Synapomorphies Research Articles

Bioelectrical impedance analysis-based nomogram construction for predicting secondary loss of response to infliximab in bio-naïve Crohn’s disease patients

BackgroundInfliximab is emerging as the first-line therapy for Crohn’s disease (CD); however, the rate of secondary loss of response (SLR) can exceed 50%. This study aimed to construct a nomogram based on bioelectrical impedance analysis (BIA) indexes and laboratory markers to predict SLR to infliximab in biologically naïve CD patients. MethodsData of 136 biologically naïve CD patients treated between September 2019 and March 2021 were retrospectively retrieved. BIA-based body composition parameters and laboratory markers were obtained before the infliximab therapy. Predictor selection was conducted using the least absolute shrinkage and selection operator (LASSO) and univariate logistic regression. The nomogram was developed using multivariable logistic regression, and internal validation was made by ten-fold cross-validation. ResultsSLR occurred in 51% of the CD patients during 54 weeks. The nomogram predictors included hemoglobin, albumin, serum iron, and BIA scores. The nomogram showed significant discrimination (area under the curve [AUC], 0.920; 95% confidence interval, 0.873–0.967) and calibration (mean error = 0.012). Decision curve analysis (DCA) indicated that the nomogram provided net clinical benefit when the risk probability was between 2% and 83%. Internal validation assessment of the nomogram robustness found an AUC of 0.904 and an accuracy of 0.841. ConclusionsThis BIA-based body composition parameters- and laboratory markers-based novel nomogram could act as a predictive tool to evaluate SLR to infliximab therapy, crucial for optimizing treatment strategies and switching biologics in CD.

Assessing Damages to Built and Natural Environments: Linking Hydrodynamic and Geospatial Enviro-Economical Models

In this study, a novel framework was developed to provide a holistic damage assessment caused by severe hydrologic events whether individually or as a compound event. The novel framework uses a developed hurricane-specific water quality model, Environmental Fluid Dynamic Code-Storm Surge model (EFDC-SS) and an ArcGIS-based framework, the Facility Economic Damage and Environmental Release Planning (FEDERAP) to assess damages to the built and natural environment. The developed framework could be used to compare different hurricanes and storms with a focus on land inundation, spill destination in both land and water and their associated risks, as well as economic loss including both physical and secondary losses. The results showed different spreading mechanisms during surge and rainfall-based hurricanes. While storm surge pushed contaminants (from spills) upstream, the rainfall-based hurricane caused a larger footprint of contamination on land. Though different in spreading patterns, spills during both hurricane types can widely spread miles away from the release location in a very short period of time. The FEDERAP economic loss model showed that facility area, average land elevation, the number of storage tanks and process units at the facility, and daily production are key drivers in the calculated total losses for a given hydrologic event.

Swapping Versus Dose Optimization in Patients Losing Response to Adalimumab With Adequate Drug Levels

In cases of loss of response due to mechanistic failure under antitumor necrosis factor agents, it is recommended to switch to another class of biologics. Two different strategies were compared in patients with inflammatory bowel disease (IBD) who were treated with nonoptimized adalimumab (ADA) and experienced a loss of response despite therapeutic trough levels of adalimuma-either ADA dose optimization or switching to vedolizumab or ustekinumab. Patients under maintenance therapy with ADA monotherapy (40 mg every 14 days) and who experienced a secondary loss of response with trough levels > 4.9 μg/mL were included prospectively in this nonrandomized study. The primary end point was the survival rate without therapeutic discontinuation after ADA dose optimization or switching to another class of biologics. Adalimumab was optimized (n = 61 patients, 42 Crohn's disease, 19 ulcerative colitis) or swapped for vedolizumab (n = 40, 20 ulcerative colitis) or ustekinumab (n = 30, 30 Crohn's disease). At 24 months, 11 out of 70 patients (14.8%) in the swap group discontinued treatment compared with 36 out of 61 (59.6%) patients in the optimization group (P < 0.001). The median time without therapeutic discontinuation was significantly longer in the swap group (>24 months) than in the optimization group (13.3 months, P < 0.001). In the optimization group, treatment discontinuation was positively associated with baseline fecal calprotectin >500 μg/g (HR, 3.53; 95% CI, 1.16-10.72; P = 0.026) and inversely associated with variation of trough levels of adalimumab (>2 µg/mL from baseline to week 8 after optimization; HR, 0.51; 95% CI, 0.13-0.82; P = 0.03). In the swap group, no factor was associated with treatment discontinuation. In IBD patients under ADA maintenance therapy who experience a secondary loss of response and in whom trough levels are >4.9µg/mL, swapping to another class is better than optimizing ADA, which is, however, appropriate in a subgroup of patients.

A Comprehensive Literature Review and Expert Consensus Statement on Therapeutic Drug Monitoring of Biologics in Inflammatory Bowel Disease.

Therapeutic drug monitoring (TDM) of biologics is a rapidly evolving field. We aimed to provide a consensus statement regarding the clinical utility of TDM for biologics in inflammatory bowel disease (IBD). A modified Delphi method was applied to develop consensus statements. A comprehensive literature review was performed regarding TDM of biologic therapies in IBD, and 45 statements were subsequently formulated on the potential application of TDM in IBD. The statements, along with literature, were then presented to a panel of 10 gastroenterologists with expertise in IBD and TDM who anonymously rated them on a scale of 1-10 (1 = strongly disagree and 10 = strongly agree). An expert consensus development meeting was held virtually to review, discuss, refine, and reformulate statements that did not meet criteria for agreement or that were ambiguous. During the meeting, additional statements were proposed. Panelists then confidentially revoted, and statements rated ≥7 by 80% or more of the participants were accepted. During the virtual meeting, 8 statements were reworded, 7 new statements were proposed, and 19 statements were rerated. Consensus was finally reached in 48/49 statements. The panel agreed that reactive TDM should be used for all biologics for both primary nonresponse and secondary loss of response. It was recommended that treatment discontinuation should not be considered for infliximab or adalimumab until a drug concentration of at least 10-15 μg/mL was achieved. Consensus was also achieved regarding the utility of proactive TDM for anti-tumor necrosis factor therapy. It was recommended to perform proactive TDM after induction and at least once during maintenance. Consensus was achieved in most cases regarding the utility of TDM of biologics in IBD, specifically for reactive and proactive TDM of anti-tumor necrosis factors.

Degradation shifts plant communities from S- to R-strategy in an alpine meadow, Tibetan Plateau

The replacement of dominant sedges/grasses with secondary forbs is common in alpine rangelands, but the underlying plant ecological strategies and their relevance to leaf traits and their variabilities of different plant functional groups remain largely unknown. Here, we measured key leaf traits and analyzed the competitor, stress-tolerator and ruderal (CSR) strategies of major species with different functional groups (sedges, grasses and forbs) in an alpine meadow along a degradation gradient on the Tibetan Plateau. Our results indicated that S-selected species were dominant in both non-degraded (C:S:R = 1:95:4%) and severely degraded (C:S:R = 2:87:11%) meadows. However, there was a shift from S- to R-strategy in the communities after rangeland degradation. More specifically, sedges and grasses with a “conservative” strategy maintained stronger S-strategy to tolerate degraded and stressful conditions. In contrast, forbs with an “opportunistic” strategy (increase 9.5% in R-score) tended to adapt to degraded stages. Moreover, 51.1% and 23.9% of the increased R-scores in forbs were accounted by leaf mass per area and specific leaf area, respectively. Generally, higher leaf water and nitrogen contents coupled with larger variations in leaf traits and flexible SR strategies in forbs enabled them to capitalize on lower soil water and nutrient availability. Our findings highlighted that the contrasting strategies of plant species in response to the decrease in available resources might lead to niche expansion of secondary forbs and loss of diversity in the degraded alpine meadow. The emerging alternative stable states in the degraded rangelands might bring about a predicament for rangeland restoration.

Unsteady flows of a highly loaded turbine blade with flat endwall and contoured endwall

Strong secondary flow results in substantial aerodynamic loss for highly-loaded turbine. Accurate prediction of the complicated flow structures proposes challenges to the widely used Reynolds Average Navier-Stokes (RANS) approach. This work employs the hybrid RANS/Large Eddy Simulation (LES) method to study the unsteady flows for a highly-loaded turbine blade, with both flat endwall and optimized contoured endwall. Evolution of the unsteady flows in the endwall region is analyzed, with emphasis on the loss generation mechanism. Results show that for the flat endwall, the horseshoe vortex system is highly unsteady and is a significant source of unsteadiness in both the passage and the wake region. It contributes to the unsteady passage vortex, also the earlier breakdown of the trailing edge shedding vortex. The Probability Density Function (PDF) histogram of velocity in the wake region is bimodal, implying the perturbations from two mechanisms. For the contoured endwall, the unsteady evolution of the horseshoe vortex is blocked, which results in significantly reduced unsteadiness, also the merge between the horseshoe vortex with the passage vortex is prevented. Effect of the flow unsteadiness on the loss generation is assessed based on the entropy generation rates contributed by the time-averaged flow and the fluctuations. The effect of unsteadiness is two-fold: unsteady perturbations trigger the vortex breakdown into small-scale structures and thus weakened wake velocity deficit and loss generation; however, in both the passage and the wake region the entropy generation by the fluctuations are remarkable. For the contoured endwall, due to the reduced flow unsteadiness, loss generation contributed by the fluctuations are much smaller compared to the flat endwall. The results highlight the importance of including the loss generation by the fluctuations, also a possible mechanism to reduce the secondary loss by attenuating the flow unsteadiness with the contoured endwall.

Re-induction with intravenous Ustekinumab after secondary loss of response is a valid optimization strategy in Crohn's disease.

Re-induction with intravenous ustekinumab after secondary loss of response in Crohn's disease is a relatively new strategy to regain efficacy. This real-world cohort study aimed to evaluate its effectiveness and safety. Crohn's disease patients with loss of response after initial response to ustekinumab and treated with a second intravenous dose of ustekinumab were included. Clinical, biochemical and endoscopic data were collected. Primary outcome was drug survival. Secondary effectiveness outcomes included clinical remission, primary nonresponse and adverse events. In total, 31 Crohn's disease patients were included after re-induction with intravenous ustekinumab. All patients had failed prior biologic therapy, that is 77% were exposed to two or more antitumor necrosis factor agents and 65% were exposed to vedolizumab prior to initiation of ustekinumab treatment. Median treatment duration between initial treatment and re-induction with intravenous ustekinumab was 11.1 months (interquartile range 6.9-19.5). Ustekinumab therapy after a second dose of intravenous ustekinumab was maintained in 74 and 71% of the patients at weeks 20 and 52. Clinical remission rates after re-induction at weeks 8, 20 and 52 were 37, 56 and 45%, respectively. Nonresponse occurred in 16% of the patients. Adverse events were reported in four patients. Re-induction with intravenous ustekinumab after secondary loss of response results in continuation of ustekinumab treatment for at least 1 year in almost three-quarters of patients and in clinical remission in half of patients after 1 year. Therefore, ustekinumab re-induction may be considered an important rescue treatment option in patients with refractory Crohn's disease.

Loss Characterization of a Conventional Variable Inlet Guide Vane

Variable inlet guide vanes (VIGVs) are most commonly used as the major control unit of integrally geared centrifugal compressors (IGCCs). In order to enhance the efficient operating range of the compressor, the loss mechanisms and utilization limits of state-of-the-art VIGVs need to be better understood. Field measurements in the wake of a typical, commercially used configuration were therefore conducted at the VIGV test facility of the Bundeswehr University Munich. The investigations were carried out at application oriented subsonic flow conditions and stagger angles from 50∘ to 90∘ covering the full low-loss operating range, including the limits of efficient operation. For a precise local loss characterization, an inflow correlation was developed and applied to consider total pressure inhomogeneities caused by the radial inflow velocity profile and minor circumferential velocity deviations. Contrary to previous research efforts, not only the profile losses, but also the secondary flow losses induced by the open blade tips and wall-blade interactions were resolved in full detail. For this reason, a more precise and comprehensive loss assessment of realistic VIGV cascades is acquired.

Twenty-five years of biologicals in IBD: What´s all the hype about?

Twenty-five years ago the field was revolutionized by the introduction of infliximab as the first hybrid anti-TNF-antibody. Subsequently, other humanized anti-TNFs were developed and marketed, followed by antibodies to new targets including integrins (vedolizumab) and interleukin 12/23 (ustekinumab). All these so-called biologicals were shown in registrational trials to induce remission superior to placebo but consistently were effective in only a minority of patients. Even though in most trials only the responders were selected to continue on the respective medication for maintenance, many experienced a secondary loss of response and only a minority of usually <25% of the initial cohort achieved long-term (1 year) remission. In 'real life studies', the outcome was somewhat better, probably due to proper selection of patients and open, mostly retrospective study designs. A clear benefit of biologicals is apparent in otherwise treatment refractory patients, in extraintestinal manifestations and in Crohn´s disease (CD) with fistulizing complications. Biologicals achieve mucosal healing (MH) more often than corticosteroids or thiopurines, and MH is associated with improved prognosis. However, this does not justify escalating treatment until MH is reached since controlled trials proving this point of 'treat to target' are lacking both in ulcerative colitis and CD. Surgical rates have decreased with increasing use of biologicals, but disease progression has not been proven to improve. With the exception of opportunistic infections, serious adverse events are rare. In conclusion, biologicals have changed the scene considerably and expanded our armamentarium, but there is also a marketing hype fostering expectations without evidence.

Proton Pump Inhibitors Inhibit PHOSPHO1 Activity and Matrix Mineralisation In Vitro

Proton pump inhibitors (PPIs) have been associated with an increased risk of fragility fractures in pharmaco-epidemiological studies. The mechanism is unclear, but it has been speculated that by neutralising gastric acid, they may reduce intestinal calcium absorption, causing secondary hyperparathyroidism and bone loss. Here we investigated that hypothesis that the skeletal effects of PPI might be mediated by inhibitory effects on the bone-specific phosphatase PHOSPHO1. We found that the all PPIs tested inhibited the activity of PHOSPHO1 with IC50 ranging between 0.73 µM for esomeprazole to 19.27 µM for pantoprazole. In contrast, these PPIs did not inhibit TNAP activity. We also found that mineralisation of bone matrix in primary osteoblast cultures was inhibited by several PPIs in a concentration dependent manner. In contrast, the histamine-2 receptor antagonists (H2RA) nizatidine, famotidine, cimetidine and ranitidine had no inhibitory effects on PHOSPHO1 activity. Our experiments show for the first time that PPIs inhibit PHOSPHO1 activity and matrix mineralisation in vitro revealing a potential mechanism by which these widely used drugs are associated with the risk of fractures.

Vedolizumab as first-line biological therapy in elderly patients and those with contraindications for anti-TNF therapy: a real-world, nationwide cohort of patients with inflammatory bowel diseases

Background Data from real-life populations about vedolizumab as first-line biological therapy for ulcerative colitis (UC) and Crohn’s disease (CD) are emerging. Objective To investigate the efficacy and safety of vedolizumab in bio-naïve patients with UC and CD. Methods A Danish nationwide cohort study was conducted between November 2014 and November 2019. Primary outcomes were clinical remission, steroid-free clinical remission, and sustained clinical remission from weeks 14 through 52. Results The study included 56 patients (UC:31, CD:25) who initiated treatment with vedolizumab mainly because of contraindications to anti-TNFs, of whom 54.8 and 24.0%, respectively received systemic steroids at the initiation. Rates of clinical remission at weeks 6, 14, and 52 were 32.0, 48.0, and 40.0%, respectively, in UC, and 36.8, 36.8, and 47.4% in CD. Steroid-free clinical remission at week 52 was achieved among 36.0 and 47.4% of UC and CD patients, while sustained clinical remission was achieved in 32.0 and 36.8%. Lack of remission was associated with being female (68.8 vs. 11.1%, p = .01) in UC and non‐structuring, non‐penetrating behavior in CD (90.0 vs. 44.4%, p = .03); however, this was not confirmed in multivariate analysis. Discontinuation due to primary non-response occurred in 20.0 and 5.3% of UC and CD patients, respectively, while rates of secondary loss of response were 12.0 and 5.3% after 52 weeks of follow-up. Vedolizumab was well-tolerated as only one UC patient experienced a serious adverse event. Conclusion Vedolizumab is effective in the achievement of short-term, long-term, and steroid-free clinical remission in bio-naïve UC and CD patients.

Efficacy and safety of infliximab in the treatment of pediatirc Crohn's disease

Objective: To analyze the efficacy and safety of the biological agent infliximab (IFX) in the treatment of pediatric Crohn's disease. Methods: A total of 86 children with Crohn's disease who had received IFX in three hospitals (Ruijin Hospital, Ruijin Hospital North and Shanghai Children's Hospital) in Shanghai from January 2007 to December 2017 were included in this retrospective study. The efficacy of IFX was assessed by comparing clinical and laboratory data before and after IFX treatment. Student t test, Mann-Whitney U test or chi-square test were used to analyze the data of the two groups. Logistic reggression analysis were used to analyze the effects of variables such as age, clinical characteristics, disease behavior and combined medications on the efficacy and safety of IFX. Results: Among the 86 children with Crohn's disease in the study, 50 were males and 36 females. The IFX treatment was initiated at 12.0 (7.1, 13.6) years of age, and the follow-up period was 94.1 (47.8, 185.5) weeks. Efficacy analysis showed that in the induction remission phase, the clinical response rate was 97% (79/81) and the remission rate was 74% (60/81). In the maintenance remission phase, the clinical response rate was 75% (51/68) and the remission rate was 68% (46/68). After 34 weeks of treatment with IFX, pediatric Crohn's disease activity index (PCDAI) (5 (0, 10) vs. 36 (26, 45)), C-reactive protein (3 (1, 8) vs. 8 (3, 31) mg/L), erythrocyte sedimentation rate (10 (6, 10) vs. 35 (20, 50) mm/1 h), platelet ( (327±107)×109 vs. (438±159) ×109/L), albumin ((37±6) vs. (30±6) g/L), hemoglobin ((116±16) vs. (103±18) g/L), change of body weight (-0.5±1.2 vs. -1.0±0.9), anemia (29% (20/68) vs. 75% (51/68)), and perianal disease (13/21 vs. 0) were significantly improved (all P<0.05). By the end of 34 weeks of IFX treatment, 25% (17/68) of children experienced secondary loss of response to IFX. Logistic reggression analysis showed that PCDAI>30 was positively correlated with secondary loss of response (OR=3.823, 95%CI 1.015-15.328, P=0.048), and combined with azathioprine was conducive to maintaining efficacy of IFX (OR=0.440, 95%CI 0.106-1.033, P=0.044). The IFX-related adverse events included infusion reactions in 17% (15/86) and infections in 42% (36/86) of children. Analysis showed that age<6 years was a risk factor for infusion reactions (χ2=6.556, P=0.010), and combined use of steroids (χ2=5.230, P=0.022) may increase the incidence of infection. Conclusions: IFX is effective in the treatment of pediatric Crohn's disease with favorable safety. Reducing secondary loss of response to IFX is an urgent issue that need to be addressed. At the same time, it is necessary to pay close attention to the adverse events during IFX treatment.

Long-term efficacy and safety of ustekinumab for moderate-to-severe psoriasis: A 9-year real-life experience from a tertiary referral center in Turkey.

There is a paucity of data on long-term (≥5-year) outcomes of ustekinumab therapy for psoriasis in real-life clinical practice. This observational, retrospective study aimed to evaluate the long-term efficacy and safety profile of ustekinumab in 52 adult patients with moderate-to-severe chronic plaque psoriasis who were treated with ustekinumab for at least 28 weeks and a maximum of 105 months in our tertiary referral center in Turkey, between 2010 and 2019. Response to therapy was assessed using Psoriasis Area and Severity Index (PASI). Logistic regression analysis was performed to determine significant associations (p-value <0.05) with response to treatment. The PASI50, PASI75, PASI90, and PASI100 response rates were 97.8%, 88.9%, 53.3%, and 35.5%, respectively, at year 1 and 100%, 80.0%, 60.0%, and 40.0%, respectively, at year 5. Non-obesity was independently associated with PASI90 response at year 2 (p=0.043), while biologic-naivety was independently associated with PASI90 responses at year 2 (p=0.047) and year 3 (p=0.021). An absolute PASI score of ≤3 was achieved by 82.2% and 80.0% of the patients at year 1 and year 5, respectively. Nine patients received adjuvant therapy and nine underwent ustekinumab dose escalation. These strategies were effective for recapturing clinical response in most patients. Ustekinumab was generally well-tolerated with no dose-related and cumulative toxicity, or drug interaction over a mean of 33.5 ± 21.1months. The main reasons for discontinuation were secondary failure and loss to follow-up. Our 9-year real-life clinical experience demonstrates that ustekinumab is an efficacious and safe treatment option for long-term therapy of moderate-to-severe plaque psoriasis.

Allogeneic Stem Cell Transplantation for the Treatment of Lymphoproliferative Disorders in Patients Affected By Primary Immunodeficiencies: The UK Experience

▪Malignancies represent a significant morbidity for patients (pts) affected by primary immunodeficiency (PID). 4-25% of pts with PID will develop a malignancy during the course of their life, lymphoproliferative disorders being the most common. Dysfunctional T-cell surveillance, particularly against EBV, and impaired DNA repair mechanisms lie at the basis of this susceptibility. Malignancies in PID pts are difficult to treat as these pts often harbor co-morbidities that increase the risk of treatment-related toxicity. Allogeneic stem cell transplantation (SCT) offers a treatment for both PID and LPD. Data on the outcome of pts referred to SCT for LPD in PID are scant, as PID are rare and sometimes under diagnosed.We retrospectively collected data on pts 0-18 years referred to SCT for LPD in PID in the 12 pediatric SCT centres in the UK from 2000 to 2015. Centralized review for histopathology specimens and radiological imaging was performed to confirm the LPD diagnosis and the disease staging/remission status at SCT. Ethical approval was obtained.40 patients affected by 13 different PIDs were identified, X-linked lymphoproliferative disease being the most common (15% of the pts).Median age at LPD diagnosis was 6.1 years (range 0.2-17.2). Pts were diagnosed with a B-cell lymphoma (60%), Hodgkin lymphoma (15%), polymorphic LPD (10%), plasmacytic hyperplasia (7%), T-cell lymphoma (5%) or atypical lymphoid proliferation (3%). 83% of the pts presented with stage III/IV disease, 4% had CNS involvement. LPD proved EBER positive in 66% of the tested samples. Pts received a median of 2 lines of chemo/immunotherapy to treat LPD, which proved resistant to front line treatment in 64% of the pts. 7 pts were referred for SCT but did not receive one due to disease progression (3), donor unavailability (1) or medical decision (3). Among the non-transplanted pts, 1 died from sepsis during chemotherapy, 4 died from disease progression; the OS of this group is 28% at a median follow up of 10 months from LPD diagnosis. For the 33 pts who underwent SCT, median age at SCT was 8.4 yrs (range 0.6-17.7). 58% of the pts had 1 or more comorbidities at SCT (chronic lung disease being most common). Of these, 67% of the pts receiving SCT were in complete remission (CR), 24% in partial remission, and 10% had active disease when starting their conditioning regimen.7 different types of conditioning regime were used, as per participating center local policies. In 94% of the cases a reduced intensity conditioning (RIC) was used. 74% of treated pts received in vivo T cell depletion with Alemtuzumab (71%) or Anti-Thymocyte Globulin (3%). 27% of the pts received the graft from a matched related, 39% matched unrelated and 33% mismatched donor. Bone marrow and peripheral blood were the most common sources of stem cells (46% and 42% of the cases, respectively).All pts achieved neutrophil engraftment and secondary graft loss was experienced by 2 pts (6%). 4 pts (12%) died from SCT related toxicity (3 infections, 1 pulmonary VOD/hemorrhage). Acute GVHD grade I-IV developed in 42% of the pts. LPD recurred in 2 cases (1 after secondary graft loss) and was successfully treated with surgery/chemotherapy. With a median follow up of 48 months, 88.0% patients are alive, in CR post SCT. 76% of the evaluable patients exhibited a full donor engraftment at the latest follow up.Disease stage, histology, underlying PID and remission status at SCT did not impact on the patients´ outcomes. Overall survival was significantly higher in SCT recipients as compared to patients who did not receive SCT (88 vs 28%, p= 0.03). Even among the 3 pts who underwent SCT without achieving LPD remission, OS was 67%, thus underlying that restoring competent immunity might play a role in this context, allowing for LPD control post SCT via the newly grafted T-cells.This cohort of pts is the largest described of its kind. We conclude that SCT with RIC is safe and efficacious for pts affected by LPD in PID. While larger cohorts of pts are required to confirm these data, our study suggests that remission status at SCT plays a partial role in LPD control. As a consequence, limited pre-SCT chemotherapy might be required and SCT indication might be plausible for pts not achieving CR. DisclosuresLucchini:Alexion: Membership on an entity's Board of Directors or advisory committees.

Genetic Fusion to Factor XIII B-Subunit Improves the Pharmacokinetic Properties of Factor IX

Background: Hemophilia B is a X-linked recessive bleeding disorder characterized by coagulation factor IX (FIX) deficiency. FIX concentrates are used in the prevention and treatment of bleeding episodes in patients with hemophilia B. Prophylaxis is currently considered as the optimal care for severe hemophilia. For patients and their families one of the major problems with prophylaxis is the need for frequent venepunctures. The half-life of standard FIX concentrates is approximately 18 h, which requires 2 or 3 intravenous infusions per week to achieve bleeding prevention. Prolonging the half-life of FIX can therefore reduce the frequency of infusions. Recently, extended half-life FIX concentrates have been developed using two major strategies: i) (glyco) PEGylation(1), ii) genetic fusion to immunoglobulin Fc fragments(2), or to albumin(3). These technologies may have some potential disadvantages such as reduced specific activity, unknown long-term adverse effects of PEG exposure and immunological reactivity which are currently under investigation.The aim of the present study was to develop a new strategy to prolong half-life of recombinant human FIX molecule (rFIX) using an innovative approach of fusion.Factor XIII (FXIII) is a protransglutaminase that circulates in plasma as a heterotetramer composed of two catalytic A subunits and two B subunits (FXIIIB). FXIIIB subunits act as a carrier protein that stabilizes the structure of the A subunits and protects FXIII from proteolysis. It has been reported that a primary deficiency of FXIIIB resulted in the secondary rapid loss of A subunit from the plasma (4). Thus, FXIII-B is responsible for the long half-life of the FXIII molecule (10 to 12 days).We designed a new rFIX molecule fused to coagulation FXIII subunit B (FXIIIB) and separated by a short linker sequence containing an activated Factor X-cleavable site (rFIX-LXa-FXIIIB). Thus, we expected that the carrier protein will be removed as soon as traces of (activated factor X) FXa will be generated, leaving rFIX free to perform its enzymatic role in the tenase complex.Methods: Recombinant FIX-LXa-FXIIIB molecules were expressed in human hepatic Huh-7 cell line and purified via a two-step protocol prior to in vitro and in vivo biochemical and pharmacokinetic characterizations.Results: rFIX-LXa-FXIIIB was correctly expressed by Huh-7 cells at the expected molecular weight of 150 kDa and presented similar procoagulant activity compared to rFIX-WT (106.5 UI/dL ; p> 0.05). We showed that the LXa linker was cleavable by FXa, releasing free rFIX molecule before its activation. After cleavage, rFIX was fully activable by activated FXI. Both rFIX-WT and rFIX-LXa-FXIIIB showed similar thrombin generation capacity both in vitro and in vivo after injection in FIX-deficient mice (Area under the thrombin generation curve =300nM.min ; p>0.05).The half-life (T1/2) of rFIX-LXa-FXIIIB molecule was determined in wild-type mice and rats. In mice, as commercially available extended half-life FIX products, the improvement of the half-life was very limited and in rats, it was 2.5 fold longer compared to rFIX-WT (T1/2 10h vs 4h ; p<0.05).A potential advantage of this new molecule is its capacity to bind to fibrinogen via FXIIIB. It has been recently reported that excess plasma FXIIIB2 is not free, but rather circulates bound to fibrinogen (5). We can hypothesize that the rFIX-LXa-FXIIIB fusion protein can circulate bound to fibrinogen and might therefore enhance/accelerate the transformation of fibrinogen into fibrin. In vivo experiments using mice saphenous vein bleeding model are currently conducted in our laboratory to test this hypothesis.Conclusion: We report here a new fusion protein strategy using FXIIIB. The fusion protein has normal specific activity and normal thrombin generating capacity, associated with improved pharmacokinetics in small animal models. These encouraging results suggest that genetic fusion of rFIX to FXIIIB might be a valuable concept to improve the half-life of FIX molecules. The binding capacity of this novel fusion protein to fibrinogen might be an additional advantage that may improve haemostatic capacity of the molecule.1. Negrier C et al. Blood. 2011;118:2695-701.2. Peters RT et al. Blood. 2010;115:2057-64.3. Metzner HJ et al. Thromb Haemost. 2009;102:634-44.4. Miloszewski K et al. Br J Haematol. 1970;19:685-90.5. Byrnes JR et al. Blood. 2016 Oct 13;128:1969-1978 DisclosuresLe Quellec:LFB: Honoraria; Novo Nordisk: Honoraria; Shire: Honoraria. Negrier:Baxter: Research Funding; Alnylam: Research Funding; Bayer: Honoraria, Research Funding, Speakers Bureau; Biogen/SOBI: Honoraria, Research Funding, Speakers Bureau; CSL Behring: Honoraria, Research Funding, Speakers Bureau; Inspiration: Research Funding; Novo Nordisk: Honoraria, Research Funding, Speakers Bureau; Octapharma: Honoraria, Research Funding, Speakers Bureau; Pfizer: Honoraria, Research Funding, Speakers Bureau; Baxalta: Honoraria, Speakers Bureau; LFB: Honoraria, Speakers Bureau. Dargaud:BMS: Honoraria, Research Funding; Baxalta/Shire: Honoraria, Research Funding; Pfizer: Honoraria, Research Funding; LFB: Honoraria, Research Funding; CSL Behring: Honoraria, Research Funding; Bayer: Honoraria, Research Funding; Stago: Honoraria; Octapharma: Honoraria, Research Funding; Alnylam: Research Funding.

Systematic review: efficacy of escalated maintenance anti-tumour necrosis factor therapy in Crohn's disease.

Loss of response to anti-TNF agents is a common clinical problem. Dose escalation may be effective for reestablishing clinical response in Crohn's disease (CD). To perform a systematic review assessing the efficacy of escalated maintenance anti-TNF therapy in CD. EMBASE, MEDLINE, Web of Science, and CENTRAL databases were searched for English language publications through to April 25, 2021. Full-text articles evaluating escalated maintenance treatment (infliximab or adalimumab) in adult CD patients were included. A total of 4733 records were identified, and 68 articles met eligibility criteria. Rates of clinical response (33%-100%) and remission (15%-83%) after empiric dose escalation for loss of response to standard anti-TNF therapy were high but varied across studies. Dose intensification strategies (doubling the dose versus shortening the therapeutic interval) were similarly efficacious. Dose-escalated patients tended to have higher serum drug levels compared to those on standard dosing. An exposure-response relationship following dose escalation was found in a number of observational studies. Randomised controlled trials comparing therapeutic drug monitoring (TDM) to empiric treatment intensification have failed to reach their primary end-points. Strategies including Bayesian dashboard-dosing and early treatment escalation targeting biomarker normalisation were found to be associated with improved long-term outcomes. Empiric escalation of maintenance anti-TNF therapy can recapture clinical response in a majority of patients with secondary loss of response to standard maintenance doses. Proactive optimisation of maintenance dosing might prolong time to loss of response in some patients.

Fragmentation reactions of protonated α,ω-diamino carboxylic acids: The importance of functional group interactions.

Protonated members of a homologous series of biologically significant α,ω-diamino carboxylic acids were subjected to collision induced dissociation (CID). The resulting fragmentation patterns were studied using isotopic labeling, quantum mechanical computations, and pseudo MS3 experiments conducted primarily on an ion trap mass spectrometer. Each protonated α,ω-diamino acid showed a primary neutral loss of either ammonia or water; a clear explanation was developed for the observed variation of the two losses within the series. Protonated 2,3-diaminopropanoic acid, 2,4-diaminobutanoic acid, and 2,7-diaminoheptanoic acid gave secondary losses of water, carbon monoxide, and a loss of water plus carbon monoxide, respectively. In the parallel pathways characterized for the fragmentations of protonated ornithine and lysine, the α-nitrogen of the diamino acid was maintained in the cyclic iminium product formed by successive losses of NH3 and (H2 O + CO), whereas the side-chain nitrogen was retained by consecutive losses of H2 O and (CO, NH3 ). The 1-piperideine ion from protonated lysine was fragmented further, losing ethylene from carbons 4 and 5. Protonated 2,6-diaminopimelic acid fragmented by analogous reactions. Detailed mechanistic schemes for the fragmentation of both protonated 2,3-diaminopropanoic and ornithine were generated from MP2/DFT computations. This work highlights the participation of the side-chain amino group, which distinguishes the gas-phase chemistry of protonated α,ω-diamino acids from the well-documented fragmentation reactions of protonated α-amino acids bearing a hydrogen atom or an alkyl side chain. In general, the results further illustrate the importance of intramolecular separations affecting the specific interactions between functional groups leading to the fragmentation of multifunctional ions.

Chronic histiocytic intervillositis: manifestation of placental alloantibody-mediated rejection

Chronic histiocytic intervillositis (chronic intervillositis) is defined by a diffuse infiltration of monocytes into the intervillous space, which often leads to poor obstetrical outcomes, including recurrent intrauterine growth restriction, miscarriage, and fetal death. The pathogenesis of chronic intervillositis is still poorly defined, and there is an unmet medical need for improved management. This study aimed to demonstrate the role of anti-human leukocyte antigen alloantibodies in the pathogenesis of chronic intervillositis through the application of criteria used in solid-organ transplantation for the diagnosis of antibody-mediated rejection. A multidisciplinary research study based on thorough immunologic and pathologic investigations was carried out for 2 separate couples who experienced recurrent secondary fetal losses following a first normal pregnancy associated with histologic evidence of chronic intervillositis. Very high levels of complement-fixing, fetus-specific antibodies targeting mismatched human leukocyte antigen alleles, harbored by the 2 paternal haplotypes, were identified in both cases. Polymorphic human leukocyte antigens were expressed on the surface of trophoblastic villi of the inflamed placenta but not in healthy placental tissue. The binding of alloantibodies to paternal human leukocyte antigens induced dramatic activation of the complement classical pathway in trophoblastic villi, leading to C4d deposition and formation of the terminal complex C5b-9. All requirements for the diagnosis of antibody-mediated placental rejection were fulfilled according to the criteria used in the Banff classification of allograft pathology. In silico analysis was performed using a human leukocyte antigen epitope viewer to reconstitute the human leukocyte antigen sensitization history. Reactivity against a single mismatched epitope present in the first-born healthy child accounted for a broad sensitization to human leukocyte antigens, including those harbored by the 2 paternal haplotypes. This finding explained the high rates of chronic intervillositis recurrence during subsequent pregnancies. This study provides novel mechanistic insights into the pathogenesis of chronic intervillositis and provides new avenues for individualized counseling and therapeutic options.

New Targeted Therapies and Immunotherapies for Locally Advanced Periocular Malignant Tumours: Towards a New 'Eye-Sparing' Paradigm?

Simple SummaryManaging locally advanced periocular malignant tumours, especially those invading the orbit, is challenging. Orbital exenteration has long been considered the gold standard. The development of conservative surgical techniques in the early 2000s, followed by the emergence of new targeted therapies and immunotherapies over the past decade, has led to a paradigm shift towards the use of ‘eye-sparing’ strategies.The management of periocular skin malignant tumours is challenging. Surgery remains the mainstay of treatment for localised eyelid cancers. For more locally advanced cancers, especially those invading the orbit, orbital exenteration has long been considered the gold standard; however, it is a highly disfiguring and traumatic surgery. The last two decades have been marked by the emergence of a new paradigm shift towards the use of ‘eye-sparing’ strategies. In the early 2000s, the first step consisted of performing wide conservative eyelid and orbital excisions. Multiple flaps and grafts were needed, as well as adjuvant radiotherapy in selected cases. Although being incredibly attractive, several limitations such as the inability to treat the more posteriorly located orbital lesions, as well as unbearable diplopia, eye pain and even secondary eye loss were identified. Therefore, surgeons should distinguish ‘eye-sparing’ from ‘sight-sparing’ strategies. The second step emerged over the last decade and was based on the development of targeted therapies and immunotherapies. Their advantages include their potential ability to treat almost all tumours, regardless of their locations, without performing complex surgeries. However, several limitations have been reported, including their side effects, the appearance of primary or secondary resistances, their price and the lack of consensus on treatment regimen and exact duration. The aim of this article was to review the evolution of the management of locally advanced periocular malignant tumours over the last three decades and highlight the new paradigm shift towards the use of ‘eye-sparing’ strategies.

Effectiveness and Safety of Adalimumab Biosimilar SB5 in Inflammatory Bowel Disease: Outcomes in Originator to SB5 Switch, Double Biosimilar Switch and Bio-Naïve SB5 Observational Cohorts.

Background and AimsMultiple adalimumab [ADA] biosimilars are now approved for use in inflammatory bowel disease [IBD]; however, effectiveness and safety data remain scarce. We aimed to investigate long-term outcomes of the ADA biosimilar SB5 in IBD patients following a switch from the ADA originator [SB5-switch cohort] or after start of SB5 [SB5-start cohort].MethodsWe performed an observational cohort study in a tertiary IBD referral centre. All IBD patients treated with Humira underwent an elective switch to SB5. We identified all these patients in a biological prescription database that prospectively registered all ADA start and stop dates including brand names. Data on IBD phenotype, C-reactive protein [CRP], drug persistence, ADA drug and antibody levels, and faecal calprotectin were collected.ResultsIn total, 481 patients were treated with SB5, 256 in the SB5-switch cohort (median follow-up: 13.7 months [IQR 8.6–15.2]) and 225 in the SB5-start cohort [median follow-up: 8.3 months [4.2–12.8]). Of the SB5-switch cohort, 70.8% remained on SB5 beyond 1 year; 90/256 discontinued SB5, mainly due to adverse events [46/90] or secondary loss of response [37/90]. In the SB5-start cohort, 81/225 discontinued SB5, resulting in SB5-drug persistence of 60.3% beyond 1 year. No differences in clinical remission [p = 0.53], CRP [p = 0.80], faecal calprotectin [p = 0.40] and ADA trough levels [p = 0.55] were found between baseline, week 26 and week 52 following switch. Injection site pain was the most frequently reported adverse event.ConclusionSwitching from ADA originator to SB5 appeared effective and safe in this study with over 12 months of follow-up.