Clinical Reviews in Allergy & Immunology

, Volume 54, Issue 1, pp 88–101 | Cite as

Urticaria and Angioedema: an Update on Classification and Pathogenesis

  • Susanne Radonjic-HoesliEmail author
  • Kathrin Scherer Hofmeier
  • Sara Micaletto
  • Peter Schmid-Grendelmeier
  • Andreas Bircher
  • Dagmar SimonEmail author


Urticaria is a common, mast cell-driven disease presenting with wheals or angioedema or both. In the last years, urticaria has increasingly attracted notice to clinicians and researchers, last but not least inspired by the approval of omalizumab, an anti-IgE antibody, for urticaria treatment. There is wide consensus on the clinical classification based on duration and elicitation. However, the pathogenesis is incompletely understood. This review summarizes current guidelines for the management and novel insights in the pathogenesis of urticaria with special focus on their impact on clinical praxis. The classification of urticaria subgroups is mainly based on clinical criteria: acute and chronic urticaria (CU). Chronic urticaria comprises both chronic spontaneous urticaria (CSU) and chronic inducible urticaria (CIndU) that includes physical and non-physical urticarias. Recent research focused on characterizing the role of cells and mediators involved in the pathogenesis of urticaria, identifying the mechanisms of mast cell activation, and investigating underlying autoimmune processes in chronic spontaneous urticarial. Currently, non-sedating antihistamines and omalizumab, an antiimmunoglobulin E antibody, are recommended for the therapy of chronic urticaria, as both exhibit a favorable efficacy and safety profile. Novel therapeutic strategies aim at specifically targeting cells and mediators involved in the pathogenesis of urticaria.


Angioedema Mast cell Histamine Omalizumab Urticaria 



Angiotensin converting enzyme


Acquired cold urticaria




Autoimmune urticaria


Autologous serum skin test


Cholinergic urticaria


Chronic indicible urticaria


Chemoattractant receptor–homologous molecule expressed on TH2 cells


Chronic urticaria


Chronic spontaneous urticaria


Delayed pressure urticaria








Solar urticaria


Tumor necrosis factor




Urticaria activity score


Compliance with Ethical Standards

Conflict of Interest

The authors declare that they have no conflict of interest.



Research Involving Human Participants and/or Animals

Not applicable.

Ethical Approval and Informed Consent

Not applicable.


  1. 1.
    Fine LM, Bernstein JA (2016) Guideline of chronic urticaria beyond. Allergy Asthma Immunol Res 8:396–403. doi: 10.4168/aair.2016.8.5.396 PubMedPubMedCentralCrossRefGoogle Scholar
  2. 2.
    Zuberbier T, Aberer W, Asero R, Bindslev-Jensen C et al (2014) The EAACI/GA2LEN/EDF/WAO Guideline for the definition, classification, diagnosis, and management of urticaria: the 2013 revision and update. Allergy 69:868–887. doi: 10.1111/all.12313 PubMedCrossRefGoogle Scholar
  3. 3.
    Wu MA, Perego F, Zanichelli A et al (2016) Angioedema phenotypes: disease expression and classification. Clinic Rev Allerg Immunol 51:162. doi: 10.1007/s12016-016-8541-z CrossRefGoogle Scholar
  4. 4.
    Magerl M, Altrichter S, Borzova E, Giménez-Arnau A, Grattan CE, Lawlor F, Mathelier-Fusade P, Meshkova RY, Zuberbier T, Metz M, Maurer M (2016) The definition, diagnostic testing, and management of chronic inducible urticarias—the EAACI/GA(2) LEN/EDF/UNEV consensus recommendations 2016 update and revision. Allergy 71:780–802. doi: 10.1111/all.12884 PubMedCrossRefGoogle Scholar
  5. 5.
    Weller K, Maurer M, Grattan C, Nakonechna A, Abuzakouk M, Bérard F, Sussman G, Giménez-Arnau AM, Ortiz de Frutos J, Knulst A, Canonica GW, Hollis K, McBride D, Balp MM (2015) ASSURE-CSU: a real-world study of burden of disease in patients with symptomatic chronic spontaneous urticaria. Clin Transl Allergy 5:29. doi: 10.1186/s13601-015-0072-9 PubMedPubMedCentralCrossRefGoogle Scholar
  6. 6.
    Doong JC, Chichester K, Oliver ET, Schwartz LB, Saini SS (2017) Chronic idiopathic urticaria: systemic complaints and their relationship with disease and immune measures. J Allergy Clin Immunol Pract Epub ahead of print doi. doi: 10.1016/j.jaip.2016.11.037
  7. 7.
    Lapi F, Cassano N, Pegoraro V, Cataldo N, Heiman F, Cricelli I, Levi M, Colombo D, Zagni E, Cricelli C, Vena GA (2016) Epidemiology of chronic spontaneous urticaria: results from a nationwide, population-based study in Italy. Br J Dermatol 174:996–1004. doi: 10.1111/bjd.14470 PubMedCrossRefGoogle Scholar
  8. 8.
    Sánchez J, Amaya E, Acevedo A, Celis A, Caraballo D, Cardona R (2017) Prevalence of inducible urticaria in patients with chronic spontaneous urticaria: associated risk factors. J Allergy Clin Immunol Pract 5:464–470. doi: 10.1016/j.jaip.2016.09.029 PubMedCrossRefGoogle Scholar
  9. 9.
    Kolkhir P, Church MK, Weller K, Metz M, Schmetzer O, Maurer M (2016) Autoimmune chronic spontaneous urticaria: what we know and what we do not know. J Allergy Clin Immunol Epub ahead of print doi. doi: 10.1016/j.jaci.2016.08.050
  10. 10.
    Konstantinou GN, Asero R, Ferrer M, Knol EF, Maurer M, Raap U, Schmid-Grendelmeier P, Skov PS, Grattan CE (2013) EAACI taskforce position paper: evidence for autoimmune urticaria and proposal for defining diagnostic criteria. Allergy 68:27–36. doi: 10.1111/all.12056 PubMedCrossRefGoogle Scholar
  11. 11.
    Dice JP (2004) Physical urticaria. Immunol Allergy Clin N Am 24:225–246CrossRefGoogle Scholar
  12. 12.
    TaÍkapan O, Harmanyeri Y (2006) Evaluation of patients with symptomatic dermographism. JEADV 20:58–62Google Scholar
  13. 13.
    Mlynek A, Vieira dos Santos R, Ardelean E, Weller K, Magerl M, Church MK, Maurer M (2013) A novel, simple, validated and reproducible instrument for assessing provocation threshold levels in patients with symptomatic dermographism. Clin Exp Dermatol 38:360–366. doi: 10.1111/ced.12107 PubMedCrossRefGoogle Scholar
  14. 14.
    Martinez-Escala ME, Curto-Barredo L, Carnero L, Pujol RM, Gimenez-Arnau AM (2015) Temperature thresholds in assessment of the clinical course of acquired cold contact urticaria: a retrospective observational one year study. Acta Derm Venereol 95:278–282. doi: 10.2340/00015555-1918 PubMedCrossRefGoogle Scholar
  15. 15.
    Alangari AA, Twarog FJ, Shih MC et al (2004) Clinical features and anaphylaxis in children with cold urticaria. Pediatrics 113:e313–e317PubMedCrossRefGoogle Scholar
  16. 16.
    Siebenhaar F, Weller K, Mlynek A, Magerl M, Altrichter S, Vieira dos Santos R, Maurer M, Zuberbier T (2007) Acquired cold urticaria: clinical picture and update on diagnosis and treatment. Clin Exp Dermatol 32:241–245PubMedCrossRefGoogle Scholar
  17. 17.
    Wanderer AA, Hoffman HM (2004) The spectrum of acquired and familial cold induced urticaria/urticaria-like syndromes. Immunol Allergy Clin N Am 24:259–286CrossRefGoogle Scholar
  18. 18.
    Abajian M, Schoepke N, Altrichter S, Zuberbier T, Maurer M (2014) Physical urticarias and cholinergic urticaria. Immunol Allergy Clin N Am 34:73–88. doi: 10.1016/j.iac.2013.09.010 CrossRefGoogle Scholar
  19. 19.
    Du-Thanh A, Debu A, Lalheve P et al (2013) Solar urticaria: a time-extended retrospective series of 61 patients and review of literature. Eur J Dermatol 23:202–207. doi: 10.1684/ejd.2013.1933 PubMedGoogle Scholar
  20. 20.
    Horio T (1978) Photoallergic urticaria induced by visible light. Additional cases and further studies. Arch Dermatol 114:1761–1764PubMedCrossRefGoogle Scholar
  21. 21.
    Duchini G, Baumler W, Bircher AJ, Scherer K (2011) Failure of omalizumab (Xolair®) in the treatment of a case of solar urticaria caused by ultraviolet A and visible light. Photodermatol Photoimmunol Photomed 27:336–337. doi: 10.1111/j.1600-0781.2011.00624.x PubMedCrossRefGoogle Scholar
  22. 22.
    Terrani I, Bircher AJ, Scherer Hofmeier K (2016) Solar urticaria induced by visible light: successful treatment with omalizumab. Clin Exp Dermatol 41:890–892. doi: 10.1111/ced.12951 PubMedCrossRefGoogle Scholar
  23. 23.
    Zuberbier T, Althaus C, Chatraine-Hess S et al (1994) Prevalence of cholinergic urticaria in young adults. J Am Acad Dermatol 31:978–981PubMedCrossRefGoogle Scholar
  24. 24.
    Ramam M, Pahwa P (2012) Is cholincergic urticaria a seasonal disorder in some patients? Indian J Dermatol Venereol Leprol 78:190–191. doi: 10.4103/0378-6323.93641 PubMedCrossRefGoogle Scholar
  25. 25.
    Takahagi S, Tanaka T, Ishii K et al (2009) Sweat antigen induces histamine release form basophils of patients with cholinergic uticaria associated with atopic diathesis. Br J Dermatol 160:426–428. doi: 10.1111/j.1365-2133.2008.08862.x PubMedCrossRefGoogle Scholar
  26. 26.
    Petalas K, Kontou-Fili K, Gratziou C (2009) Bronchial hyperresponsiveness in patients with cholinergic urticaria. Ann Allergy Asthma Immunol 102:416–421. doi: 10.1016/S1081-1206(10)60514-5 PubMedCrossRefGoogle Scholar
  27. 27.
    Sawada Y, Nakamura M, Bito T, Sakabe J, Kabashima-Kubo R, Hino R, Kobayashi M, Tokura Y (2014) Decreased expression of acetylcholine esterase in cholinergic urticaria with hypohidrosis or anhidrosis. J Invest Dermatol 134:276–279. doi: 10.1038/jid.2013.244 PubMedCrossRefGoogle Scholar
  28. 28.
    Fukunaga A, Washio K, Hatakeyama M, Oda Y, Ogura K, Horikawa T, Nishigori C (2017) Cholinergic urticaria: epidemiology, physiopathology, new categorization, and management. Clin Auton Res Epub ahead of print doi. doi: 10.1007/s10286-017-0418-6
  29. 29.
    Horikawa T, Fukunaga A, Nishigori C (2009) New concepts of hive formation in cholinergic urticaria. Curr Allergy Asthma Rep 9:273–279PubMedCrossRefGoogle Scholar
  30. 30.
    Bito T, Sawada Y, Tokura Y (2012) Pathogenesis of cholinergic urticaria in relation to sweating. Allergol Int 61:539–544. doi: 10.2332/allergolint.12-RAI-0485 PubMedCrossRefGoogle Scholar
  31. 31.
    Fukunaga A, Hatakeyama M, Tsujimoto M, Oda Y, Washio K, Nishigori C (2015) Steroid treatment can improve the impaired quality of life of patients with acquired idiopathic generalized anhidrosis. Br J Dermatol 172:537–538. doi: 10.1111/bjd.13285 PubMedCrossRefGoogle Scholar
  32. 32.
    Kalathoor I (2015) Snoring-induced vibratory angioedema. Am J Case Rep 16:700-702. doi: 10.12659/AJCR.894636Google Scholar
  33. 33.
    Aloyouny A, Stoopler ET (2016) Vibrational angioedema: considerations for oral health care providers. Spec Care Dentist 36:335–338. doi: 10.1111/scd.12185 PubMedCrossRefGoogle Scholar
  34. 34.
    Boyden SE, Desai A, Cruse G, Young ML, Bolan HC, Scott LM, Eisch AR, Long RD, Lee CC, Satorius CL, Pakstis AJ, Olivera A, Mullikin JC, Chouery E, Mégarbané A, Medlej-Hashim M, Kidd KK, Kastner DL, Metcalfe DD, Komarow HD (2016) Vibratory urticaria associated with a missense variant in ADGRE2. N Engl J Med 374:656–663. doi: 10.1056/NEJMc1604757 PubMedPubMedCentralCrossRefGoogle Scholar
  35. 35.
    Zuberbier T (2003) Urticaria. Allergy 58:1224–1234PubMedCrossRefGoogle Scholar
  36. 36.
    Wedi B, Kapp A (2006) Current position of the role of allergic and non-allergic food hypersensitivity in urticaria. Hautarzt 57:101–107PubMedCrossRefGoogle Scholar
  37. 37.
    Williams JD, Lee AY, Matheson MC, Frowen KE, Moonan AM, Nixon RL (2008) Occupational contact urticaria: Australian data. Br J Dermatol 159:125–131. doi: 10.1111/j.1365-2133.2008.08583.x PubMedCrossRefGoogle Scholar
  38. 38.
    Rothbaum R, McGee JS (2016) Aquagenic urticaria: diagnostic and management challenges. J Asthma Allergy 9:209–213PubMedPubMedCentralCrossRefGoogle Scholar
  39. 39.
    Kulthanan K, Chiawsirikajorn Y, Jiamton S (2008) Acute urticaria: etiologies, clinical course and quality of life. Asian Pac J Allergy Immunol 26:1–9PubMedGoogle Scholar
  40. 40.
    Zelić SB, Rubeša G, Brajac I, Peitl MV, Pavlović E (2016) Satisfaction with life and coping skills in the acute and chronic urticaria. Psychiatr Danub 28:34–38PubMedGoogle Scholar
  41. 41.
    Dias GA, Pires GV, Valle SO, Dortas SD Júnior, Levy S, França AT, Baiardini I, Canonica WG (2016) Impact of chronic urticaria on the quality of life of patients followed up at a university hospital. An Bras Dermatol 91:754–759. doi:  10.1590/abd1806-4841.20165071
  42. 42.
    Mendelson MH, Bernstein JA, Gabriel A, Balp MM, Tian H, Vietri J, Lebwohl M (2016) Patient-reported impact of chronic urticaria compared with psoriasis in the United States. J Dermatol Treat Epub ahead of print. doi: 10.1080/09546634.2016.1227421
  43. 43.
    Mlynek A, Zalewska-Janowska A, Martus P, Staubach P, Zuberbier T, Maurer M (2008) How to assess disease activity in patients with chronic urticaria? Allergy 63:777–780. doi: 10.1111/j.1398-9995.2008.01726.x PubMedCrossRefGoogle Scholar
  44. 44.
    Baiardini I, Braido F, Bindslev-Jensen C, Bousquet PJ et al (2011) Recommendations for assessing patient-reported outcomes and health-related quality of life in patients with urticaria: a GA2LEN taskforce position paper. Allergy 66:840–844. doi: 10.1111/j.1398-9995.2011.02580.x PubMedCrossRefGoogle Scholar
  45. 45.
    Mathias SD, Dreskin SC, Kaplan A, Saini SS, Spector S, Rosen KE (2010) Development of a daily diary for patients with chronic idiopathic urticaria. Ann Allergy Asthma Immunol 105:142–148. doi: 10.1016/j.anai.2010.06.011 PubMedCrossRefGoogle Scholar
  46. 46.
    Stull D, McBride D, Tian H, Gimenez Arnau A, Maurer M, Marsland A, Balp MM, Khalil S, Grattan C (2017) Analysis of disease activity categories in chronic spontaneous/idiopathic urticaria. Br J Dermatol Epub ahead of print. doi: 10.1111/bjd.15454
  47. 47.
    Staubach P (2007) Differential diagnosis of urticaria. Hautarzt 58:314–317PubMedCrossRefGoogle Scholar
  48. 48.
    Jachiet M, Flageul B, Deroux A, Le Quellec A, Maurier F, Cordoliani F, Godmer P, Abasq C, Astudillo L, Belenotti P, Bessis D, Bigot A, Doutre MS, Ebbo M, Guichard I, Hachulla E, Héron E, Jeudy G, Jourde-Chiche N, Jullien D, Lavigne C, Machet L, Macher MA, Martel C, Melboucy-Belkhir S, Morice C, Petit A, Simorre B, Zenone T, Bouillet L, Bagot M, Frémeaux-Bacchi V, Guillevin L, Mouthon L, Dupin N, Aractingi S, Terrier B, French Vasculitis Study Group (2015) The clinical spectrum and therapeutic management of hypocomplementemic urticarial vasculitis: data from a French nationwide study of fifty-seven patients. Arthritis Rheumatol 67:527–534. doi: 10.1002/art.38956 PubMedCrossRefGoogle Scholar
  49. 49.
    Feliciani C, Joly P, Jonkman MF, Zambruno G, Zillikens D, Ioannides D, Kowalewski C, Jedlickova H, Kárpáti S, Marinovic B, Mimouni D, Uzun S, Yayli S, Hertl M, Borradori L (2015) Management of bullous pemphigoid: the European Dermatology Forum consensus in collaboration with the European Academy of Dermatology and Venereology. Br J Dermatol 172:867–877. doi: 10.1111/bjd.13717 PubMedCrossRefGoogle Scholar
  50. 50.
    Kolkhir P, Pogorelov D, Olisova O, Maurer M (2016) Comorbidity and pathogenic links of chronic spontaneous urticaria and systemic lupus erythematosus—a systematic review. Clin Exp Allergy 46:275–287. doi: 10.1111/cea.12673 PubMedCrossRefGoogle Scholar
  51. 51.
    Confino-Cohen R, Chodick G, Shalev V, Leshno M, Kimhi O, Goldberg A (2012) Chronic urticaria and autoimmunity: associations found in a large population study. J Allergy Clin Immunol 129:1307–1313. doi: 10.1016/j.jaci.2012.01.043 PubMedCrossRefGoogle Scholar
  52. 52.
    Wekell P, Karlsson A, Berg S, Fasth A (2016) Review of autoinflammatory diseases, with a special focus on periodic fever, aphthous stomatitis, pharyngitis and cervical adenitis syndrome. Acta Paediatr 105:1140–1151. doi: 10.1111/apa.13531 PubMedPubMedCentralCrossRefGoogle Scholar
  53. 53.
    Kastner DL, Aksentijevich I, Goldbach-Mansky R (2010) Autoinflammatory disease reloaded: a clinical perspective. Cell 140:784–790. doi: 10.1016/j.cell.2010.03.002 PubMedPubMedCentralCrossRefGoogle Scholar
  54. 54.
    Krause K, Grattan CE, Bindslev-Jensen C, Gattorno M, Kallinich T, de Koning HD, Lachmann HJ, Lipsker D, Navarini AA, Simon A, Traidl-Hoffmann C, Maurer M (2012) How not to miss autoinflammatory diseases masquerading as urticaria. Allergy 67:1465–1474. doi: 10.1111/all.12030 PubMedCrossRefGoogle Scholar
  55. 55.
    Kuemmerle-Deschner JB, Ozen S, Tyrrell PN, et al. (2016) Diagnostic criteria for cryopyrin-associated periodic syndrome (CAPS) Ann Rheum Dis. Oct 4. doi:  10.1136/annrheumdis-2016-209686
  56. 56.
    Gusdorf L, Asli B, Barbarot S, Néel A, Masseau A, Puéchal X, Gottenberg JE, Grateau G, Blanchard-Delaunay C, Rizzi R, Lifermann F, Kyndt X, Aubin F, Bessis D, Boye T, Gayet S, Rongioletti F, Sauleau E, Fermand JP, Lipsker D (2017) Schnitzler syndrome: validation and applicability of diagnostic criteria in real-life patients. Allergy 72:177–182. doi: 10.1111/all.13035 PubMedCrossRefGoogle Scholar
  57. 57.
    Navarini AA, Satoh TK, French LE (2016) Neutrophilic dermatoses and autoinflammatory diseases with skin involvement—innate immune disorders. Semin Immunopathol 38:45–56. doi: 10.1007/s00281-015-0549-6 PubMedCrossRefGoogle Scholar
  58. 58.
    Webb K, Hlela C, Jordaan HF, Suliman S, Scriba T, Lipsker D, Scott C (2015) A review and proposed approach to the neutrophilic dermatoses of childhood. Pediatr Dermatol 32:437–446. doi: 10.1111/pde.12502 PubMedCrossRefGoogle Scholar
  59. 59.
    de Graauw E, Beltraminelli H, Simon HU, Simon D (2015) Eosinophilia in dermatologic disorders. Immunol Allergy Clin N Am 35:545–560. doi: 10.1016/j.iac.2015.05.005 CrossRefGoogle Scholar
  60. 60.
    Landolt B, Staubli G, Lips U, Weibel L (2013) Skin disorders encountered in a Swiss pediatric emergency department. Swiss Med Wkly 143:w13731. doi: 10.4414/smw.2013.13731 PubMedGoogle Scholar
  61. 61.
    Demoly P, Adkinson NF, Brockow K, Castells M, Chiriac AM, Greenberger PA, Khan DA, Lang DM, Park HS, Pichler W, Sanchez-Borges M, Shiohara T, Thong BY (2014) International consensus on drug allergy. Allergy 69:420–437. doi: 10.1111/all.12350 PubMedCrossRefGoogle Scholar
  62. 62.
    Taylor D, Pappo E, Aronson IK (2016) Polymorphic eruption of pregnancy. Clin Dermatol 34:383–391. doi: 10.1016/j.clindermatol.2016.02.011 PubMedCrossRefGoogle Scholar
  63. 63.
    Bork K (2014) Angioedema. Immunol Allergy Clin N Am 34:23–31. doi: 10.1016/j.iac.2013.09.004 CrossRefGoogle Scholar
  64. 64.
    Beltrami L, Zanichelli A, Zingale L, Vacchini R, Carugo S, Cicardi M (2011) Long-term follow-up of 111 patients with angiotensin-converting enzyme inhibitor-related angioedema. J Hypertens 29:2273–2277. doi: 10.1097/HJH.0b013e32834b4b9b PubMedCrossRefGoogle Scholar
  65. 65.
    Simons FE, Ebisawa M, Sanchez-Borges M, Thong BY, Worm M, Tanno LK, Lockey RF, El-Gamal YM, Brown SG, Park HS, Sheikh A (2015) 2015 update of the evidence base: World Allergy Organization anaphylaxis guidelines. World Allergy Organ J 8:32. doi: 10.1186/s40413-015-0080-1 PubMedPubMedCentralCrossRefGoogle Scholar
  66. 66.
    Renaudin JM, Beaudouin E, Ponvert C, Demoly P, Moneret-Vautrin DA (2013) Severe drug-induced anaphylaxis: analysis of 333 cases recorded by the Allergy Vigilance Network from 2002 to 2010. Allergy 68:929–937. doi: 10.1111/all.12168 PubMedCrossRefGoogle Scholar
  67. 67.
    Kowalski ML, Woessner K, Sanak M. (2015) Approaches to the diagnosis and management of patients with a history of nonsteroidal anti-inflammatory drug-related urticaria and angioedema. J Allergy Clin Immunol 136:245–251. doi:  10.1016/j.jaci.2015.06.021
  68. 68.
    Valent P, Akin C, Hartmann K, Nilsson G et al (2017) Advances in the classification and treatment of mastocytosis: current status and outlook toward the future. Cancer Res 77:1261–1270. doi: 10.1158/0008-5472 PubMedPubMedCentralCrossRefGoogle Scholar
  69. 69.
    Maurer M, Church MK, Marsland AM, Sussman G, Siebenhaar F, Vestergaard C, Broom B (2016) Questions and answers in chronic urticaria: where do we stand and where do we go? J Eur Acad Dermatol Venereol 30:7–15. doi: 10.1111/jdv.13695 PubMedCrossRefGoogle Scholar
  70. 70.
    Wernersson S, Pejler G (2014) Mast cell secretory granules: armed for battle. Nat Rev Immunol 14:478–494. doi: 10.1038/nri3690 PubMedCrossRefGoogle Scholar
  71. 71.
    Kaplan AP, Horáková Z, Katz SI (1978) Assessment of tissue fluid histamine levels in patients with urticaria. J Allergy Clin Immunol 61:350–354. doi: 10.1016/0091-6749(78)90113-6 PubMedCrossRefGoogle Scholar
  72. 72.
    Hong GU, Ro JY, Bae Y, Kwon IH, Park GH, Choi YH, Choi JH (2016) Association of TG2 from mast cells and chronic spontaneous urticaria pathogenesis. Ann Allergy Asthma Immunol 117:290–297. doi: 10.1016/j.anai.2016.06.026 PubMedCrossRefGoogle Scholar
  73. 73.
    Kay AB, Clark P, Maurer M, Ying S (2015) Elevations in T-helper-2-initiating cytokines (interleukin-33, interleukin-25 and thymic stromal lymphopoietin) in lesional skin from chronic spontaneous (‘idiopathic’) urticaria. Br J Dermatol 172:1294–1302. doi: 10.1111/bjd.13621 PubMedCrossRefGoogle Scholar
  74. 74.
    Ying S, Kikuchi Y, Meng Q, Kay AB, Kaplan AP (2002) TH1/TH2 cytokines and inflammatory cells in skin biopsy specimens from patients with chronic idiopathic urticaria: comparison with the allergen-induced late-phase cutaneous reaction. J Allergy Clin Immunol 109:694–700PubMedCrossRefGoogle Scholar
  75. 75.
    Altrichter S, Koch K, Church MK, Maurer M (2016) Atopic predisposition in cholinergic urticaria patients and its implications. J Eur Acad Dermatol Venereol 30:2060–2065. doi: 10.1111/jdv.13765 PubMedCrossRefGoogle Scholar
  76. 76.
    Tedeschi A, Asero R, Marzano AV et al (2009) Plasma levels and skin-eosinophil-expression of vascular endothelial growth factor in patients with chronic urticaria. Allergy 64:1616–1622. doi: 10.1111/j.1398-9995.2009.02069.x PubMedCrossRefGoogle Scholar
  77. 77.
    Tedeschi A, Asero R, Lorini M et al (2010) Plasma levels of matrix metalloproteinase-9 in chronic urticaria patients correlate with disease severity and C-reactive protein but not with circulating histamine-releasing factors. Clin Exp Allergy 40:875–881. doi: 10.1111/j.1365-2222.2010.03473.x PubMedCrossRefGoogle Scholar
  78. 78.
    Kasperska-Zajac A, Sztylc J, Machura E et al (2011) Plasma IL-6 concentration correlates with clinical disease activity and serum C-reactive protein concentration in chronic urticaria patients. Clin Exp Allergy 41:1386–1391. doi: 10.1111/j.1365-2222.2011.03789.x PubMedCrossRefGoogle Scholar
  79. 79.
    Kaplan AP, Giménez-Arnau AM, Saini SS (2017) Mechanisms of action that contribute to efficacy of omalizumab in chronic spontaneous urticarial. Allergy 72:519–533. doi: 10.1111/all.13083 PubMedCrossRefGoogle Scholar
  80. 80.
    Oliver ET, Sterba PM, Saini SS (2015) Interval shifts in basophil measures correlate with disease activity in chronic spontaneous urticaria. Allergy 70:601–603. doi: 10.1111/all.12578 PubMedCrossRefGoogle Scholar
  81. 81.
    Oliver ET, Sterba PM, Devine K, Vonakis BM, Saini SS (2016) Altered expression of chemoattractant receptor–homologous molecule expressed on TH2 cells on blood basophils and eosinophils in patients with chronic spontaneous urticaria. J Allergy Clin Immunol 137:304–306. doi: 10.1016/j.jaci.2015.06.004 PubMedCrossRefGoogle Scholar
  82. 82.
    Raap U, Gehring M, Kleiner S, Rüdrich U, Eiz-Vesper B, Haas H, Kapp A, Gibbs BF (2017) Human basophils are differentially activated by and are a source of IL-31. Clin Exp Allergy 47:499–508. doi: 10.1111/cea.12875 PubMedCrossRefGoogle Scholar
  83. 83.
    Chen Q, Zhai Z, Xu J, Chen W, Chen S, Zhong H, Huang X, Hao F, Song Z (2017) Basophil CD63 expression in chronic spontaneous urticaria: correlation with allergic sensitization, serum autoreactivity and basophil reactivity. J Eur Acad Dermatol Venereol 31:463–468. doi: 10.1111/jdv.13912 PubMedCrossRefGoogle Scholar
  84. 84.
    Jain S (2014) Pathogenesis of chronic urticarial: an overview. Dermatol Res Pract 2014:674709.doi  10.1155/2014/674709
  85. 85.
    Sterba PM, Hamilton RG, Saini SS (2015) Suppression of basophil FcεRI activation by serum from active chronic idiopathic/spontaneous urticaria (CIU/CSU) subjects. J Invest Dermatol 135:1454–1456. doi: 10.1038/jid.2015.13 PubMedPubMedCentralCrossRefGoogle Scholar
  86. 86.
    Kay AB, Ying S, Ardelean E, Mlynek A, Kita H, Clark P, Maurer M (2014) Elevations in vascular markers and eosinophils in chronic spontaneous urticarial weals with low-level persistence in uninvolved skin. Br J Dermatol 171:505–511. doi: 10.1111/cea.12348 PubMedPubMedCentralCrossRefGoogle Scholar
  87. 87.
    Fujisawa D, Kashiwakura J, Kita H, Kikukawa Y, Fujitani Y, Sasaki-Sakamoto T, Kuroda K, Nunomura S, Hayama K, Terui T, Ra C, Okayama Y (2014) Expression of Mas-related gene X2 on mast cells is upregulated in the skin of patients with severe chronic urticaria. J Allergy Clin Immunol 134:622–633. doi: 10.1016/j.jaci.2014.05.004 PubMedCrossRefGoogle Scholar
  88. 88.
    Cugno M, Marzano AV, Tedeschi A, Fanoni D, Venegoni L, Asero R (2009) Expression of tissue factor by eosinophils in patients with chronic urticaria. Int Arch Allergy Clin Immunol 148:170–174. doi: 10.1159/000155748 CrossRefGoogle Scholar
  89. 89.
    Fiebiger E, Maurer D, Holub H, Reininger B, Hartmann G, Woisetschläger M, Kinet JP, Stingl G (1995) Serum IgG autoantibodies directed against the alpha chain of Fc epsilon RI: a selective marker and pathogenetic factor for a distinct subset of chronic urticaria patients? J Clin Invest 96:2606–1262PubMedPubMedCentralCrossRefGoogle Scholar
  90. 90.
    Kikuchi Y, Kaplan AP (2002) A role for C5a in augmenting IgG-dependent histamine release from basophils in chronic urticaria. J Allergy Clin Immunol 109:114–118PubMedCrossRefGoogle Scholar
  91. 91.
    Lu T, Jiao X, Si M, He P, Zou J, Zhang S, Zeng K (2016) The correlation of serums CCL11, CCL17, CCL26, and CCL27 and disease severity in patients with urticaria. Dis Markers 1381760. doi: 10.1155/2016/1381760
  92. 92.
    Vonakis BM, Vasagar K, Gibbons SP Jr, Gober L, Sterba PM, Chang H, Saini SS (2007) Basophil FcεRI histamine release parallels expression of Src-homology 2-containing inositol phosphatases in chronic idiopathic urticaria. J Allergy Clin Immunol 119:441–448PubMedCrossRefGoogle Scholar
  93. 93.
    Ayuso P, Plaza-Serón Mdel C, Blanca-López N, Doña I, Campo P, Canto G, Laguna JJ, Bartra J, Soriano-Gomis V, Blanca M, Cornejo-García JA, Perkins JR (2015) Genetic variants in arachidonic acid pathway genes associated with NSAID-exacerbated respiratory disease. Pharmacogenomics 16:825–839. doi: 10.2217/pgs.15.43 PubMedCrossRefGoogle Scholar
  94. 94.
    Asero R, Tedeschi A, Coppola R, Griffini S, Paparella P, Riboldi P, Marzano AV, Fanoni D, Cugno M (2007) Activation of the tissue factor pathway of blood coagulation in patients with chronic urticaria. J Allergy Clin Immunol 119:705–710PubMedCrossRefGoogle Scholar
  95. 95.
    Asero R, Tedeschi A, Riboldi P, Griffini S, Bonanni E, Cugno M (2008) Severe chronic urticaria is associated with elevated plasma levels of D-dimer. Allergy 63:176–180PubMedGoogle Scholar
  96. 96.
    Takahagi S, Mihara S, Iwamoto K, Morioke S, Okabe T, Kameyoshi Y, Hide M (2010) Coagulation/fibrinolysis and inflammation markers are associated with disease activity in patients with chronic urticaria. Allergy 65:649–656. doi: 10.1111/j.1398-9995.2009.02222.x PubMedCrossRefGoogle Scholar
  97. 97.
    Puccetti A, Bason C, Simeoni ME, Millo E, Tinazzi E, Beri R, Peterlana D, Zanoni G, Senna G, Corrocher R, Lunardi C (2005) In chronic idiopathic urticaria autoantibodies against Fc epsilonRII/CD23 induce histamine release via eosinophil activation. Clin Exp Allergy 35:1599–1607PubMedCrossRefGoogle Scholar
  98. 98.
    Bossi F, Frossi B, Radillo O, Cugno M, Tedeschi A, Riboldi P, Asero R, Tedesco F, Pucillo C (2011) Mast cells are critically involved in serum-mediated vascular leakage in chronic urticaria beyond high-affinity IgE receptor stimulation. Allergy 66:1538–1545. doi: 10.1111/j.1398-9995.2011.02704.x PubMedCrossRefGoogle Scholar
  99. 99.
    Krause K, Giménez-Arnau A, Martinez-Escala E, Farré-Albadalejo M, Abajian M, Church MK, Maurer M (2013) Platelet-activating factor (PAF) induces wheal and flare skin reactions independent of mast cell degranulation. Allergy 68:256–258. doi: 10.1111/all.12083 PubMedCrossRefGoogle Scholar
  100. 100.
    Tokura Y (2016) New etiology of cholinergic urticaria. Curr Probl Dermatol 51:94–100. doi: 10.1159/000446787 PubMedCrossRefGoogle Scholar
  101. 101.
    Pan XF, Gu JQ, Shan ZY (2015) The prevalence of thyroid autoimmunity in patients with urticaria: a systematic review and meta-analysis. Endocrine 48:804–810. doi: 10.1007/s12020-014-0367-y PubMedCrossRefGoogle Scholar
  102. 102.
    Kikuchi Y, Fann T, Kaplan AP (2003) Antithyroid antibodies in chronic urticaria and angioedema. J Allergy Clin Immunol 112:218PubMedCrossRefGoogle Scholar
  103. 103.
    Altrichter S, Peter HJ, Pisarevskaja D, Metz M, Martus P, Maurer M (2011) IgE mediated autoallergy against thyroid peroxidase—a novel pathomechanism of chronic spontaneous urticaria? PLoS One 6(4):e14794. doi: 10.1371/journal.pone.0014794 PubMedPubMedCentralCrossRefGoogle Scholar
  104. 104.
    Curth HM, Dinter J, Nigemeier K, Kütting F, Hunzelmann N, Steffen HM (2015) Effects of helicobacter pylori eradication in chronic spontaneous urticaria: results from a retrospective cohort study. Am J Clin Dermatol 16:553–558. doi: 10.1007/s40257-015-0152-6 PubMedCrossRefGoogle Scholar
  105. 105.
    Dreyfus DH (2016) Serological evidence that activation of ubiquitous human herpesvirus-6 (HHV-6) plays a role in chronic idiopathic/spontaneous urticaria (CIU). Clin Exp Immunol 183:230–238. doi: 10.1111/cei.12704 PubMedCrossRefGoogle Scholar
  106. 106.
    Kolkhir P, Balakirski G, Merk HF, Olisova O, Maurer M (2016) Chronic spontaneous urticaria and internal parasites—a systematic review. Allergy 71:308–322. doi: 10.1111/all.12818 PubMedCrossRefGoogle Scholar
  107. 107.
    Bakker RA, Wieland K, Timmerman H, Leurs R (2000) Constitutive activity of the histamine H(1) receptor reveals inverse agonism of histamine H(1) receptor antagonists. Eur J Pharmacol 387:5–7CrossRefGoogle Scholar
  108. 108.
    Weller K, Ziege C, Staubach P, Brockow K, Siebenhaar F, Krause K, Altrichter S, Church MK, Maurer M (2011) H1-antihistamine up-dosing in chronic spontaneous urticaria: patients’ perspective of effectiveness and side effects—a retrospective survey study. PLoS One 6:e23931. doi: 10.1371/journal.pone.0023931 PubMedPubMedCentralCrossRefGoogle Scholar
  109. 109.
    Krause K, Spohr A, Zuberbier T, Church MK, Maurer M (2013) Up-dosing with bilastine results in improved effectiveness in cold contact urticaria. Allergy 68:921–928. doi: 10.1111/all.12171 PubMedPubMedCentralCrossRefGoogle Scholar
  110. 110.
    Staevska M, Gugutkova M, Lazarova C, Kralimarkova T, Dimitrov V, Zuberbier T, Church MK, Popov TA (2014) Night-time sedating H1-antihistamine increases daytime somnolence but not treatment efficacy in chronic spontaneous urticaria: a randomized controlled trial. Br J Dermatol 171:148–154. doi: 10.1111/bjd.12846 PubMedPubMedCentralCrossRefGoogle Scholar
  111. 111.
    Maurer M, Rosén K, Hsieh HJ, Saini S, Grattan C, Gimenéz-Arnau A, Agarwal S, Doyle R, Canvin J, Kaplan A, Casale T (2013) Omalizumab for the treatment of chronic idiopathic or spontaneous urticaria. N Engl J Med 368:924–935. doi: 10.1056/NEJMoa1215372 PubMedCrossRefGoogle Scholar
  112. 112.
    Aubin F, Avenel-Audran M, Jeanmougin M, Adamski H, Peyron JL, Marguery MC, Léonard F, Puyraveau M, Viguier M; Société Française de Photodermatologie (2016) Omalizumab in patients with severe and refractory solar urticaria: a phase II multicentric study. J Am Acad Dermatol 74:574–575. doi:  10.1016/j.jaad.2015.11.021
  113. 113.
    Chicharro P, Rodríguez P, de Argila D (2016) Omalizumab in the treatment of chronic inducible urticaria. Actas Dermosifiliogr. doi: 10.1016/
  114. 114.
    Kaplan A, Ferrer M, Bernstein JA, Antonova E, Trzaskoma B, Raimundo K, Rosén K, Omachi TA, Khalil S, Zazzali JL (2015) Timing and duration of omalizumab response in patients with chronic idiopathic/spontaneous urticaria. J Allergy Clin Immunol 137:474–481. doi: 10.1016/j.jaci.2015.08.023 PubMedCrossRefGoogle Scholar
  115. 115.
    Maurer M, Sofen H, Ortiz B, Kianifard F, Gabriel S, Bernstein JA (2016) Positive impact of omalizumab on angioedema and quality of life in patients with refractory chronic idiopathic/spontaneous urticaria: analyses according to the presence or absence of angioedema. J Eur Acad Dermatol Venereol. doi: 10.1111/jdv.14075
  116. 116.
    Gericke J, Metz M, Ohanyan T, Weller K, Altrichter S, Skov PS, Falkencrone S, Brand J, Kromminga A, Hawro T, Church MK, Maurer M (2016) Serum autoreactivity predicts time to response to omalizumab therapy in chronic spontaneous urticaria. J Allergy Clin Immunol 139:1059–1061. doi: 10.1016/j.jaci.2016.07.047 PubMedCrossRefGoogle Scholar
  117. 117.
    Bongiorno MR, Crimi N, Corrao S, Allotta A, Arena A, Brusca I, Heffler E, Malara G, Milioto M, Pistone G, Porto M, Raia E, Valenti G (2016) Omalizumab for the treatment of chronic spontaneous urticaria in clinical practice. Ann Allergy Asthma Immunol 117:703–707. doi: 10.1016/j.anai.2016.08.006 PubMedCrossRefGoogle Scholar
  118. 118.
    Metz M, Ohanyan T, Church MK, Maurer M (2014) Retreatment with omalizumab results in rapid remission in chronic spontaneous and inducible urticaria. JAMA Dermatol 150:288e290. doi: 10.1016/j.jdermsci.2013.08.011 CrossRefGoogle Scholar
  119. 119.
    Sussman G, Hébert J, Barron C, Bian J, Caron-Guay RM, Laflamme S, Stern S (2014) Real-life experiences with omalizumab for the treatment of chronic urticaria. Ann Allergy Asthma Immunol 112:170–174. doi: 10.1016/j.anai.2013.12.005 PubMedCrossRefGoogle Scholar
  120. 120.
    Vestergaard C, Toubi E, Maurer M, Triggiani M, Ballmer-Weber B, Marsland A, Ferrer M, Knulst A, Giménez-Arnau A (2017) Treatment of chronic spontaneous urticaria with an inadequate response to H1-antihistamines: an expert opinion. Eur J Dermatol 27:10–19. doi: 10.1684/ejd.2016.2905 PubMedGoogle Scholar
  121. 121.
    Seth S, Khan DA (2017) The comparative safety of multiple alternative agents in refractory chronic urticaria patients. J Allergy Clin Immunol Pract 5:165–170. doi: 10.1016/j.jaip.2016.08.010 PubMedCrossRefGoogle Scholar
  122. 122.
    Sand FL, Thomsen SF (2015) Off-label use of TNF-alpha inhibitors in a dermatological university department: retrospective evaluation of 118 patients. Dermatol Ther 28:158–165. doi: 10.1111/dth.12222 PubMedCrossRefGoogle Scholar
  123. 123.
    Kocatürk E, Maurer M, Metz M, Grattan C (2017) Looking forward to new targeted treatments for chronic spontaneous urticaria. Clin Transl Allergy 7:1. doi: 10.1186/s13601-016-0139-2 PubMedPubMedCentralCrossRefGoogle Scholar
  124. 124.
    Arm JP, Bottoli I, Skerjanec A, Floch D, Groenewegen A, Maahs S, Owen CE, Jones I, Lowe PJ (2014) Pharmacokinetics, pharmacodynamics and safety of QGE031 (ligelizumab), a novel high-affinity anti-IgE antibody, in atopic subjects. Clin Exp Allergy 44(11):1371–1385. doi: 10.1111/cea.12400 PubMedPubMedCentralCrossRefGoogle Scholar
  125. 125.
    Harris JM, Cabanski CR, Scheerens H, Samineni D, Bradley MS, Cochran C, Staubach P, Metz M, Sussman G, Maurer M (2016) A randomized trial of quilizumab in adults with refractory chronic spontaneous urticaria. J Allergy Clin Immunol 138:1730–1732. doi: 10.1016/j.jaci.2016.06.023 PubMedCrossRefGoogle Scholar
  126. 126.
    Dubois EA, Rissmann R, Cohen AF (2011) Rilonacept and canakinumab. Br J Clin Pharmacol 71(5):639–641. doi: 10.1111/j.1365-2125.2011.03958.x PubMedPubMedCentralCrossRefGoogle Scholar
  127. 127.
    Thorp WA, Goldner W, Meza J, Poole JA (2010) Reduced vitamin D levels in adult subjects with chronic urticaria. J Allergy Clin Immunol 126:413. doi: 10.1016/j.jaci.2010.04.040 PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC 2017

Authors and Affiliations

  1. 1.Department of Dermatology, InselspitalBern University Hospital, University of BernBernSwitzerland
  2. 2.Department of Dermatology, Allergy UnitUniversity Hospital BaselBaselSwitzerland
  3. 3.Department of Dermatology and AllergyUniversity Hospital ZurichZurichSwitzerland

Personalised recommendations