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Tao S, Chen Y, Hu W, Shen K, Xu J. Is the identification of caseating granuloma in the intestine indicative of tuberculosis? a rare case of Crohn's disease. Diagn Pathol 2024; 19:139. [PMID: 39438897 PMCID: PMC11494966 DOI: 10.1186/s13000-024-01566-2] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/14/2024] [Accepted: 10/20/2024] [Indexed: 10/25/2024] Open
Abstract
BACKGROUND Crohn's disease (CD) is a chronic intestinal inflammatory disorder, the etiology of which remains unknown, and is characterized by symptoms such as chronic abdominal pain, diarrhea, obstruction, and perianal lesions. Histopathology is widely regarded as the preferred method for diagnosing CD, although the histological diagnosis may lack specificity. The identification of granulomas is commonly believed to be the most reliable diagnostic indicator for CD, surpassing all other clinical features in significance. Nevertheless, research indicates that the detection rate of granulomas in CD exhibits considerable variability. Furthermore, granulomas can manifest in various specific infections including tuberculosis and Yersinia, as well as in a range of diseases characterized by macrophage reactions such as sarcoidosis and drug-induced enteritis. Granulomas associated with CD typically do not exhibit necrosis. However, the formation of caseous granulomas may occur as a result of secondary infections related to anti-CD drug treatment or perforation of the intestinal wall. CASE PRESENTATION In this study, we present a case of a 28-year-old female patient diagnosed with CD exhibiting histologic granulomas, including both caseating and non-caseating forms, which demonstrated a positive response to medical treatment. CONCLUSION In clinical practice, various forms of granulomas may indicate diverse underlying diseases, yet lack specificity. It is suggested that the presence of caseous granulomas should not be considered as a definitive exclusion criterion for the diagnosis when clinical, endoscopic, imaging and other histopathological features are consistent with CD. This study is the first report of caseous granulomas in CD without concomitant tuberculosis infection.
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Affiliation(s)
- Siqi Tao
- Department of Pathology, The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, China
| | - Yan Chen
- Center for Inflammatory Bowel Disease, Department of Gastroenterology, The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, China
| | - Wen Hu
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, National Clinical Research Center for Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, National Medical Center for Infectious Diseases, Zhejiang University School of Medicine, Hangzhou, Zhejiang, China
| | - Keren Shen
- Department of Radiology, The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, China
| | - Jinghong Xu
- Department of Pathology, The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, China.
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2
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Li X, Paccoud O, Chan KH, Yuen KY, Manchon R, Lanternier F, Slavin MA, van de Veerdonk FL, Bicanic T, Lortholary O. Cryptococcosis Associated With Biologic Therapy: A Narrative Review. Open Forum Infect Dis 2024; 11:ofae316. [PMID: 38947739 PMCID: PMC11212009 DOI: 10.1093/ofid/ofae316] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/05/2024] [Accepted: 06/17/2024] [Indexed: 07/02/2024] Open
Abstract
Cryptococcus is an opportunistic fungal pathogen that can cause disseminated infection with predominant central nervous system involvement in patients with compromised immunity. Biologics are increasingly used in the treatment of neoplasms and autoimmune/inflammatory conditions and the prevention of transplant rejection, which may affect human defense mechanisms against cryptococcosis. In this review, we comprehensively investigate the association between cryptococcosis and various biologics, highlighting their risks of infection, clinical manifestations, and clinical outcomes. Clinicians should remain vigilant for the risk of cryptococcosis in patients receiving biologics that affect the Th1/macrophage activation pathways, such as tumor necrosis factor α antagonists, Bruton tyrosine kinase inhibitors, fingolimod, JAK/STAT inhibitors (Janus kinase/signal transducer and activator of transcription), and monoclonal antibody against CD52. Other risk factors-such as age, underlying condition, and concurrent immunosuppressants, especially corticosteroids-should also be taken into account during risk stratification.
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Affiliation(s)
- Xin Li
- Department of Infectious Diseases and Tropical Medicine, Université Paris Cité, Necker-Enfants Malades University Hospital, Assistance Publique–Hôpitaux de Paris, IHU Imagine, Paris, France
- Department of Microbiology, School of Clinical Medicine, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Pokfulam, Hong Kong SAR, China
| | - Olivier Paccoud
- Department of Infectious Diseases and Tropical Medicine, Université Paris Cité, Necker-Enfants Malades University Hospital, Assistance Publique–Hôpitaux de Paris, IHU Imagine, Paris, France
| | - Koon-Ho Chan
- Department of Medicine, School of Clinical Medicine, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Pokfulam, Hong Kong SAR, China
| | - Kwok-Yung Yuen
- Department of Microbiology, School of Clinical Medicine, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Pokfulam, Hong Kong SAR, China
| | - Romain Manchon
- Department of Infectious Diseases and Tropical Medicine, Université Paris Cité, Necker-Enfants Malades University Hospital, Assistance Publique–Hôpitaux de Paris, IHU Imagine, Paris, France
| | - Fanny Lanternier
- Department of Infectious Diseases and Tropical Medicine, Université Paris Cité, Necker-Enfants Malades University Hospital, Assistance Publique–Hôpitaux de Paris, IHU Imagine, Paris, France
- Institut Pasteur, National Reference Center for Invasive Mycoses and Antifungals, Mycology Translational Research Group, Mycology Department, Université Paris Cité, Paris, France
| | - Monica A Slavin
- Department of Infectious Diseases, Peter MacCallum Cancer Centre, Melbourne, Australia
- Sir Peter MacCallum Department of Oncology, University of Melbourne, Melbourne, Australia
- Victorian Infectious Diseases Service, Royal Melbourne Hospital, Melbourne, Australia
| | - Frank L van de Veerdonk
- Department of Internal Medicine, Radboud Center for Infectious Diseases, Radboudumc, Nijmegen, the Netherlands
| | - Tihana Bicanic
- Institute of Infection and Immunity, St George's University of London, London, UK
| | - Olivier Lortholary
- Department of Infectious Diseases and Tropical Medicine, Université Paris Cité, Necker-Enfants Malades University Hospital, Assistance Publique–Hôpitaux de Paris, IHU Imagine, Paris, France
- Institut Pasteur, National Reference Center for Invasive Mycoses and Antifungals, Mycology Translational Research Group, Mycology Department, Université Paris Cité, Paris, France
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A rare localization of tuberculosis under infliximab treatment: Testicular involvement. Turk J Phys Med Rehabil 2021; 67:374-377. [PMID: 34870127 PMCID: PMC8607004 DOI: 10.5606/tftrd.2021.5135] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/06/2019] [Accepted: 12/27/2019] [Indexed: 11/21/2022] Open
Abstract
Infliximab is an inhibitory of tumor necrosis factor-alpha which is used successfully for the treatment of inflammatory bowel disease and rheumatic disease. It has various side effects including injection-induced reactions, immunosuppression, demyelinating diseases, and cardiac effects. One of the most serious side effects is tuberculosis. In particular, the immunosuppressant drugs have a high risk of reactivating latent tuberculosis infection. Its activation probably may occur as an extra-pulmonary and, occasionally, may result in an unusual infection. Herein, we report a 30-year-old male case treated with infliximab and suffered from isolated testicular tuberculosis.
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4
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Marques E, Paluch Z, Boháč P, Slanař O, Běláček J, Hercogová J. The safety profile of biologic agents in comparison with non-biologic systemic agents, and topical compounds in the management of psoriasis-A 30-month prospective, observational cohort study. Int J Clin Pract 2021; 75:e14915. [PMID: 34551188 DOI: 10.1111/ijcp.14915] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/08/2021] [Revised: 09/18/2021] [Accepted: 09/21/2021] [Indexed: 11/29/2022] Open
Abstract
BACKGROUND Although biologic agents (BAs) are very effective, solid data proving they are safer than other therapies in psoriasis are still lacking. METHODS A total of 289 psoriatic patients were followed for 30 months; of which number 118 were treated with topical agents alone, 112 received BAs, and the remaining 59 patients were on non-biologic systemic agents (NBSAs). The rates of adverse events in these groups were recorded and statistically analysed. RESULTS Patients treated with BAs had higher rates of adverse events (P = .017), including overall infections (P = .003), respiratory infections (P < .001), renal, urinary (P < .001), musculoskeletal, connective tissue (P < .001, and P = .021) and oral cavity-related (P = .046) disorders. Except for the incidence of infections, all the above adverse events occurred more often in our study than in clinical trials. The occurrence of serious adverse events was P = .066, with the incidence of serious infections being P = .164. Unlike patients on topical therapy and NBSAs, patients treated with BAs were forced to discontinue their therapies (P = .001). The Psoriasis Area Severity Index (PASI) and body surface area (BSA) scores were the lowest among patients on BAs. CONCLUSION While BAs were the most effective therapies, they were associated with higher rates of treatment discontinuation and adverse events in comparison with other forms of therapy.
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Affiliation(s)
- Emanuel Marques
- Department of Dermatovenereology, Third Faculty of Medicine, Charles University and Králosvské Vinohrady University Hospital, Prague, Czech Republic
- Department of Pharmacology, Second Faculty of Medicine, Charles University, Prague, Czech Republic
| | - Zoltán Paluch
- Department of Pharmacology, Second Faculty of Medicine, Charles University, Prague, Czech Republic
- St. John Nepomucene Neumann Institute, Příbram, Czech Republic, St. Elisabeth University of Health Care and Social Work, Bratislava, Slovak Republic
| | - Petr Boháč
- Department of Dermatovenerology, Second Faculty of Medicine, Charles University and Bulovka University Hospital, Prague, Czech Republic
| | - Ondřej Slanař
- Department of Pharmacology, First Faculty of Medicine, Charles University, Prague, Czech Republic
| | - Jaromír Běláček
- Department of Statistics and Operation Analysis, Faculty of Business and Economics of Brno, Mendel University in Brno, Brno, Czech Republic
| | - Jana Hercogová
- Department of Dermatovenerology, Second Faculty of Medicine, Charles University and Bulovka University Hospital, Prague, Czech Republic
- Department of Dermatovenerology, Second Faculty of Medicine, Charles University, Prague, Czech Republic
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Athimni S, Slouma M, Dhahri R, Gharsallah I, Metouia L, Louzir B. Tuberculosis infection under anti-TNF alpha treatment. Curr Drug Saf 2021; 17:235-240. [PMID: 34751125 DOI: 10.2174/1574886316666211109092354] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/03/2021] [Revised: 06/15/2021] [Accepted: 08/29/2021] [Indexed: 11/22/2022]
Abstract
BACKGROUND Anti-tumor necrosis factor-α (TNF-α) is a life-changing treatment leading to quality-of-life improvement. Nonetheless, this treatment is associated with a high risk of infection, especially tuberculosis. OBJECTIVE Our study aimed to determine the frequency of active tuberculosis in our patients with chronic rheumatic disease and treated with TNF-α. METHODS We conducted a retrospective study including patients with Rheumatoid Arthritis and Spondylarthritis diagnosed according to ACR/EULAR 2009 criteria and ASAS 2010, respectively, and treated with biological agents for at least 6 months. We collected data regarding tuberculosis screening and the occurrence of active tuberculosis during follow-up. RESULTS 82 patients were included (37 men and 45 women). The mean age was 42 ± 3.4 years. At inclusion, no patient had a medical history of tuberculosis. The diagnosis of latent tuberculosis infection was established in 17 patients (20.7%). Prophylactic treatment was prescribed in all these cases for three months. Two cases (2.4%) of active tuberculosis occurred under biologic (infliximab). It was two severe forms of tuberculosis. The first case had miliary tuberculosis associated with hepatic and peritoneal involvement. The second one had pleural tuberculosis. These two patients received anti-tuberculosis therapy, and the biological treatment was interrupted. Given the high disease activity, the anti-TNF-α was restarted after 3 and 4 months. There was no recurrence of tuberculosis after 7 years of follow-up. CONCLUSION The use of TNF-α blockers is associated with a risk of disseminated forms of tuberculosis. Tuberculosis screening, which is recommended before the biological onset, is also necessary under this treatment. Restarting the anti-TNF-α after appropriate treatment of tuberculosis seemed to be safe. .
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Affiliation(s)
- Salma Athimni
- Department of Rheumatology, Military Hospital, Faculty of Medicine, University Manar, Tunis. Tunisia
| | - Maroua Slouma
- Department of Rheumatology, Military Hospital, Faculty of Medicine, University Manar, Tunis. Tunisia
| | - Rim Dhahri
- Department of Rheumatology, Military Hospital, Faculty of Medicine, University Manar, Tunis. Tunisia
| | - Imen Gharsallah
- Department of Rheumatology, Military Hospital, Faculty of Medicine, University Manar, Tunis. Tunisia
| | - Leila Metouia
- Department of Rheumatology, Military Hospital, Faculty of Medicine, University Manar, Tunis. Tunisia
| | - Bassem Louzir
- Department of Internal Medicine Department, Military Hospital, Faculty of Medicine, University Manar, Tunis . Tunisia
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Screening for latent tuberculosis before starting TNF-alpha inhibitors in a population with high BCG vaccination rates. Rheumatol Int 2021; 42:1443-1451. [PMID: 34228162 DOI: 10.1007/s00296-021-04926-z] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/12/2021] [Accepted: 06/14/2021] [Indexed: 10/20/2022]
Abstract
It is assumed that in candidates for TNF-alpha inhibitor (TNFi) treatment, tuberculin skin test (TST) may be unreliable, since BCG vaccination causes false positive and drugs cause false negative results, favoring the use of Quantiferon or T-spot assays. However, these tests may not be readily available in all parts of the world. We aimed to determine the reliability of TST with respect to BCG vaccination and drugs in candidates for TNFi treatment, and how isoniazid is tolerated, assuming that the use of TST would result in increased isoniazid use. We included 1031 adult patients who were prescribed a TNFi for the first time. We analysed the association of BCG and drugs with TST and Quantiferon results, the determinants of a positive TST, and evaluated the tolerability of isoniazid. BCG vaccination and male sex were associated with positive TST (OR 3.56, 95% CI 1.98-6.41 and OR 2.54, 95% CI 1.75-3.68, respectively), while prednisolone and azathioprine were associated with negative TST (OR 0.63, 95% CI 0.43-0.91 and OR 0.40, 95% CI 0.11-0.76). Isoniazid was prescribed to 684 (66.3%) patients and had to be discontinued in 12.2% of these before 9 months, most commonly due to hepatotoxicity (44%). One patient developed tuberculosis despite isoniazid use. BCG vaccination may be associated with false positive TST, despite a long time since vaccination in candidates for TNFi treatment. Prednisolone and azathioprine use were associated with negative TST. Despite the high frequency of isoniazid use associated with using TST instead of QTF, isoniazid was generally well tolerated.
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7
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Yamana H, Iba A, Tomio J, Ono S, Jo T, Yasunaga H. Treatment of latent tuberculosis infection in patients receiving biologic agents. J Infect Chemother 2020; 27:243-249. [PMID: 33036893 DOI: 10.1016/j.jiac.2020.09.028] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/20/2020] [Revised: 08/31/2020] [Accepted: 09/24/2020] [Indexed: 11/16/2022]
Abstract
INTRODUCTION Treatment of latent tuberculosis infection is recommended in patients receiving biologics. However, evidence is weak regarding the efficacy of treatment regimens in this population, and the real-world practice pattern has not been elucidated. METHODS Using a large-scale health insurance claims database in Japan, we identified patients who started treatment of immune-mediated inflammatory diseases with tumor necrosis factor inhibitors or other biologics. Treatment with isoniazid within 12 months of starting a biologic was summarized to evaluate the duration of treatment for latent tuberculosis infection and the time between start of isoniazid and initiation of a biologic. RESULTS Among 2064 patients starting biologics, 10% received treatment for latent tuberculosis infection with isoniazid. Among the patients with biologics and isoniazid, isoniazid was started in the same month as initiating biologics or 1 month before in 82%. In addition to the recommended 6- and 9-month treatments, 20% of patients were receiving isoniazid at 12 months after starting treatment and 20% received a prescription for 350 days or more. CONCLUSIONS In patients starting biologics, treatment for latent tuberculosis infection was provided for different durations, including not only the recommended periods but also longer periods. Research on safety and effectiveness of the treatment in this population is necessary.
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Affiliation(s)
- Hayato Yamana
- Department of Health Services Research, Graduate School of Medicine, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo, 113-0033, Japan.
| | - Arisa Iba
- Department of Public Health, Graduate School of Medicine, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo, 113-0033, Japan
| | - Jun Tomio
- Department of Public Health, Graduate School of Medicine, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo, 113-0033, Japan
| | - Sachiko Ono
- Department of Eat-loss Medicine, Graduate School of Medicine, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo, 113-0033, Japan
| | - Taisuke Jo
- Department of Health Services Research, Graduate School of Medicine, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo, 113-0033, Japan
| | - Hideo Yasunaga
- Department of Clinical Epidemiology and Health Economics, School of Public Health, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo, 113-0033, Japan
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8
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Li X, Lau SK, Woo PC. Fungal infection risks associated with the use of cytokine antagonists and immune checkpoint inhibitors. Exp Biol Med (Maywood) 2020; 245:1104-1114. [PMID: 32640893 DOI: 10.1177/1535370220939862] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022] Open
Abstract
IMPACT STATEMENT The risk of opportunistic infections due to fungi is relatively less well addressed in patients receiving biologic agents, compared with other opportunistic bacterial and viral infections. There is a lack of consensus guideline on the screening, prophylaxis, and management of fungal infection in patients anticipated to receive or actively receiving biologic therapy. In addition, invasive mycosis in immunocompromised patients is associated with high mortality and morbidity. This review highlighted the risk of fungal infection in patients receiving cytokine antagonists and immune checkpoint inhibitors, two big categories of biologic agents that are widely used in the treatment of various autoimmune and malignant conditions, often in combination with other immunomodulatory or immunosuppressive agents but also as standalone therapy. The adverse outcomes of opportunistic fungal infection in these patients can be reduced by heightened awareness, active case finding, and prompt treatment.
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Affiliation(s)
- Xin Li
- Department of Microbiology, The University of Hong Kong, Hong Kong
| | - Susanna Kp Lau
- Department of Microbiology, The University of Hong Kong, Hong Kong.,State Key Laboratory of Emerging Infectious Diseases, The University of Hong Kong, Hong Kong.,Collaborative Innovation Centre for Diagnosis and Treatment of Infectious Diseases, The University of Hong Kong, Hong Kong
| | - Patrick Cy Woo
- Department of Microbiology, The University of Hong Kong, Hong Kong.,State Key Laboratory of Emerging Infectious Diseases, The University of Hong Kong, Hong Kong.,Collaborative Innovation Centre for Diagnosis and Treatment of Infectious Diseases, The University of Hong Kong, Hong Kong
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9
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Abstract
Biologic drugs have revolutionized the treatment of certain hematologic, autoimmune, and malignant diseases, but they may place patients at risk for reactivation or acquisition of tuberculosis. This risk is highest with the tumor necrosis factor-alpha (TNF-α) inhibitors. Amongst this class of drugs, the monoclonal antibodies (infliximab, adalimumab, golimumab) and antibody fragment (certolizumab) carry an increased risk compared to the soluble receptor fusion molecule, etanercept. Treatment of latent TB is critical to decrease the risk of reactivation. Data continues to emerge regarding tuberculosis risk associated with novel biologics targeting cytokines involved in tuberculosis control.
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10
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Safety results of ixekizumab with 1822.2 patient-years of exposure: an integrated analysis of 3 clinical trials in adult patients with psoriatic arthritis. Arthritis Res Ther 2020; 22:14. [PMID: 31964419 PMCID: PMC6975022 DOI: 10.1186/s13075-020-2099-0] [Citation(s) in RCA: 28] [Impact Index Per Article: 5.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/03/2019] [Accepted: 01/09/2020] [Indexed: 02/08/2023] Open
Abstract
Background The long-term safety was assessed in patients with psoriatic arthritis who were treated with ixekizumab in three clinical trials (SPIRIT-P1/-P2/-P3). Methods Integrated safety data from three trials (controlled and uncontrolled), including two pivotal phase 3, randomized, double-blind clinical trials: SPIRIT-P1 and SPIRIT-P2, were assessed. Safety data were integrated from the all ixekizumab exposure safety population (defined as all patients receiving ≥ 1 dose of ixekizumab). We report exposure-adjusted incidence rates (IRs) per 100 patient-years (PY) at 1-year intervals up to 3 years for adverse events. Results Total exposure to IXE reached 1822.2 PY (1118 patients). The IRs/100 PY for the following treatment discontinuations were as follows: adverse events (5.3); serious infections (1.3); injection-site reactions (12.7); infections (34.2); and deaths (0.3). The IRs for treatment-emergent adverse events decreased or remained stable over time, the most common being upper respiratory tract infection, nasopharyngitis, and injection-site reactions. The IRs for serious adverse events and serious infections remained stable over time, whereas for injection-site reactions and general infections, IRs decreased with longer ixekizumab exposure. Opportunistic infections were limited to oral and esophageal candida and localized herpes zoster. No suicide or self-injury-related behaviors were reported. The IRs/100 PY for safety topics of special interest included inflammatory bowel disease (adjudicated; 0.1), depression (1.6), malignancies (0.7), and major adverse cardiovascular events (0.6). Conclusions The findings of this integrated safety analysis in patients with psoriatic arthritis are consistent with the known safety profile of ixekizumab. No unexpected safety signals were observed with ixekizumab treatment in patients with psoriatic arthritis. Trial registration SPIRIT-P1 (NCT01695239; Registered August 08, 2012), SPIRIT-P2 (NCT02349295; September 23, 2014), and SPIRIT-P3 (NCT02584855; August 04, 2015).
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11
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Mezouar S, Diarra I, Roudier J, Desnues B, Mege JL. Tumor Necrosis Factor-Alpha Antagonist Interferes With the Formation of Granulomatous Multinucleated Giant Cells: New Insights Into Mycobacterium tuberculosis Infection. Front Immunol 2019; 10:1947. [PMID: 31475008 PMCID: PMC6702871 DOI: 10.3389/fimmu.2019.01947] [Citation(s) in RCA: 26] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/12/2019] [Accepted: 08/01/2019] [Indexed: 12/21/2022] Open
Abstract
More than half of tuberculosis cases in the world are due to resuscitation of dormant Mycobacterium tuberculosis (Mtb) sequestered into cell-derived structures called granulomas. It is fairly admitted that cytokines and more particularly Tumor Necrosis Factor (TNF)-α is critical in the control of Mtb infections and that anti-TNF-α drugs constitute one of the main risk factors for reactivation of latent Mtb infection. The aim of this study was to evaluate the role of etanercept, a dimeric fusion protein consisting of the extracellular ligand-binding portion of the human p75 TNF receptor linked to the Fc portion of human IgG1, in an in vitro model of human tuberculous granuloma. We showed that etanercept slightly delayed the formation of granuloma and reduced the generation of multinuclear giant cells (MGCs). In addition, etanercept exacerbated the expression of M1 polarization genes but also induced interleukin (IL)-10 release. In addition, our results indicated that etanercept inhibited cell fusion in an IL-10-dependent manner. Moreover, adalimumab, a human monoclonal anti-TNF-α IgG1 inhibited MGC formation in granuloma, without altering IL-10 secretion and induced macrophage apoptosis. Taken together, our data provides new insights into the role of TNF-α blockers in MGCs formation and the impact of such immunomodulatory drugs on tuberculous granuloma maturation.
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Affiliation(s)
- Soraya Mezouar
- Aix-Marseille Université, IRD, APHM, MEPHI, Marseille, France.,IHU-Méditerranée Infection, Marseille, France
| | - Issa Diarra
- Aix-Marseille Université, IRD, APHM, MEPHI, Marseille, France.,IHU-Méditerranée Infection, Marseille, France
| | - Jean Roudier
- Department of Rheumatology, Institut du Mouvement et de l'appareil Locomoteur, APHM, Marseille, France
| | - Benoit Desnues
- Aix-Marseille Université, IRD, APHM, MEPHI, Marseille, France.,IHU-Méditerranée Infection, Marseille, France
| | - Jean-Louis Mege
- Aix-Marseille Université, IRD, APHM, MEPHI, Marseille, France.,IHU-Méditerranée Infection, Marseille, France.,APHM, IHU Méditerranée Infection, UF Immunologie, Marseille, France
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12
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Holroyd CR, Seth R, Bukhari M, Malaviya A, Holmes C, Curtis E, Chan C, Yusuf MA, Litwic A, Smolen S, Topliffe J, Bennett S, Humphreys J, Green M, Ledingham J. The British Society for Rheumatology biologic DMARD safety guidelines in inflammatory arthritis. Rheumatology (Oxford) 2018; 58:e3-e42. [DOI: 10.1093/rheumatology/key208] [Citation(s) in RCA: 64] [Impact Index Per Article: 9.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/07/2018] [Indexed: 12/31/2022] Open
Affiliation(s)
- Christopher R Holroyd
- Rheumatology Department, University Hospital Southampton NHS Foundation Trust, Southampton, UK
| | - Rakhi Seth
- Rheumatology Department, University Hospital Southampton NHS Foundation Trust, Southampton, UK
| | - Marwan Bukhari
- Rheumatology Department, University Hospitals of Morecombe Bay NHS Foundation Trust, Lancaster, UK
| | - Anshuman Malaviya
- Rheumatology Department, Mid Essex hospitals NHS Trust, Chelmsford, UK
| | - Claire Holmes
- Rheumatology Department, University Hospital Southampton NHS Foundation Trust, Southampton, UK
| | - Elizabeth Curtis
- MRC Lifecourse Epidemiology Unit, University of Southampton, Southampton, UK
| | - Christopher Chan
- Rheumatology Department, University Hospital Southampton NHS Foundation Trust, Southampton, UK
| | - Mohammed A Yusuf
- Rheumatology Department, Mid Essex hospitals NHS Trust, Chelmsford, UK
| | - Anna Litwic
- MRC Lifecourse Epidemiology Unit, University of Southampton, Southampton, UK
- Rheumatology Department, Salisbury District Hospital, Salisbury, UK
| | - Susan Smolen
- Rheumatology Department, Mid Essex hospitals NHS Trust, Chelmsford, UK
| | - Joanne Topliffe
- Rheumatology Department, Mid Essex hospitals NHS Trust, Chelmsford, UK
| | - Sarah Bennett
- Rheumatology Department, University Hospital Southampton NHS Foundation Trust, Southampton, UK
| | - Jennifer Humphreys
- Arthritis Research UK Centre for Epidemiology, University of Manchester, Manchester, UK
| | - Muriel Green
- National Rheumatoid Arthritis Society, Queen Alexandra Hospital, Portsmouth, UK
| | - Jo Ledingham
- Rheumatology Department, Queen Alexandra Hospital, Portsmouth, UK
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13
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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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Frieder J, Kivelevitch D, Fiore CT, Saad S, Menter A. The impact of biologic agents on health-related quality of life outcomes in patients with psoriasis. Expert Rev Clin Immunol 2017; 14:1-19. [PMID: 29110556 DOI: 10.1080/1744666x.2018.1401468] [Citation(s) in RCA: 20] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/13/2023]
Abstract
INTRODUCTION Psoriasis is a common, immune-mediated skin disease often associated with significant physical and psychosocial impairment. Antipsoriatic biologic agents offer patients unparalleled treatment potential in regard to greater skin clearance and overall improved quality of life. Evaluation of the therapeutic efficacy of biologic agents on the full psoriasis disease burden must account for their impact on both physical symptoms, as well as patient-reported, health-related quality of life (HRQoL) measurements. Areas covered: Results from numerous clinical trials demonstrate the significant clinical efficacy of biological agents targeting tumor necrosis factor-α (TNF-α) and the interleukin (IL)-12/23 and IL-17 immune pathways. However, relatively limited data is available evaluating their full effect on quality of life outcomes. This review will discuss the most relevant and up-to-date clinical data on HRQoL measurements related to treatment with these aforementioned biologic agents. Expert commentary: Patient-reported outcomes (i.e. Dermatology Life Quality Index) are being used with increasing frequency in clinical trials, and provide valuable information on the impact of psoriasis on numerous aspects of day-to-day living. These outcomes must also be incorporated in clinical practice, in addition to physical assessment of disease severity, treatment decisions, and therapeutic response in the psoriasis patient population.
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Affiliation(s)
- Jillian Frieder
- a Division of Dermatology , Baylor University Medical Center , Dallas , TX , USA
| | - Dario Kivelevitch
- a Division of Dermatology , Baylor University Medical Center , Dallas , TX , USA
| | - Connie Tran Fiore
- a Division of Dermatology , Baylor University Medical Center , Dallas , TX , USA
| | - Saadeddine Saad
- b Texas A&M Health Science Center College of Medicine , Bryan , TX , USA
| | - Alan Menter
- a Division of Dermatology , Baylor University Medical Center , Dallas , TX , USA
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Cagatay T, Bingol Z, Kıyan E, Yegin Z, Okumus G, Arseven O, Erkan F, Gulbaran Z, Erelel M, Ece T, Cagatay P, Kılıçaslan Z. Follow‐up of 1887 patients receiving tumor necrosis‐alpha antagonists: Tuberculin skin test conversion and tuberculosis risk. CLINICAL RESPIRATORY JOURNAL 2017; 12:1668-1675. [DOI: 10.1111/crj.12726] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Received: 05/16/2017] [Revised: 09/03/2017] [Accepted: 10/08/2017] [Indexed: 11/30/2022]
Affiliation(s)
- Tulin Cagatay
- Department of Pulmonary, Istanbul Medical Faculty, Istanbul UniversityIstanbul Turkey
| | - Zuleyha Bingol
- Department of Pulmonary, Istanbul Medical Faculty, Istanbul UniversityIstanbul Turkey
| | - Esen Kıyan
- Department of Pulmonary, Istanbul Medical Faculty, Istanbul UniversityIstanbul Turkey
| | - Zeynep Yegin
- Department of Pulmonary, Istanbul Medical Faculty, Istanbul UniversityIstanbul Turkey
| | - Gulfer Okumus
- Department of Pulmonary, Istanbul Medical Faculty, Istanbul UniversityIstanbul Turkey
| | - Orhan Arseven
- Department of Pulmonary, Istanbul Medical Faculty, Istanbul UniversityIstanbul Turkey
| | - Feyza Erkan
- Department of Pulmonary, Istanbul Medical Faculty, Istanbul UniversityIstanbul Turkey
| | - Ziya Gulbaran
- Department of Pulmonary, Istanbul Medical Faculty, Istanbul UniversityIstanbul Turkey
| | - Mustafa Erelel
- Department of Pulmonary, Istanbul Medical Faculty, Istanbul UniversityIstanbul Turkey
| | - Turhan Ece
- Department of Pulmonary, Istanbul Medical Faculty, Istanbul UniversityIstanbul Turkey
| | - Penbe Cagatay
- High School of Health Care Professions Biostatistic, Istanbul UniversityIstanbul Turkey
| | - Zeki Kılıçaslan
- Department of Pulmonary, Istanbul Medical Faculty, Istanbul UniversityIstanbul Turkey
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Disseminated cryptococcosis in a patient taking tocilizumab for Castleman's disease. J Infect Chemother 2017; 24:138-141. [PMID: 29021093 DOI: 10.1016/j.jiac.2017.09.009] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/09/2017] [Revised: 09/12/2017] [Accepted: 09/14/2017] [Indexed: 01/10/2023]
Abstract
Infections occur more frequently in patients receiving biologics. However, cryptococcal infection is uncommon in patients receiving tocilizumab, an interleukin-6 inhibitor, in contrast to patients receiving tumor necrosis factor-α inhibitors. In this report, we describe a case of disseminated cryptococcosis in a 55-year-old man who was receiving tocilizumab every 2 weeks along with daily prednisolone and cyclosporine for Castleman's disease. He initially developed cellulitis on both upper limbs, and his condition worsened despite antibacterial therapy. Chest X-ray scanning and computed tomography demonstrated bilateral pulmonary infiltration. Cryptococcus neoformans was detected in blood, skin, and sputum cultures. He was diagnosed with disseminated cryptococcosis, and successfully treated with liposomal amphotericin B for a week followed by oral fluconazole for 11 months. The findings of this study indicate that cryptococcosis should be considered during the differential diagnosis of infection in patients receiving tocilizumab, especially in the presence of other risk factors for infections or a short tocilizumab dosing interval.
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Lee EH, Kang YA, Leem AY, Park MS, Kim YS, Kim SK, Chang J, Kim SY. Active Tuberculosis Incidence and Characteristics in Patients Treated with Tumor Necrosis Factor Antagonists According to Latent Tuberculosis Infection. Sci Rep 2017; 7:6473. [PMID: 28743918 PMCID: PMC5526863 DOI: 10.1038/s41598-017-06899-1] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/26/2017] [Accepted: 06/20/2017] [Indexed: 11/24/2022] Open
Abstract
This study aimed to determine the incidence and characteristics of active tuberculosis (TB) in patients treated with tumor necrosis factor (TNF) antagonists according to baseline latent tuberculosis infection (LTBI). Data were retrospectively obtained from 702 patients aged ≥20 years treated with TNF antagonists between November 2005 and June 2016 at Severance Hospital, a tertiary referral hospital in Seoul, South Korea. The interferon-gamma release assay (IGRA) with or without a tuberculin skin test (TST) was used to diagnose LTBI. Of the total of 702 patients, LTBI was diagnosed in 255 (36.3%) patients. 23.9% (168/702) had positive IGRA results, and 32.2% (165/512) had positive TST results. Five patients developed active TB after LTBI treatment, and 6 developed TB despite baseline negative LTBI results. After adjustment for age and sex, the standardized TB incidence ratio was 6.01 (95% CI 1.94–14.04) in the LTBI group and 5.14 (95% CI 1.88–11.18) in the baseline negative LTBI group. Clinicians should be aware of the risk of active TB in patients treated with TNF antagonists despite baseline negative LTBI screening results. Regular monitoring and serial tests should be considered during long-term TNF antagonist therapy, especially in intermediate to high TB burden country.
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Affiliation(s)
- Eun Hye Lee
- Division of Pulmonology, Department of Internal Medicine, Institute of Chest Diseases, Severance Hospital, Yonsei University College of Medicine, Seoul, Republic of Korea
| | - Young Ae Kang
- Division of Pulmonology, Department of Internal Medicine, Institute of Chest Diseases, Severance Hospital, Yonsei University College of Medicine, Seoul, Republic of Korea
| | - Ah Young Leem
- Division of Pulmonology, Department of Internal Medicine, Institute of Chest Diseases, Severance Hospital, Yonsei University College of Medicine, Seoul, Republic of Korea
| | - Moo Suk Park
- Division of Pulmonology, Department of Internal Medicine, Institute of Chest Diseases, Severance Hospital, Yonsei University College of Medicine, Seoul, Republic of Korea
| | - Young Sam Kim
- Division of Pulmonology, Department of Internal Medicine, Institute of Chest Diseases, Severance Hospital, Yonsei University College of Medicine, Seoul, Republic of Korea
| | - Se Kyu Kim
- Division of Pulmonology, Department of Internal Medicine, Institute of Chest Diseases, Severance Hospital, Yonsei University College of Medicine, Seoul, Republic of Korea
| | - Joon Chang
- Division of Pulmonology, Department of Internal Medicine, Institute of Chest Diseases, Severance Hospital, Yonsei University College of Medicine, Seoul, Republic of Korea
| | - Song Yee Kim
- Division of Pulmonology, Department of Internal Medicine, Institute of Chest Diseases, Severance Hospital, Yonsei University College of Medicine, Seoul, Republic of Korea.
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Iwata K, Oka S, Tsuno H, Furukawa H, Shimada K, Hashimoto A, Komiya A, Tsuchiya N, Katayama M, Tohma S. Biomarker for nontuberculous mycobacterial pulmonary disease in patients with rheumatoid arthritis: Anti-glycopeptidolipid core antigen immunoglobulin A antibodies. Mod Rheumatol 2017; 28:271-275. [DOI: 10.1080/14397595.2017.1336866] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/19/2022]
Affiliation(s)
- Kanako Iwata
- Clinical Research Center for Allergy and Rheumatology, Sagamihara National Hospital, National Hospital Organization, Kanagawa, Japan
| | - Shomi Oka
- Clinical Research Center for Allergy and Rheumatology, Sagamihara National Hospital, National Hospital Organization, Kanagawa, Japan
- Molecular and Genetic Epidemiology Laboratory, Faculty of Medicine, University of Tsukuba, Ibaraki, Japan
| | - Hirotaka Tsuno
- Department of Rheumatology, Sagamihara National Hospital, National Hospital Organization, Kanagawa, Japan
| | - Hiroshi Furukawa
- Clinical Research Center for Allergy and Rheumatology, Sagamihara National Hospital, National Hospital Organization, Kanagawa, Japan
- Molecular and Genetic Epidemiology Laboratory, Faculty of Medicine, University of Tsukuba, Ibaraki, Japan
| | - Kota Shimada
- Department of Rheumatology, Sagamihara National Hospital, National Hospital Organization, Kanagawa, Japan
- Department of Rheumatic Diseases, Tokyo Metropolitan Tama Medical Center, Tokyo, Japan
| | - Atsushi Hashimoto
- Department of Rheumatology, Sagamihara National Hospital, National Hospital Organization, Kanagawa, Japan
| | - Akiko Komiya
- Clinical Research Center for Allergy and Rheumatology, Sagamihara National Hospital, National Hospital Organization, Kanagawa, Japan
| | - Naoyuki Tsuchiya
- Molecular and Genetic Epidemiology Laboratory, Faculty of Medicine, University of Tsukuba, Ibaraki, Japan
| | - Masao Katayama
- Department of Internal Medicine, Nagoya Medical Center, National Hospital Organization, Aichi, Japan
| | - Shigeto Tohma
- Clinical Research Center for Allergy and Rheumatology, Sagamihara National Hospital, National Hospital Organization, Kanagawa, Japan
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Abstract
ABSTRACT
Treatment with biologic agents, in particular tumor necrosis factor alpha (TNF-α) inhibitors, is associated with an increased risk of tuberculosis (TB), and screening and treatment for latent TB infection (LTBI) in patients undergoing such treatment is therefore indicated. The risk of TB associated with different biologics varies significantly, with the highest relative risks, 29.3 and 18.6, associated with adalimumab and infliximab, respectively. The risk of TB with newer TNF-α inhibitors and other biologics appears to be lower. Performance of LTBI screening tests is affected by immune-mediated inflammatory diseases and immunosuppressive therapy in patients due to commence TNF-α inhibitor treatment. Interferon gamma release assays (IGRAs) have a higher specificity than the tuberculin skin test (TST) in patients with Bacillus Calmette–Guérin (BCG) vaccination and have probably a better sensitivity than TST in immunosuppressed patients. LTBI screening programs prior to commencement of anti-TNF-α treatment significantly reduce the incidence of TB, but the optimal screening algorithm, in particular the question of whether a combination of IGRA and TST or a single test only should be used, is a matter of ongoing debate. Use of TST in combination with IGRA is justified to increase sensitivity. Repeat testing for LTBI should be limited to patients at increased risk of TB. If TB develops during anti-TNF-α treatment, it is more likely to be disseminated and extrapulmonary than are other TB cases. Discontinuation of anti-TNF-α treatment in patients diagnosed with TB is associated with an increased risk of immune reconstitution inflammatory syndrome, which is probably best managed by reintroduction of anti-TNF-α treatment.
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Abstract
Many of the molecular pathways associated with psoriasis pathogenesis are also involved in host defense mechanisms that protect against common pathogens. Candida can stimulate the production of cytokines that trigger or exacerbate psoriasis, and many systemic psoriasis treatments may put patients at increased risk for developing oral, cutaneous, and genitourinary candidiasis. Therefore, dermatologists should regularly screen patients with psoriasis for signs of Candida infection, and take steps to effectively treat these infections to prevent worsening of psoriasis symptoms. This review provides an overview of candidiasis epidemiology in patients with psoriasis, followed by a primer on the diagnosis and treatment of superficial Candida infections, with specific guidance for patients with psoriasis. Candidiasis in patients with psoriasis typically responds to topical or oral antifungal therapy. While biologic agents used to treat moderate-to-severe psoriasis, such as tumor necrosis factor-α inhibitors and interleukin-17 inhibitors, are known to increase patients’ risk of developing localized candidiasis, the overall risk of infection is low, and candidiasis can be effectively managed in most patients while receiving systemic psoriasis therapies. Thus, the development of candidiasis does not usually necessitate changes to psoriasis treatment regimens.
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Abstract
Treatment of sarcoidosis is not required in all patients with the diagnosis. The decision to treat and the strategy for how to treat usually require input and shared decision making by the patient. Some common consequences of sarcoidosis are not caused by granulomatous inflammation, but may be the dominant disease manifestation and should be actively considered when formulating a treatment plan. The medication regimen should be tailored to each patient. Steroid-sparing medications should be prescribed early as part of a long-term strategy.
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Affiliation(s)
- Marlies S Wijsenbeek
- Department of Pulmonary Medicine, Erasmus Medical Center, University Medical Center Rotterdam, Gravendijkwal 230, 3015 CE Rotterdam, The Netherlands
| | - Daniel A Culver
- Department of Pulmonary Medicine, Respiratory Institute, Cleveland Clinic, 9500 Euclid Avenue, Cleveland, OH 44195, USA; Department of Pathobiology, Lerner Research Institute, Cleveland Clinic, 9500 Euclid Avenue, Cleveland, OH 44195, USA.
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Guenther L, Lynde C, Ho V. Practical Considerations for the Initiation and Maintenance of Etanercept in the Treatment of Psoriasis. J Cutan Med Surg 2016. [DOI: 10.2310/7750.2006.00072] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/18/2022]
Abstract
Etanercept is a new treatment for moderate to severe psoriasis. In contrast to traditional systemic agents, which can be given orally, etanercept is given by subcutaneous injection. Patient selection, transitioning, dosing, safety, monitoring, duration of therapy, and patient support programs are reviewed.
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Affiliation(s)
- Lyn Guenther
- From the Division of Dermatology, University of Western Ontario, London, ON; The Guenther Dermatology Research Centre, London, ON; University Health Network, University of Toronto, Toronto, ON; Lynde Centre for Dermatology, Markham, ON; and Department of Dermatology, University of British Columbia, Vancouver, BC
| | - Charles Lynde
- From the Division of Dermatology, University of Western Ontario, London, ON; The Guenther Dermatology Research Centre, London, ON; University Health Network, University of Toronto, Toronto, ON; Lynde Centre for Dermatology, Markham, ON; and Department of Dermatology, University of British Columbia, Vancouver, BC
| | - Vincent Ho
- From the Division of Dermatology, University of Western Ontario, London, ON; The Guenther Dermatology Research Centre, London, ON; University Health Network, University of Toronto, Toronto, ON; Lynde Centre for Dermatology, Markham, ON; and Department of Dermatology, University of British Columbia, Vancouver, BC
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Affiliation(s)
- Richard G. Langley
- From the Division of Dermatology, Department of Medicine, Dalhousie University, Halifax, NS; Department of Medicine, University of Toronto, Toronto, ON; The Rebecca MacDonald Centre for Arthritis and Autoimmune Disease, Toronto, ON; Division of Advanced Therapeutics in Arthritis, Mount Sinai Hospital, Toronto, ON; Division of Dermatology, University of Montreal, Montreal, QC; Innovaderm Research Incorporated, Montreal, QC; Probity Medical Research, Waterloo, ON
| | - Edward C. Keystone
- From the Division of Dermatology, Department of Medicine, Dalhousie University, Halifax, NS; Department of Medicine, University of Toronto, Toronto, ON; The Rebecca MacDonald Centre for Arthritis and Autoimmune Disease, Toronto, ON; Division of Advanced Therapeutics in Arthritis, Mount Sinai Hospital, Toronto, ON; Division of Dermatology, University of Montreal, Montreal, QC; Innovaderm Research Incorporated, Montreal, QC; Probity Medical Research, Waterloo, ON
| | - Robert Bissonnette
- From the Division of Dermatology, Department of Medicine, Dalhousie University, Halifax, NS; Department of Medicine, University of Toronto, Toronto, ON; The Rebecca MacDonald Centre for Arthritis and Autoimmune Disease, Toronto, ON; Division of Advanced Therapeutics in Arthritis, Mount Sinai Hospital, Toronto, ON; Division of Dermatology, University of Montreal, Montreal, QC; Innovaderm Research Incorporated, Montreal, QC; Probity Medical Research, Waterloo, ON
| | - Kim A. Papp
- From the Division of Dermatology, Department of Medicine, Dalhousie University, Halifax, NS; Department of Medicine, University of Toronto, Toronto, ON; The Rebecca MacDonald Centre for Arthritis and Autoimmune Disease, Toronto, ON; Division of Advanced Therapeutics in Arthritis, Mount Sinai Hospital, Toronto, ON; Division of Dermatology, University of Montreal, Montreal, QC; Innovaderm Research Incorporated, Montreal, QC; Probity Medical Research, Waterloo, ON
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Papp KA, Keystone EC, Shear NH. Mechanism of Action, Pharmacokinetics, and Drug Interactions of Etanercept in Dermatology. J Cutan Med Surg 2016. [DOI: 10.2310/7750.2006.00069] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/26/2023]
Abstract
Etanercept, a dimeric soluble form of the p75 tumor necrosis factor (TNF) receptor, has been shown to be efficacious for the treatment of psoriatic arthritis and moderate to severe chronic plaque psoriasis, as well as rheumatoid arthritis, juvenile rheumatoid arthritis, and ankylosing spondylitis. In this article, we review the mechanism of action, pharmacokinetics, and drug interactions of etanercept. Differences between etanercept and other anti-TNF antagonists with respect to membrane binding, the effect on T lymphocytes, the effect on the blood-brain barrier, adverse event profiles, and disease efficacy are also discussed.
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Affiliation(s)
- Kim A. Papp
- From Probity Medical Research, Waterloo, ON; Departments of Medicine and Dermatology, University of Toronto, Toronto, ON; The Rebecca MacDonald Centre for Arthritis and Autoimmune Disease, Toronto, ON; and Division of Dermatology, Sunnybrook Health Sciences Centre, Toronto, ON
| | - Edward C. Keystone
- From Probity Medical Research, Waterloo, ON; Departments of Medicine and Dermatology, University of Toronto, Toronto, ON; The Rebecca MacDonald Centre for Arthritis and Autoimmune Disease, Toronto, ON; and Division of Dermatology, Sunnybrook Health Sciences Centre, Toronto, ON
| | - Neil H. Shear
- From Probity Medical Research, Waterloo, ON; Departments of Medicine and Dermatology, University of Toronto, Toronto, ON; The Rebecca MacDonald Centre for Arthritis and Autoimmune Disease, Toronto, ON; and Division of Dermatology, Sunnybrook Health Sciences Centre, Toronto, ON
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Winthrop KL, Park SH, Gul A, Cardiel MH, Gomez-Reino JJ, Tanaka Y, Kwok K, Lukic T, Mortensen E, Ponce de Leon D, Riese R, Valdez H. Tuberculosis and other opportunistic infections in tofacitinib-treated patients with rheumatoid arthritis. Ann Rheum Dis 2016; 75:1133-8. [PMID: 26318385 PMCID: PMC4893093 DOI: 10.1136/annrheumdis-2015-207319] [Citation(s) in RCA: 164] [Impact Index Per Article: 18.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/16/2015] [Revised: 07/02/2015] [Accepted: 07/05/2015] [Indexed: 12/30/2022]
Abstract
OBJECTIVES To evaluate the risk of opportunistic infections (OIs) in patients with rheumatoid arthritis (RA) treated with tofacitinib. METHODS Phase II, III and long-term extension clinical trial data (April 2013 data-cut) from the tofacitinib RA programme were reviewed. OIs defined a priori included mycobacterial and fungal infections, multidermatomal herpes zoster and other viral infections associated with immunosuppression. For OIs, we calculated crude incidence rates (IRs; per 100 patient-years (95% CI)); for tuberculosis (TB) specifically, we calculated rates stratified by patient enrolment region according to background TB IR (per 100 patient-years): low (≤0.01), medium (>0.01 to ≤0.05) and high (>0.05). RESULTS We identified 60 OIs among 5671 subjects; all occurred among tofacitinib-treated patients. TB (crude IR 0.21, 95% CI of (0.14 to 0.30)) was the most common OI (n=26); median time between drug start and diagnosis was 64 weeks (range 15-161 weeks). Twenty-one cases (81%) occurred in countries with high background TB IR, and the rate varied with regional background TB IR: low 0.02 (0.003 to 0.15), medium 0.08 (0.03 to 0.21) and high 0.75 (0.49 to 1.15). In Phase III studies, 263 patients diagnosed with latent TB infection were treated with isoniazid and tofacitinib concurrently; none developed TB. For OIs other than TB, 34 events were reported (crude IR 0.25 (95% CI 0.18 to 0.36)). CONCLUSIONS Within the global tofacitinib RA development programme, TB was the most common OI reported but was rare in regions of low and medium TB incidence. Patients who screen positive for latent TB can be treated with isoniazid during tofacitinib therapy.
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Affiliation(s)
- K L Winthrop
- Oregon Health and Science University, Portland, Oregon, USA
| | - S-H Park
- Division of Rheumatology, Department of Internal Medicine, Seoul St. Mary's Hospital, The Catholic University of Korea, Seoul, South Korea
| | - A Gul
- Istanbul Faculty of Medicine, Istanbul University, Istanbul, Turkey
| | - M H Cardiel
- Centro de Investigación Clínica de Morelia SC, Morelia, Mexico
| | - J J Gomez-Reino
- Hospital Clínico Universitario de Santiago, Santiago de Compostela, Spain
| | - Y Tanaka
- University of Occupational and Environmental Health, Kitakyushu, Japan
| | - K Kwok
- Pfizer Inc, New York, New York, USA
| | - T Lukic
- Pfizer Inc, New York, New York, USA
| | | | | | - R Riese
- Pfizer Inc, Groton, Connecticut, USA
| | - H Valdez
- Pfizer Inc, New York, New York, USA
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Wallis RS. Mathematical Models of Tuberculosis Reactivation and Relapse. Front Microbiol 2016; 7:669. [PMID: 27242697 PMCID: PMC4869524 DOI: 10.3389/fmicb.2016.00669] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/17/2015] [Accepted: 04/22/2016] [Indexed: 11/13/2022] Open
Abstract
The natural history of human infection with Mycobacterium tuberculosis (Mtb) is highly variable, as is the response to treatment of active tuberculosis. There is presently no direct means to identify individuals in whom Mtb infection has been eradicated, whether by a bactericidal immune response or sterilizing antimicrobial chemotherapy. Mathematical models can assist in such circumstances by measuring or predicting events that cannot be directly observed. The 3 models discussed in this review illustrate instances in which mathematical models were used to identify individuals with innate resistance to Mtb infection, determine the etiologic mechanism of tuberculosis in patients treated with tumor necrosis factor blockers, and predict the risk of relapse in persons undergoing tuberculosis treatment. These examples illustrate the power of various types of mathematic models to increase knowledge and thereby inform interventions in the present global tuberculosis epidemic.
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Patel D, Madani S, Patel S, Guglani L. Review of pulmonary adverse effects of infliximab therapy in Crohn's disease. Expert Opin Drug Saf 2016; 15:769-75. [PMID: 26923135 DOI: 10.1517/14740338.2016.1160053] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/13/2023]
Abstract
INTRODUCTION Anti-inflammatory therapies are the mainstay for the treatment of inflammatory bowel disease (IBD) in children and adults, including biologics such as infliximab. While there is extensive literature on the general side effects of therapy with infliximab, the data on pulmonary adverse effects remains sparse. This article summarizes the literature related to pulmonary adverse effects of Infliximab therapy in Crohn's Disease. AREA COVERED Published reports of specific pulmonary complications during ongoing therapy with infliximab in patients with IBD were included in the review. A wide variety of infectious and non-infectious complications have been reported with the use of infliximab therapy in IBD. EXPERT OPINION It is important to carefully evaluate respiratory signs and symptoms in patients with IBD, especially those receiving biologic therapies. Besides infectious complications, other non-infectious pulmonary adverse effects associated with the use of infliximab should be considered in patients with IBD. Further, it is important to differentiate primary pulmonary involvement of IBD from pulmonary adverse effects of infliximab therapy. An algorithm for assessing patients with IBD presenting with pulmonary symptoms is provided as a guide for clinicians for medical decision-making.
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Affiliation(s)
- Dhiren Patel
- a Pediatric Gastroenterology, The Carman and Ann Adams Department of Pediatrics, Children's Hospital of Michigan , Wayne State University School of Medicine , Detroit , MI , USA
| | - Shailender Madani
- a Pediatric Gastroenterology, The Carman and Ann Adams Department of Pediatrics, Children's Hospital of Michigan , Wayne State University School of Medicine , Detroit , MI , USA
| | - Shraddha Patel
- b Department of Emergency Medicine , Wayne State University , Detroit , MI , USA
| | - Lokesh Guglani
- c Pulmonology, Allergy/Immunology, Cystic Fibrosis and Sleep Medicine (PACS) Division, Department of Pediatrics, Children's Healthcare of Atlanta , Emory University School of Medicine , Atlanta , GA , USA
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Gallitano SM, McDermott L, Brar K, Lowenstein E. Use of tumor necrosis factor (TNF) inhibitors in patients with HIV/AIDS. J Am Acad Dermatol 2016; 74:974-80. [PMID: 26774690 DOI: 10.1016/j.jaad.2015.11.043] [Citation(s) in RCA: 49] [Impact Index Per Article: 5.4] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/29/2015] [Revised: 11/11/2015] [Accepted: 11/26/2015] [Indexed: 01/03/2023]
Abstract
Patients with HIV and AIDS are living longer because of advancements in antiretroviral therapy. These patients are often susceptible to debilitating inflammatory disorders that are refractory to standard treatment. We discuss the relationship of tumor necrosis factor-alpha and HIV and then review 27 published cases of patients with HIV being treated with tumor necrosis factor-alpha inhibitors. This review is limited because no randomized controlled trials have been performed with this patient population. Regardless, we propose that reliable seropositive patients, who are adherent to medication regimens and frequent monitoring and have failed other treatment modalities, should be considered for treatment with tumor necrosis factor-alpha inhibitors.
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Affiliation(s)
- Stephanie M Gallitano
- Department of Dermatology, State University of New York-Downstate, Brooklyn, New York.
| | - Laura McDermott
- Department of Dermatology, State University of New York-Downstate, Brooklyn, New York
| | - Kanwaljit Brar
- Division of Pediatric Allergy and Immunology, National Jewish Health, Denver, Colorado
| | - Eve Lowenstein
- Department of Dermatology, State University of New York-Downstate, Brooklyn, New York
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Harigai M, Ishiguro N, Inokuma S, Mimori T, Ryu J, Takei S, Takeuchi T, Tanaka Y, Takasaki Y, Yamanaka H, Watanabe M, Tamada H, Koike T. Postmarketing surveillance of the safety and effectiveness of abatacept in Japanese patients with rheumatoid arthritis. Mod Rheumatol 2016; 26:491-8. [PMID: 26635183 PMCID: PMC4898160 DOI: 10.3109/14397595.2015.1123211] [Citation(s) in RCA: 74] [Impact Index Per Article: 8.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/23/2022]
Abstract
Objective: To perform a postmarketing surveillance study evaluating the safety and effectiveness of abatacept in Japanese patients with rheumatoid arthritis (RA). Methods: Safety and effectiveness data were collected for all RA patients (at 772 sites) treated with intravenous abatacept between September 2010 and June 2011. Patients were treated by the approved dosing regimen according to the package insert. Treatment effectiveness was evaluated at baseline and at weeks 4, 12, and 24 using Disease Activity Score 28 (DAS28) according to erythrocyte sedimentation rate or serum C-reactive protein concentrations. Results: Overall, 3882 and 3016 abatacept-naïve RA patients were included in safety and effectiveness analyses, respectively. Adverse drug reactions (ADRs) were reported for 15.66% of patients and serious ADRs were detected for 2.52% of patients. The incidence of serious infections was 1.03% and these were mainly attributed to different types of bacterial pneumonia. Disease activity improved significantly over 6 months. Separate multivariate analysis identified predictors of severe ADR, and severe infections and factors predictive of clinically meaningful DAS28 improvement after 6 months of treatment with abatacept. Conclusions: Abatacept was efficacious and well tolerated in a clinical setting. No new safety concerns were detected.
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Affiliation(s)
- Masayoshi Harigai
- a Graduate School of Medical and Dental Sciences , Tokyo Medical and Dental University , Tokyo , Japan
| | - Naoki Ishiguro
- b Graduate School & Faculty of Medicine , Nagoya University , Nagoya , Japan
| | | | - Tsuneyo Mimori
- d Kyoto University Graduate School of Medicine , Kyoto , Japan
| | - Junnosuke Ryu
- e Nihon University School of Medicine , Tokyo , Japan
| | - Syuji Takei
- f Faculty of Medicine, School of Health Sciences , Kagoshima University , Kagoshima , Japan
| | | | - Yoshiya Tanaka
- h University of Occupational and Environmental Health , Fukuoka , Japan
| | | | | | | | | | - Takao Koike
- l NTT Sapporo Medical Center Minami , Sapporo , Japan , and.,m Hokkaido University Graduate School of Medicine , Sapporo , Japan
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Abstract
BACKGROUND Patients in daily rheumatological care differ in their individual risk profiles from participants in randomized controlled trials (RCT), e.g. due to comorbidities and age. Transferring results from RCTs into routine daily practice is therefore limited. OBJECTIVE The aim of this study was to evaluate the contribution of observational studies for decision-making in routine rheumatology practice. MATERIAL AND METHODS We used data from the German biologics register RABBIT which includes patients with rheumatoid arthritis (RA) when starting synthetic (s) or biologic (b) disease-modifying antirheumatic drugs (DMARD). They are observed for at least 5 years. Comorbidities and clinically relevant aspects (e.g. history of malignancies) are reported at baseline and adverse events at regular follow-up. RESULTS Only one out of three patients treated with bDMARDs in RABBIT would have fulfilled the inclusion criteria of the respective pivotal study. Register data enabled developing a risk scoring model which evaluates the individual risk of a patient for serious infections depending on different risk factors and the respective DMARD treatment. Open online access to the score provides the possibility of risk estimation for all rheumatologists. Further results identified long-standing high disease activity as a dominant risk factor for a worsening of prevalent comorbidities. In patients with heart failure it was shown that effective treatment and control of disease activity with tumor necrosis factor (TNF) inhibitors was more likely to be protective than harmful. CONCLUSION Observational studies contribute essentially to the assessment of individual risks of patients. The results provide valuable information to support clinical decision-making and therefore strengthen the evidence when treating patients of higher age or with existing comorbidities.
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Affiliation(s)
- A Strangfeld
- Programmbereich Epidemiologie, Gruppe Pharmakoepidemiologie, DRFZ - Deutsches Rheuma-Forschungszentrum, Charitéplatz 1, 10117, Berlin, Deutschland,
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31
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Lieske NV, Tonby K, Kvale D, Dyrhol-Riise AM, Tasken K. Targeting Tuberculosis and HIV Infection-Specific Regulatory T Cells with MEK/ERK Signaling Pathway Inhibitors. PLoS One 2015; 10:e0141903. [PMID: 26544592 PMCID: PMC4636186 DOI: 10.1371/journal.pone.0141903] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/23/2015] [Accepted: 10/14/2015] [Indexed: 02/02/2023] Open
Abstract
Human regulatory T cells (Tregs) are essential in maintaining immunological tolerance and suppress effector T cells. Tregs are commonly up-regulated in chronic infectious diseases such as tuberculosis (TB) and human immunodeficiency virus (HIV) infection and thereby hamper disease-specific immune responses and eradication of pathogens. The MEK/ERK signaling pathway is involved in regulation of the FoxP3 transcription factor, which directs a lineage-specific transcriptional program to define Tregs and control their suppressive function. Here, we aimed to target activation of disease-specific Tregs by inhibition of the MEK/ERK signaling pathway based on the hypothesis that this would improve anti-HIV and anti-TB immunity. Stimulation of T cells from untreated TB (n = 12) and HIV (n = 8) patients with disease-specific antigens in vitro in the presence of the MEK inhibitor (MEKI) trametinib (GSK1120212) resulted in significant down-regulation of both FoxP3 levels (MFI) and fractions of resting (CD45RA+FoxP3+) and activated (CD45RA−FoxP3++) Tregs. MEKI also reduced the levels of specific T effector cells expressing the pro-inflammatory cytokines (IFN-γ, TNF-α and IL-2) in both HIV and TB patients. In conclusion, MEKIs modulate disease antigen-specific Treg activation and may have potential application in new treatment strategies in chronic infectious diseases where reduction of Treg activity would be favorable. Whether MEKIs can be used in current HIV or TB therapy regimens needs to be further investigated.
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Affiliation(s)
- Nora V. Lieske
- Centre for Molecular Medicine Norway, Nordic EMBL Partnership, University of Oslo, Oslo, Norway
| | - Kristian Tonby
- Institute of Clinical Medicine, University of Oslo, Oslo, Norway
- Department of Infectious Diseases, Oslo University Hospital, Oslo, Norway
| | - Dag Kvale
- Institute of Clinical Medicine, University of Oslo, Oslo, Norway
- Department of Infectious Diseases, Oslo University Hospital, Oslo, Norway
- Kristian Gerhard Jebsen Inflammation Research Centre, University of Oslo, Oslo, Norway
| | - Anne M. Dyrhol-Riise
- Institute of Clinical Medicine, University of Oslo, Oslo, Norway
- Department of Infectious Diseases, Oslo University Hospital, Oslo, Norway
- Kristian Gerhard Jebsen Inflammation Research Centre, University of Oslo, Oslo, Norway
| | - Kjetil Tasken
- Centre for Molecular Medicine Norway, Nordic EMBL Partnership, University of Oslo, Oslo, Norway
- Department of Infectious Diseases, Oslo University Hospital, Oslo, Norway
- Kristian Gerhard Jebsen Inflammation Research Centre, University of Oslo, Oslo, Norway
- Biotechnology Centre, University of Oslo, Oslo, Norway
- * E-mail:
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Recommendations for the diagnosis and treatment of latent and active tuberculosis in inflammatory joint diseases candidates for therapy with tumor necrosis factor alpha inhibitors - March 2008 update. REVISTA PORTUGUESA DE PNEUMOLOGIA 2015; 14:271-83. [PMID: 25966834 DOI: 10.1016/s0873-2159(15)30235-x] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/27/2023] Open
Abstract
The Portuguese Society of Rheumatology and the Portuguese Society of Pulmonology have updated the guidelines for the diagnosis and treatment of latent tuberculosis infection (LTBI) and active tuberculosis (ATB) in patients with inflammatory joint diseases (IJD) that are candidates to therapy with tumour necrosis factor alpha (TNFα) antagonists. In order to reduce the risk of tuberculosis (TB) reactivation and the incidence of new infections, TB screening is recommended to be done as soon as possible, ideally at the moment of IJD diagnosis, and patient assessment repeated before starting anti-TNFα therapy. Treatment for ATB and LTBI must be done under the care of a TB specialist. When TB treatment is indicated, it should be completed prior to starting anti-TNFα therapy. If the IJD activity justifies the need for immediate treatment, anti-TNFα therapy can be started two months after antituberculous therapy has been initiated, in the case of ATB, and one month after in the case of LTBI. Chest X-ray is mandatory for all patients. If Gohn's complex is present, the patient should be treated for LTBI; healed lesions require the exclusion of ATB. In cases of suspected active lesions, ATB should be excluded/confirmed and adequate therapy initiated. Tuberculin skin test, with two units of RT23, should be performed in all patients. If the induration is <5 mm, the test should be repeated within 1 to 2 weeks, on the opposite forearm, and will be considered negative only if the result is again <5 mm. Positive TST implicates LTBI treatment, unless previous proper treatment was provided. If TST is performed in immunossuppressed IJD patients, LTBI treatment should be offered to the patient before starting anti-TNF-α therapy, even in the presence of a negative test, after risk / benefit assessment. Rev Port Pneumol 2007; XIV (2): 271-283.
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Gabbita SP, Johnson MF, Kobritz N, Eslami P, Poteshkina A, Varadarajan S, Turman J, Zemlan F, Harris-White ME. Oral TNFα Modulation Alters Neutrophil Infiltration, Improves Cognition and Diminishes Tau and Amyloid Pathology in the 3xTgAD Mouse Model. PLoS One 2015; 10:e0137305. [PMID: 26436670 PMCID: PMC4593589 DOI: 10.1371/journal.pone.0137305] [Citation(s) in RCA: 39] [Impact Index Per Article: 3.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/14/2014] [Accepted: 08/15/2015] [Indexed: 01/22/2023] Open
Abstract
Cytokines such as TNFα can polarize microglia/macrophages into different neuroinflammatory types. Skewing of the phenotype towards a cytotoxic state is thought to impair phagocytosis and has been described in Alzheimer’s Disease (AD). Neuroinflammation can be perpetuated by a cycle of increasing cytokine production and maintenance of a polarized activation state that contributes to AD progression. In this study, 3xTgAD mice, age 6 months, were treated orally with 3 doses of the TNFα modulating compound isoindolin-1,3 dithione (IDT) for 10 months. We demonstrate that IDT is a TNFα modulating compound both in vitro and in vivo. Following long-term IDT administration, mice were assessed for learning & memory and tissue and serum were collected for analysis. Results demonstrate that IDT is safe for long-term treatment and significantly improves learning and memory in the 3xTgAD mouse model. IDT significantly reduced paired helical filament tau and fibrillar amyloid accumulation. Flow cytometry of brain cell populations revealed that IDT increased the infiltrating neutrophil population while reducing TNFα expression in this population. IDT is a safe and effective TNFα and innate immune system modulator. Thus small molecule, orally bioavailable modulators are promising therapeutics for Alzheimer’s disease.
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Affiliation(s)
| | - Ming F. Johnson
- Veterans Administration-Greater Los Angeles Healthcare System, Los Angeles, California, United States of America
| | - Naomi Kobritz
- Veterans Administration-Greater Los Angeles Healthcare System, Los Angeles, California, United States of America
| | - Pirooz Eslami
- Veterans Administration-Greater Los Angeles Healthcare System, Los Angeles, California, United States of America
| | - Aleksandra Poteshkina
- Veterans Administration-Greater Los Angeles Healthcare System, Los Angeles, California, United States of America
| | - Sridhar Varadarajan
- University of North Carolina Wilmington, Department of Chemistry and Biochemistry, Wilmington, North Carolina, United States of America
| | - John Turman
- University of North Carolina Wilmington, Department of Chemistry and Biochemistry, Wilmington, North Carolina, United States of America
| | - Frank Zemlan
- P2D Bioscience, Inc., Cincinnati, Ohio, United States of America
| | - Marni E. Harris-White
- Veterans Administration-Greater Los Angeles Healthcare System, Los Angeles, California, United States of America
- University of California Los Angeles, David Geffen School of Medicine, Los Angeles, California, United States of America
- * E-mail:
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Sehgal VN, Pandhi D, Khurana A. Biologics in dermatology: adverse effects. Int J Dermatol 2015; 54:1442-60. [PMID: 26147909 DOI: 10.1111/ijd.12802] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/23/2013] [Revised: 01/13/2014] [Accepted: 06/25/2014] [Indexed: 12/13/2022]
Abstract
Biologics are a group of drugs that precisely affect certain specific steps in the immune response and are an extremely useful group when used in an appropriate setting. However, their use can often be a double-edged sword. Careful patient selection and thorough knowledge of adverse effects is a key to their successful use in various disorders. The initial enthusiasm has gradually given way to a more cautious approach wherein a balance is sought between clinical usefulness and expected side effects. The adverse effects of the biologics most commonly used in dermatology have been carefully listed for ready reference. The plausible causes of the adverse reactions are succinctly outlined along with their incriminating factor(s). Besides, in brief, the attention has been focused on their management. The content should provide an essential didactic content for educating the practitioner.
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Affiliation(s)
- Virendra N Sehgal
- Dermato-Venereology (Skin/VD) Center, Sehgal Nursing Home, Delhi, India
| | - Deepika Pandhi
- Department of Dermatology and STD, University College of Medical Sciences, and Associated Guru Teg Bahadur Hospital, Shahdara, Delhi, India
| | - Ananta Khurana
- Department of Dermatology and STD, Dr RML hospital and PGIMER, New Delhi, India
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Risk of infection with biologic antirheumatic therapies in patients with rheumatoid arthritis. Best Pract Res Clin Rheumatol 2015; 29:290-305. [PMID: 26362745 DOI: 10.1016/j.berh.2015.05.009] [Citation(s) in RCA: 59] [Impact Index Per Article: 5.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/01/2014] [Accepted: 05/08/2015] [Indexed: 12/11/2022]
Abstract
There are currently 10 licensed biologic therapies for the treatment of rheumatoid arthritis in 2014. In this article, we review the risk of serious infection (SI) for biologic therapies. This risk has been closely studied over the last 15 years within randomised controlled trials, long-term extension studies and observational drug registers, especially for the first three antitumour necrosis factor (TNF) drugs, namely infliximab, etanercept and adalimumab. The risk of SI with the newer biologics rituximab, tocilizumab, abatacept and tofacitinib is also reviewed, although further data from long-term observational studies are awaited. Beyond all-site SI, we review the risk of tuberculosis, other opportunistic infections and herpes zoster, and the effect of screening on TB rates. Lastly, we review emerging opportunities for stratifying the risk. Patients can be risk-stratified based on both modifiable and non-modifiable patient characteristics such as age, co-morbidity, glucocorticoid use, functional status and recent previous SI.
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36
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Abreu C, Rocha-Pereira N, Sarmento A, Magro F. Nocardia infections among immunomodulated inflammatory bowel disease patients: A review. World J Gastroenterol 2015; 21:6491-6498. [PMID: 26074688 PMCID: PMC4458760 DOI: 10.3748/wjg.v21.i21.6491] [Citation(s) in RCA: 44] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/08/2015] [Accepted: 03/31/2015] [Indexed: 02/06/2023] Open
Abstract
Human nocardiosis, caused by Nocardia spp., an ubiquitous soil-borne bacteria, is a rare granulomatous disease close related to immune dysfunctions. Clinically can occur as an acute life-threatening disease, with lung, brain and skin being commonly affected. The infection was classically diagnosed in HIV infected persons, organ transplanted recipients and long term corticosteroid treated patients. Currently the widespread use of immunomodulators and immunossupressors in the treatment of inflammatory diseases changed this scenario. Our purpose is to review all published cases of nocardiosis in immunomodulated patients due to inflammatory diseases and describe clinical and laboratory findings. We reviewed the literature concerning human cases of nocardiosis published between 1980 and 2014 in peer reviewed journals. Eleven cases of nocardiosis associated with anti-tumor necrosis factor (TNF) prescription (9 related with infliximab and 2 with adalimumab) were identified; 7 patients had inflammatory bowel disease (IBD), 4 had rheumatological conditions; nocardia infection presented as cutaneous involvement in 3 patients, lung disease in 4 patients, hepatic in one and disseminated disease in 3 patients. From the 10 cases described in IBD patients 7 were associated with anti-TNF and 3 with steroids and azathioprine. In conclusion, nocardiosis requires high levels of clinical suspicion and experience of laboratory staff, in order to establish a timely diagnosis and by doing so avoid worst outcomes. Treatment for long periods tailored by the susceptibility of the isolated species whenever possible is essential. The safety of restarting immunomodulators or anti-TNF after the disease or the value of prophylaxis with cotrimoxazole is still debated.
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Host susceptibility to non-tuberculous mycobacterial infections. THE LANCET. INFECTIOUS DISEASES 2015; 15:968-80. [PMID: 26049967 DOI: 10.1016/s1473-3099(15)00089-4] [Citation(s) in RCA: 174] [Impact Index Per Article: 17.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Received: 08/16/2014] [Revised: 10/29/2014] [Accepted: 11/11/2014] [Indexed: 11/22/2022]
Abstract
Non-tuberculous mycobacteria cause a broad range of clinical disorders, from cutaneous infections, such as cervical or intrathoracic lymphadenitis in children, to disseminated infections at all ages. Recognition of the underlying immune defect is crucial for rational treatment, preventive care, family screening, and, in some cases, transplantation. So far, at least seven autosomal mutations (in IL12B, IL12RB1, ISG15, IFNGR1, IFNGR2, STAT1, and IRF8) and two X-linked mutations (in IKBKG and CYBB), mostly presenting in childhood, have been reported to confer susceptibility to disseminated non-tuberculous mycobacterial infection. GATA2 deficiency and anti-interferon γ autoantibodies also give rise to disseminated infection, typically in late childhood or adulthood. Furthermore, isolated pulmonary non-tuberculous mycobacterial infection has been increasing in prevalence in people without recognised immune dysfunction. In this Review, we discuss how to detect and differentiate host susceptibility factors underlying localised and systemic non-tuberculous mycobacterial infections.
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Latent tuberculosis infection: myths, models, and molecular mechanisms. Microbiol Mol Biol Rev 2015; 78:343-71. [PMID: 25184558 DOI: 10.1128/mmbr.00010-14] [Citation(s) in RCA: 162] [Impact Index Per Article: 16.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022] Open
Abstract
The aim of this review is to present the current state of knowledge on human latent tuberculosis infection (LTBI) based on clinical studies and observations, as well as experimental in vitro and animal models. Several key terms are defined, including "latency," "persistence," "dormancy," and "antibiotic tolerance." Dogmas prevalent in the field are critically examined based on available clinical and experimental data, including the long-held beliefs that infection is either latent or active, that LTBI represents a small population of nonreplicating, "dormant" bacilli, and that caseous granulomas are the haven for LTBI. The role of host factors, such as CD4(+) and CD8(+) T cells, T regulatory cells, tumor necrosis factor alpha (TNF-α), and gamma interferon (IFN-γ), in controlling TB infection is discussed. We also highlight microbial regulatory and metabolic pathways implicated in bacillary growth restriction and antibiotic tolerance under various physiologically relevant conditions. Finally, we pose several clinically important questions, which remain unanswered and will serve to stimulate future research on LTBI.
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Abstract
Improved treatments are needed for nearly all forms of Mycobacterium tuberculosis infection. Adjunctive host-directed therapies have the potential to shorten tuberculosis treatment duration, prevent resistance and reduce lung injury by promoting autophagy, antimicrobial peptide production and other macrophage effector mechanisms, as well as by modifying specific mechanisms that cause lung inflammation and matrix destruction. The range of candidates is broad, including several agents approved for other clinical indications that are ready for evaluation in Phase II clinical trials. The promise of new and existing host-directed therapies that could accelerate response and improve tuberculosis treatment outcomes is discussed in this Opinion article.
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Brode SK, Jamieson FB, Ng R, Campitelli MA, Kwong JC, Paterson JM, Li P, Marchand-Austin A, Bombardier C, Marras TK. Risk of mycobacterial infections associated with rheumatoid arthritis in Ontario, Canada. Chest 2015; 146:563-572. [PMID: 24384637 DOI: 10.1378/chest.13-2058] [Citation(s) in RCA: 45] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/15/2023] Open
Abstract
OBJECTIVE Patients with rheumatoid arthritis (RA) are at increased risk of TB. Little is known about the risk of nontuberculous mycobacteria (NTM) disease in these patients. We sought to ascertain the rate of NTM infection and TB in all residents of Ontario, Canada, with and without RA. METHODS In a cohort study, all Ontarians aged ≥ 15 years in January 2001 were followed until December 2010. Individuals with RA were identified using a validated algorithm to search hospitalization and physician billing claims. We linked Public Health Ontario Laboratory data to identify all cases of laboratory-confirmed TB and NTM disease. Analysis was performed using Cox proportional hazards regression. RESULTS We identified 113,558 Ontarians with RA and 9,760,075 Ontarians without RA. Relative to the non-RA group, adjusted hazard ratios (HRs) and 95% CIs for TB (1.92, [1.50-2.47]) and NTM disease (2.07, [1.84-2.32]) demonstrated increased risks in the RA group. Among those with RA, per 100,000 person-years, NTM disease (HR, 41.6; 95% CI, 37.1-46.5) was more common than TB (HR, 8.5; 95% CI, 6.5-10.8). After full adjustment, people with RA who developed NTM disease were 1.81 times as likely to die than uninfected people with RA. CONCLUSIONS Mycobacterial infections are more common in Ontarians with RA, with NTM disease more likely than TB. NTM disease is associated with an increased risk of death in patients with RA. Given the rising rates of NTM disease worldwide, determining whether this risk is due to the use of immunosuppressive medications vs RA itself is an important objective for future research.
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Affiliation(s)
- Sarah K Brode
- Joint Division of Respirology, University Health Network, Mount Sinai Hospital, Toronto; Westpark Healthcare Centre, Toronto; Department of Medicine, Management and Evaluation, University of Toronto, Toronto
| | - Frances B Jamieson
- Department of Laboratory Medicine and Pathobiology, Management and Evaluation, University of Toronto, Toronto; Public Health Ontario, Toronto
| | - Ryan Ng
- Department of Medicine, Management and Evaluation, University of Toronto, Toronto
| | | | - Jeffrey C Kwong
- Department of Medicine and Toronto Western Family Health Team, University Health Network, Mount Sinai Hospital, Toronto; Department of Family and Community Medicine, Management and Evaluation, University of Toronto, Toronto; Public Health Ontario, Toronto; Institute for Clinical Evaluative Sciences, Toronto
| | - J Michael Paterson
- Institute of Health Policy, Management and Evaluation, University of Toronto, Toronto; Institute for Clinical Evaluative Sciences, Toronto; Department of Family Medicine, McMaster University, Hamilton
| | - Ping Li
- Institute for Clinical Evaluative Sciences, Toronto
| | | | - Claire Bombardier
- Institute of Health Policy, Management and Evaluation, University of Toronto, Toronto; Toronto General Hospital Research Institute, Toronto, ON, Canada
| | - Theodore K Marras
- Joint Division of Respirology, University Health Network, Mount Sinai Hospital, Toronto; Department of Medicine, Management and Evaluation, University of Toronto, Toronto.
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Abstract
PURPOSE OF REVIEW Novel treatment modalities for previously fatal diseases, including newer chemotherapeutic and biologic agents and the expansion of the indications for solid organ and stem cell transplantation, have resulted in prolonged patient survival and a significant increase in the population of immunocompromised hosts (ICHs). RECENT FINDINGS This review discusses the increasing spectrum of opportunistic infections in the ICH, the general approach for early diagnosis and treatment of pulmonary infections in this population, and the current and novel diagnostic modalities available to establish a rapid and specific microbiologic diagnosis, focusing on recent controversies and advances. SUMMARY Early diagnosis and prompt initiation of effective therapy for infection help reduce morbidity in ICHs. Advances in diagnostic assays using nonculture-based methods, such as nucleic acid amplification, may allow for earlier targeted therapy. Invasive procedures including bronchoscopy and biopsy remain essential and should be vigorously pursued in ICHs given the broad differential diagnosis of possible pulmonary pathogens in this population, and the need to establish a specific diagnosis to allow accurate targeted therapy.
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Diagnostic Performance of a Cytokine and IFN-γ–Induced Chemokine mRNA Assay after Mycobacterium tuberculosis–Specific Antigen Stimulation in Whole Blood from Infected Individuals. J Mol Diagn 2015; 17:90-9. [DOI: 10.1016/j.jmoldx.2014.08.005] [Citation(s) in RCA: 22] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/26/2014] [Revised: 06/25/2014] [Accepted: 08/11/2014] [Indexed: 12/11/2022] Open
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Samra SR, Habeeb M, Halim AA, Shebl E. Tuberculosis chemoprophylaxis in rheumatoid arthritic patients receiving tumor necrosis factor inhibitors or conventional therapy. EGYPTIAN JOURNAL OF CHEST DISEASES AND TUBERCULOSIS 2015. [DOI: 10.1016/j.ejcdt.2014.11.027] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/24/2022] Open
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Pulmonary Mycobacterium kansasii Infection Mimicking Malignancy on the (18)F-FDG PET Scan in a Patient Receiving Etanercept: A Case Report and Literature Review. Case Rep Pulmonol 2014; 2014:973573. [PMID: 25389506 PMCID: PMC4217353 DOI: 10.1155/2014/973573] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/31/2014] [Accepted: 10/02/2014] [Indexed: 12/21/2022] Open
Abstract
A 66-year-old male presented with chest pain, malaise, generalized weakness, and weight loss. He had been receiving etanercept injection for rheumatoid arthritis. Chest X-ray revealed a right upper lobe mass. Chest computed tomography (CT) showed a right apical mass, highly suggestive of a Pancoast tumor. The thoracic fluorine-18 fluoro-deoxy-glucose (18F-FDG) positron emission tomography (PET) scan demonstrated significantly high metabolic pulmonary lesions with the standardized uptake value (SUV) of 12.5, consistent with lung cancer. The patient underwent bronchoscopy and bronchoalveolar lavage (BAL). BAL cytology was negative for malignant cells. BAL acid fast bacilli (AFB) smears were positive, and Mycobacterium kansasii was eventually isolated. He received a 12-month course of rifampin, isoniazid, and ethambutol. Interval resolution of pulmonary lesions was noted on follow-up serial CT chest studies. There has been increasing incidence of nontuberculous mycobacterial infections reported in patients treated with the antitumor necrosis factor-alpha (anti-TNF-alpha) agents. Infectious foci have an increased glucose metabolism which potentially causes a high FDG uptake on the 18F-FDG PET scan, leading to undue anxiety and cost to the patients. This is the first reported case of pulmonary M. kansasii infection with a positive thoracic 18F-FDG PET study mimicking malignancy in a patient on etanercept.
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Falkenstern-Ge RF, Husemann K, Kohlhäufl M. Prolonged paradoxical reaction to anti-tuberculous treatment after discontinuation of TNF-alpha- blocker therapy with adalimumab. Rare clinical documentation. Open Med (Wars) 2014; 10:39-43. [PMID: 28352675 PMCID: PMC5152954 DOI: 10.1515/med-2015-0009] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/28/2013] [Accepted: 01/08/2014] [Indexed: 11/15/2022] Open
Abstract
In the past decades, tumor necrosis factor alpha (TNF-a) antagonist has been a milestone in the treatment of many chronic inflammatory diseases. TNF antagonist can increase patients' susceptibility to many different kinds of infections especially those requiring granuloma formations despite regular performance of Screening for latent tuberculosis infection (LTBI). We report 2 cases of patients who developed tuberculosis under treatment with adalimumab, which was discontinued after the diagnosis of tuberculosis. During the tuberculosis therapy they unexpectedly developed a prolonged paradoxical reaction. In both cases we were only able to manage the progress of the paradoxical reaction through high steroid doses. Patients undergoing therapy with TNF- alpha-blocker are prone to develop tuberculosis infection, which could in turn lead to severe prolonged paradoxical reaction during anti-tuberculous treatment. An increased steroid dose may be required and is sometimes necessary.
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Affiliation(s)
| | - Kim Husemann
- Division of Pulmonology, Klinik Schillerhoehe, Center for Pulmonology and Thoracic Surgery, Teaching Hospital of the University of Tuebingen, Solitude Str. 18, 70839 Stuttgart- Gerlingen, Germany
| | - Martin Kohlhäufl
- Division of Pulmonology, Klinik Schillerhoehe, Center for Pulmonology and Thoracic Surgery, Teaching Hospital of the University of Tuebingen, Solitude Str. 18, 70839 Stuttgart- Gerlingen, Germany
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Souto A, Maneiro JR, Salgado E, Carmona L, Gomez-Reino JJ. Risk of tuberculosis in patients with chronic immune-mediated inflammatory diseases treated with biologics and tofacitinib: a systematic review and meta-analysis of randomized controlled trials and long-term extension studies. Rheumatology (Oxford) 2014; 53:1872-85. [DOI: 10.1093/rheumatology/keu172] [Citation(s) in RCA: 108] [Impact Index Per Article: 9.8] [Reference Citation Analysis] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/20/2023] Open
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Hirano T, Matsuura M, Nakase H. Pulmonary Mycobacterium avium Infection in a Patient with Crohn's Disease under Azathioprine Treatment. Case Rep Gastroenterol 2014; 8:182-5. [PMID: 24932166 PMCID: PMC4049012 DOI: 10.1159/000363376] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/19/2022] Open
Abstract
Anti-tumor necrosis factor alpha therapy is known as a risk factor of non-tuberculous mycobacteria (NTM) infection. However, there are few reports of NTM infection under treatment with thiopurine agents. We herein report a first case of pulmonary infection caused by Mycobacterium avium complex (MAC) in a patient with Crohn's disease under treatment with thiopurine. After starting antibiotics therapy for NTM including clarithromycin, rifampicin, ethambutol and streptomycin, MAC infection was well controlled, and she kept clinical remission even without azathioprine. In conclusion, our case emphasizes the importance of considering NTM infection in respiratory complications of inflammatory bowel disease patients under immunosuppressive therapies.
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Affiliation(s)
- Tomonori Hirano
- Department of Gastroenterology and Hepatology, Kyoto University Hospital, Kyoto, Japan
| | - Minoru Matsuura
- Department of Gastroenterology and Hepatology, Kyoto University Hospital, Kyoto, Japan
| | - Hiroshi Nakase
- Department of Gastroenterology and Hepatology, Kyoto University Hospital, Kyoto, Japan
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Abstract
Introduction: Rheumatoid arthritis (RA) is a systemic inflammatory disease that causes increased morbidity and mortality. The treatment of the disease has considerably advanced with the addition of biological agents targeting pro-inflammatory cytokines such as tumor necrosis factor (TNF). Adalimumab (ADA) is one of the currently available five TNF inhibitors for clinical use in RA. It is a fully humanized monoclonal antibody which may be prescribed as monotherapy or in combination with methotrexate or other disease-modifying antirheumatic drugs. Areas covered: This review summarizes the recent available data on efficacy and safety of ADA in patients with early and established RA as well as improvement of quality of life and finally we provide data on biologic drug comparison. Expert opinion: ADA has been evaluated in various randomized placebo-controlled trials in RA, prospective observational studies as well as open-label extensions of the original double-blind trials providing experience and data about the long-term efficacy and safety of the drug. Effectiveness of the drug is sustained, while in most cases RA patients treated with ADA experienced a slower radiographic progression and consequently less disability and improved health-related quality of life outcomes. Clinical trials demonstrated no new safety signals and a safety profile consistent with that of the anti-TNF class.
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Affiliation(s)
- Paraskevi V Voulgari
- University of Ioannina Medical School, Department of Internal Medicine, Rheumatology Clinic , 45110 Ioannina , Greece
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Yoshitaka T, Ishida S, Mukai T, Kittaka M, Reichenberger EJ, Ueki Y. Etanercept administration to neonatal SH3BP2 knock-in cherubism mice prevents TNF-α-induced inflammation and bone loss. J Bone Miner Res 2014; 29:1170-82. [PMID: 24978678 PMCID: PMC4131552 DOI: 10.1002/jbmr.2125] [Citation(s) in RCA: 25] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/29/2013] [Revised: 09/30/2013] [Accepted: 10/14/2013] [Indexed: 12/19/2022]
Abstract
Cherubism is a genetic disorder of the craniofacial skeleton caused by gain-of-function mutations in the signaling adaptor protein, SH3-domain binding protein 2 (SH3BP2). In a knock-in mouse model for cherubism, we previously demonstrated that homozygous mutant mice develop T/B cell-independent systemic macrophage inflammation leading to bone erosion and joint destruction. Homozygous mice develop multiostotic bone lesions whereas cherubism lesions in humans are limited to jawbones. We identified a critical role of tumor necrosis factor α (TNF-α) in the development of autoinflammation by creating homozygous TNF-α-deficient cherubism mutants, in which systemic inflammation and bone destruction were rescued. In this study, we examined whether postnatal administration of an anti-TNF-α antagonist can prevent or ameliorate the disease progression in cherubism mice. Neonatal homozygous mutants, in which active inflammation has not yet developed, were treated with a high dose of etanercept (25 mg/kg, twice/week) for 7 weeks. Etanercept-treated neonatal mice showed strong rescue of facial swelling and bone loss in jaws and calvariae. Destruction of joints was fully rescued in the high-dose group. Moreover, the high-dose treatment group showed a significant decrease in lung and liver inflammatory lesions. However, inflammation and bone loss, which were successfully treated by etanercept administration, recurred after etanercept discontinuation. No significant effect was observed in low-dose-treated (0.5 mg/kg, twice/week) and vehicle-treated groups. In contrast, when 10-week-old cherubism mice with fully active inflammation were treated with etanercept for 7 weeks, even the high-dose administration did not decrease bone loss or lung or liver inflammation. Taken together, the results suggest that anti-TNF-α therapy may be effective in young cherubism patients, if treated before the inflammatory phase or bone resorption occurs. Therefore, early genetic diagnosis and early treatment with anti-TNF-α antagonists may be able to prevent or ameliorate cherubism, especially in patients with a mutation in SH3BP2.
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Affiliation(s)
- Teruhito Yoshitaka
- Department of Oral and Craniofacial Sciences, School of Dentistry, University of Missouri-Kansas City, Kansas City, MO, USA
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Navarra SV, Tang B, Lu L, Lin HY, Mok CC, Asavatanabodee P, Suwannalai P, Hussein H, Rahman MU. Risk of tuberculosis with anti-tumor necrosis factor-α therapy: substantially higher number of patients at risk in Asia. Int J Rheum Dis 2013; 17:291-8. [PMID: 24131578 PMCID: PMC4034594 DOI: 10.1111/1756-185x.12188] [Citation(s) in RCA: 49] [Impact Index Per Article: 4.1] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/15/2022]
Abstract
AIM To assess the potential risk of tuberculosis (TB) in patients treated with anti-tumor necrosis factor-alpha (TNF-α) agents in Asia. METHODS Absolute risk increase (ARI) of TB was estimated for three widely used anti-TNF-α therapies using published standardized incidence ratios (SIR) from the French Research Axed on Tolerance of bIOtherapies registry and incidence (absolute risk [AR]) of TB in Asia. Assuming an association of increased TB risk with anti-TNF-α therapy and country TB AR (incidence), the ARI of TB by country was calculated by multiplying the SIR of the anti-TNF-α therapy by the country's TB AR. The numbers needed to harm (NNH) for each anti-TNF-α agent and numbers needed to treat (NNT) to reduce one TB event using etanercept therapy instead of adalimumab or infliximab were also calculated for each country. RESULTS The ARI of TB with anti-TNF-α therapies in Asian countries is substantially higher than Western Europe and North America and the difference between etanercept versus the monoclonal antibodies becomes more evident. The NNH for Asian countries ranged from 8 to 163 for adalimumab, 126 to 2646 for etanercept and 12 to 256 for infliximab. The NNT to reduce one TB event using etanercept instead of adalimumab therapy ranged from 8 to 173, and using etanercept instead of infliximab therapy the NNT ranged from 13 to 283. CONCLUSION Higher numbers of patients are at risk of developing TB with anti-TNF-α therapy in Asia compared with Western Europe and North America. The relative lower risk of TB with etanercept may be particularly relevant for Asia, an endemic area for TB.
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Affiliation(s)
- Sandra V Navarra
- Rheumatology Section, University of Santo Tomas, Manila, Philippines
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