Anti-drug antibodies against anti-TNF in patients with inflammatory bowel disease: an evaluation of possible strategies.

OBJECTIVE: Immunogenicity against anti-TNF antibodies usually leads to loss of response. We aimed to evaluate the efficacy of clinical strategies to improve clinical remission and pharmacokinetics upon detection of anti-drug antibodies (ADA). METHODS: Inflammatory bowel disease (IBD) patients with ADA against infliximab or adalimumab were identified through a single centre database search covering 2004-2022. Criteria for successful intervention upon ADA detection (baseline) were clinical remission after 1 year without further change in strategy. RESULTS: Two-hundred-and-fifty-five IBD patients (206 Crohn's disease) were identified. At baseline, median ADA level was 77 AU/ml; 50.2% of patients were in clinical remission. Implemented strategies were: (1) 81/255 (32%) conservative management, (2) 102/255 (40%) anti-TNF optimisation, (3) 72/255 (28%) switch within or out of class. Switching was the most successful strategy for clinical remission (from 19% at baseline to 69% at 1 year, p < 0.001). Patients that continued the same dose anti-TNF or discontinued biological therapy were often in clinical remission, but deteriorated significantly (-22.7%, p = 0.004). Anti-TNF dose intensification with immunomodulator optimisation was the fastest (median 3.0 months, p = 0.009) and most effective (65% ADA suppression, p < 0.001) strategy to suppress ADA compared to solely anti-TNF or immunomodulator optimisation. CONCLUSIONS: Switching therapy, within or out of class, is the most successful strategy to regain and maintain clinical remission upon immunogenicity. When switching to another anti-TNF, concomitant immunomodulatory therapy should be started or continued to prevent repeated immunogenic loss of response. Anti-TNF dose escalation with concomitant immunomodulator optimisation is the fastest and most effective strategy to suppress ADA.

Immunogenicity against anti-TNF antibodies is associated with loss of response in patients with inflammatory bowel diseases and remains a clinical challenge. We investigated potential therapeutic strategies in a retrospective patient cohort focusing on clinical efficacy and pharmacokinetics.

Remission Is Maintained after Switch from Dose-Optimised Intravenous Treatment to Subcutaneous Treatment with Vedolizumab in Inflammatory Bowel Disease.

Background and Objectives: The subcutaneous (SC) formulation of vedolizumab has proven to be effective for the maintenance of remission after intravenous induction. Little is known about the efficacy of switching from intravenous maintenance treatment to SC. We aimed to assess the real-world efficacy of switching to SC treatment and to assess the impact of a baseline treatment regimen. Materials and Methods: In this observational cohort study, adult patients with inflammatory bowel disease who were switched to SC vedolizumab maintenance treatment were enrolled. Patients after intravenous induction and patients who switched from intravenous maintenance treatment (every 8 weeks or every 4 weeks) were included. The SC vedolizumab dosing was 108 mg every 2 weeks, regardless of the previous regimen. The clinical, biochemical, and endoscopic disease activity parameters and vedolizumab serum concentrations at the time of the switch and at the follow-up were assessed. Results: In total, 135 patients (38% Crohn's disease, 62% ulcerative colitis) were switched to SC vedolizumab treatment. The median time to the first follow-up (FU) was 14.5 weeks (IQR 12-26), and the median time to the second FU was 40 weeks (IQR 36-52). Nine patients (7%) discontinued SC vedolizumab treatment, with two-thirds of them discontinuing due to active disease. In all dosing regimens, there were no significant changes in the clinical scores and CRP at the baseline and first and second FUs. Clinical and biochemical remission appeared to be maintained irrespective of the previous dosing regimen. Conclusions: The results of this real-world study suggest that the maintenance of clinical and biomarker remission can be achieved in patients who switched from intravenous to SC vedolizumab. The baseline vedolizumab dosing regimen (every 4 weeks versus every 8 weeks) did not have an impact on outcomes.

CORE-IBD: A Multidisciplinary International Consensus Initiative to Develop a Core Outcome Set for Randomized Controlled Trials in Inflammatory Bowel Disease.

BACKGROUND & AIMS: End points to determine the efficacy and safety of medical therapies for Crohn's disease (CD) and ulcerative colitis (UC) are evolving. Given the heterogeneity in current outcome measures, harmonizing end points in a core outcome set for randomized controlled trials is a priority for drug development in inflammatory bowel disease. METHODS: Candidate outcome domains and outcome measures were generated from systematic literature reviews and patient engagement surveys and interviews. An iterative Delphi process was conducted to establish consensus: panelists anonymously voted on items using a 9-point Likert scale, and feedback was incorporated between rounds to refine statements. Consensus meetings were held to ratify the outcome domains and core outcome measures. Stakeholders were recruited internationally, and included gastroenterologists, colorectal surgeons, methodologists, and clinical trialists. RESULTS: A total of 235 patients and 53 experts participated. Patient-reported outcomes, quality of life, endoscopy, biomarkers, and safety were considered core domains; histopathology was an additional domain for UC. In CD, there was consensus to use the 2-item patient-reported outcome (ie, abdominal pain and stool frequency), Crohn's Disease Activity Index, Simple Endoscopic Score for Crohn's Disease, C-reactive protein, fecal calprotectin, and co-primary end points of symptomatic remission and endoscopic response. In UC, there was consensus to use the 9-point Mayo Clinic Score, fecal urgency, Robarts Histopathology Index or Geboes Score, fecal calprotectin, and a composite primary end point including both symptomatic and endoscopic remission. Safety outcomes should be reported using the Medical Dictionary for Regulatory Activities. CONCLUSIONS: This multidisciplinary collaboration involving patients and clinical experts has produced the first core outcome set that can be applied to randomized controlled trials of CD and UC.

Existing Bowel Preparation Quality Scales Are Reliable in the Setting of Centralized Endoscopy Reading.

BACKGROUND: Development of bowel preparation products has been based upon colon cleansing rating by a local endoscopist. It is unclear how bowel preparation scales perform when centrally evaluated. AIMS: To evaluate the reliability of bowel preparation quality scales when assessed by central readers. METHODS: Four central readers evaluated 52 videos in triplicate, 2 weeks apart, during the entire endoscopic procedure (insertion/withdrawal of the colonoscope) and exclusively on colonoscope withdrawal using the Boston Bowel Preparation Scale (BBPS), Chicago Bowel Preparation scale, Harefield Cleansing Scale, Ottawa Bowel Preparation Quality Scale (OBPQS), Aronchick score, a visual analogue scale, and additional items proposed in a modified Research and Development/University of California Los Angeles appropriateness process. Reliability was assessed with intraclass correlation coefficients. RESULTS: Intraclass correlation coefficients (95% confidence interval) for inter-rater reliability of the quality scales ranged from 0.51 to 0.65 (consistent with moderate to substantial inter-rater reliability) during the entire procedure. Corresponding intraclass correlation coefficients for intra-rater reliability ranged from 0.69 to 0.77 (consistent with substantial intra-rater reliability). Reliability was highest in the right colon and lowest in the left colon. No differences were observed in reliability when assessed for the procedure overall (insertion/withdrawal) relative to assessment on withdrawal alone. CONCLUSION: All five bowel preparation quality scales had moderate to substantial inter-rater reliability. Panelists considered the Aronchick score too simplistic for clinical trials and recognized that assessment of residual fluid in the Ottawa Bowel Preparation Quality Scale was not amenable to central assessment.

An unusual case of severe gastrointestinal bleeding.

We present the case of a 58-year-old female with a history of a bleeding duodenal peptic ulcer. Endoscopic hemostasis was unsuccessful; therefore, a transcatheter arterial embolization of a culprit vessel was performed. She was admitted to the hospital two months later because of obstruction of the common bile duct with cholangitis. Attempts to endoscopically place a biliary stent failed. The treating medical team opted for a surgical choledocho-jejunostomy. After 20 months, she presented with a melena and a severe anemia. Diagnostic work-up revealed portal vein thrombosis with portal cavernoma and bleeding choledocho-jejunostomy varices. The case presents and discusses rare complications of duodenal ulcer disease, as well as possible causes and treatment options.

Performance of European and American Societies of Gastrointestinal Endoscopy Guidelines for Prediction of Choledocholithiasis in Patients with Acute Biliary Pancreatitis.

Background and Objectives: Up to one-third of patients with acute biliary pancreatitis also present with choledocholithiasis. Guidelines from the European Society of Gastrointestinal Endoscopy (ESGE) and the American Society for Gastrointestinal Endoscopy (ASGE) for investigating suspected choledocholithiasis suggest endoscopic retrograde cholangiopancreatography in patients with high-likelihood (ESGE)/high-probability (ASGE) predictors and endoscopic ultrasound in those with intermediate-likelihood (ESGE)/intermediate-probability (ASGE) predictors. Although both guidelines are similar, they are not identical. Furthermore, these algorithms were mainly developed from cohorts of patients without pancreatitis and are therefore poorly validated in a subset of patients with acute pancreatitis. We aimed to assess the performance of the ESGE and ASGE algorithms for the prediction of choledocholithiasis in patients with acute biliary pancreatitis. Materials and Methods: This was a retrospective analysis of 86 consecutive patients admitted to a tertiary referral centre in the year 2020 due to acute biliary pancreatitis. Results: Choledocholithiasis was confirmed in 29/86 (33.7%) of patients (13 with endoscopic retrograde cholangiopancreatography and 16 with endoscopic ultrasound). All 10/10 (100%) ESGE high-likelihood and 14/19 (73.7%) ASGE high-probability patients had choledocholithiasis. Only 19/71 (26.8%) patients with ESGE intermediate likelihood and 15/67 (22.4%) with ASGE intermediate probability had choledocholithiasis. Only 8/13 (61.5%) patients with the ASGE high-probability predictor of dilated common bile duct plus bilirubin > 68.4 µmol/mL had choledocholithiasis. Since this predictor is not considered high likelihood by ESGE, this resulted in a superior specificity of the European compared to the American guideline (100% vs. 91.2%). Following the American instead of the European guidelines would have resulted in five unnecessary endoscopic retrograde cholangiopancreatographies and five unnecessary endoscopic ultrasound examinations. Conclusions: This retrospective analysis suggests that the European guidelines may perform better than the American guidelines at predicting choledocholithiasis in the setting of acute pancreatitis. This was because dilated common bile duct plus bilirubin > 68.4 µmol/mL was not a reliable predictor for persistent bile duct stones.

Early Combined Immunosuppression Reduces Complications in Long-standing Crohn's Disease: A Post Hoc Analysis of REACT.

Crohn's disease (CD) can lead to bowel damage, stricturing, and obstruction thereby resulting in surgery and hospitalization. The Randomized Evaluation of an Algorithm for Crohn's Treatment (REACT) trial showed that early combined immunosuppression (ECI) with symptom-based treatment escalation for 24 months resulted in a lower risk of surgery, hospitalization, or CD-related complications compared with conventional management (CM).1 Treatment earlier in the disease course may be associated with reduced risk of complications compared with later initiation, although data are sparse.2 We performed a post hoc analysis of REACT to evaluate the impact of baseline disease duration on surgery, hospitalization, or CD-related complications in patients treated with ECI compared with CM.

Responsiveness of Magnetic Resonance Enterography Indices for Evaluation of Luminal Disease Activity in Crohn's Disease.

BACKGROUND & AIMS: Magnetic resonance enterography (MRE) is having an increasing role in Crohn's disease; however, fully validated indices are needed. We evaluated the responsiveness of 4 MRE indices in luminal Crohn's disease. METHODS: Paired MRE images (pretreatment and post-treatment at weeks 12 or 14) from 41 patients were scored by 3 blinded radiologists. Disease activity was scored for 4 MRE indices (magnetic resonance index of activity [MaRIA], simplified MaRIA, London index, and London extended index) and a 100-mm visual analog scale (VAS) of overall disease activity. The criterion for change was an improvement by at least one half of an SD in the VAS after treatment. Responsiveness was evaluated using the standardized effect size (SES). Longitudinal validity was evaluated using correlations between changes in MRE index scores and disease activity measures including endoscopy and the VAS. RESULTS: The SES was 1.17 (95% CI, 0.56-1.77) for the simplified MaRIA, 0.98 (95% CI, 0.42-1.55) for the MaRIA, 0.95 (95% CI, 0.38-1.51) for the London extended index, and 0.85 (95% CI, 0.31-1.39) for the London index. The simplified MaRIA was significantly more responsive than the London index (ΔSES, 0.32; 95% CI, 0.05-0.58) but not the MaRIA (ΔSES, 0.18; 95% CI, -0.01 to 0.38) or the London extended index (ΔSES, 0.22; 95% CI, -0.05 to 0.50). Correlations with endoscopy (simplified MaRIA: r = 0.72) were not different from correlations with the VAS (London extended index: r = 0.70). CONCLUSIONS: Evaluated MRE indices showed moderate-to-large responsiveness and are suitable for use in clinical trials. The simplified MaRIA may be preferred because of its responsiveness and nonreliance on gadolinium administration.

Increased Risk of Infections with Anti-TNF Agents in Patients with Crohn's Disease After Elective Surgery: Meta-Analysis.

BACKGROUND: Postoperative complication rates in patients with inflammatory bowel disease (IBD) receiving preoperative biologics have been analyzed without considering the surgical context. Emergency surgery may be associated with an increased risk of infectious complications, compared to elective operations. AIMS: To conduct a systematic review and meta-analysis investigating the relationship between preoperative biologic therapy and postoperative outcomes in Crohn's disease (CD) and ulcerative colitis (UC), focusing on elective surgery. METHODS: Electronic databases were searched up to February 12, 2020, for studies of patients with IBD undergoing elective abdominal surgery receiving biologic therapy within 3 months before surgery compared to no therapy, or another biologic therapy. Certainty of evidence was evaluated using GRADE. The primary outcomes were the rate of infections and total complications within 30 days. Pooled odds ratios (ORs) and 95% confidence intervals (CIs) were calculated. RESULTS: Thirty-three studies were included. Preoperative treatment with anti-tumor necrosis factor (TNF) therapy in patients with CD undergoing elective surgery was associated with increased odds of infection (OR 2.05; 95% CI 1.40-3.01), but not total complications (OR 1.03; 95% CI 0.71-1.51). In elective surgery for UC, preoperative anti-TNF therapy was not associated with infectious (OR 1.03; 95% CI 0.34-3.07) or total complications (OR 0.67; 95% CI 0.29-1.58). Limited data indicate that emergency surgery did not significantly affect the rate of complications. CONCLUSIONS: Anti-TNF therapy prior to elective surgery may increase the odds of postoperative infection in CD, although the certainty of evidence is very low. More evidence is needed, particularly for newer biologics.

Peak Concentrations of Ustekinumab After Intravenous Induction Therapy Identify Patients With Crohn's Disease Likely to Achieve Endoscopic and Biochemical Remission.

BACKGROUND & AIMS: Little is known about the relationship between ustekinumab exposure during the first 2 weeks of treatment and outcomes of patients with Crohn's disease (CD). We investigated the relationship between serum concentrations of ustekinumab during the first 2 weeks of treatment and endoscopic and biochemical remission in patients with CD. METHODS: In a prospective observational study, we measured concentrations of ustekinumab in serum samples from 41 consecutive patients who started treatment with ustekinumab (approximately 6 mg/kg, intravenously, then 90 mg every 8 weeks), due to endoscopic markers of active CD, at a single center from October 2017 through January 2019. We measured ustekinumab exposure parameters during the first 2 weeks (peak concentration measured immediately after intravenous infusion, week 2 concentration, and area under the curve through week 2). We investigated the correlation between these parameters and endoscopic remission (simple endoscopic score for CD scores of 3 or less without ulceration, assessed centrally) and biochemical remission (level of fecal calprotectin below 100 mg/kg) using the Mann-Whitney U test. RESULTS: Endoscopic remission was achieved in 10 patients (24.4%) at week 24; biochemical remission was achieved in 17 patients (41.5%) at week 8, 17 patients (41.5%) at week 16, and 21 patients (51.2%) at week 24. Peak concentrations associated with endoscopic remission (area under the receiver operating characteristic curve, 0.717; 95% CI, 0.517-0.916); 6 of 13 patients (46%) with peak concentrations above 105 µg/mL (upper tercile) achieved endoscopic remission, compared with only 1 of 14 patients (7%) with peak concentrations below 88 µg/mL (lower tercile). All exposure parameters during the first 2 weeks were associated with biochemical remission. There was no significant difference between the associations of peak concentrations, week-2 concentrations, area under the curve through week 2, or later exposure measures (at weeks 4 and 8) with biochemical or endoscopic remission. CONCLUSIONS: In a prospective study, we found that serum concentrations of ustekinumab as early as 1 hour after intravenous infusion might be used to identify patients with CD most likely to achieve endoscopic remission. This early measurement might be used to optimize treatment of CD.

Success and safety of high infliximab trough levels in inflammatory bowel disease.

OBJECTIVE: A prospective trial suggests target infliximab trough levels of 3-7 µg/mL, yet data on additional therapeutic benefits and safety of higher trough levels are scarce. AIM: To explore whether high infliximab trough levels (≥7 µg/mL) are more effective and still safe. MATERIAL AND METHODS: In this cohort study of 183 patients (109 Crohn's disease and 74 ulcerative colitis) on infliximab maintenance treatment at a tertiary referral center we correlated fecal calprotectin and C-reactive protein to trough levels (426 samples) at different time points during treatment. Rates of infections were compared in quadrimesters (four-month periods) with high trough levels to quadrimesters with trough levels <7 µg/mL during 420 patient-years. RESULTS: Fecal calprotectin and C-reactive protein (median [interquartile range]) were lower in patients with high trough levels (fecal calprotectin 66 mg/kg [30-257]; C-reactive protein 3 mg/L [3-3]) compared to trough levels below 7 µg/mL (fecal calprotectin 155 mg/kg [72-474]; C-reactive protein 3 mg/L [3-14.5]) (p < .001). High trough levels were superior also after excluding samples with trough levels <3 µg/mL from analysis. No differences in rates of infections were observed in quadrimesters with high trough levels (16/129 [12.4%]) compared to quadrimesters with trough levels <7 µg/mL (32/344 [9.3%]) (p = .32). Maintaining high trough levels resulted in 32% (interquartile range: 2-54%) increase of infliximab consumption. CONCLUSION: High infliximab trough levels provide better control of inflammation in inflammatory bowel disease without increasing the risk of infection.

Improving Arterial Wall Characteristics in Patients After Myocardial Infarction with a Very Low Dose of Fluvastatin and Valsartan: A Proof-of-Concept Study.

BACKGROUND We tested the concept of improving arterial wall characteristics by treatment with a very low-dose combination of fluvastatin and valsartan (low-flu/val) in stable, post-myocardial infarction (MI) patients. MATERIAL AND METHODS We enrolled 36 post-MI middle-aged males in the treatment (n=20) or control (n=16) group receiving low-flu/val (10 mg/20 mg) or placebo, respectively. The parameters of endothelial function (flow-mediated dilatation (FMD), reactive hyperemia index), and arterial stiffness (carotid-femoral pulse wave velocity (cf-PWV), local carotid PWV, and beta stiffness coefficient) were measured before and after 30 days of therapy, and 10 weeks later. RESULTS Treatment with low-flu/val improved FMD from 3.1±1.3% to 4.8±1.5% (p<0.001; by 54.8%) and cf-PWV from 7.8±1.1 to 6.7±1.5 m/s (p<0.01; by 14.1%) without affecting either lipids or blood pressure. In the treatment group, FMD and/or cf-PWV significantly improved in 17 patients, but the improvements did not correlate. The benefits obtained were still detectable 10 weeks after complete treatment cessation. No changes were obtained in the control group. No other vascular parameters changed. CONCLUSIONS Low-flu/val added "on top of" optimal therapy substantially improves endothelial function and arterial stiffness in post-MI patients. Since these improved parameters are well-known predictors of future coronary events, such treatment could decrease cardiovascular risk. Further studies are therefore warranted.

A Combination of Low Doses of Fluvastatin and Valsartan Decreases Arterial Stiffness in Patients After Myocardial Infarction: A Pilot Study.

BACKGROUND: Despite optimum treatment, patients who experience myocardial infarction are still at high risk for future events. OBJECTIVE: We evaluated the effect of 30 days of treatment with combination of low, subtherapeutic doses of fluvastatin and valsartan on arterial stiffness in patients after myocardial infarction, a therapy that has not been used yet. METHODS: Fourteen male patients with a history of myocardial infarction were enrolled into a pilot double-blind randomized controlled study. They were allocated to receive 10 mg fluvastatin and 20 mg valsartan or placebo for 30 days in addition to their regular pharmacotherapy. Carotid-femoral pulse wave velocity was measured on inclusion, after 30 days, and after 3 months. RESULTS: Mean (SD) carotid-femoral pulse wave velocity decreased significantly in the treatment group after 30 days and persisted at lower values after 3 months (from 8.4 [1.5] m/sec to 7.3 [1.1] m/sec to 7.2 [0.8] m/sec; P < 0.05). The 95% CI for decrease after 30 days in the treatment group was 0.5-1.6. Only nonsignificant changes were observed in the control group. Serum lipid levels and arterial blood pressure did not change significantly in any group. CONCLUSIONS: The treatment resulted in a significant and sustained improvement of arterial stiffness in male patients with a history of myocardial infarction, which highlights the need for further study of this new approach.

Upadacitinib for the treatment of moderate-to-severe Crohn's disease.

Despite an increasing number of therapies for Crohn's disease (CD), half of patients do not respond to initial treatment or lose response over time, highlighting the need for novel therapies. Inhibition of Janus kinases (JAKs) has emerged as an important therapeutic target for CD. Upadacitinib is an orally administered selective JAK1 inhibitor, which is effective for the induction and maintenance of remission in moderately-to-severely active CD, including in patients with prior failure of biological therapy. Nonselective JAK inhibition has been associated with thromboembolic disease, cardiovascular events and malignancy in patients older than 50 years with rheumatoid arthritis and pre-existing cardiovascular risk factors, which should be considered upon prescription. Upadacitinib is the first and currently only oral advanced therapy for CD.

Not all patients with Crohn's disease (CD) get better with treatment. Blocking Janus kinases (JAKs), enzymes that promote inflammation in the gut, could help these patients. The treatment upadacitinib blocks JAK1 (an enzyme transmitting inflammatory signals) and decreases inflammation in the gut. It eases symptoms. It also resolves gut inflammation in patients with CD. Regarding side effects, JAK inhibitors can cause blood clots in veins, and in the lungs, heart attacks, cancer and infections. Further studies are needed, but caution is advised. Upadacitinib is the first advanced therapy for CD given by mouth.

Differences Between the 2016 and 2022 Food and Drug Administration Guidance-Implications for Design and Interpretation of Clinical Trials in Ulcerative Colitis.

Background: In 2022, the Food and Drug Administration (FDA) updated its draft guidance for drug development in ulcerative colitis, replacing the version from 2016. Several changes from the 2016 version merit further discussion as they impact clinical trial design and the interpretation of trial results. Methods: We compared both documents and critically appraised the changes and implications for future clinical trials. Results: The 2022 guidance recommends full colonoscopy, rather than flexible sigmoidoscopy, to document disease activity in all involved segments of the colon. The concordance between the findings of the 2 procedures is very high and there is little evidence to support colonoscopy over sigmoidoscopy. The use of colonoscopy, rather than sigmoidoscopy, is also associated with a higher burden to trial participants who must undergo full bowel preparation, cost, and a potential for more adverse events. The definition of the Mayo endoscopic score of 0 was changed from the original publication to "normal appearance of mucosa," which suggests that endoscopic signs of prior disease, such as pseudopolyps and scarring, are incompatible with a score 0, even though they are not associated with active disease. The term "mucosal healing" has been abolished and histologic outcomes defined as exploratory. A welcome change is that shorter washout periods than 5 half-lives will be considered to reduce patient exposure to corticosteroids as bridging therapy. Conclusions: The 2022 FDA draft guidance includes changes which for the most part are not informed by empirical evidence, which may ultimately complicate interpretation of future trials and preclude comparisons with past trials.

Scoring Indices for Perianal Fistulising Crohn's Disease: A Systematic Review.

BACKGROUND AND AIMS: In this systematic review we summarise existing scoring indices for assessing disease activity and quality of life in perianal fistulising Crohn's disease [PFCD], and highlight gaps in the literature. METHODS: MEDLINE, EMBASE, and CENTRAL were searched from August 24, 2022, to identify studies evaluating clinical, radiological, or patient-reported outcome measures [PROMS] in PFCD. The primary objective was to identify all available scoring indices and describe the operating properties of these indices. RESULTS: A total of 53 studies reported on the use of one clinical index [Perianal Disease Activity Index: PDAI], three PROMs, and 10 radiological indices; 25 studies evaluated the operating properties of these indices. The PDAI demonstrated content validity, construct validity, and responsiveness but criterion validity or reliability were not assessed. The Van Assche Index [VAI], modified VAI, and the Magnetic Resonance Index for Assessing Fistulas in Patients with CD [MAGNIFI-CD] were the most studied radiological indices. These indices demonstrated responsiveness and reliability. The VAI and MAGNIFI-CD demonstrated construct validity; criterion and content validity and feasibility have not been assessed. Among the three PROMs, the Crohn's Anal Fistula Quality of Life index demonstrated content and construct validity, inter-observer reliability, and responsiveness; criterion validity, intra-observer reliability, and feasibility have not been assessed for this index. CONCLUSIONS: There are no fully valid, reliable, and responsive clinical disease or radiological indices for PFCD. Although the radiological indices demonstrated responsiveness and reliability, well-defined cut-offs for response and remission are lacking. Future research should focus on establishing standardised definitions and thresholds for outcomes.