General obesity has been positively associated with risk of liver and probably with biliary tract cancer, but little is known about abdominal obesity or weight gain during adulthood. We used ...multivariable Cox proportional hazard models to investigate associations between weight, body mass index, waist and hip circumference, waist‐to‐hip and waist‐to‐height ratio (WHtR), weight change during adulthood and risk of hepatocellular carcinoma (HCC), intrahepatic (IBDC) and extrahepatic bile duct system cancer EBDSC including gallbladder cancer (GBC) among 359,525 men and women in the European Prospective Investigation into Cancer and Nutrition study. Hepatitis B and C virus status was measured in a nested case–control subset. During a mean follow‐up of 8.6 years, 177 cases of HCC, 58 cases of IBDC and 210 cases of EBDSC, including 76 cases of GBC, occurred. All anthropometric measures were positively associated with risk of HCC and GBC. WHtR showed the strongest association with HCC relative risk (RR) comparing extreme tertiles 3.51, 95% confidence interval (95% CI): 2.09–5.87; ptrend < 0.0001 and with GBC (RR: 1.56, 95% CI: 1.12–2.16 for an increment of one unit in WHtR). Weight gain during adulthood was also positively associated with HCC when comparing extreme tertiles (RR: 2.48, 95% CI: 1.49–4.13; <0.001). No statistically significant association was observed between obesity and risk of IBDC and EBDSC. Our results provide evidence of an association between obesity, particularly abdominal obesity, and risk of HCC and GBC. Our findings support public health recommendations to reduce the prevalence of obesity and weight gain in adulthood for HCC and GBC prevention in Western populations.
Biopharmaceutical products (BPs) are widely used to treat autoimmune diseases, but immunogenicity limits their efficacy for an important proportion of patients. Our knowledge of patient-related ...factors influencing the occurrence of antidrug antibodies (ADAs) is still limited.
The European consortium ABIRISK (Anti-Biopharmaceutical Immunization: prediction and analysis of clinical relevance to minimize the RISK) conducted a clinical and genomic multicohort prospective study of 560 patients with multiple sclerosis (MS, n = 147), rheumatoid arthritis (RA, n = 229), Crohn's disease (n = 148), or ulcerative colitis (n = 36) treated with 8 different biopharmaceuticals (etanercept, n = 84; infliximab, n = 101; adalimumab, n = 153; interferon IFN-beta-1a intramuscularly IM, n = 38; IFN-beta-1a subcutaneously SC, n = 68; IFN-beta-1b SC, n = 41; rituximab, n = 31; tocilizumab, n = 44) and followed during the first 12 months of therapy for time to ADA development. From the bioclinical data collected, we explored the relationships between patient-related factors and the occurrence of ADAs. Both baseline and time-dependent factors such as concomitant medications were analyzed using Cox proportional hazard regression models. Mean age and disease duration were 35.1 and 0.85 years, respectively, for MS; 54.2 and 3.17 years for RA; and 36.9 and 3.69 years for inflammatory bowel diseases (IBDs). In a multivariate Cox regression model including each of the clinical and genetic factors mentioned hereafter, among the clinical factors, immunosuppressants (adjusted hazard ratio aHR = 0.408 95% confidence interval (CI) 0.253-0.657, p < 0.001) and antibiotics (aHR = 0.121 0.0437-0.333, p < 0.0001) were independently negatively associated with time to ADA development, whereas infections during the study (aHR = 2.757 1.616-4.704, p < 0.001) and tobacco smoking (aHR = 2.150 1.319-3.503, p < 0.01) were positively associated. 351,824 Single-Nucleotide Polymorphisms (SNPs) and 38 imputed Human Leukocyte Antigen (HLA) alleles were analyzed through a genome-wide association study. We found that the HLA-DQA1*05 allele significantly increased the rate of immunogenicity (aHR = 3.9 1.923-5.976, p < 0.0001 for the homozygotes). Among the 6 genetic variants selected at a 20% false discovery rate (FDR) threshold, the minor allele of rs10508884, which is situated in an intron of the CXCL12 gene, increased the rate of immunogenicity (aHR = 3.804 2.139-6.764, p < 1 × 10-5 for patients homozygous for the minor allele) and was chosen for validation through a CXCL12 protein enzyme-linked immunosorbent assay (ELISA) on patient serum at baseline before therapy start. CXCL12 protein levels were higher for patients homozygous for the minor allele carrying higher ADA risk (mean: 2,693 pg/ml) than for the other genotypes (mean: 2,317 pg/ml; p = 0.014), and patients with CXCL12 levels above the median in serum were more prone to develop ADAs (aHR = 2.329 1.106-4.90, p = 0.026). A limitation of the study is the lack of replication; therefore, other studies are required to confirm our findings.
In our study, we found that immunosuppressants and antibiotics were associated with decreased risk of ADA development, whereas tobacco smoking and infections during the study were associated with increased risk. We found that the HLA-DQA1*05 allele was associated with an increased rate of immunogenicity. Moreover, our results suggest a relationship between CXCL12 production and ADA development independent of the disease, which is consistent with its known function in affinity maturation of antibodies and plasma cell survival. Our findings may help physicians in the management of patients receiving biotherapies.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Anti-hypertensive treatment with the angiotensin II receptor antagonist olmesartan is a rare cause of severe Sprue-like enteropathy. To substantiate the hypothesis that olmesartan interferes with gut ...immune homeostasis, clinical, histopathological and immune features were compared in olmesartan-induced-enteropathy (OIE) and in autoimmune enteropathy (AIE).
Medical files of seven patients with OIE and 4 patients with AIE enrolled during the same period were retrospectively reviewed. Intestinal biopsies were collected for central histopathological review, T cell Receptor clonality and flow cytometric analysis of isolated intestinal lymphocytes.
Among seven olmesartan-treated patients who developed villous atrophy refractory to a gluten free diet, three had extra-intestinal autoimmune diseases, two had antibodies reacting with the 75 kilodalton antigen characteristic of AIE and one had serum anti-goblet cell antibodies. Small intestinal lesions and signs of intestinal lymphocyte activation were thus reminiscent of the four cases of AIE diagnosed during the same period. Before olmesartan discontinuation, remission was induced in all patients (7/7) by immunosuppressive drugs. After interruption of both olmesartan and immunosuppressive drugs in six patients, remission was maintained in 4 but anti-TNF-α therapy was needed in two.
This case-series shows that olmesartan can induce intestinal damage mimicking AIE. OIE usually resolved after olmesartan interruption but immunosuppressive drugs may be necessary to achieve remission. Our data sustain the hypothesis that olmesartan interferes with intestinal immuno regulation in predisposed individuals.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
The aims of this study were to describe outcomes in patients with Crohn's disease who fail anti-tumor necrosis factor (TNF) and either vedolizumab or ustekinumab.
Multicenter, retrospective study of ...100 patients with Crohn's disease who failed anti-TNF and either vedolizumab or ustekinumab from 2015 to 2019. Using multivariable Cox regression, we sought to identify factors associated with need for surgery.
75 patients received a third line treatment, resulting in 23 (30.7%) clinical remission at week 48. Among the 71 patients included after vedolizumab failure, 46 received ustekinumab, resulting in 46 (28.3%) clinical remission; 13 patients were retreated with an anti-TNF, resulting in 13 (46.2%) clinical remission. Among the 29 patients included after ustekinumab failure, 12 were retreated with an anti-TNF, resulting in 2 (16.7%) clinical remission. The rate of surgery-free survival at 48 weeks was 76.5% (95% confidence interval 68.4% - 85.4%). In multivariable analysis, ileal disease localization (hazard ratio 9.0, 95% confidence interval 1.0–81.9) was associated with a higher risk of surgery.
In patients with Crohn's disease who have failed anti-TNF and either vedolizumab or ustekinumab, at week 48, the surgery rate is 23.5% and the remission rate after a third line biologic therapy is 30.7%.
The chimeric antibodies anti-CD20 rituximab (Rtx) and anti-TNFα infliximab (Ifx) induce antidrug antibodies (ADAs) in many patients with inflammatory diseases. Because of the key role of CD4 T ...lymphocytes in the initiation of antibody responses, we localized the CD4 T cell epitopes of Rtx and Ifx. With the perspective to anticipate immunogenicity of therapeutic antibodies, identification of the CD4 T cell epitopes was performed using cells collected in healthy donors. Nine T cell epitopes were identified in the variable chains of both antibodies by deriving CD4 T cell lines raised against either Rtx or Ifx. The T cell epitopes often exhibited a good affinity for human leukocyte antigen (HLA)-DR molecules and were part of the peptides identified by MHC-associated peptide proteomics assay from HLA-DR molecules of dendritic cells (DCs) loaded with the antibodies. Two-third of the T cell epitopes identified from the healthy donors stimulated peripheral blood mononuclear cells from patients having developed ADAs against Rtx or Ifx and promoted the secretion of a diversity of cytokines. These data emphasize the predictive value of evaluating the T cell repertoire of healthy donors and the composition of peptides bound to HLA-DR of DCs to anticipate and prevent immunogenicity of therapeutic antibodies.
INTRODUCTION:
The objective of this study was to describe the efficacy and safety of infliximab (IFX) reintroduction in Crohn's disease (CD) after stopping for loss of response or intolerance.
...METHODS:
We conducted a prospective multicenter observational cohort study including adult patients with clinically (CD Activity Index >150) and objectively active luminal CD in whom IFX was reintroduced after at least 6 months of discontinuation. The reasons for the initial discontinuation could be a secondary loss of response or IFX intolerance. The reintroduction schedule included 3 IFX infusions at weeks 0, 4, and 8, after a systematic premedication. The primary end point was the efficacy of IFX retreatment at week 26 defined by a CD Activity Index of <150 in the absence of IFX discontinuation or use of corticosteroids, surgery, or other biologic.
RESULTS:
At week 26, 24 patients (35%) among the 69 analyzed reached the primary end point. No significant difference was observed between rates of clinical remission at week 26 in patients with prior LOR (n = 48) and those with IFX intolerance (n = 21) (35% and 33%,
P
= 0.87, respectively). Thirty-two acute infusion reactions were recorded in 27 patients, leading to withdrawal of IFX in 20 patients. No pharmacokinetic characteristic at baseline but detection of positive anti-drug antibodies at week 4 was predictive of IFX failure or infusion reaction at week 26.
DISCUSSION:
In this first prospective cohort study, IFX retreatment was safe and effective in one-third of the patients with CD, regardless the reason of prior discontinuation. Early detection of anti-drug antibodies can predict subsequent IFX reintroduction failure and infusion reactions.
Background
The Vienna classification of Crohn's disease (CD) distinguishes three patient subgroups according to disease behavior: stricturing, penetrating, and inflammatory. Our aim was to assess the ...long‐term evolution of the disease behavior of CD and to determine the predictive factors and prognostic implications of this evolution.
Methods
Occurrence and predictive factors of a stricturing and/or a penetrating complication were searched for in 2,002 patients with CD studied retrospectively. In addition, the 1995–2000 disease course was assessed prospectively in a cohort of 646 patients with disease duration >5 years, classified according to their previous disease behavior.
Results
1,199 patients (60%) developed a stricturing (n = 254) or a penetrating (n = 945) complication. Twenty‐year actuarial rates of inflammatory, stricturing, and penetrating disease were 12, 18, and 70%, respectively. The initial location of lesions was the main determinant of the time and type of the complication. In the cohort study, year‐by‐year activity and therapeutic requirements did not show significant sustained differences between behavioral subgroups.
Conclusion
Most patients with CD will eventually one day develop a stricturing or a perforating complication. Initial location determines the type of the complication. Classification of patients into a behavioral group from previous history has no impact upon activity during the following years.
Ulcerative colitis (UC) is a chronic inflammatory bowel disease that is thought to affect 1780000 patients in USA and Europe. Its incidence is increasing rapidly in Asia. Drugs with proven clinical ...activity that are currently used in UC patients include salicylates, steroids, azathioprine and infliximab. None of them is active in every patient and all carry significant side effects. There is a need for other active drugs in UC. Low dose methotrexate has been used for decades in psoriasis, rheumatoid arthritis and Crohn's disease. In these diseases, it is an active, well tolerated and cheap drug. In UC there have been several open series, most of which are retrospective. Overall, these studies have shown promising results, with response rates of 50 to 72 %. There have been two randomized clinical trials of methotrexate vs placebo in UC. Both were negative but methotrexate was prescribed orally at suboptimal doses. So far, there is no evidence for the efficacy of methotrexate in UC. Therefore, there is a need for clinical trials with methotrexate using adequate dosage and the parenteral route. Two multicenter randomized trials of methotrexate 25 mg/week parenterally vs placebo are either ongoing (METEOR, the European trial) or being built up (MERIT, the US trial). These trials should determine if methotrexate is a valuable therapeutic option in UC.
Antiprogrammed death-1 (anti-PD1) and antiprogrammed death ligand-1 (anti-PD-L1) antibodies are effective checkpoint inhibitors that stimulate the immune system against many types of cancers. The ...flip side of these immunotherapies is the generation of immune-related adverse events, which can theoretically affect all organs. Among these side effects, lipase increase is frequently observed; however the meaning of this biological abnormality remains poorly understood. We investigate in this case study all the lipase increases greater or equal to grade 2 that occurred in patients receiving anti-PD-1 or anti-PD-L1 treatments, to determine their biological and clinical significance. Twenty-one patients were retained with lipase increase related to the immune checkpoint inhibitor. Most of them (71%) were treated for a metastatic melanoma. The peak of lipase increase was observed at a median of 2.8 (range, 0.4-11.4) months after the initiation of the anti-PD1 or anti-PD-L1 treatment, which correlates with cycle 5 of treatment. Three of 21 patients (14%) had a clinical or radiologic immune-related pancreatitis that led to a permanent discontinuation of the treatment. In 15 of 21 (71%) patients, the lipase increase was not considered as clinically significant, and the treatment was continued without complications. The 3 remaining patients discontinued the treatment for progressive disease. These data indicate that lipase increase related to anti-PD1 or anti-PD-L1 is not associated with a significant clinical event in most cases. On the basis of these data, we propose that lipase increase in an asymptomatic patient and without radiographic abnormalities of the pancreas can be reasonably regarded as a not clinically significant event, allowing the continuation of the anti-PD-1 or anti-PD-L1 treatment.
This study aimed to examine the relationship between diet and cholecystectomy risk, using three approaches, in a large French cohort.
In a prospective cohort study in French women who completed a ...food-frequency questionnaire at baseline, we analyzed diet with three approaches: food groups, dietary patterns obtained by factor analysis, and the Mediterranean diet score. The primary outcome was cholecystectomy. We used Cox proportional hazards regression to assess the relationship between diet and cholecystectomy risk, adjusting for the main potential confounders.
During 1,033,955 person years of follow-up, we identified 2,778 incident cases of cholecystectomy. Higher intakes of legumes, fruit, vegetable oil, and wholemeal bread were associated with decreased cholecystectomy risk. Two dietary patterns were identified by factor analysis: "Western" (essentially processed meat, pizza, pies, high-alcohol beverages, French fries, sandwiches…) and "Mediterranean" (essentially fruits, vegetables, seafood, and olive oil). The "Mediterranean" pattern was inversely associated with cholecystectomy risk in the subgroup of postmenopausal women who ever used menopausal hormone therapy (hazard ratio for quartile 4 vs. 1=0.79, 95% confidence interval (CI): 0.65-0.95; P for linear trend=0.008). High adherence to the Mediterranean diet was associated with decreased risk of cholecystectomy (hazard ratio for a 6-9 score vs. 0-3=0.89, 95% CI: 0.80-0.99; P for linear trend=0.02).
Adherence to a diet rich in fruit, vegetables, legumes, and olive oil was associated with a reduction in cholecystectomy risk in French women. Further studies in different settings are requested.
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