Combination Of Biological Agents Research Articles

Revisiting biochemical pathways for lead and cadmium tolerance by domain bacteria, eukarya, and their joint action in bioremediation.

With the advent rise is in urbanization and industrialization, heavy metals (HMs) such as lead (Pb) and cadmium (Cd) contamination have increased considerably. It is among the most recalcitrant pollutants majorly affecting the biotic and abiotic components of the ecosystem like human well-being, animals, soil health, crop productivity, and diversity of prokaryotes (bacteria) and eukaryotes (plants, fungi, and algae). At higher concentrations, these metals are toxic for their growth and pose a significant environmental threat, necessitating innovative and sustainable remediation strategies. Bacteria exhibit diverse mechanisms to cope with HM exposure, including biosorption, chelation, and efflux mechanism, while fungi contribute through mycorrhizal associations and hyphal networks. Algae, especially microalgae, demonstrate effective biosorption and bioaccumulation capacities. Plants, as phytoremediators, hyperaccumulate metals, providing a nature-based approach for soil reclamation. Integration of these biological agents in combination presents opportunities for enhanced remediation efficiency. This comprehensive review aims to provide insights into joint action of prokaryotic and eukaryotic interactions in the management of HM stress in the environment.

Prospective study of an adalimumab combined with partial enteral nutrition in the induction period of Crohn’s disease

BackgroundAdalimumab monotherapy can suppress gut inflammation and induce remission in active Crohn’s disease but has some limitations. Exclusive enteral nutrition (EEN) is recommended for patients with mild to moderate Crohn’s disease (CD), but implementation is challenging.AimTo evaluate the effectiveness of adalimumab combined with partial enteral nutrition (PEN) in the induction therapy for Crohn’s disease.MethodsA prospective cohort study was designed and a total of 56 patients with active CD who met the criteria for enteral nutrition (EN) treatment in our hospital were selected. The baseline data of all patients were collected including age, sex and other general information. The changes in fecal calprotectin, C-reactive protein (CRP), albumin(Alb), hemoglobin (Hb), platelets (Plt), erythrocyte sedimentation rate (ESR), Crohn’s disease activity index score (CDAI), simple endoscopic score (SES-CD) and body mass index (BMI) were compared between the adalimumab combined with enteral nutrition (ADA+EN) group (N = 37) the adalimumab group (ADA) (N = 19) at week 0 (W0) and treatment outcomes at week 12(W12). Additionally, the differences between the two groups before and after treatment were evaluated. Then the ADA+EN group was divided into an adalimumab combined with exclusive enteral nutrition subgroup (ADA+EEN) and an adalimumab combined with partial nutrition subgroup (ADA+PEN) according to enteral nutrition intake. The changes in fecal calprotectin, CRP, Alb, Hb, Plt, ESR and CDAI, SES-CD and BMI were compared between the ADA+EEN group and the ADA+PEN group at week 0 (W0) and treatment outcomes at week 12(W12). The differences between the two groups before and after treatment were evaluated. To evaluate the effectiveness of the two treatments on patients’ quality of life, nutritional recovery and body composition, patients in the ADA+EN group were needed to complete the Inflammatory Bowel Disease Questionnaire (IBDQ), EQ-5D-5L, the EuroQol visual analogue scale (EQ-VAS) and body composition analysis.A total of 28 patients completed all questionnaires and body composition analyses at week 0 and week 12, including 10 patients in the ADA+EEN group and 18 patients in the ADA+PEN group, respectively. The differences of in IBDQ, EQ-5D-5L and body composition analysis were compared between the two groups at week 0 (W0) and treatment outcomes at week 12(W12). Additionally, the differences between the two groups before and after treatment were evaluated.ResultsThese investigated indexes such as calprotectin, Hb, Plt, ESR, Alb, BMI, CRP, CDAI and SES-CD scores were significantly different before and after treatment in the ADA+EN group (p < 0.01). However, fecal calprotectin, Hb, SES-CD scores and Alb in the ADA group were not statistically significantly different from W0 to W12 (p > 0.05). The fecal calprotectin and CDAI scores in the ADA+EN group were significantly lower than those in the ADA group after treatment. The differences in all factors before and after treatment between the ADA+PEN group and the ADA+EEN group were statistically significant (p < 0.05). However, there was no significant difference between the two groups at week 12 (p > 0.05).ConclusionAdalimumab combined with EN are more effective than ADA monotherapy in terms of endoscopy and clinical remission. By comparing the investigated indicators such as calprotectin, Hb, Plt, ESR ,CRP and SES-CD scores, it was proven that adalimumab combined with partial enteral nutrition or exclusive enteral nutrition has the same remission effect in induced Crohn’s disease. The combination of biological agents and partial nutrition can improve medical order compliance, psychological burden and quality of life. Therefore, adalimumab combined with partial nutrition can be used as the first-line treatment for CD induced remission.

Dual-Targeted Therapy in Pediatric Inflammatory Bowel Disease: A Comprehensive Review.

Inflammatory bowel disease (IBD) is a chronic systemic immune-mediated disorder. The disease is triggered and perpetuated by a complex interplay between genetic predisposition, dysregulated immune responses, and environmental factors. Pediatric IBD is considered to be more aggressive compared with adult-onset IBD, and commonly requires more intensive pharmacological and surgical treatments. Although the use of targeted therapy, such as biologic therapy and small molecule therapy, is on the rise, there are children with IBD who are refractory to all current therapeutic options. For them, a combination of biologic agents or a biologic agent with small molecules as dual-targeted therapy (DTT) may be a possible therapeutic option. The main indications for DTT are high inflammatory burden and refractoriness to standard therapy, extra-intestinal manifestations of IBD, adverse effects of therapy, and co-existing immune-mediated inflammatory disorders. Several combination therapies were described for pediatric refractory IBD. The main ones were anti-tumor necrosis factor (TNF) agents and vedolizumab (VDZ), anti-TNF and ustekinumab (UST), VDZ and UST, and biologic agents with tofacitinib. DTT exhibits high efficacy, with high rates of clinical response and remission as well as biomarker remission. The data on endoscopic and radiologic remission are scarce. Most of the adverse effects reported under DTT were mild; however, the serious ones that had been observed mandate a profoundly cautious approach when considering it. Triple immunosuppressive therapy and combinations of biologics with emergent therapies such as selective Janus kinase inhibitors, sphingosine-1-phosphate receptor modulators, and anti-interleukin-23 agents, are potential future regimens for children with IBD who are refractory to current therapeutic options. This review provides an update of publications on these issues.

Precision medicine in inflammatory bowel disease: Individualizing the use of biologics and small molecule therapies.

The advent of biologics and small molecules in inflammatory bowel disease (IBD) has marked a significant turning point in the prognosis of IBD, decreasing the rates of corticosteroid dependence, hospitalizations and improving overall quality of life. The introduction of biosimilars has also increased affordability and enhanced access to these otherwise costly targeted therapies. Biologics do not yet represent a complete panacea: A subset of patients do not respond to first-line anti-tumor necrosis factor (TNF)-alpha agents or may subsequently demonstrate a secondary loss of response. Patients who fail to respond to anti-TNF agents typically have a poorer response rate to second-line biologics. It is uncertain which patient would benefit from a different sequencing of biologics or even a combination of biologic agents. The introduction of newer classes of biologics and small molecules may provide alternative therapeutic targets for patients with refractory disease. This review examines the therapeutic ceiling in current treatment strategies of IBD and the potential paradigm shifts in the future.

Dual Biologic Therapy in Patients with Familial Mediterranean Fever and Spondyloarthritis: Case-Based Review.

Patients with familial Mediterranean fever and spondylitis often fail to respond to conventional and biologic therapies. Achieving remission in these patients usually requires conventional and biologic treatment combinations. Combination of biologic agents may be a promising option for patients with familial Mediterranean fever and spondylitis who have refractory disease. Until recently, limited evidence existed regarding the efficacy and safety of this treatment strategy. To address this, our report presented a case series of 4 patients with familial Mediterranean fever and spondylitis who were resistant to standard treatments and in whom remission is achieved only with dual biologic therapy. The authors also conducted a literature search for studies that reported dual biological therapy in inflammatory diseases.

P534 Dual biologic or small molecules therapy in refractory paediatric inflammatory bowel disease (DOUBLE-PIBD): A multi-center study from the paediatric IBD Porto group of ESPGHAN

Abstract Background Current data on dual biologic or small molecules therapy in children are limited. The aim of the study was to evaluate the effectiveness and safety of dual therapy in paediatric patients with IBD. Methods This was a retrospective multicenter study from 14 centers affiliated with the IBD interest and Porto groups of ESPGHAN. We included children with IBD who were treated with combination of biologic agents or biologic and small molecule, with at least 3 months of follow-up under this therapy. Demographic, clinical, laboratory, endoscopic and imaging data were collected. Adverse events were recorded. All analyses were done in the intention-to-treat population. Children that discontinued therapy were considered treatment failures and were imputed for non-response, while missing data was imputed according to the last observation carried forward method. Results Sixty-two children [35 Crohn’s disease (CD), 27 ulcerative colitis (UC)], with a median age of 15.5 (IQR 13.1-16.8) years and disease duration of 3.8 (IQR 2.5-6.1) years were included. All children failed previous biologics and 47 (76%) failed at least two biologic agents. The dual therapy included anti-TNF agent and vedolizumab in 30 children (48%), anti-TNF and ustekinumab in 21 children (34%), vedolizumab and ustekinumab in 8 children (13%), and tofacitinib and other biologics in 3 children (5%). Clinical remission was observed in 21 (35%), 30 (50%) and 38 (63%) children at 3, 6 and 12 months, respectively. Of 27 children who were treated with corticosteroids at baseline, 20 (74.1%) were weaned within 3 months after the initiation of dual therapy. At 12 months of follow up, normalization of C-reactive protein and decrease in fecal calprotectin to &amp;lt; 250 mcg/g were achieved in 75% and 64%, respectively. Endoscopic and transmural healing were observed in 2/23 (9%) and 5/16 (31%) children, respectively. Male sex and diagnosis of UC were associated with higher likelihood of clinical remission (p=0.017 and p=0.020, respectively). Adverse events were reported in 29 (47%) children. While most adverse event were mild, 8 were regarded as serious and 6 (10%) led to discontinuation of dual therapy. The serious adverse events included infusion reaction to infliximab, fatigue and headache following vedolizumab infusion, severe skin eruptions (3 patients), cellulitis and skin abscess, elevated liver enzymes and deep vein thrombosis. Conclusion Dual biologic or small molecules therapy may be effective in children with otherwise refractory IBD. The risk of serious adverse events should be considered before recommending dual therapy.

Biological Control of Two-Spotted Spider Mite Using &lt;em&gt;Phytoseiulus persimilis&lt;/em&gt; (Athias-Henriot) and &lt;em&gt;Neoseiulus californicus&lt;/em&gt; (McGregor)

Two-spotted spider mite (TSSM), Tetranichus urticae Koch is a major pest wherever strawberry plants are grown in Sri Lanka. This pest was not controlled by the Department of Agriculture recommended synthetic insecticide Abamectin in many instances. Use of biological agents for the control of TSSM is globally a common practice and thus Phytoseiulus persimilis (Athias-Henriot) and Neoseiulus californicus (McGregor) were imported from Koppert biological systems, Netherlands. An experiment was conducted to investigate the possibility of using and N. californicus (McGregor) and P. persimilis (Athias-Henriot) in combination and N. californicus (McGregor) alone to control TSSM under laboratory conditions. The results indicated that the use of N. californicus alone was not effective in controlling the TSSM, though the TSSM population was maintained at low levels. However, the combination of biological agents was very effective by controlling the TSSM population with an 85% reduction. There was no population growth of biological agents after introduction and their population was reduced over the time. Further, there was a significant redcution in TSSM population after fifth week when the biocontrol agents were applied in combination. It was concluded that the application of P. persimilis and N. californicus was effective in controlling T. urticae rather than applying N. californicus alone. The biological control can be proposed as an alternative to insecticide, Abamectin.

S47 Combined Therapy With Ustekinumab and Vedolizumb in Severe Colitis in HIV Patients

Background: Combined therapy as well as drug sequencing, using induction and maintenance with different therapeutic classes, are possibilities of treatment in inflammatory bowel diseases. Among the different combined biological therapy options, the combination of ustekinumab and vedolizumab is among the most cited since they use different mechanisms of action with a good safety profile. Combined biological therapy has been suggested as an option to achieve better results in cases that are refractory to previous biological treatments or with a high risk of developing complications, and in the concomitance of uncontrolled extra-intestinal manifestation. There is a scarcity in the literature regarding the treatment of IBD and HIV, however, in individuals with controlled disease, there seems to be no restriction on any of the available options. In the presence of severe UC and a history of infections, the ideal therapeutic agent should have a rapid onset of action and a good safety profile in the maintenance treatment. Methods: The present study is a clinical case followed at the Oswaldo Cruz University Hospital, Recife-PE, during the period from February to August 2022, with data collected from the medical records. Results: A 53-year-old male patient with HIV for 14 years, on antiretroviral treatment for 10 years, currently with CD4 308 and an undetectable viral load. He was diagnosed with ulcerative colitis (UC), Montreal E2, in march 2021, with irregular follow-up, frequent hospitalizations until readmission in december 2021 with severe UC activity. He remained dependent on high doses of corticosteroids for about 5 months and presented several infectious complications, such as neurotoxoplasmosis and CMV colitis. He was discharged with disease under clinical control but readmitted for urinary infection and severe UC activity after 4 days of undue corticosteroid suspension. Given the severity and availability of intravenos ustekinumab per donation, it was decided to administer the dose of induction (260 mg). After 2 weeks, there was little clinical improvement, at which time he had access to vedolizumab by the public health system. UC became mildly active at week 2 of induction and the patient was discharged. He is currently in clinical and biomarker remission, on regular maintenance infusions of vedolizumab and steroid-free since week 6 of induction. Conclusion: In the present report, we considered that prolonged and recurrent hospitalizations, prolonged use of corticosteroids and previous infectious complications in patients with severe UC and HIV justified the combination of biological agents. A rapid induction strategy with ustekinumab followed by reinduction and maintenance with vedolizumab was chosen, given its best safety profile. Such association proved to be safe and effective. Although the results are attractive, there is still no formal indication in clinical practice for its use. Thus, combined biological therapy should be prescribed with caution, under consent, with close monitoring and individually indicated.

Microencapsulation of Bacillus velezensis Using Alginate-Gum Polymers Enriched with TiO2 and SiO2 Nanoparticles.

Bacillus bacteria are a group of plant growth stimulants that increase plant growth and resistance to plant pathogens by producing various metabolites. With their large surface area and small size, nanoparticles can be used in controlled-release formulations and increase the efficiency of the desired product. Encapsulation of biological agents in combination with nanoparticles can be an essential step in increasing the performance of these agents in adverse environmental conditions. In this study, which is the result of a collaboration between scientists from Italy and Iran, Bacillus velezensis was encapsulated in alginate combined with whey protein and zedo, mastic, and tragacanth gums in the presence of silica and titania nanoparticles to obtain two-layer and multilayer assemblies acting as novel, smart micro-encapsulation systems. The results of laboratory studies showed that the B. velezensis could produce protease, lipase, siderophore, auxin, and a dissolution of mineral phosphate. Scanning electron microscopy images (SEM) showed that the studied microcapsules were almost spherical. Moisture affinity, swelling, and efficiency of each microcapsule were examined. The results showed that the highest encapsulation efficiency (94.3%) was related to the multilayer formulation of alginate-whey protein-zedo. XRD and FTIR spectroscopy showed that the alginate, whey protein, and zedo were mixed properly and no incompatible composition occurred in the reaction. This study aimed to provide a suitable formulation of biofertilizers based on biodegradable compounds as an alternative to chemical fertilizers, which is low cost and very effective without harming humans and the environment.

Simultaneous Laparotomy Resection of Recurrent Colorectal Cancer and Liver Metastases Followed by FOLFIRI Adjuvant Chemotherapy: A Case Report

Background: Colorectal cancer is one of the most common cancers in the world. Combination of systemic therapies with liver resection in colorectal liver metastasis has been shown to be effective in providing promising survival benefits. Here, we present a case of colorectal liver metastases in which we devised a multidisciplinary treatment plan for a better prognosis Objectives and methods: We report a case of a 68 year old male who developed recurrent colorectal cancer with liver metastases after six cycles of chemotherapy one year previously. Radiological examination before liver resection demonstrated evident tumor from metastatic lesion in segment 4b and segment 8 of the liver (figure 1). Simultaneous laparotomy resection of the colorectal cancer and the liver metastasis was performed. The patient is now undergoing adjuvant combination chemotherapy with folinic acid, fluorouracil, and irinotecan (FOLFIRI) and has no signs of recurrence. Results: Time interval from the initial colorectal surgery to first hepatic surgery has a median 11 months. Tumor recurrence after resection of colorectal metastasis remains a major problem, about 50% to 75% of the patients develop a recurrence of the disease within two years. A multidisciplinary approach including systemic chemotherapy with or without biologic agents in combination with colorectal liver metastases resection are recommended for all patients, unless there are some contraindications Conclusions: The combination of surgery and adjuvant chemotherapy is a possible treatment of choice to cure colorectal liver metastases. Planned surveillance after metastasectomy may be necessary for the early detection of recurrence.

The application of biopriming using trichoderma and Streptomyces spp. on the germination stage of soybean

Biopriming is one way to overcome the stunted plant growth due to a decline in the quality of seed physiology by using a combination of biological agents. This study aims to improve the quality of seed germination and vigor with a combination of biological agents in the form of Trichoderma harzianum and Streptomyces spp. This research was conducted at the Laboratory of Bio-Science and Plant Reproductive Biotechnology, Department of Agriculture Cultivation, Faculty of Agriculture, Hasanuddin University, which took place from January to April 2019. This study used a Split Plot Design, the main plot was the duration of biopriming consisting of four levels, 3 hours, 6 hours, 12 hours and 24 hours. Type of microbes as subplots consisting of three levels, namely water, Trichoderma harzianum and Streptomyces spp. The results show that the duration of biopriming 12 hours with Streptomyces spp. able to produce the highest average percentage of normal sprouts (96.48%). The duration of biopriming treatment for 12 hours with water produced the highest average percentage of abnormal sprouts (15.09%). Treatment duration of biopriming for 6 hours with Streptomyces spp. able to produce the highest average length of root sprouts (11.91 cm). Streptomyces spp. gave the highest yield at an average germination rate (90.42%).

Increase Resistance to Maydis Leaf Blight and Productivity of Maize in Ultisol Soils with A Combination of Organic Material and Biological Agents Biofresh

Background: Low nutrient content in ultisol soils and the result of Maydis leaf rot are a major problem in efforts to increase corn productivity in Southeast Sulawesi Province, Indonesia. The use of organic materials and biological agents is one of the solutions in increasing disease resistance and corn productivity in the environmentally friendly ultisol lands. This study aims to assess the effectiveness of the biological agent Biofresh combined with various types of organic material to increase resistance to Maydis leaf rot and maize productivity in ultisol lands. Methods: Research in April-August 2017 in Southeast Sulawesi, Indonesia. With 21 units of experiments using a random block design with 7 treatments in combination of Biofresh with organic material ‘Bokashi’. consists of: B0 = Inorganic fertilizer; B1 = Organic material of cow dung; B2 = Biofresh Biological Agent; B3 = Biofresh biological agent combined with cow dung organic matter; B4 = Biofresh biological agent combination with bokashi cow dung and straws; B5 = Biofresh combination of biological agents with bokashi cow dung and soybean Sitter; B6 = Biofresh Biological agent combination with all Cow, straw and soybean bokashi. Result: The results showed that the combination of Biofresh with organic material in the form of bokashi at a dose of 5 tons ha-1 was very effective in increasing the durability and productivity of corn plants in ultisol land. The combination of Biofresh biological agents with bokashi containing cow’s feses, straw, and soy litter can reduce Maydis leaf blight leaf blight disease by 47.36% and increase production by 53.54%. Disease suppression index is positively correlated with maize crop productivity in Ultisol land.

Combination of Biological Agents in Moderate to Severe Pediatric Inflammatory Bowel Disease: A Case Series and Review of the Literature.

BackgroundTreatment with biological agents such as anti-tumor necrosis factors (TNFs) has become standard of care in moderate to severe pediatric inflammatory bowel disease (IBD). However, a significant proportion of patients experience loss of response to anti-TNFs, need treatment escalation, or develop side effects. There is no data in the literature regarding combination of biological agents in pediatric IBD.MethodsAt our hospital, which is a tertiary referral center, we have combined the anti-TNF infliximab with either vedolizumab or ustekinumab in patients with severe pediatric IBD. The indications for dual biological therapy were insufficient efficacy of infliximab or vedolizumab monotherapy, or side effects such as psoriasis due to anti-TNFs.ResultsEight patients (four boys) aged 14–17.5 years received a combination of infliximab and vedolizumab due to only a partial response to infliximab, four with Crohn’s disease (CD) and four with ulcerative colitis (UC). Clinical remission was achieved in four patients (3 UC) and four had a colectomy (3 CD, 1 UC). Five CD patients (3 girls) aged 11–17 years, on maintenance therapy with infliximab, developed psoriasis resistant to topical treatment. A combination of infliximab and ustekinumab resulted in clinical remission of CD without skin symptoms. No serious adverse events occurred in any of the patients on combination therapy. Thirteen publications report on combining biologicals, all in adult IBD.ConclusionIn pediatric IBD, combining biological agents seems to be safe and beneficial in selected patients. The safety should be addressed in long-term follow-up studies.

Efficacy and safety of regorafenib in combination with chemotherapy as second-line therapy in patients with metastatic colorectal cancer: A network meta-analysis.

115 Background: Recent studies have shown efficacy of chemotherapy (CTX) in combination with different biological agents including regorafenib (REG) in second-line treatment of metastatic colorectal cancer (mCRC). As there is no evidence on the relative efficacy and safety of REG as compared to other biological agents in combination with CTX, we evaluated the same in this network meta-analysis (NMA). Methods: Randomized controlled trials (RCTs) comparing efficacy and safety of biological agents + CTX against CTX alone as second-line treatment of mCRC were retrieved from PubMed, EMBASE and Cochrane databases. Progression free survival (PFS) was the primary outcome, while objective response rate (ORR), overall survival (OS) and safety were secondary outcomes. Outcomes were compared by random/mixed-effects NMA using Bayesian (R software, Gemtc package) and frequentist (R software, netmeta package) approaches. Results: Twelve RCTs comparing 9 different treatment regimens with a total of 6805 patients were included for analysis. Hazard ratios (HR)/ odds ratio (OR)/ relative risk (RR) and 95% confidence intervals (CI) for PFS, ORR and grade&gt; 3 adverse events (AE) of selected comparisons from the results of the NMA are shown in table. Conclusions: REG combined with CTX might be a potential alternative to conventional therapeutic options and could be considered as the best option for treating KRAS and BRAF mutated mCRC patients. Future RCTs are needed to confirm our results. [Table: see text]

Adjuvant therapies for the enhancement of microfracture technique in cartilage repair

The classic technique of microfracture does not promote hyaline cartilage restoration. Subchondral bone perforations lead to the formation of a clot containing pluripotent progenitor cells and finally the cartilage defect is filled by fibrocartilage tissue. Researchers have focused on enhancing the quality of the newly formed tissue in cartilage defects after microfracture arthroscopic surgery. Adjuvant treatments are categorized in four main groups: scaffolds, pharmaceutical agents, growth factors and combinations of the aforementioned. Several experimental studies utilize pharmaceutical or biological agents in combination with microfracture, to improve the quality of the regenerated cartilage. The mechanism of action of the agents used is either to exert a chondroprotective effect on the newly formed fibrocartilage tissue, or to induce the recruitment of mesenchymal stem cells towards chondrogenesis instead of osteogenesis during microfracture repair. Additionally, scaffolds have been used for both release of the biological agents and mechanical support of the newly formed blood clot. This review highlights current data regarding the combination of microfracture technique with adjuvant treatments in order to ameliorate the final outcome.

Safety and tolerability of idelalisib, lenalidomide, and rituximab in relapsed and refractory lymphoma: the Alliance for Clinical Trials in Oncology A051201 and A051202 phase 1 trials

A new generation of biological and targeted agents might potentially replace traditional cytotoxic agents in lymphoma. Lenalidomide plus rituximab was felt to be a safe and promising backbone based on available data. Idelalisib is an oral phosphatidylinositol 3-kinase delta (PI3Kδ) inhibitor that has promising activity as a monotherapy in refractory indolent lymphomas. The primary objective of these two trials was to determine the maximum tolerated dose of lenalidomide in combination with rituximab and idelalisib in relapsed follicular and mantle cell lymphoma. A051201 (mantle cell lymphoma) and A051202 (follicular lymphoma) were phase 1 trials. Patients with histologically documented relapsed mantle cell lymphoma who had not received previous lenalidomide or idelalisib (A051201) were started with oral lenalidomide 15 mg on days 1-21 in a 28 day cycle, oral idelalisib 150 mg twice a day with continuous 28-day cycles, and intravenous rituximab 375 mg/m2 weekly during cycle 1. Patients with histologically documented relapsed follicular lymphoma and time to progression 6 months or longer from last rituximab-containing regimen (A051202) were started with oral lenalidomide 10 mg on days 1-21 every 28 days and oral idelalisib 150 mg twice a day with continuous 28-day cycles, and intravenous rituximab 375 mg/m2 on cycle 1, day 8, day 15, day 22, and cycle 2, day 1. The primary endpoints of the studies were safety and tolerability of combining idelalisib with lenalidomide and rituximab in patients with relapsed mantle cell lymphoma (A051201) and relapsed follicular lymphoma (A051202). All analyses were by intention to treat. The trials were registered at ClinicalTrials.gov, number NCT01838434 (A051201) and number NCT01644799 (A051202). Between July 9, 2013, and Sept 30, 2014, 11 patients (three with mantle cell lymphoma and eight with follicular lymphoma) were enrolled. Among the first eight patients, four experienced unexpected dose-limiting toxicities: grade 4 sepsis syndrome, grade 4 hypotension with grade 3 rash and fevers, grade 4 aspartate aminotransferase (AST) or alanine aminotransferase (ALT) elevation with fevers, and grade 3 pulmonary infection with grade 3 maculopapular rash. Symptom onset was 9-20 days after treatment initiation, coinciding with rituximab infusions. Both studies were amended to remove rituximab, but two of three additional patients had grade 3 rashes and one had grade 3 AST elevation. Both trials were permanently closed. The most common grade 3-4 adverse events were ALT elevation (two [67%] of three) and rash (two [67%] of three) for patients with mantle cell lymphoma and neutropenia (five [63%] of eight) and rash (four [50%] of eight) for patients with follicular lymphoma. The primary endpoint of safety and tolerability was not met. The combination of idelalisib, lenalidomide, and rituximab in these trials is excessively toxic, and these trials serve as cautionary notes as new combinations are proposed. Off-target effects, drug-drug interactions, and emerging toxicities should be carefully assessed when investigating biological agents in combination and should never be done outside of a clinical trial setting. National Cancer Institute of the National Institutes of Health.

Frequency and Factors Associated with Biologic Monotherapy in Patients with Rheumatoid Arthritis; Experience from an Argentine Center

Introduction/objectives: The combination of biologic agents and synthetic disease modifying anti-rheumatic drugs has proven to be effective for the treatment of patients with active Rheumatoid Arthritis; notwithstanding monotherapy was only exceptionally considered. However, with the advent of biologic agents with other modes of action and evidence contributed by tocilizumab studies, this option begun to be considered. The aim of this study was to evaluate the prevalence of monotherapy with biologic agents in patients with RA and factors associated with the use of this type of treatment, in the context of everyday practice. Method: An observational, analytical, cross-sectional study was carried out, including patients over 18 years old who were diagnosed with RA, according to ACR/EULAR 2010 classification criteria, and who were treated with biologics. Demographic, clinical and treatment variables were evaluated. Results: From a total 450 patients with RA, 171 treated with biologic agents were evaluated. 31.6% received biologic monotherapy, most frequently due to MTX adverse effects. The most commonly used anti-Tumor Necrosis Factor as monotherapy was adalimumab. Monotherapy with biologic agents was seen to be associated with the use of drugs with other mechanisms than TNF blockers, most frequently tocilizumab. Bivariate and multivariate analyses have shown that monotherapy is an independent factor for no NSAID use. Corticosteroid use was lower in patients receiving monotherapy, although it did not reach statistical significance. Conclusion: The biologic monotherapy frequency was 31.6%. The associated factors were use modes of action other than anti-TNF and a decreased use of NSAIDs.

Combination of Biologic Agents in the Management of Severe Refractory Crohnʼs Disease: A Case Report of Concomitant Treatment with Vedolizumab and Adalimumab

A 23-year-old female with Crohn's disease (CD) enterocolitis diagnosed at age 8, initially treated with elemental diet, mesalamine, prednisone and 6-mercaptopurine (6MP). In 2002, she transitioned to episodic infliximab. Although she initially responded, her symptoms recurred and developed an infusion reaction. She was switched to adalimumab (ADA) and 6MP in 2006 with good initial response, but loss of response despite weekly dosing in 2012. She had no benefit from certolizumab pegol and 6-MP. A colonoscopy showed moderately active extensive colitis, no inflammation in the terminal ileum, and perianal involvement. Vedolizumab (VDZ), 6MP, and prednisone were started. She was unable to taper the steroids and continued to have severe symptoms including 20-lb weight loss requiring hospital admission. Her CRP was 79 mg/L, ESR 115 mm/h, albumin 3.2 g/dL. Sigmoidoscopy revealed severe colitis. MRI enterography did not reveal ileal disease. She was treated with IV steroids, cyclosporine (CYP), and total parenteral nutrition (TPN). She discontinued CYP after 3 weeks and was started on ADA with induction doses, in combination with VDZ infusions every 8 weeks. At follow-up, she reported clinical improvement, CRP and ESR decreased, and TPN was discontinued. A colonoscopy performed after 3 months of combination biologic therapy showed scattered mucosal improvement with residual linear ulcers primarily in the descending colon. She stopped the steroids and 6-MP, and VDZ was also discontinued after 6 months. She continued monotherapy ADA 40 mg every two weeks. At her most recent visit, she had no active symptoms and inflammatory markers normalized. Switching biologic agents in CD is practiced when there is an inadequate response or intolerable adverse events. The alternative options include switching to a different anti-TNF, switching to a different non-TNF-biologic, or recycling a previously used anti-TNF agent. Concomitant use of two different biologics is of interest, as it may combine different mechanisms of action. Additional research is needed to assess the risk:benefit ratio, safety and validity of specific combinations of biologic use in CD. With different target-specific biologics now available and improved immunological understanding of CD, there may be an opportunity to better tailor and personalize our therapies for patients.Figure 1Figure 2Figure 3

An Update on Calcineurin Inhibitor-Free Regimens: The Need Persists, but the Landscape has Changed.

Calcineurin inhibitors (CNIs) have failed to improve long-term renal allograft survival. Their association with cardiovascular morbidity in addition to their suboptimal inhibition of a chronic alloimmune response has shifted investigative efforts toward CNI-free regimens. Sotrastaurin, a small molecule targeting protein kinase C isoforms, failed to provide adequate immunosuppression, whereas the Janus kinase 3 inhibitor tofacitinib's success in the treatment of rheumatoid arthritis led to biopharma's abandonment of it as a transplant agent. Like tofacitinib, tocilizumab, a biologic targeting the IL-6 pathway, has been approved for use in rheumatoid arthritis and interest in transplantation has been confined to several investigator-initiated trials. Belatacept, a second-generation, higher avidity variant of CTLA4Ig (abatacept), was approved by the Food and Drug Administration for prophylaxis of transplant rejection in 2011. Long-term follow-up of recipients on belatacept has demonstrated superior glomerular filtration rates as compared with CNIs, albeit with an increased risk of early and histologically severe rejection. Focus on optimizing belatacept-inclusive regimens has led to studies using lymphocyte depletion as induction and maintenance therapy with target of rapamycin inhibitors. ASKP1240, the most advanced of the anti-CD40 antibodies targeting the CD40/CD154 costimulatory pathway has just completed a phase II trial with a CNI-free arm. Animal models suggest that its highest efficacy may be in combination with belatacept. Finally, nonagonistic CD28 antibodies, which would allow CTLA4 and PD-LI binding of CD80/CD86 and activation of inhibitory pathways, have re-emerged with 2 anti-CD28 candidates in preclinical development. A reliable nontoxic CNI-free regimen may ultimately require the combination of biologic agents that provide efficacy as well as safety.

Increased Risk of Oral Cancer in Patients With Inflammatory Bowel Diseases.

Epidemiology studies have consistently found an increased risk of oral malignancies in organ transplant recipients, patients with graft-versus-host disease, and people with human immunodeficiency virus infection. We assessed the risk of oral cancer in patients with inflammatory bowel diseases (IBD). We collected data on 7294 patients with IBD (3785 women) seen at Mount Sinai Medical Center, New York, from 2000 through 2011. The expected incidence of oral cancer was calculated for each sex-specific and 5-year age-specific stratum by specific incidence rates using the Surveillance, Epidemiology and End Results 18 registry data (2000-2011), adjusted for age to the 2000 United States population (census P25-1130). Eleven patients (7 men) were found to have biopsy-proven oral cancer. Six patients had cancer of the tongue; 2 patients had cancer of the hard palate; and the remaining 3 had tonsillar, buccal, or mandibular sarcoma. Before the cancer diagnosis, IBD had been treated in 4 patients with azathioprine or mercaptopurine, in 1 patient with infliximab, and 3 in patients with combination of biologic agents and azathioprine; 4 of the patients had not been treated for IBD. The age- and sex-adjusted standardized incidence ratio (SIR) for oral cancer in patients with IBD was 9.77 (95% confidence interval [CI], 5.14-16.98). In women, the SIR was 12.07 (95% CI, 3.84-29.11), and in men the SIR was 8.49 (95% CI, 3.71-16.78). The age-adjusted SIR for tongue cancer was 18.91 (95% CI, 7.66-39.33): 17.06 for men (95% CI, 5.42-41.15) and 22.10 for women (95% CI, 3.70-73.01). We found patients with IBD to be at increased risk for oral cancers, especially tongue cancer. Women are at higher risk than men.