Background: Loss of response to infliximab or adalimumab in ulcerative colitis occurs frequently, and dose escalation may aid in regaining clinical benefit. This study aimed to systematically assess the annual loss of response and dose escalation rates for infliximab and adalimumab in ulcerative colitis. Methods: A systematic search was conducted from August 1999 to July 2021 for studies reporting loss of response and dose escalation during infliximab and/or adalimumab use in ulcerative colitis patients with primary response. Annual loss of response, dose escalation rates, and clinical benefit after dose escalation were calculated. Subgroup analyses were performed for studies with 1-year follow-up or less. Results: We included 50 unique studies assessing loss of response (infliximab, n = 24; adalimumab, n = 21) or dose escalation (infliximab, n = 21; adalimumab, n = 16). The pooled annual loss of response for infliximab was 10.1% (95% confidence interval [CI], 7.1-14.3) and 13.6% (95% CI, 9.3-19.9) for studies with 1-year follow-up. The pooled annual loss of response for adalimumab was 13.4% (95% CI, 8.2-21.8) and 23.3% (95% CI, 15.4-35.1) for studies with 1-year follow-up. Annual pooled dose escalation rates were 13.8% (95% CI, 8.7-21.7) for infliximab and 21.3% (95% CI, 14.4-31.3) for adalimumab, regaining clinical benefit in 72.4% and 52.3%, respectively. Conclusions: Annual loss of response was 10% for infliximab and 13% for adalimumab, with higher rates during the first year. Annual dose escalation rates were 14% (infliximab) and 21% (adalimumab), with clinical benefit in 72% and 52%, respectively. Uniform definitions are needed to facilitate more robust evaluations.

Currently, the gold standard for diagnosis of coeliac disease (CD) is based on serology and gastroduodenoscopy with histology of duodenal mucosal biopsies. The aim of this study was to evaluate the potential of faecal volatile organic compounds (VOCs) analysis as a novel, non-invasive tool to discriminate between CD in remission in patients on a gluten-free diet (GFD), refractory coeliac disease (RCD) and controls without CD. Patients with an established diagnosis of CD on a GFD, RCD and healthy controls (HC) were instructed to collect a faecal sample. All subjects completed questionnaires on clinical symptoms, lifestyle and dietary information. Faecal VOCs were measured using gas chromatography-ion mobility spectrometry. A total of 13 CD, 7 RCD and 10 HC were included. A significant difference in VOC profiles between CD and RCD patients (area under the curve (AUC) ± 95% CI: 0.91 (0.79–1) p = 0.000) and between CD and HC (AUC ± 95% CI: 0.71 (0.51–0.91) p = 0.0254) was observed. We found no significant differences between faecal VOC patterns of HC and RCD. Based on faecal VOCs, CD could be discriminated from RCD and HC. This implies that faecal VOC analysis may hold potential as a novel non-invasive biomarker for RCD. Future studies should encompass a larger cohort to further investigate and validate this prior to application in clinical practice.

Background: The quality of testosterone assays has been a matter of debate for several years. Known limitations of testosterone immunoassays are the cross-reactivity with other steroids and a high variation in the low concentration range. We hypothesized that one of the additional limitations of testosterone immunoassays is an ineffective displacement of testosterone from its binding protein. Methods: Thirty samples from women not using oral contraceptives (OAC), 30 samples from women using OAC, and 30 samples from pregnant women were used to measure testosterone by an isotope dilution (ID)-LC-MS/MS method and by 6 commercially available testosterone immunoassays (UniCel^®, ARCHITECT^®, Centaur^®, Cobas^®, Immulite^®, and Liaison^®). In addition, sex hormone–binding globulin (SHBG)⁴ was measured by immunoassay (ARCHITECT). Results: The first-generation immunoassays (UniCel, Centaur, Immulite, and Liaison) showed inaccurate testosterone results in the method comparisons with the ID-LC-MS/MS method (R between 0.61 and 0.86) and for some assays (UniCel and Liaison) also a very poor standardization (slopes of 0.59 and 0.67, respectively). On average, SHBG concentrations were lowest in women not using OAC and highest in pregnant women, and overall ranged from 18.5 to 633 nmol/L. In the first-generation immunoassays, but not in the second-generation immunoassays, we observed an inverse relationship between SHBG concentrations and deviations in testosterone from the ID-LC-MS/MS results. Conclusions: Widely used first-generation testosterone immunoassays are influenced by SHBG concentrations, which lead to inaccurate results in samples from patients with high or low SHBG concentrations, respectively. Laboratory specialists, clinicians, and researchers should be aware of this limitation in testosterone assays.

Both methotrexate and tioguanine can be considered as treatment options in patients with Crohn’s disease after failure of conventional thiopurines. This study aimed to compare tolerability and drug survival of methotrexate and tioguanine therapy after failure of conventional thiopurines in patients with Crohn’s disease. We conducted a retrospective, multicentre study, including patients with Crohn’s disease initiating monotherapy methotrexate or tioguanine after failure [all causes] of conventional thiopurines. Follow-up duration was 104 weeks or until treatment discontinuation. The primary outcome was cumulative therapy discontinuation incidence due to adverse events. Secondary outcomes included total number of [serious] adverse events, and ongoing monotherapy. In total, 219 patients starting either methotrexate [n = 105] or tioguanine [n = 114] were included. In all 65 [29.7%] patients (methotrexate 43.8% [46/105 people], tioguanine 16.7% [19/114 people], p <0.001) discontinued their treatment due to adverse events during follow-up. Median time until discontinuation due to adverse events was 16 weeks (interquartile range [IQR] 7-38, p = 0.812). Serious adverse events were not significantly different. Patients treated with methotrexate experienced adverse events more often [methotrexate 83%, tioguanine 46%, p <0.001]. Total monotherapy drug survival after 104 weeks was 22% for methotrexate and 46% for tioguanine [p <0.001]. We observed a higher cumulative discontinuation incidence due to adverse events for methotrexate [44%] compared with tioguanine [17%] in Crohn’s disease patients after failure of conventional thiopurines. The total adverse events incidence during methotrexate use was higher, whereas serious adverse events incidence was similar. These favourable results for tioguanine treatment may guide the selection of immunosuppressive therapy after failure of conventional thiopurines.

Background: Thiopurines including azathioprine [AZA], mercaptopurine [MP] and tioguanine [TG] are cornerstone therapies in the maintenance treatment of inflammatory bowel diseases (IBD). Withdrawal in patients in stable remission may reduce the risk of infections and malignancies, but little is known about the subsequent risk of relapse. This study aimed to assess the relapse rate after discontinuation of thiopurines in IBD patients in stable remission. Methods: Patients with IBD discontinuing thiopurine therapy were prospectively included in, 14 Dutch hospitals if they used a thiopurine for at least one year, and were in steroid-free clinical remission for one year or longer. Clinical, biochemical, endoscopic and radiological data were collected at baseline (thiopurine cessation), and at, 3, 6, 12 and, 24 months thereafter. The primary endpoint was disease relapse, defined as: induction or escalation of therapy, or, if available, endoscopic activity, indicated by simple endoscopic score (SES-CD) >, 4 for Crohn’s disease (CD) or endoscopic Mayo >, 1 for ulcerative colitis and IBD unclassified (UC/IBDU). Cox regression analysis was used to determine predictors of relapse. Results: We enrolled, 134 patients (94 CD [70%]; AZA, 56%, MP, 20%, TG, 25%) with a median age of, 44.0 years (IQR, 30.8–59.0). Fifty-three (40%) patients received concomitant anti-tumour necrosis factor alpha (anti-TNF) at baseline. The median therapy duration before cessation was, 61.5 months (IQR, 40.0–111.0), median time of clinical remission before cessation was, 43.5 months (IQR, 27.8–65.5). During the median follow-up time of, 14.0 (IQR, 11.9–19.7) months after cessation, 37 (28%) patients relapsed (Figure, 1). Relapse rates at, 12 and, 24 months were, 28% and, 40%, respectively. Median time to relapse was, 10.9 (IQR, 5.5–16.5) months. UC/IBDU patients had a higher risk of relapse (HR, 2.603 [95% CI, 1.364 -4.965], p=0.004). Relapse free survival probability in patients with and without concomitant anti-TNF was not significantly different (anti-TNF, 82%, no anti-TNF, 87%, log rank=0.494, Figure, 2). Type of thiopurine, concomitant, 5-ASA, remission duration, therapy duration before cessation, baseline mucosal healing, and baseline faecal calprotectin were not predictive of relapse. After relapse, 27 patients received steroids (18 budesonide, 9 prednisone), 15 (re)started thiopurines, 8 initiated anti-TNF, and, 8 intensified concomitant anti-TNF. Figure 1 Figure 2 Conclusion: This prospective study showed relapse rates of, 28% and, 40% at, 12 and, 24 months, respectively, after cessation of thiopurines for stable remission. UC/IBDU patients had a higher risk of relapse. Type of thiopurine, remission duration, concomitant, 5-ASA or anti-TNF were not predictive of continuing remission.