Biological tumor necrosis factor (TNF) inhibitors have revolutionized the treatment of inflammatory bowel disease and redefined treatment goals to include mucosal healing. Clinicians are faced with ...challenges such as inadequate responses, treatment failures, side effects, and high drug costs. The objective is to review optimization of anti-TNF therapy by use of personalized treatment strategies based on circulating drug levels and antidrug antibodies (Abs), i.e. therapeutic drug monitoring (TDM). Furthermore, to outline TDM-related pitfalls and their prevention.
Literature review.
Circulating anti-TNF drug trough level is a marker for the pharmacokinetics (PK) of TNF inhibitors. Because of a number of factors, including antidrug antibodies, PK varies between and within patients across time leading to variable clinical outcomes. Differences in intestinal inflammatory phenotype influencing the pharmacodynamic (PD) responses to TNF inhibitors also affect treatment outcomes. As an alternative to handling anti-TNF-treated patients by empiric strategies, TDM identifies underlying PK and PD-related reasons for treatment failure and aids decision making to secure optimal clinical and economic outcomes. Although promising, evidence does not the support use of TDM to counteract treatment failure in quiescent disease. Use of TDM is challenged by methodological biases, difficulties related to differentiation between PK and PD problems, and temporal biases due to lack of chronology between changes in PK versus symptomatic and objective disease activity manifestations. Biases can be accommodated by knowledgeable interpretation of results obtained by validated assays with clinically established thresholds, and by repeated assessments over time using complimentary techniques.
TDM-guided anti-TNF therapy at treatment failure has been brought from bench to bedside.
Treatment of severe COVID-19 is currently limited by clinical heterogeneity and incomplete description of specific immune biomarkers. We present here a comprehensive multi-omic blood atlas for ...patients with varying COVID-19 severity in an integrated comparison with influenza and sepsis patients versus healthy volunteers. We identify immune signatures and correlates of host response. Hallmarks of disease severity involved cells, their inflammatory mediators and networks, including progenitor cells and specific myeloid and lymphocyte subsets, features of the immune repertoire, acute phase response, metabolism, and coagulation. Persisting immune activation involving AP-1/p38MAPK was a specific feature of COVID-19. The plasma proteome enabled sub-phenotyping into patient clusters, predictive of severity and outcome. Systems-based integrative analyses including tensor and matrix decomposition of all modalities revealed feature groupings linked with severity and specificity compared to influenza and sepsis. Our approach and blood atlas will support future drug development, clinical trial design, and personalized medicine approaches for COVID-19.
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•Blood atlas delineating innate and adaptive immune dysregulation in COVID-19•Shared and specific immune signatures of COVID-19, influenza and all cause sepsis•Multi-omic immune profiling differentiates hospitalized patient severity in COVID-19•Immune activation and proliferation involving AP-1/p38MAPK associated with COVID-19
A multi-omic analysis of patient blood samples reveals both similarities and specific features of COVID-19 when compared with samples obtained from sepsis or influenza patients, which could yield better targeted therapies for severe COVID-19.
Cost-effective guidance of therapeutic strategy in Crohn's disease patients with secondary infliximab (IFX) treatment failure may be achieved by serum IFX and anti-IFX antibody (Ab) measurements by ...radioimmunoassay (RIA). This study investigated implications of using other techniques for this purpose.
This is a post hoc analysis of randomized clinical trial including 66 Crohn's disease patients with IFX failure in whom IFX and anti-IFX Ab measurements by RIA had been used for therapeutic guidance. Samples were additionally assessed by enzyme-linked immunosorbent assay (ELISA), homogeneous mobility shift assay (HMSA), and functional cell-based reporter gene assay (RGA).
IFX detection was comparable between assays (82% RIA, 76% ELISA, 88% HMSA, and 74% RGA), and it correlated significantly (Pearson's r=0.91-0.97, P<0.0001). However, IFX concentrations varied systematically between all pair of assays except RIA-RGA. Anti-IFX Ab detection was variable (27% RIA, 9% ELISA, 33% HMSA, and 11% RGA), but correlated significantly (Pearson's r=0.77-0.96; P<0.0001). Anti-IFX Abs detected by RIA and HMSA were often from sera without drug-neutralizing activity (RGA). Assays agreed on classification of underlying mechanism for treatment failure in most cases (79-94%). The majority (74-88%) failed IFX owing to pharmacodynamic problems, or had noninflammatory pathophysiology for symptoms resembling relapse. Applied threshold for therapeutic vs. subtherapeutic IFX level influenced classifications. The four different assays did not differ in terms of the ability to predict response to interventions defined by the algorithm.
Despite variable analytical properties, common assays result in similar classifications and interventions in patients with IFX treatment failure, and with comparable clinical outcomes. Implications are, however, profound for the minority classified differently.
To investigate if the combined assessment of anti-infliximab antibodies (Ab) and the degree of TNF-alpha binding capacity (TNF-alpha-BC) afforded by infliximab may predict the response to infliximab ...treatment in patients with Crohn's disease (CD).
Three groups of CD patients, in total 33 patients, treated with infliximab were retrospectively selected: (a) patients with a maintained response throughout treatment; (b) patients with good initial response, but subsequent loss of response; and (c) patients with inadequate response to the first two or three doses. Blood samples were analyzed for TNF-alpha-BC and Ab using fluid-phase radioimmunoassay (RIA).
At 8 wk after last infliximab infusion, TNF-alpha-BC was significantly higher (P = 0.002) in patients maintaining response (median interquartile range 2.9 0.9-4.3 microg/mL), as compared to patients losing response (0.0 0-0.1 microg/mL). Conversely, Ab levels were significantly lower (P < 0.0001) in patients maintaining response (1.3 0-6% bound tracer/total tracer), as compared to patients losing response (19 14-27%). Ab were not present and TNF-alpha-BC was high (30 20-32) in patients with no primary response.
While secondary loss of response to infliximab is associated with high levels of Ab and low levels of TNF-alpha-BC, primary response failure may be seen in the presence of high effective levels of TNF-alpha-BC afforded by infliximab. The results suggest that combined assessment of anti-infliximab Ab and serum TNF-alpha-BC may pave the way for a more rational use of infliximab in patients with CD.
We develop all of the components needed to construct an adaptive finite element code that can be used to approximate fractional partial differential equations, on non-trivial domains in d≥1 ...dimensions. Our main approach consists of taking tools that have been shown to be effective for adaptive boundary element methods and, where necessary, modifying them so that they can be applied to the fractional PDE case. Improved a priori error estimates are derived for the case of quasi-uniform meshes which are seen to deliver sub-optimal rates of convergence owing to the presence of singularities. Attention is then turned to the development of an a posteriori error estimate and error indicators which are suitable for driving an adaptive refinement procedure. We assume that the resulting refined meshes are locally quasi-uniform and develop efficient methods for the assembly of the resulting linear algebraic systems and their solution using iterative methods, including the multigrid method. The storage of the dense matrices along with efficient techniques for computing the dense matrix–vector products needed for the iterative solution is also considered. The performance and efficiency of the resulting algorithm is illustrated for a variety of examples.
•Construct an adaptive finite element code that can be used to approximate fractional partial differential equations, on non-trivial domains in d≥1 dimensions.•Improved a priori error estimates are derived for the case of quasi-uniform meshes.•Development of an a posteriori error estimate and error indicators which are suitable for driving an adaptive refinement procedure.•Develop efficient methods for the assembly of the resulting linear algebraic systems and their solution using iterative methods, including the multigrid method.•The storage of the dense matrices along with efficient techniques for computing the dense matrix–vector products needed for the iterative solution is also considered.
Background
In Crohn’s disease patients failing infliximab therapy, interventions defined by an algorithm based on infliximab and anti-infliximab antibody measurements have proven more cost-effective ...than intensifying the infliximab regimen.
Aim
This study investigated long-term economic outcomes at the week 20 follow-up study visit and after 1 year. Clinical outcomes were assessed at week 20.
Methods
Follow-up from a 12-week, single-blind, clinical trial where patients with infliximab treatment failure were randomized to infliximab intensification (5 mg/kg every 4 weeks) (
n
= 36), or algorithm-defined interventions (
n
= 33). Accumulated costs, expressed as mean costs per patient, were based on the Danish National Patient Registry.
Results
At the scheduled week 20 follow-up study visit, response and remission rates were similar in all study subpopulations between patients treated by the algorithm or by infliximab intensification. However, the sum of healthcare costs related to Crohn’s disease was substantially lower (31 %) for patients randomized to algorithm-based interventions than infliximab intensification in the intention-to-treat population: $11,940 versus $17,236;
p
= 0.005. For per-protocol patients (
n
= 55), costs at the week 20 follow-up visit were even lower (49 %) in the algorithm group: $8,742 versus $17,236;
p
= 0.002. Figures were similar for patients having completed the 12-week trial as per protocol (50 % reduction in costs) (
n
= 45). Among patients continuing the allocated study intervention throughout the entire 20-week follow-up period (
n
= 29), costs were reduced by 60 % in algorithm-treated patients: $7,056 versus $17,776;
p
< 0.001. Cost-reduction percentages remained stable throughout one year.
Conclusion
Economic benefit of algorithm-based interventions at infliximab failure is maintained throughout 1 year.
We derive a fractional Cahn-Hilliard equation (FCHE) by considering a gradient flow in the negative order Sobolev space H-α, α ϵ 0,1, where the choice α = 1 corresponds to the classical Cahn-Hilliard ...equation while the choice α = 0 recovers the Allen-Cahn equation. The existence of a unique solution is established and it is shown that the equation preserves mass for all positive values of fractional order α and that it indeed reduces the free energy. We then turn to the delicate question of the L∞ boundedness of the solution and establish an L∞ bound for the FCHE in the case where the nonlinearity is a quartic polynomial. As a consequence of the estimates, we are able to show that the Fourier-Galerkin method delivers a spectral rate of convergence for the FCHE in the case of a semidiscrete approximation scheme. Finally, we present results obtained using computational simulation of the FCHE for a variety of choices of fractional order α. It is observed that the nature of the solution of the FCHE with a general α > 0 is qualitatively (and quantitatively) closer to the behavior of the classical Cahn-Hilliard equation than to the Allen-Cahn equation, regardless of how close to zero the value of α is. An examination of the coarsening rates of the FCHE reveals that the asymptotic rate is rather insensitive to the value of α and, as a consequence, is close to the well-established rate observed for the classical Cahn-Hilliard equation.
If the nodes for the spectral element method are chosen to be the Gauss—Legendre—Lobatto points and a Lagrange basis is used, then the resulting mass matrix is diagonal and the method is sometimes ...then described as the Gauss-point mass lumped finite element scheme. We study the dispersive behavior of the scheme in detail and provide both a qualitative description of the nature of the dispersive and dissipative behavior of the scheme along with precise quantitative statements of the accuracy in terms of the mesh-size and the order of the scheme. We prove that (a) the Gauss-point mass lumped scheme (i.e., spectral element method) tends to exhibit phase lag whereas the (consistent) finite element scheme tends to exhibit phase lead; (b) the absolute accuracy of the spectral element scheme is 1/p times better than that of the finite element scheme despite the use of numerical integration; (c) when the order p, the mesh-size h, and the frequency of the wave ω satisfy 2p + 1 ≈ ωh the true wave is essentially fully resolved. As a consequence, one obtains a proof of the general rule of thumb sometimes quoted in the context of spectral element methods: π modes per wavelength are needed to resolve a wave.
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