Abstract Background Perianal disease is an increasingly recognised complication of ulcerative colitis (UC) (1). Variant rs4151651 in complement factor B (CFB) is associated with severe phenotype UC and, more recently, implicated in the pathogenesis of perianal Crohn’s disease (CD) (2, 3). In our previous work, we have shown the minor allele frequency (MAF) for the rs4151651 variant to be 0.03 for non-IBD affected control patients, 0.05 in patients with mild UC, and 0.13 in patients with severe phenotype UC (3). Here, we aim to determine the MAF for the rs4151651 variant in UC patients with perianal disease. Methods Ulcerative colitis patients with perianal disease were identified from our extensive inflammatory bowel disease (IBD) biobank. Perianal disease was defined as perianal abscesses or fistulae (haemorrhoids and anal fissures were excluded). Appropriate consent was obtained from all participants (HREC/14/QRBW/323). Demographic and phenotypic data were collected, and UC diagnoses were confirmed by expert IBD pathologists through histological review. To further confirm accurate phenotyping of our UC cohort, and to distinguish it from CD, we also present MAF data from the NOD2 gene, where available. Genotyping was either previously performed by genome-wide association study (GWAS) analysis or performed using the rs4151651 single nucleotide polymorphism (SNP). Results Forty-one patients were identified. Baseline demographics and clinical characteristics are presented in Table 1. Phenotypically and histologically all patients had disease consistent with UC. The MAFs for the NOD2 variants rs2066844, rs2066845 and rs2066847 were 0.04, 0.01 and 0.01 respectively. Eight patients had both a perianal abscess and a fistula, 1 patient had a perianal abscess only, and 33 patients had perianal fistulae only. Twenty-four patients in our cohort had a prior colectomy. The MAF for the rs4151651 variant in the 41 UC patients with perianal disease was 0.28. In the 21 patients who had extensive disease (E3), the MAF was 0.29. In the 24 patients who had a prior colectomy, the MAF was 0.30 (Figure 1). Conclusion The rs4151651 variant on the CFB gene is associated with perianal disease in UC patients. These findings align with prior studies linking the rs4151651 variant to a more severe UC phenotype. This SNP could be a valuable biomarker in predicting perianal complications for patients with severe UC undergoing colectomy and considering reconstructive (pouch) surgery. References 1.Choi YS, Kim DS, Lee DH, Lee JB, Lee EJ, Lee SD, et al. Clinical Characteristics and Incidence of Perianal Diseases in Patients With Ulcerative Colitis. Ann Coloproctol. 2018;34(3):138-43. 2.Akhlaghpour M, Haritunians T, More SK, Thomas LS, Stamps DT, Dube S, et al. Genetic coding variant in complement factor B (CFB) is associated with increased risk for perianal Crohn’s disease and leads to impaired CFB cleavage and phagocytosis. Gut. 2023;72(11):2068-80. 3.Mortlock S, Lord A, Montgomery G, Zakrzewski M, Simms LA, Krishnaprasad K, et al. An Extremes of Phenotype Approach Confirms Significant Genetic Heterogeneity in Patients with Ulcerative Colitis. J Crohns Colitis. 2023;17(2):277-88.

Abstract Background An episode of acute severe ulcerative colitis (UC) is a watershed event during the disease course with a heightened risk of colectomy during and following these episodes.1 The prompt identification of these events followed by the early implementation of appropriate treatment is essential to obtaining the best clinical outcomes for these unwell patients. The majority of published risk scores predicting the important clinical outcomes of intravenous corticosteroid therapy failure and colectomy-by-discharge rely on clinical data from days 1–3 of therapy.2 There is a paucity of tools that allow for a simple and individualised prediction of risk of corticosteroid therapy failure during the earliest stages of admission. Methods Data were prospectively obtained from 349 presentations of moderate–severe UC requiring hospital admission to a tertiary referral hospital. The failure of intravenous corticosteroid therapy was strictly defined by the (Oxford) Day 3 and Day 7 criteria.3 Seventeen clinical, laboratory and endoscopic variables all available within 24 h of hospital presentation were assessed for their ability to differentiate intravenous corticosteroid therapy responders from non-responders. A stepwise generalised linear model was formulated based on the results of the initial univariate analyses. Results Intravenous corticosteroid therapy failure occurred in 208/349 (60%) of presentations. The formulated risk score included the variables of oral corticosteroid therapy failure, bowel frequency and serum albumin concentration with or without the Mayo endoscopic subscore (MES). With the addition of the MES, the area under the curve (AUC) of the risk score was 0.758. When the positive predictive value of the score (threshold) for correctly predicting intravenous corticosteroid therapy failure was set at 85%, 105/275 (38%) of presentations with available data were identified as high risk for corticosteroid therapy failure (Figure 1). Conclusion This practical risk assessment tool provides clinicians with a personalised prediction of the likelihood of success of a course of intravenous corticosteroid therapy in moderate–severe UC. It enables the identification of individuals at high risk of treatment failure who may be suitable for consideration of early treatment escalation or screening for appropriate clinical trials. References

Abstract Background Anti-tumor necrosis factor-α (anti-TNFa) therapy have been established as an effective maintenance treatment for complicated Crohn’s Disease (CD). However, the efficacy of Infliximab (IFX) and Adalimumab (ADM) may be affected by low serum levels and/or the presence of anti-drug antibodies (ADA). This reinforces the importance of therapeutic drug monitoring (TDM). We aim to assess the clinical benefit of proactive vs. reactive TDM. Secondly, to assess the impact of TDM on clinical management. Thirdly, to identify risk factors for low serum drug levels and the development of ADA in CD patients. Methods This was a single-centred observational cohort study performed at a tertiary hospital, comprising of total 229 CD patients: 142 received IFX and 87 received ADM, who have had a trough drug level, tested using enzyme-linked immunosorbent assay. Demographic and clinical data were retrospectively collected from electronic medical records. Fisher’s Exact Test was used to determine if there are nonrandom associations between variables. A p-value of less than 0.05 was considered statistically significant. Results One hundred and fourteen patients (49%) receiving a standard anti-TNFa regimen had subtherapeutic drug levels (67 had IFX < 3 μg/ml and 47 had ADM < 5 μg/ml). Interestingly, almost half of this cohort were asymptomatic. Reactive TDM completed among symptomatic patients have shown to have a statistically significant benefit in detecting subtherapeutic drug level (p = 0.0001). Following these results, only fifty-two patients (46%) had a change of therapy (29 IFX, 25 ADM); while the remaining sixty-two patients (54%) continued the same dosing regimen with only one documented admission within 90-days following the drug level being taken. Eight patients (4%) were found to have positive ADA, all in the presence of subtherapeutic drug levels. Two of these had a subsequent flare of their disease. They were all switched to another class of biologic therapy. Non-smoking status at diagnosis and the concomitant use of immunomodulator were found to have statistically significant associations with a therapeutic drug level (p = 0.0176 and p = 0.0001, respectively). Similarly, both of these risk factors were associated with lower risk of ADA formation (p = 0.0057 and p = 0.0165, respectively). Conclusion This study suggests that a large proportion of patients have subtherapeutic drug levels at standard dosing schedules. However, low drug levels do not correlate with a higher risk of complications if patients are in clinical remission. The results of this study also indicate that non-smoking status at diagnosis and the concomitant use of immunomodulator are associated with higher serum drug levels and lower risk of developing anti-drug antibodies.

BACKGROUND:Up to 40% of patients who present with acute severe ulcerative colitis (UC) fail to make an adequate response to intravenous corticosteroids. Ciclosporin or infliximab are currently employed as salvage therapy in this clinical scenario.AIM:To compare clinical outcomes in patients treated with ciclosporin or infliximab in the setting of steroid-refractory acute severe UC.METHODS:A prospective study of 83 consecutive presentations of steroid-refractory acute severe UC from 1999 to 2009 was conducted. All study participants satisfied the Truelove and Witts' criteria for acute severe UC. The primary outcome measures were rates of colectomy at discharge from hospital and at 3 months and 12 months following admission.RESULTS:Eighty-three steroid-refractory acute severe UC events were generated by 83 patients. Salvage therapy was instituted with ciclosporin in 45 patients and infliximab in the remaining 38 patients. Of those patients who received ≥72 h of ciclosporin (2-4 mg/kg), 56% (24/43) avoided colectomy at the time of discharge, while this figure was 84% (32/38) for those administered one dose of infliximab (5 mg/kg) (P = 0.006). At 3 months, the colectomy-free rate was 53% for ciclosporin (23/43) vs. 76% for infliximab (28/37) (P = 0.04), and 42% (18/43) vs. 65% (24/37) at 12 months (P = 0.04). There were no deaths and two serious adverse events, both occurring in the ciclosporin group.CONCLUSIONS:In this large cohort of patients presenting with acute severe UC, we have observed that infliximab salvage therapy is associated with lower rates of both severe adverse events and colectomy than ciclosporin in the short-term and medium-term.

AIM:The advent of rescue medical therapy (cyclosporin or infliximab) and laparoscopic surgery has shifted the paradigm in managing steroid refractory acute severe ulcerative colitis (ASUC). We investigated prospectively the impact of rescue therapy on timing and postoperative complications of urgent colectomy and subsequent restorative surgery for steroid refractory ASUC.METHOD:All consecutive presentations of steroid refractory ASUC at the Royal Brisbane Hospital (1996-2009) were entered in the study. Data collated included demographics, clinical and laboratory parameters on admission, medical therapy and operative and postoperative details. Steroid refractory ASUC patients undergoing immediate colectomy were compared with those failing rescue therapy and requiring same admission colectomy.RESULTS:Of 108 steroid refractory ASUC presentations, 19 (18%) received intravenous steroids only and proceeded directly to colectomy. Rescue medical therapy was instituted in 89 (82%) patients with 30 (34%) failing to respond and proceeding to colectomy. There was no significant difference in the median time from admission to colectomy for rescue therapy compared with steroid-only cases (12 vs 10 days, P = 0.70) or 30-day complication rates (27%vs 47%, P = 0.22). The interval from colectomy to a subsequent restorative procedure was significantly longer for patients who failed rescue therapy (12 vs 5 months, P = 0.02). Furthermore 30-day complications following pouch surgery were significantly higher in patients who failed rescue therapy (32%vs 0%, P = 0.01).CONCLUSION:Rescue therapy in steroid refractory ASUC is not related to delay in urgent colectomy or increased post-colectomy complications.

*Department of Gastroenterology, Royal Brisbane and Women’s Hospital, Brisbane, Queensland, Australia. Department of Gastroenterology, St Vincent’s Hospital, Sydney, NSW, Australia. The Australian E-Health Research Centre, Royal Brisbane and Women’s Hospital, Brisbane, Queensland, Australia. CSIRO Preventative Health Flagship, Parkville, Melbourne, Victoria, Australia. CSIRO Mathematics and Information Sciences, Macquarie University, Sydney, NSW, Australia. **IBD Group, Queensland Institute of Medical Research and University of Queensland School of Medicine, Herston Campus, Brisbane, Queensland, Australia. E-mail: anthony.croft@gmail.com

We would like to thank our colleagues for their interest in our recent article.4 They are correct in their assertion that there was a period (1999–2001) when ciclosporin was the sole salvage agent available. As indicated in the paper, there was also an 18-month period at the conclusion of the study when infliximab was the only salvage agent used. Treatment allocation was patient-led and based upon an informed decision after detailed discussion with one of two IBD specialists at our centre. This included details of previous published studies and the centre's own experience. This approach is recommended in the Laharie study (page 1914).3 The consistency of the clinical protocols and decision-making inherent to a single-centre study design were presented as strengths of the study. The study was designed to test the two salvage agents with all other variables remaining the same during the study period. In addition, we believe this study has a high degree of external validity due to the utilisation of standardised treatment algorithms that were consistently applied to a patient cohort that is typical of those encountered in larger IBD centres. The path to colectomy is a unique journey for each ulcerative colitis-affected patient who undergoes this procedure. The timing of surgery is influenced by many variables, including obtaining informed consent. We disagree that this end point is ‘subjective and predetermined’ as consistent age-appropriate criteria were applied to patients when this clinical decision was made, as in previously published studies.4 Indeed, previous salvage therapy was not a variable considered in the making of this clinically important decision. Colectomy is a tangible, objective outcome that is reflective of the disease burden either acutely or cumulatively in the case of refractory disease. The authors’ declarations of personal and financial interests are unchanged from those in the original article.2

Introduction: Low bone mass is a frequent complication of Crohn's disease (CD) and is associated with increased risk for fracture compared to healthy populations. The pathogenesis of bone loss in CD is multifactorial although we have previously shown that muscle mass is a significant contributor to bone density in CD. However, it remains unclear if the muscle-bone unit, which provides insight into whether bone strength is adequately adapted to muscle mass or strength, is at an adequate level and similar to that in non-CD persons. The status of the muscle-bone unit has implications in the design of exercise programs for this clinical population. For instance, if bone mass is not adequate for muscle mass then a specific bone-loading program would be required. Therefore, the aim of this study was to assess the muscle-bone unit in CD patients. Methods: Twenty-two male CD patients aged 20–53 years with apparently good medical control and 20 similarly aged healthy controls served as subjects. Bone strength parameters and body composition were assessed using peripheral quantitative computed tomography (pQCT) and dual-energy X-ray absorptiometry (DXA). Isometric and isokinetic strength was determined by dynamometry. Results: For pQCT measures, CD patients had lower (P < 0.05) tibial shaft mass, tibial shaft cortical cross-sectional area (CSA), and proximal tibia bone mineral density (BMD). CD subjects also had significantly lower areal BMD by DXA than controls at the total body (P = 0.038) and hip (P = 0.019). Controls had consistently higher isometric and isokinetic muscle force values than the CD group; however these differences did not reach statistical significance except for knee extensor strength. There were no significant differences between groups for any of the muscle-bone indices assessed, such as bone mineral content (BMC)/muscle CSA and bone CSA/muscle strength. Conclusions: These results suggest that bone mass/size is adequate for muscle mass/strength in our CD patients. This implies that a specific bone-loading regimen or a specific anabolic exercise program to enhance muscle mass to re-establish an appropriate bone-muscle unit relationship is not required. However, these results are preliminary and need to be confirmed in larger samples of CD patients of both genders and with varying levels of disease management.

BackgroundAcute severe ulcerative colitis (ASUC) is a common and serious complication of UC. For those cases refractory to intravenous steroid therapy Cyclosporin or, more recently, Infliximab therapy is the current standard of care. Although there have been no published studies comparing and contrasting these agents, clinical experience has previously indicated their effectiveness to be equable in this clinical context.