Mitogen-activated protein kinases (MAPK) are among the major widespread transduction pathways in humans. They are involved in several inflammatory disorders, including the pathogenesis of ...inflammatory bowel disease (IBD). A recent paper showed that activated MAPK are up-regulated on endothelium and fibroblasts from intestinal biopsies of active IBD patients. In vitro experiments demonstrated that MAPK activation on intestinal endothelial cells and fibroblasts are responsible for the production of certain chemokines, increased leukocyte adhesion and transmigration. Specific local inhibition of MAPK activity on endothelial cells and fibroblasts may provide a new mechanism to control mucosal inflammation and leukocyte recruitment into the intestine of active IBD patients.
Several studies have shown that inflammatory bowel diseases (IBD) patients treated with thiopurines have an increased risk of developing skin cancer.
This review is based on recent published ...literature regarding the use of thiopurines in IBD and skin malignancies.
Exposure to thiopurines is significantly associated with nonmelanoma skin cancer, but not with melanoma. Primary and secondary prevention including sun-protective measures and regular dermatologic screening are recommended in IBD patients, particularly in those exposed to thiopurines.
Both when and how immunosuppressive therapy should be resumed in patients with a prior history of skin cancer still remain debatable topics.
The benefit-risk balance between thiopurine therapy and risk of skin cancer should be evaluated in the drug decision process.
The approval of new effective strategies requires the re-evaluation of the positioning of thiopurines within the therapeutic algorithm based on an increasingly individualized approach.
Introduction: Ulcerative colitis (UC) is a chronic relapsing disorder of the colonic tract. Dysregulated innate and adaptive immune pathways contribute to intestinal inflammation in IBD, and ...cytokines, including IL-12 and IL-23, play a key role. The blockade of both IL-12 and IL-23 may have an impact on different pathways of inflammation and could be effective for the treatment of inflammatory bowel diseases.
Ustekinumab is a fully human IgG1κ monoclonal antibody which binds to the shared p40 protein subunit of IL-12 and −23. It is currently approved for several immune-mediated diseases such as moderate to severe plaque psoriasis, psoriatic arthritis, and Crohn's disease, and has shown promising results in UC.
Areas covered: A review of the literature was performed to understand several aspects including the role of IL-12 and −23 in UC, the potential therapeutic role of ustekinumab in inflammatory bowel disease, and the positioning of ustekinumab in the therapeutic algorithm of UC, based on extrapolated data from available randomized clinical trials.
Expert opinion: Ustekinumab is effective and safe in UC, and shows potential advantages compared to other drugs in moderate-to-severe UC.
Abstract
Background
Infliximab (IFX) biosimilars CT-P13 and SB2 have comparable efficacy, safety, and immunogenicity to the originator Remicade (RMC). However, concerns about cross-switching patients ...between the 3 brands were raised in the absence of cross reactivity data between them. We aimed to determine whether antibodies to infliximab (ATI) in inflammatory bowel disease (IBD) patients cross-react with RMC, CT-P13, and SB2.
Methods
Based on previous ATI status, samples from 34 patients participating in the BIOSIM01 study (13 RMC, 9 CT-P13, and 12 switchers) were selected. Patients were treated with either RMC only, or CT-P13 only, or with RMC switched to CT-P13. Additionally, 28 IFX-naïve patients were assayed as controls. In total, 180 samples were analyzed. ATI trough levels were measured in parallel with 3 different bridging Enzyme Linked Immunosorbent Assays constructed using the 3 drugs. Spearman′s coefficient and percentages of agreement were used to study the correlation between each assay.
Results
In total, 76 samples out of 152 IFX-treated patient samples were ATI-positive (30 RMC, 14 CT-P13, and 32 switchers). All resulted ATI-positive when either CT-P13 or SB2 bridging assays were used. The overall percentage of agreement was 100% when compared either with CT-P13 or SB2 assays. No significant differences were found among ATI levels and coefficients (Spearman's 0.98 to 1.0, P < 0.0001).
Conclusions
ATI of RMC-treated, CT-P13-treated or RMC to CT-P13 switched patients show full cross-reactivity with CT-P13 and SB2. Findings suggest that immunodominant epitopes in the reference and CT-P13 drugs are equally present in SB2. Data support full interchangeability between biosimilars in regard to immunogenicity.
The role of new psychological factors such as psychopathological patterns and defense mechanisms in the care of inflammatory bowel disease (IBD) has been poorly investigated. We aimed to assess the ...psychological characteristics and defense mechanisms of IBD patients.
This was a single-center, observational, cross-sectional study. Consecutive adult IBD patients were enrolled and stratified according to disease activity. Sociodemographic and clinical data were collected, and validated questionnaires (Symptom Checklist-90-R SCL-90-R) for psychological distress, Defense Mechanism Inventory (DMI) for psychological defense mechanisms, and Inflammatory Bowel Disease Questionnaire (IBDQ) for quality of life (QoL) were administered.
Two hundred one patients were enrolled: 101 in remission and 100 with active disease. The mean score for IBDQ was below the cutoff level (156.8 ± 37.8), with a significantly greater impairment of QoL in subjects with flares (136.5 vs 177.5, P < 0.001). Lower scores were associated with female gender. No patients had psychological scores above the cutoff for normality. Statistically higher SCL-90-R scores were found in active patients for obsessive-compulsive disorder (P = 0.026), depression (P = 0.013), anxiety (P = 0.013), phobic anxiety (P = 0.002), psychoticism (P = 0.007), global severity index (GSI) (P = 0.005) and positive symptom total (PST) (P = 0.001). A significantly increased probability of higher global indexes was associated with Crohn's disease and disease flares. None of the defensive Defense Mechanism Inventory (DMI) styles resulted above the cutoff in our cohort.
Further data are needed to demonstrate the potential key role of psychological intervention in the therapeutic strategies utilized for IBD patients, and the identification of specific psychological patterns based on the patients profile is necessary to optimize psychological intervention.
Peroral endoscopic myotomy (POEM) has been recommended for achalasia treatment. To prevent the potential of infective risk, antibiotic prophylaxis is usually administered, whereas the additional need ...of antibiotic therapy after POEM is uncertain. The primary endpoint was to determine whether prophylaxis versus prophylaxis plus short therapy was needed after POEM.
Consecutive patients scheduled for POEM were randomly assigned (1:1) to group A (prophylactic cefazolin 2 g IV) or group B (prophylaxis + cefazolin 2 g IV × 3 followed by oral amoxicillin/clavulanate 3 g/day). Infective risk was assessed by means of host response, namely body temperature and serum levels of white blood cells and C-reactive protein; immune response (the cytokines interleukin IL-6, IL-1β, and tumor necrosis factor-α and microbial translocation mediators lipopolysaccharide binding protein and soluble CD14); and blood cultures at time points before (t0) and after (t1, t2) POEM.
After POEM, none of the 124 enrolled patients (54.6 ± 12.6 years old; 64 men) developed any fever (body temperature: t0, 36.56± .49°C; t1, 36.53± .52°C; t2, 36.48± .41°C), without any differences between groups at any time point. Regarding systemic inflammation, no difference was reported between groups in serum levels of C-reactive protein and white blood cells. Considering microbial translocation mediated response, lipopolysaccharide binding protein (group A: t0, 1539 ± 168.6 pg/mL; t1, 1321 ± 149.1 pg/mL; t2, 2492 ± 283.2 pg/mL; group B: t0, 1318 ± 115.9 pg/mL; t1, 1492 ± 163.8 pg/mL; t2, 2600 ± 328.2 pg/mL) and soluble CD14 (group A: t0, 2.16 ± .15 μg/mL; t1, 1.89 ± .15 μg/mL; t2, 2.2 ± .15 μg/mL; group B: t0, 2.1 ± .13 μg/mL; t1, 2 ± .13 μg/mL; t2, 2.5 ± .2 μg/mL) were similar between the 2 groups; the immune response cytokines IL-6, IL-1β, and tumor necrosis factor-α also were similar in the 2 groups. In relation to blood cultures, at t1 the group B bacteremia rate was 3.2% (2/62) and group A was 1.6% (1/62) with no difference (P = .6). All subsequent blood cultures were negative at t2.
According to our study, postprophylactic short-term antimicrobial therapy after POEM is not required because of a very low residual infective risk. (Clinical trial registration number: NCT03587337.)
Introduction: Biosimilars represent great potential in cost saving and re-investment opportunities in healthcare and allow patients greater access to effective mAbs. Infliximab biosimilars are ...successfully used in all indications for whom the reference product (RP) was approved.
Areas covered: In late 2018, adalimumab biosimilars will also be available in patients with inflammatory bowel disease (IBD).
ABP501, BI 695501, GP2017, and SB5 have been approved by the EMA for the same indications of the reference product (RP, Humira®). Preclinical data show high similarity between all biosimilars and the RP. Clinical data in patients with rheumatoid arthritis and psoriasis also show no differences in terms of efficacy, safety, and immunogenicity. Data in IBD patients are still lacking.
Expert opinion: Biosimilars of adalimumab appear to be clinically equivalent to the RP. Decisions based on choosing the ideal patient to receive or to be switched to a biosimilar of adalimumab, or choosing one biosimilar vs. another, or cross-switching among biosimilars remain the next challenge in the field of IBD.
Inflammatory bowel diseases (IBDs) are immune-mediated chronic inflammatory disorders of the gastrointestinal tract whose pathogenesis is not yet fully understood. Despite the advent of biological ...agents, there are still unmet needs for IBD patients, due to suboptimal rate of sustained remission achieved. Small molecule drugs (SMDs), the next generation of selective drugs in IBD, show promising results in ongoing trials.
We describe the pharmacodynamics and pharmacokinetic features of novel SMDs and their main differences with biologic agents.
Small molecule drugs are a promising class of drugs for the treatment of ulcerative colitis and Crohn's disease with good results in inducing and maintaining remission. Hence, over the next few years physicians will have numerous options of small molecule drugs for the treatment of patients with IBD. This group of drugs are potentially easier to use over biological agents due to pharmacokinetic features such as oral administration, short half-life, high volume of distribution, and lack of immunogenicity. On the other hand, drug-drug interactions can happen with small-molecule drugs, principally due to competitive metabolic and clearance mechanisms.
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