Comorbidities associated with psoriasis in the Newfoundland and Labrador founder population

Transcription

1 Comorbidities associated with psoriasis in the Newfoundland and Labrador founder population Don MacDonald, PhD(c), Wayne Gulliver, MD, FRCPC, Neil Gladney, BTech, MSc (c), Kayla D. Collins, PhD(c), Jeff Dowden, MAS, Reza Alaghehbandan, MD NewLab Clinical Research Inc. Research and Evaluation Department, Centre for Health Information August 2008

2 Table of Contents LIST OF TABLES HIGHLIGHTS INTRODUCTION PURPOSE ETHICAL CONSIDERATIONS MATERIALS AND METHODS Data Sources Data Quality Data Linkage Statistical Analysis Mortality Hospitalizations Physician Services DISCUSSION Appendix A: Study protocol using multiple databases and linkage approach Appendix B: Underlying causes of death for psoriasis patients vs. general population, Appendix C: Leading causes of death by disease severity (n=106) Appendix D: Leading causes of death by age of onset (n=87) Appendix E: Leading Causes of Death by Genotype (n=31) Appendix F: Comorbidities associated with acute care hospital separations Appendix G: Fee-for-Service specialty utilized by psoriasis patients, 1995/ /05 (n=3,200)

3 LIST OF TABLES Table 1 Reasons for records removal from the NewLab Psoriasis Clinical Database Table 2 Available data, NewLab Psoriasis Clinical Database (n=3,226) Table 3 Demographic and clinical characteristics of patients with psoriasis, NewLab Psoriasis Clinical Database (n=3,226) Table 4 Age* distribution of psoriatic patients by sex (n=3,226) Table 5 Available data, deceased psoriasis patients (N = 202) Table 6 Demographic and prognostic factors of deceased psoriasis patients, (n = 202) Table 7 Mean age of patients with psoriasis at death by demographic/prognostic factors Table 8 Underlying causes of death for psoriasis patents vs. NL General Population, Table 9 Leading causes of death by psoriasis disease severity (n=106) Table 10 Leading causes of death by age of onset (n=87) Table 11 Leading causes of death by HLA-Cw6 genotype (n=31) Table 12 Hospital utilization characteristics of patients with psoriasis, 1995/ /06 Table 13 Available data for patients with and without hospitalizations (N = 3,226) Table 14 Comparison of demographic/prognostic factors between psoriatic patients with and without acute care hospitalizations, 1995/96 to 2005/06 (n=3,226) Table 15 Comorbidities associated with hospitalizations for psoriasis patients (N = 1,494) Table 16 Number of comorbidities associated with psoriasis per patient (n=1,494) Table 17 Most common comorbidities associated with hospitalization for psoriasis patients by disease severity (n = 1,300) Table 18 Most common comorbidities associated with hospitalization for psoriasis patients by age of onset (n = 942) Table 19 Comorbidities associated with hospitalization by HLA-Cw6 genotype status (n = 356) Table 20 Fee-for-Service Physician Visits characteristics of patients with psoriasis, 1995/ /05 Table 21 Available data, NPCD and Physician Data (n=3,200) Table 22 Distribution of top ten specialties utilized, 1995/ /05 (n=3,200) - 3 -

4 HIGHLIGHTS Approximately half of patients with psoriasis were identified as having at least one hospitalization during the study period. Patients with psoriasis were hospitalized more and had a longer length of stay than the Newfoundland and Labrador general population. For those patients who had had at least one hospitalization, more than half had moderate/severe psoriasis (54.8%) and were diagnosed after age 25 years (52.4%). Two hundred and five (57.6%) tested HLA-Cw6 positive. Digestive and circulatory system diseases were the leading comorbidities among hospitalized psoriasis patients (27.4% and 25.8%, respectively). Digestive system, skin/sub-cutaneous disease and mental disorders were significantly higher among moderate/severe psoriasis patients; neoplasm and congenital abnormalities were significantly higher among patients with mild psoriasis. Individuals who tested HLA-Cw6 positive had a significantly higher rate of hospitalization for neoplasm. Those patients who were HLA-Cw6 negative had a significantly higher rate of hospitalization for diseases of the circulatory system. Mean age at death for psoriatic patients was lower than that for the Newfoundland and Labrador general population (70.0 vs. 73.9) (P < 0.001). More than half of deceased patients with psoriasis (53.7%) had moderate/severe psoriasis, were diagnosed after age of 25 years (84.6%), and tested HLA-Cw6 positive (47.7%). Mean age at death among psoriasis patients who were diagnosed at or before age 25 was significantly lower than those diagnosed after age 25 (59.3 vs years, P =0.001). The leading causes of death among psoriatic patients were circulatory system disease and neoplasm (39.2% and 37.5%, respectively), with neoplasm being significantly higher among psoriasis patients (37.5%) compared to the general population (27.6%) (P=0.015). Among patients with moderate/severe psoriasis, diseases of the circulatory system were the leading cause of death (41.8%); for those with mild psoriasis, neoplasm was the leading cause of death (43.1%). Diseases of the circulatory system was identified as the leading cause of death for those patients with an age of onset later than 25 years (42.1%); neoplasm was the leading cause of death for those patients with an age of onset at or before age 25 (45.4%)

5 The leading cause of death for patients who tested HLA-Cw6 positive was diseases of the circulatory system (42.9%); neoplasm was the leading cause of death for those who tested HLA-Cw6 negative (47.1%). On average, a psoriasis patient utilized physician services 10.7 times annually over the study period, which is significantly higher than 5.0 times for the general population (P < 0.001)

6 INTRODUCTION Psoriasis is a common, inherited inflammatory disorder of the skin that affects approximately 2% of the world's population, with men and women being equally affected [1-4]. In the United States (US), about 250,000 new cases of psoriasis are observed annually, affecting almost 2.2% of the US population [3, 5, 6]. Psoriasis accounted for nearly 2.25 million visits to ambulatory care centres during 1996 in the US [3, 7]. Psoriasis is a serious condition that strongly affects the way a person sees themselves and the way they are seen by others. Psoriasis is linked with social stigmatization, pain, discomfort, physical disability and psychological distress. It also has economic and financial consequences. Total cost for treating psoriasis is estimated to be in the range of $1.6 billion to $4.3 billion dollars annually in the U.S. [8-11]. As a result of the chronic, incurable nature of psoriasis, associated morbidity can be significant. Reduction in quality of life can encompass functional, psychological, and social dimensions. About one in four patients experience major psychological distress, and the extent to which they feel socially stigmatized and excluded is significant [2, 3]. Patients experience reductions in quality of life, which is comparable to that of other major diseases such as cancer, heart disease, and diabetes [3, 13]. Patients with severe psoriasis appear to have at least a two to threefold increase in mortality from cardiovascular disease [2], as well as increased risk for a variety of malignancies [2], particularly lymphoma and non-melanoma skin cancer. It has also been suggested that there is a relationship between psoriasis, ankylosing spondylitis, sacroiliitis, peripheral arthropathy and inflammatory bowel disease [14]. More recently, research has suggested that there may be other comorbidities such as lymphoma, obesity, type 2 diabetes, dyslipidemia, hypertension, cardiovascular disease and skin cancers associated with psoriasis as well [15-19]. Given that psoriasis is a complex disorder involving a variety of factors, a multifactorial approach is needed to integrate the various theoretical and clinical dimensions of the - 6 -

7 illness. Newfoundland and Labrador (NL) has a large population of families with psoriasis, making it an ideal setting for understanding the genetics of psoriasis and identifying factors that may cause the disease. Although the prevalence of psoriasis is estimated at 2-3% of the NL population [20], limited information on its associated comorbidities is available. Investigating the epidemiological characteristics of psoriasis and associated comorbidities is important and can be used: 1) in understanding the role genetics plays in psoriasis and associated comorbidities, and 2) to find possible links between psoriasis and specific diseases/conditions in the Newfoundland and Labrador founder population. PURPOSE The purpose of the study was to investigate comorbidities associated with psoriasis and possible prognostic factors such as age of onset, severity of disease, and genetic markers among a sample of psoriasis patients in the Newfoundland and Labrador founder population during the 11-year period, 1995/96 to 2005/06. ETHICAL CONSIDERATIONS The protocol for the study was approved by the Human Investigations Committee of Memorial University of Newfoundland. All personal identifiers were removed from the database prior to analysis. Only those individuals working directly on data analysis had access to the de-identified data files. All study data was stored on a stand-alone, password-protected computer and backed-up on CD, both of which have been stored on a secure floor of the Newfoundland and Labrador Centre for Health Information (NLCHI). MATERIALS AND METHODS This is a cross-sectional study linking medical records of confirmed cases of psoriasis to administrative health databases. Medical records of patients with psoriasis, obtained from a private dermatology clinic in St. John s (NewLab Clinical Research Inc.), were linked to the provincial hospital separation data, fee-for-service physician claims data and mortality data. The study was carried out by the Newfoundland and Labrador - 7 -

8 Centre for Health Information (NLCHI). Data Sources The following data sources were linked, through a multi-step data linkage approach (Appendix A), to create a comprehensive psoriasis database: 1) the NewLab Psoriasis Clinical Database (NPCD); 2) the NLCHI Mortality System; 3) Statistics Canada Annual Mortality Data Files; 4) the Clinical Database Management System (CDMS; hospital separation database); and 5) the Newfoundland and Labrador Medical Care Plan (MCP) fee-for-service physician claims database. The NewLab Psoriasis Clinical Database (NPCD), maintained by NewLab Clinical Research Inc, includes demographic, clinical and genetic data on a sample of confirmed psoriatic patients in the Province from 1989 to This data was obtained from a clinical chart review of psoriasis patients attending the dermatology clinic at NewLab Clinical Research Inc. and was compiled by staff internal to that clinic. Variables for each patient included their provincial health insurance number (MCP), date of birth, sex, age-of-onset of psoriasis, age at first dermatologist visit, severity of disease, and HLA- Cw6 genotype status. For the purpose of this study, disease severity and age of onset were defined by dermatologists of NewLab Clinical Research Inc., and were classified as: 1) early onset (type 1 psoriasis), defined as onset of psoriasis on or before the age of 25 years; or 2) late onset (type 2 psoriasis), defined as onset of psoriasis at greater than 25 years of age. Severity was classified as: 1) mild or 2) moderate/severe psoriasis. Mild psoriasis was defined as psoriasis affecting less than 5% of the body surface area (BSA); moderate/severe psoriasis is psoriasis affecting greater than or equal to 5% of BSA and the face, palms, or genital area regardless of the percentage of BSA affected. Genotype status is presented as either negative or positive, depending on the absence or presence of the gene HLA-Cw6. The NLCHI Mortality System contains data extracted from provincial death notifications including demographics, health insurance number and data on the conditions surrounding each death; data is available for 1991 to Conditions and/or - 8 -

9 diseases present at death are recorded but there is no indication which of these conditions/diseases lead directly to death (i.e. the Underlying Cause of Death ). The Statistic Canada Annual Mortality Data Files is a compilation of data from provincial and territorial offices of vital statistics which are submitted annually to Statistics Canada and contain data on deaths in Canada; data is available for 1993 to While data contained in the NLCHI Mortality system is more current, the Statistics Canada Annual Mortality Data Files include the Underlying Cause of Death. The underlying cause of death as reported in the Statistics Canada Annual Mortality Data Files represents the disease or injury that initiated the sequence of morbid events leading to an individual s death [21]. The Statistics Canada Annual Mortality Data Files did not contain an individuals MCP number as a source of identification. The Clinical Database Management System (CDMS) contains hospital separation data for fiscal years 1995/96 to 2005/06, and is maintained at NLCHI. The CDMS captures demographic and clinical data for individuals receiving care in the province on an inpatient or surgical day care basis. Variables extracted for this study included care episode id, care episode type (acute care or surgical day care), admission and discharges dates, diagnosis code and diagnosis type. Diagnosis codes correspond with the condition or conditions associated with the hospitalization and are based on the International Classification of Disease (ICD) versions nine (1995/96 to 2000/2001) and ten (2001/02 to 2005/06). Diagnosis type is related to the relevance of the diagnosis code within an episode of care and include: 1) most responsible diagnosis, the one diagnosis or condition that can be identified as being most responsible for the patient s hospital stay; 2) pre-admission comorbidity, a condition that existed prior to admission that significantly influences the patient s hospitalization; and 3) post-admission comorbidity, a condition that arises during the patient s hospitalization. The NL Fee-for-Service (MCP) Physician Claims Database captures demographic and clinical information on services provided to NL residents by physicians on a fee-forservice basis between 1995/96 and 2004/05. Data extracted for this study included sex, age at time of service, date of service, diagnosis and procedure code. The physician - 9 -

10 claims database does not capture data relating to services provided by salaried physicians (~ 33% of all physicians in the province) [22]. Data Quality Quality assurance processes were carried out on the NPCD to remove duplicate records and correct invalid or missing data. Three variables were used to identify potential duplicate records: patient name, date of birth and MCP number. Where all three variables matched for more than one record, the record was flagged as a duplicate and removed from the NPCD. Where only two of the three variables matched for more than one record, the record was flagged as a potential duplicate and further investigated. This included consultation with NewLab Clinical Research Inc. to confirm the duplicate record by validating the patient s name, date of birth and/or MCP number. Where data was missing or invalid, the clinic was informed and the patient chart was reviewed again to provide updated data if available. Data Linkage Using a multi-step data linkage approach (Appendix A), the NPCD was linked to other administrative databases: Step 1 Linkage to NLCHI Mortality System: Records of all patients with psoriasis (NPCD) were linked to the NLCHI Mortality System (via MCP number) to identify those patients who are deceased and the conditions/diseases present at the time of their deaths. Step 2 Linkage to Statistics Canada Annual Mortality Data Files: As the Statistics Canada Annual Mortality data Files do not include MCP numbers, a unique id was generated by combining the first four characters of the patient s last name, first four characters of their first name and their date of birth. To determine the underlying cause

11 of death, psoriasis patients identified as deceased in the NLCHI Mortality System (step 1) were linked to the Statistics Canada Mortality Database. Step 3 Linkage to Hospital Data: The NPCD was linked to the CDMS (via MCP number) to identify patients who had at least one hospital separation between 1995/96 and 2005/06. Step 4 - Linkage to Physician Data: Records of all psoriatic patients were linked to the fee-for-service physician claims database (via MCP number) to capture data related to physician utilization between 1995/96 and 2004/05. Following the linkage of all datasets and completion of data quality assurance, all personal identifiers were removed from the data file. Only a study ID remained as a unique identifier in the linked data file; a study key for this database was created and stored in a separate data file within a secure location at NLCHI. Only those individuals having access to the original data have access to this study key. Statistical Analysis Analysis was carried out to describe the sample by age, sex, age of onset, severity of disease and presence of HLA-Cw6 genetic markers. Chi-Square and T-Test were performed to determine if there was a difference between sex, age and and prognostic factors. Further statistics were generated to describe psoriatic patients who were both deceased and alive by sex, age-of-onset, severity of disease, and presence of HLA-Cw6 genetic markers. Chi-square analysis was conducted to determine associations between sex and age at death, disease severity, age of onset and by genotype. T-tests were carried out to compare mean age-at-death between sexes, severity of disease, age-of-onset and by genotype. The sub-sample that had at least one hospitalization during the study period was

12 described by age (mean ± SD), sex, age of onset, severity of disease, and genetic markers (HLA-Cw6). Hospitalization profiles were created to describe the frequency and rate of hospitalization as well as comorbidities associated with the hospitalization. For the purpose of this study, comorbidity was defined as any condition that co-existed at the time of hospital admission or developed during the hospitalization and significantly affected the treatment received by the patient [23]. Chi-square analysis and T-tests were used to investigate differences between sex, age, age-of-onset, severity of disease and HLA-Cw6 genetic markers for each of the following: 1) psoriatic patients with comorbidities (i.e. one or more hospitalizations with diagnosis other than psoriasis). 2) psoriatic patients without comorbidities (i.e. hospitalization with no diagnosis other than psoriasis). 3) total sample (i.e. with and without comorbidities) Inferential statistical tests were not performed where a large proportion of data was missing for a specific factor as results would be considered unreliable. The Statistical Package for the Social Sciences (SPSS) version 15.0 and Statistical Analysis System (SAS) version 9.0 were used for all analysis

13 RESULTS A total of 3,880 records for psoriasis patients were initially provided by NewLab Clinical Research Inc. Data quality processes resulted in the removal of 654 records from the dataset (NPCD), resulting in a total of 3,226 unique patient records. Table 1 presents the reasons for removal of the 654 records. Table 1. Reasons for record removal from the NewLab Psoriasis Clinical Database Reason for Record Removal Number of Records Removed Duplicate record 249 Invalid/Missing MCP Number 207 Psoriasis Diagnosis not confirmed 198 Total 654 Table 2 presents a breakdown of available data following further quality assurance processes. The final database had 463 records with missing data for disease severity, 1,224 records had missing values for age of onset, and there were 2,426 records where genotype information was not available. Table 2. Available data, NewLab Psoriasis Clinical Database (n=3,226) Demographic/Prognostic factor Missing values Valid values Sex Age Disease Severity Age of Onset Genotype All data elements 2580* 646 *Represents the number of records with one or more data elements missing

14 Cohort Characteristic Demographic and clinical characteristics of patients with psoriasis in the NPCD are presented in Table 3. The sex distribution included 1,664 females and 1,562 males (51.6% and 48.4%, respectively). Mean (±SD) age as of January 1, 2007 was 49.5 years (±17.3); mean age for males was significantly higher than that of females (50.0 and 48.9 respectively; P = 0.04). For the sub-sample of patients for which information on the severity of disease was available (n=2,763), approximately half were identified as having moderate/severe psoriasis (52.6%). Of the 2,002 patients whose information on age of onset was available, 52.9% had an early age of onset (type 1 or 25 years). Further, an association was found between sex and age of onset (P=0.005), where females accounted for a larger proportion of those with early onset and males for a larger proportion of those with a late onset. Of the 800 psoriatic patients who were tested for genotype, 448 patients (56.0%) tested positive for the HLA-Cw6 gene. There was no association between genotype and sex. Table 3. Demographic and clinical characteristics of patients with psoriasis, NewLab Psoriasis Clinical Database (n=3,226) Characteristics Female Male Total P-value (n=1664) (n=1562) (n=3226) Mean Age (± SD) 48.9 (±18.0) 50.0 (±16.4) 49.5 (±17.3) P = 0.04 Severity (n = 2,763) Age of Onset (n = 2,002) Mild 49.9% (710) 44.7% (599) Moderate/Severe 50.1% (714) 55.3% (740) 25 years 56.0% (582) 49.7% (478) 47.4% (1309) 52.6% (1454) 52.9% (1060) > 25 years 44.0% (458) 50.3% (484) 47.1% (942) P = 0.07 P = Genotype Positive 57.6% (239) 54.3% (209) 56.0% (448) (n=800) Negative 42.4% (176) 45.7% (176) 44.0% (352) P =

15 Age distribution of patients with psoriasis (n=3,226) by sex is presented in Table 4. Overall, the majority of patients (73.4%) were between the age of 25 and 64; 18.8% were 65 years or older and 7.8% were less than 25 years of age. Within each age group, the distribution of females and males was consistent, with females accounting for a slightly higher proportion per group. Table 4. Age* distribution of psoriatic patients by sex (n=3,226) Age Group (years) Female Male Total (n = 3,226) (n = 1664) (n = 1562) < % (144) 6.9% (108) 7.8% (252) % (1203) 74.6% (1165) 73.4% (2368) % (317) 18.5% (289) 18.8% (606) Total 100.0% (1664) 100.0% (1562) 100.0% (3226) *age as of January 2007 Mortality Linkage of the NPCD and the NLCHI Mortality System identified 202 of the 3,226 (6.3%) psoriasis patients had died between 1991 and Presented in Table 5 is a breakdown of available data for those patients identified as deceased. Further review of the clinic charts did not change the number of missing values presented in Table 5. Table 5. Avaliable data, deceased psoriasis patients (N = 202) Demographic/Prognostic factor Missing values Valid values Sex Age Disease Severity Age of Onset Genotype All data elements 172* 30 *Represents the number of records with one or more data elements missing

16 Demographic and prognostic factors for deceased patients are presented in Table 6. Of the 202 deceased patients with psoriasis, 111 (55.0%) were male. Mean (±SD) age at death for psoriatic patients was 70.0 (±13.3) years; mean age at death for the Newfoundland and Labrador general population for the same time period was 73.9 (±15.4) years (P < 0.001) (data not shown). The mean age at death was significantly higher for females as compared to males (73.0 vs. 67.5, P=0.003). Approximately half (53.7%, 95/177) of the deceased patients with known age of onset had moderate/severe psoriasis; 84.6% (121/143) were diagnosed after the age of 25 years. Of the 44 deceased psoriatic patients that were tested for the HLA-Cw6 genotype, 52.3% (23/44) were negative. Table 6. Demographic and prognostic factors of deceased psoriasis patients, (n = 202) Characteristics Female Male Total (n=91) (n=111) (n=202) P-Value Age at death (mean± SD) 73.0 (±13.5) 67.5 (±12.7) 70.0 (±13.3) Severity Mild 45.8% (38) 46.8% (44) 46.3% (82) (n = 177) Moderate/Severe 54.2% (45) 53.2% (50) 53.7% (95) Age of Onset 25 years 19.7% (12) 12.2% (10) 15.4% (22) (n = 143) > 25 years 80.3% (49) 87.8% (72) 84.6% (121) 0.22 Genotype (HLA-Cw6) Positive 60.0% (12) 37.5% (9) 47.7% (21) (n = 44) Negative 40.0% (8) 62.5% (15) 52.3% (23)

17 Table 7 presents mean age at death by demographic/prognostic factors. The mean age at death was significantly higher for females as compared to males (73.0 vs. 67.5, P=0.003). There was no significant difference between deceased patients with moderate/severe psoriasis (69.2 years) and mild psoriasis (70.6 years) (P=0.474). Patients with early age of onset of psoriasis died earlier than patients with late onset psoriasis (59.3 vs years, P=0.001). Those that were positive for HLA-Cw6 had a mean age at death of 64.1 years compared to 68.4 years for those who were negative for the genotype, however the difference was not significant (P=0.283). Table 7. Mean age of patients with psoriasis at death by demographic/prognostic factors Demographic/prognostic factors Mean age at death (±SD) P-value Sex Severity Age of Onset Genotype Females 73.0 (±13.5) Males 67.5 (±12.7) P = Mild 70.6 (±13.5) Moderate/Severe 69.2 (±14.0) P = years 59.3 (±14.2) > 25 years 71.2 (±12.5) P = Positive 64.1 (±13.5) Negative 68.4 (±12.3) P =

18 To determine an individuals underlying cause of death, deceased psoriasis patients identified in the provincial mortality system were linked to the Statistics Canada Mortality system; data within the Statistics Canada Mortality System was available for years 1993 to Table 8 presents a comparison of the most common underlying causes of death for psoriasis patients compared to the general population during the same time period in NL (see Appendix B for further breakdown). For patients with psoriasis, the leading causes of death were circulatory system disease and neoplasm (39.2% and 37.5%, respectively), with neoplasm among psoriasis patients (37.5%) being significantly higher compared to the general population (27.6%) (P=0.015). Deaths due to diseases of the circulatory system were similar among psoriasis patients and the NL general population (39.2% and 40.3%, respectively). All other causes of death were grouped due to small cell counts. Table 8. Underlying causes of death for psoriasis patents vs. NL general population, Underlying Cause of Death Psoriasis Patients (n = 120) NL General Population (n = 45203) % (n) % (n) P-value Circulatory System Disease 39.2% (47) 40.4% (18262) Neoplasm 37.5% (45) 27.6% (12476) Other Underlying Cause of Death* 23.3% (28) 30.6% (13850) N/A * Does not include congenital abnormalities, blood diseases, perinatal conditions, skin diseases, complications pregnancy/childbirth, given they were not an underlying cause of death for any patient with psoriasis

19 Table 9 presents the leading causes of death by disease severity. Among the 120 patients for which the underlying cause of death was available, 106 had disease severity recorded; 48.1% were mild and 51.9% were moderate/severe. Among patients with moderate/severe psoriasis, 41.8% died due to diseases of the circulatory system, compared to 35.3% with mild psoriasis (P > 0.05). A reverse pattern was found for those patients who died due to neoplasms, where neoplasm was the leading cause of death for 43.1% of patients with mild psoriasis, compared to 32.7% for moderate/severe psoriasis (P=0.269) (see Appendix C for a further breakdown of other underlying causes of death). Table 9. Leading causes of death by psoriasis disease severity (n=106) Underlying Cause of Death Mild (n = 51) Disease Severity Moderate /Severe (n = 55) P-value Circulatory System Disease 35.3% (18) 41.8% (23) Neoplasm 43.1% (22) 32.7% (18) Other Underlying Causes of Death* 21.6% (11) 25.5% (14) N/A * Causes of death grouped due to low cell counts

20 Table 10 presents the leading causes of death by age of onset. For those with early age of onset, the most common cause of death was neoplasm (45.4%), followed by circulatory system disease (18.2%). Among those with late age on onset, the reverse was found; the most common cause of death was circulatory system disease (42.1%), followed by neoplasm (39.5%). No significant differences were found between early versus late age of onset for diseases of the circulatory system and neoplasm (see Appendix D for a further breakdown of other underlying causes of death). Table 10. Leading causes of death by age of onset (n=87) Underlying Cause of Death 25 years (n = 11) Age of Onset > 25 years (n=76) P-value Circulatory System Disease 18.2% (2) 42.1% (32) Neoplasm 45.4% (5) 39.5% (30) Other Underlying Causes of Death* 36.4% (4) 18.4% (14) N/A * Causes of death grouped due to low cell counts

21 Table 11 presents the leading causes of death by HLA-Cw6 genotype. Fourteen deceased patients (45.2%) had tested positive for the HLA-Cw6 gene. The leading cause of death among those who were HLA-Cw6 positive was circulatory system disease, followed by neoplasm (42.9% and 35.7%, respectively). The reverse pattern was found for those testing negative for the HLA-Cw6 gene. Among this group, the leading cause of death was neoplasm (47.1%), followed by circulatory system disease (29.4%) (see Appendix E for a further breakdown of other underlying causes of death). Recognizing that there was a large proportion of unavailable data for genotype status (89/120, 74.2%), tests of significance were not performed due to the potential of unreliable results. Table 11. Leading causes of death by HLA-Cw6 genotype (n=31) Underlying Cause of Death Positive (n=14) HLA-Cw6 Negative (N = 17) Circulatory System Disease 42.9% (6) 29.4% (5) Neoplasm 35.7% (5) 47.1% (8) Other Underlying Causes of Death* 21.4% (3) 23.5% (4) * Causes of death grouped due to low cell counts

22 Hospitalizations Of the 3,226 patients with psoriasis, 1,494 (46.3%) had at least one acute care hospitalizations between 1995/96 and 2005/06. Table 12 presents the hospital utilization for psoriatic patients compared to the general population in NL. For those patients with psoriasis, the mean number of hospital separations per individual was significantly higher than the general population over the 10-year study period (2.8 vs. 2.1, P < 0.001). Patients with psoriasis were found to have a longer length of stay than the general population (9.35 vs. 8.36, respectively) although the results were not significantly different (P=0.200) Table 12: Hospital utilization characteristics of patients with psoriasis, 1995/ /06 Psoriasis NL General Characteristics Patients Population P-value Number of patients 1, ,333 - No. of hospital separations 4, ,528 - Mean No. of unique acute hospital separations per patient < Median No. of unique acute hospital separations per patient Mean length of stay per separation (days) Median length of stay per separation (days) Total length of stay (days) 39,387 5,622,

23 Table 13 presents a breakdown of the number of records with available data for those with and without hospitalization history. Overall, there were 289 records where all data elements were available for those with at least one hospitalization over the study period; 357 for those with no hospitalization. Only patients with complete data for the indicator under study were included in the analysis. Table 13. Available data for patients with and without hospitalizations (N = 3,226) Valid Records With Without Demographic/Prognostic factor Total hospitalization hospitalization (n = 3,226) (n=1,494) (n = 1,732) Sex Disease Severity Age of Onset Genotype Patients having data for all four indicators

24 Table 14 compares demographic and prognostics factors for psoriasis patients with and without hospitalizations during the study period. Female patients with psoriasis had a higher proportion of hospital utilization than male patients (P<0.001); those with late age of onset psoriasis had a higher proportion of hospital utilization compared to those with early onset (52.4% vs. 47.6%, P<0.001), and those with moderate/severe psoriasis had a higher proportion of hospital utilization compared to those with mild psoriasis (54.8% vs. 45.2%, P=0.03). No statistically significant association was found between hospitalization and genotype. Table 14. Comparison of demographic/prognostic factors between psoriatic patients with and without acute care hospitalizations, 1995/96 to 2005/06 (n=3,226) Characteristics With Hospitalization Without hospitalization P-value (n=1,494) (n = 1,732) Sex Females 58.6% (876) 45.5% (788) Males 41.4% (618) 54.5% (944) <0.001 Severity Mild 45.2% (588) 49.3% (721) Moderate/Severe 54.8% (712) 50.7% (742) Age of 25 years 47.6% (448) 57.7% (612) onset >25 years 52.4% (494) 42.3% (448) <0.001 Genotype Negative 42.4% (151) 45.3% (201) Positive 57.6% (205) 54.7% (243)

25 Table 15 presents the distribution of comorbidities by ICD Chapter for the 1,494 psoriatic patients that had at least one hospitalization during the study period. The most common comorbidity associated with hospitalization was diseases of the digestive system (27.3%), followed by diseases of the circulatory system (25.8%). Approximately twenty per cent (20.5%) had a diagnosis of genitourinary disease and 19.7% had a diagnosis of respiratory system disease. Patients with psoriasis had higher rates of hospital utilization for skin and mental disorders, and diseases of the digestive, circulatory, musculoskeletal, endocrine, and blood systems than the NL general population (see Appendix F). Table 15. Comorbidities associated with hospitalizations for psoriasis patients (n = 1,494) Comorbirity (ICD Chapter) % (n) Digestive System Disease 27.3% (408) Circulatory System Disease 25.8% (386) Genitourinary Disease 20.5% (307) Respiratory System Disease 19.7% (295) Musculoskeletal/Connective Tissue Disease 13.3% (198) Neoplasm 13.3% (198) Skin and Sub-cutaneous Disease 12.4% (185) Endocrine/Nutritional/Metabolic Disorder 12.1% (181) Mental Disorder 11.2% (167) Nervous System/Sense Organs Disease 8.0% (120) Blood Disease 6.9% (103) Infectious Disease 4.3% (64) Congenital Abnormalities 0.7% (11) Note: Percentages do not sum to 100% as a patient may have had multiple co-morbidities associated with a single hospitalization and/or more than one hospitalization

26 The number of comorbidities associated with hospitalization per patient is presented in Table 16. A majority of patients had one comorbidity associated with hospitalization (45.4%). The mean (±SD) number of comorbidities per psoriasis patient was 2.5 (±2.04); median was 2.0 (data not shown). Table 16. Number of comorbidities associated with hospitalization per psioriasis patient (n=1,494) Number of comorbidities Number of Unique Patients % % % % % % % % % % % > %

27 Table 17 presents cormorbidities associated with hospitalizations for psoriasis patients by disease severity. Disease severity was available for 1,300 patients (87.0%), and included 588 (45.2%) patients with mild psoriasis and 712 (54.8%) with moderate/severe psoriasis. The most common comorbidities for patients in both groups were diseases of the digestive, circulatory, genitourinary and respiratory systems. Compared to those with mild psoriasis, a significantly higher percentage of those with moderate/severe psoriasis had diseases of the digestive system (29.6% vs. 24.5%, P=0.03), skin and sub-cutaneous disorders (16.3% vs. 8.0%, P < 0.001), and mental disorders (13.2% vs. 8.7%, P=0.01). A significantly higher percentage of those with mild psoriasis had neoplasm (15.3% vs. 11.2%, P=0.03) and congenital abnormalities (1.2% vs. 0.3%, P=0.049), compared to those with moderate/severe psoriasis. Table 17. Most common comorbidities associated with hospitalization for psoriasis patients by disease severity (n = 1,300) ICD Chapter Mild Mod/Severe n=588 Rank n=712 Rank Total P-value Digestive System Disease 24.5% (144) % (211) Circulatory System Disease 25.3% (149) % (191) Genitourinary Disease 20.4% (120) % (145) Respiratory System Disease 19.4% (114) % (139) Musculoskeletal/Connective Tissue Disease 12.2% (72) % (92) Neoplasm 15.3% (90) % (80) Skin and Sub-Cutaneous Disease 8.0% (47) % (116) < Endocrine/Nutritional/Metabolic Disorder 11.9% (70) % (90) Mental Disorder 8.7% (51) % (94) Nervous System/Sense Organs Disease 8.5% (50) 9 7.6% (54) Blood Disease 7.1% (42) % (54) Infectious Disease 4.3% (25) % (29) Congenital Abnormalities 1.2% (7) % (2) Note: Percentages do not sum to 100% as a patient may have had multiple co-morbidities associated with a single hospitalization and/or more than one hospitalization

28 Presented in Table 18 are comorbidities associated with hospitalizations by age of onset. The most common comorbidities among both groups were diseases of the digestive, circulatory, genitourinary and respiratory systems. Compared to those with early age of onset ( 25 years), a significantly higher percentage of those with late onset (>25 years) had diseases of the circulatory system (35.4% vs. 14.3%, P < 0.001), genitourinary disease (25.3% vs. 15.6%, P< 0.001), respiratory system (23.9% vs.16.1%, P=0.003), neoplasm (16.6% vs. 7.8%, P < 0.001), endocrine/nutritional/metabolic disorders (16.6% vs. 7.6%, P < 0.001), mental disorders (14.0% vs. 8.9%, P = 0.016) and blood diseases (9.7% vs. 5.1%, P = 0.008). Table 18. Most common comorbidities associated with hospitalization for psoriasis patients by age of onset (n = 942) 25 years of Age > 25 years of Age ICD Chapter (Acute Care episodes) Total n=448 Rank n=494 Rank Note: Percentages do not sum to 100% as a patient may have had multiple co-morbidities associated with a single hospitalization and/or more than one hospitalization P-value Digestive System Disease 26.3% (118) % (140) Circulatory System Disease 14.3% (64) % (175) < Genitourinary Disease 15.6% (70) % (125) < Respiratory System Disease 16.1% (72) % (118) Musculoskeletal/Connective Tissue Disease 10.7% (48) % (72) Neoplasm 7.8% (35) % (82) < Skin and Sub-Cutaneous Disease 12.3% (55) % (64) Endocrine/Nutritional/Metabolic Disorder 7.6% (34) % (82) < Mental Disorder 8.9% (40) % (69) Nervous System/Sense Organs Disease 8.0% (36) 8 8.9% (44) Blood Disease 5.1% (23) % (48) Infectious Disease 4.2% (19) % (20) Congenital Abnormalities 0.9% (4) % (1)

29 Distribution of comorbidities associated with psoriasis by HLA-Cw6 genotype status is presented in Table 19. Genetic information was available for 356 (23.8%) patients who had at least one hospitalization during the study period. Among those who tested negative for the HLA-Cw6 genotype (n=151), the most common comorbidity was diseases of the circulatory system (29.1%), followed by digestive (26.5%), respiratory (19.2%) and genitourinary diseases (17.9%). Among those who tested positive (n=205), the most common comorbidity was diseases of the digestive system (25.9%), followed by circulatory system (19.5%), genitourinary (18.5%) and neoplasm (16.6%). A significantly higher percentage of patients with HLA-Cw6 negative had diseases of the circulatory system compared to those who tested positive (29.1% vs. 19.5%, P=0.034), whereas a significantly higher percentage of those who tested positive had neoplasm, compared to patients who tested negative (16.6% vs. 8.6%, P=0.028). Table 19. Comorbidities associated with hospitalization by HLA-Cw6 genotype status (n = 356) HLA-Cw6 Negative HLA-Cw6 Positive ICD Chapter Total P-Value n = 151 Rank n = 205 Rank Digestive System Disease 26.5% (40) % (53) Circulatory System Disease 29.1% (44) % (40) Genitourinary Disease 17.9% (27) % (38) Respiratory System Disease 19.2% (29) % (29) Musculoskeletal System/Connective Tissue Disease 16.6% (25) 5 9.8% (20) Neoplasm 8.6% (13) % (34) Skin and Sub-Cutaneous Disease 11.9% (18) 7 9.3% (19) Endocrine/Nutritional/Metabolic Disorder 13.2% (20) % (26) Mental Disorder 9.3% (14) % (21) Nervous System/Sense Organs Disease 6.6% (10) % (22) Blood Disease 6.6% (10) % (15) Infectious Disease 4.0% (6) % (9) Congenital Abnormalities 0.0% (0) % (2) Note: Percentages do not sum to 100% as a patient may have had multiple co-morbidities associated with a single hospitalization and/or more than one hospitalization

30 Physician Services Linkage of the NPCD to the fee-for-service physician claim database identified 3,200 patients who had at least one physician service over the study period. Data for salaried physicians was not available and are not included in this analysis. The 3,200 unique patients included in this analysis accounted for 341,363 physician visits/services between 1995/96 and 2004/05. A comparison of physician utilization by psoriasis patients to that of the NL general population is presented in Table 20. Psoriatic patients utilized physician services 10.7 times annually over the study period, which is significantly higher than 5.0 times for the general population (P < 0.001). Table 20. Fee-for-Service Physician Visits characteristics of patients with psoriasis, 1995/ /05 Psoriasis Patients NL General Population Number of patients 3, ,084 - Total Number of physician Visits 341,363 32,576,613 - P-value Mean number of physician visits per individual (annual) < Median Number of physician visits per individual (annual)

31 Table 21 presents a summary of available data for each demographic/prognostic indicator for physician data. Overall, there were 646 records where all data elements were available for those who utilized a physician service one or more times during the study period. Table 21. Available data, NPCD and Physician Data (n=3,200) Demographic/Prognostic factor Missing values Valid values Total Sex Age Disease Severity Age of Onset Genotype Patients where all factors present

32 Presented in Table 22 is the distribution of physician visits between 1995/96 and 2004/05 by specialty utilized. Nearly ninety-nine percent (98.9%) of patients with psoriasis visited a general practitioner at least once over the study period. Approximately ninety percent utilized services of a diagnostic radiologist (93.4%) and/or a dermatologist (86.7%) (see Appendix E for a more comprehensive list of service utilized). Table 22. Distribution of top ten specialties utilized, 1995/ /05 (n=3,200) Specialty Utilized % (n) General Practice 98.9% (3166) Diagnostic Radiologist 93.4% (2990) Dermatologist 86.7% (2775) Internist 52.0% (1663) Cardiologist 47.1% (1506) General Surgeon 39.2% (1255) Anesthetist 38.4% (1229) Ophthalmologist 36.8% (1176) Otolaryngologist 35.8% (1144) Orthopedic Surgeon 33.7% (1079) Note: Percentages do not sum to 100% as a patient may have utilized multiple specialties over the study period

33 DISCUSSION In this study we examined health service utilization, comorbidities associated with hospitalization and mortality among a cohort of patients with psoriasis in NL. This was achieved through linking administrative data specific to mortality, physician visits and hospitalizations for psoriasis patients attending a dermatology clinic at NewLab Clinical Research Inc. Mean age at death for psoriatic patients in this study was significantly younger than the NL general population (70.0 vs. 73.9). The mean age at death among psoriatic patients was also 10 years younger than the national life expectancy (80.4 years), reported by Statistics Canada [24]. Additionally, the mean age of death for female psoriatic patients was significantly higher than that of males (73.0 vs. 67.5, P=0.003). Although death due to psoriasis is very unlikely, infections, dehydration, and severe electrolytes imbalances can lead to death in these patients [25]. The pattern of underlying causes of death among both the psoriatic patients and the NL general population were similar (disease of the circulatory system and neoplasms). However, our findings showed that neoplasms among deceased psoriasis patients were significantly higher than the NL general population. This is consistent the Stern et al. study [26] where they found a slight increase in mortality due to noncutaneous cancer among patients with psoriasis. They also suggested that patients with psoriasis have a risk of systemic and cutaneous cancer that is comparable to the risk for the general population (in Sweden). Our study found that death due to neoplasm occurred at a significantly higher rate among psoriasis patients compared to the general population. We also found that patients with an early onset of psoriasis died at a significantly younger age compared to patients who developed psoriasis after the age of 25. The majority of the deceased psoriatic patients had moderate/severe psoriasis (53.7%), were diagnosed after the age of 25 years (84.6%), and were tested HLA-Cw6 negative (52.3%). Although there is a lack of literature with respect to the potential association between mortality and disease severity, age of onset and psoriasis genotype, our

34 findings suggest that prognostic factors (e.g., disease severity, age of onset and psoriasis genotype) may play a role in mortality among psoriatic patients. Diseases of the circulatory system were identified as the leading cause of death for those patients with an age of onset later than 25 years, whereas neoplasm was the leading cause of death for those patients with an age of onset at or before age 25. This pattern may be due to the fact that chronic inflammatory processes in psoriasis and carcinogenic effects of systemic treatments increase the risk of neoplasms in these patients [27]. A large majority of psoriasis patients had between one and three comorbidities associated with hospitalization. Patients with psoriasis were hospitalized more and had a longer length of stay than the general population, which is in agreement with findings of previous studies [28, 29]. Our findings also showed that most of the psoriatic patients, who had at least one hospitalization, had moderate/severe psoriasis (54.8%) and were diagnosed after age 25 years (52.4%). Digestive and circulatory system diseases were found to be the most frequent comorbidities among hospitalized psoriasis patients. Further, our study found that psoriatic patients with late age of onset had a significantly higher percentage of hospitalizations than those with early onset due to diseases of the circulatory system, genitourinary disease, respiratory system, neoplasm, endocrine/nutritional/metabolic disorders, mental disorders and blood diseases. This may be due to the fact that psoriatic patients with late age of onset on average were older than those with early age of onset. Digestive system, skin/subcutaneous disease and mental disorders were significantly higher among moderate/severe psoriasis patients, while neoplasm and congenital abnormalities were significantly higher among patients with mild psoriasis. Further, patients with psoriasis were found to have higher rates of hospital utilization for skin and mental disorders, and diseases of the digestive, circulatory, musculoskeletal, endocrine, and blood systems than the NL general population. It has been suggested that chronic inflammation may be responsible for the association between psoriasis with other disorders such as chronic metabolic and cardiovascular disorders that may require hospitalization [30]. Limitations of this study include:

35 1) The NewLab Psoriasis Clinical Database used in this study did not include all psoriatic patients in the province; 2) The coding classification system in the hospital separation database changed from ICD-9 to ICD-10 in April 2001, presenting challenges in describing/classifying the hospital utilization over time, given that there is not a 1:1 relationship between the two coding schemes; 3) Approximately two-thirds of the province s physicians (general practitioners and specialists) are paid on a fee-for-service basis while the remainder are paid on a salary basis [22] Although it is anticipated that the majority of psoriatic patients are from the St. John s region because the clinic is in St. John s, (i.e., a region with high proportion of fee-for-service physicians [~85%]), results related to feefor-service physician visits should be carefully interpreted; and 4) Records removed due to unavailable or missing data may have resulted in bias due to non-linkages, causing under-estimation. In conclusion, our study supports previous studies that suggest an association between psoriasis and other diseases (e.g. circulatory, endocrine, neoplasm, etc.). Further investigation is needed to support this observation