Does perioperative biological therapy increase 30-day post-operative complication rates in inflammatory bowel disease patients undergoing intra-abdominal surgery? A systematic review

BackgroundBiopharmaceuticals revolutionised inflammatory bowel disease (IBD) treatment. However, it is postulated they compromise immunity, collagen production and angiogenesis resulting in infective post-operative complications and altered wound/anastomotic healing. Research has failed to agree on risks associated with perioperative biologics therefore it was anticipated that a systematic review may provide a consensus and contribute recommendations for clinical practice.MethodsA systematic review conducted as per PRISMA guidelines included a methodical search of PubMed, Google Scholar, EMBASE/Ovid and Cochrane Library using MeSH and/or keywords for papers published between 01/01/1998 and 04/02/2019.The population analysed included adult ulcerative colitis, Crohn's disease, Indeterminate Colitis or IBD unclassified patients. The intervention was intra-abdominal surgery in patients treated with biological therapy in the preceding 12 weeks compared to patients who had intra-abdominal surgery without biological therapy within the defined timeframe. The primary outcome was surgical site infection (SSI) with secondary outcomes including wound dehiscence, intra-abdominal sepsis/abscess, systemic infection and anastomotic breakdown within 30 days post-procedure. Papers were evaluated by two independent reviewers and those included were assessed for quality/bias using the Newcastle–Ottowa scale.Results2064 UC, Crohn's and IC patients were analysed across 8 included studies. Several studies' multivariate analyses demonstrated corticosteroids to be independent predictors of morbidity. There are no increased complications associated with anti-TNFα exposure while vedolizumab increased SSI and small bowel obstruction.ConclusionProspective studies and randomised control trials are required to clarify study outcomes and recommendations published to date. Presently, biologics should continue to be used and considered beneficial in this population.     

Therapeutic drug monitoring with biologic agents in immune mediated inflammatory diseases

ABSTRACT

Introduction: Biologic therapy has revolutionized the treatment of immune mediated inflammatory diseases (IMID), such as inflammatory bowel disease (IBD), rheumatoid and psoriatic arthritis, ankylosing spondylitis and psoriasis. Nevertheless, some patients exhibit primary nonresponse (PNR) or secondary loss of response (SLR) to biologics.

Areas covered: This collaborative review provides data on the role of therapeutic drug monitoring (TDM) in IMID for optimizing biologic therapy including infliximab, adalimumab, certolizumab pegol etanercept and golimumab vedolizumab, secukinumab and ustekinumab.

Expert opinion: Most exposure-response relationship studies show a positive correlation between biologic drug concentrations and favorable therapeutic outcomes in IMID with higher drug concentrations typically associated with more objective outcomes. Clinically, reactive TDM rationalizes the management of PNR and SLR to anti-tumor necrosis factor therapy and is emerging as the new standard of care in IBD as it is also more cost-effective than empiric dose escalation. Preliminary data suggest that proactive TDM with the goal to achieve a threshold drug concentration is associated with better therapeutic outcomes when compared to empiric drug optimization and/or reactive TDM of infliximab and adalimumab in IBD. However, more data from well-designed prospective studies are needed to prove the benefit of TDM-based algorithms in real life clinical practice in IMID.     

阿夫唑嗪联合莫西沙星治疗慢性前列腺炎

【摘要】 目的 探讨阿夫唑嗪联合莫西沙星治疗慢性前列腺炎的临床疗效。 方法 选取2018年2月～2019年2月我院收治的103例慢性前列腺炎患者，采用抽签法分为三组，即阿夫唑嗪组（n=34)，莫西沙星组(n=34)，联合组(n=35)。阿夫唑嗪组给予阿夫唑嗪治疗，莫西沙星组给予莫西沙星治疗，联合组给予阿夫唑嗪联合莫西沙星治疗。比较三组临床疗效、巨噬细胞集落刺激因子（M-CSF）、血清胰石蛋白（PSP）、神经生长因子(NGF)、白细胞介素4（IL-4）、白细胞介素8（IL-8）、肿瘤坏死因子（TNF-α）、最大尿流率（MFR）、平均尿流率（AFR）变化情况及并发症发生情况。 结果 治疗后，联合组临床疗效总有效率均显著高于阿夫唑嗪组、莫西沙星组（P＜0.05）；治疗前，联合组和单药组血清M-CSF、PSP、NGF、IL-4、IL-8、TNF-α水平对比均无显著差异（P＞0.05）；治疗后，三组血清M-CSF、PSP、NGF、IL-4、IL-8、TNF-α〖JP〗均随着时间的推移而下降，且联合组均显著低于阿夫唑嗪组、莫西沙星组（P＜0.05）；治疗前，联合组和单药组排尿情况水平对比无显著差异（P＞0.05）；治疗后，三组MFR、AFR均随着时间的推移而升高，且联合组显著高于阿夫唑嗪组、莫西沙星组（P＜0.05）；联合组并发症发生率与阿夫唑嗪组、莫西沙星组比较，差异无统计学意义（P＞0.05）。 结论 阿夫唑嗪联合莫西沙星治疗慢性前列腺炎疗效显著，可有效改善患者排尿功能，降低炎症反应，且并发症较少,有利于患者康复。     

The role of FKBP51 in the prognosis of ulcerative colitis-associated colorectal cancer

PurposeUlcerative colitis (UC) carries a high risk of developing colorectal cancer (CRC). FK506-binding protein 51 (FKBP51) is a key regulator of glucocorticoid resistance and inflammatory tumor microenvironment. This study aimed to investigate the role of FKBP51 in UC-CRC prognosis.Materials and methodsThe FKBP51 expression was measured by immunohistochemistry, qRT-PCR and western blot in control and tumor-containing tissues from UC-CRC patients. H&E staining was used to analyze the inflammatory status of each sample. The relationship between FKBP51 expression and UC-CRC prognosis was assessed by Kaplan–Meier curves and Mann-Whitney U test, and receiver-operating characteristic curves were generated to clarify the role of FKBP51 in predicting survival period and recurrence of UC-CRC patients.ResultsThe FKBP51 expression was significantly (p ​< ​0.01) increased by 36.3% in tumor-containing tissues compared to control tissues in UC-CRC patients. Nuclear enrichment of FKBP51 in tumor-containing tissues was significantly (p ​< ​0.001) increased by 78.5%. The UC-CRC patients with higher levels of FKBP51 expression ratio between tumor-containing tissues and control tissues had shorter survival periods, but greater neutrophil invasion and neutrophils to lymphocytes ratio (NLR) in peripheral blood. Moreover, the FKBP51 expression ratio was more helpful in predicting the survival periods and recurrence in the UC-CRC patients than the NLR in peripheral blood.ConclusionsThe FKBP51 expression ratio between tumor-containing tissue and control tissue may be an important biomarker of inflammatory tumor microenvironment and more helpful for the UC-CRC prognosis.     

The effect of appendectomy on the course of ulcerative colitis: a systematic review

Aim Previous studies have shown significantly lower appendectomy rates in ulcerative colitis (UC) patients compared with healthy controls. Evidence indicating that the appendix has an immunomodulatory role in UC has been accumulating. To examine the latest evidence on the effect of appendectomy on the disease course of UC. Method PubMed, The Cochrane Library and EMBASE were searched. Primary end‐points were number of relapses, use of steroids, number of hospital admissions and number of colectomies. Results The search resulted in six observational studies (five case–control studies and one cohort study) totalling 2532 patients. Owing to clinical heterogeneity, no meta‐analysis could be conducted. One study found lower relapse rates in patients appendectomized before the onset of UC [absolute risk reduction (ARR) = 21.5%; 95% CI: 1.71–45.92%]. Another two studies found a reduced requirement for immunosuppression in appendectomized patients (ARR = 20.2%; 95% CI: 9.67–30.46% in the first study and ARR = 21.4%; 95% CI: 10.32–32.97% in the second study). In addition, one study found lower colectomy rates in nonappendectomized patients (ARR = 8.7%; 95% CI: 1.29–18.66%) and two studies found lower colectomy rates in appendectomized patients (ARR = 21.4%; 95% CI: 13.17–28.79% in the first study and ARR = 18.7%; 95% CI: 7.50–29.97% in the second study). Conclusion There are limited and conflicting data available regarding the effect of appendectomy on the disease course of UC. Most studies suggest a beneficial effect and the minority find no, or a negative, effect.     

Association between microRNA polymorphisms and chronic pancreatitis

BackgroudMicroRNAs play important roles in the development and progression of many human diseases. mir-146a could significantly suppress the induction of proinflammatory cytokines IL-1β, IL-6, TNF-α, NF-κB and chemokine MCP-1, which might play important roles in chronic pancreatitis. This study was conducted to evaluate the association between mir-146a rs2910164, a functional polymorphism in the pre-mir-146a, and chronic pancreatitis risk.MethodsThe rs2910164 genotypes were determined in 165 patients with chronic pancreatitis and 200 healthy controls who were frequency matched for age and gender. One single nucleotide polymorphism (rs2910164) was genotyped by polymerase chain reaction-restriction fragment length polymorphism (PCR-RLFP).ResultsThe frequency of individuals who carried [G] allele was significantly higher in cases (62.7%) than in controls (53.7%, p = 0.015), which resulted in a statistically significant pathogenic effect associated with this variant allele (OR: 1.448, CI: 1.076–1.950; p = 0.015). The GC and GG genotypes showed strong and significant increased risk for complication of chronic pancreatitis (OR = 3.668, 95%CI = 1.233–10.916, p = 0.019; OR = 5.667, 95%CI = 1.852–17.336, p = 0.002). The individuals carrying G allele confer a lower expression level of mature mir-146a.ConclusionThese findings suggest that the mir-146a rs2910164 may contribute to genetic susceptibility to chronic pancreatitis, and that mir-146a might be involved in chronic pancreatitis development.     

TL1A blocking ameliorates intestinal fibrosis in the T cell transfer model of chronic colitis in mice

Tumor necrosis factor like cytokine 1A (TL1A) is a member of the TNF superfamily. Accumulating evidence demonstrated the importance of TL1A in the pathogenesis of inflammatory bowel disease (IBD) and suggested a potential role of TL1A blocking in IBD therapy. Here we aimed to explore whether the anti-TL1A antibody could ameliorate intestinal inflammation and fibrosis in IBD. A T cell transfer model of chronic colitis was induced by intraperitoneal injection of CD4⁺CD45RB^high naive T cells isolated from either C57BL/6 wild type (WT) mice or LCK-CD2-Tl1a-GFP transgenic (L-Tg) mice into recombinase activating gene-1-deficient (RAG^?/?) mice. The colitis model mice were treated prophylactically or therapeutically with anti-Tl1a antibody or IgG isotype control. Haematoxylin and eosin staining (H&E staining), Masson's trichrome staining (MT staining) and sirius red staining were used to detect histopathological changes in colonic tissue; immunohistochemical staining was used to detect the expressions of collagen I, collagen III, TIMP1, vimentin, α-SMA and TGF-β1/Smad3. Results showed that anti-Tl1a antibody could reduce intestinal inflammation and fibrosis by inhibiting the activation of intestinal fibroblasts and reducing the collagen synthesis in the T cell transfer model of chronic colitis. The mechanism may be related to the inhibition of TGF-1/Smad3 signaling pathway.     

Feeding associated neonatal necrotizing enterocolitis (Primary NEC) is an inflammatory bowel disease

Neonatal necrotizing enterocolitis which develops after feeding preterm infants is characterized by severe intestinal inflammation and profound systemic metabolic acidosis. The fermentation of undigested dietary carbohydrate by colonic flora yields gases (CO₂ and H₂) and short chain organic acids. These organic acids can disrupt the intestinal mucosa and initiate inflammation driven predominantly by resident mast cells and by granulocytes which are recruited from blood. A systemic acidosis ensues derived from intestinal acids, not classic lactic acidosis produced from anaerobic metabolism. The systemic acidosis further compromises inflamed bowel leading to bowel necrosis.