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Jin L, Wang Z, Peng C, He M, Wang F, He H, Liu C. Microneedle Assisted Melittin-Chondroitin Sulfate Administration for the Transdermal Therapy of Rheumatoid Arthritis. Adv Healthc Mater 2025; 14:e2400543. [PMID: 39972637 PMCID: PMC11973948 DOI: 10.1002/adhm.202400543] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/26/2024] [Revised: 06/09/2024] [Indexed: 02/21/2025]
Abstract
Rheumatoid arthritis (RA), a persistent and debilitating chronic disease characterize by joint damage and deformity, significantly impairs the life quality of patients and presents challenges for conventional drug administration due to organ damage and unsatisfactory therapeutic outcomes. To address these challenges, this study introduces an innovative hydrogel cryo-microneedle patch (CMNP)-mediated local administration system, primarily composed of chondroitin sulfate (CS), to deliver the potent anti-inflammatory drug melittin (MEL). This innovative approach not only circumvents organ impairment but also enhances patient compliance. The acute toxicity of MEL is effectively mitigated by electrostatic binding with CS molecules, forming MC complexes that induce apoptosis in fibroblast-like synoviocytes (FLS). The MC-loaded CMNPs (MC@CCMNPs) exhibit remarkable therapeutic capacity with a notably meliorated joint damage and suppressed arthritis severity in the RA rat model. Therefore, MC@CCMNPs emerge as a promising anti-inflammatory and safe therapy for RA treatment, as well as for other inflammation related chronic diseases.
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Affiliation(s)
- Lili Jin
- Frontiers Science Center for Materiobiology and Dynamic ChemistryEast China University of Science and TechnologyShanghai200237P. R. China
- Engineering Research Center for Biomedical Materials of Ministry of EducationEast China University of Science and TechnologyShanghai200237P. R. China
- School of Material Science and EngineeringEast China University of Science and TechnologyShanghai200237P. R. China
| | - Zhenhui Wang
- Engineering Research Center for Biomedical Materials of Ministry of EducationEast China University of Science and TechnologyShanghai200237P. R. China
- School of Material Science and EngineeringEast China University of Science and TechnologyShanghai200237P. R. China
| | - Cheng Peng
- The Education Ministry Key Lab of Resource ChemistryJoint International Research Laboratory of Resource Chemistry of Ministry of EducationShanghai Key Laboratory of Rare Earth Functional MaterialsShanghai Frontiers Science Center of Biomimetic CatalysisShanghai Normal UniversityShanghai200234P. R. China
| | - Miao He
- Engineering Research Center for Biomedical Materials of Ministry of EducationEast China University of Science and TechnologyShanghai200237P. R. China
| | - Feng Wang
- The Education Ministry Key Lab of Resource ChemistryJoint International Research Laboratory of Resource Chemistry of Ministry of EducationShanghai Key Laboratory of Rare Earth Functional MaterialsShanghai Frontiers Science Center of Biomimetic CatalysisShanghai Normal UniversityShanghai200234P. R. China
| | - Hongyan He
- Frontiers Science Center for Materiobiology and Dynamic ChemistryEast China University of Science and TechnologyShanghai200237P. R. China
- Engineering Research Center for Biomedical Materials of Ministry of EducationEast China University of Science and TechnologyShanghai200237P. R. China
- School of Material Science and EngineeringEast China University of Science and TechnologyShanghai200237P. R. China
| | - Changsheng Liu
- Frontiers Science Center for Materiobiology and Dynamic ChemistryEast China University of Science and TechnologyShanghai200237P. R. China
- Engineering Research Center for Biomedical Materials of Ministry of EducationEast China University of Science and TechnologyShanghai200237P. R. China
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Huo R, Wei C, Yang Y, Lin J, Huang X. Hydroxychloroquine: A double‑edged sword (Review). Mol Med Rep 2025; 31:102. [PMID: 39981928 PMCID: PMC11868775 DOI: 10.3892/mmr.2025.13467] [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: 09/19/2024] [Accepted: 01/14/2025] [Indexed: 02/22/2025] Open
Abstract
Hydroxychloroquine (HCQ) is an antimalarial drug that has historically been used to treat and prevent malaria. However, its mechanism of action has not yet been fully elucidated. HCQ affects various cellular and molecular pathways through different mechanisms. HCQ has also been shown to be a disease‑improving agent for the treatment of rheumatic diseases, including systemic lupus erythematosus, antiphospholipid syndrome, rheumatoid arthritis and primary Sjögren's syndrome. Although generally considered safe, adverse reactions have been reported with the use of HCQ and clinicians should carefully monitor patients with rheumatism when prescribing these drugs. The purpose of the present review is to strengthen the clinical use of HCQ for autoimmune diseases while highlighting the adverse effects that may occur during treatment.
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Affiliation(s)
- Rongxiu Huo
- Department of Rheumatology and Immunology, Guangxi Academy of Medical Sciences, The People's Hospital of Guangxi Zhuang Autonomous Region, Nanning, Guangxi Zhuang Autonomous Region 530016, P.R. China
| | - Chengcheng Wei
- Department of Rheumatology and Immunology, Guangxi Academy of Medical Sciences, The People's Hospital of Guangxi Zhuang Autonomous Region, Nanning, Guangxi Zhuang Autonomous Region 530016, P.R. China
| | - Yanting Yang
- Department of Rheumatology and Immunology, Guangxi Academy of Medical Sciences, The People's Hospital of Guangxi Zhuang Autonomous Region, Nanning, Guangxi Zhuang Autonomous Region 530016, P.R. China
| | - Jinying Lin
- Department of Rheumatology and Immunology, Guangxi Academy of Medical Sciences, The People's Hospital of Guangxi Zhuang Autonomous Region, Nanning, Guangxi Zhuang Autonomous Region 530016, P.R. China
| | - Xinxiang Huang
- Department of Rheumatology and Immunology, Guangxi Academy of Medical Sciences, The People's Hospital of Guangxi Zhuang Autonomous Region, Nanning, Guangxi Zhuang Autonomous Region 530016, P.R. China
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Liao KP, Cai T. Artificial intelligence as an assistant for studying treatment response in rheumatoid arthritis. Semin Arthritis Rheum 2025; 70S:152591. [PMID: 39562277 PMCID: PMC11761357 DOI: 10.1016/j.semarthrit.2024.152591] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/17/2024] [Accepted: 10/28/2024] [Indexed: 11/21/2024]
Affiliation(s)
- Katherine P Liao
- Division of Rheumatology Inflammation and Immunity, Brigham and Women's Hospital, USA; Department of Medicine, Harvard Medical School, USA; Department of Biomedical Informatics, Harvard Medical School,USA; Section of Rheumatology, VA Boston Healthcare System,USA.
| | - Tianxi Cai
- Department of Biomedical Informatics, Harvard Medical School,USA; Department of Biostatistics, Harvard T.H. Chan School of Public Health, USA
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Yang Y, Hong Q, Zhang X, Liu Z. Bifidobacterium animalis BD400 protects from collagen-induced arthritis through histidine metabolism. Front Immunol 2025; 16:1518181. [PMID: 39911381 PMCID: PMC11794514 DOI: 10.3389/fimmu.2025.1518181] [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: 10/28/2024] [Accepted: 01/02/2025] [Indexed: 02/07/2025] Open
Abstract
Background Rheumatoid arthritis (RA) is a common chronic and systemic autoimmune disease. Numerous clinical studies have indicated a correlation between alterations in gut microbiota and the onset and progression of RA. This research aims to restore intestinal microbiota to a healthy state through the oral administration of Bifidobacterium in the early stages with the goal of delaying the onset and progression of RA. Methods Collagen-induced arthritis (CIA) rat model was constructed to assess the development of RA using arthritis clinical scores, paw thickness, pathological analysis of knee joint. The immune response was evaluated by determinating specific antibodies and cytokines in serum and synovial fluid. The expression of intestinal barrier protein was analyzed by qPCR to evaluate the intestinal barrier function. Alterations in gut microbiota and metabolites were assessed by 16S rDNA and non-targeted metabolomics. Results The findings reveal that administering Bifidobacterium animalis BD400 orally led to a significant reduction in arthritis clinical scores and paw swelling thickness in CIA rats. Additionally, there was a decrease in osteo-facial fusion and calcified cartilage thickening in the knee joint. Furthermore, the oral administration of B. animalis BD400 resulted in the down-regulation of inflammatory factors TNF-α and collagenase MMP-13 in the knee joint. Levels of specific antibodies (anti-CII IgG, anti-CII IgG1, and anti-CII IgG2a) and cytokine IL-17A in serum, as well as cytokines (TNF-α and IL-1β) in the synovial fluid of B. animalis BD400-treated CIA rats, were significantly reduced (p < 0.05). The gene expression levels of intestinal barrier proteins (occludin-1, MUC-2, and ZO-1) showed a significant increase (p < 0.05) in B. animalis BD400-treated CIA rats. The oral administration of B. animalis BD400 altered the composition of intestinal microorganisms in CIA rats at the phylum and genus levels, particularly affecting the genus HT002. B. animalis BD400 alleviates RA by down-regulating 1-methyl-L-histidine and urocanate in the histidine metabolism, laying a foundation for the RA prevention. Conclusion By affecting genus HT002 and histidine metabolism in the gut microbiota of CIA rats, B. animalis BD400 restored intestinal permeability, inhibited systemic inflammatory response, and ultimately slowed down the development of RA.
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Affiliation(s)
- Yang Yang
- State Key Laboratory of Dairy Biotechnology, Shanghai Engineering Research Center of Dairy Biotechnology, Shanghai, China
- Dairy Research Institute, Bright Dairy & Food Co., Ltd., Shanghai, China
| | - Qing Hong
- State Key Laboratory of Dairy Biotechnology, Shanghai Engineering Research Center of Dairy Biotechnology, Shanghai, China
- Dairy Research Institute, Bright Dairy & Food Co., Ltd., Shanghai, China
| | - Xuehong Zhang
- State Key Laboratory of Microbial Metabolism, and School of Life Sciences and Biotechnology, Shanghai Jiao Tong University, Shanghai, China
| | - Zhenmin Liu
- State Key Laboratory of Dairy Biotechnology, Shanghai Engineering Research Center of Dairy Biotechnology, Shanghai, China
- Dairy Research Institute, Bright Dairy & Food Co., Ltd., Shanghai, China
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Sciascia S, Barilaro G, Radin M, Cervera R, Roccatello D. Is it time for treat-to-target in antiphospholipid syndrome? Autoimmun Rev 2025; 24:103690. [PMID: 39566649 DOI: 10.1016/j.autrev.2024.103690] [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: 08/14/2024] [Revised: 11/03/2024] [Accepted: 11/12/2024] [Indexed: 11/22/2024]
Abstract
A treat-to-target (T2T) approach aims to the identification of a clinically relevant therapeutic target and applies tight control (periodic visits at prespecified time-points and treatment adjustments) to achieve it with the goal of improving disease outcomes. The application of a T2T strategy appears to be less feasible in APS compared to other autoimmune diseases. This is primarily explicable by the disease's kaleidoscopic clinical presentation, along with the lack of a definitive tool (biomarkers or scoring system) to assess disease activity, making it complex to recognize a singular, effective therapeutic target for APS patients. Nevertheless, the conceptualization of T2T strategies should be considered a key objective when managing APS, aiming to achieve optimal disease control (including lowering the risk for recurrences), to reduce damage accumulation, and, ultimately, to enhance patients' quality of life.
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Affiliation(s)
- Savino Sciascia
- University Center of Excellence on Nephrologic, Rheumatologic and Rare Diseases (ERK-Net, ERN-Reconnect and RITA-ERN Member) with Nephrology and Dialysis Unit and Center of Immuno-Rheumatology and Rare Diseases (CMID), Coordinating Center of the Interregional Network for Rare Diseases of Piedmont and Aosta Valley, ASL Città di Torino and Department of Clinical and Biological Sciences, University of Turin, Spain.
| | - Giuseppe Barilaro
- Department of Autoimmune Diseases, Reference Centre (UEC/CSUR) for Systemic Autoimmune Diseases, Vasculitis and Autoinflammatory Diseases / Member of ERN-ReCONNET-RITA. Hospital Clinic, Universitat de Barcelona, Barcelona, Catalonia, Spain; Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Barcelona, Catalonia, Spain
| | - Massimo Radin
- University Center of Excellence on Nephrologic, Rheumatologic and Rare Diseases (ERK-Net, ERN-Reconnect and RITA-ERN Member) with Nephrology and Dialysis Unit and Center of Immuno-Rheumatology and Rare Diseases (CMID), Coordinating Center of the Interregional Network for Rare Diseases of Piedmont and Aosta Valley, ASL Città di Torino and Department of Clinical and Biological Sciences, University of Turin, Spain
| | - Ricard Cervera
- Department of Autoimmune Diseases, Reference Centre (UEC/CSUR) for Systemic Autoimmune Diseases, Vasculitis and Autoinflammatory Diseases / Member of ERN-ReCONNET-RITA. Hospital Clinic, Universitat de Barcelona, Barcelona, Catalonia, Spain; Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Barcelona, Catalonia, Spain
| | - Dario Roccatello
- University Center of Excellence on Nephrologic, Rheumatologic and Rare Diseases (ERK-Net, ERN-Reconnect and RITA-ERN Member) with Nephrology and Dialysis Unit and Center of Immuno-Rheumatology and Rare Diseases (CMID), Coordinating Center of the Interregional Network for Rare Diseases of Piedmont and Aosta Valley, ASL Città di Torino and Department of Clinical and Biological Sciences, University of Turin, Spain
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Álvaro-Gracia Álvaro JM, Díaz Del Campo Fontecha P, Andréu Sánchez JL, Balsa Criado A, Cáliz Cáliz R, Castrejón Fernández I, Corominas H, Gómez Puerta JA, Manrique Arija S, Mena Vázquez N, Ortiz García A, Plasencia Rodríguez C, Silva Fernández L, Tornero Molina J. Update of the Consensus Statement of the Spanish Society of Rheumatology on the use of biological and synthetic targeted therapies in rheumatoid arthritis. REUMATOLOGIA CLINICA 2024; 20:423-439. [PMID: 39341701 DOI: 10.1016/j.reumae.2024.09.002] [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: 05/13/2024] [Accepted: 05/24/2024] [Indexed: 10/01/2024]
Abstract
OBJECTIVE To update the consensus document of the Spanish Society of Rheumatology (SER) regarding the use of targeted biological and synthetic therapies in rheumatoid arthritis (RA) with the aim of assisting clinicians in their therapeutic decisions. METHODS A panel of 13 experts was assembled through an open call by SER. We employed a mixed adaptation-elaboration-update methodology starting from the 2015 Consensus Document of the Spanish Society of Rheumatology on the use of biological therapies in RA. Starting with systematic reviews (SR) of recommendations from EULAR 2019, American College of Rheumatology 2021, and GUIPCAR 2017, we updated the search strategies for the PICO questions of GUIPCAR. An additional SR was conducted on demyelinating disease in relation to targeted biological and synthetic therapies. Following the analysis of evidence by different panelists, consensus on the wording and level of agreement for each recommendation was reached in a face-to-face meeting. RESULTS The panel established 5 general principles and 15 recommendations on the management of RA. These encompassed crucial aspects such as the importance of early treatment, therapeutic goals in RA, monitoring frequency, the use of glucocorticoids, the application of conventional synthetic disease-modifying antirheumatic drugs (csDMARDs), biological DMARDs (bDMARDs), and targeted synthetic DMARDs. Additionally, recommendations on dose reduction of these drugs in stable patients were included. This update also features recommendations on the use of bDMARDs and Janus Kinase inhibitors in some specific clinical situations, such as patients with lung disease, a history of cancer, heart failure, or demyelinating disease. CONCLUSIONS This update provides recommendations on key aspects in the management of RA using targeted biological and synthetic therapies.
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Affiliation(s)
- José María Álvaro-Gracia Álvaro
- Servicio de Reumatología, Hospital General Universitario Gregorio Marañón, IiSGM, Universidad Complutense Madrid, Madrid, Spain.
| | | | - José Luis Andréu Sánchez
- Servicio de Reumatología, H.U. Puerta de Hierro Majadahonda, Facultad de Medicina, Universidad Autónoma de Madrid, Madrid, Spain
| | | | | | - Isabel Castrejón Fernández
- Servicio de Reumatología, Instituto de Investigación Sanitaria Gregorio Marañón, Hospital Gregorio Marañón, Departamento de Medicina, Universidad Complutense de Madrid, Madrid, Spain
| | - Hèctor Corominas
- Servicio de Reumatología, Hospital Universitari de la Santa Creu i Sant Pau & Hospital Dos de Maig, Barcelona, Spain
| | | | - Sara Manrique Arija
- Instituto de Investigación Biomédica de Málaga (IBIMA)-Plataforma Bionand, UGC de Reumatología, Hospital Regional Universitario de Málaga, Departamento de Medicina, Universidad de Málaga, Málaga, Spain
| | - Natalia Mena Vázquez
- UGC de Reumatología, Instituto de Investigación Biomédica de Málaga (IBIMA)-Plataforma Bionand, Hospital Regional Universitario de Málaga, Universidad de Málaga, Málaga, Spain
| | - Ana Ortiz García
- Servicio de Reumatología, Hospital Universitario de La Princesa, Instituto de Investigación Sanitaria Hospital Universitario de La Princesa, Madrid, Spain
| | | | - Lucía Silva Fernández
- Servicio de Reumatología, Complexo Hospitalario Universitario de A Coruña, A Coruña, Spain
| | - Jesús Tornero Molina
- Servicio de Reumatología, Hospital Universitario de Guadalajara, Departamento de Medicina, Universidad de Alcalá de Henares, Alcalá de Henares, Madrid, Spain
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Abstract
Juvenile idiopathic arthritis (JIA) is the most common rheumatic disease in children. The International League of Associations for Rheumatology (ILAR) has defined JIA as "arthritis of unknown etiology persisting for ≥6 wk with an onset at <16 y of age, after excluding other causes of joint inflammation". Synovial inflammation is the result of a complex interplay of aberrant immune systems (both adaptive and innate) in a genetically susceptible individual, with possible external stimuli/triggers. Diagnosis of JIA essentially remains clinical, and laboratory investigations usually help to assess the severity of disease activity. Few investigations like antinuclear antibodies (ANA), human leukocyte antigen (HLA)-B27, and rheumatoid factor (RF) help to categorize or prognosticate a child with JIA. Timely use of effective therapeutic interventions including biological has shown good long-term outcomes of JIA.
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Affiliation(s)
- Murugan Sudhakar
- Pediatric Rheumatology Division, Department of Pediatrics, Christian Medical College, Vellore, 632004, Tamil Nadu, India
| | - Sathish Kumar
- Pediatric Rheumatology Division, Department of Pediatrics, Christian Medical College, Vellore, 632004, Tamil Nadu, India.
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Bertrand D, Joly J, Neerinckx B, Durez P, Lenaerts J, Joos R, Thevissen K, Zwaenepoel T, Vanhoof J, Di Romana S, Taelman V, Van Essche E, Corluy L, Ribbens C, Vanden Berghe M, Devinck M, Ajeganova S, Durnez A, Boutsen Y, Margaux J, Peene I, Van Offel J, Doumen M, Pazmino S, De Meyst E, Kulyk M, Creten N, Westhovens R, Verschueren P. Effectiveness of methotrexate and bridging glucocorticoids with or without early introduction of a 6-month course of etanercept in early RA: results of the 2-year, pragmatic, randomised CareRA2020 trial. RMD Open 2024; 10:e004535. [PMID: 39117445 PMCID: PMC11409310 DOI: 10.1136/rmdopen-2024-004535] [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: 05/15/2024] [Accepted: 07/17/2024] [Indexed: 08/10/2024] Open
Abstract
OBJECTIVES To investigate if patients with early rheumatoid arthritis responding insufficiently to initial methotrexate (MTX) and bridging glucocorticoids (GCs) could benefit from early but temporary etanercept introduction as a second remission-induction attempt. METHODS CareRA2020 (NCT03649061) was a 2-year, open-label, multicentre, pragmatic randomised controlled trial. Treatment-naïve patients started MTX and GC bridging (COBRA-Slim: CS). Within a time window from week (W) 8 until W32, early insufficient responders (28-joint Disease Activity Score - C-reactive Protein (DAS28-CRP) >3.2 between W8 and W32 or ≥2.6 at W32) were randomised to a Standard-CS strategy (adding leflunomide first) or Bio-induction-CS strategy (adding etanercept for 24 weeks). Additional treatment adaptations followed the treat-to-target principle. Longitudinal disease activity (DAS28-CRP) over 104 weeks (primary outcome), achievement of DAS28-CRP <2.6 28 weeks after randomisation, and biologic or targeted synthetic disease-modifying antirheumatic drug (b/tsDMARD) use at W104 were compared between randomisation groups. RESULTS Following CS treatment, 142 patients were early responders; 55 early insufficient responders received Standard-CS and 55 Bio-induction-CS. Superiority of Bio-induction-CS over Standard-CS could not be demonstrated (ß=-0.204, (95% CI -0.486 to 0.078), p=0.157) for the primary outcome. More patients on Bio-induction-CS achieved DAS28-CRP <2.6 at 28 weeks after randomisation (59% (95% CI 44% to 72%) vs 44% (95% CI 31% to 59%) in Standard-CS) and they were treated less frequently with b/tsDMARDs at W104 (19/55, 35%) compared with Standard-CS (29/55, 53%). CONCLUSION Half of the patients responded well to initial COBRA-Slim induction therapy. In early insufficient responders, adding etanercept for 6 months did not improve disease control over 104 weeks versus adding leflunomide first. However, temporary introduction of etanercept resulted in improved disease control early after randomisation and less patients on b/tsDMARDs at W104. TRIAL REGISTRATION NUMBER NCT03649061. CTR PILOT APPROVAL BELGIUM S59474, EudraCT number: 2017-004054-41.
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Affiliation(s)
- Delphine Bertrand
- Department of Development and Regeneration, Skeletal Biology and Engineering Research Center, KU Leuven, Leuven, Flanders, Belgium
| | - Johan Joly
- Department of Rheumatology, UZ Leuven, Leuven, Vlaams-Brabant, Belgium
| | - Barbara Neerinckx
- Department of Development and Regeneration, Skeletal Biology and Engineering Research Center, KU Leuven, Leuven, Flanders, Belgium
- Department of Rheumatology, UZ Leuven, Leuven, Vlaams-Brabant, Belgium
| | - Patrick Durez
- Department of Rheumatology, Cliniques universitaires Saint-Luc, Bruxelles, Belgium
| | - Jan Lenaerts
- Department of Rheumatology, UZ Leuven, Leuven, Vlaams-Brabant, Belgium
- Reuma Instituut, Hasselt, Belgium
| | - Rik Joos
- Department of Rheumatology, ZNA Jan Palfijn, Merksem, Belgium
| | - Kristof Thevissen
- Reumacentrum, Genk, Belgium
- Department of Rheumatology, Ziekenhuis Oost-Limburg, Genk, Limburg, Belgium
| | - Tom Zwaenepoel
- Department of Rheumatology, OLV Ziekenhuis, Aalst, Oost-Vlaanderen, Belgium
| | | | - Silvana Di Romana
- Department of Rheumatology, CHU Saint-Pierre, Bruxelles, Bruxelles, Belgium
| | - Veerle Taelman
- Department of Rheumatology, Regionaal Ziekenhuis Heilig Hart Leuven, Leuven, Vlaams Brabant, Belgium
| | - Els Van Essche
- Department of Rheumatology, Imeldaziekenhuis, Bonheiden, Belgium
| | - Luk Corluy
- Department of Rheumatology, AZ Herentals, Herentals, Belgium
| | - Clio Ribbens
- Department of Rheumatology, CHU de Liège, Liège, Belgium
| | - Marc Vanden Berghe
- Department of Rheumatology, Grand Hôpital de Charleroi Site Saint-Joseph, Gilly, Hainaut, Belgium
| | - Mieke Devinck
- Department of Rheumatology, AZ Sint-Lucas Brugge, Brugge, West-Vlaanderen, Belgium
| | - Sofia Ajeganova
- Department of Rheumatology, UZ Brussel, Brussel, Belgium
- Department of Medicine, Karolinska Institute, Stockholm, Sweden
| | - Anne Durnez
- Department of Rheumatology, AZ Jan Portaels, Vilvoorde, Vlaams Brabant, Belgium
| | - Yves Boutsen
- Department of Rheumatology, CHU UCL Namur, Yvoir, Namur, Belgium
| | - Joëlle Margaux
- Department of Rheumatology, Hôpital Erasme, Bruxelles, Belgium
| | - Isabelle Peene
- Department of Rheumatology, AZ Sint-Jan Brugge AV, Brugge, West-Vlaanderen, Belgium
| | - Jan Van Offel
- Department of Rheumatology, UZA, Edegem, Antwerp, Belgium
| | - Michaël Doumen
- Department of Development and Regeneration, Skeletal Biology and Engineering Research Center, KU Leuven, Leuven, Flanders, Belgium
- Department of Rheumatology, UZ Leuven, Leuven, Vlaams-Brabant, Belgium
| | - Sofia Pazmino
- Department of Development and Regeneration, Skeletal Biology and Engineering Research Center, KU Leuven, Leuven, Flanders, Belgium
- Department of Chronic Diseases and Metabolism, Clinical and Experimental Endocrinology, KU Leuven, Leuven, Flanders, Belgium
| | - Elias De Meyst
- Department of Development and Regeneration, Skeletal Biology and Engineering Research Center, KU Leuven, Leuven, Flanders, Belgium
- Department of Rheumatology, UZ Leuven, Leuven, Vlaams-Brabant, Belgium
| | - Myroslava Kulyk
- Department of Development and Regeneration, Skeletal Biology and Engineering Research Center, KU Leuven, Leuven, Flanders, Belgium
- Bogomolets National Medical University, Kiiv, Ukraine
| | | | - René Westhovens
- Department of Development and Regeneration, Skeletal Biology and Engineering Research Center, KU Leuven, Leuven, Flanders, Belgium
- Department of Rheumatology, UZ Leuven, Leuven, Vlaams-Brabant, Belgium
| | - Patrick Verschueren
- Department of Development and Regeneration, Skeletal Biology and Engineering Research Center, KU Leuven, Leuven, Flanders, Belgium
- Department of Rheumatology, UZ Leuven, Leuven, Vlaams-Brabant, Belgium
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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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10
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Mok TC, Mok CC. Non-TNF biologics and their biosimilars in rheumatoid arthritis. Expert Opin Biol Ther 2024; 24:599-613. [PMID: 38766765 DOI: 10.1080/14712598.2024.2358165] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/07/2024] [Accepted: 05/17/2024] [Indexed: 05/22/2024]
Abstract
INTRODUCTION Rheumatoid arthritis (RA) is a chronic inflammatory rheumatic disease that affects both the articular and extra-articular structures, leading to significant joint damage, disability and excess mortality. The treatment algorithm of RA has changed tremendously in the past 1-2 decades because of the emergence of novel biological therapies that target different mechanisms of action in addition to TNFα. AREAS COVERED This article summarizes the evidence and safety of the non-TNF biological DMARDs in the treatment of RA, including those that target B cells, T-cell co-stimulation, interleukin (IL)-6 and granulocyte-monocyte colony-stimulating factor (GM-CSF). The targeted synthetic DMARDs such as the Janus kinase inhibitors are not included. The availability of the less costly biosimilars has enabled more patients to receive biological therapy earlier in the course of the disease. The evidence for the non-TNF biosimilar compounds in RA is also reviewed. EXPERT OPINION There are unmet needs of developing novel therapeutic agents to enhance the response rate and provide more options for difficult-to-treat RA. These include the newer generation biologic and targeted synthetic DMARDs. A personalized treatment strategy in RA requires evaluation of the cellular, cytokine, genomic and transcriptomic profile that would predict treatment response to biologic or targeted DMARDs of different mechanisms of action.
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Affiliation(s)
- Tsz Ching Mok
- Department of Medicine, Ruttonjee Hospital, Hong Kong, China
| | - Chi Chiu Mok
- Department of Medicine, Tuen Mun Hospital, Hong Kong, China
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Momen Majumder MS, Hasan ATMT, Choudhury MR, Ahmed S, Miah MT, Amin MR, Shahin MA, Islam A, Shazzad MN, Hassan MM, Ahmedullah AK, Rahman MM, Yesmeen S, Uddin T, Haq SA. 2023 Management Recommendations of Bangladesh Rheumatology Society on Pharmacological Treatment of Rheumatoid Arthritis With Synthetic and Biologic Disease-Modifying Drugs. Cureus 2024; 16:e59395. [PMID: 38707172 PMCID: PMC11070067 DOI: 10.7759/cureus.59395] [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] [Accepted: 04/30/2024] [Indexed: 05/07/2024] Open
Abstract
Rheumatoid arthritis (RA) is the most common inflammatory polyarthritis in Bangladesh. Bangladesh Rheumatology Society (BRS) proposes these management recommendations to treat the considerable burden of RA in the resource-constrained situation based on the best current evidence combined with societal challenges and opportunities. BRS formed a task force (TF) comprising four rheumatologists. The TF searched for all available literature, including updated American College of Rheumatology (ACR), European Alliance of Associations for Rheumatology (EULAR), and Asia-Pacific League of Associations for Rheumatology (APLAR) and several other guidelines, and systematic literature reviews until October 2023, and then a steering committee was formed, which included rheumatologists and internists. We followed the EULAR standard operating procedures to categorize levels of evidence and grading of recommendations. This recommendation has two parts -- general (diagnosis of RA, nomenclature of disease-modifying anti-rheumatic drugs [DMARDs], disease activity indices) and management portion. The TF agreed on four overarching principles and 12 recommendations. Overarching principles deal with early diagnosis and disease activity monitoring. Recommendations 1-5 discuss using glucocorticoids, NSAIDs, and conventional synthetic DMARDs (csDMARD). Recommendations 6-9 stretch the use of targeted synthetic DMARDs (tsDMARDs) and biological DMARDs (bDMARDs). The suggested DMARD therapy includes initiation with methotrexate (MTX) or another csDMARD (in case of contraindication to MTX) in the first phase and the addition of a tsDMARD in the second phase, switching to an alternative tsDMARDs or bDMARDs in the subsequent phases. The TF included the Padua prediction score for the thromboembolism risk estimation. Recommendations 10-12 cover infection screening, vaccination, and DMARD tapering. Bangladesh has a higher prevalence of RA. This recommendation will serve as a tool to treat this high burden of patients with RA scientifically and more effectively.
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Affiliation(s)
| | | | | | - Shamim Ahmed
- Rheumatology, Bangabandhu Sheikh Mujib Medical University, Dhaka, BGD
| | - Md Titu Miah
- Internal Medicine, Directorate General of Medical Education, Mohakhali, Dhaka, BGD
| | - Md Robed Amin
- Internal Medicine, Directorate General of Health Services (DGHS), Dhaka, BGD
| | - Md A Shahin
- Rheumatology, Bangabandhu Sheikh Mujib Medical University, Dhaka, BGD
| | - Ariful Islam
- Rheumatology, Bangabandhu Sheikh Mujib Medical University, Dhaka, BGD
| | | | - M Masudul Hassan
- Rheumatology, Bangabandhu Sheikh Mujib Medical University, Dhaka, BGD
| | | | | | - Sabrina Yesmeen
- Rheumatology, BIRDEM (Bangladesh Institute of Research and Rehabilitation in Diabetes, Endocrine and Metabolic Disorders) General Hospital, Dhaka, BGD
| | - Taslim Uddin
- Rehabilitation Medicine, Bangabandhu Sheikh Mujib Medical University, Dhaka, BGD
| | - Syed A Haq
- Rheumatology, Bangabandhu Sheikh Mujib Medical University, Dhaka, BGD
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12
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Baker JF, ODell JR, England BR, Giles JT, Newcomb JA, George MD, Thiele G, Moreland L, Bridges SL, Curtis JR, Mikuls TR. Lower body mass and lower adiposity are associated with differential responses to two treatment strategies for rheumatoid arthritis. Ann Rheum Dis 2024; 83:429-436. [PMID: 38171598 PMCID: PMC11019773 DOI: 10.1136/ard-2023-225014] [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: 09/18/2023] [Accepted: 12/18/2023] [Indexed: 01/05/2024]
Abstract
PURPOSE To determine if body mass index (BMI) and adipokine levels identify rheumatoid arthritis (RA) patients most likely to benefit from initiation of tumour necrosis factor inhibitors (TNFi) after methotrexate inadequate response. METHODS This is a secondary analysis of the Rheumatoid Arthritis Comparison of Active Treatments (RACAT) trial and the (TEAR) trial. Both studies compared treatment strategies starting with conventional disease-modifying anti-rheumatic drugs (DMARDs) (triple therapy) versus etanercept plus methotrexate. We compared response rates between TNFi and triple therapy among patients with different BMI. Adipokines were measured at enrolment and associations with treatment response were examined using regression, adjusting for age, sex, BMI and baseline disease activity. RESULTS In RACAT (n=306), participants who were normal/underweight were more likely to benefit from TNFi versus triple therapy, with greater change in Disease Activity Score in 28 and greater ACR20 response (ACR 20: 64% vs 23%, p=0.001). In contrast, overweight/obese participants had similar response to TNFi versus triple therapy (p-for-interaction=0.001). Similarly, but modest patterns were observed in TEAR (n=601; ACR20: 67% vs 52%, p=0.05). In RACAT, adipokine scores consistent with lower adiposity also predicted greater response to TNFi (ACR20: 58% vs 37%, p=0.01) with better model fit compared with BMI alone. CONCLUSIONS Lower BMI and evidence of lower adiposity based on adipokine profiles were associated with a superior response to TNFi compared with triple therapy. There was no difference between treatments among overweight/obese participants. The results support TNFi being a particularly important therapeutic among normal/underweight patients, with implications for clinical decisions and trial design.
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Affiliation(s)
- Joshua F Baker
- University of Pennsylvania, Philadelphia, Pennsylvania, USA
- Department of Biostatistics, Epidemiology, and Informatics, University of Pennsylvania, Philadelphia, Pennsylvania, USA
| | - James R ODell
- University of Nebraska Medical Center, Omaha, Nebraska, USA
| | - Bryant R England
- Rheumatology, University of Nebraska Medical Center, Omaha, Nebraska, USA
- Rheumatology, VA Nebraska-Western Iowa Health Care System, Omaha, Nebraska, USA
| | - Jon T Giles
- Division of Rheumatology, Columbia University, College of Physicians and Surgeons, New York, New York, USA
| | - Jefferey A Newcomb
- Department of Internal Medicine, University of Nebraska Medical Center, Omaha, Nebraska, USA
| | | | - Geoffrey Thiele
- Internal Medicine, University of Nebraska Medical Center, Omaha, Nebraska, USA
- Research Services, 151, Omaha VA Medical Center, Omaha, Nebraska, USA
| | - Larry Moreland
- Orthopedics, University of Colorado, Denver, Colorado, USA
| | | | - Jeffrey R Curtis
- University of Alabama at Birmingham Department of Medicine, Birmingham, Alabama, USA
| | - Ted R Mikuls
- Department of Internal Medicine, University of Nebraska Medical Center, Omaha, Nebraska, USA
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Mochizuki T, Koenuma N, Yano K, Ikari K, Hiroshima R, Okazaki K. Intensive treatment for the progression of joint damage in rheumatoid arthritis patients with low disease activity or remission. Mod Rheumatol 2024; 34:329-333. [PMID: 37267207 DOI: 10.1093/mr/road041] [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: 01/05/2023] [Revised: 03/13/2023] [Accepted: 04/21/2023] [Indexed: 06/04/2023]
Abstract
OBJECTIVES To investigate the effects of intensive treatment on joint damage in patients with rheumatoid arthritis (RA) showing progression of joint damage and low disease activity or remission. METHODS Eighty-nine patients who had change in the van der Heijde modified total Sharp score (TSS) of >0.5 points at baseline when compared with the score 1 year ago were enrolled and categorized into two groups to receive intensive (intensive group) or current (current group) treatment. The intensive and current groups were compared for change (Δ) from baseline to 1 year of erosion score, joint space narrowing score, and TSS. RESULTS The ΔTSS values at 1 year in the intensive and current groups were 0.67 ± 1.09 and 1.79 ± 1.70, respectively (P < 0.001). In the intensive and current groups, the ΔTSS ≤ 0.5 at 1 year were 66.7% and 32.4%, respectively (P = 0.010). CONCLUSIONS The intensive treatment was more effective at suppressing joint damage than the current treatment. The progression of joint damage is an important target to consider for intensive treatment.
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Affiliation(s)
- Takeshi Mochizuki
- Department of Orthopaedic Surgery, Kamagaya General Hospital, Chiba, Japan
| | - Naoko Koenuma
- Department of Orthopaedic Surgery, Tokyo Women's Medical University, Tokyo, Japan
| | - Koichiro Yano
- Department of Orthopaedic Surgery, Tokyo Women's Medical University, Tokyo, Japan
| | - Katsunori Ikari
- Department of Orthopaedic Surgery, Tokyo Women's Medical University, Tokyo, Japan
- Division of Multidisciplinary Management of Rheumatic Diseases, Tokyo Women's Medical University, Tokyo, Japan
| | - Ryo Hiroshima
- Department of Orthopaedic Surgery, Kamagaya General Hospital, Chiba, Japan
| | - Ken Okazaki
- Department of Orthopaedic Surgery, Tokyo Women's Medical University, Tokyo, Japan
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Curtis JR, Strand V, Golombek SJ, Karpouzas GA, Zhang L, Wong A, Patel K, Dines J, Akmaev VR. Decision Impact Analysis to Measure the Influence of Molecular Signature Response Classifier Testing on Treatment Selection in Rheumatoid Arthritis. Rheumatol Ther 2024; 11:61-77. [PMID: 37948030 PMCID: PMC10796853 DOI: 10.1007/s40744-023-00618-1] [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: 09/15/2023] [Accepted: 10/17/2023] [Indexed: 11/12/2023] Open
Abstract
INTRODUCTION Clinical guidelines offer little guidance for treatment selection following inadequate response to conventional synthetic disease-modifying antirheumatic drug (csDMARD) in rheumatoid arthritis (RA). A molecular signature response classifier (MSRC) was validated to predict tumor necrosis factor inhibitor (TNFi) inadequate response. The decision impact of MSRC results on biologic and targeted synthetic disease-modifying antirheumatic drug (b/tsDMARD) selection was evaluated. METHODS This is an analysis of AIMS, a longitudinal, prospective database of patients with RA tested using the MSRC. This study assessed selection of b/tsDMARDs class after MSRC testing by surveying physicians, the rate of b/tsDMARD prescriptions aligning with MSRC results, and the percentage of physicians utilizing MSRC results for decision-making. RESULTS Of 1018 participants, 70.7% (720/1018) had treatment selected after receiving MSRC results. In this MSRC-informed cohort, 75.6% (544/720) of patients received a b/tsDMARD aligned with MSRC results, and 84.6% (609/720) of providers reported using MSRC results to guide treatment selection. The most prevalent reason reported (8.2%, 59/720) for not aligning treatment selection with MSRC results from the total cohort was health insurance coverage issues. CONCLUSION This study showed that rheumatologists reported using the MSRC test to guide b/tsDMARD selection for patients with RA. In most cases, MSRC test results appeared to influence clinical decision-making according to physician self-report. Wider adoption of precision medicine tools like the MSRC could support rheumatologists and patients in working together to achieve optimal outcomes for RA.
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Affiliation(s)
- Jeffrey R Curtis
- Division of Clinical Immunology and Rheumatology, The University of Alabama at Birmingham, Birmingham, AL, USA
| | - Vibeke Strand
- Division of Immunology/Rheumatology, Stanford University, Palo Alto, CA, USA
| | - Steven J Golombek
- Allergy, Asthma and Arthritis Associates, St. Clare's Health, Denville, NJ, USA
| | - George A Karpouzas
- Harbor-UCLA Medical Center, Torrance, CA, USA
- The Lundquist Institute of Biomedical Innovation, Torrance, CA, USA
| | - Lixia Zhang
- Scipher Medicine Corporation, 221 Crescent Street, Suite 103A, Waltham, MA, 02453, USA
| | - Angus Wong
- Scipher Medicine Corporation, 221 Crescent Street, Suite 103A, Waltham, MA, 02453, USA
| | - Krishna Patel
- Scipher Medicine Corporation, 221 Crescent Street, Suite 103A, Waltham, MA, 02453, USA
| | - Jennifer Dines
- Scipher Medicine Corporation, 221 Crescent Street, Suite 103A, Waltham, MA, 02453, USA
| | - Viatcheslav R Akmaev
- Scipher Medicine Corporation, 221 Crescent Street, Suite 103A, Waltham, MA, 02453, USA.
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Dhiman K, Hall M, Crump T, Hoens AM, Lacaille D, Rankin JA, Then KL, Hazlewood G, Barnabe C, Katz S, Sutherland J, Dempsey E, Barber CEH. Content validity testing of the INTERMED Self-Assessment in a sample of adults with rheumatoid arthritis and rheumatology healthcare providers. Health Expect 2024; 27:e13978. [PMID: 38366795 PMCID: PMC10873686 DOI: 10.1111/hex.13978] [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: 04/12/2023] [Revised: 01/10/2024] [Accepted: 01/12/2024] [Indexed: 02/18/2024] Open
Abstract
BACKGROUND Care complexity can occur when patients experience health challenges simultaneously with social barriers including food and/or housing insecurity, lack of transportation or other factors that impact care and patient outcomes. People with rheumatoid arthritis (RA) may experience care complexity due to the chronicity of their condition and other biopsychosocial factors. There are few standardised instruments that measure care complexity and none that measure care complexity specifically in people with RA. OBJECTIVES We assessed the content validity of the INTERMEDS Self-Assessment (IMSA) instrument that measures care complexity with a sample of adults with RA and rheumatology healthcare providers (HCPs). Cognitive debriefing interviews utilising a reparative framework were conducted. METHODS Patient participants were recruited through two existing studies where participants agreed to be contacted about future studies. Study information was also shared through email blasts, posters and brochures at rheumatology clinic sites and trusted arthritis websites. Various rheumatology HCPs were recruited through email blasts, and divisional emails and announcements. Interviews were conducted with nine patients living with RA and five rheumatology HCPs. RESULTS Three main reparative themes were identified: (1) Lack of item clarity and standardisation including problems with item phrasing, inconsistency of the items and/or answer sets and noninclusive language; (2) item barrelling, where items asked about more than one issue, but only allowed a single answer choice; and (3) timeframes presented in the item or answer choices were either too long or too short, and did not fit the lived experiences of patients. Items predicting future healthcare needs were difficult to answer due to the episodic and fluctuating nature of RA. CONCLUSIONS Despite international use of the IMSA to measure care complexity, patients with RA and rheumatology HCPs in our setting perceived that it did not have content validity for use in RA and that revision for use in this population under a reparative framework was unfeasible. Future instrument development requires an iterative cognitive debriefing and repair process with the population of interest in the early stages to ensure content validity and comprehension. PATIENT OR PUBLIC CONTRIBUTION Patient and public contributions included both patient partners on the study team and people with RA who participated in the study. Patient partners were involved in study design, analysis and interpretation of the findings and manuscript preparation. Data analysis was structured according to emergent themes of the data that were grounded in patient perspectives and experiences.
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Affiliation(s)
- Kiran Dhiman
- Department of Medicine, Cumming School of MedicineUniversity of CalgaryCalgaryAlbertaCanada
| | - Marc Hall
- Faculty of NursingUniversity of CalgaryCalgaryAlbertaCanada
| | - Trafford Crump
- Department of Community Health Sciences, Cumming School of MedicineUniversity of CalgaryCalgaryAlbertaCanada
- Department of Surgery, Cumming School of MedicineUniversity of CalgaryCalgaryAlbertaCanada
| | - Alison M. Hoens
- Arthritis Research CanadaVancouverBritish ColumbiaCanada
- Department of Physical TherapyUniversity of British ColumbiaVancouverBritish ColumbiaCanada
- Arthritis Patient Advisory Board, Arthritis Research CanadaVancouverBritish ColumbiaCanada
| | - Diane Lacaille
- Arthritis Research CanadaVancouverBritish ColumbiaCanada
- Department of MedicineUniversity of British ColumbiaVancouverBritish ColumbiaCanada
| | | | - Karen L. Then
- Faculty of NursingUniversity of CalgaryCalgaryAlbertaCanada
| | - Glen Hazlewood
- Department of Medicine, Cumming School of MedicineUniversity of CalgaryCalgaryAlbertaCanada
- Department of Community Health Sciences, Cumming School of MedicineUniversity of CalgaryCalgaryAlbertaCanada
- Arthritis Research CanadaVancouverBritish ColumbiaCanada
- McCaig Institute for Bone and Joint HealthCalgaryAlbertaCanada
| | - Cheryl Barnabe
- Department of Medicine, Cumming School of MedicineUniversity of CalgaryCalgaryAlbertaCanada
- Department of Community Health Sciences, Cumming School of MedicineUniversity of CalgaryCalgaryAlbertaCanada
- Arthritis Research CanadaVancouverBritish ColumbiaCanada
- McCaig Institute for Bone and Joint HealthCalgaryAlbertaCanada
| | - Steven Katz
- Department of MedicineUniversity of AlbertaEdmontonAlbertaCanada
| | - Jason Sutherland
- Centre for Health Services and Policy ResearchUniversity of British ColumbiaVancouverBritish ColumbiaCanada
| | - Erika Dempsey
- Department of Medicine, Cumming School of MedicineUniversity of CalgaryCalgaryAlbertaCanada
| | - Claire E. H. Barber
- Department of Medicine, Cumming School of MedicineUniversity of CalgaryCalgaryAlbertaCanada
- Department of Community Health Sciences, Cumming School of MedicineUniversity of CalgaryCalgaryAlbertaCanada
- Arthritis Research CanadaVancouverBritish ColumbiaCanada
- McCaig Institute for Bone and Joint HealthCalgaryAlbertaCanada
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16
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Lee YH, Song GG. Relative remission rates of Janus kinase inhibitors in comparison with adalimumab in patients with active rheumatoid arthritis: a network meta-analysis. Z Rheumatol 2024; 83:88-96. [PMID: 35142908 DOI: 10.1007/s00393-022-01165-w] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 01/10/2022] [Indexed: 11/24/2022]
Abstract
OBJECTIVES The relative remission rates of tofacitinib, baricitinib, upadacitinib, and filgotinib compared with those of adalimumab were assessed in patients with rheumatoid arthritis (RA) who responded poorly to methotrexate (MTX). METHODS We performed a Bayesian network meta-analysis to combine direct and indirect evidence from randomized controlled trials (RCTs) to examine the Disease Activity Score in 28 joints with C‑reactive protein (DAS28-CRP), the Clinical Disease Activity Index (CDAI), the Simplified Disease Activity Index (SDAI), and the Boolean remission of tofacitinib, baricitinib, upadacitinib, filgotinib, and adalimumab in RA patients with inadequate responses to MTX. RESULTS Four RCTs, comprising 3507 patients, met the inclusion criteria. The filgotinib 200 mg + MTX and upadacitinib 15 mg + MTX groups showed a significantly higher DAS28-CRP < 2.6 than adalimumab 40 mg + MTX. Upadacitinib 15 mg + MTX showed a significantly higher CDAI (≤ 2.8) than adalimumab 40 mg + MTX (odds ratio [OR]: 1.62; 95% credible interval [CrI]: 1.16-2.29). The ranking probability based on the surface under the cumulative ranking curve (SUCRA) indicated that upadacitinib 15 mg + MTX had the highest probability of being the best treatment as it achieved a CDAI ≤ 2.8, followed by filgotinib 200 mg + MTX, baricitinib 4 mg + MTX, tofacitinib 5 mg + MTX, and adalimumab 40 mg + MTX. The Boolean remission showed the same distribution pattern as that of the CDAI ≤ 2.8. Upadacitinib 15 mg + MTX showed a significantly higher SDAI ≤ 3.3 than adalimumab 40 mg + MTX (OR: 1.62; 95% CrI: 1.16-2.28). SUCRA ranking based on SDAI ≤ 3.3 indicated that upadacitinib 15 mg + MTX had the highest probability of being the best treatment for achieving an SDAI ≤ 3.3, followed by baricitinib 4 mg + MTX, filgotinib 200 mg + MTX, tofacitinib 5 mg + MTX, and adalimumab 40 mg + MTX. CONCLUSIONS In RA patients with an inadequate response to MTX, remission rates with JAK inhibitors were significantly higher; there is evidence for differences in efficacy regarding remission among the different JAK inhibitors.
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Affiliation(s)
- Young Ho Lee
- Division of Rheumatology, Department of Internal Medicine, Korea University Anam Hospital, Korea University College of Medicine, 73, Goryeodae-ro, Seongbuk-gu, 02841, Seoul, Korea (Republic of).
| | - Gwan Gyu Song
- Division of Rheumatology, Department of Internal Medicine, Korea University Anam Hospital, Korea University College of Medicine, 73, Goryeodae-ro, Seongbuk-gu, 02841, Seoul, Korea (Republic of)
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Venetsanopoulou AI, Voulgari PV, Drosos AA. Advances in non-biological drugs for the treatment of rheumatoid arthritis. Expert Opin Pharmacother 2024; 25:45-53. [PMID: 38126739 DOI: 10.1080/14656566.2023.2297798] [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: 11/01/2023] [Accepted: 12/18/2023] [Indexed: 12/23/2023]
Abstract
INTRODUCTION Rheumatoid arthritis (RA) is a complex autoimmune disease that affects millions of people worldwide, with a systemic impact. This review explores the role of non-biological conventional synthetic disease-modifying antirheumatic drugs (csDMARDs) in its management. AREAS COVERED We discuss the effectiveness and safety of key csDMARDs such as Nonsteroidal anti-inflammatory drugs, corticosteroids, Hydroxychloroquine, Sulfasalazine, Methotrexate, and Leflunomide in relieving symptoms and slowing the progression of the disease. We also highlight the importance of combination therapy using csDMARDs, supported by clinical studies demonstrating the benefits of various csDMARD combinations. Early intervention with these drugs is emphasized to prevent joint damage, improve clinical symptoms, and enhance patient outcomes. EXPERT OPINION Overall, csDMARDs have proven pivotal in managing RA, providing cost-effective and versatile treatment options. We acknowledge the advantages of biologics but highlight the associated challenges, making the choice between non-biological and biological drugs a personalized decision. This comprehensive overview aims to provide a deeper understanding of RA treatment strategies, contributing to improving the quality of life for patients with this chronic condition.
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Affiliation(s)
- Aliki I Venetsanopoulou
- Department of Rheumatology, School of Health Sciences, Faculty of Medicine, University of Ioannina, Ioannina, Greece
| | - Paraskevi V Voulgari
- Department of Rheumatology, School of Health Sciences, Faculty of Medicine, University of Ioannina, Ioannina, Greece
| | - Alexandros A Drosos
- Department of Rheumatology, School of Health Sciences, Faculty of Medicine, University of Ioannina, Ioannina, Greece
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18
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Elghouneimy MA, Ramadan MA, Farrag EA, Ibrahim HF, Khirala SK, Seliem N, Kasim SA, Moazen EM, Attia AA, Mohammed FI, Ghamry AA. Impact of miR-155 rs767649 Polymorphism on Rheumatoid Arthritis Activity in Egyptian Patients. Cureus 2023; 15:e49297. [PMID: 38351964 PMCID: PMC10862083 DOI: 10.7759/cureus.49297] [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] [Accepted: 11/23/2023] [Indexed: 02/16/2024] Open
Abstract
BACKGROUND Rheumatoid arthritis (RA) is a chronic inflammatory condition that impacts not only the musculoskeletal system but also various other systems in the body, including the cutaneous, ocular, respiratory, cardiovascular, and circulatory systems. MicroRNAs (miRNAs) are a class of naturally occurring and highly conserved transcripts that primarily function in the regulation of gene expression. They accomplish this by facilitating the degradation of messenger RNA (mRNA) or by repressing mRNA translation. miRNAs are well-known regulators of a variety of cellular processes. Therefore, we aimed to detect the impact of miR-155 rs767649 polymorphism on RA activity. METHODS This case-control study included 66 Egyptian patients with RA who visited Al-Zhraa University Hospital, Internal Medicine Department, Cairo, Egypt, and 50 apparently healthy control subjects matched for age and sex. The participants were subjected to full clinical evaluation, including assessments of the disease activity score (DAS), erythrocyte sedimentation rate (ESR), liver and kidney function, anti-cyclic citrullinated peptide antibody (anti-CCP), and miR-155 polymorphism using real-time polymerase chain reaction (PCR). RESULTS In the RA group, the majority (98.5%) were female, with a mean age of 43 years, while in the control group, 94% were female, with a mean age of 43.4 years. Comparison of laboratory parameters indicated significantly lower hemoglobin levels, higher ESR, and higher serum creatinine and anti-CCP levels in the RA group than in the control group. The RA group had a significantly higher frequency of TT genotypes and significantly lower frequencies of TA and TT genotypes than the control group. Considering the TT genotype and T allele as references, TA, AA, and TA/AA genotypes in the dominant model; AA in the recessive model; and A allele were significantly associated with protective effects against RA development (p<0.05, odds ratio<1). CONCLUSION rs767649, the functional variant of miR-155, plays an important role in susceptibility to the increased risk of RA, suggesting that miR-155 can be used as a therapeutic target for the treatment of Egyptian patients with RA.
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Affiliation(s)
| | - Marwa A Ramadan
- Clinical Pathology Department, Faculty of Medicine for Girls, Al-Azhar University, Cairo, EGY
| | - Enas A Farrag
- Clinical Pathology Department, Faculty of Medicine for Girls, Al-Azhar University, Cairo, EGY
| | - Hanan F Ibrahim
- Medical Microbiology and Immunology Department, Faculty of Medicine for Girls, Al-Azhar University, Cairo, EGY
| | - Seham K Khirala
- Medical Microbiology and Immunology Department, Faculty of Medicine for Girls, Al-Azhar University, Cairo, EGY
| | - Nora Seliem
- Biochemistry Department, Faculty of Medicine for Girls, Al-Azhar University, Cairo, EGY
| | - Sammar A Kasim
- Internal Medicine Department, Faculty of Medicine for Girls, Al-Azhar University, Cairo, EGY
| | - Eman M Moazen
- Department of Chest Disease, Faculty of Medicine, Al-Azhar University, Cairo, EGY
| | - Asmaa A Attia
- Internal Medicine Department, Faculty of Medicine for Girls, Al-Azhar University, Cairo, EGY
| | - Faten I Mohammed
- Physiology Department, Faculty of Medicine for Girls, Al-Azhar University, Cairo, EGY
| | - Aya A Ghamry
- Medical Microbiology and Immunology Department, Faculty of Medicine for Girls, Al-Azhar University, Cairo, EGY
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Assefi M, Lewandrowski KU, Lorio M, Fiorelli RKA, Landgraeber S, Sharafshah A. Network-Based In Silico Analysis of New Combinations of Modern Drug Targets with Methotrexate for Response-Based Treatment of Rheumatoid Arthritis. J Pers Med 2023; 13:1550. [PMID: 38003865 PMCID: PMC10672378 DOI: 10.3390/jpm13111550] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/22/2023] [Revised: 10/22/2023] [Accepted: 10/27/2023] [Indexed: 11/26/2023] Open
Abstract
BACKGROUND Methotrexate (MTX), sulfonamides, hydroxychloroquine, and leflunomide have consistently resulted in remission with relatively mild to moderate adverse effects in patients with rheumatoid arthritis (RA). Modern medications outperform traditional treatments in that they target the pathological processes that underlie the development of RA. METHODS Following PRISMA guidelines, the authors accomplished a systematic review of the clinical efficacy of RA drugs, including the biologics such as Tumor Necrosis Factor-alpha inhibitors (TNF-α i) like Etanercept, Infliximab, Golimumab, and Adalimumab, kinase inhibitors (JAK inhibitors including Baricitinib and Tofacitanib), SyK inhibitors like Fos-tamatinib, MAPK inhibitors such as Talmapimod, T-cell inhibitors (Abatacept), IL6 blockers (Tocilizumab), and B cells depleters (Rituximab). These drugs have been found to increase remission rates when combined with MTX. A bioinformatics-based network was designed applying STRING-MODEL and the DrugBank database for the aforementioned drugs and MTX and, finally, employed for this systematic review. RESULTS Current research demonstrates that non-TNF-α inhibitor biologicals are particularly helpful in treating patients who did not respond well to conventional medications and TNF-α inhibitors. Despite being effective, these innovative drugs have a higher chance of producing hazardous side effects. The in silico investigations suggested an uncovered molecular interaction in combining MTX with other biological drugs. The STRING-MODEL showed that DHFR, TYMS, and ATIC, as the receptors of MTX, interact with each other but are not connected to the major interacted receptors. CONCLUSIONS New game-changing drugs including Mavrilimumab, Iguratimod, Upadacitinib, Fenebrutinib, and nanoparticles may be crucial in controlling symptoms in poorly managed RA patients. Emerging therapeutic targets like Toll-like 4 receptors, NLRP3 inflammasome complexes, and mesenchymal stem cells can further transform RA therapy.
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Affiliation(s)
- Marjan Assefi
- Marie Curie Science Research Center, Greensboro, NC 27407, USA;
| | - Kai-Uwe Lewandrowski
- Center for Advanced Spine Care of Southern Arizona, 4787 E Camp Lowell Drive, Tucson, AZ 85712, USA;
- Department of Orthopaedics, Fundación Universitaria Sanitas, Bogotá 111321, Colombia
- Department of Orthopedics, Hospital Universitário Gaffre e Guinle, Universidade Federal do Estado do Rio de Janeiro, Rio de Janeiro 21941-590, RJ, Brazil
| | - Morgan Lorio
- Advanced Orthopaedics, 499 E. Central Pkwy, Ste. 130, Altamonte Springs, FL 32701, USA;
| | - Rossano Kepler Alvim Fiorelli
- Department of General and Specialized Surgery, Gaffrée e Guinle University Hospital, Federal University of the State of Rio de Janeiro (UNIRIO), Rio de Janeiro 22290-240, RJ, Brazil;
| | - Stefan Landgraeber
- Klinik für Orthopädie und Orthopädische Chirurgie Gebäude 37, EG, Zimmer 56, 66421 Homburg, Germany;
| | - Alireza Sharafshah
- Marie Curie Science Research Center, Greensboro, NC 27407, USA;
- Cellular and Molecular Research Center, School of Medicine, Guilan University of Medical Sciences, Rasht P.O. Box 4144654839, Iran
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Chen F, Lang Y, Geng S, Wang X, Lu L, Ye S, Zhang L, Li T. The effective threshold dose of etanercept in patients with methotrexate-resistant rheumatoid arthritis. Clin Rheumatol 2023; 42:2777-2786. [PMID: 37415053 PMCID: PMC10497429 DOI: 10.1007/s10067-023-06659-9] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/07/2023] [Revised: 05/17/2023] [Accepted: 06/01/2023] [Indexed: 07/08/2023]
Abstract
INTRODUCTION The therapy of rheumatoid arthritis (RA) was advanced by biological agents, yet costly. This study aims to identify the effective threshold dose of etanercept (ENT) and cost-effectiveness in methotrexate (MTX)-resistant RA in real world. METHODS Eligible patients had an inadequate response (DAS28-ESR > 3.2) to initial MTX monotherapy, and subsequently received etanercept. The effective cut-off value of cumulative dose was identified to maintain remission response (DAS28-ESR < 2.6) at month 24 by using restricted cubic splines. Remission rate, low disease activity (LDA) rate, glucocorticoid exposure, safety, and cost-effectiveness were compared between the saturated and non-saturated dose groups divided by the cut-off dose. RESULTS Seventy-eight (14.2%) of 549 enrolled patients were eligible, and 72 patients completed follow-up. The 2-year cumulative cut-off dose that maintained remission response at 24 months was 1975 mg. And the recommended threshold dosing strategy of etanercept was twice weekly (BIW) for the first 6 months, every week (QW) for the next 6 months, and every 2 weeks (Q2W) and every month (QM) for the second year. Greater net changes in DAS28-ESR score were observed in the ENT saturated dose group than in the non-saturated dose group (average change 0.569, 95%CI 0.236-0.901, p = 0.001). The proportion of patients achieving remission (27.8% vs 72.2%, p < 0.001) and LDA (58.3% vs 83.3%, p = 0.020) in the non-saturated group was both significantly lower than that in the saturated group at 24 months. The incremental cost-effectiveness ratio of the saturated group referred to the non-saturated group was 5791.2 $/QALY. CONCLUSIONS In refractory RA patients, the effective cumulative cut-off dose of etanercept for sustained remission at 24 months was calculated as 1975 mg, and receiving saturated dose was more effective and cost-effective than with non-saturated dose. Key Points • The effective cumulative cut-off dose of etanercept for sustained remission at 24 months in RA patients is calculated as 1975 mg. • Receiving saturated dose of etanercept is more effective and cost-effective than with non-saturated dose in refractory RA patients.
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Affiliation(s)
- Fangfang Chen
- Department of Rheumatology, Ren Ji Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, People's Republic of China
| | - Yitian Lang
- Department of Pharmacy, Huangpu Branch, Shanghai Ninth People's Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, China
| | - Shikai Geng
- Department of Rheumatology, Ren Ji Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, People's Republic of China
| | - Xiaodong Wang
- Department of Rheumatology, Ren Ji Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, People's Republic of China
| | - Liangjing Lu
- Department of Rheumatology, Ren Ji Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, People's Republic of China
| | - Shuang Ye
- Department of Rheumatology, Ren Ji Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, People's Republic of China
| | - Le Zhang
- Department of Rheumatology, Ren Ji Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, People's Republic of China.
- Department of Pharmacy, Ren Ji Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, China.
| | - Ting Li
- Department of Rheumatology, Ren Ji Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, People's Republic of China.
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Lu B, Li C, Jing L, Zhuang F, Xiang H, Chen Y, Huang B. Rosmarinic acid nanomedicine for rheumatoid arthritis therapy: Targeted RONS scavenging and macrophage repolarization. J Control Release 2023; 362:631-646. [PMID: 37708976 DOI: 10.1016/j.jconrel.2023.09.012] [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: 05/28/2023] [Revised: 08/30/2023] [Accepted: 09/04/2023] [Indexed: 09/16/2023]
Abstract
The infiltration of inflammatory cells, especially macrophages, integrated with the production of reactive oxygen and nitrogen species (RONS) and the release of inflammatory cytokines play a crucial role in the pathogenesis of rheumatoid arthritis (RA). Synergistic combination of RONS scavenging and macrophage repolarization from pro-inflammatory M1 phenotype towards anti-inflammatory M2 phenotype, provides a promising strategy for efficient RA treatment. Herein, this study reported a unique self-assembly strategy to construct distinct rosmarinic acid nanoparticles (RNPs) for efficient RA treatment using the naturally occurring polyphenol-based compound, rosmarinic acid (RosA). The designed RNPs exhibited favorable capability in scavenging RONS and pro-inflammatory cytokines produced by macrophages. Attributing to the widened vascular endothelial-cell gap at inflammation sites, RNPs could target and accumulate at the inflammatory joints of collagen-induced arthritis (CIA) rats for guaranteeing therapeutic effect. In vivo investigation demonstrated that RNPs alleviated the symptoms of RA, including joint swelling, synovial hyperplasia, cartilage degradation, and bone erosion in CIA rats. Additionally, the designed RNPs promoted macrophage polarization from M1 phenotype towards M2 phenotype, resulting in the suppressed progression of RA. Therefore, this research represents the representative paradigm for RA therapy using antioxidative nanomedicine deriving from the natural polyphenol-based compound.
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Affiliation(s)
- Beilei Lu
- Department of Ultrasound, Zhongshan Hospital, Fudan University, Shanghai 200032, PR China; Shanghai Institute of Medical Imaging, Shanghai 200032, PR China; Institute of Medical Ultrasound and Engineering, Fudan University, Shanghai 200032, PR China
| | - Cuixian Li
- Department of Ultrasound, Zhongshan Hospital, Fudan University, Shanghai 200032, PR China; Shanghai Institute of Medical Imaging, Shanghai 200032, PR China; Institute of Medical Ultrasound and Engineering, Fudan University, Shanghai 200032, PR China
| | - Luxia Jing
- Department of Ultrasound, Zhongshan Hospital, Fudan University, Shanghai 200032, PR China; Shanghai Institute of Medical Imaging, Shanghai 200032, PR China; Institute of Medical Ultrasound and Engineering, Fudan University, Shanghai 200032, PR China
| | - Fan Zhuang
- Department of Ultrasound, Zhongshan Hospital, Fudan University, Shanghai 200032, PR China; Shanghai Institute of Medical Imaging, Shanghai 200032, PR China; Institute of Medical Ultrasound and Engineering, Fudan University, Shanghai 200032, PR China
| | - Huijing Xiang
- Materdicine Lab, School of Life Sciences, Shanghai University, Shanghai 200444, PR China.
| | - Yu Chen
- Materdicine Lab, School of Life Sciences, Shanghai University, Shanghai 200444, PR China.
| | - Beijian Huang
- Department of Ultrasound, Zhongshan Hospital, Fudan University, Shanghai 200032, PR China; Shanghai Institute of Medical Imaging, Shanghai 200032, PR China; Institute of Medical Ultrasound and Engineering, Fudan University, Shanghai 200032, PR China.
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22
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den Broeder N, den Broeder AA, Verhoef LM, van den Hoogen FHJ, van der Maas A, van den Bemt BJF. Non-Medical Switching from Tocilizumab to Sarilumab in Rheumatoid Arthritis Patients with Low Disease Activity, an Observational Study. Clin Pharmacol Ther 2023; 114:810-814. [PMID: 37429827 DOI: 10.1002/cpt.2999] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/06/2023] [Accepted: 06/29/2023] [Indexed: 07/12/2023]
Abstract
Tocilizumab and sarilumab are IL-6-receptor antagonists registered for rheumatoid arthritis (RA), with equal effectiveness and safety. Switching from tocilizumab to sarilumab could be a strategy to reduce injection burden, in case of drug shortages, and to reduce costs. This study therefore aims to investigate the effectiveness and safety of switching patients with RA with well-controlled disease under tocilizumab treatment to sarilumab. Patients with RA with low Disease Activity Score 28 (DAS28;-CRP < 2.9 or < 3.5 with clinical judgment), on stable dose tocilizumab (> 6 months) were offered to switch to sarilumab. Patients who switched and consented were followed for 6 months. Sarilumab was started at 200 mg and double the last tocilizumab interval. Co-primary outcomes at 6 months were (i) the 90% confidence interval (CI) of DAS28-CRP change from baseline compared with the non-inferiority margin of 0.6 and (ii) the 90% CI of the proportion of patients persisting with sarilumab, compared with a prespecified minimum of 70%. Of 50 invited patients, 25 agreed to switch to sarilumab, and 23 patients switched and were included. One patient was lost to follow-up immediately after inclusion, therefore 22 patients are included in the analyses. At 6 months, mean change in DAS28-CRP was 0.48 (90% CI: 0.11-0.87), compared with the non-inferiority margin of 0.6. Sarilumab persistence was 68% (90% CI: 51-82%, 15 out of 22 patients), compared with the prespecified minimum of 70%. Non-medical switching from tocilizumab to sarilumab in patients doing well on tocilizumab failed to show non-inferiority regarding disease activity and drug persistence.
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Affiliation(s)
- Nathan den Broeder
- Department of Rheumatology, Sint Maartenskliniek, Nijmegen, The Netherlands
- Radboud Institute for Health Sciences, Radboud University Medical Center, Nijmegen, The Netherlands
| | | | - Lise M Verhoef
- Department of Rheumatology, Sint Maartenskliniek, Nijmegen, The Netherlands
| | | | - Aatke van der Maas
- Department of Rheumatology, Sint Maartenskliniek, Nijmegen, The Netherlands
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Ibrahim F, Scott IC, Scott DL, Ayis SA. Heterogeneity of treatment responses in rheumatoid arthritis using group based trajectory models: secondary analysis of clinical trial data. BMC Rheumatol 2023; 7:33. [PMID: 37749588 PMCID: PMC10518927 DOI: 10.1186/s41927-023-00348-5] [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: 11/05/2022] [Accepted: 07/20/2023] [Indexed: 09/27/2023] Open
Abstract
BACKGROUND Traditionally rheumatoid arthritis (RA) trials classify patients as responders and non-responders; they ignore the potential range of treatment responses. Group Based Trajectory Models (GBTMs) provide a more refined approach. They identify patient subgroups with similar outcome trajectories. We used GBTMs to classify patients into subgroups of varying responses and explore factors associated with different responses to intensive treatment in a secondary analysis of intensive treatment in the TITRATE clinical trial. METHODS The TITRATE trial enrolled 335 patients with RA: 168 patients were randomised to receive intensive management, which comprised monthly assessments including measures of the disease activity score for 28 joints (DAS28), treatment escalation when patients were not responding sufficiently and psychosocial support; 163 of these patients completed the trial. We applied GBTMs to monthly DAS28 scores over one year to these patients who had received intensive management. The control group had standard care and were assessed every 6 months; they had too few DAS28 scores for applying GBTMs. RESULTS GBTMs identified three distinct trajectories in the patients receiving intensive management: good (n = 40), moderate (n = 76) and poor (n = 47) responders. Baseline body mass index (BMI), disability, fatigue and depression levels were significantly different between trajectory groups. Few (10%) good responders were obese, compared to 38% of moderate, and 43% of poor responders (P = 0.002). Few (8%) good responders had depression, compared to 14% moderate responders, and 38% poor responders (P < 0.001). The key difference in treatments was using high-cost biologics, used in only 5% of good responders but 30% of moderate and 51% of poor responders (P < 0.001). Most good responders had endpoint remissions and low disability, pain, and fatigue scores; few poor responders achieved any favourable outcomes. CONCLUSION GBTMs identified three trajectories of disease activity progression in patients receiving intensive management for moderately active RA. Baseline variables like obesity and depression predicted different treatment responses. Few good responders needed biologic drugs; they responded to conventional DMARDs alone. GBTMs have the potential to facilitate precision medicine enabling patient-oriented treatment strategies based on key characteristics. REGISTRATION TITRATE Trial ISRCTN 70160382.
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Affiliation(s)
- Fowzia Ibrahim
- Centre for Rheumatic Diseases, Department of Inflammation Biology, School of Immunology and Microbial Sciences, Faculty of Life Sciences and Medicine, King's College London Cutcombe Road, London, SE5 9RJ, UK.
| | - Ian C Scott
- Primary Care Centre Versus Arthritis, School of Medicine, Keele University, Keele, UK
- Haywood Academic Rheumatology Centre, Midlands Partnership University NHS Foundation Trust, High Lane, Burslem, Staffordshire, UK
| | - David L Scott
- Centre for Rheumatic Diseases, Department of Inflammation Biology, School of Immunology and Microbial Sciences, Faculty of Life Sciences and Medicine, King's College London Cutcombe Road, London, SE5 9RJ, UK
| | - Salma Ahmed Ayis
- School of Life Course and Population Sciences, King's College London, London, UK
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Huang Y, Agarwal SK, Chen H, Chatterjee S, Johnson ML, Aparasu RR. Real-world Comparative Effectiveness of Methotrexate-based Combinations for Rheumatoid Arthritis: A Retrospective Cohort Study. Clin Ther 2023; 45:e177-e186. [PMID: 37573225 DOI: 10.1016/j.clinthera.2023.06.024] [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: 11/08/2022] [Revised: 05/24/2023] [Accepted: 06/28/2023] [Indexed: 08/14/2023]
Abstract
PURPOSE Guidelines recommend using disease-modifying antirheumatic drugs (DMARDs) in combination with methotrexate (MTX) for patients with rheumatoid arthritis (RA) after monotherapy. Little is known about the real-world comparative effectiveness of these MTX-DMARD combinations. This study compared the effectiveness of various MTX-based DMARD combinations for patients with RA initiating MTX-DMARD combination therapy using administrative claims database. METHODS This retrospective cohort study included adults (aged ≥18 years) with RA who initiated MTX combination treatment with conventional synthetic DMARDs (csDMARDs), tumor necrosis factor inhibitor (TNFi) biologic DMARDs (bDMARDs), non-TNFi bDMARDs, or targeted synthetic DMARDs (tsDMARDs) between July 1, 2012, and December 31, 2013 (index date), from the MarketScan Commercial Claims Data. Patients had continuous enrollment from the 6 months of preindex period until the 12 months of postindex period. The MTX-based DMARD combination therapy cohort was defined as ≥1 MTX prescription in the first 30 days from the index date and ≥14 days overlapping use of the prescription fills of the MTX and the index DMARD. Effectiveness was measured by using the claims algorithm (dosing, switching, addition, oral glucocorticoid use, or multiple glucocorticoid injection). Propensity score analysis with the inverse probability of treatment weighting (PS-IPTW), estimated by using the generalized boosted machine learning method, was used to balance the distribution of baseline variables between the combination groups. Multivariable logistic regression using PS-IPTW was conducted to compare the effectiveness of the combination groups. Sensitivity analysis evaluated the modified effectiveness algorithms or the time to the first treatment failure. FINDINGS A total of 3174 adult patients with RA starting an MTX-DMARD combination therapy were identified (mean [SD] age, 50 [9] years), including 1568 (49%) initiating a csDMARD + MTX, 1343 (42%) initiating TNFi + MTX, and 240 (8%) initiating non-TNFi bDMARD + MTX, and 23 (1%) initiating tsDMARD + MTX. Owing to the small sample, the tsDMARD combination group was not included in the comparative analysis. Algorithm-based therapy effectiveness was found in 9.95% of the csDMARD + MTX, 20.48% of the TNFi + MTX, and 20.83% of the non-TNFi + MTX groups. PS-IPTW showed that the csDMARD combination is less effective (adjusted odds ratio, 0.422; 95% CI, 0.341-0.524) than the TNFi combination; however, the non-TNFi biologic combination had similar effectiveness (aOR, 1.063; 95% CI, 0.680-1.662) compared to the TNFi combination. Sensitivity analyses confirmed the main results. IMPLICATIONS Among RA patients initiating MTX-DMARD combinations, both non-TNFi biologics and TNFi-based combinations with MTX were equally effective, but csDMARD + MTX was less effective than the TNFi plus MTX.
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Affiliation(s)
- Yinan Huang
- Department of Pharmacy Administration, School of Pharmacy, University of Mississippi, Oxford. Mississippi, USA
| | - Sandeep K Agarwal
- Section of Immunology, Allergy & Rheumatology, Department of Medicine, Baylor College of Medicine, Houston, Texas, USA
| | - Hua Chen
- Department of Pharmaceutical Health Outcomes and Policy, College of Pharmacy, University of Houston, Houston, Texas, USA
| | - Satabdi Chatterjee
- Department of Pharmaceutical Health Outcomes and Policy, College of Pharmacy, University of Houston, Houston, Texas, USA
| | - Michael L Johnson
- Department of Pharmaceutical Health Outcomes and Policy, College of Pharmacy, University of Houston, Houston, Texas, USA
| | - Rajender R Aparasu
- Department of Pharmaceutical Health Outcomes and Policy, College of Pharmacy, University of Houston, Houston, Texas, USA.
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Pardey N, Zeidler J, Nellenschulte TF, Stahmeyer JT, Hoeper K, Witte T. [Methotrexate treatment before use of biologics in rheumatoid arthritis : Analysis of guideline compliance]. Z Rheumatol 2023; 82:573-579. [PMID: 34545429 PMCID: PMC10495498 DOI: 10.1007/s00393-021-01086-0] [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] [Accepted: 08/12/2021] [Indexed: 10/20/2022]
Abstract
BACKGROUND With the introduction of biologics the treatment landscape for patients with rheumatoid arthritis (RA) has rapidly expanded; however, according to German and European treatment guidelines the use of biologic disease-modifying antirheumatic drugs (bDMARD) is only indicated after insufficient response under methotrexate (MTX) doses of at least 20 mg/week (first-line treatment). The aim of the study was to analyze the guideline compliance of MTX prescription in the outpatient sector prior to treatment with biologics. MATERIAL AND METHODS Claims data from the AOK Lower Saxony from 2013 to 2016 were provided for all insured patients with a diagnosis of RA and bDMARD prescription during the study period. Within a patient-specific observational period of 180 days prior to the first bDMARD prescription, the maximum prescribed MTX dosage was examined. RESULTS Data from 90 incident and 315 prevalent RA patients were analyzed. A maximum MTX prescription of < 20 mg/week was observed in 60.0% of incident patients and in 67.0% of prevalent patients. Men had a higher mean MTX maximum dose (17.1 ± 4.8 mg) than women (14.9 ± 5.0 mg; p < 0.0001). Of the study population 29.6% received oral only prescriptions during the observational period. In 12.4% of patients a switch to parenteral administration was made. DISCUSSION Targeted use of the full spectrum of therapies provided prior to initiation of bDMARD treatment may contribute to cost-effective RA care. This study showed indications for potential deficits in outpatient MTX prescription practice and can raise awareness for efficient treatment.
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Affiliation(s)
- Nicolas Pardey
- Center for Health Economics Research Hannover (CHERH), Leibniz Universität Hannover, Otto-Brenner-Str. 7, 30159, Hannover, Deutschland.
| | - Jan Zeidler
- Center for Health Economics Research Hannover (CHERH), Leibniz Universität Hannover, Otto-Brenner-Str. 7, 30159, Hannover, Deutschland
| | | | - Jona T Stahmeyer
- Stabsbereich Versorgungsforschung, AOK Niedersachsen, Hannover, Deutschland
| | - Kirsten Hoeper
- Klinik für Rheumatologie und Immunologie, Medizinische Hochschule Hannover, Hannover, Deutschland
| | - Torsten Witte
- Klinik für Rheumatologie und Immunologie, Medizinische Hochschule Hannover, Hannover, Deutschland
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Huang Y, Chatterjee S, Agarwal SK, Chen H, Johnson ML, Aparasu RR. Factors influencing prescribing the first add-on disease-modifying antirheumatic drugs in patients initiating methotrexate for rheumatoid arthritis. EXPLORATORY RESEARCH IN CLINICAL AND SOCIAL PHARMACY 2023; 11:100296. [PMID: 37521021 PMCID: PMC10372178 DOI: 10.1016/j.rcsop.2023.100296] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/21/2022] [Revised: 05/31/2023] [Accepted: 06/13/2023] [Indexed: 08/01/2023] Open
Abstract
Background Advances in Disease-Modifying Antirheumatic Drugs (DMARDs) have expanded the treatment landscape for Rheumatoid Arthritis (RA). Guidelines recommend adding either conventional synthetic (cs), biologic (b), or targeted synthetic (ts) DMARDs to methotrexate (MTX) for managing RA. Limited evidence exists regarding the factors that contribute to adding a DMARD agent to the MTX regimen. This study examined the factors associated with adding the first DMARD in RA patients initiating MTX. Methods This retrospective cohort study utilized the MarketScan data (2012-2014) involving adults (aged ≥18) with RA initiating an MTX (index date) between Jul 1, 2012 and Dec 30, 2013, and with continuous enrollment for the 6-month pre-index period. The combination therapy users received the first treatment addition of DMARD starting from day 30 after the index MTX over one year period. The study focused on the addition of csDMARDs, Tumor Necrosis Factor Inhibitors (TNFi) bDMARDs, non-TNFi bDMARDs, or tsDMARDs. Baseline covariates were measured in the 6-month pre-index and grouped into predisposing, enabling, and need factors, as per the Andersen Behavior Model. Multivariable logistic regression examined the factors associated with the addition of TNFi compared to adding a csDMARD. An additional regression model evaluated the factors associated with adding any biologic (combining TNFi and non-TNFi biologics). Results Among 8350 RA patients starting MTX, 31.92% (n = 2665) initiated any DMARD within the 1-year post-index period. Among RA patients initiating a DMARD prescription after starting MTX, 945 (11.32%) received combination therapy with treatment addition of a DMARD to MTX regimen; majority added TNFi (550, 58%), followed by csDMARD (352, 37%); non-TNF biologic (40, 4%), or tsDMARD (3, 0.3%). The tsDMARD group was limited and was not included for further analysis. The multivariable model found Preferred Provider Organization insurance coverage (odds ratio [OR], 1.43; 95% confidence interval (CI), 1.06-1.93), chronic pulmonary disease (OR, 1.98; 95% CI, 1.14-3.44), liver disease (OR, 5.24; 95% CI, 1.77-15.49), and Elixhauser score (OR, 0.91; 95% CI, 0.86-0.97) were significantly associated with the addition of TNF-α inhibitors. The separate multivariable model additionally found that patients from metropolitan areas (OR, 1.50; 95% CI, 1.04-2.16) were positively associated with adding any biological agent. Conclusions TNFi are often added to MTX for managing RA. Enabling and need factors contribute to the prescribing of a TNFi add-on therapy in RA. Future research should examine the impact of these combination therapies on RA management.
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Affiliation(s)
- Yinan Huang
- Department of Pharmacy Administration, University of Mississippi, Oxford, MS, United States of America
| | - Satabdi Chatterjee
- Department of Pharmaceutical Health Outcomes and Policy, College of Pharmacy, University of Houston, TX, United States of America
| | - Sandeep K. Agarwal
- Section of Immunology, Allergy & Rheumatology, Department of Medicine, Baylor College of Medicine, Houston, TX, United States of America
| | - Hua Chen
- Department of Pharmaceutical Health Outcomes and Policy, College of Pharmacy, University of Houston, TX, United States of America
| | - Michael L. Johnson
- Department of Pharmaceutical Health Outcomes and Policy, College of Pharmacy, University of Houston, TX, United States of America
| | - Rajender R. Aparasu
- Department of Pharmaceutical Health Outcomes and Policy, College of Pharmacy, University of Houston, TX, United States of America
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Arshad M, Jalil F, Jaleel H, Ghafoor F. Bone marrow derived mesenchymal stem cells therapy for rheumatoid arthritis - a concise review of past ten years. Mol Biol Rep 2023; 50:4619-4629. [PMID: 36929285 DOI: 10.1007/s11033-023-08277-9] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/23/2022] [Accepted: 01/11/2023] [Indexed: 03/18/2023]
Abstract
Rheumatoid arthritis is an autoimmune disorder characterized by swelling in synovial joints and erosion of bones. The disease is normally treated with conventional drugs which provide only temporary relief to the symptoms. Over the past few years, mesenchymal stromal cells have become the center of attention for treating this disease due to their immuno-modulatory and anti-inflammatory characteristics. Various studies on treatment of rheumatoid arthritis by using these cells have shown positive outcomes in terms of reduction in the level of pain as well as improvement of the function and structure of joints. Mesenchymal stromal cells can be derived from multiple sources, however, the ones derived from bone marrow are considered most beneficial for treating several disorders including rheumatoid arthritis on account of being safer and more effective. This review summarizes all the preclinical and clinical studies which were conducted over the last ten years for therapy of rheumatoid arthritis utilizing these cells. The literature was reviewed using the terms "mesenchymal stem/stromal cells and rheumatoid arthritis'' and "bone marrow derived mesenchymal stromal cells and therapy of rheumatoid arthritis''. Data was extracted to enable the readers to have access to the most relevant information regarding advancement in therapeutic potential of these stromal cells. Additionally, this review will also help in fulfilling any gap in current knowledge of readers about the outcome of using these cells in animal models, cell line and in patients suffering from rheumatoid arthritis and other autoimmune disorders as well.
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Affiliation(s)
- Maria Arshad
- Department of Research & Innovation, Shalamar Institute of Health Sciences, Lahore, Pakistan.
| | - Fazal Jalil
- Department of Biotechnology, Abdul Wali Khan University, Mardan, Pakistan
| | - Hadiqa Jaleel
- Department of Research & Innovation, Shalamar Institute of Health Sciences, Lahore, Pakistan
| | - Farkhanda Ghafoor
- Department of Research & Innovation, Shalamar Institute of Health Sciences, Lahore, Pakistan
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Affiliation(s)
- Ellen M Gravallese
- From the Division of Rheumatology, Inflammation, and Immunity, Brigham and Women's Hospital, Boston (E.M.G.); and the Division of Rheumatology, Allergy, and Immunology, University of California at San Diego School of Medicine, La Jolla (G.S.F.)
| | - Gary S Firestein
- From the Division of Rheumatology, Inflammation, and Immunity, Brigham and Women's Hospital, Boston (E.M.G.); and the Division of Rheumatology, Allergy, and Immunology, University of California at San Diego School of Medicine, La Jolla (G.S.F.)
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Goldberg A, Bakhireva LN, Page K, Henrie AM. A Qualitative Scoping Review of Early-Terminated Clinical Trials Sponsored by the Department of Veterans Affairs Cooperative Studies Program From 2010 to 2020. Epidemiol Rev 2022; 44:110-120. [PMID: 36193844 PMCID: PMC10362930 DOI: 10.1093/epirev/mxac009] [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: 05/28/2021] [Revised: 08/29/2022] [Accepted: 08/29/2022] [Indexed: 12/29/2022] Open
Abstract
Increasing attention has been paid to the risks and benefits of terminating large clinical trials before reaching prespecified targets, because such decisions can greatly affect the implementation of findings. The Department of Veterans Affairs (VA) Cooperative Studies Program (CSP) is a research infrastructure dedicated to conducting high-quality clinical research. A scoping review was performed to characterize barriers preventing the attainment of prespecified recruitment, statistical power, or sample-size targets in VA CSP trials. A trial was eligible for inclusion if the trial was sponsored by the VA CSP, primary findings were published within the last 10 years, and a decision was made to terminate enrollment or follow-up before meeting a priori recruitment or endpoint targets. In 11 of 29 included trials (37.9%), a decision was made to terminate the trial early. The most common reason for early termination was related to under-recruitment (n = 5). Other reasons included early detection of safety signals (n = 2), futility (n = 1), and benefit (n = 1). This review highlights recruitment as a critical facet of trial conduct that may hinder the production of high-quality data and thus warrant additional attention. Solutions to enhance recruitment now implemented by the VA CSP, including dedicated enrollment infrastructure and screening facilitated by informatics approaches, show promise in reducing this cause for early termination.
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Affiliation(s)
- Alexa Goldberg
- Correspondence to Dr. Alexa Goldberg, Cooperative Studies Program Clinical Research Pharmacy Coordinating Center, 2401 Centre Avenue, SE, Albuquerque, NM 87106 (e-mail: )
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Darlington M, Scarica R, Chavez-Pacheco X, Blamplain Segar L, Durand-Zaleski I. Decrementally cost-effective health technologies in non-inferiority studies: A systematic review. Front Pharmacol 2022; 13:1025326. [PMID: 36545305 PMCID: PMC9760952 DOI: 10.3389/fphar.2022.1025326] [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: 08/22/2022] [Accepted: 10/31/2022] [Indexed: 12/07/2022] Open
Abstract
Background: HTA guidance has generally been driven by situations where innovative and usually more expensive technologies are compared to the prevailing standards of care. Cheaper and less efficacious interventions have received scarce attention, although strategies with minimal individual efficacy losses might produce collective health gains when savings are redistributed. Purpose: This systematic review of health economic evaluations identified interventions that are both cost and outcome reducing to procure a list of candidate decrementally cost-effective technologies. Data Sources: English language searches were performed in PubMed, EMBASE and ClinicalTrials.gov covering 2005 to September 2021. Study Selection: Full economic evaluations reporting in English decrementally cost-effective health technologies based on RCT data, modelling or mixed methods. Data Synthesis: After filtering 4,975 studies found through the systematic database search, 107 decrementally cost-effective health technologies (HTs) were identified. Nearly a third were services (n = 29) and similarly for drugs (n = 31). For over half of the studies (n = 54) health outcomes were measured in QALYs and the cost-utility ratios varied from €140 to €5 million saved per QALY lost, albeit with time horizons varying from 4 days of follow-up to lifetime extrapolations. Less than a quarter of the studies were carried out from the societal perspective. Limitations: Despite including ClinicalTrials.gov as data source, unpublished studies may have been missed. Conclusions: Our results show a growth in recent years in the number of economic publications demonstrating decrementally cost-effective HTs. Economic tools are needed to facilitate the adoption of such HTs by policy-makers at the national level to maximise health outcomes at the population level. Systematic Review Registration: https://www.crd.york.ac.uk/prospero/display_record.php?RecordID=95504, identifier CRD42018095504.
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Affiliation(s)
- Meryl Darlington
- Assistance Publique-Hôpitaux de Paris (AP-HP), Hôpital Hôtel Dieu, Clinical Research Unit Eco Ile de France, Paris, France,*Correspondence: Meryl Darlington,
| | - Raffaele Scarica
- Assistance Publique-Hôpitaux de Paris (AP-HP), Hôpital Hôtel Dieu, Clinical Research Unit Eco Ile de France, Paris, France
| | - Xyomara Chavez-Pacheco
- Assistance Publique-Hôpitaux de Paris (AP-HP), Hôpital Hôtel Dieu, Clinical Research Unit Eco Ile de France, Paris, France
| | - Laeticia Blamplain Segar
- Assistance Publique-Hôpitaux de Paris (AP-HP), Hôpital Hôtel Dieu, Clinical Research Unit Eco Ile de France, Paris, France
| | - Isabelle Durand-Zaleski
- Assistance Publique-Hôpitaux de Paris (AP-HP), Hôpital Hôtel Dieu, Clinical Research Unit Eco Ile de France, Paris, France,Université de Paris Est Creteil INSERM UMRS, Paris, France
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31
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Niemann B, Puleo A, Stout C, Markel J, Boone BA. Biologic Functions of Hydroxychloroquine in Disease: From COVID-19 to Cancer. Pharmaceutics 2022; 14:pharmaceutics14122551. [PMID: 36559044 PMCID: PMC9787624 DOI: 10.3390/pharmaceutics14122551] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/30/2022] [Revised: 11/05/2022] [Accepted: 11/10/2022] [Indexed: 11/23/2022] Open
Abstract
Chloroquine (CQ) and Hydroxychloroquine (HCQ), initially utilized in the treatment of malaria, have now developed a long list of applications. Despite their clinical relevance, their mechanisms of action are not clearly defined. Major pathways by which these agents are proposed to function include alkalinization of lysosomes and endosomes, downregulation of C-X-C chemokine receptor type 4 (CXCR4) expression, high-mobility group box 1 protein (HMGB1) inhibition, alteration of intracellular calcium, and prevention of thrombus formation. However, there is conflicting data present in the literature. This is likely the result of the complex overlapping pathways between these mechanisms of action that have not previously been highlighted. In fact, prior research has focused on very specific portions of particular pathways without describing these in the context of the extensive CQ/HCQ literature. This review summarizes the detailed data regarding CQ/HCQ's mechanisms of action while also providing insight into the overarching themes. Furthermore, this review provides clinical context to the application of these diverse drugs including their role in malaria, autoimmune disorders, cardiovascular disease, thrombus formation, malignancies, and viral infections.
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Affiliation(s)
- Britney Niemann
- Department of Surgery, West Virginia University, Morgantown, WV 26506, USA
- Correspondence: ; Tel.: +1-304-293-1254
| | - Amanda Puleo
- Department of Surgery, West Virginia University, Morgantown, WV 26506, USA
| | - Conley Stout
- Department of Surgery, West Virginia University, Morgantown, WV 26506, USA
| | - Justin Markel
- Department of Surgery, West Virginia University, Morgantown, WV 26506, USA
| | - Brian A. Boone
- Department of Surgery, West Virginia University, Morgantown, WV 26506, USA
- Department of Microbiology, Immunology and Cell Biology, West Virginia University, Morgantown, WV 26506, USA
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Zhao J, Zhou W, Wu Y, Yan X, Yang L, Zhang Z. Efficacy, safety, and cost-effectiveness of triple therapy in preventing relapse in rheumatoid arthritis: A randomized controlled trial (ESCoRT study). Chin Med J (Engl) 2022; 135:2200-2209. [PMID: 36525606 PMCID: PMC9771172 DOI: 10.1097/cm9.0000000000002336] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/18/2022] [Indexed: 12/23/2022] Open
Abstract
BACKGROUND Biological agents, such as tumor necrosis factor inhibitors (TNFi), have been widely used in rheumatoid arthritis (RA) patients and greatly improved goal achievement. The aim of this study was to investigate whether conventional synthetic disease-modifying anti-rheumatic drugs (csDMARDs) combination was better in reducing relapse than methotrexate (MTX) monotherapy, and more cost-effective than continuing TNFi plus MTX in RA patients who achieved low disease activity (LDA) with TNFi and MTX therapy. METHODS RA patients who failed to csDMARDs received an induction therapy of MTX plus TNFi for maximally 12 weeks. Those achieving LDA in 12 weeks were randomly assigned at a 1:1:1 ratio into three groups: (A) adding hydroxychloroquine and sulfasalazine for the first 12 weeks and then discontinuing TNFi for the following 48 weeks; (B) maintaining TNFi and MTX for 60 weeks; and (C) maintaining TNFi and MTX for the first 12 weeks and then discontinuing TNFi for the following 48 weeks. The primary outcome was relapse. RESULTS A total of 117 patients were enrolled for induction therapy and 67 patients who achieved LDA within 12 weeks were randomized, with 24, 21, and 22 patients in groups A, B, and C, respectively. The relapse rates of groups A and B during the entire 60 weeks were comparable [10/22 (45.5%) vs. 7/20 (35.0%), χ2 = 0.475, P = 0.491], however, significantly lower than that of group C [10/22 (45.5%) vs. 17/20 (85.0%), χ2 = 5.517, P = 0.019; 7/20 (35.0%) vs. 17/20 (85.0%), χ2 = 11.035, P = 0.004, respectively]. Taking RMB 100,000 Yuan as the threshold of willingness to pay, compared to MTX monotherapy (group C), both TNFi maintenance and triple csDMARDs therapies were cost-effective, but triple csDMARDs therapy was better. CONCLUSION For RA patients who have achieved LDA with TNFi and MTX, csDMARDs triple therapy was a cost-effective option in favor of reducing relapse. TRIAL REGISTRATION ClinicalTrials.gov, NCT02320630.
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Affiliation(s)
- Juan Zhao
- Department of Rheumatology and Clinical Immunology, Peking University First Hospital, Beijing 100034, China
| | - Wei Zhou
- Department of Rheumatology and Clinical Immunology, Peking University First Hospital, Beijing 100034, China
| | - Yangfeng Wu
- Peking University Clinical Research Institute (PUCRI), Beijing 100083, China
| | - Xiaoyan Yan
- Peking University Clinical Research Institute (PUCRI), Beijing 100083, China
| | - Li Yang
- Peking University School of Public Health, Beijing 100083, China
| | - Zhuoli Zhang
- Department of Rheumatology and Clinical Immunology, Peking University First Hospital, Beijing 100034, China
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Rosina S, Giancane G, Ruperto N. Emerging therapies for juvenile arthritis: agents in early clinical trials. Expert Opin Investig Drugs 2022; 31:1109-1124. [PMID: 36066506 DOI: 10.1080/13543784.2022.2121698] [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: 11/04/2022]
Abstract
INTRODUCTION Juvenile idiopathic arthritis (JIA) is the most common chronic inflammatory rheumatic condition in childhood. The management of JIA has been revolutionized thanks to the development of new powerful drugs and the possibility to conduct controlled clinical trials with support from legislative initiatives and availability of international collaborative networks. Trials are still needed in children because we now have new drugs related to specific JIA category. AREAS COVERED The review is centered on the latest achievements in the field, focusing on new investigational drugs which are currently or have been recently tested for JIA treatment, encompassing agents in early phase of clinical development. EXPERT OPINION Despite the tremendous improvement witnessed in the field of JIA treatment in the past 20 years, there are still many unmet needs to be prioritized. Studies on disease pathogenesis will hopefully help in the identification of new treatment targets for individual JIA categories, that could possibly favor a stricter disease control and contribute to solve the issue of refractory JIA. Novel strategies aimed at the prevention of the risk of long-term joint damage are also desirable, as well as the discovery of predictive biomarkers for treatment efficacy and safety in the individual patient.
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Affiliation(s)
- Silvia Rosina
- Clinica Pediatrica e Reumatologia, IRCCS Istituto Giannina Gaslini, Genova, Italy
| | - Gabriella Giancane
- Clinica Pediatrica e Reumatologia, IRCCS Istituto Giannina Gaslini, Genova, Italy.,Dipartimento di Neuroscienze, Riabilitazione, Oftalmologia, Genetica e Scienze Materno-Infantili (DiNOGMI), Università degli Studi di Genova, Genova, Italy
| | - Nicolino Ruperto
- Clinica Pediatrica e Reumatologia, IRCCS Istituto Giannina Gaslini, Genova, Italy.,UOSID Centro trial, IRCCS Istituto Giannina Gaslini, Genova, Italy
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Pang M, Sun Z, Zhang H. Biologic DMARDs and targeted synthetic DMARDs and the risk of all-cause mortality in rheumatoid arthritis: A systematic review and meta-analysis. Medicine (Baltimore) 2022; 101:e29838. [PMID: 35960132 PMCID: PMC9371573 DOI: 10.1097/md.0000000000029838] [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] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/04/2023] Open
Abstract
BACKGROUND The aim of this study was to perform a meta-analysis to compare the risk of all-cause mortality between biological/targeted synthetic disease-modifying antirheumatic drugs (b/tsDMARDs) and non-b/tsDMARDs involving patients with rheumatoid arthritis (RA). METHODS We performed a systematic review of articles published up to August 2021 using electronic databases. We included studies that reported all-cause mortality in RA patients and compared b/tsDMARDs and non-b/tsDMARDs. RESULTS We included a total of 77 studies involving 64,428 patients. These comprised 44,227 patients treated with b/tsDMARDs and 20,201 treated with non-b/tsDMARDs. The occurrence of all-cause mortality was the primary outcome. The risk of all-cause mortality between the 2 treatments was not significantly different (relative risk = 1.08; 95% confidence interval = 0.98-1.19). However, subgroup analyses showed significant increase in risks of mortality in anti-TNFs users with RA compared with non-b/tsDMARDs (relative risk = 1.47, 95% confidence interval = 1.02-2.12). No significant differences were found after subgroup analyses based on other molecules involved and study duration. CONCLUSION In comparison with non-b/tsDMARDs, our results suggest that antitumor necrosis factor therapy is associated with observed increased risks of mortality and further investigation is needed.
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Affiliation(s)
- Mengduan Pang
- Department of Rheumatology and Immunology, The First Affiliated Hospital of Dalian Medical University, Shahekou District, Dalian, China
| | - Zhe Sun
- Department of Thoracic Surgery, The First Affiliated Hospital of Dalian Medical University, Shahekou District, Dalian, China
| | - Hongfeng Zhang
- Department of Rheumatology and Immunology, The First Affiliated Hospital of Dalian Medical University, Shahekou District, Dalian, China
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35
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Nozaki Y, Oribe M, Tomita D, Itami T, Hayashi S, Maeda T, Fukuda K, Kuroda R, Funahashi K, Matsubara T, Kinoshita K, Matsumura I. Iguratimod Versus Salazosulfapyridine in Rheumatoid Arthritis Patients with an Inadequate Response to Methotrexate: Adjusted with Propensity Score Matching. Mod Rheumatol 2022; 33:472-480. [PMID: 35695707 DOI: 10.1093/mr/roac060] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/11/2022] [Revised: 05/17/2022] [Accepted: 06/08/2022] [Indexed: 11/13/2022]
Abstract
OBJECTIVES Methotrexate (MTX) is recommended as a first-line conventional synthetic disease-modifying anti-rheumatic drug (csDMARD) for treating rheumatoid arthritis (RA). No studies have established which csDMARDs are useful as add-on drugs for RA patients with an inadequate response (IR) to MTX. This retrospective study sought to identify an add-on csDMARD treatment strategy for RA patients with MTX-IR. PATIENTS AND METHODS We collected the cases of RA patients treated with salazosulfapyridine (SASP) or iguratimod (IGU) as the additional csDMARD for MTX-IR during a 24-month follow-up at four institutions in Japan. We performed propensity score matching to evaluate the retention rate, clinical efficacy, and safety profile (n=54, each group). RESULTS The retention rates at 24 months of combination therapy in the patients with any-reason discontinuations were 38.5% (MTX+SASP group) and 67.8% (MTX+IGU group). At 3 and 6 months of follow-up, the MTX+IGU group's DAS28-CRP was significantly decreased versus the MTX+SASP group, and at 3 months the MTX+IGU group's good-responder percentage (22.9%) was significantly higher versus the MTX+SASP group's (10.7%). Conversely, compared to the MTX+SASP group, the MTX+IGU group showed a greater reduction in the eGFR from baseline after 3 months during follow-up. CONCLUSIONS IGU is a useful add-on csDMARD for RA patients with MTX-IR; its high retention rate and good clinical response make it a useful combination therapy for controlling RA disease activity. However, the renal function of these patients should be monitored during follow-up.
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Affiliation(s)
- Yuji Nozaki
- Department of Hematology and Rheumatology, Kindai University School of Medicine, Osaka, Japan
| | | | - Daisuke Tomita
- Department of Hematology and Rheumatology, Kindai University School of Medicine, Osaka, Japan
| | - Tetsu Itami
- Department of Hematology and Rheumatology, Kindai University School of Medicine, Osaka, Japan
| | - Shinya Hayashi
- Department of Orthopaedic Surgery, Kobe University Graduate School of Medicine, Kobe, Hyogo, Japan
| | - Toshihisa Maeda
- Department of Orthopaedic Surgery, Kobe University Graduate School of Medicine, Kobe, Hyogo, Japan
| | - Koji Fukuda
- Department of Orthopaedic Surgery, Kobe University Graduate School of Medicine, Kobe, Hyogo, Japan.,Matsubara Mayflower Hospital, Kato, Hyogo, Japan
| | - Ryosuke Kuroda
- Department of Orthopaedic Surgery, Kobe University Graduate School of Medicine, Kobe, Hyogo, Japan
| | | | | | - Koji Kinoshita
- Department of Hematology and Rheumatology, Kindai University School of Medicine, Osaka, Japan
| | - Itaru Matsumura
- Department of Hematology and Rheumatology, Kindai University School of Medicine, Osaka, Japan
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Barbulescu A, Askling J, Saevarsdottir S, Kim SC, Frisell T. Combined Conventional Synthetic Disease Modifying Therapy vs. Infliximab for Rheumatoid Arthritis: Emulating a Randomized Trial in Observational Data. Clin Pharmacol Ther 2022; 112:836-845. [PMID: 35652244 PMCID: PMC9540175 DOI: 10.1002/cpt.2673] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/23/2022] [Accepted: 05/19/2022] [Indexed: 11/29/2022]
Abstract
Observational studies are often considered unreliable for evaluating relative treatment effectiveness, but it has been suggested that following target trial protocols could reduce bias. Using observational data from patients with rheumatoid arthritis (RA) in the Swedish Rheumatology Quality Register (SRQ), between 2006 and 2020, we emulated the protocol of the Swedish Farmacotherapy trial (SWEFOT) and compared the results. SWEFOT was a pragmatic trial nested in SRQ, between 2002 and 2005, where methotrexate (MTX) insufficient responders were randomized to receive additional infliximab or sulfasalazine (SSZ) + hydroxychloroquine (HCQ). Patients with RA initiating infliximab (N = 313) or SSZ + HCQ (N = 196) after MTX were identified in SRQ and the Prescribed Drugs Register, mimicking the SWEFOT eligibility criteria. The primary outcome was the proportion of European Alliance of Associations for Rheumatology (EULAR) good responders at 9 months, classifying patients who discontinued treatment as “nonresponders.” Through sensitivity analyses, we assessed the impact of relaxing eligibility criteria. The observed proportions reaching EULAR good response were close to those reported in SWEFOT: 39% (vs. 39% in SWEFOT) for infliximab and 28% (vs. 25%) for SSZ + HCQ. The crude observed response ratio was 1.39 (95% confidence interval (CI) 1.04–1.86), increasing to 1.48 (95% CI 0.98–2.24) after confounding adjustment, compared to 1.59 (95% CI 1.10–2.30) in SWEFOT. Results remained close to SWEFOT when relaxing eligibility criteria until allowing prior disease‐modifying anti‐rheumatic drug (DMARD) use which reduced the observed difference between treatments. By applying a prespecified trial emulation protocol to observational clinical registry data, we could replicate the results of SWEFOT, favoring infliximab over SSZ + HCQ combination therapy at 9 months.
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Affiliation(s)
- Andrei Barbulescu
- Clinical Epidemiology Division, Department of Medicine Solna, Karolinska Institutet, Stockholm, Sweden
| | - Johan Askling
- Clinical Epidemiology Division, Department of Medicine Solna, Karolinska Institutet, Stockholm, Sweden.,Rheumatology, Theme Inflammation and Ageing, Karolinska University Hospital, Stockholm, Sweden
| | - Saedis Saevarsdottir
- Clinical Epidemiology Division, Department of Medicine Solna, Karolinska Institutet, Stockholm, Sweden.,Faculty of Medicine, School of Health Sciences, University of Iceland, Reykjavík, Iceland
| | - Seoyoung C Kim
- Division of Pharmacoepidemiology and Pharmacoeconomics, Brigham and Women's Hospital/Harvard Medical School, Boston, Massachusetts, USA.,Division of Rheumatology, Inflammation, and Immunity, Brigham and Women's Hospital/Harvard Medical School, Boston, Massachusetts, USA
| | - Thomas Frisell
- Clinical Epidemiology Division, Department of Medicine Solna, Karolinska Institutet, Stockholm, Sweden
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The Impact of Traditional Chinese Medicine QingreHuoxue Treatment and the Combination of Methotrexate and Hydroxychloroquine on the Radiological Progression of Active Rheumatoid Arthritis: A 52-Week Follow-Up of a Randomized Controlled Clinical Study. EVIDENCE-BASED COMPLEMENTARY AND ALTERNATIVE MEDICINE 2022; 2022:5808400. [PMID: 35463097 PMCID: PMC9019417 DOI: 10.1155/2022/5808400] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 10/29/2021] [Accepted: 02/09/2022] [Indexed: 11/17/2022]
Abstract
Traditional Chinese medicine (TCM) has been used successfully to treat rheumatoid arthritis (RA). QingreHuoxue treatment (QingreHuoxue decoction [QRHXD]/QingreHuoxue external preparation [QRHXEP]) is a Chinese medicine treatment for RA. To date, very few studies have compared the long-term effects of QRHXD with those of conventional disease-modifying antirheumatic drugs on RA disease activity and radiological progression. QRHXD delayed the radiological progression and showed long-term clinical efficacy of RA. In clinical experiments, the clinical evidence of delaying the radiological progression of RA patients was obtained. A portion of the patients who participated in the “Traditional Chinese Medicine QingreHuoxue Treatment vs. the Combination of Methotrexate and Hydroxychloroquine for Active Rheumatoid Arthritis” study were followed up for 52 weeks, and intention-to-treat (ITT) and compliance protocol (PP) analyses were used to collect and compare the clinical indicators and imaging data between baseline and week 52. Two radiologists who were blind to treatment scored the images independently. Of the 468 subjects, 141 completed the 52-week follow-up. There were no significant differences among the three groups: the traditional Chinese medicine comprehensive treatment group, the Western medicine treatment group, and the integrated traditional Chinese and Western medicine treatment group. There were no differences in the total Sharp score, joint space stenosis score, and joint erosion score at baseline or 52 weeks. In the comparison of the estimated annual radiographic progression (EARP) and the actual annual Sharp total score changes among the three groups, the actual changes were much lower than the EARP at baseline. The radiological progress in all three groups was well controlled. Results of the ITT and PP data sets showed that the disease activity score 28 level of the three groups at 52 weeks was significantly lower than that at baseline. During the 52-week treatment period, the clearance of heat and promotion of blood circulation controlled disease activity and delayed the radiological progress of active RA.
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Tripterygium wilfordii Hook. f. Preparations for Rheumatoid Arthritis: An Overview of Systematic Reviews. EVIDENCE-BASED COMPLEMENTARY AND ALTERNATIVE MEDICINE 2022; 2022:3151936. [PMID: 35463070 PMCID: PMC9019410 DOI: 10.1155/2022/3151936] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 10/29/2021] [Accepted: 02/07/2022] [Indexed: 12/03/2022]
Abstract
Objectives To summarize the quantity and quality of evidence for using Tripterygium wilfordii Hook. f. (TwHF) preparations in patients with rheumatoid arthritis (RA) and to find the reasons of the disparity by comprehensively appraising the related systematic reviews (SRs). Methods We performed an overview of evidence for the effectiveness and safety of TwHF preparations for patients with RA. We searched seven literature databases from inception to July 15, 2021. We included SRs of TwHF preparations in the treatment of RA. Four tools were used to evaluate the reporting quality, methodological quality, risk of bias, and the certainty of evidence for the included SRs, which are the PRISMA, the AMSTAR-2, the ROBIS, and the GRADE approach. Results We included 27 SRs (with 385 studies and 33,888 participants) for this overview. The AMSTAR-2 showed that 19 SRs had critically low methodological quality and the remaining 8 had low methodological quality. The rate of overlaps was 68.31% (263/385), and the CCA (corrected covered area) was 0.53, which indicated the degree of overlap is slight. Based on the assessment of ROBIS, all 27 SRs were rated as low risk in phase 1; one SR was rated as low risk in domain 1, 9 SRs were in low risk in domain 2, 16 SRs were in low risk in domain 3, and 16 SRs were in low risk in domain 4 in phase 2; 7 SRs were rated as low risk in phase 3. Among 27 items of PRISMA, 15 items were reported over 70% of compliance, the reporting quality of 16 SRs was rated as “fair,” and 11 were “good.” Using GRADE assessment, moderate quality of evidence was found in 5 outcomes, and 5 outcomes were low quality. Conclusion The use of TwHF preparations for the treatment of RA may be clinically effective according to the moderate-quality evidence. There are methodological issues, risk of bias, and reporting deficiencies still needed to be improved. SRs with good quality and further randomized clinical trials that focus on clinical important outcomes are needed.
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Kim MJ, Park EH, Shin A, Ha YJ, Lee YJ, Lee EB, Baek HJ, Kang EH. Assessment on Treatments With Conventional Synthetic Disease-modifying Drugs Before Initiating Biologics in Patients With Rheumatoid Arthritis in Korea: A Population-based Study. JOURNAL OF RHEUMATIC DISEASES 2022; 29:79-88. [PMID: 37475897 PMCID: PMC10351359 DOI: 10.4078/jrd.2022.29.2.79] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/31/2021] [Revised: 10/14/2021] [Accepted: 10/19/2021] [Indexed: 07/22/2023]
Abstract
Objective To assess pre-biologic treatments with conventional synthetic disease-modifying drugs (csDMARDs) prior to biologics initiation among patients with rheumatoid arthritis (RA). Methods Using Korea National Health Insurance database, we examined pre-biologic treatments of RA patients on the following four items whether 1) initial methotrexate (MTX) therapy was given, 2) MTX dose was escalated up to ≥15 mg/week within 1-year post-diagnosis, 3) prednisone-equivalent glucocorticoid was used at a dose of ≤7.5 mg/day, and 4) glucocorticoid was discontinued within 6 months of treatment. Multivariable logistic regressions identified predictors of items 2) and 4) fulfillment. Results Among 6,986 biologics initiators with RA, 54.9% used MTX as the 1st csDMARD. Within 1-year post-diagnosis, 85.2% used MTX with half of them achieving a dose of ≥15 mg/week. The majority (75.2%) of patients used glucocorticoids initially and 64.5% were still on glucocorticoids at 6 months, mostly at a dose of ≤7.5 mg/day. csDMARD combination was observed in 85.7%. Item 2) fulfillment was associated with males, younger age, glucocorticoid, combination therapy, cyclo-oxygenase-2 inhibitors, and viral hepatitis. Item 4) fulfillment was associated with males, MTX dose of ≥15 mg/week, combination therapy, viral hepatitis, and hospitalizations. Conclusion RA patients in Korea were predominantly treated with MTX-based csDMARD combination plus glucocorticoids before initiating biologics, without sufficient MTX dose escalation or glucocorticoid discontinuation. Items 2) and 4) fulfillments were associated with patient age and gender, concomitant treatments, and comorbidities.
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Affiliation(s)
- Min Jung Kim
- Department of Internal Medicine, Seoul Metropolitan Government-Seoul National University Boramae Medical Center, Seoul, Korea
| | - Eun Hye Park
- Division of Rheumatology, Department of Internal Medicine, Chung-Ang University College of Medicine, Seoul, Korea
| | - Anna Shin
- Division of Rheumatology, Department of Internal Medicine, Seoul National University Bundang Hospital, Seongnam, Korea
| | - You-Jung Ha
- Division of Rheumatology, Department of Internal Medicine, Seoul National University Bundang Hospital, Seongnam, Korea
| | - Yun Jong Lee
- Division of Rheumatology, Department of Internal Medicine, Seoul National University Bundang Hospital, Seongnam, Korea
| | - Eun Bong Lee
- Division of Rheumatology, Department of Internal Medicine, Seoul National University Hospital, Seoul, Korea
| | - Han Joo Baek
- Division of Rheumatology, Department of Internal Medicine, Gil Medical Center, Gachon University College of Medicine, Incheon, Korea
| | - Eun Ha Kang
- Division of Rheumatology, Department of Internal Medicine, Seoul National University Bundang Hospital, Seongnam, Korea
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Li L, Wang X, Gao R, Zhang B, Liu Y, Zhou J, Fu L, Wang J. Inflammation-Triggered Supramolecular Nanoplatform for Local Dynamic Dependent Imaging-Guided Therapy of Rheumatoid Arthritis. ADVANCED SCIENCE (WEINHEIM, BADEN-WURTTEMBERG, GERMANY) 2022; 9:e2105188. [PMID: 35023331 PMCID: PMC8895155 DOI: 10.1002/advs.202105188] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 11/16/2021] [Indexed: 05/20/2023]
Abstract
The aging of population has resulted in a significant increase in the prevalence of rheumatoid arthritis (RA), which is a persistent and recurrent synovial inflammation caused by abnormal immune activation. Herein, the authors designed an inflammation-triggered disassembly (ITD) nanoplatform by a supramolecular assembly method, which controls the decomposition and drug release through changes in cytokine concentrations and redox potentials during the onset of arthritis, and its dual-targeted synergistic effect on collagen-induced arthritis (CIA) rats resulted in higher cell death rate and immunosuppressive rate. Meanwhile, they propose the local dynamic dependent imaging (LDDI) technology to diagnose the disease status, which may produce corresponding changes with the fluctuation of inflammatory activity and improve the accuracy of dual-target therapy by monitoring the synovial changes through in situ photoactivation of the second near infrared light (NIR-II). Very importantly, histological analysis shows that ITD strategy relieved joint destruction and cartilage degeneration and its clinical score is similar to that of the healthy group. Their work provides an effective strategy for the early diagnosis and treatment of acute and chronic inflammation diseases, which can interfere to abnormal immune activation, rather than affecting the normal function of immune system.
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Affiliation(s)
- Luoyuan Li
- School of Pharmaceutical SciencesKey Laboratory of Bioorganic Phosphorous Chemistry & Chemical Biology (Ministry of Education)Tsinghua UniversityBeijing100084P. R. China
- The Eighth Affiliated HospitalSun Yat‐sen UniversityShenzhenGuangdong518033P. R. China
| | - Xuelong Wang
- The Eighth Affiliated HospitalSun Yat‐sen UniversityShenzhenGuangdong518033P. R. China
| | - Rongyao Gao
- Department of ChemistryRenmin University of ChinaBeijing100872P. R. China
| | - Bei Zhang
- School of Pharmaceutical SciencesKey Laboratory of Bioorganic Phosphorous Chemistry & Chemical Biology (Ministry of Education)Tsinghua UniversityBeijing100084P. R. China
| | - Yuxin Liu
- Department of ChemistryCapital Normal UniversityBeijing100048P. R. China
| | - Jing Zhou
- Department of ChemistryCapital Normal UniversityBeijing100048P. R. China
| | - Limin Fu
- Department of ChemistryRenmin University of ChinaBeijing100872P. R. China
| | - Jian Wang
- School of Pharmaceutical SciencesKey Laboratory of Bioorganic Phosphorous Chemistry & Chemical Biology (Ministry of Education)Tsinghua UniversityBeijing100084P. R. China
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Edache EI, Uzairu A, Mamza PA, Shallangwa GA. Structure-based simulated scanning of rheumatoid arthritis inhibitors: 2D-QSAR, 3D-QSAR, docking, molecular dynamics simulation, and lipophilicity indices calculation. SCIENTIFIC AFRICAN 2022. [DOI: 10.1016/j.sciaf.2021.e01088] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/19/2022] Open
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Gao Y, Vogus D, Zhao Z, He W, Krishnan V, Kim J, Shi Y, Sarode A, Ukidve A, Mitragotri S. Injectable hyaluronic acid hydrogels encapsulating drug nanocrystals for long-term treatment of inflammatory arthritis. Bioeng Transl Med 2022; 7:e10245. [PMID: 35111947 PMCID: PMC8780912 DOI: 10.1002/btm2.10245] [Citation(s) in RCA: 17] [Impact Index Per Article: 5.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/27/2021] [Revised: 07/26/2021] [Accepted: 07/30/2021] [Indexed: 01/20/2023] Open
Abstract
Antiproliferative chemotherapeutic agents offer a potential effective treatment for inflammatory arthritis. However, their clinical application is limited by high systemic toxicity, low joint bioavailability as well as formulation challenges. Here, we report an intra-articular drug delivery system combining hyaluronic acid hydrogels and drug nanocrystals to achieve localized and sustained delivery of an antiproliferative chemotherapeutic agent camptothecin for long-term treatment of inflammatory arthritis. We synthesized a biocompatible, in situ-forming injectable hyaluronic acid hydrogel using a naturally occurring click chemistry: cyanobenzothiazole/cysteine reaction, which is the last step reaction in synthesizing D-luciferin in fireflies. This hydrogel was used to encapsulate camptothecin nanocrystals (size of 160-560 nm) which released free camptothecin in a sustained manner for 4 weeks. In vivo studies confirmed that the hydrogel remained in the joint over 4 weeks. By using the collagen-induced arthritis rat model, we demonstrate that the hydrogel-camptothecin formulation could alleviate arthritis severity as indicated by the joint size and interleukin-1β level in the harvested joints, as well as from histological and microcomputed tomography evaluation of joints. The hydrogel-nanocrystal formulation strategy described here offers a potential solution for intra-articular therapy for inflammatory arthritis.
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Affiliation(s)
- Yongsheng Gao
- School of Engineering and Applied SciencesHarvard UniversityCambridgeMassachusettsUSA
- Wyss Institute of Biologically Inspired EngineeringBostonMassachusettsUSA
| | - Douglas Vogus
- School of Engineering and Applied SciencesHarvard UniversityCambridgeMassachusettsUSA
- Wyss Institute of Biologically Inspired EngineeringBostonMassachusettsUSA
| | - Zongmin Zhao
- School of Engineering and Applied SciencesHarvard UniversityCambridgeMassachusettsUSA
- Wyss Institute of Biologically Inspired EngineeringBostonMassachusettsUSA
| | - Wei He
- School of Engineering and Applied SciencesHarvard UniversityCambridgeMassachusettsUSA
- Wyss Institute of Biologically Inspired EngineeringBostonMassachusettsUSA
| | - Vinu Krishnan
- School of Engineering and Applied SciencesHarvard UniversityCambridgeMassachusettsUSA
- Wyss Institute of Biologically Inspired EngineeringBostonMassachusettsUSA
| | - Jayoung Kim
- School of Engineering and Applied SciencesHarvard UniversityCambridgeMassachusettsUSA
- Wyss Institute of Biologically Inspired EngineeringBostonMassachusettsUSA
| | - Yujie Shi
- School of Engineering and Applied SciencesHarvard UniversityCambridgeMassachusettsUSA
- Wyss Institute of Biologically Inspired EngineeringBostonMassachusettsUSA
| | - Apoorva Sarode
- School of Engineering and Applied SciencesHarvard UniversityCambridgeMassachusettsUSA
- Wyss Institute of Biologically Inspired EngineeringBostonMassachusettsUSA
| | - Anvay Ukidve
- School of Engineering and Applied SciencesHarvard UniversityCambridgeMassachusettsUSA
- Wyss Institute of Biologically Inspired EngineeringBostonMassachusettsUSA
| | - Samir Mitragotri
- School of Engineering and Applied SciencesHarvard UniversityCambridgeMassachusettsUSA
- Wyss Institute of Biologically Inspired EngineeringBostonMassachusettsUSA
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Wang DD, Wu XY, Dong JY, Cheng XP, Gu SF, Olatunji OJ, Li Y, Zuo J. Qing-Luo-Yin Alleviated Experimental Arthritis in Rats by Disrupting Immune Feedback Between Inflammatory T Cells and Monocytes: Key Evidences from Its Effects on Immune Cell Phenotypes. J Inflamm Res 2021; 14:7467-7486. [PMID: 35002280 PMCID: PMC8723919 DOI: 10.2147/jir.s346365] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/26/2021] [Accepted: 12/17/2021] [Indexed: 11/23/2022] Open
Abstract
BACKGROUND Qing-Luo-Yin (QLY) is an anti-rheumatic herbal formula. Despite the well-investigated therapeutic efficacy of QLY, its immune regulatory properties are largely unknown. CD4+ T cells and monocytes are two key parameters in rheumatoid arthritis (RA). This study investigated the changes in these cells in QLY-treated RA animal models. MATERIALS AND METHODS RA models were induced in male SD rats and were orally treated with QLY. Dynamic metabolic changes in collagen-induced arthritis (CIA) rats were monitored by 1H NMR approach. The immunity profiles of CIA and adjuvant-induced arthritis (AIA) rats were evaluated using immunohistochemical, PCR, ELISA, cytokine chip, flow cytometry, and immunofluorescence experiments. The bioactive components in QLY were identified by bioinformatic-guided LC-MS analyses. The compounds with high abundance in QLY decoction and easily absorbed were taken as key anti-rheumatic components and used to treat blood-derived immune cells using in vitro experiments. RESULTS The results indicated that QLY decreased Th17 cells frequency and T cells-released IL-6, IL-17 and GM-CSF in CIA rats, which was attributed to the impaired lymphocyte maturation and altered differentiation. QLY inhibited lactic acid production and inflammatory polarization in the monocytes during the peak period of AIA and CIA. AIA monocytes elicited significant increase in Th17 cells counts, IL-6 and IL-1β secretion in co-cultured splenocytes, which was abrogated by QLY. QLY-containing serum suppressed the phosphorylation of JNK and p65 in AIA lymphocyte-stimulated normal monocytes and consequently inhibited iNOS and IL-1β expression as well as IL-6 and IL-1β production. Matrine, sinomenine and sophocarpine were identified as major bioactive compounds in QLY. These identified compounds effectively inhibited the development of inflammatory T cells using concentrations detected in QLY-treated rats. At higher concentrations (20-fold increase), the chemical stimuli significantly suppressed the production of IL-1β in AIA monocytes by inhibiting JNK and p65 pathways. CONCLUSION By targeting inflammatory T cells and monocytes as well as disrupting their interplay, QLY improved immune environment in RA models especially during the active stages of disease.
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Affiliation(s)
- Dan-Dan Wang
- Xin’an Medicine Research Center, The First Affiliated Hospital of Wannan Medical College (Yijishan Hospital), Wuhu, 241000, People’s Republic of China
- Research Center of Integration of Traditional Chinese and Western Medicine, Wannan Medical College, Wuhu, 241000, People’s Republic of China
| | - Xin-Yue Wu
- Department of Electronic Science, Xiamen University, Xiamen, 361005, People’s Republic of China
| | - Ji-Yang Dong
- Department of Electronic Science, Xiamen University, Xiamen, 361005, People’s Republic of China
| | - Xiu-Ping Cheng
- Xin’an Medicine Research Center, The First Affiliated Hospital of Wannan Medical College (Yijishan Hospital), Wuhu, 241000, People’s Republic of China
- Research Center of Integration of Traditional Chinese and Western Medicine, Wannan Medical College, Wuhu, 241000, People’s Republic of China
| | - Shao-Fei Gu
- Xin’an Medicine Research Center, The First Affiliated Hospital of Wannan Medical College (Yijishan Hospital), Wuhu, 241000, People’s Republic of China
- Research Center of Integration of Traditional Chinese and Western Medicine, Wannan Medical College, Wuhu, 241000, People’s Republic of China
| | - Opeyemi Joshua Olatunji
- Faculty of Traditional Thai Medicine, Prince of Songkla University, Hat Yai, 90110, Thailand
| | - Yan Li
- Xin’an Medicine Research Center, The First Affiliated Hospital of Wannan Medical College (Yijishan Hospital), Wuhu, 241000, People’s Republic of China
- Research Center of Integration of Traditional Chinese and Western Medicine, Wannan Medical College, Wuhu, 241000, People’s Republic of China
| | - Jian Zuo
- Xin’an Medicine Research Center, The First Affiliated Hospital of Wannan Medical College (Yijishan Hospital), Wuhu, 241000, People’s Republic of China
- Key Laboratory of Non-Coding RNA Transformation Research of Anhui Higher Education Institution, Wannan Medical College, Wuhu, 241000, People’s Republic of China
- Anhui Provincial Engineering Laboratory for Screening and Re-Evaluation of Active Compounds of Herbal Medicines in Southern Anhui, Wuhu, 241000, People’s Republic of China
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Pokharel G, Deardon R, Johnson SR, Tomlinson G, Hull PM, Hazlewood GS. Effectiveness of initial methotrexate-based treatment approaches in early rheumatoid arthritis: an elicitation of rheumatologists' beliefs. Rheumatology (Oxford) 2021; 60:3570-3578. [PMID: 33367919 DOI: 10.1093/rheumatology/keaa803] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/06/2020] [Revised: 10/12/2020] [Indexed: 11/14/2022] Open
Abstract
OBJECTIVES To quantify rheumatologists' beliefs about the effectiveness of triple therapy (MTX + HCQ + SSZ) and other commonly used initial treatments for RA. METHODS In a Bayesian belief elicitation exercise, 40 rheumatologists distributed 20 chips, each representing 5% of their total weight of belief on the probability that a typical patient with moderate-severe early RA would have an ACR50 response within 6 months with MTX (oral and s.c.), MTX + HCQ (dual therapy) and triple therapy. Parametric distributions were fit, and used to calculate pairwise median relative risks (RR), with 95% credible intervals, and estimate sample sizes for new trials to shift these beliefs. RESULTS In the pooled analysis, triple therapy was perceived to be superior to MTX (RR 1.97; 1.35, 2.89) and dual therapy (RR 1.32; 1.03, 1.73). A pessimistic subgroup (n = 10) perceived all treatments to be similar, whereas an optimistic subgroup (n = 10) believed triple therapy to be most effective of all (RR 4.03; 2.22, 10.12). Similar variability was seen for the comparison between oral and s.c. MTX. Assuming triple therapy is truly more effective than MTX, a trial of 100 patients would be required to convince the pessimists; if triple therapy truly has no-modest effect (RR <1.5), a non-inferiority trial of 475 patients would be required to convince the optimists. CONCLUSION Rheumatologists' beliefs regarding the effectiveness of triple therapy vary, which may partially explain the variability in its use. Owing to the strength of beliefs, some may be reluctant to shift, even with new evidence.
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Affiliation(s)
- Gyanendra Pokharel
- Department of Mathematics and Statistics, Faculty of Science, University of Winnipeg, Winnipeg, Canada
| | - Rob Deardon
- Departments of Mathematics and Statistics and Production Animal Health, Faculties of Science and Veterinary Medicine, University of Calgary, Calgary, Canada
| | - Sindhu R Johnson
- Division of Rheumatology, Toronto Western Hospital, Mount Sinai Hospital, Toronto, Toronto, Ontario, Canada.,Institute of Health Policy, Management and Evaluation, University of Toronto, Toronto, Ontario, Canada
| | - George Tomlinson
- Institute of Health Policy, Management and Evaluation, University of Toronto, Toronto, Ontario, Canada
| | - Pauline M Hull
- Department of Community Health Sciences, Calgary, Canada
| | - Glen S Hazlewood
- Department of Community Health Sciences, Calgary, Canada.,Department of Medicine, Cumming School of Medicine, University of Calgary, Calgary, Canada
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Olofsson T, Wallman JK, Jöud A, Schelin MEC, Ernestam S, van Vollenhoven R, Saevarsdottir S, Lampa J. Pain Over Two Years After Start of Biologic Versus Conventional Combination Treatment in Early Rheumatoid Arthritis: Results From a Swedish Randomized Controlled Trial. Arthritis Care Res (Hoboken) 2021; 73:1312-1321. [PMID: 32433827 DOI: 10.1002/acr.24264] [Citation(s) in RCA: 20] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/20/2019] [Accepted: 05/12/2020] [Indexed: 01/04/2023]
Abstract
OBJECTIVE To compare the pain course between methotrexate (MTX)-refractory early rheumatoid arthritis (RA) patients randomized to infliximab (IFX) versus sulfasalazine (SSZ) plus hydroxychloroquine (HCQ). METHODS The randomized, controlled, open-label Swedish Pharmacotherapy (SWEFOT) trial enrolled new-onset RA patients from October 2002 to December 2005. After 3 months of receiving MTX, patients not reaching low disease activity (Disease Activity Score in 28 joints score ≤3.2) were randomized to adding IFX (n = 128) or SSZ plus HCQ (n = 130) and followed for 21 months. Here, outcomes included area under the curve (AUC) for visual analog scale (VAS) scores for pain, unacceptable pain (VAS pain score >40 mm [range 0-100]), and unacceptable pain despite inflammation control (refractory pain; VAS pain score >40 plus C-reactive protein level <10 mg/liter). Between-group differences were analyzed with multivariate regression models. RESULTS Overall, 50% of randomized patients (n = 258) in the crude setting reported unacceptable pain at randomization, declining to 29% at 21 months (P < 0.001), when refractory pain constituted 82% of all unacceptable pain. Comparing randomized arms (intent-to-treat analysis), the AUC for VAS pain was lower in the MTX plus IFX group (P = 0.01), and at 21 months, 32% of patients receiving MTX plus IFX and 45% receiving MTX plus SSZ plus HCQ had unacceptable pain (adjusted relative risk 0.68 [95% confidence interval 0.51, 0.90]; P = 0.008). Regarding refractory pain, no between-group differences were observed. CONCLUSION Despite active combination treatment, almost one-third of new-onset RA patients reported unacceptable pain after 21 months, and refractory pain constituted more than 4/5 of this pain load. Adding IFX versus SSZ plus HCQ to MTX reduced both cumulative pain and unacceptable pain at 21 months, suggesting less long-term pain for the biologic therapy. These results display insufficient effects of current treatment strategies on inflammation-independent pain components, warranting alternative approaches in affected patients.
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Affiliation(s)
- Tor Olofsson
- Lund University, Skåne University Hospital, Lund, Sweden
| | | | | | | | - Sofia Ernestam
- Academic Specialist Centre, Stockholm Health Services and Karolinska Institutet, Stockholm, Sweden
| | | | - Saedis Saevarsdottir
- Karolinska Institutet, Stockholm, Sweden, and University of Iceland and deCODE genetics, Reykjavik, Iceland
| | - Jon Lampa
- Karolinska Institutet, Stockholm, Sweden
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Curtis JR, Palmer JL, Reed GW, Greenberg J, Pappas DA, Harrold LR, Kremer JM. Real-World Outcomes Associated With Methotrexate, Sulfasalazine, and Hydroxychloroquine Triple Therapy Versus Tumor Necrosis Factor Inhibitor/Methotrexate Combination Therapy in Patients With Rheumatoid Arthritis. Arthritis Care Res (Hoboken) 2021; 73:1114-1124. [PMID: 32374918 DOI: 10.1002/acr.24253] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/14/2019] [Accepted: 04/28/2020] [Indexed: 11/06/2022]
Abstract
OBJECTIVE Though randomized controlled trials have demonstrated relatively comparable clinical outcomes with triple therapy (methotrexate [MTX], sulfasalazine [SSZ], and hydroxychloroquine [HCQ]) compared to combination therapy (tumor necrosis factor inhibitor [TNFi] and MTX), real-world experiences comparing these strategies have not been well studied. METHODS We evaluated the clinical effectiveness and effects of medication discontinuation of triple therapy with MTX/SSZ/HCQ versus combination therapy with TNFi/MTX in rheumatoid arthritis (RA) patients enrolled in the Corrona RA Drug Safety & Effectiveness Registry. Propensity score matching was used to match patients up to a ratio of 1:3 to adjust for imbalances between treatment groups, with stratification performed according to biologics-naive or biologics-exposed status of study participants. RESULTS Patients eligible for analysis in this study included biologics-naive RA patients (3,926 who received combination therapy with TNFi/MTX and 262 who received triple therapy with MTX/SSZ/HCQ) and biologics-exposed RA patients (3,365 who received combination therapy with TNFi/MTX and 130 patients who received triple therapy with MTX/SSZ/HCQ). Before propensity score matching, numerous factors were imbalanced between the treatment groups, with triple therapy patients generally being older, having a longer disease duration of RA and lower RA disease activity, and more likely having a history of malignancy and other comorbidities. After matching, almost all (93-98%) triple therapy patients could be matched to TNFi/MTX therapy patients, and cohort characteristics were generally well balanced. Discontinuation of medication was greater in triple therapy patients referent to TNFi/MTX therapy patients (adjusted hazard ratio [HR] of 2.17 [95% confidence interval 1.63-2.88] in the biologics-naive group; adjusted HR of 1.51 [95% confidence interval 1.06-2.15] in the biologics-exposed group). At 6 months, the proportion of biologics-naive patients attaining low disease activity was significantly greater in the TNFi/MTX treatment group (49.2% in TNFi/MTX therapy patients versus 33.3% in triple therapy patients), as was the mean change in Clinical Disease Activity Index scores (-9.3 units versus -5.5 [95% confidence interval -1.5, -6.1]). Corresponding results in the biologics-exposed patients numerically favored TNFi/MTX therapy compared to triple therapy but did not reach statistical significance. CONCLUSION Few patients receive triple therapy with MTX/SSZ/HCQ in the US. In the present study, drug persistence and clinical effectiveness outcomes were less favorable in triple therapy patients compared to TNFi/MTX therapy patients.
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Affiliation(s)
| | | | - George W Reed
- University of Massachusetts Medical School, Worcester
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Scott DL, Ibrahim F, Hill H, Tom B, Prothero L, Baggott RR, Bosworth A, Galloway JB, Georgopoulou S, Martin N, Neatrour I, Nikiphorou E, Sturt J, Wailoo A, Williams FMK, Williams R, Lempp H. Intensive therapy for moderate established rheumatoid arthritis: the TITRATE research programme. PROGRAMME GRANTS FOR APPLIED RESEARCH 2021. [DOI: 10.3310/pgfar09080] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 11/22/2022]
Abstract
Background
Rheumatoid arthritis is a major inflammatory disorder and causes substantial disability. Treatment goals span minimising disease activity, achieving remission and decreasing disability. In active rheumatoid arthritis, intensive management achieves these goals. As many patients with established rheumatoid arthritis have moderate disease activity, the TITRATE (Treatment Intensities and Targets in Rheumatoid Arthritis ThErapy) programme assessed the benefits of intensive management.
Objectives
To (1) define how to deliver intensive therapy in moderate established rheumatoid arthritis; (2) establish its clinical effectiveness and cost-effectiveness in a trial; and (3) evaluate evidence supporting intensive management in observational studies and completed trials.
Design
Observational studies, secondary analyses of completed trials and systematic reviews assessed existing evidence about intensive management. Qualitative research, patient workshops and systematic reviews defined how to deliver it. The trial assessed its clinical effectiveness and cost-effectiveness in moderate established rheumatoid arthritis.
Setting
Observational studies (in three London centres) involved 3167 patients. These were supplemented by secondary analyses of three previously completed trials (in centres across all English regions), involving 668 patients. Qualitative studies assessed expectations (nine patients in four London centres) and experiences of intensive management (15 patients in 10 centres across England). The main clinical trial enrolled 335 patients with diverse socioeconomic deprivation and ethnicity (in 39 centres across all English regions).
Participants
Patients with established moderately active rheumatoid arthritis receiving conventional disease-modifying drugs.
Interventions
Intensive management used combinations of conventional disease-modifying drugs, biologics (particularly tumour necrosis factor inhibitors) and depot steroid injections; nurses saw patients monthly, adjusted treatment and provided supportive person-centred psychoeducation. Control patients received standard care.
Main outcome measures
Disease Activity Score for 28 joints based on the erythrocyte sedimentation rate (DAS28-ESR)-categorised patients (active to remission). Remission (DAS28-ESR < 2.60) was the treatment target. Other outcomes included fatigue (measured on a 100-mm visual analogue scale), disability (as measured on the Health Assessment Questionnaire), harms and resource use for economic assessments.
Results
Evaluation of existing evidence for intensive rheumatoid arthritis management showed the following. First, in observational studies, DAS28-ESR scores decreased over 10–20 years, whereas remissions and treatment intensities increased. Second, in systematic reviews of published trials, all intensive management strategies increased remissions. Finally, patients with high disability scores had fewer remissions. Qualitative studies of rheumatoid arthritis patients, workshops and systematic reviews helped develop an intensive management pathway. A 2-day training session for rheumatology practitioners explained its use, including motivational interviewing techniques and patient handbooks. The trial screened 459 patients and randomised 335 patients (168 patients received intensive management and 167 patients received standard care). A total of 303 patients provided 12-month outcome data. Intention-to-treat analysis showed intensive management increased DAS28-ESR 12-month remissions, compared with standard care (32% vs. 18%, odds ratio 2.17, 95% confidence interval 1.28 to 3.68; p = 0.004), and reduced fatigue [mean difference –18, 95% confidence interval –24 to –11 (scale 0–100); p < 0.001]. Disability (as measured on the Health Assessment Questionnaire) decreased when intensive management patients achieved remission (difference –0.40, 95% confidence interval –0.57 to –0.22) and these differences were considered clinically relevant. However, in all intensive management patients reductions in the Health Assessment Questionnaire scores were less marked (difference –0.1, 95% confidence interval –0.2 to 0.0). The numbers of serious adverse events (intensive management n = 15 vs. standard care n = 11) and other adverse events (intensive management n = 114 vs. standard care n = 151) were similar. Economic analysis showed that the base-case incremental cost-effectiveness ratio was £43,972 from NHS and Personal Social Services cost perspectives. The probability of meeting a willingness-to-pay threshold of £30,000 was 17%. The incremental cost-effectiveness ratio decreased to £29,363 after including patients’ personal costs and lost working time, corresponding to a 50% probability that intensive management is cost-effective at English willingness-to-pay thresholds. Analysing trial baseline predictors showed that remission predictors comprised baseline DAS28-ESR, disability scores and body mass index. A 6-month extension study (involving 95 intensive management patients) showed fewer remissions by 18 months, although more sustained remissions were more likley to persist. Qualitative research in trial completers showed that intensive management was acceptable and treatment support from specialist nurses was beneficial.
Limitations
The main limitations comprised (1) using single time point remissions rather than sustained responses, (2) uncertainty about benefits of different aspects of intensive management and differences in its delivery across centres, (3) doubts about optimal treatment of patients unresponsive to intensive management and (4) the lack of formal international definitions of ‘intensive management’.
Conclusion
The benefits of intensive management need to be set against its additional costs. These were relatively high. Not all patients benefited. Patients with high pretreatment physical disability or who were substantially overweight usually did not achieve remission.
Future work
Further research should (1) identify the most effective components of the intervention, (2) consider its most cost-effective delivery and (3) identify alternative strategies for patients not responding to intensive management.
Trial registration
Current Controlled Trials ISRCTN70160382.
Funding
This project was funded by the National Institute for Health Research (NIHR) Programme Grants for Applied Research programme and will be published in full in Programme Grants for Applied Research; Vol. 9, No. 8. See the NIHR Journals Library website for further project information.
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Affiliation(s)
- David L Scott
- Centre for Rheumatic Diseases, Department of Inflammation Biology, School of Immunology and Microbial Sciences, King’s College London, London, UK
| | - Fowzia Ibrahim
- Centre for Rheumatic Diseases, Department of Inflammation Biology, School of Immunology and Microbial Sciences, King’s College London, London, UK
| | - Harry Hill
- ScHARR Health Economics and Decision Science, The University of Sheffield, Sheffield, UK
| | - Brian Tom
- MRC Biostatistics Unit, University of Cambridge, Cambridge, UK
| | - Louise Prothero
- Centre for Rheumatic Diseases, Department of Inflammation Biology, School of Immunology and Microbial Sciences, King’s College London, London, UK
| | - Rhiannon R Baggott
- Centre for Rheumatic Diseases, Department of Inflammation Biology, School of Immunology and Microbial Sciences, King’s College London, London, UK
| | | | - James B Galloway
- Centre for Rheumatic Diseases, Department of Inflammation Biology, School of Immunology and Microbial Sciences, King’s College London, London, UK
| | - Sofia Georgopoulou
- Centre for Rheumatic Diseases, Department of Inflammation Biology, School of Immunology and Microbial Sciences, King’s College London, London, UK
| | - Naomi Martin
- Centre for Rheumatic Diseases, Department of Inflammation Biology, School of Immunology and Microbial Sciences, King’s College London, London, UK
| | - Isabel Neatrour
- Centre for Rheumatic Diseases, Department of Inflammation Biology, School of Immunology and Microbial Sciences, King’s College London, London, UK
| | - Elena Nikiphorou
- Centre for Rheumatic Diseases, Department of Inflammation Biology, School of Immunology and Microbial Sciences, King’s College London, London, UK
| | - Jackie Sturt
- Department of Adult Nursing, Florence Nightingale Faculty of Nursing, Midwifery & Palliative Care, King’s College London, London, UK
| | - Allan Wailoo
- ScHARR Health Economics and Decision Science, The University of Sheffield, Sheffield, UK
| | - Frances MK Williams
- Twin Research and Genetic Epidemiology, School of Life Course Sciences, King’s College London, St Thomas’ Hospital, London, UK
| | - Ruth Williams
- Centre for Rheumatic Diseases, Department of Inflammation Biology, School of Immunology and Microbial Sciences, King’s College London, London, UK
| | - Heidi Lempp
- Centre for Rheumatic Diseases, Department of Inflammation Biology, School of Immunology and Microbial Sciences, King’s College London, London, UK
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Roudsari PP, Alavi-Moghadam S, Rezaei-Tavirani M, Goodarzi P, Tayanloo-Beik A, Sayahpour FA, Larijani B, Arjmand B. The Outcome of Stem Cell-Based Therapies on the Immune Responses in Rheumatoid Arthritis. ADVANCES IN EXPERIMENTAL MEDICINE AND BIOLOGY 2021; 1326:159-186. [PMID: 32926346 DOI: 10.1007/5584_2020_581] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 02/12/2023]
Abstract
Rheumatoid arthritis as a common autoimmune inflammatory disorder with unknown etiology can affect 0.5-1% of adults in developed countries. It involves more than just the patient's joints and can be accompanied by several comorbidities and affect cardiovascular, pulmonary, and some other systems of the human body. Although cytokine-mediated pathways are mentioned to have a central role in RA pathogenesis, adaptive and innate immune systems and intracellular signaling pathways all have important roles in this process. Non-steroidal anti-inflammatory drugs, glucocorticoids, conventional disease-modifying anti-rheumatic drugs, and biological agents are some mentioned medications used for RA. They are accompanied by some adverse effects and treatment failures which elucidates the needing for novel and more powerful therapeutic approaches. Stem cell-based therapies and their beneficial effects on therapeutic processes of different diseases have been founded so far. They can be an alternative and promising therapeutic approach for RA, too; due to their effects on immune responses of the disease. This review, besides some explanations about RA characteristics, addresses the outcome of the stem cell-based therapies including mesenchymal stem cell transplantation and hematopoietic stem cell transplantation for RA and explains their effects on the disease improvement.
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Affiliation(s)
- Peyvand Parhizkar Roudsari
- Metabolomics and Genomics Research Center, Endocrinology and Metabolism Molecular Cellular Sciences Institute, Tehran University of Medical Sciences, Tehran, Iran
| | - Sepideh Alavi-Moghadam
- Cell Therapy and Regenerative Medicine Research Center, Endocrinology and Metabolism Molecular-Cellular Sciences Institute, Tehran University of Medical Sciences, Tehran, Iran
| | | | - Parisa Goodarzi
- Brain and Spinal Cord Injury Research Center, Neuroscience Institute, Tehran University of Medical Sciences, Tehran, Iran
| | - Akram Tayanloo-Beik
- Metabolomics and Genomics Research Center, Endocrinology and Metabolism Molecular Cellular Sciences Institute, Tehran University of Medical Sciences, Tehran, Iran
| | - Forough Azam Sayahpour
- Department of Stem Cells and Developmental Biology, Cell Science Research Center, Royan Institute for Stem Cell Biology and Technology, ACECR, Tehran, Iran
| | - Bagher Larijani
- Endocrinology and Metabolism Research Center, Endocrinology and Metabolism Clinical Sciences Institute, Tehran University of Medical sciences, Tehran, Iran
| | - Babak Arjmand
- Metabolomics and Genomics Research Center, Endocrinology and Metabolism Molecular Cellular Sciences Institute, Tehran University of Medical Sciences, Tehran, Iran. .,Cell Therapy and Regenerative Medicine Research Center, Endocrinology and Metabolism Molecular-Cellular Sciences Institute, Tehran University of Medical Sciences, Tehran, Iran.
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49
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Fraenkel L, Bathon JM, England BR, St.Clair EW, Arayssi T, Carandang K, Deane KD, Genovese M, Huston KK, Kerr G, Kremer J, Nakamura MC, Russell LA, Singh JA, Smith BJ, Sparks JA, Venkatachalam S, Weinblatt ME, Al-Gibbawi M, Baker JF, Barbour KE, Barton JL, Cappelli L, Chamseddine F, George M, Johnson SR, Kahale L, Karam BS, Khamis AM, Navarro-Millán I, Mirza R, Schwab P, Singh N, Turgunbaev M, Turner AS, Yaacoub S, Akl EA. 2021 American College of Rheumatology Guideline for the Treatment of Rheumatoid Arthritis. Arthritis Care Res (Hoboken) 2021; 73:924-939. [PMID: 34101387 PMCID: PMC9273041 DOI: 10.1002/acr.24596] [Citation(s) in RCA: 503] [Impact Index Per Article: 125.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/08/2020] [Accepted: 03/15/2021] [Indexed: 12/14/2022]
Abstract
OBJECTIVE To develop updated guidelines for the pharmacologic management of rheumatoid arthritis. METHODS We developed clinically relevant population, intervention, comparator, and outcomes (PICO) questions. After conducting a systematic literature review, the Grading of Recommendations Assessment, Development and Evaluation (GRADE) approach was used to rate the certainty of evidence. A voting panel comprising clinicians and patients achieved consensus on the direction (for or against) and strength (strong or conditional) of recommendations. RESULTS The guideline addresses treatment with disease-modifying antirheumatic drugs (DMARDs), including conventional synthetic DMARDs, biologic DMARDs, and targeted synthetic DMARDs, use of glucocorticoids, and use of DMARDs in certain high-risk populations (i.e., those with liver disease, heart failure, lymphoproliferative disorders, previous serious infections, and nontuberculous mycobacterial lung disease). The guideline includes 44 recommendations (7 strong and 37 conditional). CONCLUSION This clinical practice guideline is intended to serve as a tool to support clinician and patient decision-making. Recommendations are not prescriptive, and individual treatment decisions should be made through a shared decision-making process based on patients' values, goals, preferences, and comorbidities.
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Affiliation(s)
- Liana Fraenkel
- Berkshire Medical Center, Pittsfield, Massachusetts, and Yale University School of Medicine, New Haven, Connecticut
| | - Joan M. Bathon
- Columbia University Irving Medical Center, New York Presbyterian Hospital, New York, New York
| | - Bryant R. England
- University of Nebraska Medical Center and VA Nebraska–Western Iowa Health Care System, Omaha, Nebraska
| | | | | | | | | | - Mark Genovese
- Stanford University Medical Center, Palo Alto, California
| | - Kent Kwas Huston
- The Center for Rheumatic Disease/Allergy and Immunology, Kansas City, Missouri
| | - Gail Kerr
- Veterans Affairs Medical Center, Georgetown and Howard University, Washington, DC
| | - Joel Kremer
- Albany Medical College and The Center for Rheumatology, Albany, New York
| | | | | | - Jasvinder A. Singh
- University of Alabama at Birmingham and Birmingham Veterans Affairs Medical Center, Birmingham, Alabama
| | - Benjamin J. Smith
- State University College of Medicine School of Physician Assistant Practice, Tallahassee
| | - Jeffrey A. Sparks
- Brigham and Women’s Hospital and Harvard Medical School, Boston, Massachusetts
| | | | | | | | - Joshua F. Baker
- Corporal Michael J. Crescenz VA Medical Center and the University of Pennsylvania, Philadelphia, Pennsylvania
| | | | - Jennifer L. Barton
- Oregon Health & Science University and VA Portland Health Care System, Portland, Oregon
| | | | | | | | - Sindhu R. Johnson
- Toronto Western Hospital, Mount Sinai Hospital, Institute of Health Policy, Management and Evaluation, University of Toronto, Toronto, Ontario, Canada
| | - Lara Kahale
- American University of Beirut, Beirut, Lebanon
| | | | | | | | - Reza Mirza
- University of Toronto, Toronto, Ontario, Canada
| | - Pascale Schwab
- Oregon Health & Science University and VA Portland Health Care System, Portland, Oregon
| | | | | | | | | | - Elie A. Akl
- American University of Beirut, Beirut, Lebanon
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50
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Fraenkel L, Bathon JM, England BR, St Clair EW, Arayssi T, Carandang K, Deane KD, Genovese M, Huston KK, Kerr G, Kremer J, Nakamura MC, Russell LA, Singh JA, Smith BJ, Sparks JA, Venkatachalam S, Weinblatt ME, Al-Gibbawi M, Baker JF, Barbour KE, Barton JL, Cappelli L, Chamseddine F, George M, Johnson SR, Kahale L, Karam BS, Khamis AM, Navarro-Millán I, Mirza R, Schwab P, Singh N, Turgunbaev M, Turner AS, Yaacoub S, Akl EA. 2021 American College of Rheumatology Guideline for the Treatment of Rheumatoid Arthritis. Arthritis Rheumatol 2021; 73:1108-1123. [PMID: 34101376 DOI: 10.1002/art.41752] [Citation(s) in RCA: 408] [Impact Index Per Article: 102.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/08/2020] [Accepted: 03/15/2021] [Indexed: 12/13/2022]
Abstract
OBJECTIVE To develop updated guidelines for the pharmacologic management of rheumatoid arthritis. METHODS We developed clinically relevant population, intervention, comparator, and outcomes (PICO) questions. After conducting a systematic literature review, the Grading of Recommendations Assessment, Development and Evaluation (GRADE) approach was used to rate the certainty of evidence. A voting panel comprising clinicians and patients achieved consensus on the direction (for or against) and strength (strong or conditional) of recommendations. RESULTS The guideline addresses treatment with disease-modifying antirheumatic drugs (DMARDs), including conventional synthetic DMARDs, biologic DMARDs, and targeted synthetic DMARDs, use of glucocorticoids, and use of DMARDs in certain high-risk populations (i.e., those with liver disease, heart failure, lymphoproliferative disorders, previous serious infections, and nontuberculous mycobacterial lung disease). The guideline includes 44 recommendations (7 strong and 37 conditional). CONCLUSION This clinical practice guideline is intended to serve as a tool to support clinician and patient decision-making. Recommendations are not prescriptive, and individual treatment decisions should be made through a shared decision-making process based on patients' values, goals, preferences, and comorbidities.
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Affiliation(s)
- Liana Fraenkel
- Berkshire Medical Center, Pittsfield, Massachusetts, and Yale University School of Medicine, New Haven, Connecticut, United States
| | - Joan M Bathon
- Columbia University Irving Medical Center, New York Presbyterian Hospital, New York, New York, United States
| | - Bryant R England
- University of Nebraska Medical Center and VA Nebraska-Western Iowa Health Care System, Omaha, Nebraska, United States
| | | | | | | | | | - Mark Genovese
- Stanford University Medical Center, Palo Alto, California, United States
| | - Kent Kwas Huston
- The Center for Rheumatic Disease/Allergy and Immunology, Kansas City, Missouri, United States
| | - Gail Kerr
- Veterans Affairs Medical Center, Georgetown and Howard University, Washington, DC, United States
| | - Joel Kremer
- Albany Medical College and The Center for Rheumatology, Albany, New York, United States
| | | | - Linda A Russell
- Hospital for Special Surgery, New York, New York, United States
| | - Jasvinder A Singh
- University of Alabama at Birmingham and Birmingham Veterans Affairs Medical Center, Birmingham, Alabama, United States
| | - Benjamin J Smith
- Florida State University College of Medicine School of Physician Assistant Practice, Tallahassee
| | - Jeffrey A Sparks
- Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts, United States
| | | | - Michael E Weinblatt
- Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts, United States
| | | | - Joshua F Baker
- Corporal Michael J. Crescenz VA Medical Center and the University of Pennsylvania, Philadelphia, Pennsylvania, United States
| | - Kamil E Barbour
- Centers for Disease Control and Prevention, Atlanta, Georgia, United States
| | - Jennifer L Barton
- Oregon Health & Science University and VA Portland Health Care System, Portland, Oregon, United States
| | - Laura Cappelli
- Johns Hopkins Medicine, Baltimore, Maryland, United States
| | | | | | - Sindhu R Johnson
- Toronto Western Hospital, Mount Sinai Hospital, Institute of Health Policy, Management and Evaluation, University of Toronto, Toronto, Ontario, Canada
| | - Lara Kahale
- American University of Beirut, Beirut, Lebanon
| | | | | | | | - Reza Mirza
- University of Toronto, Toronto, Ontario, Canada
| | - Pascale Schwab
- Oregon Health & Science University and VA Portland Health Care System, Portland, Oregon, United States
| | | | - Marat Turgunbaev
- American College of Rheumatology, Atlanta, Georgia, United States
| | - Amy S Turner
- American College of Rheumatology, Atlanta, Georgia, United States
| | | | - Elie A Akl
- American University of Beirut, Beirut, Lebanon
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