Mutation of a new gene encoding a putative pyrin-like protein causes familial cold autoinflammatory syndrome and Muckle-Wells syndrome.

Familial cold autoinflammatory syndrome (FCAS, MIM 120100), commonly known as familial cold urticaria (FCU), is an autosomal-dominant systemic inflammatory disease characterized by intermittent episodes of rash, arthralgia, fever and conjunctivitis after generalized exposure to cold. FCAS was previously mapped to a 10-cM region on chromosome 1q44 (refs. 5,6). Muckle-Wells syndrome (MWS; MIM 191900), which also maps to chromosome 1q44, is an autosomal-dominant periodic fever syndrome with a similar phenotype except that symptoms are not precipitated by cold exposure and that sensorineural hearing loss is frequently also present. To identify the genes for FCAS and MWS, we screened exons in the 1q44 region for mutations by direct sequencing of genomic DNA from affected individuals and controls. This resulted in the identification of four distinct mutations in a gene that segregated with the disorder in three families with FCAS and one family with MWS. This gene, called CIAS1, is expressed in peripheral blood leukocytes and encodes a protein with a pyrin domain, a nucleotide-binding site (NBS, NACHT subfamily) domain and a leucine-rich repeat (LRR) motif region, suggesting a role in the regulation of inflammation and apoptosis.

Familial cold autoinflammatory syndrome: phenotype and genotype of an autosomal dominant periodic fever.

BACKGROUND: Familial cold autoinflammatory syndrome (FCAS), commonly known as familial cold urticaria, is a rare autosomal dominant inflammatory disorder with episodic symptoms precipitated by exposure to cold. OBJECTIVE: The goal of this study was to formulate clinical diagnostic criteria for FCAS in a large cohort in whom the diagnosis of FCAS was supported by genetic linkage to chromosome 1q44. METHODS: We assessed 45 affected and 68 unaffected members from 6 American families. DNA analysis was performed to confirm linkage to chromosome 1q44. Clinical characteristics were determined by means of analysis of detailed questionnaires and medical histories. RESULTS: Pedigree and genetic analyses confirmed autosomal dominant transmission and linkage to chromosome 1q44 in all families. The most consistent symptoms during attacks were rash (100%), fever (93%), arthralgia (96%), and conjunctivitis (84%). Age of onset was within the first 6 months of life in 95% of affected subjects. The average delay between cold exposure and onset of symptoms was 2.5 hours, and the average duration of an episode was 12 hours. Renal disease with amyloidosis occurs infrequently in FCAS (2%). CONCLUSION: The most consistent clinical characteristics of FCAS that discriminate it from other periodic fevers are association with cold exposure, conjunctivitis, age of onset, duration of episodes, and an autosomal dominant inheritance pattern. On the basis of the analysis of genotype and phenotype of FCAS, we formulated clinical diagnostic criteria that can be used to distinguish FCAS from other hereditary periodic fever syndromes.

Identification of a locus on chromosome 1q44 for familial cold urticaria.

Familial cold urticaria (FCU) is a rare autosomal dominant inflammatory disorder characterized by intermittent episodes of rash with fever, arthralgias, conjunctivitis, and leukocytosis. These symptoms develop after generalized exposure to cold. Some individuals with FCU also develop late-onset reactive renal amyloidosis, which is consistent with Muckle-Wells syndrome. By analyzing individuals with FCU from five families, we identified linkage to chromosome 1q44. Two-point linkage analysis revealed a maximum LOD score (Zmax) of 8.13 (recombination fraction 0) for marker D1S2836; multipoint linkage analysis identified a Zmax of 10. 92 in the same region; and haplotype analysis defined a 10.5-cM region between markers D1S423 and D1S2682. Muckle-Wells syndrome was recently linked to chromosome 1q44, which suggests that the two disorders may be linked to the same locus.

Absence of growth retardation in children with perennial allergic rhinitis after one year of treatment with mometasone furoate aqueous nasal spray.

OBJECTIVE: Intranasal corticosteroids are used widely for the treatment of allergic rhinitis because they are effective and well tolerated. However, their potential to suppress growth of pediatric subjects with allergic rhinitis continues to be a concern, particularly in light of reports of growth suppression after treatment with intranasal beclomethasone dipropionate or intranasal budesonide (see the article by Skoner et al in this month's issue). A 1-year study of prepubertal patients between 3 and 9 years of age with perennial allergic rhinitis was conducted to assess the effects on growth of mometasone furoate aqueous nasal spray (MFNS), a new once-daily (QD) intranasal corticosteroid with negligible bioavailability. METHODS: This was a randomized, placebo-controlled, double-blind, multicenter study. Ninety-eight subjects were randomized to treatment with either MFNS 100 microg QD or placebo for 1 year. Each subject's height was required to be between the 5th and 95th percentile at baseline, and skeletal age at screening was required to be within 2 years of chronological age, as determined by left wrist x-rays. Washout periods for medications that affect either childhood growth or allergic rhinitis symptoms were established based on estimated period of effect, and these medications were prohibited during the study. However, short courses of either oral prednisone lasting no longer than 7 days or low-potency topical dermatologic corticosteroids lasting no longer than 10 days were permitted if necessary. Height was measured with a calibrated stadiometer at baseline and at 4, 8, 12, 26, 39, and 52 weeks, and the primary safety variable was the change in standing height. The rate of growth was also calculated for each subject as the slope (linear regression) of the change in height from baseline using data from all visits of subjects who had at least 2 visits. Hypothalamic-pituitary-adrenocortical- (HPA)-axis function was assessed via cosyntropin stimulation testing at baseline and at 26 and 52 weeks. All analyses were based on all randomized subjects (intent-to-treat principle). The change from baseline in standing height was analyzed by a 2-way analysis of variance that extracted sources of variation attributable to treatment, center, and treatment-by-center interaction. RESULTS: Demographic characteristics were similar at baseline. Eighty-two subjects completed the study (42 in the MFNS group and 40 in the placebo group), and 93% of subjects achieved at least 80% compliance with therapy. After 1 year of treatment, no suppression of growth was seen in subjects treated with MFNS, and mean standing heights were similar for both treatment groups at all time points. For the primary safety variable (change in height from baseline), both treatment groups were similar at all time points except for weeks 8 and 52. Subjects treated with MFNS had a slightly greater mean increase in height than subjects treated with placebo at these time points: the change in height was 6.95 cm versus 6.35 cm at the 1-year time point. However, the rate of growth (.018 cm/day) averaged for all time points over the course of the study was similar for both treatment groups. Additional analyses found that MFNS did not retard growth in any sex or age subgroup of subjects. The use of exogenous corticosteroids other than the study drug was also similar among the 2 treatment groups. Results from cosyntropin stimulation testing confirmed the absence of systemic effects of MFNS. The change from baseline in the difference between prestimulation and poststimulation levels was similar for both treatment groups after 1 year of treatment, with no evidence of HPA-axis suppression in MFNS-treated subjects at any time point. Incidences of treatment-related adverse events were similar for both treatment groups, with 16% of MFNS-treated subjects reporting adverse events, compared with 22% of placebo-treated subjects. CONCLUSIONS: (ABSTRACT TRUNCATED)

Dose-ranging study of a new steroid for asthma: mometasone furoate dry powder inhaler.

A new formulation of mometasone furoate (MF) for administration by dry powder inhaler (DPI) was evaluated for the treatment of asthma. A 12-week, double-blind, placebo-controlled dose-ranging study compared the efficacy and safety of three doses of MF DPI (100, 200 and 400 mcg b.i.d) with beclomethasone dipropionate (BDP) 168 mcg b.i.d. administered by metered dose inhaler in 365 adult or adolescent patients being treated with inhaled glucocorticoids. The mean change from baseline to endpoint (last treatment visit) for forced expiratory volume in 1 sec (FEV1) was the primary efficacy variable. Secondary efficacy variables included other objective measures of pulmonary function [forced vital capacity (FVC), forced expiratory flow 25-75% (FEV25-75%.) and peak expiratory flow rate (PEFR)] as well as subjective measures of therapeutic response (patients' daily evaluation of asthma symptoms and physicians' evaluation). At endpoint, all four active treatments were significantly more effective than placebo (P < 0.01) in improving FEV1 (MF DPI 5 to 7%, BDP 3%, placebo -6.6%) and all other measures of pulmonary function (FVC: MF DPI 4 to 5%, BDP 2%, placebo -4.7%; FEF25-75%: MF DPI 6 to 18%, BDP 7.5%, placebo -9.5%; PEFR (AM): MF DPI 5 to 10%, BDP 5.7%, placebo -7%). A consistent trend was observed for better improvement in patients treated with MF DPI 200 mcg b.i.d. than with MF DPI 100 mcg b.i.d., with no apparent additional benefit of MF DPI 400 mcg b.i.d. Results for the MF DPI 100 mcg b.i.d. and BDP 168 mcg b.i.d. treatment groups were similar. Patients' and physicians' subjective evaluations of symptoms found similar improvement in the MF DPI 200 and 400 mcg b.i.d. treatment groups, which were slightly better than that in the MF DPI 100 mcg b.i.d. group. Symptoms tended to worsen in the placebo group. MF DPI was well tolerated at all dose levels and the most frequently reported treatment-related adverse effects were headache, pharyngitis and oral candidiasis. No evidence of HPA-axis suppression was detected in any treatment group. In summary, all doses of MF DPI were well tolerated and significantly improved lung function and MF DPI 400 mcg (200 mcg b.i.d.) was the optimal dose in this study of patients with moderate persistent asthma.

Rapid onset of control with budesonide Turbuhaler in patients with mild-to-moderate asthma.

BACKGROUND: Budesonide (Pulmicort) is an inhaled corticosteroid with high topical potency but low systemic activity. Turbuhaler is a novel breath-actuated, multi-dose, dry-powder inhaler. OBJECTIVES: This study was conducted to determine the efficacy and safety of two different dose regimens of budesonide Turbuhaler, compared with placebo, in adult patients with mild-to-moderate asthma not well-controlled with bronchodilator therapy. METHODS: This double-blind, randomized, placebo-controlled, parallel-group, multicenter study compared the efficacy and safety of 200 microg and 400 microg of budesonide, administered twice daily via Turbuhaler, with placebo, in 273 adult patients (aged 19 to 70 years) with mild-to-moderate asthma (FEV1 67% of predicted normal), not well-controlled with bronchodilator therapy. Efficacy was assessed by pulmonary function tests and patient assessments of asthma symptom control. Safety was assessed in terms of adverse events, laboratory evaluations, and physical examinations. RESULTS: Two hundred and 400 microg of budesonide bid were significantly more effective than placebo at improving morning PEF (mean differences from placebo of 43.63 L/min and 40.10 L/min, respectively; P < .001) and FEV1 (mean differences from placebo of 0.44 L, and 0.50 L, respectively; P < .001) over the 12-week treatment period. Onset of action as assessed by morning PEF was within two days. Basal and stimulated plasma cortisol concentrations were not significantly affected by budesonide treatment compared with placebo. CONCLUSIONS: Treatment of adults suffering from mild-to-moderate asthma with budesonide Turbuhaler is well tolerated and results in a rapid onset of asthma control which is maintained over time.

Tri-Nasal triamcinolone acetonide nasal spray 200 and 400 micrograms qd versus placebo and Nasacort triamcinolone acetonide nasal aerosol 440 micrograms qd in patients suffering from seasonal allergic rhinitis during the grass season.

Tri-Nasal Nasal Spray is an investigational solution of triamcinolone acetonide (TAA) currently being evaluated as a treatment for allergic rhinitis. The safety and efficacy of 200 and 400 micrograms once daily doses of Tri-Nasal Nasal Spray, an active control (440 micrograms once daily of Nasacort Nasal aerosol), and Tri-Nasal Nasal Spray placebo were compared over a 2-week treatment period in a double-blind (the Nasacort treatment was not blinded), parallel design trial. A total of 377 adult patients in 13 centers were enrolled during the grass pollen season. The primary efficacy variable was the weekly average of the SSI (Symptom Severity Index), the sum of daily nasal congestion, rhinorrhea, and sneezing severity scores from the patient diary. A total of 355 patients completed the study. All active treatments were significantly more effective than placebo in relieving nasal symptoms at each treatment week. The 400 micrograms Tri-Nasal Nasal Spray and Nasacort treatments had a rapid onset of action, demonstrating significant improvement in the SSI versus placebo by the second day of treatment. Results for the individual nasal symptoms and other secondary efficacy measures paralleled those of the primary efficacy variables. Tri-Nasal Nasal Spray and Nasacort were comparable in safety, and in treating the nonocular symptoms of seasonal allergic rhinitis.

Efficacy and safety of loratadine plus pseudoephedrine in patients with seasonal allergic rhinitis and mild asthma.

BACKGROUND: Antihistamines have been shown to have a variety of therapeutic effects in asthma. Although nasal obstruction may play an important role in modulating lower airway function, no prior trial has used a decongestant in combination with an antihistamine in patients with allergic rhinitis and concomitant asthma. OBJECTIVE: We sought to determine the efficacy and safety of loratadine (5 mg) plus pseudoephedrine (120 mg) (L/P) twice daily in patients with seasonal allergic rhinitis and mild asthma. METHODS: We conducted a randomized, double-blind, placebo-controlled trial of L/P in 193 subjects during the fall allergy season. Nasal and chest symptoms, albuterol use, and peak expiratory flow rates were recorded daily for 6 weeks. Spirometry was measured at baseline and after 1, 2, 4, and 6 weeks of therapy, and health-related quality of life was rated at the beginning and end of the study. RESULTS: Total rhinitis and asthma symptom severity scores were significantly reduced in patients receiving active therapy compared with those receiving placebo throughout the 6-week study. Peak expiratory flow rates improved significantly in patients treated with L/P during weeks 2 through 6 (peak effect [mean +/- SEM]: L/P, 26.23 +/- 4.64 L/min vs placebo, 8.52 +/- 3.53 L/min, p = 0.002) as did FEV1 (peak effect [mean +/- SEM]: L/P, 170 +/- 53 ml vs placebo, 20 +/- 40 ml, p = 0.01) at all clinic visits. In addition, select measures of asthma-specific quality of life improved significantly relative to placebo. CONCLUSIONS: L/P significantly improved nasal and asthma symptoms, pulmonary function, and quality of life in patients with seasonal allergic rhinitis and concomitant mild asthma.

Detection characteristics of a commercially available sulfite detection test (SULFITEST): problems with decreased sensitivity and false negative reactions.

Recently, a product (SULFITEST; Center Laboratories) has become available for detecting the presence of sulfiting agents in foods. Testing with SULFITEST by the indirect method (ie, holding the test strip above the food product) or the direct method (ie, touching the test strip directly on the food) was associated with false negative results in five out of nine acidic sulfite-containing foods. Quantitative studies also confirmed that low pH conditions and/or the presence of ascorbic acid caused SULFITEST results by the direct method to significantly underestimate known concentrations of sulfites. Dependence on this sulfite detection strip may lead to unrecognized ingestion of sulfiting agents, especially in acidic and/or ascorbic acid-containing foods.

Clinical characteristics of cold-induced systemic reactions in acquired cold urticaria syndromes: recommendations for prevention of this complication and a proposal for a diagnostic classification of cold urticaria.

The acquired cold urticaria (ACU) syndromes consists of nonfamilial heterogeneous disorders characterized by urticaria, angioedema, and occasionally symptoms of hypotension after cold exposure. In a study of 50 consecutive patients with ACU syndromes, it was observed that 70% experienced cold-induced systemic reactions, most frequently with aquatic activities. Patients with ACU syndromes were categorized by their response to an experimental cold-stimulation time test (CSTT) i.e., minimum time threshold of cold stimulation required to induce a coalescent wheal. One subpopulation of patients with ACU syndromes with positive CSTTs of 3 minutes or less experienced the highest incidence (68%; 13/19) of severe systemic reactions with hypotensive symptoms after natural cold exposure. However, 32% of patients with ACU syndromes (6/19) who experienced cold-induced systemic reactions with hypotension had a negative CSTT or a positive test of greater than 3 minutes. These observations indicate that all patients with ACU with active histories of cold urticaria are at risk to develop systemic reactions to cold and should therefore refrain from participating in aquatic activities. In addition, high-risk patients should receive prophylactic medications (i.e., cyproheptadine or doxepin) that are effective in suppressing this disorder. A diagnostic classification of cold urticaria is presented. This classification permits a more specific definition of the various cold urticaria disorders that comprise the ACU syndromes.

Association of platelet-activating factor with primary acquired cold urticaria.

We investigated the possibility that the inflammatory reaction in primary acquired cold urticaria might be associated with the release of platelet-activating factor. Six patients with the disease and five normal controls were subjected to cold-water challenges during which blood samples were obtained for measurement of the release of possible mediators: i.e., histamine, neutrophilic chemotactic activity, and platelet-activating factor-like lipid (PAF-LL). Four of the patients had pronounced experimentally induced cold urticaria with angioedema and release of mediators. Levels of the three mediators were not elevated in five normal controls or in two patients in whom cold challenges induced only mild urticaria and angioedema. The effective suppression of cold-induced urticaria in three patients treated with doxepin correlated with inhibition of PAF-LL release but not inhibition of histamine or neutrophilic chemotactic activity release. These data suggest a positive correlation between PAF-LL release and cold urticaria, although the exact relation between PAF-LL and cutaneous lesions of primary acquired cold urticaria has not yet been established.

Urticarial leukocytoclastic vasculitis with cold urticaria. Report of a case and review of the literature.

A patient was seen with cold urticaria and urticarialike lesions with palpable purpura, acquired hypocomplementemia, low levels of circulating immune complexes, and skin biopsy evidence of necrotizing vasculitis. The association of cold urticaria with urticarialike vasculitis may represent a previously unrecognized subset of urticarial vasculitis.

Primary acquired cold urticaria. Double-blind comparative study of treatment with cyproheptadine, chlorpheniramine, and placebo.

Eight subjects with primary-acquired cold urticaria were treated with chlorpheniramine maleate, cyproheptadine hydrochloride, and placebo in a double-blind clinical trial. During three separate seven-day treatment periods, each patient took 4 mg of either active drug or lactose placebo three times a day. Objective measurements were made at the beginning and end of each treatment period by establishing the minimum time (MT) of cold stimulus application required to provoke urtication. In addition, the spontaneous appearance of cold urticaria lesions was recorded during each treatment period. The MT required for induction of urtication with a cold stimulus was significantly greater for eight patients receiving cyproheptadine as compared to chlorpheniramine or placebo (P less than .01). The study demonstrated that cyproheptadine had a significant suppressive action on experimental cold-induced urticaria, while placebo and chlorpheniramine proved ineffective.