Portal de Periódicos da CAPES

Uncontrolled allergic rhinitis during treatment and its impact on quality of life: A cluster randomized trial

2010; Elsevier BV; Volume: 126; Issue: 3 Linguagem: Inglês

10.1016/j.jaci.2010.06.034

1097-6825

Philippe‐Jean Bousquet, Claus Bachert, Giorgio Walter Canonica, Thomas B. Casale, Joaquim Mullol, J.‐M. Klossek, Torsten Zuberbier, Jean Bousquet,

Dermatology and Skin Diseases

To the Editor: The treatment of allergic rhinitis is now well established. Although the majority of patients present with controlled symptoms during treatment, many are still uncontrolled, leading to the concept of severe chronic upper airway disease (SCUAD).1Bousquet J. Bachert C. Canonica G.W. Casale T.B. Cruz A.A. Lockey R.J. et al.Unmet needs in severe chronic upper airway disease (SCUAD).J Allergy Clin Immunol. 2009; 124: 428-433Abstract Full Text Full Text PDF PubMed Scopus (199) Google Scholar Patients with SCUAD are likely to have an impaired quality of life affecting social functioning, sleep, school results, and/or work performance. However, this concept requires validation. As a pilot study to investigate SCUAD, the prevalence of uncontrolled rhinitis after 2 weeks of treatment and its impact on quality of life and work productivity were assessed on the basis of a post hoc analysis carried out from a published pragmatic, cluster-randomized trial.2Bousquet J. Bodez T. Gehano P. Klossek J.M. Liard F. Neukirch F. et al.Implementation of guidelines for allergic rhinitis in specialist practices: a randomized pragmatic controlled trial.Int Arch Allergy Immunol. 2009; 150: 75-82Crossref PubMed Scopus (21) Google Scholar Methods have been described2Bousquet J. Bodez T. Gehano P. Klossek J.M. Liard F. Neukirch F. et al.Implementation of guidelines for allergic rhinitis in specialist practices: a randomized pragmatic controlled trial.Int Arch Allergy Immunol. 2009; 150: 75-82Crossref PubMed Scopus (21) Google Scholar and are summarized in this article's Online Repository at www.jacionline.org. For the treatment of patients with allergic rhinitis during the grass pollen season, allergy or ears, nose and throat specialists were randomized to follow a strategy based on Allergic Rhinitis and its Impact on Asthma (ARIA)3Bousquet J. Van Cauwenberge P. Khaltaev N. Allergic rhinitis and its impact on asthma.J Allergy Clin Immunol. 2001; 108: S147-S334Abstract Full Text Full Text PDF PubMed Google Scholar or free-choice treatment, according to their practice. The study was performed in France. Outcomes included a Rhinitis Total Symptom Score (RTSS4: nasal obstruction, pruritus, sneezing, and rhinorrhea) monitored daily for 14 days using a diary. The self-administered disease-specific Rhinoconjunctivitis Quality of Life Questionnaire (RQLQ; 28 questions),4Juniper E.F. Thompson A.K. Ferrie P.J. Roberts J.N. Validation of the standardized version of the Rhinoconjunctivitis Quality of Life Questionnaire.J Allergy Clin Immunol. 1999; 104: 364-369Abstract Full Text Full Text PDF PubMed Scopus (184) Google Scholar the Allergy-Specific Work Productivity and Impairment questionnaire (WPAI-AS),5Reilly M.C. Zbrozek A.S. Dukes E.M. The validity and reproducibility of a work productivity and activity impairment instrument.Pharmacoeconomics. 1993; 4: 353-365Crossref PubMed Google Scholar and a visual analog scale (VAS) for the global evaluation of rhinitis6Bousquet P.J. Combescure C. Neukirch F. Klossek J.M. Mechin H. Daures J.P. et al.Visual analog scales can assess the severity of rhinitis graded according to ARIA guidelines.Allergy. 2007; 62: 367-372Crossref PubMed Scopus (143) Google Scholar were measured at baseline and after 14 days of treatment. Ocular symptoms were assessed both by questionnaire and the RQLQ eye symptom domain (E-RQLQ). An a priori definition of SCUAD was used: a VAS level for the global evaluation of rhinitis ≥5 cm (0-10 cm scale) and/or severe ocular symptoms defined by the occurrence of ocular symptoms in the diary and RQLQ (E-RQLQ ≥2.5, cutoff level at the 75th percentile of E-RQLQ). The only patients considered for the analysis were those who completed the evaluation of all of the outcomes at baseline and after treatment. Because data were not normally distributed after treatment, medians 25th to 75th percentiles and nonparametric tests were used. Patients were recruited between March 8 and July 15, 2002. A total of 399 physicians enrolled 796 patients. Two hundred ten patients (26.4%) were excluded from the analysis (see this article's Fig E1 in the Online Repository at www.jacionline.org). At baseline, characteristics of the patients were similar and not clinically different between treatment groups (see this article's Table E1 in the Online Repository at www.jacionline.org). Most of the patients at baseline presented with moderate/severe allergic rhinitis as defined by ARIA (see this article's Fig E2 in the Online Repository at www.jacionline.org). Individual outcomes were normally distributed at baseline and skewed after treatment. After treatment, symptom scores were reduced, and quality of life and productivity were improved. The differences between free-choice treatment and ARIA appear to be small, even if significantly different (see this article's Table E2 in the Online Repository at www.jacionline.org). Eighty-two patients presented a VAS ≥5 cm, 52 (18.1%) in the free-choice treatment and 30 (10.3%) in the ARIA-based strategy. Patients with bothersome eye symptoms (ocular symptoms and E-RQLQ ≥2.5) corresponded respectively to 9.1% (26) and 9.0% (27). Overall, 111 (18.9%) patients presented an uncontrolled rhinitis after treatment (VAS ≥5 cm and/or bothersome eye symptoms): 58 with a VAS ≥5 cm, 29 with an E-RQLQ ≥2.5, and 24 with both VAS ≥5 cm and E-RQLQ ≥2.5. At baseline, patients in the SCUAD group were slightly younger (P =.04), but there were no differences in sex, tobacco-smoking habits, or asthma. They did not have more severe disease at baseline than controlled patients. In the current study, it was found that SCUAD, a newly described phenotype of allergic rhinitis,1Bousquet J. Bachert C. Canonica G.W. Casale T.B. Cruz A.A. Lockey R.J. et al.Unmet needs in severe chronic upper airway disease (SCUAD).J Allergy Clin Immunol. 2009; 124: 428-433Abstract Full Text Full Text PDF PubMed Scopus (199) Google Scholar is present in around 10% to 20% of patients with allergic rhinitis. Patients with SCUAD present uncontrolled nasal and/or ocular symptoms and an impaired quality of life and work performance. We used a cluster-randomized trial aiming to mimic real life. There was no exclusion of patients at randomization, as is often the case in clinical trials, because we wanted to study the whole range of patients regularly seen by physicians. Although the treatment was administered by specialists, it was found that the ARIA-based strategy was more effective than the free-choice treatment.2Bousquet J. Bodez T. Gehano P. Klossek J.M. Liard F. Neukirch F. et al.Implementation of guidelines for allergic rhinitis in specialist practices: a randomized pragmatic controlled trial.Int Arch Allergy Immunol. 2009; 150: 75-82Crossref PubMed Scopus (21) Google Scholar Some limitations may exist in this article. Many methods assess the efficacy of a treatment for allergic rhinitis, but in outpatient clinics, there is no validated objective test.7Bousquet J. Khaltaev N. Cruz A.A. Denburg J. Fokkens W.J. Togias A. et al.Allergic Rhinitis and its Impact on Asthma (ARIA) 2008 update (in collaboration with the World Health Organization, GA(2)LEN and AllerGen).Allergy. 2008; 63: 8-160Crossref PubMed Scopus (3840) Google Scholar Symptom scores and quality of life measurements have been used. These 2 methods assess the different characteristics of the patients. The VAS is a technique used to measure subjective phenomena, and changes in VAS within patients are more appropriate for study purposes than single measurements. This is why, in the current study, we used a cutoff level (≥5 cm) probably greater than needed to characterize uncontrolled rhinitis. In a recent article in the same population, we found that a cutoff level of 3 cm was sufficient when the VAS was measured at 2 intervals. There was no validated ocular symptom outcome, so we selected E-RQLQ in patients with ocular symptoms reported in a diary. The cutoff level was set at the 75th percentile. In asthma, control is a key outcome, independent of asthma medications. A similar independent relationship was proposed in allergic rhinitis.1Bousquet J. Bachert C. Canonica G.W. Casale T.B. Cruz A.A. Lockey R.J. et al.Unmet needs in severe chronic upper airway disease (SCUAD).J Allergy Clin Immunol. 2009; 124: 428-433Abstract Full Text Full Text PDF PubMed Scopus (199) Google Scholar However, this concept had never been defined in a study. In this study, it has been shown that the SCUAD phenotype is a common problem, as suspected in clinical practice. SCUAD should apply only to patients who, despite adequate treatment, are still uncontrolled. It was found that SCUAD was present in around 10% to 20% of these patients when VAS and ocular symptoms were considered. Impact on quality of life and work productivity is highly relevant in SCUAD. Although improved by comparison to pretreatment, patients with SCUAD had a significantly impaired quality of life (median RQLQ before treatment and during treatment, 2.77 and 2.04, respectively) whereas the median RQLQ of controlled patients was 0.58. Moreover, all RQLQ domains were significantly altered in SCUAD when compared with controlled patients. Similar results were observed for work productivity. Patients with SCUAD require a more effective treatment since their quality of life and work productivity remain impaired. They may be ideal candidates for specific immunotherapy or novel treatments yet to be developed. Because the current study is a post hoc analysis, further studies are needed to confirm the concept. This investigator cluster-randomized, multicenter, multinational, open-label, parallel study compared 2 therapeutic strategies in allergic rhinitis during a 2-week treatment period. Allergy, ears, nose, and throat and chest specialists practicing in all regions of France were randomized into 2 groups and were to enroll 2 patients only. Each physician recruited the first 2 patients who, during the grass pollen season, suffered from allergic rhinitis due to pollen allergy. Physicians from the first group enrolled patients and followed a simple strategy based on the ARIA guidelinesE1Bousquet J. Van Cauwenberge P. Khaltaev N. Allergic rhinitis and its impact on asthma.J Allergy Clin Immunol. 2001; 108: S147-S334Abstract Full Text Full Text PDF PubMed Scopus (2156) Google Scholar using a VAS level to assess severity. Patients with a VAS level ≥5 cm (scale, 0-10 cm) were considered as having moderate to severe rhinitis.E2Bousquet P.J. Combescure C. Klossek J.M. Daures J.P. Bousquet J. Change in visual analog scale score in a pragmatic randomized cluster trial of allergic rhinitis.J Allergy Clin Immunol. 2009; 123: 1349-1354Abstract Full Text Full Text PDF PubMed Scopus (101) Google Scholar Physicians from the second group (free-choice treatment group) enrolled patients and treated them as usual in normal practice. The investigators assigned to the free-choice treatment group were not instructed to use the results of the VAS. Only depot corticosteroids were disallowed. Patients were included in the study after approval of the protocol by the Ethics Committee of Montpellier, France, and after written informed consent was obtained. All patients fulfilled the following inclusion criteria: (1) a history of allergic rhinitis for at least 2 yearsE3International consensus report on diagnosis and management of rhinitis International Rhinitis Management Working Group.Allergy. 1994; 49: 1-34Google Scholar during the grass pollen season, (2) a diagnosis of grass pollen allergy using skin prick tests and/or serum grass pollen–specific IgE (Pharmacia CAP System), and (3) no concomitant treatment. None of the patients were excluded for comorbidity. Outcomes included an RTSS4 monitored daily using a diary,E4Bousquet J. Bodez T. Gehano P. Klossek J.M. Liard F. Neukirch F. et al.Implementation of guidelines for allergic rhinitis in specialist practices: a randomized pragmatic controlled Trial.Int Arch Allergy Immunol. 2009; 150: 75-82Crossref PubMed Scopus (45) Google Scholar the disease-specific RQLQ (28 questions),E5Juniper E.F. Thompson A.K. Ferrie P.J. Roberts J.N. Validation of the standardized version of the Rhinoconjunctivitis Quality of Life Questionnaire.J Allergy Clin Immunol. 1999; 104: 364-369Abstract Full Text Full Text PDF PubMed Scopus (319) Google Scholar the WPAI-AS,E6Reilly M.C. Zbrozek A.S. Dukes E.M. The validity and reproducibility of a work productivity and activity impairment instrument.Pharmacoeconomics. 1993; 4: 353-365Crossref PubMed Scopus (1942) Google Scholar and VAS for the global evaluation of rhinitis.E7Bousquet P.J. Combescure C. Neukirch F. Klossek J.M. Mechin H. Daures J.P. et al.Visual analog scales can assess the severity of rhinitis graded according to ARIA guidelines.Allergy. 2007; 62: 367-372Crossref PubMed Scopus (362) Google Scholar There was no validated ocular symptom outcome. We therefore used ocular symptoms which were assessed both by questionnaire and E-RQLQ. The only patients considered for the analysis were those who completed the evaluation of all outcomes at baseline and after treatment. Patients were asked to fill in the RQLQ and WPAI-AS questionnaires at baseline and after 14 days of treatment, and to send them back to the central monitoring office. VAS levels were monitored by the physicians before and at the end of the treatment period. Patients were asked to read the text of the VAS and to indicate their perception of the disease, but were not informed about how to use it. However, in the free-choice treatment group, VAS was not used to determine the strategy because it is not used in practice. Uncontrolled allergic rhinitis was defined by a VAS level of global assessment of rhinitis and/or ocular symptoms at the end of a 2-week treatment. The VAS was chosen because it has been widely used for the assessment of subjective symptoms such as pain,E8Langley G.B. Sheppeard H. The visual analogue scale: its use in pain measurement.Rheumatol Int. 1985; 5: 145-148Crossref PubMed Scopus (345) Google Scholar and it is considered to be a robust, sensitive, and reproducible method of expressing severity. Even if the VAS is of most value when looking at change within individuals rather than comparing across a group of individuals at 1 time point,E9Wewers M.E. Lowe N.K. A critical review of visual analogue scales in the measurement of clinical phenomena.Res Nurs Health. 1990; 13: 227-236Crossref PubMed Scopus (1820) Google Scholar the latter comparison is still allowed. That comparison is of interest because the within-group comparisons do not provide information about the control of the disease during treatment, the residual level of impairment not being the end point investigated. In a previous study,E7Bousquet P.J. Combescure C. Neukirch F. Klossek J.M. Mechin H. Daures J.P. et al.Visual analog scales can assess the severity of rhinitis graded according to ARIA guidelines.Allergy. 2007; 62: 367-372Crossref PubMed Scopus (362) Google Scholar at a single time point, a cutoff of 5 cm (0-10 cm scale) was able to differentiate mild and moderate/severe allergic rhinitis, as defined by ARIA.E1Bousquet J. Van Cauwenberge P. Khaltaev N. Allergic rhinitis and its impact on asthma.J Allergy Clin Immunol. 2001; 108: S147-S334Abstract Full Text Full Text PDF PubMed Scopus (2156) Google Scholar In the current study, the characterization of patient severity before treatment was made using a VAS level of ≥5 cm.E2Bousquet P.J. Combescure C. Klossek J.M. Daures J.P. Bousquet J. Change in visual analog scale score in a pragmatic randomized cluster trial of allergic rhinitis.J Allergy Clin Immunol. 2009; 123: 1349-1354Abstract Full Text Full Text PDF PubMed Scopus (101) Google Scholar, E10Bousquet J. Lund V.J. Van Cauwenberge P. Bremard-Oury C. Mounedji N. Stevens M.T. et al.Implementation of guidelines for seasonal allergic rhinitis: a randomized controlled trial.Allergy. 2003; 58: 733-741Crossref PubMed Scopus (149) Google Scholar We therefore used this cutoff level to define uncontrolled rhinitis during treatment. Ocular symptoms are bothersome for patients,E11Bousquet P.J. Bousquet-Rouanet L. Co Minh H.B. Urbinelli R. Allaert F.A. Demoly P. ARIA (Allergic Rhinitis and Its Impact on Asthma) classification of allergic rhinitis severity in clinical practice in France.Int Arch Allergy Immunol. 2007; 143: 163-169Crossref PubMed Scopus (34) Google Scholar, E12Canonica G.W. Bousquet J. Mullol J. Scadding G.K. Virchow J.C. A survey of the burden of allergic rhinitis in Europe.Allergy. 2007; 62: 17-25Crossref PubMed Scopus (370) Google Scholar and these are the least controlled during pharmacologic treatment.E4Bousquet J. Bodez T. Gehano P. Klossek J.M. Liard F. Neukirch F. et al.Implementation of guidelines for allergic rhinitis in specialist practices: a randomized pragmatic controlled Trial.Int Arch Allergy Immunol. 2009; 150: 75-82Crossref PubMed Scopus (45) Google Scholar, E10Bousquet J. Lund V.J. Van Cauwenberge P. Bremard-Oury C. Mounedji N. Stevens M.T. et al.Implementation of guidelines for seasonal allergic rhinitis: a randomized controlled trial.Allergy. 2003; 58: 733-741Crossref PubMed Scopus (149) Google Scholar In the current study, ocular symptoms were assessed both by questionnaire and E-RQLQ, because used alone, neither of these 2 measurements appeared sufficient for the characterization of uncontrolled symptoms. The questionnaire ("Do you have ocular symptoms? Yes or No") could not quantify symptoms. Although within-group differences between pretreatment and during treatment are used to assess the significance between quality of life results in randomized trials,E5Juniper E.F. Thompson A.K. Ferrie P.J. Roberts J.N. Validation of the standardized version of the Rhinoconjunctivitis Quality of Life Questionnaire.J Allergy Clin Immunol. 1999; 104: 364-369Abstract Full Text Full Text PDF PubMed Scopus (319) Google Scholar, E13Guyatt G. Walter S. Norman G. Measuring change over time: assessing the usefulness of evaluative instruments.J Chronic Dis. 1987; 40: 171-178Abstract Full Text PDF PubMed Scopus (1561) Google Scholar these do not provide information about the control of the disease during treatment. Moreover, although the minimal clinically-relevant difference for the global RQLQ score has been tested, the E-RQLQ as a single domain has not been validated. We therefore decided to group answers to both questions and proposed a cutoff level at the 75th percentile of E-RQLQ in patients presenting with ocular symptoms (E-RQLQ ≥ 2.5). Because the current analysis was an exploratory post hoc analysis, the sample size was not calculated. Physicians were randomized by computer allocation from the list of French physicians. However, it was ensured that 2 or more physicians working in the same practice group were not randomized to the 2 different strategies as this might have induced a bias. In this case, only the first was enrolled. Qualitative data were expressed in percentages and frequencies. Normality of distributions was studied by using the Kurtosis and Skewness tests. Because distributions were not normal after treatment, medians and 25th to 75th percentiles defined quantitative data. Because the current analysis was part of a larger study, comparisons for the principal patient characteristics at inclusion were carried out between included and nonincluded patients by using χ2 and Wilcoxon-Mann-Whitney tests, respectively. Comparisons between the first and the second visit were made by using the Wilcoxon paired test. The analysis was performed with SAS version 8.1 (SAS Institute, Cary, NC), with the significance level set at 5% (.05). Compliance was assessed by query at the end of the posttreatment period. Of the 839 patients considered for analysis of efficacy, 164 (19.5%) missed answering the question, 82 in each treatment group. Six hundred thirty-nine patients (76.2%) declared they were compliant, 312 (74.8%) in the guidelines group and 327 (77.5%) in the free-choice treatment group. Thirty-six (4.3%) declared they were not compliant, 23 (5.5%) and 13 (3.1%) in each group, respectively. Tabled 1Demographic characteristicsFree-choice treatmentARIA-based strategyNo.287299Men%12844.6%12943.1%Age (y)33.5 (24.6-41.9)35.5 (27.4-43.1)Asthma%7024.4%60201%Tobaccono18965.8%19264.2%Results are frequencies and percentages or medians and interquartiles. Open table in a new tab Results are frequencies and percentages or medians and interquartiles. Tabled 1Efficacy of the 2 treatment strategiesFree-choice treatmentARIA-based strategyVAS V16.5 (5.0-7.7)6.8 (5.0-8.0) V22.0 (1.0-4.0)∗P < .001 by comparison to V1 (Wilcoxon paired test).1.7 (0.7-3.0)P < .001 by comparison to V1 and P < .01 by comparison to free-choice treatment (Wilcoxon-Mann-Whitney test).RQLQ global score V12.8 (2.0-3.5)2.7 (2.0-3.4) V20.9 (0.4-1.6)∗P < .001 by comparison to V1 (Wilcoxon paired test).0.6 (0.3-1.3)P < .001 by comparison to V1 and P < .01 by comparison to free-choice treatment (Wilcoxon-Mann-Whitney test).RTSS4 V18.0 (7.0-9.0)8.0 (6.0-9.0) V22.0 (1.0-4.0)∗P < .001 by comparison to V1 (Wilcoxon paired test).2.0 (0.0-3.0)∗P < .001 by comparison to V1 (Wilcoxon paired test).WPAIS-AS—missed productivity at work V130 (20-50)30 (20-50) V210 (0-30)∗P < .001 by comparison to V1 (Wilcoxon paired test).10 (0-20)P < .001 by comparison to V1 and P < .01 by comparison to free-choice treatment (Wilcoxon-Mann-Whitney test).WPAIS-AS—missed daily activities V140 (30-60)40 (30-60) V220 (10-30)∗P < .001 by comparison to V1 (Wilcoxon paired test).10 (0-20)P < .001 by comparison to V1 and P < .01 by comparison to free-choice treatment (Wilcoxon-Mann-Whitney test).Eye symptoms V1191 (66.6%)187(62.5%) V2107 (37.3%)100 (33.4%)V1, Visit at baseline; V2, visit after 2 weeks of treatment.Results are frequencies and percentages or medians and interquartiles.∗ P < .001 by comparison to V1 (Wilcoxon paired test).∗∗ P < .001 by comparison to V1 and P < .01 by comparison to free-choice treatment (Wilcoxon-Mann-Whitney test). Open table in a new tab V1, Visit at baseline; V2, visit after 2 weeks of treatment. Results are frequencies and percentages or medians and interquartiles.