San Diego--The development of a novel anti-immunoglobulin E (IgE) monoclonal antibody may prove to be a major breakthrough in the treatment of allergic disorders, such as asthma and rhinitis, according to a study presented at the 56th annual meeting of the American Academy of Allergy, Asthma, and Immunology. Other highlights of the meeting included findings that echinacea may cause allergic reactions and that pet exposure during infancy may protect against allergic sensitization.

WEEKLY IL-4 RECEPTOR STABILIZES LUNG FUNCTION IN PERSISTENT ASTHMA

Soluble interleukin-4 receptor (IL-4R) has been shown to be a safe, well-tolerated, and effective approach to the management of moderate persistent asthma.

The findings are based on a phase I/II double-blind, placebo-controlled study involving 62 patients with moderate atopic asthma. Larry C. Borish, MD, of the National Jewish Medical and Research Center in Denver, and colleagues randomized the patients to 12 once-weekly inhalations of IL-4R (0.75 mg, 1.5 mg, or 3.0 mg) or placebo.

During screening, dependence on inhaled corticosteroids was documented if an exacerbation of asthma could be induced by one or two 50% reductions in the corticosteroid dose over a two-week period. After restabilization at the lowest dose at which symptoms were controlled, the inhaled corticosteroids were discontinued, and patients were randomized to study medication or placebo on day 0.

As expected, patients in the placebo group demonstrated a significant decline in forced expiratory volume in one second (FEV1) following discontinuation of inhaled corticosteroids. In contrast, patients taking 3 mg IL-4R experienced continued asthma control over the treatment period. They not only maintained their FEV1 but showed an improvement in both morning and evening FEV1 levels.

Daily morning peak expiratory flow showed a marked improvement in the 3-mg treatment group at one month but declined in the placebo group. Furthermore, asthma symptom scores were increased at one month in the 3 mg IL-4R group but not in the placebo group.

Overall, treatment with IL-4R was well tolerated and safe. No serious adverse events related to the study drug were reported. The most common side effects were headache, nausea, upper respiratory infection, and pain, all of which were mild and transient.

ANTI-IgE MONOCLONAL ANTIBODY FOR PEDIATRIC ALLERGIC ASTHMA

Anti-IgE therapy with a recombinant humanized monoclonal antibody (olizumab/rhuMAb-E25, or E25) appears to be a breakthrough in the treatment of pediatric allergic asthma--it reduces the incidence of asthma exacerbations even after inhaled corticosteroids are markedly reduced or completely withdrawn, said Henry Milgrom, MD, senior staff physician at the National Jewish Medical and Research Center in Denver.

In a phase III clinical trial, 334 children (age 6 to 12 years) whose asthma was well-controlled with beclomethasone dipropionate (BDP) and albuterol were randomized to 28 weeks of treatment with placebo or subcutaneous E25 (150 to 300 mg every four weeks or 225 to 375 mg every two weeks, depending on body weight and total serum IgE levels). After the BDP dose was adjusted for optimal asthma control, the dose remained unchanged for 16 weeks (the stabilization period) except for treatment of exacerbations. The BDP dose was gradually tapered during the next eight weeks, and the lowest tolerated dose was maintained for four weeks; in some cases, corticosteroids were completely eliminated. (The 12 weeks during which the corticosteroid doses were tapered or eliminated was called the steroid-reduction period.)

The number of asthma exacerbations was significantly lower in the E25 group than in the placebo group throughout the entire study. Asthma exacerbations were reported by 23% of the placebo patients versus 16% of the E25-treated patients during the stabilization period and by 39% versus 18%, respectively, during the steroid-reduction period. Additionally, a greater proportion of the E25 group completely withdrew from inhaled steroids than did patients taking placebo (55% vs 39%).

Albuterol rescue medication use was markedly lower in the E25 group than in the placebo group. Also, quality of life scores showed greater improvement in the E25 group than in the placebo group.

Adverse events were comparable among the active treatment and placebo groups. Headache and upper respiratory tract infection were the most frequent adverse events in both groups.

In a related study, E25 showed efficacy in the treatment of seasonal allergic rhinitis in adults. Beginning about two weeks before the start of the pollen season, 536 adults with a history of moderate to severe ragweed-induced seasonal allergic rhinitis were randomized to placebo or E25 for 12 weeks.

E25 produced dose-dependent decreases in serum free IgE levels; 4%, 33%, and 63% of patients treated with 50, 150, and 300 mg E25, respectively, achieved serum free IgE concentrations of less than 25 ng/mL, reported Thomas B. Casale, MD, of the Nebraska Medical Research Institute in Papillion, and colleagues. In comparison, only 3% of patients in the placebo group showed such a reduction.

PET EXPOSURE DURING INFANCY REDUCES RISK OF ALLERGIC DISEASE

Living with an indoor cat or dog during the first year of life protects against allergic sensitization, reducing the risk of allergic disease later in childhood, stated Christine Cole Johnson, PhD, of the Henry Ford Health System in Detroit, and colleagues.

Data were collected prenatally (from mothers' histories), at birth, and at regular intervals until age 6 to 7 years, when the children underwent clinical evaluations, such as methacholine challenge, serum IgE measurement, and skin testing for a battery of allergens, including cat and dog. Of the 724 children enrolled in the study, 23.1% lived with a cat during the first year of life, 38.7% lived with a dog, and 51.9% lived with either animal. A total of 496 children were clinically evaluated between age 6 and 7 years.

Overall, children exposed to cats or dogs in the first year of life were less likely to show any sign of allergy later in childhood than were children not exposed to those animals. When only first-born children were considered, the results were more striking, with pet exposure in the first year of life strongly protective against the detection of cat-specific or dog-specific IgE and against having a positive skin test to cat or dog allergens at age 6 to 7 years.

ECHINACEA MAY CAUSE ALLERGIC REACTIONS

Echinacea may cause allergic reactions, particularly in atopic people. Given the widespread, largely unsupervised use of echinacea, mild reactions--which may include transient rashes and aggravation of asthma--may go unreported, noted Raymond Mullins, MD, of the John James Medical Centre in Canberra, Australia.

Dr. Mullins reviewed reports to the Australian Adverse Drug Reactions Advisory Committee and identified 23 cases of allergic reactions to echinacea that were consistent with IgE-mediated hypersensitivity. These reactions included anaphylaxis, acute asthma, and urticaria/angioedema. Causality was described as certain in two cases, probable in 10 cases, and possible in 11 cases. Forty-three percent of the patients were atopic, and 13% were nonatopic; in 44% of cases, the patients' atopy status was not reported.

Furthermore, after studying 100 atopic people who had never taken echinacea, Dr. Mullins found that 20% had positive skin tests to the herb. Of those with positive skin test results, 94% also reacted to grass allergens; much smaller percentages (4% to 56%) reacted to other allergens, such as dust mites, Alternaria, and animal dander.

"One potential explanation for positive skin test reactivity to echinacea in exposure-naive subjects is cross-reactivity between echinacea and other environmental allergens," Dr. Mullins noted. Furthermore, "since atopic subjects are over-represented in those experiencing reactions to echinacea, they should be cautioned appropriately," he believes.

COCKROACH ALLERGEN REMAINS DESPITE EXTERMINATION, CLEANING

While successful cockroach extermination in inner-city homes is possible, allergen levels may remain high enough to cause disease--despite rigorous cleaning with sodium hypochlorite.

Peyton A. Eggleston, MD, and colleagues from The Johns Hopkins University investigated the effects of extermination and cleaning in 14 homes with known cockroach infestation. The homes were exterminated on two occasions, two weeks apart, and all washable surfaces were professionally cleaned with a solution containing 0.5% sodium hypochlorite before and after extermination. The homeowners were asked to use the solution for all routine cleaning during the six-month study. Three additional homes served as controls.

After six months, median cockroach allergen levels decreased by 91% in the treated kitchens, by 77% in the treated living rooms, and by 78% in the treated bedrooms. In contrast, cockroach allergen levels rose in the three control homes, possibly because of seasonal effects (the study was initiated in January and ended in August). Nevertheless, at the end of the study, the allergen levels in the treated bedrooms were still high enough to cause disease (range, 0 to 568 U/g).

INDOOR ALLERGENS AND ASTHMA RISK

The importance of eliminating indoor allergens proven to be the cause of asthma has been underscored in another study. Bruce P. Lanphear, MD, MPH, of the Children's Hospital Medical Center in Cincinnati, and colleagues reported that the elimination of such allergens could potentially result in an almost 40% decline in asthma cases among children younger than age 6 years.

The researchers examined data from the Third National Health and Nutrition Examination Survey, a cross-sectional survey conducted from 1988 to 1994. A total of 8,257 children younger than age 6 years participated in the survey.

Overall, 6% of the children had been diagnosed with asthma. The prevalence rate was higher among boys than girls (6.7% vs 5.1%) and among black children than white children (8.9% vs 5.2%).

Independent predictors of asthma are listed in Table 1. The researchers estimated that 39% of all asthma cases among children younger than age 6 years in the United States could be attributed to one or more residential exposures. This would amount to 532,972 more cases of asthma among these children. In contrast, a family history of atopy would account for 300,000 additional cases of asthma.

HORMONE HAS POTENTIAL VALUE IN AUTOIMMUNITY OR TRANSPLANTATION

The hormone 1,25-dihydroxyvitamin D3 (1,25-OH2D3) has a significant immunosuppressive effect and, when combined with a corticosteroid, has synergistic immunomodulatory and significant steroid-sparing effects, a new study has shown. The findings suggest a potential for use in autoimmune diseases or transplantation, according to Orathai Jirapongsananuruk, MD, and colleagues from the National Jewish Medical and Research Center in Denver.

The study investigators isolated peripheral blood mononuclear cells from eight healthy people. The cells were cultured in anti-CD3 antibodies and phytohemagglutinin with or without differential concentrations of dexamethasone and/or 1,25-OH2D3.

Compared with cells cultured in ethanol (controls), cells treated with 1,25-OH2D3 at concentrations of 10^-8, 10^-7, and 10^-6 mol/L had significantly decreased lymphocyte proliferation. Furthermore, the concentration of dexamethasone needed to suppress lymphocyte proliferation decreased significantly when differential concentrations of 1,25-OH2D3 were added in the same culture.

In addition, interferon-gamma production was significantly reduced among cells treated with either dexamethasone or 1,25-OH2D3, compared with control cells. When both agents were added together, interferon-gamma production was significantly lower than when 1,25-OH2D3 or dexamethasone was used alone.

A NEW OPTION FOR PSORIATIC ARTHRITIS AND PSORIASIS

Etanercept, a fusion protein that inhibits tumor necrosis factor (TNF), may be a potential addition to physicians' armamentarium against psoriatic arthritis and psoriasis, said Philip Mease, MD, medical director of the division of clinical research and clinical associate professor at the University of Washington in Seattle.

TNF is known to be present in cutaneous lesions of patients with psoriasis and in the joints of patients with psoriatic arthritis, and the TNF inhibitor etanercept has shown efficacy in improving the symptoms and limiting the progression of rheumatoid arthritis. Thus, a new study was undertaken to examine the effects of the drug in patients with psoriatic arthritis and psoriasis.

Sixty patients with active disease (ie, swollen and tender joints and disability) were randomized to etanercept (25 mg twice weekly) or placebo for three months. Patients could continue to receive methotrexate, nonsteroidal anti-inflammatory drugs, and low-dose corticosteroids; but all topical immunomodulatory medications were discontinued. Four patients in the placebo group withdrew prematurely from the study.

Articular improvement was measured by psoriatic arthritis response criteria (PsARC). Patients with more than 3% total body surface affected by psoriasis were evaluated for skin improvement by the Psoriasis Area and Severity Index (PASI) and target lesion assessment.

A significantly greater proportion of the etanercept group than the placebo group showed marked improvement on the PsARC (87% vs 23%), with a prompt and dramatic drop in tender joint and stiffness scores. In fact, 77% of the etanercept group had a positive response within one month. Furthermore, among the patients treated with etanercept, four individuals had no tender joints, seven persons reported no swollen joints, and 23 patients had normalization of C-reactive protein.

Measurements of skin involvement also showed significantly greater improvement in the etanercept-treated patients than in the placebo group. The median improvement on the PASI was 46% versus 9%, respectively, and the median improvement in the prospectively identified target lesion was 50% versus 0%, respectively. No serious adverse events were reported.

--Lawrence M. Prescott, PhD
--Kristin Della Volpe

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