Lymphomas in two IBD patients treated with anti-TNF-α mono or combination therapy: Is hepatosplenic lymphoma really the “old maid”?

2011 ◽  
Vol 17 (9) ◽  
pp. 2025-2026 ◽  
Author(s):  
Tamás Molnár ◽  
Klaudia Farkas ◽  
Ferenc Nagy ◽  
Zoltán Szepes ◽  
Tibor Wittmann
2021 ◽  
Vol 19 ◽  
pp. 205873922110005
Author(s):  
Yongle Sun ◽  
Jing Geng ◽  
Deyu Wang

Aging is the crucial co-morbidity that prevents the full cardioprotection against myocardial ischemia/reperfusion (I/R) injury. Combination therapy as a promising strategy may overcome this clinical problem. This study aimed to investigate the cardioprotective effects of Ginsenoside compound-Mc1 (GMc1) and Dendrobium Nobile Lindl (DNL) in myocardial I/R injury and explore the involvement of the TLR4/NF-κB signaling pathway in aged rats. In vivo I/R injury and myocardial infarction was established by temporary coronary ligation in 22–24 months’ old Sprague Dawley male rats. GMc1 (10 mg/kg) and DNL (80 mg/kg) were administered intraperitoneally for 4 weeks and orally for 14 days, respectively, before I/R injury. Infarct size was measured through triphenyl-tetrazolium-chloride staining. ELISA assay was conducted to quantify the levels of cardiotroponin, and myocardial content of TNF-α and glutathione. Western blotting was employed to detect the expression of TLR4/MyD88/NF-κB proteins. GMc1 and DNL significantly reduced the infarct size to a similar extent ( p < 0.05) but their combined effect was greater than individual ones ( p < 0.01). Combination therapy significantly restored the left ventricular end-diastolic and developed pressures at the end of reperfusion as compared with the untreated group ( p < 0.01). Although the GMc1 and DNL reduced the levels of inflammatory cytokine TNF-α and increased the contents of antioxidant glutathione significantly, their individual effects on the reduction of protein expression of TLR4/MyD88/NF-κB pathway were not consistent. However, their combination could significantly reduce all parameters of this inflammatory pathway as compared to untreated I/R rats ( p < 0.001). Therefore, the combined treatment with GMc1 and DNL increased the potency of each intervention in protecting the aged hearts against I/R injury. Reduction in the activity of the TLR4/MyD88/NF-κB signaling pathway and subsequent modulation of the activity of inflammatory cytokines and endogenous antioxidants play an important role in this cardioprotection.


Digestion ◽  
2003 ◽  
Vol 68 (1) ◽  
pp. 1-4 ◽  
Author(s):  
U. Schiemann ◽  
J. Glas ◽  
P. Török ◽  
C. Simperl ◽  
K. Martin ◽  
...  

2020 ◽  
Vol 18 (1) ◽  
Author(s):  
Takashi Inoue ◽  
Shokei Murakami ◽  
Kenji Matsumoto ◽  
Akio Matsuda

Abstract Background Kawasaki disease (KD) is the most common pediatric systemic vasculitides of unknown etiology. Recent clinical studies led to reappraisal of the usefulness of initial combination therapy of intravenous immunoglobulin (IVIG) plus a corticosteroid for patients with severe KD. However, the molecular mechanisms underlying the clinical benefits of that combination therapy remain unclear. Here, we used cultured human coronary artery endothelial cells (HCAECs), as a mimic of KD, to study the possible mechanisms responsible for the clinical benefits of adding a corticosteroid to standard IVIG therapy for patients with severe KD. Methods HCAECs were stimulated with TNF-α, IL-1α or IL-1β in the presence and absence of high-dose IgG and/or dexamethasone (DEX). The mRNA and protein concentrations for high-mobility group box-1 (HMGB1), IL-1α, IL-6 and granulocyte-colony stimulating factor (G-CSF) in the culture supernatants were measured by quantitative PCR (qPCR) and ELISA, respectively. Apoptosis was evaluated by the caspase 3/7 activities. Results DEX, but not IgG, significantly inhibited apoptosis caused by inflammatory stimuli, resulting in effective reduction of HMGB1 and IL-1α protein release by HCAECs. As previously reported, DEX or IgG alone significantly suppressed TNF-α-induced production of IL-6 and G-CSF and mRNA expression, but induction of those cytokines by IL-1 s (IL-1α and IL-1β) was resistant to high-dose IgG. Conclusions A corticosteroid can effectively inhibit the release of HMGB1 and IL-1α, which may be involved in IVIG resistance in KD. Since high-dose IgG does not have such beneficial anti-cytotoxic effects, adding a corticosteroid to standard IVIG therapy may help prevent the progression of IVIG resistance in KD.


Author(s):  
Ken Lund ◽  
Michael Due Larsen ◽  
Torben Knudsen ◽  
Jens Kjeldsen ◽  
Rasmus Gaardskær Nielsen ◽  
...  

Abstract Background and Aims In paediatric patients with Crohn’s disease, the role of combination therapy, infliximab plus immunomodulators [thiopurine or methotrexate], is debated and data are sparse. We examined whether infliximab plus immunomodulators, compared to infliximab therapy alone, reduces the risk of treatment failure measured by intestinal surgery or switching type of anti-tumour necrosis factor [TNF] α agent within 24 months. Design Using Danish registries, we identified patients with Crohn’s disease, aged ≤ 20 years at the time of the first infliximab treatment, and retrieved data on their co-medications. We used Cox regression models to examine surgery or switching type of anti-TNFα agent from January 1, 2003 to December 31, 2015. Results We included 581 patients. The 2-year cumulative percentage of surgery was 8.5% among patients receiving combination therapy and 14.5% in those receiving infliximab alone. The adjusted 2-year hazard ratio [HR] of surgeries was 0.53 (95% confidence interval [CI] 0.32–0.88) in patients receiving combination therapy, compared to patients receiving infliximab alone. When examining a switch of anti-TNFα we included 536 patients. Within 2 years, 18.3% experienced a switch among patients receiving combination therapy and 24.8% in patients treated with infliximab alone, corresponding to an adjusted HR of 0.66 [95% CI 0.45–0.97] in patients receiving combination therapy. Conclusions The HR of intestinal surgeries and the risk of a switch to another anti-TNFα was reduced in paediatric and adolescent patients receiving combination therapy, compared to patients receiving only infliximab. These results suggest a benefit for infliximab therapy combined with immunomodulators, but these need to be confirmed in data with additional clinical information.


2008 ◽  
Vol 22 (S2) ◽  
pp. 473-473
Author(s):  
Debra Bryce Gardner ◽  
Ashlyn Bassiri ◽  
Peter Bugelski ◽  
Robert Sarisky ◽  
Bailin Liang

2021 ◽  
Vol 39 (15_suppl) ◽  
pp. 2584-2584
Author(s):  
Penghui Xing ◽  
Jinyan Zhang ◽  
Rongfeng Liu ◽  
Junyan Wang ◽  
Ming Ma ◽  
...  

2584 Background: PD-1 inhibitors have transformed the treatment landscape for patients (pts) with many advanced malignancies. Combination therapy with PD-1 inhibitors for cancer is a trend. However, Biomarkers for the efficacy of combination therapy remains unknown. In order for the benefited population to be screened out, biomarkers need to be established. we will conduct the following study, to explore the IFN-α, IFN-γ, IL-2 combined with TNF-α for predicting efficacy of PD-1 inhibitors combination therapy. Methods: Using postoperative without lesions as control group (n=7). Pts with lesions as the experimental group (n=66). 27 of 66 pts received chemoradiotherapy (group A), 39 of 66 pts received PD-1 inhibitors combined with therapy (group B). IFN-α, IFN-γ, IL-2, TNF-α in peripheral blood of all pts were measured using flow cytometry. Results: 1) There was significant difference in proportion above normal concentrations (ANCs) of IFN-α between two groups (57.1% vs 43.5%, P<0.05), but there was no significant difference in IFN-γ, IL-2 and TNF-α between two groups (IFN-γ 57.1% vs 52.2%, IL-2 14.3% vs 5.8%, TNF-α 42.9% vs 43.5%, P>0.05). 2) The normal ratios of IFN-α, IFN-γ and TNF-α in group B was significantly higher than that in group A (IFN-α 64.1% vs 51.9%, IFN-γ 59% vs 37%, TNF-α 69.2% vs 44.4%, P<0.05). The proportion ANCs of IFN-α, IFN-γ, and TNF-α were lower in group A (IFN-α 35.9% vs 63%, P>0.05; IFN-γ 41% vs 63%, P<0.05; TNF-α 30.8% vs 55.6%, P<0.05). However, the proportion ANCs of IL-2 detection was lower (7.4% vs 5.1%). 3) In group B, 21 of 39 pts were evaluable. ORR was 52.4% (11/21) and DCR was 85.7% (18/21). The proportion ANCs of IFN-α, IFN-γ and TNF-α in the pts with PR was higher than that with SD (IFN-α 37.5% vs 28.6%, IFN-γ 37.5% vs 28.6%, TNF-α 50% vs 38.8%, P<0.05). 4) We found that the coincidence rate of IFN-α+ IFN-γ and IFN-α+ IFN-γ+TNF-α was higher in group B (Table). Conclusions: Our results suggest that the proportion ANCs of IFN-α, IFN-γ, and TNF-α in the pts with lesions were lower than that without lesions, it may be the decrease of immune function with lesions. There was positive correlation between proportion ANCs of IFN-α, IFN-γ and TNF-α and efficacy in these pts. IL-2 was not used as a routine detection indicator. The coincidence rate of IFN-α, IFN-γ combined with TNF-α was higher, it may help predict the outcome of PD-1 inhibitors combination therapy in pts with solid cancers, and helpful to screen the benefit population. Further study is needed.[Table: see text]


Author(s):  
Noriaki Tanaka ◽  
Hiromasa Kasino ◽  
Akira Gouchi ◽  
Akio Hizuta ◽  
Yoshio Naomoto ◽  
...  

2020 ◽  
Vol 2020 ◽  
pp. 1-10
Author(s):  
Shaoxue Ding ◽  
Xiaowei Liang ◽  
Tian Zhang ◽  
Rong Fu

Severe aplastic anemia (SAA) is a rare disease characterized by severe pancytopenia and bone marrow failure. Most patients with AA respond to immunosuppressive therapy (IST), usually as antithymocyte globulin (ATG) and cyclosporine (CsA), but some relapse on CsA withdrawal or require long-term administration of CsA to maintain blood counts. Recent research has found that rapamycin (Rapa) was an effective therapy in mouse models of immune-mediated bone marrow failure. However, it has not achieved a satisfactory effect in clinical application. At present, many studies have confirmed that eltrombopag (ELT) combined with IST can improve the curative effect of AA patients. Then, whether Rapa combined Elt in the treatment of AA will acquire better efficacy than a single drug application remains unclear. In this study, an immune attack-mediated AA mouse model was constructed by total body irradiation (TBI) and allo-lymphocyte infusion. In our study, we tested the efficacy of Rapa combined with Elt as a new treatment in mouse models of immune-mediated bone marrow failure. It showed that treatment with Rapa in combination Elt in the AA mouse model ameliorated pancytopenia and extended animal survival in a manner comparable to the standard dose of CsA and Rapa alone. However, there was no significant improvement effect on the number and function of NK cells and their subsets, mDCs, and CD4+/CD8+ ratio in AA mice after the therapy of Rapa combined with Elt compared with Rapa alone. Furthermore, the secretion of IL-10 of Tregs in AA mice increased significantly after the therapy of Rapa combined with Elt, but there was no significant difference in the number of Treg cells. We did not observe the difference in the curative effect of the Rapa group and CsA group, but for IL-10/Tregs ratio, the Rapa group was superior to the CsA group. And the IFN-r secretion of CD8+T cells in AA mice decreased significantly after the combination therapy of Rapa and Elt than Rapa alone. Compared with the AA group, the level of plasma IFN-γ, IL-2, and TNF-α decreased significantly ( P < 0.05 ), but IL-10, IL-4, IL-5, and IL-1β increased significantly in the Rapa group ( P < 0.05 ). As for IL-10, IL-12p70, IL-2, IL-6, KC/GRO, and TNF-α, the therapy of Rapa combined with Elt showed a more significant effect than Rapa alone in AA mice. To some extent, this study had shown a relatively better synergistic effect in murine models of immune-mediated bone marrow failure after the combination therapy of Rapa and Elt, which was a promising clinical utility in SAA treatment.


2017 ◽  
Vol 35 (1-2) ◽  
pp. 56-60 ◽  
Author(s):  
Wolfgang Kruis ◽  
Phuong G. Nguyen ◽  
Julia Morgenstern

The efficiency of the existing methods of treating inflammatory bowel disease (IBD) is limited. There are 2 ways to address this problem - either create new treatment modalities or optimize current therapies. Optimisation may be accomplished by using combinations of established therapeutic strategies. With regard to topically acting compounds such as 5-aminosalicylic acid, combining oral and rectal preparations is a commonly used method. Another commonly used combination is anti-tumor necrosis factor (TNF)-α antibody modalities together with immunosuppressants (thiopurines, methotrexate). Several aspects favour those combinations such as increased effectivity, prevention of immunogenicity and perhaps less adverse events. Currently, discussion on directly additive therapeutic effects is in progress, which have been demonstrated in some clinical trials. As on date, the combination of infliximab with azathioprine is most likely the most effective treatment of Crohn's disease. On the other hand, a combination therapy with both compounds affecting the immune system has, of course, risks. For sure, the frequency with which serious infectious complications are arising is increasing. Furthermore, the number of patients experiencing malignancies such as hepato-splenic lymphoma or melanoma is strongly suspected to be on the rise. In summary, combinations of current treatments for IBD are widely established. Various strategies have been studied and significant improvements of therapeutic effects have been demonstrated. Unfortunately, some of those proven combinations increase therapeutic risks, for example, increase the frequency of serious infections and also of some malignancies. Therefore, great caution has to be exercised when applying combination therapies.


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