Tumor necrosis factor-α monoclonal antibodies in the treatment of inflammatory bowel disease: clinical practice pharmacology

In the last 10 years, anti-tumor necrosis factor (TNF)-α therapy has become a cornerstone in the management of autoimmune diseases. Clinical trial data have consistently found that infliximab, adalimumab, and recently certolizumab pegol offer therapeutic benefits to patients with inflammatory bowel diseases (Crohn's disease and ulcerative colitis). Recent understanding on how these monoclonal antibodies evoke changes at the physiological and molecular levels have provided insights into disease pathogenesis and helped to identify new targets for future drug therapy. With increased experience in the use of these anti-TNF-α antibodies the long-term safety data, use in pregnancy have become available. This article provides an overview of the current knowledge regarding anti-TNF-α therapies for clinicians caring for patients with Crohn's disease and ulcerative colitis.     

Withdrawal of anti-tumour necrosis factor α therapy in inflammatory bowel disease

Anti-tumour necrosis factor α(anti-TNFα) therapy is an established treatment in inflammatory bowel disease.However, this treatment is associated with high costs and the possibility of severe adverse events representing a true challenge for patients, clinicians and health care systems.Consequently, a crucial question is raised namely if therapy can be stopped once remission is achieved and if so, how and in whom.Additionally, in a real-life clinical setting, discontinuation may also be considered for other reasons such as the patient's preference, pregnancy, social reasons as moving to countries or continents with less access, or different local policy or reimbursement.In contrast to initiation of anti-TNFα therapy guidelines regarding stopping of this treatment are missing.As a result, the decision of discontinuation is still a challenging aspect in the use of anti-TNFα therapy.Currently this is typically based on an estimated, case-by-case, benefit-risk ratio.This editorial is intended to provide an overview of recent data on this topic and shed light on the proposed drug withdrawal strategies.     

Role of matrix metalloproteinase, tissue inhibitor of metalloproteinase and tumor necrosis factor-α single nucleotide gene polymorphisms in inflammatory bowel disease

AIM:To study the (functional) relevance of single nucleotide polymorphisms (SNPs) in genes encoding matrix metalloproteinases (MMP)-1,-2,-3,-9,tissue inhibitors of metalloproteinases (TIMP)-1,-2 and tumor necrosis factor (TNF)-α in the etiopathogenesis of inflammatory bowel diseases (IBD),that may enhance susceptibility and/or disease severity. METHODS:Genomic DNA from 134 Crohn's disease (CD),111 ulcerative colitis (UC) patients and 248 control subjects was isolated from resected intestinal tissue or blood. Allelic composition at SNP loci was determined by PCR-RFLP or tetra primer ARMS PCR. RESULTS:The TIMP-1 genotype TT in women and T in men at SNP +372 T/C was found to increase CD susceptibility (39% vs 23.8%,P=0.018 and 67.9% vs 51.6%,P=0.055,respectively),while women with this genotype were less prone to development of fistulae during follow-up (41.4% vs 68.3%,P=0.025). Male IBD or CD patients carrying the TIMP-1 +372 T-allele expressed lower levels of TIMP-1 in surgically resected macroscopically inflamed tissue (0.065 < P < 0.01). The 5T5T genotype at MMP-3 SNP -1613 5T/6T increased the chance of stenotic complications in CD during follow-up (91.2% vs 71.8%,P = 0.022) but seemed to protect against colonic involvement of this disease at first endoscopic/radiologic examination (35.3% vs 59.5%,P=0.017). CONCLUSION:Allelic composition at the examinedSNPs in genes coding for TIMP-1 and MMP-3 affect CD susceptibility and/or phenotype,i.e.,fistulizing disease,stricture pathogenesis and first disease localisation. These findings reinforce the important role of these proteins in IBD.     

IL-10 and its related cytokines for treatment of inflammatory bowel disease

Inflammatory bowel diseases (IBDs),including Crohn'sdisease and ulcerative colitis are chronic inflammatorydisorders of gastrointestinal tract.Although the etiology isincompletely understood,initiation and aggravation of theinflammatory process seem to be due to a massive localmucosal immune response.Interleukin-10 (IL-10) is aregulatory cytokine which inhibits both antigen presentationand subsequent pro-inflammatory cytokine release,and itis proposed as a potent anti-inflammatory biological therapyin chronic IBD.Many methods of IL-10 as a treatment forIBD have been published.The new strategies of IL-10treatment,including recombinant IL-10,the use of geneticallymodified bacteria,gelatine microsphere containing IL-10,adenoviral vectors encoding IL-10 and combining regulatoryT cells are discussed in this review.The advantages anddisadvantages of these IL-10 therapies are summarized.Although most results of recombinant IL-10 therapies aredisappointing in clinical testing because of lacking efficacyor side effects,therapeutic strategies utilizing gene therapymay enhance mucosal delivery and increase therapeuticresponse.Novel IL-10-related cytokines,including IL-19,IL-20,IL-22,IL-24,IL-26,IL-28 and IL-29,are involved inregulation of inflammatory and immune responses.The useof IL-10 and IL-10-related cytokines will provide new insightsinto cell-based and gene-based treatment against IBD innear future.     

Effects of anti–TNF-alpha therapy on hemoglobin levels and anemia in patients with inflammatory bowel disease

BackgroundTumor necrosis factor-α (TNF-α) is involved in inducing inflammatory anemia. The potential effect of anti–TNF-α agents on anemia in inflammatory bowel diseases (IBD) is still unknown.MethodsAnalytical data and disease characteristics from 362 IBD patients [271 CD/91UC) treated with anti-TNF-α drugs were retrospectively collected. Effects on disease activity, blood markers and prevalence of anemia were assessed after 6 and 12 months of therapy.Results29.3% patients presented anemia at baseline, and significantly reduced to 14.4% and 7.8% after 6 and 12 months of therapy, respectively. Mean ± SD Hb levels increased significantly at month 6, and this increase was sustained at 12 months. Serum markers of iron metabolism increased significantly compared to baseline, as disease activity measured by C-reactive protein (CRP) was reduced. All these effects were observed independently for CD and UC, and were independent of iron supplementation during treatment. Anemia at baseline (OR 4.09; 95%CI 1.98–8.45) and elevated CRP (OR 3.45; 95CI 1.29–9.22) were independently associated with risk of persistent anemia, as well as iron replacement during therapy (OR 4.36; 95%CI 2.07–9.16).ConclusionsControlling disease activity with anti-TNF- α therapy significantly and independently associated with resolution of anemia in IBD, with no relevant role for iron replacement therapy.     

Interaction of the major inflammatory bowel disease susceptibility alleles in Crohn��s disease patients

AIM: To investigate the interaction of interleukin-23 receptor (IL23R) (rs1004819 and rs2201841), autophagy-related 16-like 1 (ATG16L1) (rs2241880), caspase recruitment domain-containing protein 15 (CARD15) genes, and IBD5 locus in Crohn’s disease (CD) patients.METHODS: A total of 315 unrelated subjects with CD and 314 healthy controls were genotyped. Interactions and specific genotype combinations of a total of eight variants were tested. The variants of IBD5 locus (IGR2198a_1 rs11739135 and IGR2096a_1 rs12521868), CARD15 (R702W rs2066845 and L1007fs rs2066847), ATG16L1 (rs2241880) and IL23R (rs1004819, rs2201841) genes were genotyped by PCR-RFLP, the G908R (rs2066844) in CARD15 was determined by direct sequencing.RESULTS: The association of ATG16L1 T300A with CD was confirmed [P = 0.004, odds ratio (OR) = 1.69, 95% CI: 1.19-2.41], and both IL23R variants were found to represent significant risk for the disease (P = 0.008, OR = 2.05, 95% CI: 1.20-3.50 for rs1004819 AA; P < 0.001, OR = 2.97, 95% CI: 1.65-5.33 for rs2201841 CC). Logistic regression analysis of pairwise interaction of the inflammatory bowel disease (IBD) loci indicated that IL23R, ATG16L1, CARD15 and IBD5 (IGR2198a_1) contribute independently to disease risk. We also analysed the specific combinations by pair of individual ATG16L1, IL23R rs1004819, rs2201841, IGR2198a_1, IGR2096a_1 and CARD15 genotypes for disease risk influence. In almost all cases, the combined risk of susceptibility pairs was higher in patients carrying two different risk-associated gene variants together than individuals with just one polymorphism. The highest OR was found for IL23R rs2201841 homozygous genotype with combination of positive CARD15 status (P < 0.001, OR = 9.15, 95% CI: 2.05-40.74).CONCLUSION: The present study suggests a cumulative effect of individual IBD susceptibility loci.     

Iron treatment and inflammatory bowel disease: What happens in real practice?

Background and aimsIron deficiency anaemia (IDA), the most common extra-intestinal complication of inflammatory bowel disease (IBD), negatively impacts quality of life. We audited the recent practice of anaemia treatment in an unselected IBD population.MethodsA questionnaire was distributed to adult IBD outpatients in a university hospital to assess the form and frequency of iron prescribed, duration of use, side effects, and completion of therapy. The efficacy of treatment was determined by the resolution of anaemia and change in haemoglobin from baseline.ResultsOf 87 IBD patients (60 patients with Crohn's disease, 25 with ulcerative colitis, 2 with microscopic colitis), 85 received various dosing regimens of iron tablets; 15 patients also received IV iron. Side effects were reported in 43 (51%) patients, with no clear relationship to dose prescribed and 26 (32%) patients were unable to complete the intended course. Only 36 (42%) patients completed the course of oral iron without side effects and in these patients, haemoglobin normalised in about 30%. Their median haemoglobin change was 12.5 (5.3–23.5) g/l. The median duration of treatment in those without side effects was 4.5 months, and in those with adverse effects was 2 months. Only one adverse effect was reported for IV iron.ConclusionsTreatment with oral iron results in failure to control anaemia in 2 out of 3 IBD patients, which is likely in part to be due to the side effects reported by over half of patients. Patients failing to tolerate or adequately respond to therapy should be offered alternative treatment.     

Recent advances in basic and clinical aspects of inflammatory bowel disease： Which steps in the mucosal inflammation should we block for the treatment of inflammatory bowel disease？

There are four steps in the interaction between intestinal microbes and mucosal inflammation in genetically predisposed individuals from the viewpoints of basic and clinical aspects of inflammatory bowel disease （IBD）. The first step is an interaction between intestinal microbes or their components and intestinal epithelial cells via receptors, the second step an interaction between macrophages and dendritic cells and mucosal lymphocytes, the third step an interaction between lymphocytes and vascular endothelial cells, and the fourth step an interaction between lymphocytes and granulocytes producing proinflammatory cytokines or free radicals and mucosal damage and repair. Recent therapeutic approaches for IBD aim to block these four steps in the intestinal inflammation of patients with IBD.     

Emerging drugs in the treatment of inflammatory bowel disease: beyond anti-TNF-α

Understanding of the pathophysiology of inflammatory bowel disease (IBD) is constantly evolving and, recently, a number of biologic agents have been developed. They selectively target specific molecule or pathways and correct the imbalance of the gut immune system. Among them, antibody to tumor necrosis factor (anti-TNF-a) is the first developed drugs, and it dramatically improved the IBD management. However, more than one-third of the patients do not respond to the drugs due to antibody formation. To increase treatment efficacy, enormous effort to develop novel anti-cytokines which can be an alternative to anti-TNF-a has been made. They are anti CD4+ T cell cytokine including interleukin (IL)-12/23 and IL-17 blockers, selective anti-adhesion molecule known as natalizumab, vedolizumab and alicaforsen, T-cell proliferation inhibitor, anti-inflammatory cytokine, immune stimulator, growth factor, and mitogen-activated protein kinase inhibitor. The efficacy and safety of each drugs are under investigation. Some drugs reported very promising data, however, others showed disappointing and different results. In addition, most of the trials were done in a very small number of patients, and there is no trial comparing to anti-TNF-a. The present paper reviews the action mechanism, short or long term efficacy and safety of variable drugs other than anti-TNF-a in IBD.     

YouTube® and inflammatory bowel disease

Background and aimsNearly half of all patients with inflammatory bowel disease (IBD) use the Internet as a source of information for their disease. We analyzed the source, content and accuracy of IBD videos found on YouTube® – one of the most popular websites in the United States – and assessed the demographic variables of the viewers.MethodsThe 100 most viewed videos with relevant information on IBD were analyzed. We included only English language videos that were less than 20 min in length and primarily focused on IBD. Those with no sound/poor sound quality were excluded. More than 30 variables were analyzed.ResultsAdults of 45–54 years old (95.1%) comprised the most common age group of viewers. Forty-eight percent of videos focused on Crohn's disease (CD), 32.0% on ulcerative colitis (UC), and 20.0% on both. Overall content for patient education was poor. Videos discussing alternative treatment options were more likely to depict patients' personal experience (73.9% vs. 2.4%) (p < 0.001) and be an advertisement compared to patient education videos (78.3% vs. 0) (p < 0.001). Videos discussing patient education had a higher number of favorites (mean 25.0 vs. 5.5) (p < 0.001), comments (mean 22.0 vs. 5.0) (p < 0.022) and “likes” (mean 19.0 vs. 9.0) (p = 0.025) than the ones discussing alternative treatment options.ConclusionsYouTube® videos on IBD are popular but a poor source of patient education. Healthcare providers and professional societies should provide more educational materials using this powerful Internet tool to counteract the misleading information, especially for the targeted age group (45–54 years).     

Patients’ perceptions of quality of care and follow-up in inflammatory bowel disease

Background and aims Quality of care (QoC) has gained increased attention in IBD. A better QoC has, historically, been linked to improved treatment outcomes. Even so, factors of equal importance to patients may be quality of life (QoL), patient–physician communication and access to care. Recent surveys suggest that IBD care in Europe is suboptimal. Methods Patients were recruited from nine hospitals in the south-eastern and western part of Norway as a part of an observational, multicenter study In addition to clinical and socio-demographic factors; a purposely designed 26 item questionnaire was used to quantify aspects related to IBD care, including QoC. Moreover, the Fatigue Questionnaire (FQ) was used to investigate fatigue. Results In total, 411 patients were included. Of these, 231 were diagnosed with CD and 180 with UC. Furthermore, 86.1% (354/411) were satisfied with the quality of IBD follow-up and only 4.1% (17/411) were dissatisfied. Most dissatisfaction was related to: lack of focus on personal relations (18.2%), HRQoL (15.1%), general practitioner knowledge of IBD (13.9%), ability to talk about important topics (7.8%), and hospital discharge communication (9.4%). Higher age and longer disease duration was associated with improved QoC scores in both UC and CD. Fatigue was associated with decreased QoC scores in both diagnoses. Conclusions Patients are satisfied with quality of care in IBD. However, communication seems to be an important area of improvement – not only related to patient–physician communication, but also to transitional communication between different health-care levels.     

Prevalence and natural history of hepatitis B and C infections in a large population of IBD patients treated with anti-tumor necrosis factor-α agents

BackgroundThe prevalence rates of hepatitis B virus (HBV) and hepatitis C virus (HCV) in patients with inflammatory bowel disease (IBD) have been reported to be higher than rates of infection among the general population. Although several cases of HBV infection reactivation in IBD patients treated with anti-TNF-α agents have been described, no evidence exists that anti-TNF-α therapy exacerbates the course of HCV. The aims of this study were to assess the prevalence of HBV and HCV and the rate of HBV vaccination in a population of IBD patients; and to investigate the long-term effects of anti-TNF-α therapy in the subgroup with HBV or HCV infections.Methods301 patients were studied. Prior to the initiation of anti-TNF-α therapy, serum samples were tested for HBsAg and anti-HBc, anti-HBs and anti-HCV antibodies. During the follow-up, HBsAg and anti-HBc positive patients underwent periodic blood testing for viral markers, HBV-DNA and liver function; anti-HCV positive patients were assessed for liver function and HCV-RNA.ResultsOne patient was HBsAg positive (0.3%), and 22 (7.3%) tested positive for anti-HBc. Seventy-two patients (23.9%) had been vaccinated for HBV. Four patients tested positive for anti-HCV (1.3%). During anti-TNF-α therapy, none of the patients experienced HBV or HCV reactivation.ConclusionsHBV and HCV infection rates were similar to infection rates among the general population. Less than one quarter of the patients had been vaccinated against HBV. Anti-TNF-α agents appear to be safe for patients with HBV infection; more data are needed for patients with HCV infection.     

Extraintestinal manifestations of inflammatory bowel disease：Do they influence treatment and outcome？

Crohn’s disease and ulcerative colitis are chronic inflammatory bowel diseases that often involve organs other than those of the gastrointestinal tract. Immune-related extraintestinal manifestations (EIMs) are usually related to disease activity, but sometimes may take an independent course. Globally, about one third of patients develop these systemic manifestations. Phenotypic classification shows that certain subsets of patients are more susceptible to developing EIMs, which frequently occur simultaneousl...