Abstract
Background
Inflammatory bowel diseases IBD―ulcerative colitis and Crohn’s disease―are commonly treated with biologic drugs. However, only approximately two-thirds of patients have an initial ...response to these therapies. Personalised medicine has the potential to optimise efficacy, decrease the risk of adverse drug events, and reduce costs by establishing the most suitable therapy for a selected patient.
Aim
The present study reviews the potential predictors of short-term primary response to biologic treatment, including not only anti-tumour necrosis factor TNF agents such as infliximab, adalimumab, certolizumab, and golimumab but also vedolizumab and ustekinumab.
Methods
We performed a systematic bibliographical search to identify studies investigating predictive factors of response to biologic therapy.
Results
For anti-TNF agents, most of the evaluated factors have not demonstrated usefulness, and many others are still controversial. Thus, only a few factors may have a potential role in the prediction of the response, including disease behaviour/phenotype, disease severity, C-reactive protein, albumin, cytokine expression in serum, previous anti-TNF therapy, some proteomic markers, and some colorectal mucosa markers. For vedolizumab, the availability of useful predictive markers seems to be even lower, with only some factors showing a limited value, such as the expression of α4β7 integrin in blood, the faecal microbiota, some proteomic markers, and some colorectal mucosa markers. Finally, in the case of ustekinumab, no predictive factor has been reported yet to be helpful in clinical practice.
Conclusion
In summary, currently no single marker fulfils all criteria for being an appropriate prognostic indicator of response to any biologic treatment in IBD.
To review the frequency with which infliximabloses its effect and dose "intensification" is required for Crohn's disease treatment.
Bibliographical searches were performed in MEDLINE, and European ...(ECCO) and American (DDW) Congresses. Studies evaluating loss of efficacy and requirement of infliximab dose intensification-defined either as an increase of the infliximab dose (generally from 5 mg/kg to 10 mg/kg) or as a decrease in the frequency of infusion (to as often as every 4 weeks)-in Crohn's disease patients were included.
Sixteen studies evaluating the incidence of loss of response to infliximab in Crohn's disease patients were found. A total of 2,236 patients were included (the majority of them receiving a three-dose induction regimen at weeks 0, 2, and 6, followed by maintenance therapy every 8 weeks), providing 6,284 patient-years of follow-up. The mean percentage of patients with loss of infliximab response was 37%. However, as the follow-up time varied markedly among studies, the risk of losing response to infliximab is better expressed as the incidence of this complication per patient-year of follow-up. Therefore, the annual risk for loss of infliximab response was calculated to be 13% per patient-year.
A variable but relevant proportion of Crohn's disease patients on long-term infliximab treatment lose response. This may be interpreted in two different but compatible ways: a positive view, highlighting that infliximab therapy is relatively durable, with the majority of patients predicted to continue infliximab treatment at least during the first year; or a negative view, interpreting that a significant proportion of Crohn's disease patients-more than 10% per patient-year of infliximab treatment-on long term will lose response and will require an increase in dose and/or decrease in infusion interval.
Two new biological drugs (vedolizumab and ustekinumab) and one small molecule (tofacitinib) have been recently approved for the treatment of inflammatory bowel disease. Therefore, we must be familiar ...with the safety of these “new” drugs during pregnancy and breastfeeding. In the present article, we critically review available data on the safety of new biologics (vedolizumab and ustekinumab) and small molecules (tofacitinib) during pregnancy and breastfeeding, with special focus on women with inflammatory bowel disease. Bibliographical searches (MEDLINE) up to April 2020 were performed. The timing and mechanisms of placental transfer of vedolizumab and ustekinumab are expected to be similar to anti-TNF agents. Animal studies show no evidence of adverse effects on pre- or post-natal development after administration of vedolizumab and ustekinumab. Just a few studies including patients treated with vedolizumab or ustekinumab during pregnancy have been published, reporting uneventful pregnancies in most cases. The clinical programme of both drugs and post-marketing studies showed no new safety concerns. Due to the expected safety of vedolizumab and ustekinumab during pregnancy, it may be recommended to plan the final pregnancy dose approximately 8 or 12 weeks, respectively, before the estimated date of delivery. Live vaccines should be avoided for up to a year in children exposed in utero to vedolizumab or ustekinumab unless drug elimination has been documented. Miniscule amounts of vedolizumab and ustekinumab are transferred to breast milk, so breastfeeding is probably safe. There is no evidence of adverse effect of vedolizumab or ustekinumab paternal exposure. Regarding tofacitinib, it is reasonable to assume that this molecule crosses the placenta from the beginning of pregnancy. In animal studies, tofacitinib was feticidal and teratogenic in rats and rabbits, although at exposures many times greater than the standard human dose. Reported outcomes of pregnancy cases identified from tofacitinib randomised controlled trials, post-approval and non-interventional studies, and spontaneous adverse-event reporting appear similar to those observed in the general population. Nevertheless, at present, the use of tofacitinib during pregnancy should be avoided. Although no human studies have reported outcomes of breastfeeding with small molecules such as tofacitinib, this drug is present in lactating rat milk so, at present, breastfeeding should be avoided. Pregnancy among patients with paternal exposure to tofacitinib appears to be safe. In summary, we can conclude that new biologic agents (vedolizumab and ustekinumab) and small molecules (tofacitinib) should be used during pregnancy only if the benefits to the mother outweigh the risks to the mother and unborn child.
Although susceptibility-guided therapy is frequently recommended for Helicobacter pylori infection, the evidence available to date supporting this strategy is limited. The aim of the present article ...is to review the advantages and limitations of the susceptibility-guided and the empirical strategies to treat this infection. We performed a bibliographic search to identify studies investigating H. pylori susceptibility-guided therapy. Culture is not the only way to assess antibiotic resistance, as different polymerase chain reaction-based approaches have been developed as alternative methods. For detecting H. pylori antimicrobial resistance, a molecular approach based on a stool sample might enable more convenient, time-saving methods. Unfortunately, the antimicrobial susceptibility cannot be obtained in all cases. Furthermore, antibiotic susceptibility testing in clinical practice yields useful information only for a few antibiotics: clarithromycin, metronidazole, and quinolones. In addition, susceptibility towards clarithromycin and metronidazole in vitro does not necessarily lead to eradication in vivo. In the case of H. pylori therapy failure, we should not re-administer any of the antibiotics against which H. pylori has probably become resistant. Our updated meta-analysis showed that susceptibility-guided treatment is not better than empirical treatment of H. pylori infection in first-line therapy if the most updated quadruple regimens are empirically prescribed, and similar efficacy results were also demonstrated with the two strategies for second-line therapy. Cumulative H. pylori eradication rate with several successive rescue therapies empirically prescribed reaches almost 100%. Finally, the studies that have evaluated the cost-effectiveness of the susceptibility-guided treatment have achieved contradictory results. In summary, we can conclude that the evidence is too limited to support the generalized use of susceptibility-guided therapy for H. pylori treatment in routine clinical practice, either as first-line or as rescue treatment. Nevertheless, it would be recommended that susceptibility tests are performed routinely, even before prescribing first-line treatment, in specialized centers with an interest in H. pylori management.
To perform a meta-analysis of the risk of relapse after discontinuation of anti-tumor necrosis factor (anti-TNF) therapy in patients with Crohn's disease (CD) and ulcerative colitis (UC), to evaluate ...risk factors for relapse, and to assess the response to retreatment with the same anti-TNF.
Studies evaluating the incidence of relapse after anti-TNF discontinuation in patients with CD or UC who reached clinical remission with anti-TNFs were included. Bibliographies up to January 2015 were searched. Frequency of relapse after discontinuation of anti-TNF agents was determined; meta-analyses were performed using the inverse-variance method.
We included 27 studies (21 infliximab and 6 infliximab/adalimumab). The overall risk of relapse after discontinuation of anti-TNF therapy was 44% for CD (95% confidence interval (CI) 36-51%; I(2)=79%; 912 patients) and 38% for UC (23-52%; I(2)=82%; 266 patients). In CD, the relapse rate was 38% at 6 months after discontinuation (short term), 40% at 12 months (medium term), and 49% at >25 months (long term). In UC, 28% of patients relapsed at 12 months. In CD, when clinical remission was the only criterion for stopping anti-TNF therapy, the relapse rate after 1 year was 42%, which decreased to 26% when endoscopic remission was also required. Retreatment with the same anti-TNF induced remission again in 80% of cases (68-91%).
Approximately one-third of patients with inflammatory bowel disease in remission under anti-TNF treatment relapsed 1 year after discontinuation. This proportion increased to half in the long term. In CD patients, the risk of relapse was lower when the criterion for discontinuation was endoscopic remission and not only clinical remission. Response to retreatment with the same anti-TNF agent was favorable.
infection is the main cause of gastritis, gastroduodenal ulcer disease, and gastric cancer. Fluoroquinolones such as levofloxacin, or more recently moxifloxacin or sitafloxacin, are efficacious ...alternatives to standard antibiotics for
eradication. The aim of the present review is to summarize the role of quinolone-based eradication therapies, mainly focusing on the optimization strategies aimed to increase their efficacy. Several meta-analyses have shown that, after failure of a first-line eradication treatment, a levofloxacin-containing rescue regimen is at least equally effective, and better tolerated, than the generally recommended bismuth quadruple regimen. Compliance with the levofloxacin regimens is excellent, and the safety profile is favourable. Higher cure rates have been reported with longer treatments (>10-14 days), and 500 mg levofloxacin daily is the recommended dose. Adding bismuth to the standard triple regimen (PPI-amoxicillin-levofloxacin) has been associated with encouraging results. Unfortunately, resistance to quinolones is easily acquired and is increasing in most countries, being associated with a decrease in the eradication rate of
. In summary, a quinolone (mainly levofloxacin)-containing regimen is an encouraging second-line (or even third-line) strategy, and a safe and simple alternative to bismuth quadruple therapy in patients whose previous
eradication therapy has failed.
This review summarizes important studies regarding Helicobacter pylori therapy published from April 2019 to April 2020. The main themes that emerge involve studies assessing antibiotic resistance, ...and there is also growing momentum behind the utility of vonoprazan as an alternative to proton pump inhibitor (PPI) therapy and also bismuth‐based regimens as a first‐line regimen. Antibiotic resistance is rising wherever it is being assessed, and clarithromycin resistance in particular has reached a point where it may no longer be a viable therapy without previous testing in many regions of the world. The evidence for the efficacy of a bismuth‐based quadruple therapy as a first‐line therapy is now very clearly established, and there is substantial evidence that it is the best performing first‐line therapy. The utility of vonoprazan as an alternative to PPI therapy, especially in resistant and difficult‐to‐treat groups, has also been considered in great detail this year, and it may offer an opportunity in the near future to reduce the problem of antibiotic resistance.
Nowadays, apart from having to know first-line
eradication regimens well, we must also be prepared to face treatment failures. The aim of this review is to summarize the role of rifabutin in the ...management of
infection. Bibliographical searches were performed in PubMed. Data on resistance and efficacy of rifabutin-containing regimens on
eradication were meta-analyzed. Mean
rifabutin resistance rate (39 studies, including 9721 patients) was 0.13%; when studies only including patients naïve to
eradication treatment were considered, this figure was even lower (0.07%). Mean
eradication rate (by intention-to-treat) with rifabutin-containing regimens (3052 patients) was 73%. Respective cure rates for second-, third-, fourth- and fifth-line therapies, were 79%, 69%, 69% and 72%. Most studies administered rifabutin 300 mg/day, which seemed to be more effective than 150 mg/day. The ideal length of treatment remains unclear, but 10-12-day regimens are generally recommended. Adverse events to rifabutin treatment in
studies were relatively infrequent (15%), and severe adverse events were exceptional (myelotoxicity was the most significant, although always reversible). In summary, rifabutin-containing therapy represents an encouraging strategy generally restricted, at present, to patients where previous (usually multiple) eradication regimens have failed.
Abstract Background & aims Helicobacter pylori infection is increasingly difficult to treat. The purpose of these consensus statements is to review the literature and provide specific, updated ...recommendations for eradication therapy in adults. Methods A systematic literature search identified studies on H. pylori treatment. The quality of evidence and strength of recommendations were rated according to the Grading of Recommendation Assessment, Development, and Evaluation (GRADE) approach. Statements were developed through an online platform, finalized and voted on by an international working group of specialists chosen by the Canadian Association of Gastroenterology. Results Because of increasing failure of therapy, the consensus group strongly recommended that all H. pylori eradication regimens now be given for 14 days. Recommended first-line strategies include concomitant non-bismuth quadruple therapy (proton pump inhibitor, PPI + amoxicillin + metronidazole + clarithromycin, PAMC), and traditional bismuth quadruple therapy (PPI + bismuth + metronidazole + tetracycline, PBMT). PPI triple therapy (PPI + clarithromycin and either amoxicillin or metronidazole) was restricted to areas with known low clarithromycin resistance or high eradication success with these regimens. Recommended rescue therapies include PBMT and levofloxacin-containing therapy (PPI + amoxicillin + levofloxacin, PAL). Rifabutin regimens should be restricted to patients who fail at least 3 prior options. Conclusions Optimal treatment of H. pylori requires careful attention to local antibiotic resistance and eradication patterns. Quadruple therapies PAMC or PBMT should play a more prominent role in H. pylori eradication and all treatments should be given for 14 days.
A number of double, triple, and quadruple therapies have been proposed as first-line empiric treatments for Helicobacter pylori infection. However, knowledge of their worldwide and regional ...comparative efficacy is lacking. We examined the comparative effectiveness of all empirically used first-line regimens tested against standard triple treatment using a network meta-analysis of published randomized controlled trials.
Data extracted from eligible randomized controlled trials were entered into a Bayesian network meta-analysis to investigate the comparative efficacy of H pylori infection empiric first-line regimens and to explore their effectiveness rank order. The ranking probability for each regimen was evaluated by means of surfaces under cumulative ranking values.
Sixty-eight eligible randomized controlled trials were included, giving a total of 92 paired comparisons with 22,975 patients randomized to 8 first-line regimens. The overall results showed that only vonoprazan triple therapy and reverse hybrid therapy achieved cure rates of >90%. Levofloxacin triple therapy performed best in Western countries (eradication rate 88.5%). The comparative effectiveness ranking showed that vonoprazan triple therapy had the best results, whereas standard triple therapy was the least efficacious regimen (surfaces under cumulative ranking 92.4% vs 4.7% respectively; odds ratio, 3.80; 95% credible interval, 1.62–8.94).
For first-line empiric treatment of H pylori infection, vonoprazan triple therapy and reverse hybrid therapy achieved high eradication rates of >90%. Levofloxacin triple therapy achieved the highest eradication rates in Western countries. Standard triple therapy was the least efficacious regimen in this network meta-analysis.
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This network meta-analysis, examining the comparative effectiveness of Helicobacter pylori first-line dual, triple, and quadruple therapies showed that vonoprazan-based triple therapy was the most effective worldwide and standard triple therapy was the least efficacious.
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