PLoS One. 2016;11(6):e0158017.
Corticosteroid use and complications in a US inflammatory bowel disease cohort.
Waljee AK, Wiitala WL, Govani S, et al.

BACKGROUND AND AIMS: Corticosteroids are effective for the short-term treatment of inflammatory bowel disease (IBD). Long-term use, however, is associated with significant adverse effects. To define the: (1) frequency and duration of corticosteroid use, (2) frequency of escalation to corticosteroid-sparing therapy, (3) rate of complications related to corticosteroid use, (4) rate of appropriate bone density measurements (dual energy X-ray absorptiometry [DEXA] scans), and (5) factors associated with escalation and DEXA scans.
METHODS: Retrospective review of Veterans Health Administration (VHA) data from 2002-2010.
RESULTS: Of the 30,456 Veterans with IBD, 32% required at least one course of corticosteroids during the study time period, and 17% of the steroid users had a prolonged course. Among these patients, only 26.2% underwent escalation of therapy. Patients visiting a gastroenterology (GI) physician were significantly more likely to receive corticosteroid-sparing medications. Factors associated with corticosteroid-sparing medications included younger age (OR = 0.96 per year,95%CI:0.95, 0.97), male gender (OR = 2.00,95%CI:1.16,3.46), GI visit during the corticosteroid evaluation period (OR = 8.01,95%CI:5.85,10.95) and the use of continuous corticosteroids vs. intermittent corticosteroids (OR = 2.28,95%CI:1.33,3.90). Rates of complications per 1000 person-years after IBD diagnosis were higher among corticosteroid users (venous thromboembolism [VTE] 9.0%; fragility fracture 2.6%; Infections 54.3) than non-corticosteroid users (VTE 4.9%; fragility fracture 1.9%; Infections 26.9). DEXA scanutilization rates amongcorticosteroiduserswereonly 7.8%.
CONCLUSIONS: Prolonged corticosteroid therapy for the treatment of IBD is common and is associated with significant harm to patients. Patients with prolonged use of corticosteroids for IBD should be referred to gastroenterology early and universal efforts to improve the delivery of high quality care should be undertaken.

Ann Gastroenterol. 2016;29(3):341-7.
Systematic review and meta-analysis of third-line salvage therapy with infliximab or cyclosporine in severe ulcerative colitis.
Feuerstein JD, Akbari M, Tapper EB, et al

BACKGROUND: In patients with ulcerative colitis who fail corticosteroids and are treated with rescue therapy (e.g. infliximab or cyclosporine) but fail to respond, salvage therapy with infliximab or cyclosporine can be considered. We sought to assess the efficacy and safety of this third-line salvage therapy.
METHODS: We performed a meta-analysis of trials published in PubMed up to January 2015 relating to the use of third-line salvage therapy following failure of intravenous corticosteroids and infliximab or cyclosporine. Pooled outcome rates for each salvage strategy and pooled odds ratio comparing the two strategies were calculated using the random effects model. Heterogeneity was assessed by the Q and I(2) statistics.
RESULTS: The search strategy yielded 40 articles of which 4 were eligible for inclusion. Four articles assessed patients who were treated with infliximab after failure of cyclosporine and 2 articles assessed the use of cyclosporine after failure of infliximab. There were 138 patients using infliximab as a third-line salvage therapy and 30 patients using cyclosporine. When comparing these two strategies, there was no significant difference in clinical response (RR 1.03, 95%CI 0.7-1.46 P=0.87), clinical remission (RR 0.69, 95%CI 0.30-1.57 P=0.37), or colectomy at 12 months (RR 1.14, 95%CI 0.79-1.67 P=0.48). Similarly, there was no significant difference in total (RR 1.91, 95% CI0.38-9.64 p=0.43) or serious adverse events (RR 1.18, 95%CI 0.34-4.07 P=0.80).
CONCLUSION: While third-line salvage therapy may be efficacious in achieving short-term clinical response/remission, there remains a significant risk of colectomy and adverse events.

TherapAdvGastroenterol. 2016;9(4):548-59.
Current approaches for optimizing the benefit of biologic therapy in ulcerative colitis.
Sofia MA, Rubin DT.

As biologic-based medication options for ulcerative colitis expand, our understanding of their optimal use in clinical practice is advancing as well. The appropriate use of combination therapy with immunomodulators can reduce the immunogenicity of biologic agents and raise serum drug levels of the biologic. A treat-to-target strategy with objective assessments of disease activity clearly defines the goals of biologic drug treatment. Mucosal healing is an evolving treatment goal and is associated with long-term remission and reduced incidence of colectomy. Furthermore, regular reassessments and therapeutic drug monitoring can allow clinicians to make evidence-based changes in therapy. Biologic drug de-escalation or re-initiation are less well developed topics, but are emerging areas of study. We review the evidence underlying these advances and a modern approach to the use of biologic therapy in ulcerative colitis.

Health Technol Assess. 2016;20(44):1-320.
Comparison of infliximab and ciclosporin in steroid resistant ulcerative colitis: pragmatic randomised trial and economic evaluation (CONSTRUCT).
Williams JG, Alam MF, Alrubaiy L, et al.

BACKGROUND: The efficacy of infliximab and ciclosporin in treating severe ulcerative colitis (UC) is proven, but there has been no comparative evaluation of effectiveness.
OBJECTIVE: To compare the clinical effectiveness and cost-effectiveness of infliximab and ciclosporin in treating steroid-resistant acute severe UC.
METHOD: Between May 2010 and February 2013 we recruited 270 participants from 52 hospitals in England, Scotland and Wales to an open-label parallel-group, pragmatic randomised trial. Consented patients admitted with severe colitis completed baseline quality-of-life questionnaires before receiving intravenous hydrocortisone. If they failed to respond within about 5 days, and met other inclusion criteria, we invited them to participate and used a web-based adaptive randomisation algorithm to allocate them in equal proportions between 5 mg/kg of intravenous infliximab at 0, 2 and 6 weeks or 2 mg/kg/day of intravenous ciclosporin for 7 days followed by 5.5 mg/kg/day of oral ciclosporin until 12 weeks from randomisation. Further treatment was at the discretion of physicians responsible for clinical management. The primary outcome was quality-adjusted survival (QAS): the area under the curve (AUC) of scores derived from Crohn's and Ulcerative Colitis Questionnaires completed by participants at 3 and 6 months, and then 6-monthly over 1-3 years, more frequently after surgery. Secondary outcomes collected simultaneously included European Quality of Life-5 Dimensions (EQ-5D) scores and NHS resource use to estimate cost-effectiveness. Blinding was possible only for data analysts. We interviewed 20 trial participants and 23 participating professionals. Funded data collection finished in March 2014. Most participants consented to complete annual questionnaires and for us to analyse their routinely collected health data over 10 years.
RESULTS: The 135 participants in each group were well matched at baseline. In 121 participants analysed in each group, we found no significant difference between infliximab and ciclosporin in QAS [mean difference in AUC/day 0.0297 favouringciclosporin, 95% confidence interval (CI) -0.0088 to 0.0682; p = 0.129]; EQ-5D scores (quality-adjusted life-year mean difference 0.021 favouringciclosporin, 95% CI -0.032 to 0.096; p = 0.350); Short Form questionnaire-6 Dimensions scores (mean difference 0.0051 favouringciclosporin, 95% CI -0.0250 to 0.0353; p = 0.737). There was no statistically significant difference in colectomy rates [odds ratio (OR) 1.350 favouring infliximab, 95% CI 0.832 to 2.188; p = 0.223]; numbers of serious adverse reactions (event ratio = 0.938 favouringciclosporin, 95% CI 0.590 to 1.493; p = 0.788); participants with serious adverse reactions (OR 0.660 favouringciclosporin, 95% CI 0.282 to 1.546; p = 0.338); numbers of serious adverse events (event ratio 1.075 favouring infliximab, 95% CI 0.603 to 1.917; p = 0.807); participants with serious adverse events (OR 0.999 favouring infliximab, 95% CI 0.473 to 2.114;p = 0.998); deaths (all three who died received infliximab; p = 0.247) or concomitant use of immunosuppressants. The lower cost of ciclosporin led to lower total NHS costs (mean difference -£5632, 95% CI -£8305 to -£2773; p < 0.001). Interviews highlighted the debilitating effect of UC; participants were more positive about infliximab than ciclosporin. Professionals reported advantages and disadvantages with both drugs, but nurses disliked the intravenous ciclosporin.
CONCLUSIONS: Total cost to the NHS was considerably higher for infliximab than ciclosporin. Nevertheless, there was no significant difference between the two drugs in clinical effectiveness, colectomy rates, incidence of SAEs or reactions, or mortality, when measured 1-3 years post treatment. To assess long-term outcome participants will be followed up for 10 years post randomisation, using questionnaires and routinely collected data. Further studies will be needed to evaluate the efficacy and effectiveness of new anti-tumour necrosis factor drugs and formulations of ciclosporin.

ClinGastroenterolHepatol. 2016 Jul 5.
Systematic review of tumour necrosis factor antagonists in extraintestinal manifestations in inflammatory bowel disease.
Peyrin-Biroulet L, Van Assche G, Gómez-Ulloa D, et al.

BACKGROUND AND AIMS: This systematic review investigated the efficacy and the effectiveness of biologic drugs in extraintestinal manifestations (EIMs) in inflammatory bowel disease (IBD).
METHODS: Literature search was conducted in PubMed, Embase and Cochrane until October 2015. Main inclusion criteria were adults with IBD, use of a biologic drug, evolution of EIMs, interventional study (IS) or non-interventional study (NIS).
RESULTS: Nine IS [two randomized controlled trials (RCTs) (n=797), seven open label (OL) trials (n=1143)] and 13 NIS (n=914) were included. Tumour necrosis factor (TNF) antagonists achieved complete response for pyoderma gangrenosum in 21-25% of patients in IS and in 92-100% patients in NIS, with similar results for other cutaneous manifestations such as erythema nodosum or stomatitis. Adalimumab significantly reduced the prevalence of anaemia vs. placebo after 56 weeks in one RCT. In two NIS, anti-TNF therapy improved anaemia in the short-term (67%) and in the long-term (34%). Complete response after anti-TNF treatment was reported in IS, including arthralgia (reduction in prevalence from 47.1% to 26.8% in the mid-term in one OL trial) and arthritis (reduction in prevalence from 8.7% to 2.1% and from 58% to 12.5% in two OL trials). Anti-TNFs were beneficial for a majority of patients with ocular manifestations. Infliximab was associated with improved outcomes in bone formation and bone mineral density.CONCLUSIONS: Anti-TNFs appear to be effective alternatives for certain EIMs associated with IBD including musculoskeletal, cutaneous and ocular manifestations while some beneficial effect may be obtained in metabolic bone disease, and on hematologic or vascular EIMs.

ClinGastroenterolHepatol. 2016 Jul 9.
Prevention of anti-drug antibody formation to infliximab in Crohn's patients with prior failure of thiopurines.
Bar-Yoseph H, Waterman M, Almog R, et al .

BACKGROUND: Combination thiopurine-infliximab (IFX) therapy is associated with reduced generation of anti-drug antibodies (ADA) compared with IFX monotherapy. Whether past clinical response to thiopurine therapy bears an effect on ADA prevention is unknown.
METHODS: This was a retrospective observational multicenter study of Crohn's disease (CD) patients treated by IFX and thiopurines who had serial ADA measurements. Therapy was classified into past thiopurine response or its lack of, de-novo combination or IFX monotherapy. The primary end-point was risk of ADA appearance.
RESULTS: Out of 494 patients with serial ADA measurements 207 eligible patients were included in the final analysis. The 1 year cumulative risk of ADA development was similar in past thiopurine responders (19.3%) compared to past thiopurine failures (16.1%) (Log-Rank p=0.54). ADA were found in 46.6% of the monotherapy group and was significantly different compared to past thiopurine responders (p=0.007) and past thiopurine failures (p=0.007). The adjusted hazards for ADA development were significantly lower in past responders and past failures compared with the monotherapy group ((HR 0.47 (95% CI 0.22-1.00) and HR 0.32 (95% CI 0.11-0.93), respectively).
CONCLUSION: Thiopurines-IFX co-therapy in CD patients is associated with reduced ADA formation compared with IFX monotherapy. Thisisprobablyregardlessofinitialthiopurinetherapeuticeffect.

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