The risk of infection associated with tumor necrosis factor antagonists (anti-TNF) and thiopurines (combination therapy) is uncertain. We assessed the risk of serious and opportunistic infections in ...patients with inflammatory bowel disease (IBD) treated with thiopurine monotherapy, anti-TNF monotherapy, or combination therapy in a large cohort of patients in France.
We performed a nationwide population-based study of patients (18 years or older) with a diagnosis of IBD in the French national health insurance database; we collected data from January 1, 2009 until December 31, 2014. The risks of serious and opportunistic infections associated with exposure to combination therapy, anti-TNF, and thiopurine monotherapies were compared using marginal structural Cox proportional hazard models adjusted for baseline and time-varying sociodemographic characteristics, medications, and comorbidities.
Among the 190,694 patients with IBD included in our analysis, 8561 serious infections and 674 opportunistic infections occurred. Compared with anti-TNF monotherapy, combination therapy was associated with increased risks of serious infection (hazard ratio HR, 1.23; 95% confidence interval CI, 1.05–1.45) and opportunistic infection (HR, 1.96; 95% CI, 1.32–2.91). Compared with thiopurine monotherapy, anti-TNF monotherapy was associated with increased risks of serious infection (HR, 1.71; 95% CI, 1.56–1.88), mycobacterial infection (HR, 1.98; 95% CI, 1.15–3.40), and bacterial infection (HR, 2.38; 95% CI, 1.23–4.58, respectively). Conversely, anti-TNF monotherapy was associated with decreased risk of opportunistic viral infection compared with thiopurine monotherapy (HR, 0.57; 95% CI, 0.38–0.87).
In a nationwide cohort study of patients with IBD in France, we found heterogeneity in risks of serious and opportunistic infections in patients treated with immune-suppressive regimens. These should be carefully considered and weighed against potential benefits for IBD treatment in patient management.
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Inhibition of immune checkpoints using anti-programmed cell death-1 (PD-1) or anti cytotoxic-T-lymphocyte-associated antigen 4 (CTLA-4) monoclonal antibodies has revolutionized the management of ...patients with advanced-stage melanoma and is among the most promising treatment approaches for many other cancers. Use of CTLA-4 and PD-1 inhibitors, either as single agents, or in combination, has been approved by the US FDA for the treatment of metastatic melanoma. Treatment with these novel immunotherapies results in a unique and distinct spectrum of adverse events, which are mostly related to activation of the immune system and are, therefore, an unwanted consequence of their mechanisms of action. Adverse effects of CTLA-4 and/or PD-1 inhibition are most commonly observed in the skin, gastrointestinal tract, liver and endocrine systems and include pruritus, rash, nausea, diarrhoea and thyroid disorders. In this Review, the authors describe the adverse event profile of checkpoint inhibitors targeting CTLA-4 and PD-1, used both as monotherapies and in combination and aim to provide some general guidelines, based upon the mechanisms of action of these therapies and on the management of these immune-related adverse events.
Gut microbiota composition influences the clinical benefit of immune checkpoints in patients with advanced cancer but mechanisms underlying this relationship remain unclear. Molecular mechanism ...whereby gut microbiota influences immune responses is mainly assigned to gut microbial metabolites. Short-chain fatty acids (SCFA) are produced in large amounts in the colon through bacterial fermentation of dietary fiber. We evaluate in mice and in patients treated with anti-CTLA-4 blocking mAbs whether SCFA levels is related to clinical outcome. High blood butyrate and propionate levels are associated with resistance to CTLA-4 blockade and higher proportion of Treg cells. In mice, butyrate restrains anti-CTLA-4-induced up-regulation of CD80/CD86 on dendritic cells and ICOS on T cells, accumulation of tumor-specific T cells and memory T cells. In patients, high blood butyrate levels moderate ipilimumab-induced accumulation of memory and ICOS + CD4 + T cells and IL-2 impregnation. Altogether, these results suggest that SCFA limits anti-CTLA-4 activity.
Diet composition has long been suspected to contribute to inflammatory bowel disease (IBD), but has not been thoroughly assessed, and has been assessed only in retrospective studies that are prone to ...recall bias. The aim of the present study was to evaluate the role of dietary macronutrients in the etiology of IBD in a large prospective cohort.
The Etude Épidémiologique des femmes de la Mutuelle Générale de l'Education Nationale cohort consists of women living in France, aged 40-65 years, and free of major diseases at inclusion. A self-administered questionnaire was used to record dietary habits at baseline. Questionnaires on disease occurrence and lifestyle factors were completed every 24 months. IBDs were assessed in each questionnaire until June 2005, and subsequently validated using clinical and pathological criteria. We estimated the association between nutrients or foods and IBD using Cox proportional hazards models adjusted for energy intake.
Among 67,581 participants (705,445 person-years, mean follow-up since completion of the baseline dietary questionnaire 10.4 years), we validated 77 incident IBD cases. High total protein intake, specifically animal protein, was associated with a significantly increased risk of IBD, (hazards ratio for the third vs. first tertile and 95% confidence interval being 3.31 and 1.41-7.77 (P trend=0.007), and 3.03 and 1.45-6.34 (P trend=0.005) for total and animal protein, respectively). Among sources of animal protein, high consumption of meat or fish but not of eggs or dairy products was associated with IBD risk.
High protein intake is associated with an increased risk of incident IBD in French middle-aged women.
To describe drug prescription for gastrointestinal symptoms during pregnancy.
Using the French national health database, we identified pregnancies ending with a birth between April 2010 and December ...2018, in France. We studied prescription of antacids, antispasmodics, antinauseants, laxatives and antidiarrheals during pregnancy, between two trimesters before and two trimesters after delivery. We also assessed hospitalization for gastrointestinal symptoms during pregnancy.
Among 6,365,471 pregnancies, 4,452,779 (74.0%) received at least one gastrointestinal drug during pregnancy; 2,228,275 (37.0%) received an antacid, 3,096,858 (51.5%) an antispasmodic, 1,861,731 (31.0%) an antinauseant, 919,116 (15.3%) a laxative and 617,808 (10.3%) an antidiarrheal. Prescription of proton pump inhibitors doubled from 12.2% in 2010 to 26.0% in 2018, while domperidone use decreased from 18.3% in 2010 to 2.2% in 2018. In addition, prescription of antacids increased from 7.0% during the trimester before pregnancy to 11.8% during the 1st trimester, 17.0% during the 2nd trimester and 23.4% during the 3rd trimester. Antispasmodic use was 10.6% during the trimester before pregnancy, 23.1% during the 1st trimester, 25.2% during the 2nd trimester and 24.0% during the 3rd trimester. Prescription of antinauseant drugs increased from 5.0% during the trimester before pregnancy to 25.7% during the 1st trimester, then decreased to 6.4% during the 2nd trimester and 3.2% during the 3rd trimester. Nausea/vomiting was the most common cause of hospitalization for gastrointestinal symptoms or diseases during pregnancy, although it accounted for only 1.0% of pregnancies.
Approximately three-quarters of women use drugs for gastrointestinal symptoms during pregnancy in France. Prescription of gastrointestinal drugs during pregnancy should be the subject of more detailed risk-benefit assessment and recommendations.
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DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Background & Aims Immunomodulator therapy is effective for patients with Crohn’s disease (CD) but has not been shown to affect disease progression, presumably because it is given too late after ...diagnosis. We compared the efficacy of early treatment (within 6 months after diagnosis) with azathioprine versus conventional management of patients at high risk for disabling disease. Methods We performed an open-label trial of adults with a diagnosis of CD for less than 6 months who were at risk for disabling disease. From July 2005 to November 2010, patients at 24 French centers were randomly assigned to treatment with azathioprine (2.5 mg ∙ kg−1 ∙ day−1 , n = 65) or conventional management (azathioprine only in cases of corticosteroid dependency, chronic active disease with frequent flares, poor response to corticosteroids, or development of severe perianal disease) (n = 67). The primary end point was the proportion of trimesters spent in corticosteroid-free and anti–tumor necrosis factor (TNF)—free remission during the first 3 years after inclusion. Results During the 3-year follow-up period, 16 patients in the azathioprine group were switched to mercaptopurine or methotrexate therapy because of intolerance or poor efficacy. Forty-one patients in the conventional management group required immunosuppressant therapy (61%; median time to first prescription, 11 months). In the azathioprine group, a median 67% of trimesters were spent in remission (interquartile range, 11%–85%) compared with 56% in the conventional management group (interquartile range, 29%–73%) ( P = .69). Among secondary outcomes, a higher cumulative proportion of patients in the azathioprine group were free of perianal surgery than in the conventional management group (96% ± 3% and 82% ± 6% at month 36, respectively; P = .036). The cumulative proportion of patients free of intestinal surgery and anti-TNF therapy did not differ between groups. Conclusions Based on results from a clinical trial, administration of azathioprine within 6 months of diagnosis of CD was no more effective than conventional management in increasing time of clinical remission. Clinicaltrials.gov , Number NCT00546546.
To estimate the systemic serious adverse event (SAE) rates after colonoscopy and to identify their risk factors.
A nationwide cohort study was conducted using the comprehensive French claims ...databases SNDS (National Health Data System). Patients aged 30 years and over who underwent a first screening or diagnostic colonoscopy in 2010-2015 were included. The rates of cardiovascular and renal SAEs were estimated within 5 days after colonoscopy. The standardized incidence ratios were calculated to compare these incidence rates with those of the same events in the general population, and the associated risk factors were assessed by multilevel logistic regression.
Among the 4,088,799 included patients (median age, 59 years interquartile range = 50-67; 55.2% women; 30.1% with a Charlson index score ≤1), the 5-day SAE incidence rate was 2.8/10,000 procedures for shock, 0.87/10,000 for myocardial infarction, 1.9/10,000 for stroke, 2.9/10,000 for pulmonary embolism, 5.5/10,000 for acute renal failure, and 3.3/10,000 for urolithiasis. These SAEs occurred 3.3 to 15.8 times more often during the first 5 days after colonoscopy than expected in the general population. Thirty-day mortality rates ranged from 2.2/1,000 cases of urolithiasis to 268.1/1,000 cases of shock. Increasing age was associated with an increasing incidence of SAEs. Risks of shock and acute renal failure were associated with a greater number of comorbidities than the other SAEs. Colonoscopies in university hospitals were associated with higher risks, reflecting patient selection processes.
The systemic SAEs can be associated with a substantial mortality. They should be taken into account when deciding colonoscopy, in addition to perforation and bleeding, particularly in elderly patients with multiple comorbidities.
Summary Background Ciclosporin and infliximab are potential rescue treatments to avoid colectomy in patients with acute severe ulcerative colitis refractory to intravenous corticosteroids. We ...compared the efficacy and safety of these drugs for this indication. Methods In this parallel, open-label, randomised controlled trial, patients were aged at least 18 years, had an acute severe flare of ulcerative colitis defined by a Lichtiger score greater than 10 points, and had been given an unsuccessful course of high-dose intravenous steroids. None of the patients had previously received ciclosporin or infliximab. Between June 1, 2007, and Aug 31, 2010, patients at 27 European centres were randomly assigned (via computer-derived permutation tables; 1:1) to receive either intravenous ciclosporin (2 mg/kg per day for 1 week, followed by oral drug until day 98) or infliximab (5 mg/kg on days 0, 14, and 42). In both groups, azathioprine was started at day 7 in patients with a clinical response. Neither patients nor investigators were masked to study treatment. The primary efficacy outcome was treatment failure defined by absence of a clinical response at day 7, a relapse between day 7 and day 98, absence of steroid-free remission at day 98, a severe adverse event leading to treatment interruption, colectomy, or death. Analysis was by intention to treat. This trial is registered with EudraCT (2006-005299-42) and ClinicalTrials.gov ( NCT00542152 ). Findings 115 patients were randomly assigned; 58 patients were allocated to receive ciclosporin and 57 to receive infliximab. Treatment failure occurred in 35 (60%) patients given ciclosporin and 31 (54%) given infliximab (absolute risk difference 6%; 95% CI −7 to 19; p=0·52). Nine (16%) patients in the ciclosporin group and 14 (25%) in the infliximab group had severe adverse events. Interpretation Ciclosporin was not more effective than infliximab in patients with acute severe ulcerative colitis refractory to intravenous steroids. In clinical practice, treatment choice should be guided by physician and centre experience. Funding Association François Aupetit, Société Nationale Française de Gastroentérologie, and the International Organization for the study of Inflammatory Bowel Disease.
Immune checkpoint inhibitors (ICIs), such as anti–CTLA-4 and anti–PD-1 antibodies, are effective against several malignancies. They are associated with gastrointestinal immune-related adverse events ...(GI-IrAEs), which may be severe and lead to ICI discontinuation. We assessed the risk of evolution of GI-IrAEs to chronic GI inflammation and the risk of recurrence after a second line of ICI.
This was a single-centre study. Included patients had a GI-IrAE due to ICIs between September 2010 and July 2017. We assessed the persistence of symptoms, endoscopic and/or histological inflammation, and the risk of recurrent GI-IrAEs after the second line of ICIs.
Eighty patients were included. The median follow-up was 8.4 months (0.36–72.3). The median duration of GI symptoms was 1.5 months (5 days–10.3 months): 1.4 months (7 days–4.9 months) with anti–CTLA-4, 2.0 months (5 days–10.3 months) with anti–PD-1 and 1.0 month (8 days–3.4 months) with combination therapy (log-rank test: p = 0.02). Three and 6 months after the beginning of GI-IrAEs, 22% (95% confidence interval: 14%–33%) and 5.4% (2.0%–14.7%) of patients had persistent symptoms, respectively. After a median of 6 months, 20/27 patients had endoscopic and/or histological inflammation, of whom, seven were symptom free. After the first episode, 6/26 patients relapsed after receiving another course of ICIs. Among these 26, 89% (77%–100%) had no recurrence after 3 months, 71% or 95% if the second line was anti–CTLA-4 or anti–PD-1, respectively.
GI-IrAEs seem to be acute or subacute, not chronic. Reintroduction of ICIs is possible in patients who had GI-IrAE.
•Gastrointestinal immune-related adverse events (GI-IrAEs) due to immune checkpoint inhibitors (ICIs) appear time limited:•Seventy-eight percent of patients with GI-IrAEs are symptom free 3 months after the first symptoms.•Symptoms persist longer in those treated with anti–PD-1 than with anti–CTLA-4.•The risk of recurrent GI-IrAEs after ICI reintroduction seems limited:•Eighty-nine percent of patients have no recurrence after 3 months.
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