [4,6].Disease course and prognosisCSU, by definition, persists for at least six weeks and itscourse is typically characterized by exacerbations and re-missions. From 10% to 50% of patients have CSU forlonger than 5 years. Longer duration of illness is asso-ciated with severe disease. Elevated plasma levels ofC-reactive protein, prothrombin 1 and 2, and D-dimerare reported to function as markers of CSU severity [7].Practice guidelinesUrticaria guidelines published in 2014 include new infor-mation on CSU classification, investigations, instrumentsavailable to grade severity and impact on quality of life,as well as new recommendations for management [2,3].InvestigationsDiagnosis of CSU is based on a thorough history andphysical examination. Specific questioning about use ofnon-steroidal anti-inflammatory drugs(NSAIDs)is im-portant because up to 30% to 50% of CSU patients haveexacerbations associated with NSAID ingestion [1,2]. Allpatients require a complete physical examination, in-cluding visualization and confirmation of characteristicpruritic, raised erythematous lesions (Figure 1). Serialphotographs are useful for documenting the extent andSussman et al. Allergy, Asthma & Clinical Immunology  (2015) 11:7 Page 2 of 7Figure 1 Chronic spontaneous urticaria.Depending on the history, other investigations may beindicated (Table 2). A skin biopsy should be performedin patients with atypical urticaria; for example, thosewith burning or painful hives that persist for longer than72 hours, suggestive of urticarial vasculitis. Patients withhyperpigmented lesions should have the skin strokedfirmly to elicit Darier’s sign (whealing) suggestive of cu-Table 1 Classification of chronic urticaria subtypes(presenting with wheals, angioedema, or both)Acute urticaria Chronic urticariaCharacteristics Persists for lessthan 6 weeksChronic spontaneous urticariaPersists for at least 6 weeksInducible urticariaOccurs in response to anidentifiable (physical) trigger.Subtypes include:● Physical urticaria (dermographism,cold urticaria, delayed pressureurticaria, solar urticaria, heaturticaria, vibratory angioedema)● Cholinergic urticariaFigure 3 Dermographism.Sussman et al. Allergy, Asthma & Clinical Immunology  (2015) 11:7 Page 3 of 7severity of the urticaria. The frequency, pattern, and dur-ation of lesions should be recorded.Inducible urticarial lesions typically persist for lessthan two hours, with the exception of delayed pressureurticaria, which can last for more than 24 hours. Patientswith CSU should be tested for dermographic urticariausing a tongue depressor or, if available, a standardizedinstrument, to stroke the skin firmly and induce whealformation (Figure 3). Physical challenge tests for cold-induced urticaria using an ice cube or, if available, astandardized instrument, or tests for other subtypes ofinducible urticaria, should be considered in patients witha history of exacerbations from these stimuli (Figure 4,Table 2).Guidelines now recommend that the initial investiga-tion of CSU should generally be limited to a complete● Contact urticaria● Aquagenic urticariablood count (CBC) and differential, and measurement ofinflammation markers such as erythrocyte sedimentationrate (ESR) or C-reactive protein (CRP) [2,3] (Table 2).Figure 2 Angioedema.taneous mastocytosis and a baseline serum tryptase levelto rule out mastocytosis; a lesional biopsy should be per-formed if indicated. Allergy skin tests generally have lim-ited diagnostic value. The autologous serum skin test(ASST), performed by intradermal injection of autolo-gous serum using careful sterile technique, is rarely usedin practice. A positive ASST suggests the presence ofauto-antibodies to the high-affinity IgE receptor or toIgE; however, this test is not specific for CSU [7]. Assaysfor auto-antibodies to the high-affinity IgE receptor orto IgE are only available in specialized research laborator-ies. Newer tests for auto-antibodies are being developed.Impact on quality of lifeCSU has been shown to cause significant morbidity andto have a negative impact on all aspects of a patient’s life,including work, school, social activities, diet and sleep.In an attempt to quantify this, new instruments havebeen developed to grade urticaria severity. The UrticariaActivity Score, recorded daily for a week (UAS7), iscomprised of an extent of wheals score and a pruritusscore (Table 3). A UAS7 score of 6 or less is generallyhas been validated in Canada in both English andFrench. Validated angioedema activity scores and a QoLFigure 4 The dermographometer, or FricTest®, (left), a standardized instrument for diagnosis of dermatographic urticaria and theTempTest® (right) a new tool for diagnosing cold urticaria. Both instruments are produced by Moxie GmbH (Berlin, Germany).tSussman et al. Allergy, Asthma & Clinical Immunology  (2015) 11:7 Page 4 of 7considered to indicate well controlled chronic urticaria.The impact of urticaria on quality of life can be assessedby a Quality of Life questionnaire (CU-Q2oL) [8], whichTable 2 Recommended investigations in urticaria accordingType Subtype Initial testsSpontaneous urticaria Acute spontaneousurticariaNoneChronic spontaneousurticariaCBC with differential andInducible urticaria Cold urticaria Cold provocation and thice cube to the skin for 5use a TempTest; urticariaDelayed pressure urticaria Pressure testHeat urticaria Heat provocation and thSolar urticaria UV and visible light of diSymptomaticdermographismElicit dermographism bya tongue depressor or, ifAquagenic urticaria Wet cloths at body tempfor 20 minCholinergic urticaria Exercise and hot bath prContact urticariaCBC, complete blood count; ESR, erythrocyte sedimentation rate; CRP, C-reactive pr*Acute urticaria and angioedema can also occur in the context of anaphylaxis. Such paepisode, eg. foods, stinging insect venoms or medications (references [2,3]).score for angioedema are also available and are import-ant tools for assessing the disability associated with dis-figuring angioedema [9]. Recently, the urticaria controlo type and subtypeMore extensive testsNone*ESR or CRP (i) Allergen skin testing, and measurementof allergen-specific IgE levels are seldomrequired in CSU. Measurement of IgG levelsto foods has no diagnostic value. (ii) functionalautoantibodies; (iii) thyroid hormones andautoantibodies; (iv) physical tests; (v) tryptase;(vi) autologous serum skin test; (vii) lesionalskin biopsyreshold test: apply anmin, or, if available,appears on re-warmingCBC with differential and ESR/CRP cryoproteinsNonereshold test Nonefferent wave lengths Rule out other light-induced dermatosesstroking skin firmly withavailable, use a FricTestNoneerature applied Noneovocation NoneNoneotein; NSAID, non-steroidal anti-inflammatory drug.tients should be tested to allergens relevant to the history of their anaphylactictest (UCT) has been validated for grading severity ofurticaria. This tool permits the assessment of chronicurticaria, angioedema, and inducible urticaria [10].ManagementThe overall goal is complete symptom control and dis-ease remission. Factors that exacerbate CSU, includingstress and ingestion of NSAIDs should be avoided.Montelukast can be used as add-on second-line treat-ment in H1-antihistamine refractory CSU, althoughsome clinical trials have not shown a significant benefit[17]. H2-antihistamines are no longer recommended asfirst-, second-, or third-line treatment, as the level of evi-dence supporting their use is low [18].At any stage of treatment, a short course of an oralcorticosteroid can be added on an empirical basis toTable 3 The Urticaria Activity Score (UAS7) for assessing disease activity in chronic spontaneous urticariaScore Wheals Pruritus0 None None1 Mild (<20 wheals/24 h) Mild (present but not annoying or troublesome)2 Moderate (20–50 wheals/24 h) Moderate (troublesome but does not interfere with normal daily activity or sleep)3 Intense (>50 wheals/24 h or large confluent areas of wheals) Intense (severe pruritus, which is sufficiently troublesome to interfere with normaldaily activity or sleep)stioSussman et al. Allergy, Asthma & Clinical Immunology  (2015) 11:7 Page 5 of 7Second-generation non-impairing non-sedating H1-anti-histamines, which are effective, safe, and inexpensive,are recommended as first-line treatment. They shouldbe taken on a regular daily basis, not on an as-neededbasis. There is no advantage in using more than one H1-antihistamine at the same time (Table 4) [2,3,11,12].Up-dosing with two, three, or four times the licensed dos-age, for example, desloratadine up to 20 mg, is suggested assecond-line treatment to be implemented if the licenseddosage of an H1-antihistamine is not effective [13-15].First-generation sedating impairing H1-antihistaminesare no longer recommended for use in urticaria, becausethey potentially interfere with restful (rapid eye move-ment) sleep, cause hangovers or “morning-after” effects,impair learning and memory, and reduce work effi-ciency. Impairment is not necessarily accompanied bysedation [10,16].Table 4 Urticaria treatment algorithmFirst lineSecond-generation non-impairing non-sedating antihistamines if symptompersist after 2 weeks↓Second-lineIncrease dosage up to four-times the standard dose1,2 of a second-generanon-impairing non-sedating antihistamine or, if symptoms persist after 4 furthweeks, add montelukast for a 3–4 week trialExacerbation: oral corticosteroid↓Third lineAdd-on to second-line treatment: omalizumab, cyclosporine A, considerspecialist referral to allergist/dermatologist. Exacerbation: oral corticosteroid1Standard dose means the usual recommended dose.2Double the initial recommended pediatric dose in case of non-response.3Can cause sedation at these doses.provide rescue treatment of a CSU exacerbation. Oneexample of a suggested corticosteroid treatment regimenis an initial dose of 0.3 – 0.5 mg/kg of prednisone orequivalent, followed by tapering of the dose in half every3–7 days over a maximum duration of 2–4 weeks [19].Recommended third-line treatments include omalizu-mab, or off-label use of cyclosporine A [2,3,17,20-25].A trial of cyclosporine A is recommended as add-ontreatment to a second-generation H1-antihistamine inpatients who fail to respond adequately to treatmentwith an H1-antihistamine alone (high level of evidence).Administered in a dose of 3–5 mg/kg divided twicedaily, cyclosporine can lead to complete remission of ur-ticaria; however, regular monitoring of blood pressure,complete blood count, and renal function, followed bydose adjustment when needed, is advised in order to re-duce the possibility of toxicity [17].Standard dosing. Desloratadine 5 mg OD. Loratadine 10 mg OD.Cetirizine HCI 10 mg OD. Fexofenadine HCI 60 mg BIDn Up-dosing to the limit specified, eg. Desloratadine up to 20 mg OD.er Cetirizine HCI up to 40 mg OD3. Montelukast 10 mg ODRe-evaluate response to treatment every 3 monthsOmalizumab 150 mg or 300 mg, SC Q4 wks. CyclosporineA 2.5-5 mg/kg/day and taper with responseOral corticosteroids, for example, 0.3-0.5 mg/kg of prednisoneor equivalent, followed by tapering of the dose in half every3–7 days over a maximum duration of 2–4 weekstakes months, years, or decades, the therapeutic goal re-Sussman et al. Allergy, Asthma & Clinical Immunology  (2015) 11:7 Page 6 of 7mains complete relief of itching and other symptoms.ConclusionsThe urticarias are a heterogeneous group of disorders,classified as acute or chronic (which can be spontaneousor inducible). In the new terminology, the term “spontan-eous” replaces the term “idiopathic” and the term “indu-cible” replaces the term “physical”. Chronic spontaneousurticaria (CSU) affects 0.5% to 1% of the population, andhas a negative impact on all aspects of quality of life.After the correct clinical diagnosis is made, most pa-tients need only limited testing. Careful history, physicalexamination, and follow-up will identify those who re-quire additional investigations.Second-generation non-impairing non-sedating H1-anti-histamines are recommended as first-line medications forinitial treatment. New effective and safe therapeutic op-tions have emerged for treatment of patients with CSU re-fractory to the standard dosage of an H1-antihistamine.Up-dosing with a second-generation non-impairing non-sedating H1-antihistamine such as desloratadine in 2, 3, or4 times the licensed dosage is recommended as second-line treatment. Omalizumab injections subcutaneously atmonthly intervals are recommended as a novel effectiveand safe therapeutic option for CSU refractory to theabove. Research in progress will help to define some spe-Omalizumab, an anti-IgE humanized monoclonal anti-body, can be used as add-on therapy to a non-sedatingsecond-generation H1-antihistamine as a third-line treat-ment for CSU (high level of evidence) [20,21]. Its efficacyand safety have been demonstrated in large, well-designed,randomized double-blind, placebo-controlled trials in pa-tients with CSU refractory to H1-antihistamine treatment[20,21]. Some studies suggest that 300 mg omalizumabinjected subcutaneously every four weeks is the effectivedose; however, others suggest that 150 mg is effective [21].Additional investigations are needed to define the optimaldose, dose schedule, and duration of treatment [24].Theseissues are important from a cost-effectiveness perspective.In 2014, in Canada, the United States and in Europe, oma-lizumab was approved by regulatory agencies for treat-ment of H1-antihistamine-refractory chronic urticaria inadults and adolescents age 12 years and older [25].Use of other pharmacologic agents as third-line treat-ments, including hydroxychloroquine, dapsone, mycophe-nolate mofentil, tacrolimus, intravenous gamma-globulinand sulfasalazine, is based mainly on case reports and un-controlled trials [15].CSU is self-limited and eventually remits completelyin most patients. Until remission occurs, whether thiscific aspects of these new approaches and further establishtheir place in the treatment algorithm.ConsentWritten informed consent was obtained for publicationof the accompanying images in this review. A copy ofthe written consent is available for review by the Editor-in-Chief of this journal.AbbreviationsCSU: Chronic spontaneous urticaria; NSAIDS: Non-steroidal anti-inflammatorydrugs; CBC: Complete blood count; ESR: Erythrocyte sedimentation rate;CRP: C-reactive protein; ASST: Autologous serum skin test; UAS7: UrticariaActivity score recorded daily for a week; CU-Q2oL: Quality of Lifequestionnaire; UTC: Urticaria control test.Competing interestsDr. Sussman reports grants and personal fees from Novartis, outside thesubmitted work. Dr. Hebert reports personal fees from Novartis, Merck, Teva,CSL Behring, Baxter, Shire, GSK, Circassia, Pfizer, Roche, and Johnson andJohnson, outside the submitted work. Dr. Gulliver reports grants andpersonal fees from Novartis, outside the submitted work. Dr. Lynde reportsother from Novartis, Merck, Eli Lilly, AbbVie, Amgen, Pfizer, and Stiefel/GSK,outside the submitted work. Dr. Waserman reports personal fees fromNovartis, outside the submitted work. Dr. Kanani reports personal fees fromNovartis, outside the submitted work. Dr. Ben-Shoshan reports personal feesfrom Novartis, from null, outside the submitted work. Dr. Betschel reportsgrants and personal fees from CSL, and personal fees from Shire, Viropharma,Baxter, Novartis, and Canadian Blood Services, outside the submitted work.Dr. Yang reports personal fees from Novartis, outside the submitted work.Dr. Dutz reports personal fees from Novartis, outside the submitted work.Dr. Kobayashi reports personal fees from Novartis, outside the submitted work.Authors’ contributionsFERS and GS played leadership roles in the project and acted to ensure thequality and coherence of this manuscript. Following a consensus meeting byall authors GS prepared the first draft of the manuscript. The other authorsprovided input at teleconference meetings and also provided feedback oncirculated drafts of the manuscript. Following each circulation, commentsand corrections were incorporated into a new draft. The final manuscripttherefore results from a collaborative effort. All authors read and approvedthe final manuscript.Author details1University of Toronto, Medicine, Toronto, ON, Canada. 2Université Laval,Medicine, Quebec, QC, Canada. 3Memorial University, Medicine, Quebec, QC,Canada. 4McMaster University Medicine, Hamilton, ON, Canada. 5University ofBritish Columbia, Medicine, Kelowna, BC, Canada. 6McGill University,Medicine, Montreal, QC, Canada. 7University of Ottawa, Medicine, Ottawa,ON, Canada. 8Dalhousie University, Medicine, Halifax, NS, Canada. 9Universityof Manitoba, Medicine, Winnipeg, MB, Canada.Received: 6 December 2014 Accepted: 14 January 2015References1. 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