Appropriate Therapeutic Drug Monitoring of Biologic Agents for Patients With Inflammatory Bowel Diseases.

BACKGROUND & AIMS: Therapeutic drug monitoring (TDM) is widely available for biologic therapies in patients with inflammatory bowel disease (IBD). We reviewed current data and provided expert opinion regarding the clinical utility of TDM for biologic therapies in IBD. METHODS: We used a modified Delphi method to establish consensus. A comprehensive literature review was performed regarding the use of TDM of biologic therapy in IBD and presented to international IBD specialists. Subsequently, 28 statements on the application of TDM in clinical practice were rated on a scale of 1 to 10 (1 = strongly disagree and 10 = strongly agree) by each of the panellists. Statements were accepted if 80% or more of the participants agreed with a score ≥7. The remaining statements were discussed and revised based on the available evidence followed by a second round of voting. RESULTS: The panel agreed on 24 (86%) statements. For anti-tumor necrosis factor (anti-TNF) therapies, proactive TDM was found to be appropriate after induction and at least once during maintenance therapy, but this was not the case for the other biologics. Reactive TDM was appropriate for all agents both for primary non-response and secondary loss of response. The panellists also agreed on several statements regarding TDM and appropriate drug and anti-drug antibody (ADA) concentration thresholds for biologics in specific clinical scenarios. CONCLUSION: Consensus was achieved towards the utility of TDM of biologics in IBD, particularly anti-TNF therapies. More data are needed especially on non-anti-TNF biologics to further define optimal drug concentration and ADA thresholds as these can vary depending on the therapeutic outcomes assessed.

Appropriateness of Combination Therapy for Patients With Inflammatory Bowel Diseases: One Size Still Does Not Fit All.

Randomized controlled trials (RCTs) have demonstrated that therapies targeting tumor necrosis factor (TNF) and α4ß7 integrin are effective when given as monotherapy in inducing and/or maintaining remission in patients with ulcerative colitis (UC) or Crohn's disease (CD), but data from RCTs are less clear on whether concomitant immunomodulator (IM) therapy confers additional benefit. In CD, RCT data are mixed,1,2 as are results of systematic reviews and meta-analyses, showing no benefit overall,3 minimal benefit with individual agents,4 and comparative benefit over some monotherapies but not others.5 For example, concomitant azathioprine with infliximab is more effective than either drug alone in patients with CD naive to both drugs,2 but whether combination therapy is more effective than monotherapy with infliximab in nonnaive patients, or with other approved biologic drugs in any population, remains unknown. In UC, RCTs have shown that the benefit may be limited to specific populations,6 whereas systematic reviews suggest no benefit at all.7.

A Pleiotropic Missense Variant in SLC39A8 Is Associated With Crohn's Disease and Human Gut Microbiome Composition.

BACKGROUND & AIMS: Genome-wide association studies have identified 200 inflammatory bowel disease (IBD) loci, but the genetic architecture of Crohn's disease (CD) and ulcerative colitis remain incompletely defined. Here, we aimed to identify novel associations between IBD and functional genetic variants using the Illumina ExomeChip (San Diego, CA). METHODS: Genotyping was performed in 10,523 IBD cases and 5726 non-IBD controls. There were 91,713 functional single-nucleotide polymorphism loci in coding regions analyzed. A novel identified association was replicated further in 2 independent cohorts. We further examined the association of the identified single-nucleotide polymorphism with microbiota from 338 mucosal lavage samples in the Mucosal Luminal Interface cohort measured using 16S sequencing. RESULTS: We identified an association between CD and a missense variant encoding alanine or threonine at position 391 in the zinc transporter solute carrier family 39, member 8 protein (SLC39A8 alanine 391 threonine, rs13107325) and replicated the association with CD in 2 replication cohorts (combined meta-analysis P = 5.55 × 10(-13)). This variant has been associated previously with distinct phenotypes including obesity, lipid levels, blood pressure, and schizophrenia. We subsequently determined that the CD risk allele was associated with altered colonic mucosal microbiome composition in both healthy controls (P = .009) and CD cases (P = .0009). Moreover, microbes depleted in healthy carriers strongly overlap with those reduced in CD patients (P = 9.24 × 10(-16)) and overweight individuals (P = 6.73 × 10(-16)). CONCLUSIONS: Our results suggest that an SLC39A8-dependent shift in the gut microbiome could explain its pleiotropic effects on multiple complex diseases including CD.

Appropriateness of Testing for Anti-Tumor Necrosis Factor Agent and Antibody Concentrations, and Interpretation of Results.

BACKGROUND & AIMS: The availability of tests for blood concentrations of anti-tumor necrosis factor (TNF) agents and antibodies against these drugs could improve dose selection for patients with inflammatory bowel disease (IBD). However, there is little consensus on when to test and how to interpret test results. We used the RAND/UCLA Appropriateness Method to determine when these tests are appropriate and how to clinically interpret their results. METHODS: We conducted a systematic literature search in November 2013 to identify observational or experimental studies of the measurement of anti-TNF drug and antibody concentrations in patients with IBD and interpretation of their results. We developed 35 scenarios that assessed the appropriateness of testing and 143 scenarios that addressed clinical strategies in response to test results, and presented the findings to an expert panel. The appropriateness of each scenario was rated before and after an in-person meeting with the panel. Panelists rated the appropriateness of various clinical management options including changing therapy within class, switching out of class, adjusting drug dose or interval, adding or adjusting concomitant immune modulators, and doing nothing for each of 6 permutations of high versus low drug concentrations and high, low, or undetectable antibody concentrations. Disagreement was assessed using a validated index. RESULTS: Assessment of anti-TNF drug and antibody concentrations was rated appropriate at the end of induction therapy in primary nonresponders, in secondary nonresponders, at least once during the first year of maintenance therapy, and following a drug holiday. Routine assessment in responders at the end of induction was rated uncertain. In nearly all scenarios, escalation of drug dosing was rated appropriate when drug concentration was low in the absence of antibodies, and switching within class was rated appropriate when antibodies were present. Other recommendations depended on the specific clinical scenario for which the test was obtained. CONCLUSIONS: Based on the RAND/UCLA Appropriateness Method of analysis, an expert panel recommends testing for drug and antibody concentrations in many clinical scenarios. The appropriate timing and best way to respond to anti-TNF drug and antibody testing for IBD depends on the specific clinical scenario. These recommendations can help guide clinicians to best optimize anti-TNF therapy.

Recommendations for Quality Colonoscopy Reporting for Patients with Inflammatory Bowel Disease: Results from a RAND Appropriateness Panel.

BACKGROUND: Consensus on what constitutes a quality colonoscopy report for patients with inflammatory bowel disease (IBD) is lacking. We developed a template for quality colonoscopy reporting that can be used broadly by endoscopists. METHODS: After a literature review of topics relevant to colonoscopy reporting, members of the Building Research in Inflammatory Bowel Disease Globally (BRIDGe) group and 2 external experts proposed candidate reporting elements. The RAND/University of California, Los Angeles appropriateness method was applied to rate the importance and feasibility of elements for inclusion in colonoscopy reports for patients with IBD. Panelists used the modified Delphi method to anonymously rate the importance and feasibility of candidate elements on a 1-to-9 scale (1-3: not important/feasible, 4-6: moderately important/feasible, 7-9: very important/feasible). Disagreement was assessed using a validated index. The panelists then met in person for discussion followed by a second round of voting. Elements rated a median of 7 or higher on importance after rerating were retained. RESULTS: One hundred two reporting elements were proposed. A total of 48 elements were retained across the four themes of "disease background," "findings and interventions," "Crohn's disease with an ileocolonic anastomosis," and "pouchoscopy." CONCLUSIONS: A comprehensive list of recommended elements for quality IBD colonoscopy reporting stratified by clinical scenario has been described, using a rigorous and evidence-based approach. These elements can be incorporated into endoscopy reporting software platforms. Standardized endoscopy reporting may improve the quality of care in IBD.

Correlation of anemia status with worsening bowel damage as measured by Lémann Index in patients with Crohn's disease.

BACKGROUND: There is evidence that anemia in Crohn's disease (CD) is a predictor of disease severity. AIM: To evaluate if patterns of anemia over time showed correlation with aggressive disease trajectory, as characterized by change in Lémann Index (LI), which is a metric that quantifies bowel damage. METHODS: CD patients with 5 year (y) follow-up from a prospective registry were included. LI was calculated from the first (LI1) and last (LI2) clinical encounters. The change in score (LI2-LI1) or the Delta LI (DLI) was recorded. Patterns of anemia, healthcare utilization and disease activity scores were analyzed. RESULTS: A total of 389 CD patients with 5y follow-up formed the study population [median age 40y (IQR: 31-53); 57.3% female; median disease duration 12y (IQR: 6-20.5), overall surgical exposure 69%]. Patients with anemia had significantly higher LI1, LI2, DLI and also significantly higher healthcare utilization and indices of disease activity, than patients without anemia (p<0.001). CD patients with anemia for any duration during the study had OR of 2.15 (95% CI 1.29-3.57, p=0.003) for worsening bowel damage over the 5y. CONCLUSION: Based on a longitudinal analysis of CD patients, anemia status over time shows significant correlation with increasing Lémann index and aggressive disease trajectory.

Association of Vitamin D Level With Clinical Status in Inflammatory Bowel Disease: A 5-Year Longitudinal Study.

OBJECTIVES: Emerging data suggest that vitamin D has a significant role in inflammatory bowel disease (IBD). Prospective data evaluating the association of vitamin D serum status and disease course are lacking. We sought to determine the relationship between vitamin D status and clinical course of IBD over a multiyear time period. METHODS: IBD patients with up to 5-year follow-up from a longitudinal IBD natural history registry were included. Patients were categorized according to their mean serum 25-OH vitamin D level. IBD clinical status was approximated with patterns of medication use, health-care utilization, biochemical markers of inflammation (C-reactive protein (CRP) and erythrocyte sedimentation rate (ESR)), pain and clinical disease activity scores, and health-related quality of life. RESULTS: A total of 965 IBD patients (61.9% Crohn's disease, 38.1% ulcerative colitis) formed the study population (mean age 44 years, 52.3% female). Among them, 29.9% had low mean vitamin D levels. Over the 5-year study period, subjects with low mean vitamin D required significantly more steroids, biologics, narcotics, computed tomography scans, emergency department visits, hospital admissions, and surgery compared with subjects with normal mean vitamin D levels (P<0.05). Moreover, subjects with low vitamin D levels had worse pain, disease activity scores, and quality of life (P<0.05). Finally, subjects who received vitamin D supplements had a significant reduction in their health-care utilization. CONCLUSIONS: Low vitamin D levels are common in IBD patients and are associated with higher morbidity and disease severity, signifying the potential importance of vitamin D monitoring and treatment.

Demographic and Clinical Predictors of High Healthcare Use in Patients with Inflammatory Bowel Disease.

BACKGROUND: Inflammatory bowel disease (IBD) is a heterogeneous chronic inflammatory condition requiring significant healthcare expenditure. Subgroups of individuals contribute disproportionately to spending. We aimed to determine demographic and clinical factors predictive of high healthcare expenditures for IBD patients followed over a multiyear period. METHODS: This was a registry analysis using a prospective observational, consented, natural history registry from a tertiary IBD center and associated medical charges, not including pharmacy expenses. The 100 patients with the highest medical charges (top 5%) were compared with the median 300 patients. Logistic regression determined demographic and clinical factors associated with high charge patients. RESULTS: IBD patients in the high charge group had significantly more unemployment (P < 0.0001), were of black race (P = 0.013), comorbid psychiatric illness (P = 0.002), hypertension (P = 0.01), diabetes (P = 0.004), opiate use (P < 0.0001), perianal involvement (P = 0.002), penetrating disease (P < 0.0001), and extensive colitis (P = 0.01). In multivariate analysis, unemployment (Crohn's disease [CD]: odds ratio [OR], 3.04; 95% confidence interval [CI], 1.32-7.02; ulcerative colitis [UC]: OR, 2.68; 95% CI, 1.20-5.99), psychiatric illness (UC: OR, 2.08; 95% CI, 1.03-4.19), opiates (CD: OR, 5.61; 95% CI, 2.67-11.82; UC: OR, 5.14; 95% CI, 2.52-10.48), prior surgery (CD: OR, 3.29; 95% CI, 1.59-6.82; UC: OR, 2.72; 95% CI, 1.39-5.32), penetrating CD (OR, 3.29; 95% CI, 1.02-10.62), and corticosteroid requirement (CD: OR, 3.78; 95% CI, 1.86-7.65; UC: OR, 2.98; 95% CI, 1.51-5.90) remained independently associated with high charges. CONCLUSIONS: High expenditure IBD patients were affected by more severe disease. The high prevalence of depression, anxiety, and chronic pain in these patients suggests the need for focused treatment of these comorbidities ultimately to reduce financial burden.

Five-Year Period Prevalence and Characteristics of Anemia in a Large US Inflammatory Bowel Disease Cohort.

BACKGROUND: Anemia is a common manifestation of inflammatory bowel disease (IBD), but its prevalence in the United States is not well defined. Aim of this study was to determine the prevalence and characteristics of anemia in IBD patients who were followed in a US referral center. MATERIALS AND METHODS: Demographic, clinical, laboratory, and treatment data from a prospective, consented longitudinal IBD registry between the years 2009 and 2013 were analyzed. Disease activity was evaluated using Harvey-Bradshaw index in Crohn's disease (CD) and ulcerative colitis (UC) activity index in UC as well as C-reactive protein and erythrocyte sedimentation rate. Anemia was defined based on the World Health Organization criteria. RESULTS: A total of 1821 IBD patients (1077 with CD, 744 with UC, median age 43.8 y, 51.9% female) were included. The 5-year period prevalence of anemia in IBD patients was 50.1%, (CD: 53.3% vs. UC: 44.7%, P=0.001). In multivariate logistic regression analysis, anemia was associated with surgery for IBD [odds ratio (OR)=2.77; 95% confidence interval (CI), 2.21-3.48; P<0.0001], female gender (OR=1.29; 95% CI, 1.04-1.61; P=0.02), C-reactive protein (OR=1.26; 95% CI, 1.16-1.37; P<0.0001), erythrocyte sedimentation rate (OR=1.02; 95% CI, 1.01-1.03; P=0.0002), and use of biologics (OR=2.00; 95% CI, 1.58-2.52; P=0.0001) or immunomodulators (OR=1.51; 95% CI, 1.21-1.87; P=0.0003). Iron replacement therapy was administered to 46.8% of the anemic patients. CONCLUSION: Anemia has a high period prevalence in IBD patients followed at a tertiary center. Anemia is more common in CD than in UC, is associated with disease activity, and in current practice is undertreated.

Association Between Long-Term Lipid Profiles and Disease Severity in a Large Cohort of Patients with Inflammatory Bowel Disease.

BACKGROUND: Inflammatory bowel disease (IBD) has been linked to an increased risk of coronary heart disease and stroke. Dyslipidemia is a well-established risk factor for cardiovascular disease. The aim of this study was to investigate the long-term lipid profiles in a large cohort of IBD patients. METHODS: Data of patients from an IBD registry who had more than one measurement of total cholesterol and triglyceride levels during the follow-up period were analyzed. The lipid profiles of IBD patients were compared to those of the general population according to National Health and Nutrition Examination Survey (2009-2012). Quartiles of cholesterol or triglyceride levels in relation to surrogate markers of disease severity were analyzed. RESULTS: Seven hundred and one IBD patients [54% Crohn's disease (CD), 46% ulcerative colitis (UC)] were included. IBD patients had less frequent high total cholesterol and high LDL cholesterol (6 vs. 13 and 5 vs. 10%) and more frequent low HDL and high triglycerides (24 vs. 17 and 33 vs. 25%) compared to the general population (all p < 0.001). Median total cholesterol levels were lower and median triglycerides higher in CD compared to UC (171 vs. 184; 123 vs. 100 mg/dL; both p < 0.001). In the multiple regression analysis, lipid profile was independently associated with hospitalizations (low cholesterol) and IBD surgeries (low cholesterol and high triglycerides). CONCLUSIONS: Low total cholesterol and high triglyceride levels are more frequent in IBD patients (in particular CD) compared to healthy controls and are independently associated with more severe disease.

Delineation of Crohn's Disease Trajectories Using Change in Lémann Index: A Natural History Study.

BACKGROUND: Crohn's disease (CD) causes lifelong, progressive bowel damage, which may be quantified using the Lémann Index (LI). We aimed to analyze patterns of LI and its association with 5-year clinical course, in an independent cohort of CD patients. METHODS: CD patients with 5-year follow-up from a registry maintained at a tertiary center were included. LI was calculated using a computerized metric from the first (LI1) and last (LI2) clinical encounters during the 5 years. Groups were created based on change in score (LI2-LI1) or the delta Lémann Index (DLI) as showing improvement, no change, or deterioration and used for association analysis with patterns of health care utilization, disease activity, and quality-of-life scores. RESULTS: A total of 363 CD patients with 5-year follow-up formed the study population [median age 43 y (interquartile range (IQR), 33.3 to 55 y); 57% female; median disease duration 12 y (IQR, 3 to 19 y), overall surgical exposure 69.7%]. Median (IQR) LI1, LI2, and DLI were 8 (0 to 54), 9 (0 to 75), and 0 (-22 to -47), respectively. Patients were stratified based on DLI into 3 groups: A: DLI<0; B: DLI=0; and C: DLI>0; which comprised 16.5%, 35.3%, and 48.2% of the cohort, respectively. Patients in group C had significantly higher CD-related surgical exposure, health care utilization, and annual use of steroids and biological agents. DLI showed independent significant positive correlation with perianal disease (P=0.044), steroid use (P=0.007), clinical visits (P<0.001), and new surgeries (P=0.001). CONCLUSIONS: Change in LI over time could function as a marker of disease trajectory for risk substratification and prognostication in CD.

Multiyear Patterns of Serum Inflammatory Biomarkers and Risk of Colorectal Neoplasia in Patients with Ulcerative Colitis.

BACKGROUND: Patients with ulcerative colitis (UC) are at increased risk of colorectal neoplasia (CRN) presumably because of chronic inflammation. Data on the relationship between long-term serum inflammatory biomarkers and the development of CRN in UC are limited. METHODS: We performed a 5-year study (2009-2013) of demographic, clinical, laboratory, and treatment data of patients with UC from an inflammatory bowel disease registry in relation to the development of CRN. Disease activity was evaluated by UC activity index and by serum biomarkers such as C-reactive protein (CRP), erythrocyte sedimentation rate, hemoglobin, platelets, and albumin levels. A score based on the combination of median CRP and median albumin levels (0: both normal, 1: one of them abnormal, 2: both abnormal) was also evaluated. RESULTS: A total of 773 patients with UC (median age 46 yr, 46.4% women) were included. Fifty-five patients (7.1%) developed CRN. Patients with UC and CRN had significantly higher median CRP, erythrocyte sedimentation rate, and platelets and lower hemoglobin and albumin levels compared with those without CRN. The prevalence of a CRP-albumin score (1 or 2) was significantly higher in the CRN group (40.0% or 30.9% versus 14.2% or 6.0%, respectively, P < 0.0001). In the multivariate logistic regression analysis, CRN was associated with male gender (P = 0.01), disease duration (P = 0.04), extensive colitis (P = 0.03), concomitant primary sclerosing cholangitis (P = 0.0003), median albumin levels (P = 0.03), and an increased CRP-albumin score (score 1 or 2) (P = 0.0002). CONCLUSIONS: Long-term serum inflammatory markers including the CRP-albumin score are associated with increased risk of CRN in patients with UC.

Impact of Obesity on the Management and Clinical Course of Patients with Inflammatory Bowel Disease.

BACKGROUND: Obesity has been linked with a proinflammatory state and the development of inflammatory diseases. Data on the clinical course and treatment of obese patients with inflammatory bowel disease (IBD) are limited. We used an institutional IBD registry to investigate the impact of obesity on IBD severity and treatment. METHODS: This was a retrospective analysis of prospectively collected data for 3 years (2009-2011). Patients with IBD were categorized by body mass index (BMI). IBD-related quality of life, biochemical markers of inflammation, comorbidities, health care utilization, and treatment were characterized. Obesity was defined as a BMI ≥30 (type I: 30-34.9, type II: 35-39.9, and type III ≥40). RESULTS: Among 1494 patients with IBD, 71.9% were above their ideal BMI and 31.5% were obese. Obesity was more common in ulcerative colitis compared with patients with Crohn's disease (P = 0.04). Obese class II and class III patients were predominantly female. Obesity in IBD was associated with female gender (P < 0.0001), diabetes mellitus (P < 0.001), hypertension (P < 0.001), hyperlipidemia (P < 0.001), poor quality of life (P < 0.0001), and increased rates of C-reactive protein elevation (P = 0.008). In logistic regression analysis, quality of life and C-reactive protein elevation were not independently correlated with obesity. There was no association between increasing BMI and annual prednisone use, emergency department visits, hospitalization, and surgery. Obesity was associated with lower milligrams per kilogram doses of purine analogs and biologics. CONCLUSIONS: Obesity in IBD is not associated with increased health care utilization and IBD-related surgeries. Optimal regimens for drug dosing in obese patients with IBD have yet to be defined.

Patterns of Antibiotic Exposure and Clinical Disease Activity in Inflammatory Bowel Disease: A 4-year Prospective Study.

BACKGROUND: Antimicrobial treatment is known to cause short- and long-term changes in the composition of normal human microbiota. The relationship between antibiotic use and overall clinical behavior in inflammatory bowel disease (IBD) has not been explored. We aim to prospectively characterize patterns of antibiotic use and clinical IBD activity in a large IBD cohort. METHODS: Prospective observational study from a longitudinal IBD natural history registry between 2009 and 2012. Antibiotic prescriptions were identified and categorized using electronic medical record data. Cumulative rates over the 4-year study period were compared. Demographic, clinical, laboratory, health care utilization, and treatment data of the patients with IBD were collected and analyzed. Quality of life was measured by Short IBD Questionnaire data. Primary outcomes were markers of disease activity including Short IBD Questionnaire scores, C-reactive protein levels, health care utilization, and medication use. RESULTS: Seven hundred eighteen patients followed over 4 years were included (47.6% male; mean age, 46.7 ± 15.2 yr), 59.9% had Crohn's disease, whereas 38.6% had ulcerative colitis. Most patients (66.3%) were exposed to antibiotics during the study period. Antibiotic-exposed patients were more likely to have Crohn's disease (63% versus 53.7%; P = 0.05), require narcotics (43.7% versus 14.9%; P < 0.0001), receive antidepressants (43.1% versus 18.6%; P < 0.001), prednisone (52.7% versus 31%; P < 0.0001), or biological therapy (52% versus 36.5%; P < 0.0001). Antibiotic-exposed patients had a lower mean Short IBD Questionnaire (50.2 ± 11.5 versus 56.4 ± 9.5; P < 0.0001), higher rates of C-reactive protein elevation (49.2% versus 31.8%; P < 0.0001), and higher health care utilization compared with nonantibiotic-exposed patients. CONCLUSIONS: The majority of patients with IBD receive antibiotic treatment, and these individuals demonstrate a more severe clinical course.

Effects of Concomitant Immunomodulator Therapy on Efficacy and Safety of Anti-Tumor Necrosis Factor Therapy for Crohn's Disease: A Meta-analysis of Placebo-controlled Trials.

BACKGROUND & AIMS: There is debate over whether patients with Crohn's disease who start anti-tumor necrosis factor (TNF) therapy after failed immunomodulator therapy should continue to receive concomitant immunomodulators. We conducted a meta-analysis of subgroups from randomized controlled trials (RCTs) of anti-TNF agents to compare the efficacy and safety of concomitant immunomodulator therapy vs anti-TNF monotherapy. METHODS: We performed a systematic review of literature published from 1980 through 2008 and identified 11 RCTs of anti-TNF agents in patients with luminal or fistulizing Crohn's disease. We excluded RCTs of patients who were naive to anti-TNF and immunomodulator therapy. The primary end points were clinical response at weeks 4-14 and 24-30 and remission at weeks 24-30. Secondary end points included infusion site or injection site reactions and selected adverse events. A priori subgroup analyses were performed to evaluate fistula closure and the efficacy and safety of combination therapy with different anti-TNF agents. RESULTS: Overall, combination therapy was no more effective than monotherapy in inducing 6-month remission (odds ratio [OR], 1.02; 95% confidence interval [CI], 0.80-1.31), inducing a response (OR, 1.08; 95% CI, 0.79-1.48), maintaining a response (OR, 1.53; 95% CI, 0.67-3.49), or inducing partial (OR, 1.25; 95% CI, 0.84-1.88) or complete fistula closure (OR, 1.10; 95% CI, 0.68-1.78). In subgroup analyses of individual anti-TNF agents, combination therapy was not more effective than monotherapy in inducing 6-month remission in those treated with infliximab (OR, 1.73; 95% CI, 0.97-3.07), adalimumab (OR, 0.88; 95% CI, 0.58-1.35), or certolizumab (OR, 0.93; 95% CI, 0.65-1.34). Overall, combination therapy was not associated with an increase in adverse events, but inclusion of infliximab was associated with fewer injection site reactions (OR, 0.46; 95% CI, 0.26-0.79.) CONCLUSIONS: On the basis of a meta-analysis, continued use of immunomodulator therapy after starting anti-TNF therapy is no more effective than anti-TNF monotherapy in inducing or maintaining response or remission. RCTs are needed to adequately assess the efficacy of continued immunomodulator therapy after anti-TNF therapy is initiated.