The immunosuppressant drug cyclophosphamide may attenuate the decline in lung function that comes with scleroderma, according to a recent multicenter trial.

The investigation findings suggest that differences in lung function as small as 2%–3% may brighten the quality of life among scleroderma patients.

Loss of vital capacity in scleroderma “shortens life and increases morbidity,” coauthor of the trial, Philip Clements, M.D., of the University of California, Los Angeles, said in an interview. Although lung function did not improve in patients taking cyclophosphamide (Cytoxan) in the trial, it deteriorated less than in those who took placebo, he said.

Some 60%–70% of patients with scleroderma die within 10 years. Most develop interstitial lung disease (ILD). Some 15% of patients will go on to severe lung disease with forced vital capacity (FVC) of less than 50% of normal.

The new trial, known as the Scleroderma Lung Study, is the first large, randomized, controlled, double-blind trial to investigate the influence of cyclophosphamide on lung function in scleroderma patients with ILD. The goal is to see whether cyclophosphamide is effective early in the course of ILD, before the disease does irreversible damage.

Dr. Clements and his colleagues enrolled 156 patients with scleroderma of less than 7 years' duration, who had shortness of breath, the appearance of “ground glass” on lung CT scans, and FVC less than 85% of predicted normal.

The researchers randomized patients to receive either cyclophosphamide or placebo (1 mg/kg per day initially, followed by increases of 25 mg every 4 weeks until the daily dose reached 2 mg/kg per day or was limited by toxicity). On average, the subjects were 48 years old and had had scleroderma for 3 years; 71% were female. Their FVC was 68%, total lung capacity was 70%, and diffusing capacity was 47%.

Of the 80 patients in the cyclophosphamide group, 72 were available for FVC measurements at either 9 or 12 months, as were 70 of 76 patients in the placebo group.

The authors recently presented the 12-month results of their 2-year study during a symposium at the 2005 annual meeting of the American Thoracic Society in San Diego

The results suggest that cyclophosphamide is modestly effective. Decline in FVC was 2.3% better in the cyclophosphamide group than in the placebo group.

The difference in lung function between groups is statistically significant, said Dr. Clements. “But whether it is clinically significant could be argued,” he acknowledged.

Dr. Clements pointed out that cyclophosphamide might not help patients with long-standing, chronic disease. “The caveat here is that we looked only at early disease.” Fibrosis in later disease may be more intractable, he suggested.

Results of the study's secondary outcomes were encouraging. Patients taking cyclophosphamide scored significantly better on the Transition Dyspnea Index, a measure of changes in breathlessness over time.

“It's pretty clear that the people who got Cytoxan had less shortness of breath,” said Dr. Clements. “The people who took placebo got worse. It was a very strong effect.” Skin thickening scores also improved significantly more in patients with diffuse scleroderma who received cyclophosphamide.

Cyclophosphamide appeared to provide significant improvements in subtle, subjective measures of self-rated health—in vitality and peppiness (as scored by the SF-36 scale) as well in health over time. Changes in the Health Assessment Questionnaire disability index scores were significantly better in the cyclophosphamide group at the 12-month mark, although these were considered “minimally clinically significant.”

The news was not all good, however.

Dropouts in both groups were substantial. In the cyclophosphamide group, 26 of 80 patients (33%) stopped taking the drug by 12 months, according to Dr. Clements. In the control group, 21 of 76 patients (28%) stopped taking placebo.

Two side effects—a decreased white blood cell count and blood in the urine—were significantly higher in the cyclophosphamide group (at 19% and 11%) than in the placebo group (0% and 4%).

Patients taking cyclophosphamide had a higher number of serious adverse events (17 vs. 11), but the difference was not statistically significant. There was also no significant difference in the number of patients who developed pneumonia (five vs. one).

The authors attributed many of the adverse events to the natural course of the illness. “Scleroderma is a nasty disease,” said Dr. Clements.

“You have not only potential lung disease, but also gut disease, heart disease, and kidney disease that are part of the scleroderma disease.” With the exception of low white blood cell counts, he said, “The events are not necessarily related to the drug but to the disease.”

Dr. Clements pointed out that some observers believe cyclophosphamide might be more effective than this trial suggests. Many patients with severe disease would simply not enroll in a placebo-controlled trial.

The decline in lung function among untreated patients with severe disease might have been greater than was seen in this trial, and thus would lead to a more pronounced difference between groups, these observers argue.

The best therapy for lung disease in scleroderma remains unknown.

According to Dr. Clements, preliminary results of a trial in the United Kingdom by Athol Wells, M.D., of Royal Brompton Hospital, London, and colleagues show dramatic improvements in lung function among patients receiving intravenous cyclophosphamide for 6 months—a 3% boost, compared with a 3% decline among those receiving placebo. After 6 months, the patients in the U.K. trial are switched to Imuran (azathioprine), a lesser immunosuppressive.

“In that context we have a confirmation that Cytoxan works and that immunosuppression helps,” said Dr. Clements. Nevertheless, he added, less noxious drugs would clearly be preferable.

Cyclophosphamide is “a sledge hammer,” he said. “Whether it is the right drug, we're still not sure.”

The immunosuppressant drug cyclophosphamide may attenuate the decline in lung function that comes with scleroderma, according to a recent multicenter trial.

The investigation findings suggest that differences in lung function as small as 2%–3% may brighten the quality of life among scleroderma patients.

Loss of vital capacity in scleroderma “shortens life and increases morbidity,” coauthor of the trial, Philip Clements, M.D., of the University of California, Los Angeles, said in an interview. Although lung function did not improve in patients taking cyclophosphamide (Cytoxan) in the trial, it deteriorated less than in those who took placebo, he said.

Some 60%–70% of patients with scleroderma die within 10 years. Most develop interstitial lung disease (ILD). Some 15% of patients will go on to severe lung disease with forced vital capacity (FVC) of less than 50% of normal.

The new trial, known as the Scleroderma Lung Study, is the first large, randomized, controlled, double-blind trial to investigate the influence of cyclophosphamide on lung function in scleroderma patients with ILD. The goal is to see whether cyclophosphamide is effective early in the course of ILD, before the disease does irreversible damage.

Dr. Clements and his colleagues enrolled 156 patients with scleroderma of less than 7 years' duration, who had shortness of breath, the appearance of “ground glass” on lung CT scans, and FVC less than 85% of predicted normal.

The researchers randomized patients to receive either cyclophosphamide or placebo (1 mg/kg per day initially, followed by increases of 25 mg every 4 weeks until the daily dose reached 2 mg/kg per day or was limited by toxicity). On average, the subjects were 48 years old and had had scleroderma for 3 years; 71% were female. Their FVC was 68%, total lung capacity was 70%, and diffusing capacity was 47%.

Of the 80 patients in the cyclophosphamide group, 72 were available for FVC measurements at either 9 or 12 months, as were 70 of 76 patients in the placebo group.

The authors recently presented the 12-month results of their 2-year study during a symposium at the 2005 annual meeting of the American Thoracic Society in San Diego

The results suggest that cyclophosphamide is modestly effective. Decline in FVC was 2.3% better in the cyclophosphamide group than in the placebo group.

The difference in lung function between groups is statistically significant, said Dr. Clements. “But whether it is clinically significant could be argued,” he acknowledged.

Dr. Clements pointed out that cyclophosphamide might not help patients with long-standing, chronic disease. “The caveat here is that we looked only at early disease.” Fibrosis in later disease may be more intractable, he suggested.

Results of the study's secondary outcomes were encouraging. Patients taking cyclophosphamide scored significantly better on the Transition Dyspnea Index, a measure of changes in breathlessness over time.

“It's pretty clear that the people who got Cytoxan had less shortness of breath,” said Dr. Clements. “The people who took placebo got worse. It was a very strong effect.” Skin thickening scores also improved significantly more in patients with diffuse scleroderma who received cyclophosphamide.

Cyclophosphamide appeared to provide significant improvements in subtle, subjective measures of self-rated health—in vitality and peppiness (as scored by the SF-36 scale) as well in health over time. Changes in the Health Assessment Questionnaire disability index scores were significantly better in the cyclophosphamide group at the 12-month mark, although these were considered “minimally clinically significant.”

The news was not all good, however.

Dropouts in both groups were substantial. In the cyclophosphamide group, 26 of 80 patients (33%) stopped taking the drug by 12 months, according to Dr. Clements. In the control group, 21 of 76 patients (28%) stopped taking placebo.

Two side effects—a decreased white blood cell count and blood in the urine—were significantly higher in the cyclophosphamide group (at 19% and 11%) than in the placebo group (0% and 4%).

Patients taking cyclophosphamide had a higher number of serious adverse events (17 vs. 11), but the difference was not statistically significant. There was also no significant difference in the number of patients who developed pneumonia (five vs. one).

The authors attributed many of the adverse events to the natural course of the illness. “Scleroderma is a nasty disease,” said Dr. Clements.

“You have not only potential lung disease, but also gut disease, heart disease, and kidney disease that are part of the scleroderma disease.” With the exception of low white blood cell counts, he said, “The events are not necessarily related to the drug but to the disease.”

Dr. Clements pointed out that some observers believe cyclophosphamide might be more effective than this trial suggests. Many patients with severe disease would simply not enroll in a placebo-controlled trial.

The decline in lung function among untreated patients with severe disease might have been greater than was seen in this trial, and thus would lead to a more pronounced difference between groups, these observers argue.

The best therapy for lung disease in scleroderma remains unknown.

According to Dr. Clements, preliminary results of a trial in the United Kingdom by Athol Wells, M.D., of Royal Brompton Hospital, London, and colleagues show dramatic improvements in lung function among patients receiving intravenous cyclophosphamide for 6 months—a 3% boost, compared with a 3% decline among those receiving placebo. After 6 months, the patients in the U.K. trial are switched to Imuran (azathioprine), a lesser immunosuppressive.

“In that context we have a confirmation that Cytoxan works and that immunosuppression helps,” said Dr. Clements. Nevertheless, he added, less noxious drugs would clearly be preferable.

Cyclophosphamide is “a sledge hammer,” he said. “Whether it is the right drug, we're still not sure.”

The immunosuppressant drug cyclophosphamide may attenuate the decline in lung function that comes with scleroderma, according to a recent multicenter trial.

The investigation findings suggest that differences in lung function as small as 2%–3% may brighten the quality of life among scleroderma patients.

Loss of vital capacity in scleroderma “shortens life and increases morbidity,” coauthor of the trial, Philip Clements, M.D., of the University of California, Los Angeles, said in an interview. Although lung function did not improve in patients taking cyclophosphamide (Cytoxan) in the trial, it deteriorated less than in those who took placebo, he said.

Some 60%–70% of patients with scleroderma die within 10 years. Most develop interstitial lung disease (ILD). Some 15% of patients will go on to severe lung disease with forced vital capacity (FVC) of less than 50% of normal.

The new trial, known as the Scleroderma Lung Study, is the first large, randomized, controlled, double-blind trial to investigate the influence of cyclophosphamide on lung function in scleroderma patients with ILD. The goal is to see whether cyclophosphamide is effective early in the course of ILD, before the disease does irreversible damage.

Dr. Clements and his colleagues enrolled 156 patients with scleroderma of less than 7 years' duration, who had shortness of breath, the appearance of “ground glass” on lung CT scans, and FVC less than 85% of predicted normal.

The researchers randomized patients to receive either cyclophosphamide or placebo (1 mg/kg per day initially, followed by increases of 25 mg every 4 weeks until the daily dose reached 2 mg/kg per day or was limited by toxicity). On average, the subjects were 48 years old and had had scleroderma for 3 years; 71% were female. Their FVC was 68%, total lung capacity was 70%, and diffusing capacity was 47%.

Of the 80 patients in the cyclophosphamide group, 72 were available for FVC measurements at either 9 or 12 months, as were 70 of 76 patients in the placebo group.

The authors recently presented the 12-month results of their 2-year study during a symposium at the 2005 annual meeting of the American Thoracic Society in San Diego

The results suggest that cyclophosphamide is modestly effective. Decline in FVC was 2.3% better in the cyclophosphamide group than in the placebo group.

The difference in lung function between groups is statistically significant, said Dr. Clements. “But whether it is clinically significant could be argued,” he acknowledged.

Dr. Clements pointed out that cyclophosphamide might not help patients with long-standing, chronic disease. “The caveat here is that we looked only at early disease.” Fibrosis in later disease may be more intractable, he suggested.

Results of the study's secondary outcomes were encouraging. Patients taking cyclophosphamide scored significantly better on the Transition Dyspnea Index, a measure of changes in breathlessness over time.

“It's pretty clear that the people who got Cytoxan had less shortness of breath,” said Dr. Clements. “The people who took placebo got worse. It was a very strong effect.” Skin thickening scores also improved significantly more in patients with diffuse scleroderma who received cyclophosphamide.

Cyclophosphamide appeared to provide significant improvements in subtle, subjective measures of self-rated health—in vitality and peppiness (as scored by the SF-36 scale) as well in health over time. Changes in the Health Assessment Questionnaire disability index scores were significantly better in the cyclophosphamide group at the 12-month mark, although these were considered “minimally clinically significant.”

The news was not all good, however.

Dropouts in both groups were substantial. In the cyclophosphamide group, 26 of 80 patients (33%) stopped taking the drug by 12 months, according to Dr. Clements. In the control group, 21 of 76 patients (28%) stopped taking placebo.

Two side effects—a decreased white blood cell count and blood in the urine—were significantly higher in the cyclophosphamide group (at 19% and 11%) than in the placebo group (0% and 4%).

Patients taking cyclophosphamide had a higher number of serious adverse events (17 vs. 11), but the difference was not statistically significant. There was also no significant difference in the number of patients who developed pneumonia (five vs. one).

The authors attributed many of the adverse events to the natural course of the illness. “Scleroderma is a nasty disease,” said Dr. Clements.

“You have not only potential lung disease, but also gut disease, heart disease, and kidney disease that are part of the scleroderma disease.” With the exception of low white blood cell counts, he said, “The events are not necessarily related to the drug but to the disease.”

Dr. Clements pointed out that some observers believe cyclophosphamide might be more effective than this trial suggests. Many patients with severe disease would simply not enroll in a placebo-controlled trial.

The decline in lung function among untreated patients with severe disease might have been greater than was seen in this trial, and thus would lead to a more pronounced difference between groups, these observers argue.

The best therapy for lung disease in scleroderma remains unknown.

According to Dr. Clements, preliminary results of a trial in the United Kingdom by Athol Wells, M.D., of Royal Brompton Hospital, London, and colleagues show dramatic improvements in lung function among patients receiving intravenous cyclophosphamide for 6 months—a 3% boost, compared with a 3% decline among those receiving placebo. After 6 months, the patients in the U.K. trial are switched to Imuran (azathioprine), a lesser immunosuppressive.

“In that context we have a confirmation that Cytoxan works and that immunosuppression helps,” said Dr. Clements. Nevertheless, he added, less noxious drugs would clearly be preferable.

Cyclophosphamide is “a sledge hammer,” he said. “Whether it is the right drug, we're still not sure.”

How idiopathic is chronic idiopathic urticaria (CIU)? With the fast pace of scientific and medical discovery, it is anomalous that diseases with no known cause remain. However, despite the fact that CIU is less well understood than many other diseases, recent findings have partially illuminated this condition's etiology. At least 2 subgroups of patients with CIU exist. One group is composed of 30% to 50% of patients with CIU with autoimmune chronic urticaria caused by autoantibodies against either the high-affinity immunoglobulin E (IgE) receptor FcεRI or, less commonly, IgE.1,2 Patients in this subgroup have an increased likelihood of thyroid autoimmunity; thyroid autoantibodies, Hashimoto thyroiditis, and Graves disease are recognized as being associated with CIU.3 Indeed, 27% of patients with CIU have high-titre antithyroglobulin, antithyroid peroxidase autoantibodies, or both, and 19% have abnormal thyroid function.3 However, the remaining 50% to 70% of patients with CIU are truly idiopathic, because there is no known cause for the disease.1 In keeping with the illusive nature of CIU, the prevalence of the disease has not been firmly established.4 Most recent estimates suggest that 15% to 20% of the US population experience at least one episode of urticaria in their lifetime, and up to 3% of the population are diagnosed with CIU.5,6 Interestingly, middle-aged women are more likely to experience the condition than other groups7; also, women are approximately 3 times more likely than men to acquire any autoimmune disease during their lifetime,⁸ supporting the notion that CIU is often an autoimmune disease.

Quality of Life
The impact of a disease extends beyond physical signs and symptoms; health-related quality of life (QOL) also should play a pivotal role in the evaluation of the effect of a disease or its treatment. This parameter is particularly pertinent to CIU, as evidenced by O'Donnell et al9 whose analysis of a disease-specific, purpose-designed questionnaire and the Nottingham Health Profile demonstrated that patients with chronic urticaria experienced considerable disability, handicap, and reduced QOL. Part 1 of the health profile showed that patients were restricted in areas of mobility, sleep, and energy and experienced pain, social isolation, and altered emotional reactions. Part 2 showed that patients experienced problems in relation to work, home management, social life, relationships, sex life, hobbies, and holidays. Interestingly, patients in this survey had almost identical scores for part 1 of the health profile as did patients with coronary artery disease; both groups experienced lack of energy, feelings of social isolation, and emotional upset.9 Perhaps because skin diseases are so visible and thus potentially stigmatizing, dermatology patients can be impacted significantly in terms of QOL; however, the effect of CIU appears to be particularly acute. Using the validated Dermatology Life Quality Index (DLQI), a survey of 170 consecutive patients had results that showed that patients with CIU experienced greater QOL impairment than outpatients with either psoriasis, acne, or vitiligo and experienced a comparable level of impairment to patients with severe atopic dermatitis.10 Because of CIU's devastating effect on health-related QOL and the discomfort of CIU, appropriate treatment selection is crucial. The ideal treatment for CIU would not only rid the patient of the wheals, edema, and pruritus that characterize the condition but also improve QOL. This review outlines the treatment options available, focusing on oral H1 antihistamines, and offers a means of differentiating this class of agent. 

Antihistamines in the Treatment of CIU
It is well established that elevated tissue levels of histamine are found in the skin of patients with different forms of chronic urticaria.11-13 Although more subclasses of histamine receptors have been identified, those initially isolated—H1 and H2—are involved in the cutaneous responses seen in urticaria. Specifically, the binding of histamine to the H1 receptor causes erythema (by vasodilation), edema (by increasing vascular permeability), and itching. The same responses, with the exception of itching, are caused by histamine binding to the H2 receptor. In 30% to 50% of patients diagnosed with CIU, histamine release from mast cells leads to wheal formation because of an autoimmune process. In contrast, patients with CIU without this autoimmune response experience the same effects of mast cell degranulation and subsequent release of histamine by a process yet to be elucidated. The sentinel involvement of histamine in CIU is, therefore, unequivocal; irrespective of etiology, the appropriate use of H1 antihistamines—which stabilize an active conformation of the H1 receptor and thus prevent activation by histamine—remains the basis of treatment.14 However, for patients unresponsive to conventional H1-antihistamine monotherapy, adjunctive treatments often are prescribed including a combination of H1 antihistamines (either 2 different newer-generation agents concurrently or a newer-generation agent plus a first-generation agent at night), H2 antihistamines, tricyclic antidepressants (principally doxepin), antileukotriene therapy, and intermittent pulses of corticosteroids.15 In the event of inadequate symptom control after these therapies have been explored, immunomodulatory agents such as cyclosporine have been used to treat patients refractory to conventional therapy.14 The method of activity for the adjunctive treatments is based on the following approaches: blocking H1 and H2 receptors, blocking nonhistamine mediators of urticaria, and blocking the cellular and inflammatory components of the urticarial reaction. In summary, because H1 antihistamines are first-line therapy for CIU, and for many patients remain the only option available, the selection of the optimal antihistamine is of vital importance. 

Selection of Antihistamines
The first antihistamine was developed in 1937; in the 1940s, phenbenzamine became the first commercially available antihistamine, followed by similar H1-receptor antagonists such as chlorpheniramine, brompheniramine, and diphenhydramine. Despite its relative antiquity, diphenhydramine remains the most widely used antihistamine in the United States.16 These first-generation H1-receptor antagonists, though effective in the treatment of urticaria and allergic rhinitis, were shown to cause undesired side effects for 2 distinct reasons: their lack of selectivity for the H1 receptor and their propensity to cross the blood-brain barrier and affect the central nervous system.17 As a result of their lack of selectivity, older-generation agents cause anticholinergic effects such as dry mouth, headache, and urinary retention.18-20 Furthermore, at supraclinical doses, some antihistamines are toxic¹⁶ and have been shown to cause sinus tachycardia.21 Children have been known to experience severe toxic reactions and even death following overdose of older-generation antihistamines because of the drug's lack of selectivity.22-25 Because older-generation antihistamines can bind to H1 receptors in the brain and histamine in the brain plays a role in central nervous system arousal and alertness, these agents also are associated with sedation and cognitive impairment (eg, impaired sensorimotor coordination and decreases in attention span, memory function, ability to process information, and psychomotor performance16,26,27). The binding of first-generation antihistamines to cerebral H1 receptors has been demonstrated in many studies employing objective psychometric tests and also by the relatively new technique of positron emission tomographic imaging.28-30

Newer-Generation Antihistamines
Newer-generation antihistamines were developed in the early 1980s with the aim of being more specific for the H1 receptor, as well as of overcoming the adverse events observed with older agents. As testament to achieving this goal, allergists agree that newer-generation antihistamines are preferred to first-generation agents because of their more favorable efficacy:safety ratio.16,18 Although there is no such formal consensus among dermatologists and those specifically treating CIU, it is likely the same logic would apply if equivalent efficacy between old and new antihistamines can be established for CIU. This review explores the newer-generation antihistamines available in the United States for the treatment of CIU: fexofenadine, loratadine, desloratadine, and cetirizine. An evidence-based analysis of the efficacy of these agents and an analysis of the therapeutic window of these antihistamines, with particular focus on their sedation and cognitive impairment potential, are emphasized (Table).

Efficacy of Newer-Generation Antihistamines
Numerous randomized double-blind clinical studies have demonstrated the efficacy of fexofenadine,31-34 loratadine,35,36 desloratadine,37,38 and cetirizine39,40 in relieving the symptoms of CIU. Fexofenadine—The safety and efficacy of various doses of fexofenadine at relieving the symptoms of CIU has been established in several large randomized controlled clinical trials. Two similar CIU studies investigated the efficacy of fexofenadine HCl using doses of 20, 60, 120, and 240 mg twice daily (BID). In both studies, doses of 60 mg or more BID were shown to reduce severity of pruritus, number of wheals, and interference with sleep and normal daily activities compared with placebo.33,34 Furthermore, studies in Japanese and Thai patients have indicated that the effectiveness of fexofenadine 60 mg BID is not limited by ethnicity or genotype.41,42 Although many studies have examined some QOL parameters as secondary endpoints as a component of efficacy studies, fexofenadine has been studied using the validated DLQI and Work Productivity and Activity Impairment questionnaires.⁴³ Two identically designed 4-week, multicenter, randomized, double-blind, placebo-controlled, parallel-group trials examined the effects of 60 mg BID on patients aged 12 to 65 years with moderate to severe CIU. Fexofenadine treatment significantly improved overall DLQI score compared with placebo (P≤.0002), and also significantly increased work productivity (P≤.014). In addition, a trend toward increased classroom productivity and significant improvements in 5 of the 6 individual DLQI domains were observed.43 The efficacy and safety of a range of once-daily (QD) doses of fexofenadine have been evaluated in a large, multicenter, double-blind, placebo-controlled, parallel-group, dose-ranging study.31 Adults (N=222) were randomized to receive either fexofenadine HCl 60, 120, 180, or 240 mg QD or placebo QD for 6 weeks. The combined fexofenadine groups showed a significant reduction in mean total symptom score (pruritus score and number of wheals) compared with placebo (P=.0019). The study suggested that 180 mg QD is the optimal dose for the treatment of CIU because this dose alone significantly reduced the number of wheals compared with placebo (P=.0064) and significantly improved mean total symptom score consistently over the 6-week study period (P<.05).31 Supporting the efficacy of this once-daily dose, a recent double-blind placebo-controlled study of fexofenadine HCl 180 mg QD was shown to produce a beneficial effect on urticaria.32
Loratadine—The relative efficacy of loratadine and the first-generation antihistamine hydroxyzine has been established in a large 4-week (optional 12-week) trial comparing the 2 compounds with placebo in 172 patients with CIU. Patients were randomized to receive either: 10 mg loratadine QD and placebo BID; hydroxyzine 3 times daily; or placebo 3 times daily. As measured by all efficacy evaluations (physician and patient evaluations of the effect of treatment at each visit plus patient daily diary cards), loratadine and hydroxyzine were found to be more effective than placebo and clinically comparable to each other.35
In the only placebo-controlled comparative study between 2 newer-generation antihistamines in the treatment of CIU, Guerra et al44 showed that loratadine was more effective than cetirizine in some aspects of controlling the symptoms of CIU. In this double-blind study, 116 patients with CIU were randomly assigned loratadine 10 mg, cetirizine 10 mg, or placebo QD for 28 days. Both active drugs significantly reduced global clinical symptoms (P<.05), but loratadine was more rapid in developing its activity than cetirizine (P<.01 at day 3) and also appeared to be safer when the frequency of treatment-emergent side effects were compared.44
Desloratadine—Desloratadine is the major active metabolite of loratadine, which has been available in the United States since 2002 for the treatment of CIU. The efficacy of the drug has been evaluated in 2 major randomized controlled clinical trials.37,38
Ring et al37 reported that desloratadine exhibited superior efficacy compared with placebo in a multicenter, randomized, double-blind trial of 190 patients with a history of CIU. Patients were assigned to receive either desloratadine 5 mg QD or placebo QD for 6 weeks. The active treatment was superior to placebo at reducing pruritus and overall symptoms after the first dose and throughout the 6-week study.37 Similarly, therapeutic response and global CIU status, as well as QOL measures such as interference with sleep, were improved with desloratadine compared with placebo throughout the study period.37 Using the same dose (5 mg QD), a further 6-week placebo-controlled study of desloratadine indicated the effectiveness of this agent at relieving CIU symptoms.38 Over the study period, the mean total CIU symptom score was significantly improved compared with placebo, as were the individual scores of pruritus, number of hives, and the size of the largest hive. Interference with sleep was reduced and performance of daily activities was improved with desloratadine. These statistically and clinically significant improvements were seen within the first 24 hours of treatment and were sustained throughout the 6-week treatment period.38
Cetirizine—As with loratadine, cetirizine has been shown to be as effective as first-generation hydroxyzine at relieving the symptoms of CIU.40 For example, a 4-week, multicenter, randomized, double-blind, double-dummy trial investigated the efficacy and safety of cetirizine 10 mg QD and hydroxyzine 25 mg 3 times daily compared with placebo in patients with CIU. Patients in the cetirizine and hydroxyzine groups showed significant reductions during weeks 1, 2, 3, and 4 in the number and size of lesions and in the severity of pruritus compared with patients who received placebo. In addition, physician and patient evaluations at the end of week 4 revealed an improvement in urticarial symptoms for the cetirizine and hydroxyzine groups compared with the placebo group.40
All 4 newer-generation H1 antihistamines (fexofenadine, loratadine, desloratadine, and cetirizine) have been shown to be superior to placebo at treating the symptoms of CIU, and both loratadine and cetirizine have been proven to be as effective as first-generation hydroxyzine.35,40 Although no trials have evaluated fexofenadine and desloratadine compared with hydroxyzine, comparisons demonstrating equivalence have been made with their parent compounds (loratadine35 and terfenadine45).
There are few controlled studies in which newer-generation antihistamines have been directly compared, and there is no evidence-based data demonstrating statistical superiority of one second-generation agent over another in the treatment of CIU. For example, although a recent trial compared the efficacy of cetirizine with fexofenadine, the results are weakened by the study design. Patients with CIU were randomized to either cetirizine 10 mg (n=52) or fexofenadine 180 mg (n=45); at 28 days, 51.9% (27) and 4.4% (2) of cetirizine and fexofenadine patients, respectively, were symptom free (P=.00001), while partial improvement was experienced by 36.5% (19) of cetirizine patients and 42.2% (19) of fexofenadine patients.46 However, there was no control group, baseline symptom severity data were not provided, and the authors did not describe how the patients’ symptoms were assessed.46 Therefore, a definitive assessment of the relative efficacy of newer-generation antihistamines cannot be achieved by reviewing published trials alone.Anti-inflammatory Properties
Due to the absence of well-designed placebo-controlled comparisons of newer-generation antihistamines, other properties have been examined to aid treatment comparisons. For example, it has been suggested that some H1-receptor antagonists may achieve anti-inflammatory effects in a clinical context, which could prove advantageous in the treatment of CIU because the disease is characterized by tissue inflammation.47
To investigate the anti-inflammatory activity of fexofenadine, an immunohistochemical evaluation of the agent was undertaken in patients with CIU.48 Twenty patients received fexofenadine HCl 180 mg QD for 4 weeks; the expression of adhesion molecules, mast cell proteases, and proinflammatory cytokines were evaluated before and after treatment, as were the patients’ assessments of urticarial symptoms. After treatment with fexofenadine, significant decreases in the expression of endothelial leukocyte adhesion molecule-1 (P=.02), vascular cell adhesion molecule-1 (P=.04), and tryptase (P=.04) were observed, confirming the hypothesis that fexofenadine has some anti-inflammatory properties.
This study in humans must be put into context with the numerous in vitro, ex vivo, and animal studies that have been conducted in this area. A review of such data suggests that all newer-generation antihistamines inhibit the release or generation of multiple inflammatory mediators, including IL-4, IL-6, IL-8, IL-13, prostaglandin D3, leukotriene C, tryptase, histamine, and the tumor necrosis factor α­induced chemokine regulated upon activation normal T cell expressed and secreted, in addition to eosinophil chemotaxis and adhesion molecules.47 For example, both loratadine and desloratadine (10 μmol/L) significantly inhibited the expression of intercellular adhesion molecule-1 and class II HLA antigen (HLA-DE) in nasal epithelial cells in vitro.49 However, many of these anti-inflammatory effects have only been observed at high drug concentrations.47 For example, an in vitro study of cetirizine assessing the inhibition of IL-5­ dependent eosinophil survival revealed a concentration of 100 μmol/L was required to achieve significant inhibition—much higher than that used clinically.47,50
Clearly, if clinical anti-inflammatory effects necessitate doses higher than those recommended for allergic diseases, drugs that can be used at higher doses without causing unwanted side effects such as sedation and cognitive impairment may be of the greatest utility in the treatment of CIU. This is a particularly pertinent point because patients with CIU may be prescribed much higher doses than recommended to manage symptoms effectively.17
The Therapeutic Window—Because of the lack of rigorously designed clinical trials comparing the efficacy of second-generation antihistamines and the putative anti-inflammatory activities of these agents that may occur at higher-than-recommended dosing levels, the relative safety of agents may direct the selection of the optimum antihistamine for the treatment of CIU. Ideally, an agent would be effective at a wide range of doses without causing unwanted side effects. This is because a wide therapeutic window permits the physician to optimize treatment to the individual. The safety of the newer-generation antihistamines has been assessed in numerous clinical trials, usually as secondary analyses to efficacy parameters; indeed, all of the efficacy studies described here indicated a good safety and tolerability profile for each of the antihistamines.
Clinical trials, however, do not always reflect the reality of clinical practice. Patients taking antihistamines frequently overcomply with their medication,51 particularly if they do not experience immediate relief. Furthermore, as previously mentioned, it is occasionally necessary for dermatologists to prescribe high doses of antihistamines for patients who do not respond to standard-dose first-line therapy.17 Thus, it is valid to examine the safety of the different antihistamines at high doses to obtain a true picture of how drugs may be affecting patients.
Sedation and Impairment—A number of studies using objective psychometric tests have indicated that newer-generation antihistamines generally have better sedative profiles than first-generation agents; however, at higher doses, sedation and impairment become evident.
Two meta-analyses of published data on antihistamines report that newer drugs had lower impairment/nonimpairment ratios than older agents.28,29 That is, proportionally more studies indicated nonimpairment versus impairment with the newer agents compared with their predecessors. However, the same meta-analyses revealed that both loratadine and cetirizine were associated with sedation/impairment in a number of tests, often when they were used at higher-than-recommended doses. In contrast, fexofenadine, even at doses of up to 360 mg, was not associated with any sedation or impairment and had an impairment:nonimpairment ratio of zero.28,29
A study by Mann et al52 corroborates the finding that different newer-generation antihistamines have the potential to cause sedation, with fexofenadine being the least likely of those studied to do so. This prescription-event monitoring study showed that the odds ratios for the incidence of sedation were 0.63 for fexofenadine and 5.53 for cetirizine compared with loratadine.52 Higher-than-recommended doses of loratadine53 and desloratadine54 also can cause sedation.
A recent approach to the question of blood-brain barrier penetration involves the use of positron emission tomography. This technique has been used to study the binding of antihistamines to cerebral H1 receptors. Tashiro et al30 used positron emission tomographic imaging to compare fexofenadine with cetirizine by examining relative H1 receptor occupancy in the brain. Quantitative analysis showed that fexofenadine did not occupy H1 receptors in the cerebral cortex, while cetirizine occupied between 20% to 50% of the H1 receptors, depending on the brain region.30 These findings support evidence from comparative trials that indicate that although cetirizine is less sedating than older antihistamines, it causes more sedation and impairment of performance than other second-generation antihistamines. As a result, the US Food and Drug Administration has classified cetirizine as sedating rather than nonsedating, and the product carries the full sedation precaution.
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Comment
Antihistamines can be used effectively to control the symptoms of CIU; newer-generation antihistamines have been shown to be as effective as their predecessors at relieving patients of their symptoms35,40 and improving their QOL.43 However, there is a paucity of well-designed placebo-controlled comparative clinical trials; the data available indicate that agents are effective and safe, but they do not provide a means to assess which agent is the safest and most effective. Instead, we must examine alternative sources of evidence to help us select the optimum antihistamine for the treatment of CIU.
Evidence from pharmacologic studies indicates that newer agents demonstrate some anti-inflammatory activity, which could provide additional therapeutic benefit. However, these studies have largely been limited to in vitro tests and animal modeling and do not yet provide the means to differentiate agents.
Newer-generation antihistamines vary in their propensity to cause sedation and cognitive impairment, with cetirizine representing the most impairing of the class, as recognized by its sedating description by the US Food and Drug Administration. At recommended doses, fexofenadine, loratadine, and desloratadine have not been found to cause significant impairment and are labeled as nonsedating by the US Food and Drug Administration. However, patients with urticaria are known to take above-recommended doses51 and physicians occasionally prescribe off-label doses to achieve the desired level of symptom control. The risk of sedation caused by these 2 factors should be considered in practice when selecting an antihistamine.
Sedation and impairment affect QOL and manifest as decreased classroom learning ability and decreased work productivity.28 Furthermore, it has been suggested that cerebral H1-receptor blockade is associated with falls in the elderly and cognitive slowing, and is a contributing factor in traffic accidents.27
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Conclusion
In controlled clinical studies of CIU, the second-generation H1-antihistamines have been proven to be clinically comparable to the most potent of the first-generation antihistamines, such as hydroxyzine. Clinical studies comparing these agents are few and have shown no statistically significant differences in efficacy.
If sedation and cognitive impairment are to be considered relevant to the choice of therapy for CIU because of their impact on QOL and safety, then newer-generation agents should be selected over older-generation antihistamines.37,40 Furthermore, of the new agents, those that are labeled nonsedating at recommended doses (fexofenadine, loratadine, and desloratadine) should be selected over cetirizine. However, in cases where the physician judges that a higher-than-recommended dose should be prescribed or when the patient is likely to take a higher dose, fexofenadine should be considered. In addition to its proven efficacy in treating the symptoms of CIU,31,33,34 fexofenadine is the only antihistamine that is nonsedating, even at doses 2 to 4 times above the recommended levels.

How idiopathic is chronic idiopathic urticaria (CIU)? With the fast pace of scientific and medical discovery, it is anomalous that diseases with no known cause remain. However, despite the fact that CIU is less well understood than many other diseases, recent findings have partially illuminated this condition's etiology. At least 2 subgroups of patients with CIU exist. One group is composed of 30% to 50% of patients with CIU with autoimmune chronic urticaria caused by autoantibodies against either the high-affinity immunoglobulin E (IgE) receptor FcεRI or, less commonly, IgE.1,2 Patients in this subgroup have an increased likelihood of thyroid autoimmunity; thyroid autoantibodies, Hashimoto thyroiditis, and Graves disease are recognized as being associated with CIU.3 Indeed, 27% of patients with CIU have high-titre antithyroglobulin, antithyroid peroxidase autoantibodies, or both, and 19% have abnormal thyroid function.3 However, the remaining 50% to 70% of patients with CIU are truly idiopathic, because there is no known cause for the disease.1 In keeping with the illusive nature of CIU, the prevalence of the disease has not been firmly established.4 Most recent estimates suggest that 15% to 20% of the US population experience at least one episode of urticaria in their lifetime, and up to 3% of the population are diagnosed with CIU.5,6 Interestingly, middle-aged women are more likely to experience the condition than other groups7; also, women are approximately 3 times more likely than men to acquire any autoimmune disease during their lifetime,⁸ supporting the notion that CIU is often an autoimmune disease.

Quality of Life
The impact of a disease extends beyond physical signs and symptoms; health-related quality of life (QOL) also should play a pivotal role in the evaluation of the effect of a disease or its treatment. This parameter is particularly pertinent to CIU, as evidenced by O'Donnell et al9 whose analysis of a disease-specific, purpose-designed questionnaire and the Nottingham Health Profile demonstrated that patients with chronic urticaria experienced considerable disability, handicap, and reduced QOL. Part 1 of the health profile showed that patients were restricted in areas of mobility, sleep, and energy and experienced pain, social isolation, and altered emotional reactions. Part 2 showed that patients experienced problems in relation to work, home management, social life, relationships, sex life, hobbies, and holidays. Interestingly, patients in this survey had almost identical scores for part 1 of the health profile as did patients with coronary artery disease; both groups experienced lack of energy, feelings of social isolation, and emotional upset.9 Perhaps because skin diseases are so visible and thus potentially stigmatizing, dermatology patients can be impacted significantly in terms of QOL; however, the effect of CIU appears to be particularly acute. Using the validated Dermatology Life Quality Index (DLQI), a survey of 170 consecutive patients had results that showed that patients with CIU experienced greater QOL impairment than outpatients with either psoriasis, acne, or vitiligo and experienced a comparable level of impairment to patients with severe atopic dermatitis.10 Because of CIU's devastating effect on health-related QOL and the discomfort of CIU, appropriate treatment selection is crucial. The ideal treatment for CIU would not only rid the patient of the wheals, edema, and pruritus that characterize the condition but also improve QOL. This review outlines the treatment options available, focusing on oral H1 antihistamines, and offers a means of differentiating this class of agent. 

Antihistamines in the Treatment of CIU
It is well established that elevated tissue levels of histamine are found in the skin of patients with different forms of chronic urticaria.11-13 Although more subclasses of histamine receptors have been identified, those initially isolated—H1 and H2—are involved in the cutaneous responses seen in urticaria. Specifically, the binding of histamine to the H1 receptor causes erythema (by vasodilation), edema (by increasing vascular permeability), and itching. The same responses, with the exception of itching, are caused by histamine binding to the H2 receptor. In 30% to 50% of patients diagnosed with CIU, histamine release from mast cells leads to wheal formation because of an autoimmune process. In contrast, patients with CIU without this autoimmune response experience the same effects of mast cell degranulation and subsequent release of histamine by a process yet to be elucidated. The sentinel involvement of histamine in CIU is, therefore, unequivocal; irrespective of etiology, the appropriate use of H1 antihistamines—which stabilize an active conformation of the H1 receptor and thus prevent activation by histamine—remains the basis of treatment.14 However, for patients unresponsive to conventional H1-antihistamine monotherapy, adjunctive treatments often are prescribed including a combination of H1 antihistamines (either 2 different newer-generation agents concurrently or a newer-generation agent plus a first-generation agent at night), H2 antihistamines, tricyclic antidepressants (principally doxepin), antileukotriene therapy, and intermittent pulses of corticosteroids.15 In the event of inadequate symptom control after these therapies have been explored, immunomodulatory agents such as cyclosporine have been used to treat patients refractory to conventional therapy.14 The method of activity for the adjunctive treatments is based on the following approaches: blocking H1 and H2 receptors, blocking nonhistamine mediators of urticaria, and blocking the cellular and inflammatory components of the urticarial reaction. In summary, because H1 antihistamines are first-line therapy for CIU, and for many patients remain the only option available, the selection of the optimal antihistamine is of vital importance. 

Selection of Antihistamines
The first antihistamine was developed in 1937; in the 1940s, phenbenzamine became the first commercially available antihistamine, followed by similar H1-receptor antagonists such as chlorpheniramine, brompheniramine, and diphenhydramine. Despite its relative antiquity, diphenhydramine remains the most widely used antihistamine in the United States.16 These first-generation H1-receptor antagonists, though effective in the treatment of urticaria and allergic rhinitis, were shown to cause undesired side effects for 2 distinct reasons: their lack of selectivity for the H1 receptor and their propensity to cross the blood-brain barrier and affect the central nervous system.17 As a result of their lack of selectivity, older-generation agents cause anticholinergic effects such as dry mouth, headache, and urinary retention.18-20 Furthermore, at supraclinical doses, some antihistamines are toxic¹⁶ and have been shown to cause sinus tachycardia.21 Children have been known to experience severe toxic reactions and even death following overdose of older-generation antihistamines because of the drug's lack of selectivity.22-25 Because older-generation antihistamines can bind to H1 receptors in the brain and histamine in the brain plays a role in central nervous system arousal and alertness, these agents also are associated with sedation and cognitive impairment (eg, impaired sensorimotor coordination and decreases in attention span, memory function, ability to process information, and psychomotor performance16,26,27). The binding of first-generation antihistamines to cerebral H1 receptors has been demonstrated in many studies employing objective psychometric tests and also by the relatively new technique of positron emission tomographic imaging.28-30

Newer-Generation Antihistamines
Newer-generation antihistamines were developed in the early 1980s with the aim of being more specific for the H1 receptor, as well as of overcoming the adverse events observed with older agents. As testament to achieving this goal, allergists agree that newer-generation antihistamines are preferred to first-generation agents because of their more favorable efficacy:safety ratio.16,18 Although there is no such formal consensus among dermatologists and those specifically treating CIU, it is likely the same logic would apply if equivalent efficacy between old and new antihistamines can be established for CIU. This review explores the newer-generation antihistamines available in the United States for the treatment of CIU: fexofenadine, loratadine, desloratadine, and cetirizine. An evidence-based analysis of the efficacy of these agents and an analysis of the therapeutic window of these antihistamines, with particular focus on their sedation and cognitive impairment potential, are emphasized (Table).

Efficacy of Newer-Generation Antihistamines
Numerous randomized double-blind clinical studies have demonstrated the efficacy of fexofenadine,31-34 loratadine,35,36 desloratadine,37,38 and cetirizine39,40 in relieving the symptoms of CIU. Fexofenadine—The safety and efficacy of various doses of fexofenadine at relieving the symptoms of CIU has been established in several large randomized controlled clinical trials. Two similar CIU studies investigated the efficacy of fexofenadine HCl using doses of 20, 60, 120, and 240 mg twice daily (BID). In both studies, doses of 60 mg or more BID were shown to reduce severity of pruritus, number of wheals, and interference with sleep and normal daily activities compared with placebo.33,34 Furthermore, studies in Japanese and Thai patients have indicated that the effectiveness of fexofenadine 60 mg BID is not limited by ethnicity or genotype.41,42 Although many studies have examined some QOL parameters as secondary endpoints as a component of efficacy studies, fexofenadine has been studied using the validated DLQI and Work Productivity and Activity Impairment questionnaires.⁴³ Two identically designed 4-week, multicenter, randomized, double-blind, placebo-controlled, parallel-group trials examined the effects of 60 mg BID on patients aged 12 to 65 years with moderate to severe CIU. Fexofenadine treatment significantly improved overall DLQI score compared with placebo (P≤.0002), and also significantly increased work productivity (P≤.014). In addition, a trend toward increased classroom productivity and significant improvements in 5 of the 6 individual DLQI domains were observed.43 The efficacy and safety of a range of once-daily (QD) doses of fexofenadine have been evaluated in a large, multicenter, double-blind, placebo-controlled, parallel-group, dose-ranging study.31 Adults (N=222) were randomized to receive either fexofenadine HCl 60, 120, 180, or 240 mg QD or placebo QD for 6 weeks. The combined fexofenadine groups showed a significant reduction in mean total symptom score (pruritus score and number of wheals) compared with placebo (P=.0019). The study suggested that 180 mg QD is the optimal dose for the treatment of CIU because this dose alone significantly reduced the number of wheals compared with placebo (P=.0064) and significantly improved mean total symptom score consistently over the 6-week study period (P<.05).31 Supporting the efficacy of this once-daily dose, a recent double-blind placebo-controlled study of fexofenadine HCl 180 mg QD was shown to produce a beneficial effect on urticaria.32
Loratadine—The relative efficacy of loratadine and the first-generation antihistamine hydroxyzine has been established in a large 4-week (optional 12-week) trial comparing the 2 compounds with placebo in 172 patients with CIU. Patients were randomized to receive either: 10 mg loratadine QD and placebo BID; hydroxyzine 3 times daily; or placebo 3 times daily. As measured by all efficacy evaluations (physician and patient evaluations of the effect of treatment at each visit plus patient daily diary cards), loratadine and hydroxyzine were found to be more effective than placebo and clinically comparable to each other.35
In the only placebo-controlled comparative study between 2 newer-generation antihistamines in the treatment of CIU, Guerra et al44 showed that loratadine was more effective than cetirizine in some aspects of controlling the symptoms of CIU. In this double-blind study, 116 patients with CIU were randomly assigned loratadine 10 mg, cetirizine 10 mg, or placebo QD for 28 days. Both active drugs significantly reduced global clinical symptoms (P<.05), but loratadine was more rapid in developing its activity than cetirizine (P<.01 at day 3) and also appeared to be safer when the frequency of treatment-emergent side effects were compared.44
Desloratadine—Desloratadine is the major active metabolite of loratadine, which has been available in the United States since 2002 for the treatment of CIU. The efficacy of the drug has been evaluated in 2 major randomized controlled clinical trials.37,38
Ring et al37 reported that desloratadine exhibited superior efficacy compared with placebo in a multicenter, randomized, double-blind trial of 190 patients with a history of CIU. Patients were assigned to receive either desloratadine 5 mg QD or placebo QD for 6 weeks. The active treatment was superior to placebo at reducing pruritus and overall symptoms after the first dose and throughout the 6-week study.37 Similarly, therapeutic response and global CIU status, as well as QOL measures such as interference with sleep, were improved with desloratadine compared with placebo throughout the study period.37 Using the same dose (5 mg QD), a further 6-week placebo-controlled study of desloratadine indicated the effectiveness of this agent at relieving CIU symptoms.38 Over the study period, the mean total CIU symptom score was significantly improved compared with placebo, as were the individual scores of pruritus, number of hives, and the size of the largest hive. Interference with sleep was reduced and performance of daily activities was improved with desloratadine. These statistically and clinically significant improvements were seen within the first 24 hours of treatment and were sustained throughout the 6-week treatment period.38
Cetirizine—As with loratadine, cetirizine has been shown to be as effective as first-generation hydroxyzine at relieving the symptoms of CIU.40 For example, a 4-week, multicenter, randomized, double-blind, double-dummy trial investigated the efficacy and safety of cetirizine 10 mg QD and hydroxyzine 25 mg 3 times daily compared with placebo in patients with CIU. Patients in the cetirizine and hydroxyzine groups showed significant reductions during weeks 1, 2, 3, and 4 in the number and size of lesions and in the severity of pruritus compared with patients who received placebo. In addition, physician and patient evaluations at the end of week 4 revealed an improvement in urticarial symptoms for the cetirizine and hydroxyzine groups compared with the placebo group.40
All 4 newer-generation H1 antihistamines (fexofenadine, loratadine, desloratadine, and cetirizine) have been shown to be superior to placebo at treating the symptoms of CIU, and both loratadine and cetirizine have been proven to be as effective as first-generation hydroxyzine.35,40 Although no trials have evaluated fexofenadine and desloratadine compared with hydroxyzine, comparisons demonstrating equivalence have been made with their parent compounds (loratadine35 and terfenadine45).
There are few controlled studies in which newer-generation antihistamines have been directly compared, and there is no evidence-based data demonstrating statistical superiority of one second-generation agent over another in the treatment of CIU. For example, although a recent trial compared the efficacy of cetirizine with fexofenadine, the results are weakened by the study design. Patients with CIU were randomized to either cetirizine 10 mg (n=52) or fexofenadine 180 mg (n=45); at 28 days, 51.9% (27) and 4.4% (2) of cetirizine and fexofenadine patients, respectively, were symptom free (P=.00001), while partial improvement was experienced by 36.5% (19) of cetirizine patients and 42.2% (19) of fexofenadine patients.46 However, there was no control group, baseline symptom severity data were not provided, and the authors did not describe how the patients’ symptoms were assessed.46 Therefore, a definitive assessment of the relative efficacy of newer-generation antihistamines cannot be achieved by reviewing published trials alone.Anti-inflammatory Properties
Due to the absence of well-designed placebo-controlled comparisons of newer-generation antihistamines, other properties have been examined to aid treatment comparisons. For example, it has been suggested that some H1-receptor antagonists may achieve anti-inflammatory effects in a clinical context, which could prove advantageous in the treatment of CIU because the disease is characterized by tissue inflammation.47
To investigate the anti-inflammatory activity of fexofenadine, an immunohistochemical evaluation of the agent was undertaken in patients with CIU.48 Twenty patients received fexofenadine HCl 180 mg QD for 4 weeks; the expression of adhesion molecules, mast cell proteases, and proinflammatory cytokines were evaluated before and after treatment, as were the patients’ assessments of urticarial symptoms. After treatment with fexofenadine, significant decreases in the expression of endothelial leukocyte adhesion molecule-1 (P=.02), vascular cell adhesion molecule-1 (P=.04), and tryptase (P=.04) were observed, confirming the hypothesis that fexofenadine has some anti-inflammatory properties.
This study in humans must be put into context with the numerous in vitro, ex vivo, and animal studies that have been conducted in this area. A review of such data suggests that all newer-generation antihistamines inhibit the release or generation of multiple inflammatory mediators, including IL-4, IL-6, IL-8, IL-13, prostaglandin D3, leukotriene C, tryptase, histamine, and the tumor necrosis factor α­induced chemokine regulated upon activation normal T cell expressed and secreted, in addition to eosinophil chemotaxis and adhesion molecules.47 For example, both loratadine and desloratadine (10 μmol/L) significantly inhibited the expression of intercellular adhesion molecule-1 and class II HLA antigen (HLA-DE) in nasal epithelial cells in vitro.49 However, many of these anti-inflammatory effects have only been observed at high drug concentrations.47 For example, an in vitro study of cetirizine assessing the inhibition of IL-5­ dependent eosinophil survival revealed a concentration of 100 μmol/L was required to achieve significant inhibition—much higher than that used clinically.47,50
Clearly, if clinical anti-inflammatory effects necessitate doses higher than those recommended for allergic diseases, drugs that can be used at higher doses without causing unwanted side effects such as sedation and cognitive impairment may be of the greatest utility in the treatment of CIU. This is a particularly pertinent point because patients with CIU may be prescribed much higher doses than recommended to manage symptoms effectively.17
The Therapeutic Window—Because of the lack of rigorously designed clinical trials comparing the efficacy of second-generation antihistamines and the putative anti-inflammatory activities of these agents that may occur at higher-than-recommended dosing levels, the relative safety of agents may direct the selection of the optimum antihistamine for the treatment of CIU. Ideally, an agent would be effective at a wide range of doses without causing unwanted side effects. This is because a wide therapeutic window permits the physician to optimize treatment to the individual. The safety of the newer-generation antihistamines has been assessed in numerous clinical trials, usually as secondary analyses to efficacy parameters; indeed, all of the efficacy studies described here indicated a good safety and tolerability profile for each of the antihistamines.
Clinical trials, however, do not always reflect the reality of clinical practice. Patients taking antihistamines frequently overcomply with their medication,51 particularly if they do not experience immediate relief. Furthermore, as previously mentioned, it is occasionally necessary for dermatologists to prescribe high doses of antihistamines for patients who do not respond to standard-dose first-line therapy.17 Thus, it is valid to examine the safety of the different antihistamines at high doses to obtain a true picture of how drugs may be affecting patients.
Sedation and Impairment—A number of studies using objective psychometric tests have indicated that newer-generation antihistamines generally have better sedative profiles than first-generation agents; however, at higher doses, sedation and impairment become evident.
Two meta-analyses of published data on antihistamines report that newer drugs had lower impairment/nonimpairment ratios than older agents.28,29 That is, proportionally more studies indicated nonimpairment versus impairment with the newer agents compared with their predecessors. However, the same meta-analyses revealed that both loratadine and cetirizine were associated with sedation/impairment in a number of tests, often when they were used at higher-than-recommended doses. In contrast, fexofenadine, even at doses of up to 360 mg, was not associated with any sedation or impairment and had an impairment:nonimpairment ratio of zero.28,29
A study by Mann et al52 corroborates the finding that different newer-generation antihistamines have the potential to cause sedation, with fexofenadine being the least likely of those studied to do so. This prescription-event monitoring study showed that the odds ratios for the incidence of sedation were 0.63 for fexofenadine and 5.53 for cetirizine compared with loratadine.52 Higher-than-recommended doses of loratadine53 and desloratadine54 also can cause sedation.
A recent approach to the question of blood-brain barrier penetration involves the use of positron emission tomography. This technique has been used to study the binding of antihistamines to cerebral H1 receptors. Tashiro et al30 used positron emission tomographic imaging to compare fexofenadine with cetirizine by examining relative H1 receptor occupancy in the brain. Quantitative analysis showed that fexofenadine did not occupy H1 receptors in the cerebral cortex, while cetirizine occupied between 20% to 50% of the H1 receptors, depending on the brain region.30 These findings support evidence from comparative trials that indicate that although cetirizine is less sedating than older antihistamines, it causes more sedation and impairment of performance than other second-generation antihistamines. As a result, the US Food and Drug Administration has classified cetirizine as sedating rather than nonsedating, and the product carries the full sedation precaution.
back to top
Comment
Antihistamines can be used effectively to control the symptoms of CIU; newer-generation antihistamines have been shown to be as effective as their predecessors at relieving patients of their symptoms35,40 and improving their QOL.43 However, there is a paucity of well-designed placebo-controlled comparative clinical trials; the data available indicate that agents are effective and safe, but they do not provide a means to assess which agent is the safest and most effective. Instead, we must examine alternative sources of evidence to help us select the optimum antihistamine for the treatment of CIU.
Evidence from pharmacologic studies indicates that newer agents demonstrate some anti-inflammatory activity, which could provide additional therapeutic benefit. However, these studies have largely been limited to in vitro tests and animal modeling and do not yet provide the means to differentiate agents.
Newer-generation antihistamines vary in their propensity to cause sedation and cognitive impairment, with cetirizine representing the most impairing of the class, as recognized by its sedating description by the US Food and Drug Administration. At recommended doses, fexofenadine, loratadine, and desloratadine have not been found to cause significant impairment and are labeled as nonsedating by the US Food and Drug Administration. However, patients with urticaria are known to take above-recommended doses51 and physicians occasionally prescribe off-label doses to achieve the desired level of symptom control. The risk of sedation caused by these 2 factors should be considered in practice when selecting an antihistamine.
Sedation and impairment affect QOL and manifest as decreased classroom learning ability and decreased work productivity.28 Furthermore, it has been suggested that cerebral H1-receptor blockade is associated with falls in the elderly and cognitive slowing, and is a contributing factor in traffic accidents.27
back to top
Conclusion
In controlled clinical studies of CIU, the second-generation H1-antihistamines have been proven to be clinically comparable to the most potent of the first-generation antihistamines, such as hydroxyzine. Clinical studies comparing these agents are few and have shown no statistically significant differences in efficacy.
If sedation and cognitive impairment are to be considered relevant to the choice of therapy for CIU because of their impact on QOL and safety, then newer-generation agents should be selected over older-generation antihistamines.37,40 Furthermore, of the new agents, those that are labeled nonsedating at recommended doses (fexofenadine, loratadine, and desloratadine) should be selected over cetirizine. However, in cases where the physician judges that a higher-than-recommended dose should be prescribed or when the patient is likely to take a higher dose, fexofenadine should be considered. In addition to its proven efficacy in treating the symptoms of CIU,31,33,34 fexofenadine is the only antihistamine that is nonsedating, even at doses 2 to 4 times above the recommended levels.

How idiopathic is chronic idiopathic urticaria (CIU)? With the fast pace of scientific and medical discovery, it is anomalous that diseases with no known cause remain. However, despite the fact that CIU is less well understood than many other diseases, recent findings have partially illuminated this condition's etiology. At least 2 subgroups of patients with CIU exist. One group is composed of 30% to 50% of patients with CIU with autoimmune chronic urticaria caused by autoantibodies against either the high-affinity immunoglobulin E (IgE) receptor FcεRI or, less commonly, IgE.1,2 Patients in this subgroup have an increased likelihood of thyroid autoimmunity; thyroid autoantibodies, Hashimoto thyroiditis, and Graves disease are recognized as being associated with CIU.3 Indeed, 27% of patients with CIU have high-titre antithyroglobulin, antithyroid peroxidase autoantibodies, or both, and 19% have abnormal thyroid function.3 However, the remaining 50% to 70% of patients with CIU are truly idiopathic, because there is no known cause for the disease.1 In keeping with the illusive nature of CIU, the prevalence of the disease has not been firmly established.4 Most recent estimates suggest that 15% to 20% of the US population experience at least one episode of urticaria in their lifetime, and up to 3% of the population are diagnosed with CIU.5,6 Interestingly, middle-aged women are more likely to experience the condition than other groups7; also, women are approximately 3 times more likely than men to acquire any autoimmune disease during their lifetime,⁸ supporting the notion that CIU is often an autoimmune disease.

Quality of Life
The impact of a disease extends beyond physical signs and symptoms; health-related quality of life (QOL) also should play a pivotal role in the evaluation of the effect of a disease or its treatment. This parameter is particularly pertinent to CIU, as evidenced by O'Donnell et al9 whose analysis of a disease-specific, purpose-designed questionnaire and the Nottingham Health Profile demonstrated that patients with chronic urticaria experienced considerable disability, handicap, and reduced QOL. Part 1 of the health profile showed that patients were restricted in areas of mobility, sleep, and energy and experienced pain, social isolation, and altered emotional reactions. Part 2 showed that patients experienced problems in relation to work, home management, social life, relationships, sex life, hobbies, and holidays. Interestingly, patients in this survey had almost identical scores for part 1 of the health profile as did patients with coronary artery disease; both groups experienced lack of energy, feelings of social isolation, and emotional upset.9 Perhaps because skin diseases are so visible and thus potentially stigmatizing, dermatology patients can be impacted significantly in terms of QOL; however, the effect of CIU appears to be particularly acute. Using the validated Dermatology Life Quality Index (DLQI), a survey of 170 consecutive patients had results that showed that patients with CIU experienced greater QOL impairment than outpatients with either psoriasis, acne, or vitiligo and experienced a comparable level of impairment to patients with severe atopic dermatitis.10 Because of CIU's devastating effect on health-related QOL and the discomfort of CIU, appropriate treatment selection is crucial. The ideal treatment for CIU would not only rid the patient of the wheals, edema, and pruritus that characterize the condition but also improve QOL. This review outlines the treatment options available, focusing on oral H1 antihistamines, and offers a means of differentiating this class of agent. 

Antihistamines in the Treatment of CIU
It is well established that elevated tissue levels of histamine are found in the skin of patients with different forms of chronic urticaria.11-13 Although more subclasses of histamine receptors have been identified, those initially isolated—H1 and H2—are involved in the cutaneous responses seen in urticaria. Specifically, the binding of histamine to the H1 receptor causes erythema (by vasodilation), edema (by increasing vascular permeability), and itching. The same responses, with the exception of itching, are caused by histamine binding to the H2 receptor. In 30% to 50% of patients diagnosed with CIU, histamine release from mast cells leads to wheal formation because of an autoimmune process. In contrast, patients with CIU without this autoimmune response experience the same effects of mast cell degranulation and subsequent release of histamine by a process yet to be elucidated. The sentinel involvement of histamine in CIU is, therefore, unequivocal; irrespective of etiology, the appropriate use of H1 antihistamines—which stabilize an active conformation of the H1 receptor and thus prevent activation by histamine—remains the basis of treatment.14 However, for patients unresponsive to conventional H1-antihistamine monotherapy, adjunctive treatments often are prescribed including a combination of H1 antihistamines (either 2 different newer-generation agents concurrently or a newer-generation agent plus a first-generation agent at night), H2 antihistamines, tricyclic antidepressants (principally doxepin), antileukotriene therapy, and intermittent pulses of corticosteroids.15 In the event of inadequate symptom control after these therapies have been explored, immunomodulatory agents such as cyclosporine have been used to treat patients refractory to conventional therapy.14 The method of activity for the adjunctive treatments is based on the following approaches: blocking H1 and H2 receptors, blocking nonhistamine mediators of urticaria, and blocking the cellular and inflammatory components of the urticarial reaction. In summary, because H1 antihistamines are first-line therapy for CIU, and for many patients remain the only option available, the selection of the optimal antihistamine is of vital importance. 

Selection of Antihistamines
The first antihistamine was developed in 1937; in the 1940s, phenbenzamine became the first commercially available antihistamine, followed by similar H1-receptor antagonists such as chlorpheniramine, brompheniramine, and diphenhydramine. Despite its relative antiquity, diphenhydramine remains the most widely used antihistamine in the United States.16 These first-generation H1-receptor antagonists, though effective in the treatment of urticaria and allergic rhinitis, were shown to cause undesired side effects for 2 distinct reasons: their lack of selectivity for the H1 receptor and their propensity to cross the blood-brain barrier and affect the central nervous system.17 As a result of their lack of selectivity, older-generation agents cause anticholinergic effects such as dry mouth, headache, and urinary retention.18-20 Furthermore, at supraclinical doses, some antihistamines are toxic¹⁶ and have been shown to cause sinus tachycardia.21 Children have been known to experience severe toxic reactions and even death following overdose of older-generation antihistamines because of the drug's lack of selectivity.22-25 Because older-generation antihistamines can bind to H1 receptors in the brain and histamine in the brain plays a role in central nervous system arousal and alertness, these agents also are associated with sedation and cognitive impairment (eg, impaired sensorimotor coordination and decreases in attention span, memory function, ability to process information, and psychomotor performance16,26,27). The binding of first-generation antihistamines to cerebral H1 receptors has been demonstrated in many studies employing objective psychometric tests and also by the relatively new technique of positron emission tomographic imaging.28-30

Newer-Generation Antihistamines
Newer-generation antihistamines were developed in the early 1980s with the aim of being more specific for the H1 receptor, as well as of overcoming the adverse events observed with older agents. As testament to achieving this goal, allergists agree that newer-generation antihistamines are preferred to first-generation agents because of their more favorable efficacy:safety ratio.16,18 Although there is no such formal consensus among dermatologists and those specifically treating CIU, it is likely the same logic would apply if equivalent efficacy between old and new antihistamines can be established for CIU. This review explores the newer-generation antihistamines available in the United States for the treatment of CIU: fexofenadine, loratadine, desloratadine, and cetirizine. An evidence-based analysis of the efficacy of these agents and an analysis of the therapeutic window of these antihistamines, with particular focus on their sedation and cognitive impairment potential, are emphasized (Table).

Efficacy of Newer-Generation Antihistamines
Numerous randomized double-blind clinical studies have demonstrated the efficacy of fexofenadine,31-34 loratadine,35,36 desloratadine,37,38 and cetirizine39,40 in relieving the symptoms of CIU. Fexofenadine—The safety and efficacy of various doses of fexofenadine at relieving the symptoms of CIU has been established in several large randomized controlled clinical trials. Two similar CIU studies investigated the efficacy of fexofenadine HCl using doses of 20, 60, 120, and 240 mg twice daily (BID). In both studies, doses of 60 mg or more BID were shown to reduce severity of pruritus, number of wheals, and interference with sleep and normal daily activities compared with placebo.33,34 Furthermore, studies in Japanese and Thai patients have indicated that the effectiveness of fexofenadine 60 mg BID is not limited by ethnicity or genotype.41,42 Although many studies have examined some QOL parameters as secondary endpoints as a component of efficacy studies, fexofenadine has been studied using the validated DLQI and Work Productivity and Activity Impairment questionnaires.⁴³ Two identically designed 4-week, multicenter, randomized, double-blind, placebo-controlled, parallel-group trials examined the effects of 60 mg BID on patients aged 12 to 65 years with moderate to severe CIU. Fexofenadine treatment significantly improved overall DLQI score compared with placebo (P≤.0002), and also significantly increased work productivity (P≤.014). In addition, a trend toward increased classroom productivity and significant improvements in 5 of the 6 individual DLQI domains were observed.43 The efficacy and safety of a range of once-daily (QD) doses of fexofenadine have been evaluated in a large, multicenter, double-blind, placebo-controlled, parallel-group, dose-ranging study.31 Adults (N=222) were randomized to receive either fexofenadine HCl 60, 120, 180, or 240 mg QD or placebo QD for 6 weeks. The combined fexofenadine groups showed a significant reduction in mean total symptom score (pruritus score and number of wheals) compared with placebo (P=.0019). The study suggested that 180 mg QD is the optimal dose for the treatment of CIU because this dose alone significantly reduced the number of wheals compared with placebo (P=.0064) and significantly improved mean total symptom score consistently over the 6-week study period (P<.05).31 Supporting the efficacy of this once-daily dose, a recent double-blind placebo-controlled study of fexofenadine HCl 180 mg QD was shown to produce a beneficial effect on urticaria.32
Loratadine—The relative efficacy of loratadine and the first-generation antihistamine hydroxyzine has been established in a large 4-week (optional 12-week) trial comparing the 2 compounds with placebo in 172 patients with CIU. Patients were randomized to receive either: 10 mg loratadine QD and placebo BID; hydroxyzine 3 times daily; or placebo 3 times daily. As measured by all efficacy evaluations (physician and patient evaluations of the effect of treatment at each visit plus patient daily diary cards), loratadine and hydroxyzine were found to be more effective than placebo and clinically comparable to each other.35
In the only placebo-controlled comparative study between 2 newer-generation antihistamines in the treatment of CIU, Guerra et al44 showed that loratadine was more effective than cetirizine in some aspects of controlling the symptoms of CIU. In this double-blind study, 116 patients with CIU were randomly assigned loratadine 10 mg, cetirizine 10 mg, or placebo QD for 28 days. Both active drugs significantly reduced global clinical symptoms (P<.05), but loratadine was more rapid in developing its activity than cetirizine (P<.01 at day 3) and also appeared to be safer when the frequency of treatment-emergent side effects were compared.44
Desloratadine—Desloratadine is the major active metabolite of loratadine, which has been available in the United States since 2002 for the treatment of CIU. The efficacy of the drug has been evaluated in 2 major randomized controlled clinical trials.37,38
Ring et al37 reported that desloratadine exhibited superior efficacy compared with placebo in a multicenter, randomized, double-blind trial of 190 patients with a history of CIU. Patients were assigned to receive either desloratadine 5 mg QD or placebo QD for 6 weeks. The active treatment was superior to placebo at reducing pruritus and overall symptoms after the first dose and throughout the 6-week study.37 Similarly, therapeutic response and global CIU status, as well as QOL measures such as interference with sleep, were improved with desloratadine compared with placebo throughout the study period.37 Using the same dose (5 mg QD), a further 6-week placebo-controlled study of desloratadine indicated the effectiveness of this agent at relieving CIU symptoms.38 Over the study period, the mean total CIU symptom score was significantly improved compared with placebo, as were the individual scores of pruritus, number of hives, and the size of the largest hive. Interference with sleep was reduced and performance of daily activities was improved with desloratadine. These statistically and clinically significant improvements were seen within the first 24 hours of treatment and were sustained throughout the 6-week treatment period.38
Cetirizine—As with loratadine, cetirizine has been shown to be as effective as first-generation hydroxyzine at relieving the symptoms of CIU.40 For example, a 4-week, multicenter, randomized, double-blind, double-dummy trial investigated the efficacy and safety of cetirizine 10 mg QD and hydroxyzine 25 mg 3 times daily compared with placebo in patients with CIU. Patients in the cetirizine and hydroxyzine groups showed significant reductions during weeks 1, 2, 3, and 4 in the number and size of lesions and in the severity of pruritus compared with patients who received placebo. In addition, physician and patient evaluations at the end of week 4 revealed an improvement in urticarial symptoms for the cetirizine and hydroxyzine groups compared with the placebo group.40
All 4 newer-generation H1 antihistamines (fexofenadine, loratadine, desloratadine, and cetirizine) have been shown to be superior to placebo at treating the symptoms of CIU, and both loratadine and cetirizine have been proven to be as effective as first-generation hydroxyzine.35,40 Although no trials have evaluated fexofenadine and desloratadine compared with hydroxyzine, comparisons demonstrating equivalence have been made with their parent compounds (loratadine35 and terfenadine45).
There are few controlled studies in which newer-generation antihistamines have been directly compared, and there is no evidence-based data demonstrating statistical superiority of one second-generation agent over another in the treatment of CIU. For example, although a recent trial compared the efficacy of cetirizine with fexofenadine, the results are weakened by the study design. Patients with CIU were randomized to either cetirizine 10 mg (n=52) or fexofenadine 180 mg (n=45); at 28 days, 51.9% (27) and 4.4% (2) of cetirizine and fexofenadine patients, respectively, were symptom free (P=.00001), while partial improvement was experienced by 36.5% (19) of cetirizine patients and 42.2% (19) of fexofenadine patients.46 However, there was no control group, baseline symptom severity data were not provided, and the authors did not describe how the patients’ symptoms were assessed.46 Therefore, a definitive assessment of the relative efficacy of newer-generation antihistamines cannot be achieved by reviewing published trials alone.Anti-inflammatory Properties
Due to the absence of well-designed placebo-controlled comparisons of newer-generation antihistamines, other properties have been examined to aid treatment comparisons. For example, it has been suggested that some H1-receptor antagonists may achieve anti-inflammatory effects in a clinical context, which could prove advantageous in the treatment of CIU because the disease is characterized by tissue inflammation.47
To investigate the anti-inflammatory activity of fexofenadine, an immunohistochemical evaluation of the agent was undertaken in patients with CIU.48 Twenty patients received fexofenadine HCl 180 mg QD for 4 weeks; the expression of adhesion molecules, mast cell proteases, and proinflammatory cytokines were evaluated before and after treatment, as were the patients’ assessments of urticarial symptoms. After treatment with fexofenadine, significant decreases in the expression of endothelial leukocyte adhesion molecule-1 (P=.02), vascular cell adhesion molecule-1 (P=.04), and tryptase (P=.04) were observed, confirming the hypothesis that fexofenadine has some anti-inflammatory properties.
This study in humans must be put into context with the numerous in vitro, ex vivo, and animal studies that have been conducted in this area. A review of such data suggests that all newer-generation antihistamines inhibit the release or generation of multiple inflammatory mediators, including IL-4, IL-6, IL-8, IL-13, prostaglandin D3, leukotriene C, tryptase, histamine, and the tumor necrosis factor α­induced chemokine regulated upon activation normal T cell expressed and secreted, in addition to eosinophil chemotaxis and adhesion molecules.47 For example, both loratadine and desloratadine (10 μmol/L) significantly inhibited the expression of intercellular adhesion molecule-1 and class II HLA antigen (HLA-DE) in nasal epithelial cells in vitro.49 However, many of these anti-inflammatory effects have only been observed at high drug concentrations.47 For example, an in vitro study of cetirizine assessing the inhibition of IL-5­ dependent eosinophil survival revealed a concentration of 100 μmol/L was required to achieve significant inhibition—much higher than that used clinically.47,50
Clearly, if clinical anti-inflammatory effects necessitate doses higher than those recommended for allergic diseases, drugs that can be used at higher doses without causing unwanted side effects such as sedation and cognitive impairment may be of the greatest utility in the treatment of CIU. This is a particularly pertinent point because patients with CIU may be prescribed much higher doses than recommended to manage symptoms effectively.17
The Therapeutic Window—Because of the lack of rigorously designed clinical trials comparing the efficacy of second-generation antihistamines and the putative anti-inflammatory activities of these agents that may occur at higher-than-recommended dosing levels, the relative safety of agents may direct the selection of the optimum antihistamine for the treatment of CIU. Ideally, an agent would be effective at a wide range of doses without causing unwanted side effects. This is because a wide therapeutic window permits the physician to optimize treatment to the individual. The safety of the newer-generation antihistamines has been assessed in numerous clinical trials, usually as secondary analyses to efficacy parameters; indeed, all of the efficacy studies described here indicated a good safety and tolerability profile for each of the antihistamines.
Clinical trials, however, do not always reflect the reality of clinical practice. Patients taking antihistamines frequently overcomply with their medication,51 particularly if they do not experience immediate relief. Furthermore, as previously mentioned, it is occasionally necessary for dermatologists to prescribe high doses of antihistamines for patients who do not respond to standard-dose first-line therapy.17 Thus, it is valid to examine the safety of the different antihistamines at high doses to obtain a true picture of how drugs may be affecting patients.
Sedation and Impairment—A number of studies using objective psychometric tests have indicated that newer-generation antihistamines generally have better sedative profiles than first-generation agents; however, at higher doses, sedation and impairment become evident.
Two meta-analyses of published data on antihistamines report that newer drugs had lower impairment/nonimpairment ratios than older agents.28,29 That is, proportionally more studies indicated nonimpairment versus impairment with the newer agents compared with their predecessors. However, the same meta-analyses revealed that both loratadine and cetirizine were associated with sedation/impairment in a number of tests, often when they were used at higher-than-recommended doses. In contrast, fexofenadine, even at doses of up to 360 mg, was not associated with any sedation or impairment and had an impairment:nonimpairment ratio of zero.28,29
A study by Mann et al52 corroborates the finding that different newer-generation antihistamines have the potential to cause sedation, with fexofenadine being the least likely of those studied to do so. This prescription-event monitoring study showed that the odds ratios for the incidence of sedation were 0.63 for fexofenadine and 5.53 for cetirizine compared with loratadine.52 Higher-than-recommended doses of loratadine53 and desloratadine54 also can cause sedation.
A recent approach to the question of blood-brain barrier penetration involves the use of positron emission tomography. This technique has been used to study the binding of antihistamines to cerebral H1 receptors. Tashiro et al30 used positron emission tomographic imaging to compare fexofenadine with cetirizine by examining relative H1 receptor occupancy in the brain. Quantitative analysis showed that fexofenadine did not occupy H1 receptors in the cerebral cortex, while cetirizine occupied between 20% to 50% of the H1 receptors, depending on the brain region.30 These findings support evidence from comparative trials that indicate that although cetirizine is less sedating than older antihistamines, it causes more sedation and impairment of performance than other second-generation antihistamines. As a result, the US Food and Drug Administration has classified cetirizine as sedating rather than nonsedating, and the product carries the full sedation precaution.
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Comment
Antihistamines can be used effectively to control the symptoms of CIU; newer-generation antihistamines have been shown to be as effective as their predecessors at relieving patients of their symptoms35,40 and improving their QOL.43 However, there is a paucity of well-designed placebo-controlled comparative clinical trials; the data available indicate that agents are effective and safe, but they do not provide a means to assess which agent is the safest and most effective. Instead, we must examine alternative sources of evidence to help us select the optimum antihistamine for the treatment of CIU.
Evidence from pharmacologic studies indicates that newer agents demonstrate some anti-inflammatory activity, which could provide additional therapeutic benefit. However, these studies have largely been limited to in vitro tests and animal modeling and do not yet provide the means to differentiate agents.
Newer-generation antihistamines vary in their propensity to cause sedation and cognitive impairment, with cetirizine representing the most impairing of the class, as recognized by its sedating description by the US Food and Drug Administration. At recommended doses, fexofenadine, loratadine, and desloratadine have not been found to cause significant impairment and are labeled as nonsedating by the US Food and Drug Administration. However, patients with urticaria are known to take above-recommended doses51 and physicians occasionally prescribe off-label doses to achieve the desired level of symptom control. The risk of sedation caused by these 2 factors should be considered in practice when selecting an antihistamine.
Sedation and impairment affect QOL and manifest as decreased classroom learning ability and decreased work productivity.28 Furthermore, it has been suggested that cerebral H1-receptor blockade is associated with falls in the elderly and cognitive slowing, and is a contributing factor in traffic accidents.27
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Conclusion
In controlled clinical studies of CIU, the second-generation H1-antihistamines have been proven to be clinically comparable to the most potent of the first-generation antihistamines, such as hydroxyzine. Clinical studies comparing these agents are few and have shown no statistically significant differences in efficacy.
If sedation and cognitive impairment are to be considered relevant to the choice of therapy for CIU because of their impact on QOL and safety, then newer-generation agents should be selected over older-generation antihistamines.37,40 Furthermore, of the new agents, those that are labeled nonsedating at recommended doses (fexofenadine, loratadine, and desloratadine) should be selected over cetirizine. However, in cases where the physician judges that a higher-than-recommended dose should be prescribed or when the patient is likely to take a higher dose, fexofenadine should be considered. In addition to its proven efficacy in treating the symptoms of CIU,31,33,34 fexofenadine is the only antihistamine that is nonsedating, even at doses 2 to 4 times above the recommended levels.

BOSTON — Heightened activity of anti-double-stranded DNA antibodies may contribute to the poor cholesterol profiles of patients with active systemic lupus erythematosus, according to study findings.

Patients with SLE are often afflicted with a complex triad of risk factors involving high levels of serum triglycerides, high levels of VLDL cholesterol, and low levels of HDL cholesterol. These can hasten the development of premature atherosclerosis and coronary artery disease. Though researchers have posited several theories to explain this phenomenon, its etiology remains unknown.

Sara Kashef, M.D., and colleagues from the Shiraz University of Medical Sciences in Fars, Iran, compared serum lipoprotein levels and antibody activity in 30 patients with active lupus with that of 16 patients with inactive lupus, and 41 healthy controls matched for age and sex. Lupus activity was measured using the SLE disease activity index (SLEDAI). Dr. Kashef presented the study in a poster session at the annual meeting of the Federation of Clinical Immunology Societies.

Compared with healthy controls and people with inactive SLE, patients with active SLE had significantly higher levels of triglycerides and VLDL cholesterol, and lower levels of HDL cholesterol.

Moreover, poor cholesterol profiles were significantly more likely to appear in patients who tested positive for anti-dsDNA antibodies than in those who tested negative. There was no correlation between dyslipoproteinemia and anticardiolipin antibody activity, another suspect in the genesis of SLE atherosclerosis.

“The appearance of this pattern of dyslipoproteinemia—high triglycerides and VLDL cholesterol and low HDL cholesterol—in this selected group of patients seems to be a consequence of disease activity and SLE disease itself,” according to the authors. “Titers of anti-dsDNA correlated significantly with increased SLEDAI scores and low HDL cholesterol,” they noted.

Recent research suggests that the enzyme, lipoprotein lipase (LPL), may play a key role. LPL breaks down VLDL cholesterol. And when LPL is impaired, VLDL cholesterol proliferates, leading to an unhealthy duet of high triglycerides with low HDL cholesterol, the investigators explained.

Although antibodies to LPL were not measured, previous research suggests that increases in such antibodies are common in SLE patients (Arthritis Rheum. 2002;46:2957–63).

“These results reflect that one of the contributory causes of dyslipoproteinemia in active SLE is probably increased cross-reactivity of anti-dsDNA antibodies with LPL due to high production of these antibodies in the active phase of disease,” the investigators suggested.

Although these findings support an underlying autoimmune cause of dyslipoproteinemia in lupus patients with active disease, other factors likely contribute as well, the researchers said. These include inflammatory mediators (e.g., tumor necrosis factor, interleukin, interferon) that are known to suppress LPL activity and cause dyslipoproteinemia in SLE (Arthritis Rheum. 2003;48:2533–40), as well as physical inactivity.

BOSTON — Heightened activity of anti-double-stranded DNA antibodies may contribute to the poor cholesterol profiles of patients with active systemic lupus erythematosus, according to study findings.

Patients with SLE are often afflicted with a complex triad of risk factors involving high levels of serum triglycerides, high levels of VLDL cholesterol, and low levels of HDL cholesterol. These can hasten the development of premature atherosclerosis and coronary artery disease. Though researchers have posited several theories to explain this phenomenon, its etiology remains unknown.

Sara Kashef, M.D., and colleagues from the Shiraz University of Medical Sciences in Fars, Iran, compared serum lipoprotein levels and antibody activity in 30 patients with active lupus with that of 16 patients with inactive lupus, and 41 healthy controls matched for age and sex. Lupus activity was measured using the SLE disease activity index (SLEDAI). Dr. Kashef presented the study in a poster session at the annual meeting of the Federation of Clinical Immunology Societies.

Compared with healthy controls and people with inactive SLE, patients with active SLE had significantly higher levels of triglycerides and VLDL cholesterol, and lower levels of HDL cholesterol.

Moreover, poor cholesterol profiles were significantly more likely to appear in patients who tested positive for anti-dsDNA antibodies than in those who tested negative. There was no correlation between dyslipoproteinemia and anticardiolipin antibody activity, another suspect in the genesis of SLE atherosclerosis.

“The appearance of this pattern of dyslipoproteinemia—high triglycerides and VLDL cholesterol and low HDL cholesterol—in this selected group of patients seems to be a consequence of disease activity and SLE disease itself,” according to the authors. “Titers of anti-dsDNA correlated significantly with increased SLEDAI scores and low HDL cholesterol,” they noted.

Recent research suggests that the enzyme, lipoprotein lipase (LPL), may play a key role. LPL breaks down VLDL cholesterol. And when LPL is impaired, VLDL cholesterol proliferates, leading to an unhealthy duet of high triglycerides with low HDL cholesterol, the investigators explained.

Although antibodies to LPL were not measured, previous research suggests that increases in such antibodies are common in SLE patients (Arthritis Rheum. 2002;46:2957–63).

“These results reflect that one of the contributory causes of dyslipoproteinemia in active SLE is probably increased cross-reactivity of anti-dsDNA antibodies with LPL due to high production of these antibodies in the active phase of disease,” the investigators suggested.

Although these findings support an underlying autoimmune cause of dyslipoproteinemia in lupus patients with active disease, other factors likely contribute as well, the researchers said. These include inflammatory mediators (e.g., tumor necrosis factor, interleukin, interferon) that are known to suppress LPL activity and cause dyslipoproteinemia in SLE (Arthritis Rheum. 2003;48:2533–40), as well as physical inactivity.

BOSTON — Heightened activity of anti-double-stranded DNA antibodies may contribute to the poor cholesterol profiles of patients with active systemic lupus erythematosus, according to study findings.

Patients with SLE are often afflicted with a complex triad of risk factors involving high levels of serum triglycerides, high levels of VLDL cholesterol, and low levels of HDL cholesterol. These can hasten the development of premature atherosclerosis and coronary artery disease. Though researchers have posited several theories to explain this phenomenon, its etiology remains unknown.

Sara Kashef, M.D., and colleagues from the Shiraz University of Medical Sciences in Fars, Iran, compared serum lipoprotein levels and antibody activity in 30 patients with active lupus with that of 16 patients with inactive lupus, and 41 healthy controls matched for age and sex. Lupus activity was measured using the SLE disease activity index (SLEDAI). Dr. Kashef presented the study in a poster session at the annual meeting of the Federation of Clinical Immunology Societies.

Compared with healthy controls and people with inactive SLE, patients with active SLE had significantly higher levels of triglycerides and VLDL cholesterol, and lower levels of HDL cholesterol.

Moreover, poor cholesterol profiles were significantly more likely to appear in patients who tested positive for anti-dsDNA antibodies than in those who tested negative. There was no correlation between dyslipoproteinemia and anticardiolipin antibody activity, another suspect in the genesis of SLE atherosclerosis.

“The appearance of this pattern of dyslipoproteinemia—high triglycerides and VLDL cholesterol and low HDL cholesterol—in this selected group of patients seems to be a consequence of disease activity and SLE disease itself,” according to the authors. “Titers of anti-dsDNA correlated significantly with increased SLEDAI scores and low HDL cholesterol,” they noted.

Recent research suggests that the enzyme, lipoprotein lipase (LPL), may play a key role. LPL breaks down VLDL cholesterol. And when LPL is impaired, VLDL cholesterol proliferates, leading to an unhealthy duet of high triglycerides with low HDL cholesterol, the investigators explained.

Although antibodies to LPL were not measured, previous research suggests that increases in such antibodies are common in SLE patients (Arthritis Rheum. 2002;46:2957–63).

“These results reflect that one of the contributory causes of dyslipoproteinemia in active SLE is probably increased cross-reactivity of anti-dsDNA antibodies with LPL due to high production of these antibodies in the active phase of disease,” the investigators suggested.

Although these findings support an underlying autoimmune cause of dyslipoproteinemia in lupus patients with active disease, other factors likely contribute as well, the researchers said. These include inflammatory mediators (e.g., tumor necrosis factor, interleukin, interferon) that are known to suppress LPL activity and cause dyslipoproteinemia in SLE (Arthritis Rheum. 2003;48:2533–40), as well as physical inactivity.

VIENNA — Prolonged intrauterine exposure to high-dose dexamethasone appears to be largely devoid of clinically significant adverse effects on normal T-cell development when evaluated up to a dozen years later, Paolo Airo, M.D., said at the annual European congress of rheumatology.

This has been a controversial issue. Some physicians are concerned that prolonged intrauterine exposure to corticosteroids might steer T-cell differentiation within the fetal thymus in a direction that predisposes to clinical immune dysfunction. They point to an increased rate of hospitalizations for infectious diseases during the first years of life in children with a history of prenatal steroid therapy for prematurity. But a corticosteroid effect is only one of a number of plausible explanations for such an association, said Dr. Airo of the University of Brescia (Italy).

To examine the effect of prenatal high-dose steroids on the T-cell component of the immune system, he and his coinvestigators studied eight children with a history of such therapy given after they were diagnosed in utero with neonatal lupus.

Neonatal lupus, he explained, is a serious condition occurring in children whose mothers have anti-Rho/SSA antibodies, which can cross the placenta. The most important clinical manifestation is congenital heart block; it is associated with significant mortality and permanent morbidity.

When affected fetuses are identified, they are typically treated with several weeks of a high-dose steroid given to the woman. Dexamethasone is the agent used most widely. Since it is a fluorinated corticosteroid, it is not inactivated by placental enzymes, so it can reach the fetus in its active form. The purpose of this therapy is to slow the inflammatory process to prevent progression of incomplete to complete congenital heart block, as well as to treat fetal hydrops and/or myocarditis.

The mean age of the children was 6.6 years, with a range of 2–12 years. All had a pacemaker. None had clinical or laboratory indications of autoimmune disease. A total of 31 age-matched healthy children served as controls, he said at the congress, sponsored by the European League Against Rheumatism.

The results showed that the children with a history of in utero steroid therapy had no abnormalities in the various measures of T-cell number or function having the most clear-cut potential clinical consequences. Thymic output—a key study end point—was normal in children with prolonged fetal exposure to steroids; this was shown by the number of T-cell receptor excision circles (TRECs) in their peripheral blood mononuclear cells, which were measured by real-time polymerase chain reaction. The total number of T cells circulating in peripheral blood was similar to that of controls, as was T-cell subset diversity. Nor did the patients' lymphocyte proliferative response to mitogens differ from that seen in control subjects. Peripheral blood mononuclear cell interferon-γ production and apoptotic response were also similar to that in controls.

The one abnormality seen in children with a history of fetal exposure to steroids involved evidence of oligoclonal T-cell expansion. Similar changes have been reported in animals with in utero exposure to high-dose steroids. However, such changes also can be readily observed in humans after a viral infection. And the clinical significance of this sort of alteration in T-cell repertoire remains unclear, Dr. Airo said.

“We don't know if there is a link between these kinds of changes in PCR repertoire and autoimmunity, but we know that this kind of restriction is frequently detected in patients with rheumatoid arthritis and other autoimmune disorders. And it has been reported that children with neonatal lupus are at increased risk of developing autoimmune disorders in their first years,” according to the rheumatologist.

Aside from the question of the effects on T cells of intrauterine steroid exposure, other adverse consequences have been reported by various investigators. These include increased rates of obstetric complications, adrenal insufficiency, hypertension, and neuropsychiatric impairment.

“We didn't observe any signs of neuropsychiatric impairment in a series of nine children treated with dexamethasone in utero for neonatal lupus,” he said.

VIENNA — Prolonged intrauterine exposure to high-dose dexamethasone appears to be largely devoid of clinically significant adverse effects on normal T-cell development when evaluated up to a dozen years later, Paolo Airo, M.D., said at the annual European congress of rheumatology.

This has been a controversial issue. Some physicians are concerned that prolonged intrauterine exposure to corticosteroids might steer T-cell differentiation within the fetal thymus in a direction that predisposes to clinical immune dysfunction. They point to an increased rate of hospitalizations for infectious diseases during the first years of life in children with a history of prenatal steroid therapy for prematurity. But a corticosteroid effect is only one of a number of plausible explanations for such an association, said Dr. Airo of the University of Brescia (Italy).

To examine the effect of prenatal high-dose steroids on the T-cell component of the immune system, he and his coinvestigators studied eight children with a history of such therapy given after they were diagnosed in utero with neonatal lupus.

Neonatal lupus, he explained, is a serious condition occurring in children whose mothers have anti-Rho/SSA antibodies, which can cross the placenta. The most important clinical manifestation is congenital heart block; it is associated with significant mortality and permanent morbidity.

When affected fetuses are identified, they are typically treated with several weeks of a high-dose steroid given to the woman. Dexamethasone is the agent used most widely. Since it is a fluorinated corticosteroid, it is not inactivated by placental enzymes, so it can reach the fetus in its active form. The purpose of this therapy is to slow the inflammatory process to prevent progression of incomplete to complete congenital heart block, as well as to treat fetal hydrops and/or myocarditis.

The mean age of the children was 6.6 years, with a range of 2–12 years. All had a pacemaker. None had clinical or laboratory indications of autoimmune disease. A total of 31 age-matched healthy children served as controls, he said at the congress, sponsored by the European League Against Rheumatism.

The results showed that the children with a history of in utero steroid therapy had no abnormalities in the various measures of T-cell number or function having the most clear-cut potential clinical consequences. Thymic output—a key study end point—was normal in children with prolonged fetal exposure to steroids; this was shown by the number of T-cell receptor excision circles (TRECs) in their peripheral blood mononuclear cells, which were measured by real-time polymerase chain reaction. The total number of T cells circulating in peripheral blood was similar to that of controls, as was T-cell subset diversity. Nor did the patients' lymphocyte proliferative response to mitogens differ from that seen in control subjects. Peripheral blood mononuclear cell interferon-γ production and apoptotic response were also similar to that in controls.

The one abnormality seen in children with a history of fetal exposure to steroids involved evidence of oligoclonal T-cell expansion. Similar changes have been reported in animals with in utero exposure to high-dose steroids. However, such changes also can be readily observed in humans after a viral infection. And the clinical significance of this sort of alteration in T-cell repertoire remains unclear, Dr. Airo said.

“We don't know if there is a link between these kinds of changes in PCR repertoire and autoimmunity, but we know that this kind of restriction is frequently detected in patients with rheumatoid arthritis and other autoimmune disorders. And it has been reported that children with neonatal lupus are at increased risk of developing autoimmune disorders in their first years,” according to the rheumatologist.

Aside from the question of the effects on T cells of intrauterine steroid exposure, other adverse consequences have been reported by various investigators. These include increased rates of obstetric complications, adrenal insufficiency, hypertension, and neuropsychiatric impairment.

“We didn't observe any signs of neuropsychiatric impairment in a series of nine children treated with dexamethasone in utero for neonatal lupus,” he said.

VIENNA — Prolonged intrauterine exposure to high-dose dexamethasone appears to be largely devoid of clinically significant adverse effects on normal T-cell development when evaluated up to a dozen years later, Paolo Airo, M.D., said at the annual European congress of rheumatology.

This has been a controversial issue. Some physicians are concerned that prolonged intrauterine exposure to corticosteroids might steer T-cell differentiation within the fetal thymus in a direction that predisposes to clinical immune dysfunction. They point to an increased rate of hospitalizations for infectious diseases during the first years of life in children with a history of prenatal steroid therapy for prematurity. But a corticosteroid effect is only one of a number of plausible explanations for such an association, said Dr. Airo of the University of Brescia (Italy).

To examine the effect of prenatal high-dose steroids on the T-cell component of the immune system, he and his coinvestigators studied eight children with a history of such therapy given after they were diagnosed in utero with neonatal lupus.

Neonatal lupus, he explained, is a serious condition occurring in children whose mothers have anti-Rho/SSA antibodies, which can cross the placenta. The most important clinical manifestation is congenital heart block; it is associated with significant mortality and permanent morbidity.

When affected fetuses are identified, they are typically treated with several weeks of a high-dose steroid given to the woman. Dexamethasone is the agent used most widely. Since it is a fluorinated corticosteroid, it is not inactivated by placental enzymes, so it can reach the fetus in its active form. The purpose of this therapy is to slow the inflammatory process to prevent progression of incomplete to complete congenital heart block, as well as to treat fetal hydrops and/or myocarditis.

The mean age of the children was 6.6 years, with a range of 2–12 years. All had a pacemaker. None had clinical or laboratory indications of autoimmune disease. A total of 31 age-matched healthy children served as controls, he said at the congress, sponsored by the European League Against Rheumatism.

The results showed that the children with a history of in utero steroid therapy had no abnormalities in the various measures of T-cell number or function having the most clear-cut potential clinical consequences. Thymic output—a key study end point—was normal in children with prolonged fetal exposure to steroids; this was shown by the number of T-cell receptor excision circles (TRECs) in their peripheral blood mononuclear cells, which were measured by real-time polymerase chain reaction. The total number of T cells circulating in peripheral blood was similar to that of controls, as was T-cell subset diversity. Nor did the patients' lymphocyte proliferative response to mitogens differ from that seen in control subjects. Peripheral blood mononuclear cell interferon-γ production and apoptotic response were also similar to that in controls.

The one abnormality seen in children with a history of fetal exposure to steroids involved evidence of oligoclonal T-cell expansion. Similar changes have been reported in animals with in utero exposure to high-dose steroids. However, such changes also can be readily observed in humans after a viral infection. And the clinical significance of this sort of alteration in T-cell repertoire remains unclear, Dr. Airo said.

“We don't know if there is a link between these kinds of changes in PCR repertoire and autoimmunity, but we know that this kind of restriction is frequently detected in patients with rheumatoid arthritis and other autoimmune disorders. And it has been reported that children with neonatal lupus are at increased risk of developing autoimmune disorders in their first years,” according to the rheumatologist.

Aside from the question of the effects on T cells of intrauterine steroid exposure, other adverse consequences have been reported by various investigators. These include increased rates of obstetric complications, adrenal insufficiency, hypertension, and neuropsychiatric impairment.

“We didn't observe any signs of neuropsychiatric impairment in a series of nine children treated with dexamethasone in utero for neonatal lupus,” he said.

SAN FRANCISCO — The risk for preeclampsia in pregnant women with lupus tripled if they had thrombocytopenia at conception, according to a review of data from a 10-year period at one institution.

This previously unreported finding was highly statistically significant, but prospective studies will be needed to confirm the association, study investigator Maurice L. Druzin, M.D., said at a meeting on antepartum and intrapartum management sponsored by the University of California, San Francisco.

“We certainly are going to be looking at patients with thrombocytopenia very closely,” said Dr. Druzin, professor of ob.gyn. and chief of maternal and fetal medicine at Stanford (Calif.) University.

The review of all pregnancies complicated by systemic lupus erythematosus seen at the university from 1991 to 2001 covered 63 pregnancies in 48 patients with a mean maternal age of 30 years. Lupus had been present for a mean of 4 years in these patients, and the disease was active at conception in 63% of pregnancies. As a group, these were sicker patients than those usually seen by an ob.gyn.

Preeclampsia occurred in 22% of all pregnancies. Thrombocytopenia at conception predicted the development of preeclampsia, according to multivariate analyses to identify clinical predictors of prematurity and preeclampsia.

Gestational diabetes occurred in 5% of pregnancies, and 4% of the cohort developed hemolysis, elevated liver, low platelet (HELLP) syndrome.

Among the pregnancies with active maternal lupus at conception, treatments included prednisone in 48%, hydroxychloroquine in 21%, and antihypertensives in 13%.

Maternal antiphospholipid antibodies were detected in about half of all pregnancies. The cohort had a higher likelihood of having anti-Ro/SSA or anti-La/SSB antibodies than generally is seen in patients with lupus—38% vs. 25%—again emphasizing the select nature of this referral population. Maternal renal disease was present in 35% of pregnancies, and maternal CNS disease affected 10% of pregnancies.

Despite this, birth outcomes were “very good,” with 54 live births, Dr. Druzin said. “When a woman with lupus comes to you, you can tell her that she has a very good chance of having a live birth, which was not true 25 years ago.” The remaining pregnancies ended in first-trimester losses or therapeutic abortions.

As in other studies of pregnancy and lupus, premature delivery was the main fetal problem, occurring n 54% of pregnancies. However, 46% of these were delivered at 32–37 weeks' gestation. “In modern intensive care units, those babies tend to do very well,” he said. An additional 4% were born at 28–32 weeks, and 4% were delivered earlier than 28 weeks.

Lupus flares occurred in 68% of pregnancies. Of these, 71% were mild to moderate flares and were treated with 4–20 mg of additional prednisone. The risk for flare nearly doubled if lupus was active at conception. Prednisone use at conception predicted a 57% increased risk of flare, and a higher disease activity index score predicted a 56% increased risk for flare.

A severe flare was associated with nearly a doubling in risk for premature delivery. Maternal use of antihypertensives or prednisone at conception was associated with an 83% or 77% increase, respectively, in risk for premature birth.

Among 13 women on hydroxychloroquine at conception, severe flares occurred in 2 of 11 women who stopped taking the medication after conception but not in women who continued treatment or stopped before conception, he noted. This difference was not significant, but the finding plus other data suggest that hydroxychloroquine is safe to use in pregnancy.

The review will be published in the American Journal of Obstetrics and Gynecology. The lead author of the paper is Eliza F. Chakravarty, M.D., a rheumatology fellow at Stanford University.

SAN FRANCISCO — The risk for preeclampsia in pregnant women with lupus tripled if they had thrombocytopenia at conception, according to a review of data from a 10-year period at one institution.

This previously unreported finding was highly statistically significant, but prospective studies will be needed to confirm the association, study investigator Maurice L. Druzin, M.D., said at a meeting on antepartum and intrapartum management sponsored by the University of California, San Francisco.

“We certainly are going to be looking at patients with thrombocytopenia very closely,” said Dr. Druzin, professor of ob.gyn. and chief of maternal and fetal medicine at Stanford (Calif.) University.

The review of all pregnancies complicated by systemic lupus erythematosus seen at the university from 1991 to 2001 covered 63 pregnancies in 48 patients with a mean maternal age of 30 years. Lupus had been present for a mean of 4 years in these patients, and the disease was active at conception in 63% of pregnancies. As a group, these were sicker patients than those usually seen by an ob.gyn.

Preeclampsia occurred in 22% of all pregnancies. Thrombocytopenia at conception predicted the development of preeclampsia, according to multivariate analyses to identify clinical predictors of prematurity and preeclampsia.

Gestational diabetes occurred in 5% of pregnancies, and 4% of the cohort developed hemolysis, elevated liver, low platelet (HELLP) syndrome.

Among the pregnancies with active maternal lupus at conception, treatments included prednisone in 48%, hydroxychloroquine in 21%, and antihypertensives in 13%.

Maternal antiphospholipid antibodies were detected in about half of all pregnancies. The cohort had a higher likelihood of having anti-Ro/SSA or anti-La/SSB antibodies than generally is seen in patients with lupus—38% vs. 25%—again emphasizing the select nature of this referral population. Maternal renal disease was present in 35% of pregnancies, and maternal CNS disease affected 10% of pregnancies.

Despite this, birth outcomes were “very good,” with 54 live births, Dr. Druzin said. “When a woman with lupus comes to you, you can tell her that she has a very good chance of having a live birth, which was not true 25 years ago.” The remaining pregnancies ended in first-trimester losses or therapeutic abortions.

As in other studies of pregnancy and lupus, premature delivery was the main fetal problem, occurring n 54% of pregnancies. However, 46% of these were delivered at 32–37 weeks' gestation. “In modern intensive care units, those babies tend to do very well,” he said. An additional 4% were born at 28–32 weeks, and 4% were delivered earlier than 28 weeks.

Lupus flares occurred in 68% of pregnancies. Of these, 71% were mild to moderate flares and were treated with 4–20 mg of additional prednisone. The risk for flare nearly doubled if lupus was active at conception. Prednisone use at conception predicted a 57% increased risk of flare, and a higher disease activity index score predicted a 56% increased risk for flare.

A severe flare was associated with nearly a doubling in risk for premature delivery. Maternal use of antihypertensives or prednisone at conception was associated with an 83% or 77% increase, respectively, in risk for premature birth.

Among 13 women on hydroxychloroquine at conception, severe flares occurred in 2 of 11 women who stopped taking the medication after conception but not in women who continued treatment or stopped before conception, he noted. This difference was not significant, but the finding plus other data suggest that hydroxychloroquine is safe to use in pregnancy.

The review will be published in the American Journal of Obstetrics and Gynecology. The lead author of the paper is Eliza F. Chakravarty, M.D., a rheumatology fellow at Stanford University.

SAN FRANCISCO — The risk for preeclampsia in pregnant women with lupus tripled if they had thrombocytopenia at conception, according to a review of data from a 10-year period at one institution.

This previously unreported finding was highly statistically significant, but prospective studies will be needed to confirm the association, study investigator Maurice L. Druzin, M.D., said at a meeting on antepartum and intrapartum management sponsored by the University of California, San Francisco.

“We certainly are going to be looking at patients with thrombocytopenia very closely,” said Dr. Druzin, professor of ob.gyn. and chief of maternal and fetal medicine at Stanford (Calif.) University.

The review of all pregnancies complicated by systemic lupus erythematosus seen at the university from 1991 to 2001 covered 63 pregnancies in 48 patients with a mean maternal age of 30 years. Lupus had been present for a mean of 4 years in these patients, and the disease was active at conception in 63% of pregnancies. As a group, these were sicker patients than those usually seen by an ob.gyn.

Preeclampsia occurred in 22% of all pregnancies. Thrombocytopenia at conception predicted the development of preeclampsia, according to multivariate analyses to identify clinical predictors of prematurity and preeclampsia.

Gestational diabetes occurred in 5% of pregnancies, and 4% of the cohort developed hemolysis, elevated liver, low platelet (HELLP) syndrome.

Among the pregnancies with active maternal lupus at conception, treatments included prednisone in 48%, hydroxychloroquine in 21%, and antihypertensives in 13%.

Maternal antiphospholipid antibodies were detected in about half of all pregnancies. The cohort had a higher likelihood of having anti-Ro/SSA or anti-La/SSB antibodies than generally is seen in patients with lupus—38% vs. 25%—again emphasizing the select nature of this referral population. Maternal renal disease was present in 35% of pregnancies, and maternal CNS disease affected 10% of pregnancies.

Despite this, birth outcomes were “very good,” with 54 live births, Dr. Druzin said. “When a woman with lupus comes to you, you can tell her that she has a very good chance of having a live birth, which was not true 25 years ago.” The remaining pregnancies ended in first-trimester losses or therapeutic abortions.

As in other studies of pregnancy and lupus, premature delivery was the main fetal problem, occurring n 54% of pregnancies. However, 46% of these were delivered at 32–37 weeks' gestation. “In modern intensive care units, those babies tend to do very well,” he said. An additional 4% were born at 28–32 weeks, and 4% were delivered earlier than 28 weeks.

Lupus flares occurred in 68% of pregnancies. Of these, 71% were mild to moderate flares and were treated with 4–20 mg of additional prednisone. The risk for flare nearly doubled if lupus was active at conception. Prednisone use at conception predicted a 57% increased risk of flare, and a higher disease activity index score predicted a 56% increased risk for flare.

A severe flare was associated with nearly a doubling in risk for premature delivery. Maternal use of antihypertensives or prednisone at conception was associated with an 83% or 77% increase, respectively, in risk for premature birth.

Among 13 women on hydroxychloroquine at conception, severe flares occurred in 2 of 11 women who stopped taking the medication after conception but not in women who continued treatment or stopped before conception, he noted. This difference was not significant, but the finding plus other data suggest that hydroxychloroquine is safe to use in pregnancy.

The review will be published in the American Journal of Obstetrics and Gynecology. The lead author of the paper is Eliza F. Chakravarty, M.D., a rheumatology fellow at Stanford University.

MIAMI BEACH — Neurologists are less likely than cardiologists to favor closure of patent foramen ovale in an attempt to prevent stroke, according to survey results presented at the annual meeting of the American Academy of Neurology.

Although there is a higher prevalence of patent foramen ovale (PFO) among patients who experience a stroke when no other cause is identified, studies have yet to prove that percutaneous closure makes a difference in outcomes. “It is not yet proven that closing the PFO through cardiac catheterization is better than medication,” Steven R. Messe, M.D., told this newspaper during an interview at his poster presentation.

To compare how different specialists manage these patients, Dr. Messe and his colleagues surveyed 129 cardiologists and 108 neurologists. All the physicians were investigators in the CLOSURE-I trial, a study comparing percutaneous closure with medical therapy.

The response rate was 39.5%, with 36% of cardiologists and 44% of neurologists answering the survey. The 17-item questionnaire assessed practice regarding PFO diagnosis, high-risk characteristics, treatment choices, and alternative indications for PFO closure.

According to the survey, 78% of the cardiologists and 65% of the neurologists believe that PFO is relevant to future stroke risk regardless of age.

Despite insufficient outcome data, cardiologists said they recommend percutaneous closure for 55% of patients with a PFO, compared with neurologists, who recommend it for only 20%.

“Closure in general is being used frequently without data at this point, for one in five neurology patients,” said Dr. Messe, attending neurologist, Hospital of the University of Pennsylvania, Philadelphia.

“Interventional cardiologists do the procedure, and they are eager to do it. Neurologists are more conservative,” Dr. Messe said.

A minority, 9% of cardiologists and 2% of neurologists, have recommended closure for asymptomatic PFO patients. A total of 24% of cardiologists and 6% of neurologists would close a patent foramen ovale in a patient who scuba dives, according to the survey. In addition, 14% of cardiologists but no neurologists said they have recommended PFO closure for migraine treatment.

Neurologists prescribe antiplatelet therapy, such as warfarin, for 49% of patients with a PFO. Cardiologists prescribe the same medications for 26% of patients.

Most neurologists may be waiting for more evidence of improved outcomes, Dr. Messe said. “I think neurologists will be excited to refer PFO patients for closure once it's proven to make a difference in prevention of stroke.”

MIAMI BEACH — Neurologists are less likely than cardiologists to favor closure of patent foramen ovale in an attempt to prevent stroke, according to survey results presented at the annual meeting of the American Academy of Neurology.

Although there is a higher prevalence of patent foramen ovale (PFO) among patients who experience a stroke when no other cause is identified, studies have yet to prove that percutaneous closure makes a difference in outcomes. “It is not yet proven that closing the PFO through cardiac catheterization is better than medication,” Steven R. Messe, M.D., told this newspaper during an interview at his poster presentation.

To compare how different specialists manage these patients, Dr. Messe and his colleagues surveyed 129 cardiologists and 108 neurologists. All the physicians were investigators in the CLOSURE-I trial, a study comparing percutaneous closure with medical therapy.

The response rate was 39.5%, with 36% of cardiologists and 44% of neurologists answering the survey. The 17-item questionnaire assessed practice regarding PFO diagnosis, high-risk characteristics, treatment choices, and alternative indications for PFO closure.

According to the survey, 78% of the cardiologists and 65% of the neurologists believe that PFO is relevant to future stroke risk regardless of age.

Despite insufficient outcome data, cardiologists said they recommend percutaneous closure for 55% of patients with a PFO, compared with neurologists, who recommend it for only 20%.

“Closure in general is being used frequently without data at this point, for one in five neurology patients,” said Dr. Messe, attending neurologist, Hospital of the University of Pennsylvania, Philadelphia.

“Interventional cardiologists do the procedure, and they are eager to do it. Neurologists are more conservative,” Dr. Messe said.

A minority, 9% of cardiologists and 2% of neurologists, have recommended closure for asymptomatic PFO patients. A total of 24% of cardiologists and 6% of neurologists would close a patent foramen ovale in a patient who scuba dives, according to the survey. In addition, 14% of cardiologists but no neurologists said they have recommended PFO closure for migraine treatment.

Neurologists prescribe antiplatelet therapy, such as warfarin, for 49% of patients with a PFO. Cardiologists prescribe the same medications for 26% of patients.

Most neurologists may be waiting for more evidence of improved outcomes, Dr. Messe said. “I think neurologists will be excited to refer PFO patients for closure once it's proven to make a difference in prevention of stroke.”

MIAMI BEACH — Neurologists are less likely than cardiologists to favor closure of patent foramen ovale in an attempt to prevent stroke, according to survey results presented at the annual meeting of the American Academy of Neurology.

Although there is a higher prevalence of patent foramen ovale (PFO) among patients who experience a stroke when no other cause is identified, studies have yet to prove that percutaneous closure makes a difference in outcomes. “It is not yet proven that closing the PFO through cardiac catheterization is better than medication,” Steven R. Messe, M.D., told this newspaper during an interview at his poster presentation.

To compare how different specialists manage these patients, Dr. Messe and his colleagues surveyed 129 cardiologists and 108 neurologists. All the physicians were investigators in the CLOSURE-I trial, a study comparing percutaneous closure with medical therapy.

The response rate was 39.5%, with 36% of cardiologists and 44% of neurologists answering the survey. The 17-item questionnaire assessed practice regarding PFO diagnosis, high-risk characteristics, treatment choices, and alternative indications for PFO closure.

According to the survey, 78% of the cardiologists and 65% of the neurologists believe that PFO is relevant to future stroke risk regardless of age.

Despite insufficient outcome data, cardiologists said they recommend percutaneous closure for 55% of patients with a PFO, compared with neurologists, who recommend it for only 20%.

“Closure in general is being used frequently without data at this point, for one in five neurology patients,” said Dr. Messe, attending neurologist, Hospital of the University of Pennsylvania, Philadelphia.

“Interventional cardiologists do the procedure, and they are eager to do it. Neurologists are more conservative,” Dr. Messe said.

A minority, 9% of cardiologists and 2% of neurologists, have recommended closure for asymptomatic PFO patients. A total of 24% of cardiologists and 6% of neurologists would close a patent foramen ovale in a patient who scuba dives, according to the survey. In addition, 14% of cardiologists but no neurologists said they have recommended PFO closure for migraine treatment.

Neurologists prescribe antiplatelet therapy, such as warfarin, for 49% of patients with a PFO. Cardiologists prescribe the same medications for 26% of patients.

Most neurologists may be waiting for more evidence of improved outcomes, Dr. Messe said. “I think neurologists will be excited to refer PFO patients for closure once it's proven to make a difference in prevention of stroke.”