Prevalence of Extraintestinal Manifestations in Inflammatory Bowel Disease: A Systematic Review and Meta-analysis.

BACKGROUND: Inflammatory bowel disease (IBD) is a multisystem disease impacting various body systems including musculoskeletal, ocular, skin, hepatobiliary, pulmonary, cardiac, and haematological systems. The extraintestinal manifestations of IBD are frequent, common in both ulcerative colitis (UC) and Crohn's disease (CD), and impact the morbidity and mortality of patients. METHODS: The Embase, Embase classic, and PubMed databases were searched between January 1979 and December 2021. A random effects model was performed to find the pooled prevalence of joint, ocular, and skin extraintestinal manifestations of UC and CD. RESULTS: Fifty-two studies were included that reported on 352 454 patients. The prevalence of at least 1 joint, ocular, or skin extraintestinal manifestation in all IBD, UC, and CD was 24%, 27%, and 35% respectively. The prevalence between UC and CD were similar for pyoderma gangrenosum and axial joint manifestations. Ocular manifestations were found to be more common in CD than in UC. Peripheral joint manifestations and erythema nodosum were found to be more common in CD than UC. DISCUSSION: To our knowledge, this is the first meta-analysis that reports on the prevalence of at least 1 joint, ocular, or skin extraintestinal manifestation in IBD. Our results are largely consistent with figures and statements quoted in the literature. However, our findings are based on significantly larger cohort sizes. Thus, our results have the potential to better power studies and more accurately counsel patients.

The prevalence of joint, ocular, or skin extraintestinal manifestations in IBD, UC, and CD was 24%, 27%, and 35% respectively. Ocular manifestations were more common in CD. Peripheral joint manifestations and erythema nodosum were more common in CD.

Sensitivity and specificity of diagnostic modalities in pouchitis: a systematic review and meta-analysis.

Restorative proctocolectomy (RPC) is the most common surgical procedure to restore gastrointestinal continuity after surgical resection of the colon and rectum. Pouchitis is a common complication with several different modalities that can be used to aid diagnosis. This systematic review and meta-analysis aimed at exploring the sensitivity and specificity these diagnostic modalities. The medical literature was searched using MEDLINE, EMBASE and EMBASE classic and PubMed from 1978 to June 2022. We calculated descriptive statistics using sensitivity, specificity, and false-positive rate of the primary studies and also their positive and negative likelihood ratios, and their diagnostic odds ratios. The screen found 5477 records with 13 studies being included. Faecal lactoferrin was found to have the highest pooled sensitivity and specificity of 98% and 88% respectively with imaging modalities coming in second and faecal calprotectin third with pooled sensitivities and specificities of 87% and 79% and 74% and 81% respectively. Faecal biomarkers particularly lactoferrin and imaging modalities may have an important role to play in diagnosing pouchitis. Importantly due to delays in availability of pouchoscopy, our data supports early ordering of these tests to help delineate from other causes. Further studies are required with larger cohort sizes to further validate these tests.

Prevalence of NUDT15 Genetic Variants and Incidence of Thiopurine-induced Leukopenia in Inflammatory Bowel Disease: A Systematic Review and Meta-analysis.

BACKGROUND AND AIMS: Nudix hydrolase 15 [NUDT15] genetic variants confer an increased risk of thiopurine-induced leukopenia [TIL]; however, their global prevalence in inflammatory bowel disease [IBD] patients is unknown. We aimed to evaluate the global prevalence of NUDT15 variants in IBD patients and incidence of TIL in these patients. METHODS: Six databases were searched from inception until July 2022. Studies reporting the frequency of any NUDT15 variant and/or frequency of leukopenia in adult IBD patients with these variants were included. A random effects model was performed to estimate the pooled prevalence of variants, incidence of early [≤8 weeks] and late [>8 weeks] leukopenia, and relative risk of developing leukopenia. RESULTS: Twenty studies comprising 5232 patients were included. The pooled prevalence of the *1/*3 c.415C > T C/T diplotype was 13% (95% confidence interval [CI]: 10-18%), *3/*3 c.415C > T T/T diplotype was 2% [95% CI: 1-2%], *1/*5 c.52G > A G/A diplotype was 2% [95% CI: 1-3%], and *1/*6 c.36_37insGGAGTC ins/- diplotype was 7% [95% CI: 4-12%]. The pooled prevalence of *1/*3 was high in Japanese [20%, 95% CI: 16-24%] and Chinese patients [18%, 95% CI: 12-27%]. The incidence of early leukopenia was 20% [95% CI: 16-26%] in *1/*3 patients, 99% [95% CI: 7-100%] in *3/*3 patients, and 49% [95% CI: 29-69%] in *1/*6 patients. The incidence of late leukopenia was 36% [95% CI: 26-49%] in *1/*3 patients. CONCLUSIONS: NUDT15 variants are common and strongly predict TIL in IBD patients. Pre-treatment NUDT15 genotyping should be considered particularly in Asian populations, to guide thiopurine dosing and prevent myelotoxicity.

Network meta-analysis: efficacy and safety of treatments for fistulising Crohn's disease.

INTRODUCTION: Fistulas are a debilitating complication of Crohn's disease and treatment options remain limited. There is a lack of head-to-head comparisons between treatments. To our knowledge, this is the first network meta-analysis on the efficacy of medical therapies in achieving fistula remission and maintenance of fistula closure in Crohn's disease. METHODS: Biomedical databases and the Cochrane Central Registry were searched between 1978 and 2022 for randomized controlled trials (RCTs) reporting on treatments. A network meta-analysis was performed using the frequentist model with pooled relative risks (RRs) and P -scores used to rank treatments. RESULTS: Twenty-five RCTs were included for analysis with 2239 patients included. At the 16-24 week time point, infliximab produced the only statistically significant result with the 5 mg/kg dose proving the most effective [RR, 2.30; 95% confidence interval (CI), 1.40-3.77]. At 44 weeks, ustekinumab was found to be most superior with it being 2.38 times (RR, 2.38; 95% CI, 1.24-4.56) more superior to placebo, with adalimumab (RR, 2.06; 95% CI, 1.06-3.99) and infliximab 5 mg/kg (RR, 1.68; 95% CI, 1.03-2.75) also producing a statistically significant result. CONCLUSION: Despite infliximab being favoured in international guidelines for the treatment of perianal fistulising Crohn's disease, biologics such as ustekinumab, vedolizumab and adalimumab show promising results.

Ileoanal pouch cancers in ulcerative colitis and familial adenomatous polyposis: A systematic review and meta-analysis.

INTRODUCTION: Restorative proctocolectomy results in the formation of a pouch that adapts to a more colonic phenotype. The incidence of cancer of the pouch is thought to be low with most societal guidelines differing on their recommendations for surveillance. AIMS: We conducted a systematic review with meta-analysis to report the incidence of cancer in all pouch patients. METHODS: The Embase, Embase classic and PubMed databases were searched between June 1979- June 2021. A random effects model was performed to find the pooled incidence of pouch cancer. In addition, we also looked for risk factors for pouch cancers. RESULTS: Forty-six studies were included. In 19,964 patients with Ulcerative Colitis (UC) the pooled incidence of pouch cancer was 0.0030 (95% CI: 0.0016 -0.0055). In 3741 patients with Familial Adenomatous Polyposis (FAP) the pooled incidence of pouch cancer was 0.01 (95% CI: 0.01 - 0.02). In UC most pouch cancers were found to occur in the pouch body (0.59 (95% CI: 0.29-0.84)). CONCLUSIONS: The findings suggest that the pooled incidence of pouch cancer in UC is similar to that which was previously published, and this is the first meta-analysis to report a pooled incidence for pouch cancer in FAP.

Network meta-analysis: efficacy of treatment for acute, chronic, and prevention of pouchitis in ulcerative colitis.

INTRODUCTION: Pouchitis is a clinically significant complication of ileal pouch-anal anastomosis. There is a paucity of head-to-head comparisons between treatments and no data were available about how each treatment rank against each other. A network meta-analysis of the different treatments used for acute, chronic and prevention of pouchitis was conducted. METHODS: Biomedical databases and the Cochrane Central registry were searched between 1978 and 2021 for randomised controlled trials examining treatment for acute, chronic and prevention of pouchitis. A network meta-analysis was performed using the frequentist model with pooled relative risks and P scores used to rank treatments. RESULTS: 18 studies were included from a screen of 4291 abstracts. When compared to placebo, rifaximin was found to be the best antibiotic for acute pouchitis whereas ciprofloxacin ranked highest against metronidazole. For chronic pouchitis, metronidazole followed by probiotics was statistically significant and effective treatments in inducing remission although metronidazole had the highest adverse events. Adalimumab and bismuth were also found to be superior to placebo; however, they did not reach statistical significance. Probiotics proved superior to placebo in the prevention of pouchitis development. CONCLUSIONS: This is the first network meta-analysis which compares the efficacy and tolerability of treatments in the management and prevention of acute and chronic pouchitis. It confirms that antimicrobial therapy remains the mainstay of treatment and adds weight to current guideline recommendations. Our results demonstrate that rifaximin and probiotics may deserve a more prominent role. While biologics are starting to show promise, large-scale head-to-head comparisons are warranted to validate the efficacy of these treatments.

The impact of the ileoanal pouch on female fertility in ulcerative colitis: A systematic review and meta-analysis.

AIM: Ileal pouch-anal anastomosis is a restorative option for patients with ulcerative colitis (UC) requiring surgery. The primary outcome of this study was the relative risk of infertility in women with UC undergoing restorative proctocolectomy (RPC) compared to the same patients before undergoing RPC. Infertility was defined as the inability to conceive after 1 year of regular sexual intercourse without contraception. METHODS: A systematic review and meta-analysis were performed to include all relevant articles from 1946 from MEDLINE, Embase and Cochrane Central Register of Controlled Trials. Studies included reported on the fertility rate of a cohort with UC and also reported the rate after RPC in those within the cohort who underwent surgery. This study was registered on PROSPERO (CRD42021259745). RESULTS: Thirteen studies met the inclusion criteria and accounted for 793 patients pre-pouch and 802 post-pouch. The mean and median age of the patients at analysis was 36.8 and 32.7 years respectively; and the median duration of follow-up following ileal pouch-anal anastomosis was 110.4 (68-139) months. Our results highlight that following RPC the relative risk of infertility is 4.17 (95% CI 1.99, 8.74) compared with patients before RPC who had UC. CONCLUSIONS: The findings of this meta-analysis provide an update on a previous meta-analysis published over a decade ago and results remain congruent. This suggests that despite advancements in surgical techniques the risk to fertility remains similar to a decade ago. However, further high quality studies are needed to try and decipher independent risk factors associated with a decrease in infertility.

Biologics recommendations in the ECCO guidelines on therapeutics in Crohn's disease: medical treatment.

In 2019, the European Crohn's and Colitis Organisation released guidelines for the medical management of Crohn's disease, concerning the induction of remission, the maintenance of remission and the treatment of fistulising perianal disease. This review summarises the key recommendations regarding the use of biologics in these settings.

Prevalence of pouchitis in both ulcerative colitis and familial adenomatous polyposis: A systematic review and meta-analysis.

AIM: Pouchitis is a clinically significant complication of ileal pouch-anal anastomosis with its prevalence varying in the literature. Pouchitis is thought to occur more commonly in patients with ulcerative colitis (UC) than in patients with familial adenomatous polyposis (FAP). We conducted a systematic review with meta-analysis of all published literature to report the prevalence of pouchitis in all pouch patients as well as specifically in UC and FAP. We also investigated the prevalence of acute and chronic pouchitis in UC and FAP. METHODS: A meta-analysis was conducted by searching the Embase, Embase Classic and PubMed databases between 1978 and 2021 exploring the prevalence of pouchitis in UC and FAP. We then performed a random effects model in order to find the pooled prevalence of pouchitis and used odds ratios to report differences in the prevalence of pouchitis in UC and FAP. RESULTS: Fifty-nine full papers and conference abstracts were included in the meta-analysis comprising 18 117 patients with UC and 860 with FAP. The prevalence of pouchitis in UC was 0.32 (95% CI 0.27-0.37) and in FAP was found to be 0.06 (95% CI 0.03-0.15). The odds ratio of pouchitis in UC patients compared with FAP patients was 4.95 (95% CI 3.17-7.72, P < 0.0001). CONCLUSIONS: Our findings support the consensus that the prevalence of pouchitis is higher in UC than in FAP. More significantly our findings suggest that the true prevalence of pouchitis is higher than commonly reported in the literature. This literature may help counsel patients prior to undergoing restorative proctocolectomy.

Strontium substituted bioactive glasses for tissue engineered scaffolds: the importance of octacalcium phosphate.

Porous bioactive glasses are attractive for use as bone scaffolds. There is increasing interest in strontium containing bone grafts, since strontium ions are known to up-regulate osteoblasts and down regulate osteoclasts. This paper investigates the influence of partial to full substitution of strontium for calcium on the dissolution and phase formation of a multicomponent high phosphate content bioactive glass. The glasses were synthesised by a high temperature melt quench route and ground to a powder of <38 microns. The dissolution of this powder and its ability to form apatite like phases after immersion in Tris buffer (pH 7.4) and simulated body fluid (SBF) was followed by inductively coupled plasma optical emission spectroscopy (ICP), Fourier transform infra red spectroscopy (FTIR), X-ray powder diffraction (XRD) and (31)P solid state nuclear magnetic resonance spectroscopy up to 42 days of immersion. ICP indicated that all three glasses dissolved at approximately the same rate. The all calcium (SP-0Sr-35Ca) glass showed evidence of apatite like phase formation in both Tris buffer and SBF, as demonstrated after 3 days by FTIR and XRD analysis of the precipitate that formed during the acellular dissolution bioactivity studies. The strontium substituted SP-17Sr-17Ca glass showed no clear evidence of apatite like phase formation in Tris, but evidence of an apatite like phase was observed after 7 days incubation in SBF. The SP-35Sr-0Ca glass formed a new crystalline phase termed "X Phase" in Tris buffer which FTIR indicated was a form of crystalline orthophosphate. The SP-35Sr-0Ca glass appeared to support apatite like phase formation in SBF by 28 days incubation. The results indicate that strontium substitution for calcium in high phosphate content bioactive glasses can retard apatite like phase formation. It is proposed that apatite formation with high phosphate bioactive glasses occurs via an octacalcium phosphate (OCP) precursor phase that subsequently transforms to apatite. The equivalent octa-strontium phosphate does not exist and consequently in the absence of calcium, apatite formation does not occur. The amount of strontium that can be substituted for calcium in OCP probably determines the amount of strontium in the final apatite phase and the speed with which it forms.