Serum Infliximab Concentrations Research Articles

Covering the Cover

Covering the Cover

Loss of Infliximab Into Feces Is Associated With Lack of Response to Therapy in Patients With Severe Ulcerative Colitis

It is not clear why some patients with ulcerative colitis (UC) do not respond to treatment with anti-tumor necrosis factor (TNF) agents, such as infliximab. It could be that some patients have high level of inflammation, with large quantities of TNF to be neutralized by the drug. We investigated whether loss of anti-TNF agents through ulcerated intestinal mucosa reduces the efficacy of these drugs in patients with severe UC. We collected fecal samples from 30 consecutive patients with moderate to severely active UC during the first 2 weeks of infliximab therapy at the University of Amsterdam hospital. Infliximab concentrations were measured in serum and supernatants of fecal samples using an enzyme-linked immunosorbent assay (Sanquin Biologicals Laboratory, Amsterdam, The Netherlands). Clinical and endoscopic responses were assessed 2 and 8 weeks and 3 months after treatment began. Infliximab was detected in 129 of 195 fecal samples (66%); the highest concentrations were measured in the first days after the first infusion. Patients that were clinical nonresponders at week 2 had significantly higher fecal concentrations of infliximab after the first day of treatment than patients with clinical responses (median concentration, 5.01 μg/mL in nonresponders vs 0.54 μg/mL in responders; P= .0047). We did not observe a correlation between fecal and serum concentrations of infliximab. Infliximab is lost into stools of patients with UC. High fecal concentrations of infliximab in the first days after therapy begins are associated with primary nonresponse. Additional studies are needed to determine how therapeutic antibodies are lost through the intestinal mucosa and how this process affects treatment response. Clinical trial ID: NL41310.018.12.

Changes in serum trough levels of infliximab during treatment intensification but not in anti-infliximab antibody detection are associated with clinical outcomes after therapeutic failure in Crohn's disease.

Intensification of the infliximab (IFX) regimen is recommended if the treatment effect is inadequate. However, the rationale for this is not well defined as the underlying mechanisms vary. The aim of this study was to explore the association between changes in serum IFX and anti-IFX antibodies (Abs) after IFX intensification and clinical outcomes. We performed a post hoc analysis of a randomized clinical trial including 42 Crohn's disease patients with IFX treatment failure, all treated with an intensified IFX regimen (5mg/kg every 4 week) for 12 weeks. Trough serum IFX and anti-IFX Ab concentrations were measured by a homogeneous mobility shift binding assay (HMSA) and a functional cell-based reporter gene assay (RGA) at treatment failure and the end of the trial. Twenty-one patients (50%) regained clinical response on the intensified IFX regimen. The increase in serum trough levels of IFX during treatment intensification was higher among responders than non-responders (RGA, 8.8 versus 3.0 μg/mL, p = 0.035; HMSA, 9.9 versus 4.7 μg/mL, p = 0.040), and differentiated patients by clinical outcome (RGA, area under receiver operating characteristic curve [AUC] 0.75 [0.53-0.97], p = 0.035; HMSA, AUC 0.74 [0.53-0.95], p = 0.042). All responders exhibited an IFX increase ≥2.6 μg/mL (sensitivity 100%, specificity 50%). Anti-IFX Abs detected by HMSA in 13 patients (32%) were often non-functional and became undetectable during IFX intensification. However, even functional anti-IFX Abs detected by RGA in six patients (15%) became undetectable. Increase in IFX levels following treatment intensification was associated with improved clinical outcomes, indicating insufficient drug levels in a subgroup of patients. Anti-IFX Abs may become undetectable during treatment intensification, suggesting lowered production or the formation of immune complexes.

Serum infliximab concentrations in psoriatic patients treated with infliximab: a systematic review.

The efficacy of infliximab is influenced by individual variability in its pharmacokinetics and pharmacodynamics. Serum infliximab concentrations could therefore be related to the efficacy and tolerance of infliximab, and assist adjustment of treatment. The aim of this systematic review was to assess the value of measuring serum infliximab concentrations in psoriatic patients. A bibliographic search was performed on MEDLINE, CENTRAL, EMBASE, LILACS for original studies on serum infliximab concentrations in psoriatic patients treated with infliximab. Ten articles were included, representing evaluation of serum infliximab concentrations in 733 patients. Predictive value of higher serum infliximab concentrations on long-term response maintenance was suggested in 3 studies. There was no information regarding the value of such measurements for adjustment of infliximab dosage. Trough serum infliximab concentrations that are at least detectable (>0.1 mg/L) at steady state (week 22) seem to be associated with maintaining a clinical response in the long term.

Detection of serum infliximab concentration for evaluation of treatment efficacy in inflammatory bowel disease

Detection of serum infliximab concentration for evaluation of treatment efficacy in inflammatory bowel disease

Patient factors that increase infliximab clearance and shorten half-life in inflammatory bowel disease: a population pharmacokinetic study.

Infliximab (IFX) is effective therapy for ulcerative colitis and Crohn's disease, but it may be associated with side effects and loss of response. One loss of response mechanism is increased IFX clearance (IFX-CL), resulting in short half-life and decreased troughs. Patients were recruited, and relevant demographic, clinical, and laboratory data were recorded. IFX serum concentrations and antibodies against IFX (ATI) were measured for therapeutic drug monitoring and modeled using NONMEM. There were 169 IFX concentrations (Crohn's disease = 73, ulcerative colitis = 92, and diagnosis undetermined = 4). Patient factors significantly associated with high IFX-CL were low albumin, high body weight, and the presence of ATI (P ≤ 0.001). Disease type did not affect IFX-CL. The typical IFX-CL was 0.381 L/d. ATI formation was associated with a 259% increase in IFX-CL. The estimated median IFX effective half-life was 5.6 ± 2.4 days. Patients with low weight are more likely to have low troughs because IFX CL is not linearly related to weight, but IFX dosing is weight-based (in mg/kg). Simulations investigating alternative dose strategies suggested that more reliably measurable concentrations over the dose interval were achieved when the dose interval was shortened than by increasing administered dose. IFX-CL is significantly influenced by patient factors, specifically, albumin, body weight, and ATI. There should be a decreasing IFX dose interval strategy, particularly for low albumin patients. Higher starting doses may benefit low body weight patients. Pharmacokinetic models and therapeutic drug monitoring may ensure that patients maintain measurable concentrations throughout dose intervals. Individualized dosing may improve outcomes for IFX-treated patients with Crohn's disease and ulcerative colitis.

Tailoring Treatment to the Individual Patient: Drug Monitoring

Understanding why drug concentrations vary between patients and which drug concentrations are associated with efficacy allow the development of rational treatment algorithms. Factors that affect the clearance of monoclonal antibodies include: (1) the presence of antidrug antibodies (increased clearance), (2) concomitant immunosuppression (decreased clearance), (3) increased serum CRP concentration (increased clearance), (4) decreased serum albumin concentration (increased clearance), (5) decreased body weight (increased clearance), and (6) increased fecal infliximab concentration (increased clearance). These factors can result in marked variability in drug clearance. Higher serum infliximab and adalimumab concentrations are associated with increased rates of clinical response and mucosal healing, and lower rates of colectomy. Treatment algorithms incorporate the following principles: (1) patients who have symptoms of active disease and in whom high concentrations of antibodies to infliximab or adalimumab are present should switch to another TNF antagonist, (2) patients who have symptoms of active disease and in whom there are low concentrations of infliximab or adalimumab should have dose intensification, and (3) patients who are negative for antidrug antibody and who have a therapeutic drug concentration should undergo evaluation to confirm the presence of active disease by endoscopy or radiology studies, and if active disease is confirmed, then these patients should discontinue anti-TNF therapy and switch to another class of medications or consider surgical options.

Prior response to infliximab and early serum drug concentrations predict effects of adalimumab in ulcerative colitis.

Data for adalimumab in ulcerative colitis after prior use of infliximab are scarce. To study adalimumab response rates and predictors of response in ulcerative colitis, including drug concentrations. In this single centre cohort study 73 UC patients, previously exposed to infliximab, were assessed for response to adalimumab at weeks 12 and 52. Serum samples prior to week 12 were available and included in multivariate analysis to predict response. Overall clinical response at week 12 and 52 were 75% and 52%, respectively. Adalimumab was continued without need for dose escalation throughout year 1 in 16 patients, 22 needed dose escalation and 35 discontinued treatment within 1year. Prior response to infliximab and early serum concentrations correlated with response. Receiver operator characteristic curve analysis yielded optimal adalimumab concentrations of 4.58μg/mL for week 12 and 7.0μg/mL for week 52. Independent predictors for response at week 12 were primary response to infliximab [odds ratio (OR) 8.33; 95% confidence interval (CI) 1.8-33.3; P=0.006] and an adalimumab concentration ≥4.58μg/mL at week 4 (OR 4.85; 95% CI 1.3-18.6; P=0.009). Positive predictors for week 52 response were primary response to infliximab (OR 5.2; 95% CI 1.14-23.8; P=0.034) and adalimumab concentration at week 4 of ≥7μg/mL (OR 3.56; 95% CI 1.17-10.79; P=0.025). Prior response to infliximab and high early adalimumab serum concentrations predict week 12 and year 1 responses to adalimumab in ulcerative colitis.

Factors Associated With Short- and Long-Term Outcomes of Therapy for Crohn’s Disease

Our post hoc analysis assessed the association of early (at weeks 26-30) clinical, endoscopic, biologic, and pharmacokinetic outcomes with corticosteroid-free remission at week 50 (CSFR50); CSFR50 was observed in 55.2% and 65.4% of patients treated with infliximab, alone or in combination with azathioprine, respectively. We analyzed data from 203 patients: 96 received infliximab monotherapy and 107 received combination therapy. Receiver operating characteristic analysis was used to set cut-off points for the week 30 trough serum infliximab concentration (SIC30) and percentage change, from baseline, in the C-reactive protein (CRP) level at week 26, to predict CSFR50. Univariate and multivariate procedures analyzed predictive parameters of CSFR50 (odds ratio [OR] and 95% confidence interval [CI]). Mucosal healing (MH, zero ulcers) and CRP normalization (<8.0 mg/L) also were assessed. Trough SIC30 was higher in patients with than without CSFR50. Patients given combination therapy had higher trough SIC30s than those given monotherapy. Median trough SIC30 was significantly higher in patients with than without CSFR50 among those on infliximab monotherapy (2.14 vs 0.80 μg/mL; P= .006), but not for those on combination therapy (3.56 vs 3.54 μg/mL; P=.31). In patients with increased baseline levels of CRP (n= 120), corticosteroid-free remission at week 26 (CSFR26) (OR, 4.09; 95% CI, 1.65-10.11), and trough SIC30s of 3.0 μg/mL or greater (OR, 3.20; 95% CI, 1.38-7.42) were associated significantly with CSFR50. In patients evaluable for MH (n= 123), trough SIC30s of 3.0 μg/mL or greater (OR, 3.34; 95% CI, 1.53-7.28) and CRP normalization (OR, 2.69; 95% CI, 1.10-6.54) were associated significantly with MH at week 26 (MH26). Furthermore, CSFR26 (OR, 4.43; 95% CI, 1.81-10.82) and MH26 (OR, 3.01; 95% CI, 1.33-6.81) were associated significantly with CSFR50. Trough SIC30 is associated positively with MH26; CSFR26 and MH26 are independent predictors of CSFR50. Trough SIC30 of 3.0 μg/mL or greater early during maintenance treatment is an important determinant of clinical and endoscopic Crohn's disease outcomes. ClinicalTrials.gov number, NCT00094458.

Association Between Serum Concentration of Infliximab and Efficacy in Adult Patients With Ulcerative Colitis

We analyzed data collected during the Active Ulcerative Colitis Trials (ACT-1 and ACT-2) to assess relationships between serum concentrations of infliximab and outcomes of adults with moderate-to-severe ulcerative colitis. We compared serum concentrations of infliximab with outcomes of 728 patients with moderately-to-severely active ulcerative colitis who participated in ACT-1 or ACT-2; efficacy data were collected at weeks 8, 30, and 54 (for ACT-1 only). Relationships between serum concentration of infliximab and efficacy outcomes were assessed using trend, logistic regression, and receiver operating characteristic curve analyses. We also evaluated factors that affected the relationship between exposure and response. Median serum concentrations of infliximab at weeks 8, 30, and/or 54 were significantly higher in patients with clinical response, mucosal healing, and/or clinical remission than in patients who did not meet these response criteria. There were statistically significant relationships between quartile of infliximab serum concentration and efficacy at these time points (P < .01). Infliximab therapy was effective for a smaller proportion of patients in the lowest quartile, and these patients had lower serum levels of albumin and a higher incidence of antibodies to infliximab than patients in other quartiles. Although the relationship between exposure to infliximab and response varied among patients, approximate serum concentrations of 41 μg/mL infliximab at week 8 of induction therapy and 3.7 μg/mL at steady-state during maintenance therapy produced optimal outcomes in patients. Serum concentrations of infliximab are associated with efficacy in patients with moderate-to-severe ulcerative colitis; however, complex factors determine the relationship between exposure to this drug and response. A prospective evaluation of the value of measuring serum concentrations of infliximab should be performed before these data can be included in patient management strategies. Clinicaltrials.gov numbers: NCT00036439 and NCT00096655.

Infliximab efficacy in rheumatoid arthritis after an inadequate response to etanercept or adalimumab: results of a target-driven active switch study

Objective:Evaluate efficacy of infliximab with response-driven dosing in patients with active RA.Research design and methods:Patients (n = 203) with active RA despite methotrexate + etanercept/adalimumab, participated in this active-infliximab-switch study. Infliximab 3 mg/kg was infused at Weeks 0, 2, 6, 14, and 22 with escalation to 5 or 7 mg/kg depending on EULAR response at Weeks 14 and 22. The primary endpoint was EULAR response at Week 10. Safety was assessed through Week 30. Infliximab levels and antibodies to infliximab (ATI) were measured at Weeks 0, 6, 14, and 26.Clinical trial registration:NCT 00714493, EudraCT 2007-003288-36.Results:Of 197 evaluable patients, 120/77 previously received etanercept/adalimumab. Baseline mean (SD) swollen and tender joint counts were 17.3 (10.54) and 30.2 (16.89), respectively; mean DAS28-ESR was 6.19 (0.981). At Week 10, 98 (49.7%; 95% CI: 42.6%, 56.9%) patients achieved EULAR response, with a significantly improved DAS28-ESR score (mean [SD] change −1.1 [1.15]; p < 0.001). EULAR response was achieved by 41.7%/62.3% of patients previously receiving etanercept/adalimumab (p = 0.006). At Week 26, 51.8% (95% CI: 44.6%, 58.9%) of patients achieved or maintained EULAR response. Infliximab dose was escalated in 100 patients, 52% of whom achieved EULAR response at Week 26. Median serum concentration levels at Week 26 showed that dose escalation helped EULAR non-responders achieve levels similar to or higher than the levels seen in responders. ATI were associated with lower serum concentrations of infliximab, consistent with lower efficacy rates among ATI-positive patients.Conclusion:Infliximab, in treat-to-target settings with individual dose escalation, demonstrated significant efficacy at Weeks 10 and 26 in patients switched to infliximab after inadequate response to etanercept/adalimumab. The observed efficacy indicated that the switch to infliximab and ability to increase dose in a targeted fashion were beneficial.Key limitations:Given the relatively short duration of study follow-up, these safety findings require confirmation in a longer-term study.

THU0164 Tnf-Alpha Bioactivity: A New Biomarker of Aspa Activity in Patients with Tnf-Alpha Blockers

BackgroundInfliximab is a chimeric monoclonal antibody targeting tumor necrosis factor alpha (TNFα) indicated in active axial sponsyloarthritis (aSpA).ObjectivesWe determine association between blood levels of infliximab, antibodies toward infliximab (ATI), TNFα,...

THU0166 Usefulness of the Acid Dissociation in Inmunogenicity Detection in Patients in Treatment with Anti-TNF Drugs

ObjectivesTo evaluate the application in clinical practice, of the acid dissociation in the patients' monitoring with subtherapeutic serum concentrations of infliximab (IFX), adalimumab (ADL) and etanercept (ETN), using an immmunoassay...

Mo1195 Impact of Perioperative Serum Infliximab Concentration on Surgical Site Infection in Patients With Inflammatory Bowel Diseases

Mo1195 Impact of Perioperative Serum Infliximab Concentration on Surgical Site Infection in Patients With Inflammatory Bowel Diseases

A prospective cohort study to determine the relationship between serum infliximab concentration and efficacy in patients with luminal Crohn's disease

Patients with Crohn's disease (CD) may experience disease relapse on maintenance infliximab. Anti-drug antibodies likely contribute to loss of response, and serum infliximab levels likely correlate with efficacy. To prospectively evaluate the relationship between trough serum infliximab concentration and disease activity. Adult patients (N = 327) with a diagnosis of CD who had received at least five consecutive infliximab infusions and who planned to receive at least two additional infusions were enrolled. The Crohn's Disease Activity Index (CDAI), serum infliximab, C-reactive protein (CRP) and antibodies-to-infliximab (ATI) were assessed at baseline, week 4 and week 8. Receiver operating characteristic (ROC) analysis examined the relationship between infliximab concentrations and disease activity. The mean CDAI score, which decreased 1.05 points between infusions, did not correlate with the mean change in trough infliximab concentration (+0.39 μg/mL; r = 0.099, P = 0.083), but was associated with the mean change in CRP concentration (r = 0.19, P < 0.001). Trough infliximab concentrations below 2.8-4.6 μg/mL best predicted a ≥ 70 point increase in the CDAI between infusions, and those below 2.7-2.8 μg/mL best predicted CRP >5 mg/mL at the second infusion. ATI at either visit decreased the proportion of patients with therapeutic infliximab trough levels compared with patients who were ATI negative (17.5% vs. 77.3% at visit 1 and 13.8% vs. 75.6% at visit 3; P < 0.001 for both comparisons). This prospective study confirms the relationship between trough infliximab concentrations, inflammation and antibodies-to-infliximab. Infliximab trough concentrations below 3 μg/mL may increase the likelihood of symptoms and inflammation (ClinicalTrials.gov identifier: NCT00676988).

P048 In vitro pancreas toxicity by azathioprine but not 6-mercaptopurine

BACKGROUND: The impact of perioperative use of anti-TNFα on post-operative complications such as infection and wound healing is controversial. There are few studies that reveal relationship between pre-operative serum anti-TNFα concentration and post-operative outcomes in inflammatory bowel diseases. Moreover, perioperative change in serum concentration of anti-TNFα remains to be defined. PURPOSE: The current study assessed perioperative change in serum infliximab concentration of inflammatory bowel diseases and its impact on post-operative surgical site infection (SSI). METHODS: This observation study enrolled 22 ulcerative colitis (UC) and 22 Crohn's disease (CD) patients between January 2010 and October 2013. Patients underwent bowel resections within 8 weeks of last infliximab infusion. Serum samples were collected just before and after surgery, infliximab concentration of each sample was determined by an enzyme-linked immunosorbent assay. The relationships between these concentrations and post-operative SSIs were evaluated. RESULTS: Pre-operative serum infliximab were detected in 12 UC patients (54.5%) and 19 CD patients (86.4%). In UC patients who were detected pre-operative serum infliximab (cut-off value<1.0μg/ dL), there was no significant change from mean pre-operative infliximab concentration (6.20±4.56μg/dL) to post-operative infliximab concentration (5.03±3.88μg/dL) (-18.9%, p= 0.45). On the other hand, in CD patients who were detected pre-operative serum infliximab, there was a significant reduction from pre-operative concentration (5.63±22.5μg/dL) to postoperative concentration (3.93±3.65μg/dL) (-30.2%, p<0.01). SSIs occurred in 4 (19.4%) UC and 6 (27.3%) CD patients. Among 12 UC patients with positive serum infliximab, 3 (25.0%) patients, and 4 of 19 (21.1%) patients in CD developed SSIs. There was no significant difference in the incidence of SSI compared to patients with negative serum infliximab of both patients (UC; 1/9, 10%, p=0.36) (CD; 2/3, 66.7%, P=0.099). Mean pre-operative serum infliximab concentrations with SSIs were 5.78±3.51μg/dL in UC patients and 6.01±4.23μg/ dL in CD patients, there was no significant differences compared with non-SSI groups (UC; 7.46±7.90μg/dL, P=0.93) (CD; 4.04±0.99μg/dL, P=0.76). In addition, no significant association was found between post-operative serum infliximab concentration and with or without SSI in both patients (UC; 4.17±7.60 vs 7.60±7.18μg/dL, p=0.52) (CD; 4.38±3.92 vs 2.26±1.86μg/dL, p=0.32). CONCLUSIONS: Serum infliximab concentrationwas significantly decreased during surgery in patients with CD but UC. However, there was no influence of perioperative serum infliximab concentration on SSI in patients with inflammatory bowel diseases.

Antidrug antibodies in psoriasis: a systematic review

Antidrug antibodies (ADAs) against biological agents may be clinically significant and potentially alter a biological drug's treatment efficacy. This systematic review aims to (i) determine the prevalence of ADAs against infliximab, etanercept, adalimumab and ustekinumab in patients with psoriasis; (ii) ascertain whether ADAs are associated with changes in drug efficacy; and (iii) explore the use of concomitant methotrexate to prevent ADA formation. Through a systematic search using Medline and Embase from 29 January 1950 to 29 March 2013, we identified 25 studies that met the inclusion criteria. Of 7969 patients with psoriasis, 950 tested positive for ADAs. Antibodies against infliximab, etanercept, adalimumab and ustekinumab were reported in 5·4-43·6%, 0-18·3%, 6-45% and 3·8-6% of patients, respectively. Anti-infliximab antibodies were associated with lower serum infliximab concentrations in three studies, and decreased treatment response in five studies. ADAs against etanercept were non-neutralizing and not associated with any apparent effects on clinical response. Antiadalimumab antibodies were associated with lower serum adalimumab concentrations in three of five studies, and reduced clinical efficacy in four studies. Two of six studies reported that antiustekinumab antibodies were associated with lower Psoriasis Area and Severity Index responses, and three ustekinumab studies noted that most of these antibodies were neutralizing. Although the use of concomitant methotrexate with biological agents to prevent ADA formation in other immune-mediated diseases is promising, their use in psoriasis is sparse. ADA development remains a challenge with biological therapies and therefore should be considered in patients with psoriasis who experience diminished treatment response.

Pharmacokinetics of Infliximab in Children with Moderate-to-Severe Ulcerative Colitis

To assess infliximab pharmacokinetics in pediatric ulcerative colitis (UC). This phase 3, randomized, open-label multicenter study enrolled 60 children (6-17 yr) with moderate-to-severely active UC (Mayo score, 6-12; endoscopic subscore, ≥2), despite conventional therapy. Patients received infliximab 5-mg/kg induction infusions at weeks 0, 2, and 6. Week 8 clinical responders (n = 45) were randomized to infliximab 5 mg/kg given every 8 weeks (q8w) through week 46 or every 12 weeks (q12w) through week 42. Patients losing response during maintenance infliximab were eligible to increase the dose (5→10 mg/kg) and/or shorten the dosing interval (q12w→q8w). Blood samples were collected for infliximab concentration and pharmacokinetic determinations. Infliximab pharmacokinetics were not influenced by age (6-11 yr versus 12-17 yr), baseline immunomodulator use, or the extent of UC. At week 8, higher serum infliximab concentrations (≥41.1 μg/mL) were associated with greater proportions of patients achieving efficacy endpoints (clinical response, 92.9%; mucosal healing, 92.9%; and clinical remission, 64.3%) versus those with lower serum concentrations (<18.1 μg/mL; 53.9%, 53.9%, and 30.8%, respectively). At week 30, higher median trough serum infliximab concentrations were observed with infliximab 5 mg/kg q8w (1.9 μg/mL) versus q12w (0.8 μg/mL) and with infliximab 10 mg/kg (2.9 μg/mL) versus 5 mg/kg (1.1 μg/mL) among patients who are regimen adjusted. Infliximab pharmacokinetics/exposure-response relationship in patients with UC aged 6 to 17 years were generally comparable with those observed in reference adult UC populations, supporting using infliximab 5 mg/kg at weeks 0, 2, and 6 followed by maintenance dosing with 5 mg/kg q8w in these patients. A positive relationship was noted between serum infliximab level and clinical effect following induction therapy similar to adults.

Serum concentrations of infliximab in patients with Behçet's disease

AbstractPurpose We investigated the relationship between the serum concentrations of infliximab (IFX), an anti‐tumor necrosis factor‐alpha monoclonal antibody, and its therapeutic effect in patients with Behçet's disease (BD) who were receiving IFX therapy.Methods Nine BD patients (7 males and 2 females) with uveitis who were receiving IFX therapy for 1 years or longer were included in this study. IFX (5‐6 mg/kg) was administered at weeks 0, 2, and 6 and thereafter every 8 weeks. After informed consent was obtained, peripheral blood samples were collected before the IFX infusion. The serum concentrations of IFX were measured by enzyme‐linked immunosorbent assay.Results In the 6 patients who did not develop any uveitis attacks, the mean serum concentration of IFX was 3.6‐13.5 μg/ml, while the mean concentration was &lt; 0.1‐1.58 μg/ml in three patients who had uveitis attacks. We speculate that the uveitis attacks occurred in the three patients because of the low IFX concentrations, and shortened the IFX administration interval from 8 weeks to 6 or 7 weeks. Thereafter, two of the three patients did not have any uveitis attacks. The serum concentration of IFX in the two patients was increased from 0.1 to 5.5 μg/ml and 0.2 to 3.6 μg/ml, respectively, whereas the concentration in one patient who had uveitis attacks was &lt;0.1 μg/ml, and the neutralizing antibody titre to IFX was negative. The serum concentration of IFX was correlated with its efficacy.Conclusion Measurement of IFX serum concentration is useful to predict treatment efficacy in BD patients.

Comprehensive review: antitumor necrosis factor agents in inflammatory bowel disease and factors implicated in treatment response.

Antitumor necrosis factor α (anti-TNF) agents have dramatically influenced management of refractory inflammatory bowel disease (IBD). However, not all patients respond to treatment and some lose response or become intolerant over time. Immunogenicity, a well established phenomenon with anti-TNF agents, may have important clinical implications in patients with IBD. A comprehensive review of available evidence demonstrating how drug concentrations, immunogenicity, and other factors influence outcomes with anti-TNF agents was performed. PubMed, EMBASE, Biosis, Dialog, and Conference Papers Index were searched from 1 January 1995 to 7 April 2012 to identify clinical trials in adult and pediatric patients with IBD treated with anti-TNF agents for Crohn's disease or ulcerative colitis. Data on serum drug levels and immunogenicity and their relationship with clinical efficacy and safety outcomes were extracted and examined. Serum infliximab concentrations correlated with clinical efficacy and treatment outcomes in patients with IBD; this relationship is less well characterized with adalimumab and certolizumab pegol concentrations. In multiple studies, the presence and level of antibodies to infliximab correlated with loss of clinical efficacy and increased risk of infusion reactions. The incidence and clinical impact of antibody formation with adalimumab or certolizumab in IBD is becoming evident as more data become available. Current, enzyme-linked immunosorbent assay based anti-TNF antibody assays are suboptimal in that results are often inconclusive and comparisons between agents cannot be made. Measurement of anti-TNF agent drug concentrations and assessment of immunogenicity has the potential to positively impact clinical decision making during anti-TNF therapy for IBD. As assays are optimized, it is expected that the clinical impact of these determinations will be better characterized.