Safety of anti-tumor necrosis factor therapy during pregnancy in patients with inflammatory bowel disease

Treatment of inflammatory bowel disease has significantly improved since the introduction of biological agents, such as infliximab, adalimumab, certolizumab pegol, and golimumab. The Food and Drug Administration has classified these factors in category B, which means that they do not demonstrate a fetal risk. However, during pregnancy fetuses are exposed to high anti-tumor necrosis factor(TNF) levels that are measurable in their plasma after birth. Since antibodies can transfer through the placenta at the end of the second and during the third trimesters, it is important to know the safety profile of these drugs, particularly for the fetus, and whether maintaining relapse of the disease compensates for the potential risks of fetal exposure. The limited data available for the anti-TNF drugs to date have not demonstrated any significant adverse outcomes in the pregnant women who continued their therapy from conception to the first trimester of gestation. However, data suggest that antiTNFs should be discontinued during the third trimester, as they may affect the immunological system of the newborn baby. Each decision should be individualized, based on the distinct characteristics of the patient and her disease. Considering all the above, there is a need for more clinical studies regarding the effect of antiTNF therapeutic agents on pregnancy outcomes.     

Safety of anti-tumor necrosis factor therapy in inflammatory bowel disease

Inflammatory bowel disease （IBD）, in particular Crohn＇s disease refractory to conventional therapy, fistulizing Crohn＇s disease and chronic active ulcerative colitis,generally respond well to anti-tumor necrosis factor（TNF） therapy. However, serious side effects do occur,necessitating careful monitoring of therapy. Potentialside effects of anti-TNF therapy include opportunistic infections, which show a higher incidence whenconcomitant immunosuppression is used. Furthermore,antibody formation against anti-TNF is associated with decreased efficacy and an increased frequency of infusion reactions. The hypothesis of a slightlyincreased risk of lymphomas in IBD patients treated with anti TNF-therapy is debatable, since most studieslack the specific design to properly address this issue.Alarmingly, the occurrence of hepatosplenic T-cell lymphomas coincides with combined immunosuppressive therapy. Despite the potential serious side effects, anti-TNF therapy is an effective and relatively safe treatment option for refractory IBD. Future research is needed to answer important questions, such as the long-term risk of malignancies, safety during pregnancy, when to discontinue and when to switch anti-TNF therapy, as well as to determine the balance between therapeutic and toxic effects.     

New concepts in anti-tumor necrosis factor therapy for inflammatory bowel disease

Crohn's disease is a T helper type 1 response immune disease characterized by increased production of interleukin-12 tumor necrosis factor-a (TNF-a), and interferon-g. Clinical trials have demonstrated that inhibition of TNF is effective for the treatment of Crohn's disease. Adverse events reported in patients treated with anti-TNF agents include immunogenicity, acute infusion reactions, delayed hypersensitivity-type reactions, autoimmune diseases including drug-induced lupus and demyelination, and infection. This article reviews new concepts in the treatment of Crohn's disease and ulcerative colitis with a variety of anti-TNF biologic therapies: infliximab, adalimumab, CDP870, CDP571, etanercept, and onercept.     

Indicators of suboptimal tumor necrosis factor antagonist therapy in inflammatory bowel disease

BackgroundInflammatory bowel disease (IBD) is refractory to treatment in one-half of patients.AimsTo evaluate the occurrence of suboptimal therapy among patients with IBD treated with tumor necrosis factor antagonists (anti-TNFs).MethodsA multinational chart review in Europe and Canada was conducted among IBD patients diagnosed with ulcerative colitis (UC) or Crohn’s disease (CD) who initiated anti-TNF therapy between 2009 and 2013. The primary endpoint was the cumulative incidence of suboptimal therapy during a two-year follow-up period, defined by the presence of the following indicators: dose escalation, discontinuation, switching, non-biologic therapy escalation, or surgery.ResultsThe study included 1195 anti-TNF initiators (538 UC and 657 CD). The majority of patients (64% of UC and 58% of CD) had at least one indicator of suboptimal therapy. The median time to suboptimal therapy indicator was 12.5 and 17.5 months for UC and CD patients, respectively. Among the 111 UC and 174 CD anti-TNF switchers, 51% and 56% had an indicator of suboptimal therapy, respectively. The median time to suboptimal therapy indicator with the second anti-TNF was 14.3 and 13.0 months for UC and CD patients, respectively.ConclusionThe majority of IBD patients showed suboptimal therapy with current anti-TNFs.     

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炎症性肠病(inflammatory bowel disease,IBD)包括溃疡性结肠炎(ulcerative colitis,UC)和克罗恩病(Crohn's diseases,CD).其病因和发病机制尚不清楚,与遗传、环境、微生物、免疫等多个因素密切相关,其中免疫因素引起人们极大关注.     

Optimizing anti-tumor necrosis factor strategies in inflammatory bowel disease

The introduction of infliximab, a mouse/human chimeric monoclonal antibody to tumor necrosis factor (TNF), is an important advance in the treatment of Crohn’s disease. Infliximab is effective for induction and maintenance of remission in patients with inflammatory luminal and fistulizing disease. The development of human antichimeric antibodies (HACAs) has led to infusion reactions and loss of efficacy in patients treated with infliximab. Strategies to reduce the frequency of HACA formation include induction of immunologic tolerance with a three-dose regimen at 0, 2, and 6 weeks followed by systematic maintenance dosing every 8 weeks; concomitant immunosuppressive therapy with azathioprine, 6-mercaptopurine, or methotrexate; and premedication with intravenous corticosteroids. Humanized or fully human anti-TNF biotechnologic agents, including CDP571, CDP870, etanercept, adalimumab, and onercept, are theoretically less immunogenic than the chimeric antibody infliximab. Etanercept is not effective for Crohn’s disease. CDP571 is not effective in unselected patients with active Crohn’s disease, but it may be effective in patients with elevated C-reactive protein. The efficacy of CDP870, adalimumab, and onercept is under investigation. The different mechanisms of action of these anti-TNF agents may account for their variable efficacy. Their benefits, however, must be considered in the context of their risks, including infusion reaction; delayed hypersensitivitylike reaction; new onset of autoimmunity, with rare cases of drug-induced lupus and new-onset demyelination; and the potential for rare but serious infections.     

HLA disparity determines disease activity through pregnancy in women with inflammatory bowel disease

OBJECTIVES: Inflammatory bowel disease (IBD) activity during pregnancy is variable and factors influencing the course unknown. We studied the relationship between maternal-fetal HLA disparity and IBD course. METHODS: Women with IBD and childbirth were recruited and medical records were reviewed for five time periods. Twenty milliliters of blood was obtained from mother and child for genotyping. Each mother/child pair was assigned an HLA disparity status (+/-) for HLA A, B, C, DRB1, and DQ loci. Odds ratios were calculated comparing HLA disparity in women whose IBD improved versus those whose disease worsened or remained active. RESULTS: Fifty pregnancies in 38 women were studied. Forty-two of 50 pregnancies (84%) were disparate at the DRB1 locus; 34 (68%) were mismatched at the DQ locus. There was no difference in average disease score or overall activity score based on DRB1 or DQ disparity (p > 0.05 for all comparisons). There were 31 pregnancies disparate at both DRB1 and DQ loci; a significant difference was found in average disease scores and overall activity scores between women mismatched at both loci versus only one or neither locus (OR 8.4 [1.5-14, p = 0.01). Logistic regression identified prepartum disease activity and disparity at both DRB1 and DQ as significant predictors of overall disease activity during pregnancy. CONCLUSION: Improvement of IBD symptoms during pregnancy is associated with disparity in HLA class II antigens between mother and fetus. This suggests that the maternal immune response to paternal HLA antigens plays a role in pregnancy-induced remission. What is accepted and what this research adds are as follows: .The course of IBD during pregnancy is variable. .The factors involved with disease course are unknown. .The data presented here provides a scientific mechanism for disease course during pregnancy. .This is a novel work and it corroborates what has been seen in other autoimmune conditions.     

Integrating anti-tumor necrosis factor therapy in inflammatory bowel disease: current and future perspectives

Crohn's disease and ulcerative colitis are two idiopathic inflammatory disorders of the GI tract. Manifestations of disease can be severe and lead to long term therapy with a variety of medications and/or surgery. Standard medical therapy consists of agents that either treat suppurative complications or modulate the inflammatory cascade in a nonspecific manner. Many specific chemokine and cytokine effectors that promote intestinal inflammation have been identified. Such work has led to experimental clinical trials with a variety of cytokine antagonists. Compounds directed against one such cytokine, tumor necrosis factor alpha (TNF), have demonstrated the greatest clinical efficacy to date. This is consistent with scientific observations that suggest a central role for TNF in the inflammatory cascade. Infliximab is a chimeric monoclonal antibody against TNF that has been demonstrated to be effective for the treatment of Crohn's disease. Infliximab is Food and Drug Administration approved for the treatment of Crohn's disease. There exist several other TNF antagonists in various phases of investigation, including the monoclonal antibody CDP 571, the fusion peptide etanercept, the phosphodiesterase inhibitor oxpentifylline, and thalidomide. The clinical efficacy of these agents and the role of TNF in the pathogenesis of inflammatory bowel disease is reviewed.     

Antitumor necrosis factor treatment for pediatric inflammatory bowel disease

Infliximab, adalimumab, and certolizumab are monoclonal antibodies against tumor necrosis factor-α (TNFα), a proinflammatory cytokine with an increased expression in the inflamed tissues of inflammatory bowel disease (IBD) patients. Currently, infliximab is the only anti-TNF drug that has been approved for use in refractory pediatric Crohn's disease (CD). Nevertheless, adalimumab and certolizumab have been used off-label to treat refractory pediatric IBD. Over the past 10 years, anti-TNF treatment has been of great benefit to many pediatric IBD patients, but their use is not without risks (infections, autoimmune diseases, malignancies). Despite the growing experience with these drugs in children with IBD, optimal treatment strategies still need to be determined. The purpose of this review is to summarize the current knowledge on the use of anti-TNF drugs in pediatric IBD and to discuss the yet-unsolved issues.     

Clinical courses and pregnancy outcomes in Japanese women with inflammatory bowel disease

In this study, we analyzed the clinical courses and the pregnancy outcomes in Japanese women with inflammatory bowel disease (IBD) in our hospital in the recent 10 years. We analyzed 49 pregnancies in 38 patients with ulcerative colitis (UC) and 24 pregnancies in 16 patients with Crohn's disease (CD) retrospectively. The results indicated that pregnancy has less influence on the clinical courses of IBD and that IBD also has less influence on the pregnancy outcomes. However, we should pay attention to the results that the patients with CD tend to deteriorate if conception occurs when CD is active and that patients with active UC tend to have more adverse pregnancy outcomes than patients in remission. In conclusion, patients with IBD are recommended to become pregnant when the diseases are in remission and treatment using selected safe medications should be continued during the pregnancy.     

Discontinuation of anti-tumor necrosis factor therapy in inflammatory bowel disease patients: a prospective observation

Background: Discontinuation of anti-TNF therapy in patients with inflammatory bowel diseases (IBD) in remission remains a controversial issue. The aims of our study were to assess the proportion of patients who relapse after cessation of biological treatment, and to identify potential risk factors of disease relapse. Methods: Consecutive IBD patients who discontinued anti-TNF therapy in steroid-free clinical and endoscopic remission were prospectively followed. Multiple logistic regression and Cox proportional-hazards models were used to assess the predictors of disease relapse. Results: Seventy-eight IBD patients (Crohn's disease, CD 61; ulcerative colitis, UC 17) were included and followed for a median of 30 months (range 7–47). A total of 32 (53%) CD patients and nine (53%) UC patients relapsed by the end of the follow-up with a median time to relapse of 8 months (range 1–25) in CD patients and 14 months (range 4–37) in UC patients, respectively. The cumulative probabilities of maintaining remission at 6, 12, and 24 months were 82%, 59%, and 51% in CD patients, and 77%, 77%, and 64% in UC patients, respectively. Survival of CD patients who were in deep remission (clinical and endoscopic healing; faecal calprotectin <150?mg/kg; CRP ≤5?mg/l) was not better compared with those who did not fulfill these criteria. In multivariate models, only colonic CD protected patients from disease relapse. Conclusions: Approximately half of the IBD patients relapsed within 2 years after anti-TNF discontinuation. In CD patients, no difference between those who were or were not in deep remission was found. Colonic localization protected patients from relapse.     

Pregnancy outcome in four women with inflammatory bowel disease treated with budesonide MMX

Background: Maintaining disease remission throughout pregnancy in women with inflammatory bowel disease is of the utmost importance to decrease the risk of adverse outcome. In general, corticosteroids are safe to use during pregnancy, but no data exist in the specific use of budesonide MMX. We report four cases of budesonide MMX in pregnancy and pregnancy outcome.

Methods: Four women with inflammatory bowel disease experienced disease activity during pregnancy. They were treated with budesonide MMX in an attempt to obtain clinical remission. Disease activity was assessed through physician’s global assessment as well as lower endoscopy.

Results: Budesonide MMX proved effective in achieving remission in three out of four women. One woman had an uncomplicated colectomy in the second trimester. All children were born normal for gestational age, with no congenital abnormalities and have reached all their developmental milestones. The four children have received vaccines according to the national immunization program without complications.

Conclusion: No adverse pregnancy outcomes were reported after the use of budesonide MMX. To our knowledge, this is the first report on the safety of budesonide MMX treatment in pregnant women with inflammatory bowel disease.     

Paradoxical psoriasiform reactions of anti‐tumour necrosis factor therapy in inflammatory bowel disease patients

Anti‐tumour necrosis factor (TNF) agents have demonstrated efficacy in inflammatory bowel disease (IBD). Cutaneous reactions such as new onset psoriasis or psoriasiform‐like reactions are among the most common adverse reactions. We retrospectively identified cases of anti‐TNF‐induced psoriasis or psoriasiform manifestations in IBD patients at a tertiary centre in Australia. A total of 10 (six females) of 270 (3.7%) IBD patients treated with anti‐TNF therapy developed drug‐induced psoriatic or psoriasiform‐like reactions: five patients were treated with infliximab and five with adalimumab; nine had Crohn disease. The time from initiation of anti‐TNF agent to onset of rash was 7.5 months on average. The most frequent distributions were the scalp (7/10) and extremities (6/10). Three patients discontinued anti‐TNF treatment with resolution of the rash. Topical treatment of the lesions allowed continued use of biological agent in the majority. Paradoxical psoriatic lesions are recognised adverse events associated with anti‐TNF therapy, but discontinuation of therapy due to dermatological complications is required only rarely, even in patients with psoriasiform lesions.     

Practical guidelines for treating inflammatory bowel disease safely with anti‐tumour necrosis factor therapy in Australia

Anti‐tumour necrosis factor (TNF) therapy is an effective but expensive option for treating inflammatory bowel disease (IBD). Its use is generally reserved for patients with severe refractory disease, often involving long‐term administration. Anti‐TNF therapy has the potential to be associated with various adverse effects, such as infection, malignancy and immunogenicity. Clinicians and patients should be familiar with these possibilities and adopt appropriate precautions prior to and during treatment to minimize risk. Guidelines have been developed for Australian prescribers intending to use anti‐TNF therapy in IBD by a Working Party commissioned by IBD‐Australia, a Special Interest Group affiliated with the Gastroenterology Society of Australia.     

Outcome of pregnancies when fathers are treated with 6-mercaptopurine for inflammatory bowel disease

OBJECTIVE: The outcomes of pregnancies after maternal use of 6-mercaptopurine (6-MP) for inflammatory bowel disease (IBD) during pregnancy have been reported, but data are lacking for outcomes when the fathers use this drug. METHODS: Subjects were male patients with IBD seen at one center between 1970 and 1997. Patients and their wives were interviewed. Group 1 comprised pregnancies fathered by men who were taking 6-MP. This group was further subdivided into those conceived within 3 months of 6-MP use and those conceived at least 3 months after 6-MP was stopped. Group 2 comprised pregnancies fathered by men with IBD, similar in characteristics to group 1, who had not taken 6-MP before fertilization. Information was collected regarding the fathers, the mothers, and the pregnancies, as well as the health of the children, in a historical cohort study. RESULTS: There were 50 pregnancies in group 1 (13 in 1A and 37 in 1B) and 90 pregnancies in group 2. Four of the 13 pregnancies in group 1A were associated with complications. There were two spontaneous abortions, and two congenital anomalies including a missing thumb in one and acrania with multiple digital and limb abnormalities in the other. Risk of complications was significantly increased when compared with group 1B (p < 0.013) and group 2 (p < 0.002). CONCLUSION: The incidence of pregnancy-related complications was significantly increased when the fathers used 6-MP within 3 months of conception.     

Therapeutic drug monitoring of tumor necrosis factor antagonists in inflammatory bowel disease

Although tumor necrosis factor (TNF) antagonists have shown clear benefits over conventional treatments for inducing and maintaining clinical remission in both Crohn's disease and ulcerative colitis, a high proportion of patients lose response over time. Given the scarce alternative of treatments when treatment failure occurs, it is highly desirable to optimize both initial response and long-term continuation of TNF antagonists. One of the most well-characterized factors associated with loss of response to these agents is the development of immunogenicity, whereby the production of neutralizing antidrug antibodies accelerates drug clearance, leading to subtherapeutic drug concentrations and, ultimately, to treatment failure. However, other patient-related factors, such as sex and/or body size, and disease severity, including TNF burden and serum albumin concentration among others, also may influence the pharmacokinetics of these agents. Nevertheless, the evidence generated to date about these complex interactions is scarce, and further prospective studies evaluating their influence on the pharmacokinetics of TNF antagonists are needed. Drug adjustment empirically based on clinical symptoms often is inaccurate and may lead to suboptimal outcomes. Recent evidence shows that maintenance of an optimal therapeutic drug concentration is associated with improved clinical outcomes. Therefore, incorporation of therapeutic drug monitoring into clinical practice may allow clinicians to optimize treatment by maintaining effective drug concentrations over time.