Anti-tumor Necrosis Factor-alpha Antibody Research Articles

The improvement of a refractory enterocutaneous fistula with colchicine in a patient with Crohn's disease who had an MEFV gene mutation.

Enterocutaneous fistulas (ECFs) occurring in the setting of Crohn's disease (CD) are difficult to cure with medical treatment alone and affects a patient's quality of life. A 39-year-old man was diagnosed with an ileocolitis-type CD in 2007. His inflammation was insufficiently controlled despite the administration of an anti-tumor necrosis factor-alpha antibody. Therefore, he underwent subtotal colectomy, terminal ileal resection, and ileostomy for multiple colon and anal stenoses in Dec 2015. The patient subsequently received ustekinumab; however, purulent discharge was observed from a postoperative scar around the umbilicus in July 2019. In July 2021, enteroscopy and magnetic resonance imaging (MRI) showed an ECF extending from the small intestine to the umbilicus. Upon referral to our hospital, laboratory data showed elevated C-reactive protein (CRP) and serum amyloid A (SAA). After receiving colchicine, his purulent discharge disappeared, and his CRP and SAA levels rapidly decreased. Enteroscopy and MRI performed 1year and 5months after the administration of colchicine revealed ECF closure. Genetic analysis revealed that the patient harbored an MEFV exon 1 (E84K) mutation.

Steroidal nanoformulations for the treatment of uveitis: potential, promises and future perspectives.

Intraocular inflammation, commonly referred to as uveitis, is a prevalent ocular disease. The categorization of uveitis may be based on the prevailing anatomical site, which includes anterior, intermediate, and posterior uveitis. There exists a significant body of evidence indicating that T cells play a pivotal role in the pathogenesis of autoimmune uveitis. In addition to the presence of T cells, an elevation in levels of inflammatory cytokines and a reduction in regulatory cytokines were also noted. The primary pharmacological interventions for uveitis comprise of corticosteroids, methotrexate, anti-vascular endothelial growth factor (VEGF) agents, anti-tumor necrosis factor-alpha (TNF-α) antibodies, and sirolimus. These medications offer prompt alleviation for inflammation. Nevertheless, prolonged administration of corticosteroids invariably leads to unfavorable adverse reactions. The traditional topical corticosteroids exhibit certain limitations, including inadequate transcorneal permeation and low corneal retention, leading to reduced ocular bioavailability. Consequently, there is a growing inclination towards the creation of innovative steroid drug delivery systems with the aim of reducing the potential for adverse effects, while simultaneously enhancing the drug's corneal permeation and retention. This review is an attempt to compile all the research work done so far in this field and provides a brief overview of the global efforts to develop innovative nanocarrier-based systems for corticosteroids.

Serial Changes in Intestinal Stenotic Stiffness in Patients with Crohn's Disease Treated with Biologics: A Pilot Study Using Ultrasound Shear Wave Elastography.

Intestinal strictures represent an important serious complication of Crohn's disease. Shear wave elastography is a promising noninvasive ultrasound technique for assessing tissue stiffness. This study aimed to evaluate stiffness in the areas of intestinal stricture in patients with Crohn's disease using shear wave elastography and the changes in stiffness after biologics. We enrolled 21 Crohn's disease patients having intestinal stricture. The patients consisted of 3 groups, which were the infliximab naïve (n = 6) group, the ustekinumab naïve (n = 8), and the bio-switch from infliximab to ustekinumab (n = 7) group. Bowell wall thickness was examined by ultrasound sonography, and the stiffness of Crohn's disease stricture lesions was evaluated using Shear wave speed before and 1 year after anti-tumor necrosis factor-alpha antibody infliximab, anti-interleukin 12/23 antibody ustekinumab, and bio-switch from infliximab to ustekinumab. Bowell wall thickness was significantly improved after infliximab, ustekinumab, and the bio-switch. However, shear wave speed indices only in the ustekinumab group significantly decreased after treatment (P = .028), but not in the other group. Shear wave elastography might be a useful method to evaluate stiffness in the areas of intestinal stricture in patients with Crohn's disease treated with biologics. However, a prospective randomized study evaluating the development of obstruction after biological treatment is needed to validate the study findings.

Pulmonary Arterial Hypertension Induced by Immune Checkpoint Inhibitor Combined Therapy in a Patient with Intrahepatic Cholangiocarcinoma: A Case Report.

Immune Checkpoint Inhibitors (ICIs) have dramatically revolutionized the therapeutic approaches by which we treat a series of cancers accompanied by immune-related adverse events (irAEs). Herein, we reported an intrahepatic cholangiocarcinoma male patient with a history of ankylosing spondylitis developing pulmonary arterial hypertension (PAH) under ICI combined therapy with pembrolizumab and lenvatinib. The indirect measurement of cardiac ultrasound showed a pulmonary artery pressure (PAP) of 72mmHg after 21 three-week cycles of ICI combined therapy. The patient partially responded to the treatment of glucocorticoid and mycophenolate mofetil. The PAP decreased to 55mmHg 3 months after the ICI combined therapy was discontinued, but increased to 90mmHg after the ICI combined therapy was rechallenged. We treated him with adalimumab -an antitumor necrosis factor-alpha (ani-TNF-α) antibody- combined with glucocorticoid and immunosuppressants under lenvatinib monotherapy. The patient responded again with PAP decreasing to 67mmHg after 2 two-week cycles of adalimumab. Accordingly, we diagnosed him to have irAE-related PAH. Our findings supported the use of glucocorticoid disease-modifying antirheumatic drugs (DMARDs) as a treatment option in refractory PAH.

Leveraging in vitro and pharmacokinetic models to support bench to bedside investigation of XTMAB-16 as a novel pulmonary sarcoidosis treatment.

Background: Sarcoidosis is a chronic, multisystem inflammatory disorder characterized by non-caseating epithelioid granulomas; infiltration of mononuclear cells; and destruction of microarchitecture in the skin, eye, heart, and central nervous system, and the lung in >90% of cases. XTMAB-16 is a chimeric anti-tumor necrosis factor alpha (TNFα) antibody, distinct from other anti-TNF antibodies based on its molecular structure. The efficacy of XTMAB-16 has not been clinically demonstrated, and it is still undergoing clinical development as a potential treatment for sarcoidosis. The current study demonstrates the activity of XTMAB-16 in a well-established in vitro sarcoidosis granuloma model, although XTMAB-16 is not yet approved by the United States Food and Drug Administration (FDA) for treatment of sarcoidosis, or any other disease. Objective: To provide data to guide safe and efficacious dose selection for the ongoing clinical development of XTMAB-16 as a potential treatment for sarcoidosis. Methods: First, XTMAB-16 activity was evaluated in an established in vitro model of granuloma formation using peripheral blood mononuclear cells from patients with active pulmonary sarcoidosis to determine a potentially efficacious dose range. Second, data obtained from the first-in-human study of XTMAB-16 (NCT04971395) were used to develop a population pharmacokinetic (PPK) model to characterize the pharmacokinetics (PK) of XTMAB-16. Model simulations were performed to evaluate the sources of PK variability and to predict interstitial lung exposure based on concentrations in the in vitro granuloma model. Results: XTMAB-16 dose levels of 2 and 4mg/kg, once every 2weeks (Q2W) or once every 4 weeks (Q4W) for up to 12weeks, were supported by data from the non-clinical, in vitro secondary pharmacology; the Phase 1 clinical study; and the PPK model developed to guide dose level and frequency assumptions. XTMAB-16 inhibited granuloma formation and suppressed interleukin-1β (IL-1β) secretion in the in vitro granuloma model with a half maximal inhibitory concentration (IC50) of 5.2 and 3.5μg/mL, respectively. Interstitial lung concentrations on average, following 2 or 4mg/kg administered Q2W or Q4W, are anticipated to exceed the in vitro IC50 concentrations. Conclusion: The data presented in this report provide a rationale for dose selection and support the continued clinical development of XTMAB-16 for patients with pulmonary sarcoidosis.

Clinical and Endoscopic Response to Anti-Tumor Necrosis Factor-Alpha Antibody Therapy in a Patient With Cronkhite-Canada Syndrome.

Cronkhite-Canada syndrome (CCS) is an acquired polyposis syndrome with gastrointestinal and extraintestinal manifestations. Given its rarity and lack of standard treatment, diagnosis and treatment are challenging. Steroid therapy and nutritional support are conventional treatments. There is no consensus on management of steroid-refractory cases. Here, we report the diagnosis and treatment course of a 54-year-old Asian male with CCS, whose initial treatment with prednisone 60 mg a day led to partial response and disease flare up during prednisone tapering. The use of infliximab and azathioprine led to promising remission of his symptoms.

Tumor necrosis factor-alpha antibody labeled-polyethylene glycol-coated nanoparticles: A mesenchymal stem cells-based drug delivery system in the rat model of cisplatin-induced nephrotoxicity.

A delivery system consisting of bone marrow mesenchymal stem cells (MSCs) loaded with polyethylene glycol (PEG) coated superparamagnetic iron oxide nanoparticles (SPIONs) was constructed to treat a rat model of cisplatin (Cis)-induced nephrotoxicity with 1/10 of the common dose of anti-tumor necrosis factor-alpha (TNF-α) antibodies (infliximab). Morphology, size, crystallinity, molecular structure, and magnetic properties of uncoated and PEG-coated SPIONs were analyzed. A delivery system consisting of MSCs containing infliximab-labeled PEG-coated SPIONs (Infliximab-PEG-SPIONs-MSCs) was generated and optimized before treatment. Fifty female Wistar rats were divided into five equal groups: Group 1: Untreated control; Group 2 (Cis): Rats were administered Cis through intraperitoneal (i.p.) injection (8 mg/kg) once a week for 4 weeks; Group 3 (Infliximab): Rats were injected once with infliximab (5 mg/kg), i.p. 3 days before Cis administration; Group 4 (Cis + MSCs): Rats were injected with Cis followed by an injection of 2 × 106 MSCs into the tail vein twice at a 1-week interval; and Group 5 (Cis + Infliximab (500 mg/kg)-PEG-SPIONs-MSCs): Rats were injected with the delivery system into the tail vein twice at a 1-week interval. Besides histological examination of the kidney, the Doppler ultrasound scanner was used to scan the kidney with the Gray-color-spectral mode. In vivo, intra-renal iron uptake indicates the traffic of the delivery system from venous blood to renal tissues. Cis-induced nephrotoxicity resulted in a significant increase in TNF-α and malondialdehyde (MDA) (p < 0.05), bilirubin, creatinine, and uric acid (p < 0.01) levels compared with the untreated control group. The different treatments used in this study resulted in the amelioration of some renal parameters. However, TNF-α levels significantly decreased in Cis + Infliximab and Cis + MSCs (p < 0.05) groups. The serum levels of MDA significantly decreased in Cis + Infliximab (p < 0.05), Cis + MSCs (p < 0.05), and Cis + Infliximab-PEG-SPIONs-MSCs (p < 0.01). Furthermore, the serum activities of antioxidant enzymes were significantly elevated in the Cis + MSCs and Cis + Infliximab-PEG-SPIONs-MSCs groups (p < 0.05) compared to the Cis-induced nephrotoxicity rat model. With the support of the constructed MSCs-SPIONs infliximab delivery system, it will be possible to track and monitor cell homing after therapeutic application. This infliximab-loading system may help overcome some challenges regarding drug delivery to the target organ, optimize therapeutics' efficacy, and reduce the dose. The outcomes of the current study provide a better understanding of the potential of combining MSCs and antibodies-linked nanoparticles for the treatment of nephrotoxicity. However, further investigation is recommended using different types of other drugs. For new approaches development, we should evaluate whether existing toxicity analysis and risk evaluation strategies are reliable and enough for the variety and complexity of nanoparticles.

Autoinflammatory keratinization diseases

As predisposing factors and pathogenic mechanisms of inflammatory keratinization disorders of the skin have become increasingly elucidated in recent years, a number of inflammatory keratinization disorders are now known to have the excessive activation of innate immunity as their pathogenesis. Autoinflammation-associated pathogeneses have been clarified in patients with generalized pustular psoriasis (GPP), pityriasis rubra pilaris (PRP) type V, and familial keratosis lichenoides chronica (KLC). Thus, based on these findings, in 2017, we proposed the clinical entity “autoinflammatory keratinization disease (AiKD),” which comprehensively includes inflammatory keratinization disorders with pathogenic mechanisms related to autoinflammation (the excessive activation of innate immunity). In 2017, GPP and associated diseases, PRP type V, and familial KLC came to be considered as AiKDs. In addition to these diseases, hidradenitis suppurative, porokeratosis, keratosis linearis with ichthyosis congenita and sclerosing keratoderma syndrome, and AiKDs with hepatitis and autism have been newly recognized as AiKDs. The concept of AiKD may contribute to the selection of novel treatment methods. For example, recognizing hidradenitis suppurativa precisely as an AiKD has resulted in the application of adalimumab, an anti-tumor necrosis factor alpha antibody, as a treatment. The concept of AiKD is thought to be useful toward our accurate understanding of the pathogeneses of inflammatory keratinization disorders and our choice of appropriate treatment methods. As the pathogenic mechanisms of inflammatory keratinization disorders are further elucidated, it is presumed that the number of keratinization diseases whose pathogeneses are associated with autoinflammation will increase and that the number of diseases recognized as AiKDs will grow more and more.

The impact of gender and sex in psoriasis: What to be aware of when treating women with psoriasis.

Background:Psoriasis is a common chronic inflammatory skin disease with an exceptionally high burden for women.Objective:Sex-dependent differences in disease manifestation, severity, treatment choices, subjective disease perception, and the impact on quality of life and risk factors are described and comprehensively discussed.Methods:A literature search was conducted using MEDLINE (PubMed) and the Cochrane Library for systematic reviews to investigate the challenges in treating women with psoriasis.Results and conclusions:The incidence, prevalence, and manifestation of psoriasis of the skin are similar between different sexes. Genetic and environmental factors such as obesity and metabolic syndrome are risk factors and are not equally relevant or pronounced in women and men. Overall, women have a lower disease severity measured by the Psoriasis Area Severity Index, which is associated with a higher impairment of their life quality measured by the Dermatology Life Quality Index compared with men. In addition, women with psoriasis are more likely to have depression than men. Hormonal factors affect psoriasis, with a correlation of high estrogen levels and improvement of psoriasis. Data regarding differences in prescribing patterns of systemic treatments and the severity of psoriasis are not entirely consistent. Registry studies show that men tend to have more severe psoriasis and, in some cases, are prescribed systemic therapies more frequently. Women tend to respond better to systemic treatments and to experience more adverse events. Treatment options are the same for both sexes, except during pregnancy and lactation. Various treatment options are contraindicated due to fear of fetal or neonate harm and lack of data. Topical steroids can be prescribed with a high degree of safety during pregnancy. For other topical therapies (calcineurin inhibitors and vitamin D analogs), no studies of adverse effects in pregnancy are available, and safety data mainly stem from studies examining effects after systemic administration. Antitumor necrosis factor monoclonal antibodies (except for certolizumab pegol) have been associated with a possible increased risk of preterm birth, low gestational age, and cesarean deliveries. Prospective data on the safety of biologics other than antitumor necrosis factor-alpha antibodies to accurately assess whether novel biologics (eg, anti-interleukin 17, 12/23, 23) can be used for systemic therapy in pregnancy are lacking or currently being conducted.

Cytomegalovirus retinitis in Crohn's disease treated with anti-tumor necrosis factor-alpha antibody

Cytomegalovirus (CMV) is a double-stranded DNA virus. It is an opportunistic infection that usually affects individuals with AIDS or with profound immunosuppression. CMV retinitis is the most frequent ocular manifestation. Infrequently, this pathology has been observed in patients undergoing immunosuppressive treatment due to autoimmune diseases. This article presents a case of Crohn's disease with systemic and ocular involvement by CMV after starting treatment with infliximab (anti-tumor necrosis factor-alpha antibody).

Early-Phase Partial Mayo Score following Golimumab Treatment Is Associated with Endoscopic Improvement at 1 Year in Ulcerative Colitis: A post hoc Analysis of PURSUIT-J Randomized Controlled Trial

Introduction: Golimumab (GLM) is an anti-tumor necrosis factor-alpha antibody therapy for moderately to severely active ulcerative colitis (UC). Endoscopic improvement is considered one of UC treatment’s main goals, and earlier prediction of future endoscopic improvement has clinical implications. We retrospectively analyzed data from the PURSUIT-J, a phase III randomized controlled trial evaluating the efficacy of GLM in the maintenance phase, to find predictors for endoscopic improvement after 60 weeks of GLM treatment. Methods: Ninety-two patients who had completed the maintenance phase of the PURSUIT-J were divided into two groups: those with mucosal healing (MH: Mayo endoscopic subscore of 0 or 1) and those without MH at week 60 (non-MHs). Multivariate logistic regression analysis was conducted using baseline data in the induction phase to determine predictive factors for MHs compared to non-MHs. Results: Twenty-nine patients were classified as MHs and 63 as non-MHs. The multivariate logistic regression analysis showed that the odds ratio for partial Mayo (pMayo) score was highest in MHs (1.87 [95% CI: 1.18–2.98]) at baseline in the induction phase. The receiver operating characteristic analysis to determine the timing of predictions of MHs using pMayo showed that an area under the curve reached 0.8 at week 14 after the first GLM administration. Discussion/Conclusion: pMayo scores at week 14 of GLM treatment are associated with MH at week 60. These results suggest the timing when a clinical decision to continue GLM based on the patient-reported outcomes and the physician’s general assessment could be considered.

Long-term outcomes of endoscopic balloon dilation for intestinal strictures in patients with Crohn's disease during maintenance treatment with anti-tumor necrosis factor alpha antibodies.

Efficacy of endoscopic balloon dilation (EBD) for intestinal strictures in patients with Crohn's disease (CD) receiving anti-tumor necrosis factor alpha antibodies (anti-TNF) as maintenance therapy is unclear. We investigated the long-term efficacy and safety of EBD for intestinal strictures in patients with CD receiving anti-TNF. We retrospectively analyzed data from patients with CD who received anti-TNF as maintenance therapy from 2008 to 2017, underwent EBD, and were followed up for ≥6 months. The primary endpoint was the cumulative surgery-free rate. The main secondary endpoints were technical success, repeat EBD rate, risk factors affecting surgical outcomes, and safety. Seventy-two patients with CD were assessed. The median observation period after EBD was 50 months. The technical success rate was 67%. The 3- and 5-year cumulative surgery-free rates were 81.1% and 73.5%, respectively. The repeat EBD rate was 74%. Multivariable analyses showed that risk factors affecting surgical outcomes were age at disease onset ≤16 years (hazard ratio 3.69; 95% confidence interval 1.36-10.01; P = 0.011). Serious complications requiring surgery developed in three patients. Endoscopic balloon dilation was an effective and safe short-term treatment and a useful long-term treatment for CD patients with intestinal strictures receiving anti-TNF as maintenance therapy.

Microsporidiosis in Humans.

Microsporidia are obligate intracellular pathogens identified ∼150 years ago as the cause of pébrine, an economically important infection in silkworms. There are about 220 genera and 1,700 species of microsporidia, which are classified based on their ultrastructural features, developmental cycle, host-parasite relationship, and molecular analysis. Phylogenetic analysis suggests that microsporidia are related to the fungi, being grouped with the Cryptomycota as a basal branch or sister group to the fungi. Microsporidia can be transmitted by food and water and are likely zoonotic, as they parasitize a wide range of invertebrate and vertebrate hosts. Infection in humans occurs in both immunocompetent and immunodeficient hosts, e.g., in patients with organ transplantation, patients with advanced human immunodeficiency virus (HIV) infection, and patients receiving immune modulatory therapy such as anti-tumor necrosis factor alpha antibody. Clusters of infections due to latent infection in transplanted organs have also been demonstrated. Gastrointestinal infection is the most common manifestation; however, microsporidia can infect virtually any organ system, and infection has resulted in keratitis, myositis, cholecystitis, sinusitis, and encephalitis. Both albendazole and fumagillin have efficacy for the treatment of various species of microsporidia; however, albendazole has limited efficacy for the treatment of Enterocytozoon bieneusi. In addition, immune restoration can lead to resolution of infection. While the prevalence rate of microsporidiosis in patients with AIDS has fallen in the United States, due to the widespread use of combination antiretroviral therapy (cART), infection continues to occur throughout the world and is still seen in the United States in the setting of cART if a low CD4 count persists.

Enfermedad de Crohn con compromiso extenso y manifestaciones extradigestivas inusuales: a propósito de un caso

La enfermedad de Crohn (EC) es considerada una entidad inmunológicamente mediada que compromete el tracto digestivo. Su compromiso suele ser transmural y puede afectar cualquier parte del tubo digestivo, desde la cavidad oral hasta el ano. Aunque se sabe que su extensión es variable, es poco habitual ver un compromiso extenso y multiorgánico. Se presenta el caso de un paciente joven, quien debutó con síntomas pulmonares asociados con la EC y años más tarde se presentaron los síntomas digestivos y de la vía biliar. El tratamiento se basó en la terapia con anticuerpos contra el factor de necrosis tumoral alfa (TNF-α), con lo cual se obtuvo una respuesta clínica satisfactoria. La relevancia clínica de este caso es la forma de presentación clínica tan florida, tanto por el compromiso gastrointestinal extenso como por las manifestaciones extradigestivas tan infrecuentes.

An update on the diagnosis and management of ocular sarcoidosis.

Ocular sarcoidosis is one of the most common causes of uveitis worldwide. The diagnosis and treatment of patients with ocular sarcoidosis remains challenging in some cases. It is important for clinicians to keep up to date with new diagnostic and treatment tools for this disease. The International Workshop on Ocular Sarcoidosis diagnostic criteria were first proposed in 2009 and revised in 2017. The new criteria contained two parts: ocular presentation and systemic investigation. The diagnostic value of liver enzymes was reduced in the new criteria, whereas the value placed of lymphopenia and the CD4/CD8 ratio in bronchoalveolar lavage fluid were increased. Despite not being included in the criteria, recent studies have also highlighted the diagnostic value of serum soluble interleukin-2 receptors. Recent ophthalmologic imaging also provides useful insights for the differential diagnosis.Many new treatments for ocular sarcoidosis have been developed in recent years. The introduction of biological immunomodulatory agents for uveitis treatment represents a big improvement. Antitumor necrosis factor-alpha antibodies, including adalimumab, have been proven to be effective for treating ocular sarcoidosis. Many studies have also suggested that other biological agents could be effective and well tolerated. Newer intravitreal dexamethasone and fluocinolone implants have been developed. Patients treated with these implants have experienced good and sustained control of their intraocular inflammation. Diagnosis and treatment options for ocular sarcoidosis have changed over time. However, challenges still exist in some difficult patients. Future studies should focus on finding more sensitive biomarkers and developing more effective immunomodulatory treatments with longer efficacy and less side effects.

Reporter cell assay-based functional quantification of TNF-α-antagonists in serum – a proof-of-principle study for adalimumab

Quantification of therapeutic antibodies is commonly based on physico-chemical assays such as enzyme-linked immunoabsorption assays (ELISA) and lately on mass spectrometry. However, the functional integrity of evaluated immunoglobulins is yet not assessed. Consequently, a commercially available reporter cell line was used to quantify the functional concentration of the anti-tumor necrosis factor alpha (TNF-α) antibody adalimumab present in serum of a healthy beagle dog treated with 3 mg intravenous adalimumab (Humira®). HEK-Blue™-hTLR3 cells express a secreted alkaline phosphatase under the control of a nuclear factor kappa B (NF-κB) response element. Its enzymatic activity can be recorded using colorimetry, which reports activity of extracellular NF-κB stimuli such as TNF-α. Using an adalimumab concentration-response calibration curve, the functional concentration of serum adalimumab was estimated to be 4.9 ± 1.4 μg/ml, which was in excellent agreement with ELISA results (4.8 μg/ml). The obtained data suggest that this simple, easy-to-handle reporter cell assay can be used for the functional quantification of adalimumab present in samples from in vitro or pre-clinical in vivo experiments. Moreover, this assay could be used in vitro to compare the pharmacodynamics of adalimumab biosimilars or different anti-TNF-α compounds, respectively.

Neurological Adverse Effects Associated With Anti-tumor Necrosis Factor Alpha Antibodies in Pediatric Inflammatory Bowel Diseases.

Neurological adverse effects (NAEs) induced by biotherapies have been reported in the literature mainly in adult patients with inflammatory bowel disease (IBD), rheumatic diseases, or psoriasis. There are scant data in children. Aims of this study are to report and describe noninfective NAE associated with anti-TNFα antibodies in pediatric IBD, and to evaluate their incidence. We retrospectively collected all reports of NAE in pediatric IBD treated with anti-TNFα antibodies recorded in the French Pharmacovigilance Database. To estimate the national incidence of NAEs, we extrapolated data from the French regional inception population-based cohort EPIMAD. Between 2000 and 2018, 231 adverse events in pediatric IBD exposed to anti-TNFα antibodies were reported to this Database. Seventeen NAEs (7.36%) were collected: 8 severe NAE (1 demyelinating neuropathy, 1 optic neuritis, 1 acute transverse myelitis, 1 polyradiculoneuritis, 1 sensorineural hearing loss, 1 seizure, 1 stroke, and 1 glioma), 7 moderate NAE (headaches), and 2 neuropsychic events. The median delay between anti-TNFα start and NAE occurrence was 6 months (range: 13 days to 26 months). In 10 of 17 patients, anti-TNFα antibodies were stopped. Nine of 17 patients had a complete resolution (including 2 severe NAE) and 8 of 17 a partial resolution (including 6 severe NAE). We estimate the incidence of severe NAE in pediatric IBD treated with anti-TNFα antibodies at 1 case for 10,000 patients-year in France. NAE associated with anti-TNFα antibodies in pediatric IBD are rare. In severe NAE, we recommend to discontinue anti-TNFα therapy and to consider alternative treatment.

Topical Therapy with Antisense Tumor Necrosis Factor Alpha Using Novel β-Glucan-Based Drug Delivery System Ameliorates Intestinal Inflammation.

Anti-tumor necrosis factor alpha (TNF-α) antibodies are effective in patients with inflammatory bowel disease (IBD). However, the effect is not optimal because a sufficient concentration of antibodies cannot be maintained at the site of inflammation. Thus, a macromolecular complex was developed with schizophyllan (SPG) and antisense oligonucleotides. In the present study, an SPG-antisense TNF-α complex was prepared, and its therapeutic efficacy was examined using a dextran sodium sulfate (DSS)-induced colitis model. The TNF-α production in CD11b+ macrophages significantly increased in the colon of DSS-treated mice. Dectin-1, a receptor of SPG, binds with SPG and is subsequently taken into the cells via phagocytosis. The expression of dectin-1 by CD11b+ macrophages significantly increased in DSS-treated mice. Flow cytometry revealed that the uptake of SPG-antisense TNF-α in the macrophages was efficient. TNF-α production was suppressed significantly by SPG-antisense TNF-α in vitro, which was administered via enema to evaluate its efficacy. The intrarectal administration of SPG-antisense TNF-α ameliorated the intestinal inflammation. In this study, we showed that the delivery system that conjugates SPG and antisense can have higher therapeutic efficacy. Thus, the new therapeutic approach presented in this study may be used in the management of IBD.

A Population Pharmacokinetic and Exposure-Response Model of Golimumab for Targeting Endoscopic Remission in Patients With Ulcerative Colitis.

Unlike other anti-tumor necrosis factor alpha antibodies, golimumab does not deliver on its promise of effectiveness for treating patients with ulcerative colitis. We investigated the value of therapeutic drug monitoring for optimizing golimumab therapy. We analyzed the golimumab pharmacokinetics data of 56 patients with moderate to severe ulcerative colitis. Induction and maintenance golimumab concentrations (296 venipuncture, 414 serum) were used to develop a population pharmacokinetic model. Exposure-response relationships were analyzed using the data of 40/56 patients with available endoscopy data. Receiver operating characteristic curve analysis was performed, and an exposure-response Markov model was developed, linking golimumab exposure to probabilities of transitioning between Mayo endoscopic subscore (MES) states from baseline to week (w)14. Golimumab pharmacokinetics was best described by a 2-compartment model with linear absorption and elimination. Antibodies to golimumab and previous biological therapy reduced golimumab exposure. Still, interindividual pharmacokinetic variability (IIVPK) remained largely unexplained. Endoscopic remission (ER; MESw14 ≤ 1) was achieved in 14/40 (35%) patients. Golimumab serum trough concentration thresholds of 7.4 mg/L (w6) and 3.2 mg/L (w14) predicted ER at w14 (positive predictive values [pv+] 83% and 91%, pv- 82% and 67%, respectively). The 3.2-mg/L target predicted 38% and 44% chances of achieving ER in patients with MESbaseline of 3 and 2, respectively. Personalized, model-based induction dosing aiming at here-established target concentrations may account for IIVPK and thus provide patients with more equal chances of achieving ER. As <50% of patients attained the exposure targets, higher golimumab induction dosing requires investigation to secure its future in clinical practice.

Su1899 – Expression Profiles of Helper T-Cell-Related Genes in the Intestinal Mucosa May Predict the Effect of Anti-Tumor Necrosis Factor-Alpha Antibody Agents in Ulcerative Colitis Patients

Su1899 – Expression Profiles of Helper T-Cell-Related Genes in the Intestinal Mucosa May Predict the Effect of Anti-Tumor Necrosis Factor-Alpha Antibody Agents in Ulcerative Colitis Patients