Azathioprine and 6-mercaptopurine for maintenance of surgically-induced remission in Crohn’s disease

Background Crohn’s disease (CD) is a chronic relapsing inflammatory condition. Many patients fail to achieve remission with medical management and require surgical interventions. Purine analogues have been used to maintain surgically-induced remission in CD, but the effectiveness of these agents is unclear. Objectives The objectives were to evaluate the efficacy and safety of purine analogues for maintenance of surgically-induced remission in CD. Search methods We searched the following databases from inception to 30 April 2014: PubMed, MEDLINE, EMBASE, CENTRAL, and the Cochrane Inflammatory Bowel Disease and Functional Bowel Disorders Group Specialized Trials Register).We also searched the reference lists of all included studies, and contacted personal sources and drug companies to identify additional studies. The searches were not limited by language. Selection criteria Randomised controlled trials (RCTs) that compared purine analogues to placebo or another intervention, with treatment durations of at least six months were considered for inclusion. Participants were patients of any age with CD in remission following surgery. Data collection and analysis Two authors independently assessed trial eligibility and extracted data. Methodological quality was assessed using the Cochrane risk of bias tool. The primary outcome measures were clinical and endoscopic relapse as defined by the primary studies. Secondary outcomes included adverse events, withdrawal due to adverse events and serious adverse events. Data were analysed on an intention-to-treat basis where patients with missing final outcomes were assumed to have relapsed. We calculated the risk ratio (RR) and corresponding 95% confidence interval (95% CI) for dichotomous outcomes. The Chi2 and I2 statistics were used to assess heterogeneity. The overall quality of the evidence supporting the primary outcomes and selected secondary outcomes was assessed using the GRADE criteria. Main results Seven RCTs (n = 584 patients) were included in the review. Three studies compared azathioprine to 5-aminosalicylic acid (5-ASA).One small study compared azathioprine to both 5-ASA and adalimumab. One study compared azathioprine to placebo and another study compared 6-mercaptopurine to 5-ASA and placebo. One small study compared azathioprine to infliximab. Three studies were judged to be at low risk of bias. Four studies were judged to be at high risk of bias due to blinding. The study (n = 22) comparing azathioprine to infliximab found that the effects on the proportion of patients who had a clinical (RR 2.00, 95% CI 0.21 to 18.98) or endoscopic relapse (RR 4.40, 95% CI 0.59 to 3.07) were uncertain. One study (n = 33) found decreased clinical (RR 5.18, 95% CI 1.35 to 19.83) and endoscopic relapse (RR 10.35, 95% CI 1.50 to 71.32) rates favouring adalimumab over azathioprine. A pooled analysis of two studies (n = 168 patients) showed decreased clinical relapse rates at one or two years favouring purine analogues over placebo. Forty eight per cent of patients in the purine analogue group experienced a clinical relapse compared to 63% of placebo patients (RR 0.74, 95% CI 0.58 to 0.94). A GRADE analysis indicated that the overall quality of the evidence supporting this outcome was low due to high risk of bias (one study was single-blind) and sparse data (93 events). One study (87 patients) found a reduction in endoscopic relapse rates favouring 6-mercaptopurine over placebo. Seventeen per cent of 6-mercaptopurine patients had an endoscopic relapse at two years compared to 42% of placebo patients (RR 0.40, 95% CI 0.19 to 0.83). A GRADE analysis indicated that the overall quality of the evidence for this outcome was low due to very sparse data (25 events). A pooled analysis of five studies (n = 425 patients) showed no difference in clinical relapse rates at one or two years between purine analogues and 5-ASA agents. Sixty-three per cent of patients in the purine analogues group experienced a clinical relapse compared to 54% of 5-ASA patients (RR 1.15, 95% CI 0.99 to 1.34). A GRADE analysis indicated that the overall quality of the evidence supporting this outcome was very low due to high risk of bias (two open-label studies), sparse data (249 events) and moderate heterogeneity (I2 = 45%). There was no difference in endoscopic relapse at 12 months between azathioprine and 5-ASA (RR 0.78, 95% CI 0.52 to 1.17; 1 study, 35 patients). A GRADE analysis indicated that the overall quality of the evidence for this outcome was very low due to high risk of bias (open-label study) and very sparse data (26 events). There was a reduction in endoscopic relapse at 24 months favouring 6-mercaptopurine over 5-ASA patients. Seventeen per cent of 6-mercaptopurine patients had an endoscopic relapse compared to 48% of 5-ASA patients (RR 0.36, 95% CI 0.18 to 0.72; 1 study, 91 patients). A GRADE analysis indicated that the overall quality of the evidence for this outcome was low due to very sparse data (29 events). Adverse events that required withdrawal were more common in the purine analogue group compared to 5-ASA. Twenty per cent of patients in the purine analogue group withdrew due to adverse events compared to 10% of 5-ASA patients (RR 2.07, 95% CI 1.26 to 3.39; 5 studies, 423 patients).The results for withdrawal due to adverse events between purine analogues and placebo or for other comparisons were uncertain. Commonly reported adverse events across all studies included leucopenia, arthralgia, abdominal pain or severe epigastric intolerance, elevated liver enzymes, nausea and vomiting, pancreatitis, anaemia, exacerbation of Crohn’s disease, nasopharyngitis, and flatulence. Authors’ conclusions Purine analogues may be superior to placebo for maintenance of surgically-induced remission in patients with CD, although this is based on two small studies. The results for efficacy outcomes between purine analogues and 5-ASA agents were uncertain. However, patients taking purine analogues were more likely than 5-ASA patients to discontinue therapy due to adverse events. No firm conclusions can be drawn from the two small studies that compared azathioprine to infliximab or adalimumab. Adalimumab may be superior to azathioprine but further research is needed to confirm these results. Further research investigating the efficacy and safety of azathioprine and 6-mercaptopurine in comparison to other active medications in patients with surgically-induced remission of CD is warranted

Quality of life in patients with moderate to severe ulcerative colitis and the impact of treatment: A narrative review.

As a chronic inflammatory disease, ulcerative colitis has significant negative impact on the quality of life (QoL) of patients. Since the disease affects many aspects of QoL, comprising multiple domains, treatments that induce and maintain remission can provide benefits beyond hard clinical endpoints. Effective treatment of ulcerative colitis can restore QoL and return it to normal or near normal levels. Biological therapies have shown consistent improvement in the QoL of patients with ulcerative colitis during the induction phase, with benefits that are generally maintained in the long-term. Current medical treatment options broadly comprise aminosalicylates, corticosteroids, thiopurines, and calcineurin inhibitors, as well as biologic therapies. Conventional therapies do not always adequately control disease in a sizeable portion of patients, while anti-TNF antibodies are associated with several issues such as contraindications, intolerance, primary non-response, and loss of response in some patients. JAK inhibitors have been associated with clinical improvements in disease manifestations and long-term improvement in QoL outcomes. However, additional studies are needed to better understand the comparative effects of different treatments on QoL and patient preferences for therapy. Herein, the available evidence is reviewed regarding the impact of various treatments on QoL in patients with moderate to severe ulcerative colitis

Update on the management of inflammatory bowel disease: specific role of adalimumab

Anti-tumor necrosis factor alpha (TNF-α) medications are a class of biologics employed in the treatment of patients with inflammatory bowel disease (IBD). Adalimumab is the first fully human monoclonal immunoglobulin directed against TNF-α, which binds with high affinity and specificity to membrane and soluble TNF. Adalimumab administered subcutaneously has demonstrated efficacy in the treatment of rheumatoid arthritis, ankylosing spondylitis, psoriatic arthritis, and severe chronic psoriasis. Studies have shown that adalimumab is effective for inducing and maintaining remission of moderate-to-severe active Crohn’s disease (CD) patients at an induction dose of 160/80 mg (week 0 and 2) and at a maintenance dose of 40 mg every other week. The efficacy of adalimumab as a second-line therapy has also been documented for patients with loss of response or intolerance to infliximab. Adalimumab is also superior to placebo for inducing and maintaining complete perianal fistula closure. It also seems effective for reducing extraintestinal manifestations. The safety profile is similar to that of other anti-TNF therapy in CD patients, with lower immunogenicity and rate of adverse injection reactions than infliximab. Adalimumab is not approved for the treatment of ulcerative colitis (UC). Recently, however, the results of the first randomized, controlled trial on adalimumab for UC showed that adalimumab at 160/80 mg induction dose was safe and effective for inducing remission and clinical response after 8 weeks in patients with moderately-to-severely active UC failing treatment with corticosteroids and/or immunosuppressants. More data are necessary to clarify the therapeutic role of adalimumab in UC. This review of the literature summarizes available data on the efficacy and safety profile adalimumab in patients with IBD

Higher risk of tuberculosis reactivation when anti-TNF is combined with immunosuppressive agents. A systematic review of randomized controlled trials

Objective. Treatment with tumour necrosis factor antagonists (anti-TNF) has been recognized as a risk factor for tuberculosis (TB) reactivation. Our aim was to evaluate risk of TB reactivation in rheumatologic and non-rheumatologic diseases treated with the same anti-TNF agents with and without concomitant therapies. Methods. We searched for randomized controlled trials (RCTs) evaluating infliximab, adalimumab, and certolizumab in both rheumatologic and non-rheumatologic diseases until 2012. Results were calculated as pooled rates and/or pooled odd ratios (OR). Results. Overall, 40 RCTs with a total of 14,683 patients (anti-TNF: 10,010; placebo: 4673) were included. TB reactivation was 0.26% (26/10,010) in the anti-TNF group and 0% (0/4673) in the control group, corresponding to an OR of 24.8 (95% CI 2.4-133). TB risk was higher when anti-TNF agents were combined with methotrexate or azathioprine as compared with either controls (24/4241 versus 0/4673; OR 54; 95% CI 5.3-88) or anti-TNF monotherapy (24/4241 versus 2/5769; OR 13.3; 95% CI 3.7-100). When anti-TNF was used as monotherapy, TB risk tended to be higher than placebo (2/5769 versus 0/4673; OR 4; 95% CI 0.2-15.7). Conclusions. TB risk with anti-TNF agents appeared to be increased when these agents were used in combination with methotrexate or azathioprine as compared with monotherapy regimen. TB risk seemed to be higher than placebo, even when monotherapy is prescribed

The export sales regime in the VAT system

La tesi è il risultato di un’analisi europea integrata sulla natura di quelle che la disciplina europea qualifica come “Esenzioni all’esportazione”, alla luce del ruolo svolto dal principio di territorialità nel sistema dell’imposta sul valore aggiunto relativamente alle operazioni di commercio con l’estero (dove per estero, in seguito dalla disciplina specifica dettata per le operazioni intracomunitarie si intendono, oggi, i Paesi terzi rispetto al territorio Europeo) in una prospettiva di crescente armonizzazione europea e di continuo allineamento ai principi internazionali. A questo proposito si sottolinea che, nei rapporti con i mercati internazionali, l’armonizzazione non riguarda il modello di tassazione come nel mercato unico, ma è il regime necessario per attuare, anche in questo contesto, il criterio territoriale adottato nel mercato europeo. Tale criterio prevede, sin dalle prime direttive, la tassazione delle importazioni e la detassazione delle esportazioni. L’opzione per tale articolazione è dipesa dalla considerazione che la diversità di imposte indirette fra i Paesi coinvolti nell’operazione potesse alterare la competitività internazionale dei rispettivi prodotti, per questo si è optato per un sistema che prevedesse il rimborso ai cedenti, al momento dell’esportazione, delle imposte indirette incorporate nei beni venduti e che, allo stesso tempo, implicasse l’applicazione di un’imposta di conguaglio sulle le merci importate, pari all’imposta che avrebbero dovuto pagare se fossero state prodotte nello Stato importatore. In particolare il regime delle cessioni all’esportazione mette in evidenza la centralità degli aspetti esecutivi legati al trasporto dei beni fuori dal territorio doganale europeo. Si è, però, ritenuto che quelle all’esportazione non si apprezzino come fattispecie particolari collocate in una dimensione di specialità rispetto alle ordinarie cessioni di beni – come individuate dall’art. 14 della Direttiva rifusa e, per quanto riguarda l’ordinamento italiano, dall’art. 2 del Decreto IVA – ma, al contrario, che vadano ricostruite in una visione di sistema.This doctoral dissertation is the result of an European integrated analysis based on the legal nature of the arrangements governing exemption of exports, in the light of the role played by the territorial principle in the VAT system regarding the external trade (e.g. non EU countries) in a perspective of a growing harmonization and in line with the international principles. In this regard, in the relationship with international markets, the harmonization does not concern the scheme for charging tax, as in the internal market, but it represents the general statutory scheme to implement, also in this context, the territorial criterion adopted in the European internal market. This criterion implies, from the earliest Directives, the taxation of imports and the exemption of exports. This choice depends essentially on the consideration that the variety of indirect taxes in the countries involved in a given operation could affect the international competitiveness of those same countries’ products; for this reason the choice has fallen on a system that implies a refund of the indirect taxes, incorporated by the sold goods, paid by the seller at the moment of the exportation and, at the same time, the application of a balancing tax for the imported goods, which should have the same value of the tax that would have been paid if those same goods were produced in the importing country. In particular, this export sales regime focuses on the importance of the executive and practical aspects of transportation of goods outside the European Union. However, it is argued that export sales do not have to be identified as a special kind of ordinary sales – as for art. 14 of the VAT Directive and art. 2 of the Italian VAT law – but, to the contrary, that they should be contextualized in the same system

Enhancing treatment success in inflammatory bowel disease: Optimising the use of anti-TNF agents and utilising their biosimilars in clinical practice.

Abstract Anti-tumour necrosis factor (TNF) agents such as infliximab and adalimumab have greatly altered the treatment landscape in inflammatory bowel disease (IBD). However, there are remaining unmet needs and opportunities to optimise their use. Recent data suggest that proactive therapeutic drug monitoring may lead to more efficient usage of these agents, with potential for higher rates of corticosteroid-free clinical remission than with reactive monitoring. Expanded application of faecal calprotectin measurements may also be valuable, given the ease of use of the assay and its proven effectiveness as a diagnostic tool and predictor of relapse risk. From a practical viewpoint, improved multidisciplinary working may be essential to optimise patient care, with IBD nurse specialists playing an increasingly central role within this model. Finally, the availability of biosimilars of the anti-TNF agents allow drug costs to be reduced without compromising safety or efficacy – thereby providing opportunities to improve accessibility. Alongside extensive data on originator to biosimilar infliximab switch, new studies are beginning to demonstrate the safety of biosimilar to biosimilar switch, as well as adalimumab biosimilar transitions. The risk of a nocebo effect when switching to a biosimilar can be reduced through improved patient education and preparation

IBD Flare in the COVID-19 Pandemic: Therapy Discontinuation Is to Blame

Lay Summary This prospective case-control study investigated the impact of severe acute respiratory syndrome coronavirus 2 infection on inflammatory bowel disease course and looked for risk factors associated with flares. In the severe acute respiratory syndrome coronavirus 2 pandemic era, inflammatory bowel disease course is not influenced by infection, while therapy discontinuation is a risk factor for disease flare

BoBafit: A copy number clustering tool designed to refit and recalibrate the baseline region of tumors’ profiles

Human cancer arises from a population of cells that have acquired a wide range of genetic alterations, most of which are targets of therapeutic treatments or are used as prognostic factors for patient's risk stratification. Among these, copy number alterations (CNAs) are quite frequent. Currently, several molecular biology technologies, such as microarrays, NGS and single-cell approaches are used to define the genomic profile of tumor samples. Output data need to be analyzed with bioinformatic approaches and particularly by employing computational algorithms. Molecular biology tools estimate the baseline region by comparing either the mean probe signals, or the number of reads to the reference genome. However, when tumors display complex karyotypes, this type of approach could fail the baseline region estimation and consequently cause errors in the CNAs call. To overcome this issue, we designed an R-package, BoBafit, able to check and, eventually, to adjust the baseline region, according to both the tumor-specific alterations’ context and the sample-specific clustered genomic lesions. Several databases have been chosen to set up and validate the designed package, thus demonstrating the potential of BoBafit to adjust copy number (CN) data from different tumors and analysis techniques. Relevantly, the analysis highlighted that up to 25% of samples need a baseline region adjustment and a redefinition of CNAs calls, thus causing a change in the prognostic risk classification of the patients. We support the implementation of BoBafit within CN analysis bioinformatics pipelines to ensure a correct patient's stratification in risk categories, regardless of the tumor type