1、Cataracts: Unforeseen Complication of Inhaled Corticosteroids,Roshni Aggarwal, M4 University of Michigan Medical School,Inhaled Corticosteroids (ICS),Standard-of-care controller medication for asthmaAlso widely used in treatment of COPDBlocks multiple inflammatory pathways involved in the pathogenes
2、is of asthmaCurrently available ICS include:- beclomethasone dipropionate- budesonide- fluticasone propionate- mometasone furoate- triamcinolone acetonide,Indications for ICS in Asthmatics,Based on stepwise approach to management of asthmaICS is first-line treatment for asthma in most stages,Nationa
3、l Asthma Education and Prevention Program Expert Panel Report Guidelines for the Diagnosis and Management of Asthma- Update 2002,Inhalation as a Novel Drug Delivery Method,Inhalation permits delivery of steroid in high concentration to target sites in lung and minimizes amount of drug reaching syste
4、mic circulationInitially physicians hypothesized that this form of drug delivery might entirely eliminate systemic side effects of ICSHowever, this has not been confirmed by clinical trials or experience,Mechanism of ICS Entry into Systemic Circulation,Rossi et al. Pulm Pharm 20:23-35,All types of I
5、CS have the potential to cause systemic side effects ICS vary in terms of oral bioavailability, % drug deposition in lung, % first-pass hepatic inactivation etc. (factors that influence amount of drug reaching systemic circulation),Possible Systemic Side Effects of ICS,Based on known systemic side e
6、ffects of oral corticosteroids: HPA-axis suppressionDecrease in growth velocity and leg growth in childrenDecrease in bone mineral densityBone fracturesOsteoporosisSkin thinning and bruising GlaucomaCataracts,Link Between Corticosteroids and Cataracts,Use of systemic corticosteroids is established r
7、isk factor for development of posterior subcapsular cataracts (PSC)- prevalence of PSC 0-54% (mean 9%) based on meta-analysis by Gallant et al. (1986) of 9 studies involving 343 asthmatics treated with oral corticosteroidsCase report by Kewley (1980) first suggested that ICS may also lead to develop
8、ment of cataracts- case reports often confounded by previous exposure of asthmatic patients to oral corticosteroids,What is the risk of cataract development secondary to ICS? What is the effect of dose and/or duration of ICS use?How does this risk vary with age?How do ICS compare with oral corticost
9、eroids in terms of risk of cataract?,So do we have the answers to these questions,Lets look at the results of four retrospective studies,1 - The Blue Mountains Eye Study,Community-based cross-sectional study in Blue Mountains, AustraliaRecruited 3,654 people (49-97 years old)Questionnaire used to co
10、llect information regarding steroid use, including:- current or prior use of ICS, including puffs per week and duration- current or prior use of corticosteroids, including dosage and durationOphthalmologic exams performed on each patient to record presence, type, and severity of cataracts,Cumming et
11、 al. Use of inhaled corticosteroids and the risk of cataracts. NEJM 1997;337(1):8-14.,BMES Patient Population,Of 3,313 subjects who provided information about corticosteroid use:370 subjects used ICS alone or in combination with oral steroids (164 currently, 206 previously)Subjects matched with rega
12、rds to other potential risk factors for cataracts (age, sex, DM, HTN, smoking history, sun damage),Increased Prevalence of Cataracts Among ICS Users,1. Relative Prevalence of Cataracts Secondary to ICS Use (past and present)*,2. Relative Prevalence of Cataracts Secondary to Current ICS Use Only*,* A
13、ll trends remained the same when subjects with current or prior use of systemic corticosteroids were removed from the analysis. Relative prevalence of PSC secondary to current ICS use increased to 3.2 (95% CI 1.7-6.1) in that model.,3. Relative Prevalence of PSC With Increasing Weekly Beclomethasone
14、 Dose,Dose-Response Relation Between Beclomethasone and Cataracts,* This dose-response relation became less evident (p=0.06) in the model restricted to subjects with no current or prior use of systemic corticosteroids.,4. Relative Prevalence of PSC With Increasing Lifetime Beclomethasone Dose*,Key F
15、indings of Blue Mountain Eye Study,ICS use associated with increased prevalence of PSC and nuclear cataracts (even after controlling for the use of systemic corticosteroids)Results consistent with known relation between use of systemic corticosteroids and presence of PSCPossible dose-response relati
16、on between beclomethasone and PSC (though may have been influenced by confounding use of systemic corticosteroids),2 - The RAMQ Database Study,Case-control studyUtilized Quebecs universal health insurance plan database (RAMQ)Enrolled 3,677 patients 70 years old with cataract extraction between 1992
17、and 1994 Randomly selected 21,868 controls from patients without diagnosis of cataract and matched them to cases Excluded patients with systemic steroid treatmentAdjusted for age, sex, DM, HTN, glaucoma, ophthalmic steroids, and # physician claims for services,Garbe et al. Association of inhaled cor
18、ticosteroid use with cataract extraction in elderly patients. JAMA 1998;280(6):539-543.,Increased Risk of Cataracts with Prolonged ICS Use,Odds Ratio of Cataract Extraction According to Cumulative Treatment Duration with ICS (excluding patients with oral steroid use),Increased Risk of Cataracts with
19、 Long-Term High Dose ICS,Odds Ratio of Cataract Extraction According to Average Daily Dose of ICS Stratified by Cumulative Duration of ICS Use*,Excluding patients with use of oral steroids, flunisolide, or triamcinolone. Low to medium dose, average daily dose of up to 1mg beclomethasone or budesonid
20、e. High dose, average daily dose of more than 1 mg beclomethasone or budesonide.,Risk of Cataracts with Oral Corticosteroids,Odds Ratio of Cataract Extraction According to Cumulative Treatment Duration with Oral Corticosteroids,Key Findings of RAMQ Database Study,ICS use associated with 3-fold incre
21、ased risk of cataracts in the elderly population after 3 years of cumulative treatmentHigh daily dose beclomethasone or flunisolide with cumulative treatment duration 2 years associated with increased risk of cataractsOral corticosteroid use associated with increased risk of cataracts after only 1 y
22、ear of cumulative treatment (compared to 3 years for ICS)Based on 1.75% baseline incidence of cataract extraction in study population, prolonged use of ICS will give rise to 361 additional cases of cataract extraction per 10,000 elderly persons per year,3 The United Kingdom GPRD Study #1,Retrospecti
23、ve observational cohort study with nested case-control analysisUtilized United Kingdom-based General Practice Research DatabaseSelected total 201,816 patients (3-90 years old)Observational cohort study compared ICS users to non-users, all of whom had a diagnosis of asthma or COPD (103,289 ICS users
24、vs. 98,257 non-users)Nested case-control analysis compared patients with diagnosis of cataracts to control patients without a diagnosis of cataracts from the base cohort of non-users and ICS-users (1,194 cases vs. 2,387 matched controls),Jick et al. The risk of cataract among users of inhaled steroi
25、ds. Epidemiology 2001;12(2):229-234.,Risk of Cataracts with ICS vs. Systemic Steroids,* Each relative risk estimate is adjusted for age and sex. + Reference group.,Jick et al. Epidemiology 2001;12(2):229-234.,Risk of Cataracts with Increasing ICS Use in All Age Groups,Risk of Cataracts with Increasi
26、ng ICS Use Stratified by Age,Key Findings of United Kingdom GPRD Study #1,Age modifies association between ICS use and risk of cataract with the greatest effect among the oldest patients at the highest dosages of ICSpossible differential effect of ICS at different ages or diagnostic bias/uncontrolle
27、d confounders among older patients (e.g. asthma severity, age-related exposure)No apparent increase in risk of cataracts with ICS use in children and young adults- suggests that results of previous related studies conducted in older patients may not be applicable to all age groups,4 The United Kingd
28、om GPRD Study #2,Population-based case-control studyUtilized newer version of General Practice Research Database in UKSelected 15,749 patients with cataract and 15,479 patients without cataracts (cases and controls matched for age, sex, practice, and observation period)Mean age 75 years old (SD 10.0
29、)Adjusted for systemic corticosteroid exposure and consultation rate,Smeeth et al. A population based case-control study of cataract and inhaled corticosteroids. Br J Ophthalmol 2003;87(10):1247-1251.,Crude odds ratio for association between any recorded exposure to ICS and cataract: 1.58 (95% CI 1.
30、46-1.71)After adjusting for systemic steroid exposure and consultation rate,* odds ratio for association between any ICS use and cataract was reduced: 1.10 (95% CI 1.00-1.20)* UK GPRD Study #1 by Jicks et al. did not control for consultation rate in UK health system.,Systemic Steroid Use and Consult
31、ation Rate as Confounders,Risk of Cataract with Increasing ICS Use,Comparisons Between the United Kingdom GPRD Studies,Smeeth et al. (study #2): Selected larger case and control populationsBased study on newer version of United Kingdom GPRDControlled for not only systemic steroid exposure but also c
32、onsultation rate, another important confounder based on the results of this studyShowed evidence of dose-response relation and gradient with increasing duration of ICS use similar to study #1 by Jick et al.Did not investigate association between ICS use and cataracts in younger age populations unlik
33、e study #1 by Jick et al.,Meta-Analysis of Four Retrospective Studies,Analysis included studies by Cumming et al., Garbe et al., Jick et al., and Smeeth et al. (all 4 discussed earlier)Approximately 20,000 cases and 50,000 controls,Uboweja et al. Effect of inhaled corticosteroids on risk of developm
34、ent of cataract: a meta-analysis. Fund 20:305-309.,Uboweja et al. Fund 20:305-309.,Pooled OR 1.48 (95% CI 1.30-1.68),Results of Meta-Analysis,Funnel Plot,ICS associated with increased risk of cataract independent of exposure to other types of corticosteroids Number needed to harm (NNH) = 16 (95% CI
35、13-19)given large number of patients who receive ICS, total # of patients at risk of developing cataract quite insignificantNegative heterogeneity test assures no real differences between 4 pooled studiesFunnel plot shows asymmetric distribution of studies; cannot rule out publication bias Still nee
36、d 9 negative studies to make results of meta-analysis insignificant,Key Conclusions from Meta-Analysis,Risk of increased cataract with ICS use needs to be weighted against benefits of ICS for managing symptoms of asthma and COPDNeed placebo-controlled prospective trials to fully evaluate relation-sh
37、ip between ICS use and cataract development- difficult given large time interval required between exposure and effectFurther evaluation required to clarify causal association between dosage and duration of drug use,Further Considerations,Whats on the Horizon for Safe and Effective ICS Use?,Manipulat
38、ion of physiochemical properties of ICS in order to:optimize pharmacodynamic and pharmacokinetic propertiesproduce an agent that effectively controls asthma with minimal local and systemic side effectsDevelopment of new-generation ICS,Ciclesonide,Ciclesonide: A Non-Halogenated ICS,Rossi et al. Pulm
39、Pharm 20:23-35.,Parent compound with almost no binding affinity to gluco-corticoid receptorCleaved by endogenous esterases in airway to form active metabolite, des-CICdes-CIC lipophilic and readily conjugates to fatty acids at C-21 OHResults in increased uptake of drug into target cellsActs as low-r
40、elease reservoir from which drug gradually becomes available after hydrolysis by intracellular lipases,High efficacysmall particle size (1 order of magnitude lower than that of budesonide when administered by MDI at same doselow risk of oral side effects such as candidiasis and hoarsenessLow risk of
41、 systemic side effects- oral bioavailability of ciclesonide and its active metabolite 1%- high degree of serum protein binding (99%)- high first-pass hepatic extraction- rapid metabolism and clearance (ciclesonide t1/2 0.94 h, des-CIC t1/2 2.79 h),Favorable Physiochemical Properties of Ciclesonide,D
42、ata on efficacyprovides lung function control superior to that of placebo and comparable with that of budesonide and fluticasoneFEV1 significantly improved in asthmatics who switched to ciclesonide while it significantly decreased in asthmatics who switched to placeboData on safetysafety of cicleson
43、ide at various dosages was evaluated in through two identical, multi-center, double-blind, placebo-controlled studies in 1031 childrenrate of systemic adverse events low and comparable in all treatment groupsserum and 24-h urine cortisol levels similar to placebo with no effect on HPA axis,Clinical
44、Trials To-Date Support Efficacy and Safety of Ciclesonide,Conclusions,ICS therapy is first-line treatment for asthma of most severities and is also widely used in treatment of COPDRetrospective studies show evidence of increased risk of cataract with ICS use, particularly in elderly patients who rec
45、eive prolonged high-dose ICS therapyGoal is to minimize long-term systemic ICS burden with lowest possible maintenance dose for optimal control of asthma and improved quality of lifeNewer generation ICS, such as ciclesonide, can be designed with improved pharmokinetic and pharmacodynamic properties
46、that result in enhanced efficacy and reduced systemic side effects,References,Cumming et al. Use of inhaled corticosteroids and the risk of cataracts. NEJM 1997;337(1):8-14.Gallant et al. Oral glucocorticoids and their complications: A review. J Am Acad Dermatol 1986;14(2):161-77Garbe et al. Associa
47、tion of inhaled corticosteroid use with cataract extraction in elderly patients. JAMA 1998;280(6):539-543.Jick et al. The risk of cataract among users of inhaled steroids. Epidemiology 2001;12(2):229-234.Kewley GD. Possible association between beclomethasone dipropionate aerosol and cataracts. Aust
48、Paediatr J 1980;16:117-118.Lipworth BJ. Systemic adverse effects of inhaled corticosteroids therapy. Arch Intern Med 1999;159(9):941-955.National Asthma Education and Prevention Program Expert Panel Report Guidelines for the Diagnosis and Management of Asthma- Update on Selected Topics 2002 (NIH Publication No. 97-4051).Rossi et al. Safety of inhaled corticosteroids: Room for improvement. Pulm Pharm 20:305-309.,
