Subcutaneous Infliximab in Refractory Crohn's Disease Patients: A Possible Biobetter?

Background: A subcutaneous formulation of infliximab (IFX-SC) approved to treat patients with inflammatory bowel disease may offer improved efficacy versus intravenous infliximab. Methods: Patients with refractory Crohn's disease (CD, n = 32) previously treated unsuccessfully with at least 2 biologics were treated with IFX-SC and followed from baseline at Week 0 (W0) to Week 30 (W30). The study's primary endpoint was the treatment's persistence at W30, while secondary goals included the analysis of serum infliximab trough levels (TL IFX), dynamics of anti-IFX antibodies (ATIs), and clinical, serum and fecal markers of CD activity during IFX-SC treatment. Results: Midterm treatment persistence with the continuation of treatment after W30 was 53%. TL IFX median values showed rapid, significant upward dynamics and exceeded 15.5 µg/mL at W30, whereas median ATI levels significantly declined. Among ATI-negative patients at W0 (n = 15), only one showed IFX immunogenicity with newly developed ATIs at W30. Among ATI-positive patients at W0, ATI seroconversion from ATI-positive to ATI-negative status was observed in 10 of 17 patients (58.8%). Patients who had continued IFX-SC treatment at W30 showed significant decreases in C-reactive protein (P = .0341), fecal calprotectin (P = .0002), and Harvey-Bradshaw index (P = .0029) since W0. Conclusions: Patients with refractory CD previously treated with at least 2 biologics exhibited clinically relevant improvement with IFX-SC, which showed less immunogenic potential than IFX-IV and highly stable TL IFX.

Early Ultrasound Response and Progressive Transmural Remission After Treatment With Ustekinumab in Crohn's Disease.

BACKGROUND & AIMS: In this STARDUST substudy, the effect of ustekinumab on transmural bowel inflammation was assessed in adults with moderate-to-severe Crohn's disease (CD) by using intestinal ultrasound (IUS), a noninvasive imaging procedure. METHODS: STARDUST was an international, multicenter, phase 3b, interventional, randomized controlled trial specifically designed to compare treat-to-target and standard-of-care treatment strategies in ustekinumab-treated CD patients. In this substudy, the most affected bowel segment at baseline by IUS was used for all analyses. Key IUS endpoints (centrally read, parameter-blinded) were IUS response, transmural remission, bowel wall thickness (BWT), blood flow, bowel wall stratification, and inflammatory fat. RESULTS: Seventy-seven patients were evaluated. IUS response could be determined 4 weeks after treatment initiation, with progressive improvement through week 48. IUS response and transmural remission rates at week 48 were 46.3% and 24.1%, respectively. IUS response, transmural remission, BWT, and blood flow normalization rates were more pronounced in the colon and biologic-naive patients. Fair/moderate reliability (κ = 0.21-0.51) was observed between week 4 IUS response and week 48 overall endoscopic response and fecal calprotectin/complete biomarker outcomes. Endoscopy and IUS baseline agreement was >90% in determining the terminal ileum as the most affected bowel segment. IUS response absence at week 4 was associated with no endoscopic response (based on the simplified endoscopic score for Crohn's disease terminal ileum subscore) at week 48 (negative predictive value = 73%). CONCLUSIONS: In this first international, multicenter, interventional study, IUS showed that ustekinumab-treated CD patients achieved progressive IUS response (46.3%) and transmural remission (24.1%) through week 48, with a more robust response in the colon and biologic-naive patients. CLINICALTRIALS: gov number: NCT03107793.

Cellular and Humoral Immune Responses to SARS-CoV-2 Vaccination in Inflammatory Bowel Disease Patients.

BACKGROUND AND AIMS: Knowledge on the immunogenicity of anti-SARS-CoV-2 vaccines in inflammatory bowel disease [IBD] patients is limited. Therefore, SARS-CoV-2-specific T-cell responses and antibodies were analysed in 60 IBD vaccine recipients and 30 controls. METHODS: SARS-CoV-2 IgG antibodies against the viral spike protein were measured at baseline and at 8 and 26 weeks after the second vaccine dose. SARS-CoV-2 IgG antibodies against the nucleocapsid antigens were measured at week 26. A SARS-CoV-2 interferon-gamma released assay [IGRA] was performed in all vaccinees at week 26. RESULTS: At weeks 0 and 8, no differences were found in anti-spike antibodies between cohorts. At week 26, the decrease in antibody levels was more significant in the IBD cohort compared to the healthy cohort, and anti-nucleocapsid antibodies were not detected in either group. At week 26, 16 of 90 [18%] vaccinated individuals had a negative IGRA test result, seven of 90 [8%] were borderline and 67 [74%] had a positive IGRA result; 22 of the 23 individuals with negative or borderline IGRA results belonged to the IBD cohort. However, the overall functional ability of T-lymphocytes to produce interferon-gamma after the unspecific mitogen stimulation was lower in IBD patients. In vaccinated individuals with low or borderline IGRA, treatment with tumour necrosis factor-alpha inhibitors was the most frequent. In individuals with a significant drop in anti-spike antibody levels, plasmatic interferon-gamma concentrations after the specific SARS-CoV-2 stimulation were also insufficient. CONCLUSIONS: Simple humoral and cellular post-vaccination monitoring is advisable in IBD patients so that repeated vaccine doses may be scheduled.

Anti-SARS-CoV-2 Vaccination and Antibody Response in Patients With Inflammatory Bowel Disease on Immune-modifying Therapy: Prospective Single-Tertiary Study.

BACKGROUND: Patients with inflammatory bowel disease (IBD) on immune-modifying treatment could be at an increased risk for severe coronavirus disease 2019 (COVID-19); thus, data on the efficacy and safety of severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) vaccines are essential. We conducted a prospective study of IBD patients vaccinated with BNT162b2, CX-024414, and ChAdOx1 nCoV-19 vaccines. The aim was to evaluate the rate and magnitude of seroconversion, assess the effect of different immune-modifying treatment modalities on the magnitude of anti-SARS-CoV-2 IgG antibody levels, and analyze the impact of anti-SARS-CoV-2 vaccination on the inflammatory biomarkers of IBD. METHODS: The study included 602 IBD patients and 168 immunocompetent health care workers serving as controls. Serum anti-SARS-CoV-2 IgG antibodies were measured by chemiluminescent microparticle immunoassay before the vaccination and 8 weeks after the vaccination. RESULTS: Of IBD patients, 82.2% were receiving biological treatment: most of them were treated with antitumor necrosis factor (TNF)-α inhibitors (48.5%), and just under half of them were treated with concomitant thiopurines or methotrexate, followed by vedolizumab (18.6%) and ustekinumab (15.1%). Only 8.1% of patients were on 5-aminosalicylates, and a minority (2.2%) were treatment-free. The postvaccine seropositivity rate among IBD patients and controls was 97.8% vs 100%. Median anti-SARS-CoV-2 IgG levels were lower among IBD recipients of ChAdOx1 nCoV-19 compared with 2 other vaccines (P < .0001) and control ChAdOx1 nCoV-19 recipients (P = .01). No correlation was found between serum trough levels and anti-SARS-CoV-2 IgG concentrations for any of the biological drugs used. The TNF-α inhibitors with concomitant immunosuppressive treatment but no other treatment modalities were associated with a lower postvaccination antibody response (P < .0001). When evaluating the laboratory activity of IBD by C-reactive protein and fecal calprotectin levels, no significant differences were found before the vaccination and 8 weeks after its completion. CONCLUSIONS: Our findings warrant particular attention to the anti-SARS-CoV-2 vaccination of IBD patients treated with TNF-α inhibitors with concomitant immunomodulators and show the priority of mRNA vaccines in this specific group of patients.

Safety of Anti-TNF-Alpha Therapy During Pregnancy on Long-term Outcome of Exposed Children: A Controlled, Multicenter Observation.

BACKGROUND: Evidence of the impact of in utero exposure to anti-tumor necrosis factor (TNF)-alpha on long-term childhood development is limited. The aim was to assess the impact of in utero exposure to anti-TNF-alpha due to mothers' inflammatory bowel disease (IBD) on long-term postnatal development of exposed children. METHODS: We included consecutive children (≥12 months of age) born to mothers with IBD (2007-2016) treated with anti-TNF-alpha during pregnancy in 3 centers in the Czech Republic. A control group was comprised of unexposed children of non-IBD mothers undergoing mandatory check-ups at general pediatricians' offices. Data on perinatal period, psychomotor development, vaccination, infections, antibiotics, and allergy were collected by treating pediatricians using a predefined questionnaire. RESULTS: Seventy-two exposed and 69 unexposed children were included (median age, 35 and 50 months, respectively). Exposed children had growth and psychomotor development similar to controls. There was no significant difference in infectious complications within the first year of life (23.9% vs 17.4%; P = 0.36) or during the whole follow-up between exposed infants and controls (P = 0.32). Concomitant immunosuppressants during pregnancy and anti-TNF-alpha levels in cord blood were not associated with elevated infection rate within the first year of life (P > 0.05). Over 95% of exposed children had adequate serologic response to vaccination, except for haemophilus and mumps vaccines. Clinically manifested allergy was similar between the groups (P = 0.98). CONCLUSIONS: Anti-TNF-alpha exposure in utero does not seem to have a negative impact on postnatal development of children with regard to infectious complications, allergy, growth, or psychomotor development when compared with unexposed children of non-IBD women.

Pentane and other volatile organic compounds, including carboxylic acids, in the exhaled breath of patients with Crohn's disease and ulcerative colitis.

A study has been carried out on the volatile organic compounds (VOCs) in the exhaled breath of patients suffering from inflammatory bowel disease (IBD), comprising 136 with Crohn's disease (CD) and 51 with ulcerative colitis (UC), together with a cohort of 14 healthy persons as controls. Breath samples were collected by requesting the patients to inflate Nalophan bags, which were then quantitatively analysed using selected ion flow tube mass spectrometry (SIFT-MS). Initially, the focus was on n-pentane that had previously been quantified in single exhalations on-line to SIFT-MS for smaller cohorts of IBD patients. It was seen that the median concentration of pentane was elevated in the bag breath samples of the IBD patients compared to those of the healthy controls, in accordance with the previous study. However, the absolute median pentane concentrations in the bag samples were about a factor of two lower than those in the directly analysed single exhalations-a good illustration of the dilution of VOCs in the samples of breath collected into bags. Accounting for this dilution effect, the concentrations of the common breath VOCs, ethanol, propanol, acetone and isoprene, were largely as expected for healthy controls. The concentrations of the much less frequently measured hydrogen sulphide, acetic acid, propanoic acid and butanoic acid were seen to be more widely spread in the exhaled breath of the IBD patients compared to those for the healthy controls. The relative concentrations of pentane and these other VOCs weakly correlate with simple clinical activity indices. It is speculated that, potentially, hydrogen sulphide and these carboxylic acids could be exhaled breath biomarkers of intestinal bacterial overgrowth, which could assist therapeutic intervention and thus alleviate the symptoms of IBD.

Efficacy of Infliximab Biosimilar CT-P13 Induction Therapy on Mucosal Healing in Ulcerative Colitis.

INTRODUCTION: CT-P13 is the first biosimilar to infliximab that has been approved for the same indications as its originator infliximab. No data are available on the effect of infliximab biosimilar on mucosal healing. The aim of this study was to evaluate the efficacy of CT-P13 induction therapy on mucosal healing in patients with ulcerative colitis [UC]. PATIENTS AND METHODS: UC patients, who received CT-P13 therapy from its local introduction at three Hungarian and one Czech inflammatory bowel disease centres, were prospectively enrolled. Sigmoidoscopy was performed after the end of the induction therapy at week 14. Mucosal healing was defined as Mayo endoscopic subscore 0 or 1. Complete mucosal healing was defined as Mayo endoscopic subscore 0. Trough level of CT-P13 was measured at week 14. RESULTS: Sixty-three UC patients who underwent CT-P13 induction therapy were enrolled in the study. Indication for the therapy was acute, severe flare up and chronic, refractory activity in 24 and 39 patients, respectively. Cumulative clinical response and steroid-free remission at week 14 were achieved in 82.5% and 47.6% of the patients, respectively. Sigmoidoscopy revealed steroid-free mucosal healing in 47.6% of the patients, and complete mucosal healing was present in 27%. Mayo endoscopic subscore decreased significantly at week 14 compared to baseline. Trough levels of infliximab correlated with mucosal healing. CONCLUSION: This is, to our knowledge, the first study examining the efficacy of CT-P13 induction therapy on mucosal healing in UC. The results indicate that mucosal healing is achieved in two-thirds of UC patients by the end of the induction treatment with CT-P13.

Serum trough infliximab levels: A comparison of three different immunoassays for the monitoring of CT-P13 (infliximab) treatment in patients with inflammatory bowel disease.

BACKGROUND: CT-P13 is a biosimilar drug of reference infliximab and is approved in some countries for use in some indications for which reference infliximab is approved, including inflammatory bowel disease (IBD). The CT-P13 formulation is identical to that of reference infliximab and has similar physiochemical characteristics. However, even a small molecular distinction could lead to different behavior of CT-P13 in immunoanalytical detection systems. AIM: To determine the correlation between three different enzyme-linked immunosorbent assays for infliximab detection in the measurement of CT-P13 trough serum levels. METHODS: Serum samples (n = 42) from IBD patients (n = 22) treated with CT-P13 Remsima™ (Celltrion, Korea) were evaluated in a blinded way in infliximab assays manufactured by (A) Matriks Biotek (Turkey), (B) Theradiag (France), and (C) R-Biopharm (Germany). RESULTS: All assays showed excellent qualitative correlation (Cohen's kappa = 0.90 for A vs. B, 0.76 for A vs. C, and 0.83 for B vs. C). A linear quantitative correlation was satisfactory as well (Spearman's r = 0.91 for A vs. B, 0.86 for A vs. C and 0.92 for B vs. C). Assay C did not detect CT-P13 in 6 samples detected by A and/or B. CONCLUSION: There is a good correlation of CT-P13 serum level detection between these assays.

Discontinuation of anti-tumor necrosis factor therapy in inflammatory bowel disease patients: a prospective observation.

BACKGROUND: Discontinuation of anti-TNF therapy in patients with inflammatory bowel diseases (IBD) in remission remains a controversial issue. The aims of our study were to assess the proportion of patients who relapse after cessation of biological treatment, and to identify potential risk factors of disease relapse. METHODS: Consecutive IBD patients who discontinued anti-TNF therapy in steroid-free clinical and endoscopic remission were prospectively followed. Multiple logistic regression and Cox proportional-hazards models were used to assess the predictors of disease relapse. RESULTS: Seventy-eight IBD patients (Crohn's disease, CD 61; ulcerative colitis, UC 17) were included and followed for a median of 30 months (range 7-47). A total of 32 (53%) CD patients and nine (53%) UC patients relapsed by the end of the follow-up with a median time to relapse of 8 months (range 1-25) in CD patients and 14 months (range 4-37) in UC patients, respectively. The cumulative probabilities of maintaining remission at 6, 12, and 24 months were 82%, 59%, and 51% in CD patients, and 77%, 77%, and 64% in UC patients, respectively. Survival of CD patients who were in deep remission (clinical and endoscopic healing; faecal calprotectin <150 mg/kg; CRP ≤5 mg/l) was not better compared with those who did not fulfill these criteria. In multivariate models, only colonic CD protected patients from disease relapse. CONCLUSIONS: Approximately half of the IBD patients relapsed within 2 years after anti-TNF discontinuation. In CD patients, no difference between those who were or were not in deep remission was found. Colonic localization protected patients from relapse.

Impact of anti-tumor necrosis factor alpha antibodies administered to pregnant women with inflammatory bowel disease on long-term outcome of exposed children.

BACKGROUND: Prenatal exposure to anti-tumor necrosis factor α (TNF-α) antibodies seems to be safe for fetal development. Data on long-term outcome of exposed children are missing. Our aim was to assess long-term postnatal development of children exposed to anti-TNF-α during pregnancy. METHODS: Consecutive children aged ≥ 12 months exposed to anti-TNFs prenatally for maternal inflammatory bowel disease in 3 centers in the Czech Republic were enrolled. Data on psychomotor development, infections, antibiotics, vaccination, and allergy were retrospectively obtained from mothers, treating pediatricians, and children's vaccination cards. Furthermore, standardized laboratory tests on humoral and cellular immunity were performed. RESULTS: Twenty-five children exposed to biologicals were included (median age, 34 mo; range, 14-70 mo). All children had normal growth, and all but 1 had normal psychomotor development. Majority (80%) experienced at least 1 infection (mainly respiratory), and 60% of infants received antibiotics, 32% of those within the first year of life. Vaccination was undertaken according to vaccination protocol to 23 infants (92%). Fifteen children also had tuberculosis vaccination without serious complication. Immunological investigation was performed with 17 children (68%). Cellular immunity was normal in all infants, and 7 children had mild decrease in IgA and/or IgG immunoglobulins without clinical significance. All children had a detectable serologic response to vaccination. CONCLUSIONS: Exposure to anti-TNF-α antibodies seems to be safe for growth and psychomotor development of children, although clinical significance of relatively high frequency of infections and antibiotic use among infants remains questionable because of the lack of a control group. Continuous follow-up of exposed children is absolutely warranted.

Quantification of pentane in exhaled breath, a potential biomarker of bowel disease, using selected ion flow tube mass spectrometry.

RATIONALE: Inflammatory bowel disease has a relatively large incidence in modern populations and the current diagnostic methods are either invasive or have limited sensitivity or specificity. Thus, there is a need for new non-invasive methods for its diagnosis and therapeutic monitoring, and breath analysis represents a promising direction in this area of research. Specifically, a method is needed for the absolute quantification of pentane in human breath. METHODS: Selected ion flow tube mass spectrometry (SIFT-MS) has been used to study the kinetics of the O2(+) reaction with pentane. Product ions at m/z 42 and 72 were chosen as characteristic ions useful for the quantification of pentane and the reactivity of these ions with water vapour was characterized. A pilot study has been carried out of pentane in the exhaled breath of patients with Crohn's disease (CD) and ulcerative colitis (UC) and of healthy volunteers. RESULTS: Accurate data on the kinetics of the gas phase reaction of the O2(+•) ions with pentane have been obtained: rate coefficient 8 × 10(-10) cm(3) s(-1) (±5%) and branching ratios into the following product ions C5H12(+•) (m/z 72, 31%); C4H9(+) (m/z 57, 8%); C3H7(+) (m/z 43, 40%), C3H6(+•) (m/z 42, 21%). A method of calculation of absolute pentane concentration in exhaled breath was formulated using the count rates of the ions at m/z 32, 42, 55 and 72. Pentane was found to be significantly elevated in the breath of both the CD (mean 114 ppbv) and the UC patients (mean 84 ppbv) relative to the healthy controls (mean 40 ppbv). CONCLUSIONS: SIFT-MS can be used to quantify pentane in human breath in real time avoiding sample storage. This method of analysis can ultimately form the basis of non-invasive screening of inflammatory processes, including inflammatory bowel disease.

Pregnancy and newborn outcome of mothers with inflammatory bowel diseases exposed to anti-TNF-α therapy during pregnancy: three-center study.

OBJECTIVE: Substantial number of women with inflammatory bowel disease (IBD) conceives while on anti-TNF-α therapy. The aim was to assess the safety and efficacy of anti-TNF-α treatment during pregnancy and to analyze relationship of neonatal and maternal anti-TNF-α levels at delivery with gestational age at the last exposure. MATERIAL AND METHODS: Women with IBD exposed to anti-TNF-α therapy during pregnancy were included. Data on anti-TNF-α treatment, disease activity, concomitant medication, pregnancy and newborn outcome were recorded. Anti-TNF-α levels from cord blood were assessed by ELISA. RESULTS: Forty-one pregnancies (27 Crohn's disease; 14 ulcerative colitis) were exposed to infliximab (IFX; 32) and adalimumab (ADA; 9). Ten (24%) women had active disease at conception and 31 (76%) were in remission with 3 patients experiencing relapse during pregnancy. Anti-TNF-α therapy started prior to and after conception in 32 and 9 women, respectively. There were 34 (83%) live births (median birth weight 3145 g) of which 28 were at-term and 6 preterm deliveries. Five (12%) pregnancies ended in spontaneous and two in therapeutic abortion. No congenital malformations except for one case of hip dysplasia were observed. Similarly, no serious perinatal complication occurred. IFX cord levels measured in 11 children positively correlated with gestational week at the last drug administration and maternal levels at delivery, while no such correlation was found in case of ADA. CONCLUSIONS: The results confirm that anti-TNFs are effective and safe during pregnancy. A positive correlation between IFX cord levels and gestational week of last exposure as well as maternal serum levels was observed.

Infliximab trough levels may predict sustained response to infliximab in patients with Crohn's disease.

BACKGROUND AND AIMS: Over 10% of Crohn's disease (CD) patients annually lose response to infliximab. Infliximab trough levels (TL), concomitant immunosuppressants and endoscopic healing were proposed as predictors of favourable infliximab outcome. We assessed infliximab TL measured after induction therapy as predictors of sustained clinical response. Furthermore, we tried to identify other predictors of long-term benefit of infliximab therapy. METHODS: We included CD patients treated with infliximab between October 2007 and March 2010 who responded to 3-dose induction followed by maintenance therapy and in whom blood samples taken at treatment week 14 or 22 were available in blood bank. Sustained response to infliximab was defined as absence of treatment failure due to loss of response or drug intolerance. RESULTS: Eighty four patients were included. Sustained response to infliximab was observed in 47 (56%) patients during a median follow-up of 25 months (14-37). Infliximab TL>3µg/ml were associated with a decreased risk of treatment failure (HR 0.34; 95% CI: 0.16-0.75), whereas the presence of antibodies against infliximab and need for corticosteroids increased this risk (HR 4.34; 95% CI: 1.51-12.5 and HR 2.49, 95% CI: 1.08-5.73, respectively). No impact of concomitant thiopurines was observed, although patients receiving thiopurines had higher infliximab TL than those without immunomodulators (5.51 vs. 0.71µg/ml; p=0.01). CONCLUSION: During a median follow up of 2 years sustained response to infliximab was observed in slightly more than half of CD patients. Infliximab TL>3µg/ml at the start of maintenance regime were predicative of sustained response to infliximab.

Impaired deoxyribonuclease I activity in patients with inflammatory bowel diseases.

Background and Aims. Deoxyribonuclease I (DNaseI) is an endonuclease that facilitates chromatin breakdown and promotes susceptibility to autoimmune disorders. The aim of current study was to investigate serum DNase I activity in patients with inflammatory bowel diseases (IBD). Patients and Methods. A cohort of 110 IBD patients was evaluated, aged 35 ± 12 years, 77 with Crohn's disease (CD) and 33 with ulcerative colitis (UC). 50 SLE patients and 50 healthy blood donors were examined as control groups. Results. DNase I activity in IBD patients was significantly lower than in healthy individuals, but higher than in SLE patients (P < .0001). Patients with UC showed higher DNase I activity than CD patients, P = .21. DNase I activity in female patients with IBD was significantly lower than in males, P = .024; however, no differences in DNase I activity were found in relation to gender in healthy individuals. DNase I activity has shown a strong negative correlation with the serum concentration of anti-nucleosomal antibodies in the autoimmune (SLE + IBD) cohort, as well as in the separate IBD cohort. Conclusions. Reduced serum DNase I activity probably has pathogenetic consequences in IBD. Induction of autoantibodies towards nucleosomes could be a reflection of impaired DNase I activity.