Evaluation of tolerance to mercaptopurine in patients with inflammatory bowel disease and gastrointestinal intolerance to azathioprine / Evaluación de la tolerancia a la mercaptopurina en los pacientes con enfermedad inflamatoria intestinal e intolerancia gastrointestinal a la azatioprina

Background Thiopurines such as azathioprine (AZA) and mercaptopurine (MP) are commonly utilized to treat inflammatory bowel disease (IBD). Their use is frequently restricted due to gastrointestinal intolerance (GI). Previous retrospective studies have reported that AZA-intolerant patients may benefit from a switch to MP; yet the effectiveness of this strategy has not been prospectively evaluated.AimsTo assess GI tolerance to MP in patients who are intolerant to AZA, and to identify clinical predictors of GI intolerance to AZA or MP.MethodsA prospective, observational, single-cohort study was performed in 92 thiopurine-naïve IBD patients. They were started on a 50mg dose of AZA and escalated to 2.5mg/kg per day by week 2. Those with GI intolerance were rechallenged with a 50% dose of AZA, after which another dose escalation attempt was made. If symptoms persisted, they were switched to MP.ResultsThirty (32.6%) of the recruited patients suffered from GI intolerance to AZA. Of these, 15 did not present recurrence of symptoms after rechallenge with lower doses. Of 15 intolerant patients, 14 were switched to MP. Within the MP cohort, 8 patients (57%) were also intolerant to MP, 5 (36%) had no symptoms, and 1 (7%) was lost to follow-up. Female gender was the only independent predictor of GI intolerance to AZA.ConclusionsUp to half of the AZA-intolerant patients tolerated a 50% dose rechallenge that was successfully escalated. A switch to MP was tolerated in over a third of cases whom rechallenge failed. Our strategy (challenge–rechallenge–switch) achieved an overall GI tolerance to thiopurines in most of the patients. (AU)

Antecedentes Las tiopurinas como la azatioprina (AZA) y la mercaptopurina (MP) se utilizan comúnmente para tratar la enfermedad inflamatoria intestinal (EII). Su uso está frecuentemente restringido debido a la intolerancia gastrointestinal. Estudios retrospectivos anteriores han informado que los pacientes intolerantes a la AZA pueden beneficiarse de un cambio a MP; sin embargo, la eficacia de esta estrategia no ha sido evaluada prospectivamente.ObjetivosEvaluar la tolerancia gastrointestinal a MP en pacientes que son intolerantes a AZA e identificar predictores clínicos de intolerancia gastrointestinal a AZA o MP.MétodosSe realizó un estudio prospectivo, observacional y de cohorte única en 92 pacientes con EII que nunca habían recibido tiopurinas. Comenzaron con una dosis de 50mg de AZA y se aumentó a 2,5mg/kg por día en la semana 2. En aquellos con intolerancia gastrointestinal se administró una dosis del 50% de AZA que se fue incrementando en función de la tolerancia. Si los síntomas persistían, se cambiaba a MP.ResultadosTreinta (32,6%) de los pacientes reclutados presentaron intolerancia gastrointestinal a la AZA. De estos, 15 no presentaron recurrencia de los síntomas después de la nueva exposición. De los 15 pacientes que no toleraron una dosis más baja, 14 recibieron MP. De los que recibieron MP, 8 pacientes (57%) también eran intolerantes a MP, 5 (36%) no tenían síntomas y uno (7%) se perdió durante el seguimiento. El género femenino fue el único predictor independiente de intolerancia gastrointestinal a la AZA.ConclusionesHasta la mitad de los pacientes intolerantes a la AZA toleran una nueva exposición al 50% de la dosis. Se toleró un cambio a MP en más de un tercio de los casos en los que la reexposición fracasó. Nuestra estrategia logró la tolerancia gastrointestinal a tiopurinas en la mayoría de los pacientes. (AU)

Evaluation of tolerance to mercaptopurine in patients with inflammatory bowel disease and gastrointestinal intolerance to azathioprine.

BACKGROUND: Thiopurines such as azathioprine (AZA) and mercaptopurine (MP) are commonly utilized to treat inflammatory bowel disease (IBD). Their use is frequently restricted due to gastrointestinal intolerance (GI). Previous retrospective studies have reported that AZA-intolerant patients may benefit from a switch to MP; yet the effectiveness of this strategy has not been prospectively evaluated. AIMS: To assess GI tolerance to MP in patients who are intolerant to AZA, and to identify clinical predictors of GI intolerance to AZA or MP. METHODS: A prospective, observational, single-cohort study was performed in 92 thiopurine-naïve IBD patients. They were started on a 50mg dose of AZA and escalated to 2.5mg/kg per day by week 2. Those with GI intolerance were rechallenged with a 50% dose of AZA, after which another dose escalation attempt was made. If symptoms persisted, they were switched to MP. RESULTS: Thirty (32.6%) of the recruited patients suffered from GI intolerance to AZA. Of these, 15 did not present recurrence of symptoms after rechallenge with lower doses. Of 15 intolerant patients, 14 were switched to MP. Within the MP cohort, 8 patients (57%) were also intolerant to MP, 5 (36%) had no symptoms, and 1 (7%) was lost to follow-up. Female gender was the only independent predictor of GI intolerance to AZA. CONCLUSIONS: Up to half of the AZA-intolerant patients tolerated a 50% dose rechallenge that was successfully escalated. A switch to MP was tolerated in over a third of cases whom rechallenge failed. Our strategy (challenge-rechallenge-switch) achieved an overall GI tolerance to thiopurines in most of the patients.

Automated Whole-Liver MRI Segmentation to Assess Steatosis and Iron Quantification in Chronic Liver Disease.

Background Standardized manual region of interest (ROI) sampling strategies for hepatic MRI steatosis and iron quantification are time consuming, with variable results. Purpose To evaluate the performance of automatic MRI whole-liver segmentation (WLS) for proton density fat fraction (PDFF) and iron estimation (transverse relaxometry [R2*]) versus manual ROI, with liver biopsy as the reference standard. Materials and Methods This prospective, cross-sectional, multicenter study recruited participants with chronic liver disease who underwent liver biopsy and chemical shift-encoded 3.0-T MRI between January 2017 and January 2021. Biopsy evaluation included histologic grading and digital pathology. MRI liver sampling strategies included manual ROI (two observers) and automatic whole-liver (deep learning algorithm) segmentation for PDFF- and R2*-derived measurements. Agreements between segmentation methods were measured using intraclass correlation coefficients (ICCs), and biases were evaluated using Bland-Altman analyses. Linear regression analyses were performed to determine the correlation between measurements and digital pathology. Results A total of 165 participants were included (mean age ± standard deviation, 55 years ± 12; 96 women; 101 of 165 participants [61%] with nonalcoholic fatty liver disease). Agreements between mean measurements were excellent, with ICCs of 0.98 for both PDFF and R2*. The median bias was 0.5% (interquartile range, -0.4% to 1.2%) for PDFF and 2.7 sec-1 (interquartile range, 0.2-5.3 sec-1) for R2* (P < .001 for both). Margins of error were lower for WLS than ROI-derived parameters (-0.03% for PDFF and -0.3 sec-1 for R2*). ROI and WLS showed similar performance for steatosis (ROI AUC, 0.96; WLS AUC, 0.97; P = .53) and iron overload (ROI AUC, 0.85; WLS AUC, 0.83; P = .09). Correlations with digital pathology were high (P < .001) between the fat ratio and PDFF (ROI r = 0.89; WLS r = 0.90) and moderate (P < .001) between the iron ratio and R2* (ROI r = 0.65; WLS r = 0.64). Conclusion Proton density fat fraction and transverse relaxometry measurements derived from MRI automatic whole-liver segmentation (WLS) were accurate for steatosis and iron grading in chronic liver disease and correlated with digital pathology. Automated WLS estimations were higher, with a lower margin of error than manual region of interest estimations. © RSNA, 2021 Online supplemental material is available for this article. See also the editorial by Moura Cunha and Fowler in this issue.

Digital pathology: accurate technique for quantitative assessment of histological features in metabolic-associated fatty liver disease.

BACKGROUND: Histological evaluation of metabolic-associated fatty liver disease (MAFLD) biopsies is subjective, descriptive and with interobserver variability. AIMS: To examine the relationship between different histological features (fibrosis, steatosis, inflammation and iron) measured with automated whole-slide quantitative digital pathology and corresponding semiquantitative scoring systems, and the distribution of digital pathology measurements across Fatty Liver Inhibition of Progression (FLIP) algorithm and Steatosis, Activity and Fibrosis (SAF) scoring system METHODS: We prospectively included 136 consecutive patients who underwent liver biopsy for MAFLD at three Spanish centres (January 2017-January 2020). Biopsies were scored by two blinded pathologists according to the Non-alcoholic Steatohepatitis (NASH) Clinical Research Network system for fibrosis staging, the FLIP/SAF classification for steatosis and inflammation grading and Deugnier score for iron grading. Proportionate areas of collagen, fat, inflammatory cells and iron deposits were measured with computer-assisted digital image analysis. A test-retest experiment was performed for precision repeatability evaluation. RESULTS: Digital pathology showed strong correlation with fibrosis (r = 0.79; P < 0.001), steatosis (r = 0.85; P < 0.001) and iron (r = 0.70; P < 0.001). Performance was lower when assessing the degree of inflammation (r = 0.35; P < 0.001). NASH cases had a higher proportion of collagen and fat compared to non-NASH cases (P < 0.005), whereas inflammation and iron quantification did not show significant differences between categories. Repeatability evaluation showed that all the coefficients of variation were ≤1.1% and all intraclass correlation coefficient values were ≥0.99, except those of collagen. CONCLUSION: Digital pathology allows an automated, precise, objective and quantitative assessment of MAFLD histological features. Digital analysis measurements show good concordance with pathologists´ scores.

Adaptation of TECCU App Based on Patients´ Perceptions for the Telemonitoring of Inflammatory Bowel Disease: A Qualitative Study Using Focus Groups.

Background: Despite the continuous adaptation of eHealth systems for patients with inflammatory bowel disease (IBD), a significant disconnection persists between users and developers. Since non-adherence remains high, it is necessary to better understand the patients' perspective on telemonitoring for IBD. Accordingly, this study aimed to adapt the TECCU telemonitoring app to the preferences and needs of IBD patients. Methods: A qualitative study was carried out using successive focus groups of IBD patients. Meetings were audio-recorded and a thematic analysis was employed until data saturation was achieved. The first group included patients who had used the TECCU App in a pilot clinical trial, and subsequent meetings included patients with Crohn's disease and ulcerative colitis recruited from the Spanish Confederation of patient associations. The information collected at each meeting guided consecutive changes to the platform. Results: Data saturation was reached after three focus groups involving a total of 18 patients. Three main themes emerged: (1) platform usability, (2) the communication process, and (3) platform content. All participants indicated that TECCU is easy to use, permitting continuous and personalized feedback. According to patients´ perspectives, the platform was adapted to foster a flexible follow-up and shared decision-making using open and safe communication networks. Many participants appreciated the educational elements and, consequently, the app was connected to reliable and continuously updated webpages. Conclusions: IBD patients valued the usability and personalized monitoring offered by the TECCU App. Improvements in the messaging system and continuously updated educational content were introduced to address patients´ needs and favor their engagement.

Telemonitoring of Crohn's Disease and Ulcerative Colitis (TECCU): Cost-Effectiveness Analysis.

BACKGROUND: Although electronic health interventions are considered safe and efficient, evidence regarding the cost-effectiveness of telemonitoring in inflammatory bowel disease is lacking. OBJECTIVE: We aimed to evaluate the cost-effectiveness and cost-utility of the Telemonitorización de la Enfermedad de Crohn y Colitis Ulcerosa (Telemonitoring of Crohn's Disease and Ulcerative Colitis [TECCU]) Web platform (G_TECCU intervention group) for telemonitoring complex inflammatory bowel disease, compared with standard care (G_control) and nurse-assisted telephone care (G_NT intervention group). METHODS: We analyzed cost-effectiveness from a societal perspective by comparing the 3 follow-up methods used in a previous 24-week randomized controlled trial, conducted at a tertiary university hospital in Spain. Patients with inflammatory bowel disease who initiated immunosuppressants or biologic agents, or both, to control inflammatory activity were recruited consecutively. Data on the effects on disease activity (using clinical indexes) and quality-adjusted life-years (using the EuroQol 5 dimensions questionnaire) were collected. We calculated the costs of health care, equipment, and patients' productivity and social activity impairment. We compared the mean costs per patient, utilities, and bootstrapped differences. RESULTS: We included 63 patients (21 patients per group). TECCU saved €1005 (US $1100) per additional patient in remission compared with G_control (95% CI €-13,518 to 3137; US $-14,798 to 3434), with a 79.96% probability of being more effective at lower costs. Compared with G_NT, TECCU saved €2250 (US $2463) per additional patient in remission (95% CI €-15,363 to 11,086; US $-16,817 to 12,135), and G_NT saved €538 (US $589) compared with G_control (95% CI €-6475 to 5303; US $-7088 to 5805). G_TECCU and G_NT showed an 84% and 67% probability, respectively, of producing a cost saving per additional quality-adjusted life-year (QALY) compared with G_control, considering those simulations that involved negative incremental QALYs as well. CONCLUSIONS: There is a high probability that the TECCU Web platform is more cost-effective than standard and telephone care in the short term. Further research considering larger cohorts and longer time horizons is required. TRIAL REGISTRATION: ClinicalTrials.gov NCT02943538; https://clinicaltrials.gov/ct2/show/NCT02943538 (http://www. webcitation.org/746CRRtDN).