Effect of disease duration and other characteristics on efficacy outcomes in clinical trials of tocilizumab for rheumatoid arthritis.

OBJECTIVE: To determine the extent to which disease duration, alone or in combination with other baseline clinical and non-clinical factors, explains variations in outcome of tocilizumab initiated in biologic-naïve patients with established RA. METHODS: In this pooled analysis of phase 3 and 4 clinical trials conducted by the sponsor, predictors of response, including demographics, disease characteristics at baseline (start of tocilizumab dosing) and study characteristics (e.g. patient inclusion criteria, tocilizumab dosing regimen) were evaluated. Response was measured as change from baseline to week 24 in Clinical Disease Activity Index (CDAI) and HAQ-Disability Index (HAQ-DI) scores and as the proportions of patients who experienced ≥50% improvement based on ACR criteria (ACR50) and CDAI remission (≤2.8) rates at week 24. RESULTS: Improvements in all outcomes investigated were observed in patients receiving tocilizumab. Although disease duration was statistically significant in the models, it accounted for <2% of variation in CDAI and HAQ-DI score changes from baseline to week 24; baseline CDAI and HAQ-DI values accounted for 32% and 15% of variations, respectively. Doubling of disease duration reduced the odds of achieving an ACR50 response by only 9%, and each additional 5-year period of disease duration decreased the odds of achieving CDAI remission by only 15%. CONCLUSION: RA duration, alone or in combination with other baseline characteristics, had a statistically significant but clinically small effect on the outcomes of tocilizumab initiated in biologic-naïve patients with established RA.

Effect on efficacy and safety trial outcomes of also enrolling patients on ongoing glucocorticoid therapy in rheumatoid arthritis clinical trials of tocilizumab or adalimumab or methotrexate monotherapy.

BACKGROUND: In rheumatoid arthritis (RA) trials, inclusion of patients on background treatment with glucocorticoids (GCs) might impact efficacy and safety outcomes. OBJECTIVES: To determine if inclusion of patients on background GC use influenced efficacy and safety outcomes of RA randomised clinical trials on initiation of tocilizumab (TCZ) or adalimumab (ADA) or methotrexate (MTX) monotherapy. METHODS: Data of four double-blind RA randomised controlled trials (AMBITION, ACT-RAY, ADACTA and FUNCTION) with in total four TCZ, one ADA and two MTX monotherapy arms were analysed. Analyses of covariance of changes from baseline to week 24 in efficacy endpoints and radiographic progression up to week 104 were performed, correcting for relevant covariates. Incidence rates of serious adverse events (SAEs) were assessed. RESULTS: No statistically significant differences were found in efficacy parameters between background GC users and non-GC users, except for less radiographic progression associated with GC usage in one MTX arm. SAE rates were not statistically significantly different between GC users and non-GC users in the treatment arms. CONCLUSION: No effect of including patients on background GC treatment on efficacy and safety trial outcomes was found, with the exception of reduced radiological joint damage in one MTX arm.

Evaluating cimetidine for GFR estimation in liver transplant recipients.

Background. Serum creatinine (Scr)-based equations lack accuracy in predicting glomerular filtration rate (GFR) in patients with liver disease. Cimetidine has been shown to improve the performance of Scr-based GFR formulae. Methods. We evaluated the use of cimetidine on the performance of GFR-estimating equations in 39 liver transplant recipients. The patients received oral cimetidine (800 mg tid) during a 24-h urine collection. The next day, the patients underwent radionucleotide GFR (rGFR) determination and Scr was measured for creatinine clearance (CrCl) and GFR estimation using the Cockcroft-Gault, Nankivell and modified diet in renal disease (MDRD) equations. Data were analysed using the Pearson correlation statistic and Bland-Altman plots. Results. The mean rGFR was 65 +/- 26.4 mL/min. The use of cimetidine increased the bias between rGFR and the Nankivell and MDRD equations. The combined root mean square error for the CrCl, Cockcroft-Gault, Nankivell and MDRD equations without cimetidine were 20.2, 15.6, 17.0 and 15.5 and cimetidine-aided were 28.2, 23.2, 23.7 and 24.3, respectively. Conclusions. All the tested equations without using cimetidine predicted GFR with modest accuracy. The addition of cimetidine decreased the precision and increased the bias of all the GFR-estimating equations. In the absence of accurate GFR-estimating equations, rGFR should be used to monitor kidney function in liver transplant recipients.

Factors associated with a decrease in the prevalence of drug resistance in newly HIV-1 infected individuals in Montreal.

OBJECTIVE: A decrease in the prevalence of drug resistance (DR) has been observed among recently infected (RI) individuals in Montreal. A study of chronically infected (CI) patients, who represent potential HIV-1 transmitters, was carried out in order to ascertain biological factors associated with this trend change. DESIGN AND METHODS: Retrospective analysis of CI patients was performed for the period 1996-2003. Changes in mean viral load and DR prevalence were assessed in CI patients (n = 2328) and compared to those in RI patients (n = 180) living in the same geographic area. RESULTS: A decrease was observed in the prevalence of DR among RI patients, from 13.0% in 1997-2000 to 4.0% in 2001-2003 (P = 0.04). From 1996 to 2000, the mean viral load in the CI patients decreased by 1.34 log10, to remain steady thereafter. The proportion of CI patients who interrupt treatment increased steadily over 1997-2003 from 3.1% to 16.5% (P < 0.0001). Since 1999, when genotyping analysis became available, we have observed a 0.9 log10 decrease in mean viral load among 602 genotyped CI patients harbouring any major mutations. CONCLUSION: The decrease in transmission of DR documented in Montreal since 2000 coincides with the drop in mean viral load observed in CI patients. Factors that contribute to the decrease in viral load include routine access to genotyping and availability of more potent antiretroviral drugs. Plasma viral load seems to represent the main predictor for the transmission of DR.

Parathyroid hormone-related peptide and survival of patients with cancer and hypercalcemia.

PURPOSE: Parathyroid hormone-related peptide (PTHrP) is the predominant cause of malignancy-associated hypercalcemia. However, its prognostic utility is unclear. We aimed to determine the prognostic value of serum PTHrP levels in patients who had hypercalcemia associated with malignancy. METHODS: In this prospective case series, we evaluated 76 patients with a diagnosis of cancer and hypercalcemia (serum calcium level >/=10.3 mg/dL on at least two occasions). PTHrP levels >/=1 pmol/L were considered elevated. We used multivariate Cox regression analysis to identify factors associated with mortality. RESULTS: Fifty patients (66%) died during follow-up. In a multivariate analysis, higher pretreatment calcium levels and elevated PTHrP levels were associated with increased mortality, with effects of PTHrP varying by age (P = 0.03). Survival was associated with pretreatment calcium levels both in patients over 65 years of age (hazard ratio [HR] per mg/dL = 1.5; 95% confidence interval [CI]: 1.2 to 1.8; P <0.001) and in patients aged 65 years or less (HR = 1.3; 95% CI: 1.1 to 1.5; P = 0.003). Adjusted for pretreatment calcium levels, elevated PTHrP levels were associated with increased mortality in patients aged

Meta-analysis and the reversed Theorem of the Means.

Conventional meta-analysis estimators are weighted means of study measures, meant to estimate an overall population measure. For measures such as means, mean differences and risk differences, a weighted arithmetic mean is the conventional estimator. When the measures are ratios, such as odds ratios, logarithms of the study measures are most frequently used, and the back-transform is a weighted geometric mean, rather than the arithmetic mean. For numbers needed to treat, a weighted harmonic mean is the back-transform. The Theorem of the Means effectively states that unless all of the studies have an equal result, the arithmetic mean must be greater than the geometric mean, which must be greater than the harmonic mean. When the weights are fixed sampling weights, the inequalities are in the expected direction. However, when the weights are the usual reciprocal variance estimates, the inequalities go in the opposite direction. The use of reciprocal variance weights is therefore questioned as perhaps having a fundamental flaw. An example is shown of a meta-analysis of frequencies of two classes of drug-resistant HIV-1 mutations.

Calcineurin inhibitor substitution with sirolimus vs. reduced-dose calcineurin inhibitor plus sirolimus is associated with improved renal dysfunction in heart transplant patients.

Heart transplant (HTx) patients are at risk of developing renal dysfunction. Sirolimus has been used as an alternative for calcineurin inhibitors (CNI) in transplant patients with renal dysfunction. Recent data suggest that the combination of sirolimus with a CNI is associated with a deterioration of renal function in renal transplant patients. The purpose of the present study was to compare the effect on the creatinine clearance (CrCl) of heart transplant (HTx) patients with renal dysfunction (RD) on CNI-based sirolimus-free regimens of conversion to either reduced-dose CNI plus sirolimus or outright substitution of CNI with sirolimus. We retrospectively identified 29 treatment switches for 26 patients with RD defined as a decline in the CrCl > 25% post-HTx. Treatment switches were divided into two groups. Group 1 included 13 switches in 13 patients (four women, nine men, age 62 +/- 10 yr) in whom sirolimus replaced CNI. Group 2 included 16 switches in 15 patients [two women, 13 men (one man underwent two such switches), age 61 +/- 9 yr] in whom CNI dose was reduced and sirolimus was added. Two men appear in both groups. Average follow-up was 10.4 +/- 3.2 months. Overall mortality, rejection, and side-effects rates were comparable between groups. At 12-months post-switch, the mean CrCl had increased from 48 +/- 15 at time of treatment switch to 56 +/- 22 mL/min in group 1 and decreased from 53 +/- 19 to 47 +/- 17 mL/min in group 2 (p = 0.02). In conclusion, substitution of CNI with sirolimus provided improved renal recovery compared with lower-dose CNI plus sirolimus in HTx patients with renal dysfunction.

Statistical analysis of correlated data using generalized estimating equations: an orientation.

The method of generalized estimating equations (GEE) is often used to analyze longitudinal and other correlated response data, particularly if responses are binary. However, few descriptions of the method are accessible to epidemiologists. In this paper, the authors use small worked examples and one real data set, involving both binary and quantitative response data, to help end-users appreciate the essence of the method. The examples are simple enough to see the behind-the-scenes calculations and the essential role of weighted observations, and they allow nonstatisticians to imagine the calculations involved when the GEE method is applied to more complex multivariate data.

Malignancy after renal transplantation: incidence and role of type of immunosuppression.

BACKGROUND: Cancer, particularly skin cancer and lymphoma, is a complication of posttransplantation immunosuppression. We investigated the characteristics of cancers in our renal transplant population, the role of type of immunosuppression on cancer incidence, and whether newer, more potent immunosuppressive agents produce cancers sooner after transplantation. METHODS: The charts of patients who developed cancer after renal transplantation between 1958 and 2000 were reviewed. Statistical analyses were performed with the mid-P version of Fisher's exact test for 2 x 2 tables for incidence comparison of cancer and with Student's t-test for differences between mean times to cancer. RESULTS: Between 1958 and 2000, 924 transplantations in 760 patients were performed. We found a cancer incidence of 12.2%. The most frequent cancers were skin and genitourinary. The overall mortality was 54%. We found an increased incidence of cancer in the group of patients in the cyclosporine era and for patients >or=45 years at transplantation. Cancer did not develop sooner in the cyclosporine group. CONCLUSIONS: The distribution of types of cancer was similar to that reported in the literature. The mortality rate was high. The incidence of cancer was higher in the cyclosporine era in patients >or=45 years at transplantation.

Psychosocial determinants of relapse in ulcerative colitis: a longitudinal study.

OBJECTIVES: To determine the association between psychosocial characteristics and time to relapse in patients with inactive ulcerative colitis. METHODS: Sixty patients with clinically and endoscopically inactive ulcerative colitis were followed for 1 yr, or less if they relapsed. Demographic, psychosocial, and clinical data were obtained. Stressful life events (Psychiatric Epidemiology Research Interview Life Events Scale), psychological distress (Symptom Checklist-90R), and perceived stress (Perceived Stress Scale) were recorded monthly by self-report. Multivariate time-dependent Cox regression was used to identify the independent determinants of earlier time to clinical relapse. RESULTS: The patients' mean age was 39 yr (SD = 9.4), 37 (62%) were female, and 22 (37%) relapsed during the 1-yr follow-up. Univariate Cox regression indicated a weak association between number of stressful events in the preceding month and time to relapse (p = 0.09). This association strengthened in multivariate analysis (p = 0.02, hazard ratio = 1.26 per event, 95% CI = 1.04-1.53) after adjustment for significant covariates. CONCLUSIONS: After controlling for demographic and clinical variables, more recent stressful events were associated with earlier time to relapse. These findings, which support a biopsychosocial model of disease, might help clinicians identify patients who might benefit from more intensive maintenance medical therapy and behavioral medicine interventions to reduce stress and improve coping.