Neurourology and Urodynamics 35:48–54 (2016)
The Impact of Lower Urinary Tract Symptoms on Health-Related Quality of Life Among Patients With Multiple Sclerosis Kristin M. Khalaf,1* Karin S. Coyne,2 Denise R. Globe,3 Daniel C. Malone,4 Edward P. Armstrong,4 Vaishali Patel,1 and Jack Burks5 1
Allergan, Inc., Irvine, California 2 Evidera, Bethesda, Maryland 3 Formerly Allergan, Inc., Irvine, California 4 College of Pharmacy, University of Arizona, Tucson, Arizona 5 Department of Neurology, Florida International University, Miami, Florida Aims: Lower urinary tract symptoms are commonly experienced among patients with multiple sclerosis (MS), however, their impact on health-related quality of life (HRQOL) has not been well characterized. Herein the incremental impact of lower urinary tract symptoms on HRQOL among patients with MS has been evaluated. Methods: A cross-sectional online survey was administered to US residents with a self-reported MS diagnosis. Data pertaining to demographics, disease history, urinary symptoms, and HRQOL, including the Short Form 36, version 2 (SF-36v2), were collected. Patients were stratified into four urinary symptom groups: no/minimal urinary symptoms, urinary urgency (UU), urinary urgency incontinence (UUI), and other lower urinary tract symptoms. Multiple linear regression models evaluated the impact of these symptoms. Results: Out of the 1,052 respondents, mean age was 47.8 10.6 years; mean time since MS diagnosis was 8.5 7.8 years. UUI and UU subgroups showed the greatest adjusted HRQOL decrement compared with the no/minimal urinary symptoms group, scoring 2.8 (SE 0.7, UUI) and 3.5 (SE 0.8, UU) points lower on SF-36v2 Physical Component Summary, respectively, and 3.7 (SE 1.0, UUI) and 5.0 (SE 1.2, UU) points lower on SF-36v2 Mental Component Summary (P < 0.001 for all), respectively. Conclusions: Both UU and UUI symptoms contribute to a decrement in HRQOL among patients with MS. Neurourol. Urodynam. 35:48–54, 2016. # 2014 The Authors. Neurourology and Urodynamics published by Wiley Periodicals, Inc. This is an open access article under the terms of the Creative Commons Attribution-NonCommercial-NoDerivs License, which permits use and distribution in any medium, provided the original work is properly cited, the use is non-commercial and no modifications or adaptations are made. Key words: epidemiology; outcome assessment; quality of life INTRODUCTION
Multiple sclerosis (MS) is the leading cause of neurological disability in young adults in the US. Demyelinating lesions commonly lead to urinary tract dysfunction.1 Over 90% of MS patients present with some urological symptoms after 10 years from disease onset. Although the incidence increases as the disease progresses, these symptoms are not necessarily related to the duration of the disease or degree of disability.2 Many urinary symptoms may arise as a result of neurogenic detrusor overactivity (NDO), which is characterized by involuntary detrusor contractions during bladder filling with urodynamic testing.3 Symptoms of NDO are often times characterized by urinary urgency with or without urinary urgency incontinence (UUI). The independent negative impact of both MS and lower urinary tract symptoms (LUTS) on health-related quality of life (HRQOL) has been demonstrated4–9; however, the incremental impact of LUTS within an MS population has not been quantified. The purpose of this research was to evaluate the incremental impact of LUTS on HRQOL among MS patients.
METHODS
A cross-sectional online survey was conducted among individuals with a self-reported diagnosis of MS. Participants were recruited through MS-specific advocacy organizations (National MS Society ([NMSS; http://www.nmss.org], MS #
Foundation [MSF]; http://www.msfocus.org), and MS World (http://www.msworld.org). A study advertisement was placed in the research section of the NMSS Web site, selected NMSS local chapter social media Web sites and newsletters, monthly MSF e-newsletters, and weekly MS World e-newsletters. The advertisement directed the participant back to the Web link for the online survey about their general health. Individuals who Roger Dmochowski led the peer-review process as the Associate Editor responsible for the paper. Potential conflict of interest: This study and its analysis were sponsored by Allergan, Inc., Irvine, CA. Kristin M. Khalaf is currently a PhD student at the University of Arizona, as well as an employee of Allergan, Inc. Karin S. Coyne has been a paid scientific consultant to Allergan, Inc. on this project. Denise R. Globe was an employee of Allergan, Inc. at the time this work was done. Vaishali Patel is an employee of Allergan, Inc. Jack Burks is a consultant for Acorda Therapeutics, Allergan, Inc., Avanir Pharmaceuticals, Bayer HealthCare Pharmaceuticals, EMD Serono, and Sanofi-Aventis, in which he receives honoraria. Burks is also on the speaker’s bureau for Acorda Therapeutics, Allergan, Inc., Avanir Pharmaceuticals, Bayer HealthCare Pharmaceuticals, and EMD Serono, in which he receives honoraria. Burks does not own stock in any of the pharmaceutical companies that he is a consultant for or a member of their speaker’s bureau. Grant sponsor: Allergan Inc. Irvine CA The present address of Denise R. Globe is Novartis Corporation, New York, New York Correspondence to: Kristin M. Khalaf, Allergan, Inc., 2525 Dupont Drive, Irvine, CA 92612. E-mail: [email protected] Received 12 May 2014; Accepted 1 August 2014 Published online 18 October 2014 in Wiley Online Library (wileyonlinelibrary.com). DOI 10.1002/nau.22670
2014 The Authors. Neurourology and Urodynamics published by Wiley Periodicals, Inc.
49
Lower Urinary Tract Symptoms in MS Patients were interested in participating in the study accessed the Web link. After providing informed consent to the study, all potential participants were screened regarding their MS. To be eligible, potential participants had to reside in the US, be 18– 89 years of age, report being diagnosed with MS by a physician, and report taking any of nine-listed MS medications (or report medications not included in the list). Screening criteria were employed in an attempt to ensure the participant was an MS patient. Following informed consent, participants had a 72-hr window to complete the survey, and were compensated with a US$25 gift card upon completion of the study. The survey included preliminary questions on basic demographics and disease history. Additional instruments examined disease severity, HRQOL, work productivity, and urinary symptoms. Patients reporting any urinary symptoms were asked additional questions about urinary symptom treatment patterns and the impact of urinary symptoms on work productivity. The total number of items each participant answered varied based upon the presence and characteristics of their urinary symptoms, ranging from 85 to 126 items. The study was approved by the University of Arizona Human Subjects Protection program. Selected Survey Instruments
The Patient Determined Disease Steps (PDDS) was used to classify patients by level of MS severity.10 PDDS is a selfreported disability assessment with scores ranging from 0 (normal, defined as having mild symptoms that are mostly sensory and do not limit activity) to 8 (bedridden, defined as unable to sit in a wheelchair for >1 hr). It has been shown to
yield results similar to the physician-scored Expanded Disability Status Scale, a universally used clinical scale developed to measure disability status in patients with MS.10 NDO-associated OAB symptoms are characterized by urgency, with or without UUI, usually with frequency and nocturia.3 Urinary symptoms were assessed by the LUTS Tool, developed in accordance with those defined by the International Continence Society,11 is based upon qualitative research conducted by Coyne et al.,12 and was previously used to assess the prevalence of LUTS in the EpiLUTS study.13 This 15-item tool contains nongender-specific questions about the presence and bother of all LUTS (storage, voiding, and post-micturition symptoms), allowing for a comprehensive assessment of all LUTS experienced in the MS population.12 Patients were stratified into four urinary symptom groups based on their responses to the LUTS Tool: (i) no/ minimal urinary symptoms (NS); (ii) urinary urgency (UU); (iii) UUI; and (iv) other LUTS (O-LUTS) (Table I). NS was comprised of patients with no incontinence and 3 dry urinary symptoms. Patients who reported experiencing urgency without incontinence were placed into the UU group, and patients who reported urgency associated with incontinence (UUI) were placed in the UUI group. O-LUTS consisted of patients with incontinence not related to UU (e.g., stress UI, leak for no reason, post-void incontinence) and/or >3 dry urinary symptoms. The Short Form 36, version 2 (SF-36v2), questionnaire was used, as it has been shown to be valid and to appropriately measure generic HRQOL in the MS population.4,14 It is comprised of 36 total items; eight subscale scores, and two
TABLE I. Demographic Characteristics Across LUTS Groups
Age, mean SD, years Sex,a n (%) Female Marital status,a n (%) Single Married or long-term partner Divorced Separated Widowed Education level,a n (%) Less than high school High school graduate Some college Associate degree Bachelor’s degree Master’s degree Doctorate degree Race/Ethnicity, n (%) American Indian/Alaskan Native, Native Hawaiian, or Other Pacific Islander Asian Black/African American Hispanic white Non-Hispanic white
NS (n ¼ 126)
O-LUTS (n ¼ 199)
UU (n ¼ 172)
UUI (n ¼ 551)
P-value
45.2 11.2
44.7 10.0
45.8 11.2
50.1 9.9
0.05, no pairwise comparisons were conducted. For all pairwise comparisons, P < 0.001 for age between UUI and all subgroups and not significant for other comparisons. LUTS, lower urinary tract symptoms; NS, no/minimal urinary symptoms; O-LUTS, other lower urinary tract symptoms; UU, urinary urgency; UUI, urinary urgency incontinence. a
Denotes variable is mutually exclusive.
Neurourology and Urodynamics DOI 10.1002/nau
50
Khalaf et al.
summary measures (Physical Component Summary [PCS] and Mental Component Summary [MCS]). Scores for each of the subscales range from 1 to 100 and are derived from the 2009 norm-based scores, with higher scores indicating better physical and mental functioning and 50 10 representing the average score of the US general population.15 Each of the eight subscales contributes to the derivation of both component summary measures. The Short Form version of the Overactive Bladder Questionnaire (OAB-q SF) was administered to the entire sample to assess symptom bother and the impact of OAB symptoms in NDO patients on HRQOL, capture patients who may have bladder dysfunction that does not necessarily manifest as incontinence, and measure differences in HRQOL between patients with symptoms of urgency and UUI.16 The Symptom Bother scale and HRQOL scale are each scored separately by summing up the item value totals and transforming the value to a 0–100 scale, with higher scores indicating greater symptom bother and lower scores indicating poorer HRQOL.
The Incontinence Quality of Life (I-QOL) questionnaire assessed differences in disease-specific HRQOL between urinary symptom subgroups. It is comprised of 22 statements designed to elicit subjective evaluations of urinary incontinence (UI)related effects and concerns. The calculated total score ranges from 1 to 100, where lower scores indicate greater HRQOL impairment.17 This instrument was only administered to patients who reported that they experienced any type of incontinence. Statistical Analyzes
Stata Data Analysis and Statistical Software, version 11 (Stata Corporation, College Station, TX), was used for all statistical analyses. Missing data were not imputed except in accordance with the developer’s recommendations for the SF-36v2,15 OABq SF,16 and I-QOL.17 The type I error level was set at a ¼ 0.05 for all statistical tests. The chi–square test was used to evaluate differences across groups for categorical variables. Analysis of
TABLE II. Clinical Characteristics Across LUTS Groups NS (n ¼ 126) Disease duration, mean SD, years 7.5 7.3 PDDS score, mean SD 1.6 1.9 MS type,a n (%) Relapsing-remitting 104 (82.5) Primary progressive 8 (6.3) Secondary progressive 5 (4.0) Progressive relapsing 0 Not sure 9 (7.1) Other (free text) 0 Current MS symptoms/symptom flare,a n (%) Yes 54 (42.9) MS medications, n (%) Steroids 11 (8.7) Interferon-b 48 (38.1) Glatiramer acetate 45 (35.7) Natalizumab injection 12 (9.5) Fingolimod 5 (4.0) Azathioprine 1 (0.8) Mitoxantrone 1 (0.8) IVIG 3 (2.4) Plasma exchange 0 Comorbidities, n (%) None 30 (23.8) Anxiety 27 (21.4) Arthritis 12 (9.5) Asthma 11 (8.7) Depression 34 (27.0) Diabetes 2 (1.6) Epilepsy 2 (1.6) Eye disorders 25 (19.8) Fibromyalgia 4 (3.2) Heart disease 2 (1.6) Hypertension 24 (19.0) High cholesterol 23 (18.3) Irritable bowel syndrome 13 (10.3) Migraines 17 (13.5)
O-LUTS (n ¼ 199)
UU (n ¼ 172)
UUI (n ¼ 551)
P-value
6.4 6.4 2.0 1.9
7.5 7.8 2.8 2.1
9.8 8.1 3.5 2.0
The Impact of Lower Urinary Tract Symptoms on Health-Related Quality of Life Among Patients With Multiple Sclerosis Kristin M. Khalaf,1* Karin S. Coyne,2 Denise R. Globe,3 Daniel C. Malone,4 Edward P. Armstrong,4 Vaishali Patel,1 and Jack Burks5 1
Allergan, Inc., Irvine, California 2 Evidera, Bethesda, Maryland 3 Formerly Allergan, Inc., Irvine, California 4 College of Pharmacy, University of Arizona, Tucson, Arizona 5 Department of Neurology, Florida International University, Miami, Florida Aims: Lower urinary tract symptoms are commonly experienced among patients with multiple sclerosis (MS), however, their impact on health-related quality of life (HRQOL) has not been well characterized. Herein the incremental impact of lower urinary tract symptoms on HRQOL among patients with MS has been evaluated. Methods: A cross-sectional online survey was administered to US residents with a self-reported MS diagnosis. Data pertaining to demographics, disease history, urinary symptoms, and HRQOL, including the Short Form 36, version 2 (SF-36v2), were collected. Patients were stratified into four urinary symptom groups: no/minimal urinary symptoms, urinary urgency (UU), urinary urgency incontinence (UUI), and other lower urinary tract symptoms. Multiple linear regression models evaluated the impact of these symptoms. Results: Out of the 1,052 respondents, mean age was 47.8 10.6 years; mean time since MS diagnosis was 8.5 7.8 years. UUI and UU subgroups showed the greatest adjusted HRQOL decrement compared with the no/minimal urinary symptoms group, scoring 2.8 (SE 0.7, UUI) and 3.5 (SE 0.8, UU) points lower on SF-36v2 Physical Component Summary, respectively, and 3.7 (SE 1.0, UUI) and 5.0 (SE 1.2, UU) points lower on SF-36v2 Mental Component Summary (P < 0.001 for all), respectively. Conclusions: Both UU and UUI symptoms contribute to a decrement in HRQOL among patients with MS. Neurourol. Urodynam. 35:48–54, 2016. # 2014 The Authors. Neurourology and Urodynamics published by Wiley Periodicals, Inc. This is an open access article under the terms of the Creative Commons Attribution-NonCommercial-NoDerivs License, which permits use and distribution in any medium, provided the original work is properly cited, the use is non-commercial and no modifications or adaptations are made. Key words: epidemiology; outcome assessment; quality of life INTRODUCTION
Multiple sclerosis (MS) is the leading cause of neurological disability in young adults in the US. Demyelinating lesions commonly lead to urinary tract dysfunction.1 Over 90% of MS patients present with some urological symptoms after 10 years from disease onset. Although the incidence increases as the disease progresses, these symptoms are not necessarily related to the duration of the disease or degree of disability.2 Many urinary symptoms may arise as a result of neurogenic detrusor overactivity (NDO), which is characterized by involuntary detrusor contractions during bladder filling with urodynamic testing.3 Symptoms of NDO are often times characterized by urinary urgency with or without urinary urgency incontinence (UUI). The independent negative impact of both MS and lower urinary tract symptoms (LUTS) on health-related quality of life (HRQOL) has been demonstrated4–9; however, the incremental impact of LUTS within an MS population has not been quantified. The purpose of this research was to evaluate the incremental impact of LUTS on HRQOL among MS patients.
METHODS
A cross-sectional online survey was conducted among individuals with a self-reported diagnosis of MS. Participants were recruited through MS-specific advocacy organizations (National MS Society ([NMSS; http://www.nmss.org], MS #
Foundation [MSF]; http://www.msfocus.org), and MS World (http://www.msworld.org). A study advertisement was placed in the research section of the NMSS Web site, selected NMSS local chapter social media Web sites and newsletters, monthly MSF e-newsletters, and weekly MS World e-newsletters. The advertisement directed the participant back to the Web link for the online survey about their general health. Individuals who Roger Dmochowski led the peer-review process as the Associate Editor responsible for the paper. Potential conflict of interest: This study and its analysis were sponsored by Allergan, Inc., Irvine, CA. Kristin M. Khalaf is currently a PhD student at the University of Arizona, as well as an employee of Allergan, Inc. Karin S. Coyne has been a paid scientific consultant to Allergan, Inc. on this project. Denise R. Globe was an employee of Allergan, Inc. at the time this work was done. Vaishali Patel is an employee of Allergan, Inc. Jack Burks is a consultant for Acorda Therapeutics, Allergan, Inc., Avanir Pharmaceuticals, Bayer HealthCare Pharmaceuticals, EMD Serono, and Sanofi-Aventis, in which he receives honoraria. Burks is also on the speaker’s bureau for Acorda Therapeutics, Allergan, Inc., Avanir Pharmaceuticals, Bayer HealthCare Pharmaceuticals, and EMD Serono, in which he receives honoraria. Burks does not own stock in any of the pharmaceutical companies that he is a consultant for or a member of their speaker’s bureau. Grant sponsor: Allergan Inc. Irvine CA The present address of Denise R. Globe is Novartis Corporation, New York, New York Correspondence to: Kristin M. Khalaf, Allergan, Inc., 2525 Dupont Drive, Irvine, CA 92612. E-mail: [email protected] Received 12 May 2014; Accepted 1 August 2014 Published online 18 October 2014 in Wiley Online Library (wileyonlinelibrary.com). DOI 10.1002/nau.22670
2014 The Authors. Neurourology and Urodynamics published by Wiley Periodicals, Inc.
49
Lower Urinary Tract Symptoms in MS Patients were interested in participating in the study accessed the Web link. After providing informed consent to the study, all potential participants were screened regarding their MS. To be eligible, potential participants had to reside in the US, be 18– 89 years of age, report being diagnosed with MS by a physician, and report taking any of nine-listed MS medications (or report medications not included in the list). Screening criteria were employed in an attempt to ensure the participant was an MS patient. Following informed consent, participants had a 72-hr window to complete the survey, and were compensated with a US$25 gift card upon completion of the study. The survey included preliminary questions on basic demographics and disease history. Additional instruments examined disease severity, HRQOL, work productivity, and urinary symptoms. Patients reporting any urinary symptoms were asked additional questions about urinary symptom treatment patterns and the impact of urinary symptoms on work productivity. The total number of items each participant answered varied based upon the presence and characteristics of their urinary symptoms, ranging from 85 to 126 items. The study was approved by the University of Arizona Human Subjects Protection program. Selected Survey Instruments
The Patient Determined Disease Steps (PDDS) was used to classify patients by level of MS severity.10 PDDS is a selfreported disability assessment with scores ranging from 0 (normal, defined as having mild symptoms that are mostly sensory and do not limit activity) to 8 (bedridden, defined as unable to sit in a wheelchair for >1 hr). It has been shown to
yield results similar to the physician-scored Expanded Disability Status Scale, a universally used clinical scale developed to measure disability status in patients with MS.10 NDO-associated OAB symptoms are characterized by urgency, with or without UUI, usually with frequency and nocturia.3 Urinary symptoms were assessed by the LUTS Tool, developed in accordance with those defined by the International Continence Society,11 is based upon qualitative research conducted by Coyne et al.,12 and was previously used to assess the prevalence of LUTS in the EpiLUTS study.13 This 15-item tool contains nongender-specific questions about the presence and bother of all LUTS (storage, voiding, and post-micturition symptoms), allowing for a comprehensive assessment of all LUTS experienced in the MS population.12 Patients were stratified into four urinary symptom groups based on their responses to the LUTS Tool: (i) no/ minimal urinary symptoms (NS); (ii) urinary urgency (UU); (iii) UUI; and (iv) other LUTS (O-LUTS) (Table I). NS was comprised of patients with no incontinence and 3 dry urinary symptoms. Patients who reported experiencing urgency without incontinence were placed into the UU group, and patients who reported urgency associated with incontinence (UUI) were placed in the UUI group. O-LUTS consisted of patients with incontinence not related to UU (e.g., stress UI, leak for no reason, post-void incontinence) and/or >3 dry urinary symptoms. The Short Form 36, version 2 (SF-36v2), questionnaire was used, as it has been shown to be valid and to appropriately measure generic HRQOL in the MS population.4,14 It is comprised of 36 total items; eight subscale scores, and two
TABLE I. Demographic Characteristics Across LUTS Groups
Age, mean SD, years Sex,a n (%) Female Marital status,a n (%) Single Married or long-term partner Divorced Separated Widowed Education level,a n (%) Less than high school High school graduate Some college Associate degree Bachelor’s degree Master’s degree Doctorate degree Race/Ethnicity, n (%) American Indian/Alaskan Native, Native Hawaiian, or Other Pacific Islander Asian Black/African American Hispanic white Non-Hispanic white
NS (n ¼ 126)
O-LUTS (n ¼ 199)
UU (n ¼ 172)
UUI (n ¼ 551)
P-value
45.2 11.2
44.7 10.0
45.8 11.2
50.1 9.9
0.05, no pairwise comparisons were conducted. For all pairwise comparisons, P < 0.001 for age between UUI and all subgroups and not significant for other comparisons. LUTS, lower urinary tract symptoms; NS, no/minimal urinary symptoms; O-LUTS, other lower urinary tract symptoms; UU, urinary urgency; UUI, urinary urgency incontinence. a
Denotes variable is mutually exclusive.
Neurourology and Urodynamics DOI 10.1002/nau
50
Khalaf et al.
summary measures (Physical Component Summary [PCS] and Mental Component Summary [MCS]). Scores for each of the subscales range from 1 to 100 and are derived from the 2009 norm-based scores, with higher scores indicating better physical and mental functioning and 50 10 representing the average score of the US general population.15 Each of the eight subscales contributes to the derivation of both component summary measures. The Short Form version of the Overactive Bladder Questionnaire (OAB-q SF) was administered to the entire sample to assess symptom bother and the impact of OAB symptoms in NDO patients on HRQOL, capture patients who may have bladder dysfunction that does not necessarily manifest as incontinence, and measure differences in HRQOL between patients with symptoms of urgency and UUI.16 The Symptom Bother scale and HRQOL scale are each scored separately by summing up the item value totals and transforming the value to a 0–100 scale, with higher scores indicating greater symptom bother and lower scores indicating poorer HRQOL.
The Incontinence Quality of Life (I-QOL) questionnaire assessed differences in disease-specific HRQOL between urinary symptom subgroups. It is comprised of 22 statements designed to elicit subjective evaluations of urinary incontinence (UI)related effects and concerns. The calculated total score ranges from 1 to 100, where lower scores indicate greater HRQOL impairment.17 This instrument was only administered to patients who reported that they experienced any type of incontinence. Statistical Analyzes
Stata Data Analysis and Statistical Software, version 11 (Stata Corporation, College Station, TX), was used for all statistical analyses. Missing data were not imputed except in accordance with the developer’s recommendations for the SF-36v2,15 OABq SF,16 and I-QOL.17 The type I error level was set at a ¼ 0.05 for all statistical tests. The chi–square test was used to evaluate differences across groups for categorical variables. Analysis of
TABLE II. Clinical Characteristics Across LUTS Groups NS (n ¼ 126) Disease duration, mean SD, years 7.5 7.3 PDDS score, mean SD 1.6 1.9 MS type,a n (%) Relapsing-remitting 104 (82.5) Primary progressive 8 (6.3) Secondary progressive 5 (4.0) Progressive relapsing 0 Not sure 9 (7.1) Other (free text) 0 Current MS symptoms/symptom flare,a n (%) Yes 54 (42.9) MS medications, n (%) Steroids 11 (8.7) Interferon-b 48 (38.1) Glatiramer acetate 45 (35.7) Natalizumab injection 12 (9.5) Fingolimod 5 (4.0) Azathioprine 1 (0.8) Mitoxantrone 1 (0.8) IVIG 3 (2.4) Plasma exchange 0 Comorbidities, n (%) None 30 (23.8) Anxiety 27 (21.4) Arthritis 12 (9.5) Asthma 11 (8.7) Depression 34 (27.0) Diabetes 2 (1.6) Epilepsy 2 (1.6) Eye disorders 25 (19.8) Fibromyalgia 4 (3.2) Heart disease 2 (1.6) Hypertension 24 (19.0) High cholesterol 23 (18.3) Irritable bowel syndrome 13 (10.3) Migraines 17 (13.5)
O-LUTS (n ¼ 199)
UU (n ¼ 172)
UUI (n ¼ 551)
P-value
6.4 6.4 2.0 1.9
7.5 7.8 2.8 2.1
9.8 8.1 3.5 2.0
