Publications by authors named "Miles P Sparrow"

67 Publications

De-escalation from Dose-Intensified Anti-TNF Therapy Is Successful in the Majority of IBD Patients at 12 Months.

Dig Dis Sci 2021 Mar 25. Epub 2021 Mar 25.

Department of Gastroenterology, Alfred Health and Monash University, Melbourne, 3004, Australia.

Background: Data on outcomes following de-escalation of intensified anti-TNF therapy in inflammatory bowel disease (IBD) are limited and concerns about relapse limit willingness to de-escalate.

Aims: To evaluate rates of successful de-escalation at 12 months and to determine factors that may predict success.

Methods: Single-centre experience of IBD patients that were de-escalated following deep remission on dose-intensified infliximab (IFX) or adalimumab (ADA) for secondary loss of response. Patients were classified as 'successes' if remaining on reduced anti-TNF or 'failures' if requiring re-escalation, steroids, surgery or enrolment into a clinical trial at 12 months. Patient demographics, disease characteristics, biomarkers (faecal calprotectin, C-reactive protein, albumin) and anti-TNF drug levels were collected 6-monthly.

Results: Of 25 patients (20 CD, 5 UC), 16 (64%) were successes 12 months post-de-escalation. Median time to failure was 6 months. Six of the nine failures required anti-TNF re-escalation and three entered a clinical trial. Re-escalation recaptured response in all six patients. There was no significant difference in baseline biomarker activity between the two groups. There was no difference in infliximab levels between successes and failures at the time of de-escalation (5.5 vs. 5.3, p = 0.63) as well as 6 months (3.1 vs. 4.6, p = 0.95) and 12 months (3.2 vs. 4.5, p = 0.58) post-de-escalation.

Conclusion: Nearly two-thirds of patients remained on reduced anti-TNF dosing 12 months after de-escalation. All patients who failed de-escalation were recaptured after dose re-escalation. De-escalation with close monitoring may be considered in patients on intensified anti-TNF therapy in sustained remission.
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http://dx.doi.org/10.1007/s10620-021-06937-zDOI Listing
March 2021

A Single Educational Intervention Improves Pregnancy-Related Knowledge and Emotional Health Among Women With IBD Who Are Pregnant or Wish to Conceive.

Inflamm Bowel Dis 2021 Mar 11. Epub 2021 Mar 11.

Department of Gastroenterology, St. Vincent's Hospital, Melbourne, Australia.

Background: There is considerable interest in improving the education and care of women with inflammatory bowel disease (IBD) to improve pregnancy outcomes. Despite increased awareness, not all women with IBD have access to pregnancy-related education and the quality of counseling is variable. We aimed to assess the effectiveness of a simple educational intervention for improving pregnancy-related knowledge and to evaluate the effect of education on patient outcomes including anxiety, depression, and quality of life in women with IBD.

Methods: This prospective study of women with IBD who were pregnant or planning a pregnancy evaluated the effectiveness of a single gastroenterologist-led educational intervention in improving pregnancy-related knowledge, measured using the Crohn's and Colitis Pregnancy Knowledge score 1 month postintervention. Secondary outcomes included the effect on anxiety and depression, quality of life, medication adherence, and patient satisfaction.

Results: One hundred women with IBD were recruited. Fifty percent were pregnant at the time of the intervention. Baseline knowledge scores were similar independent of the patients' pregnancy status or whether they had previously received counseling from their gastroenterologist. Median Crohn's and Colitis Pregnancy Knowledge scores postintervention (n = 82) were higher than preintervention scores (14/17 vs 10/17; P < 0.001). In addition, 32% of patients had poor knowledge at baseline (score ≤7/17), compared to only 5% after the intervention (P < 0.001). There was a significant improvement in total anxiety and depression and quality of life scores postintervention. Medication adherence and patient satisfaction were excellent.

Conclusions: Uptake of this gastroenterologist-led educational intervention has the potential to improve pregnancy knowledge, promote medication adherence, and enhance quality of life for women with IBD globally.
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http://dx.doi.org/10.1093/ibd/izab021DOI Listing
March 2021

Maternal thiopurine metabolism during pregnancy in inflammatory bowel disease and clearance of thiopurine metabolites and outcomes in exposed neonates.

Aliment Pharmacol Ther 2021 04 19;53(7):810-820. Epub 2021 Feb 19.

Melbourne, Vic., Australia.

Background: Azathioprine and mercaptopurine are considered safe during pregnancy. However, the pharmacokinetic effects of pregnancy on thiopurine metabolism are undefined.

Aims: To characterise thiopurine metabolism in pregnancy and measure infant metabolite levels and outcomes.

Methods: Women with IBD who were taking a thiopurine and pregnant or trying to conceive were recruited. Maternal thiopurine metabolites were measured pre-conception, in each trimester, at delivery and post-partum. Infant metabolite levels, full blood examination and liver function testing were performed at birth, and repeated until levels undetectable and haematological and biochemical abnormalities resolved.

Results: Forty patients were included with measurements on at least two occasions, and two with only mother-baby levels at delivery. The median maternal 6-TGN level dropped in the second trimester compared with post-partum (179.0 vs 323.5 pmol/8 × 10 RBCs, P < 0.001) and the median 6-MMP level increased in the second trimester compared with post-partum (1103.0 vs 329.5 pmol/8 × 10 RBCs, P < 0.01). At delivery, the median 6-TGN level was lower in infants (n = 20) than mothers (78.5 vs 217 pmol/8 × 10 RBCs) (P < 0.001). Metabolites were not detected at 6 weeks in any infants. Anaemia was not seen, but thrombocytosis and abnormal liver biochemistry were detected in 80% of infants from 6 weeks, which gradually improved.

Conclusions: 6-TGN levels decrease and 6-MMP levels increase in the second trimester of pregnancy. Infants are exposed to thiopurine metabolites at low levels with clearance by 6 weeks and no anaemia. The cause of infant thrombocytosis and abnormal liver biochemistry in the absence of metabolites is unclear.
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http://dx.doi.org/10.1111/apt.16294DOI Listing
April 2021

Long-term safety and efficacy of the anti-MAdCAM-1 monoclonal antibody ontamalimab (SHP647) for the treatment of ulcerative colitis: the open-label study TURANDOT II.

J Crohns Colitis 2021 Feb 18. Epub 2021 Feb 18.

University Hospitals Leuven, Leuven, Belgium.

Background And Aims: Ontamalimab, a fully-human monoclonal antibody targeting MAdCAM1, induced remission in patients with moderate-to-severe ulcerative colitis (UC) in TURANDOT. We assessed long-term safety, tolerability and efficacy of ontamalimab in TURANDOT II.

Methods: TURANDOT II was a phase 2, multicentre, open-label (OL) study in patients with moderate-to-severe UC who completed TURANDOT on placebo or ontamalimab. Patients were randomized to 75mg or 225mg ontamalimab every 4 weeks for 72 weeks (OL1). Dosage could be increased to 225mg from week 8 at the investigator's discretion. All patients then received 75mg every 4 weeks for 72 weeks (OL2), followed by 6-month safety follow-up. The primary objective was safety, measured by adverse events (AEs), serious AEs (SAEs) and AEs leading to withdrawal. Mucosal healing (MH; centrally read endoscopy) was assessed.

Results: Of 330 patients, 180 completed OL1; 94 escalated to 225mg; 127 completed OL2. Overall, 36.1% experienced drug-related AEs. The most common SAE (10.0%) was worsening/ongoing UC; 5.5% of patients had serious infections, the most common being gastroenteritis (0.9%). One death and four cancers (all unrelated to ontamalimab) occurred. No PML/lymphoproliferative disorders occurred. Geometric mean hsCRP and faecal calprotectin decreased across OL1 in both dose groups. The proportion of patients assigned placebo in TURANDOT achieving MH increased from 8.8% (6/68) at baseline to 35.3% at week 16 (24/68; non-responder imputation). The corresponding increase in the ontamalimab group was from 23.3% (61/262) to 26.7% (70/262).

Conclusions: Ontamalimab was well tolerated up to 144 weeks in patients with moderate-to-severe UC, with good safety and efficacy.
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http://dx.doi.org/10.1093/ecco-jcc/jjab023DOI Listing
February 2021

A pragmatic stepwise approach to the diagnosis and management of refractory acute pouchitis.

Expert Opin Pharmacother 2021 Apr 4;22(5):531-533. Epub 2021 Feb 4.

Department of Gastroenterology, Alfred Health and Monash University, Melbourne, Australia.

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http://dx.doi.org/10.1080/14656566.2021.1882422DOI Listing
April 2021

Editorial: anti-drug antibodies and the benefit of assay validation.

Aliment Pharmacol Ther 2021 01;53(1):194-195

Department of Gastroenterology, Alfred Hospital, Melbourne, VIC, Australia.

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http://dx.doi.org/10.1111/apt.16159DOI Listing
January 2021

Evolving Role of Thiopurines in Inflammatory Bowel Disease in the Era of Biologics and New Small Molecules.

Dig Dis Sci 2020 Oct 19. Epub 2020 Oct 19.

Department of Gastroenterology, Alfred Health, 55 Commercial Road, Melbourne, 3004, VIC, Australia.

In recent years, with the increasing availability of biologic therapies and due to safety concerns, the role of thiopurines in the management of inflammatory bowel disease has been questioned. While acknowledging that the benefit/risk ratio of biologic therapies is very high, they are expensive and are not required by a majority of patients. Therefore, thiopurines do retain an important role as steroid-sparing and maintenance agents when used as monotherapy, and in combination therapy with biologics due to their clinical and pharmacokinetic optimization of anti-tumor necrosis factor agents in particular. Safety concerns with thiopurines are real but also relatively rare, and with careful pre-treatment screening and ongoing monitoring thiopurine benefits outweigh risks in the majority of appropriately selected patients. Measurement of newer pharmacogenomic markers such as nudix hydrolase 15 (NUDT15), when combined with knowledge of existing known mutations (e.g., thiopurine S-methyltransferase-TPMT), will hopefully minimize the risk of potentially life-threatening leukopenia by allowing for pre-treatment dosing stratification. Further optimization of thiopurine dosing via measurement of thiopurine metabolites should be performed routinely and is superior to weight-based dosing. The association of thiopurines with malignancies including lymphoproliferative disorders needs to be recognized in all patients and individualized in each patient. The decrease in lymphoma risk after thiopurine cessation provides an incentive for thiopurine de-escalation in appropriate patients after a period of prolonged deep remission. This review will summarize the current role of thiopurines in inflammatory bowel disease management and provide recommendations for commencing and monitoring therapy, and when to consider de-escalation.
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http://dx.doi.org/10.1007/s10620-020-06662-zDOI Listing
October 2020

Infliximab, adalimumab and vedolizumab concentrations across pregnancy and vedolizumab concentrations in infants following intrauterine exposure.

Aliment Pharmacol Ther 2020 11 27;52(10):1551-1562. Epub 2020 Sep 27.

Fitzroy, VIC, Australia.

Background: The impact of pregnancy on levels of biologic agents in patients with IBD is undefined and time to elimination in vedolizumab-exposed infants is unknown.

Aims: To determine the effect of pregnancy on infliximab, adalimumab and vedolizumab levels and to study infant vedolizumab clearance METHODS: In a prospective observational study, maternal drug levels were measured pre-conception, in each trimester, at delivery and postpartum. The association between drug levels and gestation in weeks was assessed using generalised estimating equation modelling. Infant vedolizumab levels were performed at birth (cord blood), 6 weeks and 3 months or until undetectable.

Results: We included 50 IBD patients (23 on infliximab, 15 on adalimumab and 12 on vedolizumab) with at least two intrapartum observations, plus 5 patients on vedolizumab with only mother and baby samples at delivery. Modelling showed no change in adalimumab levels, an increase in infliximab levels of 0.16 (95% CI 0.08-0.24) µg/L/week (P < 0.001) and a decrease of 0.18 (95% CI: -0.33 to -0.02) µg/L/week (P = 0.03) for vedolizumab. In 17 mother-baby pairs, median infant vedolizumab levels at birth were lower than maternal levels (P < 0.05) with an infant:maternal ratio of 0.7 (IQR 0.5-0.9). Vedolizumab was undetectable between 15 and 16 weeks of age in all 12 infants completing follow-up testing.

Conclusions: During pregnancy, adalimumab levels remain stable, while infliximab levels increase and vedolizumab levels decrease. However, the increments were small suggesting that intrapartum therapeutic drug monitoring and dose adjustment are not indicated. Unlike infliximab and adalimumab, infant vedolizumab levels are lower in cord blood than in mothers and appear to clear rapidly.
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http://dx.doi.org/10.1111/apt.16102DOI Listing
November 2020

Review article: the impact of diet on ileoanal pouch function and on the pathogenesis of pouchitis.

Aliment Pharmacol Ther 2020 10 10;52(8):1323-1340. Epub 2020 Sep 10.

Department of Gastroenterology, Alfred Health and Monash University, Melbourne, VIC, Australia.

Background: There is expanding interest in the role that diet plays in ileoanal pouch function and in the pathogenesis of pouchitis.

Aims: To present a narrative review of published literature regarding the relationship of diet with pouch function and the pathogenesis of pouchitis, and to provide potentially beneficial dietary strategies.

Methods: Current relevant literature was summarised and critically examined.

Results: Dietary components influence pouch function via their effect on upper gastrointestinal transit, small bowel water content and the structure and fermentative activity of the pouch microbiota. FODMAPs in fruits and vegetables appear to affect pouch function the most, with intake positively associated with increased stool frequency and reduced consistency. Dietary factors that influence the pathogenesis of pouchitis appear different and, at times, opposite to those better for optimising function. For example, risk of pouchitis appears to be inversely associated with intake of fruits. The food components mechanistically responsible for this observation are not known, but a rich supply of fermentable fibres and micronutrients in such foods might play a beneficial role via modulation of microbial community structure (such as increasing diversity and/or changing microbial communities to favour 'protective' over 'pathogenic' bacteria) and function and/or anti-inflammatory effects.

Conclusion: Available data are weak but suggest tailoring dietary recommendations according to pouch phenotype/behaviour and pouchitis risk might improve outcomes. More sophisticated dietary strategies that utilise the physiological and pathophysiological effects of dietary components on ileoanal pouches have potential to further improve outcomes. Well designed, adequately powered studies are required.
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http://dx.doi.org/10.1111/apt.16085DOI Listing
October 2020

Development of a Simple, Serum Biomarker-based Model Predictive of the Need for Early Biologic Therapy in Crohn's Disease.

J Crohns Colitis 2021 Apr;15(4):583-593

Department of Gastroenterology, Eastern Health, Melbourne, VIC, Australia.

Background: Early or first-line treatment with biologics, as opposed to conventional immunomodulators, is not always necessary to achieve remission in Crohn's disease [CD] and may not be cost-effective. This study aimed to develop a simple model to predict the need for early biologic therapy, in order to risk-stratify CD patients and guide initial treatment selection.

Methods: A model-building study using supervised statistical learning methods was conducted using a retrospective cohort across two tertiary centres. All biologic-naïve CD patients who commenced an immunomodulator between January 1, 2004 and December 31, 2016, were included. A predictive score was derived using Cox regression modelling of immunomodulator failure, and was internally validated using bootstrap resampling.

Results: Of 410 patients [median age 37 years, 47% male, median disease duration 4.7 years], 229 [56%] experienced immunomodulator failure [39 required surgery, 24 experienced a new stricture, 44 experienced a new fistula/abscess, 122 required biologic escalation] with a median time to failure of 16 months. Independent predictors of treatment failure included raised C-reactive protein [CRP], low albumin, complex disease behaviour, younger age, and baseline steroids. Highest CRP and lowest albumin measured within the 3 months preceding immunomodulator initiation outperformed baseline measurements. After model selection, only highest CRP and lowest albumin remained and the resultant Crohn's Immunomodulator CRP-Albumin [CICA] index demonstrated robust optimism-corrected discriminative performance at 12, 24, and 36 months (area under the curve [AUC] 0.84, 0.83, 0.81, respectively).

Conclusions: The derived CICA index based on simple, widely available markers is feasible, internally valid, and has a high utility in predicting immunomodulator failure. This requires external, prospective validation.
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http://dx.doi.org/10.1093/ecco-jcc/jjaa194DOI Listing
April 2021

Thiopurines and their optimization during infliximab induction and maintenance: A retrospective study in Crohn's disease.

J Gastroenterol Hepatol 2021 Apr 10;36(4):990-998. Epub 2020 Sep 10.

Department of Gastroenterology, Alfred Hospital, Melbourne, Victoria, Australia.

Background And Aim: Combining therapy with a thiopurine is favored when commencing infliximab in Crohn's disease; however, the optimal 6-thioguanine nucleotide (TGN) level and how long to continue thiopurines after induction are uncertain. We aimed to compare outcomes after induction and during maintenance in combination therapy versus infliximab monotherapy in Crohn's and to examine whether TGN levels were associated with outcomes.

Methods: Crohn's patients induced with infliximab with or without concomitant thiopurines were retrospectively identified. Response to induction and clinical outcomes in subsequent 6-month maintenance semesters were analyzed. A TGN level ≥235 pmol/8 × 10 red blood cells was considered therapeutic.

Results: In 89 patients, response to induction was higher in combination therapy than monotherapy (74 vs 47%, P = 0.04). This benefit was only seen in patients with a therapeutic TGN (odds ratio 3.72, confidence interval 1.07-13.0, P = 0.04). Combination therapy during induction yielded a three times longer time to subsequent need for treatment escalation or treatment failure compared with monotherapy (29 vs 9 months, P = 0.01), with both therapeutic and subtherapeutic TGNs independent predictors on multivariate analysis. Among 370 semesters, there was no difference in outcomes between combination therapy and monotherapy (P = 0.42), nor when combination semesters were stratified by therapeutic versus subtherapeutic TGN (P = 0.56). In semester 1 only, a significantly higher remission rate was observed with therapeutic compared with subtherapeutic TGN (76% vs 33%, P = 0.02).

Conclusions: Combination therapy dosed with an optimized thiopurine was superior to infliximab monotherapy for induction of response, durability of response, and clinical outcomes in the first 6 months following induction. Thereafter, combination therapy yielded no clinical advantage, supporting consideration of thiopurine withdrawal on a case-by-case basis.
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http://dx.doi.org/10.1111/jgh.15245DOI Listing
April 2021

Thiopurines vs methotrexate: Comparing tolerability and discontinuation rates in the treatment of inflammatory bowel disease.

Aliment Pharmacol Ther 2020 10 14;52(7):1174-1184. Epub 2020 Aug 14.

Department of Gastroenterology and Hepatology, Monash University, Eastern Health Clinical School, Victoria, Australia.

Background: There are safety concerns regarding immunomodulators (thiopurines and methotrexate) for treatment of inflammatory bowel disease (IBD).

Aim: To compare the long-term tolerability, and persistence of thiopurine and methotrexate therapy in IBD.

Methods: A retrospective cohort study was performed at two hospitals between 1 January 2004 and 31 December 2016 for patients commenced on thiopurines or methotrexate for IBD. Treatment discontinuation rates, intolerances and disease activity were obtained from medical records.

Results: There were 782 patients commenced on immunomodulator therapy; 244 (31%) on methotrexate with folate (67% subcutaneous therapy) and 538 (69%) on thiopurine (73% azathioprine). Median follow-up was 42 vs 47 months (P = 0.09). In patients on thiopurines, median 6-TGN was 298 pmol/8 x 10 RBCs, while the median dose of methotrexate was 25 mg weekly. Methotrexate recipients had a higher rate of prior immunomodulator intolerance, were typically older and had a longer disease duration (54% vs 3%, median 43 vs 36 years, 6 vs 5 years, respectively, each P < 0.05). Overall, 208 (27%) discontinued therapy due to adverse events, (40% on methotrexate vs 19% on thiopurines, P < 0.001), including nausea (18% vs 4%), fatigue (7% vs 2%) and hepatotoxicity (8% vs 2%, each P < 0.001). Hospitalisations from adverse events (0.8% vs 0.9%) and serious infections (9% vs 12%), and deaths (1% vs 0%) were comparable between groups (all P > 0.05). Discontinuation due to adverse events occurred later in patients on methotrexate than on thiopurines (median 7 vs 5 months, P = 0.08).

Conclusion: Discontinuation of methotrexate occurred at rates twice that of dose-optimised thiopurine therapy.
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http://dx.doi.org/10.1111/apt.16039DOI Listing
October 2020

A virtual clinic increases anti-TNF dose intensification success via a treat-to-target approach compared with standard outpatient care in Crohn's disease.

Aliment Pharmacol Ther 2020 06 7;51(12):1342-1352. Epub 2020 May 7.

Department of Medicine, Monash University, Melbourne, Vic., Australia.

Background: Virtual clinics represent a novel model of care in inflammatory bowel disease. Their effectiveness in promoting high quality use of biologic therapy and facilitating a treat-to-target approach is unknown.

Aim: To evaluate clinical and process-driven outcomes in a virtual clinic compared to standard outpatient care amongst patients receiving intensified anti-TNF therapy for secondary loss of response.

Methods: We performed a retrospective multi-centre, parallel, observational cohort study of Crohn's disease patients receiving intensified anti-TNF therapy for secondary loss of response. Objective assessments of disease activity and anti-TNF trough levels at secondary loss of response and during subsequent 6-month semesters, were compared longitudinally between virtual clinic and standard outpatient care cohorts. The primary endpoint was treatment success, with appropriateness of dose intensification, tight disease monitoring and treatment de-escalation representing secondary outcomes.

Results: Of 149 patients with similar baseline characteristics, 69 were managed via a virtual clinic and 80 via standard outpatient care. There were higher rates of treatment success in the virtual clinic cohort (60.9 vs 35.0%, P < 0.002). Rates of appropriate dose intensification (82.6% vs 40.0%, P < 0.001), biomarker remission (faecal calprotectin P = 0.002), tight-disease monitoring (84.1% vs 28.8%, P < 0.001) and treatment de-escalation (21.3% vs 10.0%, P = 0.027) also favoured the virtual clinic cohort.

Conclusion: This study favoured a virtual clinic-led model-of-care over standard outpatient care in facilitating treatment success as part of an effective treat-to-target approach in Crohn's disease. A virtual clinic model-of-care also improved treatment outcomes and quality of use of intensified anti-TNF therapy through processes that promoted appropriate dose intensification and tight-disease monitoring, while encouraging more frequent dose de-escalation.
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http://dx.doi.org/10.1111/apt.15742DOI Listing
June 2020

A Personalized Approach to Managing Patients With an Ileal Pouch-Anal Anastomosis.

Front Med (Lausanne) 2019 29;6:337. Epub 2020 Jan 29.

Department of Gastroenterology, The Alfred Hospital, Monash University, Melbourne, VIC, Australia.

Quality of life after ileal pouch-anal anastomosis (IPAA) surgery is generally good. However, patients can be troubled by pouch-related symptoms and pouch disorders that can be inflammatory, mechanical/surgical, and functional. Management of patients with IPAA begins with measures to maintain a healthy pouch such as optimizing pouch function, providing tailored advice on a healthy diet and lifestyle, screening for and addressing metabolic complications of IPAA, pouch surveillance, and risk stratification for risk of pouchitis and pouch failure. Pouchitis is the most common inflammatory disorder. Primary pouchitis is a spectrum currently classified into three progressive phases-an antibiotic-responsive, an antibiotic-dependent, and an antibiotic-refractory phase. It is predominately microbially mediated in acute antibiotic-responsive pouchitis and predominately immune mediated in chronic antibiotic-refractory pouchitis (CARP). Secondary prophylaxis is recommended for recurrent antibiotic-responsive and for antibiotic-dependent pouchitis. Secondary causes of antibiotic-refractory pouchitis should be ruled out before a diagnosis of CARP is made. CARP is best classified as primary sclerosing cholangitis associated, immunoglobulin G4-associated, and autoimmune. Primary sclerosing cholangitis-associated CARP can be treated with budesonide or oral vancomycin. Early recognition of immunoglobulin G4-associated pouchitis minimizes ineffective antibiotic use. Autoimmune CARP can be managed in a manner similar to UC. The current place of immunosuppressives in the treatment algorithm depends on availability and early access to biological agents. Vedolizumab and ustekinumab are the preferred first- and second-line biologics for autoimmune CARP owing to their efficacy, better side effect profile, and low immunogenicity and need for concomitant immunomodulatory therapy. Antitumor necrosis factor should be reserved for autoimmune CARP failing the above and for CD of the pouch. There are no guidelines for the surveillance of pouches for dysplasia. Incidence varies based on a patient's risk. Since incidence is low, a risk-stratified approach is recommended.
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http://dx.doi.org/10.3389/fmed.2019.00337DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7000529PMC
January 2020

Review article: determination of the therapeutic range for therapeutic drug monitoring of adalimumab and infliximab in patients with inflammatory bowel disease.

Aliment Pharmacol Ther 2020 03 21;51(6):612-628. Epub 2020 Jan 21.

Departments of Gastroenterology, The Alfred Hospital, Melbourne, VIC, Australia.

Background: Clinical application of therapeutic drug monitoring (TDM) to optimise anti-TNF therapies in patients with IBD depends upon target ranges.

Aims: To review methodology used to determine therapeutic ranges and critically compare and contrast its application to infliximab and adalimumab.

Methods: A systematic review was performed, and relevant literature was summarised and critically examined.

Results: Upper limits of the therapeutic range are determined by toxicity, a plateau response and cost. Lower limits are determined by optimal concentration on the target of action in vitro and/or in vivo, or by correlation of drug levels with clinical efficacy using area-under-receiver-operator-curve (AUROC) analysis. In 43 studies, there were huge variations in time at which infliximab and adalimumab levels were measured, the end-points used (clinical remission to mucosal healing), the clinical setting (active disease vs maintenance phase) and the reason for TDM (proactive vs reactive). In the maintenance phase for infliximab, lower trough limits 2.8-5.7 µg/mL are reported depending upon end-points used, with consistent AUROC 0.68-0.77. Adalimumab TDM targets are even less consistent with a lower limit 5.9-11.8 µg/mL (AUROC 0.66-0.83) in some studies, but no cut-off can be identified that is significantly associated with outcome in others, related to inherent pharmacokinetic and pharmacodynamic differences, and heterogeneity of study design.

Conclusions: Evidence for exposure-response relationship is stronger for infliximab than adalimumab. Due to heterogeneity in settings for drug level measurements, therapeutic ranges vary. These factors need to be taken into account when interpreting the evidence and extending this to therapeutic strategies for IBD patients.
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http://dx.doi.org/10.1111/apt.15643DOI Listing
March 2020

Therapeutic Drug Monitoring of Biologics During Induction to Prevent Primary Non-Response.

J Crohns Colitis 2020 May;14(4):542-556

Gastroenterology Unit, University Hospital of Saint Etienne, Saint-Etienne, France.

Biologic therapies have revolutionized the management of inflammatory bowel disease [IBD], but primary and secondary non-responses occur in a significant proportion of patients. Therapeutic drug monitoring [TDM] now has an established role in the treatment algorithm for managing secondary loss of response to anti-tumour necrosis factor [anti-TNF] agents during maintenance therapy. Data to support the use of TDM in the management of secondary loss of response to vedolizumab and ustekinumab are emerging. The potential to prevent primary non-response to biologic agents during induction is of equal, and potentially greater, clinical importance. Again, most data supporting the use of 'proactive' TDM during induction pertains to the use of anti-TNF agents, but signals of efficacy for the use of TDM during induction with other biologic classes are now appearing. This review aims to summarize data on the use of TDM during induction to prevent pharmacokinetic primary non-response to all three classes of biologic therapy currently available for the treatment of IBD.
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http://dx.doi.org/10.1093/ecco-jcc/jjz162DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7392326PMC
May 2020

Dietary fat and the faecal microbiome: where collinearity may lead to incorrect attribution of effects to fat.

Gut 2020 09 6;69(9). Epub 2019 Sep 6.

Gastroenterology, Alfred Health, Monash University, Melbourne, Victoria, Australia.

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http://dx.doi.org/10.1136/gutjnl-2019-319628DOI Listing
September 2020

Anti-TNF Therapy in Pregnant Women With Inflammatory Bowel Disease: Effects of Therapeutic Strategies on Disease Behavior and Birth Outcomes.

Inflamm Bowel Dis 2020 01;26(1):93-102

Department of Gastroenterology, St Vincent's Hospital, and University of Melbourne, Melbourne, Australia.

Background: Active inflammatory bowel disease (IBD) adversely affects pregnancy outcomes. Little is known about the risk of relapse after stopping anti-tumor necrosis factor (anti-TNF) treatment during pregnancy. We assessed the risk of relapse before delivery in women who discontinued anti-TNF treatment before gestational week (GW) 30, predictors of reduced infant birth weight, a marker associated with long-term adverse outcomes, and rates and satisfaction with counseling.

Methods: Pregnant women with IBD receiving anti-TNF treatment were prospectively invited to participate in an electronic questionnaire carried out in 22 hospitals in Denmark, Australia, and New Zealand from 2011 to 2015. Risk estimates were calculated, and birth weight was investigated using t tests and linear regression.

Results: Of 175 women invited, 153 (87%) responded. In women in remission, the relapse rate did not differ significantly between those who discontinued anti-TNF before GW 30 (1/46, 2%) compared with those who continued treatment (8/74, 11%; relative risk, 0.20; 95% confidence interval [CI], 0.02 to 1.56; P = 0.08). Relapse (P = 0.001) and continuation of anti-TNF therapy after GW 30 (P = 0.007) were independently associated with reduced mean birth weight by 367 g (95% CI, 145 to 589 g; relapse) and 274 g (95% CI, 77 to 471 g; anti-TNF exposure after GW 30). Of 134 (88%) women who received counseling, 116 (87%) were satisfied with the information provided.

Conclusions: To minimize fetal exposure in women in remission, discontinuation of anti-TNF before GW 30 seems safe. Relapse and continuation of anti-TNF therapy after GW 30 were each independently associated with lower birth weight, although without an increased risk for birth weight <2500 g. Most women received and were satisfied with counseling.
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http://dx.doi.org/10.1093/ibd/izz110DOI Listing
January 2020

Comparison of Adalimumab Serum Drug Levels When Delivered by Pen Versus Syringe in Patients With Inflammatory Bowel Disease. An International, Multicentre Cohort Analysis.

J Crohns Colitis 2019 Dec;13(12):1527-1536

Department of Gastroenterology, Alfred Health and Monash University, Melbourne, VIC, Australia.

Background: Adalimumab is administered via a pre-filled syringe or spring-loaded pen. In a previous study in Crohn's disease, higher drug levels were observed in syringe users. The aim of this study was to evaluate the impact of delivery device on adalimumab drug levels in patients with Crohn's disease.

Methods: Consecutive Crohn's disease patients treated with maintenance adalimumab [40 mg fortnightly] were recruited from five centres. The first recorded drug level with matched clinical and biochemical markers of disease activity was compared between pen and syringe users.

Results: Of 218 patients, 64% used pen, with a median faecal calprotectin 110 μg/g and serum C-reactive protein 4 mg/L. In comparison to pen, syringe users had higher albumin [39 vs 42 g/L; p = 0.016], lower Harvey-Bradshaw Index [2 vs 1; p = 0.017], and higher rates of concomitant immunomodulation [54% vs 71%; p = 0.014]. Drug levels were equivalent between pen and syringe users [median 5.3 vs 5.2 μg/ml; p = 0.584], even after controlling for disease activity and immunomodulation. Syringe users at Alfred Health had higher drug levels than pen [6.1 vs 4.5 μg/ml; p = 0.039]; a greater proportion achieved therapeutic levels [75% vs 44%; p = 0.045]. A higher proportion of pen users from Saint-Étienne had therapeutic levels [79% vs 42%; p = 0.027], yet no significant difference in drug levels [7.9 vs 4.5 μg/ml; p = 0.119].

Conclusions: Delivery device does not appear to significantly affect adalimumab drug levels. Given differences between study sites, studies evaluating administration education and technique are warranted.
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http://dx.doi.org/10.1093/ecco-jcc/jjz103DOI Listing
December 2019

Appropriate Therapeutic Drug Monitoring of Biologic Agents for Patients With Inflammatory Bowel Diseases.

Clin Gastroenterol Hepatol 2019 08 27;17(9):1655-1668.e3. Epub 2019 Mar 27.

Dartmouth-Hitchcock Medical Center, Lebanon, New Hampshire.

Background & Aims: Therapeutic drug monitoring (TDM) is widely available for biologic therapies in patients with inflammatory bowel disease (IBD). We reviewed current data and provided expert opinion regarding the clinical utility of TDM for biologic therapies in IBD.

Methods: We used a modified Delphi method to establish consensus. A comprehensive literature review was performed regarding the use of TDM of biologic therapy in IBD and presented to international IBD specialists. Subsequently, 28 statements on the application of TDM in clinical practice were rated on a scale of 1 to 10 (1 = strongly disagree and 10 = strongly agree) by each of the panellists. Statements were accepted if 80% or more of the participants agreed with a score ≥7. The remaining statements were discussed and revised based on the available evidence followed by a second round of voting.

Results: The panel agreed on 24 (86%) statements. For anti-tumor necrosis factor (anti-TNF) therapies, proactive TDM was found to be appropriate after induction and at least once during maintenance therapy, but this was not the case for the other biologics. Reactive TDM was appropriate for all agents both for primary non-response and secondary loss of response. The panellists also agreed on several statements regarding TDM and appropriate drug and anti-drug antibody (ADA) concentration thresholds for biologics in specific clinical scenarios.

Conclusion: Consensus was achieved towards the utility of TDM of biologics in IBD, particularly anti-TNF therapies. More data are needed especially on non-anti-TNF biologics to further define optimal drug concentration and ADA thresholds as these can vary depending on the therapeutic outcomes assessed.
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http://dx.doi.org/10.1016/j.cgh.2019.03.037DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6661210PMC
August 2019

Higher Mucosal Healing with Tumor Necrosis Factor Inhibitors in Combination with Thiopurines Compared to Methotrexate in Crohn's Disease.

Dig Dis Sci 2019 06 17;64(6):1622-1631. Epub 2018 Dec 17.

Department of Gastroenterology and Hepatology, Eastern Health, Box Hill Hospital, Level 2, 5 Arnold Street, Box Hill, VIC, 3128, Australia.

Background: The differential impact of anti-tumor necrosis factor (anti-TNF) therapy with methotrexate versus thiopurine co-therapy on endoscopic remission remains uncertain.

Aims: To compare rates of endoscopic remission based on methotrexate or thiopurine co-therapy used with anti-TNF therapy in Crohn's disease.

Methods: A retrospective observational study at two tertiary centers between 2010 and 2016 compared endoscopic remission rates and persistence on anti-TNF therapy in combination with methotrexate versus thiopurines for at least 3 months.

Results: Of 412 patients on anti-TNF therapy, 278 (67%) received immunomodulator co-therapy for ≥ 3 months and 269 (65%) had complete data for analysis. Methotrexate was used in 77 (29%) and thiopurines in 192 (71%) patients plus either infliximab (156, 58%) or adalimumab (113, 42%), with median follow-up of 2.8 years. The methotrexate group had greater prior immunomodulator intolerance (62% vs 20%, p < 0.01). Endoscopic remission rates were higher in those treated with thiopurine compared to methotrexate co-therapy at 12 m (58% vs 17%, p < 0.01) and at last review (59% vs 40%, p = 0.03). Endoscopic remission rates were higher with thiopurines than methotrexate when combined with adalimumab (49% vs 6%, p < 0.01) but not with infliximab (65% vs 54%, p = 0.09). In multivariate analysis, thiopurine co-therapy, elevated baseline CRP, and therapeutic anti-TNF drug levels were each associated with longer persistence of co-therapy (each p < 0.05). There were no significant differences in adverse events, malignancy or infection rates.

Conclusion: In this cohort, anti-TNF and thiopurine co-therapy resulted in higher rates of mucosal healing than methotrexate, the difference is most pronounced with adalimumab and conversely with low-dose methotrexate.
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http://dx.doi.org/10.1007/s10620-018-5422-8DOI Listing
June 2019

Patchy colitis, and young age at diagnosis and at the time of surgery predict subsequent development of Crohn's disease after ileal pouch-anal anastomosis surgery for ulcerative colitis.

JGH Open 2018 Feb 4;2(1):8-14. Epub 2018 Jan 4.

Department of Gastroenterology The Alfred Hospital Melbourne Victoria Australia.

Background And Aim: A proportion of patients having total proctocolectomy and ileal pouch-anal anastomosis (IPAA) for ulcerative colitis (UC) are later diagnosed with Crohn's disease (CD). The aim of this study was to identify preoperative and perioperative predictors for the subsequent development of CD in patients who had IPAA for presumed UC.

Methods: A retrospective case-control study of patients undergoing IPAA surgery for presumed UC was undertaken. Cases were patients who had a revised diagnosis of CD after surgery. Preoperative and perioperative variables were examined and analyzed.

Results: Fifteen cases were compared with 39 controls. Patients aged ≤25 years at initial UC diagnosis were more likely to develop CD compared to those aged >25 years (odds ratio, OR [95% confidence interval, CI]: 7.1 [1.6-31.3]; = 0.01). Patients aged ≤30 years at the time of colectomy had an increased risk of subsequent development of CD compared to those aged >30 years (OR [95% CI]: 4.5 [1.3-16.0]; = 0.02). Cases were more likely to have patchy colitis on their colectomy specimen (OR [95% CI]: 6.7 [1.1-41.8]; = 0.04). There was no significant difference between groups regarding transmural inflammation, ileitis, or fissuring ulcers on colectomy specimens, or preoperative C-reactive protein (CRP), albumin, family history, and smoking status.

Conclusion: Predictors of the development of CD in the pouch include young age at diagnosis and at the time of surgery, and patchy colitis in the resected colon.
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http://dx.doi.org/10.1002/jgh3.12035DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6207023PMC
February 2018

6-Thioguanine Nucleotide Levels Are Associated With Mucosal Healing in Patients With Crohn's Disease.

Inflamm Bowel Dis 2018 11;24(12):2621-2627

Department of Gastroenterology, The First Affiliated Hospital of Sun Yat-sen University, Guangzhou, China.

Background: Level of 6-thioguanine nucleotides (6-TGN) has been reported to be associated with clinical remission in patients with Crohn's disease (CD) receiving maintenance treatment with thiopurines. Whether 6-TGN levels are associated with mucosal healing (MH) has seldom been investigated. We aimed to assess the correlation between 6-TGN levels and MH in patients with CD.

Methods: This was a retrospective, cross-sectional, observational, multicenter study of 119 patients with CD treated with thiopurines in 3 inflammatory bowel disease referral centers (France, Australia, and China) between June 2012 and April 2016. Established CD patients who underwent ileocolonoscopy during thiopurine treatment were included. MH was defined as simple endoscopic score-CD <3. Univariate and multivariable regression analyses were used to evaluate variables associated with MH.

Results: The mean concentration of 6-TGN in the MH group was higher compared with that in the non-MH group (359.0 ± 226.7 pmol/8 × 108 red blood cell count [RBC] vs 277.1 ± 170.5 pmol/8 × 108 RBC; P = 0.017). The cutoff 6-TGN concentration of 397.3 pmol/8 × 108 RBC was 86.7% specific to MH, with a sensitivity of 35.3% and area under curve (AUC) of 0.631 (P = 0.010). On multivariable analysis, 6-TGN levels were associated with MH (odds ratio [OR], 3.287; 95% confidence interval [CI], 1.348-8.017; P = 0.009) whereas late initiation of AZA (longer duration from disease onset) was inversely associated with MH (OR, 0.972; 95% CI, 0.954-0.991; P = 0.004).

Conclusions: Higher 6-TGN levels are independently associated with a reduced rate of endoscopically active disease and a higher rate of mucosal healing in CD patients. Prospective studies of adequate sample size are required to confirm these findings.
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http://dx.doi.org/10.1093/ibd/izy173DOI Listing
November 2018

Therapeutic drug monitoring of vedolizumab in inflammatory bowel disease: current data and future directions.

Therap Adv Gastroenterol 2018 8;11:1756284818772786. Epub 2018 May 8.

Department of Gastroenterology and Immunology, University Hospital of Saint Etienne, Saint Etienne, France.

The introduction of vedolizumab, a lymphocyte adhesion inhibitor, has expanded the relatively limited therapeutic armamentarium available for Crohn's disease and ulcerative colitis. Despite its effectiveness, both primary nonresponse and secondary loss of response to vedolizumab do occur, as is observed with the use of anti-tumour necrosis factor (TNF) therapy. Further, in a proportion, onset of efficacy may be relatively slow. A large body of data support an exposure-response relationship with anti-TNF drug levels, which has led to therapeutic drug monitoring becoming incorporated into everyday clinical management. The influence of patient and disease factors on the pharmacokinetics of anti-TNF levels, including immunogenicity, has also been examined. The role of therapeutic drug monitoring with vedolizumab is less clear. This review summarizes the available evidence on the pharmacokinetics and pharmacodynamics of vedolizumab in inflammatory bowel disease and how drug levels, immunogenicity and other factors influence clinical outcomes. Vedolizumab clearance is increased with very high body weight and hypoalbuminaemia, but is not influenced by the addition of an immunomodulator. Immunogenicity is uncommon. α4β7 receptor saturation occurs at low serum vedolizumab drug levels, and measuring it alone is insufficient to predict clinical outcomes. Using quartile analysis of vedolizumab drug levels, there appears to be a modest exposure-response relationship during induction. Drug levels at week 6 of approximately >20 μg/ml have been shown to be associated with improved clinical outcomes, including subsequent mucosal healing rates during maintenance and avoiding the need to dose escalate due to lack of response. There are currently insufficient data to support the routine use of therapeutic drug monitoring during maintenance therapy. Further studies to elucidate the role of therapeutic drug monitoring of vedolizumab are needed.
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http://dx.doi.org/10.1177/1756284818772786DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5949937PMC
May 2018

Appropriateness of Combination Therapy for Patients With Inflammatory Bowel Diseases: One Size Still Does Not Fit All.

Clin Gastroenterol Hepatol 2018 11 2;16(11):1829-1831. Epub 2018 Mar 2.

The BRIDGe Group; Dartmouth-Hitchcock IBD Center, Lebanon, New Hampshire.

Randomized controlled trials (RCTs) have demonstrated that therapies targeting tumor necrosis factor (TNF) and α₄β₇ integrin are effective when given as monotherapy in inducing and/or maintaining remission in patients with ulcerative colitis (UC) or Crohn's disease (CD), but data from RCTs are less clear on whether concomitant immunomodulator (IM) therapy confers additional benefit. In CD, RCT data are mixed, as are results of systematic reviews and meta-analyses, showing no benefit overall, minimal benefit with individual agents, and comparative benefit over some monotherapies but not others. For example, concomitant azathioprine with infliximab is more effective than either drug alone in patients with CD naive to both drugs, but whether combination therapy is more effective than monotherapy with infliximab in nonnaive patients, or with other approved biologic drugs in any population, remains unknown. In UC, RCTs have shown that the benefit may be limited to specific populations, whereas systematic reviews suggest no benefit at all..
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http://dx.doi.org/10.1016/j.cgh.2018.02.036DOI Listing
November 2018

Infliximab Versus Adalimumab in Patients with Biologic-Naïve Crohn's Disease: Is the Difference Real?

Dig Dis Sci 2018 05;63(5):1094-1096

Department of Gastroenterology, The Alfred Hospital, 55 Commercial Road, Melbourne, 3004, Australia.

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http://dx.doi.org/10.1007/s10620-018-4952-4DOI Listing
May 2018

Therapeutic drug monitoring in inflammatory bowel disease: too little too early?-comments on the American Gastroenterology Association Guideline.

Transl Gastroenterol Hepatol 2017 19;2:113. Epub 2017 Dec 19.

Department of Gastroenterology, Alfred Health and Monash University, Melbourne, Australia.

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http://dx.doi.org/10.21037/tgh.2017.12.05DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5763035PMC
December 2017

Predicting response after infliximab salvage in acute severe ulcerative colitis.

J Gastroenterol Hepatol 2018 Jul 27;33(7):1347-1352. Epub 2018 Feb 27.

Department of Gastroenterology, Austin Health, Melbourne, Australia.

Background And Aim: Acute severe ulcerative colitis (ASUC) is a medical emergency requiring prompt therapeutic intervention. Although infliximab has been used as salvage therapy for over 15 years, clinical predictors of treatment success are lacking. We performed a retrospective analysis to identify factors that predict colectomy and may guide dose intensification.

Methods: Fifty-four hospitalized patients received infliximab for ASUC at seven Australian centers (April 2014-May 2015). Follow-up was over 12 months. The data were primarily analyzed for predictors of colectomy. Accelerated (AI) versus standard (SI) infliximab induction strategies were also compared.

Results: Of 54 patients identified, the overall colectomy rate was 15.38% (8/52) at 3 months and 26.92% (14/52) at 12 months. Two patients were lost to follow-up. There was a numerically higher colectomy rate in those treated with AI compared with SI (P = 0.3); however, those treated with AI had more severe biochemical disease. A C-reactive protein (CRP)/albumin ratio cut-off of 0.37 post-commencement of infliximab and before discharge was a significant predictor of colectomy with an area under receiver operating curve of 0.73. Pretreatment CRP and albumin levels were not predictive of colectomy. A Mayo Endoscopic Score of 2 had a 94% PPV for avoidance of colectomy following infliximab salvage.

Conclusions: The baseline Mayo Endoscopic Score and the CRP/albumin ratio following infliximab salvage are significant predictors of treatment response for ASUC and identify patients at high risk of colectomy. Whether this risk can be mitigated using infliximab dose intensification requires prospective evaluation before the CRP/albumin ratio can be integrated into ASUC management algorithms.
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http://dx.doi.org/10.1111/jgh.14072DOI Listing
July 2018

Exploration of Predictive Biomarkers of Early Infliximab Response in Acute Severe Colitis: A Prospective Pilot Study.

J Crohns Colitis 2018 Feb;12(3):289-297

Department of Gastroenterology, Eastern Health and Monash University, Melbourne, Australia.

Background: The outcomes of acute severe ulcerative colitis [ASUC] appear to be dependent on early intervention with the first and/or further infliximab [IFX] doses, although parameters to guide decision-making remain uncertain.

Aim: To assess whether serum/faecal IFX levels and inflammatory biomarkers early after IFX dose can predict ASUC outcomes.

Methods: This prospective pilot study consecutively recruited inpatients with steroid-refractory ASUC, who then received 1-3 IFX rescue doses [5 mg/kg per dose] at the discretion of the treating clinician. Serum IFX, C-reactive protein [CRP], albumin and faecal calprotectin [FC] concentrations were measured daily as an inpatient, and then 7, 14, 28 and 42 days post-first IFX. Faecal IFX was measured 1 day post-IFX. The primary end point was clinical remission (partial Mayo [PM] = 0) and CRP ≤3 mg/l at 6 weeks. Secondary end points were 12-week clinical remission or colectomy during follow-up.

Results: Of 24 ASUC patients with a median follow-up of 28 months [range 13-44], 10 [42%] achieved remission at 6 weeks, 12 [50%] achieved 12-week remission, six [25%] had colectomy. In total, 97% received either two or three IFX doses. Post-first dose, receiver-operator curve-derived cutoffs of the area-under-curve [AUC, Days 4-7] concentrations for serum IFX, FC and PM scores each predicted the primary end point with 100% sensitivity, and predicted future colectomy with 89-94% sensitivity. In multivariate analyses, faecal IFX >1 µg/g (odds ratio [OR] 0.04 [0.2, 0.9]), PM AUCd1-3 < 20 (OR 20.2 [1.01, 404], each P < 0.05), FC AUCd1-3 < 10000 µg/ml [OR 13.6 [0.6, 294], trend only, p = 0.09) were each associated with clinical and CRP remission [6 weeks].

Conclusions: In ASUC, post-first dose IFX, early assessment of serum/faecal IFX, calprotectin and PM scores can accurately predict future remission and colectomy, and thus potentially aid in decision-making, i.e. accelerated IFX dosing or surgical planning if/when needed.
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http://dx.doi.org/10.1093/ecco-jcc/jjx146DOI Listing
February 2018

Anti-TNF Re-induction Is as Effective, Simpler, and Cheaper Compared With Dose Interval Shortening for Secondary Loss of Response in Crohn's Disease.

J Crohns Colitis 2018 Feb;12(3):280-288

Department of Gastroenterology, Eastern Health, Melbourne, VIC, Australia.

Background And Aims: The optimal duration of dose-intensified therapy following secondary loss of response [LOR] to anti-tumour necrosis factor [TNF] therapy remains unclear. Anti-TNF re-induction involves a finite period of intensified therapy and may be a cost-effective means of re-capturing response. This study aimed to compare the efficacy, durability, and cost of anti-TNF re-induction and dose interval shortening [DIS] for secondary LOR in Crohn's disease [CD].

Methods: This was a retrospective observational study in CD patients who developed secondary LOR to maintenance anti-TNF therapy, requiring subsequent re-induction and/or DIS. The primary outcome was treatment failure within 12 months. Secondary outcomes included factors associated with time to failure, disease activity, and incremental anti-TNF costs.

Results: Of 423 patients with CD on anti-TNF therapy, 80 [19%] developed secondary LOR, with 33 and 55 patients undergoing subsequent anti-TNF re-induction and DIS, respectively. There was no significant difference in the incidence of treatment failure at 12 months following re-induction and DIS, respectively [p = 0.27]. Factors predictive of a longer time to failure included a higher baseline serum albumin, male sex, and thiopurine co-therapy [each p < 0.05], whereas higher baseline faecal calprotectin was associated with shorter time to failure. There was no significant difference in clinical remission or objective disease activity across both groups. The median incremental cost of re-induction and DIS was AUD 4 838 and AUD 13 190, respectively.

Conclusions: In patients with CD who develop secondary LOR, re-induction may represent an effective and less expensive first-line strategy, reserving dose intensification strategies such as DIS for non-responders.
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http://dx.doi.org/10.1093/ecco-jcc/jjx144DOI Listing
February 2018