Abstract
Background
Inflammatory bowel disease (IBD) comprises a group of chronic conditions characterized by relapsing and remitting inflammation of the gastrointestinal tract. The incidence is ...increasing worldwide, and the therapeutic options for management are expanding. Endoscopy is the gold standard investigation for diagnosis of IBD and for assessing mucosal healing, which is increasingly being used as a measure of disease control. However, it is an invasive procedure that is unpleasant for patients and expensive and time-consuming for hospitals. Fecal calprotectin has been shown to be an accurate surrogate marker of gastrointestinal inflammation in IBD.
Content
Fecal calprotectin was initially used for the diagnosis of IBD but is now recognized as having a role in assisting in assessment of disease activity, prediction of relapse, and informing decisions around therapy and may help to minimize requirement for endoscopy. However, there are various preanalytical and analytical factors that can affect interpretation of the results; these need to be understood to optimize clinical care.
Summary
Preanalytical and analytical factors that can potentially influence fecal calprotectin concentrations are examined, and an overview is provided of clinical situations in which fecal calprotectin is commonly measured.
Delayed second dose SARS-CoV-2 vaccination trades maximal effectiveness for a lower level of immunity across more of the population. We investigated whether patients with inflammatory bowel disease ...treated with infliximab have attenuated serological responses to a single dose of a SARS-CoV-2 vaccine.
Antibody responses and seroconversion rates in infliximab-treated patients (n=865) were compared with a cohort treated with vedolizumab (n=428), a gut-selective anti-integrin α4β7 monoclonal antibody. Our primary outcome was anti-SARS-CoV-2 spike (S) antibody concentrations, measured using the Elecsys anti-SARS-CoV-2 spike (S) antibody assay 3-10 weeks after vaccination, in patients without evidence of prior infection. Secondary outcomes were seroconversion rates (defined by a cut-off of 15 U/mL), and antibody responses following past infection or a second dose of the BNT162b2 vaccine.
Geometric mean (SD) anti-SARS-CoV-2 antibody concentrations were lower in patients treated with infliximab than vedolizumab, following BNT162b2 (6.0 U/mL (5.9) vs 28.8 U/mL (5.4) p<0.0001) and ChAdOx1 nCoV-19 (4.7 U/mL (4.9)) vs 13.8 U/mL (5.9) p<0.0001) vaccines. In our multivariable models, antibody concentrations were lower in infliximab-treated compared with vedolizumab-treated patients who received the BNT162b2 (fold change (FC) 0.29 (95% CI 0.21 to 0.40), p<0.0001) and ChAdOx1 nCoV-19 (FC 0.39 (95% CI 0.30 to 0.51), p<0.0001) vaccines. In both models, age ≥60 years, immunomodulator use, Crohn's disease and smoking were associated with lower, while non-white ethnicity was associated with higher, anti-SARS-CoV-2 antibody concentrations. Seroconversion rates after a single dose of either vaccine were higher in patients with prior SARS-CoV-2 infection and after two doses of BNT162b2 vaccine.
Infliximab is associated with attenuated immunogenicity to a single dose of the BNT162b2 and ChAdOx1 nCoV-19 SARS-CoV-2 vaccines. Vaccination after SARS-CoV-2 infection, or a second dose of vaccine, led to seroconversion in most patients. Delayed second dosing should be avoided in patients treated with infliximab.
ISRCTN45176516.
Both the biology and the therapeutic potential of the phosphoinositide 3-kinase (PI3K) signalling axis have been the subject of intense investigation; however, little is known about the regulation of ...PI3K expression. Emerging evidence indicates that PI3K levels change in response to cellular stimulation with insulin and nuclear receptor ligands, and during various physiological and pathological processes including differentiation, regeneration, hypertension and cancer. Recently identified mechanisms that control PI3K production include increased gene copy number in cancer, and transcriptional regulation of the p110α PI3K gene by FOXO3a, NF-κB and p53, and of the PI3K regulatory subunits by STAT3, EBNA-2 and SREBP. In most instances, however, the impact of alterations in PI3K expression on PI3K signalling and disease remains to be established.
Antitumour necrosis factor (anti-TNF) drugs impair protective immunity following pneumococcal, influenza and viral hepatitis vaccination and increase the risk of serious respiratory infections. We ...sought to determine whether infliximab-treated patients with IBD have attenuated serological responses to SARS-CoV-2 infections.
Antibody responses in participants treated with infliximab were compared with a reference cohort treated with vedolizumab, a gut-selective anti-integrin α4β7 monoclonal antibody that is not associated with impaired vaccine responses or increased susceptibility to systemic infections. 6935 patients were recruited from 92 UK hospitals between 22 September and 23 December 2020.
Rates of symptomatic and proven SARS-CoV-2 infection were similar between groups. Seroprevalence was lower in infliximab-treated than vedolizumab-treated patients (3.4% (161/4685) vs 6.0% (134/2250), p<0.0001). Multivariable logistic regression analyses confirmed that infliximab (vs vedolizumab; OR 0.66 (95% CI 0.51 to 0.87), p=0.0027) and immunomodulator use (OR 0.70 (95% CI 0.53 to 0.92), p=0.012) were independently associated with lower seropositivity. In patients with confirmed SARS-CoV-2 infection, seroconversion was observed in fewer infliximab-treated than vedolizumab-treated patients (48% (39/81) vs 83% (30/36), p=0.00044) and the magnitude of anti-SARS-CoV-2 reactivity was lower (median 0.8 cut-off index (0.2-5.6) vs 37.0 (15.2-76.1), p<0.0001).
Infliximab is associated with attenuated serological responses to SARS-CoV-2 that were further blunted by immunomodulators used as concomitant therapy. Impaired serological responses to SARS-CoV-2 infection might have important implications for global public health policy and individual anti-TNF-treated patients. Serological testing and virus surveillance should be considered to detect suboptimal vaccine responses, persistent infection and viral evolution to inform public health policy.
ISRCTN45176516.
Background & Aims Many patients with inflammatory bowel disease (IBD) fail to respond to anti–tumor necrosis factor (TNF) agents such as infliximab and adalimumab, and etanercept is not effective for ...treatment of Crohn’s disease. Activated matrix metalloproteinase 3 (MMP3) and MMP12, which are increased in inflamed mucosa of patients with IBD, have a wide range of substrates, including IgG1 . TNF-neutralizing agents act in inflamed tissues; we investigated the effects of MMP3, MMP12, and mucosal proteins from IBD patients on these drugs. Methods Biopsy specimens from inflamed colon of 8 patients with Crohn’s disease and 8 patients with ulcerative colitis, and from normal colon of 8 healthy individuals (controls), were analyzed histologically, or homogenized and proteins were extracted. We also analyzed sera from 29 patients with active Crohn’s disease and 33 patients with active ulcerative colitis who were candidates to receive infliximab treatment. Infliximab, adalimumab, and etanercept were incubated with mucosal homogenates from patients with IBD or activated recombinant human MMP3 or MMP12 and analyzed on immunoblots or in luciferase reporter assays designed to measure TNF activity. IgG cleaved by MMP3 or MMP12 and antihinge autoantibodies against neo-epitopes on cleaved IgG were measured in sera from IBD patients who subsequently responded (clinical remission and complete mucosal healing) or did not respond to infliximab. Results MMP3 and MMP12 cleaved infliximab, adalimumab, and etanercept, releasing a 32-kilodalton Fc monomer. After MMP degradation, infliximab and adalimumab functioned as F(ab’)2 fragments, whereas cleaved etanercept lost its ability to neutralize TNF. Proteins from the mucosa of patients with IBD reduced the integrity and function of infliximab, adalimumab, and etanercept. TNF-neutralizing function was restored after incubation of the drugs with MMP inhibitors. Serum levels of endogenous IgG cleaved by MMP3 and MMP12, and antihinge autoantibodies against neo-epitopes of cleaved IgG, were higher in patients who did not respond to treatment vs responders. Conclusions Proteolytic degradation may contribute to the nonresponsiveness of patients with IBD to anti-TNF agents.
Abstract
Background and Aims
Infliximab attenuates serological responses to SARS-CoV-2 infection. Whether this is a class effect, or if anti-tumour necrosis factor anti-TNF level influences ...serological responses, remains unknown.
Methods
Seroprevalence and the magnitude of SARS-CoV-2 nucleocapsid antibody responses were measured in surplus serum from 11 422 (53.3% 6084 male; median age 36.8 years) patients with immune-mediated inflammatory diseases, stored at six therapeutic drug monitoring laboratories between January 29 and September 30, 2020. Data were linked to nationally held SARS-CoV-2 PCR results to July 11, 2021.
Results
Rates of PCR-confirmed SARS-CoV-2 infection were similar across treatment groups. Seroprevalence rates were lower in infliximab- and adalimumab- than vedolizumab-treated patients (infliximab: 3.0% 178/5893, adalimumab: 3.0% 152/5074, vedolizumab: 6.7% 25/375, p = 0.003). The magnitude of SARS-CoV-2 reactivity was similar in infliximab- vs adalimumab-treated patients (median 4.30 cut-off index COI 1.94–9.96 vs 5.02 2.18–18.70, p = 0.164), but higher in vedolizumab-treated patients (median 21.60 COI 4.39–68.10, p < 0.004). Compared to patients with detectable infliximab and adalimumab drug levels, patients with undetectable drug levels <0.8 mg/L were more likely to be seropositive for SARS-CoV-2 antibodies. One-third of patients who had PCR testing prior to antibody testing failed to seroconvert, all were treated with anti-TNF. Subsequent positive PCR-confirmed SARS-CoV-2 was seen in 7.9% 12/152 of patients after a median time of 183.5 days 129.8–235.3, without differences between drugs.
Conclusion
Anti-TNF treatment is associated with lower SARS-CoV-2 nucleocapsid seroprevalence and antibody reactivity when compared to vedolizumab-treated patients. Higher seropositivity rates in patients with undetectable anti-TNF levels support a causal relationship, although confounding factors, such as combination therapy with a immunomodulator, may have influenced the results.
Objectives
Evaluate the management of pregnant women with inflammatory bowel disease.
Method
We collected data from maternity records for women with IBD who gave birth at The Royal London Hospital ...between January 2018 and February 2019.
Results
Twenty-three pregnancies were identified where 8/23 (35%) women had a peri-conception flare and 7/23 (30%) had a flare during pregnancy. Two women received pre-conception counselling. The obstetric medicine team reviewed a patient on average three times and the gastroenterologists twice, during pregnancy. Nine women (39%) gave birth pre-term. Mean birthweight was lower in the group with active disease at conception compared with those in remission (2173 g vs. 2807 g, p = 0.03).
Conclusions
Women with IBD should all receive pre-conception counselling to reduce the risk of pregnancy complications. By developing a multidisciplinary care pathway for pregnant women with IBD (which includes a joint obstetric/gastroenterology clinic), this will ensure care is standardised throughout the pregnancy and puerperium.
Infant health outcomes are a key consideration in decisions regarding therapy for pregnant and breast-feeding women with inflammatory bowel disease (IBD). A recent study by Kanis et al reported ...outcomes from 1000 children born to mothers with IBD (196 exposed to anti-TNFs) with no increased risk of adverse outcomes associated with anti-TNF exposure.1 Anti-TNF therapy should be continued through all trimesters to avoid maternal flares and consequent adverse fetal outcomes.2 3 Discontinuation in the third trimester is not associated with a decrease in infant infection risks.2 As the infant will be exposed to anti-TNF by active placental transfer, live vaccinations for the infant should be delayed to avoid potentially fatal infant outcomes.3
The intestinal mucosa in inflammatory bowel disease (IBD) contains increased frequencies of lymphocytes and a disproportionate increase in plasma cells secreting immunoglobulin (Ig)G relative to ...other isotypes compared to healthy controls. Despite consistent evidence of B lineage cells in the mucosa in IBD, little is known of B cell recruitment to the gut in IBD. Here we analyzed B cells in blood of patients with Crohn's disease (CD) and ulcerative colitis (UC) with a range of disease activities. We analyzed the frequencies of known B cell subsets in blood and observed a consistent reduction in the proportion of CD27
IgD
B cells expressing all Ig isotypes in the blood in IBD (independent of severity of disease and treatment) compared to healthy controls. Successful treatment of patients with biologic therapies did not change the profile of B cell subsets in blood. By mass cytometry we demonstrated that CD27
IgD
B cells were proportionately enriched in the gut-associated lymphoid tissue (GALT) in IBD. Since production of TNFα is a feature of IBD relevant to therapies, we sought to determine whether B cells in GALT or the CD27
IgD
subset in particular could contribute to pathology by secretion of TNFα or IL-10. We found that donor matched GALT and blood B cells are capable of producing TNFα as well as IL-10, but we saw no evidence that CD27
IgD
B cells from blood expressed more TNFα compared to other subsets. The reduced proportion of CD27
IgD
B cells in blood and the increased proportion in the gut implies that CD27
IgD
B cells are recruited from the blood to the gut in IBD. CD27
IgD
B cells have been implicated in immune responses to intestinal bacteria and recruitment to GALT, and may contribute to the intestinal inflammatory milieu in IBD.
Epidemiological associations have implicated factors associated with Westernization, including the Western diet, in the development of inflammatory bowel disease (IBD). The role of diet in IBD ...etiopathogenesis, disease control and symptom management remains incompletely understood. Few studies have collected data on the dietary habits of immigrant populations living with IBD. Our aim was to describe the dietary practices and beliefs of British South Asians with IBD.
A 30-item questionnaire was developed and consecutively administered to 255 British South Asians with IBD attending gastroenterology clinics in the United Kingdom.
Fifty-one percent of participants believed diet was the initiating factor for their IBD and 63% felt diet had previously triggered disease relapse. Eighty-nine percent avoided certain dietary items in the belief that this would prevent relapse. The most commonly avoided foods and drinks were spicy and fatty foods, carbonated drinks, milk products, alcohol, coffee, and red meat. A third of patients had tried a whole food exclusion diet, most commonly lactose- or gluten-free, and this was most frequently reported amongst those with clinically active IBD (P= 0.02). Almost 60% of participants avoided eating the same menu as their family, or eating out, at least sometimes, to prevent IBD relapse.
British South Asians with IBD demonstrate significant dietary beliefs and food avoidance behaviors with increased frequency compared to those reported in Caucasian IBD populations. Studies in immigrant populations may offer valuable insights into the interaction between diet, Westernization and cultural drift in IBD pathogenesis and symptomatology.
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