Health-related quality of life and costs of switching originator infliximab to biosimilar one in treatment of inflammatory bowel disease

Effectiveness, efficacy and safety of biosimilar infliximab (CT-P13) in inflammatory bowel disease (IBD) patients has been shown in previous studies. Limited data exist on health-related quality of life (HRQoL) of switching originator to biosimilar infliximab (IFX) in IBD patients. The objective of this study was to evaluate impact of switching originator to biosimilar IFX on HRQoL, disease activity, and health care costs in IBD maintenance treatment. In this single-center prospective observational study, all IBD patients receiving maintenance IFX therapy were switched to biosimilar IFX. HRQoL was measured using the generic 15D health-related quality of life instrument (15D) utility measurement and the disease-specific Inflammatory Bowel Disease Questionnaire (IBDQ). Crohn Disease Activity Index (CDAI) or Partial Mayo Score (pMayo), and fecal calprotectin (FC) served for evaluation of disease activity. Data were collected at time of switching and 3 and 12 months after switching. Patients' characteristics, clinical background information and costs were collected from patient records and the hospital's electronic database. Fifty-four patients were included in the analysis. No statistically significant changes were observed in 15D, CDAI, pMayo, and FC during 1-year follow-up. IBDQ scores were higher (P = .018) in Crohn disease 3 months after switching than at time of switching. Costs of biosimilar IFX were one-third of costs of originator one. Total costs related to secondary health care (excluding costs of IFX), were similar before and after the onset of biosimilar IFX. HRQoL and disease activity were after switching from originator to biosimilar IFX comparable, but the costs of biosimilar IFX were only one-third of those of the originator one.Peer reviewe

Bacterial and Fungal Profiles as Markers of Infliximab Drug Response in Inflammatory Bowel Disease

Tulehdukselliset suolistosairaudet (IBD) Crohnin tauti (CD) ja haavainen paksusuolentulehdus (UC) ovat maailmanlaajuisesti lisääntyviä sairauksia, joihin liittyy muuntunut suoliston mikrobisto. Infliksimabi (IFX) on TNF-alfan estäjä, jota käytetään IBD:n hoidossa, vaikkakin kolmas osa potilaista voi jäädä ilman hoitovastetta tai menettää sen. Luotettavia testejä hoitovasteen ennustamiseksi ei ole vielä saatavilla. Tutkimuksemme tavoitteena oli selvittää potilaiden ulosteen bakteerit, sienet ja hiivat infliksimabihoidon aikana sekä etsiä hoitovastetta ennustavia mittareita IBD potilailta. Tutkimuksessamme 72 IBD-potilasta (25 CD ja 47 UC) aloitti infliksimabihoidon ja heitä seurattiin vuoden ajan hoidon aloituksesta tai hoidon keskeytykseen saakka. Potilaiden ulostenäytteistä määritettiin sekvensointia hyödyntäen erikseen suoliston bakteerit (16S rRNA geenistä) sekä hiivat ja sienet (ITS1 geenin alueesta). Mikrobiston profiilit määritettiin ennen hoidon aloitusta, 2, 6, 12 viikkoa sekä 1 vuosi hoidon aloituksen jälkeen. IFX hoidon vaste määritettiin kolonoskopialla ja kliinisesti 12 viikon hoidon jälkeen. Tutkimuksessa havaittiin, että potilaiden ulosteen bakteerit sekä sienet ja hiivat erosivat merkittävästi toisistaan infliksimabihoitovasteen mukaan jo ennen hoidon aloitusta. Potilailla, jotka eivät saaneet vastetta hoidosta, oli vähemmän lyhytketjuisia rasvahappoja tuottavia bakteereja erityisesti Clostridia-luokasta sekä enemmän tulehdusta aiheuttavia bakteereja ja sieniä mm. Candida-suvusta. Tämä tulos testattiin bakteerien osalta myös ennustetestillä (ROC), joka erotti toisistaan ne potilaat, jotka saivat hyvän vasteen ja ne, jotka eivät saaneet vastetta (area under the curve > 0.8). Tulosten perusteella ulosteen bakteerit ja hiivat voisivat sopia ennustaviksi mittareiksi IBD-potilaiden infliksimabihoidon vasteen ennustamiseen.Peer reviewe

The BDSF quorum sensing receptor RpfR regulates Bep exopolysaccharide synthesis in Burkholderia cenocepacia via interaction with the transcriptional regulator BerB

The polysaccharide Bep is essential for in vitro biofilm formation of the opportunistic pathogen Burkholderia cenocepacia. We found that the Burkholderia diffusible signaling factor (BDSF) quorum sensing receptor RpfR is a negative regulator of the bep gene cluster in B. cenocepacia. An rpfR mutant formed wrinkled colonies, whereas additional mutations in the bep genes or known bep regulators like berA and berB restored the wild-type smooth colony morphology. We found that there is a good correlation between intracellular c-di-GMP levels and bep expression when the c-di-GMP level is increased or decreased through ectopic expression of a diguanylate cyclase or a c-di-GMP phosphodiesterase, respectively. However, when the intracellular c-di-GMP level is changed by site directed mutagenesis of the EAL or GGDEF domain of RpfR there is no correlation between intracellular c-di-GMP levels and bep expression. Except for rpfR, deletion mutants of all 25 c-di-GMP phosphodiesterase and diguanylate cyclase genes encoded by B. cenocepacia showed no change to berA and bep gene expression. Moreover, bacterial two-hybrid assays provided evidence that RpfR and BerB physically interact and give specificity to the regulation of the bep genes. We suggest a model where RpfR binds BerB at low c-di-GMP levels to sequester this RpoN-dependent activator to an RpfR/RpfF complex. If the c-di-GMP levels rise, possibly by the enzymatic action of RpfR, BerB binds c-di-GMP and is released from the RpfR/RpfF complex and associates with RpoN to activate transcription of berA, and the BerA protein subsequently activates transcription of the bep genes

Switching maintenance infliximab therapy to biosimilar infliximab in inflammatory bowel disease patients

Background: Clinical use of biosimilar infliximab (CT-P13) in inflammatory bowel diseases (IBDs) is based on extrapolation of indication from clinical studies performed in rheumatological diseases. Only few data exist of behaviour of infliximab trough levels (TLs) and anti-drug antibodies (ADAs) during switching.Aim: The objective of this study was to evaluate changes in TLs, ADA formation and disease activity after switching from originator infliximab to biosimilar one.Methods: All our IBD patients receiving maintenance infliximab therapy were switched to biosimilar infliximab. TLs and ADAs were measured before the last originator infusion and before the third biosimilar infusion. Laboratory values, disease activity indices (partial Mayo score and Harvey-Bradshaw index) and demographic data were collected from patient records.Results: A total of 62 patients were included in the final analysis (32 Crohn's disease, 30 ulcerative colitis (UC) or IBD-unclassified). No significant changes in median TLs before (5.5mg/l) and after switching (5.5mg/l, p=.05) occurred in the entire study group or in the Crohn's disease (CD) subgroup (5.75 and 6.5mg/l, p=.68). However, in the subgroup of ulcerative colitis, the change in median TL was significantly different (from 5.2 to 4.25mg/l, p=.019). Two patients developed ADAs after switching. No changes in disease activity were detected during switching and no safety concerns occurred.Conclusions: Switching from originator to biosimilar infliximab resulted in statistically significant differences in infliximab TLs in patients with UC but not in patients with Crohn's disease. The clinical significance for this difference is doubtful and in neither group changes in disease activity occurred.Peer reviewe

Normal tau polarisation as a sensitive probe of CP violation in chargino decay

CP violation in the spin-spin correlations in chargino production and subsequent two-body decay into a tau and a tau-sneutrino is studied at the ILC. From the normal polarisation of the tau, an asymmetry is defined to test the CP-violating phase of the higgsino mass parameter \mu. Asymmetries of more than \pm70% are obtained, also in scenarios with heavy first and second generation sfermions. Bounds on the statistical significances of the CP asymmetries are estimated. As a result, the normal tau polarisation in the chargino decay is one of the most sensitive probes to constrain or measure the phase \phi_\mu at the ILC, motivating further detailed experimental studies.Comment: 20 pages, 10 figures, gzipped tar fil

Key Players and Individualists of Cyclic-di-GMP Signaling in Burkholderia cenocepacia

Burkholderia cenocepacia H111 is an opportunistic pathogen associated with chronic lung infections in cystic fibrosis patients. Biofilm formation, motility and virulence of B. cenocepacia are regulated by the second messenger cyclic di-guanosine monophosphate (c-di-GMP). In the present study, we analyzed the role of all 25 putative c-di-GMP metabolizing proteins of B. cenocepacia H111 with respect to motility, colony morphology, pellicle formation, biofilm formation, and virulence. We found that RpfR is a key regulator of c-di-GMP signaling in B. cenocepacia, affecting a broad spectrum of phenotypes under various environmental conditions. In addition, we identified Bcal2449 as a regulator of B. cenocepacia virulence in Galleria mellonella larvae. While Bcal2449 consists of protein domains that may catalyze both c-di-GMP synthesis and degradation, only the latter was essential for larvae killing, suggesting that a decreased c-di-GMP level mediated by the Bcal2449 protein is required for virulence of B. cenocepacia. Finally, our work suggests that some individual proteins play a role in regulating exclusively motility (CdpA), biofilm formation (Bcam1160) or both (Bcam2836)

A nationwide real-world study on dynamic ustekinumab dosing and concomitant medication use among Crohn's disease patients in Finland

Background Real-world evidence to support optimal ustekinumab dosing for refractory Crohn's disease (CD) patients remains limited. Data from a retrospective nationwide chart review study was utilized to explore ustekinumab dosing dynamics and optimization, identify possible clinical predictors of dose intensification, and to evaluate ustekinumab trough concentrations (TCs) and concomitant medication use in Finland. Methods Information gathered from17 Finnish hospitals included clinical chart data from 155 adult CD patients who received intravenous ustekinumab induction during 2017-2018. Data on ustekinumab dosing and TCs, concomitant corticosteroid and immunosuppressant use, and antiustekinumab antibodies were analyzed in a two-year follow-up, subject to availability. Results Among 140 patients onustekinumab maintenance therapy, dose optimization was required in 55(39%) of the patients, and 41/47 dose-intensified patients (87%) persisted on ustekinumab. At baseline, dose-intensified patient group had significantly higher C-reactive protein (CRP) levels, and at week 16, significantly lower ustekinumab TCs than in patients without dose intensification. Irrespective of dose optimization, a statistically significant reduction in the use of corticosteroids was observed at both 16 weeks and one year, coupled with an increased proportion of patients on ustekinumab monotherapy. Antiustekinumab antibodies were undetectable in all 28 samples from 25 patients collected throughout the study period. Conclusions Nearly a third of all CD patients on ustekinumab maintenance therapy, with a history of treatment-refractory and long-standing disease, required dose intensification. These patients persisted on ustekinumab and had significant reduction of corticosteroid use. Increased baseline CRP was identified as the sole indicator of dose intensification.Peer reviewe

A nationwide real-world study on dynamic ustekinumab dosing and concomitant medication use among Crohn's disease patients in Finland

Background Real-world evidence to support optimal ustekinumab dosing for refractory Crohn's disease (CD) patients remains limited. Data from a retrospective nationwide chart review study was utilized to explore ustekinumab dosing dynamics and optimization, identify possible clinical predictors of dose intensification, and to evaluate ustekinumab trough concentrations (TCs) and concomitant medication use in Finland.Methods Information gathered from17 Finnish hospitals included clinical chart data from 155 adult CD patients who received intravenous ustekinumab induction during 2017-2018. Data on ustekinumab dosing and TCs, concomitant corticosteroid and immunosuppressant use, and antiustekinumab antibodies were analyzed in a two-year follow-up, subject to availability.Results  Among 140 patients onustekinumab maintenance therapy, dose optimization was required in 55(39%) of the patients, and 41/47 dose-intensified patients (87%) persisted on ustekinumab. At baseline, dose-intensified patient group had significantly higher C-reactive protein (CRP) levels, and at week 16, significantly lower ustekinumab TCs than in patients without dose intensification. Irrespective of dose optimization, a statistically significant reduction in the use of corticosteroids was observed at both 16 weeks and one year, coupled with an increased proportion of patients on ustekinumab monotherapy. Antiustekinumab antibodies were undetectable in all 28 samples from 25 patients collected throughout the study period.Conclusions Nearly a third of all CD patients on ustekinumab maintenance therapy, with a history of treatment-refractory and long-standing disease, required dose intensification. These patients persisted on ustekinumab and had significant reduction of corticosteroid use. Increased baseline CRP was identified as the sole indicator of dose intensification.</div

Ustekinumab for Crohn's disease: a nationwide real-life cohort study from Finland (FINUSTE)

Background: Ustekinumab (UST), a human anti-IL12/23p40 monoclonal antibody, has been approved for treatment of Crohn's Disease (CD) since the end of 2016. This nationwide noninterventional, retrospective chart review explored real-life data in patients receiving UST to provide guidance in UST treatment in the era of increasing prevalence of CD. Methods: The study assessed UST treatment patterns such as dosing frequency, concomitant medication and persistence in 48 CD patients commencing UST therapy in 12 Finnish hospitals during 2017. Clinical remission and response rates were explored using a modified Harvey-Bradshaw index (mHBI) and endoscopic response via the simple endoscopic score for Crohn's disease (SES-CD) as proportions of patients at week 16 and at the end of follow-up. Results: Forty patients (83%) continued UST-treatment at the end of follow-up. At week 16, clinical response and endoscopic healing was observed, where data were available; mHBI decreased from 9 to 3 (p = .0001) and SES-CD from 12 to 3 (p = .009). Clinical benefit was achieved by 83% (19/23) at week 16 and by 76% (16/21) at the end of follow-up. The proportion of patients using corticosteroids decreased from 48% to 25% at week 16 and to 13% at the end of the follow-up. Conclusion: UST showed to be effective and persistent, inducing short-term clinical benefit and endoscopic response in this real-life nationwide study of CD patients. Significant corticosteroid tapering in patients with highly treatment refractory and long-standing CD was observed

Ustekinumab for Crohn’s disease: a nationwide real-life cohort study from Finland (FINUSTE)

Background: Ustekinumab (UST), a human anti-IL12/23p40 monoclonal antibody, has been approved for treatment of Crohn?s Disease (CD) since the end of 2016. This nationwide noninterventional, retrospective chart review explored real-life data in patients receiving UST to provide guidance in UST treatment in the era of increasing prevalence of CD.Methods: The study assessed UST treatment patterns such as dosing frequency, concomitant medication and persistence in 48?CD patients commencing UST therapy in 12 Finnish hospitals during 2017. Clinical remission and response rates were explored using a modified Harvey?Bradshaw index (mHBI) and endoscopic response via the simple endoscopic score for Crohn?s disease (SES-CD) as proportions of patients at week 16 and at the end of follow-up.Results: Forty patients (83%) continued UST-treatment at the end of follow-up. At week 16, clinical response and endoscopic healing was observed, where data were available; mHBI decreased from 9 to 3 (p?=?.0001) and SES-CD from 12 to 3 (p?=?.009). Clinical benefit was achieved by 83% (19/23) at week 16 and by 76% (16/21) at the end of follow-up. The proportion of patients using corticosteroids decreased from 48% to 25% at week 16 and to 13% at the end of the follow-up.Conclusion: UST showed to be effective and persistent, inducing short-term clinical benefit and endoscopic response in this real-life nationwide study of CD patients. Significant corticosteroid tapering in patients with highly treatment refractory and long-standing CD was observed.Peer reviewe