Agroup as large as 15% to 24% of

Transcription

1 Update on Chronic Urticaria and Angioedema Sarbjit S. Saini, MD ABSTRACT PURPOSE: To review the various subtypes of angioedema and urticaria and their current standards of treatment and to highlight new therapeutic approaches to these conditions. EPIDEMIOLOGY: A group as large as 15% to 24% of the US population will experience acute urticaria and/or angioedema at some time in their lives. Approximately 50% of patients with urticaria alone will be free of lesions within 1 year, whereas 20% have involvement for more than 20 years. For patients with both conditions, 75% have continued episodes for more than 5 years and 20% for more than 20 years. REVIEW SUMMARY: Chronic urticaria and angioedema have a vast constellation of clinical presentations, triggers, and underlying causes. This article reviews the different subtypes of angioedema and urticaria and offers recommendations for diagnosis and workup. Standard treatment focuses on symptom control and rarely on avoidance of triggers that are identified through careful medical history and assessment. The cornerstone of therapy is antihistamines, but many patients do not respond to this treatment. TYPE OF AVAILABLE EVIDENCE: Systematic review, cohort studies. GRADE OF AVAILABLE EVIDENCE: Fair. CONCLUSION: Despite the unfortunate current situation in which many patients do not respond to the standard therapy of antihistamines, the future nevertheless holds hope for new therapies. (Adv Stud Med. 2005;5(2):73-78) ALLERGY/IMMUNOLOGY Agroup as large as 15% to 24% of the US population will experience acute urticaria and/or angioedema at some time in their lives, which, although typically diagnosed as an allergic reaction, also may be triggered by a host of diseases, medications, and infections. 1 Urticaria should be considered a likely diagnosis when the patient presents with pruritic (and sometimes painful or burning), erythematous, circumscribed (or coalescent) wheals. Urticarial lesions commonly involve the extremities and trunk, but they may appear on any part of the body. In contrast to urticaria, angioedema presents as deeper subcutaneous swelling. Less circumscribed than the lesions of urticaria, angioedema has a tendency to occur in areas of loose connective tissue, such as the face or mucous membranes involved with the lips or tongue. If angioedema engages the upper respiratory tract, the result can be a life-threatening obstruction of the airway. 1 Chronic urticaria is defined as the occurrence of frequent wheals and itching for at least 6 weeks; more than 80% of chronic cases are idiopathic. The remaining minority of chronic cases are due to an underlying condition, such as drug allergy, thyroid disease, autoimmune disorders with vasculitis, or chronic hepatitis. About 50% of patients with chronic idiopathic urticaria (CIU) also have angioedema. 2 Because the duration of CIU is unpredictable, patients are frequently frustrated by symptoms that may spontaneously disappear within 12 months, but that also may continue for years. Approximately 50% of patients with urticaria alone will be free of lesions within 1 year, whereas 20% have involvement for more Dr Saini is Assistant Professor, Clinical Immunology, The Johns Hopkins Medical Institutions, Baltimore, Md. Conflict of Interest: Dr Saini reports having no financial or advisory relationships with corporations related to this activity. Off-Label Product Discussion: The author of this article does not discuss off-label use of products. Correspondence to: Sarbjit Saini, MD, Division of Clinical Immunology A&A Ctr, 5501 Hopkins Bayview Circle, Baltimore, MD Johns Hopkins Advanced Studies in Medicine 73

2 ALLERGY/IMMUNOLOGY than 20 years. Of patients who have both urticaria and angioedema, 75% continue to experience episodes for more than 5 years, and 20% continue to experience them for more than 20 years, making this disorder a serious physical and emotional affliction for patients. 2 Because of a complex and varied etiology, CIU has long baffled primary care and specialty physicians alike. A number of skin conditions can manifest similarly to CIU, prompting frequent referrals to the allergist or dermatologist (Table 1). Careful history taking with regard to onset, timing, physical triggers, and systemic diseases is fundamental to developing a management plan for these disorders. The patient also should be asked about recent use of medications (including herbal remedies and supplements), food exposures, viral infections, and any occupational and natural allergen exposures that might induce acute urticaria. The physical examination should include the skin, lymph nodes, eyes, ears, throat, neck, joints, lungs, heart, and abdomen in an effort to detect an underlying causal condition. Given the vast number of potential urticarial triggers and the difficulty in identifying them, any clues uncovered by history and physical examination can be extremely important. 1 If the history does not suggest a cause, however, any routine battery of tests is unlikely to identify an occult pathogenesis. 3 Laboratory assays are used primarily to Table 1. Skin Disorders That Resemble Chronic Idiopathic Urticaria and Angioedema* Skin Disorder Contact allergic dermatitis Dermatomyositis/subacute cutaneous lupus Bullous pemphigoid Cellulitis Lymphedema Recurrent erythema multiforme Hypoalbuminemia (eg, nephrotic syndrome) Polymorphous light eruption Fixed drug eruption Crohn s disease Mastocytosis *Data from Greaves MW. 14 Comment Can occur anywhere on skin with eczematous or vesicular component to the lesion Mainly facial Occasionally occurs without bullae; lesions are fixed Mainly limbs and face; warmth and tenderness Mainly limbs and face Mainly limbs and face Angioedema of face and limbs Sun-exposed areas Solitary to a few lesions; fixed eruption for >48 hrs Angioedema of lips Pigmented lesions screen for and exclude the rare possibility of a secondary disorder that may trigger the outbreak. A biopsy is recommended if lesions persist for more than 48 hours or are clinically atypical. Other indications for biopsy include: 1) urticarial lesions that last more than 24 hours; 2) urticarial lesions that do not itch; 3) lack of significant response to properly administered and dosed H1 + H2 antagonists; 4) systemic symptoms that cooccur with urticaria; and 5) changes in pigmentation of the areas of urticarial involvement. 3 A body of clinical evidence is emerging that recommends a punch skin biopsy be performed on patients with CIU that is difficult to treat. Two types of chronic urticaria have been defined by skin biopsy results: 1) perivascular lymphocyte-predominant urticaria, and 2) perivascular polymorphonuclear-predominant urticaria (ie, neutrophils, scattered eosinophils, and mononuclear cells). Patients with lymphocyte-predominant infiltrates are more responsive to antihistamine therapy. Patients with polymorphonuclear cell-predominant infiltrates are relatively resistant to antihistamines and will more likely require oral glucocorticosteroid treatment or alternative treatments. Eosinophil activation may occur relatively later or be more persistent in patients without autoantibodies. 1 The skin biopsy also may detect unsuspected urticarial vasculitis or mastocytosis. 1 If known triggers or causes for chronic urticaria and angioedema are not discovered readily from observations involving the onset of symptoms, further evaluation and management of this chronic process become more complex. At such a point, referral to an allergist, immunologist, or dermatologist is appropriate, especially if the condition s etiology has not been determined. 1 ANGIOEDEMA SUBTYPES Table 2 presents complement levels in the angioedema subtypes that are described in the paragraphs below. DRUG-INDUCED ANGIOEDEMA Drug-induced angioedema is a common type of angioedema. The angiotensin-converting enzyme (ACE) inhibitors in particular are known to trigger angioedema, and up to 1% of patients who use ACE-inhibiting drugs have angioedema symptoms. 4 By contrast, the incidence of angioedema is much lower with the newer angiotensin II-receptor antagonists, however, one must remain vigilant to the development of swelling. 5 Temporary withholding of drugs suspected of causing angioedema or substitution with drugs of a different chemical class may help the clinician isolate the causative agent. HEREDITARY ANGIOEDEMA Hereditary angioedema (HAE) is clinically characterized by recurrent episodes of localized subcutaneous or 74 Vol. 5,. 2 February 2005

3 CHRONIC URTICARIA AND ANGIOEDEMA Diagnosing Hereditary Angioedemia Measure C1-INH level and/or function C4 should be low between swelling episodes Pruritus and urticaria are not present C1-INH = C1-esterase inhibitor. submucosal edema. It may involve the skin, upper respiratory tract, oropharynx, or gastrointestinal tract (in which it manifests as abdominal pain). Urticaria is not a feature of this disease, nor is pruritus. Estimated prevalence of this condition is estimated at 1 in to 1 in , equally distributed among males and females, and most frequently affecting those in their 20s. 6 HAE is an autosomal-dominant disorder attributable to a deficiency of the C1-esterase inhibitor (C1-INH). Approximately 85% of patients with HAE are classified as type I and have inadequate levels of C1-INH, whereas C1-INH is present but nonfunctional in 15% of patients who are classified as type II. C1-INH is a member of the serine protease inhibitor family encoded on chromosome 11, synthesized primarily by hepatocytes, which are induced by androgens. Multiple defects in the genomic sequence of this gene are responsible for HAE. Because the inheritance pattern of HAE is autosomal dominant, medical history is key. It is important to inquire whether there have been any early deaths in family members due to airway compromise. Interestingly, despite the autosomal-dominant nature of this disorder, 25% of cases are spontaneous mutations, with more than 100 different gene mutations described in the medical literature. 7 Triggers are very often difficult to pinpoint, but can include trauma, medical procedures, stress, and oral contraceptive or estrogen therapy use. Swelling attacks typically progress over 1 to 2 days, then regress over a similar time frame. If undiagnosed, mortality from HAE can be as high as 30% to 40%, mostly due to upper airway obstruction. It is important to recognize that a lack of previous upper airway involvement in HAE attacks does not predict the future lack of such involvement, so rescue medication is an important part of patient management. Management of HAE is challenging given the variable frequency of attacks among affected individuals. The current recommendation in the United States is use of attenuated androgens, with the rationale being that most of this protein is created in the liver. Use of synthetic androgens can stimulate a level of production of C1-INH that is sufficiently low to prevent the numerous attacks seen in these patients. The treatment choices for recurrent lifethreatening attacks of C1-INH deficiency, where available, are infusions of C1-INH concentrates. Should these measures fail, intubation or tracheotomy may be necessary to prevent airway closure. To prevent recurrent episodes of angioedema due to C1-INH deficiency, prophylactic management with anabolic steroids (danazol and stanazol) may be used. The lowest effective dose should be used to minimize the occurrence of side effects. 6 A recent study evaluated the efficacy of C1-INH concentrate for treating sudden airway compromise in HAE by measuring the time from injection to resolution of symptoms in 42 patients who had 517 episodes of laryngeal edema. 8 Among the 18 patients who received C1- INH concentration injections for 193 episodes, the treatment was 100% effective. The interval from injection to interruption in progress of symptoms ranged from 10 minutes to 4 hours, and the mean total duration of symptoms was 15.3 hours as compared with hours in patients who were untreated. Although these results are impressive, this therapy is not available in the United States. Other agents used in the acute setting are epinephrine, antihistamines, and fresh frozen plasma. HEREDITARY ANGIOEDEMA III A newly identified syndrome, HAE III, was first described by Bork et al in This report described 10 female probands and 26 of their female relatives who were found to suffer from episodes of angioedema identical in character to HAE, but who also were found to have normal C1-INH, C4, and C1q levels both before and during attacks. Age of onset varied from 1 to 63 years, and frequency varied from 3 to 12 episodes per year. Within this female cohort, those who used contraceptives or hormone replacement therapy had worsening of symptoms, and all women had worsening during pregnancy. This finding of HAE with normal C1-INH concentration and function represents a unique genetic disease that arises only in women. Treatment with C1- Table 2. Complement Levels in Angioedema Subtypes* *Data from Nzeako et al. 6 HAE = hereditary angioedema; C1-INH = C1-esterase inhibitor; N = normal; = decrease. Johns Hopkins Advanced Studies in Medicine 75

4 ALLERGY/IMMUNOLOGY INH concentrate, oral steroids, antihistamines, and antifibrinolytic agents was found to be ineffective, but danazol was found to be effective in some study subjects. ACQUIRED ANGIOEDEMA Acquired angioedema (AAE) also has swelling as its major symptom and is caused by increased destruction or metabolism of C1-INH. This disorder typically has onset in later decades as compared to HAE. It may develop in the setting of B-cell lymphoproliferative disease (type I). Type II AAE is secondary to an autoantibody with specificity for C1-INH, rendering it nonfunctional. 2 Treatment of AAE most often requires treatment of the underlying disease. URTICARIA Urticaria is characterized by raised, red, itchy papules of varying size (hives) that can occur on any part of the body. These occur in shallow levels of the skin, with swelling referred to as wheals. The wheals result from transient leakage of plasma from small blood vessels into the surrounding connective tissue; they are usually itchy and, at first, are frequently pale in the center. 10 Gradually they change appearance, presenting as pink superficial plaques 10 that tend to resolve in less than 24 hours without leaving permanent skin marks. As described earlier, deeper, painful swellings of the dermis and submucosal or subcutaneous tissues are called angioedema, a condition that frequently coexists with urticaria. PHYSICAL TRIGGERS Physical triggers of acute urticaria are numerous and may include extreme changes in temperature, localized heat, cholinergic reactions, and even exercise (Table 3). Contact urticaria is induced by biologic or chemical contact with the skin. 10 Certain substances interact with mast cells to directly cause degranulation and release of mediators, leading to urticaria. Opiate derivatives, polymyxin, and tubocurarine all are offenders. In addition, patients who undergo radiocontrast dye procedures may experience direct activation of mast cells from the dye, resulting in urticaria at the time of the procedure. Aspirin and other nonsteroidal anti-inflammatory drugs (NSAIDs) indirectly cause mast cell degranulation by altering the arachidonic acid pathway, which can potentially trigger urticaria. 2 CHRONIC IDIOPATHIC URTICARIA Chronic idiopathic urticaria is defined by episodes of urticaria that repeat for a duration of >6 weeks and generally lack identifiable triggers. In these chronic cases, 80% to 90% of the time an exhaustive clinical workup will show no particular cause of hives. However, a clinical investigation for an underlying Diagnosing Acquired Angioedema Distinguish the acquired from the hereditary form via laboratory evaluation of the complement system during episodes of angioedema Hallmarks of the disorder are decreases in C1-INH, C1q, and C4 levels 2 C1-INH = C1-esterase inhibitor. cause is fundamental to sound medical practice. Pertinent tests include evaluation for thyroid disease, the systemic disease most frequently associated with urticaria; 20% of patients will show abnormal results in thyroid tests. 12 More rare, occasional associations are found with chronic hepatitis infections, systemic lupus erythematosus, and rheumatoid arthritis. There is also limited evidence that the treatment of chronic infections, such as sinus or Helicobacter pylori infections, and even dental abscesses, can cause dramatic reductions in urticaria in select patients. Though this area has not been widely studied, it warrants consideration. 12,13 URTICARIAL VASCULITIS Urticarial vasculitis is another disorder mediated by immune complexes. In contrast to chronic urticaria, lesions usually last longer than 72 hours, may itch or burn, and demonstrate purpura or hyperpigmentation as they subside. 2 Patients with this form of small-vessel vasculitis may present with both urticaria and arthritis and are at risk of kidney, lung, eye, or central nervous system involvement. 10 Urticarial vasculitis can be further subdivided into 2 categories: normocomplementemic (usually idiopathic) and hypocomplementemic, sometimes associated with underlying systemic lupus erythematosus, Sjogren s syndrome, or cryoglobulinemia. The diagnosis must be confirmed via skin biopsy with direct immunofluorescence to look for immunoglobulin and complement perivascular deposition. 10 Table 3. Types of Physical Urticarias* Adrenergic Localized heat Aquagenic Solar, 3% Cholinergic, 34% Vibratory Small wheals Dermographism, 36% Warmth Cold induced,13% Delayed pressure, 11% *Data from Casale TB Vol. 5,. 2 February 2005

5 CHRONIC URTICARIA AND ANGIOEDEMA Diagnosing Chronic Urticaria Take a thorough medical history relating to onset, timing, and duration of outbreaks Exclude secondary causes (drug, food) or diseases (lupus, thyroid) with appropriate laboratory tests Consider conditions that frequently mimic CIU, such as dermographism, or skin conditions such as dermatomyositis, vasculitis, erythema multiforme, cellulitis, and contact allergic dermatitis 14 CIU = chronic idiopathic urticaria. AUTOIMMUNE URTICARIA Autoimmune urticaria represents a relatively recent diagnostic advance, and this condition is now believed to account for as many as 40% of patients with CIU. 12 Autoimmune urticaria was described about a dozen years ago in a study by Gruber and colleagues, 15 which was followed 5 years later by a report from Hide et al, 16 who investigated the role of pathogenic autoantibodies in this disorder. They found circulating autoantibodies of IgG or IgM isotypes to be targeting IgE in a small subset of CIU patients. And more often, they found that these patients had circulating autoantibodies against the IgE receptor. Circulating IgG autoantibodies were found to react with the α chain of the IgE receptor on dermal mast cells and basophils, prompting release of histamine and other elements that cause urticaria and angioedema Currently, detection of these autoantibodies is performed in a number of ways, including basophil histamine release by in vitro assay, but these tests are available only in research settings as opposed to clinical practice. Most recently, the presence of circulating autoantibodies or basophil histamine-releasing factors in asymptomatic adults has raised doubts about the specificity of these assays for chronic urticaria. 19,20 Laboratory tests recommended for workup and management of chronic urticaria are presented in Table 4. TREATMENT OF ANGIOEDEMA AND URTICARIA The cornerstone of treatment for chronic angioedema and urticaria not associated with anaphylaxis is the use of H1 antihistamines. Secondgeneration H1 antihistamines usually are preferred. When these fail, first-generation antihistamines such as hydroxyzine or diphenhydramine may be effective, although these agents are highly sedating and are therefore not recommended as first-line therapy. The use of glucocorticosteroids in the treatment of patients with chronic angioedema and urticaria rarely is necessary. If required, short courses of oral glucocorticosteroids rather than depot parenteral preparations are preferred in order to lessen the duration of systemic effects. 1 In the presence of severe pruritus, H2 blockers may be added, because approximately 15% of the skin has H2 receptors. 12 In more severe cases, the use of the tricyclic agent doxepin allows the blockade of both H1 and H2 receptors. Some data exist to support the use of leukotriene receptor antagonists, particularly in subjects who suffer from aspirin- and/or NSAID-induced aggravations of urticaria. 21 npharmacologic treatment is directed toward reducing the aggravating factors identified in the patient s history, such as heat, tight clothing, stress, and alcohol use, which can all exacerbate urticaria. Avoidance of aspirin and other NSAIDs is recommended because these drugs have been reported to aggravate chronic urticaria in about 30% of patients. 10 An algorithm for the management of chronic ordinary urticaria is presented in the Figure. CONCLUSION Because clear-cut therapeutic strategies for management of severe chronic urticaria and angioedema are a matter for continuing investigation, research will likely yield new and specific therapeutics in the coming years. Various immunomodulators, such as cyclosporine A and hydroxychloroquine, have been used with limited success in severe cases after failure of traditional approaches. Future research into suppressing the activation of skin mast cells may offer more specific new targets for control of this disorder. Table 4. Workup of Chronic Idiopathic Urticaria Complete blood count with differential for eosinophilia Screen for connective tissue diseases (eg, WESR, ANA) if history suggests any Biopsy of lesion to exclude vasculitis if lesions are prolonged in duration Complement screens in angioedema alone Thyroid functions with autoantibodies SPEP with immunofixation in patients with prolonged urticaria, fever, and elevated WESR WESR = Westegren erythrocyte sedimentation rate; ANA = antinuclear antibodies; SPEP = serum protein electrophoresis. Johns Hopkins Advanced Studies in Medicine 77

6 ALLERGY/IMMUNOLOGY Figure. Algorithm for Chronic Urticaria/Angioedema* Are individual urticarial lesions morphologically consistent with urticarial vasculitis and do they persist for more than 24 hours? Evaluate for vasculitis: Consider ESR Consider complement assays Consider biopsy Does patient have urticarial vasculitis? Manage vasculitis Patient presents with lesions and/or history consistent with chronic urticaria and/or angioedema SPECIFIC MANAGEMENT Remove factors that may augment or induce urticaria/angioedema Specific pharmacologic management MANAGE SPECIFIC CONDITION Remove factors that may augment or induce urticaria Specific pharmacologic management Does patient have angioedema only? DETAILED HISTORY INCLUDING REVIEW OF SYSTEMS: Occupational Insect sting, bite Medications Food Infection Physical sensitivity Physical Examination CONSIDER BASIC LAB TESTS: CBC, UA, ESR, LFTs Consider appropriate tests based on history, PE, ROS Are history, physical examination, and/or laboratory tests indicative of an underlying cause? Evaluate for angioedema Does evaluation suggest an underlying cause? MORE DETAILED EVALUATION as appropriate: Additional history Additional physical examination AND/OR Additional laboratory tests Consider skin biopsy Is additional evaluation suggestive of etiology? Specific management Treat patient for idiopathic urticaria and/or angioedema *Reprinted with permission from Joint Task Force on Practice Parameters. The diagnosis and management of urticaria: a practice parameter. Part II: chronic urticaria/angioedema. Ann Allergy Asthma Immunol. 2000;85(suppl 6): ESR = erythrocyte sedimentation rate; CBC = complete blood count; UA = urine analysis; LFT = liver function test; PE = physical examination; ROS = review of systems. REFERENCES 1. Joint Task Force on Practice Parameters. The diagnosis and management of urticaria: a practice parameter. Ann Allergy Asthma Immunol. 2000;85(suppl 6): Available at: www. jcaai.org/param/urticaria.htm. Accessed August 18, Kulp-Shorten CL, Callen JP. Urticaria, angioedema, and rheumatologic disease. Rheum Dis Clin rth Am. 1996;22: Beltrani VS. Urticaria and angioedema. Dermatol Clin. 1996;14: Pillans PI, Coulter DM, Black P. Angioedema and urticaria with angiotensin converting enzyme inhibitors. Eur J Clin Pharmacol. 1996;51: Smith DH. Treatment of hypertension with an angiotensin IIreceptor antagonist compared with an angiotensin-converting enzyme inhibitor: a review of clinical studies of telmisartan and enalapril. Clin Ther. 2002;24: Nzeako UC, Frigas E, Tremaine WJ. Hereditary angioedema: a broad review for clinicians. Arch Intern Med. 2001;161: Tosi M. Molecular genetics of C1 inhibitor [published correction appears in Immunobiology. 1999;200(1):166.] Immunobiology. 1998;199: Bork K, Barnstedt SE. Treatment of 193 episodes of laryngeal edema with C1 inhibitor concentrate in patients with hereditary angioedema. Arch Intern Med. 2001;161: Bork K, Barnstedt SE, Koch P, et al. Hereditary angioedema with normal C1-inhibitor activity in women. Lancet. 2000;356: Grattan CE, Sabroe RA, Greaves MW. Chronic urticaria. J Am Acad Dermatol. 2002:46; ; quiz Casale TB, Sampson HA, Hanifin J, et al. Guide to physical urticarias. J Allergy Clin Immunol. 1988;82(5, pt 1): Kaplan AP. Clinical practice. Chronic urticaria and angioedema. N Engl J Med. 2002;346: Federman DG, Kirsner RS, Moriarty JP, et al. The effect of antibiotic therapy for patients infected with Helicobacter pylori who have chronic urticaria. J Am Acad Dermatol. 2003;49: Greaves MW. Chronic idiopathic urticaria. Curr Opin Allergy Clin Immunol. 2003;3: Gruber BL, Baeza ML, Marchese MJ, et al. Prevalence and functional role of anti-ige autoantibodies in urticarial syndromes. J Invest Dermatol. 1988;90: Hide M, Francis DM, Grattan CE, et al. Autoantibodies against the high-affinity IgE receptor as a cause of histamine release in chronic urticaria. N Engl J Med. 1993;328: Fiebiger E, Maurer D, Holub H, et al. 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. 1995;96: Tong LJ, Balakrishnan G, Kochan JP, et al. Assessment of autoimmunity in patients with chronic urticaria. J Allergy Clin Immunol. 1997;99: Saini S, Vasagar K, Gibbons S Jr, et al. Signaling defects in basophils in chronic urticaria [abstract]. J Allergy Clin Immunol. 2003;111:S Vasagar K, Vonakis BM, Viksman A, et al. Evidence of in vivo basophil activation in chronic idiopathic urticaria [abstract]. J Allergy Clin Immunol. 2004;113:S Pacor ML, Di Lorenzo G, Corrocher R. Efficacy of leukotriene receptor antagonist in chronic urticaria. A double-blind, placebo-controlled comparison of treatment with montelukast and cetirizine in patients with chronic urticaria with intolerance to food additive and/or acetylsalicylic acid. Clin Exp Allergy. 2001;31: Vol. 5,. 2 February 2005