Antihistamines are effective in treating 45%-60% of patients; the remainder are refractory and achieve little or no benefit even from maximal doses. This is not surprising because chronic spontaneous urticaria should not be viewed as a disorder mediated by histamine secretion any more than rhinitis or asthma are histamine mediated. Clearly histamine is a major contributor, but allergic or allergic-like disorders characterized by a prominent cellular infiltrate (either a late-phase reaction or comparable inflammatory response) often require additional approaches. The frequent requirement for corticosteroids to treat allergic rhinitis or asthma is a testament to that proposition, and the cellular infiltrate that characterizes chronic urticaria28-30 (a non-necrotizing perivascular infiltration of CD4+ lymphocytes, monocytes, neutrophils, eosinophils, and basophils) falls into that category. By contrast, dermatographism is an example of a histamine-mediated urticaria i.e. we know of no other mediator, there is no significant cellular infiltrate, and no evident late-phase reaction once the wheal and flare reaction subsides. It responds to antihistamines but not to steroid.

Responsiveness to antihistamines is dependent on occupancy of H-1 receptors. These drugs are inverse agonists that lock the H-1 receptor into an inactive conformation. Histamine shifts the receptor equilibrium to an active conformation leading to vasodilatation and increased vascular permeability. Thus although antihistamines do not complete with histamine for binding to the H-1 receptor, as would a competitive antagonist, they do compete regarding the receptor conformation equilibrium. Thus, histamine released into the skin can lead to histamine-induced receptor effects even in the face of antihistamine therapy when the antihistamine receptor occupancy, based on the dose taken, is too low. The antihistamine will then be ineffective. That is the reason why the typical once-a-day second generation "non-sedating" antihistamine used to treat allergic rhinitis often fail to be effective in the treatment of chronic urticaria. The fact that innumerable studies of these drugs show that one/day is better than placebo,31-35 although true, is misleading because the benefit accrued, but for the mildest of patients, is too low to be of significance in terms of patient symptom relief or quality of life when the disease is moderate to severe.

This became apparent recently with the study of cold urticaria,36 a predominantly histamine-mediated urticaria, where 4 tablets per day was more effective than 3 tablets per day which was more beneficial than 2 or 1 tablet per day. This comes as no surprise although it was presented as conceptually new. The prior drug of choice was cyprohaptadine,37 a first generation antihistamine that is dispensed as 4 mg tablets and 4-8 tablets/day was required to treat most cold urticarial patients.38 Although chronic spontaneous urticarial has a lesser response to antihistamine and is a far more complex disorder, the same scenario of 4 tablets/day being better than lesser quantities39 was found. This too, is not new. For example, 4 cetirizines/day is equal to 25 mg of hydroxyzine taken 5 tablets/day and the dose of hydroxyzine found to be effective for chronic urticaria patients varied from 100-200 mg/day40 in divided doses. Although not tested in a blinded or placebo controlled fashion, the same increasing responsiveness (in those responsive to antihistamines at all) was noted, and the patient number exceeded 10,000 over 35 years.41 By this analysis, a dose of 6 cetirizines/day would be predicted to be maximal for the most severe, but still responsive patients.

The choice of antihistamine to be used favors the second generation agents which have been studied to a much greater extent than first-generation agents and are more specific for the H-1 receptor and have a better side-effect profilé.42 For example they have less sedation, and less likely to cause dry mouth, do not cross the blood-brain barrier to any appreciable extent (fexofenadine may be the only one that is truly zero), do not effect REM sleep, etc.43 Thus it is assumed that long-term therapy with first generation agents, even if equally effective as second-generation agents for treatment of chronic spontaneous urticaria, would lead to poor performance at work or at school, auto accidents, etc.

Although first generation agents were used successfully for decades before second-generation agents became available, guidelines emphasizing use of second-generation agents as a routine now, seems appropriate.1 However data demonstrating harmful side effects when first-generation agents are used chronically in patients with chronic spontaneous urticaria do not exist i.e. the conclusion may be correct but the reasons given, may be incorrect or at least substantially exaggerated. My opinion, previously published41 is based on extensive experience employing first generation agents with therapeutic success and very few side effects. The issue is that side effects of first-generation agents has not been assessed in chronic urticaria patients, but extrapolated based on what has been observed in normal subjects or those with other allergies. Second, the duration of such studies is relatively short i.e. usually a few days, and often just one or two doses of an antihistamine such as diphenhydramine is reported. But if side-effects are most prominent in the first few days and dissipate over a week, could they not be employed if the duration of therapy varies from 3 months to 2 years? Is there CNS tachyphylaxis over time (which requires crossing the blood-brain barrier)? Is the non-specificity of first-generation antihistamines helpful because of some of the additional receptor-mediated effects? These questions can be answered only by a direct comparison of high-dose therapy in patients with chronic urticaria employing closely related agents such as cetirizine vs. hydroxyzine each of which is known to be efficacious.

High dose antihistaminics (H1 receptor "antagonists") are effective in 45%-50% of patients and no other therapy is required other than tapering the dose as the patient improves. However refractory patients require addition or substitution of alternative agents. These are listed in Table; the left side includes those that are in the literature and are included in most guidelines while the right side lists only 4 (3, not including antihistamines) which are the only ones that I believe to be efficacious in a large percentage of histamine-refractory patients.

The newest and most promising approach to the treatment of refractory patients is the use of Omalizumab. A phase one trial, single blinded, and placebo controlled revealed a success rate in 11 of 12 patients with 7 of them achieving remission.44 The data are shown individually in Figure. A phase 2 trial included 80 patients and revealed the same result with a response rate of over 75% many of whom improved dramatically.45 The former study chose particularly severe patients with chronic autoimmune urticaria. All had IgG anti IgE receptor antibodies and many also had antithyroid antibodies. The latter study employed patients with chronic spontaneous urticaria; the presence or absence of autoimmunity was not assessed. Many other case reports attest to the efficacy of Omalizumab46-49 and one study employed patients without autoimmunity with virtually the same response rate.50 Two aspects of these studies indicate that IgE anti receptor antibody is not necessarily a cause of chronic urticaria, even in a subpopulation of patients. The response in those lacking autoantibodies is unexplained, while the response in those with IgG anti IgE receptor antibody is often so rapid that time sufficient for downregulation of the IgE receptor (as IgE levels plummet) has not transpired. A non-specific, rapidly occurring down-regulation of mast cell secretion is suggested.

Cyclosporine has been shown to be effective in the therapy of severe chronic urticaria unresponsive to other modalities in two double blind, placebo-controlled trials.51,52 Experience has substantiated these optimistic results with a response rate of 75%-80%. The average dose for an adult is 200 mg/day (3-3.5 mg/kg); occasional patients may require 250 mg or even 300 mg but we have never exceeded this dose. After a few quiescent months, it can be tapered at 50 mg/month down to 100 mg/day and then 25 mg/month. Cyclosporine has side effects that require monitoring including effects on blood pressure and renal function. We suggest a blood urea nitrogen, creatinine, urinalysis, and blood pressure check at the start of therapy and every 4-6 weeks thereafter. Thus it is contraindicated in patients with hypertension or renal dysfunction but can be employed in diabetics who have normal renal function where steroids would be contraindicated.

The most common drug used to treat severe chronic spontaneous urticaria is corticosteroid. Unfortunately high doses are commonly employed for protracted periods of time. Although there are no recent studies of efficacy, there is no question that patients respond. However guidelines recommend short term use for acute urticarial episodes, but do not recommend sustained use because of the risk of side effects including weight gain, hypertension, osteoporosis, cutaneous striae, cataracts, and altered fat distribution. There is no question that chronic, high-dose steroids should not be used to treat chronic urticaria. However in precluding sustained use, one potentially effective approach has been eliminated. Prior to the advocacy of cyclosporine or Omalizumab, we recommended alternate day steroid at 20-25 mg every other day which averages 10-12.5 mg each day and more recently, favor daily use starting at 10 mg/day. If a daily approach is employed, a considerable lessening in symptoms often is seen and the dose can be tapered at 1 mg/week. This is an effective, safe approach so that the duration of steroid use averages about 3 months, with the dosage gradually decreasing. When steroids were originally employed for autoimmune diseases such as rheumatoid arthritis, high daily doses were employed, and side effects were considerable. Their utility was questioned because long-term side effects exceeded any benefit. However low-dose steroid treatment was later employed with much greater utility. Even now when methotrexate plus potent biologic agents are employed, steroids have been found to be effective at the 5-10 mg/day range53 and can be used for years with severe side-effects averted even though rheumatoid arthritis is associated with periarticular osteoporosis. There is no reason why we cannot use corticosteroids in a rational way for chronic spontaneous urticaria. At present, Omalizumab is not approved by the FDA in the USA for use in chronic urticaria and the situation worldwide is likely similar. If a histamine refractory patient cannot take cyclosporine, the agent with the greatest response rate is low-dose corticosteroid.

The list on the left side of Table includes H₂ receptor antagonists and leukotriene antagonists. The literature regarding these agents is of dubious quality, involving relatively small numbers of patients, and they are more often prescribed as additives to H-1 receptor antagonists, than used individually. Experience with them has been generally disappointing. If the patient is unresponsive to high-dose H-1 antihistamines, adding these is unlikely to create a responsive individual. Other agents such as dapsone, colchicine, and hydroxychloroquine were originally suggested for urticarial vasculitis, a totally different disorder from chronic spontaneous urticaria, so that reasoning that an effect on one will necessarily lead to a positive response in the other is erroneous. Actual studies of these drugs are limited so that there is little convincing evidence that they work. None of these drugs have been studied in a double bind placebo-controlled fashion in a large enough group of patients with a response rate that exceeds the 30%-35% response to placebo. None of these achieve that level of response. Sulfasalazine is favored by some since it is effective in some arthritics and is a major agent for ulcerative colitis where 5 amino-salicylic acid is the active moiety. The best study of this agent lacks a control group54 and I am reluctant to treat hives with a sulfa compound and an aspirin derivative.