Immunomodulator comedication promotes the reversal of anti-drug antibody-mediated loss of response to anti-TNF therapy in inflammatory bowel disease.

PURPOSE: Loss of therapeutic response (LOR) due to anti-drug antibodies (ADA) against tumor necrosis factor (TNF) inhibitors is common in patients with inflammatory bowel disease (IBD). We aimed to investigate whether immunomodulator comedication can reverse the immunogenic LOR to TNF inhibitors in IBD. METHODS: In this real-world retrospective cohort study, 123 IBD patients with neutralizing ADA to infliximab or adalimumab and concomitant subtherapeutic trough levels were screened for clinical LOR. Subsequent ADA and trough level measurements and clinical outcomes were analyzed for patients who received either immunomodulator comedication or dose intensification of infliximab or adalimumab to overcome LOR. RESULTS: Following immunogenic LOR, the initial anti-TNF regimen was optimized in 33 patients. In univariable and multivariable logistic regression analyses, immunomodulator comedication was identified as the crucial factor for regaining clinical remission and ADA clearance. Detectable trough levels (≥ 0.98 or ≥ 1.00 mg/L, respectively) had optimal predictive performance for both endpoints in receiver operating characteristics curves [area under the curve 0.86 (95% confidence interval 0.68-1.00) for regaining clinical remission, 0.87 (0.71-1.00) for ADA clearance]. Furthermore, 11/20 patients (55%) on a comedication with azathioprine or methotrexate and 2/13 patients (15%) receiving anti-TNF dose intensification exclusively (P = 0.032) exhibited ADA elimination, regain of therapeutic trough levels, and clinical remission. Regain of clinical remission alone was achieved in 17/20 (85%) patients receiving comedication and 2/13 (15%) patients receiving anti-TNF dose intensification (P = 1.6 × 10-4). CONCLUSION: Immunogenic LOR to infliximab or adalimumab in IBD can be successfully reversed using immunomodulator comedication.

[Drug treatment of chronic inflammatory bowel diseases-What must the surgeon know and perioperatively pay attention to?] / Medikamentöse Therapie chronisch entzündlicher Darmerkrankungen ­ Was muss der Chirurg wissen und perioperativ beachten?

Mesalamine and topical or systemic corticosteroids form the basis of medicinal treatment of patients with chronic inflammatory bowel diseases (IBD), whereas immunosuppressants, biologicals and JAK inhibitors, so-called small molecules, are administered within so-called step-up treatment algorithms. Even though the frequency of operations has decreased during the last decades, surgical interventions still represent a relevant part of the overall concept in IBD treatment. Therefore, the effects of drug pretreatment on surgical approaches have to be put into specific perspectives and contexts. Treatment with corticosteroids unquestionably increases the rate of perioperative complications but there is no such correlation for the use of biologicals or immunosuppressants. Data from older studies pointed towards slightly increased rates of postoperative complications in patients treated with TNF-alpha antibodies; however, more recent studies have not confirmed this risk. The occurrence of postoperative complications is due to the multifactorial origin and is more dependent on the activity of the underlying disease, the comorbidities and the preoperative nutritional status. Preoperative use of the integrin inhibitor vedolizumab is comparable to TNF-alpha antibodies with respect to the postoperative complication rate. This also seems to apply to the interleukin 12/23 antagonist ustekinumab, although the data are still unreliable. The risks after treatment with the Janus kinase inhibitor tofacitinib cannot currently reliably be estimated. For the postoperative care an endoscopic follow-up should be performed within 6 months and prophylactic treatment with immunosuppressors or biologicals can be considered after taking the individual risk factors into account.

The exposure of cancer cells to hyperthermia, iron oxide nanoparticles, and mitomycin C influences membrane multidrug resistance protein expression levels.

PURPOSE: The presence of multidrug resistance-associated protein (MRP) in cancer cells is known to be responsible for many therapeutic failures in current oncological treatments. Here, we show that the combination of different effectors like hyperthermia, iron oxide nanoparticles, and chemotherapeutics influences expression of MRP 1 and 3 in an adenocarcinoma cell line. METHODS: BT-474 cells were treated with magnetic nanoparticles (MNP; 1.5 to 150 µg Fe/cm(2)) or mitomycin C (up to 1.5 µg/cm(2), 24 hours) in the presence or absence of hyperthermia (43°C, 15 to 120 minutes). Moreover, cells were also sequentially exposed to these effectors (MNP, hyperthermia, and mitomycin C). After cell harvesting, mRNA was extracted and analyzed via reverse transcription polymerase chain reaction. Additionally, membrane protein was isolated and analyzed via sodium dodecyl sulfate polyacrylamide gel electrophoresis (SDS-PAGE) and immunoblotting. RESULTS: When cells were exposed to the effectors alone or to combinations thereof, no effects on MRP 1 and 3 mRNA expression were observed. In contrast, membrane protein expression was influenced in a selective manner. The effects on MRP 3 expression were less pronounced compared with MRP 1. Treatment with mitomycin C decreased MRP expression at high concentrations and hyperthermia intensified these effects. In contrast, the presence of MNP only increased MRP 1 and 3 expression, and hyperthermia reversed these effects. When combining hyperthermia, magnetic nanoparticles, and mitomycin C, no further suppression of MRP expression was observed in comparison with the respective dual treatment modalities. DISCUSSION: The different MRP 1 and 3 expression levels are not associated with de novo mRNA expression, but rather with an altered translocation of MRP 1 and 3 to the cell membrane as a result of reactive oxygen species production, and with shifting of intracellular MRP storage pools, changes in membrane fluidity, etc, at the protein level. Our results could be used to develop new treatment strategies by repressing mechanisms that actively export drugs from the target cell, thereby improving the therapeutic outcome in oncology.