Clinical pearls

What the first 10,000 patients with chronic urticaria have

taught me: A personal journey
Allen P. Kaplan, MD Charleston, SC

Key words: Urticaria, angioedema, histamine, antihistamine, rice, lamb, and water for 5 days and recording the effect on the
corticosteroids, cyclosporine, anti-IgE receptor person’s urticaria. The study was neither controlled nor blinded.
Nevertheless, no one improved, and after the first 20 patients,
Chronic urticaria remains one of the disorders treated by we stopped. I assumed that chronic urticaria was not caused by
allergists with which there is (and has been throughout my food allergy or by uncharacterized reactions to food additives
lifetime) associated myths regarding the cause of the disorder and and have never become suspicious that this could be incorrect.
its treatment that are extremely difficult to dispel. In this brief By 1980, it was concluded that food additives precipitate hives
article I would like to address some of these beliefs, review the in 2000 of 6600 patients with chronic urticaria, and one author
literature where it exists, point out where there are gaps in our added that reactions in asthmatic subjects are even higher.4 As
understanding, and convey some of my own conclusions that will, the decades passed, the reader will note that IgE-mediated food
hopefully, become hypotheses for future investigation. Table I allergy is no longer considered to be a cause of chronic urticaria.
lists the beliefs that I think are false and potentially detrimental Even considerations such as hives caused by benzoates,5 aspirin
to the care of patients. I will expand on each of these. and natural salicylates,6 or yellow dye no. 5 are uncommonly
I became board certified in allergy and clinical immunology in seen. But the idea has now morphed into the realm of ‘‘pseudoal-
1974, and that was a period in which chronic urticaria was lergy.’’7 Here well-defined chemicals are claimed to cause or ex-
seriously considered by many to be an emotional disorder.1,2 The acerbate the symptoms of chronic urticaria. IgE antibody is not
idea remains prominent within the public at large, leading to ques- necessary, although the mechanism or mechanisms responsible
tions asked by many new patients, such as ‘‘Is it my nerves?’’ Fac- have not been discerned. Pseudoallergens include artificial food
titious urticaria is another term for dermatographism, which dyes, preservatives, and sweeteners, aromatic compounds in
implies that the skin reaction is not real or that the patient self-in- wine, tomatoes, and spices8; as well as phenols, such as D-hy-
flicts the rash and has only himself or herself to blame. It does not droxy benzoic acid, citrus and orange oil, and salicylates.9 The re-
acknowledge the severe pruritus associated with a functional skin mission rate attributed to elimination diets varies from 30% to
abnormality (yet to be defined) of cutaneous mast cells as the un- 90%, yet double-blind, placebo-controlled food challenges with
derlying problem. Angioneurotic edema is now just angioedema these substances have failed to reproduce urticaria,10 and patients
as we move away from a psychic cause of these things. The dis- whose chronic urticaria has remitted can eat anything without be-
covery of C1 esterase inhibitor deficiency as the defect in hered- coming symptomatic. The right conclusion is that foods or addi-
itary angio(neurotic)edema was particularly helpful. tives do not contribute to the pathogenesis of chronic urticaria.
Foods and food additives as a putative cause of chronic Infectious processes as a cause of chronic urticaria have been
urticaria date almost as far back as ‘‘nerves’’ as a cause. I will considered in the past but not so prominently until the discovery
mention one in particular. James and Warin3 described exacerba- of Helicobacter pylori. Soon thereafter, articles began to appear
tions of urticaria after challenge with food yeasts and Candida al- relating the presence of the organism to chronic urticaria or re-
bicans extracts; 69% of patients with a positive skin prick test porting effective treatment of chronic urticaria by using therapy
response to C albicans had a positive challenge result to food to eradicate the organism.11 However, other articles are nega-
yeast, and a ‘‘large percentage’’ responded to a low-yeast diet. tive.12 The problem lies in the fact that the presence of the orga-
At the National Institutes of Health (1978-1987), some of our first nism far exceeds the prevalence of chronic urticaria (0.5% to
observations disproved this thesis by limiting foods to a diet of 1.5%)13 and that properly controlled studies involving large num-
bers of patients have not been done.14 I have seen perhaps 500 pa-
tients with chronic urticaria who have negative test results for H
From the Department of Medicine, Medical University of South Carolina, and the pylori and about 50 who have the organism but in whom treatment
National Allergy, Asthma, and Urticaria Centers of Charleston.
Disclosure of potential conflict of interest: A. P. Kaplan has received honoraria from
directed to it failed. Of course, the successes are not referred to
Sanofi-Aventis, GlaxoSmithKline, and Novartis/Genentech; has received consulting me. Nevertheless, I have never ordered the test, and see no reason
fees from Lev Pharmaceutical; and has received research support from Lev Pharma- to do so. If one waits long enough, this idea will disappear.
ceutical and Novartis. Currently, the major ideas concerning the cause, pathogenesis,
Received for publication August 5, 2008; revised October 23, 2008; accepted for
or both of chronic urticaria are based on observations suggesting
publication October 24, 2008.
Available online December 11, 2008. that it has an autoimmune cause in 40% to 45% of patients. There
Reprint requests: Allen P. Kaplan, MD, Department of Medicine, Division of Pulmonary is the association with antithyroid antibodies,15,16 which appear to
Critical Care Medicine and Allergy and Clinical Immunology, Medical University of be a marker of autoimmunity16; the pathogenic antibodies are IgG
South Carolina, Charleston, SC-29425. E-mail: [email protected]. anti-IgE receptor17-19 or IgG anti-IgE.20,21 The IgG antibodies ac-
J Allergy Clin Immunol 2009;123:713-7.
0091-6749/$36.00
tivate the classical complement cascade,19,22 and purification of
Ó 2009 American Academy of Allergy, Asthma & Immunology IgG subclasses demonstrated histamine-releasing activity pre-
doi:10.1016/j.jaci.2008.10.050 dominantly within subclasses 1 and 3.23 If correct, future studies

713
714 KAPLAN J ALLERGY CLIN IMMUNOL
MARCH 2009

TABLE I. Myths about the cause and treatment of chronic urticaria

Myths about cause
1. Chronic urticaria is a psychosomatic disorder, with hives as a cutaneous manifestation of an emotional problem.
2. Chronic urticaria is caused by food additives or is exacerbated by pseudoallergens contained in foods.
3. Helicobacter pylori causes hives.
Myths about treatment
1. Nonsedating antihistamines in recommended doses are as efficacious as sedating antihistamines with much less toxicity.
2. Data demonstrating sedation with antihistamines as tested in healthy subjects or patients with allergic rhinitis can be extrapolated to the treatment of
chronic urticaria.
3. Thyroid hormone can be used to treat chronic urticaria if thyroid antibodies are present.

will elucidate the mechanistic details further, which might lead to conformation to an active mode. The variables are the molar
new approaches regarding therapy. If the relationship is spurious, amounts of antihistamine versus histamine present at the skin
other explanations for the presence of these autoantibodies will be site and the binding affinity of each. The first test of this concept
found. It is clear that binding methods, such as ELISA, are not was our clinical observations in treating dermatographism. This
reliable for detection of these antibodies23 and that functional is the most purely histamine-dependent form of urticaria, and
assays, such as basophil histamine release or perhaps activation not only can we stop pruritus and induced lesions with hydroxy-
markers on basophils, are essential. There are also reports of ba- zine or diphenhydramine in patients in whom nonsedating antihis-
sophil hyporesponsiveness24-26 or even hyperresponsiveness27 in tamine treatment fails, we can also dose-response the effect
subgroups of patients with chronic urticaria, and this approach between 50 and 200 mg hydroxyzine so that control of symptoms
might define additional abnormalities related to the cause/patho- is proportional to the dose used. This is an important observation
genesis of patients who are still considered to be ‘‘idiopathic.’’ because dermatographism cannot be treated with corticosteroids.
Vonakis et al26 found increased cytoplasmic phosphatases (Src The same effect was demonstrated experimentally using intrader-
homology domain 2–containing inositol phosphatase) as a possi- mal injections of histamine at 3 doses tested before and after anti-
ble explanation for diminished basophil histamine release on histamine therapy: 0.1, 2.5, and 5 mg/mL. I was the patient, and a
stimulation with anti-IgE. Decreased responsiveness, however, nurse recorded the results. The wheal-and-flare reaction was mea-
might be a consequence of having urticaria rather than its cause. sured at baseline and after 1 week of 180 mg of fexofenadine. A
However, a second focus of this narrative is to present prominent decrease in reactivity was noted, but all 3 doses are still
commonly believed concepts that I think are false and that lower 41 by using the usual methods for reading intradermal skin tests. I
the success rate in the treatment of patients with chronic urticaria. then added 2 cetirizine tablets (taken in the morning and at dinner
The most egregious is the current approach of using antihista- time) to the morning fexofenadine for a week and repeated the skin
mines. My first note of it began at the National Institutes of Health tests. A further decrease in wheal diameter and pruritus index was
in the mid-1970s. Nonsedating antihistamines entered the market, noted, and the cutaneous response to the 3 doses was 41, 21, and
and it made sense to try them in patients with chronic urticaria. The 11, respectively. I did not appreciate any sedation. I then ingested
drugs of choice at that time were hydroxyzine and diphenhydra- 50 mg of hydroxyzine 4 times daily for 1 week, and when the test
mine, and most of our patients required 4 times daily dosing with was repeated, there was no pruritus and the highest histamine dose
either 25- or 50-mg tablets. This was standard practice at the time; was ‘‘trace positive’’ (ie, less than 11). Sedation was present up to
sedation was not of particular concern. Once I switched to the day 4, and thereafter I was unaware of any. Chronic urticaria is far
nonsedating antihistamines that were marketed first (terfenadine more complex, but histamine release is certainly important, and
and loratadine), I lost the ability to treat patients other than those my thesis is that antihistamine therapy be maximized before add-
with mild urticaria, even if I doubled the dose. During the next 20 ing any other more toxic agent. Thus I adapted use of hydroxyzine
years, articles appeared demonstrating significant improvement of or diphenhydramine for chronic urticaria (idiopathic or autoim-
symptoms in patients with chronic urticaria using most available mune) based on observations such as these because there are no
nonsedating antihistamines. Nevertheless, from 1980 to 2008, at studies of long-term antihistamine therapy in patients with chronic
least 75% of patients in my practice in whom treatment with urticaria on which one can rely.
nonsedating antihistamines failed could have their symptoms When antihistamines fail, the options available include corti-
managed with hydroxyzine or diphenhydramine taken round-the- costeroids, cyclosporine, intravenous gamma globulin, metho-
clock without addition of other agents. This has never been trexate, sulfasalazine, dapsone, hydroxychloroquine, colchicine,
formally studied. The only article reporting multiple daily doses of and cytoxan. The literature on most of these (1990 to the present)
hydroxyzine at 25 mg 3 times daily suggest that it is no better than has been recently reviewed.30 Studies of relatively small numbers
10 mg of cetirizine.28 Because 10 mg cetirizine equals about 30 mg of patients suggest the efficacy of each of these in occasional sub-
of hydroxyzine, this dose of hydroxyzine might not be much better jects (excluding corticosteroids and cyclosporine), but the data are
than cetirizine taken twice daily; nevertheless, the hydroxyzine insufficient to recommend them. An example is a recent study of
dose is too low to achieve the effects of which I speak. sulfasalazine that has no placebo control.31 Dapsone, hydroxy-
Is there a dose response of antihistamine effect as the dose is chloroquine, and colchicine are, in my view, ineffective, but
increased? Because antihistamines are inverse agonists that bind more important is that the data in support of their use are based pri-
to the H1 receptor to shift its conformation to an inactive mode,29 marily on uncontrolled studies of small numbers of patients.32-34
their effectiveness will depend on the percentage occupancy of the The choice of these agents might be based on their apparent effi-
H1 receptor. This in turn relates to the amount of histamine present cacy for urticarial vasculitis or other neutrophil-dependent derma-
because histamine binds to the same receptor to shift its tologic conditions. Cytoxan is very toxic, and therefore I will
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focus on steroid use, which is the most common alternative used antihistamines beyond the approved dosage. Likewise,
by physicians referring patients to me, and cyclosporine, which re- for other forms of chronic urticaria, it is assumed that
ally works.35,36 The key to effective therapy, however, is defining H1 receptors are ‘‘blocked’’ when the amount of histamine
what is refractoriness to antihistamines. When a double dose of a present might preclude that.
nonsedating antihistamine fails to adequately alleviate symptoms 4. It is assumed that sedation to one 50-mg tablet will propor-
or affect quality of life, we use hydroxyzine at 25 to 50 mg 4 times tionately increase as the dose is increased. This is not possi-
daily and resort to the aforementioned agents only when this fails. ble based on our experience. Also, the reverse seems to be so.
The number of patients presenting with steroid toxicity (obesity, Taking it round-the-clock (preferable to a megadose at bed-
hypertension, diabetes, and steroid myopathy) who can be weaned time) leads to tolerance (ie, a perception that sedation is di-
off steroids on substituting hydroxyzine for nonsedating antihista- minished to a tolerable level). Whether performance is really
mines is at least 75%; the remainder are tapered to a reasonable affected needs to be tested after 2 weeks of therapy and not
dose (not >15 mg/d), and cyclosporine is added. Steroid is then ta- after a few hours or even 1 to 2 days. I discontinued first-gen-
pered by 1 mg every week. The most useful double-blind, placebo- eration antihistamines in about 2% of the 10,000 patients
controlled study that could be done is to test the efficiency of hy- treated because of sedation; the remainder had no com-
droxyzine at 50 mg 4 times daily versus 10 mg of cetirizine twice plaints, and I know of no serious automobile accidents.
daily or 5 mg of levocetirizine twice daily as the primary treatment
of severe chronic urticaria.
I think chronic urticaria is pretty easy to treat, even if severe.45
This recommendation would, however, now be considered
A summary of my approach emphasizes the following concepts.
extreme. But why? Sedation! This concern is emphasized by
the manufacturers of nonsedating antihistamines as they relate to 1. First use a single or double dose of any nonsedating anti-
the treatment of allergic rhinitis, and numerous studies attest to the histamine first. If it fails..
sedation associated with first-generation antihistamines,37-41 2. Then use increased doses of hydroxyzine starting at no less
including one likening the adverse effect of 50 mg of diphenhy- than 25 mg 4 times daily and increasing to no more than 50
dramine on driving performance to that seen with alcohol.37 It mg 4 times daily. If successful, nothing else is needed, and
is important to note that most other similar reports examine the the dose can be slowly tapered. If unsuccessful, addition of
effects of a single 50-mg dose of diphenhydramine in healthy in- H2 receptor antagonists, a leukotriene antagonist, or both
dividuals. Nevertheless, not all studies or reviews of these data is often advocated, but the expectation of success is low.
agree.42-44 One study compared 50 mg of diphenhydramine 3 In the future, I will eliminate use of leukotriene antagonists
times daily with 10 mg of cetirizine once daily for 3 consecutive unless new data are forthcoming and will use H2 antago-
days and found diphenhydramine to be more impairing on day 1, nists primarily for control of gastric acid secretion when
as assessed based on sleep latency (sleepiness) and a simulated corticosteroids are used.
assembly-line task, but the difference was gone by day 3.42 3. Steroids can be used for antihistamine failures but no more
This is what we find in patients with chronic urticaria. A second than 10 mg/d or 20 to 25 mg every other day with tapering,
study,44 a double-blind, placebo-controlled study of driving per- as described previously.45 If higher doses are considered for
formance, compared a single dose of diphenhydramine (50 mg) regular use beyond this range, the drug should not be used at
with 5 mg of levocetirizine or placebo given for 4 consecutive all. The problems with corticosteroid use in patients with
days. There was no difference when levocetirizine was compared chronic urticaria are due to inappropriate prescribing prac-
with placebo, but diphenhydramine adversely affected perfor- tices beyond the intrinsic adverse effects of the drug. Before
mance at all time points. Performance on day 4 improved relative the advent of cyclosporine, low-dose corticosteroids were
to that on days 1 or 2 but did not match that seen with levocetir- often the only approach that offered relief and could be
izine or placebo. However, the 95% CI for diphenhydramine at safely used for periods of up to 2 years if the above caveat
day 4 compared with day 2 indicated a change from ‘‘clinically is followed. Yet some of the worst cases of steroid side ef-
relevant driving impairment’’ to ‘‘within acceptance range.’’ Fur- fects we have seen were patients with chronic urticaria being
thermore, a meta-analysis of sedation and performance impair- treated with 30 to 60 mg of prednisone per day for many
ment of diphenhydramine and second-generation antihistamines months (eg, weight gain of 50-120 lbs, steroid myopathy
provided an equivocal answer. To quote from the report by that precluded ambulation, striae from the neck to the knees,
Bender et al43: ‘‘A clear and consistent distinction between sedat- and insulin-dependent diabetes).
ing and non-sedating antihistamines does not exist.’’43 There are, 4. Cyclosporine is an alternative to corticosteroids or can be
however, additional objections when considering antihistamine used when steroids are unsatisfactory (nonresponse or ex-
use in patients with chronic urticaria, as follows: cessive requirement for control). The adult dose is 200 to
300 mg/d. Monitoring blood pressure and blood urea nitro-
1. No sedation studies have ever been done with patients with
gen and creatinine levels every 6 weeks is essential. Blood
chronic urticaria. Their baseline performance is not likely
cyclosporine levels can be checked to assist in dose
to be ‘‘normal.’’ In fact, those who are sleepless because of
adjustment.
pruritus might perform better with approaches that include
5. Methotrexate or intravenous gamma globulin can be re-
first-generation drugs.
served for cyclosporine failures, for which they occasionally
2. Any sedation that might be seen is not comparable with the
work. Other agents listed above are useless; agents such as
side effects of corticosteroids or cyclosporine.
hydroxychloroquine, dapsone, and colchicine can be re-
3. A dose response with increasing antihistamine dosage is served for urticarial vasculitis (about 1% of patients). Sulfa-
not considered, but one can readily demonstrate that severe salazine needs further study with larger numbers of patients,
dermatographism will respond to increasing amounts of including a control group.
716 KAPLAN J ALLERGY CLIN IMMUNOL
MARCH 2009

It is important to note that first-generation antihistamines have 14. Greaves M. Chronic idiopathic urticaria and Helicobacter pylori—not directly
causative but could there be a link. Allergy Clin Immunol Int 2001;13:23-6.
additional functions that contribute to some of the side effects
15. Leznoff A, Sussman G. Syndrome of idiopathic chronic urticaria and angioedema
observed but might also contribute to the therapeutic effects with thyroid autoimmunity: a study of 90 patients. J Allergy Clin Immunol 1989;
observed. Those include antimuscarinic activity, anti–a-adrener- 84:66-71.
gic effects, antiserotonin activity, inhibition of basophil degran- 16. Kikuchi Y, Fann T, Kaplan A. Antithyroid antibodies in chronic urticaria and an-
ulation, and activity against histamine H4 receptors that contribute gioedema. J Allergy Clin Immunol 2003;112:218.
17. Hide M, Francis D, Grattan C, et al. Autoantibodies against the high-affinity IgE
to pruritus and eosinophil chemotaxis.46 Dose adjustment is re- receptor as a cause of histamine release in chronic urticaria. N Engl J Med
quired for children, and particular caution is needed in the elderly. 1993;328:1599-604.
Guidelines have been published for the treatment of chronic 18. Fiebiger E, Maurer D, Holub H, et al. Serum IgG autoantibodies directed against
urticaria (idiopathic or autoimmune).47,48 I reviewed them before 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;96:2606-12.
publication and consider them to be reasonable but not optimal.
19. Kikuchi Y, Kaplan A. Mechanisms of autoimmune activation of basophils in
Use of sedating antihistamines is viewed as extreme, use of any chronic urticaria. J Allergy Clin Immunol 2001;107:1056-62.
corticosteroid chronically is deplored, and the efficacy of cyclo- 20. Gruber B, Baeza M, Marchese M, et al. Prevalence and functional role of anti-IgE
sporine is underestimated. Although these guidelines do not com- autoantibodies in urticarial syndromes. J Invest Dermatol 1988;90:213-7.
ment on the use of thyroid hormone as a treatment for subjects 21. Grattan C, Francis D, Hide M, et al. Detection of circulating histamine releasing
autoantibodies with functional properties of anti-IgE in chronic urticaria. Clin
with euthyroid whose sera test positive for antithyroid antibodies, Exp Allergy 1992;21:695-704.
articles have appeared suggesting that this might be efficacious,49 22. Kikuchi Y, Kaplan A. A role for C5a in augmenting IgG-dependent histamine release
but the studies are uncontrolled and anecdotal, and a more recent from basophils in chronic urticaria. J Allergy Clin Immunol 2002;109:114-8.
guideline does not mention thyroid hormone therapy as an op- 23. Soundararajan S, Kikuchi Y, Joseph K, et al. Functional assessment of pathogenic
tion.30 Certainly there is little to suggest thyroid disease as a cause IgG subclasses in chronic autoimmune urticaria. J Allergy Clin Immunol 2005;115:
815-21.
of chronic urticaria or, for that matter, urticaria as a cause of thy- 24. Greaves M, Plummer V, McLaughlan P, et al. Serum and cell bound IgE in chronic
roid disease. Thus therapy for one disorder is not likely to affect urticaria. Clin Allergy 1974;4:265-71.
the other. I have therefore added thyroid hormone therapy to Table 25. Kern F, Lichtenstein L. Defective histamine release in chronic urticaria. J Clin In-
I as a myth and await a large enough properly controlled study that vest 1976;57:1369-77.
26. Vonakis B, Vasagar K, Gibbons SJ, et al. Basophil FcepsilonRI histamine release
might actually answer the question. parallels expression of Src-homology 2-containing inositol phosphatases in chronic
Before the advent of cyclosporine, steroids were overused (too idiopathic urticaria. J Allergy Clin Immunol 2007;119:441-8.
much for too long) or underused (patients with severe disease 27. Luquin E, Kaplan A, Ferrer M. Increased responsiveness of basophils of patients
were filing for disability who did not need to do so). Currently, with chronic urticaria to sera but hypo-responsiveness to other stimuli. Clin Exp
Allergy 2005;35:456-60.
steroids are frequently used chronically for difficult-to-treat
28. Breneman D. Cetirizine versus hydroxyzine and placebo in chronic idiopathic
patients, often with excessive and variable dosing, sometimes urticaria. Ann Pharmacol 1996;30:1075-9.
with patients self-medicating based on perceived need, and 29. Simons F. Advances in H1-antihistamines. N Engl J Med 2004;351:2203-17.
always with adverse consequences. Now we can do much better, 30. Morgan M, Khan DA. Therapeutic alternatives for chronic urticaria: an evidence-
and new approaches, such as omalizumab, are on the horizon.50,51 based review, part 1. Ann Allergy Asthma Immunol 2008;100:403-12.
31. McGirt L, Vasagar K, Gober L, et al. Successful treatment of recalcitrant chronic
idiopathic urticaria with sulfasalazine. Arch Dermatol 2006;142:1337-42.
32. Cassano N, D’Argento V, Filotico R, et al. Low-dose dapsone in chronic idiopathic
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