Kidney Disease Risk in Patients With Psoriasis
We conducted a population based cohort study using The Health Improvement Network (THIN), an electronic medical records database maintained by general practitioners in the United Kingdom. THIN is broadly representative of the general UK population and contains diagnostic, treatment, and laboratory data on over nine million individuals. In the UK, almost all patients are registered with a general practitioner who serves as the primary contact for healthcare and records data on diagnoses, prescriptions, and laboratory results as part of the patient's electronic medical record. THIN has been widely used for epidemiological research and has been previously validated for the study of psoriasis, chronic kidney disease, and other diagnoses. Data in this study were collected prospectively from 2003 to September 2010. The study was conducted in accordance with the STROBE statement.
We included in the study all patients with psoriasis aged 18-90 at their start date (defined below) with at least one day of observation time. THIN data are coded in Read codes, which are alphanumeric codes that group and define illnesses by using a hierarchical system. Patients with psoriasis were identified if they received a diagnostic Read code for psoriasis, as previously validated in THIN. Severe psoriasis was defined by the presence of a prescription code for treatments consistent with severe psoriasis on or after the diagnosis of psoriasis (such as phototherapy including ultraviolet B or psoralen and ultraviolet A (PUVA), methotrexate, azathioprine, cyclosporine, oral retinoids, hydroxyurea, mycophenolate mofetil, etanercept, adalimumab, infliximab, and ustekinumab). Patients without treatment codes for systemic or biologic treatment or phototherapy for psoriasis were classified as having mild disease.
Each patient with psoriasis was randomly matched with up to five unexposed patients (that is, no history of a diagnostic code for psoriasis) aged 18-90 whose ages were within five years of the exposed patient's age, who were seen in the same practice, and who had a date of observation within 180 days before or after the index date of the patient with psoriasis (defined below), thus ensuring that patients with and without psoriasis were followed up by the same practice during similar time periods. We excluded patients with diagnosis of chronic kidney disease before cohort entry.
Follow-up time began at the latest of the date when the patient's practice began recording information using THIN software, six months after the date of patient registration in the practice, and the date of psoriasis diagnosis for the exposed cohort or the closest corresponding visit for the unexposed cohort. Censoring occurred when patients developed chronic kidney disease, died, transferred out of the practice, or reached the end of the study.
The outcome of incident chronic kidney disease was defined as the patient receiving a diagnostic code or having an estimated glomerular filtration rate (eGFR) consistent with moderate to advanced (stage 3-5) chronic kidney disease, or both. We used serum creatinine data to calculate eGFR using the Modification of Diet in Renal Disease (MDRD) formula and following widely accepted classification guidelines for chronic kidney disease, which define moderate to severe chronic kidney disease as eGFR <60 mL/min/1.73m on at least two occasions more than 90 days apart. In the absence of complete laboratory data, we also used a list of 80 Read codes to identify moderate to advanced chronic kidney disease, a method that has been previously investigated within THIN. We also examined incident end stage renal disease (ESRD) as a secondary outcome, defined by a relevant diagnostic code for end stage renal disease or dialysis, or both.
We recorded known risk factors for chronic kidney disease, such as age, sex, presence of diabetes, hypertension, and cardiovascular disease, and other potential confounders including use of non-steroidal anti-inflammatory drugs, hyperlipidemia, and body mass index (BMI). Patients were classified as having diabetes, hypertension, hyperlipidemia, and cardiovascular disease if they ever received a diagnostic code for these conditions before the start of the study. BMI, use of alcohol and non-steroidal anti-inflammatory drugs, and smoking status were determined from the recorded data closest to the start date.
All patients with psoriasis who met selection criteria were included in the study, yielding 143,883 patients with psoriasis and 689,702 without. Power calculations were made before data collection and were based on estimates of eligible patients within THIN. With 131,490 patients with mild psoriasis, 3510 with severe psoriasis, and 540,000 without psoriasis, we would have 80% power to detect a hazard ratio of 1.10 and 1.62 in the mild and severe psoriasis groups, respectively.
We examined the age, sex, person time, and covariate distribution between patients with mild and severe psoriasis and unexposed controls using χ and Fisher exact tests for categorical data and Mann-Whitney and t tests for continuous variables. We compared the rates of chronic kidney disease in the mild and severe psoriasis groups versus unexposed groups with Cox proportional hazards regression. Adjustments were made for pertinent risk factors determined a priori such as age, sex, presence of hypertension, diabetes, or cardiovascular disease and BMI and use of non-steroidal anti-inflammatory drugs. As data on BMI were missing in 25% of patients, we performed multiple imputation as part of a sensitivity analysis. Smoking and alcohol use were excluded from the primary model as they are not confirmed risk factors for chronic kidney disease, though they were examined in sensitivity analyses. We also investigated interactions between age and psoriasis and between sex and psoriasis on the risk of chronic kidney disease. Log-log survival plots were examined for adequate proportionality.
We performed multiple sensitivity analyses to further assess the robustness of our results, such as excluding patients with psoriatic arthritis and patients with psoriasis treated with potentially nephrotoxic cyclosporine and methotrexate. We also adjusted for use of non-steroidal anti-inflammatory drugs during follow-up and excluded patients with rheumatoid arthritis and osteoarthritis given their propensity to use these drugs. To further ensure the validity of diabetes, hypertension, and hyperlipidemia covariates, we performed analyses requiring a prescription consistent with these diagnoses. In addition, we accounted for the time varying nature of risk factors such as diabetes. We also examined a stricter outcome definition of chronic kidney disease, defined as eGFR <60 mL/min/1.73m on at least two occasions more than 90 days apart and without any intervening or subsequent eGFR ≥90 mL/min/1.73m , and/or one of 45 diagnostic codes with known positive predictive values over 80% for chronic kidney disease. Lastly, to minimize screening bias, we conducted sensitivity analyses accounting for frequency of patient visits and/or contact with the healthcare system as well as frequency of serum creatinine screening.
All statistical analyses were performed with Stata (version 12, StataCorp, College Station, TX). Significance was determined by using two sided P values at P<0.05.
To further evaluate the relation between chronic kidney disease and severity of psoriasis, as defined by direct measures of extent of disease rather than by use of treatment, we examined a subgroup of patients aged 25-64 whose severity of disease had been assessed via questionnaires sent to their general practitioners as part of a prospective cohort called the Incident Health Outcomes and Psoriasis Events (iHOPE) study. In the iHOPE cohort, eligible patients with psoriasis were randomly sampled within age categories from individuals with at least one diagnostic code for psoriasis within two years before the survey. Patients were defined as having psoriasis if their diagnosis was confirmed by their general practitioner in the questionnaire. Of 10,474 eligible patients, their general practitioners completed 10,026 mailed surveys (95.7% response rate), confirming the diagnoses in 9056 (90.3%) patients. General practitioners directly measured the extent of psoriasis and classified it as mild (limited disease with ≤2% body surface area (BSA) affected) in 4526 (51.8%) patients, moderate (scattered disease with 3-10% BSA) in 3123 (35.8%) patients, and severe (extensive disease with >10% BSA) in 1082 (12.4%) patients. A simple categorized measurement of affected body surface area has previously shown excellent reliability and validity. Each patient with psoriasis was randomly matched to 10 control patients without psoriasis based on age category and medical practice. We conducted a cross sectional analysis of baseline data in the Incident Health Outcomes and Psoriasis Events cohort, performing conditional logistic regression to examine the prevalence odds ratios of chronic kidney disease in patients with psoriasis versus matched controls with respect to measured disease severity.
Methods
Study Design and Data Source
We conducted a population based cohort study using The Health Improvement Network (THIN), an electronic medical records database maintained by general practitioners in the United Kingdom. THIN is broadly representative of the general UK population and contains diagnostic, treatment, and laboratory data on over nine million individuals. In the UK, almost all patients are registered with a general practitioner who serves as the primary contact for healthcare and records data on diagnoses, prescriptions, and laboratory results as part of the patient's electronic medical record. THIN has been widely used for epidemiological research and has been previously validated for the study of psoriasis, chronic kidney disease, and other diagnoses. Data in this study were collected prospectively from 2003 to September 2010. The study was conducted in accordance with the STROBE statement.
Study Population, Definitions of Exposure and Outcome, and Follow-up
We included in the study all patients with psoriasis aged 18-90 at their start date (defined below) with at least one day of observation time. THIN data are coded in Read codes, which are alphanumeric codes that group and define illnesses by using a hierarchical system. Patients with psoriasis were identified if they received a diagnostic Read code for psoriasis, as previously validated in THIN. Severe psoriasis was defined by the presence of a prescription code for treatments consistent with severe psoriasis on or after the diagnosis of psoriasis (such as phototherapy including ultraviolet B or psoralen and ultraviolet A (PUVA), methotrexate, azathioprine, cyclosporine, oral retinoids, hydroxyurea, mycophenolate mofetil, etanercept, adalimumab, infliximab, and ustekinumab). Patients without treatment codes for systemic or biologic treatment or phototherapy for psoriasis were classified as having mild disease.
Each patient with psoriasis was randomly matched with up to five unexposed patients (that is, no history of a diagnostic code for psoriasis) aged 18-90 whose ages were within five years of the exposed patient's age, who were seen in the same practice, and who had a date of observation within 180 days before or after the index date of the patient with psoriasis (defined below), thus ensuring that patients with and without psoriasis were followed up by the same practice during similar time periods. We excluded patients with diagnosis of chronic kidney disease before cohort entry.
Follow-up time began at the latest of the date when the patient's practice began recording information using THIN software, six months after the date of patient registration in the practice, and the date of psoriasis diagnosis for the exposed cohort or the closest corresponding visit for the unexposed cohort. Censoring occurred when patients developed chronic kidney disease, died, transferred out of the practice, or reached the end of the study.
The outcome of incident chronic kidney disease was defined as the patient receiving a diagnostic code or having an estimated glomerular filtration rate (eGFR) consistent with moderate to advanced (stage 3-5) chronic kidney disease, or both. We used serum creatinine data to calculate eGFR using the Modification of Diet in Renal Disease (MDRD) formula and following widely accepted classification guidelines for chronic kidney disease, which define moderate to severe chronic kidney disease as eGFR <60 mL/min/1.73m on at least two occasions more than 90 days apart. In the absence of complete laboratory data, we also used a list of 80 Read codes to identify moderate to advanced chronic kidney disease, a method that has been previously investigated within THIN. We also examined incident end stage renal disease (ESRD) as a secondary outcome, defined by a relevant diagnostic code for end stage renal disease or dialysis, or both.
We recorded known risk factors for chronic kidney disease, such as age, sex, presence of diabetes, hypertension, and cardiovascular disease, and other potential confounders including use of non-steroidal anti-inflammatory drugs, hyperlipidemia, and body mass index (BMI). Patients were classified as having diabetes, hypertension, hyperlipidemia, and cardiovascular disease if they ever received a diagnostic code for these conditions before the start of the study. BMI, use of alcohol and non-steroidal anti-inflammatory drugs, and smoking status were determined from the recorded data closest to the start date.
All patients with psoriasis who met selection criteria were included in the study, yielding 143,883 patients with psoriasis and 689,702 without. Power calculations were made before data collection and were based on estimates of eligible patients within THIN. With 131,490 patients with mild psoriasis, 3510 with severe psoriasis, and 540,000 without psoriasis, we would have 80% power to detect a hazard ratio of 1.10 and 1.62 in the mild and severe psoriasis groups, respectively.
Statistical Analysis
We examined the age, sex, person time, and covariate distribution between patients with mild and severe psoriasis and unexposed controls using χ and Fisher exact tests for categorical data and Mann-Whitney and t tests for continuous variables. We compared the rates of chronic kidney disease in the mild and severe psoriasis groups versus unexposed groups with Cox proportional hazards regression. Adjustments were made for pertinent risk factors determined a priori such as age, sex, presence of hypertension, diabetes, or cardiovascular disease and BMI and use of non-steroidal anti-inflammatory drugs. As data on BMI were missing in 25% of patients, we performed multiple imputation as part of a sensitivity analysis. Smoking and alcohol use were excluded from the primary model as they are not confirmed risk factors for chronic kidney disease, though they were examined in sensitivity analyses. We also investigated interactions between age and psoriasis and between sex and psoriasis on the risk of chronic kidney disease. Log-log survival plots were examined for adequate proportionality.
We performed multiple sensitivity analyses to further assess the robustness of our results, such as excluding patients with psoriatic arthritis and patients with psoriasis treated with potentially nephrotoxic cyclosporine and methotrexate. We also adjusted for use of non-steroidal anti-inflammatory drugs during follow-up and excluded patients with rheumatoid arthritis and osteoarthritis given their propensity to use these drugs. To further ensure the validity of diabetes, hypertension, and hyperlipidemia covariates, we performed analyses requiring a prescription consistent with these diagnoses. In addition, we accounted for the time varying nature of risk factors such as diabetes. We also examined a stricter outcome definition of chronic kidney disease, defined as eGFR <60 mL/min/1.73m on at least two occasions more than 90 days apart and without any intervening or subsequent eGFR ≥90 mL/min/1.73m , and/or one of 45 diagnostic codes with known positive predictive values over 80% for chronic kidney disease. Lastly, to minimize screening bias, we conducted sensitivity analyses accounting for frequency of patient visits and/or contact with the healthcare system as well as frequency of serum creatinine screening.
All statistical analyses were performed with Stata (version 12, StataCorp, College Station, TX). Significance was determined by using two sided P values at P<0.05.
Nested Cross Sectional Study
To further evaluate the relation between chronic kidney disease and severity of psoriasis, as defined by direct measures of extent of disease rather than by use of treatment, we examined a subgroup of patients aged 25-64 whose severity of disease had been assessed via questionnaires sent to their general practitioners as part of a prospective cohort called the Incident Health Outcomes and Psoriasis Events (iHOPE) study. In the iHOPE cohort, eligible patients with psoriasis were randomly sampled within age categories from individuals with at least one diagnostic code for psoriasis within two years before the survey. Patients were defined as having psoriasis if their diagnosis was confirmed by their general practitioner in the questionnaire. Of 10,474 eligible patients, their general practitioners completed 10,026 mailed surveys (95.7% response rate), confirming the diagnoses in 9056 (90.3%) patients. General practitioners directly measured the extent of psoriasis and classified it as mild (limited disease with ≤2% body surface area (BSA) affected) in 4526 (51.8%) patients, moderate (scattered disease with 3-10% BSA) in 3123 (35.8%) patients, and severe (extensive disease with >10% BSA) in 1082 (12.4%) patients. A simple categorized measurement of affected body surface area has previously shown excellent reliability and validity. Each patient with psoriasis was randomly matched to 10 control patients without psoriasis based on age category and medical practice. We conducted a cross sectional analysis of baseline data in the Incident Health Outcomes and Psoriasis Events cohort, performing conditional logistic regression to examine the prevalence odds ratios of chronic kidney disease in patients with psoriasis versus matched controls with respect to measured disease severity.
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