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van de Laar CJ, Oude Voshaar MAH, ten Klooster P, Tedjo DI, Bos R, Jansen T, Willemze A, Versteeg GA, Goekoop-Ruiterman YPM, Kroot EJ, van de Laar M. PERFECTRA: a pragmatic, multicentre, real-life study comparing treat-to-target strategies with baricitinib versus TNF inhibitors in patients with active rheumatoid arthritis after failure on csDMARDs. RMD Open 2024; 10:e004291. [PMID: 38816210 PMCID: PMC11328659 DOI: 10.1136/rmdopen-2024-004291] [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: 03/01/2024] [Accepted: 05/08/2024] [Indexed: 06/01/2024] Open
Abstract
OBJECTIVE To compare the effectiveness of a strategy administering baricitinib versus one using TNF-inhibitors (TNFi) in patients with rheumatoid arthritis (RA) after conventional synthetic disease-modifying antirheumatic drugs (csDMARDs) failure in a real-life treat-to-target (T2T) setting. METHODS Patients with biological and targeted synthetic DMARD (b/tsDMARD) naïve RA with disease duration ≤5 years without contraindications to b/tsDMARD were randomised to either TNFi or baricitinib when csDMARD failed to achieve disease control in a T2T setting. Changes in clinical and patient-reported outcome measures (PROMs) were assessed at 12-week intervals for 48 weeks. The primary endpoint was non-inferiority, with testing for superiority if non-inferiority is demonstrated, of baricitinib strategy in the number of patients achieving American College of Rheumatology 50 (ACR50) response at 12 weeks. Secondary endpoints included 28-joint count Disease Activity Score with C reactive protein (DAS28-CRP) <2.6, changes in PROMs and radiographic progression. RESULTS A total of 199 patients (TNFi, n=102; baricitinib, n=97) were studied. Both study groups were similar. Baricitinib was both non-inferior and superior in achieving ACR50 response at week 12 (42% vs 20%). Moreover, 75% of baricitinib patients achieved DAS28-CRP <2.6 at week 12 compared with 46% of TNFi patients. On secondary outcomes throughout the duration of the study, the baricitinib strategy demonstrated comparable or better outcomes than TNFi strategy. Although not powered for safety, no unexpected safety signals were seen in this relatively small group of patients. CONCLUSION Up to present, in a T2T setting, patients with RA failing csDMARDs have two main strategies to consider, Janus Kinases inhibitor versus bDMARDs (in clinical practice, predominantly TNFi). The PERFECTRA study suggested that starting with baricitinib was superior over TNFi in achieving response at 12 weeks and resulted in improved outcomes across all studied clinical measures and PROMs throughout the study duration in these patients.
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Affiliation(s)
- Celine J van de Laar
- Transparency in Healthcare BV, Hengelo, Netherlands
- Erasmus School of Health Policy and Management, Erasmus Universiteit Rotterdam, Rotterdam, Zuid-Holland, Netherlands
| | - Martijn A H Oude Voshaar
- Department of Medical Cell BioPhysics & TechMed Center, University of Twente, Enschede, Overijssel, Netherlands
| | - Peter ten Klooster
- Transparency in Healthcare bv @ University of Twente, Hengelo, Netherlands
- Department of Technology, Human and Institutional Behaviour, University of Twente, Enschede, Overijssel, Netherlands
| | - Danyta I Tedjo
- Transparency in Healthcare bv @ University of Twente, Hengelo, Netherlands
| | - Reinhard Bos
- Rheumatology, Medical Centre Leeuwarden, Leeuwarden, Fryslân, Netherlands
| | - Tim Jansen
- Rheumatology, VieCuri Medical Centre, Venlo, Limburg, Netherlands
| | - A Willemze
- Department of Rheumatology and Clinical Immunology, Maasstad Hospital, Rotterdam, Netherlands
| | - Grada A Versteeg
- Rheumatology, Deventer Hospital, Deventer, Overijssel, Netherlands
| | | | | | - Mart van de Laar
- Transparency in Healthcare bv @ University of Twente, Hengelo, Netherlands
- Department of Technology, Human and Institutional Behaviour, University of Twente, Enschede, Overijssel, Netherlands
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2
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Pan Y, Huang X, Zhou Z, Yang X, Li L, Gao C, Zhang Y, Zhang Y. Clinical significance of a novel uric-acid-based biomarker in the prediction of disease activity and response to infliximab therapy in Crohn's disease. Scand J Gastroenterol 2023:1-7. [PMID: 36829292 DOI: 10.1080/00365521.2023.2175181] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/26/2023]
Abstract
OBJECTIVES Crohn's disease (CD) is an inflammatory bowel disease marked by a chronic remission-relapse cycle. Biomarkers are critical to reflect the bowel wall inflammation and detect the treatment response. Here, we investigated a new index-the ratio of neutrophil to uric acid (NUR)-as a predictor of CD activity and responses to infliximab (IFX) treatment. METHODS Clinical and laboratory data were retrieved for CD patients and healthy control subjects from an electronic medical records database. Disease and endoscopic activity were determined using the Crohn's Disease Activity Index (CDAI) and Simple Endoscopic Score for Crohn's Disease (SES-CD), respectively. RESULTS We found firstly that NUR was remarkably higher in CD patients (n = 162) than controls (n = 170) (0.27 ± 0.10 vs. 0.19 ± 0.04, p < .0001). NUR was positively correlated with disease activity and prior to treatment, it was lower in CD patients who responded to IFX than in those who did not (0.25 ± 0.07 vs. 0.38 ± 0.12, p = .0019). Pre-treatment NUR was effective in predicting the patients' responses to IFX (AUC = 0.8469, p = .0034). CONCLUSION The results of this study support the utility of NUR for detecting CD activity and predicting the response to IFX treatment.
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Affiliation(s)
- Yan Pan
- Department of Gastroenterology, West China Hospital, Sichuan University, Chengdu, China.,Department of Gastroenterology, Sichuan Provincial People's Hospital, University of Electronic Science and Technology of China, Chengdu, China
| | - Xijing Huang
- Department of Gastroenterology, Sichuan Provincial People's Hospital, University of Electronic Science and Technology of China, Chengdu, China.,Clinical Immunology Translational Medicine Key Laboratory of Sichuan Province, Sichuan Provincial People's Hospital, University of Electronic Science and Technology of China, Chengdu, China
| | - Zhou Zhou
- Department of Gastroenterology, Sichuan Provincial People's Hospital, University of Electronic Science and Technology of China, Chengdu, China
| | - Xue Yang
- Department of Gastroenterology, Sichuan Provincial People's Hospital, University of Electronic Science and Technology of China, Chengdu, China
| | - Liangping Li
- Department of Gastroenterology, Sichuan Provincial People's Hospital, University of Electronic Science and Technology of China, Chengdu, China
| | - Caiping Gao
- Department of Gastroenterology, Sichuan Provincial People's Hospital, University of Electronic Science and Technology of China, Chengdu, China
| | - Yan Zhang
- Department of Gastroenterology, West China Hospital, Sichuan University, Chengdu, China
| | - Yinghui Zhang
- Department of Gastroenterology, Sichuan Provincial People's Hospital, University of Electronic Science and Technology of China, Chengdu, China
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3
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Hickey SL, McKim A, Mancuso CA, Krishnan A. A network-based approach for isolating the chronic inflammation gene signatures underlying complex diseases towards finding new treatment opportunities. Front Pharmacol 2022; 13:995459. [PMCID: PMC9597699 DOI: 10.3389/fphar.2022.995459] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/15/2022] [Accepted: 08/19/2022] [Indexed: 11/13/2022] Open
Abstract
Complex diseases are associated with a wide range of cellular, physiological, and clinical phenotypes. To advance our understanding of disease mechanisms and our ability to treat these diseases, it is critical to delineate the molecular basis and therapeutic avenues of specific disease phenotypes, especially those that are associated with multiple diseases. Inflammatory processes constitute one such prominent phenotype, being involved in a wide range of health problems including ischemic heart disease, stroke, cancer, diabetes mellitus, chronic kidney disease, non-alcoholic fatty liver disease, and autoimmune and neurodegenerative conditions. While hundreds of genes might play a role in the etiology of each of these diseases, isolating the genes involved in the specific phenotype (e.g., inflammation “component”) could help us understand the genes and pathways underlying this phenotype across diseases and predict potential drugs to target the phenotype. Here, we present a computational approach that integrates gene interaction networks, disease-/trait-gene associations, and drug-target information to accomplish this goal. We apply this approach to isolate gene signatures of complex diseases that correspond to chronic inflammation and use SAveRUNNER to prioritize drugs to reveal new therapeutic opportunities.
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Affiliation(s)
- Stephanie L. Hickey
- Department of Biochemistry and Molecular Biology, Michigan State University, East Lansing, MI, United States
| | - Alexander McKim
- Department of Computational Mathematics, Science and Engineering, Michigan State University, East Lansing, MI, United States
- Genetics and Genome Sciences Program, Michigan State University, East Lansing, MI, United States
| | - Christopher A. Mancuso
- Department of Computational Mathematics, Science and Engineering, Michigan State University, East Lansing, MI, United States
- Department of Biostatistics and Informatics, Colorado School of Public Health, University of Colorado-Denver Anschutz Medical Campus, Aurora, CO, United States
| | - Arjun Krishnan
- Department of Biochemistry and Molecular Biology, Michigan State University, East Lansing, MI, United States
- Department of Computational Mathematics, Science and Engineering, Michigan State University, East Lansing, MI, United States
- Department of Biomedical Informatics, University of Colorado Anschutz Medical Campus, Aurora, CO, United States
- *Correspondence: Arjun Krishnan,
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Rob F, Hugo J, Saláková M, Šmahelová J, Gkalpakiotis S, Boháč P, Tachezy R. Prevalence of genital and oral HPV infection among psoriasis patients on biologic therapy. Dermatol Ther 2022; 35:e15735. [PMID: 35883191 DOI: 10.1111/dth.15735] [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: 04/13/2022] [Revised: 07/11/2022] [Accepted: 07/24/2022] [Indexed: 11/28/2022]
Abstract
Current knowledge about human papillomavirus (HPV) infection in psoriasis patients treated with biologics is limited. In this study we evaluated the prevalence of oral and genital HPV infection in psoriasis patients treated with biologics or topical therapy for at least 6 months. The presence of HPV DNA in oral rinse and genital smears was evaluated. In total, 267 patients who met the inclusion criteria and agreed to participate were enrolled: 110 (41.2%) on topical therapy, 84 (31.5%) on anti-TNF-alpha therapy, 31 (11.6%) on anti-IL-12/23 therapy and 42 (15.7%) on anti-IL-17 therapy. The presence of genital HPV infection was detected in 34.6% of men receiving anti-TNF-α treatment, in 25.0% of patients on anti-IL-12/23 and 18.8% of patients on anti-IL-17 therapy. The difference in prevalence was not statistically different from men on topical treatment (26.3%). Prevalence of oral HPV infection was higher across all of the biologic groups (11.9% for anti-TNF-α, 12.9% for anti-IL-12/23 and 19.0% for anti-IL-17) compared to patients on topical therapy (7.3%), but statistically significant only for anti-IL-17 (p<0.05). The presence of oral HPV infection in patients treated with biologics was significantly higher (44.0%) in patients on long-term biologic treatment (>8 years) compared to patients taking biologics for a shorter period (9.1%; p<0.01). Our results suggest that patients on biologics for psoriasis have a higher prevalence of oral HPV infection compared to patients on topical treatment. Long-term treatment with biologics seems to be associated with a higher prevalence of oral HPV infection, independent of previous conventional immunosuppressive therapy. This article is protected by copyright. All rights reserved.
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Affiliation(s)
- Filip Rob
- Dermatovenereology Department, Second Faculty of Medicine, Charles University, University Hospital Bulovka, Prague, Czech Republic
| | - Jan Hugo
- Dermatovenereology Department, Third Faculty of Medicine, Charles University, Kralovske Vinohrady University Hospital, Prague, Czech Republic
| | - Martina Saláková
- Department of Genetics and Microbiology; Faculty of Science, Charles University, Biocev, Prague, Czech Republic.,National Reference Laboratory for Papillomaviruses and Polyomaviruses, Institute of Hematology and Blood Transfusion, Prague, Czech Republic
| | - Jana Šmahelová
- Department of Genetics and Microbiology; Faculty of Science, Charles University, Biocev, Prague, Czech Republic.,National Reference Laboratory for Papillomaviruses and Polyomaviruses, Institute of Hematology and Blood Transfusion, Prague, Czech Republic
| | - Spyridon Gkalpakiotis
- Dermatovenereology Department, Third Faculty of Medicine, Charles University, Kralovske Vinohrady University Hospital, Prague, Czech Republic
| | - Petr Boháč
- Dermatovenereology Department, Second Faculty of Medicine, Charles University, University Hospital Bulovka, Prague, Czech Republic
| | - Ruth Tachezy
- Department of Genetics and Microbiology; Faculty of Science, Charles University, Biocev, Prague, Czech Republic.,National Reference Laboratory for Papillomaviruses and Polyomaviruses, Institute of Hematology and Blood Transfusion, Prague, Czech Republic
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5
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Li L, Chen R, Zhang Y, Zhou G, Chen B, Zeng Z, Chen M, Zhang S. A Novel Model Based on Serum Biomarkers to Predict Primary Non-Response to Infliximab in Crohn's Disease. Front Immunol 2021; 12:646673. [PMID: 34367126 PMCID: PMC8339550 DOI: 10.3389/fimmu.2021.646673] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/27/2020] [Accepted: 07/07/2021] [Indexed: 12/22/2022] Open
Abstract
Background Infliximab is effective in inducing and maintaining remission in patients with Crohn's disease (CD), but primary non-response (PNR) occurs in 10-30% of cases. We investigated whether serum biomarkers are effective in predicting PNR in patients with CD. Methods From January 2016 to April 2020, a total of 260 patients were recruited to this prospective and retrospective cohort study. Serum samples were collected at baseline and week 2 of infliximab treatment. Serum levels of 35 cytokines were assessed in 18 patients from the discovery cohort and were further evaluated in the 60-patient cohort 1. Then, candidate cytokines and other serological biomarkers were used to construct a predictive model by logistic regression in a 182-patient cohort 2. PNR was defined based on the change of CD activity index or clinical symptoms. Results Among the 35 cytokines, matrix metalloproteinase 3(MMP3) and C-C motif ligand 2 (CCL2) were two effective serum biomarkers associated with PNR in both the discovery cohort and cohort 1. In cohort 2, serum level of MMP3, CCL2 and C-reactive protein (CRP) at 2 weeks after infliximab injection were independent predictors of PNR, with odds ratios (95% confidence interval) of 1.108(1.059-1.159), 0.940(0.920-0.965) and 1.102(1.031-1.117), respectively. A PNR classifier combining these three indicators had a large area under the curve [0.896(95% CI:0.895-0.897)] and negative predictive value [0.918(95%CI:0.917-0.919)] to predict PNR to infliximab. Conclusions MMP3, CCL2, and CRP are promising biomarkers in prediction of PNR to infliximab, and PNR classifier could accurately predict PNR and may be useful in clinical practice for therapy selection.
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Affiliation(s)
- Li Li
- Division of Gastroenterology, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, China
| | - Rirong Chen
- Division of Gastroenterology, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, China
| | - Yingfan Zhang
- Division of Gastroenterology, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, China
| | - Gaoshi Zhou
- Division of Gastroenterology, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, China
| | - Baili Chen
- Division of Gastroenterology, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, China
| | - Zhirong Zeng
- Division of Gastroenterology, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, China
| | - Minhu Chen
- Division of Gastroenterology, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, China
| | - Shenghong Zhang
- Division of Gastroenterology, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, China
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6
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Ventin-Holmberg R, Eberl A, Saqib S, Korpela K, Virtanen S, Sipponen T, Salonen A, Saavalainen P, Nissilä E. Bacterial and Fungal Profiles as Markers of Infliximab Drug Response in Inflammatory Bowel Disease. J Crohns Colitis 2021; 15:1019-1031. [PMID: 33300552 DOI: 10.1093/ecco-jcc/jjaa252] [Citation(s) in RCA: 30] [Impact Index Per Article: 7.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
BACKGROUND AND AIMS Inflammatory bowel diseases [IBDs], Crohn's disease [CD] and ulcerative colitis [UC], are globally increasing chronic gastro-intestinal inflammatory disorders associated with altered gut microbiota. Infliximab [IFX], a tumour necrosis factor [TNF]-alpha blocker, is used to treat IBD patients successfully, though one-third of the patients do not respond to therapy. No reliable biomarkers are available for prediction of IFX response. Our aims were to investigate the faecal bacterial and fungal communities during IFX therapy and find predictors for IFX treatment response in IBD patients. METHODS A total of 72 IBD patients [25 CD and 47 UC] started IFX therapy and were followed for 1 year or until IFX treatment was discontinued. An amplicon sequencing approach, targeting the bacterial 16S rRNA gene and fungal ITS 1 region separately, was used to determine the microbiota profiles in faecal samples collected before IFX therapy and 2, 6, and 12 weeks and 1 year after initiation of therapy. The response to IFX was evaluated by colonoscopy and clinically at 12 weeks after initiation. RESULTS Both faecal bacterial and fungal profiles differed significantly between response groups before start of IFX treatment. Non-responders had lower abundances of short chain fatty acid producers, particularly of the class Clostridia, and higher abundances of pro-inflammatory bacteria and fungi, such as the genus Candida, compared with responders. This was further indicated by bacterial taxa predicting the response in both CD and UC patients [area under the curve >0.8]. CONCLUSIONS Faecal bacterial and fungal microbiota composition could provide a predictive tool to estimate IFX response in IBD patients.
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Affiliation(s)
| | - Anja Eberl
- Department of Gastroenterology, Helsinki University Hospital and University of Helsinki, Helsinki, Finland
| | - Schahzad Saqib
- Human Microbiome Research Program, University of Helsinki, Helsinki, Finland
| | - Katri Korpela
- Human Microbiome Research Program, University of Helsinki, Helsinki, Finland
| | - Seppo Virtanen
- Obstetrics and Gynaecology, University of Helsinki and Helsinki University Hospital, Helsinki, Finland
| | - Taina Sipponen
- Department of Gastroenterology, Helsinki University Hospital and University of Helsinki, Helsinki, Finland
| | - Anne Salonen
- Human Microbiome Research Program, University of Helsinki, Helsinki, Finland
| | - Päivi Saavalainen
- Translational Immunology Research Program, University of Helsinki, Helsinki, Finland
| | - Eija Nissilä
- Translational Immunology Research Program, University of Helsinki, Helsinki, Finland
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7
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Coste N, Bocquet A, Labarere J, Semecas R, Aptel F, Deroux A, Bouillet L, Chiquet C. Tolerance and efficacy of anti-TNF currently used for severe non-infectious uveitis. Autoimmun Rev 2021; 20:102752. [PMID: 33476820 DOI: 10.1016/j.autrev.2021.102752] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/26/2020] [Accepted: 11/01/2020] [Indexed: 12/20/2022]
Affiliation(s)
- Nicolas Coste
- Grenoble Alpes University, Grenoble, France; Department of Ophthalmology, Grenoble Alpes University Hospital, Grenoble, France
| | - Alexis Bocquet
- Department of Internal Medicine, Grenoble Alpes University Hospital, Grenoble, France
| | - José Labarere
- Quality of Care Unit, INSERM CIC1406, Grenoble Alpes University Hospital, Univ. Grenoble Alpes, Grenoble F-38043, France
| | - Rachel Semecas
- Grenoble Alpes University, Grenoble, France; Department of Ophthalmology, Grenoble Alpes University Hospital, Grenoble, France; Hypoxia and Physiopathology Laboratory HP2, INSERM U1042, University Grenoble Alpes, Grenoble, France
| | - Florent Aptel
- Grenoble Alpes University, Grenoble, France; Department of Ophthalmology, Grenoble Alpes University Hospital, Grenoble, France; Hypoxia and Physiopathology Laboratory HP2, INSERM U1042, University Grenoble Alpes, Grenoble, France
| | - Alban Deroux
- Department of Internal Medicine, Grenoble Alpes University Hospital, Grenoble, France
| | - Laurence Bouillet
- Department of Internal Medicine, Grenoble Alpes University Hospital, Grenoble, France.
| | - Christophe Chiquet
- Grenoble Alpes University, Grenoble, France; Department of Ophthalmology, Grenoble Alpes University Hospital, Grenoble, France; Hypoxia and Physiopathology Laboratory HP2, INSERM U1042, University Grenoble Alpes, Grenoble, France
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8
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Ben Nessib D, Fazaa A, Miladi S, Sellami M, Ouenniche K, Souabni L, Kassab S, Chekili S, Ben Abdelghani K, Laatar A. Do immunosuppressive agents hamper the vaccination response in patients with rheumatic diseases? A review of the literature. Therapie 2020; 76:215-219. [PMID: 32951867 DOI: 10.1016/j.therap.2020.08.002] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/05/2020] [Revised: 08/03/2020] [Accepted: 08/25/2020] [Indexed: 02/06/2023]
Abstract
Patients with auto-immune disease are more susceptible to infection than similar populations without auto-immune disease. Vaccination seems to be one of the most effective methods to prevent patients from possible infections, but may be impaired by concomitant immunomodulators. The aim of this review was to evaluate the effect of immunosuppressive drugs on vaccination efficiency. We found that the majority of studies confirms that neither the use of corticosteroids and conventional synthetic disease-modifying antirheumatic drugs (csDMARDs) nor the use of biological agents, except rituximab, reduce the efficacy of inactivated vaccines such as pneumococcal and influenza vaccines. Even if rituximab has been shown to reduce humoral responses following influenza and pneumococcal vaccination, this response can be modestly restored 6-10 months after rituximab administration. To sum up, treatment guidelines recommending routine use of pneumococcal and influenza vaccines for immune compromised patients should be followed in order to avoid severe infections.
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Affiliation(s)
- Dorra Ben Nessib
- Rheumatology department, Monji Slim hospital, 2046 Marsa, Tunisia; Faculty of medicine of Tunis, University Tunis el Manar, 1068 Tunis, Tunisia.
| | - Alia Fazaa
- Rheumatology department, Monji Slim hospital, 2046 Marsa, Tunisia; Faculty of medicine of Tunis, University Tunis el Manar, 1068 Tunis, Tunisia
| | - Sawsen Miladi
- Rheumatology department, Monji Slim hospital, 2046 Marsa, Tunisia; Faculty of medicine of Tunis, University Tunis el Manar, 1068 Tunis, Tunisia
| | - Meriem Sellami
- Rheumatology department, Monji Slim hospital, 2046 Marsa, Tunisia; Faculty of medicine of Tunis, University Tunis el Manar, 1068 Tunis, Tunisia
| | - Kmar Ouenniche
- Rheumatology department, Monji Slim hospital, 2046 Marsa, Tunisia; Faculty of medicine of Tunis, University Tunis el Manar, 1068 Tunis, Tunisia
| | - Leila Souabni
- Rheumatology department, Monji Slim hospital, 2046 Marsa, Tunisia; Faculty of medicine of Tunis, University Tunis el Manar, 1068 Tunis, Tunisia
| | - Salma Kassab
- Rheumatology department, Monji Slim hospital, 2046 Marsa, Tunisia; Faculty of medicine of Tunis, University Tunis el Manar, 1068 Tunis, Tunisia
| | - Salma Chekili
- Rheumatology department, Monji Slim hospital, 2046 Marsa, Tunisia; Faculty of medicine of Tunis, University Tunis el Manar, 1068 Tunis, Tunisia
| | - Kawther Ben Abdelghani
- Rheumatology department, Monji Slim hospital, 2046 Marsa, Tunisia; Faculty of medicine of Tunis, University Tunis el Manar, 1068 Tunis, Tunisia
| | - Ahmed Laatar
- Rheumatology department, Monji Slim hospital, 2046 Marsa, Tunisia; Faculty of medicine of Tunis, University Tunis el Manar, 1068 Tunis, Tunisia
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9
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Dovrolis N, Michalopoulos G, Theodoropoulos GE, Arvanitidis K, Kolios G, Sechi LA, Eliopoulos AG, Gazouli M. The Interplay between Mucosal Microbiota Composition and Host Gene-Expression is Linked with Infliximab Response in Inflammatory Bowel Diseases. Microorganisms 2020; 8:438. [PMID: 32244928 PMCID: PMC7143962 DOI: 10.3390/microorganisms8030438] [Citation(s) in RCA: 46] [Impact Index Per Article: 9.2] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/28/2020] [Revised: 03/18/2020] [Accepted: 03/19/2020] [Indexed: 12/16/2022] Open
Abstract
Even though anti-TNF therapy significantly improves the rates of remission in inflammatory bowel disease (IBD) patients, there is a noticeable subgroup of patients who do not respond to treatment. Dysbiosis emerges as a key factor in IBD pathogenesis. The aim of the present study is to profile changes in the gut microbiome and transcriptome before and after administration of the anti-TNF agent Infliximab (IFX) and investigate their potential to predict patient response to IFX at baseline. Mucosal biopsy samples from 20 IBD patients and nine healthy controls (HC) were examined for differences in microbiota composition (16S rRNA gene sequencing) and mucosal gene expression (RT-qPCR) at baseline and upon completion of IFX treatment, accordingly, via an in silico pipeline. Significant differences in microbiota composition were found between the IBD and HC groups. Several bacterial genera, which were found only in IBD patients and not HC, had their populations dramatically reduced after anti-TNF treatment regardless of response. Alpha and beta diversity metrics showed significant differences between our study groups. Correlation analysis revealed six microbial genera associated with differential expression of inflammation-associated genes in IFX treatment responders at baseline. This study shows that IFX treatment has a notable impact on both the gut microbial composition and the inflamed tissue transcriptome in IBD patients. Importantly, our results identify enterotypes that correlate with transcriptome changes and help differentiate IFX responders versus non-responders at baseline, suggesting that, in combination, these signatures can be an effective tool to predict anti-TNF response.
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Affiliation(s)
- Nikolas Dovrolis
- Laboratory of Pharmacology, Faculty of Medicine, Democritus University of Thrace, Alexandroupolis 68100, Greece; (N.D.); (K.A.); (G.K.)
| | | | - George E. Theodoropoulos
- 1st Propaedeutic University Surgery Clinic, Hippocratio General Hospital, Medical School, National and Kapodistrian University of Athens, Athens 11527, Greece;
| | - Kostantinos Arvanitidis
- Laboratory of Pharmacology, Faculty of Medicine, Democritus University of Thrace, Alexandroupolis 68100, Greece; (N.D.); (K.A.); (G.K.)
| | - George Kolios
- Laboratory of Pharmacology, Faculty of Medicine, Democritus University of Thrace, Alexandroupolis 68100, Greece; (N.D.); (K.A.); (G.K.)
| | - Leonardo A. Sechi
- Department of Biomedical Sciences, University of Sassari, Sassari 07100, Italy;
| | - Aristidis G. Eliopoulos
- Laboratory of Biology, Medical School, National and Kapodistrian University of Athens, Athens 11527, Greece;
- Centre of Basic Research, Biomedical Research Foundation of the Academy of Athens (BRFAA) 11527, Greece
| | - Maria Gazouli
- Laboratory of Biology, Medical School, National and Kapodistrian University of Athens, Athens 11527, Greece;
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10
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Noureldine HA, Nour-Eldine W, Hodroj MH, Noureldine MHA, Taher A, Uthman I. Hematological malignancies in connective tissue diseases. Lupus 2020; 29:225-235. [PMID: 31933408 DOI: 10.1177/0961203319899986] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/31/2022]
Abstract
Chronic inflammation has profound tumor-promoting effects. Inflammatory cells are the key players in immunosurveillance against tumors, and immunosuppression is known to increase the risk of tumors. Autoimmune diseases, which manifest as loss of self-tolerance and chronic immune dysregulation, provide a perfect environment for tumor development. Aside from managing the direct inflammatory consequences of autoimmune pathogenesis, cancer risk profiles should be considered as a part of a patient's treatment. In this review, we describe the various associations of malignancies with autoimmune diseases, specifically systemic lupus erythematosus, rheumatoid arthritis, systemic sclerosis, and Sjögren's syndrome, as well as discuss the mechanisms contributing to the pathogenesis of both disorders.
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Affiliation(s)
- H A Noureldine
- Gilbert and Rose-Marie Chagoury School of Medicine, Lebanese American University, Byblos, Lebanon
| | - W Nour-Eldine
- Gilbert and Rose-Marie Chagoury School of Medicine, Lebanese American University, Byblos, Lebanon
| | - M H Hodroj
- Department of Internal Medicine, American University of Beirut Medical Center, Beirut, Lebanon
| | - M H A Noureldine
- Johns Hopkins University School of Medicine, Institute for Brain Protection Sciences, Johns Hopkins All Children's Hospital, Saint Petersburg, USA
| | - A Taher
- Division of Hematology and Medical Oncology, Department of Internal Medicine, American University of Beirut Medical Center, Beirut, Lebanon
| | - I Uthman
- Division of Rheumatology, Department of Internal Medicine, American University of Beirut Medical Center, Beirut, Lebanon
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11
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A Comprehensive Review and Update on the Pathogenesis of Inflammatory Bowel Disease. J Immunol Res 2019; 2019:7247238. [PMID: 31886308 PMCID: PMC6914932 DOI: 10.1155/2019/7247238] [Citation(s) in RCA: 606] [Impact Index Per Article: 101.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/15/2019] [Accepted: 11/15/2019] [Indexed: 12/13/2022] Open
Abstract
Inflammatory bowel disease (IBD) is a chronic and life-threating inflammatory disease of gastroenteric tissue characterized by episodes of intestinal inflammation. The pathogenesis of IBD is complex. Recent studies have greatly improved our knowledge of the pathophysiology of IBD, leading to great advances in the treatment as well as diagnosis of IBD. In this review, we have systemically reviewed the pathogenesis of IBD and highlighted recent advances in host genetic factors, gut microbiota, and environmental factors and, especially, in abnormal innate and adaptive immune responses and their interactions, which may hold the keys to identify novel predictive or prognostic biomarkers and develop new therapies.
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12
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Gaujoux R, Starosvetsky E, Maimon N, Vallania F, Bar-Yoseph H, Pressman S, Weisshof R, Goren I, Rabinowitz K, Waterman M, Yanai H, Dotan I, Sabo E, Chowers Y, Khatri P, Shen-Orr SS. Cell-centred meta-analysis reveals baseline predictors of anti-TNFα non-response in biopsy and blood of patients with IBD. Gut 2019; 68:604-614. [PMID: 29618496 PMCID: PMC6580771 DOI: 10.1136/gutjnl-2017-315494] [Citation(s) in RCA: 150] [Impact Index Per Article: 25.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/20/2017] [Revised: 12/19/2017] [Accepted: 01/16/2018] [Indexed: 12/16/2022]
Abstract
OBJECTIVE Although anti-tumour necrosis factor alpha (anti-TNFα) therapies represent a major breakthrough in IBD therapy, their cost-benefit ratio is hampered by an overall 30% non-response rate, adverse side effects and high costs. Thus, finding predictive biomarkers of non-response prior to commencing anti-TNFα therapy is of high value. DESIGN We analysed publicly available whole-genome expression profiles of colon biopsies obtained from multiple cohorts of patients with IBD using a combined computational deconvolution-meta-analysis paradigm which allows to estimate immune cell contribution to the measured expression and capture differential regulatory programmes otherwise masked due to variation in cellular composition. Insights from this in silico approach were experimentally validated in biopsies and blood samples of three independent test cohorts. RESULTS We found the proportion of plasma cells as a robust pretreatment biomarker of non-response to therapy, which we validated in two independent cohorts of immune-stained colon biopsies, where a plasma cellular score from inflamed biopsies was predictive of non-response with an area under the curve (AUC) of 82%. Meta-analysis of the cell proportion-adjusted gene expression data suggested that an increase in inflammatory macrophages in anti-TNFα non-responding individuals is associated with the upregulation of the triggering receptor expressed on myeloid cells 1 (TREM-1) and chemokine receptor type 2 (CCR2)-chemokine ligand 7 (CCL7) -axes. Blood gene expression analysis of an independent cohort, identified TREM-1 downregulation in non-responders at baseline, which was predictive of response with an AUC of 94%. CONCLUSIONS Our study proposes two clinically feasible assays, one in biopsy and one in blood, for predicting non-response to anti-TNFα therapy prior to initiation of treatment. Moreover, it suggests that mechanism-driven novel drugs for non-responders should be developed.
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Affiliation(s)
- Renaud Gaujoux
- Faculty of Medicine, Technion-Israel Institute of Technology, Haifa, Israel,CytoReason
| | - Elina Starosvetsky
- Faculty of Medicine, Technion-Israel Institute of Technology, Haifa, Israel
| | - Naama Maimon
- Faculty of Medicine, Technion-Israel Institute of Technology, Haifa, Israel,Department of Gastroenterology, Rambam Health Care Campus, Haifa, Israel
| | - Francesco Vallania
- Division of Biomedical Informatics Research, Department of Medicine, Stanford University, Palo Alto, California, USA,Stanford Institute for Immunity Transplantation and Infection, Department of Medicine, Stanford University, Palo Alto, California, USA
| | - Haggai Bar-Yoseph
- Department of Gastroenterology, Rambam Health Care Campus, Haifa, Israel
| | - Sigal Pressman
- Department of Gastroenterology, Rambam Health Care Campus, Haifa, Israel
| | - Roni Weisshof
- Department of Gastroenterology, Rambam Health Care Campus, Haifa, Israel
| | - Idan Goren
- Department of Gastroenterology and Liver Diseases, IBD Center, Tel Aviv Sourasky Medical Center, Tel Aviv, Israel,Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel
| | - Keren Rabinowitz
- Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel,Division of Gastroenterology, Rabin Medical Center, Petah Tikva, Israel
| | - Matti Waterman
- Department of Gastroenterology, Rambam Health Care Campus, Haifa, Israel
| | - Henit Yanai
- Department of Gastroenterology and Liver Diseases, IBD Center, Tel Aviv Sourasky Medical Center, Tel Aviv, Israel,Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel,Division of Gastroenterology, Rabin Medical Center, Petah Tikva, Israel
| | - Iris Dotan
- Department of Gastroenterology and Liver Diseases, IBD Center, Tel Aviv Sourasky Medical Center, Tel Aviv, Israel,Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel,Division of Gastroenterology, Rabin Medical Center, Petah Tikva, Israel
| | - Edmond Sabo
- Department of Pathology, Rambam Health Care Campus, Haifa, Israel
| | - Yehuda Chowers
- Faculty of Medicine, Technion-Israel Institute of Technology, Haifa, Israel,Department of Gastroenterology, Rambam Health Care Campus, Haifa, Israel
| | - Purvesh Khatri
- Division of Biomedical Informatics Research, Department of Medicine, Stanford University, Palo Alto, California, USA,Stanford Institute for Immunity Transplantation and Infection, Department of Medicine, Stanford University, Palo Alto, California, USA
| | - Shai S Shen-Orr
- Faculty of Medicine, Technion-Israel Institute of Technology, Haifa, Israel
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13
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Auvinen P, Mäntyselkä P, Koponen H, Kautiainen H, Korniloff K, Ahonen T, Vanhala M. Elevation of tumor necrosis factor alpha levels is associated with restless legs symptoms in clinically depressed patients. J Psychosom Res 2018; 115:1-5. [PMID: 30470307 DOI: 10.1016/j.jpsychores.2018.09.008] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/19/2018] [Revised: 09/18/2018] [Accepted: 09/19/2018] [Indexed: 02/07/2023]
Abstract
BACKGROUND Restless legs syndrome is a sensorimotor disorder associated with several mental illnesses particularly depression. METHODS A cross-sectional study of primary care patients. The prevalence of restless legs symptoms was studied in 706 patients with depressive symptoms and 426 controls without a psychiatric diagnosis by using a structured questionnaire. The depressive symptoms were evaluated with the BDI and the psychiatric diagnosis was confirmed by means of a diagnostic interview (M.I.N.I.). The subjects with elevated depressive symptoms were divided into two groups subjects with depressive symptoms with and without clinical depression. RESULTS The prevalence of restless legs symptoms was 24.8% in the controls, 50.0% in the patients with clinical depression and 42.4% in the patients with depressive symptoms. CRP value was significantly higher (p = .003) in the clinically depressed patients than in the other groups. There was a higher concentration of TNF-α in the subjects with restless legs symptoms (7.4 ng/l ± 3.2) compared with the subjects without symptoms (6.7 ng/l ± 2.3)(p < .001). There was a significant difference in the TNF-α levels between the subjects with and without restless legs symptoms in the depression group (p < .001) and among the patients with depressive symptoms but no a depression diagnosis (p = .022). In these groups, restless legs symptoms were associated with elevated levels of TNF-α. CONCLUSIONS TNF-α level was associated with restless legs symptoms only among subjects with depressive symptoms whether they had clinical depression or not. We suggest that TNF-α could be an underlying factor between restless legs symptoms and comorbidities.
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Affiliation(s)
- Piritta Auvinen
- Institute of Public Health and Clinical Nutrition, University of Eastern Finland, Kuopio, Finland.
| | - Pekka Mäntyselkä
- Institute of Public Health and Clinical Nutrition, University of Eastern Finland, Kuopio, Finland; Primary Health Care Unit, Kuopio University Hospital, Kuopio, Finland
| | - Hannu Koponen
- University of Helsinki, Helsinki University Hospital, Helsinki, Finland
| | - Hannu Kautiainen
- Primary Health Care Unit, Kuopio University Hospital, Kuopio, Finland; Folkhälsan Research Center, Helsinki, Finland
| | - Katariina Korniloff
- School of Health and Social Studies, JAMK University of Applied Sciences, Jyväskylä, Finland
| | - Tiina Ahonen
- Primary Health Care Unit, Central Finland Central Hospital, Jyväskylä, Finland
| | - Mauno Vanhala
- Institute of Public Health and Clinical Nutrition, University of Eastern Finland, Kuopio, Finland
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14
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Ilan Y. Immune rebalancing by oral immunotherapy: A novel method for getting the immune system back on track. J Leukoc Biol 2018; 105:463-472. [PMID: 30476347 DOI: 10.1002/jlb.5ru0718-276rr] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/17/2018] [Revised: 10/14/2018] [Accepted: 10/17/2018] [Indexed: 12/11/2022] Open
Abstract
Immune modulating treatments are often associated with immune suppression or an opposing anti-inflammatory paradigm. As such, there is a risk of exposing patients to infections and malignancies. Contrarily, eliciting only mild immune modulation can be insufficient for alleviating immune-mediated damage. Oral immunotherapy is a novel approach that uses the inherent ability of the gut immune system to generate signals that specifically suppress inflammation at affected sites, without inducing generalized immune suppression. Oral immunotherapy is being developed as a method to rebalance systemic immunity and restore balance, getting it back on track, rather than pushing the immune response too much or too little in opposing directions. Here, I review recent preclinical and clinical data examining the technique and describe its primary advantages.
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Affiliation(s)
- Yaron Ilan
- Gastroenterology and Liver Units, Department of Medicine, Hadassah-Hebrew University Medical Center, Jerusalem, Israel
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15
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Maddaloni M, Kochetkova I, Hoffman C, Pascual DW. Delivery of IL-35 by Lactococcus lactis Ameliorates Collagen-Induced Arthritis in Mice. Front Immunol 2018; 9:2691. [PMID: 30515168 PMCID: PMC6255909 DOI: 10.3389/fimmu.2018.02691] [Citation(s) in RCA: 24] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/21/2018] [Accepted: 10/31/2018] [Indexed: 12/21/2022] Open
Abstract
IL-35, a relatively newly discovered cytokine belonging to the larger IL-12 family, shows unique anti-inflammatory properties, believed to be associated with dedicated receptors and signaling pathways. IL-35 plays a pivotal role in the development and the function of both regulatory B (Bregs) and T cells (Tregs). In order to further its therapeutic potential, a dairy Lactococcus lactis strain was engineered to express murine IL-35 (LL-IL35), and this recombinant strain was applied to suppress collagen-induced arthritis (CIA). Oral administration of LL-IL35 effectively reduced the incidence and disease severity of CIA. When administered therapeutically, LL-IL35 abruptly halted CIA progression with no increase in disease severity by reducing neutrophil influx into the joints. LL-IL35 treatment reduced IFN-γ and IL-17 3.7- and 8.5-fold, respectively, and increased IL-10 production compared to diseased mice. Foxp3+ and Foxp3- CD39+ CD4+ T cells were previously shown to be the Tregs responsible for conferring protection against CIA. Inquiry into their induction revealed that both CCR6+ and CCR6- Foxp3+or- CD39+ CD4+ T cells act as the source of the IL-10 induced by LL-IL35. Thus, this study demonstrates the feasibility and benefits of engineered probiotics for treating autoimmune diseases.
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Affiliation(s)
- Massimo Maddaloni
- Department of Infectious Diseases and Immunology, University of Florida, Gainesville, FL, United States
| | - Irina Kochetkova
- Department of Microbiology and Immunology, Montana State University, Bozeman, MT, United States
| | - Carol Hoffman
- Department of Infectious Diseases and Immunology, University of Florida, Gainesville, FL, United States
| | - David W. Pascual
- Department of Infectious Diseases and Immunology, University of Florida, Gainesville, FL, United States
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16
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Bellinger DL, Lorton D. Sympathetic Nerve Hyperactivity in the Spleen: Causal for Nonpathogenic-Driven Chronic Immune-Mediated Inflammatory Diseases (IMIDs)? Int J Mol Sci 2018; 19:ijms19041188. [PMID: 29652832 PMCID: PMC5979464 DOI: 10.3390/ijms19041188] [Citation(s) in RCA: 52] [Impact Index Per Article: 7.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/17/2018] [Revised: 04/05/2018] [Accepted: 04/05/2018] [Indexed: 12/21/2022] Open
Abstract
Immune-Mediated Inflammatory Diseases (IMIDs) is a descriptive term coined for an eclectic group of diseases or conditions that share common inflammatory pathways, and for which there is no definitive etiology. IMIDs affect the elderly most severely, with many older individuals having two or more IMIDs. These diseases include, but are not limited to, type-1 diabetes, obesity, hypertension, chronic pulmonary disease, coronary heart disease, inflammatory bowel disease, and autoimmunity, such as rheumatoid arthritis (RA), Sjőgren's syndrome, systemic lupus erythematosus, psoriasis, psoriatic arthritis, and multiple sclerosis. These diseases are ostensibly unrelated mechanistically, but increase in frequency with age and share chronic systemic inflammation, implicating major roles for the spleen. Chronic systemic and regional inflammation underlies the disease manifestations of IMIDs. Regional inflammation and immune dysfunction promotes targeted end organ tissue damage, whereas systemic inflammation increases morbidity and mortality by affecting multiple organ systems. Chronic inflammation and skewed dysregulated cell-mediated immune responses drive many of these age-related medical disorders. IMIDs are commonly autoimmune-mediated or suspected to be autoimmune diseases. Another shared feature is dysregulation of the autonomic nervous system and hypothalamic pituitary adrenal (HPA) axis. Here, we focus on dysautonomia. In many IMIDs, dysautonomia manifests as an imbalance in activity/reactivity of the sympathetic and parasympathetic divisions of the autonomic nervous system (ANS). These major autonomic pathways are essential for allostasis of the immune system, and regulating inflammatory processes and innate and adaptive immunity. Pathology in ANS is a hallmark and causal feature of all IMIDs. Chronic systemic inflammation comorbid with stress pathway dysregulation implicate neural-immune cross-talk in the etiology and pathophysiology of IMIDs. Using a rodent model of inflammatory arthritis as an IMID model, we report disease-specific maladaptive changes in β₂-adrenergic receptor (AR) signaling from protein kinase A (PKA) to mitogen activated protein kinase (MAPK) pathways in the spleen. Beta₂-AR signal "shutdown" in the spleen and switching from PKA to G-coupled protein receptor kinase (GRK) pathways in lymph node cells drives inflammation and disease advancement. Based on these findings and the existing literature in other IMIDs, we present and discuss relevant literature that support the hypothesis that unresolvable immune stimulation from chronic inflammation leads to a maladaptive disease-inducing and perpetuating sympathetic response in an attempt to maintain allostasis. Since the role of sympathetic dysfunction in IMIDs is best studied in RA and rodent models of RA, this IMID is the primary one used to evaluate data relevant to our hypothesis. Here, we review the relevant literature and discuss sympathetic dysfunction as a significant contributor to the pathophysiology of IMIDs, and then discuss a novel target for treatment. Based on our findings in inflammatory arthritis and our understanding of common inflammatory process that are used by the immune system across all IMIDs, novel strategies to restore SNS homeostasis are expected to provide safe, cost-effective approaches to treat IMIDs, lower comorbidities, and increase longevity.
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Affiliation(s)
- Denise L Bellinger
- Department of Pathology and Human Anatomy, School of Medicine, Loma Linda University, Loma Linda, CA 92350, USA.
| | - Dianne Lorton
- College of Arts and Sciences, Kent State University, Kent, OH 44304, USA.
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17
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Torres-Castiblanco JL, Carrillo JA, Hincapié-Urrego D, Rojas-Villarraga A. [Tuberculosis in the era of anti-TNF-alpha therapy: Why does the risk still exist?]. BIOMEDICA : REVISTA DEL INSTITUTO NACIONAL DE SALUD 2018; 38:17-26. [PMID: 29668129 DOI: 10.7705/biomedica.v38i0.3458] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 07/25/2016] [Revised: 11/15/2016] [Accepted: 03/28/2017] [Indexed: 06/08/2023]
Abstract
Rheumatoid arthritis is an autoimmune systemic disease characterized mainly by inflammatory compromise of diarthrodial joints. Multiple drug therapies have been developed to control the activity of rheumatoid arthritis, among them, the first line of disease-modifying antirheumatic drugs (DMARD), and novel drug therapies such as the anti-TNF alpha therapy, with satisfactory clinical outcomes.Despite this positive fact, the use of this therapy implies the risk of producing negative effects due to its mechanism of action, which has been associated with multiple infections, especially tuberculosis, making it necessary to use screen tests before resorting to this kind of drugs.We present the case of a 58-year-old female patient, with a six-year history of rheumatoid arthritis.The patient developed disseminated tuberculosis with compatible radiological and histological findings after receiving treatment with infliximab (anti-TNF therapy). No test was performed to screen for latent tuberculosis infection prior to the administration of infliximab.The performance of routine screenings tests for tuberculosis prior to anti-TNF alpha therapy plays an essential role in the detection of asymptomatic patients with latent tuberculosis. This is the only way to identify those patients who would benefit from anti-tuberculosis drugs before the initiation of anti-TNF alpha therapy, which makes the difference in the search of a significant reduction in the incidence of tuberculosis and its associated morbidity and mortality.
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Affiliation(s)
- John-Leonardo Torres-Castiblanco
- Centro de Estudio de Enfermedades Autoinmunes (CREA), Escuela de Medicina y Ciencias de la Salud, Universidad del Rosario, Bogotá, D.C., Colombia.
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18
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Adhikary R, Sultana S, Bishayi B. Clitoria ternatea flower petals: Effect on TNFR1 neutralization via downregulation of synovial matrix metalloproteases. JOURNAL OF ETHNOPHARMACOLOGY 2018; 210:209-222. [PMID: 28826781 DOI: 10.1016/j.jep.2017.08.017] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 01/18/2017] [Revised: 07/17/2017] [Accepted: 08/12/2017] [Indexed: 05/28/2023]
Abstract
ETHNOPHARMACOLOGICAL RELEVANCE Clitoria ternatea Linn. (C. ternatea) is a traditionally used herb in arthritis, and its anti-arthritic activity has been attributed to polyphenols (e.g. quercetins) from its flower petal. AIM OF THE STUDY The present study was designed to investigate whether C. ternatea or quercetin-3ß-D-glucoside (QG) support the antibody mediated TNFα-receptor 1 (TNFR1) neutralization to ameliorate arthritis in mice. MATERIALS AND METHODS Development of collagen-induced arthritis (CIA) in male Swiss mice (20-22g, 3-4 weeks of age) was followed by estimation of synovial polymorphonuclear cell (PMN) accumulation (in terms of myeloperoxidase activity), synovial and systemic release of cytokines, chemokines and C-reactive protein (CRP) by enzyme-linked immunosorbent assay (ELISA), biochemical estimation of synovial free radical generation and antioxidant status, as well as immunoblot assessment of synovial TNFR1, toll-like receptor 2(TLR2), cyclooxygenase-2(COX-2) and inducible nitric oxide synthase (iNOS) expression; and zymographic analysis of synovial matrix-metalloprotease-2 (MMP-2) activity. RESULTS CIA was induced from day 2 post-secondary immunizations as evidenced from arthritic scores and joint swelling in parallel to increased inflammatory and oxidative stress parameters in synovial joints. Long term supplementation with extract from Clitoria ternatea flower petals CTE (50mg/kg) and QG (2.5mg/kg) upto 24 days post booster immunization augmented anti-arthritic potential of TNFR1 neutralization with anti-TNFR1 antibody (10μg per mice) in terms of reduced MPO activity, decrease in release of pro-inflammatory cytokines, chemokines, reactive oxygen species (ROS)/ reactive nitrogen species (RNS) production in parallel to significant (p<0.05) reduction in TNFR1, TLR2, iNOS, COX-2 and MMP-2 expression. CONCLUSION CTE and QG possess potential anti-arthritic activity which targets synovial MMP-2 in arthritic joints and TNFR1 targeting followed by CTE or QG treatment might become a combinatorial approach in future therapeutic research in treatment of arthritis.
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Affiliation(s)
- Rana Adhikary
- Department of Physiology, Immunology and Microbiology laboratory. University of Calcutta, University Colleges of Science and Technology, 92 APC Road, Calcutta 700009, West Bengal, India
| | - Sahin Sultana
- Department of Physiology, Immunology and Microbiology laboratory. University of Calcutta, University Colleges of Science and Technology, 92 APC Road, Calcutta 700009, West Bengal, India
| | - Biswadev Bishayi
- Department of Physiology, Immunology and Microbiology laboratory. University of Calcutta, University Colleges of Science and Technology, 92 APC Road, Calcutta 700009, West Bengal, India.
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Watad A, Amital H, Shoenfeld Y. Intravenous immunoglobulin: a biological corticosteroid-sparing agent in some autoimmune conditions. Lupus 2017; 26:1015-1022. [DOI: 10.1177/0961203317696589] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 08/30/2023]
Abstract
Intravenous immunoglobulin (IVIg) is increasingly used for the treatment of autoimmune and systemic inflammatory diseases. This compound is effective in a wide range of clinical conditions other than primary immunodeficiency, including autoimmune diseases, inflammatory disorders, infections, organ transplantation, and possibly supportive therapy for cancer. Systemic corticosteroids remain the gold standard treatment for many autoimmune diseases, but their long-term use is associated with complications in diverse organs and systems. Osteoporosis, osteonecrosis, cardiovascular disease, infections, and cancer have been associated with this treatment. Therefore, physicians are occasionally forced to withdraw the treatment with steroids. Biological agents may represent a good alternative, but in addition to being very expensive, these agents may have serious side effects. This review aimed to cover the major advances in the use of IVIg as a steroid-sparing agent in some relevant autoimmune diseases.
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Affiliation(s)
- A Watad
- Department of Medicine ‘B’, Sheba Medical Center, Israel
- Zabludowicz Center for Autoimmune Diseases, Sheba Medical Center, Israel
- Sackler Faculty of Medicine, Tel-Aviv University, Tel-Aviv, Israel
| | - H Amital
- Department of Medicine ‘B’, Sheba Medical Center, Israel
- Zabludowicz Center for Autoimmune Diseases, Sheba Medical Center, Israel
- Sackler Faculty of Medicine, Tel-Aviv University, Tel-Aviv, Israel
| | - Y Shoenfeld
- Zabludowicz Center for Autoimmune Diseases, Sheba Medical Center, Israel
- Sackler Faculty of Medicine, Tel-Aviv University, Tel-Aviv, Israel
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20
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Incidence of renal cell carcinoma in inflammatory bowel disease patients with and without anti-TNF treatment. Eur J Gastroenterol Hepatol 2017; 29:84-90. [PMID: 27603297 DOI: 10.1097/meg.0000000000000735] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
OBJECTIVE We aimed to study the risk of renal cell carcinoma (RCC) with anti-tumor necrosis factor (anti-TNF) therapy in inflammatory bowel disease (IBD) and rheumatic diseases (RD) and calculate standardized incidence ratios (SIRs) in IBD. MATERIALS AND METHODS This was a retrospective case-control and cohort study spanning 25 years, including IBD and RD patients with a diagnosis of RCC (1990-2014) identified through the electronic database of a tertiary referral center. RESULTS RCC was confirmed in seven anti-TNF-exposed (TNF+) and 21 anti-TNF-naive (TNF-) IBD and one TNF+ and 26 TNF- RD patients. In IBD-RCC, younger age at RCC diagnosis [median (interquartile range) 46 (42-58) vs. 63 (52-75) years; P=0.02], immunosuppressive therapy (100 vs. 24%; P<0.0004), partial nephrectomy (86 vs. 33%; P=0.02), and surgery less than 1 month after diagnosis of RCC (71 vs. 14%; P=0.004) were associated with anti-TNF. Compared with IBD, RD patients were older at RCC diagnosis [70 (60-77) vs. 59 (47-69) years; P=0.02] with less nephron-sparing surgery (26 vs. 54%; P=0.04) and more symptomatic (44 vs. 14%; P=0.02) and advanced tumors (30 vs. 7%; P=0.04). SIRs in IBD-RCC TNF- and TNF+ were 5.4 (95% confidence interval 2.9-9.2) and 7.1 (2.3-16.5) in male patients and 8.5 (3.7-16.8) and 4.8 (0.6-17.3) in female patients, respectively. The risk for RCC associated with anti-TNF in IBD was 0.8 (0.3-2.5) in men and 1.4 (0.2-5.5) in women. CONCLUSION The favorable patient and tumor profiles in IBD with anti-TNF may suggest incidentally discovered RCC on abdominal imaging. SIRs for IBD-RCC were not increased after anti-TNF exposure.
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García-Lagunar MH, Gutiérrez-Cívicos MR, García-Simón MS, Conesa-Zamora P, Jimenez-Santos E, Cano-Vivar P, García-Márquez A, Muñoz-García I, Viney AC. Reasons for Discontinuation and Adverse Effects of TNFα Inhibitors in a Cohort of Patients With Rheumatoid Arthritis and Ankylosing Spondylitis. Ann Pharmacother 2016; 51:388-393. [PMID: 27920336 DOI: 10.1177/1060028016682330] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/17/2022] Open
Abstract
BACKGROUND The introduction of anti-tumor necrosis factor α (anti-TNFα) drugs has improved the clinical outcomes in rheumatoid arthritis (RA) and ankylosing spondylitis (AS). However, these drugs may cause adverse effects that motivate a change in or discontinuation of the treatment. OBJECTIVE To evaluate the causes of discontinuation or changes in the dosage regimen in a cohort of patients with RA and AS treated with infliximab, adalimumab, etanercept, and golimumab under clinical practice conditions. METHODS This was a retrospective observational study that included patients with RA or AS treated with anti-TNFα drugs between 2008 and 2013. Changes in the dosage regimen, reasons for treatment discontinuation, and adverse effects were recorded and analyzed. Time to discontinuation was estimated using Kaplan-Meier survival analysis. RESULTS A total of 123 patients with RA and 93 patients with AS were treated with anti-TNFα therapy. During the study, 55.3% of RA patients and 41.7% of AS patients had stopped the treatment. The most frequent changes were modifications in the dosing, and the most frequent adverse effects were reactions after the infusion or injection (53.8% and 66.7% in RA and AS, respectively). Drug survival of etanercept in RA (67.9%) is greater than for adalimumab and infliximab, whereas drug survival of infliximab in AS (70.0%) is greater than for etanercept and adalimumab at 5 years, although there were no significant differences ( P = 0.098 in RA and 0.194 in AS). CONCLUSIONS The main cause of discontinuation of anti-TNFα is therapeutic failure in both diseases. Etanercept and infliximab have the best survival rates in RA and AS, respectively.
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Affiliation(s)
| | | | - María Sergia García-Simón
- 1 Department of Hospital Pharmacy, Santa Lucía General University Hospital (HGUSL), Cartagena, Spain
| | | | | | | | - Andrés García-Márquez
- 1 Department of Hospital Pharmacy, Santa Lucía General University Hospital (HGUSL), Cartagena, Spain
| | - Iris Muñoz-García
- 1 Department of Hospital Pharmacy, Santa Lucía General University Hospital (HGUSL), Cartagena, Spain
| | - Alice Charlotte Viney
- 1 Department of Hospital Pharmacy, Santa Lucía General University Hospital (HGUSL), Cartagena, Spain
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Liberal R, Mieli-Vergani G, Vergani D. Contemporary issues and future directions in autoimmune hepatitis. Expert Rev Gastroenterol Hepatol 2016; 10:1163-1174. [PMID: 27215278 DOI: 10.1080/17474124.2016.1193004] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/23/2022]
Abstract
Autoimmune hepatitis (AIH) is a severe life-threatening hepatopathy of unknown etiology, affecting both pediatric and adult populations, and characterised by inflammatory liver histology, circulating non-organ-specific autoantibodies, and hypergammaglobulinaemia. AIH is a very heterogeneous disease with a variety of clinical presentations, ranging from asymptomatic liver test abnormalities to acute severe hepatitis or even acute liver failure. It responds very well to immunosuppressive treatment with prednisolone with or without azathioprine. Patients who are intolerant or fail to respond to standard therapy are candidates for alternative immunosuppressive regimens, the combination of steroids with mycophenolate mofetil or calcineurin inhibitors being the most frequently reported. The pathogenesis of AIH remains not completely understood, although there is evidence that genetic predisposition, molecular mimicry and defective immunoregulatory mechanisms contribute to the autoimmune liver damage. Areas covered: A literature search was conducted using the key-words 'autoimmune hepatitis', 'immunogenetics', 'regulatory T-cells' and 'immunosuppression'. The aim of this review is to discuss recent breakthroughs in the understanding AIH pathogenesis, diagnosis and treatment. Expert commentary: Progress in the understanding of AIH pathogenesis is likely to contribute to the development of novel therapeutic strategies, such as the adoptive transfer of autologous expanded antigen-specific regulatory T-cells.
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Affiliation(s)
- Rodrigo Liberal
- a Institute of Liver Studies and Paediatric Liver, GI & Nutrition Centre , King's College Hospital , London , UK
| | - Giorgina Mieli-Vergani
- a Institute of Liver Studies and Paediatric Liver, GI & Nutrition Centre , King's College Hospital , London , UK
| | - Diego Vergani
- a Institute of Liver Studies and Paediatric Liver, GI & Nutrition Centre , King's College Hospital , London , UK
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23
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Repnik K, Koder S, Skok P, Ferkolj I, Potočnik U. Transferrin Level Before Treatment and Genetic Polymorphism in HFE Gene as Predictive Markers for Response to Adalimumab in Crohn's Disease Patients. Biochem Genet 2016; 54:476-486. [PMID: 27115882 DOI: 10.1007/s10528-016-9734-0] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/17/2015] [Accepted: 04/13/2016] [Indexed: 12/19/2022]
Abstract
Tumor necrosis factor α inhibitors (anti-TNF) have improved treatment of several complex diseases, including Crohn's disease (CD). However, the effect varies and approximately one-third of the patients do not respond. Since blood parameters as well as genetic factors have shown a great potential to predict response during treatment, the aim of the study was to evaluate response to anti-TNF treatment with adalimumab (ADA) between genes HFE and TF and haematological parameters in Slovenian refractory CD patients. Single nucleotide polymorphisms (SNPs) rs1799852 in gene TF and rs2071303 in gene HFE were genotyped in 68 refractory CD patients for which response has been measured using inflammatory bowel disease questionnaire (IBDQ) index. Haematological parameters and IBDQ index were determined before therapy and after 4, 12, 20 and 30 weeks. We found novel strong association between SNP rs2071303 in gene HFE and response to ADA treatment, particularly patients with G allele comparing to A allele had better response after 20 weeks (p = 0.008). Further, we found strong association between transferrin level at baseline and treatment response after 12, 20 and 30 weeks, where average transferrin level before therapy was lower in responders (2.38 g/L) compared to non-responders (2.89 g/L, p = 0.005). Association was found between transferrin level in week 30 and SNP rs1799852 (p = 0.023), and between MCHC level before treatment and SNP rs2071303 (p = 0.007). Our results suggest that SNP in gene HFE as well as haematological markers serve as promising prognostic markers of response to anti-TNF treatment in CD patients.
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Affiliation(s)
- Katja Repnik
- Center for Human Molecular Genetics and Pharmacogenomics, Faculty of Medicine, University of Maribor, Taborska ulica 8, 2000, Maribor, Slovenia
- Laboratory for Biochemistry, Molecular Biology and Genomics, Faculty for Chemistry and Chemical Engineering, University of Maribor, Smetanova ulica 17, 2000, Maribor, Slovenia
| | - Silvo Koder
- University Medical Centre Maribor, Ljubljanska ulica 5, 2000, Maribor, Slovenia
| | - Pavel Skok
- University Medical Centre Maribor, Ljubljanska ulica 5, 2000, Maribor, Slovenia
| | - Ivan Ferkolj
- University Medical Centre Ljubljana, Zaloška cesta 2, 1000, Ljubljana, Slovenia
| | - Uroš Potočnik
- Center for Human Molecular Genetics and Pharmacogenomics, Faculty of Medicine, University of Maribor, Taborska ulica 8, 2000, Maribor, Slovenia.
- Laboratory for Biochemistry, Molecular Biology and Genomics, Faculty for Chemistry and Chemical Engineering, University of Maribor, Smetanova ulica 17, 2000, Maribor, Slovenia.
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24
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Zhao H, Wu C, Wu M, Zhou Y, Zhu H, Li Y, You Y, Luo H, Wang L, Zuo X. Tumor necrosis factor antagonists in the treatment of multicentric reticulohistiocytosis: Current clinical evidence. Mol Med Rep 2016; 14:209-17. [PMID: 27175854 PMCID: PMC4918541 DOI: 10.3892/mmr.2016.5253] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/07/2015] [Accepted: 04/04/2016] [Indexed: 12/22/2022] Open
Abstract
Multicentric reticulohistiocytosis (MRH) is a rare and debilitating systemic disorder characterized by cutaneous nodules and destructive polyarthritis. Due to its unknown etiology, the treatment of MRH varies with different rates of success, which causes treatment options to be rather independent and empirical. In the present study, a case of a 48‑year‑old woman with a 12‑month history of polyarthralgia and skin nodules was reported. Biopsy samples, which were obtained from her skin eruption exhibited dermal infiltration with histiocytes and multinucleated giant cells. Immunohistochemical staining indicated positivity for CD68. The patient was diagnosed with MRH and treated with a combination therapy of infliximab, prednisolone and methotrexate. Her symptoms improved markedly within 2 weeks. Following the results of this case study, a systematic review of 17 cases of MRH treated with tumor necrosis factor (TNF) antagonists was performed, and the efficacy of anti‑TNF treatment in MRH was analyzed.
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Affiliation(s)
- Hongjun Zhao
- Department of Rheumatology and Immunology, Xiangya Hospital, Central South University, Changsha, Hunan 410008, P.R. China
| | - Chunmei Wu
- Department of Rheumatology and Immunology, Xiangya Hospital, Central South University, Changsha, Hunan 410008, P.R. China
| | - Mengyun Wu
- Department of Rheumatology and Immunology, Xiangya Hospital, Central South University, Changsha, Hunan 410008, P.R. China
| | - Yaou Zhou
- Department of Rheumatology and Immunology, Xiangya Hospital, Central South University, Changsha, Hunan 410008, P.R. China
| | - Honglin Zhu
- Department of Rheumatology and Immunology, Xiangya Hospital, Central South University, Changsha, Hunan 410008, P.R. China
| | - Yisha Li
- Department of Rheumatology and Immunology, Xiangya Hospital, Central South University, Changsha, Hunan 410008, P.R. China
| | - Yunhui You
- Department of Rheumatology and Immunology, Xiangya Hospital, Central South University, Changsha, Hunan 410008, P.R. China
| | - Hui Luo
- Department of Rheumatology and Immunology, Xiangya Hospital, Central South University, Changsha, Hunan 410008, P.R. China
| | - Lijing Wang
- Department of Gerontology, Xiangya Hospital, Central South University, Changsha, Hunan 410008, P.R. China
| | - Xiaoxia Zuo
- Department of Rheumatology and Immunology, Xiangya Hospital, Central South University, Changsha, Hunan 410008, P.R. China
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25
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Xu X, Meng Q, Erben U, Wang P, Glauben R, Kühl AA, Wu H, Ma CW, Hu M, Wang Y, Sun W, Jia J, Wu X, Chen W, Siegmund B, Qin Z. Myeloid-derived suppressor cells promote B-cell production of IgA in a TNFR2-dependent manner. Cell Mol Immunol 2016; 14:597-606. [PMID: 27133471 DOI: 10.1038/cmi.2015.103] [Citation(s) in RCA: 37] [Impact Index Per Article: 4.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/23/2015] [Revised: 11/20/2015] [Accepted: 11/20/2015] [Indexed: 12/31/2022] Open
Abstract
Myeloid-derived suppressor cells (MDSCs) are well known for their capacity to suppress antitumor T-cell responses, but their effects on B-cell function and antibody production remain unclear. Here, we found that MDSCs that accumulated around the germinal center in the spleen of tumor-bearing mice co-located with B cells. In the presence of MDSCs, the antibody reaction to a surrogate antigen was significantly enhanced in mice, especially the immunoglobulin (Ig)A subtype. Co-culture with MDSCs promoted both proliferation and differentiation of B cells into IgA-producing plasma cells in vitro. Interestingly, the cross talk between MDSCs and B cells required cell-cell contact. MDSCs from tumor necrosis factor receptor (TNFR) 2-/- mice, but not from TNFR1-/- mice, failed to promote B-cell responses. Further investigation suggested that interleukin-10 and transforming growth factor-β1 were crucial for the MDSC-mediated promotion of IgA responses. These results demonstrate a novel mechanism of MDSC-mediated immune regulation during tumor growth.
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Affiliation(s)
- Xia Xu
- Key Laboratory of Protein and Peptide Pharmaceuticals, Chinese Academy of Sciences-University of Tokyo Joint Laboratory of Structural Virology and Immunology, Institute of Biophysics, Chinese Academy of Sciences, Beijing 100101, China
| | - Qinghong Meng
- Key Laboratory of Protein and Peptide Pharmaceuticals, Chinese Academy of Sciences-University of Tokyo Joint Laboratory of Structural Virology and Immunology, Institute of Biophysics, Chinese Academy of Sciences, Beijing 100101, China.,University of Chinese Academy of Sciences, Beijing 100049, China
| | - Ulrike Erben
- Medical Department for Gastroenterology, Infectious Diseases and Rheumatology/Research Center ImmunoSciences, Campus Benjamin Franklin, Charité-Universitätsmedizin Berlin, Berlin 12200, Germany
| | - Peigang Wang
- Key Laboratory of Protein and Peptide Pharmaceuticals, Chinese Academy of Sciences-University of Tokyo Joint Laboratory of Structural Virology and Immunology, Institute of Biophysics, Chinese Academy of Sciences, Beijing 100101, China
| | - Rainer Glauben
- Medical Department for Gastroenterology, Infectious Diseases and Rheumatology/Research Center ImmunoSciences, Campus Benjamin Franklin, Charité-Universitätsmedizin Berlin, Berlin 12200, Germany
| | - Anja A Kühl
- Medical Department for Gastroenterology, Infectious Diseases and Rheumatology/Research Center ImmunoSciences, Campus Benjamin Franklin, Charité-Universitätsmedizin Berlin, Berlin 12200, Germany
| | - Hao Wu
- Key Laboratory of Protein and Peptide Pharmaceuticals, Chinese Academy of Sciences-University of Tokyo Joint Laboratory of Structural Virology and Immunology, Institute of Biophysics, Chinese Academy of Sciences, Beijing 100101, China
| | - Chung Wah Ma
- Infinitus Chinese Herbal Immunity Research Centre, Guangzhou 510665, China
| | - Minghua Hu
- Infinitus Chinese Herbal Immunity Research Centre, Guangzhou 510665, China
| | - Yuanyuan Wang
- Infinitus Chinese Herbal Immunity Research Centre, Guangzhou 510665, China
| | - Wei Sun
- Berlin Institute for Medical Systems Biology, Max Delbrück Center for Molecular Medicine Berlin-Buch, Berlin 13125, Germany
| | - Junying Jia
- Key Laboratory of Protein and Peptide Pharmaceuticals, Chinese Academy of Sciences-University of Tokyo Joint Laboratory of Structural Virology and Immunology, Institute of Biophysics, Chinese Academy of Sciences, Beijing 100101, China
| | - Xinyi Wu
- Key Laboratory of Protein and Peptide Pharmaceuticals, Chinese Academy of Sciences-University of Tokyo Joint Laboratory of Structural Virology and Immunology, Institute of Biophysics, Chinese Academy of Sciences, Beijing 100101, China
| | - Wei Chen
- Berlin Institute for Medical Systems Biology, Max Delbrück Center for Molecular Medicine Berlin-Buch, Berlin 13125, Germany
| | - Britta Siegmund
- Medical Department for Gastroenterology, Infectious Diseases and Rheumatology/Research Center ImmunoSciences, Campus Benjamin Franklin, Charité-Universitätsmedizin Berlin, Berlin 12200, Germany
| | - Zhihai Qin
- Key Laboratory of Protein and Peptide Pharmaceuticals, Chinese Academy of Sciences-University of Tokyo Joint Laboratory of Structural Virology and Immunology, Institute of Biophysics, Chinese Academy of Sciences, Beijing 100101, China
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26
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Xu Z, Davis HM, Zhou H. Clinical impact of concomitant immunomodulators on biologic therapy: Pharmacokinetics, immunogenicity, efficacy and safety. J Clin Pharmacol 2015; 55 Suppl 3:S60-74. [PMID: 25707965 DOI: 10.1002/jcph.380] [Citation(s) in RCA: 36] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/25/2014] [Accepted: 08/07/2014] [Indexed: 12/19/2022]
Abstract
Immune-mediated inflammatory diseases encompass a variety of different clinical syndromes, manifesting as either common diseases such as rheumatoid arthritis (RA), inflammatory bowel disease (IBD) and psoriasis, or rare diseases such as cryopyrin-associated periodic syndromes. The therapy for these diseases often involves the use of a wide range of drugs including nonsteroidal anti-inflammatory drugs (NSAIDs), glucocorticoids, immunomodulators, and biologic therapies. Due to the abundance of relevant clinical data, this article provides a general overview on the clinical impact of the concomitant use of immunomodulators and biologic therapies, with a focus on anti-tumor necrosis factor-α agents (anti-TNFα), for the treatment of RA and Crohn's disease (CD). Compared to biologic monotherapy, concomitant use of immunomodulators (methotrexate, azathioprine, and 6-mercaptopurine) often increases the systemic exposure of the anti-TNFα agent and decreases the formation of antibodies to the anti-TNFα agent, consequently enhancing clinical efficacy. Nevertheless, long-term combination therapy with immunomodulators and anti-TNFα agents may be associated with increased risks of serious infections and malignancies. Therefore, the determination whether combination therapy is suitable for a patient should always be based on an individualized benefit-risk evaluation. More research should be undertaken to identify and validate prognostic markers for predicting patients who would benefit the most and those who are at greater risk from combination therapy with immunomodulators and anti-TNFα agents.
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Affiliation(s)
- Zhenhua Xu
- Janssen Research and Development, LLC., Spring House, PA, USA
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27
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Pan WJ, Köck K, Rees WA, Sullivan BA, Evangelista CM, Yen M, Andrews JM, Radford-Smith GL, Prince PJ, Reynhardt KO, Doherty DR, Patel SK, Krill CD, Zhou K, Shen J, Smith LE, Gow JM, Lee J, Treacy AM, Yu Z, Platt VM, Borie DC. Clinical pharmacology of AMG 181, a gut-specific human anti-α4β7 monoclonal antibody, for treating inflammatory bowel diseases. Br J Clin Pharmacol 2015; 78:1315-33. [PMID: 24803302 DOI: 10.1111/bcp.12418] [Citation(s) in RCA: 29] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/24/2013] [Accepted: 05/01/2014] [Indexed: 12/12/2022] Open
Abstract
AIMS AMG 181 pharmacokinetics/pharmacodynamics (PK/PD), safety, tolerability and effects after single subcutaneous (s.c.) or intravenous (i.v.) administration were evaluated in a randomized, double-blind, placebo-controlled study. METHODS Healthy male subjects (n= 68) received a single dose of AMG 181 or placebo at 0.7, 2.1, 7, 21, 70 mg s.c. (or i.v.), 210 mg s.c. (or i.v.), 420 mg i.v. or placebo. Four ulcerative colitis (UC) subjects (n= 4, male : female 2:2) received 210 mg AMG 181 or placebo s.c. (3:1). AMG 181 concentration, anti-AMG 181-antibody (ADA), α4 β7 receptor occupancy (RO), target cell counts, serum C-reactive protein, fecal biomarkers and Mayo score were measured. Subjects were followed 3-9 months after dose. RESULTS Following s.c. dosing, AMG 181 was absorbed with a median tmax ranging between 2-10 days and a bioavailability between 82% and 99%. Cmax and AUC increased dose-proportionally and approximately dose-proportionally, respectively, within the 70-210 mg s.c. and 70-420 mg i.v. ranges. The linear β-phase t1/2 was 31 (range 20-48) days. Target-mediated disposition occurred at serum AMG 181 concentrations of less than 1 μg ml(-1) . The PD effect on α4 β7 RO showed an EC50 of 0.01 μg ml(-1) . Lymphocytes, eosinophils, CD4+ T cells and subset counts were unchanged. AMG 181-treated UC subjects were in remission with mucosal healing at weeks 6, 12 and/or 28. The placebo-treated UC subject experienced colitis flare at week 6. No ADA or AMG 181 treatment-related serious adverse events were observed. CONCLUSIONS AMG 181 has PK/PD, safety, and effect profiles suitable for further testing in subjects with inflammatory bowel diseases.
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28
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Le CTK, Laidlaw G, Morehouse CA, Naiman B, Brohawn P, Mustelin T, Connor JR, McDonald DM. Synergistic actions of blocking angiopoietin-2 and tumor necrosis factor-α in suppressing remodeling of blood vessels and lymphatics in airway inflammation. THE AMERICAN JOURNAL OF PATHOLOGY 2015; 185:2949-68. [PMID: 26348576 DOI: 10.1016/j.ajpath.2015.07.010] [Citation(s) in RCA: 22] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Received: 10/03/2014] [Revised: 06/22/2015] [Accepted: 07/23/2015] [Indexed: 12/20/2022]
Abstract
Remodeling of blood vessels and lymphatics are prominent features of sustained inflammation. Angiopoietin-2 (Ang2)/Tie2 receptor signaling and tumor necrosis factor-α (TNF)/TNF receptor signaling are known to contribute to these changes in airway inflammation after Mycoplasma pulmonis infection in mice. We determined whether Ang2 and TNF are both essential for the remodeling on blood vessels and lymphatics, and thereby influence the actions of one another. Their respective contributions to the initial stage of vascular remodeling and sprouting lymphangiogenesis were examined by comparing the effects of function-blocking antibodies to Ang2 or TNF, given individually or together during the first week after infection. As indices of efficacy, vascular enlargement, endothelial leakiness, venular marker expression, pericyte changes, and lymphatic vessel sprouting were assessed. Inhibition of Ang2 or TNF alone reduced the remodeling of blood vessels and lymphatics, but inhibition of both together completely prevented these changes. Genome-wide analysis of changes in gene expression revealed synergistic actions of the antibody combination over a broad range of genes and signaling pathways involved in inflammatory responses. These findings demonstrate that Ang2 and TNF are essential and synergistic drivers of remodeling of blood vessels and lymphatics during the initial stage of inflammation after infection. Inhibition of Ang2 and TNF together results in widespread suppression of the inflammatory response.
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Affiliation(s)
- Catherine T K Le
- Department of Anatomy, Cardiovascular Research Institute, University of California San Francisco, San Francisco, California; University of California San Francisco Helen Diller Family Comprehensive Cancer Center, University of California San Francisco, San Francisco, California
| | - Grace Laidlaw
- Department of Anatomy, Cardiovascular Research Institute, University of California San Francisco, San Francisco, California; University of California San Francisco Helen Diller Family Comprehensive Cancer Center, University of California San Francisco, San Francisco, California
| | | | - Brian Naiman
- University of California San Francisco Helen Diller Family Comprehensive Cancer Center, University of California San Francisco, San Francisco, California; MedImmune LLC, Gaithersburg, Maryland
| | | | | | | | - Donald M McDonald
- Department of Anatomy, Cardiovascular Research Institute, University of California San Francisco, San Francisco, California; University of California San Francisco Helen Diller Family Comprehensive Cancer Center, University of California San Francisco, San Francisco, California.
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29
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Meroni PL, Valentini G, Ayala F, Cattaneo A, Valesini G. New strategies to address the pharmacodynamics and pharmacokinetics of tumor necrosis factor (TNF) inhibitors: A systematic analysis. Autoimmun Rev 2015; 14:812-29. [DOI: 10.1016/j.autrev.2015.05.001] [Citation(s) in RCA: 28] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/27/2015] [Accepted: 05/07/2015] [Indexed: 12/20/2022]
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30
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Chighizola CB, Favalli EG, Meroni PL. Novel mechanisms of action of the biologicals in rheumatic diseases. Clin Rev Allergy Immunol 2015; 47:6-16. [PMID: 23345026 DOI: 10.1007/s12016-013-8359-x] [Citation(s) in RCA: 20] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/08/2023]
Abstract
Biological drugs targeting pro-inflammatory or co-stimulatory molecules or depleting lymphocyte subsets made a revolution in rheumatoid arthritis (RA) treatment. Their comparable efficacy in clinical trials raised the point of the heterogeneity of RA pathogenesis, suggesting that we are dealing with a syndrome rather than with a single disease. Several tumor necrosis factor-alpha (TNF-α) blockers are available, and a burning question is whether they are biosimilar or not. The evidence of diverse biological effects in vitro is in line with the fact that a lack of efficacy to one TNF-α agent does not imply a non-response to another one. As proteins, biologicals are potentially immunogenic. It has been recently raised that anti-drug antibodies (ADA) may affect their bioavailability and eventually the clinical efficacy through local formation of immune complexes and directly by preventing the interaction between the drug and TNF-α. Regular monitoring of drug and ADA levels appears the best way to tailor anti-TNF-α therapies. Owing to the pleiotropic characteristics of the target, anti-TNF-α blockers may affect several mechanisms beyond rheumatoid synovitis. As TNF-α plays a pivotal role in the induction of early atherosclerosis, treatment with TNF-inhibitors may modulate cholesterol handling, in particular, cholesterol efflux from macrophages. Side effects are a major issue because of the systemic TNF-α blocking action. The efficacy of an anti-C5 monoclonal antibody fused to a peptide targeting inflamed synovia in experimental arthritis opened the way for new strategies: Homing to the synovium of molecules neutralizing TNF would allow to maximize the therapeutic action avoiding the side effects.
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31
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Pontes C, Gratacós J, Torres F, Avendaño C, Sanz J, Vallano A, Juanola X, de Miguel E, Sanmartí R, Calvo G. Evaluation of dose reduction versus standard dosing for maintenance of remission in patients with spondyloarthritis and clinical remission with anti-TNF (REDES-TNF): study protocol for a randomized controlled trial. Trials 2015; 16:370. [PMID: 26289076 PMCID: PMC4546086 DOI: 10.1186/s13063-015-0828-5] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/28/2015] [Accepted: 06/30/2015] [Indexed: 02/08/2023] Open
Abstract
BACKGROUND Dose reduction schedules of tumor necrosis factor antagonists (anti-TNF) as maintenance therapy in patients with spondyloarthritis are used empirically in clinical practice, despite the lack of clinical trials providing evidence for this practice. METHODS/DESIGN To address this issue the Spanish Society of Rheumatology (SER) and Spanish Society of Clinical Pharmacology (SEFC) designed a 3-year multicenter, randomized, open-label, controlled clinical trial (2 years for inclusion and 1 year of follow-up). The study is expected to include 190 patients with axial spondyloarthritis on stable maintenance treatment (≥4 months) with any anti-TNF agent at doses recommended in the summary of product characteristics. Patients will be randomized to either a dose reduction arm or maintenance of the dosing regimen as per the official labelling recommendations. Randomization will be stratified according to the anti-TNF agent received before study inclusion. Patient follow-up, visit schedule, and examinations will be maintained as per normal clinical practice recommendations according to SER guidelines. The study aims to test the hypothesis of noninferiority of the dose reduction strategy compared with standard treatment. The first patients were recruited in July 2012, and study completion is scheduled for the end of April 2015. DISCUSSION The REDES-TNF study is a pragmatic clinical trial that aims to provide evidence to support a medical decision now made empirically. The study results may help inform clinical decisions relevant to both patients and healthcare decision makers. TRIAL REGISTRATION EudraCT 2011-005871-18 (21 December 2011).
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Affiliation(s)
- Caridad Pontes
- Clinical Pharmacology Unit, Hospital de Sabadell. Institut Universitari Parc Taulí, Universitat Autònoma de Barcelona, Sabadell (Barcelona), Spain.
| | - Jordi Gratacós
- Rheumatology Service, Hospital de Sabadell. Institut Universitari Parc Taulí, Universitat Autònoma de Barcelona, 08208, Sabadell (Barcelona), Spain.
| | - Ferran Torres
- Biostatistics and Data Management Platform, IDIBAPS, Hospital Clínic, Biostatistics Unit. Faculty of Medicine, Universitat Autònoma de Barcelona, Barcelona, Spain.
| | - Cristina Avendaño
- Clinical Pharmacology Service. Hospital Puerta de Hierro-Majadahonda, Madrid, Spain.
| | - Jesús Sanz
- Rheumatology Service, Hospital Puerta de Hierro-Majadahonda, Madrid, Spain.
| | - Antoni Vallano
- Clinical Pharmacology Service, Hospital Universitario de Bellvitge - IDIBELL- Universitat de Barcelona, Bellvitge (Barcelona), Spain.
| | - Xavier Juanola
- Rheumatology Service, Hospital Universitario de Bellvitge - IDIBELL- Universitat de Barcelona, Bellvitge (Barcelona), Spain.
| | | | - Raimon Sanmartí
- Rheumatology Service, Hospital Clínic de Barcelona - Universitat de Barcelona, Barcelona, Spain.
| | - Gonzalo Calvo
- Clinical Pharmacology Service, Hospital Clínic de Barcelona - Universitat de Barcelona, Barcelona, Spain.
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32
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Etanercept administration prevents the inflammatory response induced by carrageenan in the murine air pouch model. Naunyn Schmiedebergs Arch Pharmacol 2015; 388:1247-57. [DOI: 10.1007/s00210-015-1162-x] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/04/2015] [Accepted: 07/27/2015] [Indexed: 12/19/2022]
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33
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Radfar L, Ahmadabadi RE, Masood F, Scofield RH. Biological therapy and dentistry: a review paper. Oral Surg Oral Med Oral Pathol Oral Radiol 2015; 120:594-601. [PMID: 26372436 DOI: 10.1016/j.oooo.2015.07.032] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/02/2014] [Revised: 07/21/2015] [Accepted: 07/23/2015] [Indexed: 01/08/2023]
Abstract
In recent years, a new class of drugs has revolutionized the treatment of autoimmune, allergic, infectious, and many more diseases. This new class of drugs is made of 3 groups-cytokines, monoclonal antibodies, and fusion proteins-that may target special damaged cells but not all the cells. These drugs may have side effects such as infection, hypersensitivity, hematologic disorders, cancer, hepatotoxicity, and neurologic disorders. However, there is not enough evidence or long-term studies of the mechanism of action and side effects of these drugs. Patients receiving biological therapies may need special consideration in dentistry. This paper is a review of the classification, mechanism of action, and side effects of these drugs and dental consideration for patients receiving biological therapies.
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Affiliation(s)
- Lida Radfar
- College of Dentistry, University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma.
| | - Roshanak E Ahmadabadi
- College of Dentistry, University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma
| | - Farah Masood
- College of Dentistry, University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma
| | - R Hal Scofield
- Department of Medicine, College of Medicine, University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma; Arthritis and Clinical Immunology, Oklahoma Medical Research Foundation, Oklahoma City, Oklahoma; Medical Service, Department of Veterans Affairs Medical Center, Oklahoma City, Oklahoma
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34
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Berghen N, Teuwen LA, Westhovens R, Verschueren P. Malignancies and anti-TNF therapy in rheumatoid arthritis: a single-center observational cohort study. Clin Rheumatol 2015. [DOI: 10.1007/s10067-015-3026-7] [Citation(s) in RCA: 23] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/19/2022]
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35
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Ramos JM, Pasquau F, Galipienso N, Valero B, Navarro A, Martinez A, Rosas J, Gutiérrez A, Sanchez-Martínez R. Whipple's disease diagnosed during anti-tumor necrosis factor alpha treatment: two case reports and review of the literature. J Med Case Rep 2015. [PMID: 26215452 PMCID: PMC4522104 DOI: 10.1186/s13256-015-0632-6] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/18/2022] Open
Abstract
Introduction Whipple’s disease is a rare infectious disease caused by Tropheryma whipplei with protean clinical manifestations. This infection may mimic chronic inflammatory rheumatisms. Case presentation We report two cases of Whipple’s disease diagnosed in the context of an inflammatory disease with anti-tumor necrosis factor alpha failure. The first patient was a 58-year-old white man with psoriatic spondylarthritis, who was treated with adalimumab, etanercept, infliximab, tocilizumab and golimumab. The second was a 73-year-old white man with rheumatoid arthritis, who received treatment with infliximab, then etanercept and rituximab. Conclusions Whipple’s disease should be suspected in all patients diagnosed with chronic inflammatory rheumatism, partially controlled or not controlled by treatment with tumor necrosis factor alpha blockers, whose condition worsens after treatment.
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Affiliation(s)
- Jose M Ramos
- Department of Internal Medicine, Hospital General Universitario de Alicante, c/ Pintor Baeza, 12, 03010, Alicante, Spain. .,Department of Medicine, Miguel Hernández University of Elche, Sant Joan d'Alacant, 03550, Spain. .,Servicio de Medicina Interna, Hospital General Universitario de Alicante, c/ Pintor Baeza, 12, 03010, Alicante, Spain.
| | - Francisco Pasquau
- Department of Internal Medicine, Hospital Marina Baixa, Avenida Alcalde Jaume Botella Mayor, 7, Villajoyosa, 03570, Alicante, Spain.
| | - Nora Galipienso
- Department of Internal Medicine, Hospital Marina Baixa, Avenida Alcalde Jaume Botella Mayor, 7, Villajoyosa, 03570, Alicante, Spain.
| | - Beatriz Valero
- Department of Internal Medicine, Hospital General Universitario de Alicante, c/ Pintor Baeza, 12, 03010, Alicante, Spain.
| | - Angela Navarro
- Department of Internal Medicine, Hospital Marina Baixa, Avenida Alcalde Jaume Botella Mayor, 7, Villajoyosa, 03570, Alicante, Spain.
| | - Agustín Martinez
- Department of Rheumatology, Hospital General Universitario de Alicante, c/ Pintor Baeza, 12, 03010, Alicante, Spain.
| | - José Rosas
- Department of Rheumatology, Hospital Marina Baixa, Avenida Alcalde Jaume Botella Mayor, 7, Villajoyosa, 03570, Alicante, Spain.
| | - Ana Gutiérrez
- Department of Gastroenterology, Hospital General Universitario de Alicante, c/ Pintor Baeza, 12, 03010, Alicante, Spain.
| | - Rosario Sanchez-Martínez
- Department of Internal Medicine, Hospital General Universitario de Alicante, c/ Pintor Baeza, 12, 03010, Alicante, Spain.
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Song Y, Shi YH, He C, Liu CQ, Wang JS, Zhao YJ, Guo YM, Wu RJ, Feng XY, Liu ZJ. Severe Henoch-Schönlein purpura with infliximab for ulcerative colitis. World J Gastroenterol 2015; 21:6082-6087. [PMID: 26019477 PMCID: PMC4438047 DOI: 10.3748/wjg.v21.i19.6082] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/23/2014] [Revised: 01/16/2015] [Accepted: 02/11/2015] [Indexed: 02/06/2023] Open
Abstract
Infliximab (IFX) is an anti-tumor necrosis factor chimeric antibody that is effective for treatment of autoimmune disorders such as Crohn’s disease and ulcerative colitis (UC). IFX is well tolerated with a low incidence of adverse effects such as infections, skin reactions, autoimmunity, and malignancy. Dermatological manifestations can appear as infusion reaction, vasculitis, cutaneous infections, psoriasis, eczema, and skin cancer. Here, we present an unusual case of extensive and sporadic subcutaneous ecchymosis in a 69-year-old woman with severe UC, partial colectomy and cecostomy, following her initial dose of IFX. The reaction occurred during infliximab infusion, and withdrawal of IFX led to gradual alleviation of her symptoms. We concluded that Henoch-Schönlein purpura, a kind of leukocytoclastic vasculitis, might have contributed to the development of the bruising. Although the precise mechanisms of the vasculitis are still controversial, such a case highlights the importance of subcutaneous adverse effects in the management of UC with IFX.
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Parida JR, Misra DP, Wakhlu A, Agarwal V. Is non-biological treatment of rheumatoid arthritis as good as biologics? World J Orthop 2015; 6:278-283. [PMID: 25793168 PMCID: PMC4363810 DOI: 10.5312/wjo.v6.i2.278] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/12/2014] [Revised: 04/10/2014] [Accepted: 09/06/2014] [Indexed: 02/06/2023] Open
Abstract
The management of rheumatoid arthritis (RA) in the past three decades has undergone a paradigm shift from symptomatic relief to a "treat-to-target" approach. This has been possible through use of various conventional and biologic disease modifying anti-rheumatic drugs (DMARDs) which target disease pathogenesis at a molecular level. Cost and infection risk preclude regular use of biologics in resource-constrained settings. In the recent years, evidence has emerged that combination therapy with conventional DMARDs is not inferior to biologics in the management of RA and is a feasible cost-effective option.
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38
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Willrich MAV, Murray DL, Snyder MR. Tumor necrosis factor inhibitors: clinical utility in autoimmune diseases. Transl Res 2015; 165:270-82. [PMID: 25305470 DOI: 10.1016/j.trsl.2014.09.006] [Citation(s) in RCA: 100] [Impact Index Per Article: 10.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/27/2014] [Revised: 09/09/2014] [Accepted: 09/10/2014] [Indexed: 12/17/2022]
Abstract
Tumor necrosis factor (TNF) production is amplified in several autoimmune disorders. In the 1990s, it became a validated therapeutic target used for the treatment of conditions such as rheumatoid arthritis and inflammatory bowel disease. Biologic drugs targeting TNF include engineered monoclonal antibodies and fusion proteins. Currently, there are 5 Food and Drug Administration-approved TNF inhibitors (infliximab, etanercept, adalimumab, certolizumab, and golimumab), representing close to $20 billion in sales. Clinical trials remain open to test their efficacy and safety compared with one another, as well as to measure clinical outcomes in different conditions and patient populations. The industry is also eager to develop biotherapeutics that are similar but cheaper than the currently existing biologics or are safer with higher efficacy; these are the so-called "biosimilars." Clinical utility of TNF inhibitors and indications of mono- or combined therapy with immunomodulators are reviewed here. Pharmacokinetics of the TNF inhibitors is affected by routes of administration, clearance mechanisms of immunoglobulins, and immunogenicity. Finally, strategies for management of treatment efficacy and increasing evidence for monitoring of serum concentration of TNF inhibitors are discussed, assessing for the presence of the antidrug antibodies and the different analytical methods available for laboratory testing. As clinical applications of the TNF inhibitors expand, and other classes join the revolution in the treatment of chronic inflammatory disorders, therapeutic drug monitoring of biologics will become increasingly important, with the potential to dramatically improve patient care and management.
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Affiliation(s)
- Maria A V Willrich
- Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, Minn
| | - David L Murray
- Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, Minn
| | - Melissa R Snyder
- Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, Minn.
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Maddaloni M, Kochetkova I, Jun S, Callis G, Thornburg T, Pascual DW. Milk-based nutraceutical for treating autoimmune arthritis via the stimulation of IL-10- and TGF-β-producing CD39+ regulatory T cells. PLoS One 2015; 10:e0117825. [PMID: 25629976 PMCID: PMC4309564 DOI: 10.1371/journal.pone.0117825] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/30/2014] [Accepted: 01/01/2015] [Indexed: 01/12/2023] Open
Abstract
Autoimmune diseases arise from the loss of tolerance to self, and because the etiologies of such diseases are largely unknown, symptomatic treatments rely on anti-inflammatory and analgesic agents. Tolerogenic treatments that can reverse disease are preferred, but again, often thwarted by not knowing the responsible auto-antigens (auto-Ags). Hence, a viable alternative to stimulating regulatory T cells (Tregs) is to induce bystander tolerance. Colonization factor antigen I (CFA/I) has been shown to evoke bystander immunity and to hasten Ag-specific Treg development independent of auto-Ag. To translate in treating human autoimmune diseases, the food-based Lactococcus was engineered to express CFA/I fimbriae, and Lactococcus-CFA/I fermented milk fed to arthritic mice proved highly efficacious. Protection occurred via CD39+ Tregs producing TGF-β and IL-10 to potently suppress TNF-α production and neutrophil influx into the joints. Thus, these data demonstrate the feasibility of oral nutraceuticals for treating arthritis, and potency of protection against arthritis was improved relative to that obtained with Salmonella-CFA/I.
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Affiliation(s)
- Massimo Maddaloni
- Department of Infectious Diseases & Pathology, University of Florida, Gainesville, Florida, 32611, United States of America
| | - Irina Kochetkova
- Department of Microbiology & Immunology, Montana State University, Bozeman, Montana, 59717, United States of America
| | - SangMu Jun
- Department of Infectious Diseases & Pathology, University of Florida, Gainesville, Florida, 32611, United States of America
| | - Gayle Callis
- Department of Microbiology & Immunology, Montana State University, Bozeman, Montana, 59717, United States of America
| | - Theresa Thornburg
- Department of Microbiology & Immunology, Montana State University, Bozeman, Montana, 59717, United States of America
| | - David W. Pascual
- Department of Infectious Diseases & Pathology, University of Florida, Gainesville, Florida, 32611, United States of America
- * E-mail:
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Steeland S, Puimège L, Vandenbroucke RE, Van Hauwermeiren F, Haustraete J, Devoogdt N, Hulpiau P, Leroux-Roels G, Laukens D, Meuleman P, De Vos M, Libert C. Generation and characterization of small single domain antibodies inhibiting human tumor necrosis factor receptor 1. J Biol Chem 2014; 290:4022-37. [PMID: 25538244 DOI: 10.1074/jbc.m114.617787] [Citation(s) in RCA: 67] [Impact Index Per Article: 6.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/25/2023] Open
Abstract
The cytokine TNF is a well known drug target for several inflammatory diseases such as Crohn disease. Despite the great success of TNF blockers, therapy could be improved because of high costs and side effects. Selective inhibition of TNF receptor (TNFR) 1 signaling holds the potential to greatly reduce the pro-inflammatory activity of TNF, thereby preserving the advantageous immunomodulatory signals mediated by TNFR2. We generated a selective human TNFR1 inhibitor based on Nanobody (Nb) technology. Two anti-human TNFR1 Nbs were linked with an anti-albumin Nb to generate Nb Alb-70-96 named "TNF Receptor-One Silencer" (TROS). TROS selectively binds and inhibits TNF/TNFR1 and lymphotoxin-α/TNFR1 signaling with good affinity and IC50 values, both of which are in the nanomolar range. Surface plasmon resonance analysis reveals that TROS competes with TNF for binding to human TNFR1. In HEK293T cells, TROS strongly reduces TNF-induced gene expression, like IL8 and TNF, in a dose-dependent manner; and in ex vivo cultured colon biopsies of CD patients, TROS inhibits inflammation. Finally, in liver chimeric humanized mice, TROS antagonizes inflammation in a model of acute TNF-induced liver inflammation, reflected in reduced human IL8 expression in liver and reduced IL6 levels in serum. These results demonstrate the considerable potential of TROS and justify the evaluation of TROS in relevant disease animal models of both acute and chronic inflammation and eventually in patients.
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Affiliation(s)
- Sophie Steeland
- From the Inflammation Research Center, VIB, 9052 Ghent, the Department of Biomedical Molecular Biology, Ghent University, 9000 Ghent
| | - Leen Puimège
- From the Inflammation Research Center, VIB, 9052 Ghent, the Department of Biomedical Molecular Biology, Ghent University, 9000 Ghent
| | - Roosmarijn E Vandenbroucke
- From the Inflammation Research Center, VIB, 9052 Ghent, the Department of Biomedical Molecular Biology, Ghent University, 9000 Ghent
| | - Filip Van Hauwermeiren
- From the Inflammation Research Center, VIB, 9052 Ghent, the Department of Biomedical Molecular Biology, Ghent University, 9000 Ghent
| | - Jurgen Haustraete
- the Protein Service Facility, Inflammation Research Center, VIB, Ghent University, 9052 Ghent
| | - Nick Devoogdt
- the In Vivo Cellular and Molecular Imaging Laboratory and Cellular and Molecular Immunology Laboratory, Vrije Universiteit Brussel, 1000 Brussels, the Center for Vaccinology
| | - Paco Hulpiau
- From the Inflammation Research Center, VIB, 9052 Ghent, the Department of Biomedical Molecular Biology, Ghent University, 9000 Ghent
| | | | - Debby Laukens
- Gastroenterology, Ghent University Hospital, 9000 Ghent, Belgium
| | | | - Martine De Vos
- Gastroenterology, Ghent University Hospital, 9000 Ghent, Belgium
| | - Claude Libert
- From the Inflammation Research Center, VIB, 9052 Ghent, the Department of Biomedical Molecular Biology, Ghent University, 9000 Ghent,
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41
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Fuggle NR, Howe FA, Allen RL, Sofat N. New insights into the impact of neuro-inflammation in rheumatoid arthritis. Front Neurosci 2014; 8:357. [PMID: 25414636 PMCID: PMC4222329 DOI: 10.3389/fnins.2014.00357] [Citation(s) in RCA: 50] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/01/2014] [Accepted: 10/17/2014] [Indexed: 12/28/2022] Open
Abstract
Rheumatoid arthritis (RA) is considered to be, in many respects, an archetypal autoimmune disease that causes activation of pro-inflammatory pathways resulting in joint and systemic inflammation. RA remains a major clinical problem with the development of several new therapies targeted at cytokine inhibition in recent years. In RA, biologic therapies targeted at inhibition of tumor necrosis factor alpha (TNFα) have been shown to reduce joint inflammation, limit erosive change, reduce disability and improve quality of life. The cytokine TNFα has a central role in systemic RA inflammation and has also been shown to have pro-inflammatory effects in the brain. Emerging data suggests there is an important bidirectional communication between the brain and immune system in inflammatory conditions like RA. Recent work has shown how TNF inhibitor therapy in people with RA is protective for Alzheimer's disease. Functional MRI studies to measure brain activation in people with RA to stimulus by finger joint compression, have also shown that those who responded to TNF inhibition showed a significantly greater activation volume in thalamic, limbic, and associative areas of the brain than non-responders. Infections are the main risk of therapies with biologic drugs and infections have been shown to be related to disease flares in RA. Recent basic science data has also emerged suggesting that bacterial components including lipopolysaccharide induce pain by directly activating sensory neurons that modulate inflammation, a previously unsuspected role for the nervous system in host-pathogen interactions. In this review, we discuss the current evidence for neuro-inflammation as an important factor that impacts on disease persistence and pain in RA.
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Affiliation(s)
- Nicholas R Fuggle
- Institute of Infection and Immunity, St. George's University London, UK
| | - Franklyn A Howe
- Neuroscience Research Centre, Institute of Cardiovascular and Cell Sciences, St. George's University London, UK
| | - Rachel L Allen
- Institute of Infection and Immunity, St. George's University London, UK
| | - Nidhi Sofat
- Institute of Infection and Immunity, St. George's University London, UK
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42
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Tyagi AM, Mansoori MN, Srivastava K, Khan MP, Kureel J, Dixit M, Shukla P, Trivedi R, Chattopadhyay N, Singh D. Enhanced immunoprotective effects by anti-IL-17 antibody translates to improved skeletal parameters under estrogen deficiency compared with anti-RANKL and anti-TNF-α antibodies. J Bone Miner Res 2014; 29:1981-92. [PMID: 24677326 DOI: 10.1002/jbmr.2228] [Citation(s) in RCA: 75] [Impact Index Per Article: 6.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/06/2013] [Revised: 03/07/2014] [Accepted: 03/13/2014] [Indexed: 12/19/2022]
Abstract
Activated T cell has a key role in the interaction between bone and immune system. T cells produce proinflammatory cytokines, including receptor activator of NF-κB ligand (RANKL), tumor necrosis factor α (TNF-α), and interleukin 17 (IL-17), all of which augment osteoclastogenesis. RANKL and TNF-α are targeted by inhibitors such as denosumab, a human monoclonal RANKL antibody, and infliximab, which neutralizes TNF-α. IL-17 is also an important mediator of bone loss, and an antibody against IL-17 is undergoing phase II clinical trial for rheumatoid arthritis. Although there are a few studies showing suppression of Th17 cell differentiation and induction of regulatory T cells (Tregs) by infliximab, the effect of denosumab remains poorly understood. In this study, we investigated the effects of anti-TNF-α, anti-RANKL, or anti-IL-17 antibody administration to estrogen-deficient mice on CD4(+) T-cell proliferation, CD28 loss, Th17/Treg balance and B lymphopoesis, and finally, the translation of these immunomodulatory effects on skeletal parameters. Adult Balb/c mice were treated with anti-RANKL/-TNF-α/-IL-17 subcutaneously, twice a week, postovariectomy (Ovx) for 4 weeks. Animals were then autopsied; bone marrow cells were collected for FACS and RNA analysis and serum collected for ELISA. Bones were dissected for static and dynamic histomorphometry studies. We observed that although anti-RANKL and anti-TNF-α therapies had no effect on Ovx-induced CD4(+) T-cell proliferation and B lymphopoesis, anti-IL-17 effectively suppressed both events with concomitant reversal of CD28 loss. Anti-IL-17 antibody reduced proinflammatory cytokine production and induced Tregs. All three antibodies restored trabecular microarchitecture with comparable efficacy; however, cortical bone parameters, bone biomechanical properties, and histomorphometry were best preserved by anti-IL-17 antibody, likely attributable to its inhibitory effect on osteoblast apoptosis and increased number of bone lining cells and Wnt10b expression. Based on the superior immunoprotective effects of anti-IL-17, which appears to translate to a better skeletal preservation, we propose beginning clinical trials using a humanized antibody against IL-17 for treatment of postmenopausal osteoporosis.
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Affiliation(s)
- Abdul M Tyagi
- Division of Endocrinology and Centre for Research in Anabolic Skeletal Targets in Health and Illness (ASTHI), CSIR-Central Drug Research Institute, Lucknow, India
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Liu M, Xie M, Jiang S, Liu G, Li L, Liu D, Yang X. A novel bispecific antibody targeting tumor necrosis factor α and ED-B fibronectin effectively inhibits the progression of established collagen-induce arthritis. J Biotechnol 2014; 186:1-12. [PMID: 24992210 DOI: 10.1016/j.jbiotec.2014.06.017] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/29/2014] [Revised: 06/03/2014] [Accepted: 06/17/2014] [Indexed: 02/01/2023]
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Liu MY, Hu XP, Xie M, Jiang SJ, Li LJ, Liu DX, Yang XS. Secretory expression of a bispecific antibody targeting tumor necrosis factor and ED-B fibronectin in Pichia pastoris and its functional analysis. Biotechnol Lett 2014; 36:2425-31. [PMID: 25129049 DOI: 10.1007/s10529-014-1630-2] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/10/2014] [Accepted: 08/07/2014] [Indexed: 12/19/2022]
Abstract
Specific targeting of tumor necrosis factor (TNF)-α antagonist to the inflamed site could increase its efficacy and reduce side-effects. Here, we constructed a bispecific diabody (BsDb) that targets TNF-α and ED-B-containing fibronectin, a fibronectin isoform specifically expressed in the pannus of the inflamed synovium in rheumatoid arthritis. BsDb was secreted from Pichia pastoris as functional protein and was purified to homogeneity. BsDb could simultaneously bind to human TNF-α and B-FN and neutralize TNF-α action. Additionally, BsDb showed a significant gain both in the antigen-binding affinity and in TNF-α-neutralizing ability as compared to its original antibodies, L19 and anti-TNF-α scFv, which were produced in E. coli. BsDb was constructed and was endowed with enhanced bioactivities and improved production processing. Therefore, it holds great potential for in vivo applications.
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Affiliation(s)
- Meng-yuan Liu
- Center for Infection and Immunity Research, School of Life Sciences, Hubei University, Youyi Road 368, Wuhan, 430062, China,
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45
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Sode J, Vogel U, Bank S, Andersen PS, Thomsen MK, Hetland ML, Locht H, Heegaard NHH, Andersen V. Anti-TNF treatment response in rheumatoid arthritis patients is associated with genetic variation in the NLRP3-inflammasome. PLoS One 2014; 9:e100361. [PMID: 24967817 PMCID: PMC4072633 DOI: 10.1371/journal.pone.0100361] [Citation(s) in RCA: 56] [Impact Index Per Article: 5.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/27/2014] [Accepted: 05/23/2014] [Indexed: 12/12/2022] Open
Abstract
OBJECTIVE Many patients with rheumatoid arthritis (RA) benefit from tumor necrosis factor-α blocking treatment (anti-TNF), but about one third do not respond. The objective of this study was to replicate and extend previously found associations between anti-TNF treatment response and genetic variation in the TNF-, NF-κB- and pattern recognition receptor signalling pathways. METHODS Forty-one single nucleotide polymorphisms (SNPs), including 34 functional, in 28 genes involved in inflammatory pathways were assessed in 538 anti-TNF naive Danish RA patients with clinical data. Multivariable logistic regression analyses were performed to test associations between genotypes and treatment response at 3-6 months using the European League Against Rheumatism (EULAR) response criterion. American College of Rheumatology treatment response (ACR50) and relative change in 28-joint disease activity score (relDAS28) were used as secondary outcomes. Subgroup analyses were stratified according to smoking status, type of anti-TNF drug and IgM-Rheumatoid Factor (IgM-RF) status. False discovery rate (FDR) controlling was used to adjust for multiple testing. RESULTS Statistically significant associations with EULAR response were found for two SNPs in NLRP3(rs4612666) (OR (odds ratio) for good/moderate response = 0.64 (95% confidence interval: 0.44-0.95), p = 0.025, q = 0.95) and INFG(rs2430561) (OR = 0.40 (0.21-0.76), p = 0.005, q = 0.18) and among IgM-RF positive patients for TNFRS1A(rs4149570) (0.59 (0.36-0.98), p = 0.040, q = 0.76). Current smokers who carried the NLRP3(rs4612666) variant allele were less likely to benefit from anti-TNF treatment (OR = 0.24 (0.10-0.56), p = 0.001, q = 0.04). CONCLUSIONS In a population of Danish RA patients, we confirm the NLRP3 gene as associated with EULAR anti-TNF response as previously reported. The NLRP3 variant (T) allele is associated with lower treatment response, in particular among current smokers. Furthermore, we find that a functional polymorphism in the interferon-γ gene is associated with anti-TNF response. All findings should be tested by replication in independent validation cohorts and augmented by assessing cytokine levels and activities of the relevant gene products.
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Affiliation(s)
- Jacob Sode
- Clinical Biochemistry, Immunology & Genetics, Statens Serum Institut, Copenhagen, Denmark
- Department of Rheumatology, Frederiksberg Hospital, Frederiksberg, Denmark
- Institute of Regional Health Research, University of Southern Denmark, Odense, Denmark
| | - Ulla Vogel
- National Research Centre for the Working Environment, Copenhagen, Denmark
| | - Steffen Bank
- Department of Medicine, Viborg Regional Hospital, Viborg, Denmark
- Biomedicine, University of Aarhus, Aarhus, Denmark
| | - Paal Skytt Andersen
- Department of Microbiology and Infection Control, Statens Serum Institut, Copenhagen, Denmark
| | | | - Merete Lund Hetland
- The DANBIO Registry, Copenhagen Center for Arthritis Research, Center for Rheumatology and Spine Diseases, Glostrup Hospital, Glostrup, Denmark
- Department of Clinical Medicine, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
| | - Henning Locht
- Department of Rheumatology, Frederiksberg Hospital, Frederiksberg, Denmark
| | - Niels H. H. Heegaard
- Clinical Biochemistry, Immunology & Genetics, Statens Serum Institut, Copenhagen, Denmark
| | - Vibeke Andersen
- Institute of Regional Health Research, University of Southern Denmark, Odense, Denmark
- Department of Medicine, Viborg Regional Hospital, Viborg, Denmark
- Organ Center, Hospital of Southern Jutland, Aabenraa, Denmark
- OPEN (Odense Patient data Explorative Network), Odense University Hospital, Odense, Denmark
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Brennan FR, Cauvin A, Tibbitts J, Wolfreys A. Optimized nonclinical safety assessment strategies supporting clinical development of therapeutic monoclonal antibodies targeting inflammatory diseases. Drug Dev Res 2014; 75:115-61. [PMID: 24782266 DOI: 10.1002/ddr.21173] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/22/2014] [Accepted: 02/23/2014] [Indexed: 12/19/2022]
Abstract
An increasing number of immunomodulatory monoclonal antibodies (mAbs) and IgG Fc fusion proteins are either approved or in early-to-late stage clinical trials for the treatment of chronic inflammatory conditions, autoimmune diseases and organ transplant rejection. The exquisite specificity of mAbs, in combination with their multi-functional properties, high potency, long half-life (permitting intermittent dosing and prolonged pharamcological effects), and general lack of off-target toxicity makes them ideal therapeutics. Dosing with mAbs for these severe and debilitating but often non life-threatening diseases is usually prolonged, for several months or years, and not only affects adults, including sensitive populations such as woman of child-bearing potential (WoCBP) and the elderly, but also children. Immunosuppression is usually a therapeutic goal of these mAbs and when administered to patients whose treatment program often involves other immunosuppressive therapies, there is an inherent risk for frank immunosuppression and reduced host defence which when prolonged increases the risk of infection and cancer. In addition when mAbs interact with the immune system they can induce other adverse immune-mediated drug reactions such as infusion reactions, cytokine release syndrome, anaphylaxis, immune-complex-mediated pathology and autoimmunity. An overview of the nonclinical safety assessment and risk mitigation strategies utilized to characterize these immunomodulatory mAbs and Fc fusion proteins to support first-in human (FIH) studies and futher clinical development in inflammatory disease indications is provided. Specific emphasis is placed on the design of studies to qualify animal species for toxicology studies, early studies to investigate safety and define PK/PD relationships, FIH-enabling and chronic toxicology studies, immunotoxicity, developmental, reproductive and juvenile toxicity studies and studies to determine the potential for immunosuppression and reduced host defence against infection and cancer. Nonclinical strategies to facilitate clinical and market entry in the most efficient timeframe are presented.
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Affiliation(s)
- Frank R Brennan
- Preclinical Safety, New Medicines, UCB-Celltech, Slough, SL1 3WE, UK
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Clinical guidelines and definitions of autoinflammatory diseases: contrasts and comparisons with autoimmunity-a comprehensive review. Clin Rev Allergy Immunol 2014; 45:227-35. [PMID: 23322404 DOI: 10.1007/s12016-013-8355-1] [Citation(s) in RCA: 21] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/19/2022]
Abstract
Autoinflammatory diseases (AIDs) and autoimmune diseases (ADs) are characterized by an aberrant chronic activation of the immune system which causes tissue inflammation and damage in genetically predisposed individuals. Pathogenetic mechanisms underlying this damage differ between these two types of diseases; in AIDs, the innate immune system is directly responsible for tissue inflammation, while in ADs it works by activating the adaptive immune system, which becomes the main effector of the inflammatory process. Despite the fact that AIDs have only been recently defined, they are older than ADs. The innate immune system is found in plants and animals, and it developed earlier than the adaptive immune system, which first appeared in jawed vertebrates. According to genetic background and clinical, serological, and radiological findings, AIDs and ADs might be considered as a single spectrum of disorders, with a wide range of manifestations. Indeed, autoinflammatory-like diseases have been reported in simple organisms such as Drosophila melanogaster and Caenorhabditis elegans. We analyzed here the main pathogenetic and clinical features of these two groups of diseases mostly dealing with their similarities and differences.
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Mendes D, Alves C, Batel-Marques F. Safety profiles of adalimumab, etanercept and infliximab: a pharmacovigilance study using a measure of disproportionality in a database of spontaneously reported adverse events. J Clin Pharm Ther 2014; 39:307-13. [DOI: 10.1111/jcpt.12148] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/26/2013] [Accepted: 02/06/2014] [Indexed: 11/29/2022]
Affiliation(s)
- D. Mendes
- CHAD - Centre for Health Technology Assessment and Drug Research; AIBILI - Association for Innovation and Biomedical Research on Light; Coimbra Portugal
- Central Portugal Regional Pharmacovigilance Unit; AIBILI - Association for Innovation and Biomedical Research on Light; Coimbra Portugal
- School of Pharmacy; University of Coimbra; Coimbra Portugal
| | - C. Alves
- CHAD - Centre for Health Technology Assessment and Drug Research; AIBILI - Association for Innovation and Biomedical Research on Light; Coimbra Portugal
- Central Portugal Regional Pharmacovigilance Unit; AIBILI - Association for Innovation and Biomedical Research on Light; Coimbra Portugal
- School of Pharmacy; University of Coimbra; Coimbra Portugal
- Health Sciences Research Centre; University of Beira Interior; Covilhã Portugal
| | - F. Batel-Marques
- CHAD - Centre for Health Technology Assessment and Drug Research; AIBILI - Association for Innovation and Biomedical Research on Light; Coimbra Portugal
- Central Portugal Regional Pharmacovigilance Unit; AIBILI - Association for Innovation and Biomedical Research on Light; Coimbra Portugal
- School of Pharmacy; University of Coimbra; Coimbra Portugal
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Kivitz AJ, Schechtman J, Texter M, Fichtner A, de Longueville M, Chartash EK. Vaccine responses in patients with rheumatoid arthritis treated with certolizumab pegol: results from a single-blind randomized phase IV trial. J Rheumatol 2014; 41:648-57. [PMID: 24584918 DOI: 10.3899/jrheum.130945] [Citation(s) in RCA: 60] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/31/2023]
Abstract
OBJECTIVE To evaluate the humoral immune response to pneumococcal and influenza vaccination in adults with rheumatoid arthritis (RA) receiving certolizumab pegol (CZP). METHODS In this 6-week, single-blind, placebo-controlled trial with optional 6-month open-label extension (NCT00993668), patients were stratified by concomitant methotrexate (MTX) use and randomized to receive CZP 400 mg (loading dose; according to CZP label) or placebo at weeks 0, 2, and 4. Pneumococcal (polysaccharide 23) and influenza vaccines were administered at Week 2. Satisfactory humoral immune response, defined as ≥2-fold titer increase in ≥3 of 6 pneumococcal antigens and ≥4-fold titer increase in ≥2 of 3 influenza antigens, were assessed independently 4 weeks after vaccination. RESULTS Following pneumococcal vaccination, 62.5% of placebo patients and 54.5% of CZP patients without effective titers at baseline achieved a humoral response (difference in proportions was -8.0 percentage points; 95% CI -22.5 to 6.6%). Following influenza vaccination, 61.4% of placebo and 53.5% of CZP patients without effective titers at baseline achieved a humoral response (difference in proportions: -8.0 percentage points; 95% CI -22.9 to 7.0%). In all patients, including those with effective titers at baseline, 58.2% of placebo and 53.3% of CZP patients developed satisfactory pneumococcal titers, and 54.1% of placebo and 50.5% of CZP patients developed satisfactory influenza antibody titers. Vaccine responses to pneumococcal and influenza antigens were reduced similarly in both treatment groups with concomitant MTX use. CONCLUSION Humoral immune responses to pneumococcal and influenza vaccination are not impaired when given during the loading phase of CZP treatment in patients with RA. (ClinicalTrials.gov NCT00993668).
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Affiliation(s)
- Alan J Kivitz
- From the Altoona Center for Clinical Research, Duncansville, PA; Sun Valley Arthritis Center, Peoria, AZ; UCB Pharma, Smyrna, GA, USA; UCB Pharma, Monheim, Germany; UCB Pharma, Brussels, Belgium
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Murdaca G, Spanò F, Puppo F. Current therapies for the treatment of systemic sclerosis-related pulmonary arterial hypertension: efficacy and safety. Expert Opin Drug Saf 2014; 13:295-305. [PMID: 24387049 DOI: 10.1517/14740338.2014.872238] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/05/2022]
Abstract
INTRODUCTION Systemic sclerosis (SSc) is a rare connective tissue disease characterized by chronic inflammation and fibrosis of the skin, vascular abnormalities and variable involvement of organs. Patients with limited SSc typically develop pulmonary arterial hypertension (PAH). TNF-α, VEGF, platelet-derived growth factor and endothelin-1 play a key role in the development of PAH. AREAS COVERED This paper addresses the efficacy and safety of current drugs used for the treatment of PAH. EXPERT OPINION Bosentan, ambrisentan, sildenafil, tadalafil, iloprost, epoprostenol and treprostinil were associated with hemodynamic improvements in PAH patients. Ambrisentan has a better safety profile compared with bosentan, regarding the risk of increase in hepatic transaminases. Flushing, dyspepsia and diarrhea were the most frequent adverse events in patients treated with sildenafil, while headache, myalgia and flushing were the adverse events in those receiving tadalafil. Inhaled iloprost is also effective, but it requires multiple daily nebulizations up to 15 min each and may induce cough, flushing, jaw pain and headache. Epoprostenol is considered the most effective approved therapy for severe PAH in WHO functional class III and class IV. TNF-α inhibitors reduce the systemic inflammation in patients with chronic immune-mediated diseases and improve the endothelial function, decreasing the risk of PAH progression.
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Affiliation(s)
- Giuseppe Murdaca
- University of Genova, Department of Internal Medicine, Clinical Immunology Unit , Viale Benedetto XV, n. 6, 16132 Genova , Italy +39 0103537924 ; +39 0105556950 ;
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