Anti-tumor Necrosis Factor Treatment Research Articles

Optimizing Antitumor Necrosis Factor Treatment in Pediatric Inflammatory Bowel Disease With Therapeutic Drug Monitoring.

Biological agents have revolutionized inflammatory bowel disease treatment but primary nonresponse and secondary loss of response are common with resulting adverse outcomes. Clinical trials demonstrated an association between serum drug concentrations, as well as the presence of antidrug antibodies, and loss-of-response. Therapeutic drug monitoring (TDM), defined as the evaluation of drug concentrations and antidrug antibodies, is appearing as a strategy to optimize treatment and take full advantage from these drugs. TDM appears to be a promising tool in clinical practice, especially in pediatric patients, who have pronounced fluctuations in the pharmacokinetics of the drugs.The authors present a literature review about antitumor necrosis factor therapy optimization based on personalized treatment strategies according to TDM and possible strategies to recapture loss of response, including an algorithm for practical management.

Pharmacogenetics of antitumor necrosis factor therapy in severe sarcoidosis.

Antitumor necrosis factor (TNF) treatment is an effective third-line treatment option in severe sarcoidosis. But not all patients respond to treatment. Pharmacogenetics studies the influence of genetic variations on treatment response. In sarcoidosis, only one study reported on a relationship between genetic variation in TNF and response to anti-TNF therapy. In immune-mediated inflammatory diseases (IMIDs) other than sarcoidosis, several genetic variants were associated with response to anti-TNF therapy. Genes related to TNF, the target of this group of drugs, and the pathway by which TNF exerts its effect, TNF receptor, were studied most extensively. Recent findings related genetic variations in the human leukocyte antigen region to development of antidrug antibodies.We also included new original data on genetic variations and response to anti-TNF therapy in severe sarcoidosis. We found that TNFRSF1A rs1800693 AA genotype, TNFRSF1B 196T and absence of HLA-DRB103 associate with better response after infliximab treatment in severe sarcoidosis. Data on pharmacogenetics of anti-TNF therapy in severe sarcoidosis are scarce. Findings in other IMIDs indicate there may be a role for pharmacogenetics in predicting response and adverse events in anti-TNF therapy, also in sarcoidosis. Future studies are needed to evaluate pharmacogenetics as a predicting marker in anti-TNF therapy in sarcoidosis.

Involvement of Tumor Necrosis Factor Receptor Type II in FoxP3 Stability and as a Marker of Treg Cells Specifically Expanded by Anti-Tumor Necrosis Factor Treatments in Rheumatoid Arthritis.

To study the involvement of Treg cells expressing tumor necrosis factor receptor type II (TNFRII) in exerting control of inflammation in experimental models and in the response to anti-TNF treatments in patients with rheumatoid arthritis (RA) or spondyloarthritis (SpA). The role of TNFRII in Treg cells was explored using a multilevel translational approach. Treg cell stability was evaluated by analyzing the methylation status of the Foxp3 locus using bisulfite sequencing. Two models of inflammation (imiquimod-induced skin inflammation and delayed-type hypersensitivity arthritis [DTHA]) were induced in TNFRII-/- mice, with or without transfer of purified CD4+CD25+ cells from wild-type (WT) mice. In patients with RA and those with SpA, the evolution of the TNFRII+ Treg cell population before and after targeted treatment was monitored. Foxp3 gene methylation in Treg cells was greater in TNFRII-/- mice than in WT mice (50% versus 36.7%). In cultured Treg cells, TNF enhanced the expression, maintenance, and proliferation of Foxp3 through TNFRII signaling. Imiquimod-induced skin inflammation and DTHA were aggravated in TNFRII-/- mice (P < 0.05 for mice with skin inflammation and P < 0.0001 for mice with ankle swelling during DTHA compared to WT mice). Adoptive transfer of WT mouse Treg cells into TNFRII-/- mice prevented aggravation of arthritis. In patients with RA receiving anti-TNF treatments, but not those receiving tocilizumab, the frequency of TNFRII+ Treg cells was increased at 3 months of treatment compared to baseline (mean ± SEM 65.2 ± 3.1% versus 49.1 ± 5.5%; P < 0.01). In contrast, in anti-TNF-treated patients with SpA, the frequency of TNFRII+ Treg cells was not modified. TNFRII expression identifies a subset of Treg cells that are characterized by stable expression of Foxp3 via gene hypomethylation, and adoptive transfer of TNFRII-expressing Treg cells ameliorates inflammation in experimental models. Expansion and activation of TNFRII+ Treg cells may be one of the mechanisms by which anti-TNF agents control inflammation in RA, but not in SpA.

Adherence to Subcutaneous Anti-TNF Treatment in Chronic Inflammatory Rheumatism and Therapeutic Patient Education.

ObjectivePoor patient adherence to anti-TNF treatment has proven to be a major roadblock to effective management. Therapeutic patient education (TPE) is now recognized as a crucial tool in managing conditions like chronic inflammatory rheumatism and in improving treatment adherence. This study aimed to assess whether different TPE programs might improve adherence to subcutaneous anti-tumor necrosis factor (anti-TNF) treatment in patients with rheumatoid arthritis (RA), ankylosing spondyloarthritis (AS), and psoriatic arthritis (PsA).MethodsThis was a retrospective, observational, monocentric study of current care practices. We included 193 patients (124 women; mean age 53.3 ± 14.8 years). All patients received subcutaneous anti-TNF treatment and one of three TPE models, delivered by a nurse, from 2009 to 2013. The cohort was grouped according to different educational models: M1: information (N=92); M2: individual TPE (N=80); and M3: individual and group TPE sessions (N=21). Adherence was assessed with the Morisky Medication Adherence Scale (MMAS-4™). Scores were rated as follows: good adherence (MMAS-4 = 4), moderate adherence (MMAS-4 = 2–3), and poor adherence (MMAS-4 = 0–1).ResultsThe mean disease duration was 10 years [95% CI: 5 to 18]. The cohort comprised 113 patients with RA, 73 with AS, and seven with PsA. Overall, 146 (75.7%) patients displayed good adherence, 34 (17.6%) displayed moderate adherence, and 13 (6.7%) displayed poor adherence. The M3 group displayed less adherence than the M1 and M2 groups. Old age was the only factor correlated with good adherence (p=0.005). The level of knowledge had no significant impact on adherence.ConclusionThis study demonstrated good adherence to anti-TNF treatment in patients that received TPE, particularly when it was delivered in individual sessions.

Correlation Between Chronic Pain Acceptance and Clinical Variables in Ankylosing Spondylitis and Its Prediction Role for Biologics Treatment.

Objectives: Studies have proven that improving patients' acceptance of chronic pain could be an effective therapy for alleviating pain and other symptoms. Our objectives were to investigate the correlation between chronic pain acceptance and clinical variables in ankylosing spondylitis (AS), and the prediction role of chronic pain acceptance for biologics treatment.Methods: First, 167 AS patients were recruited to complete a series of questionnaires, including the Bath Ankylosing Spondylitis Disease Activity Index (BASDAI), Bath Ankylosing Spondylitis Functional Index (BASFI), Chronic Pain Acceptance Questionnaire (CPAQ), Hospital Anxiety and Depression Scale (HADS), and Tampa Scale for Kinesiophobia (TSK). Bivariate correlation analysis was utilized to investigate the correlation between pain acceptance and clinical variables. Based on the level of chronic pain acceptance and serum C-reactive protein (CRP), patients were separated into four subgroups. Then, another 68 patients initiating anti-tumor necrosis factor (TNF) treatment were recruited to complete the questionnaires at baseline (T0) and 3 months after treatment (T3). The changes in clinical variables and treatment response were compared between multiple subgroups.Results: Chronic pain acceptance had strong correlations with anxiety, depression and fear of movement, and moderate correlations with BASFI and pain intensity. Both activity engagement (AE) and pain willingness (PW) had significant correlations with pain intensity, BASFI and psychological status. In addition, AE had a significant correlation with disease duration, while PW had a significant correlation with ASDAS-CRP. Subgroup analysis showed that patients with low chronic pain acceptance and high levels of serum CRP had the highest BASDAI. Among patients initiating anti-TNF treatment, those with high pain acceptance and high levels of serum CRP achieved the most obvious reduction in BASDAI after 3 months treatment.Conclusion: Pain acceptance is a new tool to assess pain in AS which may also reflect physical and psychological status. Clinicians should identify high-risk patients with low chronic pain acceptance and high levels of serum CRP, and give psychological and pharmacological intervention promptly. Moreover, the combination of baseline chronic pain acceptance and serum CRP level could be used to predict the treatment response in AS patients initiating biologics treatment.

P465 Therapeutic drug monitoring in Crohn’s disease patients, a comparison between homogeneous mobility shift assay and point of care method

Abstract Background Therapeutic Drug Monitoring (TDM) is a useful tool to help physicians managing patients with Inflammatory Bowel Disease treated with anti-tumour necrosis factor (TNF) drugs. Different techniques are available to evaluate serum drug concentration (TL), However, these techniques are time-consuming. A point-of-care (POC) method has been proposed to evaluate drug TL and overcome the limitations inherent to other methodologies. Our aim was to evaluate the capability of POC to discriminate between IBD relapse and remission and to evaluate the concordance of drug TL measured with POC and HMSA Methods We analysed with Quantum BlueÒ (Buhlmann Laboratories AG, Schonenbuch, Switzerland) (POC) 200 Adalimumab (ADA) and 200 Infliximab serum samples of 46 Crohn’s disease (CD) patients previously assessed with HMSA. Blood samples were drawn at standardised time points during anti-TNF treatment (2, 6, and every 8 weeks), before anti-TNF administration. Disease activity was assessed by the Harvey–Bradshaw Index (HBI, remission defined by HBI&amp;lt;5). Results We evaluated 46 CD patients responders to anti-TNF induction with ADA (n = 25, 54.3%) and IFX (n = 21, 45.6%) with a median follow-up of 83 weeks (range 16–144 weeks). At week 16, median ADA TL of patients in remission were significantly higher as compared with patients in disease relapse using both HMSA [12.7 μg/ml (range, 8.9–23.6 μg/ml) vs. 6.6 μg/ml (range, 0.7–9.6 μg/ml), p = 0.0001] and POC [17.8 μg/ml (range 7.6–35.0 μg/ml) vs. 9.8 μg/ml (range 5.8–11.4 μg/ml), p = 0.0003]. The concordance between the two different techniques has been assessed as 0.76 by Choen Kappa. Considering IFX TL, patients in remission had higher serum drug concentration using both HMSA [7.0 μg/ml (range, 0.0–21.8 μg/ml)] and POC [6.2 μg/ml (range 0.4–14.3 μg/ml)] as compared with patients who experienced disease relapse [HMSA, 0.1 μg/ml (range, 0.0–4.1 μg/ml), p = 0.019; POC, 0.45 μg/ml (range 0.4–3.3 μg/ml), p = 0.0072]. The concordance between the two different test for IFX TL was 0.81. We obtained similar results at the end of follow-up: median ADA TL was higher in remission than in disease relapse patients using both HMSA and POC [p = 0.001 and p = 0.0012] with a concordance of 0.75. Median IFX TL was higher in remission than in disease relapse patients using both HMSA and POC (p = 0.13 and p = 0.25) with a concordance of 0.70. Conclusion Both POC and HMSA are TL tests able to differentiate relapse and remission in IBD patients. The association between anti-TNF TL and disease status (remission/relapse) was better in ADA-treated patients rather than patients treated with IFX. Finally, we demonstrated a good concordance between HMSA and POC. Anti-drug antibody concentrations while available on HMSA were not available on POC

Use of Vitamin D With Anti-Tumor Necrosis Factor Therapy for Crohn's Disease.

BackgroundVitamin D (VD) has an important role in regulating gut mucosal immunity, and seems to be inversely linked to disease activity and more frequent relapses in inflammatory bowel disease. In this study, we evaluated patients with Crohn’s disease (CD) treated with anti-tumor necrosis factor (TNF) in association with VD.MethodsA double-blind, randomized, prospective study was conducted. Thirty patients with a history of moderate to severe CD, in use of anti-TNF, of both sexes, 18 to 70 years, with the dosage of VD < 75 nmol/L (30 ng/mL) were randomized and divided into three groups: group 1 (G1): 10 patients received 2,000 IU VD, per os (PO)/week for 8 weeks; group 2 (G2): 10 patients received 10,000 IU VD, PO/week for 8 weeks; group 3 (G3): 10 patients received 50,000 IU VD, PO/week for 8 weeks. Before and at the end of 8 weeks patients were submitted to VD, fecal calprotectin (FC) and C-reactive protein (CRP) dosage. Follow-up period was 52 weeks, and they are checked for disease activity recurrence (Crohn’s disease activity index (CDAI) > 150, FC > 300 and computerized tomography (CT) scan), FC, CRP, and VD levels.ResultsIncreased VD levels were observed in all groups (P < 0.0001). CRP did not change. There was a significant decrease of FC in G3 (1,014 ± 850 vs. 483 ± 564; P = 0.04), no significant decrease in G2 (76,767 ± 751 vs. 535 ± 823; P = 0.2) and increase in G1 (1,101 ± 744 vs. 1,357 ± 819; P = 0.4). During the 52-week follow-up period, it was showed that recurrent disease activity (CDAI > 150, FC > 200 and CT scan) was predominant in patients with VD < 30 group, and the remission rate was predominant in patients with VD > 30 group (P = 0.0001). A statistically significant difference in VD levels was noted in CD patients after 52 weeks that presented flare or disease remission (P = 0.001).ConclusionsUse of VD associated with anti-TNF treatment may improve clinical response in CD. VD levels greater than 30 ng/mL have better rates of remission.

Thyroid Function Tests in Ankylosing Spondylitis Patients on Anti-Tumour Necrosis Factor Treatment

Introduction: Ankylosing spondylitis (AS) is a chronic inflammatory disease. Thyroid dysfunctions are more frequent in patients with inflammatory diseases. In this study, we aimed to evaluate thyroid functions and thyroid autoantibodies in ankylosing spondylitis patients, to determine the effect of anti-tumor necrosis factor treatment in AS patients and the relationship between thyroid function and autoantibody levels, inflammatory markers and disease activity in ankylosing spondylitis patients. Materials and Methods: 74 ankylosing spondylitis patients diagnosed according to 1984 Modified New York criteria and Assessment in Spondylarthritis International Society classification criteria were included. 41 of them were receiving anti-tumor necrosis factor treatment and 33 of them were receiving nonsteroid anti-inflammatory drugs. We recorded patients' age, gender, erythrocyte sedimentation rates, C-reactive protein values, blood count, biochemical analysis, thyroid function tests, autoantibody levels, Bath Ankylosing Spondylitis Disease Activity Index. Results: Mean anti-thyroid peroxidase levels were significant at a high level in ankylosing spondylitis patients receiving anti-tumour necrosis factor compared to patients receiving nonsteroid anti-inflammatory drugs (p= 0.009).Negative correlation was found between thyrotropin-stimulating hormone and C-reactive protein(r=-0,264, p=0,023).A positive correlation was found between free thyroxine and C-reactive protein (r=0,436,p=0,009), anti-thyroid peroxidase positivity and erythrocyte sedimentation rate (r=0,384,p=0,001),anti-thyroglobulin positivity and erythrocyte sedimentation rates and C-reactive protein(r=0,329,r=0,265,p=0,004,p=0,022). Conclusion: The frequency of thyroid disorder in patients with AS receiving anti-TNF α was lower compared to patients receiving nonsteroid anti-inflammatory drugs. We can consider that anti-TNF α treatment could reduce autoimmune thyroid diseases and had a positive effect on thyroid functions.

Five-year review of corticosteroid duration and complications in the management of immune checkpoint inhibitor-related diarrhoea and colitis in advanced melanoma

BackgroundImmune-related diarrhoea/colitis (ir-D/C) is a common adverse event of immune checkpoint inhibitor (ICI) therapy. Guidelines recommend corticosteroid (CS) treatment; however, the average treatment duration for ir-D/C remains poorly defined.MethodsAll advanced melanoma patients treated with ICI therapy at the Royal Marsden Hospital between 2011 and 2016 were reviewed to identify ir-D/C cases alongside clinical variables.Results117 any-grade ir-D/C episodes occurred in 109 (21%) patients out of a total of 519 patients treated (ipilimumab=77 episodes, anti-PD1=17 (nivolumab or pembrolizumab), ipilimumab and nivolumab=23 (ipi+nivo)) (seven patients had ir-D/C more than once on different lines of treatment) and >/=grade 3 ir-D/C occurred most frequently (63/519 patients (12%) vs 29/519 (5%) grade 1, and 25/519 (5%) grade 2). Median onset (days) of all-grade ir-D/C after starting ICI therapy was 41 for ipilimumab (IQR 24 to 59, n=77), 91 for anti-PD1 (IQR 46 to 355, n=17) and 45 for ipi+nivo (IQR 24 to 67, n=23). In 71/117 (61%) patients, ir-D/C episodes were treated with CS (17% grade 2; 79% grade 3/4): 54 being steroid-responsive; 17 being steroid-refractory and received additional anti-tumor necrosis factor (TNF) treatment. Median grade 3 ir-D/C CS duration was similar across treatments, averaging 58 days. Median overall CS duration (days) was longer in the grade 3/4 D/C steroid-refractory group (94 vs 45 days). Infection developed in 11/71 (15%) CS recipients and in 6/17 (35%) anti-TNF recipients. In 65/117 (55%) patients, ir-D/C episodes were investigated with flexible sigmoidoscopy. Of these patients, 38/65 (58%) had macroscopic colitis and 12/65 (18%) had microscopic colitis. The steroid-refractory group had more macroscopic changes, 13/17 (76%), than the steroid-responsive group, 22/41 (54%).ConclusionRates of grade 3 ir-D/C were higher than reported in clinical trials. The 58-day median duration of CS therapy for grade 3 ir-D/C places a significant number of patients at risk of complications. We demonstrate that microscopic colitis is an important subgroup, advocating biopsies in ir-D/C even with macroscopically normal bowel.

FiLaC® and Crohn’s disease perianal fistulas: a pilot study of 20 consecutive patients

The aim of our study was to evaluate the efficacy of FiLaC® (Fistula Laser Closure) in the treatment of perianal fistulas in patients with Crohn's disease. All adult patients treated in our department between March 3rd 2016 and November 16th 2018 were included in the study. The fistula was considered healed when the internal and external openings were closed and the patient experienced no pain or leakage (spontaneously or under pressure). We included 20 consecutive patients (10 women) with a mean age of 32years ± 9.61. The main fistula tracks were intersphincteric (n = 1, 5%), low (n = 3, 15%) or high (n = 14, 70%) transsphincteric, suprasphincteric (n = 1, 5%), or extrasphincteric (n = 1, 5%). Secondary extension (intramural, supralevator, or horseshoe) was found in 6 cases (30%). The average number of previous surgeries was 2.45 ± 1.47. Crohn's disease extension was ileal in 2 patients (10%), ileocolonic in 8 patients (40%), and colonic in 10 patients (50%). Two patients were lost to follow up and were considered as failures. After a median follow-up period of 7.1months (range 2-22.5months), fistula healing was observed in 11 patients (55%). On univariate analysis, only the disease-modifying therapy for Crohn's disease was a predictive factor of a response to FiLaC® (p = 0.05). The specific analysis of this subgroup showed that FiLaC® was less effective when patients were treated with anti-tumor necrosis factor (TNF) alone with an OR of 13.06 [1.28; 236.66] (p = 0.02). For combination therapy, the results seemed better (5 of 6 healed versus 2 of 9 healed with anti-TNF alone), but the difference was not significant. This pilot study suggests that FiLaC® may play an important role in the management of perianal fistulas in patients with Crohn's disease.

Immune reconstitution inflammatory syndrome in the lung in non-human immunodeficiency virus patients.

We evaluated immune reconstitution inflammatory syndrome (IRIS) in the lung in non-human immunodeficiency virus (HIV) patients. We reviewed articles related to IRIS occurrence in the lung in non-HIV patients using a PubMed search. The keywords used for the search were "immune reconstitution syndrome" and "non-HIV." Only patients with lung involvement were included. Those with suggested IRIS caused by white blood cell recovery were excluded. There were 37 cases of IRIS in the lung in non-HIV patients. Complicating infections included tuberculosis (n=17), histoplasmosis (n=9), aspergillosis (n=5), cryptococcosis (n=4), and Pneumocystis pneumonia (n=2). We also evaluated the underlying diseases, IRIS pathogenesis, management, and prognosis. IRIS was most commonly encountered in patients treated with anti-tumor necrosis factor (TNF) antibody who developed disseminated or extrapulmonary tuberculosis, leading to treatment discontinuation. The diagnosis and management of IRIS in the lung in non-HIV patients should be investigated further, especially in the era of anti-TNF treatment.

Long-Chain Polyphosphate Is a Potential Agent for Inducing Mucosal Healing of the Colon in Ulcerative Colitis.

The goal of ulcerative colitis (UC) treatment has recently been shown to be “mucosal healing,” as no drug directly induces mucosal healing. Probiotics possess sufficient safety, but their efficacy in the treatment of UC remains controversial because of the influence of intestinal conditions. It is believed that the identification of bioactive molecules produced by probiotics and their application will help to solve this issue. We therefore identified a probiotic‐derived long‐chain polyphosphate as a molecule enhancing the intestinal barrier function. This study demonstrated that long‐chain polyphosphate exhibited antiinflammatory effects in a human macrophage and interleukin‐10 knockout transfusion mouse model. The first‐in‐human trial showed that 7 of the 10 enrolled patients acquired clinical remission, 4 of whom achieved endoscopic remission despite a history of treatment with anti–tumor necrosis factor (TNF)–α agents. No adverse reactions were observed. Long‐chain polyphosphate might be useful for the treatment of refractory UC, even in patients with failure or intolerance to anti‐TNF‐α therapy.

Single-centre experience with anti-tumour necrosis factor treatment in budesonide-refractory microscopic colitis patients.

Microscopic colitis is an inflammatory bowel disease that causes chronic, watery diarrhoea. Microscopic colitis is usually effectively treated with budesonide, but some patients are refractory. Data on alternative treatments are sparse. The purpose of this study was to retrospectively evaluate outcome of microscopic colitis patients receiving anti-tumour necrosis factor therapy at our centre. Treatment results, including side effects, for all microscopic colitis patients receiving anti-tumour necrosis factor therapy were registered at week 12 and at end of follow-up. Clinical remission was defined as a mean of <3 stools and <1 watery stools/day/week and clinical response as a 50% reduction of mean stool frequency/day/week. Induction and maintenance treatment was either adalimumab or infliximab. The study cohort comprised 18 patients; mean age at diagnosis was 47 years (range 19-77). Ten and eight patients, respectively, received adalimumab and infliximab as first-line anti-tumour necrosis factor; seven patients received second-line anti-tumour necrosis factor due to non-response, loss of response or side effects. At week 12, 9/18 patients had achieved remission, 6/18 were responders and 3/18 were non-responders. Of the nine remission patients, 3/18 (16%) had long-lasting clinical remission post-induction therapy alone. Five patients (28%) (one first-line, four second-line anti-tumour necrosis factor) were in remission and one patient (6%) responded to maintenance treatment; follow-up was mean 22 (range 4-60) months. Six patients (33%) had minor, reversible side effects. Over half of budesonide-refractory microscopic colitis patients can achieve clinical remission or response on anti-tumour necrosis factor agents. Prospective studies are mandatory to evaluate the efficacy and safety of anti-tumour necrosis factor treatments in budesonide-refractory microscopic colitis.

Dermatological complications of therapy with biologics in inflammatory autoimmune diseases.

Cutaneous adverse events (CAEs) occur in up to 10% of patients with immune-mediated inflammatory disease (IMID) treated with antitumor necrosis factor (TNF)α agents. The aim of this clinical study was to track and observe the course of CAEs in all biologic therapies. The population for this study consisted of patients with CAEs under biologic therapy who were examined by experienced board-certified dermatologists in the outpatient department of the University Hospital Essen, Department of Dermatology. Altogether 39 patients with a total of 45 CAEs were included in this study. In 60% of the cases a form of paradoxical psoriasis was diagnosed. Two thirds (66.6%) of the patients with CAEs were diagnosed with an underlying inflammatory bowel disease (IBD). TNFα antagonists were the triggering agents in about 95% of the cases. Changes in biological therapy were required in nearly half of the cases (46.2%). Almost 90% of the patients had either a complete (42.1%) or a partial response (47%). Management of CEAs under biological therapy can be challenging in clinical practice. Case discussions between gastroenterologists, rheumatologists and dermatologists should be undertaken to best manage patients with CAEs and avoid unnecessary changes of therapy.

813 Incidence and Indicators of Suboptimal Response to Tumor Necrosis Factor Antagonist Therapy in Inflammatory Bowel Disease in Newly Industrialized Countries: Results From the EXPLORE Study

INTRODUCTION: Inflammatory bowel disease (IBD) patients in Western countries frequently experience suboptimal response to anti-tumor necrosis factor (TNF) treatment (Tx). The EXPLORE study aimed to assess the incidence and indicators of suboptimal response to first-line anti-TNF agents in IBD patients in real-world practice in newly industrialized countries, where data are limited. METHODS: A retrospective chart review study was conducted in Asia-Pacific (APAC; South Korea, China, Taiwan, Singapore), Latin America (LatAm; Argentina, Colombia, Mexico) and Russia-Middle East (RME; Russia, Saudi Arabia, Turkey) in adult patients diagnosed with ulcerative colitis (UC) or Crohn’s disease (CD), who initiated anti-TNF Tx between March 2010 and March 2015. The cumulative incidence (CI) of suboptimal response (Kaplan-Meier method) was assessed over the first 24 months of Tx, as the occurrence of a first indicator of: IBD-related hospitalization, dose escalation (increase in frequency and/or dose), discontinuation including switch to another anti-TNF, non-biologic Tx augmentation, or IBD-related surgery. Primary non-response (PNR) and secondary loss of response (SLOR) were defined as any suboptimal response indicator at &lt; 4 and ≥4 months after anti-TNF initiation (excluding PNR patients), respectively. RESULTS: Overall, 1674 first-line anti-TNF treated patients (570 UC; 1104 CD) were included: male, UC 56.1%, CD 61.2%; median (min-max) age (years), UC 39.0 (18-82), CD 31.0 (19-83); median (min-max) disease duration (years), UC 3.0 (0-34), CD 1.0 (0-33); median (min-max) follow-up (months), UC 45.9 (24-60), CD 46.5 (14-60). At 24 months, the CI of suboptimal response to first anti-TNF Tx was 32.9% in UC and 41.2% in CD patients (unadjusted log-rank: P &lt; 0.01); the APAC region had the highest CI (UC 45.1%; CD 54.1%) (Table 1). The CI of PNR was 13.6% and 16.9% in UC and CD patients, respectively. The CI of SLOR was 22.3% in UC and 29.2% in CD patients at 24 months. The most frequent first suboptimal response indicator was ‘IBD-related hospitalization’ (UC 33.0%; CD 36.1%) followed by ‘non-biologic augmentation’ (UC 30.3%; CD 23.8%) (Table 1). CONCLUSION: Suboptimal response to first-line anti-TNF agents is common in IBD patients in newly industrialized countries and is more frequently experienced in CD than in UC. Observed regional differences in the rates of suboptimal response, PNR and SLOR, may reflect local practice variations and restrictions in the management of anti-TNF treated patients.

Screening for latent tuberculosis in patients with inflammatory bowel disease under antitumor necrosis factor: data from a Portuguese center

Portugal is one of the countries with the highest tuberculosis (TB) burden in the European Union. Patients who are receiving antitumor necrosis factor (TNF) treatment should be screened and treated for latent tuberculosis infection (LTBI). This study aimed to evaluate the prevalence of LTBI and the number of active TB cases in patients with inflammatory bowel disease (IBD) treated with anti-TNF agents. This was a retrospective study from a Portuguese center that included patients with IBD who started anti-TNF treatment between 2013 and 2017. LTBI screening was considered positive in case of positive tuberculin skin test, positive/indeterminate interferon gamma release test, or history of exposure to TB irrespective of the results of the screening. One hundred and seventeen patients were included, 56% female, mean age 40 years; 91% had Crohn's disease; infliximab was initiated in 79%, adalimumab in 21%, and golimumab in 1%. Of these, 37 (32%) presented LTBI - tuberculin skin test was positive in 18 (49%) patients; interferon gamma release test was positive in 14 (38%) patients and undetermined in seven (19%); and there was a history of exposure in 12 (32%) patients. All patients screened with LTBI were on isoniazid for 9 months. During follow-up (mean 21.6 months), one patient under infliximab developed pleural TB 5 years after receiving treatment with isoniazid. None of the patients with negative LTBI screening developed active TB. In this sample of patients with IBD, the prevalence of LTBI before starting anti-TNF treatment was significant (32%), but only one patient had active TB after LTBI treatment.

Therapeutic Drug Monitoring to Guide Clinical Decision Making in Inflammatory Bowel Disease Patients with Loss of Response to Anti-TNF: A Delphi Technique-Based Consensus

Background: Loss of response is frequently encountered in patients with inflammatory bowel disease (IBD) treated with antitumor necrosis factor (TNF) agents. Therapeutic drug monitoring (TDM) and antidrug antibody measurement are increasingly used in this setting. Methods: To establish a consensus on the use of TDM in the context of loss of response to anti-TNFs, we performed a vote using a Delphi-style process followed by an expert panel discussion among 8 IBD specialists practicing in Switzerland, Europe. Statements were rated on an even Likert-scale ranging from 1 (strong disagreement) to 4 (strong agreement), based on expert opinion and the available literature. Results: The experts agreed on the following statements: (i) loss of response is associated with inadequate drug levels in both Crohn’s disease and ulcerative colitis; (ii) best timepoint for measuring drug levels is prior to the next application (= trough levels) with different thresholds for anti-TNF agents (infliximab 5 μg/mL, adalimumab 8 μg/mL, certolizumab pegol 10 μg/mL); (iii) antidrug antibodies are predictive for loss of response; and (iv) antidrug-antibody titers and drug trough levels are key determinants in the treatment algorithm. Data about non-anti-TNF biologics were considered too limited to propose recommendations. Conclusion: A Delphi-style consensus among 8 IBD experts shows that TDM and measurement of antidrug-antibody titers are useful in the context of loss of response to anti-TNF. Optimal cutoff levels depend on the type of anti-TNF. These values are critical in the decision making process. More studies are needed to address the value of such measurements for non-anti-TNF biologics.

Cost-of-illness of inflammatory bowel disease patients treated with anti-tumour necrosis factor: A French large single-centre experience.

No study has evaluated the direct annual costs of inflammatory bowel disease patients treated with anti-tumour necrosis factor therapy. The purpose of this study was to identify annual direct costs and main cost drivers of anti-tumour necrosis factor-treated inflammatory bowel disease patients. All inflammatory bowel disease patients treated with infliximab or adalimumab at Nancy University Hospital were consecutively screened for inclusion from November 2016-February 2017. Data about hospitalisation, surgery, medication, outpatient visits, investigations and transport over the previous 12 months were retrospectively collected. A total of 108 patients (n = 83 Crohn's disease; n = 25 ulcerative colitis) were included. The mean annual cost per patient was €15,775 (standard deviation €7221), with no difference between Crohn's disease and ulcerative colitis (p = 0.2). The main cost driver was medication, which accounted for 84% of the total direct cost. Hospitalisation and surgery represented 11% and 2% of the direct costs. History of switch to another anti-tumour necrosis factor treatment was identified as the only independent predictor of greater direct costs in the multivariate analysis (p = 0.0018). In a French tertiary referral centre, direct costs of anti-tumour necrosis factor therapy-treated patients were mainly driven by medication, while hospitalisation and surgery represented only a minor part of the costs. There was no difference between Crohn's disease and ulcerative colitis patients.

P079 Best Abstract #2 The use of an observed structured clinical examination to teach communication skills surrounding therapeutic drug monitoring

BACKGROUND: According to the 2017 American College of Gastroenterology (AGA) guidelines, therapeutic drug monitoring (TDM) of drug trough concentrations and anti-drug antibodies is recommended to optimize treatment with anti-tumor necrosis factor (TNF) agents and thiopurines1. Specifically, the AGA conditionally recommends reactive TDM in patients with active symptoms of inflammatory bowel disease (IBD) while on anti-TNF agents, as such testing is crucial for differentiating between mechanistic, non-immune mediated pharmacokinetic and immune-mediated pharmacokinetic drug failure, and allows providers to appropriately tailor treatment regimens. As such algorithms for monitoring therapies in IBD have evolved, it has become incumbent on physicians caring for these patients to develop techniques to engage in patient-centered care using the technique of shared decision making. Gastroenterology (GI) trainees may not be well versed in navigating these complex interpersonal skills. The Observed Structured Clinical Examination (OSCE) is a well-validated method of assessing core competencies of communication and professionalism. While it is traditionally used at the undergraduate medical education level, it has been used at the graduate level to address disease-specific competencies. Here, we discuss the use of an OSCE to assess the performance of GI fellows in engaging in shared decision-making on the topic of TDM for a patient with complex IBD refractory to treatment. METHODS: Eleven second-year gastroenterology fellows from 4 GI fellowship programs participated in a 4 station OSCE. Previously validated OSCE checklists were used to assess the fellows' performance in IBD-specific cases, one of which will be discussed here. In the “Therapeutic Drug Monitoring” case, the objective for the fellows was to discuss the indications for infliximab trough and antibody testing and how results of this testing would impact treatment based on the AGA guidelines. Checklists were scored on a 3 and 5-point Likert Scale by the Standardized Patient (SP), mapped to the appropriate ACGME milestones by a GI medical educator and normalized on a scale from 0 to 9. Post-OSCE, the fellows were surveyed to assess their perspective on their performance as well as the exam's educational value. RESULTS: 6 ACGME milestones were assessed in this OSCE. Scores ranged from mean of 5.85 to 7.88. Fellows scored lowest on gathering and synthesizing essential and accurate information to define each patient's clinical problem(s) (PC1, mean score 5.85) with an average score of 5.85. They scored highest for overall clinical knowledge (MK1, mean score 7.88). Overall, 9/10 (90%) of fellows would be recommended for their interpersonal skills, but only 4/10 (40%) were deemed effective in their communication skills. The majority of fellows noted improvement in their understanding of when to use and how to interpret TDM after the exercise. CONCLUSION(S): This OSCE was designed to assess clinical and communication skills for gastroenterology surrounding the complex clinical arena of therapeutic drug monitoring utilizing crucial communication skills. The results suggest weaker performance linked to gathering and synthesizing clinical information, with stronger performance in clinical knowledge, developing management plans and various communication skills. This OSCE feedback and assessment can be used to develop targeted educational interventions to strengthen clinical and communication skills for providers.

A Fifty-Two-Week, Randomized, Placebo-Controlled Trial of Certolizumab Pegol in Nonradiographic Axial Spondyloarthritis.

ObjectiveThe natural history of nonradiographic axial spondyloarthritis (SpA) is incompletely characterized, and there are concerns that nonsteroidal antiinflammatory drugs provide inadequate disease control in patients with active disease. This study was undertaken to investigate the effects of certolizumab pegol (CZP), an anti–tumor necrosis factor treatment, in patients with nonradiographic axial SpA with objective signs of inflammation.MethodsIn this ongoing parallel‐group double‐blind study, adults with active disease were recruited from 80 centers in Australia, Europe, North America, and Taiwan, and were randomized 1:1 to receive placebo or CZP (400 mg at weeks 0, 2, and 4, followed by 200 mg every 2 weeks) in addition to nonbiologic background medication (NBBM). Switching to open‐label CZP (or other biologic) or making background medication changes was permitted at any point during the trial, although changes before week 12 were discouraged. The primary end point was the proportion of patients achieving major improvement (MI) (i.e., a ≥2.0‐point decrease in the score from baseline or achievement of the lowest possible score [0.6]) in the Ankylosing Spondylitis Disease Activity Score (ASDAS) at week 52.ResultsA total of 317 patients were randomized to receive placebo plus NBBM (n = 158) or CZP plus NBBM (n = 159). ASDAS‐MI at week 52 was achieved in 47.2% (75 of 159) of CZP plus NBBM patients, which was significantly greater (P < 0.0001) than the 7.0% (11 of 158) of placebo plus NBBM patients in whom ASDAS‐MI was achieved. Of the placebo plus NBBM patients, 60.8% (96 of 158) switched to open‐label treatment before week 52 compared to 12.6% (20 of 159) of the CZP plus NBBM patients.ConclusionAdding CZP to background medication is superior to adding placebo in patients with active nonradiographic axial SpA. These results indicate that remission in nonradiographic axial SpA treated without biologics occurs infrequently, demonstrating the need for treatment beyond nonbiologic therapy.