Editorial

Bringing Your “A” Game to Urticaria and Angioedema David A. Khan, MD Dallas, Tex

Urticaria and angioedema are common conditions encountered by the practicing allergist. Although we lack epidemiologic data of the accurate prevalence of urticaria and angioedema in the United States, there is a general perception among practicing allergists that we are seeing more patients with both chronic urticaria (CU) and angioedema. Whether this is due to a true increase in prevalence of CU and angioedema or that other specialists are managing these patients less frequently is unclear. In this issue of the Journal of Allergy and Clinical Immunology: In Practice, 3 review articles discuss the topics of urticaria and 2 different forms of angioedema. The most common form of angioedema is due to histamine release and may or may not be associated with urticaria. Hereditary nonhistamine-mediated angioedema has been recognized for more than a century as a different entity. Recently, there has been an explosion of literature on hereditary angioedema (HAE), partly due to newer HAE-specific therapies. For many years, investigators have noted patients with HAE-like presentations but who had normal C1INH. This condition has been referred to by several names, including HAEIII and estrogen-dependent HAE. In this issue, Riedl1 tackles this perplexing subject of hereditary angioedema with normal C1 inhibitor, which he has termed HAE-nmlC1INHdef. Riedl1 points out the clinical manifestations of this rare condition, which have many similarities with other forms of C1INH deficiency, eg, recurrent angioedema, including gastrointestinal angioedema, and the absence of urticaria. Key differentiating features of HAE-nmlC1INHdef are that the age of onset is later, some patients may develop hemorrhage into areas of angioedema, and the disease predominately affects women. Estrogen has been noted to exacerbate this condition in many patients, which potentially could be related to estrogen’s effects on bradykinin degradation. Unfortunately, the pathophysiology of this condition remains unknown, and various hypotheses are discussed by Riedl.1 Diagnostic criteria for HAE-nmlC1INHdef are also reviewed, including the requirement for a demonstration of either a factor XII mutation (rare in the United States) or a positive family history of angioedema. As discussed, this Division of Allergy and Immunology, University of Texas Southwestern Medical Center, Dallas, Tex No funding was received for this work. Conflicts of interest: D. Khan has received lecture fees from Viropharma, Merck, Genentech, and Baxter. Received for publication July 3, 2013; accepted for publication July 10, 2013. Cite this article as: Khan DA. Bringing your “A” game to urticaria and angioedema. J Allergy Clin Immunol: In Practice 2013;1:425-6. http://dx.doi.org/10.1016/ j.jaip.2013.07.001. Corresponding author: David A. Khan, MD, Division of Allergy and Immunology, University of Texas Southwestern Medical Center, 5323 Harry Hines Blvd, Dallas, TX 75390-8859. E-mail: [email protected]. J Allergy Clin Immunol: In Practice 2013;1:425-6. 2213-2198/$36.00 Ó 2013 American Academy of Allergy, Asthma & Immunology http://dx.doi.org/10.1016/j.jaip.2013.07.001

definition is imperfect but remains the current state of the art. Management for HAE-nmlC1INHdef is very similar to C1INH deficiency; however, the data are very problematic because they are based primarily on case reports and small case series. Further complicating these data is the lack of a diagnostic test to ensure that these patients actually have the disease. Although HAE-nmlC1INHdef is likely a rare disorder, patients who present with isolated angioedema are not rare. If one applies the strict criteria for diagnosis of HAE-nmlC1INHdef, then this will likely result in a reduction of patients with idiopathic angioedema being inappropriately treated with expensive HAE-specific therapies. However, because there are patients with HAE-nmlC1INHdef who are index cases and lack a family history, these individuals will be missed. As Riedl1 appropriately points out, further research is required to better characterize, diagnose, and identify appropriate treatments for patients with HAE-nmlC1INHdef. Another article in this issue focuses on angiotensin-converting enzyme (ACE) inhibitor angioedema. Baram et al2 note that the incidence of ACE-inhibitor angioedema varies, depending on the population, with black African and Caribbean Americans having a 3-4efold higher risk than whites. The severity of ACE-inhibitor angioedema can vary but is often severe, with one quoted study showing that half of admitted patients required care in an intensive care unit. ACE inhibitors impact both the renin-angiotensin cascade as well as the degradation metabolism of bradykinin. ACE inhibitors block kininase II, which is the primary peptidase involved with the degradation of bradykinin. Baram et al2 note that elevated levels of bradykinin have been demonstrated in ACEinhibitor angioedema, and they also review other proposed mechanisms, including decreased aminopeptidase P and dipeptidyl peptidase IV activity. Management of ACE-inhibitor angioedema includes discontinuation of the drug, supportive measures for the airway, and agents that can affect the bradykinin pathway. Baram et al2 review the available data on the use of icatibant and ecallantide (medications used in HAE therapy) on ACE-inhibitor angioedema. One of the intriguing findings on follow-up of ACE-inhibitor angioedema patients is that discontinuation of the ACE inhibitor does not always result in complete resolution of angioedema. Beltrami et al3 from Italy reported on their retrospective study of 111 patients with ACE-inhibitor angioedema. These patients were followed up for at least 12 months after discontinuation of the ACE inhibitor. After discontinuation of the ACE inhibitor, 46% of patients had further recurrences of angioedema; however, most of these patients had less-frequent episodes. These findings suggest that ACE inhibitors may certainly exacerbate angioedema in a large subset of patients but may not be the sole cause of angioedema. Finally in this issue, I have authored a review of treatments for refractory CU.4 Although many patients with CU can be managed with antihistamines, including higher doses of antihistamines, this is certainly not the case for all patients with CU. 425

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As a clinician in a university-based practice, the patients that I see referred from other allergists are very frequently found to be refractory to even high-dose antihistamine therapy. Although corticosteroids are frequently used for patients with refractory CU, they have frequent and fairly predictable serious systemic adverse effects. International guidelines and position papers have recommended avoidance of the use of long-term systemic corticosteroids in patients with CU in favor of alternative therapies.5,6 In this review, I have attempted to outline the evidence and practical considerations for selection of some of the more frequently used agents for the treatment of refractory CU.4 The agents discussed in the greatest detail include montelukast, hydroxychloroquine, dapsone, sulfasalazine, methotrexate, colchicine, cyclosporine, tacrolimus, mycophenolate, omalizumab, and intravenous immunoglobulin.4 For most agents, the evidence that supports their use is quite limited. Furthermore, these agents vary significantly in terms of their effectiveness, adverse effects, cost, method of administration, and potential to induce remission. There remains numerous knowledge gaps regarding the appropriate use of alternative agents in CU, and these are outlined in this review.4 Despite these obstacles, the practicing allergist-immunologist can still make a rational decision to determine, on an individual basis, what may be the most

J ALLERGY CLIN IMMUNOL: IN PRACTICE SEPTEMBER/OCTOBER 2013

appropriate alternative therapy for a patient who has refractory CU. Ultimately, the goal is to control the disease, with the minimal amount of risk and burden to the patient. Allergy-immunology specialists are clearly considered experts in the diagnosis and management of urticaria and angioedema. The review articles in this issue should certainly aid practicing allergists to bring their “A” game to the management of these patients. Read on; game on! REFERENCES 1. Riedl MA. Hereditary angioedema with normal C1-INH (HAE type III). J Allergy Clin Immunol: In Practice 2013;1:427-32. 2. Baram M, Komurri A, Sellers SA, Cohn JR. ACE inhibitoreinduced angioedema. J Allergy Clin Immunol: In Practice 2013;1:442-5. 3. Beltrami L, Zanichelli A, Zingale L, Vacchini R, Carugo S, Cicardi M. Longterm follow-up of 111 patients with angiotensin-converting enzyme inhibitorrelated angioedema. J Hypertens 2011;29:2273-7. 4. Khan DA. Alternative agents in refractory chronic urticaria: evidence and considerations on their selection and use. J Allergy Clin Immunol: In Practice 2013;1:433-40. 5. Zuberbier T, Asero R, Bindslev-Jensen C, Walter Canonica G, Church MK, Gimenez-Arnau AM, et al. EAACI/GA(2)LEN/EDF/WAO guideline: management of urticaria. Allergy 2009;64:1427-43. 6. Sanchez-Borges M, Asero R, Ansotegui IJ, Baiardini I, Bernstein JA, Canonica GW, et al. Diagnosis and treatment of urticaria and angioedema: a worldwide perspective. World Allergy Organ J 2012;5:125-47.

Bringing your "A" game to urticaria and angioedema.

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