Targeted metabolomic profiling and prediction of cardiovascular events: a prospective study of patients with psoriatic arthritis and psoriasis.

OBJECTIVE: In patients with psoriatic disease (PsD), we sought serum metabolites associated with cardiovascular (CV) events and investigated whether they could improve CV risk prediction beyond traditional risk factors and the Framingham Risk Score (FRS). METHODS: Nuclear magnetic resonance metabolomics identified biomarkers for incident CV events in patients with PsD. The association of each metabolite with incident CV events was analysed using Cox proportional hazards regression models first adjusted for age and sex, and subsequently for traditional CV risk factors. Variable selection was performed using penalisation with boosting after adjusting for age and sex, and the FRS. RESULTS: Among 977 patients with PsD, 70 patients had incident CV events. In Cox regression models adjusted for CV risk factors, alanine, tyrosine, degree of unsaturation of fatty acids and high-density lipoprotein particles were associated with decreased CV risk. Glycoprotein acetyls, apolipoprotein B and cholesterol remnants were associated with increased CV risk. The age-adjusted and sex-adjusted expanded model with 13 metabolites significantly improved prediction of CV events beyond the model with age and sex alone, with an area under the receiver operator characteristic curve (AUC) of 79.9 versus 72.6, respectively (p=0.02). Compared with the FRS alone (AUC=73.9), the FRS-adjusted expanded model with 11 metabolites (AUC=75.0, p=0.72) did not improve CV risk discrimination. CONCLUSIONS: We identify novel metabolites associated with the development of CV events in patients with PsD. Further study of their underlying causal role may clarify important pathways leading to CV events in this population.

Design of cancer trials based on progression-free survival with intermittent assessment.

Therapeutic advances in cancer mean that it is now impractical to performed phase III randomized trials evaluating experimental treatments on the basis of overall survival. As a result, the composite endpoint of progression-free survival has been routinely adopted in recent years as it is viewed as enabling a more timely and cost-effective approach to assessing the clinical benefit of novel interventions. This article considers design of cancer trials directed at the evaluation of treatment effects on progression-free survival. In particular, we derive sample size criteria based on an illness-death model that considers cancer progression and death jointly while accounting for the fact that progression is assessed only intermittently. An alternative approach to design is also considered in which the sample size is derived based on a misspecified Cox model, which uses the documented time of progression as the progression time rather than dealing with the interval censoring. Simulation studies show the validity of the proposed methods.

Exposure to ABO-nonidentical blood associated with increased in-hospital mortality in patients with group A blood.

BACKGROUND: Transfusing ABO-compatible blood avoids most acute hemolytic reactions, but donor units that are ABO compatible are not necessarily ABO identical. Emerging data have raised concerns that ABO-nonidentical blood products lead to adverse outcomes. STUDY DESIGN AND METHODS: A large multihospital registry (Transfusion Registry for Utilization, Surveillance, and Tracking) was used to determine the association between exposure to ABO-nonidentical blood and in-hospital mortality. Cox regression analyses controlled for sex, age, hemoglobin, creatinine, and in-hospital interventions and stratified by age of blood and admission year. RESULTS: Data from 18,843 non-group O patients admitted between 2002 and 2011 and receiving at least 1 unit of blood were analyzed. Overall, group A patients had significantly increased risk of in-hospital death upon receiving a nonidentical unit (RR , 1.79; 95% CI, 1.20-2.67; p = 0.005). There was no evidence of increased risk for group B or AB patients. Similar results were seen when only patients with circulatory disorders were considered. When patients with an injury or poisoning diagnosis were excluded, the risk of in-hospital death after receiving a non-identical unit was significantly higher in group A patients and significantly lower in Group B patients. CONCLUSION: Our study demonstrates an adverse effect of ABO-nonidentical blood in a broad range of patients with group A blood, after adjustment for potential confounders. Further research in this area is required to study possible mechanisms. Increased mortality associated with exposure to nonidentical blood in these patients would have a substantial impact at the population level; it would challenge how blood suppliers manage inventory and recruit donors and how health care providers administer blood.

Changing Pattern of Sputum Cell Counts During Successive Exacerbations of Chronic Obstructive Pulmonary Disease.

BACKGROUND: Chronic Obstructive Pulmonary Disease exacerbations are associated with worsening of airway inflammation, the nature of which may be neutrophilic, eosinophilic, or both. OBJECTIVE: The primary objective was to examine the cellular nature of airway inflammation in successive COPD exacerbations in order to ascertain if they changed in individual patients. The secondary objective was to estimate the relative risk indicating the extent to which a particular type of exacerbation changed as a function of the most recent exacerbation. DESIGN: This was a retrospective survey performed on a computerised sputum cell count database of a referral respiratory service in Hamilton, Canada. Recurrent event analyses were used to model the incidence of exacerbations and subtypes of exacerbations. RESULTS: 359 patients and 148 patients had sputum examined during stable condition and during exacerbations, respectively. It was found 65 patients had sputum examined during both situations. The exacerbations were eosinophilic in 15.9%, neutrophilic in 18%, combined in 2.6%, of unknown clinical significance in 19.6% and normal in 19.6%. There were missing counts for 24.3% samples. In 85.2% of patients, a different subtype of bronchitis was noted in successive exacerbations. The relative risk of a subsequent neutrophilic or eosinophilic exacerbation was 6.24 (p = 0.02) and 2.8 (p = 0.24) when the previous exacerbation was neutrophilic or eosinophilic respectively. CONCLUSIONS: This non-intervention study suggests that the cellular nature of bronchitis is largely unpredictable and needs to be examined at each COPD exacerbation This has important implications in choosing the appropriate therapy. Future intervention studies would provide further evidence.

Derivation and Internal Validation of a Disease-Specific Cardiovascular Risk Prediction Model for Patients With Psoriatic Arthritis and Psoriasis.

OBJECTIVE: To address suboptimal cardiovascular risk prediction in patients with psoriatic disease (PsD), we developed and internally validated a five-year disease-specific cardiovascular risk prediction model. METHODS: We analyzed data from a prospective cohort of participants with PsD without a history of cardiovascular events. Traditional cardiovascular risk factors and PsD-related measures of disease activity were considered as potential predictors. The study outcome included nonfatal and fatal cardiovascular events. A base prediction model included 10 traditional cardiovascular risk factors. Eight PsD-related factors were assessed by adding them to the base model to create expanded models, which were controlled for PsD therapies. Variable selection was performed using Least Absolute Shrinkage and Selection Operator (LASSO) penalized regression with 10-fold cross-validation. Model performance was assessed using measures of discrimination and calibration and measures of sensitivity and specificity. RESULTS: Between 1992 and 2020, 85 of 1,336 participants developed cardiovascular events. Discrimination of the base model (with traditional cardiovascular risk factors alone) was excellent, with an area under the receiver operator characteristic curve (AUC) of 85.5 (95% confidence interval [CI] 81.9-89.1). Optimal models did not select any of the tested disease-specific factors. In a sensitivity analysis, which excluded lipid lowering and antihypertensive treatments, the number of damaged joints was selected in the expanded model. However, this model did not improve risk discrimination compared to the base model (AUC 85.5, 95% CI 82.0-89.1). CONCLUSION: Traditional cardiovascular risk factors alone are effective in predicting cardiovascular risk in patients with PsD. A risk score based on these factors performed well, indicating excellent discrimination and calibration.

Inverse probability weighted estimating equations for randomized trials in transfusion medicine.

Thrombocytopenia is a condition characterized by extremely low platelet counts, which puts patients at elevated risk of morbidity and mortality because of bleeding. Trials in transfusion medicine are routinely designed to assess the effect of experimental platelet products on patients' platelet counts. In such trials, patients may receive multiple platelet transfusions over a predefined period of treatment, and a response is available from each such administration. The resulting data comprised multiple responses per patient, and although it is natural to want to use this data in testing for treatment effects, naive analyses of the multiple responses can yield biased estimates of the probability of response and associated treatment effects. These biases arise because only subsets of the patients randomized contribute response data on the second and subsequent administrations of therapy and the balance between treatment groups with respect to potential confounding factors is lost. We discuss the design and analysis issues involved in this setting and make recommendations for the design of future platelet transfusion trials.

Rehabilitation in home care is associated with functional improvement and preferred discharge.

OBJECTIVE: To investigate the impact of physiotherapy (PT) and occupational therapy (OT) services on long-stay home care patients with musculoskeletal disorders. DESIGN: Observational study. SETTING: Home care programs. PARTICIPANTS: All long-stay home care patients between 2003 and 2008 (N=99,764) with musculoskeletal disorders who received a baseline Resident Assessment Instrument for Home Care assessment, 1 follow-up assessment, and had discharge or death records. INTERVENTIONS: PT and OT. MAIN OUTCOME MEASURES: The effects of PT and OT services on transitions in functional state, discharge from home care with service plans complete, institutionalization, and death were assessed via multistate Markov models. RESULTS: Home care patients with deficiencies in instrumental activities of daily living and/or activities of daily living at baseline and who received home-based rehabilitation had significantly increased odds of showing functional improvements by their next assessment (for a state 3 to state 2 transition: odds ratio [OR]=1.17; 95% confidence interval [CI], 1.10-1.26; P<.0001; for a state 2 to state 1 transition: OR=1.36; 95% CI, 1.14-1.61; P=.0005). Receipt of PT/OT also significantly reduced the odds of mortality and institutionalization in this group. CONCLUSIONS: With increasing numbers of older adults with chronic conditions and limited funding for health care services, it is essential to provide the right services at the right time in a cost-effective manner. Long-stay home care patients who receive rehabilitation at home have improved outcomes and lower utilization of costly health services. Our findings suggest that investment in PT and OT services for relatively short periods may provide savings to the health care system over the longer term.

A copula model for marked point processes.

Many chronic diseases feature recurring clinically important events. In addition, however, there often exists a random variable which is realized upon the occurrence of each event reflecting the severity of the event, a cost associated with it, or possibly a short term response indicating the effect of a therapeutic intervention. We describe a novel model for a marked point process which incorporates a dependence between continuous marks and the event process through the use of a copula function. The copula formulation ensures that event times can be modeled by any intensity function for point processes, and any multivariate model can be specified for the continuous marks. The relative efficiency of joint versus separate analyses of the event times and the marks is examined through simulation under random censoring. An application to data from a recent trial in transfusion medicine is given for illustration.

Intraindividual Change in Cognitive Function Among Adults With Systemic Lupus Erythematosus: A Markov Analysis Over 7 Years.

OBJECTIVE: Cognitive impairment is prevalent in systemic lupus erythematosus (SLE). There remain gaps in understanding cognition and SLE longitudinally. We studied intraindividual change in cognition in SLE over time. METHODS: Data were from the University of California, San Francisco Lupus Outcome Study, which included 1281 adults with SLE. The Hopkins Verbal Learning Test-Revised (HVLT-R) and the Controlled Oral Word Association Test (COWAT) were administered annually over 7 years. A two-state Markov analysis was used to model transition intensities for probabilities of change in cognition. Logistic regression examined the association between clinical variables and cognitive change. RESULTS: Minimal transition between cognitive states was observed in the Markov analysis. Using the COWAT, higher levels of self-reported depression were associated with decreased likelihood of cognitive improvement (Relative Risk [RR]: 0.98; 95% confidence interval [CI]: 0.96-0.99), and higher self-reported disease severity was associated with cognitive decline (RR: 1.05; 95% CI: 1.02-1.09). Using the HVLT-R, increasing age (RR: 1.02; 95% CI: 1.01-1.03) and higher education level (RR: 1.82; 95% CI: 1.28-2.58) were associated with cognitive improvement, and higher self-reported disease severity (RR: 1.02; 95% CI: 1.01-1.03) and depression (RR: 1.05; 95% CI: 1.03-1.07) were associated with cognitive decline. CONCLUSION: Most individuals with SLE did not transition between states of high (Z score ≥ -1.5) or low (Z score < -1.5) cognition in a Markov analysis over a 7-year assessment period, highlighting a degree of relative stability in cognition over time. Increasing age and higher education levels were associated with greater likelihood of cognitive improvement. Greater self-reported SLE disease severity and depression were associated with cognitive decline.

Persistence of Biologics in the Treatment of Psoriatic Arthritis: Data From a Large Hospital-Based Longitudinal Cohort.

OBJECTIVE: To analyze the trends in biologics use at a specialized center over a period of 20 years. METHODS: We performed a retrospective analysis of 571 patients diagnosed with psoriatic arthritis enrolled in the Toronto cohort who initiated biologic therapy between January 1, 2000, and July 7, 2020. The probability of drug persistence over time was estimated nonparametrically. The time to discontinuation of first and second treatment was analyzed using Cox regression models, whereas a semiparametric failure time model with a gamma frailty was used to analyze the discontinuation of treatment over successive administrations of biologic therapy. RESULTS: The highest 3-year persistence probability was observed with certolizumab when used as first biologic treatment, while interleukin-17 inhibitors had the lowest probability. However, when used as second medication, certolizumab had the lowest drug survival even when accounting for selection bias. Depression and/or anxiety were associated with a higher rate of drug discontinuation due to all causes (relative risk [RR] 1.68, P = 0.01), while having higher education was associated with lower rates (RR 0.65, P = 0.03). In the analysis accommodating multiple courses of biologics, a higher tender joint count was associated with a higher rate of discontinuation due to all causes (RR 1.02, P = 0.01). Older age at the start of first treatment was associated with a higher rate of discontinuation due to side effects (RR 1.03, P = 0.01), while obesity had a protective role (RR 0.56, P = 0.05). CONCLUSION: Persistence in taking biologics depends on whether the biologic was used as first or second treatment. Depression and anxiety, higher tender joint count, and older age lead to drug discontinuation.

Derivation of a Multivariable Psoriatic Arthritis Risk Estimation Tool (PRESTO): A Step Towards Prevention.

OBJECTIVE: A simple, scalable tool that identifies psoriasis patients at high risk for developing psoriatic arthritis (PsA) could improve early diagnosis. We aimed to develop a risk prediction model for the development of PsA and to assess its performance among patients with psoriasis. METHODS: We analyzed data from a prospective cohort of psoriasis patients without PsA at enrollment. Participants were assessed annually by a rheumatologist for the development of PsA. Information about their demographics, psoriasis characteristics, comorbidities, medications, and musculoskeletal symptoms was used to develop prediction models for PsA. Penalized binary regression models were used for variable selection while adjusting for psoriasis duration. Risks of developing PsA over 1- and 5-year time periods were estimated. Model performance was assessed by the area under the curve (AUC) and calibration plots. RESULTS: Among 635 psoriasis patients, 51 and 71 developed PsA during the 1-year and 5-year follow-up periods, respectively. The risk of developing PsA within 1 year was associated with younger age, male sex, family history of psoriasis, back stiffness, nail pitting, joint stiffness, use of biologic medications, patient global health, and pain severity (AUC 72.3). The risk of developing PsA within 5 years was associated with morning stiffness, psoriatic nail lesion, psoriasis severity, fatigue, pain, and use of systemic nonbiologic medication or phototherapy (AUC 74.9). Calibration plots showed reasonable agreement between predicted and observed probabilities. CONCLUSIONS: The development of PsA within clinically meaningful time frames can be predicted with reasonable accuracy for psoriasis patients using readily available clinical variables.

Prognostic role of serum parathyroid hormone levels in advanced prostate cancer patients undergoing zoledronic acid administration.

BACKGROUND: Secondary hyperparathyroidism is frequent in prostate cancer patients with bone metastases, and this condition is worsened by the administration of potent bisphosphonates. Serum parathyroid hormone (PTH) elevation can impair the efficacy of these drugs in terms of survival. METHODS: The prognostic role of elevated serum PTH levels at baseline and after 3 months of zoledronic acid administration was assessed prospectively in 643 bone metastatic prostate cancer patients enrolled in a prospective randomized, placebo-controlled study. RESULTS: On multivariate analysis, after adjusting for major prognostic factors and bone turnover markers, elevated baseline serum PTH level was negatively associated with overall survival (hazard ratio [HR], 1.448; 95% confidence interval [CI], 1.045-2.006; p < .03) in zoledronic acid-treated patients but not in placebo-treated patients. In patients with normal baseline PTH levels, there was a trend but insignificant association between zoledronic acid administration and a better survival outcome than with placebo (HR, 0.81; 95% CI, 0.65-1.01; p = .065), whereas a trend in the opposite direction was observed in patients with elevated PTH levels (HR, 1.45; 95% CI, 0.87-2.39; p = .151); interaction test, p = .040. Elevated serum PTH level after 3 months of zoledronic acid treatment was not significantly associated with survival outcome. CONCLUSIONS: Secondary hyperparathyroidism has a negative prognostic impact in metastatic prostate cancer patients undergoing zoledronic acid administration. Counteracting elevated PTH levels by adequate doses of vitamin D may improve the efficacy of this drug.

Classical Regression and Predictive Modeling.

BACKGROUND: With the advent of personalized and stratified medicine, there has been much discussion about predictive modeling and the role of classical regression in modern medical research. We describe and distinguish the goals in these 2 frameworks for analysis. METHODS: The assumptions underlying and utility of classical regression are reviewed for continuous and binary outcomes. The tenets of predictive modeling are then discussed and contrasted. Principles are illustrated by simulation and through application of methods to a neurosurgical study. RESULTS: Classical regression can be used for insights into causal mechanisms if careful thought is given to the role of variables of interest and potential confounders. In predictive modeling, interest lies more in accuracy of predictions and so alternative metrics are used to judge adequacy of models and methods; methods which average predictions over several contending models can improve predictive performance but these do not admit a single risk score. CONCLUSIONS: Both classical regression and predictive modeling have important roles in modern medical research. Understanding the distinction between the 2 frameworks for analysis is important to place them in their appropriate context and interpreting findings from published studies appropriately.

Association of Cardiac Biomarkers With Cardiovascular Outcomes in Patients With Psoriatic Arthritis and Psoriasis: A Longitudinal Cohort Study.

OBJECTIVE: In patients with psoriatic disease (PsD), we determined whether cardiac troponin I (cTnI) and N-terminal pro-brain natriuretic peptide (NT-proBNP) were associated with carotid plaque burden and the development of cardiovascular events independent of the Framingham Risk Score (FRS). METHODS: Among 1,000 patients with PsD, carotid total plaque area (TPA) was measured in 358 participants at baseline. Cardiac troponin I and NT-proBNP were measured using automated clinical assays. The association between cardiac biomarkers and carotid atherosclerosis was assessed by multivariable regression after adjusting for cardiovascular risk factors. Improvement in the prediction of cardiovascular events beyond the FRS was tested using measures of risk discrimination and reclassification. RESULTS: In univariate analyses, cTnI (ß coefficient 0.52 [95% confidence interval (95% CI) 0.3, 0.74], P < 0.001) and NT-proBNP (ß coefficient 0.24 [95% CI 0.1, 0.39], P < 0.001) were associated with TPA. After adjusting for cardiovascular risk factors, the association remained statistically significant for cTnI (adjusted ß coefficient 0.21 [95% CI 0, 0.41], P = 0.047) but not for NT-proBNP (P = 0.21). Among the 1,000 patients with PsD assessed for cardiovascular risk prediction, 64 patients had incident cardiovascular events. When comparing a base model (with the FRS alone) to expanded models (with the FRS plus cardiac biomarkers), there was no improvement in predictive performance. CONCLUSION: In patients with PsD, cTnI may reflect the burden of atherosclerosis, independent of traditional cardiovascular risk factors. Cardiac troponin I and NT-proBNP are associated with incident cardiovascular events independent of the FRS, but further study of their role in cardiovascular risk stratification is warranted.

A randomized controlled trial comparing standard- and low-dose strategies for transfusion of platelets (SToP) to patients with thrombocytopenia.

A noninferiority study was performed comparing low-dose and standard-dose prophylactic platelet transfusions. A double-blind randomized controlled trial (RCT) was performed in 6 sites in 3 countries. Thrombocytopenic adults requiring prophylactic platelet transfusion were randomly allocated to standard-dose (300-600 x 10(9) platelets/product) or low-dose (150- < 300 x 10(9) platelets/product) platelets. The primary outcome (World Health Organization [WHO] bleeding > or = grade 2) was assessed daily through clinical examination, patient interview, and chart review. A WHO grade was assigned through adjudication. The Data Safety Monitoring Board stopped the study because the difference in the grade 4 bleeding reached the prespecified threshold of 5%. At this time, 129 patients had been randomized and 119 patients were included in the analysis (58 low dose; 61 standard dose). Three patients in the low-dose arm (5.2%) had grade 4 bleeds compared with none in the standard-dose arm. WHO bleeding grade 2 or higher was 49.2% (30/61) in the standard-dose arm and 51.7% (30/58) in the low-dose group (relative risk [RR], 1.052; 95% confidence interval [CI], 0.737-1.502). A higher rate of grade 4 bleeding in patients receiving low-dose prophylactic platelet transfusions resulted in this RCT being stopped. Whether this finding was due to chance or represents a real difference requires further investigation. These clinical studies are registered on (http://www.clinicaltrials.gov) as NCT00420914.

Oligoarticular vs Polyarticular Psoriatic Arthritis: A Longitudinal Study Showing Similar Characteristics.

OBJECTIVE: The objectives of this study were to determine whether patients with oligoarticular presentation differ from those with polyarticular presentation and to identify potential predictors for evolution of oligoarthritis to polyarthritis in patients with psoriatic arthritis (PsA). METHODS: Patients who entered the University of Toronto PsA clinic between 1978 and 2018 within 12 months of diagnosis were identified. Only patients with ≥ 2 clinic visits were included. Patients were followed at 6- to 12-month intervals according to standard protocol, which included demographics, clinical history, detailed clinical examination, laboratory information, and patient questionnaires. Radiographs were done at 2-year intervals. Oligoarthritiswas defined by the presence of ≤ 4 inflamed joints and progressionas an increase to ≥ 5 joints. Statistical analyses included logistic regression models as well as Weibull regression models, adjusted for age, disease duration, and sex. RESULTS: Of 407 patients, 192 (47%) presented with oligoarthritis. Whereas demographic features were similar to those with polyarthritis, more patients with polyarthritis presented with dactylitis and enthesitis. Similar joint distribution was observed, with small joints of the hands and feet being most commonly affected. Patients with polyarthritis had higher Health Assessment Questionnaire and lower 36-item Short Form Health Survey (SF-36) scores. Of the 192 oligoarticular patients, 117 (61%) remained oligoarticular and 75 (39%) progressed to polyarthritis. A lower SF-36 mental component summary (MCS) score was the predictor for progressing to polyarthritis. CONCLUSION: Oligoarticular PsA occurs in 47% of patients with PsA and is similar to polyarticular disease, with most patients having small joint involvement. The only predictor for progression to polyarthritis was lower SF-36 MCS.

The Pattern of Musculoskeletal Complaints in Patients With Suspected Psoriatic Arthritis and Their Correlation With Physical Examination and Ultrasound.

OBJECTIVE: To describe the pattern of musculoskeletal (MSK) symptoms and their correlation with clinical and sonographic findings among psoriasis patients with suspected psoriatic arthritis (PsA). METHODS: Patients with psoriasis and no prior diagnosis of PsA were referred for assessment of their MSK complaints. The study included the following steps: (1) assessment by an advanced practice physiotherapist, (2) targeted MSK ultrasound, and (3) assessment by a rheumatologist. In addition, patients were asked to complete questionnaires about the nature and duration of their MSK symptoms and to mark the location of their painful joints on a homunculus. Each patient was classified by a rheumatologist as "Not PsA," "Possible PsA," or "PsA". MSK symptoms and patient-reported outcomes (PRO) were compared between patients with PsA and Possible/Not PsA. Agreement between modalities was assessed using κ statistics. RESULTS: Two hundred three patients with psoriasis and MK symptoms were enrolled (8.8% PsA, 23.6% Possible PsA). Patients classified as PsA had worse scores on the PsA Impact of Disease (P = 0.004) and Functional Assessment of Chronic Illness Therapy-Fatigue scale (P = 0.02). There was no difference between the 2 groups in the presence, distribution, and duration of MSK symptoms. Analysis of agreement in physical examination between modalities revealed the strongest agreement between the rheumatologist and physiotherapist (κ = 0.28). The lowest levels of agreement were found between ultrasound and patient (κ = 0.08) and physiotherapist and ultrasound (κ = 0.08). CONCLUSION: The results of this study suggest that the intensity, rather than the type, duration, or distribution of MSK symptoms, is associated with PsA among patients with psoriasis.

Malignancy in psoriatic disease: Results from prospective longitudinal cohorts.

OBJECTIVES: To estimate the prevalence and incidence of malignancy and its types in psoriatic arthritis (PsA) and psoriasis without arthritis (PsC) patients, in comparison to the general population, and to identify the predictive factors for developing cancer in psoriatic disease (PsD). METHODS: PsA patients followed prospectively since 1978 and PsC patients followed since 2006 at 6-to-12 month intervals according to a standard protocol were included. Malignancies were recorded prospectively and linkages with Cancer Care Ontario and the Death Registry were carried out to confirm the presence and type of malignancy up to December 2016. Standardized incidence ratios (SIR) were calculated for overall cancers and by age and sex. Cox regression analysis was conducted to identify risk factors associated with the development of malignancy after the diagnosis of PsD. RESULTS: 2051 patients (PsD) were included of whom 228 (11%) developed cancer. 168 patients developed cancer after first clinic visit and are included in this report. Overall SIR for malignancy was 0.83 (0.68, 1.00), SIR for females was 1.06 (0.80, 1.37), and for males was 0.67 (0.50, 0.88). The most common malignancies were skin, breast, and hematological. Skin cancer was the only specific cancer that had a higher incidence than the general population with SIR = 3.37 (1.84, 5.66). There was insufficient evidence to suggest an increased risk of malignancy associated with biologics use. CONCLUSIONS: In this long-term prospective follow-up of patients with PsA and PsC the overall malignancy risk was not found to be higher than the general population, while skin cancer increased.

Predictors of response to intra-articular steroid injection in psoriatic arthritis.

OBJECTIVES: To assess the effectiveness of IA corticosteroid (IAS) injections in PsA and to determine the association between macrophage migration inhibition factor (MIF) gene polymorphism and response to IAS injections. METHODS: A cohort analysis of PsA patients who were followed prospectively was performed. Clinical response was defined as no tenderness or effusion in the injected joint at 3 months. Relapse was defined as re-occurrence of joint pain or effusion. MIF 173C > G genotyping (rs755622) was performed. RESULTS: Two hundred and twenty patients with 245 IAS injections were included in the study. The probability of responding at 3 months was 41.6%. Within 12 months, 25.5% of the joints relapsed. Clinical factors that were associated with response included duration of psoriasis [Odds ratio (OR) 1.03] and the use of MTX or anti-TNF agents at the time of injection (OR 2.68). Factors that were associated with relapse included injection into large joints (OR 4.58) and elevated sedimentation rate (OR 15.0), whereas absence of clinical and/or radiographic damage (OR 0.23) and duration of PsA (OR 0.92) reduced risk of relapse. MIF polymorphism was not associated with clinical response, but was associated with relapse (OR 3.2). On multivariate analysis including clinical covariates, the association between MIF polymorphism and relapse was lost. CONCLUSIONS: IAS injections are effective in PsA. MIF gene polymorphism is associated with relapse. However, this effect is explained by clinical variables that reflect disease activity, suggesting that MIF gene polymorphism influences inflammatory activity.

A copula-based mixed Poisson model for bivariate recurrent events under event-dependent censoring.

In many chronic disease processes subjects are at risk of two or more types of events. We describe a bivariate mixed Poisson model in which a copula function is used to model the association between two gamma distributed random effects. The resulting model is a bivariate negative binomial process in which each type of event arises from a negative binomial process. Methods for parameter estimation are described for parametric and semiparametric models based on an EM algorithm. We also consider the issue of event-dependent censoring based on one type of event, which arises when one event is sufficiently serious that its occurence may influence the decision of whether to withdraw a patient from a study. The asymptotic biases of estimators of rate and mean functions from naive marginal analyses are discussed, as well as associated treatment effects. Because the joint model is fit based on a likelihood, consistent estimates are obtained. Simulation studies are carried out to evaluate the empirical performance of the proposed estimators with independent and event-dependent censoring and applications to a trial of breast cancer patients with skeletal metastases and a study of patients with chronic obstructive pulmonary disease illustrate the approach.