Summary
Background
Therapeutic drug monitoring (TDM) in inflammatory bowel disease (IBD) patients receiving anti‐tumour necrosis factor (TNF) agents can help optimise outcomes. Consensus statements ...based on current evidence will help the development of treatment guidelines.
Aim
To develop evidence‐based consensus statements for TDM‐guided anti‐TNF therapy in IBD.
Methods
A committee of 25 Australian and international experts was assembled. The initial draft statements were produced following a systematic literature search. A modified Delphi technique was used with 3 iterations. Statements were modified according to anonymous voting and feedback at each iteration. Statements with 80% agreement without or with minor reservation were accepted.
Results
22/24 statements met criteria for consensus. For anti‐TNF agents, TDM should be performed upon treatment failure, following successful induction, when contemplating a drug holiday and periodically in clinical remission only when results would change management. To achieve clinical remission in luminal IBD, infliximab and adalimumab trough concentrations in the range of 3‐8 and 5‐12 μg/mL, respectively, were deemed appropriate. The range may differ for different disease phenotypes or treatment endpoints—such as fistulising disease or to achieve mucosal healing. In treatment failure, TDM may identify mechanisms to guide subsequent decision‐making. In stable clinical response, TDM‐guided dosing may avoid future relapse. Data indicate drug‐tolerant anti‐drug antibody assays do not offer an advantage over drug‐sensitive assays. Further data are required prior to recommending TDM for non‐anti‐TNF biological agents.
Conclusion
Consensus statements support the role of TDM in optimising anti‐TNF agents to treat IBD, especially in situations of treatment failure.
Summary
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.
Summary
Background
Crohn's disease recurs in the majority of patients after intestinal resection.
Aim
To compare the relative efficacy of thiopurines and anti‐TNF therapy in patients at high risk of ...disease recurrence.
Methods
As part of a larger study comparing post‐operative management strategies, patients at high risk of recurrence (smoker, perforating disease, ≥2nd operation) were treated after resection of all macroscopic disease with 3 months metronidazole together with either azathioprine 2 mg/kg/day or mercaptopurine 1.5 mg/kg/day. Thiopurine‐intolerant patients received adalimumab induction then 40 mg fortnightly. Patients underwent colonoscopy at 6 months with endoscopic recurrence assessed blind to treatment.
Results
A total of 101 patients 50% male; median (IQR) age 36 (25–46) years were included. There were no differences in disease history between thiopurine‐ and adalimumab‐treated patients. Fifteen patients withdrew prior to 6 months, five due to symptom recurrence (of whom four were colonoscoped). Endoscopic recurrence (Rutgeerts score i2–i4) occurred in 33 of 73 (45%) thiopurine vs. 6 of 28 (21%) adalimumab‐treated patients intention‐to‐treat (ITT); P = 0.028 or 24 of 62 (39%) vs. 3 of 24 (13%) respectively per‐protocol analysis (PPA); P = 0.020. Complete mucosal endoscopic normality (Rutgeerts i0) occurred in 17/73 (23%) vs. 15/28 (54%) (ITT; P = 0.003) and in 27% vs. 63% (PPA; P = 0.002). The most advanced disease (Rutgeerts i3 and i4) occurred in 8% vs. 4% (thiopurine vs. adalimumab).
Conclusions
In Crohn's disease patients at high risk of post‐operative recurrence adalimumab is superior to thiopurines in preventing early disease recurrence.
Summary
Background
Acute severe ulcerative colitis (ASUC) is a potentially life‐threatening complication of ulcerative colitis.
Aim
To develop consensus statements based on a systematic review of the ...literature of the management of ASUC to improve patient outcome.
Methods
Following a literature review, the Delphi method was used to develop the consensus statements. A steering committee, based in Australia, generated the statements of interest. Three rounds of anonymous voting were carried out to achieve the final results. Acceptance of statements was pre‐determined by ≥80% votes in ‘complete agreement’ or ‘agreement with minor reservation’.
Results
Key recommendations include that patients with ASUC should be: hospitalised, undergo unprepared flexible sigmoidoscopy to assess severity and to exclude cytomegalovirus colitis, and be provided with venous thromboembolism prophylaxis and intravenous hydrocortisone 100 mg three or four times daily with close monitoring by a multidisciplinary team. Rescue therapy such as infliximab or ciclosporin should be started if insufficient response by day 3, and colectomy considered if no response to 7 days of rescue therapy or earlier if deterioration. With such an approach, it is expected that colectomy rate during admission will be below 30% and mortality less than 1% in specialist centres.
Conclusion
These evidenced‐based consensus statements on acute severe ulcerative colitis, developed by a multidisciplinary group, provide up‐to‐date best practice recommendations that improve and harmonise management as well as provide auditable quality assessments.
Aim
We studied the levels of amylase in drain fluid to investigate its utility as a biomarker of anastomotic leak in ileal pouch patients who did not have a covering loop ileostomy. The luminal ...contents of the small intestine are high in amylase. Ileal J pouches are formed for restoration of continuity in patients with ulcerative colitis after removal of the colon and rectum. A drain is placed alongside the ileal pouch in the pelvis.
Method
This study is a retrospective analysis of prospectively collected daily drain fluid amylase levels in consecutive patients undergoing restorative proctectomy and ileal J pouch anal anastomosis, without a covering loop ileostomy, between November 2016 and April 2018.
Results
Thirteen patients underwent surgery without a covering loop ileostomy. Two patients suffered an anastomotic leak and were returned to theatre, one on day 5 and the other on day 6 postoperatively. The mean daily drain fluid amylase level in those who did not leak was between 25 and 46 U/l with a range of 22–139 U/l for all samples collected. In the two patients who suffered a clinical leak the drain fluid amylase level rose to 22 432 and 10 212 U/l on the day of clinical leak diagnosis. The mean rectal tube (intraluminal) amylase level was 63 097 U/l as measured on day 1 postoperatively.
Conclusion
In this small cohort of patients, the measurement of drain fluid amylase is a highly sensitive biomarker of clinical anastomotic leak.
Linked ContentThis article is linked to Costello et al papers. To view these articles visit https://doi.org/10.1111/apt.14173 and https://doi.org/10.1111/apt.14246.
Linked ContentThis article is linked to Doecke and Hartnell et al and Barreiro‐de Acosta and Gisbert papers. To view these articles visit https://doi.org/10.1111/apt.13880 and ...https://doi.org/10.1111/apt.13929.
Summary
Background
Maintenance anti‐tumour necrosis factor‐α (anti‐TNFα) treatment for Crohn's disease is the standard of care for patients with an inadequate response to corticosteroids and ...immunomodulators.
Aim
To compare the efficacy and safety of infliximab and adalimumab in clinical practice and assess the value of concomitant immunomodulator therapy.
Methods
We performed an observational cohort study in consecutive patients with Crohn's disease qualifying for anti‐TNFα treatment in Australia and New Zealand between 2007 and 2011. Demographic and clinical data were prospectively recorded to identify independent factors associated with induction and maintenance of response to infliximab or adalimumab, or to either anti‐TNFα therapy.
Results
Three hundred and twenty‐seven patients (183 infliximab, 144 adalimumab) successfully applied for treatment. Eighty‐nine percent responded in all groups and median maintenance of response was similar for the two agents. Concomitant immunomodulator with infliximab, but not adalimumab, demonstrated a significantly longer response overall (P = 0.002), and significantly fewer disease and treatment‐related complications (P = 0.017). Corticosteroids at baseline, and/or in the preceding 12 months, were associated with a 9–13 times greater risk of disease flare during maintenance treatment as compared to no corticosteroids (P < 0.0001). Maintenance of response was similar in the anti‐TNF naïve and anti‐TNF experienced subgroups.
Conclusions
In this large, real‐life study, we demonstrate infliximab and adalimumab to have similar response characteristics. However, infliximab requires concomitant immunomodulator to achieve optimal maintenance of response comparable to adalimumab monotherapy. The results of this study will assist clinicians in further optimising patient care in their day‐to‐day clinical practice.
Linked Content
This article is linked to Barreiro‐de Acosta and Gisbert and Radford and Hartnell et al papers. To view these articles visit https://doi.org/10.1111/apt.13929 and https://doi.org/10.1111/apt.13968.
As custom arrays are cheaper than generic GWAS arrays, larger sample size is achievable for gene discovery. Custom arrays can tag more variants through denser genotyping of SNPs at associated loci, ...but at the cost of losing genome-wide coverage. Balancing this trade-off is important for maximizing experimental designs. We quantified both the gain in captured SNP-heritability at known candidate regions and the loss due to imperfect genome-wide coverage for inflammatory bowel disease using immunochip (iChip) and imputed GWAS data on 61,251 and 38.550 samples, respectively. For Crohn's disease (CD), the iChip and GWAS data explained 19 and 26% of variation in liability, respectively, and SNPs in the densely genotyped iChip regions explained 13% of the SNP-heritability for both the iChip and GWAS data. For ulcerative colitis (UC), the iChip and GWAS data explained 15 and 19% of variation in liability, respectively, and the dense iChip regions explained 10 and 9% of the SNP-heritability in the iChip and the GWAS data. From bivariate analyses, estimates of the genetic correlation in risk between CD and UC were 0.75 (SE 0.017) and 0.62 (SE 0.042) for the iChip and GWAS data, respectively. We also quantified the SNP-heritability of genomic regions that did or did not contain the previous 163 GWAS hits for CD and UC, and SNP-heritability of the overlapping loci between the densely genotyped iChip regions and the 163 GWAS hits. For both diseases, over different genomic partitioning, the densely genotyped regions on the iChip tagged at least as much variation in liability as in the corresponding regions in the GWAS data, however a certain amount of tagged SNP-heritability in the GWAS data was lost using the iChip due to the low coverage at unselected regions. These results imply that custom arrays with a GWAS backbone will facilitate more gene discovery, both at associated and novel loci.
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