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Tumour necrosis factor (TNF) antagonists are an efficacious therapy used in the management of several immune-mediated inflammatory diseases, including inflammatory bowel disease (IBD) and psoriasis. However, since being prescribed more widely, reports of new-onset psoriatic lesions have began to emerge in the literature and are known as paradoxical psoriasis.To review the evidence available in both the dermatology and gastroenterology literature pertaining to the entity known as paradoxical psoriasis as it relates to IBD and to create a comprehensive guide to assist clinicians who treat this challenging patient population.A literature search was conducted in PubMed to identify manuscripts that presented, discussed or summarised data pertaining to paradoxical psoriasis presenting in individuals with IBD.Paradoxical psoriasis is now thought to be a contradictory effect of TNF antagonist therapy leading to psoriatic lesions often within the first year of treatment. The underlying pathogenesis, although not completely understood, is likely related to an imbalance of inflammatory cytokines. The histological appearance, while similar to classical psoriasis, does have unique features. The clinical presentation can vary among patients but often presents during maintenance therapy for inflammatory bowel disease. Treatment options should be determined based upon the severity of the skin lesion, activity of the underlying inflammatory bowel disease and the patient's unique clinical history.The approach to paradoxical psoriasis in IBD should be discussed with a multidisciplinary team to optimise and preserve intestinal disease remission and to ensure the resolution of debilitating skin lesions.

BACKGROUND: Endoscopy is routine in trials of ulcerative colitis therapies. AIM: To investigate agreement between central and local Mayo endoscopic subscore (MES) reads in the OCTAVE programme METHODS: Flexible sigmoidoscopy was performed in tofacitinib induction (OCTAVE Induction 1&2, NCT01465763 and NCT01458951), maintenance (OCTAVE Sustain, NCT01458574) and open-label, long-term extension (OCTAVE Open, NCT01470612) studies. Kappa statistics and Bowker's tests evaluated agreement/disagreement between centrally and locally read MES, with potential determinants of differences analysed by logistic regression. RESULTS: Moderate-to-substantial agreement was observed between central and local reads at screening (77.1% agreement; kappa 0.62 [95% confidence interval 0.59-0.66]), OCTAVE Induction 1&2 week (Wk) 8 (63.8%; 0.62 [0.59-0.66]), OCTAVE Sustain Wk 52 (55.6%; 0.56 [0.50-0.62]) and for induction non-responders at OCTAVE Open month 2 (59.9%; 0.54 [0.48-0.60]). Where disagreements occurred, local reads were systematically lower than central reads at OCTAVE Induction 1&2 Wk 8, OCTAVE Sustain Wk 52 and OCTAVE Open month 2 (Bowker's P

BACKGROUND Janus kinase (JAK) inhibitors represent a novel therapeutic class for treatment of inflammatory bowel disease. AIMS To determine the efficacy and safety of JAK inhibitors compared to placebo for the treatment of Crohn's disease (CD) and ulcerative colitis (UC). METHODS PubMed, Embase and CENTRAL were systematically searched to November 1, 2018. Randomised placebo-controlled trials (RCTs) of JAK inhibitors in adult patients with CD or UC were eligible. Open-label extension studies without a placebo comparator arm were excluded. Clinical, endoscopic, and safety outcomes were extracted and rates relative to placebo were pooled using a random-effects model. RESULTS A total of 12 RCTs (5 CD, 7 UC) were included. Patients were randomised to placebo (n = 844), tofacitinib (n = 1882), filgotinib (n = 130), peficitinib (n = 176), upadacitinib (n = 387) or TD-1473 (n = 31). JAK inhibitor treatment was associated with induction of clinical remission in CD (RR, relative risk 1.38 [95% confidence interval CI 1.04-1.83], P = 0.025, I2 = 14%) and UC (RR 3.07 [95% CI 2.03-4.63], P

BACKGROUND Physicians may be reluctant to prescribe combined immunosuppression in older patients with Crohn's disease due to perceived risk of treatment-related complications. AIM To evaluate the impact of age on risk of Crohn's disease-related complications in patients treated with early combined immunosuppression vs conventional management in a post hoc analysis of the randomised evaluation of an algorithm for Crohn's treatment (REACT), a cluster-randomised trial. METHODS We compared efficacy (time to major adverse outcome of Crohn's disease-related surgery, hospitalisation or serious complications; corticosteroid-free clinical remission) and safety outcomes at 24 months, between patients aged

BACKGROUND: Conventional medications for Crohn's disease (CD) include anti‐inflammatory drugs, immunosuppressants and corticosteroids. If an individual does not respond, or loses response to first‐line treatments, then biologic therapies such as tumour necrosis factor‐alpha (TNF‐α) antagonists such as adalimumab are considered for treating CD. Maintenance of remission of CD is a clinically important goal, as disease relapse can negatively affect quality of life. OBJECTIVES: To assess the efficacy and safety of adalimumab for maintenance of remission in people with quiescent CD. SEARCH METHODS: We searched the Cochrane IBD Group Specialized Register, CENTRAL, MEDLINE, Embase, and clinicaltrials.gov from inception to April 2019. SELECTION CRITERIA: We considered for inclusion randomized controlled trials (RCTs) comparing adalimumab to placebo or to an active comparator. DATA COLLECTION AND ANALYSIS: We analyzed data on an intention‐to‐treat basis. We calculated risk ratios (RRs) and corresponding 95% confidence intervals (95% CI) for dichotomous outcomes. The primary outcome was failure to maintain clinical remission. We define clinical remission as a Crohn's Disease Activity Index (CDAI) score of < 150. Secondary outcomes were failure to maintain clinical response, endoscopic remission, endoscopic response, histological remission and adverse events (AEs). We assessed biases using the Cochrane 'Risk of bias' tool. We used GRADE to assess the overall certainty of evidence supporting the primary outcome. MAIN RESULTS: We included six RCTs (1158 participants). We rated four trials at low risk of bias and two trials at unclear risk of bias. All participants had moderate‐to‐severe CD that was in clinical remission. Four studies were placebo‐controlled (1012 participants). Two studies (70 participants) compared adalimumab to active medication (azathioprine, mesalamine or 6‐mercaptopurine) in participants who had an ileocolic resection prior to study enrolment. Adalimumab versus placebo Fifty‐nine per cent (252/430) of participants treated with adalimumab failed to maintain clinical remission at 52 to 56 weeks, compared with 86% (217/253) of participants receiving placebo (RR 0.70, 95% CI 0.64 to 0.77; 3 studies, 683 participants; high‐certainty evidence). Among those who received prior TNF‐α antagonist therapy, 69% (129/186) of adalimumab participants failed to maintain clinical or endoscopic response at 52 to 56 weeks, compared with 93% (108/116) of participants who received placebo (RR 0.76, 95% CI 0.68 to 0.85; 2 studies, 302 participants; moderate‐certainty evidence). Fifty‐one per cent (192/374) of participants who received adalimumab failed to maintain clinical remission at 24 to 26 weeks, compared with 79% (149/188) of those who received placebo (RR 0.66, 95% CI 0.52 to 0.83; 2 studies, 554 participants; moderate‐certainty evidence). Eighty‐seven per cent (561/643) of participants who received adalimumab reported an AE compared with 85% (315/369) of participants who received placebo (RR 1.01, 95% CI 0.94 to 1.09; 4 studies, 1012 participants; high‐certainty evidence). Serious adverse events were seen in 8% (52/643) of participants who received adalimumab and 14% (53/369) of participants who received placebo (RR 0.56, 95% CI 0.39 to 0.80; 4 studies, 1012 participants; moderate‐certainty evidence) and withdrawal due to AEs was reported in 7% (45/643) of adalimumab participants compared to 13% (48/369) of placebo participants (RR 0.59, 95% CI 0.38 to 0.91; 4 studies, 1012 participants; moderate‐certainty evidence). Commonly‐reported AEs included CD aggravation, arthralgia, nasopharyngitis, urinary tract infections, headache, nausea, fatigue and abdominal pain. Adalimumab versus active comparators No studies reported failure to maintain clinical remission. One study reported on failure to maintain clinical response and endoscopic remission at 104 weeks in ileocolic resection participants who received either adalimumab, azathioprine or mesalamine as post‐surgical maintenance therapy. Thirteen per cent (2/16) of adalimumab participants failed to maintain clinical response compared with 54% (19/35) of azathioprine or mesalamine participants (RR 0.23, 95% CI 0.06 to 0.87; 51 participants). Six per cent (1/16) of participants who received adalimumab failed to maintain endoscopic remission, compared with 57% (20/35) of participants who received azathioprine or mesalamine (RR 0.11, 95% CI 0.02 to 0.75; 51 participants; very low‐certainty evidence). One study reported on failure to maintain endoscopic response at 24 weeks in ileocolic resection participants who received either adalimumab or 6‐mercaptopurine (6‐MP) as post‐surgical maintenance therapy. Nine per cent (1/11) of adalimumab participants failed to maintain endoscopic remission compared with 50% (4/8) of 6‐MP participants (RR 0.18, 95% CI 0.02 to 1.33; 19 participants). AUTHORS' CONCLUSIONS: Adalimumab is an effective therapy for maintenance of clinical remission in people with quiescent CD. Adalimumab is also effective in those who have previously been treated with TNF‐α antagonists. The effect of adalimumab in the post‐surgical setting is uncertain. More research is needed in people with recent bowel surgery for CD to better determine treatment plans following surgery. Future research should continue to explore factors that influence initial and subsequent biologic selection for people with moderate‐to‐severe CD. Studies comparing adalimumab to other active medications are needed, to help determine the optimal maintenance therapy for CD.

Background: Regulatory requirements for claims of mucosal healing in ulcerative colitis (UC) will require demonstration of both endoscopic and histologic healing. Quantifying these rates is essential for future drug development. Aims: To meta-analyse endoscopic and histologic placebo response and remission rates in UC randomised controlled trials (RCTs) and identify factors influencing these rates. Methods: MEDLINE, EMBASE and the Cochrane Library were searched from inception to March 2017 for placebo-controlled trials of pharmacological interventions for UC. Endoscopic and histologic placebo rates were pooled by random effects. Mixed effects univariable and multivariable meta-regression was used to evaluate the influence of patient, intervention and trial-related study-level covariates on these rates. Results: Fifty-six induction (placebo n = 4171) and 8 maintenance trials (placebo n = 1011) were included. Pooled placebo endoscopic remission and response rates for induction trials were 23% [95 confidence interval (CI) 19-28%] and 35% [95% CI 27-42%] respectively, and 20% [95% CI 16-24%] for maintenance of remission. The pooled histologic placebo remission rate was 14% [95% CI 8-22%] for induction trials. High heterogeneity was observed for all outcomes (I2 56.2%-88.3%). On multivariable meta-regression, central endoscopy reading was associated with significantly lower endoscopic placebo remission rates (16% vs 25%; OR = 0.52, [95% CI 0.29-0.92], P = 0.03). On univariable meta-regression, higher histologic placebo remission was associated with concomitant corticosteroids (OR = 1.17 [95% CI 1.08-1.26], P

SummaryBackground Magnetic resonance imaging (MRI) is the gold standard for assessment of perianal fistulising Crohn's disease (CD). The Van Assche index is the most commonly used MRI fistula index. Aims To assess the reliability of the Van Assche index, and to modify the instrument to improve reliability and create a novel index for fistulising CD. Methods A consensus process developed scoring conventions for existing Van Assche index component items and new items. Four experienced radiologists evaluated 50 MRI images in random order on three occasions. Reliability was assessed by estimates of intraclass correlation coefficients (ICCs). Common sources of disagreement were identified and recommendations made to minimise disagreement. A mixed effects model used a 100 mm visual anologue scale (VAS) for global severity as outcome and component items as predictors to create a modified Van Assche index. Results Intraclass correlation coefficients (95% confidence intervals) for intra-rater reliability of the original and modified Van Assche indices and the VAS were 0.86 (0.81-0.90), 0.90 (0.86-0.93) and 0.86 (0.82-0.89). Corresponding ICCs for inter-rater reliability were 0.66 (0.52-0.76), 0.67 (0.55-0.75) and 0.58 (0.47-0.66). Sources of disagreement included number, location, and extension of fistula tracts, and rectal wall involvement. A modified Van Assche index (range 0-24) was created that included seven component items. Conclusions Although “almost perfect” intra-rater reliability was observed for the assessment of MRI images for fistulising CD using the Van Assche index, inter-rater reliability was considerably lower. Our modification of this index should result in a more optimal instrument.

SummaryBackground Minimising placebo response is essential for drug development. Aim To conduct a meta-analysis to determine placebo response and remission rates in trials and identify the factors affecting these rates. Methods MEDLINE, EMBASE and CENTRAL were searched from inception to April 2014 for placebo-controlled trials of pharmacological interventions for Crohn's disease. Placebo response and remission rates for induction and maintenance trials were pooled by random-effects and mixed-effects meta-regression models to evaluate effects of study-level characteristics on these rates. Results In 100 studies containing 67 induction and 40 maintenance phases and 7638 participants, pooled placebo remission and response rates for induction trials were 18% [95% confidence interval (CI) 16–21%] and 28% (95% CI 24–32%), respectively. Corresponding values for maintenance trials were 32% (95% CI 25–39%) and 26% (95% CI 19–35%), respectively. For remission, trials enrolling patients with more severe disease activity, longer disease duration and more study centres were associated with lower placebo rates, whereas more study visits and longer study duration was associated with higher placebo rates. For response, findings were opposite such that trials enrolling patients with less severe disease activity and longer study duration were associated with lower placebo rates. Placebo rates varied by drug class and route of administration, with the highest placebo response rates observed for biologics. Conclusions Placebo rates vary according to whether trials are designed for induction or maintenance and the factors influencing them differ for the endpoints of remission and response. These findings have important implications for clinical trial design in Crohn's disease.

SummaryBackground Patient-reported outcomes (PROs) have an increasingly important role in the evaluation of new therapies for inflammatory bowel disease. The US Food and Drug Administration has issued formal guidance to describe the role of PRO instruments in evaluation of claims for product labelling. However, no validated PRO exists for ulcerative colitis. Aim To investigate whether the PROs from the Mayo Clinic Score (MCS) for UC can be modified, to develop an interim PRO for use in clinical trials, alone or in combination with endoscopy. Methods Data from an induction trial of a mesalazine (mesalamine) formulation were used to compare effect sizes between mesalazine and placebo for PRO items (stool frequency and rectal bleeding) alone and in combination with endoscopy. The operating properties of the PRO were validated using data from a phase 2 trial of MLN02, a humanised antibody to the α4β7 integrin in patients with UC. Results A two-item PRO (PRO2) consisting of rectal bleeding = 0 and stool frequency ≤1 or ≤2, combined with an endoscopy subscore ≤1 yielded statistically significant differences between active drug and placebo. This combination yielded the most similar effect sizes and placebo rates for remission, compared to the primary trials. Use of PRO items alone yielded high placebo remission rates in both data sets, although rates were lower when the items were combined and remission defined as PRO2 = 0. Conclusion Patient-reported outcomes items derived from the Mayo Clinic Score combined with endoscopy as a co-primary endpoint may be an appropriate interim outcome measure for ulcerative colitis trials.

Ulcerative colitis is a chronic, idiopathic, inflammatory bowel disease characterized by a relapsing and remitting course. A substantial proportion of patients fail conventional therapies despite therapy with immunosuppressives and tumor necrosis factor antagonists. Accordingly, newer therapeutic agents that target disease-specific inflammation and minimize adverse events are required. Central to the pathogenesis of ulcerative colitis is an aberrant host response to commensal microorganisms with a resultant dysregulation of gut immune homeostasis and lymphocyte trafficking. Recently, a newer biologic, vedolizumab, which blocks lymphocyte trafficking, has been developed for use in moderate to severe ulcerative colitis. The efficacy of this agent has been demonstrated to be similar to that of other currently available biologics, and the selectivity of this agent in blocking lymphocyte migration to the gut has substantially reduced treatment-related adverse events. The drug has now been approved for use in the United States and Europe, and, although the exact positioning of this biologic in clinical practice is yet to be defined, it represents an important new chapter in our armamentarium of treatment options for this population. In this review, we will highlight key considerations to be made by providers when using this agent in clinical practice.

This is a protocol for a Cochrane Review (Intervention). The objectives are as follows: The primary objective will be to determine the efficacy and safety of vedolizumab used for induction and maintenance of remission in CD.

BACKGROUND: Ustekinumab and briakinumab are monoclonal antibodies that target the standard p40 subunit of cytokines interleukin‐12 and interleukin‐23 (IL‐12/23p40), which are involved in the pathogenesis of Crohn's disease (CD). A significant proportion of people with Crohn's disease fail conventional therapy or therapy with biologics (e.g. infliximab) or develop significant adverse events. Anti‐IL‐12/23p40 antibodies such as ustekinumab may be an effective alternative for these individuals. OBJECTIVES: The objectives of this review were to assess the efficacy and safety of anti‐IL‐12/23p40 antibodies for maintenance of remission in CD. SEARCH METHODS: We searched the Cochrane IBD Group Specialized Register, CENTRAL, MEDLINE, Embase, and trials registers from inception to 17 September 2019. We searched references and conference abstracts for additional studies. SELECTION CRITERIA: We considered for inclusion randomized controlled trials in which monoclonal antibodies against IL‐12/23p40 were compared to placebo or another active comparator in participants with quiescent CD. DATA COLLECTION AND ANALYSIS: Two review authors independently screened studies for inclusion, extracted data, and assessed bias using the Cochrane 'Risk of bias' tool. The primary outcome measure was failure to maintain clinical remission, defined as a Crohn's disease activity index (CDAI) of < 150 points. Secondary outcomes included failure to maintain clinical response, adverse events (AE), serious adverse events (SAE), and withdrawals due to AEs. Clinical response was defined as a decrease in CDAI score of ≥ 100 points from baseline score. We calculated the risk ratio (RR) and 95% confidence intervals (95% CI) for each outcome. We analyzed all data on an intention‐to‐treat basis. We used GRADE to evaluate the overall certainty of the evidence supporting the outcomes. MAIN RESULTS: Three randomized controlled trials (646 participants) met the inclusion criteria. Two trials assessed the efficacy of ustekinumab (542 participants), and one study assessed the efficacy of briakinumab (104 participants). We assessed all of the included studies as at low risk of bias. One study (N = 145) compared subcutaneous ustekinumab (90 mg) administered at 8 and 16 weeks compared to placebo. Fifty‐eight per cent (42/72) of ustekinumab participants failed to maintain clinical remission at 22 weeks compared to 73% (53/73) of placebo participants (RR 0.80, 95% CI 0.63 to 1.02; moderate‐certainty evidence). Failure to maintain clinical response at 22 weeks was seen in 31% (22/72) of ustekinumab participants compared to 58% (42/73) of placebo participants (RR 0.53, 95% CI 0.36 to 0.79; moderate‐certainty evidence). One study (N = 388) compared subcutaneous ustekinumab (90 mg) administered every 8 weeks or every 12 weeks to placebo for 44 weeks. Forty‐nine per cent (126/257) of ustekinumab participants failed to maintain clinical remission at 44 weeks compared to 64% (84/131) of placebo participants (RR 0.76, 95% CI 0.64 to 0.91; moderate‐certainty evidence). Forty‐one per cent (106/257) of ustekinumab participants failed to maintain clinical response at 44 weeks compared to 56% (73/131) of placebo participants (RR 0.74, 95% CI 0.60 to 0.91; moderate‐certainty evidence). Eighty per cent (267/335) of ustekinumab participants had an AE compared to 84% (173/206) of placebo participants (RR 0.94, 95% CI 0.87 to 1.03; high‐certainty evidence). Commonly reported adverse events included infections, injection site reactions, CD event, abdominal pain, nausea, arthralgia, and headache. Eleven per cent of ustekinumab participants had an SAE compared to 16% (32/206) of placebo participants (RR 0.74, 95% CI 0.48 to 1.15; moderate‐certainty evidence). SAEs included serious infections, malignant neoplasm, and basal cell carcinoma. Seven per cent (5/73) of ustekinumab participants withdrew from the study due to an AE compared to 1% (1/72) of placebo participants (RR 4.93, 95% CI 0.59 to 41.18; low‐certainty evidence). Worsening CD was the most common reason for withdrawal due to an AE. One study compared intravenous briakinumab (200 mg, 400 mg, or 700 mg) administered at weeks 12, 16, and 20 with placebo. Failure to maintain clinical remission at 24 weeks was seen in 51% (32/63) of briakinumab participants compared to 61% (22/36) of placebo participants (RR 0.84, 95% CI 0.58 to 1.20; low‐certainty evidence). Failure to maintain clinical response at 24 weeks was seen in 33% (21/63) of briakinumab participants compared to 53% (19/36) of placebo participants (RR 0.64, 95% CI 0.40 to 1.02; low‐certainty evidence). Sixty‐six per cent (59/90) of briakinumab participants had an AE compared to 64% (9/14) of placebo participants (RR 1.02, 95% CI 0.67 to 1.55; low‐certainty evidence). Common AEs included upper respiratory tract infection, nausea, abdominal pain, headache, and injection site reaction. Two per cent (2/90) of briakinumab participants had an SAE compared to 7% (1/14) of placebo participants (RR 0.31, 95% CI 0.03 to 3.21; low‐certainty evidence). SAEs included small bowel obstruction, deep vein thrombosis, and respiratory distress. Withdrawal due to an AE was noted in 2% of briakinumab participants compared to 0% (0/14) of placebo participants (RR 0.82, 95% CI 0.04 to 16.34; low‐certainty evidence). The AEs leading to study withdrawal were not described. AUTHORS' CONCLUSIONS: Moderate‐certainty evidence suggests that ustekinumab is probably effective for the maintenance of clinical remission and response in people with moderate to severe CD in remission without an increased risk of adverse events (high‐certainty evidence) or serious adverse events (moderate‐certainty evidence) relative to placebo. The effect of briakinumab on maintenance of clinical remission and response in people with moderate to severe Crohn's disease in remission was uncertain as the certainty of the evidence was low. The effect of briakinumab on adverse events and serious adverse events was also uncertain due to low‐certainty evidence. Further studies are required to determine the long‐term efficacy and safety of subcutaneous ustekinumab maintenance therapy in Crohn's disease and whether it should be used by itself or in combination with other agents. Future research comparing ustekinumab with other biologic medications will help to determine when treatment with ustekinumab in CD is most appropriate. Currently, there is an ongoing study that compares ustekinumab with adalimumab. This review will be updated when the results of this study become available. The manufacturers of briakinumab have stopped production of this medication, thus further studies of briakinumab are unlikely.

This is a protocol for a Cochrane Review (Intervention). The objectives are as follows: We aim to conduct a systematic review and meta-analysis of all RCTs that compare biologic drugs (TNF-α antagonists, integrin antagonists, or ustekinumab) against placebo or an active comparator in adults with CD. Using frequentist network meta-analysis, we aim to assess the efficacy of biologic drugs to treat CD and generate a clinically useful ranking of available biological drugs according to efficacy in terms of: 1) Induction and maintenance of clinical remission in CD, defined as a Crohn's Disease Activity Index (CDAI) below 150; 2) Induction and maintenance of clinical response in CD, defined as a drop in the CDAI of at least 70 (CDAI-70) or 100 (CDAI-100) points compared to baseline; and 3) Induction of endoscopic remission in CD, defined as an absence of ulceration.

Background Several antibiotics have been evaluated in Crohn's disease (CD), however randomised controlled trials (RCTs) have produced conflicting results. Objectives To assess the efficacy and safety of antibiotics for induction and maintenance of remission in CD. Search methods We searched MEDLINE, Embase, CENTRAL, the Cochrane IBD Group Specialized Register and Clinicaltrials.gov database from inception to 28 February 2018. We also searched reference lists and conference proceedings. Selection criteria RCTs comparing antibiotics to placebo or an active comparator in adult (> 15 years) CD patients were considered for inclusion. Data collection and analysis Two authors screened search results and extracted data. Bias was evaluated using the Cochrane risk of bias tool. The primary outcomes were failure to achieve clinical remission and relapse. Secondary outcomes included clinical response, endoscopic response, endoscopic remission, endoscopic relapse, histologic response, histologic remission, adverse events (AEs), serious AEs, withdrawal due to AEs and quality of life. Remission is commonly defined as a Crohn's disease activity index (CDAI) of 150. For studies that enrolled participants with fistulizing CD, response was defined as a 50% reduction in draining fistulas. Remission was defined as complete closure of fistulas. We calculated the risk ratio (RR) and corresponding 95% confidence interval (95% CI) for dichotomous outcomes. We calculated the mean difference (MD) and corresponding 95% CI for continuous outcomes. GRADE was used to assess the certainty of the evidence. Main results Thirteen RCTs (N = 1303 participants) were eligible. Two trials were rated as high risk of bias (no blinding). Seven trials were rated as unclear risk of bias and four trials were rated as low risk of bias. Comparisons included ciprofloxacin (500 mg twice daily) versus placebo, rifaximin (800 to 2400 mg daily) versus placebo, metronidazole (400 mg to 500 mg twice daily) versus placebo, clarithromycin (1 g/day) versus placebo, cotrimoxazole (960 mg twice daily) versus placebo, ciprofloxacin (500 mg twice daily) and metronidazole (250 mg four time daily) versus methylprednisolone (0.7 to 1 mg/kg daily), ciprofloxacin (500 mg daily), metronidazole (500 mg daily) and budesonide (9 mg daily) versus placebo with budesonide (9 mg daily), ciprofloxacin (500 mg twice daily) versus mesalazine (2 g twice daily), ciprofloxacin (500 mg twice daily) with adalimumab versus placebo with adalimumab, ciprofloxacin (500 mg twice daily) with infliximab versus placebo with infliximab, clarithromycin (750 mg daily) and antimycobacterial versus placebo, and metronidazole (400 mg twice daily) and cotrimoxazole (960 mg twice daily) versus placebo. We pooled all antibiotics as a class versus placebo and antibiotics with anti-tumour necrosis factor (anti-TNF) versus placebo with anti-TNF.The effect of individual antibiotics on CD was generally uncertain due to imprecision. When we pooled antibiotics as a class, 55% (289/524) of antibiotic participants failed to achieve remission at 6 to 10 weeks compared with 64% (149/231) of placebo participants (RR 0.86, 95% CI 0.76 to 0.98; 7 studies; high certainty evidence). At 10 to 14 weeks, 41% (174/428) of antibiotic participants failed to achieve a clinical response compared to 49% (93/189) of placebo participants (RR 0.77, 95% CI 0.64 to 0.93; 5 studies; moderate certainty evidence). The effect of antibiotics on relapse in uncertain. Forty-five per cent (37/83) of antibiotic participants relapsed at 52 weeks compared to 57% (41/72) of placebo participants (RR 0.87, 95% CI 0.52 to 1.47; 2 studies; low certainty evidence). Relapse of endoscopic remission was not reported in the included studies. Antibiotics do not appear to increase the risk of AEs. Thirty-eight per cent (214/568) of antibiotic participants had at least one adverse event compared to 45% (128/284) of placebo participants (RR 0.87, 95% CI 0.75 to 1.02; 9 studies; high certainty evidence). The effect of antibiotics on serious AEs and withdrawal due to AEs was uncertain. Two per cent (6/377) of antibiotic participants had at least one adverse event compared to 0.7% (1/143) of placebo participants (RR 1.70, 95% CI 0.29 to 10.01; 3 studies; low certainty evidence). Nine per cent (53/569) of antibiotic participants withdrew due to AEs compared to 12% (36/289) of placebo participants (RR 0.86, 95% CI 0.57 to 1.29; 9 studies; low certainty evidence) is uncertain. Common adverse events in the studies included gastrointestinal upset, upper respiratory tract infection, abscess formation and headache, change in taste and paraesthesiaWhen we pooled antibiotics used with anti-TNF, 21% (10/48) of patients on combination therapy failed to achieve a clinical response(50% closure of fistulas) or remission (closure of fistulas) at week 12 compared with 36% (19/52) of placebo and anti-TNF participants (RR 0.57, 95% CI 0.29 to 1.10; 2 studies; low certainty evidence). These studies did not assess the effect of antibiotics and anti-TNF on clinical or endoscopic relapse. Seventy-seven per cent (37/48) of antibiotics and anti-TNF participants had an AE compared to 83% (43/52) of anti-TNF and placebo participants (RR 0.93, 95% CI 0.76 to 1.12; 2 studies, moderate certainty evidence). The effect of antibiotics and anti-TNF on withdrawal due to AEs is uncertain. Six per cent (3/48) of antibiotics and anti-TNF participants withdrew due to an AE compared to 8% (4/52) of anti-TNF and placebo participants (RR 0.82, 95% CI 0.19 to 3.45; 2 studies, low certainty evidence). Common adverse events included nausea, vomiting, upper respiratory tract infections, change in taste, fatigue and headache AUTHORS' CONCLUSIONS: Moderate to high quality evidence suggests that any benefit provided by antibiotics in active CD is likely to be modest and may not be clinically meaningful. High quality evidence suggests that there is no increased risk of adverse events with antibiotics compared to placebo. The effect of antibiotics on the risk of serious adverse events is uncertain. The effect of antibiotics on maintenance of remission in CD is uncertain. Thus, no firm conclusions regarding the efficacy and safety of antibiotics for maintenance of remission in CD can be drawn. More research is needed to determine the efficacy and safety of antibiotics as therapy in CD.

This is a protocol for a Cochrane Review (Intervention). The objectives are as follows: The primary aim of this systematic review is to determine the efficacy and safety of infliximab for maintaining remission in patients with CD.

This is a protocol for a Cochrane Review (Intervention). The objectives are as follows: The primary objective of this review is to assess the feasibility and safety of discontinuing immunosuppressant or biologic drugs, administered alone or in combination, in patients with quiescent CD.

This is the protocol for a review and there is no abstract. The objectives are as follows: The objective of this review is to determine the factors that influence placebo response and remission rates in induction and maintenance trials of CD in which patients with active or quiescent disease were enrolled using the CDAI or Harvey-Bradshaw Index (HBI).

BACKGROUND: Endoscopic assessment of mucosal disease activity is widely used to determine eligibility and response to therapy in clinical trials of treatment for Crohn’s disease. However, the operating properties of the currently available endoscopic indices remain unclear. OBJECTIVES: A systematic review was undertaken to evaluate the development and operating characteristics of the Crohn’s Disease Endoscopic Index of Severity (CDEIS) and Simple Endoscopic Scale for Crohn’s Disease (SES‐CD). SEARCH METHODS: Electronic searches of the MEDLINE (1966 to December 2015), EMBASE (1980 to December 2015), and Cochrane CENTRAL Register of Controlled Trials (Issue 12, 2015) databases were supplemented by manual reviews of reference listings and conference proceedings (Digestive Disease Week, United European Gastroenterology Week, European Crohn’s and Colitis Organization). SELECTION CRITERIA: Any study design (e.g. randomized controlled trials, cohort studies, case series) that evaluated either or both the CDEIS or SES‐CD in patients with Crohn’s disease was considered for inclusion. Eligible participants were adult patients (> 16 years), diagnosed with Crohn’s disease using conventional clinical, radiographic, and endoscopic criteria. DATA COLLECTION AND ANALYSIS: Two authors (RK, JKM) independently reviewed the titles and abstracts of the studies identified from the literature search. The full texts of potentially relevant citations were reviewed for inclusion and the study investigators were contacted to clarify any unclear data. Any disagreements were resolved by discussion and consensus with a third author. A standardized form was used to assess eligibility of trials for inclusion in the study and for data extraction. Two authors independently extracted and recorded data (RK, SAN). The number of patients enrolled; number of patients per treatment arm; patient characteristics including age and gender distribution; endoscopic index; and outcomes such as intra‐rater reliability, inter‐rater reliability responsiveness, validity, feasibility, construct validity, and criterion validity were recorded for each trial. MAIN RESULTS: Forty‐three reports of 30 studies fulfilled the inclusion criteria. For the SES‐CD, inter‐rater reliability was assessed in four studies. In the development study for the SES‐CD (Daperno 2004), the overall ICC (0.9815, 95% CI 0.9705 to 0.9884) and the kappa for the regions is high; however the paired raters were in the same room which introduces the potential for bias. For the CDEIS, inter‐rater reliability was assessed in six studies. Daperno 2014 reported that the ICC for the CDEIS was 0.985 (95% CI 0.939‐1.000) for average measures of video score and was 0.835 (95% CI 0.540‐0.995) for single measures of video score. With respect to validity, correlation between the CDEIS and clinical measures, including C‐reactive protein (CRP) and erythrocyte sedimentation rate (ESR), was also reported. The estimates of correlation with CRP were r = 0.521 (Sipponen 2010b), r = 0.553 (Sipponen 2008a) and r = 0.608 (Sipponen 2008c). For the SES‐CD, the corresponding values for correlation with CRP ranged from r = 0.46 (Jones 2008) to r = 0.68 (Green 2011). Responsiveness data for the CDEIS were available in nine studies. Seven studies demonstrated statistically significant decreases in the CDEIS score after administration of a treatment of known efficacy. Minimal responsiveness data were available for the SES‐CD. Sipponen 2010a and Sipponen 2010b demonstrated statistically significant changes in the SES‐CD score after subjects were administered a treatment of known efficacy. No studies were identified that explicitly evaluated the feasibility for either the SES‐CD or the CDEIS. The SES‐CD requires fewer calculations and may therefore be easier to use than the CDEIS. AUTHORS' CONCLUSIONS: Although they are used in clinical trials, the CDEIS and SES‐CD remain incompletely validated. Future research is required to determine the operating properties and to define the optimal index.

EDITORIAL COMMENT: We accepted this paper to remind even those readers who are obstetricians and/or gynaecologists that ectopic pregnancy may elude diagnosis unless the possibility is considered in any women during her reproductive years who has abdominal pain, especially when associated with anaemia and disordered menstruation. The presence of pathology in another system can be a distracter from prompt diagnosis of ruptured ectopic pregnancy as shown by these 2 cases.