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Sonomoto K, Nakayamada S, Tanaka H, Nagayasu A, Tanaka Y. Real-World Safety and Efficacy of Targeted Therapies in Rheumatoid Arthritis: A 5-Year, 5130-Case Follow-Up from FIRST Registry. Rheumatol Ther 2025; 12:561-580. [PMID: 40257743 PMCID: PMC12084202 DOI: 10.1007/s40744-025-00762-w] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/14/2024] [Accepted: 03/21/2025] [Indexed: 04/22/2025] Open
Abstract
INTRODUCTION This work aims to illustrate the evolution and ongoing challenges of rheumatoid arthritis (RA) management with targeted therapy over 20 years, using a cohort study from the world's oldest society. METHODS Data were obtained from FIRST registry, a multicenter cohort of patients with RA treated with biologic/targeted synthetic disease-modifying antirheumatic drugs (b/tsDMARDs). Patients were followed for 60 months and assessed for drug efficacy, retention, and reasons for discontinuation. RESULTS Analysis of 5130 treatments over 16,616 person-years revealed shifts in strategies and demographics. Despite an aging population (51.9-64.3 years) with increasing comorbidities (lung disease: 11.1-36.2%, malignancy: 2.2-13.1%), b/tsDMARD use expanded to include patients with lower disease activity. With better disease control, discontinuations due to adverse events decreased, and particularly infections fell from 2.1 to 0.7 per 100 person-years. Remission rates improved over time in the naïve group but remained largely unchanged in the prior b/tsDMARDs group. Retention rates varied by bDMARD class, with TNF inhibitors (TNFi) showing a decrease over time and IL-6 receptor inhibitors (IL-6Ri) and CTLA4-Ig showing an increase in retention. TNFi had high remission rates but low retention, whereas CTLA4-Ig and IL-6Ri had lower remission rates and higher retention. Changes in functional improvement were modest overall, and in patients aged 75 years and older, functional gains remained limited. CONCLUSIONS The study highlights the evolving landscape of RA management in an aging society, noting gains in efficacy and safety. However, unmet needs persist, particularly for patients not fully achieving treat-to-target goals and those with limited functional improvement.
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Affiliation(s)
- Koshiro Sonomoto
- Department of Clinical Nursing, School of Health Sciences, University of Occupational and Environmental Health, Japan, Kitakyushu, Japan
- The First Department of Internal Medicine, School of Medicine, University of Occupational and Environmental Health, Japan, Kitakyushu, Japan
| | - Shingo Nakayamada
- The First Department of Internal Medicine, School of Medicine, University of Occupational and Environmental Health, Japan, Kitakyushu, Japan
| | - Hiroaki Tanaka
- The First Department of Internal Medicine, School of Medicine, University of Occupational and Environmental Health, Japan, Kitakyushu, Japan
| | - Atsushi Nagayasu
- The First Department of Internal Medicine, School of Medicine, University of Occupational and Environmental Health, Japan, Kitakyushu, Japan
| | - Yoshiya Tanaka
- The First Department of Internal Medicine, School of Medicine, University of Occupational and Environmental Health, Japan, Kitakyushu, Japan.
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Ueda Y, Chinen N, Shimada K, Yokogawa N. Severe infection risk in triple and quadruple therapy for anti-MDA5 antibody-positive dermatomyositis. Clin Rheumatol 2025:10.1007/s10067-025-07445-5. [PMID: 40244469 DOI: 10.1007/s10067-025-07445-5] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/14/2025] [Revised: 04/09/2025] [Accepted: 04/14/2025] [Indexed: 04/18/2025]
Abstract
INTRODUCTION Anti-melanoma differentiation-associated gene 5 (MDA5) antibody-positive dermatomyositis (MDA5-DM) can be refractory to treatment, and a triple combination therapy (TCT) consisting of a glucocorticoid, cyclophosphamide, and a calcineurin inhibitor is widely used in induction therapy. For progressive or severe disease despite TCT, another immunosuppressive agent, such as a Janus kinase (JAK) inhibitor, may be added to the induction regimen. METHOD A retrospective cohort study across two centers in Japan was undertaken between January 2016 and December 2024 evaluating patients with MDA5-DM receiving TCT or quadruple combination therapy (QCT) determining the presence of severe infection. The latter therapy consisted of the addition of a JAK inhibitor to the TCT. A severe infection was defined as Grade 3 or higher according to the Common Terminology Criteria for Adverse Events (CTCAE), version 5.0. RESULTS There were 24 patients were included; TCT: n = 19 and QCT: n = 5. In the former, three (3/19, 16%), two (2/19, 11%), and three (3/19, 16%) patients had a severe bacterial infection, invasive fungal infection, and a CMV infection, respectively. In the QCT group, two (2/5, 40%), two (2/5, 40%), and four (4/5: 80%) patients had a severe bacterial infection, invasive fungal infection, and a CMV infection, respectively. CMV infections were significantly more frequent in the QCT group (p = 0.014). Both TCT and QCT groups had five patients each with a severe infection (5/19, 26% and 5/5, 100%, respectively) (p = 0.006). CONCLUSION While both TCT and QCT have infection, the QCT group may be at a higher risk, hence highlighting the need for vigilance and adequate prophylaxis.
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Affiliation(s)
- Yoshitaka Ueda
- Department of Rheumatic Diseases, Tokyo Metropolitan Tama Medical Center, Tokyo, Japan.
| | - Naofumi Chinen
- Department of Rheumatic Diseases, Tama-Nambu Chiiki Hospital, Tokyo, Japan
| | - Kota Shimada
- Department of Rheumatic Diseases, Tokyo Metropolitan Tama Medical Center, Tokyo, Japan
| | - Naoto Yokogawa
- Department of Rheumatic Diseases, Tokyo Metropolitan Tama Medical Center, Tokyo, Japan
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Patel S, Jay J, Pathak P, Antony MA, Thiriveedi M. Septic shock due to cytomegalovirus colitis associated with rituximab use: A case report. World J Virol 2025; 14:99923. [PMID: 40134838 PMCID: PMC11612876 DOI: 10.5501/wjv.v14.i1.99923] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/03/2024] [Revised: 09/27/2024] [Accepted: 10/29/2024] [Indexed: 11/28/2024] Open
Abstract
BACKGROUND Cytomegalovirus (CMV) infections can cause significant morbidity and mortality in immunocompromised individuals. CMV targets dysfunctional lymphocytes. Chronic rituximab (RTX) therapy can cause B-lymphocyte dysfunction, increasing CMV risk. Rarely, CMV infections present with critical illness such as septic shock. CASE SUMMARY A 64-year-old African American woman presented with generalized weakness and non-bloody watery diarrhea of 4-6 weeks duration. She did not have nausea, vomiting or, abdominal pain. She had been on monthly RTX infusions for neuromyelitis optica. She was admitted for septic shock due to pancolitis. Blood investigations suggested pancytopenia and serology detected significantly elevated CMV DNA. Valganciclovir treatment led to disease resolution. CONCLUSION This case illustrates an extremely rare case of CMV colitis associated with RTX use presenting with septic shock. High suspicion for rare opportunistic infections is imperative in individuals with long-term RTX use.
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Affiliation(s)
- Siddharth Patel
- Department of Internal Medicine, Decatur Morgan Hospital, Decatur, AL 35601, United States
| | - Jordan Jay
- Department of Medicine, Alabama College of Osteopathic Medicine, Dothan, AL 36303, United States
| | - Prutha Pathak
- Department of Internal Medicine, North Alabama Medical Center, Florence, AL 35630, United States
| | - Mc Anto Antony
- Department of Endocrinology, Diabetes and Metabolism, Medical University of South Carolina/AnMed Campus, Anderson, SC 29621, United States
| | - Mrudula Thiriveedi
- Department of Internal Medicine, Decatur Morgan Hospital, Decatur, AL 35601, United States
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Zhang F, Xia C, Yang G, Shang B, Huang G, Yuan K, Wang H, Gong X, Jiang Q. Multiomics analysis of human serum and animal experiments reveals the protective mechanism of Qingre Huoxue Decoction against rheumatoid arthritis. Front Immunol 2025; 16:1526110. [PMID: 40124380 PMCID: PMC11926152 DOI: 10.3389/fimmu.2025.1526110] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/11/2024] [Accepted: 02/17/2025] [Indexed: 03/25/2025] Open
Abstract
Objective Qingre Huoxue Decoction (QRHXD) is a traditional Chinese herbal prescription widely used in clinical practice with significant therapeutic effects on RA; however, its mechanism of action remains unclear. This study aimed to investigate the efficacy and underlying mechanisms of QRHXD in treating RA through clinical research, multiomics approaches, and animal experiments. Methods We conducted a 24-week clinical study in which QRHXD was the primary treatment, collecting serum samples from patients before and after treatment for integrated proteomic and metabolomic analysis to identify potential therapeutic targets. Bioinformatics analysis of differentially expressed proteins (DEPs) and differential metabolites (DMs) was performed using hierarchical clustering, volcano plots, heat maps, Gene Ontology (GO), and Kyoto Encyclopaedia of Genes and Genomes (KEGG) analysis. To validate the identified therapeutic targets, we constructed a collagen-induced arthritis (CIA) mouse model. Results Clinical research has shown that QRHXD can improve clinical symptoms and relevant indicators in RA patients, including the disease activity score-28 (DAS28), C-reactive protein (CRP), erythrocyte sedimentation rate (ESR), tender joint count (TJC), swollen joint count (SJC), visual analogue scale (VAS), patient-reported outcome (PRO), and health assessment questionnaire (HAQ). Proteomics and metabolomics analysis identified 83 DEPs and 54 DMs, including 46 upregulated and 37 downregulated proteins, as well as 11 upregulated and 43 downregulated metabolites. KEGG enrichment analysis revealed that DEPs are primarily associated with fatty acid degradation, ferroptosis, glycerolipid metabolism, and related pathways. The identified DMs are primarily associated with the AMPK signalling pathway, FoxO signalling pathway, glycolysis/gluconeogenesis, MTOR signalling pathway, and so on. GO enrichment analysis indicated that the DEPs were mainly associated with apoptotic mitochondrial changes, protein modification processes, fatty-acyl-CoA binding, and so on. Integrated proteomics and metabolomics analyses revealed a significant increase in fructose-1,6-biphosphatase 1 (FBP1) levels and a reduction in AMP-activated protein kinase (AMPK) levels in patients with RA. QRHXD inhibited FBP1 and activated AMPK signalling. Animal experiments validated the findings from proteomics and metabolomics analyses, demonstrating that QRHXD could also delay bone destruction and reduce inflammatory factor levels in CIA mice. Conclusion QRHXD may reduce the disease activity of RA, attenuate the inflammatory response, and delay bone destruction by inhibiting FBP1 and activating the AMPK signalling pathway.
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Affiliation(s)
- Fuyuan Zhang
- Guang’anmen Hospital, China Academy of Chinese Medical Sciences, Beijing, China
| | - Congmin Xia
- Guang’anmen Hospital, China Academy of Chinese Medical Sciences, Beijing, China
| | - Guang Yang
- Department of Chinese and Western Medicine, Peking University First Hospital, Beijing, China
| | - Biyue Shang
- Guang’anmen Hospital, China Academy of Chinese Medical Sciences, Beijing, China
| | - Guangrui Huang
- School of Life Sciences, Beijing University of Chinese Medicine, Beijing, China
| | - Kai Yuan
- School of Life Sciences, Beijing University of Chinese Medicine, Beijing, China
| | - Hesong Wang
- School of Life Sciences, Beijing University of Chinese Medicine, Beijing, China
| | - Xun Gong
- Guang’anmen Hospital, China Academy of Chinese Medical Sciences, Beijing, China
| | - Quan Jiang
- Guang’anmen Hospital, China Academy of Chinese Medical Sciences, Beijing, China
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Jha DK, Kakadiya R, Sharma A, Naidu S, De D, Sharma V. Assessment and management for latent tuberculosis before advanced therapies for immune-mediated inflammatory diseases: A comprehensive review. Autoimmun Rev 2025; 24:103758. [PMID: 39870187 DOI: 10.1016/j.autrev.2025.103758] [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: 05/24/2024] [Revised: 01/16/2025] [Accepted: 01/24/2025] [Indexed: 01/29/2025]
Abstract
Tuberculosis (TB), caused by Mycobacterium tuberculosis , is the most significant infectious cause of mortality across the globe. While TB disease can prey on immunocompetent individuals, it is more likely to occur in immunocompromised individuals. Immune-mediated inflammatory diseases (IMIDs) are a group of diseases (rheumatoid arthritis, inflammatory bowel disease, ankylosing spondylitis, psoriasis, hidradenitis suppurativa, autoimmune blistering diseases, and others) where there may be a need for systemic immunosuppression to control the disease manifestations, treat symptoms and improve long term outcomes. Immunosuppression may predispose them to active TB either from recent infection or reactivation of Latent TB (LTB). The major determinants of reactivation include the type of therapy (highest risk with TNF inhibitors and JAK inhibitors) and the underlying TB endemicity. The strategy to avoid TB reactivation includes the detection of LTB using tests that detect immunoreactivity to TB antigens (interferon-gamma release assays or tuberculin skin test) and treating LTB before or with initiation of IMID therapies. Available diagnostic tests have deficiencies in diagnostic sensitivity to detect LTB and even worse capability in predicting reactivation of TB. In addition to immunological tests, more stringent testing strategy utilizing one or many LTB equivalents may point towards subclinical TB. LTB equivalents include clinical (past history of TB, recent exposure to TB) and radiological criteria (use of chest roentgenogram, computed tomography, or, sometimes positron emission tomography - computed tomography). The present review summarizes the risk factors for TB reactivation in patients initiated on advanced therapies, geographically appropriate strategies for LTB testing, and treatment of LTB.
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Affiliation(s)
| | - Rinkalben Kakadiya
- Department of Gatroenterology, Surat Institute of Digestive Sciences, Surat, Gujarat, India
| | - Ananya Sharma
- Government Medical College and Hospital, Sector 32, Chandigarh, India
| | - Shankar Naidu
- Clinical Immunology and Rheumatology Services, Department of Internal Medicine Postgraduate Institute of Medical Education and Research, Chandigarh, India
| | - Dipankar De
- Department of Dermatology, Venereology and Leprology, Postgraduate Institute of Medical Education and Research, Chandigarh, India
| | - Vishal Sharma
- Department of Gastroenterology, Postgraduate Institute of Medical Education and Research, Chandigarh, India.
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Picchianti-Diamanti A, Aiello A, De Lorenzo C, Migliori GB, Goletti D. Management of tuberculosis risk, screening and preventive therapy in patients with chronic autoimmune arthritis undergoing biotechnological and targeted immunosuppressive agents. Front Immunol 2025; 16:1494283. [PMID: 39963138 PMCID: PMC11830708 DOI: 10.3389/fimmu.2025.1494283] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/10/2024] [Accepted: 01/06/2025] [Indexed: 02/20/2025] Open
Abstract
Tuberculosis (TB) is the leading cause of death in the world from an infectious disease. Its etiologic agent, the Mycobacterium tuberculosis (Mtb), is a slow-growing bacterium that has coexisted in humans for thousands of years. According to the World Health Organization, 10.6 million new cases of TB and over 1 million deaths were reported in 2022. It is widely recognized that patients affected by chronic autoimmune arthritis such as rheumatoid arthritis (RA), psoriatic arthritis (PsA), and ankylosing spondylitis (AS) have an increased incidence rate of TB disease compared to the general population. As conceivable, the risk is associated with age ≥65 years and is higher in endemic regions, but immunosuppressive therapy plays a pivotal role. Several systematic reviews have analysed the impact of anti-TNF-α agents on the risk of TB in patients with chronic autoimmune arthritis, as well as for other biologic disease-modifying immunosuppressive anti-rheumatic drugs (bDMARDs) such as rituximab, abatacept, tocilizumab, ustekinumab, and secukinumab. However, the data are less robust compared to those available with TNF-α inhibitors. Conversely, data on anti-IL23 agents and JAK inhibitors (JAK-i), which have been more recently introduced for the treatment of RA and PsA/AS, are limited. TB screening and preventive therapy are recommended in Mtb-infected patients undergoing bDMARDs and targeted synthetic (ts)DMARDs. In this review, we evaluate the current evidence from randomized clinical trials, long-term extension studies, and real-life studies regarding the risk of TB in patients with RA, PsA, and AS treated with bDMARDs and tsDMARDs. According to the current evidence, TNF-α inhibitors carry the greatest risk of TB progression among bDMARDs and tsDMARDs, such as JAK inhibitors and anti-IL-6R agents. The management of TB screening and the updated preventive therapy are reported.
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Affiliation(s)
- Andrea Picchianti-Diamanti
- Department of Clinical and Molecular Medicine, “Sapienza” University, S. Andrea University Hospital, Rome, Italy
| | - Alessandra Aiello
- Translational Research Unit, National Institute for Infectious Diseases “Lazzaro Spallanzani”- Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS), Rome, Italy
| | - Chiara De Lorenzo
- Department of Clinical and Molecular Medicine, “Sapienza” University, S. Andrea University Hospital, Rome, Italy
| | - Giovanni Battista Migliori
- Istituti Clinici Scientifici Maugeri, Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS), Tradate, Italy
| | - Delia Goletti
- Translational Research Unit, National Institute for Infectious Diseases “Lazzaro Spallanzani”- Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS), Rome, Italy
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Huang YC, Lee NY, Weng MY. Increased risk of Pneumocystis jirovecii colonization in rheumatoid arthritis patients on biologics and Janus kinase inhibitor. JOURNAL OF MICROBIOLOGY, IMMUNOLOGY, AND INFECTION = WEI MIAN YU GAN RAN ZA ZHI 2025; 58:112-119. [PMID: 39271438 DOI: 10.1016/j.jmii.2024.08.013] [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: 08/01/2023] [Revised: 08/15/2024] [Accepted: 08/26/2024] [Indexed: 09/15/2024]
Abstract
BACKGROUND The prevalence of Pneumocystis jirovecii (PJ) pneumonia among rheumatic patients is rising. PJ colonization serves as a reservoir for transmission and precedes the development of PJ pneumonia. We aim to clarify the association of PJ colonization in patients of rheumatoid arthritis (RA) treated with biologics or Janus kinase inhibitors (JAKi). METHODS A prospective cohort study was performed from March 2021 to July 2022 in the rheumatology outpatient department of National Cheng Kung University Hospital. We obtained oral-wash samples from asymptomatic RA patients treated with biologic disease-modifying antirheumatic drugs (bDMARDs) and JAKi. A real-time quantitative polymerase chain reaction assay focusing on the mitochondrial large subunit ribosomal ribonucleic acid gene of PJ was applied to detect colonization. RESULTS One hundred and ten RA patients were enrolled. Adjusted odds ratios (ORs) of PJ colonization were 6.40 (95% CI 1.34-30.57, p-value =0.02) in patients receiving bDMARDs or JAKi. Specifically, in patients treated with bDMARDs the adjusted OR was 8.08 (95% CI 1.57-41.51, p-value=0.012), and a trend toward developing PJ colonization was further identified in patients receiving JAKi (adjusted OR: 4.79, 95% CI 0.89-25.91, p=0.069). Among patients treated with bDMARDs or JAKi, medication duration >3 years and age >60 y/o are risk factors for PJ colonization. CONCLUSION RA patients on bDMARDs or JAK inhibitors have an approximately 6-fold higher risk of developing P. jirovecii colonization. Patients treated with bDMARDs had an 8-fold higher risk of P. jirovecii colonization. Risk factors of PJ colonization are medication duration >3 years and age > 60 y/o.
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Affiliation(s)
- Ya-Chun Huang
- Department of Internal Medicine, Division of Allergy, Immunology, and Rheumatology, National Cheng Kung University Hospital, College of Medicine, National Cheng Kung University, Tainan, Taiwan.
| | - Nan-Yao Lee
- Department of Internal Medicine and Center for Infection Control, National Cheng Kung University Hospital and Medical College, Tainan, Taiwan.
| | - Meng-Yu Weng
- Department of Internal Medicine, Division of Allergy, Immunology, and Rheumatology, National Cheng Kung University Hospital, College of Medicine, National Cheng Kung University, Tainan, Taiwan.
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Alshammari AD, Aldhafeeri MM, Aldhafeeri AM, Alanzi MA, Almutairi MB, Alrasheedi JA, Alsurur TA, Alshammri AD. The type of infections and the use of antibiotics among patients with rheumatoid arthritis: A review. J Family Med Prim Care 2025; 14:8-14. [PMID: 39989513 PMCID: PMC11845013 DOI: 10.4103/jfmpc.jfmpc_739_24] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/03/2024] [Revised: 05/30/2024] [Accepted: 06/29/2024] [Indexed: 02/25/2025] Open
Abstract
Patients diagnosed with rheumatoid arthritis have a heightened susceptibility to infections, which may lead to higher rates of illness and death. The heightened susceptibility may arise from the illness itself, which causes changes in the body's innate cellular defense mechanisms, or from the medications used to manage the condition. The precise level of risk for infections associated with traditional disease-modifying anti-rheumatic drugs has not been fully elucidated. This review aimed To investigate the type of infections and the use of antibiotics among patients with rheumatoid arthritis. An electronic literature search was conducted using the MEDLINE database, with the indicated search keywords: infections, antibiotics, use, patients, rheumatoid, and arthritis. To identify relevant information, the search was limited to articles published between 2017 and 2024. The researchers used suitable search terms on Google Scholar to discover and examine relevant scholarly articles. The selection of articles was determined by several inclusion criteria. The research included publications that were published from 2017 to 2024. The study was organized into many sections, each including particular categories within the analysis section.we reportrd that : Within the developing age of focused synthetic treatments for RA, severe infections persist as the primary consequence of long-term treatment. In all patients with rheumatoid arthritis, it is necessary to conduct initial screenings for hepatitis B virus and tuberculosis. Additionally, it is important to administer vaccinations for specific pathogens (such as pneumococcal, herpes zoster, and influenza) before and during treatment. Aggressive therapy should be pursued to effectively manage disease activity in RA patients, while also maintaining constant vigilance for early signs of infections. Extra care should be given to senior rheumatoid arthritis (RA) patients who are over 65 years old and have other medical conditions. These people are often more susceptible to developing infections, regardless of the medication they get. The trials conducted with different antibiotics have confirmed the effectiveness of these medications in treating rheumatoid arthritis. Thus, it is plausible that the culprit responsible for rheumatoid arthritis is a microbe, namely periodontopathic bacteria.
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Affiliation(s)
- Asma D. Alshammari
- Intensive Care Department, Maternity and Children Hospital, Hafar Albatin, Al-Qaysumah, Saudi Arabia
| | - Mona Matar Aldhafeeri
- Department of Pharmacy, College of Pharmacy, University of Hafar Albatin, Hafar Albatin, Saudi Arabia
| | - Amal M. Aldhafeeri
- Medical Laboratories Department, College of Applied Medical Sciences, University of Hafar Albatin, Hafar Albatin, Saudi Arabia
| | - Maram Asaad Alanzi
- Medical Laboratories Department, College of Applied Medical Sciences, University of Hafar Albatin, Hafar Albatin, Saudi Arabia
| | - Maha Bandar Almutairi
- Department of Pharmacy, College of Pharmacy, University of Hafar Albatin, Hafar Albatin, Saudi Arabia
| | | | - Thikra Adel Alsurur
- Department of Pharmacy, College of Pharmacy, University of Hafar Albatin, Hafar Albatin, Saudi Arabia
| | - Aeshah Dhahawi Alshammri
- Department of Pharmacy, College of Pharmacy, University of Hafar Albatin, Hafar Albatin, Al-Qaysumah, Saudi Arabia
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Khelghati F, Rahmanian M, Eghbal E, Seghatoleslami ZS, Goudarzi M, Keramatinia A, Ong CWM, Goletti D, D'Ambrosio L, Centis R, Nasiri MJ, Migliori GB. Risk of tuberculosis disease in patients receiving TNF-α antagonist therapy: A meta-analysis of randomized controlled trials. New Microbes New Infect 2024; 62:101533. [PMID: 39639969 PMCID: PMC11617757 DOI: 10.1016/j.nmni.2024.101533] [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: 09/14/2024] [Revised: 11/05/2024] [Accepted: 11/12/2024] [Indexed: 12/07/2024] Open
Abstract
Introduction Tuberculosis (TB) risk associated with tumor necrosis factor-alpha (TNF-α) antagonist therapy in patients with autoimmune diseases is a significant concern. This study aims to evaluate the risk of TB disease associated with TNF-α antagonist therapy. Methods An extensive search of PubMed/MEDLINE, EMBASE, and the Cochrane CENTRAL databases was conducted to identify randomized controlled trials (RCTs) assessing TB disease risk in patients receiving TNF-α antagonist therapy available until November 1, 2024. The pooled statistic used was the weighted odds ratio (OR) and a corresponding 95 % confidence interval (CI). Statistical analysis was performed using Comprehensive Meta-Analysis software, version 3.0 (Biostat Inc., Englewood, NJ, USA). Results Fifty-six RCTs, totaling 22,212 adult patients, met the specified eligibility criteria. Pooled analysis revealed an increased risk of TB disease associated with TNF-α antagonist therapy (OR 1.52, 95 % CI 1.03-2.26, p = 0.03). Subgroup analyses indicated a higher risk in patients with rheumatoid arthritis (RA) (OR 2.25, 95 % CI 1.13-4.45, p = 0.02), while no significant associations were found in patients with ankylosing spondylitis (AS) or psoriasis (Ps). Analyses by specific TNF-α antagonist drugs did not yield significant associations with risk of TB disease. Conclusion Our study highlights an increased risk of TB disease associated with TNF-α antagonist therapy, particularly in patients with RA. However, the absence of significant associations in AS or Ps patients suggests disease-specific variations in risk of TB disease. Further research is needed to elucidate the long-term safety profile of TNF-α antagonist drugs and their associations with risk of TB disease in different patient populations.
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Affiliation(s)
- Fatemeh Khelghati
- Department of Microbiology, School of Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Mohammad Rahmanian
- Department of Microbiology, School of Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Elaheh Eghbal
- Infectious Diseases and Tropical Medicine Research Center, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | | | - Mehdi Goudarzi
- Department of Microbiology, School of Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Aliasghar Keramatinia
- Department of Community Medicine, School of Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Catherine WM. Ong
- Division of Infectious Diseases, Department of Medicine, National University Hospital, Singapore, Singapore
| | - Delia Goletti
- Translational Research Unit, Department of Epidemiology and Preclinical Research National Institute for Infectious Diseases L. Spallanzani-IRCCS, Roma, Italy
| | | | - Rosella Centis
- Servizio di Epidemiologia Clinica delle Malattie Respiratorie, Istituti Clinici Scientifici Maugeri IRCCS, Tradate, Italy
| | - Mohammad Javad Nasiri
- Department of Microbiology, School of Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Giovanni Battista Migliori
- Servizio di Epidemiologia Clinica delle Malattie Respiratorie, Istituti Clinici Scientifici Maugeri IRCCS, Tradate, Italy
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Mousso T, Pollock SJ, Inzerillo PC, Gigliotti F, Wright TW. Protective innate immunity against Pneumocystis does not require Stat6-dependent macrophage polarization. Infect Immun 2024; 92:e0022224. [PMID: 39150267 PMCID: PMC11475768 DOI: 10.1128/iai.00222-24] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/21/2024] [Accepted: 07/23/2024] [Indexed: 08/17/2024] Open
Abstract
Pneumocystis species are respiratory fungal pathogens that cause life-threatening opportunistic infections in immunocompromised hosts. Pneumocystis typically evade pulmonary innate immunity but are efficiently eradicated by a functional adaptive immune response. FVB/NJ mice are unique in that they display protective alveolar macrophage-dependent innate immunity against Pneumocystis, and remain resistant to infection even in the absence of CD4+ T lymphocyte function. FVB/NJ alveolar macrophages (AMs) were found to display an M2-biased phenotype at baseline, which was potentiated after stimulation with Pneumocystis, suggesting that macrophage polarization may dictate the outcome of the Pneumocystis-macrophage interaction. To determine whether Stat6, a key global regulator of M2 polarization, was required for FVB/NJ innate immunity, FVB Stat6-/- mice were generated. FVB Stat6-deficient AMs were markedly impaired in their ability to polarize to an M2 phenotype when stimulated with Th2 cytokines. However, FVB Stat6-/- mice remained highly resistant to infection, indicating that Stat6 signaling is dispensable for innate FVB/NJ resistance. Despite the loss of Stat6 signaling, primary AMs from FVB Stat6-/- mice maintained baseline expression of M2 markers, and also strongly upregulated M2-associated genes following direct stimulation with Pneumocystis. Additional FVB/NJ knockout strains were generated, but only FVB MerTK-/- mice showed a marginally increased susceptibility to Pneumocystis infection. Together, these findings demonstrate that effective FVB/NJ innate immunity against Pneumocystis does not require Stat6 signaling and suggest that alternative pathways regulate M2 bias and macrophage-mediated innate resistance in FVB/NJ mice.
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Affiliation(s)
- T. Mousso
- Department of Pediatrics, University of Rochester School of Medicine and Dentistry, Rochester, New York, USA
| | - S. J. Pollock
- Department of Pediatrics, University of Rochester School of Medicine and Dentistry, Rochester, New York, USA
| | - P. C. Inzerillo
- Department of Pediatrics, University of Rochester School of Medicine and Dentistry, Rochester, New York, USA
| | - F. Gigliotti
- Department of Pediatrics, University of Rochester School of Medicine and Dentistry, Rochester, New York, USA
| | - T. W. Wright
- Department of Pediatrics, University of Rochester School of Medicine and Dentistry, Rochester, New York, USA
- Department of Microbiology and Immunology, University of Rochester School of Medicine and Dentistry, Rochester, New York, USA
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11
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Wang F, Liu J. Regulating the lncRNA DSCR9/RPLP2/PI3K/AKT axis: an important mechanism of Xinfeng capsules in improving rheumatoid arthritis. Front Immunol 2024; 15:1465442. [PMID: 39376558 PMCID: PMC11456487 DOI: 10.3389/fimmu.2024.1465442] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/16/2024] [Accepted: 09/04/2024] [Indexed: 10/09/2024] Open
Abstract
Background Rheumatoid arthritis (RA) is a systemic autoimmune disease characterized by chronic and symmetrical polyarthritis. RA patients often experience inflammatory reaction and hypercoagulable state, which together affect the self-perception of patient (SPP). Currently, inhibiting inflammation and hypercoagulable state are common treatment methods for alleviating RA symptoms. Xinfeng Capsules (XFC) has a long history of treating RA, and can effectively improve the inflammatory response and hypercoagulable state of RA. However, the potential mechanisms have not yet been determined. Purpose and study design This study elucidated the action mechanism of XFC in RA inflammation and hypercoagulability through the lncDSCR9/RPLP2/PI3K/AKT axis. Results Clinical observations indicated that there was a strong link between XFC therapy and improvements in inflammatory and coagulation biomarkers, as well as SPP among RA patients. The subsequent network pharmacology analysis results identified the PI3K/AKT signaling pathway as a potential mediator for XFC treatment of RA. Furthermore, clinical validation and sequencing results revealed that lncRNA DSCR9 expression (a gene implicated in inflammation and coagulation) was negatively correlated with clinical markers of inflammation and coagulation, while positively correlated with SF-36 indicators. Notably, XFC treatment remarkably upregulated lncRNA DSCR9 expression and downregulated PI3K and AKT expressions, showing opposite expression trends to the untreated cases.The regulatory effect of XFC on the lncRNA DSCR9/RPLP2/PI3K/AKT axis in RA was investigated using techniques such as RNA pull-down assay, Western blot analysis, RT-PCR, and EdU assay. Moreover, the administration of the PI3K/AKT agonist RMH can counteract the effects of XFC on p-PI3K, p-AKT, inflammation, and hypercoagulability, reinforcing the role of pathway. Finally, animal studies utilizing HE staining and transmission electron microscopy (TEM) demonstrated that XFC notably decreased PI3K and AKT expressions in adjuvant-induced arthritis (AA) rats, mitigated inflammation and hypercoagulability, and enhanced the ultrastructure of synovial cells. These findings underscored the potential mechanisms of XFC in the treatment of RA. Conclusion Regulating the lncRNA DSCR9/RPLP2/PI3K/AKT axis may be an important mechanism by which XFC improved RA inflammatory response and hypercoagulable state.
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Affiliation(s)
- Fanfan Wang
- The First Affiliated Hospital of Anhui University of Chinese Medicine, First Clinical Medical College, Hefei, Anhui, China
- Department of Rheumatism Immunity, The First Affiliated Hospital of Anhui University of Chinese Medicine, Hefei, Anhui, China
| | - Jian Liu
- Department of Rheumatism Immunity, The First Affiliated Hospital of Anhui University of Chinese Medicine, Hefei, Anhui, China
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So MW, Kim AR, Lee SG. Drug Persistence and Incidence of Active Tuberculosis of Tumor Necrosis Factor Alpha Inhibitors Versus Tocilizumab as the First-Line Biological Treatment in Patients with Rheumatoid Arthritis: A Nationwide Population-Based Retrospective Cohort Analysis. Rheumatol Ther 2024; 11:881-895. [PMID: 38769252 PMCID: PMC11265025 DOI: 10.1007/s40744-024-00674-1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/13/2024] [Accepted: 04/29/2024] [Indexed: 05/22/2024] Open
Abstract
INTRODUCTION Drug persistence may be a surrogate marker that reflects both long-term efficacy and safety in clinical settings, and tuberculosis (TB) is considered as one of the most important opportunistic infections after the biological treatment in rheumatoid arthritis (RA). We aimed to compare drug persistence and incidence of TB between tumor necrosis factor alpha (TNFα) inhibitors and tocilizumab in patients with RA using data from the Korean Health Insurance Review and Assessment Service database. METHODS In this analysis, 5449 patients with RA who started TNFα inhibitors, such as adalimumab, etanercept, infliximab, and golimumab or tocilizumab, as the first-line biological therapy between January 2014 and December 2017 were analyzed and followed up until December 2019. Drug persistence was defined as the duration from initiation to first discontinuation, and TB was defined as the prescription of > 2 anti-TB medications after the initiation of biologics. RESULTS TNFα inhibitors and tocilizumab were prescribed in 4202 (adalimumab, 1413; etanercept, 1100; infliximab, 769; golimumab 920) and 1247 patients with RA, respectively. During the analysis period, 2090 (49.7%) and 477 (38.3%) patients with RA discontinued TNFα inhibitors and tocilizumab, respectively, and 42 patients with RA developed TB (TNFα inhibitors, 33; tocilizumab, 9). After adjustment for confounding factors, TNFα inhibitors were significantly associated with a higher risk of discontinuation compared with tocilizumab (hazard ratio (HR) 1.63, p < 0.001). In subgroup analysis, all types of TNFα inhibitors, except for infliximab, demonstrated a significantly lower persistence rate compared with tocilizumab. There was no significant difference in TB incidence between tocilizumab and TNFα inhibitors. In subgroup analysis, infliximab has a significantly higher risk of TB compared with tocilizumab (HR 2.84, p = 0.02). CONCLUSION In this analysis, tocilizumab had longer persistence than TNFα inhibitors with a similar incidence of TB. Our analysis has limitations: (1) The HIRA database lacks clinical details like disease activity and joint damage extent, potentially influencing the analysis results. (2) Reasons for discontinuing biological agents were not available. (3) TB diagnoses may be inaccurate because of missing microbiological results. (4) We did not analyze the impact of treating latent TB infection on TB development post-biological treatment, despite mandatory screening in Korea.
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Affiliation(s)
- Min Wook So
- Department of Internal Medicine, Pusan National University School of Medicine, Yangsan, Republic of Korea
- Division of Rheumatology, Department of Internal Medicine, Pusan National University Yangsan Hospital, Yangsan, Republic of Korea
| | - A-Ran Kim
- Department of Internal Medicine, Pusan National University School of Medicine, Yangsan, Republic of Korea
- Division of Rheumatology, Department of Internal Medicine, Pusan National University School of Medicine, Pusan National University Hospital, 179 Gudeok-ro, Seo-gu, 49241, Busan, Republic of Korea
- Biomedical Research Institute, Pusan National University Hospital, Busan, Republic of Korea
| | - Seung-Geun Lee
- Department of Internal Medicine, Pusan National University School of Medicine, Yangsan, Republic of Korea.
- Division of Rheumatology, Department of Internal Medicine, Pusan National University School of Medicine, Pusan National University Hospital, 179 Gudeok-ro, Seo-gu, 49241, Busan, Republic of Korea.
- Biomedical Research Institute, Pusan National University Hospital, Busan, Republic of Korea.
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Sunar Yayla EN, Gezgin Yıldırım D, Adıgüzel Dündar H, Adrovic A, Akbörü EG, Aktay Ayaz N, Aliyev E, Avar Aydın PÖ, Aydın F, Baba Ö, Bağlan E, Bora Makay B, Bozkaya Yücel B, Çakan M, Çelikel E, Demir F, Demir S, Demirkan FG, Ekici Tekin Z, Esmeray Şenol P, Guliyeva V, Güngörer V, İşgüder R, Kalyoncu M, Karadağ ŞG, Kısaoğlu H, Kışla Ekinci RM, Kızıldağ Z, Kurt T, Özdel S, Özdemir Çiçek S, Öztürk K, Polat MC, Sezer M, Sönmez HE, Sözeri B, Şener S, Taşkın SN, Türkuçar S, Ünsal E, Yıldız Ç, Bakkaloğlu SA. Evaluation of pediatric rheumatologists' approach to rituximab use: a questionnaire study. Eur J Pediatr 2024:10.1007/s00431-024-05654-9. [PMID: 38926187 DOI: 10.1007/s00431-024-05654-9] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/09/2024] [Revised: 06/10/2024] [Accepted: 06/13/2024] [Indexed: 06/28/2024]
Abstract
Rituximab (RTX) is a chimeric monoclonal antibody that targets the CD20 antigen on B cells and is used in various autoimmune disorders. In this study, we aimed to measure the awareness of pediatric rheumatologists about the use of RTX through a survey. Between February and March 2023, a 42-question survey was sent via email to pediatric rheumatology specialists in Turkey. The participants were questioned for which diagnoses and system involvement they preferred to use RTX, which routine tests they performed, vaccination policy, and adverse events that occurred during or after infusion. Forty-one pediatric rheumatologists answered the survey. They prescribed RTX most frequently for systemic lupus erythematosus (87.8%) and ANCA-associated vasculitis (9.8%). Prior to the administration of RTX, 95% of clinicians checked renal and liver function tests, as well as immunoglobulin levels. The most frequently tested hepatitis markers before treatment were HBsAg and anti-HBs antibody (97.6%), while 85.4% of rheumatologists checked for anti-HCV. Clinicians (31.4%) reported that they postpone RTX infusion 2 weeks following an inactivated vaccine. Sixty-one percent of rheumatologists reported starting RTX treatment 1 month after live vaccines, while 26.8% waited 6 months. The most frequent adverse events were an allergic reaction during RTX infusion (65.9%), hypogammaglobulinemia (46.3%), and rash (36.6%). In the event of hypogammaglobulinemia after RTX treatment, physicians reported that they frequently (58.5%) continued RTX after intravenous immunoglobulin administration. CONCLUSIONS RTX has become a common treatment option in pediatric rheumatology in recent years. Treatment management may vary between clinician such as vaccination and routine tests. WHAT IS KNOWN • During the course of rituximab therapy, clinicians should be attentive to specific considerations in pre-treatment, during administration, and in post-treatment patient monitoring. WHAT IS NEW • There are differences in practice among clinicians in the management of RTX therapy. These practice disparities have the potential to impact the optimal course of treatment. • This study highlights that standardized guidelines are needed for RTX treatment in pediatric rheumatology, particularly for vaccination policies and routine tests.
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Affiliation(s)
- Emine Nur Sunar Yayla
- Department of Pediatrics, Division of Pediatric Rheumatology, Faculty of Medicine, Gazi University, Ankara, Turkey.
- Clinic of Pediatric Rheumatology, Ankara Etlik City Hospital, Ankara, Turkey.
| | - Deniz Gezgin Yıldırım
- Department of Pediatrics, Division of Pediatric Rheumatology, Faculty of Medicine, Gazi University, Ankara, Turkey
| | - Hatice Adıgüzel Dündar
- Clinic of Pediatric Rheumatology, İzmir Tepecik Training and Research Hospital, Izmir, Turkey
| | - Amra Adrovic
- Department of Pediatric Rheumatology, Istanbul University Cerrahpasa Faculty of Medicine, Istanbul, Turkey
| | - Elifsu Gözde Akbörü
- Department of Pediatrics, Faculty of Medicine, Gazi University, Ankara, Turkey
| | - Nuray Aktay Ayaz
- Department of Pediatrics, Division of Pediatric Rheumatology, Faculty of Medicine, İstanbul University, Istanbul, Turkey
| | - Emil Aliyev
- Department of Pediatrics, Division of Pediatric Rheumatology, Faculty of Medicine, Hacettepe University, Ankara, Turkey
| | - Pınar Özge Avar Aydın
- Clinic of Pediatric Rheumatology, Tekirdağ Dr İsmail Fehmi Cumalıoğlu City Hospital, Tekirdag, Turkey
| | - Fatma Aydın
- Department of Pediatrics, Division of Pediatric Rheumatology, Faculty of Medicine, Ankara University, Ankara, Turkey
| | - Özge Baba
- Department of Pediatrics, Division of Pediatric Rheumatology, Faculty of Medicine, Karadeniz Technical University, Trabzon, Turkey
| | - Esra Bağlan
- Clinic of Pediatric Rheumatology, Ankara Etlik City Hospital, Ankara, Turkey
| | - Balahan Bora Makay
- Department of Pediatrics, Division of Pediatric Rheumatology, Faculty of Medicine, Dokuz Eylül University, Izmir, Turkey
| | - Burcu Bozkaya Yücel
- Clinic of Pediatric Rheumatology, Samsun Training and Research Hospital, Samsun, Turkey
| | - Mustafa Çakan
- Clinic of Pediatric Rheumatology, Zeynep Kamil Women and Children's Diseases Training and Research Hospital, Istanbul, Turkey
| | - Elif Çelikel
- Clinic of Pediatric Rheumatology, Ankara City Hospital, Ankara, Turkey
| | - Ferhat Demir
- Clinic of Pediatric Rheumatology, Acıbadem Healthcare Group, Istanbul, Turkey
| | - Selcan Demir
- Department of Pediatrics, Division of Pediatric Rheumatology, Faculty of Medicine, Eskişehir Osmangazi University, Eskisehir, Turkey
| | - Fatma Gül Demirkan
- Department of Pediatrics, Division of Pediatric Rheumatology, Faculty of Medicine, İstanbul University, Istanbul, Turkey
| | | | - Pelin Esmeray Şenol
- Department of Pediatrics, Division of Pediatric Rheumatology, Faculty of Medicine, Gazi University, Ankara, Turkey
| | - Vefa Guliyeva
- Department of Pediatrics, Division of Pediatric Rheumatology, Faculty of Medicine, İstanbul University, Istanbul, Turkey
| | - Vildan Güngörer
- Clinic of Pediatric Rheumatology, Ankara City Hospital, Ankara, Turkey
| | - Rana İşgüder
- Department of Pediatrics, Division of Pediatric Rheumatology, Faculty of Medicine, Dokuz Eylül University, Izmir, Turkey
| | - Mukaddes Kalyoncu
- Department of Pediatrics, Division of Pediatric Rheumatology, Faculty of Medicine, Karadeniz Technical University, Trabzon, Turkey
| | - Şerife Gül Karadağ
- Department of Pediatrics, Division of Pediatric Rheumatology, Faculty of Medicine, İstanbul University, Istanbul, Turkey
| | - Hakan Kısaoğlu
- Department of Pediatrics, Division of Pediatric Rheumatology, Faculty of Medicine, Karadeniz Technical University, Trabzon, Turkey
| | - Rabia Miray Kışla Ekinci
- Department of Pediatrics, Division of Pediatric Rheumatology, Faculty of Medicine, Çukurova University, Adana, Turkey
| | - Zehra Kızıldağ
- Department of Pediatrics, Division of Pediatric Rheumatology, Faculty of Medicine, Dokuz Eylül University, Izmir, Turkey
| | - Tuba Kurt
- Clinic of Pediatric Rheumatology, Bursa City Hospital, Bursa, Turkey
| | - Semanur Özdel
- Clinic of Pediatric Rheumatology, Ankara Etlik City Hospital, Ankara, Turkey
| | - Sümeyra Özdemir Çiçek
- Department of Pediatrics, Division of Pediatric Rheumatology, Faculty of Medicine, Erciyes University, Kayseri, Turkey
| | - Kübra Öztürk
- Clinic of Pediatric Rheumatology, Göztepe Prof. Dr. Süleyman Yalçın City Hospital, Istanbul, Turkey
| | - Merve Cansu Polat
- Clinic of Pediatric Rheumatology, Ankara City Hospital, Ankara, Turkey
| | - Müge Sezer
- Clinic of Pediatric Rheumatology, Ankara Training and Research Hospital, Ankara, Turkey
| | - Hafize Emine Sönmez
- Department of Pediatrics, Division of Pediatric Rheumatology, Faculty of Medicine, Kocaeli University, Kocaeli, Turkey
| | - Betül Sözeri
- Clinic of Pediatric Rheumatology, Umraniye Training and Research Hospital, Istanbul, Turkey
| | - Seher Şener
- Department of Pediatrics, Division of Pediatric Rheumatology, Faculty of Medicine, Hacettepe University, Ankara, Turkey
| | - Sema Nur Taşkın
- Clinic of Pediatric Rheumatology, Eskişehir City Hospital, Eskisehir, Turkey
| | - Serkan Türkuçar
- Department of Pediatrics, Division of Pediatric Rheumatology, Faculty of Medicine, Pamukkale University, Denizli, Turkey
| | - Erbil Ünsal
- Department of Pediatrics, Division of Pediatric Rheumatology, Faculty of Medicine, Dokuz Eylül University, Izmir, Turkey
| | - Çisem Yıldız
- Department of Pediatrics, Division of Pediatric Rheumatology, Faculty of Medicine, Gazi University, Ankara, Turkey
| | - Sevcan A Bakkaloğlu
- Department of Pediatrics, Division of Pediatric Rheumatology, Faculty of Medicine, Gazi University, Ankara, Turkey
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Xu J, Jiao W, Wu DB, Yu JH, Liu LJ, Zhang MY, Chen GX. Yishen Tongbi decoction attenuates inflammation and bone destruction in rheumatoid arthritis by regulating JAK/STAT3/SOCS3 pathway. Front Immunol 2024; 15:1381802. [PMID: 38966637 PMCID: PMC11222394 DOI: 10.3389/fimmu.2024.1381802] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/04/2024] [Accepted: 06/07/2024] [Indexed: 07/06/2024] Open
Abstract
Background Yishen-Tongbi Decoction (YSTB), a traditional Chinese prescription, has been used to improve syndromes of rheumatoid arthritis (RA) for many years. Previous research has shown that YSTB has anti-inflammatory and analgesic properties. However, the underlying molecular mechanism of the anti-RA effects of YSTB remains unclear. Purpose and study design The purpose of this research was to investigate how YSTB affected mice with collagen-induced arthritis (CIA) and RAW264.7 cells induced with lipopolysaccharide (LPS). Results The findings show that YSTB could significantly improve the clinical arthritic symptoms of CIA mice (mitigate paw swelling, arthritis score, thymus and spleen indices, augment body weight), downregulated expression of pro-inflammatory cytokines like tumor necrosis factor-alpha (TNF-α), interleukin-1β (IL-1β), IL-6 and IL-17, while upregulated the level of anti-inflammatory like IL-10 and transforming growth factor-β (TGF-β). Meanwhile, YSTB inhibits bone erosion and reduces inflammatory cell infiltration, synovial proliferation, and joint destruction in CIA mice. In addition, we found that YSTB was able to suppress the LPS-induced inflammation of RAW264.7 cells, which was ascribed to the suppression of nitric oxide (NO) production and reactive oxygen species formation (ROS). YSTB also inhibited the production of inducible nitric oxide synthase and reduced the releases of pro-inflammatory cytokines TNF-α, IL-1β, and IL-6 in LPS-induced RAW264.7 cells. Furthermore, the phosphorylation expression of JAK2, JAK3, STAT3, p38, ERK and p65 protein could be suppressed by YSTB, while the expression of SOCS3 could be activated. Conclusion Taken together, YSTB possesses anti-inflammatory and prevention bone destruction effects in RA disease by regulating the JAK/STAT3/SOCS3 signaling pathway.
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Affiliation(s)
- Jia Xu
- First Clinical Medical School, Guangzhou University of Chinese Medicine, Guangzhou, China
| | - Wei Jiao
- First Clinical Medical School, Guangzhou University of Chinese Medicine, Guangzhou, China
| | - Dan-Bin Wu
- Department of Rheumatology, The First Affiliated Hospital of Guangzhou University of Chinese Medicine, Guangzhou, China
| | - Jia-Hui Yu
- First Clinical Medical School, Guangzhou University of Chinese Medicine, Guangzhou, China
| | - Li-Juan Liu
- Department of Rheumatology, The First Affiliated Hospital of Guangzhou University of Chinese Medicine, Guangzhou, China
| | - Ming-Ying Zhang
- Department of Rheumatology, The First Affiliated Hospital of Guangzhou University of Chinese Medicine, Guangzhou, China
| | - Guang-Xing Chen
- Department of Rheumatology, The First Affiliated Hospital of Guangzhou University of Chinese Medicine, Guangzhou, China
- Baiyun Hospital of The First Affiliated Hospital of Guangzhou University of Chinese Medicine, Guangzhou, China
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Sen R, Riofrio M, Singh JA. A narrative review of the comparative safety of disease-modifying anti-rheumatic drugs used for the treatment of rheumatoid arthritis. Expert Opin Drug Saf 2024; 23:687-714. [PMID: 38695151 DOI: 10.1080/14740338.2024.2348575] [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: 11/29/2023] [Accepted: 04/24/2024] [Indexed: 05/24/2024]
Abstract
INTRODUCTION Disease-modifying anti-rheumatic drugs (DMARDs) have improved the outcomes of patients with rheumatoid arthritis (RA). DMARDs are classified into three categories: conventional synthetic DMARDs, biological DMARDs (including biosimilars), and targeted synthetic DMARDs. DMARDs, by way of their effect on the immune system, are associated with increased risk of adverse events, including infections, malignancies, cardiovascular disease, gastrointestinal perforations, and other less common events. AREAS COVERED In this narrative literature review performed with searches of the PubMed database from 1 January 2010 through 1 January 2023, we compare the risk of safety events between DMARDs using data from both randomized clinical trials and observational studies. EXPERT OPINION DMARD use in RA is associated with higher rates of serious infections, tuberculosis reactivation, opportunistic infections, and possibly malignancies. Specific biologic DMARDs and higher doses are associated with elevated risks of various adverse events (gastrointestinal perforations, thromboembolism, serious infection). Shared decision-making is paramount when choosing a treatment regimen for patients based on their own comorbidities. JAKi are the newest class of medications used for RA with robust safety data provided in clinical trials. However, more real-world evidence and phase-IV pharmacovigilance data are needed to better understand comparative safety profile of DMARDs in RA.
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Affiliation(s)
- Rouhin Sen
- Division of Clinical Immunology and Rheumatology, The University of Alabama Birmingham, Birmingham, AL, USA
- Medicine/Rheumatology Birmingham Veterans Affairs Medical Center (VAMC), Birmingham, AL, USA
| | - Maria Riofrio
- Division of Clinical Immunology and Rheumatology, The University of Alabama Birmingham, Birmingham, AL, USA
| | - Jasvinder A Singh
- Division of Clinical Immunology and Rheumatology, The University of Alabama Birmingham, Birmingham, AL, USA
- Medicine/Rheumatology Birmingham Veterans Affairs Medical Center (VAMC), Birmingham, AL, USA
- Department of Epidemiology, UAB School of Public Health, Birmingham, AL, USA
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Marijam A, Vroom N, Bhavsar A, Posiuniene I, Lecrenier N, Vroling H. Systematic Literature Review on the Incidence of Herpes Zoster in Populations at Increased Risk of Disease in the EU/EEA, Switzerland, and the UK. Infect Dis Ther 2024; 13:1083-1104. [PMID: 38656653 PMCID: PMC11098998 DOI: 10.1007/s40121-024-00963-w] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/04/2024] [Accepted: 03/15/2024] [Indexed: 04/26/2024] Open
Abstract
INTRODUCTION Older adults and patients with underlying conditions such as immunocompromised (IC) populations (e.g., due to medical conditions or immunosuppressive medication) are at increased risk for herpes zoster (HZ). The first HZ recombinant vaccine for IC patients was approved in 2020. Limited evidence exists to inform decision-makers on HZ incidence in high-risk patients in Europe. This systematic literature review (SLR) assessed HZ incidence across 14 high-risk populations in the European Union/European Economic Area, Switzerland, and the United Kingdom. METHODS An SLR (Embase, Medline, 2002-2022, observational studies) was performed to identify HZ incidence (i.e., primary outcomes: rate or cumulative; secondary: relative incidence) in type 1 and 2 diabetes mellitus (DM); chronic obstructive pulmonary disease and asthma; depression; rheumatic disorders (RD); multiple sclerosis (MS); inflammatory bowel diseases (IBD); psoriasis; lupus; human immunodeficiency virus (HIV); solid organ transplantation (SOT); solid organ malignancy (SOM); hematologic malignancy (HM); and stem cell transplantation (SCT). RESULTS Of 776 unique records screened, 59 studies were included (24 reported incidence rate per 1000 person-years; two, cumulative incidence per 1000 persons; and 33, relative incidence). The highest incidence rates were reported for SOT (12.1-78.8) and SCT (37.2-56.1); HM (2.9-32.0); RD (0.41-21.5); lupus (11.0-16.5); IC mixed population (11.3-15.5); HIV/AIDS (11.8-13.0); chronic respiratory diseases (4.7-11.4); SOM (8.8-11.0); IBD (7.0-10.8); DM (4.3-9.4); depression (7.2-7.6); MS (5.7-6.3); and psoriasis (5.3-6.1). In many high-risk populations, HZ incidence was higher for older age groups, women, and some treatments. CONCLUSIONS The HZ incidence rate in Europe increased with age and varied across high-risk populations, with high rates for solid organ and stem cell transplants, cancer, and rheumatoid arthritis. Most studies were retrospective with methodological differences affecting generalizability and comparability. Future studies should stratify data by IC population, age, sex, severity, medication, and study timeframe.
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Affiliation(s)
| | - Nikki Vroom
- Pallas Health Research & Consultancy, A P95 Company, Rotterdam, The Netherlands
| | | | | | | | - Hilde Vroling
- Pallas Health Research & Consultancy, A P95 Company, Rotterdam, The Netherlands
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17
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Stefanski AL, Dörner T, Kneitz C. [Influence of underlying disease and immunosuppression on the immunocompetence in inflammatory rheumatic diseases]. Z Rheumatol 2024; 83:87-97. [PMID: 37644129 DOI: 10.1007/s00393-023-01408-4] [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] [Accepted: 06/04/2023] [Indexed: 08/31/2023]
Abstract
Patients with inflammatory rheumatic diseases have a higher risk of infections in comparison to the general population. For this patient group, in addition to cardiovascular diseases, infections play an important role with respect to morbidity and mortality. Even if it is difficult to make concrete statements with respect to individual diseases, it can be assumed that there is a lower risk of infections in inflammatory joint diseases in comparison to connective tissue diseases and vasculitides. The increased risk of infections is determined by multiple factors, whereby the underlying factors are classified into three main categories: patient-related factors (age, comorbidities, lifestyle), disease-related factors (immunological dysfunction as part of the disease pathophysiology) and drug-related factors (type and dosage of the immunosuppression and/or immunomodulation). An improved understanding of the complexity of these associations enables the optimization of treatment and disease control taking the individual risk factors into account, with the aim of a significant reduction in the risk of infections.
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Affiliation(s)
- A-L Stefanski
- Medizinische Klinik mit Schwerpunkt Rheumatologie und Klinische Immunologie, Charité - Universitätsmedizin Berlin, Charitéplatz 1, 10117, Berlin, Deutschland.
- Deutsches Rheuma-Forschungszentrum Berlin, Berlin, Deutschland.
| | - T Dörner
- Medizinische Klinik mit Schwerpunkt Rheumatologie und Klinische Immunologie, Charité - Universitätsmedizin Berlin, Charitéplatz 1, 10117, Berlin, Deutschland
- Deutsches Rheuma-Forschungszentrum Berlin, Berlin, Deutschland
| | - C Kneitz
- Rheumatologische Schwerpunktpraxis Schwerin, Schwerin, Deutschland
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Abstract
Rheumatoid arthritis (RA) is one of the most common immune mediated inflammatory diseases. People with rheumatoid arthritis present with pain, swelling, and stiffness that typically affects symmetrically distributed small and large joints. Without effective treatment, significant joint damage, disability, and work loss develop, owing to chronic inflammation of the joint lining (synovium). Over the past 25 years, the management of this condition has been revolutionized, resulting in substantially higher levels of disease remission and better long term outcomes. This improvement reflects a paradigm shift towards early and aggressive pharmacological intervention coupled with a proliferation in treatment choice, in turn related to enhanced pathobiological understanding and the advent of new drugs for rheumatoid arthritis. Following an overview of these developments from a historical perspective, and with a general audience in mind, this review focuses on newer, targeted treatments in an ever evolving landscape. The review highlights ongoing areas of debate and unmet need, including the proportion of patients with persistent, difficult-to-treat disease, despite recent advances. Also discussed are personalized, strategic approaches to individual patients, the role for imaging in clinical decision making, and the goal of sustained, drug free remission and disease prevention in the future.
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Affiliation(s)
- Philip Brown
- Translational and Clinical Research Institute, Newcastle University, Newcastle upon Tyne, UK
- National Institute for Health and Care Research Newcastle Biomedical Research Centre, Newcastle University, Newcastle upon Tyne Hospitals and Cumbria, Northumberland; and Tyne and Wear NHS Foundation Trusts, Newcastle upon Tyne, UK
| | - Arthur G Pratt
- Translational and Clinical Research Institute, Newcastle University, Newcastle upon Tyne, UK
- National Institute for Health and Care Research Newcastle Biomedical Research Centre, Newcastle University, Newcastle upon Tyne Hospitals and Cumbria, Northumberland; and Tyne and Wear NHS Foundation Trusts, Newcastle upon Tyne, UK
| | - Kimme L Hyrich
- Centre for Musculoskeletal Research, University of Manchester, Manchester Academic Health Sciences Centre, Manchester, UK
- National Institute for Health and Care Research Manchester Biomedical Research Centre, Manchester University Hospitals NHS Foundation Trust, Manchester, UK
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Morel J. Infection prevention and vaccination in the rheumatic diseases. Joint Bone Spine 2023; 90:105568. [PMID: 36990142 DOI: 10.1016/j.jbspin.2023.105568] [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] [Accepted: 07/05/2022] [Indexed: 03/29/2023]
Abstract
Patients with chronic inflammatory rheumatisms (CIR) have a higher risk of infections compared to healthy subjects. Viral and bacterial pneumonia are the most frequent infections observed in CIR with targeted disease modifying anti-rheumatic drugs (DMARDs). Moreover, drugs used to treat CIR (especially biologic and synthetic targeted DMARDs) increase the risk of infection and expose CIR patients to opportunistic infections such as tuberculosis reactivation. To limit the risk of infection, the risk-benefit ratio should be evaluated for each patient based on their characteristics and comorbidities. To prevent infections, an initial pre-treatment work-up must be performed, especially before the initiation of conventional synthetic DMARDs or biological and synthetic targeted DMARDs. This pre-treatment assessment includes the case history, laboratory and radiology findings as well. The physician must make sure a patient's vaccinations are up-to-date. The vaccines recommended for patients with CIR being treated with conventional synthetic DMARDs, bDMARDs, tsDMARDs and/or steroids should be given. Patient education is also very important. During workshops, they learn how to manage their drug treatments in at-risk situations and learn which symptoms require treatment discontinuation.
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Affiliation(s)
- Jacques Morel
- Rheumatology Department, CHU and University of Montpellier, PhyMedExp, Inserm, CNRS, Montpellier, France.
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Taylor PC, Laedermann C, Alten R, Feist E, Choy E, Haladyj E, De La Torre I, Richette P, Finckh A, Tanaka Y. A JAK Inhibitor for Treatment of Rheumatoid Arthritis: The Baricitinib Experience. J Clin Med 2023; 12:4527. [PMID: 37445562 DOI: 10.3390/jcm12134527] [Citation(s) in RCA: 11] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/06/2023] [Revised: 06/22/2023] [Accepted: 06/26/2023] [Indexed: 07/15/2023] Open
Abstract
Baricitinib, an oral selective Janus kinase (JAK)1/JAK2 inhibitor, is approved as monotherapy or in combination with methotrexate for treating adults with moderate-to-severe active rheumatoid arthritis (RA) and provides improvements in clinical signs, symptoms and patient-reported outcomes. Currently, baricitinib is approved for treating RA in more than 75 countries. In several pivotal Phase II and III RA trials (RA-BALANCE, RA-BEGIN, RA-BEAM, RA-BUILD, RA-BEACON, RA-BEYOND), up to seven years of baricitinib treatment was well tolerated and provided rapid and sustained efficacy, which was confirmed in real-world settings. Safety signals for another JAK inhibitor, tofacitinib, have emerged, as observed in the post-marketing Phase IIIb/IV trial Oral Rheumatoid Arthritis Trial (ORAL) Surveillance; safety signals were subsequently highlighted in a retrospective study of baricitinib and consequently new recommendations and warnings and precautions for all JAK inhibitors have been issued. Ongoing studies to further characterise and clarify the benefit:risk of JAK inhibitors include registries and controlled trials. This capstone review summarises clinical and real-world data outlining the benefit:risk profile of baricitinib, confirming that the improved disease activity and physical function of patients with RA treated with this JAK inhibitor observed in clinical trials is translated into effectiveness in clinical practice, with a low rate of discontinuations.
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Affiliation(s)
- Peter C Taylor
- Botnar Research Centre, Nuffield Department of Orthopaedics, Rheumatology, and Musculoskeletal Sciences, University of Oxford, Oxford OX3 7LD, UK
| | | | - Rieke Alten
- Internal Medicine II, Rheumatology, SCHLOSSPARK-KLINIK, University Medicine Berlin, 14059 Berlin, Germany
| | - Eugen Feist
- Department of Rheumatology, Helios Clinic Vogelsang-Gommern, Cooperation Partner of the Otto-von-Guericke University Magdeburg, 39245 Magdeburg, Germany
| | - Ernest Choy
- Division of Infection and Immunity, Cardiff University School of Medicine, Cardiff CF14 4YS, UK
| | - Ewa Haladyj
- Eli Lilly and Company, Indianapolis, IN 46285, USA
| | | | - Pascal Richette
- Service de Rhumatologie, Hôpital Lariboisière, 75010 Paris, France
- Inserm, UMR-S 1132, Bioscar, Université de Paris, 75010 Paris, France
| | - Axel Finckh
- Division of Rheumatology, Department of Medicine, Geneva University Hospitals, 1205 Geneva, Switzerland
| | - Yoshiya Tanaka
- First Department of Internal Medicine, University of Occupational and Environmental Health, Kitakyushu 807-0804, Japan
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Xu K, Qin X, Zhang Y, Yang M, Zheng H, Li Y, Yang X, Xu Q, Li Y, Xu P, Wang X. Lycium ruthenicum Murr. anthocyanins inhibit hyperproliferation of synovial fibroblasts from rheumatoid patients and the mechanism study powered by network pharmacology. PHYTOMEDICINE : INTERNATIONAL JOURNAL OF PHYTOTHERAPY AND PHYTOPHARMACOLOGY 2023; 118:154949. [PMID: 37418838 DOI: 10.1016/j.phymed.2023.154949] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 02/15/2023] [Revised: 06/01/2023] [Accepted: 07/01/2023] [Indexed: 07/09/2023]
Abstract
BACKGROUND Rheumatoid arthritis (RA), is a typical autoimmune disease affecting nearly 1% of the world's population. The dysfunctional hyperproliferation of synovial fibroblast (SF) in articular cartilage of RA patients is considered as the essential etiology. Traditional chemotherapeutic agents for RA treatment are imperfect for their high cost and unpredictable side-effects. L. ruthenicum anthocyanins (LRAC) is a natural product that of potential for therapeutic application against RA. METHODS LRAC was characterized by UPLC-MS/MS. Bioinformatics analyses based on network pharmacology were applied to predict the potential targets of LRAC, and to select DEGs (differentially expressed genes) caused by RA pathogenesis from GSE77298. Interactions between LRAC and the predicted targets were evaluated by molecular docking. Effects of LRAC on SFs from RA patients were examined by in vitro assays, which were analyzed by flow cytometry and western blotting (WB). RESULTS LRAC was able to inhibit the abnormal proliferation and aggressive invasion of SFs from RA patients. LRAC was mainly constituted by petunidin (82.7%), with small amount of delphinidin (12.9%) and malvidin (4.4%) in terms of anthocyanidin. Bioinformatics analyses showed that in 3738 RA-related DEGs, 58 of them were collectively targeted by delphinidin, malvidin and delphinidin. AR, CDK2, CHEK1, HIF1A, CXCR4, MMP2 and MMP9, the seven hub genes constructed a central network mediating the signal transduction. Molecular docking confirmed the high affinities between the LRAC ligands and the protein receptors encoded by the hub genes. The in vitro assays validated that LRAC repressed the growth of RASF by cell cycle arresting and cell invasion paralyzing (c-Myc/p21/CDK2), initiating cell apoptosis (HIF-1α/CXCR4/Bax/Bcl-2), and inducing pyroptosis via ROS-dependent pathway (NOX4/ROS/NLRP3/IL-1β/Caspase-1). CONCLUSION LRAC can selectively inhibit the proliferation of RASFs, without side-effecting immunosuppression that usually occurred for RA treatment using MTX (methotrexate). These findings demonstrate the potential application of LRAC as a phytomedicine for RA treatment, and provide a valid approach for exploring natural remedies against autoimmune diseases.
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Affiliation(s)
- Ke Xu
- Department of Joint Surgery, Hong Hui Hospital, Xi'an Jiaotong University, Xi'an, Shaanxi 710054, China
| | - Xinshu Qin
- College of Food Engineering and Nutritional Science, Shaanxi Normal University, Xi'an, Shaanxi 710062, China
| | - Yi Zhang
- Department of Food Science, The Pennsylvania State University, University Park, PA 16802, USA
| | - Mingyi Yang
- Department of Joint Surgery, Hong Hui Hospital, Xi'an Jiaotong University, Xi'an, Shaanxi 710054, China
| | - Haishi Zheng
- Department of Joint Surgery, Hong Hui Hospital, Xi'an Jiaotong University, Xi'an, Shaanxi 710054, China
| | - Yinglei Li
- College of Food Engineering and Nutritional Science, Shaanxi Normal University, Xi'an, Shaanxi 710062, China
| | - Xingbin Yang
- College of Food Engineering and Nutritional Science, Shaanxi Normal University, Xi'an, Shaanxi 710062, China
| | - Qin Xu
- College of Food Engineering and Nutritional Science, Shaanxi Normal University, Xi'an, Shaanxi 710062, China
| | - Ying Li
- College of Food Engineering and Nutritional Science, Shaanxi Normal University, Xi'an, Shaanxi 710062, China
| | - Peng Xu
- Department of Joint Surgery, Hong Hui Hospital, Xi'an Jiaotong University, Xi'an, Shaanxi 710054, China.
| | - Xingyu Wang
- College of Food Engineering and Nutritional Science, Shaanxi Normal University, Xi'an, Shaanxi 710062, China.
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Jo JC, Jeon Y, Kim D, Yang DH, Lee WS, Choi YS, Yi JH, Yoon DH, Kong JH, Choe JY, Kim S, Ahn K, Park T, Ju H, Kwon S, Cho SG. A non-interventional, post-marketing surveillance study evaluating the safety and effectiveness of biosimilar rituximab (CT-P10) during routine clinical practice in the Republic of Korea. Expert Opin Biol Ther 2023; 23:737-747. [PMID: 36757373 DOI: 10.1080/14712598.2023.2177101] [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: 09/13/2022] [Accepted: 02/02/2023] [Indexed: 02/10/2023]
Abstract
BACKGROUND CT-P10 was the first licensed rituximab biosimilar. This Korean post-marketing surveillance study evaluated CT-P10 safety and effectiveness in approved indications. RESEARCH DESIGN AND METHODS This prospective, open-label, observational, phase 4 study collected routine clinical practice data across 27 centers in the Republic of Korea. Patients received their first CT-P10 treatment, per prescribing information, for non-Hodgkin's lymphoma (NHL), chronic lymphocytic leukemia (CLL), rheumatoid arthritis (RA), granulomatosis with polyangiitis (GPA), or microscopic polyangiitis (MPA) during the surveillance period (16 November 2016-15 November 2020). Safety (including adverse events [AEs] and adverse drug reactions [ADRs]) and disease-specific clinical response (by best overall response [NHL/CLL], Disease Activity Score in 28-joints [RA], or Birmingham Vasculitis Activity Score for Wegener's Granulomatosis [GPA/MPA]) were assessed for ≤1 year (NHL/CLL) or ≤24 weeks (RA/GPA/MPA). RESULTS The safety population comprised 677 patients (604 NHL, 16 CLL, 42 RA, 7 GPA, 8 MPA). AEs/ADRs were reported for 68.4%/27.7% (NHL/CLL), 31.0%/14.3% (RA), and 86.7%/13.3% (GPA/MPA) of patients. Serious AEs and unexpected ADRs did not raise new safety signals. Pneumonia was the most frequent serious ADR overall. Positive effectiveness outcomes were observed. CONCLUSIONS Findings were consistent with the known CT-P10/reference rituximab safety profile, with high effectiveness observed in NHL/CLL and RA.
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Affiliation(s)
- Jae-Cheol Jo
- Department of Hematology and Oncology, Ulsan University Hospital, University of Ulsan College of Medicine, Ulsan, Republic of Korea
| | - Youngwoo Jeon
- Department of Hematology, Lymphoma and Cell Therapy-Research Center, Yeouido St. Mary's Hospital, The Catholic University of Korea, Seoul, Republic of Korea
| | - DaJung Kim
- Department of Internal Medicine, Kosin University College of Medicine, Kosin University, Seo-gu, Busan, Republic of Korea
| | - Deok-Hwan Yang
- Department of Hematology-Oncology, Chonnam National University Hwasun Hospital, Chonnam National University Medical School, Hwasun-gun, Jeollanam-do, Republic of Korea
| | - Won Sik Lee
- Department of Internal Medicine, Hemato-oncology, Inje University Busan Paik Hospital, Busangjin-gu, Busan, Republic of Korea
| | - Yoon Seok Choi
- Department of Hematology-Oncology, Ajou University Hospital, Suwon, Gyeonggi-do, Republic of Korea
| | - Jun Ho Yi
- Department of Internal Medicine, Division of Hematology and Oncology, Chung-ang University Hospital, Dongjak-gu, Seoul, Republic of Korea
| | - Dok Hyun Yoon
- Department of Oncology, Asan Medical Center, Songpa-gu, Seoul, Republic of Korea
| | - Jee Hyun Kong
- Department of Hematology-Oncology, Division of Internal Medicine, Wonju Severance Christian Hospital, Wonju, Gangwon-do, Republic of Korea
| | - Jung-Yoon Choe
- Department of Internal Medicine, Daegu Catholic University School of Medicine, Nam-gu, Daegu, Republic of Korea
| | - SungHyun Kim
- Celltrion, Inc., Yeonsu-gu, Incheon, Republic of Korea
| | - KeumYoung Ahn
- Celltrion, Inc., Yeonsu-gu, Incheon, Republic of Korea
| | - TaeHong Park
- Celltrion, Inc., Yeonsu-gu, Incheon, Republic of Korea
| | - Hana Ju
- Celltrion, Inc., Yeonsu-gu, Incheon, Republic of Korea
| | - Soonbum Kwon
- Celltrion, Inc., Yeonsu-gu, Incheon, Republic of Korea
| | - Seok-Goo Cho
- Department of Hematology, Seoul St. Mary's Hospital, The Catholic University of Korea, Seocho-gu, Seoul, Republic of Korea
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23
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Utility of Opportunistic Infections, Joints' Involvement and Accuracy of Various Screening Tests to Diagnose Rheumatoid Arthritis Patients. MEDICINA (KAUNAS, LITHUANIA) 2023; 59:medicina59020367. [PMID: 36837567 PMCID: PMC9964989 DOI: 10.3390/medicina59020367] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 11/13/2022] [Revised: 01/02/2023] [Accepted: 01/29/2023] [Indexed: 02/17/2023]
Abstract
Background and Objectives: Rheumatoid Arthritis (RA) is an auto-immune disease in which the body mistakenly considers some parts of its own system as pathogens and attacks them. Prevalence is approximately 0.75% in India. About 40% of the diseased become work disabled within 5 years from the onset of symptoms. The objective of this paper is to assess the sign/symptoms, joints' involvement, difficulties in daily activities and screening accuracy of serology tests of clinically suspected RA patients. Material and Methods: A cross-sectional cohort study design was conducted on two hundred ninety clinically suspected subjects who were referred by different OPDs of hospitals for screening. The profiles of study subjects were carried through a semi-structured, pre-tested schedule method. About 2 mL of blood samples were collected in a plain vial from each patient and tested for diagnostic tests RF, CRP and AntiCCP by using RF-Latex, CRP Latex and ELISA method, respectively, by the laboratory persons. Results: Joint pain shows to be a leading problem in RA as compared to other signs and symptoms. The majority of the study subjects suffer from knee problems (62%). Approximately equal numbers of RA-positive cases were screened by RF and AntiCCP tests. The CRP test screened about one-third of cases. CRP+ AntiCCP, RF+ AntiCCP and RF + CRP all have good sensitivity, and RF+ AntiCCP + CRP has a very high sensitivity for diagnosing RA. Conclusions: This study found that a substantiation of a major proportion of clinically suspected RA patients were suffering from knee pain. Predication of AntiCCP increased the possibility for the diagnosis of RA. However, RF was also moderately related to the diagnosis of RA, and the combination of both tests was more valuable.
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24
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Rising incidence of Pneumocystis pneumonia: A population-level descriptive ecological study in England. J Infect 2023; 86:385-390. [PMID: 36775251 DOI: 10.1016/j.jinf.2023.02.014] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/12/2022] [Revised: 02/02/2023] [Accepted: 02/08/2023] [Indexed: 02/12/2023]
Abstract
OBJECTIVES Pneumocystis pneumonia (PCP) is an opportunistic infection that causes significant morbidity and mortality in the immunocompromised population. This population is growing and diversifying, yet contemporary epidemiology is lacking. We investigated the population-level incidence of PCP over the past decade. METHODS We conducted a descriptive study of all hospital admissions in England from April 2012 to March 2022. PCP episodes, age, median length of stay, gender and episodes of other respiratory fungal infections were collected. Consumption of Trimethoprim-Sulfamethoxazole was obtained between January 2019 and May 2022. RESULTS The incidence of PCP increased from 2·2-4·5/100,000 population between 2012/2013 and 2019/2020 (p < 0·0001). There was a drop in 2020/2021 to 2·7/100,000 before returning to 3.9/100,000 in 2021/2022. PCP episodes rose as a proportion of all-cause admissions as well as a proportion of episodes due to other fungal infections. The proportion of PCP patients aged 75+ increased from 14% to 26%. The median length of stay was 13.5 days. Consumption of intravenous Trimethoprim-Sulfamethoxazole increased from 0.24 × 100,000 to 0.30 × 100,000 defined daily doses. CONCLUSIONS The incidence of PCP is rising rapidly and represents a significant burden to the healthcare system. Further study into who is at risk of PCP is needed to better determine who should be given prophylaxis.
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Jahnich N, Arkwright PD. Regional risk of tuberculosis and viral hepatitis with tumor necrosis factor-alpha inhibitor treatment: A systematic review. Front Pharmacol 2023; 14:1046306. [PMID: 36744250 PMCID: PMC9894886 DOI: 10.3389/fphar.2023.1046306] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/16/2022] [Accepted: 01/05/2023] [Indexed: 01/21/2023] Open
Abstract
Background: TNFα inhibitors are regularly used to treat autoimmune diseases. Tuberculosis (TB) and viral hepatitis B are considered potential infectious complications, and screening and surveillance are therefore recommended. Current guidelines do not take into account regional differences in endemicity of these infections. Methods: A systematic literature review of TB and viral hepatitis in patients receiving TNFα-inhibitors was performed, searching in PubMed, Embase, MEDLINE and Web of Science databases. Studies were selected against predefined eligibility criteria and assessed using the Newcastle-Ottawa scale. The number of TB and viral hepatitis cases/1,000 TNFα-inhibitor patients were evaluated, and regional variation compared. Results: 105 observational studies involving over 140,000 patients were included. Overall, 1% of patients developed TB or viral hepatitis B. TB cases/1,000 TNFα-inhibitor patients were 4-fold higher in Asia, Africa, and South America than in Europe, North America, and Australasia where only 0%-0.4% of patients developed TB. Hepatitis B cases/1,000 patients were over 15-fold higher in countries with high prevalence (China, Taiwan, South Korea, Thailand) compared with low prevalence (p < 0.00001) where only 0.4% of patients developed hepatitis B. Only three of 143 patients developed viral hepatitis C, and there was insufficient data to allow regional sub-analysis. Conclusion: TB and viral hepatitis B infections in patients treated with TNFα inhibitors are largely confined to countries with high prevalence of these infections. As only 1/2,500 patients in low prevalence countries treated with TNFα inhibitors develop TB or viral hepatitis B, we suggest an individualized, risk-based approach, rather than universal screening for all patients.
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Affiliation(s)
| | - Peter D. Arkwright
- Lydia Becker Institute of Immunology and Inflammation, Manchester Incubator Building, University of Manchester, Manchester, United Kingdom
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Van Meerhaeghe T, Néel A, Brouard S, Degauque N. Regulation of CD8 T cell by B-cells: A narrative review. Front Immunol 2023; 14:1125605. [PMID: 36969196 PMCID: PMC10030846 DOI: 10.3389/fimmu.2023.1125605] [Citation(s) in RCA: 7] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/16/2022] [Accepted: 02/27/2023] [Indexed: 03/29/2023] Open
Abstract
Activation of CD4 T cells by B cells has been extensively studied, but B cell-regulated priming, proliferation, and survival of CD8 T cells remains controversial. B cells express high levels of MHC class I molecules and can potentially act as antigen-presenting cells (APCs) for CD8 T cells. Several in vivo studies in mice and humans demonstrate the role of B cells as modulators of CD8 T cell function in the context of viral infections, autoimmune diseases, cancer and allograft rejection. In addition, B-cell depletion therapies can lead to impaired CD8 T-cell responses. In this review, we attempt to answer 2 important questions: 1. the role of B cell antigen presentation and cytokine production in the regulation of CD8 T cell survival and cell fate determination, and 2. The role of B cells in the formation and maintenance of CD8 T cell memory.
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Affiliation(s)
- Tess Van Meerhaeghe
- Department of Nephrology, Hôpital Erasme, Université libre de Bruxelles, Brussels, Belgium
- Nantes Université, INSERM, Center for Research in Transplantation and Translational Immunology (CR2TI), UMR 1064, Nantes, France
| | - Antoine Néel
- Nantes Université, INSERM, Center for Research in Transplantation and Translational Immunology (CR2TI), UMR 1064, Nantes, France
- Internal Medicine Department, Nantes University Hospital, Nantes, France
| | - Sophie Brouard
- Nantes Université, INSERM, Center for Research in Transplantation and Translational Immunology (CR2TI), UMR 1064, Nantes, France
| | - Nicolas Degauque
- Nantes Université, INSERM, Center for Research in Transplantation and Translational Immunology (CR2TI), UMR 1064, Nantes, France
- *Correspondence: Nicolas Degauque,
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27
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Blincoe A, Labrosse R, Abraham RS. Acquired B-cell deficiency secondary to B-cell-depleting therapies. J Immunol Methods 2022; 511:113385. [PMID: 36372267 DOI: 10.1016/j.jim.2022.113385] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/19/2022] [Revised: 09/26/2022] [Accepted: 10/17/2022] [Indexed: 11/13/2022]
Abstract
The advantage of the newer biological therapies is that the immunosuppressive effect is targeted, in contrast, to the standard, traditional immunomodulatory agents, which have a more global effect. However, there are unintended targets and consequences, even to these "precise" therapeutics, leading to acquired or secondary immunodeficiencies. Besides depleting specific cellular immune subsets, these biological agents, which include monoclonal antibodies against biologically relevant molecules, often have broader functional immune consequences, which become apparent over time. This review focuses on acquired B-cell immunodeficiency, secondary to the use of B-cell depleting therapeutic agents. Among the many adverse consequences of B-cell depletion is the risk of hypogammaglobulinemia, failure of B-cell recovery, impaired B-cell differentiation, and risk of infections. Factors, which modulate the outcomes of B-cell depleting therapies, include the intrinsic nature of the underlying disease, the concomitant use of other immunomodulatory agents, and the clinical status of the patient and other co-existing morbidities. This article seeks to explore the mechanism of action of B-cell depleting agents, the clinical utility and adverse effects of these therapies, and the relevance of systematic and serial laboratory immune monitoring in identifying patients at risk for developing immunological complications, and who may benefit from early intervention to mitigate the secondary consequences. Though these biological drugs are gaining widespread use, a harmonized approach to immune evaluation pre-and post-treatment has not yet gained traction across multiple clinical specialties, because of which, the true prevalence of these adverse events cannot be determined in the treated population, and a systematic and evidence-based dosing schedule cannot be developed. The aim of this review is to bring these issues into focus, and initiate a multi-specialty, data-driven approach to immune monitoring.
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Affiliation(s)
- Annaliesse Blincoe
- Department of Paediatric Immunology and Allergy, Starship Child Health, Auckland, NZ, New Zealand
| | - Roxane Labrosse
- Department of Pediatrics, CHU Sainte-Justine, University of Montreal, Montreal, Canada
| | - Roshini S Abraham
- Department of Pathology and Laboratory Medicine, Nationwide Children's Hospital, Columbus, OH, USA.
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Nasonov EL, Feist E. The prospects of interleukin-6 inhibition in rheumatoid arthritis: Olokizumab (novel monoclonal antibodies to IL-6). RHEUMATOLOGY SCIENCE AND PRACTICE 2022. [DOI: 10.47360/1995-4484-2022-505-518] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 11/15/2022]
Abstract
Rheumatoid arthritis (RA) is a chronic immune-mediated rheumatic diseases (IMRDs) manifested with progressive destruction of joints, systemic inflammation of visceral organs and a wide range of co-morbidities associated with chronic inflammation. Among the cytokines involved in the pathogenesis of RA and certain other IMRDs, the role of interleukin (IL) 6 is of special interest. The introduction of mAbs tocilizumab (TCZ) and later sarilumab (SAR), both blocking the receptor of this cytokine, into clinical practice was an important achievement in the treatment of IIRDs at the beginning of the 21st century. As a novel approach in the treatment of RA, the humanized mAb against IL-6 olokizumab (OKZ) is in development by the Russian company R-PHARM under the license agreement with UCB Pharma. The review examines new data on efficacy and safety of OKZ in RA and the prospects of its use in rheumatology
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Affiliation(s)
- E. L. Nasonov
- V.A. Nasonova Research Institute of Rheumatology; I.M. Sechenov First Moscow State Medical University of the Ministry of Health Care of Russian Federation (Sechenov University)
| | - Eugen Feist
- Department of Rheumatology, Helios Clinic VogelsangGommern, cooperation partner of the Otto-vonGuericke University Magdeburg
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29
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Gagliardi A, Iaquinta FS, Grembiale RD, De Sarro C, Fabiano A, Fraija D, Palleria C, Romeo R, De Francesco AE, Naturale MD, Citraro R, Gallelli L, Leo A, De Sarro G. Real-World Safety Profile of Biologics Used in Rheumatology: A Six-Year Observational Pharmacovigilance Study in the Calabria Region. Pharmaceutics 2022; 14:2328. [PMID: 36365146 PMCID: PMC9697719 DOI: 10.3390/pharmaceutics14112328] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/30/2022] [Revised: 10/19/2022] [Accepted: 10/26/2022] [Indexed: 08/10/2023] Open
Abstract
Background: The introduction of biological agents into the clinical armamentarium has modified the management of moderate-severe inflammatory arthritis (IA). However, these drugs can lead to serious adverse events (SAEs) and unpredictable adverse events (AEs) that are difficult to detect in pre-marketing clinical trials. This pharmacovigilance project aimed to study the AEs associated with biologics use in rheumatology. Methods: The current investigation is a multicenter, prospective, observational cohort study based on the Calabria Biologics Pharmacovigilance Program. Patients treated with one biologic agent from January 2016 to January 2022 were enrolled. Results: Overall, 729 (86.3%) of a total of 872 patients did not develop AEs or SAEs, whereas 143 (16.4%) patients experienced at least one AE, of which 16 (1.8%) had at least one SAE. The most common AEs were administration site conditions followed by gastrointestinal, nervous system and skin disorders. We reported a total of 173 switches and 156 swaps. Switches mainly occurred for inefficacy (136; 77.7%), whereas only 39 (22.3%) were due to the onset of an AE. Primary/secondary failure was the most frequent reason for swaps (124, 79%), while AEs onset led to 33 (21%) swaps. Conclusions: This study supports the validity of our program in monitoring and detecting AEs in the rheumatological area, confirming the positive beneficial/risk ratio of biologics.
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Affiliation(s)
- Agnese Gagliardi
- Department of Health Sciences, School of Medicine and Surgery, Magna Graecia University of Catanzaro, 88100 Catanzaro, Italy
| | - Francesco Salvatore Iaquinta
- Department of Health Sciences, School of Medicine and Surgery, Magna Graecia University of Catanzaro, 88100 Catanzaro, Italy
| | - Rosa Daniela Grembiale
- Department of Health Sciences, School of Medicine and Surgery, Magna Graecia University of Catanzaro, 88100 Catanzaro, Italy
| | - Caterina De Sarro
- Department of Health Sciences, School of Medicine and Surgery, Magna Graecia University of Catanzaro, 88100 Catanzaro, Italy
| | - Antonio Fabiano
- Department of Health Sciences, School of Medicine and Surgery, Magna Graecia University of Catanzaro, 88100 Catanzaro, Italy
| | - Domenico Fraija
- Department of Health Sciences, School of Medicine and Surgery, Magna Graecia University of Catanzaro, 88100 Catanzaro, Italy
| | - Caterina Palleria
- Department of Health Sciences, School of Medicine and Surgery, Magna Graecia University of Catanzaro, 88100 Catanzaro, Italy
| | - Rossella Romeo
- Department of Health Sciences, School of Medicine and Surgery, Magna Graecia University of Catanzaro, 88100 Catanzaro, Italy
| | | | | | - Rita Citraro
- Department of Health Sciences, School of Medicine and Surgery, Magna Graecia University of Catanzaro, 88100 Catanzaro, Italy
- System and Applied Pharmacology@University Magna Grecia (FAS@UMG) Research Center, Science of Health Department, School of Medicine, Magna Graecia University of Catanzaro, 88100 Catanzaro, Italy
| | - Luca Gallelli
- Department of Health Sciences, School of Medicine and Surgery, Magna Graecia University of Catanzaro, 88100 Catanzaro, Italy
- System and Applied Pharmacology@University Magna Grecia (FAS@UMG) Research Center, Science of Health Department, School of Medicine, Magna Graecia University of Catanzaro, 88100 Catanzaro, Italy
| | - Antonio Leo
- Department of Health Sciences, School of Medicine and Surgery, Magna Graecia University of Catanzaro, 88100 Catanzaro, Italy
- System and Applied Pharmacology@University Magna Grecia (FAS@UMG) Research Center, Science of Health Department, School of Medicine, Magna Graecia University of Catanzaro, 88100 Catanzaro, Italy
| | - Giovambattista De Sarro
- Department of Health Sciences, School of Medicine and Surgery, Magna Graecia University of Catanzaro, 88100 Catanzaro, Italy
- System and Applied Pharmacology@University Magna Grecia (FAS@UMG) Research Center, Science of Health Department, School of Medicine, Magna Graecia University of Catanzaro, 88100 Catanzaro, Italy
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Kastrati K, Aletaha D, Burmester GR, Chwala E, Dejaco C, Dougados M, McInnes IB, Ravelli A, Sattar N, Stamm TA, Takeuchi T, Trauner M, van der Heijde D, Voshaar MJH, Winthrop K, Smolen JS, Kerschbaumer A. A systematic literature review informing the consensus statement on efficacy and safety of pharmacological treatment with interleukin-6 pathway inhibition with biological DMARDs in immune-mediated inflammatory diseases. RMD Open 2022; 8:rmdopen-2022-002359. [PMID: 36260501 PMCID: PMC9462104 DOI: 10.1136/rmdopen-2022-002359] [Citation(s) in RCA: 21] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/22/2022] [Accepted: 07/30/2022] [Indexed: 11/08/2022] Open
Abstract
Objectives Informing an international task force updating the consensus statement on efficacy and safety of biological disease-modifying antirheumatic drugs (bDMARDs) selectively targeting interleukin-6 (IL-6) pathway in the context of immune-mediated inflammatory diseases. Methods A systematic literature research of all publications on IL-6 axis inhibition with bDMARDs published between January 2012 and December 2020 was performed using MEDLINE, EMBASE and Cochrane CENTRAL databases. Efficacy and safety outcomes were assessed in clinical trials including their long-term extensions and observational studies. Meeting abstracts from ACR, EULAR conferences and results on clinicaltrials.gov were taken into consideration. Results 187 articles fulfilled the inclusion criteria. Evidence for positive effect of IL-6 inhibition was available in various inflammatory diseases such as rheumatoid arthritis, juvenile idiopathic arthritis, giant cell arteritis, Takayasu arteritis, adult-onset Still’s disease, cytokine release syndrome due to chimeric antigen receptor T cell therapy and systemic sclerosis-associated interstitial lung disease. Newcomers like satralizumab and anti-IL-6 ligand antibody siltuximab have expanded therapeutic approaches for Castleman’s disease and neuromyelitis optica, respectively. IL-6 inhibition did not provide therapeutic benefits in psoriatic arthritis, ankylosing spondylitis and certain connective tissue diseases. In COVID-19, tocilizumab (TCZ) has proven to be therapeutic in advanced disease. Safety outcomes did not differ from other bDMARDs, except higher risks of diverticulitis and lower gastrointestinal perforations. Inconsistent results were observed in several studies investigating the risk for infections when comparing TCZ to TNF-inhibitors. Conclusion IL-6 inhibition is effective for treatment of several inflammatory diseases with a safety profile that is widely comparable to other bDMARDs.
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Affiliation(s)
- Kastriot Kastrati
- Division of Rheumatology, Department of Medicine III, Medical University of Vienna, Wien, Austria
| | - Daniel Aletaha
- Division of Rheumatology, Department of Medicine III, Medical University of Vienna, Wien, Austria
| | - Gerd R Burmester
- Rheumatology and Clinical Immunology, Charite University Hospital Berlin, Berlin, Germany
| | - Eva Chwala
- University Library, Medical University of Vienna, Wien, Austria
| | - Christian Dejaco
- Rheumatology, Medical University of Graz, Graz, Austria
- Rheumatology, Hospital of Bruneck, Bruneck, Italy
| | - Maxime Dougados
- Hopital Cochin, Rheumatology, Université Paris Descartes, Paris, France
| | - Iain B McInnes
- Institute of Infection, Immunity & Inflammation, University of Glasgow, Glasgow, UK
| | - Angelo Ravelli
- UO Pediatria II-Reumatologia, Istituto Giannina Gaslini, Genova, Italy
| | - Naveed Sattar
- Glasgow Cardiovascular Research Center, University of Glasgow, Glasgow, UK
| | - Tanja A Stamm
- Section for Outcomes Research, Medical University of Vienna, Vienna, Austria
| | - Tsutomu Takeuchi
- Division of Rheumatology, Department of Internal Medicine, Keio University School of Medicine Graduate School of Medicine, Shinjuku-ku, Japan
| | - Michael Trauner
- Division of Gastroenterology and Hepatology, Medical University of Vienna Department of Medicine III, Wien, Austria
| | | | - Marieke J H Voshaar
- Department of Pharmacy and Department of Research & Innovation, Sint Maartenskliniek, Ubbergen, The Netherlands
- Department of Pharmacy, Radboud University Medical Center, Nijmegen, The Netherlands
| | - Kevin Winthrop
- Schools of Medicine and Public Health, Oregon Health and Science University, Portland, Oregon, USA
| | - Josef S Smolen
- Division of Rheumatology, Department of Medicine III, Medical University of Vienna, Wien, Austria
| | - Andreas Kerschbaumer
- Division of Rheumatology, Department of Medicine III, Medical University of Vienna, Wien, Austria
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31
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Aletaha D, Kerschbaumer A, Kastrati K, Dejaco C, Dougados M, McInnes IB, Sattar N, Stamm TA, Takeuchi T, Trauner M, van der Heijde D, Voshaar M, Winthrop KL, Ravelli A, Betteridge N, Burmester GRR, Bijlsma JW, Bykerk V, Caporali R, Choy EH, Codreanu C, Combe B, Crow MK, de Wit M, Emery P, Fleischmann RM, Gabay C, Hetland ML, Hyrich KL, Iagnocco A, Isaacs JD, Kremer JM, Mariette X, Merkel PA, Mysler EF, Nash P, Nurmohamed MT, Pavelka K, Poor G, Rubbert-Roth A, Schulze-Koops H, Strangfeld A, Tanaka Y, Smolen JS. Consensus statement on blocking interleukin-6 receptor and interleukin-6 in inflammatory conditions: an update. Ann Rheum Dis 2022; 82:773-787. [PMID: 35953263 DOI: 10.1136/ard-2022-222784] [Citation(s) in RCA: 36] [Impact Index Per Article: 12.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/12/2022] [Accepted: 07/18/2022] [Indexed: 12/13/2022]
Abstract
BACKGROUND Targeting interleukin (IL)-6 has become a major therapeutic strategy in the treatment of immune-mediated inflammatory disease. Interference with the IL-6 pathway can be directed at the specific receptor using anti-IL-6Rα antibodies or by directly inhibiting the IL-6 cytokine. This paper is an update of a previous consensus document, based on most recent evidence and expert opinion, that aims to inform on the medical use of interfering with the IL-6 pathway. METHODS A systematic literature research was performed that focused on IL-6-pathway inhibitors in inflammatory diseases. Evidence was put in context by a large group of international experts and patients in a subsequent consensus process. All were involved in formulating the consensus statements, and in the preparation of this document. RESULTS The consensus process covered relevant aspects of dosing and populations for different indications of IL-6 pathway inhibitors that are approved across the world, including rheumatoid arthritis, polyarticular-course and systemic juvenile idiopathic arthritis, giant cell arteritis, Takayasu arteritis, adult-onset Still's disease, Castleman's disease, chimeric antigen receptor-T-cell-induced cytokine release syndrome, neuromyelitis optica spectrum disorder and severe COVID-19. Also addressed were other clinical aspects of the use of IL-6 pathway inhibitors, including pretreatment screening, safety, contraindications and monitoring. CONCLUSIONS The document provides a comprehensive consensus on the use of IL-6 inhibition to treat inflammatory disorders to inform healthcare professionals (including researchers), patients, administrators and payers.
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Affiliation(s)
- Daniel Aletaha
- Division of Rheumatology, Medical University of Vienna, Wien, Austria
| | | | - Kastriot Kastrati
- Division of Rheumatology, Medical University of Vienna, Wien, Austria
| | - Christian Dejaco
- Rheumatology, Medical University of Graz, Graz, Austria.,Rheumatology, Brunico Hospital, Brunico, Italy
| | - Maxime Dougados
- Rheumatology, Universite Paris Descartes Faculte de Medecine Site Cochin, Paris, France
| | - Iain B McInnes
- Institute of Infection, Immunity and Inflammation, University of Glasgow, Glasgow, UK
| | - Naveed Sattar
- Institute of Cardiovascular and Medical Sciences, British Heart Foundation Glasgow Cardiovascular Research Centre, Glasgow, UK
| | - Tanja A Stamm
- Section for Outcomes Research, Medical University of Vienna, Wien, Austria
| | - Tsutomu Takeuchi
- Division of Rheumatology, Department of Internal Medicine, Keio University School of Medicine Graduate School of Medicine, Shinjuku-ku, Japan
| | - Michael Trauner
- Division of Gastroenterology and Hepatology, Medical University of Vienna, Wien, Austria
| | - Désirée van der Heijde
- Rheumatology, Leiden University Medical Center, Leiden, The Netherlands.,Rheumatology, Diakonhjemmet Hospital, Oslo, Norway
| | - Marieke Voshaar
- Department of Psychology, Health and Technology, Enschede, Netherlands and Stichting Tools Patient Empowerment, University of Twente, Enschede, The Netherlands
| | - Kevin L Winthrop
- Schools of Medicine and Public Health, Division of Infectious Diseases, Oregon Health & Science University, Portland, Oregon, USA
| | - Angelo Ravelli
- UO Pediatria II-Reumatologia, IRCCS Istituto Giannina Gaslini, Genova, Italy
| | | | | | - Johannes Wj Bijlsma
- Department of Rheumatology and Clinical Immunology, University Medical Center Utrecht, Utrecht, The Netherlands
| | - Vivian Bykerk
- Rheumatology, University of Toronto, Toronto, Ontario, Canada
| | - Roberto Caporali
- Department of Clinical Sciences and Community Health, ASS G. Pini, University of Milan, Milano, Italy
| | - Ernest H Choy
- CREATE Centre, Section of Rheumatology, School of Medicine, Division of Infection and Immunity, Cardiff University, Cardiff, UK
| | - Catalin Codreanu
- Rheumatology, Carol Davila University of Medicine and Pharmacy, Bucuresti, Romania
| | - Bernard Combe
- Immunorhumatologie, CHU Lapeyronie, Montpellier, France
| | - Mary K Crow
- Mary Kirkland Center for Lupus Research, Hospital for Special Surgery, New York City, New York, USA
| | - Maarten de Wit
- Medical Humanities, Amsterdam University Medical Centres, Duivendrecht, The Netherlands
| | - Paul Emery
- University of Leeds, Leeds Institute of Rheumatic and Musculoskeletal Medicine, Leeds, UK.,Leeds Teaching Hospitals NHS Trust, NIHR Leeds Musculoskeletal Biomedical Research Unit, Leeds, UK
| | - Roy M Fleischmann
- Medicine, The University of Texas Southwestern Medical Center, Dallas, Texas, USA
| | - Cem Gabay
- Division of Rheumatology, Geneva University Hospitals, Geneve, Switzerland
| | - Merete Lund Hetland
- Department of Clinical Medicine, Copenhagen University Hospital, Kobenhavn, Denmark.,Department of Clinical Medicine, University of Copenhagen, Kobenhavn, Denmark
| | - Kimme L Hyrich
- Centre for Epidemiology Versus Arthritis, The University of Manchester, Manchester Academic Health Science Centre, Manchester, UK
| | - Annamaria Iagnocco
- Scienze Cliniche e Biologiche, Università degli Studi di Torino, Torino, Italy
| | - John D Isaacs
- Translational and Clinical Research Institute, Newcastle University, Newcastle upon Tyne, UK
| | - Joel M Kremer
- Medicine Rheumatology, Albany Medical College, Albany, New York, USA
| | - Xavier Mariette
- Rheumatology, Assistance Publique-Hôpitaux de Paris, Paris, France.,Center for Immunology of Viral Infections and Auto-immune Diseases, Université Paris-Sud, Gif-sur-Yvette, France
| | - Peter A Merkel
- Rheumatology, University of Pennsylvania, Philadelphia, Pennsylvania, USA
| | - Eduardo F Mysler
- Organización Médica de Investigación SA, Buenos Aires, Argentina
| | - Peter Nash
- Griffith University School of Medicine, Gold Coast, Queensland, Australia
| | | | - Karel Pavelka
- Rheumatology Department, Charles University, Praha, Czech Republic
| | - Gyula Poor
- National Institute of Rheumatology & Physiology, Semmelweis University, Budapest, Hungary
| | - Andrea Rubbert-Roth
- Division of Rheumatology, Kantonsspital Sankt Gallen, Sankt Gallen, Switzerland
| | - Hendrik Schulze-Koops
- Division of Rheumatology and Clinical Immunology, Internal Medicine IV, Ludwig-Maximilians-Universitat Munchen, Munchen, Germany
| | - Anja Strangfeld
- Forschungsbereich Epidemiologie, Deutsches Rheuma-Forschungszentrum Berlin, Berlin, Germany
| | - Yoshiya Tanaka
- First Department of Internal Medicine, University of Occupational and Environmental Health, Kitakyushu, Japan
| | - Josef S Smolen
- Division of Rheumatology, Medical University of Vienna, Wien, Austria
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32
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Wang S, Du Q, Sun J, Geng S, Zhang Y. Investigation of the mechanism of Isobavachalcone in treating rheumatoid arthritis through a combination strategy of network pharmacology and experimental verification. JOURNAL OF ETHNOPHARMACOLOGY 2022; 294:115342. [PMID: 35525528 DOI: 10.1016/j.jep.2022.115342] [Citation(s) in RCA: 20] [Impact Index Per Article: 6.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 01/24/2022] [Revised: 03/12/2022] [Accepted: 05/01/2022] [Indexed: 06/14/2023]
Abstract
ETHNOPHARMACOLOGY RELEVANCE Isobavachalcone (IBC) is a natural chalcone compound widely distributed in traditional Chinese medicine Psoralea corylifolia L., and Tibetan medicine Abelmoschus manihot (L.) Medik. Etc.. Among them, Psoralea corylifolia has the effect of tonifying the kidney and strengthening Yang, and it is recorded in the Medicinal theory that it can be used in managing rheumatism and arthralgia. In addition, It has been included in many prescriptions in traditional Chinese medicine as the main herb for managing rheumatoid arthritis (RA). Similarly, Abelmoschus manihot is a common Tibetan medicinal herb and is a common medicinal material in Tibetan medicine and reported in ancient medicinal books such as Jing Zhu Ben Cao and Si Bu Yi Dian to possess the effect of Ganhuangshui and thus can be used in treating Huangshui diseases (such as RA). Previous research has demonstrated IBC to possess numerous biological activities, including anti-cancer, anti-inflammatory, antibacterial and immunomodulatory. Nevertheless, its efficacy and potential mechanism in treating rheumatoid arthritis are yet to be investigated. AIM OF THE STUDY This study aimed at investigating the therapeutic efficacy and mechanism of IBC in treating RA through a combined strategy of network pharmacology, in vitro, and in vivo evaluation. MATERIALS AND METHODS The Swiss Target Prediction and GeneCards databases were consulted to predict the potential targets of IBC and RA. Additionally, the potential targets for IBC in treating RA were predicted by consulting databases such as String, Cytoscape, MCODE, and Cytohubba. R software was utilized for enrichment analysis of GO and KEGG pathways, followed by in vitro experimentation using cell lines and in vivo experimentation using animals to explore the potential mechanism of IBC in RA treatment. RESULTS By integrating the results of network pharmacological analysis, 17 genes were found to be strongly associated with RA, such as TNF, MAPK13, EGFR, PTGS2, MMP3, etc. The enrichment analysis indicated that IBC possessed tremendous therapeutic efficacy in managing RA through PI3K-AKT, rheumatoid arthritis, and TNF signaling pathways. The in vitro experimentation indicated that IBC inhibited the proliferation, migration, and invasion, and promoted apoptosis and inhibition of inflammation of MH7A cell lines stimulated with TNF-α. The IBC might also have an increasing effect on the intracellular ROS and reducing effect on the mitochondrial membrane potential. The western blotting results indicated that IBC markedly inhibited the expression of p-PI3K, p-AKT, p-JAK1, p-STAT3 and SOCS3 proteins in TNF-α stimulated MH7A cells. Furthermore, we found that IBC also significantly reduced paw swelling and arthritis severity in CIA model rats through in vivo animal studies. CONCLUSIONS In short, this study explored the effect of IBC by combining network pharmacology prediction with in vitro and in vivo experimentation. The results indicated that IBC exerts its anti-rheumatoid arthritis effect by regulating cell proliferation and survival via PI3K/AKT and JAK/STAT signaling pathways. This may open a new horizon and provide a theoretical foundation for further development and utilization of IBC in RA management.
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Affiliation(s)
- Shaohui Wang
- School of Ethnic Medicine, Chengdu University of Traditional Chinese Medicine, Chengdu, 611137, China
| | - Qinyun Du
- School of Pharmacy, Chengdu University of Traditional Chinese Medicine, Chengdu, China
| | - Jiayi Sun
- Innovative Institute of Chinese Medicine and Pharmacy, Chengdu University of Traditional Chinese Medicine, Chengdu, China
| | - Sang Geng
- University of Tibetan Medicine, Lasa, 850000, China.
| | - Yi Zhang
- School of Ethnic Medicine, Chengdu University of Traditional Chinese Medicine, Chengdu, 611137, China.
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Narazaki M, Kishimoto T. Current status and prospects of IL-6–targeting therapy. Expert Rev Clin Pharmacol 2022; 15:575-592. [DOI: 10.1080/17512433.2022.2097905] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/20/2022]
Affiliation(s)
- Masashi Narazaki
- Department of Advanced Clinical and Translational Immunology, Osaka University Graduate School of Medicine, Osaka University, Osaka, Japan
- Department of Respiratory Medicine, Clinical Immunology, Osaka University Graduate School of Medicine, Osaka University, Osaka, Japan
- Department of Immunopathology, World Premier International Immunology Frontier Research Center, Osaka University, Osaka, Japan
| | - Tadamitsu Kishimoto
- Laboratory of Immune Regulation, World Premier International Immunology Frontier Research Center, Osaka University, Osaka, Japan
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34
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Zeng X, Liu J, Liu X, Wu L, Liu Y, Liao X, Liu H, Hu J, Lu X, Chen L, Xu J, Jiang Z, Lu FA, Wu H, Li Y, Wang Q, Zhu J. Efficacy and safety of HLX01 in patients with moderate-to-severe rheumatoid arthritis despite methotrexate therapy: a phase 3 study. Arthritis Res Ther 2022; 24:136. [PMID: 35689239 PMCID: PMC9185960 DOI: 10.1186/s13075-022-02821-x] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/09/2021] [Accepted: 05/21/2022] [Indexed: 02/08/2023] Open
Abstract
BACKGROUND To evaluate the efficacy and safety of HLX01, a rituximab biosimilar, as combination therapy with methotrexate in Chinese patients with active rheumatoid arthritis who had inadequate responses to methotrexate. METHODS In this double-blind, placebo-controlled phase 3 trial, biologic-naïve patients with moderate-to-severe active rheumatoid arthritis and inadequate responses to methotrexate were randomized 2:1 to receive 1000 mg HLX01 or placebo intravenously on days 1 and 15. On the first day of weeks 24 and 26, patients in both groups received 1000 mg HLX01 via intravenous infusion. The primary endpoint was the American College of Rheumatology (ACR) 20 response rate at week 24. Secondary endpoints including efficacy, safety, immunogenicity, pharmacokinetics and pharmacodynamics were assessed up to week 48. RESULTS Between 28 May 2018 and 11 September 2020, 275 patients were randomized to the HLX01 group (n = 183) or the placebo group (n = 92). At week 24, the proportion of patients achieving ACR20 response was significantly greater in the HLX01 group compared with the placebo group in the intention-to-treat population (60.7% vs 35.9%; P < 0.001) and per-protocol set (60.3% vs 37.1%; P < 0.001). Most secondary efficacy endpoints favoured HLX01 when assessed at weeks 12, 24, 36 and 48. Incidences of treatment-emergent adverse events were similar between groups. Infusion-related reactions occurred more frequently following the initial two doses of HLX01 than the subsequent doses. CONCLUSIONS HLX01 plus methotrexate improved clinical outcomes compared with placebo in Chinese patients with rheumatoid arthritis who had inadequate responses to methotrexate. This treatment regimen was well tolerated, showing comparable safety profiles to placebo. TRIAL REGISTRATION ClinicalTrials.gov , NCT03522415 . Registered on 11 May 2018.
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Affiliation(s)
- Xiaofeng Zeng
- Department of Rheumatology, Peking Union Medical College Hospital, Beijing, China.
| | - Ju Liu
- Department of Rheumatology, Jiujiang No. 1 People's Hospital, Jiujiang, China
| | - Xiumei Liu
- Department of Rheumatology, First Hospital of Shanxi Medical University, Taiyuan, China
| | - Lijun Wu
- Department of Rheumatology, People's Hospital of Xinjiang Uygur Autonomous Region, Urumqi, China
| | - Yi Liu
- Department of Rheumatology, West China Hospital of Sichuan University, Chengdu, China
| | - Xiangping Liao
- Department of Nephrology, Chenzhou First People's Hospital, Chenzhou, China
| | - Huaxiang Liu
- Department of Rheumatology, Qilu Hospital of Shandong University, Jinan, China
| | - Jiankang Hu
- Department of Rheumatology, Jiangxi Pingxiang People's Hospital, Pingxiang, China
| | - Xin Lu
- Department of Rheumatology, China-Japan Friendship Hospital, Beijing, China
| | - Linjie Chen
- Department of Rheumatology, The First Affiliated Hospital of Bengbu Medical College, Bengbu, China
| | - Jian Xu
- Department of Rheumatology and Immunology, First Affiliated Hospital of Kunming Medical University, Kunming, China
| | - Zhenyu Jiang
- Department of Rheumatology, The First Hospital of Jilin University, Changchun, China
| | - Fu-Ai Lu
- Department of Rheumatology, The First Affiliated Hospital of Baotou Medical College, Inner Mongolia University of Science and Technology, Baotou, China
| | - Huaxiang Wu
- Department of Rheumatology, The Second Affiliated Hospital Zhejiang University School of Medicine, Hangzhou, China
| | - Ying Li
- Shanghai Henlius Biotech, Inc., Shanghai, China
| | - Qingyu Wang
- Shanghai Henlius Biotech, Inc., Shanghai, China
| | - Jun Zhu
- Shanghai Henlius Biotech, Inc., Shanghai, China
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35
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[Contributions from a multidisciplinary committee for the prevention of infections in patients with targeted immunosuppressive therapy]. Med Clin (Barc) 2021; 157:489-494. [PMID: 34103165 DOI: 10.1016/j.medcli.2021.03.031] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/23/2020] [Revised: 03/19/2021] [Accepted: 03/21/2021] [Indexed: 12/11/2022]
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36
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Handley G, Hand J. Adverse Effects of Immunosuppression: Infections. Handb Exp Pharmacol 2021; 272:287-314. [PMID: 34671868 DOI: 10.1007/164_2021_550] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/26/2022]
Abstract
Immunosuppressive therapies are currently indicated for a wide range of diseases. As new agents emerge and indications evolve the landscape grows increasingly complex. Therapies can target pathologic immune system over-activation in rheumatologic or autoimmune disease, or conditioning and graft versus host disease (GVHD) prophylactic regimens may eliminate or inhibit host immune function to improve graft survival and risk of complication in solid organ transplantation (SOT) or hematopoietic stem cell transplantation (HSCT). With immunosuppressive therapy, infections occur. Complex disease states, host factors, and concomitant therapies contribute to a "net state" of immunosuppression that must be considered and may confound perceived increased infection risks in patients receiving treatment.
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Affiliation(s)
- Guy Handley
- Division of Infectious Disease and International Medicine, Department of Internal Medicine, Morsani College of Medicine, University of South Florida, Tampa, FL, USA
| | - Jonathan Hand
- Department of Infectious Diseases, Ochsner Health, The University of Queensland School of Medicine, Ochsner Clinical School, New Orleans, LA, USA.
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37
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Ordaya EE, Johnson JR, Drekonja DM, Niehans GE, Kaka AS. Aspergillus Osteomyelitis Secondary to Chronic Necrotizing Pulmonary Aspergillosis in a Patient With Rheumatoid Arthritis. Cureus 2021; 13:e17774. [PMID: 34659985 PMCID: PMC8494381 DOI: 10.7759/cureus.17774] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 09/06/2021] [Indexed: 11/24/2022] Open
Abstract
Aspergillus spp. are ubiquitous molds that cause a wide range of clinical syndromes depending on the immune status of the host. Herein, we present a case of a patient with rheumatoid arthritis on long-term immunosuppressive medications, with a persistent dry cough and left-sided chest pain for over a year, who presented with acute sternal drainage. Computed tomography of the chest showed chronic pulmonary abnormalities, parasternal fluid, and bone destruction of the distal sternum and left sixth rib. The patient underwent debridement; sternal biopsy tissue showed septate hyphae with acute-angled branching, and Aspergillus fumigatus grew in culture. We suspected that the patient developed chronic necrotizing pulmonary aspergillosis (CNPA) that traversed tissue planes and caused chest wall osteomyelitis. The patient received voriconazole and surgical debridement, with clinical and radiological improvement. This case demonstrates the importance of considering CNPA as a diagnosis in patients with moderate degrees of immunosuppression and chronic respiratory symptoms, and Aspergillus spp. as an etiology of osteomyelitis in such patients.
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Affiliation(s)
| | - James R Johnson
- Infectious Diseases, Minneapolis Veterans Affairs Health Care System, Minneapolis, USA.,Medicine, University of Minnesota, Minneapolis, USA
| | - Dimitri M Drekonja
- Infectious Diseases, Minneapolis Veterans Affairs Health Care System, Minneapolis, USA.,Medicine, University of Minnesota, Minneapolis, USA
| | - Gloria E Niehans
- Pathology and Laboratory Medicine Service, Minneapolis Veterans Affairs Health Care System, Minneapolis, USA
| | - Anjum S Kaka
- Infectious Diseases, Minneapolis Veterans Affairs Health Care System, Minneapolis, USA.,Medicine, University of Minnesota, Minneapolis, USA
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Axelrod H, Adams M. Biologic Agents and Secondary Immune Deficiency. Immunol Allergy Clin North Am 2021; 41:639-652. [PMID: 34602234 DOI: 10.1016/j.iac.2021.07.006] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/30/2022]
Abstract
Biologics are protein-based pharmaceuticals derived from living organisms or their proteins. We discuss the mechanism of action for currently approved biologics and a give summary of the studies on immune suppression from biologics. Most of these studies have been conducted with rheumatology patients, and many in adults. Their relevance for children is explored and existing gaps in data for children are highlighted.
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Affiliation(s)
- Heather Axelrod
- Department of Pediatrics (PGY3), Children's Hospital of Michigan, Detroit, MI, USA
| | - Matthew Adams
- Division of Pediatric Rheumatology, Department of Pediatrics, Children's Hospital of Michigan, Wayne State University, 3950 Beaubien Boulevard, Detroit, MI 48201, USA.
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Waldron JL, Schworer SA, Kwan M. Hypersensitivity and Immune-related Adverse Events in Biologic Therapy. Clin Rev Allergy Immunol 2021; 62:413-431. [PMID: 34319562 DOI: 10.1007/s12016-021-08879-w] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 07/13/2021] [Indexed: 12/13/2022]
Abstract
Biologic medications are an expanding field of therapeutics for various medical conditions including cancer and inflammatory diseases. Due to their targeted approach to therapy, biologics can be less toxic than traditional systemic medications. However, as use becomes more widespread, adverse effects from biologic administration have also become apparent. Immune-related adverse events are a common mechanism by which biologics can cause on-target immune-related toxicities and both immediate and delayed-type hypersensitivity reactions. Immediate hypersensitivity reactions can be mediated by cytokine release or antibody mediated reactions, while delayed-type hypersensitivity is most often caused by serum sickness-like reactions. Additionally, biologics used for treatment of cancer using checkpoint blockade and rheumatologic disease using cytokine blockade can result in autoimmunity. Finally, when inflammatory cytokines are targeted for treatment of autoimmune or autoinflammatory disease, the host immune defense can be compromised predisposing to secondary immunodeficiency. This review will discuss the mechanisms of these reactions and discuss examples of biologics implicated in each of these adverse events.
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Affiliation(s)
- Jamie L Waldron
- Department of Medicine, Division of Rheumatology, Allergy, and Immunology, UNC School of Medicine, Chapel Hill, NC, USA
| | - Stephen A Schworer
- Department of Pediatrics, Division of Allergy & Immunology, UNC School of Medicine, Chapel Hill, NC, USA
| | - Mildred Kwan
- Department of Medicine, Division of Rheumatology, Allergy, and Immunology, UNC School of Medicine, Chapel Hill, NC, USA.
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Sánchez-Ramón S, Fernández-Paredes L, Saz-Leal P, Diez-Rivero CM, Ochoa-Grullón J, Morado C, Macarrón P, Martínez C, Villaverde V, de la Peña AR, Conejero L, Hernández-Llano K, Cordero G, Fernández-Arquero M, Gutierrez BF, Candelas G. Sublingual Bacterial Vaccination Reduces Recurrent Infections in Patients With Autoimmune Diseases Under Immunosuppressant Treatment. Front Immunol 2021; 12:675735. [PMID: 34149711 PMCID: PMC8212043 DOI: 10.3389/fimmu.2021.675735] [Citation(s) in RCA: 18] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/03/2021] [Accepted: 04/26/2021] [Indexed: 12/29/2022] Open
Abstract
Introduction Conventional or biologic disease-modifying anti-rheumatic drugs (DMARDs) are the mainstay of treatment for systemic autoimmune disease (SAD). Infectious complications are a major concern in their use. Objective To evaluate the clinical benefit of sublingual mucosal polybacterial vaccines (MV130 and MV140), used to prevent recurrent respiratory and urinary tract infections, in patients with SAD and secondary recurrent infections following conventional or biologic DMARDs. Methods An observational study in SAD patients with recurrent respiratory tract infections (RRTI) and/or recurrent urinary tract infections (RUTI) was carried out. All patients underwent mucosal (sublingual) vaccination with MV130 for RRTI or with MV140 for RUTI daily for 3 months. Clinical evaluation was assessed during 12 months of follow-up after the first dose, i.e., 3 months under treatment and 9 months once discontinued, and compared with the previous year. Results Forty-one out of 55 patients completed 1-year follow-up. All patients were on either conventional or biologic DMARDs. A significant decrease in the frequency of RUTI (p<0.001), lower respiratory tract infections (LRTI) (p=0.009) and upper respiratory tract infections (URTI) (p=0.006) at 12-mo with respect to the previous year was observed. Antibiotic prescriptions and unscheduled medical visits decreased significantly (p<0.020) in all groups. Hospitalization rate also declined in patients with RRTI (p=0.019). The clinical benefit demonstrated was concomitant to a significant increase in both anti-S. pneumoniae IgA and IgG antibodies following MV130 vaccination. Conclusions Sublingual polybacterial vaccines prevent recurrent infections in patients with SAD under treatment with immunosuppressant therapies, supporting a broad non-specific anti-infectious effect in these patients.
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Affiliation(s)
- Silvia Sánchez-Ramón
- Department of Clinical Immunology, IML and IdSSC, Hospital Clínico San Carlos, Madrid, Spain
| | - Lidia Fernández-Paredes
- Department of Clinical Immunology, IML and IdSSC, Hospital Clínico San Carlos, Madrid, Spain
| | - Paula Saz-Leal
- Department of Innovation and Development, Inmunotek S.L., Alcalá de Henares, Spain
| | - Carmen M Diez-Rivero
- Department of Innovation and Development, Inmunotek S.L., Alcalá de Henares, Spain
| | - Juliana Ochoa-Grullón
- Department of Clinical Immunology, IML and IdSSC, Hospital Clínico San Carlos, Madrid, Spain
| | - Concepción Morado
- Department of Rheumatology, Hospital Clínico San Carlos, Madrid, Spain
| | - Pilar Macarrón
- Department of Rheumatology, Hospital Clínico San Carlos, Madrid, Spain
| | - Cristina Martínez
- Department of Rheumatology, Hospital Clínico San Carlos, Madrid, Spain
| | | | | | - Laura Conejero
- Department of Innovation and Development, Inmunotek S.L., Alcalá de Henares, Spain
| | - Keyla Hernández-Llano
- Department of Clinical Immunology, IML and IdSSC, Hospital Clínico San Carlos, Madrid, Spain
| | - Gustavo Cordero
- Department of Clinical Immunology, IML and IdSSC, Hospital Clínico San Carlos, Madrid, Spain
| | | | | | - Gloria Candelas
- Department of Rheumatology, Hospital Clínico San Carlos, Madrid, Spain
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Li X, Xie Y, Kang A, Wang Y. New bitongling (NBTL) ameliorates rheumatoid arthritis in rats through inhibiting JAK2/STAT3 signaling pathway. Eur J Histochem 2021; 65:3202. [PMID: 33634679 PMCID: PMC7907992 DOI: 10.4081/ejh.2021.3202] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/19/2020] [Accepted: 01/12/2021] [Indexed: 01/04/2023] Open
Abstract
Rheumatoid arthritis (RA) is featured by a variety of physical symptoms and fibroblast-like synoviocytes (FLSs) abnormal proliferation. Increasing evidence has demonstrated that traditional Chinese medicine exerts an important role in RA treatment. New bitongling (NBTL) as one of the traditional Chinese medicine has been reported to be involved in the progression of RA, but the exact mechanism is unclear. In our study, we intended to investigate the effect of NBTL on RA to identify the mechanisms related to JAK2/STAT3 signaling pathway. Extracts of Tripterygium wilfordii (TW), a traditional Chinese herbal medicine, have been widely used for treating RA in China for several decades, so, TW was used as a positive control drug for TBNL. RA rats were constructed by immunization with collagen type II to evaluate the action of NBTL in vivo. Body weight and arthritic index were evaluated. Hematoxylin and Eosin staining was performed to analysis the morphological changes of ankle joints tissue. TUNEL and flow cytometry were performed to examine cell apoptosis, while CCK8 and Ethynyl-2'-deoxyuridine (EdU) were performed to examine cell proliferation. In addition, the markers of inflammation were detected by Western blot, ELISA, and RT-qPCR. Firstly, we find that rats treated with NBTL or TW not only reduced swelling degree and bone destruction, but also repressed IL-1 β and IL-6 levels. In addition, NBTL and TW could increase the weight of rats, and promote the level of IL-10 and IL-4 in vivo. Furthermore, NBTL inhibited inflammation of FLS, induced cell apoptosis and hindered cell proliferation, which was reversed by dipeptidyl peptidase (DPP), a JAK2/STAT3 pathway activator. Taken together, NBTL potentially retarded RA via JAK2/STAT3 pathway, highlighting novel mechanisms associated with RA.
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Affiliation(s)
- Xiang Li
- Affiliated Hospital of Nanjing University of Chinese Medicine; Jiangsu Province Hospital of Chinese Medicine, Nanjing.
| | - Yu Xie
- Jiangsu Province Hospital of Chinese Medicine, Nanjing.
| | - An Kang
- School of Pharmacology, Nanjing University of Chinese Medicine, Nanjing.
| | - Yue Wang
- Affiliated Hospital of Nanjing University of Chinese Medicine; Jiangsu Province Hospital of Chinese Medicine, Nanjing.
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Taylor PC, Atzeni F, Balsa A, Gossec L, Müller-Ladner U, Pope J. The Key Comorbidities in Patients with Rheumatoid Arthritis: A Narrative Review. J Clin Med 2021; 10:509. [PMID: 33535498 PMCID: PMC7867048 DOI: 10.3390/jcm10030509] [Citation(s) in RCA: 56] [Impact Index Per Article: 14.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/18/2020] [Revised: 01/22/2021] [Accepted: 01/23/2021] [Indexed: 02/06/2023] Open
Abstract
Comorbidities in patients with rheumatoid arthritis (RA) are often associated with poor health outcomes and increased mortality. Treatment decisions should take into account these comorbidities due to known or suspected associations with certain drug classes. In clinical practice, it is critical to balance potential treatment benefit against the possible risks for comorbidities as well as the articular manifestations of RA. This review summarises the current literature relating to prevalence and risk factors for the important comorbidities of cardiovascular disease, infections, lymphomas and nonmelanoma skin cancers in patients with RA. The impact on patient outcomes and the interplay between these comorbidities and the therapeutic options currently available, including tumour necrosis factor inhibitors and newer biological therapies, are also explored. As newer RA therapies are developed, and patients gain wider and earlier access to advanced therapies, in part due to the emergence of biosimilars, it is important to consider the prevention or treatment of comorbidities as part of the overall management of RA.
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Affiliation(s)
- Peter C. Taylor
- Botnar Research Centre, Nuffield Department of Orthopaedics, Rheumatology and Musculoskeletal Sciences, University of Oxford, Oxford OX3 7LD, UK
| | - Fabiola Atzeni
- Rheumatology Unit, Department of Clinical and Experimental Medicine, University of Messina, 98122 Messina, Italy;
| | - Alejandro Balsa
- Rheumatology Unit, Hospital Universitario La Paz, La Paz Institute for Health Research IdiPAZ, Universidad Autónoma de Madrid, Paseo de la Castellana, 261, 28046 Madrid, Spain;
| | - Laure Gossec
- Institut Pierre Louis d’Epidémiologie et de Santé Publique, Sorbonne Université, 75006 Paris, France;
- Rheumatology Department, Pitié-Salpêtrière Hospital, AP-HP, Sorbonne Université, 75013 Paris, France
| | - Ulf Müller-Ladner
- Department of Rheumatology and Clinical Immunology, Justus Liebig University Gießen, Campus Kerckhoff, 61231 Bad Nauheim, Germany;
| | - Janet Pope
- St. Joseph’s Health Care, Schulich School of Medicine, University of Western Ontario, London, ON N6A 5C1, Canada;
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Riley TR, George MD. Risk for infections with glucocorticoids and DMARDs in patients with rheumatoid arthritis. RMD Open 2021; 7:e001235. [PMID: 33597206 PMCID: PMC7893655 DOI: 10.1136/rmdopen-2020-001235] [Citation(s) in RCA: 24] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/11/2021] [Revised: 02/02/2021] [Accepted: 02/06/2021] [Indexed: 12/15/2022] Open
Abstract
Immunomodulatory therapy for rheumatoid arthritis (RA) carries risk for infectious complications. Understanding the risks of different therapeutic options is essential for making treatment decisions and appropriately monitoring patients. This review examines data on the risks for serious infections and other key infections of interest for the major classes of agents in use for RA: glucocorticoids, conventional synthetic disease-modifying antirheumatic drugs (DMARDs), biologics and Janus kinase (JAK) inhibitors. Conventional synthetic DMARDs have an excellent safety profile with recent data available supporting the relative safety of methotrexate. Tumour necrosis factor (TNF) inhibitors are associated with an increase in the risk of serious infections. Risk with other biological agents and with JAK inhibitors varies somewhat but overall appears similar to that of TNF inhibitors, with JAK inhibitors also associated with a greater risk of herpes zoster. Glucocorticoids have a dose-dependent effect on serious infection risk-at higher doses risk of infection with glucocorticoids is substantially greater than with other immunomodulatory therapies, and even low-dose therapy carries a risk of infection that appears to be similar to that of biological therapies.
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Affiliation(s)
- Thomas R Riley
- Division of Rheumatology, University of Pennsylvania, Philadelphia, Pennsylvania, USA
| | - Michael D George
- Division of Rheumatology, University of Pennsylvania, Philadelphia, Pennsylvania, USA
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Ulusoy H, Acar Cakan Ö, Tuna T. Tuberculosis Arthritis in the Wrist While Using Rituximab for Rheumatoid Arthritis Treatment. Open Access Rheumatol 2020; 12:203-206. [PMID: 32982498 PMCID: PMC7500831 DOI: 10.2147/oarrr.s268852] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/22/2020] [Accepted: 09/04/2020] [Indexed: 12/18/2022] Open
Abstract
Introduction Data from clinical trials indicate that there are no increased risk of tuberculosis (TB) infections in rheumatoid arthritis (RA) patients while using rituximab (RTX). Herein, we report a RA patient who developed TB arthritis while using RTX. Case Report A 49-year-old patient was treated with methotrexate and prednisolone along with RTX for two years. Later, she presented with increasing pain, swelling, redness and cutaneous fistulization in her left wrist for two months. The lesion on the wrist was debritted. Histopathologic evaluation revealed the presence of acid-fast bacilli. Polymerase chain reaction test and culture confirmed mycobacterium tuberculosis. RTX, methotrexate and prednisolone were withdrawn. The patient was treated with 12-month course of antituberculous treatment and responded well. The patient, who did not have pain or swelling in her other joints, was not given any treatment for RA after antituberculous treatment. Conclusion Clinicians should keep in mind that TB infections may be encountered while using RTX. Latent TB screening may be appropriate in patients using concomitant corticosteroid and living in TB endemic areas.
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Affiliation(s)
- Hasan Ulusoy
- Division of Rheumatology, Department of Physical Medicine and Rehabilitation, Faculty of Medicine, Ondokuz Mayis University, Samsun, Turkey
| | - Özge Acar Cakan
- Division of Rheumatology, Department of Physical Medicine and Rehabilitation, Faculty of Medicine, Ondokuz Mayis University, Samsun, Turkey
| | - Tibel Tuna
- Department of Pulmonary Medicine and Tuberculosis, Faculty of Medicine, Ondokuz Mayis University, Samsun, Turkey
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Perricone C, Triggianese P, Bartoloni E, Cafaro G, Bonifacio AF, Bursi R, Perricone R, Gerli R. The anti-viral facet of anti-rheumatic drugs: Lessons from COVID-19. J Autoimmun 2020; 111:102468. [PMID: 32317220 PMCID: PMC7164894 DOI: 10.1016/j.jaut.2020.102468] [Citation(s) in RCA: 74] [Impact Index Per Article: 14.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/26/2020] [Revised: 04/07/2020] [Accepted: 04/10/2020] [Indexed: 02/07/2023]
Abstract
The outbreak of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection has posed the world at a pandemic risk. Coronavirus-19 disease (COVID-19) is an infectious disease caused by SARS-CoV-2, which causes pneumonia, requires intensive care unit hospitalization in about 10% of cases and can lead to a fatal outcome. Several efforts are currently made to find a treatment for COVID-19 patients. So far, several anti-viral and immunosuppressive or immunomodulating drugs have demonstrated some efficacy on COVID-19 both in vitro and in animal models as well as in cases series. In COVID-19 patients a pro-inflammatory status with high levels of interleukin (IL)-1B, IL-1 receptor (R)A and tumor necrosis factor (TNF)-α has been demonstrated. Moreover, high levels of IL-6 and TNF-α have been observed in patients requiring intensive-care-unit hospitalization. This provided rationale for the use of anti-rheumatic drugs as potential treatments for this severe viral infection. Other agents, such as hydroxychloroquine and chloroquine might have a direct anti-viral effect. The anti-viral aspect of immunosuppressants towards a variety of viruses has been known since long time and it is herein discussed in the view of searching for a potential treatment for SARS-CoV-2 infection.
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Affiliation(s)
- Carlo Perricone
- Rheumatology, Department of Medicine, University of Perugia, Piazzale Giorgio Menghini, 1, 06129, Perugia, Italy
| | - Paola Triggianese
- Rheumatology, Allergology and Clinical Immunology, Department of "Medicina dei Sistemi", University of Rome Tor Vergata, Via Montpellier 1, 00133, Rome, Italy
| | - Elena Bartoloni
- Rheumatology, Department of Medicine, University of Perugia, Piazzale Giorgio Menghini, 1, 06129, Perugia, Italy
| | - Giacomo Cafaro
- Rheumatology, Department of Medicine, University of Perugia, Piazzale Giorgio Menghini, 1, 06129, Perugia, Italy
| | - Angelo F Bonifacio
- Rheumatology, Department of Medicine, University of Perugia, Piazzale Giorgio Menghini, 1, 06129, Perugia, Italy
| | - Roberto Bursi
- Rheumatology, Department of Medicine, University of Perugia, Piazzale Giorgio Menghini, 1, 06129, Perugia, Italy
| | - Roberto Perricone
- Rheumatology, Allergology and Clinical Immunology, Department of "Medicina dei Sistemi", University of Rome Tor Vergata, Via Montpellier 1, 00133, Rome, Italy
| | - Roberto Gerli
- Rheumatology, Department of Medicine, University of Perugia, Piazzale Giorgio Menghini, 1, 06129, Perugia, Italy.
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Evangelatos G, Koulouri V, Iliopoulos A, Fragoulis GE. Tuberculosis and targeted synthetic or biologic DMARDs, beyond tumor necrosis factor inhibitors. Ther Adv Musculoskelet Dis 2020; 12:1759720X20930116. [PMID: 32612710 PMCID: PMC7309385 DOI: 10.1177/1759720x20930116] [Citation(s) in RCA: 35] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/04/2019] [Accepted: 05/07/2020] [Indexed: 12/12/2022] Open
Abstract
Patients with autoimmune rheumatic diseases (ARD) have an increased risk for tuberculosis (TB). The use of tumor necrosis factor inhibitors (TNFi) and glucocorticoids in these patients has been associated with an increased prevalence of latent TB reactivation. Over the last few years, several biologic disease-modifying anti-rheumatic drugs (bDMARDs), other than TNFi (e.g. rituximab, abatacept, tocilizumab, secukinumab) and targeted synthetic DMARDs (tsDMARDs) [e.g. apremilast, Janus kinase (JAK) inhibitors] have been used for the treatment of patients with ARD. For many of these drugs, especially the newer ones like JAK inhibitors or antibodies against interleukin (IL)-23, most data stem from randomized clinical trials and few are available from real life clinical experience. We sought to review the current evidence for TB risk in patients with ARD treated with tsDMARDs or bDMARDs, other than TNFi. It seems that some of these drugs are associated with a lower TB risk, indirectly compared with TNFi treatment. In fact, it appears that rituximab, apremilast and inhibitors of IL-17 and IL-23 might be safer, while more data are needed for JAK inhibitors. As seen in TNFi, risk for TB is more pronounced in TB-endemic areas. Screening for latent TB must precede initiation of any tsDMARDs or bDMARDs. The growing use of non-TNFi agents has raised the need for more real-life studies that would compare the risk for TB between TNFi and other treatment modalities for ARD. Knowledge about the TB-safety profile of these drugs could help in the decision of drug choice in patients with confirmed latent TB infection or in TB endemic areas.
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Affiliation(s)
- Gerasimos Evangelatos
- Rheumatology Department, 417 Army Share Fund Hospital (NIMTS), Monis Petraki 10-12, Athens, 11521, Greece
| | - Vasiliki Koulouri
- Department of Physiology, School of Medicine, National and Kapodistrian University of Athens, Athens, Greece
| | - Alexios Iliopoulos
- Rheumatology Department, 417 Army Share Fund Hospital (NIMTS), Athens, Greece
| | - George E Fragoulis
- Rheumatology Unit, First Department of Propaedeutic Internal Medicine, School of Medicine, National and Kapodistrian University of Athens, Athens, Greece
- Institute of Infection, Immunity and Inflammation, University of Glasgow, Glasgow, UK
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Thomas K, Vassilopoulos D. Infections in Patients with Rheumatoid Arthritis in the Era of Targeted Synthetic Therapies. Mediterr J Rheumatol 2020; 31:129-136. [PMID: 32676571 PMCID: PMC7361184 DOI: 10.31138/mjr.31.1.129] [Citation(s) in RCA: 24] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/13/2020] [Revised: 05/12/2020] [Accepted: 05/18/2020] [Indexed: 12/15/2022] Open
Abstract
The third decade of the 21st century marks the beginning of a new era in the treatment of rheumatoid arthritis (RA). Recently, after the introduction in clinical practice of different biologics in the first decade, three different oral synthetic targeted agents (JAK inhibitors) have been licensed for the treatment of RA, in patients who had failed or are intolerant to disease modifying anti-rheumatic drugs (DMARDs). Despite the significant progress that these agents bring to the care of RA patients, the risk of infections is still present and clear, given that their risk for serious infections is at least comparable with that of biologic DMARDs, whereas the incidence of herpes zoster is higher than that of bDMARDs. Here, we review the most recent data regarding the risk for serious and opportunistic infections in RA patients treated with biologics or JAK inhibitors, as well the up-to-date approach for managing and preventing such infections in RA patients.
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Affiliation(s)
- Konstantinos Thomas
- 4 Department of Medicine, Attikon University Hospital, National and Kapodistrian University of Athens, School of Medicine, Athens, Greece
| | - Dimitrios Vassilopoulos
- Clinical Immunology-Rheumatology Unit, 2 Department of Medicine and Laboratory, Hippokration General Hospital, National and Kapodistrian University of Athens, School of Medicine, Athens, Greece
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Sepriano A, Kerschbaumer A, Smolen JS, van der Heijde D, Dougados M, van Vollenhoven R, McInnes IB, Bijlsma JW, Burmester GR, de Wit M, Falzon L, Landewé R. Safety of synthetic and biological DMARDs: a systematic literature review informing the 2019 update of the EULAR recommendations for the management of rheumatoid arthritis. Ann Rheum Dis 2020; 79:760-770. [PMID: 32033941 DOI: 10.1136/annrheumdis-2019-216653] [Citation(s) in RCA: 183] [Impact Index Per Article: 36.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/16/2019] [Revised: 12/23/2019] [Accepted: 12/27/2019] [Indexed: 01/04/2023]
Abstract
OBJECTIVES To perform a systematic literature review (SLR) concerning the safety of synthetic (s) and biological (b) disease-modifying anti rheumatic dugs (DMARDs) to inform the 2019 update of the EULAR recommendations for the management of rheumatoid arthritis (RA). METHODS An SLR of observational studies comparing safety outcomes of any DMARD with another intervention for the management of RA. A comparator group was required for inclusion. For treatments still without registry data (eg, sarilumab and the Janus kinase (JAK) inhibitors baricitinib, upadacitinib), randomised controlled trials (RCTs) and long-term extensions (LTEs) were used. Risk of bias (RoB) was assessed according to standard procedures. RESULTS Forty-two observational studies fulfilled the inclusion criteria, addressing safety outcomes with bDMARDs and sDMARDs. Nine studies showed no difference in the risk of serious infections across bDMARDs and two studies (high RoB) showed an increased risk with bDMARDs compared with conventional synthetic (cs) DMARDs (adjusted incidence rate ratio 3.1-3.9). The risk of Herpes zoster infection was similar across bDMARDs, but one study showed an increased risk with tofacitinib compared with abatacept (adjusted HR (aHR) 2.0). Five studies showed no increased risk of cancer for bDMARDs compared with csDMARDs. An increased risk of lower intestinal perforation was found for tocilizumab compared with csDMARDs (aHR 4.5) and tumour necrosis factor inhibitor (TNFi) (aHR 2.6-4.0). Sixty manuscripts reported safety data from RCTs/LTEs. Overall, no unexpected safety outcomes were found, except for the possibly increased risk of venous thromboembolism (VTE) with JAK inhibitors. CONCLUSION Data obtained by this SLR confirm the known safety profile of bDMARDs. The risk of VTE in RA, especially in patients on JAK inhibitors, needs further evaluation.
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Affiliation(s)
- Alexandre Sepriano
- Department of Rheumatology, Leiden University Medical Center, Leiden, The Netherlands
- NOVA Medical School, Universidade Nova de Lisboa, Lisboa, Portugal, Lisboa, Portugal
| | - Andreas Kerschbaumer
- Division of Rheumatology, Department of Medicine 3, Medical University of Vienna, Vienna, Austria
| | - Josef S Smolen
- Division of Rheumatology, Department of Medicine 3, Medical University of Vienna, Vienna, Austria
- 2nd Department of Medicine, Hietzing Hospital, Vienna, Austria
| | | | - Maxime Dougados
- Department of Rheumatology, Hôpital Cochin. Assistance Publique - Hôpitaux de Paris, Paris, France
- Clinical Epidemiology and Biostatistics, INSERM U1153, Paris, France
| | - Ronald van Vollenhoven
- Department Rheumatology and Clinical Immunology, Amsterdam University Medical Centres, Amsterdam, The Netherlands
| | - Iain B McInnes
- Institute of Infection, Immunity and Inflammation, College of Medical Veterinary and Life Sciences, University of Glasgow, Glasgow, UK
| | - Johannes W Bijlsma
- Department of Rheumatology, University Medical Centre Utrecht, Utrecht, The Netherlands
| | - Gerd R Burmester
- Department of Rheumatology and Clinical Immunology, Charité Universitätsmedizin Berlin, Berlin, Germany
| | - Maarten de Wit
- EULAR Standing Committee of People with Arthritis/Rheumatism in Europe, Zurich, Switzerland
| | - Louise Falzon
- Center for Personalized Health, Feinstein Institute for Medical Research, Northwell Health, New York, New York, USA
| | - Robert Landewé
- Amsterdam University Medical Center (ARC), Amsterdam, The Netherlands
- Department of Rheumatology, Zuyderland Medical Center, Heerlen, The Netherlands
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Vela Casasempere P, Ruiz Torregrosa P, García Sevila R. Pneumocystis jirovecii in immunocompromised patients with rheumatic diseases. ACTA ACUST UNITED AC 2020; 17:290-296. [PMID: 32466869 DOI: 10.1016/j.reuma.2020.02.006] [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: 12/07/2019] [Revised: 12/30/2019] [Accepted: 02/28/2020] [Indexed: 12/14/2022]
Abstract
Infections, including opportunistic infections, are a major and frequent cause of morbidity and mortality in patients with systemic autoimmune and rheumatic diseases. Pneumocystis jirovecii pneumonia, classically considered to be typical of HIV patients, transplanted patients or patients treated with oncological chemotherapy, is appearing increasingly frequently in these patients. Therefore, rheumatologists should know its mechanism of production, clinical manifestations, treatment and prophylaxis, all of which are addressed in this review.
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Affiliation(s)
- Paloma Vela Casasempere
- Sección de Reumatología. Hospital General Universitario de Alicante. ISABIAL, Alicante, España; Universidad Miguel Hernández, Alicante, España.
| | | | - Raquel García Sevila
- Servicio de Neumología. Hospital General Universitario de Alicante, Alicante, España
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Atzeni F, Nucera V, Gerratana E, Cirillo M, Marino F, Miceli G, Sangari D, Boccassini L, Masala IF. Concerns about the safety of anti-TNF agents when treating rheumatic diseases. Expert Opin Drug Saf 2020; 19:695-705. [DOI: 10.1080/14740338.2020.1763299] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/17/2022]
Affiliation(s)
- Fabiola Atzeni
- Rheumatology Unit, University of Messina, Messina, Italy
| | - Valeria Nucera
- Rheumatology Unit, University of Messina, Messina, Italy
| | | | | | | | | | | | - Laura Boccassini
- Department of Rheumatology, ASST Fatebenefratelli-Sacco, Milan, Italy
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