Ravy K. Vajravelu

Improved Long-term Outcomes of Patients With Inflammatory Bowel Disease Receiving Proactive Compared With Reactive Monitoring of Serum Concentrations of Infliximab

BACKGROUND & AIMS: Monitoring serum concentrations of tumor necrosis factor antagonists in patients receiving these drugs as treatment for inflammatory bowel disease (IBD), also called therapeutic drug monitoring, is performed either after patient loss of response (reactive drug monitoring) or in patients in clinical remission in which the drug is titrated to a target concentration (proactive drug monitoring). We compared long‐term outcomes of patients with IBD undergoing proactive vs reactive monitoring of serum concentrations of infliximab. METHODS: We performed a multicenter, retrospective study of 264 consecutive patients with IBD (167 with Crohns disease) receiving infliximab maintenance therapy. The subjects received proactive (n = 130) or reactive (n = 134) drug monitoring, based on measurements of first infliximab concentration and antibodies to infliximab, from September 2006 to January 2015; they were followed through December 2015 (median time of 2.4 years). We analyzed time to treatment failure, first IBD‐related surgery or hospitalization, serious infusion reaction, and detection of antibodies to infliximab. Treatment failure was defined as drug discontinuation for loss of response or serious adverse event, or need for surgery. RESULTS: Multiple Cox regression analysis independently associated proactive drug monitoring, compared with reactive monitoring, with reduced risk for treatment failure (hazard ratio [HR], 0.16; 95% confidence interval [CI], 0.09–0.27; P < .001), IBD‐related surgery (HR, 0.30; 95% CI, 0.11–0.80; P = .017), IBD‐related hospitalization (HR, 0.16; 95% CI, 0.07–0.33; P < .001), antibodies to infliximab (HR, 0.25; 95% CI, 0.07–0.84; P = .025), and serious infusion reaction (HR, 0.17; 95% CI, 0.04–0.78; P = .023). CONCLUSIONS: In a retrospective analysis of patients with IBD receiving proactive vs reactive monitoring of serum concentration of infliximab, proactive monitoring was associated with better clinical outcomes, including greater drug durability, less need for IBD‐related surgery or hospitalization, and lower risk of antibodies to infliximab or serious infusion reactions.

The Benefit to Risk Balance of Combining Infliximab with Azathioprine Varies With Age: A Markov Model

BACKGROUND & AIMS Combination therapy with infliximab and azathioprine has demonstrated benefit over monotherapy for moderate-to-severe Crohns disease. Clinical trials and models have not accounted for age-specific risks associated with these therapies, including the risk of immunosuppression-related cancer and infection. After accounting for these risks, the strategy yielding the greatest benefit may vary with age. METHODS We assessed age-specific risks and benefits of combination therapy compared with infliximab monotherapy by using Markov modeling. The base case was a 35-year-old male patient with a 1-year time horizon. We assumed the incidence of lymphoma to be 5.28-fold higher with combination therapy. Secondary analyses accounted for life expectancy, therapy beyond 1 year, and age-specific surgical and infection risks. Quality-adjusted life years (QALYs) were calculated for 25- to 75-year old individuals. RESULTS Combination therapy was found to be of greater benefit in the base case (0.7522 QALYs for combination therapy vs 0.7426 QALYs for monotherapy). Accounting for life years lost, monotherapy was the best approach if the hazard ratio for lymphoma with combination therapy was >8.1 patients who were 75 years old. Monotherapy provided greater net benefit to patients 55, 65, or 75 years old if therapy was extended for 9, 7, or 5 years, respectively. For 25-year-old men, monotherapy resulted in fewer deaths but only yielded greater QALYs if the annual incidence of hepatosplenic T-cell lymphoma exceeded 36/100,000 persons. CONCLUSIONS After accounting for age-specific risks of lymphoma, infection, and surgical complications, benefits of combination therapy outweighed the risks as a short-term and intermediate-term strategy for most patients with moderate-to-severe Crohns disease who were younger than 65 years. For young male patients, combination therapy yields greater QALYs but at cost of an increased risk of death from lymphoma.

Proactive Infliximab Monitoring Following Reactive Testing is Associated With Better Clinical Outcomes Than Reactive Testing Alone in Patients With Inflammatory Bowel Disease

Background and Aims Reactive testing has emerged as the new standard of care for managing loss of response to infliximab in inflammatory bowel disease [IBD]. Recent data suggest that proactive infliximab monitoring is associated with better therapeutic outcomes in IBD. Nevertheless, there are no data regarding the clinical utility of proactive infliximab monitoring after first reactive testing. We aimed to evaluate long-term outcomes of proactive infliximab monitoring following reactive testing compared with reactive testing alone in patients with IBD. Methods This was a retrospective multicenter cohort study of consecutive IBD patients on infliximab maintenance therapy receiving a first reactive testing between September 2006 and January 2015. Patients were divided into two groups; Group A [proactive infliximab monitoring after reactive testing] and Group B [reactive testing alone]. Patients were followed through December 2015. Time-to-event analysis for treatment failure and IBD-related surgery and hospitalization was performed. Treatment failure was defined as drug discontinuation due to either loss of response or serious adverse event. Results The study population consisted of 102 [n = 70, 69% with CD] patients [Group A, n = 33 and Group B, n = 69] who were followed for (median, interquartile range [IQR]) 2.7 [1.4-3.8] years. Multiple Cox regression analysis identified proactive following reactive TDM as independently associated with less treatment failure (hazard ratio [HR] 0.15; 95% confidence interval [CI] 0.05-0.51; p = 0.002) and fewer IBD-related hospitalizations [HR: 0.18; 95% CI 0.05-0.99; p = 0.007]. Conclusions This study showed that proactive infliximab monitoring following reactive testing was associated with greater drug persistence and fewer IBD-related hospitalizations than reactive testing alone.

Indeterminate QuantiFERON-TB Gold Increases Likelihood of Inflammatory Bowel Disease Treatment Delay and Hospitalization

Background QuantiFERON-TB Gold (QFTG) is a blood test used to diagnose latent tuberculosis infection (LTBI) prior to TNF-α inhibitor (anti-TNF) initiation. We sought to determine factors associated with indeterminate QFTG results in inflammatory bowel disease (IBD) patients and whether indeterminate results are associated with IBD-related morbidity. Methods This nested case-control study included IBD patients who underwent QFTG testing. Cases were patients with indeterminate QFTG and controls were those with negative QFTG. The association of demographic and clinical data with indeterminate QFTG result was assessed using logistic regression. We examined the clinical impact of indeterminate QFTG results on risk of hospitalization and delay in anti-TNF initiation using inverse probability-of-treatment weighting (IPTW) regression. Results We identified 411 patients with QFTG testing (320 negative, 80 indeterminate, and 11 positive results). No patient with an indeterminate result subsequently had LTBI. Systemic corticosteroid use (OR, 4.4; 95% CI, 2.0-9.6) and hospitalization at the time of QFTG (OR, 3.8; 95% CI, 1.9-7.7) were associated with indeterminate QFTG, while immunomodulator use was nearly statistically significant (OR, 3.1; 95% CI, 0.9-9.8) and anti-TNF use was not (OR, 0.9; 95% CI, 0.2-4.6). After IPTW adjustment, indeterminate QFTG was associated with a 23.1% (95% CI, 8.2%-37.9%) greater probability of delay in anti-TNF initiation beyond 30 days and an 11.9% (95% CI, 0.6%-23.1%) greater probability of hospitalization within 60 days. Conclusions Systemic corticosteroid use and hospitalization were associated with an indeterminate QFTG result. Indeterminate QFTG results were associated with delayed anti-TNF initiation and subsequent hospitalization.

Association Between Symptomatic Versus Asymptomatic Recurrence and Survival in Bladder Cancer

&NA; Routine surveillance after curative cystectomy in bladder cancer might be justified if detection of asymptomatic recurrence improves survival. We conducted a retrospective cohort study of 463 patients classified according to asymptomatic or symptomatic recurrence detection. Asymptomatic compared with symptom‐detected recurrence was associated with improved survival. Shortening surveillance intervals might allow for detection of more recurrences in an asymptomatic phase. Background: The benefit of surveillance after curative cystectomy in bladder cancer is unproven, but might be justified if detection of asymptomatic recurrence improves survival. Previous studies showing a benefit of surveillance might have been affected by lead‐time or length‐time bias. Materials and Methods: We conducted a retrospective cohort study among 463 cystectomy patients at the University of Pennsylvania. Patients were followed according to a standardized protocol and classified according to asymptomatic or symptomatic recurrence detection. Primary outcome was all‐cause mortality. Adjusted Cox regression models were used to assess the effect of mode of recurrence on survival from time of cystectomy (model 1) and time of recurrence (model 2) to account for lead and length time. Results: One hundred ninety‐seven patients (42.5%) recurred; 71 were asymptomatic (36.0%), 107 were symptomatic (54.3%), and 19 (9.6%) were unknown. Relative to patients with asymptomatic recurrence, patients with symptomatic recurrence had significantly increased risk of death (model 1: hazard ratio [HR], 1.67; 95% confidence interval [CI], 1.07‐2.61; model 2: HR, 1.74, 95% CI, 1.13‐2.69) and had lower 1‐year overall survival from time of recurrence (29.37% vs. 55.66%). Symptomatic patients were diagnosed with recurrence a median of 1.7 months before asymptomatic patients, yet their median survival from recurrence was 8.2 months less. Conclusion: Symptomatic recurrence is associated with worse outcomes than asymptomatic recurrence, which cannot be explained by lead‐ or length‐time bias. Similar methods to account for these biases should be considered in studies of cancer surveillance. Shortening surveillance intervals might allow for detection of more recurrences in an asymptomatic phase.

Medication class enrichment analysis: a novel algorithm to analyze multiple pharmacologic exposures simultaneously using electronic health record data

Objective Observational studies analyzing multiple exposures simultaneously have been limited by difficulty distinguishing relevant results from chance associations due to poor specificity. Set-based methods have been successfully used in genomics to improve signal-to-noise ratio. We present and demonstrate medication class enrichment analysis (MCEA), a signal-to-noise enhancement algorithm for observational data inspired by set-based methods. Materials and Methods We used The Health Improvement Network database to study medications associated with Clostridium difficile infection (CDI). We performed case-control studies for each medication in The Health Improvement Network to obtain odds ratios (ORs) for association with CDI. We then calculated the association of each pharmacologic class with CDI using logistic regression and MCEA. We also performed simulation studies in which we assessed the sensitivity and specificity of logistic regression compared to MCEA for ORs 0.1-2.0. Results When analyzing pharmacologic classes using logistic regression, 47 of 110 pharmacologic classes were identified as associated with CDI. When analyzing pharmacologic classes using MCEA, only fluoroquinolones, a class of antibiotics with biologically confirmed causation, and heparin products were associated with CDI. In simulation, MCEA had superior specificity compared to logistic regression across all tested effect sizes and equal or better sensitivity for all effect sizes besides those close to null. Discussion Although these results demonstrate the promise of MCEA, additional studies that include inpatient administered medications are necessary for validation of the algorithm. Conclusions In clinical and simulation studies, MCEA demonstrated superior sensitivity and specificity for identifying pharmacologic classes associated with CDI compared to logistic regression.

Achalasia Patients Are at Nutritional Risk Regardless of Presenting Weight Category

BackgroundAchalasia is an esophageal motor disorder that leads to swallowing dysfunction and weight loss. Nutritional risk in achalasia patients is not well defined.AimsThe aims of this study were to define baseline body mass index (BMI), changes in weight, and nutritional risk over time in a large cohort of achalasia patients.MethodsThis was a retrospective cohort study of achalasia patients at a tertiary care center with documented BMI, symptom severity as per Eckardt score, and nutritional risk assessment as per the Malnutrition Universal Screening Tool, which considers BMI, degree of recent weight loss, and acuity of disease.ResultsAmong the 337 patients presenting for achalasia management, 179 had confirmed disease. Upon presentation 69.8% of patients were classified as overweight or obese. Using the Malnutrition Universal Screening Tool, we found 50% of patients to be at moderate or high risk for malnutrition at presentation. Eckardt score (OR 1.15, 95% CI 1.05–1.26), duration of disease (OR for each additional month 1.04, 95% CI 1.01–1.08), and female gender (OR 1.76, 95% CI 1.02–3.03) were independent predictors of increased risk for malnutrition. Nutrition risk score decreased after therapy in 93.3% of patients.ConclusionsDespite a high prevalence of overweight and obese status in achalasia patients, many are at risk of developing nutritional complications secondary to rapid weight loss. This risk frequently resolves post-treatment. Regardless of baseline BMI, we recommend all patients undergo nutritional assessment to identify high-risk patients who may benefit from dietary intervention and expedited therapy.