Lotus Notes Document To Print: Click your browser's PRINT button. NOTE: To view the article with Web enhancements, go to: http://www.medscape.com/viewarticle/478997 Effect of Betamethasone-Loratadine Combination Therapy on Severe Exacerbations of Allergic Rhinitis A Randomised, Controlled Trial J.R. Snyman; P.C. Potter; M. Groenewald; J. Levin Clin Drug Invest 24(5):265-274, 2004. © 2004 Adis Data Information BV Posted 06/08/2004 Abstract and Introduction Abstract Objective: Corticosteroids are effective in controlling the inflammatory component of allergic rhinitis; however, evidence for the clinical efficacy of systemic corticosteroids in this disease is sparse. It is further common practice to combine oral corticosteroids with antihistamines in the treatment of acute exacerbations of allergic rhinitis. The aim of this study was to investigate the effect of low-dose oral betamethasone alone and in combination with loratadine in a group of patients with allergic rhinitis with clinically significant obstruction. Methods: In this parallel, double-blind, active controlled multicentre study, 299 patients with severe allergic rhinitis were randomly allocated to either betamethasone 1.0mg or betamethasone 1.0mg plus loratadine 10mg or betamethasone 0.5mg plus loratadine 10mg or loratadine 10mg alone for 5–7 days. Total symptom scores, nasal obstruction, and doctor and patient perception of improvement were measured as markers of disease severity. Results: Although not statistically significant, both betamethasone 1.0mg regimens resulted in a total symptom score difference of at least 1 or more from loratadine (i.e. mean [SD] change in total symptom score of 4.10 [3.10] and 4.40 [3.62] vs 3.10 [3.30], respectively, for betamethasone 1.0 mg plus loratadine, betamethasone 1.0 mg and loratadine). All corticosteroid-containing regimens were significantly better than loratadine alone with regard to the patients' (p < 0.013) and doctors' (p < 0.009) perceptions of improvement. They significantly favoured loratadine in combination with betamethasone over single-drug therapy (i.e. odds ratio: investigator ratings 0.49, 0.36 and 0.45, and patient ratings 0.47, 0.40 and 0.43, respectively, for 0.5 mg and 1.0 mg betamethasone plus loratadine and betamethasone 1.0 mg alone vs loratadine alone). Betamethasone 1.0mg plus loratadine also resulted in significant reduction of the relapse rate compared with the other therapies. Conclusions: This study demonstrated the benefit of a short course of a systemic low dosage of corticosteroids with and without antihistamine therapy during acute severe exacerbations of allergic rhinitis. Combination treatment with betamethasone 1.0mg and loratadine 10mg was significantly better in relieving symptoms of hayfever as experienced by patients. This was the first study to give evidence of benefit of systemic low-dose corticosteroids with and without an antihistamine in patients with acute exacerbations of allergic rhinitis. Introduction Allergic rhinitis affects between 15% and 20% of the population, and seasonal exacerbations account for significant morbidity in spring and summer.[1-3] Symptoms of allergic rhinoconjunctivitis that include rhinorrhoea, nasal itching, sneezing, itchy eyes and tearing are mainly attributable to histamine release from mast cells and respond significantly to antihistamine therapy.  Swelling and inflammation of the nasal mucosa and subsequent nasal obstruction are due to the release of inflammatory mediators and cytokines. There is already extensive evidence linking allergic rhinitis and other inflammatory airway conditions such as asthma, making effective treatment of allergic rhinitis a priority to prevent complications and reduce their severity. Intranasal corticosteroids are effective in controlling the inflammatory component of allergic rhinitis. [1,4,5] They are used to prevent the development of rhinitis symptoms during the pollen seasons. Clear effects on the inflammatory cell component of the disease have also been demonstrated. Evidence for the use and clinical efficacy of systemic cortico-steroids for the treatment of rhinitis is, however, sparse.[4,7] It is nonetheless common clinical practice to give short courses of systemic corticosteroids, often in combination with numerous other drugs, to patients with severe exacerbations of allergic rhinitis during the peak of the pollen season. This is in line with international guidelines for treatment of atopic rhinitis in patients with severe exacerbations poorly responding to other therapies, e.g. oral antihistamines, topical corticosteroids and decongestants.[8,9] A single study reported the benefit of methylprednisolone acetate 6 mg/day on nasal blockage in a small dose-comparing study. In this study methylprednisolone 6mg did not differ from 24 mg/day as far as blocked nose, itching and drainage were concerned.  Although oral antihistamines such as loratadine have been extensively documented for their efficacy in the treatment of seasonal and perennial allergic rhinitis, they are less effective than topical corticosteroids in relieving symptoms of nasal obstruction.[4,12] The variable nature of seasonal exacerbations in chronic allergic rhinitis have led to the development of guidelines recommending that treatment should be tailored to the severity of symptoms. [8,13] Antihistamines such as loratadine have been shown to be corticosteroid sparing in some inflammatory diseases such as asthma. Very few such studies exist for rhinitis. In one study, loratadine in combination with topical flunisolide improved symptom scores significantly more than flunisolide alone in a condition typically treated with corticosteroids only, i.e. nonallergic rhinitis with eosinophilia. One unpublished study reported significant improvement in rhinitis symptoms and in markers of inflammation when beta-methasone 0.75mg plus dexchlorpheniramine 6mg was compared with betamethasone 0.99mg, or dexchlorpheniramine 6mg alone. Study outcomes were stratified in such a manner as to make overall interpretation almost impossible. Betamethasone is marketed in South Africa as a fixed-dose combination with an antihistamine, dexchlorpheniramine (i.e. Celestamine® [Schering Plough, Isando, Johannesburg, South Africa],1 containing betamethasone 0.25mg and dexchlorpheniramine 2mg per tablet or 5mL syrup; dosing schedule 1–2 tablets four times daily), with the registered indication of acute allergic rhinitis not responding to conventional therapy. We could not find any published data of efficacy in allergic rhinitis for such a combination either as a combination or as separate components administered simultaneously. The aim of this study was therefore to investigate the effect of these low doses of betamethasone in a short-course combination with loratadine (one of the most commonly used nonsedating histamine H 1receptor blockers in South Africa) in a group of patients likely to respond to such a combination, i.e. patients with moderate to severe allergic rhinitis with clinically significant nasal obstruction. This regimen in a single morning low dosage and short duration of exposure to a systemic cortico-steroid is considered to be safer than the current practice, i.e. multiple doses for 4 days.  Since adverse effects of corticosteroids are dose and duration dependent, this regimen is considered safe, with transient effects on the hypothalamo-pituitary-adrenal (HPA) axis and no long-term metabolic effects. 1 The use of trade names is for product identification purposes only and does not imply endorsement. Patients and Methods Study Participants In this parallel, double-blind, active controlled, multicentre study, 299 patients were enrolled. Medicines were encapsulated and randomised numbers allocated by the sponsor. Patients therefore received two capsules per day, i.e. either two active capsules or one placebo and one active capsule during the active phase of the study, which was then followed by the placebo phase where patients only received single placebo capsules. Patients were scored for severity of hayfever symptoms and nasal obstruction. Patients aged over 12 years experiencing atopic rhinitis with seasonal exacerbations for two consecutive seasons caused by aero-allergens (i.e. positive skin prick test of >3mm diameter or a positive radioallergo-sorbent test [RAST] of >/=class 3 or >/=3.5 U/mL specific for tree and grass pollens) were recruited for this study. The study was performed during the high grass pollen season in South Africa, i.e. September to May, and patients with perennial symptoms had to have severe exacerbations due to these pollens as specified. The total symptoms score must have been >7 and the single symptom of nasal obstruction at least 2 for the 2 days immediately prior to inclusion. Patients without significant eye symptoms were selected. Patients had to be off the following medications prior to enrolment: 3 months for any topical or systemic corticosteroids; 2 days for antihistamines (e.g. cetirizine, fexofenadine and ebastine); 2 days for decongestants; 14 days for cromoglycate; 10 days for loratadine; and not on any other medication during the study period. The washout period was deemed appropriate for all antihistamines except loratadine (active metabolite), as their half-lives are less than 15 hours and with once-daily administration would not have reached steady-state concentrations (>90% elimination by the end of a 48-hour period). The run-in period was limited to 7 days. The study was performed in the spring-summer (2001–2002) pollen season in South Africa. Because of the severity of symptoms at inclusion the investigators believed that a placebo group was not morally justifiable. It was also decided to administer betamethasone once daily in the morning to minimise the effect on the normal rhythm of endo-genous cortisone production. Patients had to be otherwise healthy, and pregnant or breast-feeding women were excluded from entering the study. Patients with other intermittent or chronic conditions related to atopy, such as active eczema, food allergy or persistent asthma, were excluded. The study was approved by the Faculty of Health Sciences Research Ethics Committees of the Universities of Pretoria and Cape Town, as well as the South African Medical Association Research Ethics Committee, and all patients had to sign informed consent prior to entry into the study. The study was conducted in accordance with the Declaration of Helsinki (revised edition Somerset West, Republic of South Africa, October 1996). Allocation of Trial Medication Patients were randomised to receive one of the following four oral treatment modalities: betamethasone 0.5mg plus loratadine 10mg; betamethasone 1.0mg plus loratadine 10mg; betamethasone 1.0mg; or loratadine 10mg. Randomisation was carried out using random permuted blocks of size 8 and was stratified by centre. Treatment began directly after reaching the predetermined severity score for at least 2 days prior to active therapy. Active therapy was administered at about 8:00am for 5–7 days and was then followed by a further 5–7 days of placebo treatment. The dosage of betamethasone 1mg was calculated to be almost equivalent to prednisolone 7mg. Safety for the selected population for the duration of treatment was established in a previous study. In this study it was established that short-course (5-day) betamethasone 1mg treatment results in similar suppression of endogenous cortisol production to prednisolone 10mg and that normal adrenal and HPA axis functions are established within 3 days after discontinuation of therapy. Safety Data Physical examinations were performed on all participants to confirm compliance with inclusion and exclusion criteria. Peripheral venous blood samples were collected at the screening visit and at visits 2 and 3 (i.e. before and after active therapy) to evaluate liver and kidney functions, to establish an initial normal cortisol level, and to study the response to oral corticosteroid. Safety blood tests were repeated at visit 4 only if deemed clinically indicated. Evaluation of Outcomes The primary objective was to document the possible superiority of low-dose betamethasone (i.e. 0.5 or 1.0mg) in combination with loratadine over single therapy with either drug (betamethasone 1.0mg and loratadine 10mg) in relieving symptoms of allergic rhinitis (total symptoms score [TSS]). Secondary outcome parameters were the patients' and physicians' perceptions of relief and the carryover effect (sustainability after stopping therapy). An improvement difference of at least >1 TSS and an improvement of at least 1 (scale 0–3) for nasal obstruction were argued to be of clinical value. The total score of four symptoms of rhinitis, i.e. sneezing, rhinorrhoea, nasal pruritus and obstruction, each evaluated on a scale from 0 to 3, made up the TSS. Scoring was done in the morning and evening in a patient diary and the mean calculated for that day. Patients also had to judge efficacy daily on an analogue scale to measure their perception of overall symptom improvement for that day. Furthermore, at the end of the active and placebo treatment periods patients and doctors had to give their impression of improvement on a 5-point ordinal scale; i.e. no, slight, moderate, marked and complete relief of symptoms. Investigators also scored percentage nasal obstruction, using a predefined grid, judging turbinates, as >90, 80, 60 or <60% for each nostril at the beginning and at the end of each observation period. Investigators were trained to use the scoring system constantly. Relapse or sustainability of medicine effect was evaluated by looking at the deterioration of the TSS as well as the number of days taken for the TSS to deteriorate. Statistical Analysis The primary outcome measure for efficacy was the change in the TSS from baseline to the end of the active phase. The change in TSS was analysed using an analysis of covariance approach (ANCOVA), with model terms for site, treatment and baseline TSS (since the baseline TSS might affect the improvement). Importantly, there was no evidence of a site-by-treatment interaction, so this interaction term was not included in the model. Orthogonal comparisons were made to decide which treatment arm was in fact responsible for the overall treatment effect. Treatment groups were specified before the trial was conducted; the following contrasts were specified: Contrast Set 1 (i) Betamethasone versus loratadine (ii) Drug combinations versus single drug arms (iii) Corticosteroid dose in drug combinations. After a preliminary analysis of the data, it was found that the most important factor seemed to be whether the corticosteroid betamethasone was present, and this led to a second set of contrasts being proposed, namely: Contrast Set 2 (i) Higher-dose betamethasone plus loratadine versus betamethasone alone (ii) Lower-dose betamethasone versus higher dose (iii) Any betamethasone versus loratadine alone. Duncan's multiple range test, which gives the smallest difference between means that is statistically significant at the 5% level, allowing for the number of means that are being compared, was used to compare the treatment means. Thus for the change in TSS, the analysis was carried out using first the a priori contrasts, followed by the new set of contrasts and finally Duncan's multiple range test. In addition to the primary outcome, the following secondary outcome measures were analysed: 1. Improvement in the nasal blockage rating (investigator rating). This was compared between treatment arms with a χ2 test, with Fisher's Exact Test as confirmation in case of sparse cells. For case of comparison the following values were given to different percentages of obstruction: >90% = 1, 80% = 2, 60% = 3, <60% = 4, therefore allowing a maximum total score of 8 for both nostrils being less than 60% blocked (the higher the value the smaller the turbinates). 2. The analogue scale for relief score completed by the patient on each day during the active phase of treatment. The mean score was compared between treatment groups using a linear model with terms for site, treatment and baseline TSS. The treatment arms were then further compared as described for the change in TSS. 3. The degree to which any improvement was sustained is given by the increase in TSS from the end of active treatment to the end of the following week; the higher this increase, the less relief has been sustained. This was compared between treatment arms using a linear model with terms for site, treatment and baseline TSS. In addition, the change in TSS from baseline to the end of the washout period was calculated for each participant – the greater the change, the greater the long-term relief. This was also compared between treatment groups for the change in TSS at the end of active treatment. 4. The extent to which participants sustained the benefit of treatment was further explored by measuring the number of days to relapse and whether a patient relapsed. Relapse was defined as an increase in TSS of at least 2 units on a given day, where the TSS did not subsequently reduce to within 2 units of the score at the end of active therapy. Whether a patient relapsed was compared between treatment arms using a χ2 test. The number of days to relapse was compared between treatment arms using a log-rank test, and this was further explored by fitting Cox's proportional hazards regression model with terms for site, treatment and baseline TSS. The two sets of contrasts as specified for change in TSS were also examined. 5. The degree of relapse in the washout phase was also examined by looking at whether rescue medication (Drixine®, Schering Plough, Isando, Johannesburg, South Africa) was used, and if so the mean number of doses used. The comparison of whether rescue medication was used was done using a χ2 test, with further analysis using logistic regression models. 6. At the end of the trial the investigator rated the patient's response on a five-point ordinal scale (1 = complete relief, 5 = no relief or worse). These ordinal responses were compared between treatment arms using a χ2 test. Further exploration was done using McCullagh's proportional odds regression model (ordinal logistic regression). 7. Similarly, the patient rated her/his response using the same ordinal scale and this was compared between treatment arms using a χ2 test, with further analysis using ordinal logistic regression. Results Study Population Two hundred and ninety-nine patients were enrolled according to the protocol, and of these, 11 were excluded for per-protocol analysis. The excluded patients did not reach the required severity rating on randomisation. The various treatment groups were well balanced for all relevant parameters with no significant differences among them (see table I for baseline data). Outcomes Analysis of the main endpoints showed that, while not reaching statistical significance among the various treatment groups, both treatment regimens containing betamethasone 1.0mg had a TSS difference from loratadine alone of more than 1 (i.e. prespecified clinical importance). Corticosteroid-containing regimens were also significantly better than loratadine alone (p < 0.015) [table II]. The symptom score for nasal obstruction alone did not differ significantly between groups at the end of the actual treatment period. Although nasal obstruction (i.e. doctors' evaluation of turbinate swelling) was improved in more patients in the betamethasone 1.0mg plus loratadine group when compared with all other treatments, this also did not reach the predetermined level of significance. In the study 43%, 53%, 49% and 41% of patients improved, respectively, on betamethasone 0.5mg plus loratadine, betamethasone 1.0mg plus loratadine, betamethasone 1.0mg, and loratadine. Patients' perceptions of improvement as shown on a visual analogue scale of improvement demonstrated significant and clinically meaningful differences. Patients on combination therapies (corticosteroid plus antihistamine) fared significantly better (p = 0.03), and any corticosteroid-containing regimen was better than loratadine alone (p = 0.016). Loratadine in combination with betamethasone was significantly better than any single-drug therapy (p = 0.03) [table II]. The increase in TSS after the 1-week washout period was used as an indication of sustainability of effect after only 1 week's therapy. Corticosteroid-containing regimens all demonstrated good improvement from baseline (significantly different from baseline) [table II], thus allowing for relapse on stopping treatment after 1 week of therapy. The effect of betamethasone on its own and also that of the low-dose combination with loratadine were not sustainable (p = 0.005 and p = 0.039, respectively, for hazard ratios from Cox regression). Beta-methasone 1.0mg plus loratadine 10mg was significantly better and good symptom scores were retained during the placebo follow-on phase (no significant relapse). Surprisingly, in spite of this significant difference in relapse rates, there were no significant differences in the use of rescue medication among the treatment groups (p = 0.99). Investigator rating of the relief obtained clearly indicated betamethasone 1.0mg plus loratadine as the treatment with the best relief (table III). All corticosteroid-containing regimens were significantly better than loratadine alone (p = 0.009). Overall patient rating of relief echoed this, also significantly favouring the corticosteroid-containing therapies (p = 0.013). This parameter, however, demonstrated no significant differences among the betamethasone regimens. Adverse Events Patient-reported adverse events did not differ among the groups. Betamethasone resulted in a significant fall in morning cortisol after the active therapy phase. This was anticipated, and only when deemed clinically necessary were these levels repeated 7–10 days later; the latter plasma levels returned to pretreatment levels at the end of the study period. No clinical signs of adrenal suppression occurred. Discussion This study demonstrated the benefit of adding systemic low dosages of corticosteroids (short course) [betamethasone 1.0mg] to antihistamine therapy during acute severe exacerbations of allergic rhinitis. Single-agent therapy also favoured betamethasone over loratadine 10mg alone. Combination treatment with betamethasone and loratadine 10mg was significantly better in relieving symptoms of hayfever as experienced by patients. This combination containing betamethasone 1.0mg also proved superior by giving a more sustainable effect after stopping all therapy. Intergroup differences with regard to the main study outcomes (difference in TSS change and nasal obstruction score change) did not reach statistical significance. The final study size was underpowered to demonstrate such a difference. The tendency for combination betamethasone 1.0mg and loratadine 10mg to improve TSS more than other therapies should be explored further in a follow-up study. Corticosteroid-containing regimens were clinically and statistically superior to loratadine alone, with both betamethasone 1.0mg-containing regimens demonstrating a difference of >1 TSS when compared with loratadine alone. Patients and doctors favoured the combination regimens, with all corticosteroid-containing regimens being the preferred treatment, and also showed significant selection towards them on a visual analogue scale of improvement. These findings therefore support the general assumption that adding a short course of corticosteroid to the initial therapy in patients with acute exacerbations of allergic rhinitis improves symptoms and wellbeing.[4,7] The TSS is perhaps too crude a parameter to determine patient responses to therapy as a single measure of success. The development of various quality-of-life questionnaires is testimony to the importance of patients' perceptions of benefit.[23,24] In this study a rigid quality-of-life questionnaire was not used because it was argued that the short study duration would have made the existing validated scoring systems not applicable in this particular subgroup of patients. To compensate for this, the researchers included three other markers of perceived benefit: a daily visual analogue scale of improvement to be scored by the patient, and again at the end of the active treatment period a patient and doctor five-point scoring system of impression of improvement. These softer (i.e. investigator and patient perceptions such as quality of life and visual analogue scales of benefit) issues perhaps tell us more about symptom acceptability and improvement than a TSS in itself. Allergic rhinitis is but one local manifestation of a systemic reaction of the immune response to the environment. The lack of additional relief of obstruction with added beta-methasone was unexpected, as this was believed to be the single most important additional benefit that could be added by the corticosteroid.[4,10,25] Although the dose of corticosteroid was high enough to suppress adrenal corticosteroid production, it was perhaps not sufficient to inhibit the local inflammatory response significantly.[26,27] This is important, as a previous study already demonstrated the effect of methylprednisolone 6mg on nasal obstruction versus placebo. Furthermore, the anti-inflammatory activity and HPA-axis suppression by corticosteroids parallel each other and therefore HPA-axis suppression is perhaps a good measure of possible therapeutic effect. The benefit of betamethasone was therefore perhaps due to other effects of corticosteroids, e.g. inhibition of systemic cytokines with a putative feeling of well-being. This may also be due to the significant tolerance to symptoms, such as blocked nose, by individuals with chronic hayfever. This was perhaps best borne out by the fact that there was no difference in the use of rescue decongestant medication during the placebo follow-on phase. The initial exacerbation of allergic rhinitis is also known to be associated with a predominant local vasodilatory response, which may not respond early to corticosteroid therapy. The present study corroborates the findings by others who demonstrated significant benefit of an inhaled corticosteroid (fluticasone) over an antihistamine (loratadine) alone. These authors also indicated that combining a corticosteroid with an antihistamine may have significantly more benefits in some domains of quality of life compared with single corticosteroid therapy. Others demonstrated the lack of benefit of corticosteroids in all domains of rhinitis scoring (itching, running nose and sneezing).  These are typically symptoms that respond well to antihistamines. Conclusion In conclusion, this is the first study to provide evidence of benefit of a systemic short-course, low-dose corticosteroid treatment in patients with acute severe exacerbations of allergic rhinitis. Tables Table I. Study Population Demographics and Baseline Parameters of Rhinitis Treatment group B(0.5)+L B(1.0)+L B(1.0) L 72 73 73 70 29.9 (11.8) 33.1 (14.1) 29.3 (12.6) 29.4 (12.5) 0.23. male 41 37 39 51 0.34 female 59 63 61 49 asthma 15 12 18 16 0.65 food allergy 3 7 5 5 0.65 eczema 9 6 10 10 0.62 76.1 (24.5) 72.8 (17.1) 71.3 (22.2) 71.0 (16.7) 0.41 n Age (y) [mean (SD)] p-Value Sex (%) Other diseases Weight (kg) [mean (SD)] Mean (SD) baseline symptom scores TSS 9.98 (2.44) 9.85 (2.12) 10.17 (2.50) 9.91 (2.33) 0.85 nasal obstructiona 3.75 (1.31) 3.88 (1.43) 4.05 (1.46) 3.89 (1.26) 0.60 Swelling of turbinates: the higher the value the smaller the turbinates. B(0.5)+L = betamethasone 0.5mg + loratadine 10mg; B(1.0)+L = betamethasone 1.0mg + loratadine 10mg; B(1.0) = betamethasone 1.0mg; L = loratadine 10mg; TSS = total symptoms score. a Table II. Symptom Improvement at the End of the Active Treatment Period Treatment group B(0.5)+L B(1.0)+L B L 6.17 (3.28)a 5.61 (3.47)a 5.78 (3.10)a 6.72 (3.46)a TSS mean (SD) mean Δ (SD) 3.81 (3.59)b 4.10 (3.10)b 4.40 (3.62)b 3.10 (3.30) mean (SD) 4.93 (1.94) 5.39 (1.83) 5.66 (1.86) 4.96 (1.79) mean Δ in score (SD) 1.19 (2.15) 1.51 (1.85) 1.61 (2.10) 1.07 (1.90) patients improved (%) 43.1 53.4 49.3 41.4 4.58 (2.33) 4.83 (2.42)de 4.47 (2.29)e 3.93 (2.28) Nasal obstructionc Patient analogue scale for relief mean (SD) Significantly different from baseline (table I) [p = 0.05]. All corticosteroid-containing regimens (combined) significantly were better than loratadine (p = 0.015). c Swelling of turbinates: the higher the value the smaller the turbinates. Mean ? = change from baseline as in table I. d Loratadine in combination with betamethasone was significantly better than both single-drug therapies (p = 0.03). e Any corticosteroid-containing regimen was significantly better than loratadine (p = 0.016). B(0.5)+L = betamethasone 0.5mg + loratadine 10mg; B(1.0)+L = betamethasone 1.0mg + loratadine 10mg; B = betamethasone 1.0mg; L = loratadine 10mg TSS = total symptoms score; Δ = absolute change in score from baseline. a b Table III. Overall Investigator and Patient Rating of Relief Treatment group B(0.5)+L B(1.0)+L B L Patients with moderate to complete relief (%) 71.01 81.69 72.22 60.00 Odds ratio 0.49 0.36 0.45 1.0 p-Value 0.020 0.001 0.012 Patients with moderate to complete relief (%) 75.37 77.56 75.01 61.43 Odds ratio 0.47 0.40 0.43 1.0 p-Value 0.015 0.004 0.008 Investigator rating Patient rating B(0.5)+L = betamethasone 0.5mg + loratadine 10mg; B(1.0)+L = betamethasone 1.0mg + loratadine 10mg; B = betamethasone 1.0mg; L = loratadine 10mg. References 1. Davie RJ, Trigg C. Rhinitis: pathophysiology and classification. In: Holgate ST, Church MK, editors. Allergy. London: Gower Medical Publishing, 1993: 17.1-10 2. Woolcock AJ, Peat JK, Trevillion LM. Changing prevalence of allergies worldwide. In: Johanson SGO, editor. Progress in allergy and clinical immunology. Vol 3. Seattle: Hogrefe and Huber Publishers, 1994: 167-71 3. Rachelefsky GS. National guidelines needed to manage rhinitis and prevent complications. Ann Allergy Asthma Immunol 1999; 82: 296-305 4. Mygind N, Dahl R, Nielsen LP, et al. Effect of corticosteroids on nasal blockage in rhinitis measured by objective methods. Allergy 1997; 52 (S40): 39-44 5. Holm AF, Godthelp T, Fokkens WJ, et al. Longterm effects of corticosteroid nasal spray on nasal inflammatory cells in patients with perennial allergic rhinitis. Clin Exp Allergy 1998; 2: 1356-66 6. Jacobson MR, Juliasson S, Löurhagen O, et al. Effect of topical corticosteroids on seasonal increases in epithelial eosinophils and mast cells in allergic rhinitis: a comparison of nasal brush and biopsy methods. Clin Exp Allergy 1999; 29: 1347-55 7. Mygind N, Laursen LC, Dahl M. Systemic corticosteroid treatment for seasonal allergic rhinitis: a common but poorly documented therapy. Allergy 2000; 55: 11-5 8. Dykewicz MS, Fineman S, for the Workgroup on Rhinitis. Diagnosis and management of rhinitis: complete guidelines of the joint task force on practice parameters in allergy, asthma and immunology. Ann Allergy Asthma Immunol 1998; 81: 478-518 9. Prodigy Guidance: allergic rhinitis [online]. Available from URL: www.prodigy.nhs.uk/guidance.asp.gt.allergic rhinitis. [Accessed 2003 Jan] 10. Brooks CD, Karl KJ, Francon SF. Oral methylprednisolone acetate (Medrol tablets) for seasonal rhinitis: examination of dose and symptom response. J Clin Pharmacol 1993; 33: 816-22 11. Bruttman G, Charpin D, Germonty J, et al. Evaluation of the efficacy and safety of loratadine in perennial allergic rhinitis. J Allergy Clin Immunol 1989; 83: 411-6 12. Jordana G, Dolovich J, Briscoe MP, et al. Intranasal fluticasone propionate versus loratadine in the treatment of adolescent patients with seasonal allergic rhinitis. J Allergy Clin Immunol 1996; 97: 588-95 13. South African Allergic Rhinitis Working Group. South African rhinitis guidelines. S Afr Med J 1996; 86 (10 Pt 2): 1315-28 14. Youssef HH, Ali NA, Farouk AK, et al. The effects of loratadine in patients with allergic bronchial asthma. JAMA 1996; 6: 37-42 15. Purello-D'Ambriosio F, Isola S, Ricciardi L, et al. A controlled study on the effectiveness of loratadine in combination with flunisolide in the treatment of nonallergic rhinitis with eosinophilia (NARES). Clin Exp Allergy 1999; 29: 1143-7 16. Data on file, Schering-Plough (Pty) Ltd, Isando, South Africa. Effect of celestamine in nasal allergy: statistical comparison between an antihistamine, a steroid, and a combination of the two by the double-blind method 17. MIMS medical specialities (monthly medicine update from Johnnic publishing limited, JR Snyman, editor). November 2003, 43 (11): 312 18. Costa J. Corticotrophins and corticosteroids. In: Dulas MNG, Aronson JK, editors. Meylers' side effects of drugs. 14th ed. Amsterdam: Elsevier, 2000: 1364-95 19. Snyman JR, Sommers De K, Van Wyk M, et al. Short-course, low dose betamethasone therapy causes only marginal and transient hypothalamic-pituitary-adrenal-axis suppression. Clin Drug Invest 2001; 21 (7): 499-504 20. Betamethasone. In: Reynolds JEF, editor. Martindale: the extra pharmacopoeia. 30th ed. London: The Pharmaceutical Press, 1993: 724-5 21. Steel RGD, Torrie JH. Principles and procedures of statistics: a biometrical approach. Chapter 8: Multiple comparisons. 2nd ed. Tokyo: McGraw Hill, 1980: 172-94 22. McCullagh P. Regression models for ordinal data (with discussion). J Royal Stat Soc (series B) 1980; 42: 109-42 23. De Graaf-in't Veld T, Koenders S, Garrelds IM, et al. The relationship between nasal hyperreactivity, quality of life and nasal symptoms in patients with perennial allergic rhinitis. J Allergy Clin Immunol 1996; 98: 508-13 24. Juniper EF. Rhinitis management: the patients perspective. Clin Exp Allergy 1998; 28 (S6): 34-8 25. Kronholm A. Injectable depot corticosteroid therapy in hay fever. J Int Med Res 1979; 7: 314-7 26. Ohlander BO, Hansson RE, Karlsson K-E. A comparison of three injectable corticosteroids for the treatment of patients with seasonal hay fever. J Int Med Res 1980; 8: 63-9 27. Ratner PH, Van Bavel JH, Martin BG, et al. A comparison of the efficacy of fluticasone propionate aqueous nasal spray and loratadine, alone and in combination for the treatment of seasonal allergic rhinitis. J Fam Pract 1998; 47: 118-25 28. Prednisolone and prednisone. In: Dollery C, editor. Therapeutic drugs. 2nd ed. Edinburgh: Churchill Livingstone, 1999: P192-8 Acknowledgements The Claricort Study Group: P. Crossland, H. du Preez, I. Engelbrecht, K.C. Esterhuizen, E.J. Evans, M. Groenewald, L.G. Herbst, R. Heitner, M.H. Hockman, D. Lakha, L. Leaver, H. Makan, W.E. Mans, P.C. Potter, A.S. Putterman, G.J. Ras, C.J.B. Smit, J.R. Snyman, J. Steer, C.O. van Bergen, B.J. van der Merwe, A. Viljoen. Funding Information The Claricort Study Group would like to thank Schering Plough (Pty) Ltd South Africa for their sponsorship of this study and Mrs J. Bekker for secretarial support. Reprint Address Correspondence and offprints: Prof. J.R. Snyman, Department of Pharmacology, Faculty of Health Sciences, University of Pretoria, PO Box 2034, Pretoria, 0001, South Africa. E-mail: [email protected] J.R. Snyman1, P.C. Potter2, M. Groenewald3, J. Levin4, for the Claricort Study Group Department of Pharmacology, Faculty of Health Sciences, University of Pretoria, Pretoria, South Africa, Allergology Diagnostic and Clinical Research Unit, Department of Immunology, University of Cape Town, Cape Town, South Africa, 3Department of Paediatrics, 1 Military Hospital, Pretoria, South Africa, 4 Biostatistics Unit, Medical Research Council of South Africa, Pretoria, South Africa 1 2 Disclosure: The authors have no conflicts of interest that may have influenced this study.