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Chronic lung disease and multiple sclerosis: Incidence, prevalence, and temporal trends
Multiple Sclerosis and Related Disorders 8 (2016) 86–92
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Multiple Sclerosis and Related Disorders journal homepage: www.elsevier.com/locate/msard
Chronic lung disease and multiple sclerosis: Incidence, prevalence, and temporal trends Ruth Ann Marrie a,b,n, Scott Patten c, Helen Tremlett d, Lawrence W. Svenson c,e,f, Christina Wolfson g, B. Nancy Yu b,h, Lawrence Elliott b, Joanne Profetto-McGrath i, Sharon Warren j, Stella Leung b, Nathalie Jette c,k, Virender Bhan l,m, John D. Fisk m,n,1 a
Department of Internal Medicine, University of Manitoba, Winnipeg, Canada Department of Community Health Sciences, University of Manitoba, Winnipeg, Canada Department of Community Health Sciences, Cumming School of Medicine, University of Calgary, Calgary, Canada d Department of Medicine (Neurology) and Centre for Brain Health, University of British Columbia, Vancouver, Canada e Surveillance and Assessment Branch, Alberta Ministry of Health, Edmonton, Canada f School of Public Health, University of Alberta, Edmonton, Canada g Department of Epidemiology and Biostatistics and Occupational Health, McGill University, Montreal, Canada h Public Health, Manitoba Health Healthy Living and Seniors, Winnipeg, Canada i Faculty of Nursing, University of Alberta, Canada j Faculty of Rehabilitation Medicine, University of Alberta, Canada k Department of Clinical Neurosciences, Cumming School of Medicine, University of Calgary, Calgary, Canada l Department of Medicine, Dalhousie University, Halifax, Canada m Nova Scotia Health Authority, Canada n Departments of Psychiatry, Psychology & Neuroscience, and Medicine, Dalhousie University, Halifax, Canada b c
art ic l e i nf o
a b s t r a c t
Article history: Received 30 December 2015 Received in revised form 7 March 2016 Accepted 10 May 2016
Objectives: We aimed to estimate the incidence and prevalence of chronic lung disease (CLD), including asthma and chronic obstructive pulmonary disease, in the MS population versus a matched cohort from the general population. Methods: We used population-based administrative data from four Canadian provinces to identify 44,452 persons with MS and 220,849 age-, sex- and geographically-matched controls aged 20 years and older. We employed a validated case definition to estimate the incidence and prevalence of CLD over the period 1995–2005, and used Poisson regression to assess temporal trends. Results: In 2005, the crude incidence of CLD per 100,000 persons was 806 (95%CI: 701–911) in the MS population, and 757 in the matched population (95%CI: 712–803). In 2005, the crude prevalence of CLD was 13.5% (95%CI: 13.1–14.0%) in the MS population, and 12.4% (95%CI: 12.3–12.6%) in the matched population. Among persons aged 20–44 years, the average annual incidence of CLD was higher in the MS population than in the matched population (RR 1.15; 95%CI: 1.02–1.30), but did not differ between populations for those aged Z45 years. The incidence of CLD was stable, but the prevalence of CLD increased 60% over the study period. Conclusion: CLD is relatively common in the MS population. The incidence of CLD has been stable over time, but the prevalence of CLD has increased. Among persons aged 20–44 years, CLD is more common in the MS population than in a matched population. Given the prevalence of CLD in the MS population, further attention to the effects of CLD on outcomes in MS and approaches to mitigating those effects are warranted. & 2016 The Authors. Published by Elsevier B.V. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).
Keywords: Administrative data Chronic lung disease Cohort studies Incidence Multiple sclerosis Prevalence
1. Introduction n Correspondence to: Health Sciences Centre, GF 543- 820 Sherbrook Street, Winnipeg, MB R3A 1R9, Canada. E-mail address: [email protected] (R.A. Marrie). 1 For the CIHR Team in the Epidemiology and Impact of Comorbidity on Multiple Sclerosis.
Chronic lung diseases (CLD) including asthma or chronic obstructive pulmonary disease (COPD) are a leading cause of morbidity and mortality worldwide (Cruz et al., 2007) and their occurrence in multiple sclerosis (MS) remains of interest. Increasing
http://dx.doi.org/10.1016/j.msard.2016.05.009 2211-0348/& 2016 The Authors. Published by Elsevier B.V. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).
R.A. Marrie et al. / Multiple Sclerosis and Related Disorders 8 (2016) 86–92
awareness of the possible adverse effect of CLD on outcomes in MS, such as disability progression and mortality, has heightened the need to understand the relationship between these chronic conditions (Marrie 2007; Marrie et al., 2015a). However, uncertainty persists regarding the incidence and prevalence of many comorbidities in MS, including CLD (Marrie et al., 2015c) Even population-based estimates of the prevalence of CLD (not limited to asthma or COPD alone) are highly variable, ranging from 2.2% to 25% (Nuyen et al., 2006; Ponsonby et al., 2006; Kang et al., 2010; Langer-Gould et al., 2010; Marrie et al., 2013b) Some of the variability may reflect differences in study design and population characteristics, but one commonality of these studies has been the lack of age and sex-specific estimates of the incidence and prevalence of CLD in MS. Findings have been highly inconsistent with respect to whether CLD occurs more or less often in the MS population than in the general population (Marrie et al., 2015c). Therefore, we evaluated the incidence and prevalence of CLD, over a ten year period, in the MS population after diagnosis, including age-specific estimates; and compared the findings with a matched cohort selected from the general population. By employing validated methods in a large population-based sample with concurrent controls we hoped to resolve inconsistencies in the literature.
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each case. 2.3. Chronic lung disease We selected an administrative case definition for CLD that was validated in MB and NS against medical records review and selfreport questionnaires, and applied it to identify affected individuals in the MS and matched populations (Marrie et al., 2013b). The case definition required that an individual have Z1 hospital claim or Z2 physician claims with an ICD-9/10 code for asthma or COPD (493, 491.xx, 492.xx, 496.xx, J45, J46, J40, J42, J43, J44) in a five-year period to be considered affected. We did not include prescription claims in the case definition because such data were not available in all jurisdictions. We did not attempt to distinguish between asthma and COPD because of the diagnostic challenges in accurately distinguishing between these conditions (Manfreda et al., 1993; Chhabra, 2005; Richter et al., 2008; AlKassimi et al., 2011) and because diagnostic codes for asthma and COPD are frequently found in the same patients (Huzel et al., 2002). Because CLDs represent chronic conditions in adult populations, once a person met the case definition, he or she was considered affected in all years thereafter, if alive and living in the province. 2.4. Incidence and prevalence
2. Materials and methods 2.1. Data sources Health care in Canada is universal (public), and health service delivery is administered provincially. As described previously (Marrie et al., 2015b) we conducted a cohort study using population-based anonymized administrative health data from the Canadian provinces of British Columbia (BC), Manitoba (MB), Quebec (QC) and Nova Scotia (NS). Within each province, we used unique personal identification numbers to link population registries with hospital and physician claims data for the years 1990–2010, except in BC where data extended to 2008/09 (British Columbia Ministry of Health [creator], 2012a, 2012b, 2012c). The population registries capture sex, postal code, and dates of birth, death and health care coverage. The hospital discharge abstract database captures dates of admission and discharge and up to 25 diagnoses, coded using the International Classification of Disease (ICD)-9 or ICD-10-CA system. Physician claims data include the date of service and diagnosis coded using the ICD-9 system. Privacy regulations prevent line level data from leaving the province of origin; therefore we conducted the same analyses in each province, and then pooled the provincial estimates using meta-analyses. In each province, we secured ethics approval, and approval to access administrative data from the relevant body. 2.2. Study populations As described elsewhere (Marrie et al., 2015b) within each province, we employed a previously validated administrative case definition for MS (Z3 hospital or physician claims for MS (ICD-9/ 10¼ 340/G39)) (Marrie et al., 2010b, 2013a). After identifying the MS cohort, we excluded persons under age 20 years and then we selected a matched cohort from the general population. This cohort excluded anyone with any diagnostic codes (ICD-9/10) for demyelinating disease and included up to 5 controls matched on sex, exact year of birth and region of residence (full postal code or first three digits of postal code if full match impossible) to each MS case. We assigned the date of the first claim (index date) for demyelinating disease as the “date of diagnosis” for each MS case; the same date (index date) was assigned to the matched controls for
To identify incident cases of CLD in the MS cohort, the first claim for CLD had to occur after the date of MS diagnosis, and be preceded by a five-year run-in period with no such claims. For the matched cohort a CLD case was defined as incident if the first claim occurred after the index date assigned to their matched case, again preceded by a five-year run-in period. Because new cases that occur at the end of a study period may not have enough follow-up time to fully meet the case definition, incidence may artifactually drop at the end of a study period. Therefore, we report annual incidence for 1995 through 2005. We report prevalence at the mid-point of each year from 1995 through 2005 assuming, as noted above, that the numerator included all cases of CLD identified after the index date persisted as long as the person was alive and living in the province and that the denominator was the number of individuals in the study population at mid-year. We age-standardized the findings to the 2001 Canadian population (closest to the study mid-point) for consistency with earlier work. We report 95% confidence intervals (CI) assuming a Poisson distribution. To meet provincial privacy requirements, cell sizes r5 were suppressed. This meant that we could not directly model crude rates; consequently we modeled age-standardized incidence and prevalence using negative binomial regression (to account for overdispersion), including year and sex as covariates (Yasui et al., 2003). This approach accounts for age effects although age is not modeled as a covariate (Yasui et al., 2003). Due to small cell sizes in some provinces, age was categorized as 20–44, 45–59, and Z 60 years and we examined age effects in two ways. First, we compared average annual age-specific incidence over the entire study period between the two populations. Second, we compared annual age-specific prevalence adjusting for year. Both analyses used negative binomial regression models. We report incidence rates, prevalence, adjusted rate ratios (RR), and their 95%CIs. Province-specific estimates were pooled using random-effects meta-analysis and we report these rate ratios and I2 and τ2. The I2 index of heterogeneity describes the proportion of variation in point estimates due to heterogeneity of studies rather than to sampling error (Higgins et al., 2003). I2 is calculated from the Q statistic (the weighted sum of squared differences between individual study effects): I2 ¼[(Q degrees of freedom)/Q]*100. Values of I2 of o25% are considered low, and 475% are considered
R.A. Marrie et al. / Multiple Sclerosis and Related Disorders 8 (2016) 86–92
high (Higgins et al., 2003). Between study variance can be quantified using τ2. Statistical analyses were performed using SAS V9.3 (SAS Institute Inc, Cary, N.C.) and using a Microsoft Excel spreadsheet for meta-analyses (Neyeloff et al., 2012).
3. Results 3.1. Participants
1600
Average annual incidence of Chronic lung disease per 100,000 persons
88
1400 1200 1000 MS
800
Matches
600 400 200 0 20-44
As reported previously, we identified 44,452 persons with MS and 220,849 matched controls from the general population (Table e-1) (Marrie et al., 2015b).
45-59
≥60
Age group (years)
Fig. 1. Age-specific average annual incidence of chronic lung disease per 100,000 population.
3.3. Prevalence 3.2. Incidence In 2005, the pooled crude incidence of CLD in the MS population was 806 per 100,000 persons (95%CI: 701–911), and it was 757 in the matched population (95%CI: 712–803) (Supplemental Fig. 1). Over the entire study period, in the initial analysis, after adjusting for year and sex, the pooled age-standardized incidence of CLD did not differ between the MS and matched populations (Table 1). When both populations were considered, the incidence of CLD was higher among women than men in two provinces, but the pooled estimate suggested that the incidence did not differ by sex. The incidence of CLD was stable over time in both populations. Further, there was no evidence of interaction between population and time, or between population and sex. However, when we examined age-specific average annual incidence rates (over the 10-year period) some differences emerged between the MS and matched populations (Fig. 1); we observed an interaction between age group and population. Specifically, among persons aged 20–44 years, the average annual incidence of CLD was 15% higher in the MS population than in the matched population (RR 1.15; 95%CI: 1.02–1.30, Table 2). However, among persons aged 45–59 years (RR 1.06; 95%CI: 0.93–1.21), and aged Z60 years the average annual incidence of CLD did not differ between the two populations (RR 0.92; 95%CI: 0.76–1.10). Consequently, in the MS population the higher average annual incidence of CLD in the two older age groups as compared to those aged 20–44 years did not reach statistical significance. In the matched population, the average annual incidence of CLD was significantly higher in those aged Z 45 years as compared to those aged 20–44 years (Table 3).
In 2005, the pooled crude prevalence of CLD in the MS population was 13.5 per 100 persons (95%CI: 13.1–14.0), and it was 12.4 per 100 persons (95%CI: 12.3–12.6) in the matched population (Supplemental Fig. 2). However, over the 10-year study period, after adjusting for year and sex, the age-standardized prevalence of CLD did not differ between the MS and matched populations (Table 1). In both populations, women had a higher prevalence of CLD than men, and the prevalence of CLD increased over time, such that over a 10-year period the prevalence increased 60%. We did not observe any evidence of interactions between population and time, or between population and sex. When we compared age-specific prevalence between populations over the entire study period the findings were similar to those observed for average annual age-specific incidence rates (Tables 2 and 4). That is, among persons aged 20–44 years, the prevalence of CLD was 27% higher in the MS population than in the matched population after adjusting for year (RR 1.27; 95%CI: 1.12– 1.45, Table 2). However, among persons aged 45–59 years and aged Z60 years the pooled prevalence of CLD did not differ between populations, although we observed heterogeneity in these findings across provinces. Also as with the age-specific incidence rates, in the MS population the higher prevalence of CLD in the two older age groups as compared to those aged 20–44 years did not reach statistical significance while in the matched population, the prevalence of CLD was significantly higher in those aged Z 45 years as compared to those aged 20–44 years (Table 4).
Table 1 Chronic lung disease: adjusted associations of incidence and prevalence with the study population, sex and time.
Incidence MS population vs. matches Women vs. men Time/year
Prevalence MS population vs. matches Women vs. men Time/year
BC
MB
QC
NS
τ2
I2 (p-value)
Rate ratio (95% CI) 1.02 (0.93, 1.10)
Rate ratio (95% CI) 0.87 (0.72, 1.05)
Rate ratio (95% CI) 0.88 (0.78, 0.99)
Rate ratio (95% CI) 1.15 (0.92, 1.44)
0.14
Rate ratio (95% CI) 96.9 ( o 0.0001) 0.97 (0.91, 1.03)
1.16 (1.07, 1.27)
1.29 (1.07, 1.56)
0.90 (0.80, 1.01)
1.09 (0.87, 1.37)
0.15
7.43 (0.06)
1.09 (0.93, 1.28)
0.98 (0.97, 1.00)
0.99 (0.97, 1.03)
0.98 (0.96, 1.00)
0.95 (0.91, 0.98)
0.003
80.9 ( o 0.0013)
0.98 (0.97, 0.99)
Rate Ratio (95% CI) 0.93 (0.89, 0.97)
Rate Ratio (95% CI) 0.92 (0.88, 0.96)
Rate Ratio (95% CI) 1.09 (1.03, 1.16)
Rate Ratio (95% CI) 1.19 (1.14, 1.24)
0.02
Rate Ratio (95% CI) 95.7 ( o 0.0001) 1.03 (0.90, 1.17)
1.29 (1.24, 1.34)
1.34 (1.29, 1.40)
1.01 (0.95, 1.07)
1.21 (1.16, 1.26)
0.024
64.8 (o 0.0001) 1.21 (1.09, 1.34)
1.07 (1.06, 1.08)
1.067 (1.060, 1.074)
1.06 (1.05, 1.07)
1.04 (1.03, 1.05)
0.0007 86.7 ( o 0.0001) 1.06 (1.05, 1.07)
BC ¼ British Columbia, MB ¼Manitoba, QC ¼ Quebec, NS¼ Nova Scotia, Time/year ¼Increase in disease rate over time in units of one year.
Random effects estimate
R.A. Marrie et al. / Multiple Sclerosis and Related Disorders 8 (2016) 86–92
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Table 2 Age-specific incidence and prevalence of chronic lung disease in the multiple sclerosis versus matched populations.
Incidence-MS vs. match 20–44 Years 45–59 Years Z60 Years Prevalence MS vs. match 20–44 Years 45–59 Years Z60 Years
τ2
BC
MB
QC
NS
Rate ratio (95% CI)
Rate ratio (95% CI)
Rate ratio (95% CI)
Rate ratio (95% CI)
1.07 (0.96, 1.20) 1.06 (0.96, 1.18) 0.85 (0.79, 0.93)
1.37 (1.24, 1.52) 1.02 (0.93, 1.12) 0.79 (0.73, 0.85)
1.10 (0.97, 1.24) 1.15 (1.03, 1.28) 1.19 (1.10, 1.28)
1.09 (0.97, 1.23) 0.88 (0.79, 0.98) 0.88 (0.81, 0.95)
Rate ratio (95% CI)
Rate ratio (95% CI)
Rate ratio (95% CI)
Rate ratio (95% CI)
1.13 (1.09, 1.18) 0.92 (0.86, 0.98) 0.91 (0.81, 1.01)
1.27 (1.22, 1.33) 1.09 (1.06, 1.13) 0.95 (0.86, 1.06)
1.24 (1.00, 1.53) 1.13 (1.01, 1.25) 1.06 (0.87, 1.29)
1.46 (1.40, 1.53) 1.18 (1.13, 1.21) 1.13 (1.04, 1.22)
I2 (p-value)
Random effects estimate Rate ratio (95% CI)
0.13 78.6 (0.003) 1.15 (1.02, 1.30) 0.13 84.5 (0.0002) 1.06 (0.93, 1.21) 0.04 95.3 (o 0.0001) 0.92 (0.76, 1.10)
Rate ratio (95% CI) 0.03 95.6 (o 0.0001) 1.27 (1.12, 1.45) 0.06 86.6 (0.0001) 1.08 (0.99, 1.19) 0.10 75.7 (0.0063) 1.01 (0.90, 1.13)
Table 3 Chronic lung disease: average annual incidence by age group. BC
MB
QC
NS
Incidence-MS 20–44 Years (reference group) 45–59 Years Z60 Years
Rate ratio (95% CI) 1.0 1.07 (0.96, 1.18) 1.14 (0.92, 1.40)
Rate ratio (95% CI) 1.0 0.98 (0.89, 1.07) 0.96 (0.80, 1.16)
Rate ratio (95% CI) 1.0 1.23 (1.10, 1.37) 1.51 (1.20, 1.88)
Rate ratio (95% CI) 1.0 1.08 (0.96, 1.20) 1.16 (0.93, 1.45)
Incidence-matches 20–44 Years (reference group) 45–59 Years Z60 Years
Rate ratio (95% CI) 1.0 1.07 (0.96, 1.20) 1.15 (0.92, 1.43)
Rate ratio (95% CI) 1.0 1.32 (1.19, 1.45) 1.73 (1.42, 2.12)
Rate ratio (95% CI) 1.0 1.18 (1.05, 1.32) 1.39 (1.09, 1.76)
Rate ratio (95% CI) 1.0 1.34 (1.20, 1.50) 1.79 (1.43, 2.24)
τ2
I2 (p-value)
Random effects estimate Rate ratio (95% CI)
0.11 0.43
69.0 (0.021) 66.8 (0.026)
1.08 (0.99, 1.19) 1.17 (0.97, 1.41)
Rate Ratio (95% CI) 0.14 0.76
72.0 (0.013) 70.8 (0.016)
1.22 (1.10, 1.36) 1.50 (1.22, 1.83)
BC ¼ British Columbia, MB ¼ Manitoba, QC¼ Quebec, NS¼ Nova Scotia.
Table 4 Chronic lung disease: prevalence by age group. BC
MB
QC
NS
Prevalence-MS 20–44 Years (reference group) 45–59 Years Z60 Years
Rate ratio (95% CI) 1.0 0.86 (0.81, 0.92) 0.74 (0.66, 0.84)
Rate ratio (95% CI) 1.0 0.95 (0.92, 0.99) 0.91 (0.84, 0.98)
Rate ratio (95% CI) 1.0 1.45 (1.20, 1.75) 2.10 (1.44, 3.07)
Rate ratio (95% CI) 1.0 0.97 (0.93, 1.03) 0.96 (0.86, 1.07)
Prevalence-matches 20–44 Years (reference group) 45–59 Years Z60 Years
Rate ratio (95% CI) 1.0 1.06 (1.01, 1.11) 1.13 (1.02, 1.24)
Rate ratio (95% CI) 1.0 1.11 (1.05, 1.17) 1.23 (1.10, 1.38)
Rate ratio (95% CI) 1.0 1.60 (1.40, 1.82) 2.55 (1.95, 3.32)
Rate ratio (95% CI) 1.0 1.22 (1.18, 1.25) 1.49 (1.40, 1.58)
τ2
I2 (p-value)
Random effects estimate Rate ratio (95% CI)
0.02 0.09
89.7 ( o 0.0001) 90.2 ( o 0.0001)
0.99 (0.90, 1.09) 0.99 (0.81, 1.21)
Rate ratio (95% CI) 0.03 0.15
94.0 ( o 0.0001) 93.6 ( o 0.0001)
1.21 (1.09, 1.34) 1.46 (1.18, 1.81)
BC ¼ British Columbia, MB ¼ Manitoba, QC¼ Quebec, NS¼ Nova Scotia.
4. Discussion We conducted a large population-based cohort study using over 10 years of administrative health data involving 265,301 Canadians (44,452 with MS; 220,840 contemporaneous controls). Multiple previous studies have compared the prevalence of CLD in the MS population to various comparator populations (Marrie et al., 2015c) with highly inconsistent findings. Approximately one-third of studies report CLD to be more common in the MS population, one-quarter report CLD to be less common, and the remainder report CLD to be equally common in the MS population as the comparator population (Marrie et al., 2015c). Differences in the lung diseases evaluated, in the underlying characteristics of the populations studied, and in whether the study was population-based or not may account for some of these inconsistencies. Unlike these earlier studies we evaluated the incidence and prevalence of CLD over a long (ten year) period, and reported agespecific estimates. We found that CLD affected more than one in ten persons with MS. While initial analyses suggested that the
incidence and prevalence of CLD did not differ between populations, we identified potentially important differences in these associations by age group which may account for some of the inconsistencies in the literature. As prior studies did not identify such interactions, the presence or absence of associations between CLD and MS may have depended on the age distribution of their sample. We found that the average annual incidence of CLD in the MS population was 0.81%. Comparable work has been limited. Although two prior studies reported the incidence of CLD, neither was truly population-based and both focused exclusively on COPD alone rather than considering asthma and COPD together. Of these two studies, one found that the incidence of COPD was 2.5% over a 30 year period among persons with incident MS (Christiansen et al., 2010). The other reported an incidence of COPD of 0.13%, but identified COPD solely based on hospitalizations and likely underestimated its true incidence (Hemminki et al., 2011). We found that the crude prevalence of CLD was 13.5% in the MS population and 12.4% percent in the matched population in 2005.
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In 1998 the combined prevalence of asthma and COPD in the Canadian general population was reported at approximately 11% (Editorial Board, 2001) and given the increase in prevalence of these conditions over time, the findings in our matched population are consistent with expectations for the population as a whole. A recent systematic review found 21 studies that had reported the prevalence of CLD in MS, of which five were population-based and conducted in prevalent cohorts, similar to ours (Marrie et al., 2015c). Among these five studies, two reported the prevalence of CLD broadly (Nuyen et al., 2006; Marrie et al., 2013b) while the others focused on either asthma or COPD alone. The first broad study was conducted in Manitoba in 2005 using a case definition for CLD that also incorporated prescription claims but otherwise employed the same methods as the present study, albeit over a more limited time period; as expected this found a similar prevalence of CLD of 15.6% (Marrie et al., 2013b). The second broad study was conducted in the Netherlands, and found a one-year prevalence of CLD of only 3.3% based on primary care electronic records. This lower prevalence may have reflected the short period of ascertainment, or differences in coding practices. None of five population-based studies reported age-specific prevalence estimates. Unlike prior studies of CLD in the MS population, we were able to evaluate temporal trends in the incidence and prevalence of CLD over a ten year period. While we found the incidence of CLD to be stable in both populations, the prevalence of CLD increased 60% over the study period for both populations. These findings for the MS population require replication but are consistent with those reported elsewhere in Canada. Specifically, a 64% increase in the crude prevalence of COPD (Gershon et al., 2010b) and the 70.5% increase in the prevalence of asthma (Gershon et al., 2010a) have been reported in the general population of the province of Ontario over a similar time period. Because prevalence is roughly equal to incidence*disease duration, the observation of stable incidence of CLD but rising prevalence of CLD suggests that individuals are living longer with CLD, perhaps due to earlier diagnosis, improved survival or both. Our initial analyses using age-standardized estimates suggested that the incidence and prevalence of CLD were similar in the MS and matched populations. However, this was not the case when we stratified the analyses by age. The analyses demonstrated two key, related findings. First, the incidence and prevalence of CLD increased with age in the matched population but not in the MS population. Second, the incidence and prevalence of CLD were higher in the MS population than in the matched population among those aged 20–44 years. Our case definition of CLD combined asthma and COPD. Among those aged 20–44 years the prevalence of asthma is higher than of COPD, which has a prevalence of only 3.1% among those under age 40 years, but the prevalence of COPD increases with age (Editorial Board, 2001; Raherison and Girodet, 2009). Thus asthma may be driving the difference in findings between the MS and matched populations and this will require further study in populations in which these conditions can be clearly distinguished. Much of the initial interest in the association of CLD and MS focused on the hygiene hypothesis and proposed that asthma would be less common in persons with MS, on the basis that asthma was Th2-mediated and that MS was Th1-mediated (Bergamaschi et al., 2009). However, co-occurrence of allergy, asthma and autoimmunity was observed, and Th17 and T regulatory cells were recognized to influence Th1 and Th2 pathways and to be dysregulated in MS (Edwards et al., 2011). Further, the recognition of shared environmental and genetic risk factors such as smoking, obesity and vitamin D-related polymorphisms (Raherison and Girodet, 2009; Chishimba et al., 2010; Ascherio, 2013; Ilmarinen et al., 2015) support hypotheses that CLD would be more common, rather than less common in MS
(Egesten et al., 2008). Further clarification of the underlying mechanisms of these associations is needed and whether the same is true for the direction of association between MS and CLD and for asthma and COPD. Regardless, our findings demonstrate that the burden of CLD is clearly high enough to be a concern for the MS population. As noted above, the prevalence of these conditions in Canada is increasing (Gershon et al., 2010a, 2010b) while in the United States, CLD is among the leading causes of disability (McNeil, 2001). In those with MS, CLD has been associated with more rapid disability progression and reduced health-related quality of life, and is frequently a cause of death (Koch-Henriksen et al., 1998; Kirby et al., 2005; Marrie et al., 2010a, 2012). Thus, attention to the possible presence of CLD in relatively younger age cohorts with MS is warranted as modification of this underlying comorbidity may benefit MS outcomes. Avoiding smoking and access to smoking cessation programs may be particularly important for those with MS as smoking is a risk factor for multiple forms of CLD (Beasley et al., 2015; Postma et al., 2015). The presence of CLD may also complicate disease-modifying treatment use; for example as a relative contraindication to the use of fingolimod, a new therapy for MS. The incidence and prevalence of CLD varied somewhat across provinces, therefore the pooled estimate should be interpreted cautiously. The variation observed may reflect true geographic variation in disease risk or burden, differences in health services utilization for CLD due to factors other than disease burden, measurement error due to the use of administrative data, or some combination of these factors. In Canada, the self-reported prevalence of COPD among those aged Z40 years varies from 5.3– 9.5% across major cities; similar variation was identified in the prevalence when pulmonary function was measured objectively, although estimates were higher (12.9–19.3%) (Tan et al., 2011). However, differences in age and sex distribution account for much of these differences. The prevalence of asthma also varies across Canada, and variation in the use of asthma medications exceeds the variation in symptom severity (Manfreda et al., 2001). These observations suggest that the observed variation in CLD prevalence in our study population is consistent with expectations for the Canadian population. This study has strengths and limitations. Strengths include the large size of the population, its representative nature, the use of a validated case definition for MS, the use of a contemporaneous control population, and our ability to examine temporal trends over a 10-year period. We used a case definition for CLD that was highly specific, but less sensitive than desired. Thus it is unlikely that we incorrectly misclassified individuals as having CLD, but we may have missed cases of CLD. This could have lead to us underestimating the incidence and prevalence of CLD, but should not have affected the assessment of temporal trends, and might tend to bias rate ratios toward the null. More frequent health system contacts may have lead to more frequent identification of CLD in the MS population. We reported I2 as a measure of heterogeneity, but I2 tends toward 100% when sample sizes are large and precision is high (Rucker et al., 2008) suggesting we overestimated heterogeneity. This study suggests that CLD is common in the MS population. The incidence of CLD has been stable over time, but the prevalence of CLD has increased. Among persons aged 20–44 years, CLD is more common in the MS population than in an age-, sex- and geographically-matched population drawn from the general population. These findings illustrate the importance of attention to this comorbidity in relatively younger individuals with MS. In many chronic diseases including MS, clinical practice guidelines do not address the role of comorbidity in management (van Weel and Schellevis, 2006). However, the prevalence of CLD in the MS
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population demands attention to the effects of CLD on outcomes in MS and approaches to mitigate those effects.
Funding This study was supported (in part) by the Canadian Institutes of Health Research (CBG-101829), Rx & D Health Research Foundation, and Don Paty Career Development grants from the Multiple Sclerosis Society of Canada (to RAM), and a Manitoba Research Chair from Research Manitoba (to RAM).
Conflict of interest Ruth Ann Marrie receives research funding from: Canadian Institutes of Health Research, Public Health Agency of Canada, Research Manitoba, Health Sciences Centre Foundation, Multiple Sclerosis Society of Canada, Multiple Sclerosis Scientific Foundation, Rx & D Health Research Foundation, and has conducted clinical trials funded by Sanofi-Aventis. Nancy Yu receives research support from the Canadian International Development Agency, the Multiple Sclerosis Society of Canada, CIHR, and Manitoba Health and Healthy Living. Stella Leung reports no disclosures. Lawrence Elliott receives research support from the Canadian Institutes of Health Research. Sharon Warren receives research funding from the Canadian Institutes of Health Research. Christina Wolfson receives research funding from the Multiple Sclerosis Society of Canada, Canadian Institutes of Health Research, Canada Foundation for Innovation, the National MS Society and has received one speaking honorarium from Novartis. Helen Tremlett currently receives funding from: the Multiple Sclerosis Society of Canada [Don Paty Career Development Award]; US National MS Society [#RG 4202-A-2 (PI)]; Canadian Institutes of Health Research [MOP: #190898 (PI) and MOP-93646 (PI)]; Michael Smith Foundation for Health Research and is the Canada Research Chair for Neuroepidemiology and Multiple Sclerosis. She has received speaker honoraria and/or travel expenses to attend conferences from: the Consortium of MS Centres, US National MS Society, Swiss Multiple Sclerosis Society, the University of British Columbia Multiple Sclerosis Research Program, Teva Pharmaceuticals and Bayer Pharmaceutical (honoraria declined) and ECTRIMS (2011), UK MS Trust and the Chesapeake Health Education Program, US Veterans Affairs (2012, honorarium declined). Unless otherwise stated, all speaker honoraria are either donated to an MS charity or to an unrestricted grant for use by her research group. John Fisk receives research funding from the Canadian Institutes of Health Research, Rx & D Health Research Foundation; the Dalhousie Medical Research Foundation, and in the past has received grants, honoraria and consultation fees from AstraZeneca, Bayer, Biogen-Idec Canada, Heron Evidence Development Limited, Hoffmann-La Roche, MAPI Research Trust, Novartis, Sanofi-Aventis, Serono Canada, and QualityMetric Incorporated. Lawrence W. Svenson reports no disclosures. Joanne Profetto-McGrath reports no disclosures. Nathalie Jette is the holder of a Canada Research Chair Tier 2 in Neurological Health Services Research and receives research support from CIHR, AIHS, Hotchkiss Brain Institute, the University of Calgary and Pfizer Canada. Virender Bhan has received honoraria from Biogen, EMD Serono, Genzyme, Novartis and Roche for participation in Advisory Boards.
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Acknowledgements We thank Yan Wang (Health Data Nova Scotia), Bin Zhu (McGill University), Elaine Kingwell (University of British Columbia), Feng Zhu (University of British Columbia) for their assistance with data analysis and/or data access. All inferences, opinions, and conclusions drawn in this publication are those of the authors and do not reflect the opinions or policies of the Data Stewards. No official endorsement by Manitoba Health, Population Data BC, Pharmanet, the Regie D’Assurance Maladie du Quebec, or The Commission d’accès à l’information (CAI) of Quebec is intended or should be inferred. Some data used in this report were made available by Health Data Nova Scotia of Dalhousie University. Although some of this research is based on data obtained from the Nova Scotia Department of Health and Wellness, the observations and opinions expressed of those of the authors and do not represent those of either Health Data Nova Scotia or the Department of Health and Wellness. CIHR Team in the Epidemiology and Impact of Comorbidity on Multiple Sclerosis (by site): University of Manitoba (James Blanchard MD, PhD; Patricia Caetano, PhD; Lawrence Elliott, MD, MSc; Stella Leung, MSc; Ruth Ann Marrie, M.D, PhD; Bo Nancy Yu, MD, PhD) Dalhousie University (Virender Bhan, MBBS; John D. Fisk, PhD), University of Alberta (Joanne Profetto-McGrath, PhD; Sharon Warren, PhD; Larry Svenson, Ph.D.); McGill University (Christina Wolfson, PhD); University of British Columbia (Helen Tremlett, PhD); University of Calgary (Scott Patten, MD, PhD, Nathalie Jette, MD, MSc).
Appendix A. Supplementary material Supplementary data associated with this article can be found in the online version at http://dx.doi.org/10.1016/j.msard.2016.05. 009.
References Al-Kassimi, F.A., Abba, A.A., Al-Hajjaj, M.S., Alhamad, E.H., Raddaoui, E., Shaikh, S.A., 2011. Asthma masquerading as chronic obstructive pulmonary disease: a study of smokers fulfilling the GOLD definition of chronic obstructive pulmonary disease. Respiration 82 (1), 19–27. Ascherio, A., 2013. Environmental factors in multiple sclerosis. Expert Rev. Neurother. 13 (Suppl 12), S3–S9. Beasley, R., Semprini, A., Mitchell, E.A., 2015. Risk factors for asthma: is prevention possible? Lancet 386 (9998), 1075–1085. Bergamaschi, R., Villani, S., Crabbio, M., Ponzio, M., Romani, A., Verri, A., et al., 2009. Inverse relationship between multiple sclerosis and allergic respiratory diseases. Neurol. Sci. 30 (2), 115–118. British Columbia Ministry of Health [creator], 2012a. Consolidation File (MSP Registration & Premium Billin)g). Retrieved April 1, 2015, from 〈http://www.pop data.bc.ca/data〉. British Columbia Ministry of Health [creator], 2012b. Discharge Abstract Database (Hospital Separations). Retrieved April 1, 2015, from 〈http://www.popdata.bc. ca/data〉. British Columbia Ministry of Health [creator], 2012c. Medical Services Plan (MSP). Retrieved April 1, 2015, from 〈http://www.popdata.bc.ca/data〉. Chhabra, S., 2005. Acute bronchodilator response has limited value in differentiating bronchial asthma from COPD. J. Asthma 42 (5), 367–372. Chishimba, L., Thickett, D.R., Stockley, R.A., Wood, A.M., 2010. The vitamin D axis in the lung: a key role for vitamin D-binding protein. Thorax 65 (5), 456–462. Christiansen, C.F., Christensen, S., Farkas, D.K., Miret, M., Sørensen, H.T., Pedersen, L., 2010. Risk of arterial cardiovascular diseases in patients with multiple sclerosis: a population-based cohort study. Neuroepidemiology 35 (4), 267–274. Cruz, A.A., Mantzouranis, E., Matricardi, P.M., Minelli, E., Aït-Khaled, N., Bateman, E. D., et al., 2007. Global surveillance, prevention and control of chronic respiratory diseases: a comprehensive approach. J. Bousquet and N. Khaltaev. WHO, Geneva, Switzerland, pp. 5–31. Editorial Board, 2001. Respiratory Disease in Canada. Health Canada, Ottawa, Canada. Edwards, L.J., Sharrack, B., Ismail, A., Tumani, H., Constantinescu, C.S., 2011. Central inflammation versus peripheral regulation in multiple sclerosis. J. Neurol. 258
92
R.A. Marrie et al. / Multiple Sclerosis and Related Disorders 8 (2016) 86–92
(8), 1518–1527. Egesten, A., Brandt, L., Olsson, T., Granath, F., Inghammar, M., Löfdahl, C.-G., et al., 2008. Increased prevalence of multiple sclerosis among COPD patients and their first-degree relatives: a population-based study. Lung 186 (3), 173–178. Gershon, A.S., Guan, J., Wang, C., To, T., 2010a. Trends in asthma prevalence and incidence in Ontario, Canada, 1996–2005: a population study. Am. J. Epidemiol. 172 (6), 728–736. Gershon, A.S., Wang, C., Wilton, A.S., Raut, R., To, T., 2010b. Trends in chronic obstructive pulmonary disease prevalence, incidence, and mortality in ontario, Canada, 1996 to 2007: a population-based study. Arch. Intern. Med. 170 (6), 560–565. Hemminki, K., Liu, X., Ji, J., Sundquist, K., Sundquist, J., 2011. Subsequent COPD and lung cancer in patients with autoimmune disease. Eur. Respir. J. 37 (2), 463–465. Higgins, J.P.T., Thompson, S.G., Deeks, J.J., Altman, D.G., 2003. Measuring Inconsistency in Meta-Analyses. Huzel, L., Roos, L.L., Anthonisen, N.R., Manfreda, J., 2002. Diagnosing asthma: the fit between survey and administrative database. Can. Respir. J. 9 (6), 407–412. Ilmarinen, P., Tuomisto, L.E., Kankaanranta, H., 2015. Phenotypes, risk factors, and mechanisms of adult-onset asthma. Mediat. Inflamm. 2015, 514868. Kang, J.-H., Chen, Y.-H., Lin, H.-C., 2010. Comorbidities amongst patients with multiple sclerosis: a population-based controlled study. Eur. J. Neurol. 17 (9), 1215–1219. Kirby, S., Brown, M.G., Murray, T.J., Andreou, P., Fisk, J.D., Stadnyk, K., et al., 2005. Progression of multiple sclerosis in patients with other autoimmune diseases. Mult. Scler. 11 (Suppl. 1), S28–S29. Koch-Henriksen, N., Bronnum-Hansen, H., Stenager, E., 1998. Underlying cause of death in Danish patients with multiple sclerosis: results from the Danish multiple sclerosis registry. J. Neurol. Neurosurg. Psychiatry 65, 56–59. Langer-Gould, A., Albers, K., Van Den Eeden, S., Nelson, L., 2010. Autoimmune diseases prior to the diagnosis of multiple sclerosis: a population-based casecontrol study. Mult. Scler. 16 (7), 855–861. Manfreda, J., Becker, A.B., Pei-Zhong, W., Roos, L.L., Anthonisen, N.R., 1993. Trends in physician-diagnosed asthma prevalence in Manitoba between 1980 and 1990. Chest 7. Manfreda, J., Becklake, M.R., Sears, M.R., Chan-Yeung, M., Dimich-Ward, H., Siersted, H.C., et al., 2001. Prevalence of asthma symptoms among adults aged 20–44 years in Canada. Can. Med. Assoc. J. 164 (7), 995–1001. Marrie, R.A., Reider, N., Cohen, J., Stuve, O., Trojano, M., Sorensen, P.S., et al., 2015c. The incidence and prevalence of comorbid gastrointestinal, musculoskeletal, ocular, pulmonary, and renal disorders in multiple sclerosis: a systematic review. Mult. Scler. J. 21 (3), 332–341. Marrie, R.A., 2007. The Influence of Comorbid Diseases and Health Behaviors on Clinical Characteristics, Disability at Diagnosis, and Disability Progression in Multiple Sclerosis. Epidemiology and Biostatistics. Case Western Reserve University, Cleveland,. Marrie, R.A., Elliott, L., Marriott, J., Cossoy, M., Blanchard, J., Leung, S., et al., 2015a. Effect of comorbidity on mortality in multiple sclerosis. Neurology 85 (3), 240–247.
Marrie, R.A., Fisk, J., Stadnyk, K., Yu, B., Tremlett, H., Wolfson, C., et al., 2013a. The incidence and prevalence of multiple sclerosis in Nova Scotia, Canada. Can. J. Neurol. Sci. 40 (6), 824–831. Marrie, R.A., Fisk, J.D., Tremlett, H., Wolfson, C., Warren, S., Tennakoon, A., et al., 2015b. Differences in the burden of psychiatric comorbidity in MS vs the general population. Neurology 85 (22), 1972–1979. Marrie, R.A., Horwitz, R., Cutter, G., Tyry, T., 2012. Cumulative impact of comorbidity on quality of life in MS. Acta Neurol. Scand. 125 (3), 180–186. Marrie, R.A., Rudick, R., Horwitz, R., Cutter, G., Tyry, T., Campagnolo, D., et al., 2010a. Vascular comorbidity is associated with more rapid disability progression in multiple sclerosis. Neurology 74 (13), 1041–1047. Marrie, R.A., Yu, B.N., Leung, S., Elliott, L., Caetano, P., Warren, S., et al., 2013b. The utility of administrative data for surveillance of comorbidity in multiple sclerosis: a validation study. Neuroepidemiology 40 (2), 85–92. Marrie, R.A., Yu, N., Blanchard, J.F., Leung, S., Elliott, L., 2010b. The rising prevalence and changing age distribution of multiple sclerosis in Manitoba. Neurology 74 (6), 465–471. McNeil, J.M., 2001. Prevalence of disabilities and associated health conditions. United States, 1999. Morb. Mortal. Wkly. Rep. 50, 120–125. Neyeloff, J., Fuchs, S., Moreira, L., 2012. Meta-analyses and forest plots using a microsoft excel spreadsheet: step-by-step guide focusing on descriptive data analysis. BMC Res. Notes 5 (1), 52. Nuyen, J., Schellevisa, F.G., Satarianob, W.A., Spreeuwenberga, P.M., Birknerc, M.D., van den Bosd, G.A.M., et al., 2006. Comorbidity was associated with neurologic and psychiatric diseases: a general practice-based controlled study. J. Clin. Epidemiol. 59, 1274–1284. Ponsonby, A.-L., Dwyer, T., Van Der Mei, I., Kemp, A., Blizzard, L., Taylor, B., et al., 2006. Asthma onset prior to multiple sclerosis and the contribution of sibling exposure in early life. Clin. Exp. Immunol. 146 (3), 463–470. Postma, D.S., Bush, A., van den Berge, M., 2015. Risk factors and early origins of chronic obstructive pulmonary disease. Lancet 385 (9971), 899–909. Raherison, C., Girodet, P.O., 2009. Epidemiology of COPD. Eur. Respir. Rev. 18 (114), 213–221. Richter, D.C., Joubert, J.R., Nell, H., Schuurmans, M.M., Irusen, E.M., 2008. Diagnostic value of post-bronchodilator pulmonary function testing to distinguish between stable, moderate to severe COPD and asthma. Int. J. Chronic Obstr. Pulm. Dis. 3 (4) 693–9. Rucker, G., Schwarzer, G., Carpenter, J.R., Schumacher, M., 2008. Undue reliance on I (2) in assessing heterogeneity may mislead. BMC Med. Res. Methodol. 8, 79. Tan, W.C., Bourbeau, J., FitzGerald, J.M., Cowie, R., Chapman, K., Hernandez, P., et al., 2011. Can age and sex explain the variation in COPD rates across large urban cities? A population study in Canada. Int. J. Tuberc. Lung Dis. 15 (12), 1691–1698. van Weel, C., Schellevis, F.G., 2006. Comorbidity and guidelines: conflicting interests. Lancet 367 (9510), 550–551. Yasui, Y., Liu, Y., Neglia, J., Friedman, D., Bhatia, S., Meadows, A., et al., 2003. A methodological issue in the analysis of second-primary cancer incidence in long-term survivors of childhood cancers. Am. J. Epidemiol. 158 (11), 1108–1113.
Contents lists available at ScienceDirect
Multiple Sclerosis and Related Disorders journal homepage: www.elsevier.com/locate/msard
Chronic lung disease and multiple sclerosis: Incidence, prevalence, and temporal trends Ruth Ann Marrie a,b,n, Scott Patten c, Helen Tremlett d, Lawrence W. Svenson c,e,f, Christina Wolfson g, B. Nancy Yu b,h, Lawrence Elliott b, Joanne Profetto-McGrath i, Sharon Warren j, Stella Leung b, Nathalie Jette c,k, Virender Bhan l,m, John D. Fisk m,n,1 a
Department of Internal Medicine, University of Manitoba, Winnipeg, Canada Department of Community Health Sciences, University of Manitoba, Winnipeg, Canada Department of Community Health Sciences, Cumming School of Medicine, University of Calgary, Calgary, Canada d Department of Medicine (Neurology) and Centre for Brain Health, University of British Columbia, Vancouver, Canada e Surveillance and Assessment Branch, Alberta Ministry of Health, Edmonton, Canada f School of Public Health, University of Alberta, Edmonton, Canada g Department of Epidemiology and Biostatistics and Occupational Health, McGill University, Montreal, Canada h Public Health, Manitoba Health Healthy Living and Seniors, Winnipeg, Canada i Faculty of Nursing, University of Alberta, Canada j Faculty of Rehabilitation Medicine, University of Alberta, Canada k Department of Clinical Neurosciences, Cumming School of Medicine, University of Calgary, Calgary, Canada l Department of Medicine, Dalhousie University, Halifax, Canada m Nova Scotia Health Authority, Canada n Departments of Psychiatry, Psychology & Neuroscience, and Medicine, Dalhousie University, Halifax, Canada b c
art ic l e i nf o
a b s t r a c t
Article history: Received 30 December 2015 Received in revised form 7 March 2016 Accepted 10 May 2016
Objectives: We aimed to estimate the incidence and prevalence of chronic lung disease (CLD), including asthma and chronic obstructive pulmonary disease, in the MS population versus a matched cohort from the general population. Methods: We used population-based administrative data from four Canadian provinces to identify 44,452 persons with MS and 220,849 age-, sex- and geographically-matched controls aged 20 years and older. We employed a validated case definition to estimate the incidence and prevalence of CLD over the period 1995–2005, and used Poisson regression to assess temporal trends. Results: In 2005, the crude incidence of CLD per 100,000 persons was 806 (95%CI: 701–911) in the MS population, and 757 in the matched population (95%CI: 712–803). In 2005, the crude prevalence of CLD was 13.5% (95%CI: 13.1–14.0%) in the MS population, and 12.4% (95%CI: 12.3–12.6%) in the matched population. Among persons aged 20–44 years, the average annual incidence of CLD was higher in the MS population than in the matched population (RR 1.15; 95%CI: 1.02–1.30), but did not differ between populations for those aged Z45 years. The incidence of CLD was stable, but the prevalence of CLD increased 60% over the study period. Conclusion: CLD is relatively common in the MS population. The incidence of CLD has been stable over time, but the prevalence of CLD has increased. Among persons aged 20–44 years, CLD is more common in the MS population than in a matched population. Given the prevalence of CLD in the MS population, further attention to the effects of CLD on outcomes in MS and approaches to mitigating those effects are warranted. & 2016 The Authors. Published by Elsevier B.V. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).
Keywords: Administrative data Chronic lung disease Cohort studies Incidence Multiple sclerosis Prevalence
1. Introduction n Correspondence to: Health Sciences Centre, GF 543- 820 Sherbrook Street, Winnipeg, MB R3A 1R9, Canada. E-mail address: [email protected] (R.A. Marrie). 1 For the CIHR Team in the Epidemiology and Impact of Comorbidity on Multiple Sclerosis.
Chronic lung diseases (CLD) including asthma or chronic obstructive pulmonary disease (COPD) are a leading cause of morbidity and mortality worldwide (Cruz et al., 2007) and their occurrence in multiple sclerosis (MS) remains of interest. Increasing
http://dx.doi.org/10.1016/j.msard.2016.05.009 2211-0348/& 2016 The Authors. Published by Elsevier B.V. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).
R.A. Marrie et al. / Multiple Sclerosis and Related Disorders 8 (2016) 86–92
awareness of the possible adverse effect of CLD on outcomes in MS, such as disability progression and mortality, has heightened the need to understand the relationship between these chronic conditions (Marrie 2007; Marrie et al., 2015a). However, uncertainty persists regarding the incidence and prevalence of many comorbidities in MS, including CLD (Marrie et al., 2015c) Even population-based estimates of the prevalence of CLD (not limited to asthma or COPD alone) are highly variable, ranging from 2.2% to 25% (Nuyen et al., 2006; Ponsonby et al., 2006; Kang et al., 2010; Langer-Gould et al., 2010; Marrie et al., 2013b) Some of the variability may reflect differences in study design and population characteristics, but one commonality of these studies has been the lack of age and sex-specific estimates of the incidence and prevalence of CLD in MS. Findings have been highly inconsistent with respect to whether CLD occurs more or less often in the MS population than in the general population (Marrie et al., 2015c). Therefore, we evaluated the incidence and prevalence of CLD, over a ten year period, in the MS population after diagnosis, including age-specific estimates; and compared the findings with a matched cohort selected from the general population. By employing validated methods in a large population-based sample with concurrent controls we hoped to resolve inconsistencies in the literature.
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each case. 2.3. Chronic lung disease We selected an administrative case definition for CLD that was validated in MB and NS against medical records review and selfreport questionnaires, and applied it to identify affected individuals in the MS and matched populations (Marrie et al., 2013b). The case definition required that an individual have Z1 hospital claim or Z2 physician claims with an ICD-9/10 code for asthma or COPD (493, 491.xx, 492.xx, 496.xx, J45, J46, J40, J42, J43, J44) in a five-year period to be considered affected. We did not include prescription claims in the case definition because such data were not available in all jurisdictions. We did not attempt to distinguish between asthma and COPD because of the diagnostic challenges in accurately distinguishing between these conditions (Manfreda et al., 1993; Chhabra, 2005; Richter et al., 2008; AlKassimi et al., 2011) and because diagnostic codes for asthma and COPD are frequently found in the same patients (Huzel et al., 2002). Because CLDs represent chronic conditions in adult populations, once a person met the case definition, he or she was considered affected in all years thereafter, if alive and living in the province. 2.4. Incidence and prevalence
2. Materials and methods 2.1. Data sources Health care in Canada is universal (public), and health service delivery is administered provincially. As described previously (Marrie et al., 2015b) we conducted a cohort study using population-based anonymized administrative health data from the Canadian provinces of British Columbia (BC), Manitoba (MB), Quebec (QC) and Nova Scotia (NS). Within each province, we used unique personal identification numbers to link population registries with hospital and physician claims data for the years 1990–2010, except in BC where data extended to 2008/09 (British Columbia Ministry of Health [creator], 2012a, 2012b, 2012c). The population registries capture sex, postal code, and dates of birth, death and health care coverage. The hospital discharge abstract database captures dates of admission and discharge and up to 25 diagnoses, coded using the International Classification of Disease (ICD)-9 or ICD-10-CA system. Physician claims data include the date of service and diagnosis coded using the ICD-9 system. Privacy regulations prevent line level data from leaving the province of origin; therefore we conducted the same analyses in each province, and then pooled the provincial estimates using meta-analyses. In each province, we secured ethics approval, and approval to access administrative data from the relevant body. 2.2. Study populations As described elsewhere (Marrie et al., 2015b) within each province, we employed a previously validated administrative case definition for MS (Z3 hospital or physician claims for MS (ICD-9/ 10¼ 340/G39)) (Marrie et al., 2010b, 2013a). After identifying the MS cohort, we excluded persons under age 20 years and then we selected a matched cohort from the general population. This cohort excluded anyone with any diagnostic codes (ICD-9/10) for demyelinating disease and included up to 5 controls matched on sex, exact year of birth and region of residence (full postal code or first three digits of postal code if full match impossible) to each MS case. We assigned the date of the first claim (index date) for demyelinating disease as the “date of diagnosis” for each MS case; the same date (index date) was assigned to the matched controls for
To identify incident cases of CLD in the MS cohort, the first claim for CLD had to occur after the date of MS diagnosis, and be preceded by a five-year run-in period with no such claims. For the matched cohort a CLD case was defined as incident if the first claim occurred after the index date assigned to their matched case, again preceded by a five-year run-in period. Because new cases that occur at the end of a study period may not have enough follow-up time to fully meet the case definition, incidence may artifactually drop at the end of a study period. Therefore, we report annual incidence for 1995 through 2005. We report prevalence at the mid-point of each year from 1995 through 2005 assuming, as noted above, that the numerator included all cases of CLD identified after the index date persisted as long as the person was alive and living in the province and that the denominator was the number of individuals in the study population at mid-year. We age-standardized the findings to the 2001 Canadian population (closest to the study mid-point) for consistency with earlier work. We report 95% confidence intervals (CI) assuming a Poisson distribution. To meet provincial privacy requirements, cell sizes r5 were suppressed. This meant that we could not directly model crude rates; consequently we modeled age-standardized incidence and prevalence using negative binomial regression (to account for overdispersion), including year and sex as covariates (Yasui et al., 2003). This approach accounts for age effects although age is not modeled as a covariate (Yasui et al., 2003). Due to small cell sizes in some provinces, age was categorized as 20–44, 45–59, and Z 60 years and we examined age effects in two ways. First, we compared average annual age-specific incidence over the entire study period between the two populations. Second, we compared annual age-specific prevalence adjusting for year. Both analyses used negative binomial regression models. We report incidence rates, prevalence, adjusted rate ratios (RR), and their 95%CIs. Province-specific estimates were pooled using random-effects meta-analysis and we report these rate ratios and I2 and τ2. The I2 index of heterogeneity describes the proportion of variation in point estimates due to heterogeneity of studies rather than to sampling error (Higgins et al., 2003). I2 is calculated from the Q statistic (the weighted sum of squared differences between individual study effects): I2 ¼[(Q degrees of freedom)/Q]*100. Values of I2 of o25% are considered low, and 475% are considered
R.A. Marrie et al. / Multiple Sclerosis and Related Disorders 8 (2016) 86–92
high (Higgins et al., 2003). Between study variance can be quantified using τ2. Statistical analyses were performed using SAS V9.3 (SAS Institute Inc, Cary, N.C.) and using a Microsoft Excel spreadsheet for meta-analyses (Neyeloff et al., 2012).
3. Results 3.1. Participants
1600
Average annual incidence of Chronic lung disease per 100,000 persons
88
1400 1200 1000 MS
800
Matches
600 400 200 0 20-44
As reported previously, we identified 44,452 persons with MS and 220,849 matched controls from the general population (Table e-1) (Marrie et al., 2015b).
45-59
≥60
Age group (years)
Fig. 1. Age-specific average annual incidence of chronic lung disease per 100,000 population.
3.3. Prevalence 3.2. Incidence In 2005, the pooled crude incidence of CLD in the MS population was 806 per 100,000 persons (95%CI: 701–911), and it was 757 in the matched population (95%CI: 712–803) (Supplemental Fig. 1). Over the entire study period, in the initial analysis, after adjusting for year and sex, the pooled age-standardized incidence of CLD did not differ between the MS and matched populations (Table 1). When both populations were considered, the incidence of CLD was higher among women than men in two provinces, but the pooled estimate suggested that the incidence did not differ by sex. The incidence of CLD was stable over time in both populations. Further, there was no evidence of interaction between population and time, or between population and sex. However, when we examined age-specific average annual incidence rates (over the 10-year period) some differences emerged between the MS and matched populations (Fig. 1); we observed an interaction between age group and population. Specifically, among persons aged 20–44 years, the average annual incidence of CLD was 15% higher in the MS population than in the matched population (RR 1.15; 95%CI: 1.02–1.30, Table 2). However, among persons aged 45–59 years (RR 1.06; 95%CI: 0.93–1.21), and aged Z60 years the average annual incidence of CLD did not differ between the two populations (RR 0.92; 95%CI: 0.76–1.10). Consequently, in the MS population the higher average annual incidence of CLD in the two older age groups as compared to those aged 20–44 years did not reach statistical significance. In the matched population, the average annual incidence of CLD was significantly higher in those aged Z 45 years as compared to those aged 20–44 years (Table 3).
In 2005, the pooled crude prevalence of CLD in the MS population was 13.5 per 100 persons (95%CI: 13.1–14.0), and it was 12.4 per 100 persons (95%CI: 12.3–12.6) in the matched population (Supplemental Fig. 2). However, over the 10-year study period, after adjusting for year and sex, the age-standardized prevalence of CLD did not differ between the MS and matched populations (Table 1). In both populations, women had a higher prevalence of CLD than men, and the prevalence of CLD increased over time, such that over a 10-year period the prevalence increased 60%. We did not observe any evidence of interactions between population and time, or between population and sex. When we compared age-specific prevalence between populations over the entire study period the findings were similar to those observed for average annual age-specific incidence rates (Tables 2 and 4). That is, among persons aged 20–44 years, the prevalence of CLD was 27% higher in the MS population than in the matched population after adjusting for year (RR 1.27; 95%CI: 1.12– 1.45, Table 2). However, among persons aged 45–59 years and aged Z60 years the pooled prevalence of CLD did not differ between populations, although we observed heterogeneity in these findings across provinces. Also as with the age-specific incidence rates, in the MS population the higher prevalence of CLD in the two older age groups as compared to those aged 20–44 years did not reach statistical significance while in the matched population, the prevalence of CLD was significantly higher in those aged Z 45 years as compared to those aged 20–44 years (Table 4).
Table 1 Chronic lung disease: adjusted associations of incidence and prevalence with the study population, sex and time.
Incidence MS population vs. matches Women vs. men Time/year
Prevalence MS population vs. matches Women vs. men Time/year
BC
MB
QC
NS
τ2
I2 (p-value)
Rate ratio (95% CI) 1.02 (0.93, 1.10)
Rate ratio (95% CI) 0.87 (0.72, 1.05)
Rate ratio (95% CI) 0.88 (0.78, 0.99)
Rate ratio (95% CI) 1.15 (0.92, 1.44)
0.14
Rate ratio (95% CI) 96.9 ( o 0.0001) 0.97 (0.91, 1.03)
1.16 (1.07, 1.27)
1.29 (1.07, 1.56)
0.90 (0.80, 1.01)
1.09 (0.87, 1.37)
0.15
7.43 (0.06)
1.09 (0.93, 1.28)
0.98 (0.97, 1.00)
0.99 (0.97, 1.03)
0.98 (0.96, 1.00)
0.95 (0.91, 0.98)
0.003
80.9 ( o 0.0013)
0.98 (0.97, 0.99)
Rate Ratio (95% CI) 0.93 (0.89, 0.97)
Rate Ratio (95% CI) 0.92 (0.88, 0.96)
Rate Ratio (95% CI) 1.09 (1.03, 1.16)
Rate Ratio (95% CI) 1.19 (1.14, 1.24)
0.02
Rate Ratio (95% CI) 95.7 ( o 0.0001) 1.03 (0.90, 1.17)
1.29 (1.24, 1.34)
1.34 (1.29, 1.40)
1.01 (0.95, 1.07)
1.21 (1.16, 1.26)
0.024
64.8 (o 0.0001) 1.21 (1.09, 1.34)
1.07 (1.06, 1.08)
1.067 (1.060, 1.074)
1.06 (1.05, 1.07)
1.04 (1.03, 1.05)
0.0007 86.7 ( o 0.0001) 1.06 (1.05, 1.07)
BC ¼ British Columbia, MB ¼Manitoba, QC ¼ Quebec, NS¼ Nova Scotia, Time/year ¼Increase in disease rate over time in units of one year.
Random effects estimate
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Table 2 Age-specific incidence and prevalence of chronic lung disease in the multiple sclerosis versus matched populations.
Incidence-MS vs. match 20–44 Years 45–59 Years Z60 Years Prevalence MS vs. match 20–44 Years 45–59 Years Z60 Years
τ2
BC
MB
QC
NS
Rate ratio (95% CI)
Rate ratio (95% CI)
Rate ratio (95% CI)
Rate ratio (95% CI)
1.07 (0.96, 1.20) 1.06 (0.96, 1.18) 0.85 (0.79, 0.93)
1.37 (1.24, 1.52) 1.02 (0.93, 1.12) 0.79 (0.73, 0.85)
1.10 (0.97, 1.24) 1.15 (1.03, 1.28) 1.19 (1.10, 1.28)
1.09 (0.97, 1.23) 0.88 (0.79, 0.98) 0.88 (0.81, 0.95)
Rate ratio (95% CI)
Rate ratio (95% CI)
Rate ratio (95% CI)
Rate ratio (95% CI)
1.13 (1.09, 1.18) 0.92 (0.86, 0.98) 0.91 (0.81, 1.01)
1.27 (1.22, 1.33) 1.09 (1.06, 1.13) 0.95 (0.86, 1.06)
1.24 (1.00, 1.53) 1.13 (1.01, 1.25) 1.06 (0.87, 1.29)
1.46 (1.40, 1.53) 1.18 (1.13, 1.21) 1.13 (1.04, 1.22)
I2 (p-value)
Random effects estimate Rate ratio (95% CI)
0.13 78.6 (0.003) 1.15 (1.02, 1.30) 0.13 84.5 (0.0002) 1.06 (0.93, 1.21) 0.04 95.3 (o 0.0001) 0.92 (0.76, 1.10)
Rate ratio (95% CI) 0.03 95.6 (o 0.0001) 1.27 (1.12, 1.45) 0.06 86.6 (0.0001) 1.08 (0.99, 1.19) 0.10 75.7 (0.0063) 1.01 (0.90, 1.13)
Table 3 Chronic lung disease: average annual incidence by age group. BC
MB
QC
NS
Incidence-MS 20–44 Years (reference group) 45–59 Years Z60 Years
Rate ratio (95% CI) 1.0 1.07 (0.96, 1.18) 1.14 (0.92, 1.40)
Rate ratio (95% CI) 1.0 0.98 (0.89, 1.07) 0.96 (0.80, 1.16)
Rate ratio (95% CI) 1.0 1.23 (1.10, 1.37) 1.51 (1.20, 1.88)
Rate ratio (95% CI) 1.0 1.08 (0.96, 1.20) 1.16 (0.93, 1.45)
Incidence-matches 20–44 Years (reference group) 45–59 Years Z60 Years
Rate ratio (95% CI) 1.0 1.07 (0.96, 1.20) 1.15 (0.92, 1.43)
Rate ratio (95% CI) 1.0 1.32 (1.19, 1.45) 1.73 (1.42, 2.12)
Rate ratio (95% CI) 1.0 1.18 (1.05, 1.32) 1.39 (1.09, 1.76)
Rate ratio (95% CI) 1.0 1.34 (1.20, 1.50) 1.79 (1.43, 2.24)
τ2
I2 (p-value)
Random effects estimate Rate ratio (95% CI)
0.11 0.43
69.0 (0.021) 66.8 (0.026)
1.08 (0.99, 1.19) 1.17 (0.97, 1.41)
Rate Ratio (95% CI) 0.14 0.76
72.0 (0.013) 70.8 (0.016)
1.22 (1.10, 1.36) 1.50 (1.22, 1.83)
BC ¼ British Columbia, MB ¼ Manitoba, QC¼ Quebec, NS¼ Nova Scotia.
Table 4 Chronic lung disease: prevalence by age group. BC
MB
QC
NS
Prevalence-MS 20–44 Years (reference group) 45–59 Years Z60 Years
Rate ratio (95% CI) 1.0 0.86 (0.81, 0.92) 0.74 (0.66, 0.84)
Rate ratio (95% CI) 1.0 0.95 (0.92, 0.99) 0.91 (0.84, 0.98)
Rate ratio (95% CI) 1.0 1.45 (1.20, 1.75) 2.10 (1.44, 3.07)
Rate ratio (95% CI) 1.0 0.97 (0.93, 1.03) 0.96 (0.86, 1.07)
Prevalence-matches 20–44 Years (reference group) 45–59 Years Z60 Years
Rate ratio (95% CI) 1.0 1.06 (1.01, 1.11) 1.13 (1.02, 1.24)
Rate ratio (95% CI) 1.0 1.11 (1.05, 1.17) 1.23 (1.10, 1.38)
Rate ratio (95% CI) 1.0 1.60 (1.40, 1.82) 2.55 (1.95, 3.32)
Rate ratio (95% CI) 1.0 1.22 (1.18, 1.25) 1.49 (1.40, 1.58)
τ2
I2 (p-value)
Random effects estimate Rate ratio (95% CI)
0.02 0.09
89.7 ( o 0.0001) 90.2 ( o 0.0001)
0.99 (0.90, 1.09) 0.99 (0.81, 1.21)
Rate ratio (95% CI) 0.03 0.15
94.0 ( o 0.0001) 93.6 ( o 0.0001)
1.21 (1.09, 1.34) 1.46 (1.18, 1.81)
BC ¼ British Columbia, MB ¼ Manitoba, QC¼ Quebec, NS¼ Nova Scotia.
4. Discussion We conducted a large population-based cohort study using over 10 years of administrative health data involving 265,301 Canadians (44,452 with MS; 220,840 contemporaneous controls). Multiple previous studies have compared the prevalence of CLD in the MS population to various comparator populations (Marrie et al., 2015c) with highly inconsistent findings. Approximately one-third of studies report CLD to be more common in the MS population, one-quarter report CLD to be less common, and the remainder report CLD to be equally common in the MS population as the comparator population (Marrie et al., 2015c). Differences in the lung diseases evaluated, in the underlying characteristics of the populations studied, and in whether the study was population-based or not may account for some of these inconsistencies. Unlike these earlier studies we evaluated the incidence and prevalence of CLD over a long (ten year) period, and reported agespecific estimates. We found that CLD affected more than one in ten persons with MS. While initial analyses suggested that the
incidence and prevalence of CLD did not differ between populations, we identified potentially important differences in these associations by age group which may account for some of the inconsistencies in the literature. As prior studies did not identify such interactions, the presence or absence of associations between CLD and MS may have depended on the age distribution of their sample. We found that the average annual incidence of CLD in the MS population was 0.81%. Comparable work has been limited. Although two prior studies reported the incidence of CLD, neither was truly population-based and both focused exclusively on COPD alone rather than considering asthma and COPD together. Of these two studies, one found that the incidence of COPD was 2.5% over a 30 year period among persons with incident MS (Christiansen et al., 2010). The other reported an incidence of COPD of 0.13%, but identified COPD solely based on hospitalizations and likely underestimated its true incidence (Hemminki et al., 2011). We found that the crude prevalence of CLD was 13.5% in the MS population and 12.4% percent in the matched population in 2005.
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In 1998 the combined prevalence of asthma and COPD in the Canadian general population was reported at approximately 11% (Editorial Board, 2001) and given the increase in prevalence of these conditions over time, the findings in our matched population are consistent with expectations for the population as a whole. A recent systematic review found 21 studies that had reported the prevalence of CLD in MS, of which five were population-based and conducted in prevalent cohorts, similar to ours (Marrie et al., 2015c). Among these five studies, two reported the prevalence of CLD broadly (Nuyen et al., 2006; Marrie et al., 2013b) while the others focused on either asthma or COPD alone. The first broad study was conducted in Manitoba in 2005 using a case definition for CLD that also incorporated prescription claims but otherwise employed the same methods as the present study, albeit over a more limited time period; as expected this found a similar prevalence of CLD of 15.6% (Marrie et al., 2013b). The second broad study was conducted in the Netherlands, and found a one-year prevalence of CLD of only 3.3% based on primary care electronic records. This lower prevalence may have reflected the short period of ascertainment, or differences in coding practices. None of five population-based studies reported age-specific prevalence estimates. Unlike prior studies of CLD in the MS population, we were able to evaluate temporal trends in the incidence and prevalence of CLD over a ten year period. While we found the incidence of CLD to be stable in both populations, the prevalence of CLD increased 60% over the study period for both populations. These findings for the MS population require replication but are consistent with those reported elsewhere in Canada. Specifically, a 64% increase in the crude prevalence of COPD (Gershon et al., 2010b) and the 70.5% increase in the prevalence of asthma (Gershon et al., 2010a) have been reported in the general population of the province of Ontario over a similar time period. Because prevalence is roughly equal to incidence*disease duration, the observation of stable incidence of CLD but rising prevalence of CLD suggests that individuals are living longer with CLD, perhaps due to earlier diagnosis, improved survival or both. Our initial analyses using age-standardized estimates suggested that the incidence and prevalence of CLD were similar in the MS and matched populations. However, this was not the case when we stratified the analyses by age. The analyses demonstrated two key, related findings. First, the incidence and prevalence of CLD increased with age in the matched population but not in the MS population. Second, the incidence and prevalence of CLD were higher in the MS population than in the matched population among those aged 20–44 years. Our case definition of CLD combined asthma and COPD. Among those aged 20–44 years the prevalence of asthma is higher than of COPD, which has a prevalence of only 3.1% among those under age 40 years, but the prevalence of COPD increases with age (Editorial Board, 2001; Raherison and Girodet, 2009). Thus asthma may be driving the difference in findings between the MS and matched populations and this will require further study in populations in which these conditions can be clearly distinguished. Much of the initial interest in the association of CLD and MS focused on the hygiene hypothesis and proposed that asthma would be less common in persons with MS, on the basis that asthma was Th2-mediated and that MS was Th1-mediated (Bergamaschi et al., 2009). However, co-occurrence of allergy, asthma and autoimmunity was observed, and Th17 and T regulatory cells were recognized to influence Th1 and Th2 pathways and to be dysregulated in MS (Edwards et al., 2011). Further, the recognition of shared environmental and genetic risk factors such as smoking, obesity and vitamin D-related polymorphisms (Raherison and Girodet, 2009; Chishimba et al., 2010; Ascherio, 2013; Ilmarinen et al., 2015) support hypotheses that CLD would be more common, rather than less common in MS
(Egesten et al., 2008). Further clarification of the underlying mechanisms of these associations is needed and whether the same is true for the direction of association between MS and CLD and for asthma and COPD. Regardless, our findings demonstrate that the burden of CLD is clearly high enough to be a concern for the MS population. As noted above, the prevalence of these conditions in Canada is increasing (Gershon et al., 2010a, 2010b) while in the United States, CLD is among the leading causes of disability (McNeil, 2001). In those with MS, CLD has been associated with more rapid disability progression and reduced health-related quality of life, and is frequently a cause of death (Koch-Henriksen et al., 1998; Kirby et al., 2005; Marrie et al., 2010a, 2012). Thus, attention to the possible presence of CLD in relatively younger age cohorts with MS is warranted as modification of this underlying comorbidity may benefit MS outcomes. Avoiding smoking and access to smoking cessation programs may be particularly important for those with MS as smoking is a risk factor for multiple forms of CLD (Beasley et al., 2015; Postma et al., 2015). The presence of CLD may also complicate disease-modifying treatment use; for example as a relative contraindication to the use of fingolimod, a new therapy for MS. The incidence and prevalence of CLD varied somewhat across provinces, therefore the pooled estimate should be interpreted cautiously. The variation observed may reflect true geographic variation in disease risk or burden, differences in health services utilization for CLD due to factors other than disease burden, measurement error due to the use of administrative data, or some combination of these factors. In Canada, the self-reported prevalence of COPD among those aged Z40 years varies from 5.3– 9.5% across major cities; similar variation was identified in the prevalence when pulmonary function was measured objectively, although estimates were higher (12.9–19.3%) (Tan et al., 2011). However, differences in age and sex distribution account for much of these differences. The prevalence of asthma also varies across Canada, and variation in the use of asthma medications exceeds the variation in symptom severity (Manfreda et al., 2001). These observations suggest that the observed variation in CLD prevalence in our study population is consistent with expectations for the Canadian population. This study has strengths and limitations. Strengths include the large size of the population, its representative nature, the use of a validated case definition for MS, the use of a contemporaneous control population, and our ability to examine temporal trends over a 10-year period. We used a case definition for CLD that was highly specific, but less sensitive than desired. Thus it is unlikely that we incorrectly misclassified individuals as having CLD, but we may have missed cases of CLD. This could have lead to us underestimating the incidence and prevalence of CLD, but should not have affected the assessment of temporal trends, and might tend to bias rate ratios toward the null. More frequent health system contacts may have lead to more frequent identification of CLD in the MS population. We reported I2 as a measure of heterogeneity, but I2 tends toward 100% when sample sizes are large and precision is high (Rucker et al., 2008) suggesting we overestimated heterogeneity. This study suggests that CLD is common in the MS population. The incidence of CLD has been stable over time, but the prevalence of CLD has increased. Among persons aged 20–44 years, CLD is more common in the MS population than in an age-, sex- and geographically-matched population drawn from the general population. These findings illustrate the importance of attention to this comorbidity in relatively younger individuals with MS. In many chronic diseases including MS, clinical practice guidelines do not address the role of comorbidity in management (van Weel and Schellevis, 2006). However, the prevalence of CLD in the MS
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population demands attention to the effects of CLD on outcomes in MS and approaches to mitigate those effects.
Funding This study was supported (in part) by the Canadian Institutes of Health Research (CBG-101829), Rx & D Health Research Foundation, and Don Paty Career Development grants from the Multiple Sclerosis Society of Canada (to RAM), and a Manitoba Research Chair from Research Manitoba (to RAM).
Conflict of interest Ruth Ann Marrie receives research funding from: Canadian Institutes of Health Research, Public Health Agency of Canada, Research Manitoba, Health Sciences Centre Foundation, Multiple Sclerosis Society of Canada, Multiple Sclerosis Scientific Foundation, Rx & D Health Research Foundation, and has conducted clinical trials funded by Sanofi-Aventis. Nancy Yu receives research support from the Canadian International Development Agency, the Multiple Sclerosis Society of Canada, CIHR, and Manitoba Health and Healthy Living. Stella Leung reports no disclosures. Lawrence Elliott receives research support from the Canadian Institutes of Health Research. Sharon Warren receives research funding from the Canadian Institutes of Health Research. Christina Wolfson receives research funding from the Multiple Sclerosis Society of Canada, Canadian Institutes of Health Research, Canada Foundation for Innovation, the National MS Society and has received one speaking honorarium from Novartis. Helen Tremlett currently receives funding from: the Multiple Sclerosis Society of Canada [Don Paty Career Development Award]; US National MS Society [#RG 4202-A-2 (PI)]; Canadian Institutes of Health Research [MOP: #190898 (PI) and MOP-93646 (PI)]; Michael Smith Foundation for Health Research and is the Canada Research Chair for Neuroepidemiology and Multiple Sclerosis. She has received speaker honoraria and/or travel expenses to attend conferences from: the Consortium of MS Centres, US National MS Society, Swiss Multiple Sclerosis Society, the University of British Columbia Multiple Sclerosis Research Program, Teva Pharmaceuticals and Bayer Pharmaceutical (honoraria declined) and ECTRIMS (2011), UK MS Trust and the Chesapeake Health Education Program, US Veterans Affairs (2012, honorarium declined). Unless otherwise stated, all speaker honoraria are either donated to an MS charity or to an unrestricted grant for use by her research group. John Fisk receives research funding from the Canadian Institutes of Health Research, Rx & D Health Research Foundation; the Dalhousie Medical Research Foundation, and in the past has received grants, honoraria and consultation fees from AstraZeneca, Bayer, Biogen-Idec Canada, Heron Evidence Development Limited, Hoffmann-La Roche, MAPI Research Trust, Novartis, Sanofi-Aventis, Serono Canada, and QualityMetric Incorporated. Lawrence W. Svenson reports no disclosures. Joanne Profetto-McGrath reports no disclosures. Nathalie Jette is the holder of a Canada Research Chair Tier 2 in Neurological Health Services Research and receives research support from CIHR, AIHS, Hotchkiss Brain Institute, the University of Calgary and Pfizer Canada. Virender Bhan has received honoraria from Biogen, EMD Serono, Genzyme, Novartis and Roche for participation in Advisory Boards.
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Acknowledgements We thank Yan Wang (Health Data Nova Scotia), Bin Zhu (McGill University), Elaine Kingwell (University of British Columbia), Feng Zhu (University of British Columbia) for their assistance with data analysis and/or data access. All inferences, opinions, and conclusions drawn in this publication are those of the authors and do not reflect the opinions or policies of the Data Stewards. No official endorsement by Manitoba Health, Population Data BC, Pharmanet, the Regie D’Assurance Maladie du Quebec, or The Commission d’accès à l’information (CAI) of Quebec is intended or should be inferred. Some data used in this report were made available by Health Data Nova Scotia of Dalhousie University. Although some of this research is based on data obtained from the Nova Scotia Department of Health and Wellness, the observations and opinions expressed of those of the authors and do not represent those of either Health Data Nova Scotia or the Department of Health and Wellness. CIHR Team in the Epidemiology and Impact of Comorbidity on Multiple Sclerosis (by site): University of Manitoba (James Blanchard MD, PhD; Patricia Caetano, PhD; Lawrence Elliott, MD, MSc; Stella Leung, MSc; Ruth Ann Marrie, M.D, PhD; Bo Nancy Yu, MD, PhD) Dalhousie University (Virender Bhan, MBBS; John D. Fisk, PhD), University of Alberta (Joanne Profetto-McGrath, PhD; Sharon Warren, PhD; Larry Svenson, Ph.D.); McGill University (Christina Wolfson, PhD); University of British Columbia (Helen Tremlett, PhD); University of Calgary (Scott Patten, MD, PhD, Nathalie Jette, MD, MSc).
Appendix A. Supplementary material Supplementary data associated with this article can be found in the online version at http://dx.doi.org/10.1016/j.msard.2016.05. 009.
References Al-Kassimi, F.A., Abba, A.A., Al-Hajjaj, M.S., Alhamad, E.H., Raddaoui, E., Shaikh, S.A., 2011. Asthma masquerading as chronic obstructive pulmonary disease: a study of smokers fulfilling the GOLD definition of chronic obstructive pulmonary disease. Respiration 82 (1), 19–27. Ascherio, A., 2013. Environmental factors in multiple sclerosis. Expert Rev. Neurother. 13 (Suppl 12), S3–S9. Beasley, R., Semprini, A., Mitchell, E.A., 2015. Risk factors for asthma: is prevention possible? Lancet 386 (9998), 1075–1085. Bergamaschi, R., Villani, S., Crabbio, M., Ponzio, M., Romani, A., Verri, A., et al., 2009. Inverse relationship between multiple sclerosis and allergic respiratory diseases. Neurol. Sci. 30 (2), 115–118. British Columbia Ministry of Health [creator], 2012a. Consolidation File (MSP Registration & Premium Billin)g). Retrieved April 1, 2015, from 〈http://www.pop data.bc.ca/data〉. British Columbia Ministry of Health [creator], 2012b. Discharge Abstract Database (Hospital Separations). Retrieved April 1, 2015, from 〈http://www.popdata.bc. ca/data〉. British Columbia Ministry of Health [creator], 2012c. Medical Services Plan (MSP). Retrieved April 1, 2015, from 〈http://www.popdata.bc.ca/data〉. Chhabra, S., 2005. Acute bronchodilator response has limited value in differentiating bronchial asthma from COPD. J. Asthma 42 (5), 367–372. Chishimba, L., Thickett, D.R., Stockley, R.A., Wood, A.M., 2010. The vitamin D axis in the lung: a key role for vitamin D-binding protein. Thorax 65 (5), 456–462. Christiansen, C.F., Christensen, S., Farkas, D.K., Miret, M., Sørensen, H.T., Pedersen, L., 2010. Risk of arterial cardiovascular diseases in patients with multiple sclerosis: a population-based cohort study. Neuroepidemiology 35 (4), 267–274. Cruz, A.A., Mantzouranis, E., Matricardi, P.M., Minelli, E., Aït-Khaled, N., Bateman, E. D., et al., 2007. Global surveillance, prevention and control of chronic respiratory diseases: a comprehensive approach. J. Bousquet and N. Khaltaev. WHO, Geneva, Switzerland, pp. 5–31. Editorial Board, 2001. Respiratory Disease in Canada. Health Canada, Ottawa, Canada. Edwards, L.J., Sharrack, B., Ismail, A., Tumani, H., Constantinescu, C.S., 2011. Central inflammation versus peripheral regulation in multiple sclerosis. J. Neurol. 258
92
R.A. Marrie et al. / Multiple Sclerosis and Related Disorders 8 (2016) 86–92
(8), 1518–1527. Egesten, A., Brandt, L., Olsson, T., Granath, F., Inghammar, M., Löfdahl, C.-G., et al., 2008. Increased prevalence of multiple sclerosis among COPD patients and their first-degree relatives: a population-based study. Lung 186 (3), 173–178. Gershon, A.S., Guan, J., Wang, C., To, T., 2010a. Trends in asthma prevalence and incidence in Ontario, Canada, 1996–2005: a population study. Am. J. Epidemiol. 172 (6), 728–736. Gershon, A.S., Wang, C., Wilton, A.S., Raut, R., To, T., 2010b. Trends in chronic obstructive pulmonary disease prevalence, incidence, and mortality in ontario, Canada, 1996 to 2007: a population-based study. Arch. Intern. Med. 170 (6), 560–565. Hemminki, K., Liu, X., Ji, J., Sundquist, K., Sundquist, J., 2011. Subsequent COPD and lung cancer in patients with autoimmune disease. Eur. Respir. J. 37 (2), 463–465. Higgins, J.P.T., Thompson, S.G., Deeks, J.J., Altman, D.G., 2003. Measuring Inconsistency in Meta-Analyses. Huzel, L., Roos, L.L., Anthonisen, N.R., Manfreda, J., 2002. Diagnosing asthma: the fit between survey and administrative database. Can. Respir. J. 9 (6), 407–412. Ilmarinen, P., Tuomisto, L.E., Kankaanranta, H., 2015. Phenotypes, risk factors, and mechanisms of adult-onset asthma. Mediat. Inflamm. 2015, 514868. Kang, J.-H., Chen, Y.-H., Lin, H.-C., 2010. Comorbidities amongst patients with multiple sclerosis: a population-based controlled study. Eur. J. Neurol. 17 (9), 1215–1219. Kirby, S., Brown, M.G., Murray, T.J., Andreou, P., Fisk, J.D., Stadnyk, K., et al., 2005. Progression of multiple sclerosis in patients with other autoimmune diseases. Mult. Scler. 11 (Suppl. 1), S28–S29. Koch-Henriksen, N., Bronnum-Hansen, H., Stenager, E., 1998. Underlying cause of death in Danish patients with multiple sclerosis: results from the Danish multiple sclerosis registry. J. Neurol. Neurosurg. Psychiatry 65, 56–59. Langer-Gould, A., Albers, K., Van Den Eeden, S., Nelson, L., 2010. Autoimmune diseases prior to the diagnosis of multiple sclerosis: a population-based casecontrol study. Mult. Scler. 16 (7), 855–861. Manfreda, J., Becker, A.B., Pei-Zhong, W., Roos, L.L., Anthonisen, N.R., 1993. Trends in physician-diagnosed asthma prevalence in Manitoba between 1980 and 1990. Chest 7. Manfreda, J., Becklake, M.R., Sears, M.R., Chan-Yeung, M., Dimich-Ward, H., Siersted, H.C., et al., 2001. Prevalence of asthma symptoms among adults aged 20–44 years in Canada. Can. Med. Assoc. J. 164 (7), 995–1001. Marrie, R.A., Reider, N., Cohen, J., Stuve, O., Trojano, M., Sorensen, P.S., et al., 2015c. The incidence and prevalence of comorbid gastrointestinal, musculoskeletal, ocular, pulmonary, and renal disorders in multiple sclerosis: a systematic review. Mult. Scler. J. 21 (3), 332–341. Marrie, R.A., 2007. The Influence of Comorbid Diseases and Health Behaviors on Clinical Characteristics, Disability at Diagnosis, and Disability Progression in Multiple Sclerosis. Epidemiology and Biostatistics. Case Western Reserve University, Cleveland,. Marrie, R.A., Elliott, L., Marriott, J., Cossoy, M., Blanchard, J., Leung, S., et al., 2015a. Effect of comorbidity on mortality in multiple sclerosis. Neurology 85 (3), 240–247.
Marrie, R.A., Fisk, J., Stadnyk, K., Yu, B., Tremlett, H., Wolfson, C., et al., 2013a. The incidence and prevalence of multiple sclerosis in Nova Scotia, Canada. Can. J. Neurol. Sci. 40 (6), 824–831. Marrie, R.A., Fisk, J.D., Tremlett, H., Wolfson, C., Warren, S., Tennakoon, A., et al., 2015b. Differences in the burden of psychiatric comorbidity in MS vs the general population. Neurology 85 (22), 1972–1979. Marrie, R.A., Horwitz, R., Cutter, G., Tyry, T., 2012. Cumulative impact of comorbidity on quality of life in MS. Acta Neurol. Scand. 125 (3), 180–186. Marrie, R.A., Rudick, R., Horwitz, R., Cutter, G., Tyry, T., Campagnolo, D., et al., 2010a. Vascular comorbidity is associated with more rapid disability progression in multiple sclerosis. Neurology 74 (13), 1041–1047. Marrie, R.A., Yu, B.N., Leung, S., Elliott, L., Caetano, P., Warren, S., et al., 2013b. The utility of administrative data for surveillance of comorbidity in multiple sclerosis: a validation study. Neuroepidemiology 40 (2), 85–92. Marrie, R.A., Yu, N., Blanchard, J.F., Leung, S., Elliott, L., 2010b. The rising prevalence and changing age distribution of multiple sclerosis in Manitoba. Neurology 74 (6), 465–471. McNeil, J.M., 2001. Prevalence of disabilities and associated health conditions. United States, 1999. Morb. Mortal. Wkly. Rep. 50, 120–125. Neyeloff, J., Fuchs, S., Moreira, L., 2012. Meta-analyses and forest plots using a microsoft excel spreadsheet: step-by-step guide focusing on descriptive data analysis. BMC Res. Notes 5 (1), 52. Nuyen, J., Schellevisa, F.G., Satarianob, W.A., Spreeuwenberga, P.M., Birknerc, M.D., van den Bosd, G.A.M., et al., 2006. Comorbidity was associated with neurologic and psychiatric diseases: a general practice-based controlled study. J. Clin. Epidemiol. 59, 1274–1284. Ponsonby, A.-L., Dwyer, T., Van Der Mei, I., Kemp, A., Blizzard, L., Taylor, B., et al., 2006. Asthma onset prior to multiple sclerosis and the contribution of sibling exposure in early life. Clin. Exp. Immunol. 146 (3), 463–470. Postma, D.S., Bush, A., van den Berge, M., 2015. Risk factors and early origins of chronic obstructive pulmonary disease. Lancet 385 (9971), 899–909. Raherison, C., Girodet, P.O., 2009. Epidemiology of COPD. Eur. Respir. Rev. 18 (114), 213–221. Richter, D.C., Joubert, J.R., Nell, H., Schuurmans, M.M., Irusen, E.M., 2008. Diagnostic value of post-bronchodilator pulmonary function testing to distinguish between stable, moderate to severe COPD and asthma. Int. J. Chronic Obstr. Pulm. Dis. 3 (4) 693–9. Rucker, G., Schwarzer, G., Carpenter, J.R., Schumacher, M., 2008. Undue reliance on I (2) in assessing heterogeneity may mislead. BMC Med. Res. Methodol. 8, 79. Tan, W.C., Bourbeau, J., FitzGerald, J.M., Cowie, R., Chapman, K., Hernandez, P., et al., 2011. Can age and sex explain the variation in COPD rates across large urban cities? A population study in Canada. Int. J. Tuberc. Lung Dis. 15 (12), 1691–1698. van Weel, C., Schellevis, F.G., 2006. Comorbidity and guidelines: conflicting interests. Lancet 367 (9510), 550–551. Yasui, Y., Liu, Y., Neglia, J., Friedman, D., Bhatia, S., Meadows, A., et al., 2003. A methodological issue in the analysis of second-primary cancer incidence in long-term survivors of childhood cancers. Am. J. Epidemiol. 158 (11), 1108–1113.