Progress with infliximab biosimilars for inflammatory bowel disease

Introduction: Biological therapies have revolutionized the treatment of inflammatory bowel diseases (IBD) in the last two decades. Though biological drugs are effective, their use is associated with high costs and access to biological agents varies among countries. As the patent for the reference products expired, the advent of biosimilar monoclonal antibodies has been expected. Biosimilars represent less expensive alternatives compared to the reference product.

Areas covered: In this review, authors will review the literature on the clinical efficacy, safety and immunogenicity of current and future biosimilar infliximabs. Short- and medium-term data from real-life cohorts and from randomized-clinical trials in IBD demonstrated similar outcomes in terms of efficacy, safety and immunogenicity as the reference product for CT-P13. Switch data from the reference to the biosimilar product are also accumulating (including the NOR-SWITCH and the CT-P13 3.4 study).

Expert opinion: The use of biosimilar infliximab in IBD is increasing worldwide. Its use may be associated with budget savings leading to better access to biological therapies and consequently improved health outcomes. Switching from the originator to a biosimilar in patients with IBD is acceptable, although scientific and clinical evidence is lacking regarding reverse switching, multiple switching, and cross-switching among biosimilars in IBD patients.     

CT-P13: a review on a biosimilar to infliximab in the treatment of inflammatory bowel disease

ABSTRACT

Introduction: CT-P13 was developed as an infliximab biosimilar in 2013. The primary structure of CT-P13 is identical to that of original infliximab and it has highly similar higher order structure, physiochemical characteristics, and biological properties. To date, data from real-life cohorts and randomized controlled trials show comparable clinical efficacy, safety and immunogenicity of biosimilar CT-P13, and the original reference medicinal Product (RMP).

Areas covered: This article reviews the comparability of CT-P13 and the RMP and focuses on the emerging clinical trial and observational cohorts data on efficacy and safety of CT-P13 in inflammatory bowel disease (IBD) patients. The development of a subcutaneous formulation of Infliximab CT-P13 is also addressed.

Expert opinion: There is a plethora of evidence to show CT-P13 is non-inferior to infliximab RMP in IBD and that a switch from RMP to this biosimilar is feasible and safe. However, interchangeability and multiple switches can still not be endorsed for introduction into clinical practice.     

Biosimilars of adalimumab: the upcoming challenge in IBD

ABSTRACT

Introduction: Biosimilars represent great potential in cost saving and re-investment opportunities in healthcare and allow patients greater access to effective mAbs. Infliximab biosimilars are successfully used in all indications for whom the reference product (RP) was approved.

Areas covered: In late 2018, adalimumab biosimilars will also be available in patients with inflammatory bowel disease (IBD).

ABP501, BI 695501, GP2017, and SB5 have been approved by the EMA for the same indications of the reference product (RP, Humira®). Preclinical data show high similarity between all biosimilars and the RP. Clinical data in patients with rheumatoid arthritis and psoriasis also show no differences in terms of efficacy, safety, and immunogenicity. Data in IBD patients are still lacking.

Expert opinion: Biosimilars of adalimumab appear to be clinically equivalent to the RP. Decisions based on choosing the ideal patient to receive or to be switched to a biosimilar of adalimumab, or choosing one biosimilar vs. another, or cross-switching among biosimilars remain the next challenge in the field of IBD.     

Rheumatologic and extraintestinal manifestations of inflammatory bowel diseases

Inflammatory bowel diseases (IBDs) often present as a complex inflammatory process wherein colon lesions (ulcerative colitis, UC) or widespread ulceration and fissure (Crohn’s disease, CD) might be accompanied by ancillary extraintestinal manifestations (EIMs) that could involve almost every organ system, but also by autoimmune disorders ranging from psoriasis and rheumatoid arthritis to connective tissue diseases. Certain EIMs are more common related to the activity of the IBD (joint, skin, ocular and oral manifestations), other EIMs typically run a course independent of the IBD activity (hepatobiliary disorders) and some are non-specific disorders (osteoporosis and amyloidosis). This paper reviews the most common extraintestinal and rheumatologic manifestations of UC and CD. They may produce greater morbidity than the underlying intestinal disease and may even be the initial presenting symptoms of the IBD. Thus, early recognition of these manifestations should help guide therapy that will reduce overall morbidity in affected patients.

• Key Message

• A complete review on the most common extraintestinal and rheumatologic manifestations of ulcerative colitis and Crohn’s disease.

     

炎症性肠病患者的营养支持治疗

溃疡性结肠炎和克罗恩病等炎症性肠病患者常伴有营养不良及生长发育障碍。营养支持治疗在炎症性肠病治疗中占有重要地位。应常规对炎症性肠病患者进行营养风险筛查,并采用适当方法进行营养评定,以便及时进行营养支持。肠内营养支持作为儿童克罗恩病患者诱导缓解和维持治疗的首选,在成人患者中作为药物的替代治疗。有多种营养制剂,不同患者对不同的营养制剂反应不同,需选择合适的制剂,进行个体化治疗,才能发挥营养制剂的最大效用。     

Treatment of inflammatory bowel disease by leukocytapheresis

Studies about leukocytapheresis have emerged with the need of search for alternatives to conventional treatment in inflammatory bowel diseases (IBD). Leukocytapheresis is a novel non-pharmacologic approach for active ulcerative colitis (UC) and Crohn’s disease (CD), in which leukocytes are mechanically removed from the circulatory system. Patients with active IBD treated with leukocytapheresis using a Cellsorba E column between 2012 and 2015, were enrolled in Turkey. In our experience, the results of leukocytapheresis therapy in 6 patients with CD and 20 patients with active UC were overviewed. Leukocytapheresis (10 sessions for remission induction therapy, 6 sessions for maintenance therapy) was applied to the patients with their concomitant medications. Intensive leukocytapheresis (≥4 leukocytapheresis sessions within the first 2 weeks) was used in 30% patients with active severe UC. The overall clinical remission rate in patients with UC was 80%, and the mucosal healing rate was 65%. Patients were followed for an average of 24 months. It was observed that clinical remission has continued in 65% of patients with UC. Mild relapse was observed in 3 patients with UC during follow up period. In 5 patients with CD significant clinical remission was achieved except only one patient. Surgical needs were disappeared in 3 patients with obstructive type Crohn’s disease. Adverse events were seen in only 4.3% of 416 sessions. Any concomitant medications did not increase the incidence of adverse events. Our results indicate that leukocytapheresis is efficacious in improving remission rates with excellent tolerability and safety in patients with IBD.     

Fecal markers in the management of inflammatory bowel disease

Inflammatory bowel disease (IBD) is characterized by periods of symptomatic remission and relapse. Diagnosis and assessment of IBD are based on clinical evaluation, serum parameters, radiology, and endoscopy. Fecal markers have emerged as new diagnostic tools to detect and monitor intestinal inflammation. Fecal calprotectin (FC) and lactoferrin (FL) were identified decades ago as potentially revolutionary markers for IBD. Following these discoveries numerous additional markers, including S100A12, M2-PK, metalloproteinases, hemoglobin, myeloperoxidase, lysozyme, polymorphonuclear elastase, neopterin, and nitric oxide, have also been suggested as novel markers of IBD. But only FC and FL are used for the management of clinical IBD patients. The objective of this review is to introduce the clinical applications of fecal markers in the diagnosis, monitoring and prediction of outcomes of inflammatory bowel disease.     

粪菌移植治疗炎症性肠病的护理研究进展

综述国内外粪菌移植(FMT)治疗炎症性肠病(IBD)的护理研究进展,包括治疗前的护理准备、治疗中的护理配合及治疗后护理等,指出应注重病人的心理护理,辩证看待FMT治疗IBD的疗效和安全性。     

Phosphatidylinositol 3-kinase signaling pathway and inflammatory bowel disease: Current status and future prospects

Inflammatory bowel disease (IBD) is a chronic life-limiting disease of gastrointestinal tract characterized by widespread enteric inflammation. IBD is a multifactorial disease, and different environmental, microbial, and immune-related factors give rise to the development of disease. Among several factors, the preponderance of pro-inflammatory T helper 17 cells over the anti-inflammatory regulatory T cells augments inflammation in the intestinal mucosa. Prevailing evidence accentuates that PI3K signaling pathway plays a central role in the pathophysiology of the condition by regulating the inflammatory process in the gut mucosa. By recognizing the implications of PI3K in the pathogenesis of IBD, agents that could modulate this pathway have recently been at the focus of research, yielding encouraging results mainly in the experimental IBD models. In this review, we have summarized the recent advances, which may hold the keys to identify novel therapeutic strategies for IBD.     

Emerging role of dual biologic therapy for the treatment of inflammatory bowel disease

Biologic agents have now been used in the management of inflammatory bowel disease (IBD) for many years where experience, expertise and confidence in their use has developed over time. In the United Kingdom, there are well established guidelines and recommendations for both single agent biologic treatments, and with combination therapy of a biologic agent with a small molecule agent in maintenance therapy. In recent times, there has been increasing interest and experience using dual biologic therapy (DBT) in IBD, primarily in difficult to treat and refractory cases with high disease burden. However, published data on use, experience and safety profiles is limited and large-scale studies remain low in number in this developing area. We therefore aim to present a summary and review of the available published data in this area to help us better understand the emerging role of DBT in IBD.     

The anti-inflammatory and protective role of interleukin-38 in inflammatory bowel disease

Interleukin (IL)-38 exerts an anti-inflammatory function by binding to several cytokine receptors, including the IL-36 receptor. In this study, we evaluated IL-38 expression in the inflamed mucosa of patients with inflammatory bowel disease (IBD) and investigated its functions. IL-38 mRNA expression in endoscopic biopsy samples was evaluated using quantitative PCR. IL-38 protein expression was analyzed using immunohistochemical technique. Dextran sulfate sodium-induced colitis was induced in C57BL/6 background IL-38KO mice. The IL-38 mRNA and protein expression were enhanced in the active mucosa of ulcerative colitis, but not in Crohn’s disease. The ratio of IL-36γ to IL-38 mRNA expression was significantly elevated in the active mucosa of UC patients. Immunofluorescence staining revealed that B cells are the major cellular source of IL-38 in the colonic mucosa. IL-38 dose-dependently suppressed the IL-36γ-induced mRNA expression of CXC chemokines (CXCL1, CXCL2, and CXCL8) in HT-29 and T84 cells. IL-38 inhibited the IL-36γ-induced activation of nuclear-factor kappa B (NF-κB) and mitogen-activated protein kinases in HT-29 cells. DSS-colitis was significantly exacerbated in IL-38KO mice compared to wild type mice. In conclusion, IL-38 may play an anti-inflammatory and protective role in the pathophysiology of IBD, in particular ulcerative colitis, through the suppression of IL-36-induced inflammatory responses.     

Paradox of simultaneous intestinal ischaemia and hyperaemia in inflammatory bowel disease

This review has focused on evidence regarding intestinal perfusion of inflammatory bowel disease (IBD). Basic investigation has defined an altered microvascular anatomy in the affected IBD bowel, which corresponds with diminished mucosal perfusion in the setting of chronic, long‐standing inflammation. Diminished perfusion is linked to impaired wound healing, and may contribute to the continued refractory mucosal damage, which characterizes IBD. Alterations in vascular anatomy and physiology in IBD suggests additional possible mechanisms by which micro‐vessels may contribute to the initiation and perpetuation of IBD. This begs the following questions: will angiogenesis within the gut lead to sustained inflammation, does the growing vasculature generate factors that transform the surrounding tissue and does angiogenesis generate vascular anastomosis within the gut, with shunting of blood away from the mucosal surface, impairment of metabolism and potentiation of gut damage? Further studies are required to define the mechanisms that underlie the vascular dysfunction and its role in pathophysiology of IBD.     

Implications of COVID-19 for inflammatory bowel disease: Opportunities and challenges amidst the pandemic

Since the beginning of the coronavirus disease 2019 (COVID-19) pandemic various measures have been taken to mitigate the effects of the global health crisis in this unprecedented time. According to the World Health Organization, more than 5 million people have been infected with severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) and with more than 300000 deaths attributed to COVID-19 worldwide. There is emerging evidence that SARS-CoV-2 utilizes angiotensin-converting enzyme 2 receptors to enter human cells which are found in abundance in the alveoli and intestines. In addition, the infection is noted to be more severe in patients with co-morbid conditions, those who are malnourished, immunosuppressed and immunocompromised. Inflammatory bowel disease (IBD) which includes ulcerative colitis and Crohn’s disease is chronic remitting and relapsing disorders with intestinal and extraintestinal manifestation. IBD patients are often malnourished and on immunosuppressive medications and there is a hypothetical concern that IBD patients are at substantial risk of COVID-19 infection. The management of IBD patients is often complex and poses unique challenges for gastroenterologists during the pandemic. The purpose of this review article is to summarize the growing level of evidence and understanding of the management of IBD during the COVID-19 pandemic, in the light of international and national gastroenterology society guidelines. We performed a thorough literature search on IBD, SARS-CoV-2 and COVID-19 on PubMed, EMBASE, OVID Medline and Google Scholar and pertaining literature was critically examined and summarized. Per national and international society guidelines and recommendations, IBD is not a risk factor for SARS-CoV-2 infection. IBD patients should continue with their medications and they should follow universal precautions i.e. masks, hand and respiratory hygiene and avoidance of health care facilities and public toilets as general population. Among IBD patients older age, having active disease, and co-morbid conditions are risk factors for a severe SARS-CoV-2 infection. Furthermore, elective endoscopic and surgical procedures can be delayed or deferred until discussing the risks and benefits with patients.     

炎症性肠病患者凝血指标变化及其临床意义研究

目的探讨炎症性肠病(IBD)患者凝血指标的变化,及其与疾病活动程度的关系。方法回顾性分析2012年3月至2015年3月就诊的67例IBD患者及50例健康者血小板计数(PLT)、血小板平均体积(MPV)、凝血酶时间(TT)、凝血酶原时间(PT)、活化部分凝血活酶时间(APTT)、纤维蛋白原(FIB)等指标检测结果,比较患者与健康者的差异,不同病情程度患者之间的差异,以及各指标与疾病活动指数的相关性。结果与健康者相比,IBD患者PLT、PT和FIB升高,MPV下降;不同病情严重程度溃疡性结肠炎患者间PLT、MPV、PT和FIB水平比较差异有统计学意义(P0.05),不同病情严重程度克罗恩病患者间PLT、MPV和FIB水平比较差异有统计学意义(P0.05);PLT和FIB与IBD疾病活动指数呈正相关,MPV与疾病活动指数呈负相关。结论 IBD患者体内凝血功能异常,表现为PLT升高、MPV下降,PT延长及FIB升高,PLT、MPV和FIB或可作为判断IBD疾病活动性的指标。     

炎症性肠病患者肠道菌群变化及其与炎性指标的关系

目的 观察炎症性肠病（IBD）患者肠道菌群变化,并观察其与白细胞（WBC）、血小板（PLT）、红细胞沉降率（ESR）和C反应蛋白（CRP）的关系.方法 选取IBD患者65例,检测所有患者粪便标本中10种细菌的数量及WBC、PLT计数、ESR和血清CRP水平.结果 溃疡性结肠炎（UC）组和克罗恩病（CD）组肠杆菌（EMB）、肠球菌（EC）、酵母菌（SB）均较对照组显著升高（P ＜0.05或P＜0.01）,UC组小梭菌（SC）显著升高（P＜0.05）;2组消化球菌（PS）、拟杆菌（BD）、双歧杆菌（BL）、乳杆菌（LC）和真杆菌（ES）均显著下降（P＜0.05或P＜0.01）;活动组EMB、ES、SB、SC、BD、BL、LC及WBC、PLT、ESR、CRP与缓解组差异显著（P＜0.05或P＜0.01）;WBC、PLT和CRP均与EC负相关,ESR与SB正相关（P＜0.01）.结论 IBD患者存在显著肠道菌群紊乱,炎性指标与部分菌种失衡相关.     

A review and expert opinion of the use of certolizumab for Crohn's disease

Recent mechanistic studies on the role of heat-shock proteins (HSPs) to induce innate and adaptive immune responses have resulted in conflicting reports. Whereas some groups reported that HSPs have direct immunological function, others emphasised the endotoxin contamination of HSP preparations and questioned the antigen-specificity of HSP vaccines. The present review will discuss these issues and suggest that HSPs have diverse and distinct immunological functions that could be superimposed on effects resulting from endotoxin contamination or misunderstood by using experimental procedures with inadequate controls. To understand the actual function of HSPs in their interaction with the immune system, methods and procedures need to be optimised and appropriate controls need to be used. These points should also clarify the conflicting findings about HSPs and promote our knowledge about other immuologically important components that may be present in HSP preparations.     

The role of integrins in the pathogenesis of inflammatory bowel disease: Approved and investigational anti-integrin therapies

Inflammatory bowel disease (IBD) is characterized by uncontrolled inflammation in the gastrointestinal tract. The underlying pathobiology of IBD includes an increase in infiltrating gut-homing lymphocytes. Although lymphocyte homing is typically a tightly regulated and stepwise process involving multiple integrins and adhesion molecules expressed on endothelial cells, the distinct roles of integrin-expressing immune cells is not fully understood in the pathology of IBD. In this review, we detail the involvement of integrins expressed on specific lymphocyte subsets in the pathogenesis of IBD and discuss the current status of approved and investigational integrin-targeted therapies.