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Kireev FD, Lopatnikova JA, Alshevskaya AA, Sennikov SV. Role of Tumor Necrosis Factor in Tuberculosis. Biomolecules 2025; 15:709. [PMID: 40427602 DOI: 10.3390/biom15050709] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/18/2025] [Revised: 04/28/2025] [Accepted: 05/08/2025] [Indexed: 05/29/2025] Open
Abstract
Tumor necrosis factor (TNF) is a key immunoregulatory cytokine with a dual role in the host response to Mycobacterium tuberculosis. While essential for granuloma formation, macrophage activation, and containment of latent infection, TNF can also contribute to tissue damage and immune pathology. This review systematically analyzes over 300 peer-reviewed studies published between 1980 and 2024, highlighting the molecular and cellular mechanisms of TNF action in tuberculosis (TB). Particular attention is given to TNF receptor signaling pathways, the balance between protective and pathological immune responses, and the modulation of TNF activity during anti-TNF therapy in patients with autoimmune diseases. We discuss how different TNF inhibitors vary in their capacity to interfere with host defense mechanisms, with monoclonal antibodies carrying a higher reactivation risk than receptor-based agents. To enhance conceptual clarity, we provide newly developed schematic representations that integrate current knowledge on TNF-driven immune dynamics, including its interaction with other cytokines, effects on granuloma stability, and role in intracellular bacterial control. Understanding the pleiotropic functions of TNF in tuberculosis pathogenesis is crucial for developing safe immunomodulatory strategies and optimizing the clinical management of patients at risk of latent TB reactivation.
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Affiliation(s)
- Fedor D Kireev
- Laboratory of Molecular Immunology, Federal State Budgetary Scientific Institution "Research Institute of Fundamental and Clinical Immunology" (RIFCI), 630099 Novosibirsk, Russia
- Laboratory of Immune Engineering, Federal State Autonomous Educational Institution of Higher Education "I.M. Sechenov First Moscow State Medical University" under the Ministry of Health of the Russian Federation (Sechenov University), 119048 Moscow, Russia
| | - Julia A Lopatnikova
- Laboratory of Molecular Immunology, Federal State Budgetary Scientific Institution "Research Institute of Fundamental and Clinical Immunology" (RIFCI), 630099 Novosibirsk, Russia
- Laboratory of Immune Engineering, Federal State Autonomous Educational Institution of Higher Education "I.M. Sechenov First Moscow State Medical University" under the Ministry of Health of the Russian Federation (Sechenov University), 119048 Moscow, Russia
| | - Alina A Alshevskaya
- Laboratory of Immune Engineering, Federal State Autonomous Educational Institution of Higher Education "I.M. Sechenov First Moscow State Medical University" under the Ministry of Health of the Russian Federation (Sechenov University), 119048 Moscow, Russia
| | - Sergey V Sennikov
- Laboratory of Molecular Immunology, Federal State Budgetary Scientific Institution "Research Institute of Fundamental and Clinical Immunology" (RIFCI), 630099 Novosibirsk, Russia
- Laboratory of Immune Engineering, Federal State Autonomous Educational Institution of Higher Education "I.M. Sechenov First Moscow State Medical University" under the Ministry of Health of the Russian Federation (Sechenov University), 119048 Moscow, Russia
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Mauro F, Bruni S, Dupont A, Schey A, Badalini A, Inurrigarro G, Figurelli S, Barchuk S, Vecchia DLD, Deza EG, Rivenson Y, Nava A, Fernandez E, Urtreger A, Russo RC, Mercogliano MF, Schillaci R. Mucin 4 expression is associated with metastasis in triple-negative breast cancer and can be tackled by soluble TNF blockade, improving immunotherapy outcome. Transl Oncol 2025; 54:102325. [PMID: 39987883 PMCID: PMC11904514 DOI: 10.1016/j.tranon.2025.102325] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/29/2024] [Revised: 01/16/2025] [Accepted: 02/13/2025] [Indexed: 02/25/2025] Open
Abstract
PURPOSE Triple-negative breast cancer (TNBC) has the worst prognosis among breast cancers. Immunotherapy is a therapeutic option, but there is no biomarker to guide promising combination treatments. Mucin 4 (MUC4) favors metastasis in preclinical cancer models. This study evaluates the efficacy of soluble TNF (sTNF) neutralization to tackle MUC4 expression preventing metastasis in combination with immunotherapy, and the potential use of MUC4 as a prognostic and predictive biomarker in TNBC patients. EXPERIMENTAL DESIGN To explore TNF modulation of MUC4 expression, a panel of TNBC cell lines was used. To assess the effect of sTNF blockade with a dominant negative molecule in combination with anti-PD-1 antibody on lung metastasis and overall survival (OS), 4T1 and LMM3 tumors were used. MUC4, PD-L1 and Ki-67 expression was evaluated by immunohistochemistry, and tumor infiltrating lymphocytes (TILs) were assessed by H&E staining, in a cohort of 49 early TNBC patients treated with chemotherapy. RESULTS TNF neutralization reduces MUC4 expression in TNBC cell lines. Only the combination of sTNF blockade with anti-PD-1 antibody prevents metastasis and increases mice survival. In early TNBC patients MUC4 expression is inversely associated with TILs presence and PD-L1 and Ki-67 expression. Finally, MUC4 is associated with metastasis and is an independent biomarker of poor OS. CONCLUSIONS We proved the existence of a sTNF/MUC4 axis in TNBC that can be actionable by sTNF neutralization, preventing metastasis. We suggest that MUC4 is a suitable biomarker to guide immunotherapy in TNBC, together with the administration of sTNF blocking drugs to improve outcome.
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Affiliation(s)
- Florencia Mauro
- Laboratorio de Inmunología Tumoral. Instituto de Biología y Medicina Experimental (IBYME) Consejo Nacional de Investigaciones Científicas y Técnicas (CONICET). Fundación IBYME. Buenos Aires, Argentina
| | - Sofia Bruni
- Laboratorio de Inmunología Tumoral. Instituto de Biología y Medicina Experimental (IBYME) Consejo Nacional de Investigaciones Científicas y Técnicas (CONICET). Fundación IBYME. Buenos Aires, Argentina
| | - Agustina Dupont
- Servicio de Patología Sanatorio Mater Dei, Buenos Aires, Argentina; Servicio de Patología, Hospital Juan A. Fernández, Buenos Aires, Argentina
| | - Aldana Schey
- Universidad de Buenos Aires, Facultad de Medicina, Instituto de Oncología Ángel H. Roffo, Área de Investigación, Buenos Aires, Argentina
| | | | | | - Silvina Figurelli
- Servicio de Patología, Hospital Juan A. Fernández, Buenos Aires, Argentina
| | - Sabrina Barchuk
- Servicio de Ginecología, Hospital Juan A. Fernández, Buenos Aires, Argentina
| | | | | | - Yanina Rivenson
- Laboratorio de Inmunología Tumoral. Instituto de Biología y Medicina Experimental (IBYME) Consejo Nacional de Investigaciones Científicas y Técnicas (CONICET). Fundación IBYME. Buenos Aires, Argentina
| | - Agustin Nava
- DataLab, Fundación Para el Progreso de la Medicina - CONICET Córdoba, Facultad de Ciencias Exactas, Físicas y Naturales (FCEFyN) Universidad Nacional de Córdoba, Argentina
| | - Elmer Fernandez
- DataLab, Fundación Para el Progreso de la Medicina - CONICET Córdoba, Facultad de Ciencias Exactas, Físicas y Naturales (FCEFyN) Universidad Nacional de Córdoba, Argentina
| | - Alejandro Urtreger
- Universidad de Buenos Aires, Facultad de Medicina, Instituto de Oncología Ángel H. Roffo, Área de Investigación, Buenos Aires, Argentina
| | - Rosalia Cordo Russo
- Laboratorio de Inmunología Tumoral. Instituto de Biología y Medicina Experimental (IBYME) Consejo Nacional de Investigaciones Científicas y Técnicas (CONICET). Fundación IBYME. Buenos Aires, Argentina
| | - María Florencia Mercogliano
- Laboratorio de Inmunología Tumoral. Instituto de Biología y Medicina Experimental (IBYME) Consejo Nacional de Investigaciones Científicas y Técnicas (CONICET). Fundación IBYME. Buenos Aires, Argentina
| | - Roxana Schillaci
- Laboratorio de Inmunología Tumoral. Instituto de Biología y Medicina Experimental (IBYME) Consejo Nacional de Investigaciones Científicas y Técnicas (CONICET). Fundación IBYME. Buenos Aires, Argentina.
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3
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Kwon OC, Lee HS, Yang J, Park MC. Risk of Cancers According to the Use of Biological Agents in Patients With Radiographic Axial Spondyloarthritis: A Nationwide Population-Based Cohort Study. J Clin Rheumatol 2025; 31:e13-e21. [PMID: 39869756 DOI: 10.1097/rhu.0000000000002188] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/29/2025]
Abstract
OBJECTIVE As the duration of use of biological disease-modifying antirheumatic drugs (bDMARDs) in patients with radiographic axial spondyloarthritis (r-axSpA) accumulates over time, long-term real-world safety data on cancer risk are needed. This study assessed the association between tumor necrosis factor inhibitors (TNFis) and interleukin 17 inhibitors (IL-17is) exposures and cancer risk in patients with r-axSpA. METHODS From the Korean nationwide database, we assembled 41,889 patients without prior history of cancer who were diagnosed with r-axSpA from 2010 onwards. Patients were followed up through 2021. Multivariable time-varying Cox models were performed to estimate the adjusted hazards ratios (aHRs) and 95% confidence intervals (CIs) of (1) overall cancers and (2) cancer subtypes according to TNFis exposure versus bDMARDs nonexposure, IL-17is exposure versus bDMARDs nonexposure, and IL-17is exposure versus TNFis exposure. RESULTS The incident rates of overall cancers during bDMARDs nonexposure, TNFis exposure, and IL-17is exposure were 53.8, 37.6, and 67.3 per 10,000 person-years, respectively. TNFis exposure versus bDMARDs nonexposure was not associated with an increased risk of overall cancers (aHR = 0.9, 95% CI = 0.8-1.1). IL-17is exposure was not associated with an increased risk of overall cancers compared with bDMARDs nonexposure (aHR = 1.2, 95% CI = 0.5-3.0) or TNFis exposure (aHR = 1.3, 95% CI = 0.6-3.3). Similarly, no significant associations were observed between bDMARDs exposures and the risk of cancer subtypes. CONCLUSIONS In patients with r-axSpA, there was no evidence of increased cancer risk with TNFis and IL-17is exposures compared with bDMARDs nonexposure, suggesting that the use of bDMARDs is safe with respect to cancer risk in patients with r-axSpA.
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Affiliation(s)
- Oh Chan Kwon
- From the Division of Rheumatology, Department of Internal Medicine, Yonsei University College of Medicine, Seoul, South Korea
| | - Hye Sun Lee
- Biostatistics Collaboration Unit, Yonsei University College of Medicine, Seoul, South Korea
| | - Juyeon Yang
- Biostatistics Collaboration Unit, Yonsei University College of Medicine, Seoul, South Korea
| | - Min-Chan Park
- From the Division of Rheumatology, Department of Internal Medicine, Yonsei University College of Medicine, Seoul, South Korea
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Vallejo C, Meaney C, Clemens L, Yang K, Lukacova V, Zhou H. Physiologically Based Pharmacokinetic Models for Infliximab, Ipilimumab, and Nivolumab Developed with GastroPlus to Predict Hepatic Concentrations. Pharmaceutics 2025; 17:372. [PMID: 40143035 PMCID: PMC11945841 DOI: 10.3390/pharmaceutics17030372] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/13/2025] [Revised: 03/05/2025] [Accepted: 03/07/2025] [Indexed: 03/28/2025] Open
Abstract
Background/Objectives: Infliximab, ipilimumab, and nivolumab are three monoclonal antibodies that have been associated with hepatotoxicity. Three separate physiologically based pharmacokinetic (PBPK) models were developed in GastroPlus® to simulate plasma and liver concentrations in patient populations after administration of either infliximab, ipilimumab, or nivolumab. Methods: The models include distribution and clearance mechanisms specific to large molecules, FcRn binding dynamics, and target-mediated drug disposition (TNF-α for infliximab, CTLA-4 for ipilimumab, and PD-1 for nivolumab). Results: The PBPK model for each large molecule was able to reproduce observed plasma concentration data in patient populations, including patients with rheumatoid arthritis and patients with solid tumors. Liver concentrations were predicted to be between 10% and 23% of the plasma concentrations for each of the three drugs, aligning with previously reported results. This lends further validity to the PBPK models and their ability to accurately predict hepatic concentrations in the absence of direct tissue measurements. Conclusions: These results can be used to drive liver toxicity predictions using the quantitative systems toxicology model, BIOLOGXsym™, which integrates hepatic interstitial concentrations with in vitro mechanistic toxicity data to predict the extent of liver toxicity for biologics.
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Affiliation(s)
- Celeste Vallejo
- Simulations Plus, Research Triangle Park, Durham, NC 27709, USA; (C.M.); (L.C.); (K.Y.); (V.L.)
| | | | | | | | | | - Haiying Zhou
- Simulations Plus, Research Triangle Park, Durham, NC 27709, USA; (C.M.); (L.C.); (K.Y.); (V.L.)
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Picchianti-Diamanti A, Aiello A, De Lorenzo C, Migliori GB, Goletti D. Management of tuberculosis risk, screening and preventive therapy in patients with chronic autoimmune arthritis undergoing biotechnological and targeted immunosuppressive agents. Front Immunol 2025; 16:1494283. [PMID: 39963138 PMCID: PMC11830708 DOI: 10.3389/fimmu.2025.1494283] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/10/2024] [Accepted: 01/06/2025] [Indexed: 02/20/2025] Open
Abstract
Tuberculosis (TB) is the leading cause of death in the world from an infectious disease. Its etiologic agent, the Mycobacterium tuberculosis (Mtb), is a slow-growing bacterium that has coexisted in humans for thousands of years. According to the World Health Organization, 10.6 million new cases of TB and over 1 million deaths were reported in 2022. It is widely recognized that patients affected by chronic autoimmune arthritis such as rheumatoid arthritis (RA), psoriatic arthritis (PsA), and ankylosing spondylitis (AS) have an increased incidence rate of TB disease compared to the general population. As conceivable, the risk is associated with age ≥65 years and is higher in endemic regions, but immunosuppressive therapy plays a pivotal role. Several systematic reviews have analysed the impact of anti-TNF-α agents on the risk of TB in patients with chronic autoimmune arthritis, as well as for other biologic disease-modifying immunosuppressive anti-rheumatic drugs (bDMARDs) such as rituximab, abatacept, tocilizumab, ustekinumab, and secukinumab. However, the data are less robust compared to those available with TNF-α inhibitors. Conversely, data on anti-IL23 agents and JAK inhibitors (JAK-i), which have been more recently introduced for the treatment of RA and PsA/AS, are limited. TB screening and preventive therapy are recommended in Mtb-infected patients undergoing bDMARDs and targeted synthetic (ts)DMARDs. In this review, we evaluate the current evidence from randomized clinical trials, long-term extension studies, and real-life studies regarding the risk of TB in patients with RA, PsA, and AS treated with bDMARDs and tsDMARDs. According to the current evidence, TNF-α inhibitors carry the greatest risk of TB progression among bDMARDs and tsDMARDs, such as JAK inhibitors and anti-IL-6R agents. The management of TB screening and the updated preventive therapy are reported.
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Affiliation(s)
- Andrea Picchianti-Diamanti
- Department of Clinical and Molecular Medicine, “Sapienza” University, S. Andrea University Hospital, Rome, Italy
| | - Alessandra Aiello
- Translational Research Unit, National Institute for Infectious Diseases “Lazzaro Spallanzani”- Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS), Rome, Italy
| | - Chiara De Lorenzo
- Department of Clinical and Molecular Medicine, “Sapienza” University, S. Andrea University Hospital, Rome, Italy
| | - Giovanni Battista Migliori
- Istituti Clinici Scientifici Maugeri, Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS), Tradate, Italy
| | - Delia Goletti
- Translational Research Unit, National Institute for Infectious Diseases “Lazzaro Spallanzani”- Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS), Rome, Italy
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6
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Obi ON, Saketkoo LA, Maier LA, Baughman RP. Developmental drugs for sarcoidosis. J Autoimmun 2024; 149:103179. [PMID: 38548579 DOI: 10.1016/j.jaut.2024.103179] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/10/2023] [Revised: 12/04/2023] [Accepted: 02/08/2024] [Indexed: 12/15/2024]
Abstract
Sarcoidosis is a multi-organ granulomatous inflammatory disease of unknown etiology. Over 50% of patients will require treatment at some point in their disease and 10%-30% will develop a chronic progressive disease with pulmonary fibrosis leading to significant morbidity and mortality. Recently published guidelines recommend immunosuppressive therapy for sarcoidosis patients at risk of increased disease-related morbidity and mortality, and in whom disease has negatively impacted quality of life. Prednisone the currently recommended first line therapy is associated with significant toxicity however none of the other guideline recommended steroid sparing therapy is approved by regulatory agencies for use in sarcoidosis, and data in support of their use is weak. For patients with severe refractory disease requiring prolonged therapy, treatment options are limited. The need for expanding treatment options in sarcoidosis has been emphasized. Well conducted large, randomized trials evaluating currently available therapeutic options as well as novel pathways for targeting disease are necessary to better guide treatment decisions. These trials will not be without significant challenges. Sarcoidosis is a rare disease with heterogenous presentation and variable progression and clinical outcome. There are no universally agreed upon biomarkers of disease activity and measurement of outcomes is confounded by the need to balance patient centric measures and objective measures of disease activity. Our paper provides an update on developmental drugs in sarcoidosis and outlines several novel pathways that may be targeted for future drug development. Currently available trials are highlighted and ongoing challenges to drug development and clinical trial design are briefly discussed.
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Affiliation(s)
- Ogugua Ndili Obi
- Division of Pulmonary Critical Care and Sleep Medicine, Brody School of Medicine, East Carolina University, Greenville, NC, USA.
| | - Lesley Ann Saketkoo
- New Orleans Scleroderma and Sarcoidosis Patient Care and Research Center, New Orleans, USA; University Medical Center - Comprehensive Pulmonary Hypertension Center and Interstitial Lung Disease Clinic Programs, New Orleans, USA; Louisiana State University School of Medicine, Section of Pulmonary Medicine, New Orleans, LA, USA; Tulane University School of Medicine, Undergraduate Honors Department, New Orleans, LA, USA
| | - Lisa A Maier
- Division of Environmental and Occupational Health Sciences, Department of Medicine, National Jewish Health, Denver, CO, USA; Division of Pulmonary and Critical Care Sciences, Department of Medicine, University of Colorado School of Medicine, Denver, CO, USA
| | - Robert P Baughman
- Emeritus Professor of Medicine, Department of Medicine, University of Cincinnati, Cincinnati, OH, USA
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Javaid N, Ahmad B, Patra MC, Choi S. Decoy peptides that inhibit TNF signaling by disrupting the TNF homotrimeric oligomer. FEBS J 2024; 291:4372-4391. [PMID: 39003565 DOI: 10.1111/febs.17220] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/26/2023] [Revised: 04/18/2024] [Accepted: 06/24/2024] [Indexed: 07/15/2024]
Abstract
Tumor necrosis factor (TNF) is a pro-inflammatory cytokine and its functional homotrimeric form interacts with the TNF receptor (TNFR) to activate downstream apoptotic, necroptotic, and inflammatory signaling pathways. Excessive activation of these pathways leads to various inflammatory diseases, which makes TNF a promising therapeutic target. Here, 12-mer peptides were selected from the interface of TNF-TNFR based upon their relative binding energies and were named 'TNF-inhibiting decoys' (TIDs). These decoy peptides inhibited TNF-mediated secretion of cytokines and cell death, as well as activation of downstream signaling effectors. Effective TIDs inhibited TNF signaling by disrupting the formation of TNF's functional homotrimeric form. Among derivatives of TIDs, TID3c showed slightly better efficacy in cell-based assays by disrupting TNF trimer formation. Moreover, TID3c oligomerized TNF to a high molecular weight configuration. In silico modeling and simulations revealed that TID3c and its parent peptide, TID3, form a stable complex with TNF through hydrogen bonds and electrostatic interactions, which makes them the promising lead to develop peptide-based anti-TNF therapeutics.
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Affiliation(s)
- Nasir Javaid
- Department of Molecular Science and Technology, Ajou University, Suwon, Korea
- S&K Therapeutics, Suwon, Korea
| | - Bilal Ahmad
- Department of Molecular Science and Technology, Ajou University, Suwon, Korea
- S&K Therapeutics, Suwon, Korea
| | | | - Sangdun Choi
- Department of Molecular Science and Technology, Ajou University, Suwon, Korea
- S&K Therapeutics, Suwon, Korea
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Wride AM, Chen GF, Spaulding SL, Tkachenko E, Cohen JM. Biologics for Psoriasis. Dermatol Clin 2024; 42:339-355. [PMID: 38796266 DOI: 10.1016/j.det.2024.02.001] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 05/28/2024]
Abstract
Biologic therapies targeting tumor necrosis factor alpha (TNF-α) (infliximab, adalimumab, certolizumab, etanercept), the p40 subunit shared by IL-12 and IL-23 (ustekinumab), the p19 subunit of IL-23 (guselkumab, tildrakizumab, risankizumab), IL-17A (secukinumab, ixekizumab), IL-17-RA (brodalumab) and both IL-17A and IL-17F (bimekizumab) have revolutionized the treatment of psoriasis. In both the short and long term, risankizumab had highest Psoriasis Area and Severity Index 90 scores compared to other oral and injectable biologics. IL-23 inhibitors had lowest rates of short-term and long-term adverse events and most favorable long-term risk-benefit profile compared to IL-17, IL-12/23, and TNF-α inhibitors.
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Affiliation(s)
- Anthony Mitchel Wride
- Department of Dermatology, Yale School of Medicine, Yale University, 15 York Street, New Haven, CT 06510, USA
| | - Gloria F Chen
- Department of Dermatology, Yale School of Medicine, Yale University, 15 York Street, New Haven, CT 06510, USA
| | - Sarah L Spaulding
- Department of Dermatology, Yale School of Medicine, Yale University, 15 York Street, New Haven, CT 06510, USA
| | - Elizabeth Tkachenko
- Department of Dermatology, Yale School of Medicine, Yale University, 15 York Street, New Haven, CT 06510, USA
| | - Jeffrey M Cohen
- Department of Dermatology, Yale School of Medicine, Yale University, 15 York Street, New Haven, CT 06510, USA.
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Li X, Paccoud O, Chan KH, Yuen KY, Manchon R, Lanternier F, Slavin MA, van de Veerdonk FL, Bicanic T, Lortholary O. Cryptococcosis Associated With Biologic Therapy: A Narrative Review. Open Forum Infect Dis 2024; 11:ofae316. [PMID: 38947739 PMCID: PMC11212009 DOI: 10.1093/ofid/ofae316] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/05/2024] [Accepted: 06/17/2024] [Indexed: 07/02/2024] Open
Abstract
Cryptococcus is an opportunistic fungal pathogen that can cause disseminated infection with predominant central nervous system involvement in patients with compromised immunity. Biologics are increasingly used in the treatment of neoplasms and autoimmune/inflammatory conditions and the prevention of transplant rejection, which may affect human defense mechanisms against cryptococcosis. In this review, we comprehensively investigate the association between cryptococcosis and various biologics, highlighting their risks of infection, clinical manifestations, and clinical outcomes. Clinicians should remain vigilant for the risk of cryptococcosis in patients receiving biologics that affect the Th1/macrophage activation pathways, such as tumor necrosis factor α antagonists, Bruton tyrosine kinase inhibitors, fingolimod, JAK/STAT inhibitors (Janus kinase/signal transducer and activator of transcription), and monoclonal antibody against CD52. Other risk factors-such as age, underlying condition, and concurrent immunosuppressants, especially corticosteroids-should also be taken into account during risk stratification.
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Affiliation(s)
- Xin Li
- Department of Infectious Diseases and Tropical Medicine, Université Paris Cité, Necker-Enfants Malades University Hospital, Assistance Publique–Hôpitaux de Paris, IHU Imagine, Paris, France
- Department of Microbiology, School of Clinical Medicine, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Pokfulam, Hong Kong SAR, China
| | - Olivier Paccoud
- Department of Infectious Diseases and Tropical Medicine, Université Paris Cité, Necker-Enfants Malades University Hospital, Assistance Publique–Hôpitaux de Paris, IHU Imagine, Paris, France
| | - Koon-Ho Chan
- Department of Medicine, School of Clinical Medicine, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Pokfulam, Hong Kong SAR, China
| | - Kwok-Yung Yuen
- Department of Microbiology, School of Clinical Medicine, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Pokfulam, Hong Kong SAR, China
| | - Romain Manchon
- Department of Infectious Diseases and Tropical Medicine, Université Paris Cité, Necker-Enfants Malades University Hospital, Assistance Publique–Hôpitaux de Paris, IHU Imagine, Paris, France
| | - Fanny Lanternier
- Department of Infectious Diseases and Tropical Medicine, Université Paris Cité, Necker-Enfants Malades University Hospital, Assistance Publique–Hôpitaux de Paris, IHU Imagine, Paris, France
- Institut Pasteur, National Reference Center for Invasive Mycoses and Antifungals, Mycology Translational Research Group, Mycology Department, Université Paris Cité, Paris, France
| | - Monica A Slavin
- Department of Infectious Diseases, Peter MacCallum Cancer Centre, Melbourne, Australia
- Sir Peter MacCallum Department of Oncology, University of Melbourne, Melbourne, Australia
- Victorian Infectious Diseases Service, Royal Melbourne Hospital, Melbourne, Australia
| | - Frank L van de Veerdonk
- Department of Internal Medicine, Radboud Center for Infectious Diseases, Radboudumc, Nijmegen, the Netherlands
| | - Tihana Bicanic
- Institute of Infection and Immunity, St George's University of London, London, UK
| | - Olivier Lortholary
- Department of Infectious Diseases and Tropical Medicine, Université Paris Cité, Necker-Enfants Malades University Hospital, Assistance Publique–Hôpitaux de Paris, IHU Imagine, Paris, France
- Institut Pasteur, National Reference Center for Invasive Mycoses and Antifungals, Mycology Translational Research Group, Mycology Department, Université Paris Cité, Paris, France
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Berkhout LC, I'Ami MJ, Kruithof S, Vogelzang EH, Hooijberg F, Hart MHL, Bentlage AEH, Thomas D, Vermeire S, Vidarsson G, Ten Brinke A, Nurmohamed MT, Wolbink GJ, Rispens T. Formation and clearance of TNF-TNF inhibitor complexes during TNF inhibitor treatment. Br J Pharmacol 2024; 181:1165-1181. [PMID: 37859583 DOI: 10.1111/bph.16269] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/25/2023] [Revised: 06/29/2023] [Accepted: 07/31/2023] [Indexed: 10/21/2023] Open
Abstract
BACKGROUND AND PURPOSE Millions of patients with inflammatory diseases are treated with tumour necrosis factor (TNF) inhibitors (TNFi). Individual treatment response varies, in part related to variable drug clearance. The role of TNF-TNFi complexes in clearance of the different TNFi is controversial. Moreover, mechanistic insight into the structural aspects and biological significance of TNF-TNFi complexes is lacking. We hypothesized a role for Fc-mediated clearance of TNF-TNFi immune complexes. Therefore, we investigated circulating TNF-TNFi complexes upon treatment with certolizumab-lacking Fc tails-in comparison with adalimumab, golimumab, infliximab and etanercept. EXPERIMENTAL APPROACH Drug-tolerant ELISAs were developed and used to quantify TNF during adalimumab, golimumab, etanercept, certolizumab and infliximab treatment in patients with inflammatory arthritis or ulcerative colitis for a maximum follow-up of 1 year. Effects on in vitro TNF production and Fc-mediated uptake of TNF-TNFi complexes were investigated for all five TNFi. KEY RESULTS Circulating TNF concentrations were >20-fold higher during certolizumab treatment compared with adalimumab, reaching up to 23.1 ng·ml-1 . Internalization of TNF-TNFi complexes by macrophages depended on Fc valency, with efficient uptake for the full antibody TNFi (three Fc tails), but little or no uptake for etanercept and certolizumab (one and zero Fc tail, respectively). TNF production was not affected by TNFi. Total TNF load did not affect clearance rate of total TNFi. CONCLUSIONS AND IMPLICATIONS Differences in TNFi structure profoundly affect clearance of TNF, while it is unlikely that TNF itself significantly contributes to target-mediated drug disposition of TNFi.
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Affiliation(s)
- Lea Catharina Berkhout
- Department of Immunopathology, Sanquin Research, Amsterdam, The Netherlands
- Landsteiner Laboratory, Academic Medical Centre, University of Amsterdam, Amsterdam, The Netherlands
| | - Merel Jeanne I'Ami
- Amsterdam Rheumatology and Immunology Center | Reade, Amsterdam, The Netherlands
| | - Simone Kruithof
- Department of Immunopathology, Sanquin Research, Amsterdam, The Netherlands
- Landsteiner Laboratory, Academic Medical Centre, University of Amsterdam, Amsterdam, The Netherlands
| | - Erik Hans Vogelzang
- Amsterdam Rheumatology and Immunology Center | Reade, Amsterdam, The Netherlands
| | - Femke Hooijberg
- Amsterdam Rheumatology and Immunology Center | Reade, Amsterdam, The Netherlands
| | - Margaretha Hendrika Louise Hart
- Department of Immunopathology, Sanquin Research, Amsterdam, The Netherlands
- Landsteiner Laboratory, Academic Medical Centre, University of Amsterdam, Amsterdam, The Netherlands
| | - Arthur Ebel Herman Bentlage
- Landsteiner Laboratory, Academic Medical Centre, University of Amsterdam, Amsterdam, The Netherlands
- Department of Experimental Immunohematology, Sanquin Research, Amsterdam, The Netherlands
| | - Debby Thomas
- Department of Pharmaceutical and Pharmacological Sciences, Laboratory for Therapeutic and Diagnostic Antibodies, Katholieke Universiteit Leuven, Leuven, Belgium
| | - Severine Vermeire
- Department of Gastroenterology and Hepatology, University Hospitals Leuven, KU Leuven, Leuven, Belgium
- Department of Chronic Diseases, Metabolism and Ageing (CHROMETA), Translational Research Center for Gastrointestinal Disorders (TARGID), KU Leuven, Leuven, Belgium
- Translational Research in Gastrointestinal Disorders, University Hospitals Leuven, Leuven, Belgium
| | - Gestur Vidarsson
- Landsteiner Laboratory, Academic Medical Centre, University of Amsterdam, Amsterdam, The Netherlands
- Department of Experimental Immunohematology, Sanquin Research, Amsterdam, The Netherlands
| | - Anja Ten Brinke
- Department of Immunopathology, Sanquin Research, Amsterdam, The Netherlands
- Landsteiner Laboratory, Academic Medical Centre, University of Amsterdam, Amsterdam, The Netherlands
| | - Michael Twahier Nurmohamed
- Amsterdam Rheumatology and Immunology Center | Reade, Amsterdam, The Netherlands
- Amsterdam Rheumatology and Immunology Center | VU University Medical Center, Amsterdam, The Netherlands
| | - Gerrit Jan Wolbink
- Department of Immunopathology, Sanquin Research, Amsterdam, The Netherlands
- Landsteiner Laboratory, Academic Medical Centre, University of Amsterdam, Amsterdam, The Netherlands
- Amsterdam Rheumatology and Immunology Center | Reade, Amsterdam, The Netherlands
| | - Theo Rispens
- Department of Immunopathology, Sanquin Research, Amsterdam, The Netherlands
- Landsteiner Laboratory, Academic Medical Centre, University of Amsterdam, Amsterdam, The Netherlands
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11
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Bastard L, Claudepierre P, Penso L, Sbidian E, Pina Vegas L. Risk of serious infection associated with different classes of targeted therapies used in psoriatic arthritis: a nationwide cohort study from the French Health Insurance Database (SNDS). RMD Open 2024; 10:e003865. [PMID: 38485454 PMCID: PMC10941117 DOI: 10.1136/rmdopen-2023-003865] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/31/2023] [Accepted: 02/20/2024] [Indexed: 03/17/2024] Open
Abstract
OBJECTIVE To assess the risk of serious infection associated with different targeted therapies for psoriatic arthritis (PsA) in real-world settings. METHODS This nationwide cohort study used the administrative healthcare database of the French health insurance scheme linked to the hospital discharge database to identify all adults with PsA who were new users of targeted therapies (adalimumab, etanercept, golimumab, certolizumab pegol, infliximab, secukinumab, ixekizumab, ustekinumab, and tofacitinib) from 1 January 2015 to 30 June 2021. The primary outcome was a serious infection (ie, requiring hospitalisation), in a time-to-event analysis using propensity score-weighted Cox models, with adalimumab as the comparator, estimating weighted HRs (wHRs) and their 95% CIs. RESULTS A total of 12 071 patients were included (mean age 48.7±12.7 years; 6965 (57.7%) women). We identified 367 serious infections (3.0% of patients), with a crude incidence rate of 17.0 per 1000 person-years (95% CI, 15.2 to 18.7). After inverse propensity score weighting and adjustment for time-dependent covariates and calendar year, risk of serious infection was significantly lower for new users of etanercept (wHR 0.72; 95% CI, 0.53 to 0.97) or ustekinumab (wHR, 0.57; 95% CI, 0.35 to 0.93) than adalimumab new users. This risk was not statistically modified with the other targeted therapies. CONCLUSIONS The incidence of serious infection was low for PsA patients who were new users of targeted therapies in real-world settings. Relative to adalimumab new users, this risk was lower among new users of etanercept and ustekinumab and unmodified for the other molecules.
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Affiliation(s)
- Léa Bastard
- Epidemiology in Dermatology and Evaluation of Therapeutics (EpiDermE), University Paris-Est Créteil Val de Marne, Créteil, France
- Rheumatology, Hospital Henri Mondor, Créteil, France
| | - Pascal Claudepierre
- Epidemiology in Dermatology and Evaluation of Therapeutics (EpiDermE), University Paris-Est Créteil Val de Marne, Créteil, France
- Rheumatology, Hospital Henri Mondor, Créteil, France
| | - Laetitia Penso
- Epidemiology in Dermatology and Evaluation of Therapeutics (EpiDermE), University Paris-Est Créteil Val de Marne, Créteil, France
| | - Emilie Sbidian
- Epidemiology in Dermatology and Evaluation of Therapeutics (EpiDermE), University Paris-Est Créteil Val de Marne, Créteil, France
- Dermatology, Hospital Henri Mondor, Créteil, France
- Clinical Investigation Center 1430, INSERM, Créteil, France
| | - Laura Pina Vegas
- Epidemiology in Dermatology and Evaluation of Therapeutics (EpiDermE), University Paris-Est Créteil Val de Marne, Créteil, France
- Rheumatology, Hospital Henri Mondor, Créteil, France
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12
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Obi ON. Anti-inflammatory Therapy for Sarcoidosis. Clin Chest Med 2024; 45:131-157. [PMID: 38245362 DOI: 10.1016/j.ccm.2023.08.010] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/22/2024]
Abstract
Over 50% of patients with sarcoidosis will require anti-inflammatory therapy at some point in their disease course. Indications for therapy are to improve health-related quality of life, prevent or arrest organ dysfunction (or organ failure) or avoid death. Recently published treatment guidelines recommended a stepwise approach to therapy however there are some patients for whom up front combination or more intense therapy maybe reasonable. The last decade has seen an explosion of studies and trials evaluating novel therapeutic agents and treatment strategies. Currently available anti-inflammatory therapies and several novel therapies are discussed here.
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Affiliation(s)
- Ogugua Ndili Obi
- Department of Internal Medicine, Division of Pulmonary Critical Care and Sleep Medicine, Brody School of Medicine, East Carolina University, Greenville, NC, USA.
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13
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Krauthammer A, Cozacov T, Fried S, Har-Zahav A, Shamir R, Assa A, Waisbourd-Zinman O. Tissue markers may predict treatment response to antitumor necrosis factor-α agents in children with Crohn's disease. J Pediatr Gastroenterol Nutr 2024; 78:662-669. [PMID: 38299301 DOI: 10.1002/jpn3.12146] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/23/2023] [Revised: 01/15/2024] [Accepted: 01/20/2024] [Indexed: 02/02/2024]
Abstract
OBJECTIVES Patients with moderate-severe Crohn's disease (CD) who are treated with antitumor necrosis factor alpha (TNF-α) agents may be subjected to primary nonresponse or partial response. We aimed to identify tissue markers that may predict response to these agents. METHODS Pediatric patients (6-18 years) with either ileal or ileo-colonic CD who were treated with anti-TNF-α were stratified into three different groups based on their overall response to therapy at the end of induction including clinical and laboratory parameters (group 1-full responders [FR], group 2-partial responders [PR], group 3-nonresponders [NR]). Seven tissue markers (fibronectin, interleukin [IL]-23R, IL-23, TNF-α, collagen-III, IL-13R, and hypoxia-inducible factors [HIF]-1α) were evaluated. Immunofluorescence (IF) analyses were performed on biopsies from the terminal ileum, which were retrieved up to 6 months before treatment initiation. RESULTS Twenty-six CD patients (16 [61.5%] males; age 13.9 ± 2.9 years), including 8 (30.8%) with ileal disease and 18 (69.2%) with ileo-colonic disease, were enrolled. Terminal ileum biopsies from nine patients from group 1, nine from group 2, and eight from group 3 were evaluated. Three antibodies were found to be significantly different between NR and FR groups; Collagen III and fibronectin stains were significantly more prominent in NR patients, while TNF-α stain was significantly more pronounced in FR, p < 0.05 for each. PR could not have been predicted with neither of markers. CONCLUSIONS Decreased tissue IF intensity of fibronectin and collagen III and increased intensity of TNF-α may predict response to anti-TNF-α treatment.
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Affiliation(s)
- Alexander Krauthammer
- Schneider Children's Medical Center of Israel, Institute of Gastroenterology, Nutrition and Liver Diseases, Petah Tikva, Israel
- Faculty of Medicine, Tel-Aviv University, Tel-Aviv, Israel
| | - Tal Cozacov
- Schneider Children's Medical Center of Israel, Institute of Gastroenterology, Nutrition and Liver Diseases, Petah Tikva, Israel
- Felsenstein Medical Research Center, Faculty of Medicine, Tel-Aviv University, Tel-Aviv, Israel
| | - Sophia Fried
- Schneider Children's Medical Center of Israel, Institute of Gastroenterology, Nutrition and Liver Diseases, Petah Tikva, Israel
- Felsenstein Medical Research Center, Faculty of Medicine, Tel-Aviv University, Tel-Aviv, Israel
| | - Adi Har-Zahav
- Schneider Children's Medical Center of Israel, Institute of Gastroenterology, Nutrition and Liver Diseases, Petah Tikva, Israel
- Felsenstein Medical Research Center, Faculty of Medicine, Tel-Aviv University, Tel-Aviv, Israel
| | - Raanan Shamir
- Schneider Children's Medical Center of Israel, Institute of Gastroenterology, Nutrition and Liver Diseases, Petah Tikva, Israel
- Faculty of Medicine, Tel-Aviv University, Tel-Aviv, Israel
| | - Amit Assa
- The Juliet Keidan Institute of Pediatric Gastroenterology and Nutrition, Shaare Zedek Medical Center, The Hebrew University, Jerusalem, Israel
| | - Orith Waisbourd-Zinman
- Schneider Children's Medical Center of Israel, Institute of Gastroenterology, Nutrition and Liver Diseases, Petah Tikva, Israel
- Faculty of Medicine, Tel-Aviv University, Tel-Aviv, Israel
- Felsenstein Medical Research Center, Faculty of Medicine, Tel-Aviv University, Tel-Aviv, Israel
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14
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Gerassy-Vainberg S, Starosvetsky E, Gaujoux R, Blatt A, Maimon N, Gorelik Y, Pressman S, Alpert A, Bar-Yoseph H, Dubovik T, Perets B, Katz A, Milman N, Segev M, Chowers Y, Shen-Orr SS. A personalized network framework reveals predictive axis of anti-TNF response across diseases. Cell Rep Med 2024; 5:101300. [PMID: 38118442 PMCID: PMC10829759 DOI: 10.1016/j.xcrm.2023.101300] [Citation(s) in RCA: 2] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/21/2023] [Revised: 08/20/2023] [Accepted: 10/31/2023] [Indexed: 12/22/2023]
Abstract
Personalized treatment of complex diseases has been mostly predicated on biomarker identification of one drug-disease combination at a time. Here, we use a computational approach termed Disruption Networks to generate a data type, contextualized by cell-centered individual-level networks, that captures biology otherwise overlooked when performing standard statistics. This data type extends beyond the "feature level space", to the "relations space", by quantifying individual-level breaking or rewiring of cross-feature relations. Applying Disruption Networks to dissect high-dimensional blood data, we discover and validate that the RAC1-PAK1 axis is predictive of anti-TNF response in inflammatory bowel disease. Intermediate monocytes, which correlate with the inflammatory state, play a key role in the RAC1-PAK1 responses, supporting their modulation as a therapeutic target. This axis also predicts response in rheumatoid arthritis, validated in three public cohorts. Our findings support blood-based drug response diagnostics across immune-mediated diseases, implicating common mechanisms of non-response.
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Affiliation(s)
- Shiran Gerassy-Vainberg
- Faculty of Medicine, Technion-Israel Institute of Technology, Haifa 32000, Israel; Department of Gastroenterology, Rambam Health Care Campus, Haifa 3109601, Israel
| | - Elina Starosvetsky
- Faculty of Medicine, Technion-Israel Institute of Technology, Haifa 32000, Israel
| | - Renaud Gaujoux
- Faculty of Medicine, Technion-Israel Institute of Technology, Haifa 32000, Israel; CytoReason, Tel Aviv 67012, Israel
| | - Alexandra Blatt
- Department of Gastroenterology, Rambam Health Care Campus, Haifa 3109601, Israel
| | - Naama Maimon
- Faculty of Medicine, Technion-Israel Institute of Technology, Haifa 32000, Israel; Department of Gastroenterology, Rambam Health Care Campus, Haifa 3109601, Israel
| | - Yuri Gorelik
- Department of Gastroenterology, Rambam Health Care Campus, Haifa 3109601, Israel
| | - Sigal Pressman
- Department of Gastroenterology, Rambam Health Care Campus, Haifa 3109601, Israel; Clinical Research Institute, Rambam Health Care Campus, Haifa 3109601, Israel
| | - Ayelet Alpert
- Faculty of Medicine, Technion-Israel Institute of Technology, Haifa 32000, Israel
| | - Haggai Bar-Yoseph
- Faculty of Medicine, Technion-Israel Institute of Technology, Haifa 32000, Israel; Department of Gastroenterology, Rambam Health Care Campus, Haifa 3109601, Israel
| | - Tania Dubovik
- Faculty of Medicine, Technion-Israel Institute of Technology, Haifa 32000, Israel
| | - Benny Perets
- Faculty of Medicine, Technion-Israel Institute of Technology, Haifa 32000, Israel
| | | | - Neta Milman
- Faculty of Medicine, Technion-Israel Institute of Technology, Haifa 32000, Israel
| | - Meital Segev
- Faculty of Medicine, Technion-Israel Institute of Technology, Haifa 32000, Israel
| | - Yehuda Chowers
- Faculty of Medicine, Technion-Israel Institute of Technology, Haifa 32000, Israel; Department of Gastroenterology, Rambam Health Care Campus, Haifa 3109601, Israel; Clinical Research Institute, Rambam Health Care Campus, Haifa 3109601, Israel.
| | - Shai S Shen-Orr
- Faculty of Medicine, Technion-Israel Institute of Technology, Haifa 32000, Israel.
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15
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Pardridge WM. Treatment of Parkinson's disease with biologics that penetrate the blood-brain barrier via receptor-mediated transport. Front Aging Neurosci 2023; 15:1276376. [PMID: 38035276 PMCID: PMC10682952 DOI: 10.3389/fnagi.2023.1276376] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/14/2023] [Accepted: 10/27/2023] [Indexed: 12/02/2023] Open
Abstract
Parkinson's disease (PD) is characterized by neurodegeneration of nigral-striatal neurons in parallel with the formation of intra-neuronal α-synuclein aggregates, and these processes are exacerbated by neuro-inflammation. All 3 components of PD pathology are potentially treatable with biologics. Neurotrophins, such as glial derived neurotrophic factor or erythropoietin, can promote neural repair. Therapeutic antibodies can lead to disaggregation of α-synuclein neuronal inclusions. Decoy receptors can block the activity of pro-inflammatory cytokines in brain. However, these biologic drugs do not cross the blood-brain barrier (BBB). Biologics can be made transportable through the BBB following the re-engineering of the biologic as an IgG fusion protein, where the IgG domain targets an endogenous receptor-mediated transcytosis (RMT) system within the BBB, such as the insulin receptor or transferrin receptor. The receptor-specific antibody domain of the fusion protein acts as a molecular Trojan horse to ferry the biologic into brain via the BBB RMT pathway. This review describes the re-engineering of all 3 classes of biologics (neurotrophins, decoy receptor, therapeutic antibodies) for BBB delivery and treatment of PD. Targeting the RMT pathway at the BBB also enables non-viral gene therapy of PD using lipid nanoparticles (LNP) encapsulated with plasmid DNA encoding therapeutic genes. The surface of the lipid nanoparticle is conjugated with a receptor-specific IgG that triggers RMT of the LNP across the BBB in vivo.
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16
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Wong H, Sugimura R. Immune-epigenetic crosstalk in haematological malignancies. Front Cell Dev Biol 2023; 11:1233383. [PMID: 37808081 PMCID: PMC10551137 DOI: 10.3389/fcell.2023.1233383] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/02/2023] [Accepted: 09/08/2023] [Indexed: 10/10/2023] Open
Abstract
Haematological malignancies comprise a diverse set of lymphoid and myeloid neoplasms which can arise during any stage of haematopoiesis in the bone marrow. Accumulating evidence suggests that chronic inflammation generated by inflammatory cytokines secreted by tumour and the tumour-associated cells within the bone marrow microenvironment initiates signalling pathways in malignant cells, resulting in activation of master transcription factors including Smads, STAT3, and NF-κB which confer cancer stem cell phenotypes and drive disease progression. Deciphering the molecular mechanisms for how immune cells interact with malignant cells to induce such epigenetic modifications, specifically DNA methylation, histone modification, expression of miRNAs and lnRNAs to perturbate haematopoiesis could provide new avenues for developing novel targeted therapies for haematological malignancies. Here, the complex positive and negative feedback loops involved in inflammatory cytokine-induced cancer stem cell generation and drug resistance are reviewed to highlight the clinical importance of immune-epigenetic crosstalk in haematological malignancies.
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Affiliation(s)
| | - Ryohichi Sugimura
- School of Biomedical Sciences, Lee Ka Shing Faculty of Medicine, The University of Hong Kong, Pokfulam, Hong Kong SAR, China
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17
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Di Ianni A, Barbero L, Fraone T, Cowan K, Sirtori FR. Preclinical risk assessment strategy to mitigate the T-cell dependent immunogenicity of protein biotherapeutics: State of the art, challenges and future perspectives. J Pharm Biomed Anal 2023; 234:115500. [PMID: 37311374 DOI: 10.1016/j.jpba.2023.115500] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/27/2023] [Revised: 05/22/2023] [Accepted: 05/30/2023] [Indexed: 06/15/2023]
Abstract
Protein therapeutics hold a prominent role and have brought significant diversity in efficacious medicinal products. Not just monoclonal antibodies and different antibody formats (pegylated antigen-binding fragments, bispecifics, antibody-drug conjugates, single chain variable fragments, nanobodies, dia-, tria- and tetrabodies), but also purified blood products, growth factors, recombinant cytokines, enzyme replacement factors, fusion proteins are all good instances of therapeutic proteins that have been developed in the past decades and approved for their value in oncology, immune-oncology, and autoimmune diseases discovery programs. Although there was an ingrained belief that fully humanized proteins were expected to have limited immunogenicity, adverse effects associated with immune responses to biological therapies raised some concern in biotech companies. Consequently, drug developers are designing strategies to assess potential immune responses to protein therapeutics during both the preclinical and clinical phases of development. Despite the many factors that can contribute to protein immunogenicity, T cell- (thymus-) dependent (Td) immunogenicity seems to play a crucial role in the development of anti-drug antibodies (ADAs) to biologics. A broad range of methodologies to predict and rationally assess Td immune responses to protein drugs has been developed. This review aims to briefly summarize the preclinical immunogenicity risk assessment strategy to mitigate the risk of potential immunogenic candidates coming towards clinical phases, discussing the advantages and limitations of these technologies, and suggesting a rational approach for assessing and mitigating Td immunogenicity.
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Affiliation(s)
- Andrea Di Ianni
- University of Turin, Molecular Biotechnology Center, Department of Molecular Biotechnology and Health Sciences, University of Turin, 10126 Turin, Italy; NBE-DMPK Innovative BioAnalytics, Merck Serono RBM S.p.A., an affiliate of Merck KGaA, Darmstadt, Germany, Via Ribes 1, 10010 Colleretto Giacosa (TO), Italy
| | - Luca Barbero
- NBE-DMPK Innovative BioAnalytics, Merck Serono RBM S.p.A., an affiliate of Merck KGaA, Darmstadt, Germany, Via Ribes 1, 10010 Colleretto Giacosa (TO), Italy
| | - Tiziana Fraone
- NBE-DMPK Innovative BioAnalytics, Merck Serono RBM S.p.A., an affiliate of Merck KGaA, Darmstadt, Germany, Via Ribes 1, 10010 Colleretto Giacosa (TO), Italy
| | - Kyra Cowan
- New Biological Entities, Drug Metabolism and Pharmacokinetics (NBE-DMPK), Research and Development, Merck KGaA, Frankfurterstrasse 250, 64293 Darmstadt, Germany
| | - Federico Riccardi Sirtori
- NBE-DMPK Innovative BioAnalytics, Merck Serono RBM S.p.A., an affiliate of Merck KGaA, Darmstadt, Germany, Via Ribes 1, 10010 Colleretto Giacosa (TO), Italy.
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18
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Mihai IR, Burlui AM, Rezus II, Mihai C, Macovei LA, Cardoneanu A, Gavrilescu O, Dranga M, Rezus E. Inflammatory Bowel Disease as a Paradoxical Reaction to Anti-TNF-α Treatment-A Review. Life (Basel) 2023; 13:1779. [PMID: 37629636 PMCID: PMC10455403 DOI: 10.3390/life13081779] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/11/2023] [Revised: 08/06/2023] [Accepted: 08/15/2023] [Indexed: 08/27/2023] Open
Abstract
TNF-α inhibitors (TNFis) have revolutionized the treatment of certain chronic immune-mediated diseases, being widely and successfully used in rheumatic inflammatory diseases, and have also proved their efficacy in the treatment of inflammatory bowel disease (IBD). However, among the side effects of these agents are the so-called paradoxical effects. They can be defined as the appearance or exacerbation of a pathological condition that usually responds to this class of drug while treating a patient for another condition. A wide range of paradoxical effects have been reported including dermatological, intestinal and ophthalmic conditions. The causal mechanism of occurrence may implicate an imbalance of cytokines, but is still not fully understood, and remains a matter of debate. These paradoxical reactions often show improvement on discontinuation of the medication or on switching to another TNFi, but in some cases it is a class effect that could lead to the withdrawal of all anti-TNF agents. Close monitoring of patients treated with TNFis is necessary in order to detect paradoxical reactions. In this study we focus on reviewing IBD occurrence as a paradoxical effect of TNFi therapy in patients with rheumatological diseases (rheumatoid arthritis, psoriatic arthritis, ankylosing spondylitis, and juvenile idiopathic arthritis).
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Affiliation(s)
- Ioana Ruxandra Mihai
- Department of Rheumatology and Rehabilitation, Faculty of Medicine, “Grigore T. Popa” University of Medicine and Pharmacy, 700115 Iasi, Romania; (L.A.M.); (A.C.); (E.R.)
| | - Alexandra Maria Burlui
- Department of Rheumatology and Rehabilitation, Faculty of Medicine, “Grigore T. Popa” University of Medicine and Pharmacy, 700115 Iasi, Romania; (L.A.M.); (A.C.); (E.R.)
| | - Ioana Irina Rezus
- Department of Dermatovenerology, Faculty of Medicine, “Grigore T. Popa” University of Medicine and Pharmacy, 700115 Iasi, Romania;
| | - Cătălina Mihai
- Department of Gastroenterology, Faculty of Medicine, “Grigore T. Popa” University of Medicine and Pharmacy, 700115 Iasi, Romania; (C.M.); (O.G.); (M.D.)
| | - Luana Andreea Macovei
- Department of Rheumatology and Rehabilitation, Faculty of Medicine, “Grigore T. Popa” University of Medicine and Pharmacy, 700115 Iasi, Romania; (L.A.M.); (A.C.); (E.R.)
| | - Anca Cardoneanu
- Department of Rheumatology and Rehabilitation, Faculty of Medicine, “Grigore T. Popa” University of Medicine and Pharmacy, 700115 Iasi, Romania; (L.A.M.); (A.C.); (E.R.)
| | - Otilia Gavrilescu
- Department of Gastroenterology, Faculty of Medicine, “Grigore T. Popa” University of Medicine and Pharmacy, 700115 Iasi, Romania; (C.M.); (O.G.); (M.D.)
| | - Mihaela Dranga
- Department of Gastroenterology, Faculty of Medicine, “Grigore T. Popa” University of Medicine and Pharmacy, 700115 Iasi, Romania; (C.M.); (O.G.); (M.D.)
| | - Elena Rezus
- Department of Rheumatology and Rehabilitation, Faculty of Medicine, “Grigore T. Popa” University of Medicine and Pharmacy, 700115 Iasi, Romania; (L.A.M.); (A.C.); (E.R.)
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19
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Kell DB, Pretorius E. Are fibrinaloid microclots a cause of autoimmunity in Long Covid and other post-infection diseases? Biochem J 2023; 480:1217-1240. [PMID: 37584410 DOI: 10.1042/bcj20230241] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/08/2023] [Revised: 08/03/2023] [Accepted: 08/07/2023] [Indexed: 08/17/2023]
Abstract
It is now well established that the blood-clotting protein fibrinogen can polymerise into an anomalous form of fibrin that is amyloid in character; the resultant clots and microclots entrap many other molecules, stain with fluorogenic amyloid stains, are rather resistant to fibrinolysis, can block up microcapillaries, are implicated in a variety of diseases including Long COVID, and have been referred to as fibrinaloids. A necessary corollary of this anomalous polymerisation is the generation of novel epitopes in proteins that would normally be seen as 'self', and otherwise immunologically silent. The precise conformation of the resulting fibrinaloid clots (that, as with prions and classical amyloid proteins, can adopt multiple, stable conformations) must depend on the existing small molecules and metal ions that the fibrinogen may (and is some cases is known to) have bound before polymerisation. Any such novel epitopes, however, are likely to lead to the generation of autoantibodies. A convergent phenomenology, including distinct conformations and seeding of the anomalous form for initiation and propagation, is emerging to link knowledge in prions, prionoids, amyloids and now fibrinaloids. We here summarise the evidence for the above reasoning, which has substantial implications for our understanding of the genesis of autoimmunity (and the possible prevention thereof) based on the primary process of fibrinaloid formation.
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Affiliation(s)
- Douglas B Kell
- Department of Biochemistry, Cell and Systems Biology, Institute of Systems, Molecular and Integrative Biology, Faculty of Health and Life Sciences, University of Liverpool, Liverpool L69 7ZB, U.K
- The Novo Nordisk Foundation Centre for Biosustainability, Technical University of Denmark, Kemitorvet 200, 2800 Kgs Lyngby, Denmark
- Department of Physiological Sciences, Faculty of Science, Stellenbosch University, Private Bag X1 Matieland, Stellenbosch 7602, South Africa
| | - Etheresia Pretorius
- Department of Biochemistry, Cell and Systems Biology, Institute of Systems, Molecular and Integrative Biology, Faculty of Health and Life Sciences, University of Liverpool, Liverpool L69 7ZB, U.K
- Department of Physiological Sciences, Faculty of Science, Stellenbosch University, Private Bag X1 Matieland, Stellenbosch 7602, South Africa
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20
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Duran E, Ozturk ZO, Bilgin E, Büyükaşık Y, Dizdar O, Yardimci GK, Farisogullari B, Özsoy Z, Ayan G, Uzun GS, Ekici M, Unaldi E, Kilic L, Akdoğan A, Karadag O, Bilgen ŞA, Kiraz S, Kalyoncu U, Ertenli AI. Hematologic Malignancy Risk in Inflammatory Arthritis Patients Treated with TNF Inhibitors: The Real-Life Data from the HUR-BIO Registry. Rheumatol Ther 2023; 10:969-981. [PMID: 37294405 PMCID: PMC10326223 DOI: 10.1007/s40744-023-00563-z] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/02/2023] [Accepted: 05/11/2023] [Indexed: 06/10/2023] Open
Abstract
INTRODUCTION This study aimed to assess the incidence of hematologic malignancy (HM) among inflammatory arthritis (IA) patients receiving tumor necrosis factor inhibitors (TNFi) compared with the general Turkish population. METHODS HUR-BIO (Hacettepe University Rheumatology Biologic Registry) is a single-center biological disease-modifying anti-rheumatic drug (bDMARD) registry since 2005. Patients with IA, including rheumatoid arthritis, spondyloarthritis, or psoriatic arthritis who had at least one visit after the TNFi were screened from 2005 to November 2021. Standardized incidence rates (SIR) were calculated after adjustment for age and gender and compared with the 2017 Turkish National Cancer Registry (TNCR). RESULTS Of the 6139 patients registered in the HUR-BIO, 5355 used any TNFi at least once. The median follow-up duration was 2.6 years for patients receiving TNFi. Thirteen patients developed a HM on follow-up. In these patients, the median age at the IA onset was 38 (range, 26-67), and the median age at the HM diagnosis was 55.5 (range, 38-76). Patients using TNFi had an increased HM incidence (SIR 4.23, 95% confidence interval (CI) 2.35-7.05). Ten patients with HM were under 65 years of age. In this group, there was a higher incidence of HM in both men (SIR 5.15, 95% CI 1.88-11.43) and women (SIR 4.76, 95% CI 1.74-10.55). CONCLUSIONS The risk of HMs in inflammatory arthritis patients receiving TNFi was four times higher than in the general Turkish population.
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Affiliation(s)
- Emine Duran
- Division of Rheumatology, Department of Internal Medicine, Hacettepe University Faculty of Medicine, Sihhiye, 06100, Ankara, Turkey
| | - Zeynep Ozge Ozturk
- Department of Internal Medicine, Hacettepe University Faculty of Medicine, Ankara, Turkey
| | - Emre Bilgin
- Division of Rheumatology, Department of Internal Medicine, Hacettepe University Faculty of Medicine, Sihhiye, 06100, Ankara, Turkey.
| | - Yahya Büyükaşık
- Division of Hematology, Department of Internal Medicine, Hacettepe University Faculty of Medicine, Ankara, Turkey
| | - Omer Dizdar
- Department of Medical Oncology, Hacettepe University Cancer Institute, Ankara, Turkey
| | - Gozde Kubra Yardimci
- Division of Rheumatology, Department of Internal Medicine, Hacettepe University Faculty of Medicine, Sihhiye, 06100, Ankara, Turkey
| | - Bayram Farisogullari
- Division of Rheumatology, Department of Internal Medicine, Hacettepe University Faculty of Medicine, Sihhiye, 06100, Ankara, Turkey
| | - Zehra Özsoy
- Division of Rheumatology, Department of Internal Medicine, Hacettepe University Faculty of Medicine, Sihhiye, 06100, Ankara, Turkey
| | - Gizem Ayan
- Division of Rheumatology, Department of Internal Medicine, Hacettepe University Faculty of Medicine, Sihhiye, 06100, Ankara, Turkey
| | - Gullu Sandal Uzun
- Division of Rheumatology, Department of Internal Medicine, Hacettepe University Faculty of Medicine, Sihhiye, 06100, Ankara, Turkey
| | - Mustafa Ekici
- Division of Rheumatology, Department of Internal Medicine, Hacettepe University Faculty of Medicine, Sihhiye, 06100, Ankara, Turkey
| | - Erdinc Unaldi
- Division of Rheumatology, Department of Internal Medicine, Hacettepe University Faculty of Medicine, Sihhiye, 06100, Ankara, Turkey
| | - Levent Kilic
- Division of Rheumatology, Department of Internal Medicine, Hacettepe University Faculty of Medicine, Sihhiye, 06100, Ankara, Turkey
| | - Ali Akdoğan
- Division of Rheumatology, Department of Internal Medicine, Hacettepe University Faculty of Medicine, Sihhiye, 06100, Ankara, Turkey
| | - Omer Karadag
- Division of Rheumatology, Department of Internal Medicine, Hacettepe University Faculty of Medicine, Sihhiye, 06100, Ankara, Turkey
| | - Şule Apraş Bilgen
- Division of Rheumatology, Department of Internal Medicine, Hacettepe University Faculty of Medicine, Sihhiye, 06100, Ankara, Turkey
| | - Sedat Kiraz
- Division of Rheumatology, Department of Internal Medicine, Hacettepe University Faculty of Medicine, Sihhiye, 06100, Ankara, Turkey
| | - Umut Kalyoncu
- Division of Rheumatology, Department of Internal Medicine, Hacettepe University Faculty of Medicine, Sihhiye, 06100, Ankara, Turkey
| | - Ali Ihsan Ertenli
- Division of Rheumatology, Department of Internal Medicine, Hacettepe University Faculty of Medicine, Sihhiye, 06100, Ankara, Turkey
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21
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James JP, Nielsen BS, Langholz E, Malham M, Høgdall E, Riis LB. Estimating tissue-specific TNF mRNA levels prior to anti-TNFα treatment may support therapeutic optimisation in IBD patients. Scand J Gastroenterol 2023; 58:1237-1245. [PMID: 37246424 DOI: 10.1080/00365521.2023.2217313] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/22/2023] [Revised: 05/12/2023] [Accepted: 05/18/2023] [Indexed: 05/30/2023]
Abstract
BACKGROUND AND AIMS Tumour necrosis factor-α (TNF) antagonists have improved the management of inflammatory bowel disease (IBD), however, their usage and administration persist to be suboptimal. Here, we examined the relationship between tissue-specific TNF mRNA expression in mucosal biopsies from IBD patients and anti-TNF treatment response. METHODS Archived tissue samples from patients with luminal IBD that had all been or were in treatment with anti-TNF were included (18 adults and 24 paediatric patients). Patients were stratified into three groups according to anti-TNF response: responders, primary non-responders (PNR) and secondary loss of response (SLOR). TNF mRNA was detected using RNAscope in situ hybridisation (ISH) and the expression was quantified using image analysis. RESULTS The ISH analysis showed varying occurrence of TNF mRNA positive cells located in lamina propria and often with increased density in lymphoid follicles (LF). Consequently, expression estimates were obtained in whole tissue areas with and without LF. Significantly higher TNF mRNA expression levels were measured in adults compared to paediatric patients in both the analyses with and without LF (p = .015 and p = .016, respectively). Considering the relation to response, the adult and paediatric patients were evaluated separately. In adults, the TNF expression estimates were higher in PNRs compared to responders with and without LF (p = .017 and p = .024, respectively). CONCLUSION Our data indicate that adult PNR have significantly higher TNF mRNA levels than responders. This suggests that higher anti-TNF dose may be considered for IBD patients with high TNF mRNA expression estimates from the start of treatment.
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Affiliation(s)
- Jaslin P James
- Department of Pathology, Copenhagen University Hospital - Herlev and Gentofte, Herlev, Denmark
| | | | - Ebbe Langholz
- Department of Gastroenterology, Copenhagen University Hospital - Herlev and Gentofte, Herlev, Denmark
- Department of Clinical Medicine, University of Copenhagen, Copenhagen, Denmark
| | - Mikkel Malham
- The Pediatric Department, Copenhagen University Hospital - Amager and Hvidovre, Hvidovre, Denmark
- Copenhagen Center for Inflammatory Bowel Disease in Children, Adolescents and Adults, Copenhagen University Hospital - Amager and Hvidovre, Hvidovre, Denmark
| | - Estrid Høgdall
- Department of Pathology, Copenhagen University Hospital - Herlev and Gentofte, Herlev, Denmark
- Department of Clinical Medicine, University of Copenhagen, Copenhagen, Denmark
| | - Lene Buhl Riis
- Department of Pathology, Copenhagen University Hospital - Herlev and Gentofte, Herlev, Denmark
- Department of Clinical Medicine, University of Copenhagen, Copenhagen, Denmark
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22
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Bruni S, Mauro FL, Proietti CJ, Cordo-Russo RI, Rivas MA, Inurrigarro G, Dupont A, Rocha D, Fernández EA, Deza EG, Lopez Della Vecchia D, Barchuk S, Figurelli S, Lasso D, Friedrich AD, Santilli MC, Regge MV, Lebersztein G, Levit C, Anfuso F, Castiglione T, Elizalde PV, Mercogliano MF, Schillaci R. Blocking soluble TNFα sensitizes HER2-positive breast cancer to trastuzumab through MUC4 downregulation and subverts immunosuppression. J Immunother Cancer 2023; 11:jitc-2022-005325. [PMID: 36889811 PMCID: PMC10016294 DOI: 10.1136/jitc-2022-005325] [Citation(s) in RCA: 13] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 02/21/2023] [Indexed: 03/10/2023] Open
Abstract
BACKGROUND The success of HER2-positive (HER2+) breast cancer treatment with trastuzumab, an antibody that targets HER2, relies on immune response. We demonstrated that TNFα induces mucin 4 (MUC4) expression, which shields the trastuzumab epitope on the HER2 molecule decreasing its therapeutic effect. Here, we used mouse models and samples from HER2+ breast cancer patients to unravel MUC4 participation in hindering trastuzumab effect by fostering immune evasion. METHODS We used a dominant negative TNFα inhibitor (DN) selective for soluble TNFα (sTNFα) together with trastuzumab. Preclinical experiments were performed using two models of conditionally MUC4-silenced tumors to characterize the immune cell infiltration. A cohort of 91 patients treated with trastuzumab was used to correlate tumor MUC4 with tumor-infiltrating lymphocytes. RESULTS In mice bearing de novo trastuzumab-resistant HER2+ breast tumors, neutralizing sTNFα with DN induced MUC4 downregulation. Using the conditionally MUC4-silenced tumor models, the antitumor effect of trastuzumab was reinstated and the addition of TNFα-blocking agents did not further decrease tumor burden. DN administration with trastuzumab modifies the immunosuppressive tumor milieu through M1-like phenotype macrophage polarization and NK cells degranulation. Depletion experiments revealed a cross-talk between macrophages and NK cells necessary for trastuzumab antitumor effect. In addition, tumor cells treated with DN are more susceptible to trastuzumab-dependent cellular phagocytosis. Finally, MUC4 expression in HER2+ breast cancer is associated with immune desert tumors. CONCLUSIONS These findings provide rationale to pursue sTNFα blockade combined with trastuzumab or trastuzumab drug conjugates for MUC4+ and HER2+ breast cancer patients to overcome trastuzumab resistance.
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Affiliation(s)
- Sofia Bruni
- Laboratorio de Mecanismos Moleculares de Carcinogénesis, Instituto de Biología y Medicina Experimental (IBYME-CONICET), Buenos Aires, Argentina
| | - Florencia L Mauro
- Laboratorio de Mecanismos Moleculares de Carcinogénesis, Instituto de Biología y Medicina Experimental (IBYME-CONICET), Buenos Aires, Argentina
| | - Cecilia J Proietti
- Laboratorio de Mecanismos Moleculares de Carcinogénesis, Instituto de Biología y Medicina Experimental (IBYME-CONICET), Buenos Aires, Argentina
| | - Rosalia I Cordo-Russo
- Laboratorio de Mecanismos Moleculares de Carcinogénesis, Instituto de Biología y Medicina Experimental (IBYME-CONICET), Buenos Aires, Argentina
| | - Martin A Rivas
- Division of Hematology & Medical Oncology, Department of Medicine, Weill Cornell Medical College, New York, New York, USA
| | | | - Agustina Dupont
- Servicio de Patología, Sanatorio Mater Dei, Buenos Aires, Argentina
| | - Dario Rocha
- Bioscience Data Mining Group at CIDIE-CONICET-UCC, Córdoba, Argentina
| | - Elmer A Fernández
- Bioscience Data Mining Group at CIDIE-CONICET-UCC, Córdoba, Argentina
| | | | | | - Sabrina Barchuk
- Sección Patología Mamaria Hospital General de Agudos "Juan A Fernández, Buenos Aires, Argentina
| | - Silvina Figurelli
- Servicio de Patología, Hospital General de Agudos "Juan A. Fernández,", Buenos Aires, Argentina
| | - David Lasso
- Hospital Oncológico Provincial de Córdoba, Córdoba, Argentina
| | - Adrián D Friedrich
- Laboratorio de Fisiopatología de la Inmunidad Innata, Instituto de Biologia y Medicina Experimental (IBYME-CONICET), Buenos Aires, Argentina
| | - María C Santilli
- Laboratorio de Fisiopatología de la Inmunidad Innata, Instituto de Biologia y Medicina Experimental (IBYME-CONICET), Buenos Aires, Argentina
| | - María V Regge
- Laboratorio de Fisiopatología de la Inmunidad Innata, Instituto de Biologia y Medicina Experimental (IBYME-CONICET), Buenos Aires, Argentina
| | | | - Claudio Levit
- Servicio de Cirugía, Sanatorio Sagrado Corazón, Buenos Aires, Argentina
| | - Fabiana Anfuso
- Servicio de Cirugía, Sanatorio Sagrado Corazón, Buenos Aires, Argentina
| | | | - Patricia V Elizalde
- Laboratorio de Mecanismos Moleculares de Carcinogénesis, Instituto de Biología y Medicina Experimental (IBYME-CONICET), Buenos Aires, Argentina
| | - Maria F Mercogliano
- Laboratorio de Mecanismos Moleculares de Carcinogénesis, Instituto de Biología y Medicina Experimental (IBYME-CONICET), Buenos Aires, Argentina
| | - Roxana Schillaci
- Laboratorio de Mecanismos Moleculares de Carcinogénesis, Instituto de Biología y Medicina Experimental (IBYME-CONICET), Buenos Aires, Argentina
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Ravaei A, Pulsatelli L, Assirelli E, Ciaffi J, Meliconi R, Salvarani C, Govoni M, Rubini M. MTHFR c.665C>T and c.1298A>C Polymorphisms in Tailoring Personalized Anti-TNF-α Therapy for Rheumatoid Arthritis. Int J Mol Sci 2023; 24:ijms24044110. [PMID: 36835522 PMCID: PMC9962934 DOI: 10.3390/ijms24044110] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/02/2023] [Revised: 02/14/2023] [Accepted: 02/16/2023] [Indexed: 02/22/2023] Open
Abstract
Rheumatoid arthritis (RA) is an inflammatory autoimmune disease with a prevalence of 1%. Currently, RA treatment aims to achieve low disease activity or remission. Failure to achieve this goal causes disease progression with a poor prognosis. When treatment with first-line drugs fails, treatment with tumor necrosis factor-α (TNF-α) inhibitors may be prescribed to which many patients do not respond adequately, making the identification of response markers urgent. This study investigated the association of two RA-related genetic polymorphisms, c.665C>T (historically referred to as C677T) and c.1298A>C, in the MTHFR gene as response markers to an anti-TNF-α therapy. A total of 81 patients were enrolled, 60% of whom responded to the therapy. Analyses showed that both polymorphisms were associated with a response to therapy in an allele dose-dependent manner. The association for c.665C>T was significant for a rare genotype (p = 0.01). However, the observed opposite trend of association for c.1298A>C was not significant. An analysis revealed that c.1298A>C, unlike c.665C>T, was also significantly associated with the drug type (p = 0.032). Our preliminary results showed that the genetic polymorphisms in the MTHFR gene were associated with a response to anti-TNF-α therapy, with a potential significance for the anti-TNF-α drug type. This evidence suggests a role for one-carbon metabolism in anti-TNF-α drug efficacy and contributes to further personalized RA interventions.
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Affiliation(s)
- Amin Ravaei
- Medical Genetics Laboratory, Department of Neuroscience and Rehabilitation, University of Ferrara, 44121 Ferrara, Italy
| | - Lia Pulsatelli
- Laboratory of Immunorheumatology and Tissue Regeneration, IRCCS Istituto Ortopedico Rizzoli, 40136 Bologna, Italy
| | - Elisa Assirelli
- Medicine and Rheumatology Unit, IRCCS Istituto Ortopedico Rizzoli, 40136 Bologna, Italy
| | - Jacopo Ciaffi
- Medicine and Rheumatology Unit, IRCCS Istituto Ortopedico Rizzoli, 40136 Bologna, Italy
| | - Riccardo Meliconi
- Medicine and Rheumatology Unit, IRCCS Istituto Ortopedico Rizzoli, 40136 Bologna, Italy
| | - Carlo Salvarani
- Division of Rheumatology, Azienda USL-IRCCS di Reggio Emilia, 42122 Reggio Emilia, Italy
- University-Hospital of Modena, University of Modena and Reggio Emilia, 41124 Modena, Italy
| | - Marcello Govoni
- Section of Hematology and Rheumatology, Department of Medical Sciences, University of Ferrara, 44121 Ferrara, Italy
- Rheumatology Unit, Sant’Anna University Hospital, 44124 Ferrara, Italy
| | - Michele Rubini
- Medical Genetics Laboratory, Department of Neuroscience and Rehabilitation, University of Ferrara, 44121 Ferrara, Italy
- University Center for Studies on Gender Medicine, University of Ferrara, 44121 Ferrara, Italy
- Correspondence: ; Tel.: +39-0532-974473
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Delcoigne B, Kopp TI, Arkema EV, Hellgren K, Provan SA, Relas H, Aaltonen K, Trokovic N, Gudbjornsson B, Grondal G, Klami Kristianslund E, Lindhardsen J, Dreyer L, Askling J. Exposure to specific tumour necrosis factor inhibitors and risk of demyelinating and inflammatory neuropathy in cohorts of patients with inflammatory arthritis: a collaborative observational study across five Nordic rheumatology registers. RMD Open 2023; 9:e002924. [PMID: 36854568 PMCID: PMC9980369 DOI: 10.1136/rmdopen-2022-002924] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/08/2022] [Accepted: 02/12/2023] [Indexed: 03/02/2023] Open
Abstract
OBJECTIVE To compare incidences of neuroinflammatory events, including demyelinating disease (DML), inflammatory polyneuropathies (IPN) and multiple sclerosis (MS), in patients with rheumatoid arthritis (RA) or spondyloarthritis (SpA; including psoriatic arthritis) starting a tumour necrosis factor inhibitor (TNFi), investigating whether monoclonal TNFi antibodies (other TNFis (oTNFis)) confer higher risk than etanercept. METHODS This is an observational cohort study including patients from the five Nordic countries starting a TNFi in 2001-2020. Time to first neuroinflammatory event was identified through register linkages. We calculated crude incidence rates (cIR) per 1000 person-years and used multivariable-adjusted Cox regression to compare incidences of neuroinflammatory events overall and for DML, IPN and MS with oTNFi versus etanercept. We further examined individual TNFis and indications. RESULTS 33 883 patients with RA and 28 772 patients with SpA were included, initiating 52 704 and 46 572 treatment courses, respectively. In RA, we observed 135 neuroinflammatory events (65% DML) with cIR of 0.38 with oTNFi and 0.34 with etanercept. The HR of oTNFi versus etanercept was 1.07 (95% CI 0.74 to 1.54) for any neuroinflammatory event, 0.79 (95% CI 0.51 to 1.22) for DML, 2.20 (95% CI 1.05 to 4.63) for IPN and 0.73 (95% CI 0.34 to 1.56) for MS. In SpA, we observed 179 events (78% DML) with cIR of 0.68 with oTNFi and 0.65 with etanercept. The HR for any neuroinflammatory event, DML, IPN and MS was 1.06 (95% CI 0.75 to 1.50), 1.01 (95% CI 0.68 to 1.50), 1.28 (95% CI 0.61 to 2.69) and 0.94 (95% CI0.53 to 1.69), respectively. CONCLUSION The cIRs of neuroinflammatory events are higher in SpA than in RA, but the choice of specific TNFi does not seem to play an important role in the risk of neuroinflammatory events.
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Affiliation(s)
- Benedicte Delcoigne
- Department of Medicine Solna, Clinical Epidemiology Division, Karolinska Institutet, Stockholm, Sweden
| | - Tine Iskov Kopp
- Department of Neurology, Copenhagen University Hospital, Kobenhavn, Denmark
| | - Elizabeth V Arkema
- Department of Medicine Solna, Clinical Epidemiology Division, Karolinska Institutet, Stockholm, Sweden
| | - Karin Hellgren
- Department of Medicine Solna, Clinical Epidemiology Division, Karolinska Institutet, Stockholm, Sweden
| | - Sella Aarrestad Provan
- Center for treatment of Rheumatic and Musculoskeletal Diseases (REMEDY), Diakonhjemmet Hospital, Oslo, Norway
- Department of Public Health and Sport Sciences, Inland Norway University of Applied Sciences, Elverum, Norway
| | - Heikki Relas
- Department of Medicine, Division of Rheumatology, Helsinki University Central Hospital and University of Helsinki, Helsinki, Finland
| | - Kalle Aaltonen
- ROB-FIN, Pharmaceuticals Pricing Board, Ministry of Social Affairs and Health, Helsinki, Finland
| | - Nina Trokovic
- Department of Medicine, Division of Rheumatology, Helsinki University Central Hospital and University of Helsinki, Helsinki, Finland
| | - Bjorn Gudbjornsson
- Faculty of Medicine, University Hospital of Iceland, Reykjavik, Iceland
- Department of Rheumatology, Centre for Rheumatology Research, Reykjavik, Iceland
| | - Gerdur Grondal
- Department of Rheumatology Research, Landspitali University Hospital, Reykjavik, Iceland
- Faculty of Medicine, University of Iceland, Reykjavik, Iceland
| | - Eirik Klami Kristianslund
- Center for treatment of Rheumatic and Musculoskeletal Diseases (REMEDY), Diakonhjemmet Hospital, Oslo, Norway
| | - Jesper Lindhardsen
- Department of Rheumatology, Rigshospitalet, Copenhagen University, Copenhague, Denmark
| | - Lene Dreyer
- Center of Rheumatic Research Aalborg (CERRA), Aalborg University, Aalborg, Denmark
- Department of Rheumatology, Aalborg University Hospital, Aalborg, Denmark
| | - Johan Askling
- Department of Medicine Solna, Clinical Epidemiology Division, Karolinska Institutet, Stockholm, Sweden
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25
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Kyuuma M, Kaku A, Mishima-Tsumagari C, Ogawa B, Endo M, Tamura Y, Ishikura KI, Mima M, Nakanishi Y, Fujii Y. Unique structure of ozoralizumab, a trivalent anti-TNFα NANOBODY ® compound, offers the potential advantage of mitigating the risk of immune complex-induced inflammation. Front Immunol 2023; 14:1149874. [PMID: 37122706 PMCID: PMC10141648 DOI: 10.3389/fimmu.2023.1149874] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/23/2023] [Accepted: 03/24/2023] [Indexed: 05/02/2023] Open
Abstract
Biologics have become an important component of treatment strategies for a variety of diseases, but the immunogenicity of large immune complexes (ICs) and aggregates of biologics may increase risk of adverse events is a concern for biologics and it remains unclear whether large ICs consisting of intrinsic antigen and therapeutic antibodies are actually involved in acute local inflammation such as injection site reaction (ISR). Ozoralizumab is a trivalent, bispecific NANOBODY® compound that differs structurally from IgGs. Treatment with ozoralizumab has been shown to provide beneficial effects in the treatment of rheumatoid arthritis (RA) comparable to those obtained with other TNFα inhibitors. Very few ISRs (2%) have been reported after ozoralizumab administration, and the drug has been shown to have acceptable safety and tolerability. In this study, in order to elucidate the mechanism underlying the reduced incidence of ISRs associated with ozoralizumab administration, we investigated the stoichiometry of two TNFα inhibitors (ozoralizumab and adalimumab, an anti-TNFα IgG) ICs and the induction by these drugs of Fcγ receptor (FcγR)-mediated immune responses on neutrophils. Ozoralizumab-TNFα ICs are smaller than adalimumab-TNFα ICs and lack an Fc portion, thus mitigating FcγR-mediated immune responses on neutrophils. We also developed a model of anti-TNFα antibody-TNFα IC-induced subcutaneous inflammation and found that ozoralizumab-TNFα ICs do not induce any significant inflammation at injection sites. The results of our studies suggest that ozoralizumab is a promising candidate for the treatment of RA that entails a lower risk of the IC-mediated immune cell activation that leads to unwanted immune responses.
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Kim H, Bang G, Park YE, Park M, Choi JH, Oh MJ, An HJ, Yoo JS, Park YH, Kim JY, Hwang H. Advanced assessment through intact glycopeptide analysis of Infliximab's biologics and biosimilar. Front Mol Biosci 2022; 9:1006866. [PMID: 36523652 PMCID: PMC9745114 DOI: 10.3389/fmolb.2022.1006866] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/29/2022] [Accepted: 10/26/2022] [Indexed: 02/21/2025] Open
Abstract
Characterization of therapeutic monoclonal antibodies (mAbs) represents a major challenge for analytical sciences due to their heterogeneity associated with post-translational modifications (PTMs). The protein glycosylation requires comprehensive identification, which could influence on the mAbs' structure and their function. Here, we demonstrated high-resolution tandem mass spectrometry with an ultra-high-performance liquid chromatography for characterization and comparison between biologics and biosimilar of infliximab at an advanced level. Comparing the N- and O-glycopeptides profiles, a total of 49 and 54 glycopeptides was identified for each product of the biologics and biosimilar, respectively. We also discovered one novel N-glycosylation site at the light chain from both biopharmaceuticals and one novel O-glycopeptide at the heavy chain from only biosimilar. Site-specific glycopeptide analysis process will be a robust and useful technique for evaluating therapeutic mAbs and complex glycoprotein products.
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Affiliation(s)
- Hyejin Kim
- Research Center for Bioconvergence Analysis, Korea Basic Science Institute, Cheongju, South Korea
- Department of Bio and Brain Engineering, Korea Advanced Institute of Science and Technology, Daejeon, South Korea
| | - Geul Bang
- Research Center for Bioconvergence Analysis, Korea Basic Science Institute, Cheongju, South Korea
- Metabolomics Laboratory, College of Pharmacy, Korea University, Sejong, South Korea
| | - Ye Eun Park
- Research Center for Bioconvergence Analysis, Korea Basic Science Institute, Cheongju, South Korea
| | - Moonhee Park
- Department of Bio-Chemical Analysis, Korea Basic Science Institute, Cheongju, South Korea
| | - Jung Hoon Choi
- Department of Bio-Chemical Analysis, Korea Basic Science Institute, Cheongju, South Korea
| | - Myung Jin Oh
- Graduate School of Analytical Science and Technology, Chungnam National University, Daejeon, South Korea
- Asia-Pacific Glycomics Reference Site, Chungnam National University, Daejeon, South Korea
| | - Hyun Joo An
- Graduate School of Analytical Science and Technology, Chungnam National University, Daejeon, South Korea
- Asia-Pacific Glycomics Reference Site, Chungnam National University, Daejeon, South Korea
| | - Jong Shin Yoo
- Research Center for Bioconvergence Analysis, Korea Basic Science Institute, Cheongju, South Korea
- Asia-Pacific Glycomics Reference Site, Chungnam National University, Daejeon, South Korea
| | - Youngja Hwang Park
- Research Center for Bioconvergence Analysis, Korea Basic Science Institute, Cheongju, South Korea
- Metabolomics Laboratory, College of Pharmacy, Korea University, Sejong, South Korea
| | - Jin Young Kim
- Research Center for Bioconvergence Analysis, Korea Basic Science Institute, Cheongju, South Korea
| | - Heeyoun Hwang
- Research Center for Bioconvergence Analysis, Korea Basic Science Institute, Cheongju, South Korea
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27
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Zeng W, Zhou X, Yu S, Liu R, Quek CWN, Yu H, Tay RYK, Lin X, Feng Y. The Future of Targeted Treatment of Primary Sjögren's Syndrome: A Focus on Extra-Glandular Pathology. Int J Mol Sci 2022; 23:ijms232214135. [PMID: 36430611 PMCID: PMC9694487 DOI: 10.3390/ijms232214135] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/07/2022] [Revised: 11/11/2022] [Accepted: 11/11/2022] [Indexed: 11/18/2022] Open
Abstract
Primary Sjögren's syndrome (pSS) is a chronic, systemic autoimmune disease defined by exocrine gland hypofunction resulting in dry eyes and dry mouth. Despite increasing interest in biological therapies for pSS, achieving FDA-approval has been challenging due to numerous complications in the trials. The current literature lacks insight into a molecular-target-based approach to the development of biological therapies. This review focuses on novel research in newly defined drug targets and the latest clinical trials for pSS treatment. A literature search was conducted on ClinicalTrials.gov using the search term "Primary Sjögren's syndrome". Articles published in English between 2000 and 2021 were included. Our findings revealed potential targets for pSS treatment in clinical trials and the most recent advances in understanding the molecular mechanisms underlying the pathogenesis of pSS. A prominent gap in current trials is in overlooking the treatment of extraglandular symptoms such as fatigue, depression, and anxiety, which are present in most patients with pSS. Based on dryness and these symptom-directed therapies, emerging biological agents targeting inflammatory cytokines, signal pathways, and immune reaction have been studied and their efficacy and safety have been proven. Novel therapies may complement existing non-pharmacological methods of alleviating symptoms of pSS. Better grading systems that add extraglandular symptoms to gauge disease activity and severity should be created. The future of pSS therapies may lie in gene, stem-cell, and tissue-engineering therapies.
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Affiliation(s)
- Weizhen Zeng
- Department of Ophthalmology, Peking University Third Hospital, Beijing 100191, China
| | - Xinyao Zhou
- Department of Rheumatology, Guang’anmen Hospital, China Academy of Chinese Medical Sciences, Beijng 100053, China
| | - Sulan Yu
- School of Chinese Medicine, The University of Hong Kong, Hong Kong SAR, China
| | - Ruihua Liu
- Department of Rheumatology, Guang’anmen Hospital, China Academy of Chinese Medical Sciences, Beijng 100053, China
| | - Chrystie Wan Ning Quek
- Yong Loo Lin School of Medicine, National University of Singapore, Singapore 119077, Singapore
| | - Haozhe Yu
- Department of Ophthalmology, Peking University Third Hospital, Beijing 100191, China
| | - Ryan Yong Kiat Tay
- Yong Loo Lin School of Medicine, National University of Singapore, Singapore 119077, Singapore
| | - Xiang Lin
- School of Chinese Medicine, The University of Hong Kong, Hong Kong SAR, China
- State Key Laboratory of Pharmaceutical Biotechnology, The University of Hong Kong, Hong Kong SAR, China
- Correspondence: (X.L.); (Y.F.)
| | - Yun Feng
- Department of Ophthalmology, Peking University Third Hospital, Beijing 100191, China
- Correspondence: (X.L.); (Y.F.)
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Advancing Biologic Therapy for Refractory Autoimmune Hepatitis. Dig Dis Sci 2022; 67:4979-5005. [PMID: 35147819 DOI: 10.1007/s10620-021-07378-4] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/27/2021] [Accepted: 12/27/2021] [Indexed: 01/05/2023]
Abstract
Biologic agents may satisfy an unmet clinical need for treatment of refractory autoimmune hepatitis. The goals of this review are to present the types and results of biologic therapy for refractory autoimmune hepatitis, indicate opportunities to improve and expand biologic treatment, and encourage comparative clinical trials. English abstracts were identified in PubMed by multiple search terms. Full-length articles were selected for review, and secondary and tertiary bibliographies were developed. Rituximab (monoclonal antibodies against CD20 on B cells), infliximab (monoclonal antibodies against tumor necrosis factor-alpha), low-dose recombinant interleukin 2 (regulatory T cell promoter), and belimumab (monoclonal antibodies against B cell activating factor) have induced laboratory improvement in small cohorts with refractory autoimmune hepatitis. Ianalumab (monoclonal antibodies against the receptor for B cell activating factor) is in clinical trial. These agents target critical pathogenic pathways, but they may also have serious side effects. Blockade of the B cell activating factor or its receptors may disrupt pivotal B and T cell responses, and recombinant interleukin 2 complexed with certain interleukin 2 antibodies may selectively expand the regulatory T cell population. A proliferation-inducing ligand that enhances T cell proliferation and survival is an unevaluated, potentially pivotal, therapeutic target. Fully human antibodies, expanded target options, improved targeting precision, more effective delivery systems, and biosimilar agents promise to improve efficacy, safety, and accessibility. In conclusion, biologic agents target key pathogenic pathways in autoimmune hepatitis, and early experiences in refractory disease encourage clarification of the preferred target, rigorous clinical trial, and comparative evaluations.
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Ha R, Keynan Y, Rueda ZV. Increased susceptibility to pneumonia due to tumour necrosis factor inhibition and prospective immune system rescue via immunotherapy. Front Cell Infect Microbiol 2022; 12:980868. [PMID: 36159650 PMCID: PMC9489861 DOI: 10.3389/fcimb.2022.980868] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/29/2022] [Accepted: 08/15/2022] [Indexed: 11/22/2022] Open
Abstract
Immunomodulators such as tumour necrosis factor (TNF) inhibitors are used to treat autoimmune conditions by reducing the magnitude of the innate immune response. Dampened innate responses pose an increased risk of new infections by opportunistic pathogens and reactivation of pre-existing latent infections. The alteration in immune response predisposes to increased severity of infections. TNF inhibitors are used to treat autoimmune conditions such as rheumatoid arthritis, juvenile arthritis, psoriatic arthritis, transplant recipients, and inflammatory bowel disease. The efficacies of immunomodulators are shown to be varied, even among those that target the same pathways. Monoclonal antibody-based TNF inhibitors have been shown to induce stronger immunosuppression when compared to their receptor-based counterparts. The variability in activity also translates to differences in risk for infection, moreover, parallel, or sequential use of immunosuppressive drugs and corticosteroids makes it difficult to accurately attribute the risk of infection to a single immunomodulatory drug. Among recipients of TNF inhibitors, Mycobacterium tuberculosis has been shown to be responsible for 12.5-59% of all infections; Pneumocystis jirovecii has been responsible for 20% of all non-viral infections; and Legionella pneumophila infections occur at 13-21 times the rate of the general population. This review will outline the mechanism of immune modulation caused by TNF inhibitors and how they predispose to infection with a focus on Mycobacterium tuberculosis, Legionella pneumophila, and Pneumocystis jirovecii. This review will then explore and evaluate how other immunomodulators and host-directed treatments influence these infections and the severity of the resulting infection to mitigate or treat TNF inhibitor-associated infections alongside antibiotics.
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Affiliation(s)
- Ryan Ha
- Department of Medical Microbiology and Infectious Diseases, University of Manitoba, Winnipeg, MB, Canada
| | - Yoav Keynan
- Department of Medical Microbiology and Infectious Diseases, University of Manitoba, Winnipeg, MB, Canada
- Department of Community-Health Sciences, University of Manitoba, Winnipeg, MB, Canada
- Facultad de Medicina, Universidad Pontificia Bolivariana, Medellin, Colombia
| | - Zulma Vanessa Rueda
- Department of Medical Microbiology and Infectious Diseases, University of Manitoba, Winnipeg, MB, Canada
- Facultad de Medicina, Universidad Pontificia Bolivariana, Medellin, Colombia
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Biophysical differences in IgG1 Fc-based therapeutics relate to their cellular handling, interaction with FcRn and plasma half-life. Commun Biol 2022; 5:832. [PMID: 35982144 PMCID: PMC9388496 DOI: 10.1038/s42003-022-03787-x] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/11/2022] [Accepted: 08/01/2022] [Indexed: 01/07/2023] Open
Abstract
Antibody-based therapeutics (ABTs) are used to treat a range of diseases. Most ABTs are either full-length IgG1 antibodies or fusions between for instance antigen (Ag)-binding receptor domains and the IgG1 Fc fragment. Interestingly, their plasma half-life varies considerably, which may relate to how they engage the neonatal Fc receptor (FcRn). As such, there is a need for an in-depth understanding of how different features of ABTs affect FcRn-binding and transport behavior. Here, we report on how FcRn-engagement of the IgG1 Fc fragment compare to clinically relevant IgGs and receptor domain Fc fusions, binding to VEGF or TNF-α. The results reveal FcRn-dependent intracellular accumulation of the Fc, which is in line with shorter plasma half-life than that of full-length IgG1 in human FcRn-expressing mice. Receptor domain fusion to the Fc increases its half-life, but not to the extent of IgG1. This is mirrored by a reduced cellular recycling capacity of the Fc-fusions. In addition, binding of cognate Ag to ABTs show that complexes of similar size undergo cellular transport at different rates, which could be explained by the biophysical properties of each ABT. Thus, the study provides knowledge that should guide tailoring of ABTs regarding optimal cellular sorting and plasma half-life. Analysis of clinically approved antibody-based therapeutics reveals different structural designs, such as full-length IgG1 or Fc-fusions, entail distinct biophysical properties that affect FcRn binding, intracellular transport and plasma half-life.
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Douadi C, Vazeille E, Chambon C, Hébraud M, Fargeas M, Dodel M, Coban D, Pereira B, Birer A, Sauvanet P, Buisson A, Barnich N. Anti-TNF Agents Restrict Adherent-invasive Escherichia coli Replication Within Macrophages Through Modulation of Chitinase 3-like 1 in Patients with Crohn's Disease. J Crohns Colitis 2022; 16:1140-1150. [PMID: 35022663 DOI: 10.1093/ecco-jcc/jjab236] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/18/2021] [Revised: 12/01/2021] [Accepted: 01/11/2022] [Indexed: 12/13/2022]
Abstract
BACKGROUND AND AIMS The mechanism of action of anti-tumour necrosis factor [anti-TNF] agents could implicate macrophage modulation in Crohn's disease [CD]. As CD macrophages are defective in controlling CD-associated adherent-invasive Escherichia coli [AIEC], anti-TNF agents could limit AIEC replication within macrophages. We assessed the effect of anti-TNF agents on AIEC survival within monocyte-derived macrophages [MDMs] from CD patients and attempted to identify the proteins involved. METHODS Peripheral blood MDMs were obtained from 44 CD patients [22 with and 22 without anti-TNF agents]. MDMs were infected with reference strain AIEC-LF82. Proteomic analysis was performed before and 6 h after AIEC-LF82 infection. RESULTS AIEC-LF82 survival was lower in MDMs from CD patients receiving anti-TNF agents compared to those who did not [-73%, p = 0.006]. After AIEC-LF82 infection, the levels of CD82 [p = 0.007], ILF3 [Interleukin enhancer-binding factor 3; p = 0.001], FLOT-1 [Flotillin-1; p = 0.007] and CHI3L1 [Chitinase 3-like 1; p = 0.035] proteins were different within CD-MDMs depending on anti-TNF exposure. FLOT-1 [ϱ = -0.44; p = 0.038] and CHI3L1 [ϱ = 0.57, p = 0.006] levels were inversely and positively correlated with AIEC survival within MDMs from CD patients with or without anti-TNF, respectively. We observed a dose-dependent decrease of AIEC-LF82 survival after adjunction of anti-TNF within MDMs, inducing an increase of FLOT-1 and decrease of CHI3L1 mRNA levels. Neutralization of intra-macrophagic CHI3L1 protein using anti-CHI3L1 antibodies reduced AIEC survival within macrophages 6 h after infection [p < 0.05]. CONCLUSION Anti-TNF agents are able to restrict replication of pathobionts, such as AIEC, within macrophages by modulating FLOT-1 and CHI3L1 expression in CD patients.
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Affiliation(s)
- Clara Douadi
- Microbes, Intestin, Inflammation et Susceptibilité de l'Hôte (M2iSH), UMR 1071 Inserm/Université Clermont Auvergne, USC INRAE 2018, Clermont-Ferrand, France
| | - Emilie Vazeille
- Microbes, Intestin, Inflammation et Susceptibilité de l'Hôte (M2iSH), UMR 1071 Inserm/Université Clermont Auvergne, USC INRAE 2018, Clermont-Ferrand, France.,Gastroenterology Department, CHU Estaing, Clermont-Ferrand, France
| | - Christophe Chambon
- INRAE, Plateforme d'Exploration du Métabolisme, composante protéomique (PFEMcp), Saint-Genès-Champanelle, France
| | - Michel Hébraud
- INRAE, Plateforme d'Exploration du Métabolisme, composante protéomique (PFEMcp), Saint-Genès-Champanelle, France.,Université Clermont Auvergne, INRAE, UMR Microbiologie Environnement digestif Santé (MEDiS), Saint-Genès-Champanelle, France
| | - Margot Fargeas
- Microbes, Intestin, Inflammation et Susceptibilité de l'Hôte (M2iSH), UMR 1071 Inserm/Université Clermont Auvergne, USC INRAE 2018, Clermont-Ferrand, France
| | - Marie Dodel
- Gastroenterology Department, CHU Estaing, Clermont-Ferrand, France
| | - Dilek Coban
- Gastroenterology Department, CHU Estaing, Clermont-Ferrand, France
| | - Bruno Pereira
- Biostatistic Unit, CHU Estaing, Clermont-Ferrand, France
| | - Aurélien Birer
- Microbes, Intestin, Inflammation et Susceptibilité de l'Hôte (M2iSH), UMR 1071 Inserm/Université Clermont Auvergne, USC INRAE 2018, Clermont-Ferrand, France.,Centre National de Référence de la Résisitance aux antibiotiques, service de Bactériologie, CHU Gabriel-Montpied, Clermont-Ferrand, France
| | - Pierre Sauvanet
- Microbes, Intestin, Inflammation et Susceptibilité de l'Hôte (M2iSH), UMR 1071 Inserm/Université Clermont Auvergne, USC INRAE 2018, Clermont-Ferrand, France.,Surgery and Oncology Digestive Department, CHU Estaing, Clermont-Ferrand, France
| | - Anthony Buisson
- Microbes, Intestin, Inflammation et Susceptibilité de l'Hôte (M2iSH), UMR 1071 Inserm/Université Clermont Auvergne, USC INRAE 2018, Clermont-Ferrand, France.,Gastroenterology Department, CHU Estaing, Clermont-Ferrand, France
| | - Nicolas Barnich
- Microbes, Intestin, Inflammation et Susceptibilité de l'Hôte (M2iSH), UMR 1071 Inserm/Université Clermont Auvergne, USC INRAE 2018, Clermont-Ferrand, France
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Venetsanopoulou AI, Voulgari PV, Drosos AA. Janus kinase versus TNF inhibitors: where we stand today in rheumatoid arthritis. Expert Rev Clin Immunol 2022; 18:485-493. [PMID: 35535405 DOI: 10.1080/1744666x.2022.2064275] [Citation(s) in RCA: 15] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/20/2022]
Abstract
INTRODUCTION In recent decades, Rheumatoid arthritis (RA) treatment landscape has evolved with the induction of new biological and targeted therapies that provide significant therapeutic benefits in patients with sustained disease. AREAS COVERED Tumor necrosis factor inhibitors (TNFi) were the first biologics used in the treatment of RA. Although they present a significant efficacy, an insufficient response of some patients led to further research and discovery of targeted therapies, such as Janus kinase inhibitors (JAKi), which act at a molecular level, regulating many cytokines. Clinical benefits have been seen with both TNFi and JAKi as monotherapy and combined with conventional synthetic disease-modifying antirheumatic drugs. Still, some significant side effects have been reported with JAKi, and several questions remain about their safety and selectivity in action. This review summarizes the current knowledge on the mechanism of action, the clinical efficacy, and safety of TNFi vs. JAKi. EXPERT OPINION TNFi and JAKi are particularly useful in treating inflammatory arthropathies. Both drug categories are recommended by ACR and EULAR institutions in RA patients suffering from moderate to severe disease. Safety data in long-term studies are required to determine the optimal benefit to the risk profile of JAKi use.
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Affiliation(s)
- Aliki I Venetsanopoulou
- Rheumatology Clinic, Department of Internal Medicine, Medical School, University of Ioannina, Ioannina, Greece
| | - Paraskevi V Voulgari
- Rheumatology Clinic, Department of Internal Medicine, Medical School, University of Ioannina, Ioannina, Greece
| | - Alexandros A Drosos
- Rheumatology Clinic, Department of Internal Medicine, Medical School, University of Ioannina, Ioannina, Greece
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Valenzuela-Cardenas M, Gowan C, Dryja P, Bartee MY, Bartee E. TNF blockade enhances the efficacy of myxoma virus-based oncolytic virotherapy. J Immunother Cancer 2022; 10:e004770. [PMID: 35577502 PMCID: PMC9114862 DOI: 10.1136/jitc-2022-004770] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 04/04/2022] [Indexed: 11/03/2022] Open
Abstract
BACKGROUND Oncolytic virotherapy (OV) represents a method to treat a variety of solid tumors by inducing antitumor immune responses. While this therapy has been extremely efficacious in preclinical models, translating these successes into human patients has proven challenging. One of the major reasons for these failures is the existence of immune-regulatory mechanisms, which dampen the efficacy of virally induced antitumor immunity. Unfortunately, the full extent of these immune-regulatory pathways remains unclear. METHODS To address this issue, we generated a doubly recombinant, oncolytic myxoma virus which expresses both a soluble fragment of programmed cell death protein 1 (PD1) and an interleukin 12 (IL-12) fusion protein (vPD1/IL-12 (virus-expressing PD1 and IL-12)). We then tested the molecular impact and therapeutic efficacy of this construct in multiple models of disseminated disease to identify novel pathways, which are associated with poor therapeutic outcomes. RESULTS Our results demonstrate that vPD1/IL-12 causes robust inflammation during therapy including inducing high levels of tumor necrosis factor (TNF). Surprisingly, although expression of TNF has generally been assumed to be beneficial to OV, the presence of this TNF appears to inhibit therapeutic efficacy by reducing intratumoral T-cell viability. Likely because of this, disruption of the TNF pathway, either through genetic knockout or antibody-based blockade, significantly enhances the overall outcomes of vPD1/IL-12-based therapy that allows for the generation of complete cures in normally non-responsive models. CONCLUSIONS These data suggest that some aspects of OV-induced inflammation might represent a double-edged sword during therapy and that specific blockade of TNF might enhance the efficacy of these treatments.
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Affiliation(s)
- Miriam Valenzuela-Cardenas
- Department of Internal Medicine, University of New Mexico Health Sciences Center, Albuquerque, New Mexico, USA
| | - Cody Gowan
- Division of Nephrology and Hypertension, Mayo Clinical, Jacksonville, Florida, USA
| | - Parker Dryja
- Department of Internal Medicine, University of New Mexico Health Sciences Center, Albuquerque, New Mexico, USA
| | - Mee Y Bartee
- Department of Internal Medicine, University of New Mexico Health Sciences Center, Albuquerque, New Mexico, USA
| | - Eric Bartee
- Department of Internal Medicine, University of New Mexico Health Sciences Center, Albuquerque, New Mexico, USA
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Ahn SM, Kim M, Kim YJ, Lee Y, Kim YG. Risk of Acute Anterior Uveitis in Ankylosing Spondylitis According to the Type of Tumor Necrosis Factor-Alpha Inhibitor and History of Uveitis: A Nationwide Population-Based Study. J Clin Med 2022; 11:jcm11030631. [PMID: 35160082 PMCID: PMC8836742 DOI: 10.3390/jcm11030631] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/07/2022] [Revised: 01/24/2022] [Accepted: 01/24/2022] [Indexed: 01/31/2023] Open
Abstract
BACKGROUND We evaluated the risk of acute anterior uveitis (AAU) in patients with ankylosing spondylitis (AS) during treatment with tumor necrosis factor-alpha inhibitors (TNFis). METHODS This study was performed on AS patients using the Korean National Health Insurance claims database. We analyzed the first and total occurrence of AAU during the first 2 years of TNFis use according to the type of TNFis. Additionally, the occurrence of AAU was assessed in subgroups with or without prior AAU before TNFis initiation. RESULTS In total, 5938 AS patients initiated TNFis use between 2009 and 2017 and used them for more than 2 years. Among them, 1488 (25.1%) patients had a history of AAU before starting TNFis treatment. Compared to adalimumab, the use of etanercept (hazard ratio [HR] 1.77) increased the risk of AAU. The incidence rate ratio (IRR) of AAU with etanercept was significantly higher than that of adalimumab (IRR 1.78). The IRR of AAU was also higher for etanercept than adalimumab use in patients with (IRR 1.86) and without (IRR 2.92) a history of AAU. CONCLUSION These data suggest that compared to anti-TNF-alpha monoclonal antibodies, etanercept has a higher incidence of AAU regardless of a history of AAU.
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Affiliation(s)
- Soo Min Ahn
- Department of Rheumatology, Asan Medical Center, University of Ulsan College of Medicine, Seoul 05505, Korea;
| | - Minju Kim
- Department of Clinical Epidemiology and Biostatistics, Asan Medical Center, University of Ulsan College of Medicine, Seoul 05505, Korea; (M.K.); (Y.-J.K.)
| | - Ye-Jee Kim
- Department of Clinical Epidemiology and Biostatistics, Asan Medical Center, University of Ulsan College of Medicine, Seoul 05505, Korea; (M.K.); (Y.-J.K.)
| | - Yusun Lee
- AbbVie Pty, Ltd., Seoul 06182, Korea;
| | - Yong-Gil Kim
- Department of Rheumatology, Asan Medical Center, University of Ulsan College of Medicine, Seoul 05505, Korea;
- Correspondence: ; Tel.: +82-2-3010-3279
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van Beers JJBC, Damoiseaux JGMC. Treatment of Autoimmune Diseases with Therapeutic Antibodies: Lessons Learned from PID Patients Allow for Stratification of the Infection Risk. Methods Mol Biol 2022; 2313:27-44. [PMID: 34478130 DOI: 10.1007/978-1-0716-1450-1_2] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 06/13/2023]
Abstract
Over the years, a wide variety of therapeutic antibodies has been successfully introduced in the autoimmunology clinic and many more are on the edge to follow. Many of these treatments address either a pathogenic circulating molecule or a cell-bound molecule. Whereas the former target results in neutralization of the soluble factor, the latter target either inhibits cellular function or induces selective cell death. If this targeted molecule or cell is part of the immune system, this therapy evokes a state of immunodeficiency. Knowing the exact function of the respective components enables the risk stratification for possible infectious complications in patients treated with biologics. Much of the understanding of the function of immune cells and their associated molecules, in relation to redundancy in the immune system, is derived from studies in knockout mice. However, as mice are not men in terms of their life-expectancy, their infection exposure, or the composition of their immune system, the most useful knowledge for estimating the consequence of therapeutic intervention on immune competence comes from monitoring patients. In the current chapter, we focus on patients with a primary immunodeficiency (PID) because they provide us with a unique perspective to estimate the redundancy of a certain genetic defect for overall immune competence. These patients have inborn errors of the immune system that, in general, are due to single gene defects. Depending on the immunological pathway that is defective, patients can present with different types of (opportunistic) infectious diseases, as well as other clinical manifestations. Based on selected examples, we focus in this chapter on finding parallels in the infectious risk of autoimmune patients treated with biologics and PID patients with a defect in the immunological pathway that is affected by the respective biologic. The goal is to learn from the (dis)similarities between both patient populations in terms of safety profiles of biologic treatments.
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Affiliation(s)
- Joyce J B C van Beers
- Central Diagnostic Laboratory, Maastricht University Medical Center, Maastricht, The Netherlands
| | - Jan G M C Damoiseaux
- Central Diagnostic Laboratory, Maastricht University Medical Center, Maastricht, The Netherlands.
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Kroenke MA, Barger TE, Hu J, Miller MJ, Kalenian K, He L, Hsu H, Bartley Y, Chow VFS, Teixeira Dos Santos MC, Sullivan BA, Cheng LE, Parnes JR, Padaki R, Kuhns S, Mytych DT. Immune Complex Formation Is Associated With Loss of Tolerance and an Antibody Response to Both Drug and Target. Front Immunol 2022; 12:782788. [PMID: 34970265 PMCID: PMC8712722 DOI: 10.3389/fimmu.2021.782788] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/06/2021] [Accepted: 11/23/2021] [Indexed: 11/15/2022] Open
Abstract
AMG 966 is a bi-specific, heteroimmunoglobulin molecule that binds both tumor necrosis factor alpha (TNFα) and TNF-like ligand 1A (TL1A). In a first-in-human clinical study in healthy volunteers, AMG 966 elicited anti-drug antibodies (ADA) in 53 of 54 subjects (98.1%), despite a paucity of T cell epitopes observed in T cell assays. ADA were neutralizing and bound to all domains of AMG 966. Development of ADA correlated with loss of exposure. In vitro studies demonstrated that at certain drug-to-target ratios, AMG 966 forms large immune complexes with TNFα and TL1A, partially restoring the ability of the aglycosylated Fc domain to bind FcγRIa and FcγRIIa, leading to the formation of ADA. In addition to ADA against AMG 966, antibodies to endogenous TNFα were also detected in the sera of subjects dosed with AMG 966. This suggests that the formation of immune complexes between a therapeutic and target can cause loss of tolerance and elicit an antibody response against the target.
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Affiliation(s)
- Mark A Kroenke
- Clinical Immunology, Translational Medicine, Amgen, Thousand Oaks, CA, United States
| | - Troy E Barger
- Translational Safety & Bioanalytical Sciences, Amgen, Thousand Oaks, CA, United States
| | - Jenny Hu
- Translational Safety & Bioanalytical Sciences, Amgen, Thousand Oaks, CA, United States
| | - Mieke Jill Miller
- Translational Safety & Bioanalytical Sciences, Amgen, Thousand Oaks, CA, United States
| | - Kevin Kalenian
- Process Development, Attribute Sciences, Amgen, Thousand Oaks, CA, United States
| | - Lidong He
- Process Development, Attribute Sciences, Amgen, Thousand Oaks, CA, United States
| | - Hailing Hsu
- Inflammation Research, Amgen, Thousand Oaks, CA, United States
| | | | - Vincent Fung-Sing Chow
- Clinical Pharmacology, Modeling and Simulation, Translational Medicine, Amgen, Thousand Oaks, CA, United States
| | | | - Barbara A Sullivan
- Clinical Biomarkers and Diagnostics, Translational Medicine, Amgen, Thousand Oaks, CA, United States
| | - Laurence E Cheng
- Early Development, Translational Medicine, Amgen, Thousand Oaks, CA, United States
| | - Jane R Parnes
- Early Development, Translational Medicine, Amgen, Thousand Oaks, CA, United States
| | - Rupa Padaki
- Process Development, Attribute Sciences, Amgen, Thousand Oaks, CA, United States
| | - Scott Kuhns
- Process Development, Attribute Sciences, Amgen, Thousand Oaks, CA, United States
| | - Daniel T Mytych
- Clinical Immunology, Translational Medicine, Amgen, Thousand Oaks, CA, United States
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Wang CI, Chu PM, Chen YL, Lin YH, Chen CY. Chemotherapeutic Drug-Regulated Cytokines Might Influence Therapeutic Efficacy in HCC. Int J Mol Sci 2021; 22:ijms222413627. [PMID: 34948424 PMCID: PMC8707970 DOI: 10.3390/ijms222413627] [Citation(s) in RCA: 22] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/26/2021] [Revised: 12/04/2021] [Accepted: 12/16/2021] [Indexed: 12/12/2022] Open
Abstract
Hepatocellular carcinoma (HCC), the most common type of liver cancer, is the second leading cause of cancer-related mortality worldwide. Processes involved in HCC progression and development, including cell transformation, proliferation, metastasis, and angiogenesis, are inflammation-associated carcinogenic processes because most cases of HCC develop from chronic liver damage and inflammation. Inflammation has been demonstrated to be a crucial factor inducing tumor development in various cancers, including HCC. Cytokines play critical roles in inflammation to accelerate tumor invasion and metastasis by mediating the migration of immune cells into damaged tissues in response to proinflammatory stimuli. Currently, surgical resection followed by chemotherapy is the most common curative therapeutic regimen for HCC. However, after chemotherapy, drug resistance is clearly observed, and cytokine secretion is dysregulated. Various chemotherapeutic agents, including cisplatin, etoposide, and 5-fluorouracil, demonstrate even lower efficacy in HCC than in other cancers. Tumor resistance to chemotherapeutic drugs is the key limitation of curative treatment and is responsible for treatment failure and recurrence, thus limiting the ability to treat patients with advanced HCC. Therefore, the capability to counteract drug resistance would be a major clinical advancement. In this review, we provide an overview of links between chemotherapeutic agents and inflammatory cytokine secretion in HCC. These links might provide insight into overcoming inflammatory reactions and cytokine secretion, ultimately counteracting chemotherapeutic resistance.
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Affiliation(s)
- Chun-I Wang
- Radiation Biology Research Center, Institute for Radiological Research, Chang Gung Memorial Hospital, Chang Gung University, Taoyuan 333, Taiwan;
| | - Pei-Ming Chu
- Department of Anatomy, School of Medicine, China Medical University, Taichung 404, Taiwan;
| | - Yi-Li Chen
- Department of Cell Biology and Anatomy, College of Medicine, National Cheng Kung University, Tainan 70101, Taiwan;
| | - Yang-Hsiang Lin
- Liver Research Center, Chang Gung Memorial Hospital, Linkou, Taoyuan 333, Taiwan;
| | - Cheng-Yi Chen
- Department of Cell Biology and Anatomy, College of Medicine, National Cheng Kung University, Tainan 70101, Taiwan;
- Correspondence: ; Tel./Fax: +886-6-2353535 (ext. 5329)
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Pathogenetic role of tumor necrosis factor (TNF-α) for the development of peritoneal tuberculosis in an experiment. ACTA BIOMEDICA SCIENTIFICA 2021. [DOI: 10.29413/abs.2021-6.5.18] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/21/2022] Open
Abstract
Currently tuberculosis is considered as a group of diseases united by one etiological factor. The pathogenesis of certain localizations of tuberculous inflammation, in particular peritoneum tuberculosis, hasn’t been sufficiently studied. The role of cytokine mechanisms in the development of the disease and the elaboration of non-sterile immunity requires further experimental studies, in particular the creation of a reproducible model on laboratory animals.The aim: to study the effect of TNF-α on the development of tuberculosis of the serous coat of the abdominal cavity, as well as to evaluate the possibility of modeling tuberculous peritonitis in laboratory animals using infliximab.Materials and methods. The studies were conducted on 18 male rabbits, which were simulated peritoneal tuberculosis by intra-abdominal administration of a suspension of Mycobacterium tuberculosis. 10 rabbits of the experimental group were intravenously injected with an infliximab solution and an iron (III) hydroxide sucrose complex intraperitoneally a day before infection.Results. In the control group of animals, tuberculosis either didn’t develop, or in a third of cases it affected only the pulmonary parenchyma, while proliferative processes prevailed. On the contrary, in animals with inactivated TNF-α, in 100 % of observations, tuberculous peritonitis was detected with associated lung damage and the predominance of alterative caseous processes.Conclusion. The created model of tuberculous peritonitis shows the leading role of TNF-α in the activation of macrophages, as well as in attracting cells to the site of infection. This is the primary signal necessary for the formation and stability of granulomas since the neutralization of this cytokine leads to a loss of control over the infection and the destruction of the granuloma with the development of destructive tuberculosis in the serous coat of the abdominal cavity.
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Ternant D, Le Tilly O, Picon L, Moussata D, Passot C, Bejan-Angoulvant T, Desvignes C, Mulleman D, Goupille P, Paintaud G. Infliximab Efficacy May Be Linked to Full TNF-α Blockade in Peripheral Compartment-A Double Central-Peripheral Target-Mediated Drug Disposition (TMDD) Model. Pharmaceutics 2021; 13:pharmaceutics13111821. [PMID: 34834236 PMCID: PMC8623740 DOI: 10.3390/pharmaceutics13111821] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/14/2021] [Revised: 10/18/2021] [Accepted: 10/19/2021] [Indexed: 12/03/2022] Open
Abstract
Infliximab is an anti-TNF-α monoclonal antibody approved in chronic inflammatory bowel diseases (IBD). This study aimed at providing an in-depth description of infliximab target-mediated pharmacokinetics in 133 IBD patients treated with 5 mg/kg infliximab at weeks 0, 2, 14, and 22. A two-compartment model with double target-mediated drug disposition (TMDD) in both central and peripheral compartments was developed, using a rich database of 26 ankylosing spondylitis patients as a reference for linear elimination kinetics. Population approach and quasi-steady-state (QSS) approximation were used. Concentration-time data were satisfactorily described using the double-TMDD model. Target-mediated parameters of central and peripheral compartments were respectively baseline TNF concentrations (RC0 = 3.3 nM and RP0 = 0.46 nM), steady-stated dissociation rates (KCSS = 15.4 nM and KPSS = 0.49 nM), and first-order elimination rates of complexes (kCint = 0.17 day−1 and kPint = 0.0079 day−1). This model showed slower turnover of targets and infliximab-TNF complex elimination rate in peripheral compartment than in central compartment. This study allowed a better understanding of the multi-scale target-mediated pharmacokinetics of infliximab. This model could be useful to improve model-based therapeutic drug monitoring of infliximab in IBD patients.
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Affiliation(s)
- David Ternant
- EA 4245 “Transplantation, Immunology, Inflammation”, Université de Tours, 37044 Tours, France; (O.L.T.); (D.M.); (T.B.-A.); (C.D.); (G.P.)
- Department of Clinical Pharmacology, CHRU de Tours, 37044 Tour, France
- Correspondence:
| | - Olivier Le Tilly
- EA 4245 “Transplantation, Immunology, Inflammation”, Université de Tours, 37044 Tours, France; (O.L.T.); (D.M.); (T.B.-A.); (C.D.); (G.P.)
- Department of Clinical Pharmacology, CHRU de Tours, 37044 Tour, France
| | - Laurence Picon
- Department of Gastroenterology, CHRU de Tours, 37044 Tour, France;
| | - Driffa Moussata
- EA 4245 “Transplantation, Immunology, Inflammation”, Université de Tours, 37044 Tours, France; (O.L.T.); (D.M.); (T.B.-A.); (C.D.); (G.P.)
- Department of Gastroenterology, CHRU de Tours, 37044 Tour, France;
| | - Christophe Passot
- Département de Biopathologie, Institut de Cancérologie de l’Ouest, 49055 Angers, France;
| | - Theodora Bejan-Angoulvant
- EA 4245 “Transplantation, Immunology, Inflammation”, Université de Tours, 37044 Tours, France; (O.L.T.); (D.M.); (T.B.-A.); (C.D.); (G.P.)
- Department of Clinical Pharmacology, CHRU de Tours, 37044 Tour, France
| | - Céline Desvignes
- EA 4245 “Transplantation, Immunology, Inflammation”, Université de Tours, 37044 Tours, France; (O.L.T.); (D.M.); (T.B.-A.); (C.D.); (G.P.)
- Department of Clinical Pharmacology, CHRU de Tours, 37044 Tour, France
| | - Denis Mulleman
- EA 7501 “Groupe Innovation et Ciblage Cellulaire”, Université de Tours, 37044 Tour, France;
- Department of Rheumatology, CHRU de Tours, 37044 Tour, France;
| | | | - Gilles Paintaud
- EA 4245 “Transplantation, Immunology, Inflammation”, Université de Tours, 37044 Tours, France; (O.L.T.); (D.M.); (T.B.-A.); (C.D.); (G.P.)
- Department of Clinical Pharmacology, CHRU de Tours, 37044 Tour, France
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Delben AG, Martinez CAR, Sato DT, Pereira JA, Dos Santos Mendonça RL, Kanno DT, de Lourdes Setsuko Ayrizono M. Evaluation of the Effects of Biological Therapy with Infliximab in an Experimental Model of Diversion Colitis. J Gastrointest Surg 2021; 25:2681-2683. [PMID: 33754262 DOI: 10.1007/s11605-021-04981-8] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/17/2021] [Accepted: 03/04/2021] [Indexed: 01/31/2023]
Affiliation(s)
| | - Carlos Augusto Real Martinez
- Department of Surgery, Campinas State University, Campinas, São Paulo, Brazil
- Department of Surgery, São Francisco University Medical School, Av São Francisco de Assis, 218, Bragança Paulista, São Paulo, CEP 12916-900, Brazil
| | - Daniela Tiemi Sato
- Department of Surgery, Campinas State University, Campinas, São Paulo, Brazil
| | - José Aires Pereira
- Department of Pathology, São Francisco University Medical School, Av São Francisco de Assis, 218, Bragança Paulista, São Paulo, CEP 12916-900, Brazil
| | - Roberta Lais Dos Santos Mendonça
- Department of Surgery, São Francisco University Medical School, Av São Francisco de Assis, 218, Bragança Paulista, São Paulo, CEP 12916-900, Brazil
| | - Danilo Toshio Kanno
- Department of Surgery, São Francisco University Medical School, Av São Francisco de Assis, 218, Bragança Paulista, São Paulo, CEP 12916-900, Brazil
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Infliximab Treatment Does Not Lead to Full TNF-α Inhibition: A Target-Mediated Drug Disposition Model. Clin Pharmacokinet 2021; 61:143-154. [PMID: 34351609 DOI: 10.1007/s40262-021-01057-3] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 07/06/2021] [Indexed: 10/20/2022]
Abstract
BACKGROUND AND OBJECTIVE Infliximab, an anti-tumour necrosis factor (TNF)-α monoclonal antibody, has been approved in chronic inflammatory disease, including rheumatoid arthritis, Crohn's disease and ankylosing spondylitis. This study aimed to investigate and characterise target-mediated drug disposition of infliximab and antigen mass turnover during infliximab treatment. METHODS In this retrospective cohort of 186 patients treated with infliximab for rheumatoid arthritis, Crohn's disease or ankylosing spondylitis, trough infliximab concentrations were determined from samples collected between weeks 0 and 22 after treatment initiation. Target-mediated pharmacokinetics of infliximab was described using target-mediated drug disposition modelling. Target-mediated elimination parameters were determined for rheumatoid arthritis and Crohn's disease, assuming ankylosing spondylitis with no target-mediated elimination. RESULTS The quasi-equilibrium approximation of a target-mediated drug disposition model allowed a satisfactory description of infliximab concentration-time data. Estimated baseline TNF-α amounts were similar in Crohn's disease and rheumatoid arthritis (R0 = 0.39 vs 0.46 nM, respectively), but infliximab-TNF complex elimination was slower in Crohn's disease than in rheumatoid arthritis (kint = 0.024 vs 0.061 day-1, respectively). Terminal elimination half-lives were 13.5, 21.5 and 16.5 days for rheumatoid arthritis, Crohn's disease and ankylosing spondylitis, respectively. Estimated amounts of free target were close to baseline values before the next infusion suggesting that TNF-α inhibition may not be sustained over the entire dose interval. CONCLUSIONS The present study is the first to quantify the influence of target antigen dynamics on infliximab pharmacokinetics. Target-mediated elimination of infliximab may be complex, involving a multi-scale turnover of TNF-α, especially in patients with Crohn's disease. Additional clinical studies are warranted to further evaluate and fine-tune dosing approaches to ensure sustained TNF-α inhibition.
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Khella CM, Horvath JM, Asgarian R, Rolauffs B, Hart ML. Anti-Inflammatory Therapeutic Approaches to Prevent or Delay Post-Traumatic Osteoarthritis (PTOA) of the Knee Joint with a Focus on Sustained Delivery Approaches. Int J Mol Sci 2021; 22:8005. [PMID: 34360771 PMCID: PMC8347094 DOI: 10.3390/ijms22158005] [Citation(s) in RCA: 25] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/29/2021] [Revised: 07/20/2021] [Accepted: 07/22/2021] [Indexed: 12/11/2022] Open
Abstract
Inflammation plays a central role in the pathogenesis of knee PTOA after knee trauma. While a comprehensive therapy capable of preventing or delaying post-traumatic osteoarthritis (PTOA) progression after knee joint injury does not yet clinically exist, current literature suggests that certain aspects of early post-traumatic pathology of the knee joint may be prevented or delayed by anti-inflammatory therapeutic interventions. We discuss multifaceted therapeutic approaches that may be capable of effectively reducing the continuous cycle of inflammation and concomitant processes that lead to cartilage degradation as well as those that can simultaneously promote intrinsic repair processes. Within this context, we focus on early disease prevention, the optimal timeframe of treatment and possible long-lasting sustained delivery local modes of treatments that could prevent knee joint-associated PTOA symptoms. Specifically, we identify anti-inflammatory candidates that are not only anti-inflammatory but also anti-degenerative, anti-apoptotic and pro-regenerative.
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Affiliation(s)
| | | | | | | | - Melanie L. Hart
- G.E.R.N. Center for Tissue Replacement, Regeneration & Neogenesis, Department of Orthopedics and Trauma Surgery, Faculty of Medicine, Medical Center—Albert-Ludwigs—University of Freiburg, 79085 Freiburg im Breisgau, Germany; (C.M.K.); (J.M.H.); (R.A.); (B.R.)
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Vitale A, Obici L, Cattalini M, Lopalco G, Merlini G, Ricco N, Soriano A, La Torre F, Verrecchia E, Insalaco A, Dagna L, Jaber MA, Montin D, Emmi G, Ciarcia L, Barneschi S, Parronchi P, Ruscitti P, Maggio MC, Viapiana O, Sota J, Gaggiano C, Giacomelli R, Sicignano LL, Manna R, Renieri A, Lo Rizzo C, Frediani B, Rigante D, Cantarini L. Biotechnological Agents for Patients With Tumor Necrosis Factor Receptor Associated Periodic Syndrome-Therapeutic Outcome and Predictors of Response: Real-Life Data From the AIDA Network. Front Med (Lausanne) 2021; 8:668173. [PMID: 34307404 PMCID: PMC8295690 DOI: 10.3389/fmed.2021.668173] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/15/2021] [Accepted: 06/07/2021] [Indexed: 12/26/2022] Open
Abstract
Objective: To describe the role of biotechnological therapies in patients with tumor necrosis factor receptor associated periodic syndrome (TRAPS) and to identify any predictor of complete response. Methods: Clinical, laboratory, and therapeutic data from 44 Caucasian TRAPS patients treated with biologic agents were retrospectively collected in 16 Italian tertiary Centers. Results: A total of 55 biological courses with anakinra (n = 26), canakinumab (n = 16), anti-TNF-α agents (n = 10), and tocilizumab (n = 3) were analyzed. A complete response was observed in 41 (74.5%) cases, a partial response in 9 (16.4%) cases and a treatment failure in 5 (9.1%) cases. The frequency of TRAPS exacerbations was 458.2 flare/100 patients-year during the 12 months prior to the start of biologic treatment and 65.7 flare/100 patients-years during the first 12 months of therapy (p < 0.0001). The median duration of attacks was 5.00 (IQR = 10.50) days at the start of biologics and 1.00 (IQR = 0.00) days at the 12-month assessment (p < 0.0001). Likewise, a significant reduction was observed in the Autoinflammatory Disease Activity Index during the study period (p < 0.0001). A significant corticosteroid sparing effect was observed as early as the first 12 months of treatment both in the number of patients requiring corticosteroids (p = 0.025) and in the dosages employed (p < 0.0001). A significant reduction was identified in the erythrocyte sedimentation rate (p < 0.0001), C reactive protein (p < 0.0001), serum amyloid A (p < 0.0001), and in the 24-h proteinuria dosage during follow-up (p = 0.001). A relapsing-remitting disease course (OR = 0.027, C.I. 0.001-0.841, p = 0.040) and the frequency of relapses at the start of biologics (OR = 0.363, C.I. 0.301-0.953, p = 0.034) were significantly associated with a complete response. No serious adverse events were observed. Conclusions: Treatment with biologic agents is highly effective in controlling clinical and laboratory TRAPS manifestations. Patients with a relapsing-remitting course and a lower frequency of flares at the start of treatment show more likely a complete response to biologic agents.
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Affiliation(s)
- Antonio Vitale
- Department of Medical Sciences, Surgery and Neurosciences, Research Center of Systemic Autoinflammatory Diseases and Behçet's Disease and Rheumatology-Ophthalmology Collaborative Uveitis Center, University of Siena, Siena, Italy
| | - Laura Obici
- Amyloidosis Research and Treatment Center, Fondazione Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS) Policlinico San Matteo, Pavia, Italy
| | - Marco Cattalini
- Pediatric Clinic, University of Brescia and Spedali Civili di Brescia, Brescia, Italy
| | - Giuseppe Lopalco
- Rheumatology Unit, Department of Emergency and Organ Transplantation, University of Bari, Bari, Italy
| | - Giampaolo Merlini
- Amyloidosis Research and Treatment Center, Fondazione Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS) Policlinico San Matteo, Pavia, Italy
| | - Nicola Ricco
- Department of Medical Sciences, Surgery and Neurosciences, Research Center of Systemic Autoinflammatory Diseases and Behçet's Disease and Rheumatology-Ophthalmology Collaborative Uveitis Center, University of Siena, Siena, Italy
| | - Alessandra Soriano
- Department of Internal Medicine, Arcispedale Santa Maria Nuova-Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS), Reggio Emilia, Italy
| | | | - Elena Verrecchia
- Periodic Fever Research Center, Institute of Internal Medicine, Catholic University of the Sacred Heart, Fondazione Policlinico A. Gemelli, Rome, Italy
| | - Antonella Insalaco
- Division of Rheumatology, Department of Pediatric Medicine, Bambino Gesù Children's Hospital, Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS), Rome, Italy
| | - Lorenzo Dagna
- Unit of Immunology, Rheumatology, Allergy and Rare Diseases, Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS) San Raffaele Hospital, Vita-Salute San Raffaele University, Milan, Italy
| | | | - Davide Montin
- Division of Immunology and Rheumatology, Department of Paediatric Infectious Diseases, University of Turin, Regina Margherita Children's Hospital, Turin, Italy
| | - Giacomo Emmi
- Department of Experimental and Clinical Medicine, University of Florence, Florence, Italy
| | - Luisa Ciarcia
- Department of Medical Sciences, Surgery and Neurosciences, Research Center of Systemic Autoinflammatory Diseases and Behçet's Disease and Rheumatology-Ophthalmology Collaborative Uveitis Center, University of Siena, Siena, Italy
| | - Sara Barneschi
- Department of Medical Sciences, Surgery and Neurosciences, Research Center of Systemic Autoinflammatory Diseases and Behçet's Disease and Rheumatology-Ophthalmology Collaborative Uveitis Center, University of Siena, Siena, Italy
| | - Paola Parronchi
- Department of Experimental and Clinical Medicine, University of Florence, Florence, Italy
| | - Piero Ruscitti
- Division of Rheumatology, Department of Biotechnological and Applied Clinical Science, University of L'Aquila, L'Aquila, Italy
| | - Maria Cristina Maggio
- Department of Health Promotion Sciences Maternal and Infantile Care, Internal Medicine and Medical Specialties “G. D'Alessandro”, University of Palermo, Palermo, Italy
| | - Ombretta Viapiana
- Rheumatology Section, Department of Medicine, University of Verona, Verona, Italy
| | - Jurgen Sota
- Department of Medical Sciences, Surgery and Neurosciences, Research Center of Systemic Autoinflammatory Diseases and Behçet's Disease and Rheumatology-Ophthalmology Collaborative Uveitis Center, University of Siena, Siena, Italy
| | - Carla Gaggiano
- Clinical Pediatrics, Department of Molecular Medicine and Development, University of Siena, Siena, Italy
| | - Roberto Giacomelli
- Department of Medicine, Università Campus Bio-Medico di Roma, Rome, Italy
| | - Ludovico Luca Sicignano
- Periodic Fever Research Center, Institute of Internal Medicine, Catholic University of the Sacred Heart, Fondazione Policlinico A. Gemelli, Rome, Italy
| | - Raffaele Manna
- Periodic Fever Research Center, Institute of Internal Medicine, Catholic University of the Sacred Heart, Fondazione Policlinico A. Gemelli, Rome, Italy
| | - Alessandra Renieri
- Medical Genetics, University of Siena, Siena, Italy
- Genetica Medica, Azienda Ospedaliera Universitaria Senese, Siena, Italy
| | | | - Bruno Frediani
- Rheumatology Unit, Department of Medical Sciences, University Hospital of Siena (Azienda Ospedaliera Universitaria Senese, AOUS), Siena, Italy
| | - Donato Rigante
- Department of Life Sciences and Public Health, Fondazione Policlinico A. Gemelli IRCCS, Rome, Italy
- Università Cattolica Sacro Cuore, Rome, Italy
| | - Luca Cantarini
- Department of Medical Sciences, Surgery and Neurosciences, Research Center of Systemic Autoinflammatory Diseases and Behçet's Disease and Rheumatology-Ophthalmology Collaborative Uveitis Center, University of Siena, Siena, Italy
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Manrique-Suárez V, Macaya L, Contreras MA, Parra N, Maura R, González A, Toledo JR, Sánchez O. Design and characterization of a novel dimeric blood-brain barrier penetrating TNFα inhibitor. Proteins 2021; 89:1508-1521. [PMID: 34219271 DOI: 10.1002/prot.26173] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/16/2021] [Revised: 05/18/2021] [Accepted: 06/29/2021] [Indexed: 12/20/2022]
Abstract
Tumor necrosis factor-alpha (TNFα) inhibitors could prevent neurological disorders systemically, but their design generally relies on molecules unable to cross the blood-brain barrier (BBB). This research was aimed to design and characterize a novel TNFα inhibitor based on the angiopeptide-2 as a BBB shuttle molecule fused to the extracellular domain of human TNFα receptor 2 and a mutated vascular endothelial growth factor (VEGF) dimerization domain. This new chimeric protein (MTV) would be able to trigger receptor-mediated transcytosis across the BBB via low-density lipoprotein receptor-related protein-1 (LRP-1) and inhibit the cytotoxic effect of TNFα more efficiently because of its dimeric structure. Stably transformed CHO cells successfully expressed MTV, and its purification by Immobilized-Metal Affinity Chromatography (IMAC) rendered high purity degree. Mutated VEGF domain included in MTV did not show cell proliferation or angiogenic activities measured by scratch and aortic ring assays, which corroborate that the function of this domain is restricted to dimerization. The pairs MTV-TNFα (Kd 279 ± 40.9 nM) and MTV-LRP1 (Kd 399 ± 50.5 nM) showed high affinity by microscale thermophoresis, and a significant increase in cell survival was observed after blocking TNFα with MTV in a cell cytotoxicity assay. Also, the antibody staining in CHOK1 and bEnd3 cells demonstrated the adhesion of MTV to the LRP1 receptor located in the cell membrane. These results provide compelling evidence for the proper functioning of the three main domains of MTV individually, which encourage us to continue the research with this new molecule as a potential candidate for the systemic treatment of neurological disorders.
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Affiliation(s)
- Viana Manrique-Suárez
- Recombinant Biopharmaceuticals Laboratory, Pharmacology Department, School of Biological Sciences, University of Concepcion, Concepcion, Chile
| | - Luis Macaya
- Recombinant Biopharmaceuticals Laboratory, Pharmacology Department, School of Biological Sciences, University of Concepcion, Concepcion, Chile
| | - Maria Angélica Contreras
- Recombinant Biopharmaceuticals Laboratory, Pharmacology Department, School of Biological Sciences, University of Concepcion, Concepcion, Chile
| | - Natalie Parra
- Recombinant Biopharmaceuticals Laboratory, Pharmacology Department, School of Biological Sciences, University of Concepcion, Concepcion, Chile
| | - Rafael Maura
- Recombinant Biopharmaceuticals Laboratory, Pharmacology Department, School of Biological Sciences, University of Concepcion, Concepcion, Chile
| | - Alaín González
- Recombinant Biopharmaceuticals Laboratory, Pharmacology Department, School of Biological Sciences, University of Concepcion, Concepcion, Chile.,Faculty of Basic Sciences, University of Medellin, Medellin, Colombia
| | - Jorge R Toledo
- Biotechnology and Biopharmaceutical Laboratory, Pathophysiology Department, School of Biological Science, Universidad de Concepción, Concepcion, Chile.,Center of Biotechnology and Biomedicine Spa, Concepción, Chile
| | - Oliberto Sánchez
- Recombinant Biopharmaceuticals Laboratory, Pharmacology Department, School of Biological Sciences, University of Concepcion, Concepcion, Chile.,Center of Biotechnology and Biomedicine Spa, Concepción, Chile
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Nocturne G, Ly B, Paoletti A, Pascaud J, Seror R, Nicco C, Mackay F, Vincent FB, Lazure T, Ferlicot S, Stimmer L, Pascal Q, Roulland S, Krzysiek R, Hacein-Bey S, Batteux F, Mariette X. Long-term exposure to monoclonal anti-TNF is associated with an increased risk of lymphoma in BAFF-transgenic mice. Clin Exp Immunol 2021; 205:169-181. [PMID: 33864242 DOI: 10.1111/cei.13602] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/15/2020] [Revised: 03/13/2021] [Accepted: 03/22/2021] [Indexed: 11/28/2022] Open
Abstract
The impact of treatment on the risk of lymphoma in patients with rheumatoid arthritis (RA) is unclear. Here, we aimed to assess if the risk of lymphoma differs according to the type of tumor necrosis factor inhibitor (TNFi), comparing monoclonal anti-TNF antibodies to the soluble TNF receptor. We used B cell activating factor belonging to the TNF family (BAFF)-transgenic (Tg) mice as a model of autoimmunity-associated lymphoma. Six-month-old BAFF-Tg mice were treated with TNFi for 12 months. Histological examination of the spleen, assessment of the cellular composition of the spleen by flow cytometry and assessment of B cell clonality were performed at euthanasia. Crude mortality and incidence of lymphoma were significantly higher in mice treated with monoclonal anti-TNF antibodies compared to both controls and mice treated with the soluble TNF receptor, even at a high dose. Flow cytometry analysis revealed decreased splenic macrophage infiltration in mice treated with monoclonal anti-TNF antibodies. Overall, this study demonstrates, for the first time, that a very prolonged treatment with monoclonal anti-TNF antibodies increase the risk of lymphoma in B cell-driven autoimmunity. These data suggest a closer monitoring for lymphoma development in patients suffering from B cell-driven autoimmune disease with long-term exposure to monoclonal anti-TNF antibodies.
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Affiliation(s)
- Gaetane Nocturne
- Department of Rheumatology, FHU CARE, AP-HP, Hôpital Bicêtre, Le Kremlin-Bicêtre, France.,INSERM, Center for Immunology of Viral Infections and Autoimmune Diseases, Université Paris-Saclay, Le Kremlin-Bicêtre, France
| | - Bineta Ly
- INSERM, Center for Immunology of Viral Infections and Autoimmune Diseases, Université Paris-Saclay, Le Kremlin-Bicêtre, France
| | - Audrey Paoletti
- INSERM, Center for Immunology of Viral Infections and Autoimmune Diseases, Université Paris-Saclay, Le Kremlin-Bicêtre, France
| | - Juliette Pascaud
- INSERM, Center for Immunology of Viral Infections and Autoimmune Diseases, Université Paris-Saclay, Le Kremlin-Bicêtre, France
| | - Raphaele Seror
- Department of Rheumatology, FHU CARE, AP-HP, Hôpital Bicêtre, Le Kremlin-Bicêtre, France.,INSERM, Center for Immunology of Viral Infections and Autoimmune Diseases, Université Paris-Saclay, Le Kremlin-Bicêtre, France
| | - Carole Nicco
- Cochin Institute, INSERM, University Paris Descartes, Paris, France
| | - Fabienne Mackay
- QIMR Berghofer Medical Research Institute in Brisbane QLD, Herston, QLD, Australia
| | - F B Vincent
- Rheumatology Research Group, Centre for Inflammatory Diseases, School of Clinical Sciences at Monash Health, Monash University, Clayton, VIC, Australia
| | - Thierry Lazure
- Department of Pathology, AP-HP, Hôpital Bicêtre, Le Kremlin-Bicêtre, France
| | - Sophie Ferlicot
- Department of Pathology, AP-HP, Hôpital Bicêtre, Le Kremlin-Bicêtre, France
| | - Lev Stimmer
- US27 Platform for Experimental Pathology, Molecular Imaging Research Center, INSERM-CEA, Fontenay-aux-Roses, France
| | - Quentin Pascal
- US27 Platform for Experimental Pathology, Molecular Imaging Research Center, INSERM-CEA, Fontenay-aux-Roses, France
| | - Sandrine Roulland
- Aix Marseille University, CNRS, INSERM, Centre d'Immunologie de Marseille-Luminy, Marseille, France
| | - Roman Krzysiek
- Department of Immunology, AP-HP, Hôpital Bicêtre, Le Kremlin-Bicêtre, France
| | - Salima Hacein-Bey
- Department of Immunology, AP-HP, Hôpital Bicêtre, Le Kremlin-Bicêtre, France
| | - Frederic Batteux
- Cochin Institute, INSERM, University Paris Descartes, Paris, France
| | - Xavier Mariette
- Department of Rheumatology, FHU CARE, AP-HP, Hôpital Bicêtre, Le Kremlin-Bicêtre, France.,INSERM, Center for Immunology of Viral Infections and Autoimmune Diseases, Université Paris-Saclay, Le Kremlin-Bicêtre, France
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46
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Uzzan S, Azab AN. Anti-TNF-α Compounds as a Treatment for Depression. Molecules 2021; 26:molecules26082368. [PMID: 33921721 PMCID: PMC8073844 DOI: 10.3390/molecules26082368] [Citation(s) in RCA: 58] [Impact Index Per Article: 14.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/22/2021] [Revised: 04/14/2021] [Accepted: 04/17/2021] [Indexed: 12/13/2022] Open
Abstract
Millions of people around the world suffer from psychiatric illnesses, causing unbearable burden and immense distress to patients and their families. Accumulating evidence suggests that inflammation may contribute to the pathophysiology of psychiatric disorders such as major depression and bipolar disorder. Copious studies have consistently shown that patients with mood disorders have increased levels of plasma tumor necrosis factor (TNF)-α. Given these findings, selective anti-TNF-α compounds were tested as a potential therapeutic strategy for mood disorders. This mini-review summarizes the results of studies that examined the mood-modulating effects of anti-TNF-α drugs.
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Affiliation(s)
- Sarit Uzzan
- Department of Clinical Biochemistry and Pharmacology, School for Community Health Professions—Faculty of Health Sciences, Ben-Gurion University of the Negev, P.O. Box 653, Beer-Sheva 8410501, Israel;
| | - Abed N. Azab
- Department of Clinical Biochemistry and Pharmacology, School for Community Health Professions—Faculty of Health Sciences, Ben-Gurion University of the Negev, P.O. Box 653, Beer-Sheva 8410501, Israel;
- Department of Nursing, School for Community Health Professions—Faculty of Health Sciences, Ben-Gurion University of the Negev, P.O. Box 653, Beer-Sheva 8410501, Israel
- Correspondence: ; Tel.: +972-8-6479880; Fax: +972-8-6477683
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Diallo K, Simons N, Sayegh S, Baron M, Degboé Y, Boyer JF, Kruglov A, Nedospasov S, Novarino J, Aloulou M, Fazilleau N, Constantin A, Cantagrel A, Davignon JL, Rauwel B. Evidence for tmTNF reverse signaling in vivo: Implications for an arginase-1-mediated therapeutic effect of TNF inhibitors during inflammation. iScience 2021; 24:102331. [PMID: 33889824 PMCID: PMC8050384 DOI: 10.1016/j.isci.2021.102331] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/28/2020] [Revised: 11/05/2020] [Accepted: 03/16/2021] [Indexed: 12/20/2022] Open
Abstract
In order to ascertain the significance of transmembrane tumor necrosis factor (tmTNF) reverse signaling in vivo, we generated a triple transgenic mouse model (3TG, TNFR1−/−, TNFR2−/−, and tmTNFKI/KI) in which all canonical tumor necrosis factor (TNF) signaling was abolished. In bone-marrow-derived macrophages harvested from these mice, various anti-TNF biologics induced the expression of genes characteristic of alternative macrophages and also inhibited the expression of pro-inflammatory cytokines mainly through the upregulation of arginase-1. Injections of TNF inhibitors during arthritis increased pro-resolutive markers in bone marrow precursors and joint cells leading to a decrease in arthritis score. These results demonstrate that the binding of anti-TNF biologics to tmTNF results in decreased arthritis severity. Collectively, our data provide evidence for the significance of tmTNF reverse signaling in the modulation of arthritis. They suggest a complementary interpretation of anti-TNF biologics effects in the treatment of inflammatory diseases and pave the way to studies focused on new arginase-1-dependent therapeutic targets.
In vivo demonstration of tmTNF reverses signaling existence tmTNF reverse signaling induces anti-oxidative stress response tmTNF reverse signaling induces an arginase-1-mediated anti-inflammatory response Reverse signaling is a complementary mechanism to TNF neutralization by anti-TNF
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Affiliation(s)
- Katy Diallo
- INFINITy, Toulouse Institute for Infectious and Inflammatory Diseases, INSERM U1291, CNRS U5051, University Toulouse III, Toulouse, France
| | - Numa Simons
- INFINITy, Toulouse Institute for Infectious and Inflammatory Diseases, INSERM U1291, CNRS U5051, University Toulouse III, Toulouse, France.,Centre de Rhumatologie, CHU de Toulouse, Toulouse, France
| | - Souraya Sayegh
- INFINITy, Toulouse Institute for Infectious and Inflammatory Diseases, INSERM U1291, CNRS U5051, University Toulouse III, Toulouse, France
| | - Michel Baron
- INFINITy, Toulouse Institute for Infectious and Inflammatory Diseases, INSERM U1291, CNRS U5051, University Toulouse III, Toulouse, France
| | - Yannick Degboé
- INFINITy, Toulouse Institute for Infectious and Inflammatory Diseases, INSERM U1291, CNRS U5051, University Toulouse III, Toulouse, France.,Centre de Rhumatologie, CHU de Toulouse, Toulouse, France.,Faculté de Médecine, Université Paul Sabatier Toulouse III, Toulouse, France
| | | | - Andrey Kruglov
- German Rheumatism Research Center (DRFZ), a Leibniz Institute Berlin 10117, Germany.,Engelhardt Institute of Molecular Biology, Russian Academy of Sciences, Moscow 119991, Russia
| | - Sergei Nedospasov
- Engelhardt Institute of Molecular Biology, Russian Academy of Sciences, Moscow 119991, Russia
| | - Julien Novarino
- INFINITy, Toulouse Institute for Infectious and Inflammatory Diseases, INSERM U1291, CNRS U5051, University Toulouse III, Toulouse, France
| | - Meryem Aloulou
- INFINITy, Toulouse Institute for Infectious and Inflammatory Diseases, INSERM U1291, CNRS U5051, University Toulouse III, Toulouse, France
| | - Nicolas Fazilleau
- INFINITy, Toulouse Institute for Infectious and Inflammatory Diseases, INSERM U1291, CNRS U5051, University Toulouse III, Toulouse, France
| | - Arnaud Constantin
- INFINITy, Toulouse Institute for Infectious and Inflammatory Diseases, INSERM U1291, CNRS U5051, University Toulouse III, Toulouse, France.,Centre de Rhumatologie, CHU de Toulouse, Toulouse, France.,Faculté de Médecine, Université Paul Sabatier Toulouse III, Toulouse, France
| | - Alain Cantagrel
- INFINITy, Toulouse Institute for Infectious and Inflammatory Diseases, INSERM U1291, CNRS U5051, University Toulouse III, Toulouse, France.,Centre de Rhumatologie, CHU de Toulouse, Toulouse, France.,Faculté de Médecine, Université Paul Sabatier Toulouse III, Toulouse, France
| | - Jean-Luc Davignon
- INFINITy, Toulouse Institute for Infectious and Inflammatory Diseases, INSERM U1291, CNRS U5051, University Toulouse III, Toulouse, France.,Centre de Rhumatologie, CHU de Toulouse, Toulouse, France
| | - Benjamin Rauwel
- INFINITy, Toulouse Institute for Infectious and Inflammatory Diseases, INSERM U1291, CNRS U5051, University Toulouse III, Toulouse, France
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48
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Abdalla Elsayed MEA, Kozak I. Pharmacologically induced uveitis. Surv Ophthalmol 2021; 66:781-801. [PMID: 33440194 DOI: 10.1016/j.survophthal.2021.01.003] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/22/2020] [Revised: 12/31/2020] [Accepted: 01/04/2021] [Indexed: 12/26/2022]
Abstract
Treatments of numerous systemic and local diseases of different etiologies may be accompanied by an unwanted side effect in the form of uveitis. We inform readers about medications that have the potential to cause uveitis and analyze the strength of association of these medications with uveitis. Subsequently, cessation of medication or appropriate treatment can be individualized for each patient for the purpose of preventing further damage to tissue structure and function. Being aware of these associations, physicians may readily identify medications that may cause uveitis and avoid expensive and unnecessary clinical and laboratory testing.
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Affiliation(s)
| | - Igor Kozak
- Moorfields Eye Hospitals UAE, Abu Dhabi, United Arab Emirates.
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49
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Majerowski J, Gordon KB. Tumor Necrosis Factor Inhibitors. COMPREHENSIVE DERMATOLOGIC DRUG THERAPY 2021:287-301.e7. [DOI: 10.1016/b978-0-323-61211-1.00026-7] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/03/2025]
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50
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Hoogewoud F, Kowalczuk L, Bousquet E, Brézin A, Touchard E, Buggage R, Bordet T, Behar-Cohen F. [Anti-TNF-α in the treatment of non-infectious uveitis]. Med Sci (Paris) 2020; 36:893-899. [PMID: 33026332 DOI: 10.1051/medsci/2020160] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/22/2022] Open
Abstract
Non-infectious uveitis is a heterogenous group of potentially blinding ocular autoimmune diseases that may represent a manifestation of a systemic condition or may affect the eyes only. A systemically administered anti-TNF has recently been approved for the treatment of non-infectious uveitis, broadening the therapeutic arsenal available to control intraocular inflammation and reduce uveitis complications that can lead to vision loss. When uveitis affects only the eyes, a local anti-TNF-α administration strategy could optimize the ocular therapeutic effect and reduce undesirable systemic side-effects. A new ocular method of non-viral gene therapy, currently in development, may broaden the indications for ocular anti-TNF-α agents, not only for uveitis but also for other diseases in which TNF-α-mediated neuro-inflammation has been demonstrated.
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Affiliation(s)
- Florence Hoogewoud
- Ophtalmopole Hôpital Cochin; Assistance Publique-Hôpitaux de Paris; Université de Paris, 27 rue du Faubourg Saint-Jacques, 75014 Paris, France - Département d'ophtalmologie de l'université de Lausanne, Hôpital Ophtalmologique Jules-Gonin, Lausanne, Suisse
| | - Laura Kowalczuk
- Département d'ophtalmologie de l'université de Lausanne, Hôpital Ophtalmologique Jules-Gonin, Lausanne, Suisse - Centre de recherches des Cordeliers; Inserm UMR 1138, Physiopathologie des maladies oculaires : innovations thérapeutiques; Université de Paris, 15 rue de l'École de Médecine, 75006 Paris, France
| | - Elodie Bousquet
- Ophtalmopole Hôpital Cochin; Assistance Publique-Hôpitaux de Paris; Université de Paris, 27 rue du Faubourg Saint-Jacques, 75014 Paris, France - Centre de recherches des Cordeliers; Inserm UMR 1138, Physiopathologie des maladies oculaires : innovations thérapeutiques; Université de Paris, 15 rue de l'École de Médecine, 75006 Paris, France
| | - Antoine Brézin
- Ophtalmopole Hôpital Cochin; Assistance Publique-Hôpitaux de Paris; Université de Paris, 27 rue du Faubourg Saint-Jacques, 75014 Paris, France - Centre de recherches des Cordeliers; Inserm UMR 1138, Physiopathologie des maladies oculaires : innovations thérapeutiques; Université de Paris, 15 rue de l'École de Médecine, 75006 Paris, France
| | | | | | | | - Francine Behar-Cohen
- Ophtalmopole Hôpital Cochin; Assistance Publique-Hôpitaux de Paris; Université de Paris, 27 rue du Faubourg Saint-Jacques, 75014 Paris, France - Centre de recherches des Cordeliers; Inserm UMR 1138, Physiopathologie des maladies oculaires : innovations thérapeutiques; Université de Paris, 15 rue de l'École de Médecine, 75006 Paris, France
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