Chronic urticaria: background, evaluation, and treatment.

Urticaria and angioedema will affect 15% of the general population during their lifetime, and this remains one of the most vexing cutaneous conditions to evaluate and treat. Patients frequently go from one physician to another in hopes of finding a healthcare provider who can identify the cause and cure the ailment. Physicians treating hives are equally frustrated as they ponder the utility of obtaining a panel of screening laboratory tests that have previously been shown to have a low yield or obtaining selected allergy tests in a group of patients who are no more prone to allergic disease than the general public. This review presents recent information in a clinical context with the aim of aiding the physician in understanding the pathophysiology of urticaria and formulating an intelligent evaluation and treatment plan.

Immune-mediated dermatologic skin disorders in the senior patient.

The baby boomer population, marching on the journey from infancy through the portals of middle life, now enters an uncertain period of life in which the only certainty is the fact that all the biological clocks continue the countdown toward the inevitable failure of a previously well-served immune system. We are faced with the ever-increasing probability that the very immune system that sustained us so well throughout our youth will eventually falter, predisposing us to a vast array of disorders resulting in immune dysregulation. It is in this setting that I will review the dermatologic disorders that may befall the "senior" patient as we journey toward that stage of life where we, as physicians and as an aging population ourselves, encounter a whole new set of medical challenges as we make the turn at the bend in the road. Accordingly, this review will focus on autoimmune bullous disorders, cutaneous manifestations of systemic disease, endocrine disorders, skin cancers, and paraneoplastic syndromes.

Atopic eczema and the allergist.

Several decades ago, the skin was considered to be little more than a simple barrier to dehydration, environmental toxins, and extrinsic bacteria; however, we now recognize that the skin is a complex immune organ that is fully integrated with the immune functions of the bone marrow, lymph nodes, liver, and spleen. Lymphocytes possess a surface glycoprotein, referred to as the cutaneous lymphocyte-associate antigen (CLA), which specifically binds to the skin. The Langerhans cell is the primary antigen processing cell in skin, and they have been shown to traverse to regional lymph nodes where they then have an opportunity to network with lymphocytes that traffic to and from the skin. This paints the picture of the skin as being a very dynamic immune organ that is totally integrated with the other immune organs and effector cells of the body. This discussion will review clinical complexities of atopic dermatitis as a prototype of allergic skin disease.

Allergic skin disease: atopic dermatitis as a prototype.

The skin is the largest immune organ in the body. It is strategically positioned as an interface between a hostile antigenic world and a complex immune system characterized by inflammatory cells, mediators, lymphocytes, and a panoply of cytokines. These cytokines act as subcellar messengers that direct effector lymphocytes, eosinophils, mast cells, and a host of other cells to target the skin in allergic inflammation. Just as asthmas and allergic rhinitis are prototypes of IgE-mediated respiratory disease, atopic dermatitis is the prototype allergic skin disease. This article focuses on an understanding of the pathogenic mechanisms involved in atopic dermatitis and outlines the clinical spectrum of cutaneous allergic disease. Finally, a state-of-the-art approach to treatment is offered to the clinician confronted with the management of this difficult disorder.

Late-phase inflammation: influence on morbidity.

With the prevalence of asthma and other allergic diseases increasing, the question of late-phase inflammatory response, a dynamic inflammatory response to a single exposure to antigen, has come to the forefront as one possible explanation for this increase in morbidity. If this explanation is acceptable, clinicians must examine their methods of management of allergic diseases and shift from crisis intervention with beta-agonists for asthma and first-generation antihistamines or decongestants for rhinitis to disease control with antiinflammatory agents. Topical application of corticosteroids to the upper airways blocks mediator release from the early and late phases after antigen challenges. In addition, recent studies using the skin-blister chamber model have shown that some of the newer, second-generation antihistamines may attenuate the infiltration and activation of eosinophils, neutrophils, and basophils during the late-phase response. Immunotherapy may have a selective effect, targeting inflammatory aspects of the late-phase response. It is clear that corticosteroids, second-generation antihistamines, and immunotherapy play a role in modifying the late-phase response and that each of these therapeutic modalities may operate by a different mechanism.

Urticaria and angioedema: a clinical spectrum.

OBJECTIVE: The objective of this review is to give the reader a global insight into the spectrum of urticaria, focusing on differential diagnosis and pathogenic mechanisms. This review will define the role of the mast cell, explore a possible autoimmune basis for urticaria, and examine the purported role of food allergy in chronic urticaria. Last, the work-up and treatment of urticaria will be discussed in the context of the histologic diagnosis. STUDY SELECTION: The relevant past medical literature will be reviewed in the context of new and novel research into the mechanisms of chronic urticaria. RESULTS: Urticaria can be classified histopathologically into the following three categories: (1) neutrophilic vasculitis, (2) polymorphous perivascular infiltrate, and (3) sparse perivascular lymphocytic infiltrate. Each of the above histologic patterns correlates with a distinct clinical entity and the work-up and treatment of urticaria will be related to each of the above histologic types. CONCLUSIONS: Urticaria and angioedema are frustrating problems for both physicians and their patients; however, the problem can best be approached by considering urticaria as a symptom that may be part of a larger clinical spectrum. The physical examination and medical history remain the two most important pieces of information. The allergist frequently overlooks the value of a skin biopsy as an aid in sorting out the pathophysiology of urticaria and the biopsy results may help to classify urticaria into subgroups which respond differently to treatment.

Practical approaches to the treatment of atopic dermatitis.

Atopic dermatitis is a chronic pruritic cutaneous disease that occurs in 0.5% to 1% of the general population and affects almost 10% of all children. Since this is a disease that is associated with both a very high level of total IgE and a high incidence of allergic respiratory disease, it behooves the practicing allergist to become familiar with the diagnosis and treatment of atopic dermatitis. This following discussion will focus on the identification of major and minor clinical features of the disease and review the spectrum of immune dysregulation that is frequently seen with these patients. The primary focus of this review will be directed at the identification of treatment options available to allergists within the published practice guidelines of the American Academy of Dermatology and practice guidelines that are currently being developed by the American Academy of Allergy & Immunology. Atopic dermatitis is an "itch which rashes and not a rash which itches" and therefore, any patient treatment program should address the multiplicity of potential trigger factors that provoke this itching. These factors include heat, humidity, and perspiration, in addition to the ingestion of certain food allergens and the topical exposure to both dust mite antigen and animal dander. Recent studies suggest that the pathogenesis of allergic disease entails a complex inflammatory process in which the TH2 lymphocyte might play a major role in shifting the immune response in favor of disease. Accordingly, recent immunomodulating treatments, such as interferon gamma and cyclosporine, might offer therapeutic options to the physician beyond the standard topical forms of treatment.(ABSTRACT TRUNCATED AT 250 WORDS)

The effect of immunotherapy on the cutaneous late phase response to antigen.

BACKGROUND: This study used the skin chamber model to evaluate prospectively the effect of immunotherapy (IT) on the cutaneous early and late phase response (LPR) to epicutaneous antigen challenge. METHODS: Nine subjects with allergic rhinitis were studied at three time points: before starting IT, after 3 months of IT, and after 6 months of IT. Skin chamber histamine content was measured hourly for 12 hours, and cell counts performed hourly during hours 6 to 12. An intradermal skin test was placed, and the reaction was measured hourly for 12 hours. Skin biopsy specimens were obtained 8 hours after intradermal placement and evaluated for cellular infiltrate and major basic protein deposition. Serum antigen-specific IgG and IgE levels were measured at each time point to confirm physiologic effect of IT. RESULTS: Six months of IT significantly (p < 0.05) decreased both early and LPR skin test reactivity and skin chamber histamine for hours 1 to 3, 4 to 6, and 9 to 12. Skin chamber LPR cellular influx decreased significantly (p < 0.05) for neutrophils only. Decrease in LPR histamine after 6 months of IT was significantly correlated with both decrease in mononuclear cells (R2 = 0.817, p = 0.002) and decrease in neutrophils (R2 = 0.813, p = 0.009). Also significantly correlated were decrease in LPR skin test reactivity, with percent change in skin chamber mononuclear cells (R2 = 0.800, p = 0.009) and decrease in early skin test reactivity (R2 = 0.675, p = 0.01). Biopsy specimens showed no consistent change in either dermal cellular infiltrate or deposition of major basic protein. CONCLUSION: IT significantly attenuates cutaneous histamine release and skin test reactivity and is accompanied by a decrease in skin chamber LPR neutrophil influx without significantly altering the dermal infiltrate at 8 hours.

Cutaneous late-phase response in food-allergic children and adolescents with atopic dermatitis.

Food hypersensitivities contribute to disease exacerbation in a sub-group of children with atopic dermatitis (AD). It has been shown that only selected foods are capable of causing clinical reactions when ingested, whereas other foods, to which the patient is equally sensitive by skin-prick testing, may be tolerated. The purpose of this study was to examine the cutaneous late-phase response (LPR) to food antigens in food-allergic patients with AD and to determine if the skin reacted differently to 'relevant foods' (foods eliciting positive skin-prick tests and positive oral challenges) than to 'non-relevant foods' (foods eliciting positive skin tests but negative oral challenges). Using blister chambers adfixed to the skin, six children with AD were challenged epicutaneously with foods to which they had previously been shown to be sensitive. Histamine and PGD2 were measured hourly for 10-12 hr in parallel with quantitation of the cellular traffic. There appeared to be no difference in any of the measured parameters between relevant foods and non-relevant foods, and the patterns of the LPR cells and mediators were similar to those previously described with aero-allergens in patients with respiratory allergy. Histamine rose to 13.0 +/- 24 ng/ml (P < 0.005) during the first hours, declined to < 1 ng/ml by the fifth hour, and then rose a second time to 6.72 +/- 3.4 ng/ml (P < 0.05) during the 12th hour. PGD2 rose to an average of 312 pg/ml (P < 0.05) during the first 3 hr followed by a decline to baseline.(ABSTRACT TRUNCATED AT 250 WORDS)

Cutaneous IgE-mediated inflammatory lesion size is inhibited by an H1 antagonist (terfenadine) while mediator release is unaffected in vivo and in vitro.

We are interested in understanding the pathogenesis of the cutaneous IgE-mediated late phase reaction. A double-blind, placebo-controlled, randomized cross-over study with 10 subjects of the effect of the non-sedating antihistamine, terfenadine (Selddane), on the cutaneous reaction to antigen (ragweed or mixed grass) administered intradermally and over denuded blister bases was performed. The activity of terfenadine on anti-IgE-induced mediator release from the skin mast cell, lung mast cell and basophil was also examined in vitro. Terfenadine significantly inhibited the size of the cutaneous reaction at every hour between hours 1 and 9 (hr 9, control 2250 +/- 500 mm2 vs drug 1250 +/- 250 mm2, P < 0.01, n = 10) and showed some inhibitory effect at hours 10-12. While terfenadine blocks histamine release after nasal antigen challenge the release of mediators at skin blister sites was unaffected. The infiltration of leucocytes into the blister supernatant was unaffected by terfenadine although previous studies have shown significant inhibition with another antihistamine, cetirizine. In vitro, terfenadine, like other antihistamines, was found to have inhibitory activity on anti-IgE-induced mediator release at concentrations of 10(-4)-10(-5) M in lung and skin mast cells and basophils. We conclude that the effects of the newer antihistamines on cellular movement into the skin may be diverse, that terfenadine may show organ specificity in vivo and that terfenadine significantly decreases both the early and late gross inflammatory response of the skin to antigen. We cannot, as yet, explain the mechanism(s) by which this occurs.

Effect of H1 receptor blockade on the early and late response to cutaneous allergen challenge.

We investigated whether cutaneous antigen-induced inflammatory cell infiltration and mediator release were modified by H1 receptor antagonists. Three chemically unrelated antihistamines (cetirizine, promethazine and chlorpheniramine) were tested in three groups of allergic subjects in a double-blind, crossover design. Chamber fluids were collected for 12 hr and histamine release, prostaglandin D2 production and cellular infiltration were quantified. Cetirizine significantly decreased late leukocyte migration into antigen-challenged chambers: eosinophils by 68% (P less than .04), basophils by 64% (P less than .04) and neutrophils by 72% (P less than .04), whereas mononuclear cells were not significantly affected. No alteration in the numbers of peripheral blood leukocytes or eosinophils occurred while on cetirizine treatment, suggesting that the decrease in inflammatory cells during the late phase reaction in the skin is not secondary to alterations in the peripheral leukocyte pool. In contrast, neither promethazine nor chlorpheniramine induced any significant alteration in inflammatory cell infiltration. All three antihistamines caused significant inhibition of the immediate reaction to antigen without any significant alteration in late phase reaction cutaneous reactivity. None of the three antihistamines caused any significant alteration in histamine or prostaglandin D2 levels. Thus, cetirizine may be an antihistamine uniquely capable of downregulating the late phase reaction inflammatory cell milieu without altering either early or late mediator production. The mechanisms involved and the clinical relevance of these findings remain to be explored.

Interleukin-6 is released in the cutaneous response to allergen challenge in atopic individuals.

The mechanisms responsible for cutaneous response to antigen are complex. Interleukin-1 (IL-1) and interleukin-6 (IL-6) are proinflammatory cytokines that share many properties. Previous studies with a blister-chamber model have demonstrated IL-1 to be produced in the cutaneous response to antigen. Since IL-2 production by activated T cells and IL-6 production by macrophages are both stimulated by IL-1, we hypothesized that IL-2 and IL-6 may be involved in the cutaneous late-phase response (LPR) to antigen. We examined antigen-challenged sites for IL-2 immunoreactivity (ELISA) but found no difference between antigen- and diluent-challenged skin sites (N = 4). Since IL-2 has been demonstrated to be produced in response to IL-1 and IL-1 activity has been demonstrated to be greatest between hours 10 and 12, we speculated that IL-2 might not be detected until after hour 12. We were unable to demonstrate any increase in IL-2 production, even by extending our studies to 24 hours in two subjects. Antigen-challenged, skin blister-chamber fluids from atopic subjects demonstrated the appearance of IL-6 (ELISA) in pooled samples representing hours 1 1/2, 3 1/2, 5 1/2, and 7, but not at diluent control sites (p less than 0.05; N = 6). IL-6 reached a median peak of 0.66 ng/ml at 3 1/2 hours. Median levels of IL-6 fell to baseline at 8 hours, followed by a second peak of 0.25 ng/ml at hour 10. Three distinct patterns of IL-6 release were noted: early release of IL-6 followed by a sustained slower rise that peaked at hour 9 before declining to baseline levels at 12 hours, early release of IL-6 followed by a fall to baseline levels at hours 7 to 9 with a second smaller peak at hours 9 to 11, and isolated early release of IL-6. Early IL-6 production correlated with late histamine production (R = 0.801; p = 0.06), and late IL-6 production correlated with eosinophil influx (R = 0.813; p = 0.05). The area of the LPR at skin test sites correlated with early IL-6 peak levels (R = 0.977; p = 0.004) and with total early IL-6 production (R = 0.885; p = 0.05), but not with late IL-6 production.(ABSTRACT TRUNCATED AT 400 WORDS)

Prednisone inhibits the appearance of inflammatory mediators and the influx of eosinophils and basophils associated with the cutaneous late-phase response to allergen.

To better define the effect of systemic glucocorticoids on the cutaneous early and late phase response (LPR), nine atopic subjects were examined in a double-blind cross-over study using skin chambers fixed over denuded skin blisters. A challenge was carried out by placing allergen in the chamber for 60 min in subjects who received either a 3-day pretreatment with 60 mg/day of prednisone or placebo. Skin chamber cell counts and inflammatory mediators (histamine, PGD2, and leukotriene C4 (LTC4)) were measured at hourly intervals for 12 h. Prednisone pretreatment did not alter the immediate skin erythema or release of histamine but ablated the late secondary erythema and rise in histamine. The median histamine values during h 10, 11, and 12 in the placebo and prednisone pretreatment visits were 3.73 and 0.22 ng/ml, respectively (p less than or equal to 0.02). Prednisone did not alter PGD2 production; however, LTC4 production was suppressed during the LPR. The cumulative median LTC4 values during h 7, 8, and 9 were 5.6-fold (p less than or equal to 0.05) more after placebo than after prednisone pretreatment. Prednisone altered cellular traffic more dramatically than it did inflammatory mediators. The influx of eosinophils, which peaked during the 9th and 10th h in placebo-treated patients, was completely blocked by prednisone (p less than or equal to 0.02) for every h from 6 through 12. The influx of basophils, which started during the 9th h and peaked during the 12th h in placebo-treated patients, was suppressed at all time points (p less than or equal to 0.02) in prednisone-treated patients. There was no significant alteration in neutrophil transit into the skin chambers induced by prednisone. We suggest that the selective blockade of eosinophil and basophil influx by prednisone and the associated decrease in inflammatory mediators may contribute to the blockade of the clinical expression of the cutaneous LPR.