Karin Malickova

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

BACKGROUND AND AIMSnOver 10% of Crohns 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.nnnMETHODSnWe 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.nnnRESULTSnEighty 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).nnnCONCLUSIONnDuring 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.

Significantly higher procalcitonin levels could differentiate Gram-negative sepsis from Gram-positive and fungal sepsis.

Procalcitonin (PCT) levels can distinguish between infectious and non-infectious systemic inflammatory response. However, there are some differences between Gram-negative (G−), Gram-positive (G+), and fungal bloodstream infections, particularly in different cytokine profiles, severity and mortality. The aim of current study was to examine whether PCT levels can serve as a distinguishing mark between G+, G−, and fungal sepsis as well. One hundred and sixty-six septic patients with positive blood cultures were examined on C-reactive protein (CRP) and PCT on the same date of blood culture evaluation. The median (interquartile range, IQR) of CRP and PCT in G+, G−, and fungal cohorts and comparison of measured values between groups were made using the Kruskal–Wallis test with subsequent Bonferroni’s corrections, with pxa0<xa00.05. In 83/166 (50xa0%) of blood cultures, G+ microbes, 78/166 (47xa0%) G− rods, and 5/166 (3xa0%) fungi were detected. PCT concentrations (ng/ml) were significantly higher in G− compared to other cohorts: 8.90 (1.88; 32.60) in G−, 0.73 (0.22; 3.40) in G+, and 0.58 (0.35; 0.73) in fungi (pxa0<xa00.00001). CRP concentrations did not differ significantly in groups. Significantly higher PCT levels could differentiate G− sepsis from G+ and fungemia. In contrast to CRP, PCT is a good discriminative biomarker in different bloodstream infections.

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 &agr; (TNF-&agr;) 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-&agr; 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 childrens 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-&agr; 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.

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

Abstract 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 Crohns 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.

Marked increase of procalcitonin after the administration of anti-thymocyte globulin in patients before hematopoietic stem cell transplantation does not indicate sepsis: a prospective study.

IntroductionProcalcitonin (PCT) and C-reactive protein (CRP) are established markers of infection in the general population. In contrast, several studies reported falsely increased PCT levels in patients receiving T-cell antibodies. We evaluated the validity of these markers in patients scheduled for hemopoietic stem cell transplantation receiving anti-thymocyte globulin (ATG) during conditioning. We also assessed renal and liver functions and their relationship to PCT and CRP changes.MethodsTwenty-six patients without clinical signs of infection were prospectively studied. ATG was administered in up to three doses over the course of 5 days. PCT, CRP, white blood cell (WBC) count, urea, creatinine, glomerular filtration rate, bilirubin, alanin amino-transferase (ALT), and gamma-glutamyl transferase (GGT) were assessed daily during ATG administration. Pharyngeal, nose, and rectal swabs and urine samples were cultured twice weekly. Blood cultures were obtained if clinical symptoms of infection were present.ResultsBaseline (BL) levels of both PCT and CRP before ATG administration were normal. WBC count decreased after ATG administration (P = 0.005). One day after ATG administration, both PCT and CRP levels increased significantly, returning to BL levels on day 4. Microbiological results were clinically unremarkable. There was no interrelationship between PCT levels and BL markers of renal or liver functions (P > 0.05 for all comparisons). Bilirubin and GGT were increased on days 2 to 5 and ALT was increased on day 3 (P < 0.05 versus BL). No difference in renal functions was observed. Three patients developed bacterial infection on days 7 to 11 with different dynamics of PCT and CRP. There was no association between the number of ATG doses and PCT levels or between the risk of developing infection and previous PCT levels.ConclusionsATG triggered a marked early surge in PCT and CRP followed by a steady decrease over the course of 3 days. The dynamics of both PCT and CRP were similar and were not associated with infection. PCT levels were independent of renal and liver functions and were not predictive of further infectious complications. A direct effect of ATG on T lymphocytes could be the underlying mechanism. Hepatotoxic effect could be a contributing factor. Neither PCT nor CRP is a useful marker that can identify infection in patients receiving ATG.

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

BACKGROUNDnCT-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.nnnAIMnTo determine the correlation between three different enzyme-linked immunosorbent assays for infliximab detection in the measurement of CT-P13 trough serum levels.nnnMETHODSnSerum samples (nxa0=xa042) from IBD patients (nxa0=xa022) 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).nnnRESULTSnAll assays showed excellent qualitative correlation (Cohens kappaxa0=xa00.90 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 (Spearmans rxa0=xa00.91 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.nnnCONCLUSIONnThere is a good correlation of CT-P13 serum level detection between these assays.

Detection of galectin-3 in patients with inflammatory bowel diseases: new serum marker of active forms of IBD?

ObjectiveIt is an open question whether multifunctional galectin-3 can be a serum marker in inflammatory bowel disease.MethodsWestern blots and commercial ELISA detected and quantitated the lectin immunocytochemistry using double labeling localized it in tissue sections.ResultsSerum concentrations were significantly increased in specimen of patients with active and remission-stage ulcerative colitis and Crohn’s disease, associated with emerging positivity of CD14+ cells.ConclusionEnhanced concentration of galectin-3 in serum reflects presence of disease and points to its involvement in the pathogenesis.

Substantially elevated C-reactive protein (CRP), together with low levels of procalcitonin (PCT), contributes to diagnosis of fungal infection in immunocompromised patients

PurposeSerum procalcitonin (PCT) has become a routinely utilized parameter with a high prediction value of the severity of bacterial infectious complications and their immediate outcomes. Whereas the utility of PCT in differentiating between bacterial and viral infection is generally accepted, its significance in fungal infections has yet to be determined. The aim of the study was to determine the role of PCT testing in patients at high risk for invasive fungal infections.MethodsImmunocompromised hematological patients undergoing cyclic chemotherapy treatment or allogeneic hemopoietic stem cell transplantation with infectious complications in which the infectious agents were identified during the disease course were evaluated. In patients with bacterial infection, positive hemocultures were documented, and in patients with fungal infection, the presence of either proven or probable disease was confirmed according to Ascioglu criteria. C-reactive protein (CRP) and PCT were prospectively assessed from the day following fever onset, for four consecutive days.ResultsOverall, 34 patients were evaluated, 21 with bacterial and 13 with fungal infections. Significant elevations of CRP concentrations (i.e., above the upper normal limit) were observed in all patients, with a tendency toward higher levels in bacterial (both gram-positive [Gr+] and Gr-negative [Gr−]) than in fungal infections. PCT levels were significantly elevated in patients with bacterial infections (e.g., predominantly in Gr− compared to Gr+), whereas in patients with fungal infections, we identified minimal or no PCT elevations, pu2009<u20090.01. For the fungal infections, according to constructed receiver operating characteristic curves, a combination of PCT <0.5xa0μg/L and CRP 100–300xa0mg/L offers the best specificity, sensitivity and positive and negative predictive values (81, 85, 73, and 89xa0%, respectively).ConclusionAltogether, our data suggest that the finding of substantially elevated CRP combined with low PCT in immunocompromised patients may indicate systemic fungal infection. The use of this combination might simplify the diagnostic process, which otherwise can often be lengthy and arduous.

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 Crohns disease (CD) and 33 with ulcerative colitis (UC). 50u2009SLE 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.

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

Abstract 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 (Crohns 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 <150u2009mg/kg; CRP ≤5u2009mg/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.