Biological therapy in the treatment of moderate-to-severe ulcerative colitis patients: Can colectomy be prevented?

Ulcerative colitis treatment intends to induce remission, and its maintenance. Biological drugs, such as infliximab, have been indicated in moderate and severe cases of the disease, which are unresponsive to conventional medication. Randomized controlled trials proved the efficacy of biological treatment with high rates of sustained disease remission and mucosal healing. Recently, the concept of mucosal healing has been inversely associated with surgical treatment. Patients treated with infliximab have lower colectomy rates than those receiving conventional therapies. We suppose that earlier use of biological drugs in disease's course would lead to better clinical control and mucosal healing, with a consequent reduction in colectomy rates. To support this hypothesis, a literature review from January, 1996 to April, 2011 was performed.

Conventional versus biological therapy for prevention of postoperative endoscopic recurrence in patients with Crohn's disease: an international, multicenter, and observational study

Postoperative endoscopic recurrence (PER) occurs in nearly 80% of patients 1 year after ileocecal resection in patients with Crohn's disease (CD). Biological agents were more effective in reducing the rates of PER in comparison with conventional therapy, in prospective trials. The aim of this study was to compare the PER rates of biological versus conventional therapy after ileocecal resections in patients with CD in real-world practice. The MULTIPER (Multicenter International Postoperative Endoscopic Recurrence) database is a retrospective analysis of PER rates in CD patients after ileocecal resection, from 7 referral centers in 3 different countries. All consecutive patients who underwent ileocecal resections between 2008 and 2012 and in whom colonoscopies had been performed up to 12 months after surgery, were included. Recurrence was defined as Rutgeerts' score ≥i2. The patients were allocated to either biological or conventional therapy after surgery, and PER rates were compared between the groups. Initially, 231 patients were evaluated, and 63 were excluded. Of the 168 patients in the database, 96 received anti-tumor necrosis factor agents and 72 were treated with conventional therapy after resection. The groups were comparable regarding age, gender, and perianal disease. There was longer disease duration, more previous resections, and more open surgical procedures in patients on biologicals postoperatively. PER was identified in 25/96 (26%) patients on biological therapy and in 24/72 (33.3%) patients on conventional therapy (P=0.310). In this retrospective observational analysis from an international database, no difference was observed between biological and conventional therapy in preventing PER after ileocecal resections in CD patients.

Biological therapy for the prevention and treatment of postoperative endoscopic recurrence in Crohn's disease: time for acceptance?

In most patients, postoperative endoscopic recurrence (PER) occurs 1 year after abdominal resection for Crohn’s disease (CD). Preventing PER is essential for disease control, as most patients develop further clinical and surgical recurrences. Conventional therapy with nitroimidazoles, aminosalicylates, and immunomodulators have limited efficacy for preventing PER. Initial trials with biological therapy (infliximab and adalimumab) showed promising results in preventing PER, and the efficacy of these drugs seems higher than that with conventional therapy. The aim of this review is to outline the results of studies that used infliximab or adalimumab for preventing and treating PER in CD patients. Data with both agents are available, and a few, small prospective trials have shown the efficacy of these drugs in patients with a high risk for recurrence. We believe that, in 2013, biological agents will be better accepted for the prevention PER in CD patients, in addition to the already existing data. Larger trials are still underway, and their results will certainly determine the role of these agents in PER, which develops after bowel resection for CD.

Genetic susceptibility to increased bacterial translocation influences the response to biological therapy in patients with Crohn's disease

OBJECTIVE: The aetiology of Crohn's disease (CD) has been related to nucleotide-binding oligomerisation domain containing 2 (NOD2) and ATG16L1 gene variants. The observation of bacterial DNA translocation in patients with CD led us to hypothesise that this process may be facilitated in patients with NOD2/ATG16L1-variant genotypes, affecting the efficacy of anti-tumour necrosis factor (TNF) therapies. DESIGN: 179 patients with Crohn's disease were included. CD-related NOD2 and ATG16L1 variants were genotyped. Phagocytic and bactericidal activities were evaluated in blood neutrophils. Bacterial DNA, TNFα, IFNγ, IL-12p40, free serum infliximab/adalimumab levels and antidrug antibodies were measured. RESULTS: Bacterial DNA was found in 44% of patients with active disease versus 23% of patients with remitting disease (p=0.01). A NOD2-variant or ATG16L1-variant genotype was associated with bacterial DNA presence (OR 4.8; 95% CI 1.1 to 13.2; p=0.001; and OR 2.4; 95% CI 1.4 to 4.7; p=0.01, respectively). This OR was 12.6 (95% CI 4.2 to 37.8; p=0.001) for patients with a double-variant genotype. Bacterial DNA was associated with disease activity (OR 2.6; 95% CI 1.3 to 5.4; p=0.005). Single and double-gene variants were not associated with disease activity (p=0.19). Patients with a NOD2-variant genotype showed decreased phagocytic and bactericidal activities in blood neutrophils, increased TNFα levels in response to bacterial DNA and decreased trough levels of free anti-TNFα. The proportion of patients on an intensified biological therapy was significantly higher in the NOD2-variant groups. CONCLUSIONS: Our results characterise a subgroup of patients with CD who may require a more aggressive therapy to reduce the extent of inflammation and the risk of relapse

Lipidomic analysis of mesenchymal cells candidates for cell therapy

Mesenchymal stromal cells are adult stem cells found mostly in the bone marrow. They have immunosuppressive properties and they have been successfully applied as biological therapy in several clinical trials regarding autoimmune diseases. Despite the great number of clinical trials, MSCs’ action is not fully understand and there are no identified markers that correlate themselves with the immunomodulatory power. A lipidomic approach can solve some of these problems once lipids are one of the major cells’ components. Therefore, in this study cells’ lipidome was analysed and its deviations were evaluated according to the medium of culture and to the presence of pro-inflammatory stimuli, mimicking physiological conditions in which these cells are used. This was the first study ever made that aimed to analyse the differences in the phospholipid profile between mesenchymal stromal cells non-stimulated and stimulated with proinflammatory stimulus. This analysis was conducted in both cells cultured in medium supplemented with animal serum and in cells cultured in a synthetic medium. In cells cultured in the standard medium the levels of phosphatidylcholine (PC) species with shorter fatty acids (FAs) acyl chains decreased under pro-inflammatory stimuli. The level of PC(40:6) also decreased, which may be correlated with enhanced levels of lysoPC (LPC)(18:0) - an anti-inflammatory LPC - observed in cells subjected to TNF-α and IFN-γ. Simultaneously, the relative amounts of PC(36:1) and PC(38:4) increased. TNF-α and IFN- γ also enhanced the levels of phosphatidylethanolamine PE(40:6) and decreased the levels of PE(38:6). Higher expression of phosphatidylserine PS(36:1) and sphingomyelin SM(34:0) along with a decrease in PS(38:6) levels were observed. However, in cells cultured in a synthetic medium, TNF-α and IFN-γ only enhanced the levels of PS(36:1). These results indicate that lipid metabolism and signaling is modulated during mesenchymal stromal cells action.

Infliximab-induced psoriasis during therapy for Crohn's disease

Although therapy with tumor necrosis factor-alpha inhibitors (anti-TNF) provides beneficial effects in different immune inflammatory disorders, paradoxical cases of anti-THE-induced psoriasis have increasingly been reported, mostly in the setting of rheumatologic diseases. To date, less than 50 cases of infliximab-induced psoriasis in inflammatory bowel disease patients have been described. The present report was aimed at describing two new cases of infliximab-induced psoriasis during therapy for Crohn's disease and at carrying out a review on this intriguing phenomenon. (C) 2011 European Crohn's and Colitis Organisation. Published by Elsevier B.V. All rights reserved.

Induction or exacerbation of psoriatic lesions during anti-TNF-α therapy for inflammatory bowel disease: A systematic literature review based on 222 cases

Background: Paradoxical cases of psoriatic lesions induced or exacerbated by anti-tumor necrosis factor (TNF)-α therapy have been reported more frequently in recent years, but data related to inflammatory bowel disease (IBD) are rare. A systematic literature review was performed to provide information about this adverse effect in patients with IBD who receive anti-TNF therapy. Methods: Published studies were identified by a search of Medline, Embase, Cochrane, SciELO, and LILACS databases. Results: A total of 47 studies (222 patients) fulfilled the inclusion criteria and were selected for analysis. Clinical and therapeutic aspects varied considerably among these reports. Of the 222 patients, 78.38% were diagnosed with Crohn's disease, and 48.20% were female. The mean patient age was 26.50. years, and 70.72% of patients had no history of psoriasis. Patients developed psoriasiform lesions (55.86%) more often than other types of psoriatic lesions, and infliximab was the anti-TNF-α therapy that caused the cutaneous reaction in most patients (69.37%). Complete remission of cutaneous lesions was observed in 63.96% of the cases. Conclusions: We found that psoriatic lesions occurred predominantly in adult patients with Crohn's disease who received infliximab and had no previous history of psoriasis. Most patients can be managed conservatively without discontinuing anti-TNF-α therapy. © 2012 European Crohn's and Colitis Organisation.

Infliximab-induced psoriasis during therapy for Crohn's disease

Although therapy with tumor necrosis factor-alpha inhibitors (anti-TNF) provides beneficial effects in different immune inflammatory disorders, paradoxical cases of anti-THE-induced psoriasis have increasingly been reported, mostly in the setting of rheumatologic diseases. To date, less than 50 cases of infliximab-induced psoriasis in inflammatory bowel disease patients have been described. The present report was aimed at describing two new cases of infliximab-induced psoriasis during therapy for Crohn's disease and at carrying out a review on this intriguing phenomenon. (C) 2011 European Crohn's and Colitis Organisation. Published by Elsevier B.V. All rights reserved.

Management of endocrine resistant breast cancer

Metastatic breast cancer (MBC) may present de novo but more commonly develops in women initially presenting with early breast cancer despite the widespread use of adjuvant hormonal and cytotoxic chemotherapy. MBC is incurable. Hormone sensitive MBC eventually becomes resistant to endocrine therapy in most women. Anthracyclines are the agents of choice in the treatment of endocrine resistant MBC. With the widespread use of anthracyclines in the adjuvant setting, taxanes have become the agents of choice for many patients. Recently capecitabine has become established as a standard of care for patients pretreated with anthracyclines and taxanes. However, a range of agents have activity as third line treatment. These include gemcitabine, vinorelbine and platinum analogues. The sequential use of non-cross resistant single agents rather than combination therapy is preferable in most women with MBC. Even though combination therapy can improve response rates and increase progression free interval, there is no robust evidence to indicate an advantage in terms of overall survival. Moreover, combination therapy is associated with a higher toxicity rate and poor quality of life. There is no role for dose-intense therapy, high dose therapy or maintenance chemotherapy outside the context of a clinical trial. The introduction of trastuzumab, monoclonal antibody targeting growth factor receptors, has improved the therapeutic options for women with tumours overexpressing HER2/neu. DNA micro-array profiles of tumours can potentially help to individualise therapy in future. Molecular targeted therapy has the potential to revolutionise the management of MBC.

Australian data do not support current pharmaceutical benefits scheme criteria for use of tumour necrosis factor-α inhibitors in ankylosing spondylitis

On the basis of local data, we write in support of the conclusions of Smith and Ahern that current Pharmaceu- tical Benefits Scheme (PBS) criteria for tumour necrosis factor (TNF)-a inhibitors in ankylosing spondylitis (AS) are not evidence-based. 1 As a prerequisite to the appropriate use of biological therapy in AS, three aspects of the disease need to be defined: (i) diagnosis, (ii) activity and (iii) therapeutic failure (Table 1)....

Is there enough evidence with evolocumab and alirocumab (antibodies to proprotein convertase substilisin-kexin type, PCSK9) on cardiovascular outcomes to use them widely?

Introduction: Statins alone often do not reduce LDL cholesterol levels sufficiently to given maximum cardiovascular benefit. Thus, additional drugs are required to reduce the levels of LDL cholesterol. Monoclonal antibodies to PCSK9 have recently been shown to decrease LDL cholesterol, but it is not known whether they improve cardiovascular outcomes. Areas covered: Evaluation of two clinical trials reporting cardiovascular outcomes with antibodies to PCSK9; the OSLER extension with evolocumab and the ODYSSEY LONG TERM trial with alirocumab. Expert opinion: In OSLER and ODYSSEY LONG TERM, there were very few cardiovascular outcomes, but the trials do suggest that evolocumab and alirocumab may reduce these outcomes. However, there are also some safety concerns with both of these antibodies. Large clinical outcome trials are underway with both evolocumab and alirocumab, which will probably clarify both the safety concerns and any cardiovascular benefits with these antibodies. In our opinion, these antibodies may be suitable for use in subjects with familial hypercholesterolemia, who are uncontrolled with their present medications, provided intensive safety and cardiovascular monitoring is being undertaken. However, evolocumab and alirocumab should be used with caution in other subjects, until outcome studies in higher numbers of subjects, have shown acceptable safety and cardiovascular profiles.

Multifaceted roles of curcumin: two sides of a coin!

Introduction: Curcumin has been a front-line topic of mainstream scientific research for a variety of diseases from cancer to Alzheimer's to infectious diseases. Curcumin suppresses the type 1 immune response, which might lead to alleviation of type 1 immune response disorders. However, the inhibition of type 1 immune response might invite infections with opportunistic pathogens. Considering its low bioavailability, several curcumin derivatives have been designed to improve its functionality. Areas covered: This is a consolidated review which aims to compare and contrast diverse aspects of curcumin in variety of diseases. The intricate underlying mechanisms and the functional determinants of curcumin are discussed. Expert opinion: Curcumin being considered as a spicy panacea, is not a remedy for all diseases. However, its ability to act differentially as an antioxidant or pro-oxidant akin to that of a double-edged sword/friend turning foe can be either beneficial or harmful for the host. It exhibits antioxidant properties at concentrations achievable in the body, making the host vulnerable to infections due to the suppression of innate immune responses. With the increase in knowledge of its functional groups, production of analogues of curcumin is underway to enhance its bioavailability and hence its therapeutic potency.

The basics and advances of immunomodulators and antigen presentation: a key to development of potent memory response against pathogens

Introduction: Immunomodulators are agents, which can modulate the immune response to specific antigens, while causing least toxicity to the host system. Being part of the modern vaccine formulations, these compounds have contributed remarkably to the field of therapeutics. Despite the successful record maintained by these agents, the requirement of novel immunomodulators keeps increasing due to the increasing severity of diseases. Hence, research regarding the same holds great importance. Areas covered: In this review, we discuss the role of immunomodulators in improving performance of various vaccines used for counteracting most threatening infectious diseases, mechanisms behind their action and criteria for development of novel immunomodulators. Expert opinion: Understanding the molecular mechanisms underlying immune response is a prerequisite for development of effective therapeutics as these are often exploited by pathogens for their own propagation. Keeping this in mind, the present research in the field of immunotherapy focuses on developing immunomodulators that would not only enhance the protection against pathogen, but also generate a long-term memory response. With the introduction of advanced formulations including combination of different kinds of immunomodulators, one can expect tremendous success in near future.

How a different look at latency can help to develop novel diagnostics and vaccines against tuberculosis.

Mycobacterium tuberculosis is one of the most successful human pathogens. It kills every year approximately 1.5 - 2 million people, and at present a third of the human population is estimated to be infected. Fortunately, only a relatively small proportion of the infected individuals will progress to active disease, and most will maintain a latent infection. Although a latent infection is clinically silent and not contagious, it can reactivate to cause highly contagious pulmonary tuberculosis, the most prevalent form of the disease in adults. Therefore, a thorough understanding of latency and reactivation may help to develop novel control strategies against tuberculosis. The most widely held view is that the mycobacteria are imprisoned in granulomatous structures during latency, where they can survive in a non-replicating, dormant form until reactivation occurs. However, there is no hard data to sustain that the reactivating mycobacteria are indeed those that laid dormant within the granulomas. In this review an alternative model, based on evidence from early studies, as well as recent reports is presented, in which the latent mycobacteria reside outside granulomas, within non-macrophage cell types throughout the infected body. Potential implications for new diagnostic and vaccine design are discussed.