Meta-Analysis of the Risk of Immune-Related Adverse Events With Anticytotoxic T-Lymphocyte-Associated Antigen 4 and Antiprogrammed Death 1 Therapies.

We assessed the risks of immune-related adverse events with anticytotoxic T-lymphocyte-associated antigen 4 (CTLA4) and antiprogrammed death 1 (PD1) therapies by meta-analysis. Twenty-one studies including 11,144 patients were found. Anti-CTLA4 therapy was associated with a significantly higher risk of overall immune-related adverse events: diarrhea, immune-related colitis, pruritus, and rash compared to control therapies (relative risk (RR) = 2.43, 2.10, 11.39, 3.88, 3.87, 95% confidence interval (CI) = 1.77-3.34, 1.52-2.45, 6.30-20.59, 2.37-6.37, 2.39-6.27, P < 0.001 for all outcomes). Anti-PD1 therapy was associated with a significantly higher risk of pruritus (RR = 4.01, 95% CI = 1.97 to 8.17, P < 0.001); however, it did not increase the risks of other adverse events. Anti-CTLA4 and anti-PD1 therapies have distinct features of immune-related adverse events. The results of our study would aid the surveillance and management of immune-related adverse events in patients receiving these therapies.

The benefit of combination therapy depends on disease phenotype and duration in Crohn's disease.

BACKGROUND: The impact of combination therapy on disease-related morbidity in patients with established Crohn's disease (CD) or ulcerative colitis (UC) remains to be well-defined. AIM: To examine the effect of combination therapy on disease outcomes in CD and UC. METHODS: Using a multicenter prospective cohort, we classified CD and UC patients as being on monotherapy with anti-TNF or on combination with an immunomodulator. The primary outcome was a composite of new IBD-related surgery, hospitalisations, penetrating complications, need for corticosteroids or new biological at 1 year. Multivariable regression models adjusted for potential confounders. RESULTS: We included 707 patients with CD (45% combination therapy) and 164 with UC (38% combination therapy). Combination therapy was not associated with reduction in the composite outcome in either CD (OR: 0.87, 95% CI: 0.63-1.22) or UC (OR: 1.45, 95% CI: 0.63-3.38). However, while no difference was noted in those with nonstricturing, nonpenetrating CD, a significant reduction in the likelihood of the outcome was seen in those with stricturing or penetrating CD (30% vs 39%, OR: 0.58, 95% CI: 0.37-0.90). A stronger effect was also observed in those with disease duration <5 years (OR: 0.35, 95% CI: 0.14-0.87) compared to those with a longer duration (OR: 0.75, 95% CI: 0.45-1.27). A similar reduction in occurrence of composite outcome was noted with infliximab and with other anti-TNF biologics. CONCLUSION: The benefit of combination immunomodulator-biological therapy is stronger in those with complicated Crohn's disease, particularly early on in their disease course.

Systematic review with meta-analysis: the efficacy and safety of CT-P13, a biosimilar of anti-tumour necrosis factor-α agent (infliximab), in inflammatory bowel diseases.

BACKGROUND: Biosimilars of anti-tumour necrosis factor (TNF)-α agents have now become clinically available for the treatment of inflammatory bowel diseases (IBD). AIM: To perform a systematic review and meta-analysis to evaluate the efficacy and safety of biosimilars of anti-TNF-α agents in patients with IBD. METHODS: Electronic databases were searched. The outcomes were the pooled rates of clinical response or remission, sustained clinical response or remission, and adverse events in patients with IBD induced with or switched to biosimilars of anti-TNF-α agents. RESULTS: Eleven observational studies reporting outcomes in 829 patients treated with biosimilar of infliximab (CT-P13) were identified. The pooled rates of clinical response among Crohn's disease (CD) and ulcerative colitis (UC) at 8-14 weeks were 0.79 (95% confidence interval (CI) = 0.65-0.88) and 0.74 (95% CI = 0.65-0.82), respectively, and at 24-30 weeks were 0.77 (95% CI = 0.63-0.86) and 0.77 (95% CI = 0.67-0.85) respectively. Adverse events were rare (CD, 0.08 (95% CI = 0.02-0.26); UC, 0.08 (95% CI = 0.03-0.17)). The pooled rates of sustained clinical response among CD and UC after switching from infliximab to CT-P13 at 30-32 weeks were 0.85 (95% CI = 0.71-0.93) and 0.96 (95% CI = 0.58-1.00), respectively, and at 48-63 weeks were 0.75 (95% CI = 0.44-0.92) and 0.83 (95% CI = 0.19-0.99) respectively. Adverse events were rare (CD, 0.10, 95% CI = 0.02-0.31; UC, 0.22, 95% CI = 0.04-0.63). CONCLUSIONS: CT-P13 was associated with excellent clinical efficacy and safety profile, supporting its use in the treatment of IBD.

Osteopontin/Eta-1 upregulated in Crohn's disease regulates the Th1 immune response.

BACKGROUND AND AIMS: The pathogenesis of Crohn's disease (CD), a chronic inflammatory bowel disease characterised by a Th1 immune response, remains unclear. Osteopontin (OPN) is a phosphoprotein known as an adhesive bone matrix protein. Recent studies have shown that OPN plays an important role in lymphocyte migration, granuloma formation, and interleukin 12 (IL-12) production. The present study investigated expression and the pathophysiological role of OPN in CD. METHODS: Plasma OPN concentration was measured by enzyme linked immunosorbent assay. Expression of OPN in human intestinal mucosa was determined using reverse transcription-polymerase chain reaction and western blot, and localisation of OPN was examined by immunohistochemistry. Expression of integrin beta3, an OPN receptor, on lamina propria mononuclear cells (LPMC) was assessed by flow cytometry. Functional activation of OPN in LPMC was investigated by measuring the production of cytokines. RESULTS: Plasma OPN concentration was significantly higher in patients with CD compared with normal controls or patients with ulcerative colitis (UC). OPN was upregulated in intestinal mucosa from UC and CD patients. OPN producing cells were epithelial or IgG producing plasma cells, or partial macrophages. OPN was detected in areas surrounding granuloma from mucosa in CD. Integrin beta3 expressing macrophages infiltrated inflamed mucosa in UC and CD; in contrast, there was no expression of integrin beta3 on intestinal macrophages in normal mucosa. OPN induced production of IL-12 from LPMC in CD but not in normal controls or UC. CONCLUSIONS: Increased OPN expression facilitates cytokine production and is closely involved in the Th1 immune response associated with CD.

T-bet upregulation and subsequent interleukin 12 stimulation are essential for induction of Th1 mediated immunopathology in Crohn's disease.

BACKGROUND AND AIMS: Many lines of evidence suggest that T helper cell type 1 (Th1) immune responses predominate in Crohn's disease (CD). Recently, a novel transcription factor T-box expressed in T cells (T-bet) has been reported as the master regulator of Th1 development. This study was designed to investigate the role of T-bet and proinflammatory cytokines in Th1 mediated immunopathology in CD. MATERIALS: CD4+ lamina propria mononuclear cells (LPMCs) were isolated from surgically resected specimens (CD, n = 10; ulcerative colitis (UC), n = 10; normal controls (NL), n = 5). METHODS: (1) T-bet expression of CD4+ LPMCs was examined by quantitative real time polymerase chain reaction and western blotting. (2) T-bet expression of LPMCs stimulated by interleukin (IL)-12/IL-18 was analysed by western blotting. (3) Interferon gamma (IFN-gamma) production and T-bet expression of CD4+ peripheral blood mononuclear cells (PBMCs) were examined with or without stimulation by anti-CD3/CD28 monoclonal antibodies and/or IL-12. RESULTS: (1) T-bet expression of CD4+ LPMCs was increased in CD compared with UC and NL. (2) Synergistically, augmentation of IFN-gamma production by IL-12/IL-18 was independent of T-bet expression in LPMCs. (3) T-bet was induced by T cell receptor stimulation in CD4+ PBMCs. T-bet induction correlated with IFN-gamma production and with augmentation of surface expressed IL-12 receptor beta2. CONCLUSIONS: T-bet induction by antigenic stimulation and subsequent stimulation by macrophage derived IL-12/IL-18 are important for establishing Th1 mediated immunopathology in CD.

Different binding sites for the neuropeptide Y Y1 antagonists 1229U91 and J-104870 on human Y1 receptors.

The peptidic Y1 antagonist 1229U91 and the non-peptidic antagonist J-104870 have high binding affinities for the human Y1 receptor. These Y1 antagonists show anorexigenic effects on NPY-induced feeding in rats, although they have completely different structures and molecular sizes. To identify the binding sites of these ligands, we substituted amino acid residues of the human Y1 receptor with alanine and examined the abilities of the mutant receptors to bind the radio-labeled ligands. Alanine substitutions, F98A, D104A, T125A, D200A, D205A, L215A, Q219A, L279A, F282A, F286A, W288A and H298A, in the human Y1 receptor lost their affinity for the peptide agonist PYY, but not for 1229U91 and J-104870, while L303A and F173A lost affinity for 1229U91 and J-104870, respectively. N283A retained its affinity for 1229U91, but not for PYY and J-104870. Y47A and N299A retained their affinity for J-104870, but not for PYY and 1229U91. W163A and D287A showed no affinity for any of the three ligands. Taken together, these data indicate that the binding sites of 1229U91 are widely located in the shallow region of the transmembrane (TM) domain of the receptor, especially TM1, TM6 and TM7. In contrast, J-104870 recognized the pocket formed by TM4, TM5 and TM6, based on the molecular modeling of the Y1 receptor and J-104870 complex. In conclusion, 1229U91 and J-104870 have high affinities for Y1 receptors using basically different binding sites. D287 of the common binding site in the TM6 domain could be crucial for the binding of Y1 antagonists.

The novel neuropeptide Y Y(1) receptor antagonist J-104870: a potent feeding suppressant with oral bioavailability.

Neuropeptide Y (NPY) is known to induce robust feeding through the action of NPY receptors in the hypothalamus. Among the subtypes of NPY receptors, Y(1) receptors may play a key role in feeding regulation. In the present study, we demonstrated that a novel Y(1) antagonist, J-104870, shows high selectivity and potency for the Y(1) receptor with an anorexigenic effect on NPY-mediated feeding. J-104870 displaced [(125)I]peptide YY (PYY) binding to cloned human and rat Y(1) receptors with K(i) values of 0.29 and 0.54 nM, respectively, and inhibited the NPY (10 nM)-induced increase in intracellular calcium levels (IC(50) = 3.2 nM) in cells expressing human Y(1) receptors. In contrast, J-104870 showed low affinities for human Y(2) (K(i) > 10 microM), Y(4) (K(i) > 10 microM), and Y(5) receptors (K(i) = 6 microM). In rat hypothalamic membranes, J-104870 also completely displaced the binding of [(125)I]1229U91, which is known to bind to the typical Y(1) receptor, with a high affinity (K(i) = 2.0 nM). Intracerebroventricular (ICV) injection of J-104870 (200 microg) significantly suppressed NPY (5 microg)-induced feeding in satiated Sprague-Dawley rats by 74%. Furthermore, ICV and oral administration of J-104870 (200 microg and 100 mg/kg, respectively) significantly suppressed spontaneous food intake in Zucker fatty rats. These findings suggested that J-104870 is a selective and potent nonpeptide Y(1) antagonist with oral bioavailability and brain penetrability. In addition, the anorexigenic effect of J-104870 clearly revealed the participation of the Y(1) receptor in NPY-mediated feeding regulation. The potent and orally active Y(1) antagonist J-104970 is a useful tool for elucidating the physiological roles of NPY in obesity.