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Abstract
Immune checkpoint inhibitors (ICIs), used to treat many advanced cancers, activate the immune system to elicit an antitumor response. ICIs can also cause immune-related adverse events (irAEs) when nontumor tissues are affected by excess inflammation and autoimmunity. Rheumatic irAEs include inflammatory arthritis, myositis, sicca syndrome, polymyalgia rheumatica, and several other rare phenotypes. Treating rheumatic irAEs requires balancing the desire to decrease off-target inflammation while not negatively impacting the antitumor immune response. In this review, treatment recommendations for rheumatic irAEs have been discussed. Pathogenesis of rheumatic irAEs has been briefly reviewed. Knowledge about the effects of corticosteroids and steroid-sparing agents on tumor responses has been detailed to give context for treatment decisions. Recommendations ultimately depend not only on the clinical presentation and severity of the irAE but also on the goals of cancer treatment. Finally, how to safely use ICI therapy in patients with preexisting autoimmune diseases is considered.
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Affiliation(s)
- Pankti Reid
- University of Chicago, Department of Medicine, Section of Rheumatology, 5841 South Maryland Ave. MC 0930, Chicago, IL, 60637, USA.
| | - Laura C Cappelli
- Johns Hopkins University, Department of Medicine, Division of Rheumatology, 5501 Hopkins Bayview Circle, Suite 1B1, Baltimore, MD, 21224, USA.
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2
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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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3
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Genetic association and single-cell transcriptome analyses reveal distinct features connecting autoimmunity with cancers. iScience 2022; 25:104631. [PMID: 35800769 PMCID: PMC9254016 DOI: 10.1016/j.isci.2022.104631] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/17/2022] [Revised: 05/08/2022] [Accepted: 06/13/2022] [Indexed: 11/20/2022] Open
Abstract
Autoimmune diseases (ADs) are at a significantly higher risk of cancers with unclear mechanism. By searching GWAS catalog database and Medline, susceptible genes for five common ADs, including systemic lupus erythematosus (SLE), rheumatoid arthritis, Sjögren syndrome, systemic sclerosis, and idiopathic inflammatory myopathies, were collected and then were overlapped with cancer driver genes. Single-cell transcriptome analysis was performed in the comparation between SLE and related cancer. We identified 45 carcinogenic autoimmune disease risk (CAD) genes, which were mainly enriched in T cell signaling pathway and B cell signaling pathway. Integrated single-cell analysis revealed immune cell signaling was significantly downregulated in renal cancer compared with SLE, while stemness signature was significantly enriched in both renal cancer or lymphoma and SLE in specific subpopulations. Drugs targeting CAD genes were shared between ADs and cancer. Our study highlights the common and specific features between ADs and related cancers, and sheds light on a new discovery of treatments.
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Seror R, Lafourcade A, De Rycke Y, Pinto S, Castaneda J, Fautrel B, Mariette X, Tubach F. Risk of malignancy in rheumatoid arthritis patients initiating biologics: an historical propensity score matched cohort study within the French nationwide healthcare database. RMD Open 2022; 8:rmdopen-2021-002139. [PMID: 35738803 PMCID: PMC9226991 DOI: 10.1136/rmdopen-2021-002139] [Citation(s) in RCA: 10] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/02/2021] [Accepted: 05/22/2022] [Indexed: 11/15/2022] Open
Abstract
Objective To compare the risk of malignancy between patients with rheumatoid arthritis (RA) initiating their first biological disease-modifying antirheumatic drug (bDMARD) and those continuing conventional synthetic DMARDs (csDMARDs). Methods Nine-year historical Propensity Score (PS) matched cohort study within the French national healthcare database (87% of the French population; ~57 million people), including adults RA without malignancy. Exposures started with the first use of any systemic treatment (csDMARDs and/or bDMARDs). Incident users of bDMARDs were matched on a dynamic PS to patients continuing csDMARDs. Their risk of malignancy was compared by Cox model. Results From 1 January 2007 to 31 December 2014, 83 706 patients with RA started their first systemic treatment (63 837 remained on csDMARDs and 19 869 initiated a bDMARD during follow-up). After dynamic PS matching, 19 727 bDMARD initiators were compared with 19 727 RA remaining on csDMARDs. They did not statistically differ in risk of overall malignancies (HR 0.99 (95% CI 0.86 to 1.14)), solid cancer (HR 0.95 (95% CI 0.82 to 1.11)), nor lymphoma (HR 1.35 (95% CI 0.72 to 2.53)). Results were similar when bDMARDs were given as monotherapy or in association with csDMARDs. Analyses restricted to patients starting TNF inhibitor as first bDMARD compared with matched RA remaining on csDMARDs, provided similar results (HR for overall malignancy 1.03 (95% CI 0.88 to 1.21)). Sensitivity analyses, varying carry-over periods (up to 5 years) to define risk periods, provided similar results. Conclusions In this historical cohort study within the French nationwide healthcare database, the risk of overall, solid or haematological malignancies did not significantly differ between patients with RA initiating bDMARD and those continuing csDMARDs.
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Affiliation(s)
- Raphaele Seror
- Service de Rhumatologie, Assistance Publique - Hôpitaux de Paris (AP-HP), Hôpital Bicêtre, Université Paris-Saclay, FHU CARE, Le Kremlin-Bicetre, France .,INSERM UMR 1184, Université Paris-Saclay, Faculté de Médecine, Le Kremlin-Bicetre, France
| | - Alexandre Lafourcade
- Centre de Pharmacoépidémiologie (Cephepi), AP-HP. Sorbonne Université, Hôpital Universitaire Pitié Salpêtrière, Paris, France
| | - Yann De Rycke
- Département Biostatistique Santé Publique et Information Médicale, Centre de Pharmacoépidémiologie (Cephepi), CIC-1901, Sorbonne Université, Faculté de médecine Sorbonne Université, AP-HP, Hôpital Pitié-Salpêtrière, Paris, France.,Institut Pierre Louis d'epidemiologie, Sorbonne University, INSERM UMR-S 1136, Paris, France
| | - Sandrine Pinto
- Institut Pierre Louis d'epidemiologie, Sorbonne University, INSERM UMR-S 1136, Paris, France
| | - Johann Castaneda
- Centre de Pharmacoépidémiologie (Cephepi), AP-HP. Sorbonne Université, Hôpital Universitaire Pitié Salpêtrière, Paris, France
| | - Bruno Fautrel
- Institut Pierre Louis d'epidemiologie, Sorbonne University, INSERM UMR-S 1136, Paris, France.,Service de Rhumatologie, Sorbonne Université, AP-HP.Sorbonne Université, Hôpital Pitié Salpêtrière, Paris, France
| | - Xavier Mariette
- Service de Rhumatologie, Assistance Publique - Hôpitaux de Paris (AP-HP), Hôpital Bicêtre, Université Paris-Saclay, FHU CARE, Le Kremlin-Bicetre, France.,INSERM UMR 1184, Université Paris-Saclay, Faculté de Médecine, Le Kremlin-Bicetre, France
| | - Florence Tubach
- Département Biostatistique Santé Publique et Information Médicale, Centre de Pharmacoépidémiologie (Cephepi), CIC-1901, Sorbonne Université, Faculté de médecine Sorbonne Université, AP-HP, Hôpital Pitié-Salpêtrière, Paris, France.,Institut Pierre Louis d'epidemiologie, Sorbonne University, INSERM UMR-S 1136, Paris, France.,delete this affiliaton, Paris, France
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Kedra J, Nocturne G, Mariette X, Seror R. Inflammation-targeted therapies and cancer. Joint Bone Spine 2021; 88:105176. [PMID: 33771759 DOI: 10.1016/j.jbspin.2021.105176] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/15/2020] [Accepted: 02/24/2021] [Indexed: 12/28/2022]
Abstract
OBJECTIVE To review and analyze the current knowledge on the risk of malignancy associated with inflammation-targeted therapies in rheumatic diseases. METHODS We performed a non-systematic literature review on PubMEd MEDLINE by screening randomized controlled trials, meta-analyses, reviews, and observational studies focusing on malignancies and inflammation-targeted therapies including TNF inhibitors, other biologics and JAK inhibitors in rheumatic diseases. RESULTS Data from literature are reassuring regarding the overall risk of incident and recurrent cancer with TNF inhibitors. The risk of lymphoma is more difficult to analyze and data are controversial; however, in most of the studies, this risk does not seem to be significanlty increased. By contrast, there is probably an increased risk of non-melanoma skin cancer associated with TNF inhibitors, as with other immunosuppressants. There is no signal for an increased risk of malignancies with other biological DMARDs, but additional data are needed. A recent post-marketing surveillance study found out an increased risk of malignancies for tofacitinib compared with TNFi; additional data are, therefore, urgently needed to confirm or not these results. CONCLUSION Data are presently reassuring regarding the overall risk of cancer, whatever the inflammation-targeted treatment. However, additional data are needed for non-TNF biologics and JAK-inhibitors.
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Affiliation(s)
- Joanna Kedra
- Inserm U1184, service de rhumatologie, fédération hospitalo-universitaire CARE (Cancer and Autoimmunity Relationship), université Paris-Saclay, hôpital Bicêtre, AP-HP, Le-Kremlin-Bicêtre, France; Inserm UMR S1136, institut Pierre-Louis d'épidémiologie et de santé publique, Sorbonne Université, Paris, France
| | - Gaetane Nocturne
- Inserm U1184, service de rhumatologie, fédération hospitalo-universitaire CARE (Cancer and Autoimmunity Relationship), université Paris-Saclay, hôpital Bicêtre, AP-HP, Le-Kremlin-Bicêtre, France
| | - Xavier Mariette
- Inserm U1184, service de rhumatologie, fédération hospitalo-universitaire CARE (Cancer and Autoimmunity Relationship), université Paris-Saclay, hôpital Bicêtre, AP-HP, Le-Kremlin-Bicêtre, France
| | - Raphaèle Seror
- Inserm U1184, service de rhumatologie, fédération hospitalo-universitaire CARE (Cancer and Autoimmunity Relationship), université Paris-Saclay, hôpital Bicêtre, AP-HP, Le-Kremlin-Bicêtre, France.
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Li Y, Mao X, Tang X, Mao H. Efficacy and Safety of Anti-TNFα Therapy for Uveitis Associated with Juvenile Idiopathic Arthritis: A Systematic Review and Meta-Analysis. Rheumatol Ther 2021; 8:711-727. [PMID: 33721267 PMCID: PMC8217376 DOI: 10.1007/s40744-021-00296-x] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/01/2021] [Accepted: 02/13/2021] [Indexed: 12/20/2022] Open
Abstract
Introduction To investigate the efficacy and safety of anti-TNFα therapy in patients with juvenile idiopathic arthritis associated uveitis (JIA-U). Methods Embase, PubMed, Cochrane Library, and Web of Science were systematically searched for studies reporting anti-TNFα treatment in patients with JIA-U. The primary outcome was the control of intraocular inflammation (CII). The pooled proportion of CII was assessed by the random-effects method when I2 > 50%, otherwise, by the fixed-effect method. This study was registered with PROSPERO (CRD42020161749). Results Three randomized clinical trials (RCTs), twelve case series, three retrospective cohort studies, and three case reports were identified. A total of 399 patients were receiving anti-TNFα therapy, of which 201 patients were treated with adalimumab (ADA), 139 with infliximab (IFX), 36 with etanercept (ETA), 20 with golimumab (GLM), and 3 with certolizumab pegol (CZP). The pooled proportions of CII on observational studies were 82% (95% CI 63–96%) in patients receiving ADA, 56% (95% CI 30–80%) in IFX, 38% (95% CI 8–73%) in ETA and 65% (95% CI 42–86%) in GLM, respectively. All three patients treated with CZP reached improved activity. ADA therapy led to a significantly higher proportion of CII compared to IFX therapy (χ2 = 26.24, P < 0.001), or to ETA therapy (χ2 = 13.43, P < 0.001); but no statistical difference was observed between IFX and ETA (χ2 = 0.13, P = 0.71). As to safety, most reported adverse events were tolerable and two cohort studies consistently showed that ADA was safer than IFX. Conclusions The existing evidence suggests that ADA is better than IFX regarding efficacy and safety. The effectiveness of IFX is higher than ETA with no statistical difference. GLM and CZP may be proxies for ADA but the evidence is limited. Supplementary Information The online version contains supplementary material available at 10.1007/s40744-021-00296-x.
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Affiliation(s)
- Yulu Li
- Department of Rheumatology and Immunology, National Clinical Research Center for Child Health and Disorders, Chongqing Key Laboratory of Child Infection and Immunity, Ministry of Education Key Laboratory of Child Development and Disorders, Children's Hospital of Chongqing Medical University, Chongqing, China
| | - Xiaolan Mao
- Department of Rheumatology and Immunology, National Clinical Research Center for Child Health and Disorders, Chongqing Key Laboratory of Child Infection and Immunity, Ministry of Education Key Laboratory of Child Development and Disorders, Children's Hospital of Chongqing Medical University, Chongqing, China
| | - Xuemei Tang
- Department of Rheumatology and Immunology, National Clinical Research Center for Child Health and Disorders, Chongqing Key Laboratory of Child Infection and Immunity, Ministry of Education Key Laboratory of Child Development and Disorders, Children's Hospital of Chongqing Medical University, Chongqing, China
| | - Huawei Mao
- Department of Rheumatology and Immunology, National Clinical Research Center for Child Health and Disorders, Chongqing Key Laboratory of Child Infection and Immunity, Ministry of Education Key Laboratory of Child Development and Disorders, Children's Hospital of Chongqing Medical University, Chongqing, China.
- Department of Immunology, National Center for Children's Health, Beijing Children's Hospital of Capital Medical University, Beijing, China.
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Cometi L, Bruni C, Passavanti S, Tofani L, Bartoli F, Fiori G, Nacci F, Lepri G, Orlandi M, Melchiorre D, Antonuzzo L, Matucci-Cerinic M, Moggi-Pignone A. Risk of Malignancy and Biologic Therapy in Rheumatic Inflammatory Diseases: A Single-center Experience. RHEUMATOLOGY AND IMMUNOLOGY RESEARCH 2020; 1:39-45. [PMID: 36465081 PMCID: PMC9524767 DOI: 10.2478/rir-2020-0001] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Subscribe] [Scholar Register] [Received: 06/12/2020] [Accepted: 07/31/2020] [Indexed: 06/17/2023]
Abstract
Objectives Biologic disease modifying anti-rheumatic drugs (bDMARDs) have significantly improved the care of patients with rheumatic muscle-skeletal disorders (RMDs). Considering their immunosuppressive action, a theoretical increase of malignancy risk has been a major concern in the last few decades. The objective of this study is to analyze the incidence of malignancies in a cohort of patients affected by rheumatoid arthritis (RA), psoriathic arthritis (PsA), and ankylosing spondylitis (AS) treated with bDMARDs. Methods The charts of bDMARD-treated RMD patients were reviewed, and data about bDMARD exposure and malignant cancers (excluding non-melanoma skin cancer) were collected. Results 921 patients were included (median age: 50.59 years, 66.67% females); 1374 bDMARD treatments were administered, 87.12% were tumor necrosis factor inhibitors. A total of 21 malignant neoplasms were detected in 21 patients (61.90% females, median age at cancer diagnosis: 64.99 years), 66.67% in RA patients, 19.05% in PsA, and 14.28% in AS. Among them, 10 patients (47.62%) were treated with etanercept, 6 patients (28.57%) with adalimumab, and 1 case each with tocilizumab, certolizumab, golimumab, infliximab, and abatacept. The most common malignancies that we found were lung cancers, ductal mammary carcinomas, melanomas, and lymphomas. The incidence rate (IR) of malignancies in our cohort was 3.47 per 1000 person-years (p-y); the higher IRs were in RA patients (5.13 per 1000 p-y), in males (4.21 per 1000 p-y), and in patients aged >70 years (10.14 per 1000 p-y). Conclusions The results of our study showed IR of malignancies in RMD patients treated with bDMARDs that is in agreement with literature data.
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Affiliation(s)
- Laura Cometi
- Department of Experimental and Clinical Medicine, Division of Rheumatology, University of Florence, Florence, Italy
| | - Cosimo Bruni
- Department of Experimental and Clinical Medicine, Division of Rheumatology, University of Florence, Florence, Italy
| | - Saverio Passavanti
- Department of Internal Medicine, Division of Internal Medicine Unit III, Azienda Ospedaliera Universitaria Careggi, Florence, Italy
| | - Lorenzo Tofani
- Department of Experimental and Clinical Medicine, Division of Rheumatology, University of Florence, Florence, Italy
| | - Francesca Bartoli
- Department of Geriatric Medicine, Division of Rheumatology Azienda Ospedaliera Universitaria Careggi, Florence, Italy
| | - Ginevra Fiori
- Department of Geriatric Medicine, Division of Rheumatology Azienda Ospedaliera Universitaria Careggi, Florence, Italy
| | - Francesca Nacci
- Department of Experimental and Clinical Medicine, Division of Rheumatology, University of Florence, Florence, Italy
| | - Gemma Lepri
- Department of Experimental and Clinical Medicine, Division of Rheumatology, University of Florence, Florence, Italy
| | - Martina Orlandi
- Department of Experimental and Clinical Medicine, Division of Rheumatology, University of Florence, Florence, Italy
| | - Daniela Melchiorre
- Department of Experimental and Clinical Medicine, Division of Rheumatology, University of Florence, Florence, Italy
- Department of Geriatric Medicine, Division of Rheumatology Azienda Ospedaliera Universitaria Careggi, Florence, Italy
| | - Lorenzo Antonuzzo
- Medical Oncology Unit, Azienda Ospedaliera Universitaria Careggi, Florence, Italy
| | - Marco Matucci-Cerinic
- Department of Experimental and Clinical Medicine, Division of Rheumatology, University of Florence, Florence, Italy
- Department of Geriatric Medicine, Division of Rheumatology Azienda Ospedaliera Universitaria Careggi, Florence, Italy
| | - Alberto Moggi-Pignone
- Department of Internal Medicine, Division of Internal Medicine Unit III, Azienda Ospedaliera Universitaria Careggi, Florence, Italy
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Jacob S, Rahbari K, Tegtmeyer K, Zhao J, Tran S, Helenowski I, Zhang H, Walunas T, Varga J, Dematte J, Villaflor V. Lung Cancer Survival in Patients With Autoimmune Disease. JAMA Netw Open 2020; 3:e2029917. [PMID: 33315114 PMCID: PMC7737093 DOI: 10.1001/jamanetworkopen.2020.29917] [Citation(s) in RCA: 16] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/08/2023] Open
Abstract
IMPORTANCE Patients with autoimmune disease and lung cancer pose a multidisciplinary treatment challenge, particularly with the advent of immunotherapy. However, the association between autoimmune disease and lung cancer survival is largely unknown. OBJECTIVE To determine the association between autoimmune disease and lung cancer survival. DESIGN, SETTING, AND PARTICIPANTS Retrospective cohort study between 2003 and 2019 at a single academic medical center (Northwestern University). A query of the Northwestern Medicine Enterprise Data Warehouse identified 349 patients with lung cancer and several autoimmune diseases. Types of lung cancers included small cell, adenocarcinoma, squamous cell carcinoma, non-small cell not otherwise specified, and large cell carcinoma. Autoimmune diseases included rheumatoid arthritis, systemic lupus erythematosus, systemic sclerosis, mixed connective tissue disease, myositis, and Sjögren syndrome. Inclusion criteria were biopsy-confirmed lung cancer, autoimmune diagnosis confirmed by a rheumatologist, and death or an encounter listed in the electronic medical record within 2 years of study end. A control group of patients with biopsy-proven lung cancer but without autoimmune disease was identified. Data analysis was conducted from March to July 2020. EXPOSURE Presence of autoimmune disease. MAIN OUTCOMES AND MEASURES Overall survival and progression-free survival in patients with autoimmune disease. The hypothesis was that patients with autoimmune disease would have worse progression-free survival and overall survival compared with patients in the control group. RESULTS Of the original 349 patients, 177 met inclusion criteria. Mean (SD) age at lung cancer diagnosis was 67.0 (10.0) years and 136 (76.8%) were women. Most common autoimmune diseases were rheumatoid arthritis (97 [54.8%]), systemic sclerosis (43 [24.3%]), and systemic lupus erythematous (15 [8.5%]). Most common lung cancers were adenocarcinoma (99 [55.9%]), squamous cell carcinoma (29 [16.4%]), and small cell lung cancer (17 [9.6%]). A total of 219 patients (mean [SD] age at diagnosis, 65.9 [4.1] years; 173 [79.0%]) were identified as having lung cancer without autoimmune disease and included in the control cohort. Compared with patients in the control group, patients with autoimmune disease experienced no difference in overall survival (log-rank P = .69). A total of 126 patients (69.5%) with autoimmune disease received standard of care vs 213 patients (97.3%) in the control group (P < .001). No individual autoimmune disease was associated with worse prognosis, even among patients with underlying interstitial lung disease. CONCLUSIONS AND RELEVANCE Compared with institutional controls, patients with autoimmune disease experienced no difference in survival despite the fact that fewer patients in this group received standard-of-care treatment. No individual autoimmune disease was associated with worse prognosis. Future multicenter prospective trials are needed to further evaluate autoimmune disease and lung cancer survival.
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Affiliation(s)
- Saya Jacob
- Department of Medicine, Northwestern University Feinberg School of Medicine, Chicago, Illinois
| | - Kian Rahbari
- Northwestern University Feinberg School of Medicine, Chicago, Illinois
| | - Kyle Tegtmeyer
- Northwestern University Feinberg School of Medicine, Chicago, Illinois
| | - Jeffrey Zhao
- Northwestern University Feinberg School of Medicine, Chicago, Illinois
| | - Steven Tran
- Northwestern University Feinberg School of Medicine, Chicago, Illinois
| | | | - Hui Zhang
- Northwestern University, Chicago, Illinois
| | - Theresa Walunas
- Division of General Internal Medicine and Geriatrics, Department of Medicine, Northwestern University Feinberg School of Medicine, Chicago, Illinois
- Center for Health Information Partnerships, Northwestern University Feinberg School of Medicine, Chicago, Illinois
| | - John Varga
- Department of Medicine, Northwestern University Feinberg School of Medicine, Chicago, Illinois
- Department of Medicine, Northwestern Scleroderma Program, Northwestern University Feinberg School of Medicine, Chicago, Illinois
| | - Jane Dematte
- Department of Medicine, Northwestern University Feinberg School of Medicine, Chicago, Illinois
- Division of Pulmonary and Critical Care, Department of Medicine, Northwestern University Feinberg School of Medicine, Chicago, Illinois
| | - Victoria Villaflor
- Department of Medicine, Northwestern University Feinberg School of Medicine, Chicago, Illinois
- Robert H. Lurie Comprehensive Cancer Center of Northwestern University, Chicago, Illinois
- City of Hope Cancer Center, Duarte, California
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Pundole X, Zamora NV, Siddhanamatha H, Lin H, Tayar J, Leung CH, Li L, Suarez-Almazor ME. Overall survival in patients with rheumatoid arthritis and solid malignancies receiving biologic disease-modifying antirheumatic therapy. Clin Rheumatol 2020; 39:2943-2950. [PMID: 32803571 PMCID: PMC10556973 DOI: 10.1007/s10067-020-05318-7] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/11/2020] [Revised: 07/24/2020] [Accepted: 08/04/2020] [Indexed: 12/19/2022]
Abstract
INTRODUCTION/OBJECTIVES The effects of biologic disease-modifying antirheumatic drugs (bDMARDs) in patients with rheumatoid arthritis (RA) and cancer are largely unknown. We examined overall survival (OS) in patients with RA and solid malignancies receiving bDMARDs. METHODS We performed a retrospective cohort study of patients with RA and solid malignancies seen at MD Anderson Cancer Center between 2002 and 2014. Cox proportional hazard regression models, stratified by tumor type and stage, were fit evaluating use of bDMARDs as a time fixed and time varying covariate. RESULTS We identified 431 RA patients with solid malignancies: 111 (26%) received bDMARDs after their cancer diagnosis. Median OS from cancer diagnosis was 16.1 years. Of the patients receiving bDMARDs, most had localized disease, and only 14 (13%) had advanced cancer. In the stratified Cox models no statistically significant differences were observed between patients who received tumor necrosis factor inhibitors (TNFi) or patients who received nonTNFi, compared with those who did not receive bDMARDs (hazard ratio (HR), 0.67; 95% confidence interval (CI), 0.31, 1.44; HR, 1.10; 95% CI, 0.26, 4.60 respectively). In breast cancer patients, those receiving TNFi or nonTNFi had a numerically higher but statistically nonsignificant HR compared with those who did not receive bDMARD: HR, 1.40 (95% CI, 0.42, 4.73), and HR, 1.37 (95% CI, 0.22, 8.42) respectively. CONCLUSION No significant differences in OS were observed between patients who received bDMARDs and those who did not. Additional data is needed to evaluate other cancer outcomes such as recurrence and progression, and patients with advanced cancer. Key Points •We found no statistically significant differences in OS between patients with RA and concomitant solid malignancies who received bDMARDs and those who did not. •Most patients who received bDMARDs had been diagnosed with early stage cancer •As few patients with advanced cancer received bDMARDs safety for this group cannot be established •No significant differences were observed between TNFi and nonTNFi, but the sample size was small.
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Affiliation(s)
- Xerxes Pundole
- Department of Health Services Research, The University of Texas MD Anderson Cancer Center, 1515 Holcombe Blvd., Houston, TX, 77030, USA
| | - Natalia V Zamora
- Sección Reumatología, Instituto de Rehabilitación Psicofísica, Buenos Aires, Argentina
| | - Harish Siddhanamatha
- Department of Data Integrity and Analytics, Augusta University Medical Center, Augusta, GA, USA
| | - Heather Lin
- Department of Biostatistics, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Jean Tayar
- Department of General Internal Medicine, Section of Rheumatology and Clinical Immunology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Cheuk Hong Leung
- Department of Biostatistics, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Liang Li
- Department of Biostatistics, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Maria E Suarez-Almazor
- Department of Health Services Research, The University of Texas MD Anderson Cancer Center, 1515 Holcombe Blvd., Houston, TX, 77030, USA.
- Department of General Internal Medicine, Section of Rheumatology and Clinical Immunology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
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10
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Loft ND, Vaengebjerg S, Skov L. Cancer risk in patients with psoriasis: should we be paying more attention? Expert Rev Clin Immunol 2020; 16:479-492. [DOI: 10.1080/1744666x.2020.1754194] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/08/2023]
Affiliation(s)
- Nikolai Dyrberg Loft
- Department of Dermatology and Allergy, Herlev and Gentofte Hospital, University of Copenhagen, Copenhagen, Denmark
- Copenhagen Research Group for Inflammatory Skin, Herlev and Gentofte Hospital, Copenhagen, Denmark
| | - Sofie Vaengebjerg
- Department of Dermatology and Allergy, Herlev and Gentofte Hospital, University of Copenhagen, Copenhagen, Denmark
- Copenhagen Research Group for Inflammatory Skin, Herlev and Gentofte Hospital, Copenhagen, Denmark
| | - Lone Skov
- Department of Dermatology and Allergy, Herlev and Gentofte Hospital, University of Copenhagen, Copenhagen, Denmark
- Copenhagen Research Group for Inflammatory Skin, Herlev and Gentofte Hospital, Copenhagen, Denmark
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11
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A meta-analysis of biologic therapies on risk of new or recurrent cancer in patients with rheumatoid arthritis and a prior malignancy. Rheumatology (Oxford) 2019; 59:930-939. [DOI: 10.1093/rheumatology/kez475] [Citation(s) in RCA: 15] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/11/2019] [Revised: 09/11/2019] [Indexed: 01/11/2023] Open
Abstract
Abstract
Objectives
To explore the risk of new and recurrent cancer in adult RA patients with prior malignancy and subsequently exposed to biologic therapies.
Methods
Separate searches were performed of PubMed, EMBASE and Cochrane Library and conference proceedings for observational studies reporting cancer incidence or recurrence in patients with RA and prior malignancy treated with biologics and conventional synthetic DMARDs (csDMARDs). Mantel-Haenszel fixed-effects method was conducted to calculate relative risk and 95% CI.
Results
A total of 12 studies involving 13 598 patients and 32 473 patient-years of follow-up were included (10, 3 and 1 studies for TNF inhibitors [TNFi], rituximab and anakinra, respectively). The crude incidence of new and recurrent cancer per 1000 patient-years were 34.4 for TNFi, 32.3 for rituximab, 32.3 for anakinra and 31.8 for csDMARDs. In the quantitative meta-analysis, biologics were not associated with an increased risk of new or recurrent cancer compared with csDMARDs in patients with RA and prior cancer (TNFi: relative risk = 0.95, 95% CI = 0.83, 1.09; rituximab: relative risk = 0.89, 95% CI = 0.52, 1.53). Secondary analyses of stratification of cancer types, the interval between initiation of TNFi and prior cancer diagnosis, and duration of TNFi exposure, found similar results.
Conclusion
Compared with csDMARDs, there is no increased risk of developing cancer overall or some specific subtypes in RA patients with a prior cancer receiving biologics. More investigations are warranted to explore the risk of cancer development in individual cancer as well as to determine optimal time to initiate biologic therapy after the diagnosis of cancer or completion of cancer treatment.
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12
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De Cock D, Hyrich K. Malignancy and rheumatoid arthritis: Epidemiology, risk factors and management. Best Pract Res Clin Rheumatol 2019; 32:869-886. [PMID: 31427060 DOI: 10.1016/j.berh.2019.03.011] [Citation(s) in RCA: 85] [Impact Index Per Article: 14.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/17/2022]
Abstract
Rheumatoid arthritis (RA) is a chronic inflammatory condition that can result in pain and functional disability. It is also associated with an increased occurrence of comorbidities, including an increased risk of certain cancers such as lung cancer and lymphoma. The aetiopathogenesis of this increased cancer risk is likely multifactorial and includes shared risk factors as well as chronic inflammation. There is also a concern that the treatment for RA itself may increase this risk further, particularly treatment with biologic disease-modifying anti-rheumatic drugs (DMARDs). This paper aims to review the evidence for the increased risk of cancer in RA as well as the latest evidence for the association between DMARDs and tumorigenesis. It also discusses the evidence for the management of patients with biologic DMARDs in the setting of existing cancer.
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Affiliation(s)
- Diederik De Cock
- Arthritis Research UK Centre for Epidemiology, Centre for Musculoskeletal Research, University of Manchester, Manchester, United Kingdom
| | - Kimme Hyrich
- Arthritis Research UK Centre for Epidemiology, Centre for Musculoskeletal Research, University of Manchester, Manchester, United Kingdom; National Institute of Health Research Manchester Biomedical Research Centre, Manchester NHS Foundation Trust, Manchester Academic Health Science Centre, Manchester, United Kingdom.
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13
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Geller S, Xu H, Lebwohl M, Nardone B, Lacouture ME, Kheterpal M. Malignancy Risk and Recurrence with Psoriasis and its Treatments: A Concise Update. Am J Clin Dermatol 2018; 19:363-375. [PMID: 29260411 PMCID: PMC5948118 DOI: 10.1007/s40257-017-0337-2] [Citation(s) in RCA: 84] [Impact Index Per Article: 12.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/20/2022]
Abstract
Psoriasis is a common inflammatory cutaneous disease that affects approximately 120 million people worldwide. Systemic treatments have significantly improved disease burden, but concerns persist regarding their association with increased risk of malignancy. Patients with psoriasis have a slightly elevated baseline risk of lymphoproliferative diseases. Studies on methotrexate and cyclosporine, as well as older biological agents such as tumor necrosis factor inhibitors, have found no increased risk of non-cutaneous solid tumors; however, positive associations between cutaneous squamous cell carcinomas and certain therapies have been found. There is conflicting evidence regarding the risk of lymphoma and melanoma. Further studies are needed to determine the long-term safety of newer psoriasis treatments (interleukin [IL]-12/23, IL-17, Janus kinase 1/3, and phosphodiesterase-4 inhibitors), specifically their safety in patients with a history of cancer. This review summarizes the most recent studies on malignancy risk from psoriasis, and its treatments in patients and cancer survivors, with the highest available level of evidence.
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Affiliation(s)
- Shamir Geller
- Dermatology Service, Memorial Sloan Kettering Cancer Center, 16 East 60th Street, New York, NY, 10022, USA.
| | - Haoming Xu
- Dermatology Service, Memorial Sloan Kettering Cancer Center, 16 East 60th Street, New York, NY, 10022, USA
| | - Mark Lebwohl
- Department of Dermatology, Icahn School of Medicine at Mount Sinai, New York, NY, USA
| | - Beatrice Nardone
- Department of Dermatology, Feinberg School of Medicine, Northwestern University, Chicago, IL, USA
| | - Mario E Lacouture
- Dermatology Service, Memorial Sloan Kettering Cancer Center, 16 East 60th Street, New York, NY, 10022, USA
| | - Meenal Kheterpal
- Dermatology Service, Memorial Sloan Kettering Cancer Center, 16 East 60th Street, New York, NY, 10022, USA
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14
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Harrold LR, Litman HJ, Saunders KC, Dandreo KJ, Gershenson B, Greenberg JD, Low R, Stark J, Suruki R, Jaganathan S, Kremer JM, Yassine M. One-year risk of serious infection in patients treated with certolizumab pegol as compared with other TNF inhibitors in a real-world setting: data from a national U.S. rheumatoid arthritis registry. Arthritis Res Ther 2018; 20:2. [PMID: 29329557 PMCID: PMC5795286 DOI: 10.1186/s13075-017-1496-5] [Citation(s) in RCA: 22] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/31/2017] [Accepted: 12/08/2017] [Indexed: 02/05/2023] Open
Abstract
Background Registry studies provide a valuable source of comparative safety data for tumor necrosis factor inhibitors (TNFi) used in rheumatoid arthritis (RA), but they are subject to channeling bias. Comparing safety outcomes without accounting for channeling bias can lead to inaccurate comparisons between TNFi prescribed at different stages of the disease. In the present study, we examined the incidence of serious infection and other adverse events during certolizumab pegol (CZP) use vs other TNFi in a U.S. RA cohort before and after using a methodological approach to minimize channeling bias. Methods Patients with RA enrolled in the Corrona registry, aged ≥ 18 years, initiating CZP or other TNFi (etanercept, adalimumab, golimumab, or infliximab) after May 1, 2009 (n = 6215 initiations), were followed for ≤ 12 months. A propensity score (PS) model was used to control for baseline characteristics associated with the probability of receiving CZP vs other TNFi. Incidence rate ratios (IRRs) of serious infectious events (SIEs), malignancies, and cardiovascular events (CVEs) in the CZP group vs other TNFi group were calculated with 95% CIs, before and after PS matching. Results Patients were more likely to initiate CZP later in the course of therapy than those initiating other TNFi. CZP initiators (n = 975) were older and had longer disease duration, more active disease, and greater disability than other TNFi initiators (n = 5240). After PS matching, there were no clinically important differences between CZP (n = 952) and other TNFi (n = 952). Before PS matching, CZP was associated with a greater incidence of SIEs (IRR 1.53 [95% CI 1.13, 2.05]). The risk of SIEs was not different between groups after PS matching (IRR 1.26 [95% CI 0.84, 1.90]). The 95% CI of the IRRs for malignancies or CVEs included unity, regardless of PS matching, suggesting no difference in risk between CZP and other TNFi. Conclusions After using PS matching to minimize channeling bias and compare patients with a similar likelihood of receiving CZP or other TNFi, the 1-year risk of SIEs, malignancies, and CVEs was not distinguishable between the two groups. Electronic supplementary material The online version of this article (doi:10.1186/s13075-017-1496-5) contains supplementary material, which is available to authorized users.
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Affiliation(s)
- Leslie R Harrold
- University of Massachusetts Medical School, Worcester, MA, USA. .,Pharmacoepidemiology and Outcomes Research, Corrona, 352 Turnpike Road, Suite 325, Southborough, MA, 01772, USA.
| | - Heather J Litman
- Pharmacoepidemiology and Outcomes Research, Corrona, 352 Turnpike Road, Suite 325, Southborough, MA, 01772, USA
| | - Katherine C Saunders
- Pharmacoepidemiology and Outcomes Research, Corrona, 352 Turnpike Road, Suite 325, Southborough, MA, 01772, USA
| | - Kimberly J Dandreo
- Pharmacoepidemiology and Outcomes Research, Corrona, 352 Turnpike Road, Suite 325, Southborough, MA, 01772, USA
| | - Bernice Gershenson
- University of Massachusetts Medical School, Worcester, MA, USA.,Pharmacoepidemiology and Outcomes Research, Corrona, 352 Turnpike Road, Suite 325, Southborough, MA, 01772, USA
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15
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Cho SK, Lee J, Han M, Bae SC, Sung YK. The risk of malignancy and its incidence in early rheumatoid arthritis patients treated with biologic DMARDs. Arthritis Res Ther 2017; 19:277. [PMID: 29246243 PMCID: PMC5732524 DOI: 10.1186/s13075-017-1482-y] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/01/2017] [Accepted: 11/20/2017] [Indexed: 01/08/2023] Open
Abstract
Background Treatment with disease-modifying anti-rheumatic drugs (DMARDs) has raised concerns about the risk of malignancies in rheumatoid arthritis (RA) patients. However, the association between biologic DMARDs (bDMARDs) and malignancy in previous reports remains controversial. Therefore we aimed to estimate the incidence of malignancy in early RA patients and to evaluate the relative risk of malignancy with use of bDMARDs. Methods A retrospective cohort of incident RA patients was established using the Korean National Claims Database. Among a total of 14,081 RA patients identified, 1684 patients with a history of malignancy were excluded. We calculated the incidence rate of overall and individual malignancies. The standardized incidence ratio (SIR) of malignancies in bDMARD users was compared to that in nonusers. Multivariable logistic regression analysis was used to evaluate the impact of bDMARDs on the development of malignancies in early RA patients. Results A total of 12,397 early RA patients without a history of malignancy were enrolled. During 41,599 person-years (PY) of follow-up, 725 malignancies developed in 561 patients (174.3/10,000 PY) and 21 hematologic malignancies developed (5.0/10,000 PY). Patients treated with bDMARDs had a significantly lower incidence of overall malignancy compared to those not treated with bDMARDs (SIR 0.45 (95% CI 0.28–0.70)). However, this relationship was not significant with regard to hematologic malignancies (SIR 2.65 (95% CI 0.55–7.76)). On multivariable analysis, bDMARD use was a protective factor against the development of overall malignancy (odds ratio 0.42 (95% CI 0.25–0.73)). However, bDMARD use had no significant protective effect against the development of hematologic malignancies (odds ratio 1.69 (95% CI 0.38–7.59)). Conclusions In early RA patients, bDMARD use decreases the overall risk of developing malignancies; however, it does not affect the risk of developing hematologic malignancies. Electronic supplementary material The online version of this article (doi:10.1186/s13075-017-1482-y) contains supplementary material, which is available to authorized users.
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Affiliation(s)
- Soo-Kyung Cho
- Hanyang University Hospital for Rheumatic Diseases, 222-1 wangsimni-ro, Seongdong-gu, Seoul, 04763, South Korea.,Clinical Research Center for Rheumatoid Arthritis (CRCRA), 222 wangsimni-ro, Seongdong-gu, Seoul, 04763, South Korea
| | - Jiyoung Lee
- Clinical Research Center for Rheumatoid Arthritis (CRCRA), 222 wangsimni-ro, Seongdong-gu, Seoul, 04763, South Korea
| | - Minkyung Han
- Clinical Research Center for Rheumatoid Arthritis (CRCRA), 222 wangsimni-ro, Seongdong-gu, Seoul, 04763, South Korea
| | - Sang-Cheol Bae
- Hanyang University Hospital for Rheumatic Diseases, 222-1 wangsimni-ro, Seongdong-gu, Seoul, 04763, South Korea.,Clinical Research Center for Rheumatoid Arthritis (CRCRA), 222 wangsimni-ro, Seongdong-gu, Seoul, 04763, South Korea
| | - Yoon-Kyoung Sung
- Hanyang University Hospital for Rheumatic Diseases, 222-1 wangsimni-ro, Seongdong-gu, Seoul, 04763, South Korea. .,Clinical Research Center for Rheumatoid Arthritis (CRCRA), 222 wangsimni-ro, Seongdong-gu, Seoul, 04763, South Korea.
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16
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Vashisht P, O'dell J. Not all TNF inhibitors in rheumatoid arthritis are created equal: important clinical differences. Expert Opin Biol Ther 2017; 17:989-999. [PMID: 28594252 DOI: 10.1080/14712598.2017.1340453] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
INTRODUCTION Anti-TNF therapy has dramatically changed how we manage rheumatoid arthritis. There are many similarities among the five approved agents but also some important differences. Rheumatologists have 5 different options to choose from when they are ready to commence anti-TNF therapy. Although all block the TNF cytokine, there are important critical differences among them that affect their safety profile and clinical utility in certain scenarios. Unfortunately, there are no head to head trials to compare the different anti-TNF agents and none appear to be in the horizon. Areas covered: This article reviews the various clinical situations where it may be important to use a particular anti-TNF agent. The authors also give their expert opinion and future perspectives on the area. Expert opinion: Although there are many similarities among the five different TNFi that are clinically available, there are important clinical niches, where the limited data that are available, that clearly support the preferential use of a particular agent or class of agents. Assays or tests that allow us to find the 'sweet spot' of TNF inhibition at the level of each patient are long overdue.
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Affiliation(s)
| | - James O'dell
- b Internal Medicine , Chief Division of Rheumatology , Omaha , NE , USA
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17
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Giat E, Ehrenfeld M, Shoenfeld Y. Cancer and autoimmune diseases. Autoimmun Rev 2017; 16:1049-1057. [DOI: 10.1016/j.autrev.2017.07.022] [Citation(s) in RCA: 101] [Impact Index Per Article: 12.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/06/2017] [Accepted: 07/12/2017] [Indexed: 02/06/2023]
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18
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Delate T, Meyer R, Jenkins D. Patterns of Care for Biologic-Dosing Outliers and Nonoutliers in Biologic-Naive Patients with Rheumatoid Arthritis. J Manag Care Spec Pharm 2017; 23:798-808. [PMID: 28737988 PMCID: PMC10397631 DOI: 10.18553/jmcp.2017.23.8.798] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/05/2022]
Abstract
BACKGROUND Although most biologic medications for patients with rheumatoid arthritis (RA) have recommended fixed dosing, actual biologic dosing may vary among real-world patients, since some patients can receive higher (high-dose outliers) or lower (low-dose outliers) doses than what is recommended in medication package inserts. OBJECTIVE To describe the patterns of care for biologic-dosing outliers and nonoutliers in biologic-naive patients with RA. METHODS This was a retrospective, longitudinal cohort study of patients with RA who were not pregnant and were aged ≥ 18 and < 90 years from an integrated health care delivery system. Patients were newly initiated on adalimumab (ADA), etanercept (ETN), or infliximab (IFX) as index biologic therapy between July 1, 2006, and February 28, 2014. Outlier status was defined as a patient having received at least 1 dose < 90% or > 110% of the approved dose in the package insert at any time during the study period. Baseline patient profiles, treatment exposures, and outcomes were collected during the 180 days before and up to 2 years after biologic initiation and compared across index biologic outlier groups. Patients were followed for at least 1 year, with a subanalysis of those patients who remained as members for 2 years. RESULTS This study included 434 RA patients with 1 year of follow-up and 372 RA patients with 2 years of follow-up. Overall, the vast majority of patients were female (≈75%) and had similar baseline characteristics. Approximately 10% of patients were outliers in both follow-up cohorts. ETN patients were least likely to become outliers, and ADA patients were most likely to become outliers. Of all outliers during the 1-year follow-up, patients were more likely to be a high-dose outlier (55%) than a low-dose outlier (45%). Median 1- and 2-year adjusted total biologic costs (based on wholesale acquisition costs) were higher for ADA and ETA nonoutliers than for IFX nonoutliers. Biologic persistence was highest for IFX patients. Charlson Comorbidity Index score, ETN and IFX index biologic, and treatment with a nonbiologic disease-modifying antirheumatic drug (DMARD) before biologic initiation were associated with becoming high- or low-dose outliers (c-statistic = 0.79). CONCLUSIONS Approximately 1 in 10 study patients with RA was identified as a biologic-dosing outlier. Dosing outliers did not appear to have better clinical outcomes compared with nonoutliers. Before initiating outlier biologic dosing, health care providers may better serve their RA patients by prescribing alternate DMARD therapy. DISCLOSURES This study was sponsored by Janssen Scientific Affairs. It is the policy of Janssen Scientific Affairs to publish all sponsored studies unless they are exploratory studies or are determined a priori for internal use only (e.g., to inform business decisions). Meyer is an employee of Janssen Scientific Affairs and a stockholder in Johnson and Johnson, its parent company. Delate and Jenkins have nothing to disclose. Study concept and design were contributed by Delate and Meyer. Delate took the lead in data collection, along with Jenkins. All authors participated in data analysis. The manuscript was written primarily by Delate, along with Meyers and Jenkins, and was revised by Meyer, along with Delate and Jenkins.
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Affiliation(s)
- Thomas Delate
- 1 Pharmacy Department, Kaiser Permanente Colorado, Aurora, and Department of Clinical Pharmacy, Skaggs School of Pharmacy and Pharmaceutical Sciences, University of Colorado Anschutz Medical Campus, Aurora
| | - Roxanne Meyer
- 2 Health Economics and Outcomes Research, Janssen Scientific Affairs, Horsham, Pennsylvania
| | - Daniel Jenkins
- 3 Department of Clinical Pharmacy, Skaggs School of Pharmacy and Pharmaceutical Sciences, University of Colorado Anschutz Medical Campus, Aurora
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19
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Jin Y, Desai RJ, Liu J, Choi NK, Kim SC. Factors associated with initial or subsequent choice of biologic disease-modifying antirheumatic drugs for treatment of rheumatoid arthritis. Arthritis Res Ther 2017; 19:159. [PMID: 28679392 PMCID: PMC5499035 DOI: 10.1186/s13075-017-1366-1] [Citation(s) in RCA: 39] [Impact Index Per Article: 4.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/13/2016] [Accepted: 06/09/2017] [Indexed: 12/03/2022] Open
Abstract
Background Biologic disease-modifying antirheumatic drugs (DMARDs) are increasingly used for rheumatoid arthritis (RA) treatment. However, little is known based on contemporary data about the factors associated with DMARDs and patterns of use of biologic DMARDs for initial and subsequent RA treatment. Methods We conducted an observational cohort study using claims data from a commercial health plan (2004–2013) and Medicaid (2000–2010) in three study groups: patients with early untreated RA who were naïve to any type of DMARD and patients with prevalent RA with or without prior exposure to one biologic DMARD. Multivariable logistic regression models were used to examine the effect of patient demographics, clinical characteristics and healthcare utilization factors on the initial and subsequent choice of biologic DMARDs for RA. Results We identified a total of 195,433 RA patients including 78,667 (40%) with early untreated RA and 93,534 (48%) and 23,232 (12%) with prevalent RA, without or with prior biologic DMARD treatment, respectively. Patients in the commercial insurance were 87% more likely to initiate a biologic DMARD versus patients in Medicaid (OR = 1.87, 95% CI = 1.70–2.05). In Medicaid, African-Americans had lower odds of initiating (OR = 0.59, 95% CI = 0.51–0.68 in early untreated RA; OR = 0.71, 95% CI = 0.61–0.74 in prevalent RA) and switching (OR = 0.71, 95% CI = 0.55–0.90) biologic DMARDs than non-Hispanic whites. Prior use of steroid and non-biologic DMARDs predicted both biologic DMARD initiation and subsequent switching. Etanercept, adalimumab, and infliximab were the most commonly used first-line and second-line biologic DMARDS; patients on anakinra and golimumab were most likely to be switched to other biologic DMARDS. Conclusions Insurance type, race, and previous use of steroids and non-biologic DMARDs were strongly associated with initial or subsequent treatment with biologic DMARDs.
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Affiliation(s)
- Yinzhu Jin
- Division of Pharmacoepidemiology and Pharmacoeconomics, Brigham and Women's Hospital, 1620 Tremont Street, Suite 3030, Boston, MA, 02120, USA
| | - Rishi J Desai
- Division of Pharmacoepidemiology and Pharmacoeconomics, Brigham and Women's Hospital, 1620 Tremont Street, Suite 3030, Boston, MA, 02120, USA
| | - Jun Liu
- Division of Pharmacoepidemiology and Pharmacoeconomics, Brigham and Women's Hospital, 1620 Tremont Street, Suite 3030, Boston, MA, 02120, USA
| | - Nam-Kyong Choi
- Division of Pharmacoepidemiology and Pharmacoeconomics, Brigham and Women's Hospital, 1620 Tremont Street, Suite 3030, Boston, MA, 02120, USA.,Institute of Environmental Medicine, Medical Research Center, Seoul National University, Seoul, Republic of Korea.,Department of Health Convergence, Ewha Womans University, Seoul, Republic of Korea
| | - Seoyoung C Kim
- Division of Pharmacoepidemiology and Pharmacoeconomics, Brigham and Women's Hospital, 1620 Tremont Street, Suite 3030, Boston, MA, 02120, USA. .,Division of Rheumatology, Immunology and Allergy, Brigham and Women's Hospital, Boston, MA, USA.
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20
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Tarp S, Eric Furst D, Boers M, Luta G, Bliddal H, Tarp U, Heller Asmussen K, Brock B, Dossing A, Schjødt Jørgensen T, Thirstrup S, Christensen R. Risk of serious adverse effects of biological and targeted drugs in patients with rheumatoid arthritis: a systematic review meta-analysis. Rheumatology (Oxford) 2017; 56:417-425. [PMID: 28013201 DOI: 10.1093/rheumatology/kew442] [Citation(s) in RCA: 26] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/19/2016] [Indexed: 01/09/2023] Open
Abstract
Objectives To determine possible differences in serious adverse effects among the 10 currently approved biological and targeted synthetic DMARDs (b/ts-DMARDs) for RA. Methods Systematic review in bibliographic databases, trial registries and websites of regulatory agencies identified randomized trials of approved b/ts-DMARDs for RA. Network meta-analyses using mixed-effects Poisson regression models were conducted to calculate rate ratios for serious adverse events (SAEs) and deaths between each of the 10 drugs and control (i.e. no b/ts-DMARD treatment), based on subjects experiencing an event in relation to person-years. Confidence in the estimates was assessed by applying the Grading of Recommendations Assessment, Development and Evaluation approach (GRADE). Results A total of 117 trials (47 615 patients) were included. SAEs were more common with certolizumab compared with abatacept (rate ratio = 1.58, 95% CI: 1.18, 2.14), adalimumab (1.36, 95% CI: 1.02, 1.81), etanercept (1.60, 95% CI: 1.18, 2.17), golimumab (1.45, 95% CI: 1.00, 2.08), rituximab (1.63, 95% CI: 1.16, 2.30), tofacitinib (1.44, 95% CI: 1.03, 2.02) and control (1.45, 95% CI: 1.13, 1.87); and tocilizumab compared with abatacept (1.30, 95% CI: 1.03, 1.65), etanercept (1.31, 95% CI: 1.04, 1.67) and rituximab (1.34, 95% CI: 1.01, 1.78). No other comparisons were statistically significant. Accounting for study duration confirmed our findings for up to 6 months' treatment but not for longer-term treatment (6-24 months). No differences in mortality between b/ts-DMARDs and control were found. Based on the GRADE approach, confidence in the estimates was low due to lack of head-to-head comparison trials and imprecision in indirect estimates. Conclusion Despite low confidence in the estimates, our analysis found potential differences in rates of SAEs. Our data suggest caution should be taken when deciding among available drugs. Systematic review registration number PROSPERO CRD42014014842.
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Affiliation(s)
- Simon Tarp
- Musculoskeletal Statistics Unit, The Parker Institute, Copenhagen University Hospital at Bispebjerg and Frederiksberg, Copenhagen, Denmark
| | - Daniel Eric Furst
- David Geffen School of Medicine, University of California Los Angeles, CA.,Division of Rheumatology, University of Washington, Seattle, WA, USA.,Division of Rheumatology, University of Florence, Florence, Italy
| | - Maarten Boers
- Department of Epidemiology and Biostatistics.,Amsterdam Rheumatology and Immunology Center, VU University Medical Center, Amsterdam, The Netherlands
| | - George Luta
- Department of Biostatistics, Bioinformatics, and Biomathematics, Georgetown University Medical Center, Washington, DC, USA
| | - Henning Bliddal
- Musculoskeletal Statistics Unit, The Parker Institute, Copenhagen University Hospital at Bispebjerg and Frederiksberg, Copenhagen, Denmark
| | - Ulrik Tarp
- Department of Rheumatology, Aarhus University Hospital, Aarhus N
| | - Karsten Heller Asmussen
- Department of Rheumatology, Copenhagen University Hospital at Bispebjerg and Frederiksberg, Copenhagen
| | - Birgitte Brock
- Department of Clinical Biochemistry, Aarhus University Hospital, Aarhus N
| | - Anna Dossing
- Musculoskeletal Statistics Unit, The Parker Institute, Copenhagen University Hospital at Bispebjerg and Frederiksberg, Copenhagen, Denmark
| | - Tanja Schjødt Jørgensen
- Musculoskeletal Statistics Unit, The Parker Institute, Copenhagen University Hospital at Bispebjerg and Frederiksberg, Copenhagen, Denmark
| | - Steffen Thirstrup
- Department of Drug Design and Pharmacology, University of Copenhagen, Copenhagen, Denmark
| | - Robin Christensen
- Musculoskeletal Statistics Unit, The Parker Institute, Copenhagen University Hospital at Bispebjerg and Frederiksberg, Copenhagen, Denmark
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21
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Malignancy Incidence, Management, and Prevention in Patients with Rheumatoid Arthritis. Rheumatol Ther 2017; 4:333-347. [PMID: 28508282 PMCID: PMC5696277 DOI: 10.1007/s40744-017-0064-4] [Citation(s) in RCA: 48] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/03/2017] [Indexed: 12/17/2022] Open
Abstract
Traditional and biologic disease-modifying antirheumatic drugs (DMARDs) are effective medications for the management of rheumatoid arthritis (RA). However, the effects of these medications on immune function raises concern that they may increase long-term cancer risk. The baseline risk for some cancers appears to differ in patients with RA compared to the general population, with the former having an increased risk of lymphoma, lung cancer and renal cancer, but a decreased risk of colorectal and breast cancer. Some DMARDs appear to increase the rate of specific cancer types (such as bladder cancer with cyclophosphamide), but few appear to increase the overall cancer risk. Studying the link between lymphoma and disease severity in RA is complicated because patients with persistently active disease are at increased risk for lymphoma, and disease severity correlates with more intense use of immunosuppressive medications. Overall, cancer risk in patients with RA is slightly above that of the general population, with the increased risk likely secondary to an increased risk of lymphomas in those with high disease activity. Risk mitigation includes management of RA disease activity as well as age- and sex-appropriate cancer screening.
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Singh JA, Hossain A, Mudano AS, Tanjong Ghogomu E, Suarez‐Almazor ME, Buchbinder R, Maxwell LJ, Tugwell P, Wells GA, Cochrane Musculoskeletal Group. Biologics or tofacitinib for people with rheumatoid arthritis naive to methotrexate: a systematic review and network meta-analysis. Cochrane Database Syst Rev 2017; 5:CD012657. [PMID: 28481462 PMCID: PMC6481641 DOI: 10.1002/14651858.cd012657] [Citation(s) in RCA: 34] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/15/2022]
Abstract
BACKGROUND Biologic disease-modifying anti-rheumatic drugs (biologics) are highly effective in treating rheumatoid arthritis (RA), however there are few head-to-head biologic comparison studies. We performed a systematic review, a standard meta-analysis and a network meta-analysis (NMA) to update the 2009 Cochrane Overview. This review is focused on the adults with RA who are naive to methotrexate (MTX) that is, receiving their first disease-modifying agent. OBJECTIVES To compare the benefits and harms of biologics (abatacept, adalimumab, anakinra, certolizumab pegol, etanercept, golimumab, infliximab, rituximab, tocilizumab) and small molecule tofacitinib versus comparator (methotrexate (MTX)/other DMARDs) in people with RA who are naive to methotrexate. METHODS In June 2015 we searched for randomized controlled trials (RCTs) in CENTRAL, MEDLINE and Embase; and trials registers. We used standard Cochrane methods. We calculated odds ratios (OR) and mean differences (MD) along with 95% confidence intervals (CI) for traditional meta-analyses and 95% credible intervals (CrI) using a Bayesian mixed treatment comparisons approach for network meta-analysis (NMA). We converted OR to risk ratios (RR) for ease of interpretation. We also present results in absolute measures as risk difference (RD) and number needed to treat for an additional beneficial or harmful outcome (NNTB/H). MAIN RESULTS Nineteen RCTs with 6485 participants met inclusion criteria (including five studies from the original 2009 review), and data were available for four TNF biologics (adalimumab (six studies; 1851 participants), etanercept (three studies; 678 participants), golimumab (one study; 637 participants) and infliximab (seven studies; 1363 participants)) and two non-TNF biologics (abatacept (one study; 509 participants) and rituximab (one study; 748 participants)).Less than 50% of the studies were judged to be at low risk of bias for allocation sequence generation, allocation concealment and blinding, 21% were at low risk for selective reporting, 53% had low risk of bias for attrition and 89% had low risk of bias for major baseline imbalance. Three trials used biologic monotherapy, that is, without MTX. There were no trials with placebo-only comparators and no trials of tofacitinib. Trial duration ranged from 6 to 24 months. Half of the trials contained participants with early RA (less than two years' duration) and the other half included participants with established RA (2 to 10 years). Biologic + MTX versus active comparator (MTX (17 trials (6344 participants)/MTX + methylprednisolone 2 trials (141 participants))In traditional meta-analyses, there was moderate-quality evidence downgraded for inconsistency that biologics with MTX were associated with statistically significant and clinically meaningful benefit versus comparator as demonstrated by ACR50 (American College of Rheumatology scale) and RA remission rates. For ACR50, biologics with MTX showed a risk ratio (RR) of 1.40 (95% CI 1.30 to 1.49), absolute difference of 16% (95% CI 13% to 20%) and NNTB = 7 (95% CI 6 to 8). For RA remission rates, biologics with MTX showed a RR of 1.62 (95% CI 1.33 to 1.98), absolute difference of 15% (95% CI 11% to 19%) and NNTB = 5 (95% CI 6 to 7). Biologics with MTX were also associated with a statistically significant, but not clinically meaningful, benefit in physical function (moderate-quality evidence downgraded for inconsistency), with an improvement of HAQ scores of -0.10 (95% CI -0.16 to -0.04 on a 0 to 3 scale), absolute difference -3.3% (95% CI -5.3% to -1.3%) and NNTB = 4 (95% CI 2 to 15).We did not observe evidence of differences between biologics with MTX compared to MTX for radiographic progression (low-quality evidence, downgraded for imprecision and inconsistency) or serious adverse events (moderate-quality evidence, downgraded for imprecision). Based on low-quality evidence, results were inconclusive for withdrawals due to adverse events (RR of 1.32, but 95% confidence interval included possibility of important harm, 0.89 to 1.97). Results for cancer were also inconclusive (Peto OR 0.71, 95% CI 0.38 to 1.33) and downgraded to low-quality evidence for serious imprecision. Biologic without MTX versus active comparator (MTX 3 trials (866 participants)There was no evidence of statistically significant or clinically important differences for ACR50, HAQ, remission, (moderate-quality evidence for these benefits, downgraded for imprecision), withdrawals due to adverse events,and serious adverse events (low-quality evidence for these harms, downgraded for serious imprecision). All studies were for TNF biologic monotherapy and none for non-TNF biologic monotherapy. Radiographic progression was not measured. AUTHORS' CONCLUSIONS In MTX-naive RA participants, there was moderate-quality evidence that, compared with MTX alone, biologics with MTX was associated with absolute and relative clinically meaningful benefits in three of the efficacy outcomes (ACR50, HAQ scores, and RA remission rates). A benefit regarding less radiographic progression with biologics with MTX was not evident (low-quality evidence). We found moderate- to low-quality evidence that biologic therapy with MTX was not associated with any higher risk of serious adverse events compared with MTX, but results were inconclusive for withdrawals due to adverse events and cancer to 24 months.TNF biologic monotherapy did not differ statistically significantly or clinically meaningfully from MTX for any of the outcomes (moderate-quality evidence), and no data were available for non-TNF biologic monotherapy.We conclude that biologic with MTX use in MTX-naive populations is beneficial and that there is little/inconclusive evidence of harms. More data are needed for tofacitinib, radiographic progression and harms in this patient population to fully assess comparative efficacy and safety.
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Affiliation(s)
- Jasvinder A Singh
- Birmingham VA Medical CenterDepartment of MedicineFaculty Office Tower 805B510 20th Street SouthBirminghamALUSA35294
| | - Alomgir Hossain
- University of Ottawa Heart InstituteCardiovascular Research Methods Centre40 Ruskin StreetRoom H‐2265OttawaONCanadaK1Y 4W7
| | - Amy S Mudano
- University of Alabama at BirminghamDepartment of Medicine ‐ RheumatologyBirminghamUSA
| | | | - Maria E Suarez‐Almazor
- The University of Texas, MD Anderson Cancer CenterDepartment of General Internal Medicine1515 Holcombe BlvdUnit 1465HoustonTexasUSA77030
| | - Rachelle Buchbinder
- Department of Epidemiology and Preventive Medicine, School of Public Health and Preventive Medicine, Monash UniversityMonash Department of Clinical Epidemiology, Cabrini HospitalSuite 41, Cabrini Medical Centre183 Wattletree RoadMalvernVictoriaAustralia3144
| | - Lara J Maxwell
- Ottawa Hospital Research Institute (OHRI), The Ottawa Hospital ‐ General CampusCentre for Practice‐Changing Research (CPCR)501 Smyth Road, Box 711OttawaONCanadaK1H 8L6
| | - Peter Tugwell
- Faculty of Medicine, University of OttawaDepartment of MedicineOttawaONCanadaK1H 8M5
| | - George A Wells
- University of OttawaDepartment of Epidemiology and Community MedicineRoom H128140 Ruskin StreetOttawaONCanadaK1Y 4W7
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Singh JA, Hossain A, Tanjong Ghogomu E, Mudano AS, Maxwell LJ, Buchbinder R, Lopez‐Olivo MA, Suarez‐Almazor ME, Tugwell P, Wells GA, Cochrane Musculoskeletal Group. Biologics or tofacitinib for people with rheumatoid arthritis unsuccessfully treated with biologics: a systematic review and network meta-analysis. Cochrane Database Syst Rev 2017; 3:CD012591. [PMID: 28282491 PMCID: PMC6472522 DOI: 10.1002/14651858.cd012591] [Citation(s) in RCA: 30] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/19/2022]
Abstract
BACKGROUND Biologic disease-modifying anti-rheumatic drugs (DMARDs: referred to as biologics) are effective in treating rheumatoid arthritis (RA), however there are few head-to-head comparison studies. Our systematic review, standard meta-analysis and network meta-analysis (NMA) updates the 2009 Cochrane overview, 'Biologics for rheumatoid arthritis (RA)' and adds new data. This review is focused on biologic or tofacitinib therapy in people with RA who had previously been treated unsuccessfully with biologics. OBJECTIVES To compare the benefits and harms of biologics (abatacept, adalimumab, anakinra, certolizumab pegol, etanercept, golimumab, infliximab, rituximab, tocilizumab) and small molecule tofacitinib versus comparator (placebo or methotrexate (MTX)/other DMARDs) in people with RA, previously unsuccessfully treated with biologics. METHODS On 22 June 2015 we searched for randomized controlled trials (RCTs) in CENTRAL, MEDLINE, and Embase; and trials registries (WHO trials register, Clinicaltrials.gov). We carried out article selection, data extraction, and risk of bias and GRADE assessments in duplicate. We calculated direct estimates with 95% confidence intervals (CI) using standard meta-analysis. We used a Bayesian mixed treatment comparison (MTC) approach for NMA estimates with 95% credible intervals (CrI). We converted odds ratios (OR) to risk ratios (RR) for ease of understanding. We have also presented results in absolute measures as risk difference (RD) and number needed to treat for an additional beneficial outcome (NNTB). Outcomes measured included four benefits (ACR50, function measured by Health Assessment Questionnaire (HAQ) score, remission defined as DAS < 1.6 or DAS28 < 2.6, slowing of radiographic progression) and three harms (withdrawals due to adverse events, serious adverse events, and cancer). MAIN RESULTS This update includes nine new RCTs for a total of 12 RCTs that included 3364 participants. The comparator was placebo only in three RCTs (548 participants), MTX or other traditional DMARD in six RCTs (2468 participants), and another biologic in three RCTs (348 participants). Data were available for four tumor necrosis factor (TNF)-biologics: (certolizumab pegol (1 study; 37 participants), etanercept (3 studies; 348 participants), golimumab (1 study; 461 participants), infliximab (1 study; 27 participants)), three non-TNF biologics (abatacept (3 studies; 632 participants), rituximab (2 studies; 1019 participants), and tocilizumab (2 studies; 589 participants)); there was only one study for tofacitinib (399 participants). The majority of the trials (10/12) lasted less than 12 months.We judged 33% of the studies at low risk of bias for allocation sequence generation, allocation concealment and blinding, 25% had low risk of bias for attrition, 92% were at unclear risk for selective reporting; and 92% had low risk of bias for major baseline imbalance. We downgraded the quality of the evidence for most outcomes to moderate or low due to study limitations, heterogeneity, or rarity of direct comparator trials. Biologic monotherapy versus placeboCompared to placebo, biologics were associated with clinically meaningful and statistically significant improvement in RA as demonstrated by higher ACR50 and RA remission rates. RR was 4.10 for ACR50 (95% CI 1.97 to 8.55; moderate-quality evidence); absolute benefit RD 14% (95% CI 6% to 21%); and NNTB = 8 (95% CI 4 to 23). RR for RA remission was 13.51 (95% CI 1.85 to 98.45, one study available; moderate-quality evidence); absolute benefit RD 9% (95% CI 5% to 13%); and NNTB = 11 (95% CI 3 to 136). Results for withdrawals due to adverse events and serious adverse events did not show any statistically significant or clinically meaningful differences. There were no studies available for analysis for function measured by HAQ, radiographic progression, or cancer outcomes. There were not enough data for any of the outcomes to look at subgroups. Biologic + MTX versus active comparator (MTX/other traditional DMARDs)Compared to MTX/other traditional DMARDs, biologic + MTX was associated with a clinically meaningful and statistically significant improvement in ACR50, function measured by HAQ, and RA remission rates in direct comparisons. RR for ACR50 was 4.07 (95% CI 2.76 to 5.99; high-quality evidence); absolute benefit RD 16% (10% to 21%); NNTB = 7 (95% CI 5 to 11). HAQ scores showed an improvement with a mean difference (MD) of 0.29 (95% CI 0.21 to 0.36; high-quality evidence); absolute benefit RD 9.7% improvement (95% CI 7% to 12%); and NNTB = 5 (95% CI 4 to 7). Remission rates showed an improved RR of 20.73 (95% CI 4.13 to 104.16; moderate-quality evidence); absolute benefit RD 10% (95% CI 8% to 13%); and NNTB = 17 (95% CI 4 to 96), among the biologic + MTX group compared to MTX/other DMARDs. There were no studies for radiographic progression. Results were not clinically meaningful or statistically significantly different for withdrawals due to adverse events or serious adverse events, and were inconclusive for cancer. Tofacitinib monotherapy versus placeboThere were no published data. Tofacitinib + MTX versus active comparator (MTX)In one study, compared to MTX, tofacitinib + MTX was associated with a clinically meaningful and statistically significant improvement in ACR50 (RR 3.24; 95% CI 1.78 to 5.89; absolute benefit RD 19% (95% CI 12% to 26%); NNTB = 6 (95% CI 3 to 14); moderate-quality evidence), and function measured by HAQ, MD 0.27 improvement (95% CI 0.14 to 0.39); absolute benefit RD 9% (95% CI 4.7% to 13%), NNTB = 5 (95% CI 4 to 10); high-quality evidence). RA remission rates were not statistically significantly different but the observed difference may be clinically meaningful (RR 15.44 (95% CI 0.93 to 256.1; high-quality evidence); absolute benefit RD 6% (95% CI 3% to 9%); NNTB could not be calculated. There were no studies for radiographic progression. There were no statistically significant or clinically meaningful differences for withdrawals due to adverse events and serious adverse events, and results were inconclusive for cancer. AUTHORS' CONCLUSIONS Biologic (with or without MTX) or tofacitinib (with MTX) use was associated with clinically meaningful and statistically significant benefits (ACR50, HAQ, remission) compared to placebo or an active comparator (MTX/other traditional DMARDs) among people with RA previously unsuccessfully treated with biologics.No studies examined radiographic progression. Results were not clinically meaningful or statistically significant for withdrawals due to adverse events and serious adverse events, and were inconclusive for cancer.
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Affiliation(s)
- Jasvinder A Singh
- Birmingham VA Medical CenterDepartment of MedicineFaculty Office Tower 805B510 20th Street SouthBirminghamALUSA35294
| | - Alomgir Hossain
- University of Ottawa Heart InstituteCardiovascular Research Methods Centre40 Ruskin StreetRoom H‐2265OttawaONCanadaK1Y 4W7
| | | | - Amy S Mudano
- University of Alabama at BirminghamDepartment of Medicine ‐ RheumatologyBirminghamUSA
| | - Lara J Maxwell
- Ottawa Hospital Research Institute (OHRI), The Ottawa Hospital ‐ General CampusCentre for Practice‐Changing Research (CPCR)501 Smyth Road, Box 711OttawaONCanadaK1H 8L6
| | - Rachelle Buchbinder
- Department of Epidemiology and Preventive Medicine, School of Public Health and Preventive Medicine, Monash UniversityMonash Department of Clinical Epidemiology, Cabrini HospitalSuite 41, Cabrini Medical Centre183 Wattletree RoadMalvernVictoriaAustralia3144
| | - Maria Angeles Lopez‐Olivo
- The University of Texas, M.D. Anderson Cancer CenterDepartment of General Internal Medicine1515 Holcombe BlvdUnit 1465HoustonTexasUSA77030
| | - Maria E Suarez‐Almazor
- The University of Texas, M.D. Anderson Cancer CenterDepartment of General Internal Medicine1515 Holcombe BlvdUnit 1465HoustonTexasUSA77030
| | - Peter Tugwell
- Faculty of Medicine, University of OttawaDepartment of MedicineOttawaONCanadaK1H 8M5
| | - George A Wells
- University of OttawaDepartment of Epidemiology and Community MedicineRoom H128140 Ruskin StreetOttawaONCanadaK1Y 4W7
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Yu D, Ye X, Che R, Wu Q, Qi J, Song L, Guo X, Zhang S, Wu H, Ren G, Li D. FGF21 exerts comparable pharmacological efficacy with Adalimumab in ameliorating collagen-induced rheumatoid arthritis by regulating systematic inflammatory response. Biomed Pharmacother 2017; 89:751-760. [PMID: 28273637 DOI: 10.1016/j.biopha.2017.02.059] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/10/2017] [Revised: 02/09/2017] [Indexed: 12/12/2022] Open
Abstract
Previous studies have reported that Fibroblast growth factor 21 (FGF21) can regulate inflammation and may play an important role in inflammatory and immune-mediated diseases, such as autoimmune diseases. Adalimumab is one of the clinically effective anti-rheumatoid arthritis (RA) drugs. The aim of this study was to compare the therapeutic efficacy of FGF21 and Adalimumab on collagen-induced arthritis (CIA) model mice. Mice with CIA were subcutaneously treated with FGF21 or Adalimumab at dose of 1mgkg-1d-1, respectively. Our results showed that FGF21 significantly alleviated the severity of arthritis by reducing cellular immune responses and exerted the similar anti-inflammatory effects with Adalimumab in decreasing the mRNA and protein expression levels of IL-2, IL-6 and IL-17. However, the expression levels of IL-1β, RANKL and IL-10 in the mice treated with FGF21 were decreased 2.2-fold, 2.5-fold and increased 4.3-fold compared with Adalimumab, respectively. However, the levels of TNF-α in the mice treated with Adalimumab were lower than those in the mice treated with FGF21. Western blotting results demonstrated that FGF21 displayed equivalent effects with Adalimumab by inhibiting NF-κB/IκBα signaling pathway. However, FGF21 could also regulate systematic inflammatory response and the mechanism maybe related to other signal pathway. In summary, FGF21 exerts comparable pharmacological efficacy with Adalimumab by regulating systematic inflammatory response, providing that FGF21 may be a promising therapeutic agent for RA patients.
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Affiliation(s)
- Dan Yu
- Biopharmaceutical Lab, College of Life Science, Northeast Agricultural University, Harbin 150030, China
| | - Xianlong Ye
- College of Life Science, Henan Normal University, Xinxiang 453007, China
| | - Ruixiang Che
- Biopharmaceutical Lab, College of Life Science, Northeast Agricultural University, Harbin 150030, China; Key Laboratory of Agricultural Biological Functional Gene, Northeast Agricultural University, Harbin 150030, China
| | - Qiang Wu
- Biopharmaceutical Lab, College of Life Science, Northeast Agricultural University, Harbin 150030, China; Key Laboratory of Agricultural Biological Functional Gene, Northeast Agricultural University, Harbin 150030, China
| | - Jianying Qi
- College of Life Science, Henan Normal University, Xinxiang 453007, China
| | - Liying Song
- Biopharmaceutical Lab, College of Life Science, Northeast Agricultural University, Harbin 150030, China; Key Laboratory of Agricultural Biological Functional Gene, Northeast Agricultural University, Harbin 150030, China
| | - Xiaochen Guo
- Biopharmaceutical Lab, College of Life Science, Northeast Agricultural University, Harbin 150030, China; Key Laboratory of Agricultural Biological Functional Gene, Northeast Agricultural University, Harbin 150030, China
| | - Shengqi Zhang
- Biopharmaceutical Lab, College of Life Science, Northeast Agricultural University, Harbin 150030, China; Key Laboratory of Agricultural Biological Functional Gene, Northeast Agricultural University, Harbin 150030, China
| | - Hongsong Wu
- Biopharmaceutical Lab, College of Life Science, Northeast Agricultural University, Harbin 150030, China; Key Laboratory of Agricultural Biological Functional Gene, Northeast Agricultural University, Harbin 150030, China
| | - Guiping Ren
- Biopharmaceutical Lab, College of Life Science, Northeast Agricultural University, Harbin 150030, China; Key Laboratory of Agricultural Biological Functional Gene, Northeast Agricultural University, Harbin 150030, China.
| | - Deshan Li
- Biopharmaceutical Lab, College of Life Science, Northeast Agricultural University, Harbin 150030, China; Key Laboratory of Agricultural Biological Functional Gene, Northeast Agricultural University, Harbin 150030, China.
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Picchianti Diamanti A, Laganà B, Cox MC, Pilozzi E, Amodeo R, Bove M, Markovic M, Di Rosa R, Salemi S, Sorgi ML, Rosado MM, D'Amelio R. TCD4 pos lymphocytosis in rheumatoid and psoriatic arthritis patients following TNFα blocking agents. J Transl Med 2017; 15:38. [PMID: 28222785 PMCID: PMC5322781 DOI: 10.1186/s12967-017-1135-6] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/22/2016] [Accepted: 02/03/2017] [Indexed: 12/13/2022] Open
Abstract
Background Lymphocyte expansion and true lymphocytosis are commonly observed in the everyday clinical practice. The meaning of such phenomenon is often poorly understood so that discrimination between benign and malignant lymphocytosis remains difficult to establish. This is mainly true when lymphocytosis rises in patients affected by immune-mediated chronic inflammatory diseases under immunosuppressive treatment, conditions potentially associated with lymphomagenesis. In this brief report the development of mild T CD4pos lymphocytosis in a group of patients with chronic arthritis under anti-TNF-α treatment is described. Methods Two hundred eight rheumatoid arthritis (RA) and psoriatic arthritis (PsA) patients have been evaluated longitudinally for at least 1-year before and 2-years after anti-TNF-α therapy introduction for the possible appearance of a lymphocyte expansion. In patients who developed lymphocyte expansion, T, B and NK cells were analysed. Results Twenty-five out of 208 (12%) subjects developed a mild T CD4pos lymphocytosis, during anti-TNF-α therapy, which reverted after its interruption. Higher lymphocyte count, more frequent use of steroids and shorter disease duration, before biological therapy start, have emerged as risk factors for lymphocytosis development. Conclusions This is the first longitudinal cohort study evaluating the onset of lymphocytosis in RA and PsA patients under anti-TNF-α treatment and its possible clinical relevance. A mild T CD4pos lymphocytosis has been observed in 12% of RA and PsA patients probably related to anti-TNF-α treatment as previously reported by anecdotal cases. Patients with higher baseline lymphocyte count, use of steroids and shorter disease duration before the introduction of biologic therapy, seem to be prone to develop this laboratory reversible abnormality.
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Affiliation(s)
- Andrea Picchianti Diamanti
- Department of Clinical and Molecular Medicine, S. Andrea University Hospital, School of Medicine and Psychology, "Sapienza" University, Via di Grottarossa 1039, 00189, Rome, Italy.
| | - Bruno Laganà
- Department of Clinical and Molecular Medicine, S. Andrea University Hospital, School of Medicine and Psychology, "Sapienza" University, Via di Grottarossa 1039, 00189, Rome, Italy
| | | | | | | | | | - Milica Markovic
- Department of Clinical and Molecular Medicine, S. Andrea University Hospital, School of Medicine and Psychology, "Sapienza" University, Via di Grottarossa 1039, 00189, Rome, Italy
| | - Roberta Di Rosa
- Department of Clinical and Molecular Medicine, S. Andrea University Hospital, School of Medicine and Psychology, "Sapienza" University, Via di Grottarossa 1039, 00189, Rome, Italy
| | - Simonetta Salemi
- Department of Clinical and Molecular Medicine, S. Andrea University Hospital, School of Medicine and Psychology, "Sapienza" University, Via di Grottarossa 1039, 00189, Rome, Italy
| | - Maria Laura Sorgi
- Department of Clinical and Molecular Medicine, S. Andrea University Hospital, School of Medicine and Psychology, "Sapienza" University, Via di Grottarossa 1039, 00189, Rome, Italy
| | | | - Raffaele D'Amelio
- Department of Clinical and Molecular Medicine, S. Andrea University Hospital, School of Medicine and Psychology, "Sapienza" University, Via di Grottarossa 1039, 00189, Rome, Italy
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Humphreys J, Hyrich K, Symmons D. What is the impact of biologic therapies on common co-morbidities in patients with rheumatoid arthritis? Arthritis Res Ther 2016; 18:282. [PMID: 27906042 PMCID: PMC5134078 DOI: 10.1186/s13075-016-1176-x] [Citation(s) in RCA: 18] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
Biologic therapies have revolutionised disease control in patients with rheumatoid arthritis (RA). Theoretically, they have the potential to influence co-morbid disease associated with RA through better control of systemic inflammation. Conversely, co-morbidity may occur as an adverse effect of the drugs. The latest evidence from observational data shows an increased risk of infection in the first 6 months of treatment with tumour necrosis factor inhibitor (TNFi) therapies and potentially other biologic therapies. Rates of infection after the first 6 months decrease and become comparable to patients with RA treated with conventional synthetic disease modifying anti-rheumatic drugs (csDMARDs). TNFi also appear to reduce the risk of cardiovascular disease in these patients, in particular ischaemic heart disease. TNFi treatment may be associated with a small increase in the risk of developing squamous cell carcinoma of the skin; in terms of other cancers, rates appears to be no different to those seen in patients treated with csDMARDs. There is a paucity of data on the impact of other biologic therapies and the effect of all biologic therapies on other common co-morbidities.
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Affiliation(s)
- Jenny Humphreys
- Arthritis Research UK Centre for Epidemiology, University of Manchester, Manchester, UK
| | - Kimme Hyrich
- Arthritis Research UK Centre for Epidemiology, University of Manchester, Manchester, UK.,NIHR Manchester Musculoskeletal Biomedical Research Unit, Central Manchester NHS Foundation Trust, Manchester Academic Health Science Centre, Manchester, UK
| | - Deborah Symmons
- Arthritis Research UK Centre for Epidemiology, University of Manchester, Manchester, UK. .,NIHR Manchester Musculoskeletal Biomedical Research Unit, Central Manchester NHS Foundation Trust, Manchester Academic Health Science Centre, Manchester, UK. .,Arthritis Research UK Centre for Epidemiology, Manchester Academic Health Science Centre, University of Manchester, Stopford Building, Oxford Road, Manchester, M13 9PT, UK.
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Singh JA, Hossain A, Tanjong Ghogomu E, Mudano AS, Tugwell P, Wells GA, Cochrane Musculoskeletal Group. Biologic or tofacitinib monotherapy for rheumatoid arthritis in people with traditional disease-modifying anti-rheumatic drug (DMARD) failure: a Cochrane Systematic Review and network meta-analysis (NMA). Cochrane Database Syst Rev 2016; 11:CD012437. [PMID: 27855242 PMCID: PMC6469573 DOI: 10.1002/14651858.cd012437] [Citation(s) in RCA: 20] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/18/2022]
Abstract
BACKGROUND We performed a systematic review, a standard meta-analysis and network meta-analysis (NMA), which updates the 2009 Cochrane Overview, 'Biologics for rheumatoid arthritis (RA)'. This review is focused on biologic monotherapy in people with RA in whom treatment with traditional disease-modifying anti-rheumatic drugs (DMARDs) including methotrexate (MTX) had failed (MTX/other DMARD-experienced). OBJECTIVES To assess the benefits and harms of biologic monotherapy (includes anti-tumor necrosis factor (TNF) (adalimumab, certolizumab pegol, etanercept, golimumab, infliximab) or non-TNF (abatacept, anakinra, rituximab, tocilizumab)) or tofacitinib monotherapy (oral small molecule) versus comparator (placebo or MTX/other DMARDs) in adults with RA who were MTX/other DMARD-experienced. METHODS We searched for randomized controlled trials (RCTs) in the Cochrane Central Register of Controlled Trials (CENTRAL; The Cochrane Library 2015, Issue 6, June), MEDLINE (via OVID 1946 to June 2015), and Embase (via OVID 1947 to June 2015). Article selection, data extraction and risk of bias and GRADE assessments were done in duplicate. We calculated direct estimates with 95% confidence intervals (CI) using standard meta-analysis. We used a Bayesian mixed treatment comparisons (MTC) approach for NMA estimates with 95% credible intervals (CrI). We converted odds ratios (OR) to risk ratios (RR) for ease of understanding. We calculated absolute measures as risk difference (RD) and number needed to treat for an additional beneficial outcome (NNTB). MAIN RESULTS This update includes 40 new RCTs for a total of 46 RCTs, of which 41 studies with 14,049 participants provided data. The comparator was placebo in 16 RCTs (4,532 patients), MTX or other DMARD in 13 RCTs (5,602 patients), and another biologic in 12 RCTs (3,915 patients). Monotherapy versus placeboBased on moderate-quality direct evidence, biologic monotherapy (without concurrent MTX/other DMARDs) was associated with a clinically meaningful and statistically significant improvement in American College of Rheumatology score (ACR50) and physical function, as measured by the Health Assessment Questionnaire (HAQ) versus placebo. RR was 4.68 for ACR50 (95% CI, 2.93 to 7.48); absolute benefit RD 23% (95% CI, 18% to 29%); and NNTB = 5 (95% CI, 3 to 8). The mean difference (MD) was -0.32 for HAQ (95% CI, -0.42 to -0.23; a negative sign represents greater HAQ improvement); absolute benefit of -10.7% (95% CI, -14% to -7.7%); and NNTB = 4 (95% CI, 3 to 5). Direct and NMA estimates for TNF biologic, non-TNF biologic or tofacitinib monotherapy showed similar results for ACR50 , downgraded to moderate-quality evidence. Direct and NMA estimates for TNF biologic, anakinra or tofacitinib monotherapy showed a similar results for HAQ versus placebo with mostly moderate quality evidence.Based on moderate-quality direct evidence, biologic monotherapy was associated with a clinically meaningful and statistically significant greater proportion of disease remission versus placebo with RR 1.12 (95% CI 1.03 to 1.22); absolute benefit 10% (95% CI, 3% to 17%; NNTB = 10 (95% CI, 8 to 21)).Based on low-quality direct evidence, results for biologic monotherapy for withdrawals due to adverse events and serious adverse events were inconclusive, with wide confidence intervals encompassing the null effect and evidence of an important increase. The direct estimate for TNF monotherapy for withdrawals due to adverse events showed a clinically meaningful and statistically significant result with RR 2.02 (95% CI, 1.08 to 3.78), absolute benefit RD 3% (95% CI,1% to 4%), based on moderate-quality evidence. The NMA estimates for TNF biologic, non-TNF biologic, anakinra, or tofacitinib monotherapy for withdrawals due to adverse events and for serious adverse events were all inconclusive and downgraded to low-quality evidence. Monotherapy versus active comparator (MTX/other DMARDs)Based on direct evidence of moderate quality, biologic monotherapy (without concurrent MTX/other DMARDs) was associated with a clinically meaningful and statistically significant improvement in ACR50 and HAQ scores versus MTX/other DMARDs with a RR of 1.54 (95% CI, 1.14 to 2.08); absolute benefit 13% (95% CI, 2% to 23%), NNTB = 7 (95% CI, 4 to 26) and a mean difference in HAQ of -0.27 (95% CI, -0.40 to -0.14); absolute benefit of -9% (95% CI, -13.3% to -4.7%), NNTB = 2 (95% CI, 2 to 4). Direct and NMA estimates for TNF monotherapy and NMA estimate for non-TNF biologic monotherapy for ACR50 showed similar results, based on moderate-quality evidence. Direct and NMA estimates for non-TNF biologic monotherapy, but not TNF monotherapy, showed similar HAQ improvements , based on mostly moderate-quality evidence.There were no statistically significant or clinically meaningful differences for direct estimates of biologic monotherapy versus active comparator for RA disease remission. NMA estimates showed a statistically significant and clinically meaningful difference versus active comparator for TNF monotherapy (absolute improvement 7% (95% CI, 2% to 14%)) and non-TNF monotherapy (absolute improvement 19% (95% CrI, 7% to 36%)), both downgraded to moderate quality.Based on moderate-quality direct evidence from a single study, radiographic progression (scale 0 to 448) was statistically significantly reduced in those on biologic monotherapy versus active comparator, MD -4.34 (95% CI, -7.56 to -1.12), though the absolute reduction was small, -0.97% (95% CI, -1.69% to -0.25%). We are not sure of the clinical relevance of this reduction.Direct and NMA evidence (downgraded to low quality), showed inconclusive results for withdrawals due to adverse events, serious adverse events and cancer, with wide confidence intervals encompassing the null effect and evidence of an important increase. AUTHORS' CONCLUSIONS Based mostly on RCTs of six to 12-month duration in people with RA who had previously experienced and failed treatment with MTX/other DMARDs, biologic monotherapy improved ACR50, function and RA remission rates compared to placebo or MTX/other DMARDs.Radiographic progression was reduced versus active comparator, although the clinical significance was unclear.Results were inconclusive for whether biologic monotherapy was associated with an increased risk of withdrawals due to adverse events, serious adverse events or cancer, versus placebo (no data on cancer) or MTX/other DMARDs.
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Affiliation(s)
- Jasvinder A Singh
- Birmingham VA Medical CenterDepartment of MedicineFaculty Office Tower 805B510 20th Street SouthBirminghamALUSA35294
| | - Alomgir Hossain
- University of Ottawa Heart InstituteCardiovascular Research Methods Centre40 Ruskin StreetRoom H‐2265OttawaONCanadaK1Y 4W7
| | | | - Amy S Mudano
- University of Alabama at BirminghamDepartment of Medicine ‐ RheumatologyBirminghamUSA
| | - Peter Tugwell
- Faculty of Medicine, University of OttawaDepartment of MedicineOttawaONCanadaK1H 8M5
| | - George A Wells
- University of OttawaDepartment of Epidemiology and Community MedicineRoom H128140 Ruskin StreetOttawaONCanadaK1Y 4W7
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Kievit W, van Herwaarden N, van den Hoogen FH, van Vollenhoven RF, Bijlsma JW, van den Bemt BJ, van der Maas A, den Broeder AA. Disease activity-guided dose optimisation of adalimumab and etanercept is a cost-effective strategy compared with non-tapering tight control rheumatoid arthritis care: analyses of the DRESS study. Ann Rheum Dis 2016; 75:1939-1944. [PMID: 26764260 DOI: 10.1136/annrheumdis-2015-208317] [Citation(s) in RCA: 37] [Impact Index Per Article: 4.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/27/2015] [Accepted: 12/20/2015] [Indexed: 12/27/2022]
Abstract
BACKGROUND A disease activity-guided dose optimisation strategy of adalimumab or etanercept (TNFi (tumour necrosis factor inhibitors)) has shown to be non-inferior in maintaining disease control in patients with rheumatoid arthritis (RA) compared with usual care. However, the cost-effectiveness of this strategy is still unknown. METHOD This is a preplanned cost-effectiveness analysis of the Dose REduction Strategy of Subcutaneous TNF inhibitors (DRESS) study, a randomised controlled, open-label, non-inferiority trial performed in two Dutch rheumatology outpatient clinics. Patients with low disease activity using TNF inhibitors were included. Total healthcare costs were measured and quality adjusted life years (QALY) were based on EQ5D utility scores. Decremental cost-effectiveness analyses were performed using bootstrap analyses; incremental net monetary benefit (iNMB) was used to express cost-effectiveness. RESULTS 180 patients were included, and 121 were allocated to the dose optimisation strategy and 59 to control. The dose optimisation strategy resulted in a mean cost saving of -€12 280 (95 percentile -€10 502; -€14 104) per patient per 18 months. There is an 84% chance that the dose optimisation strategy results in a QALY loss with a mean QALY loss of -0.02 (-0.07 to 0.02). The decremental cost-effectiveness ratio (DCER) was €390 493 (€5 085 184; dominant) of savings per QALY lost. The mean iNMB was €10 467 (€6553-€14 037). Sensitivity analyses using 30% and 50% lower prices for TNFi remained cost-effective. CONCLUSIONS Disease activity-guided dose optimisation of TNFi results in considerable cost savings while no relevant loss of quality of life was observed. When the minimal QALY loss is compensated with the upper limit of what society is willing to pay or accept in the Netherlands, the net savings are still high. TRIAL REGISTRATION NUMBER NTR3216; Post-results.
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Affiliation(s)
- Wietske Kievit
- Radboud Institute for Health Sciences, Radboud university medical center, Nijmegen, The Netherlands
| | | | - Frank Hj van den Hoogen
- Department of Rheumatology, Sint Maartenskliniek, Nijmegen, The Netherlands Department of Rheumatology, Radboud university medical center, Nijmegen, The Netherlands
| | | | - Johannes Wj Bijlsma
- Department of Rheumatology & Immunology, Utrecht University Medical Centre, Utrecht, The Netherlands
| | - Bart Jf van den Bemt
- Department of Pharmacy, Sint Maartenskliniek, Nijmegen, The Netherlands Department of Pharmacy, Radboud university medical center, Nijmegen, The Netherlands
| | - Aatke van der Maas
- Department of Rheumatology, Sint Maartenskliniek, Nijmegen, The Netherlands
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29
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Seror R, Mariette X. Malignancy and the Risks of Biologic Therapies: Current Status. Rheum Dis Clin North Am 2016; 43:43-64. [PMID: 27890173 DOI: 10.1016/j.rdc.2016.09.006] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
Cancer is a common event in patients with rheumatic diseases. In some cases, the disease, its risk factors, or its treatment could play a role in favoring cancer. This article analyzes the current knowledge on the risk of malignancy associated with biologics in rheumatic diseases and discusses some methodological issues to be considered when evaluating the association between disease, treatments, and the risk of cancer. This article focuses on the risk of overall malignancy but also of skin cancer, lymphoma, and recurrent cancer associated with all biologics marketed for the treatment of rheumatic diseases.
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Affiliation(s)
- Raphaèle Seror
- INSERM U1184, Assistance Publique-Hôpitaux de Paris (AP-HP), Center of Research on Immunology of Viral and Autoimmune Diseases (IMVA), Université Paris-Sud, Le Kremlin Bicêtre, France; Department of Rheumatology, Hôpitaux Universitaires Paris-Sud, Hôpital Bicêtre, 78 rue du Général Leclerc, Le Kremlin Bicêtre 94275, France.
| | - Xavier Mariette
- INSERM U1184, Assistance Publique-Hôpitaux de Paris (AP-HP), Center of Research on Immunology of Viral and Autoimmune Diseases (IMVA), Université Paris-Sud, Le Kremlin Bicêtre, France; Department of Rheumatology, Hôpitaux Universitaires Paris-Sud, Hôpital Bicêtre, 78 rue du Général Leclerc, Le Kremlin Bicêtre 94275, France
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30
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Do tumor necrosis factor inhibitors increase cancer risk in patients with chronic immune-mediated inflammatory disorders? Cytokine 2016; 101:78-88. [PMID: 27688201 DOI: 10.1016/j.cyto.2016.09.013] [Citation(s) in RCA: 35] [Impact Index Per Article: 3.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/17/2016] [Revised: 09/17/2016] [Accepted: 09/19/2016] [Indexed: 02/05/2023]
Abstract
Inhibition of tumor necrosis factor (TNF) activity has profoundly changed the management of several immune-mediated inflammatory diseases with great benefit for patients. The application of TNF inhibitors (TNFi), however, also brings a new concern, malignancy. We performed a systemic review to collect the studies reporting cancer incidences and risks in TNFi users regardless of indications. TNFi were most frequently used in treating patients with rheumatoid arthritis (RA) and inflammatory bowel diseases (IBD). In RA patients without prior cancer history, the incidences of malignancies ranged from the lowest rate 0 per 1000 person-years in etanercept users regarding lymphoma to the highest rate 35.62 per 1000 person-years in adalimumab users on non-melanoma skin cancer (NMSC), while in those patients with prior cancer history, the recurrent incidences of malignancies ranged from the lowest rate 5.05 per 1000 person-years regarding melanoma to the highest rate 63.20 per 1000 person-years on basal cell carcinoma (BCC) in TNFi users. In IBD patients, incidences ranged from 0 per 1000 person-years in TNFi users on lymphoma to 34.0 per 1000 person-years in infliximab users on overall cancer. However, these incidence rates of overall cancer, lymphoma and melanoma were not higher in comparison with those patients who were not treated with TNFi. Compared to general population, incidences of lymphoma were elevated in RA patients and rates of NMSC were higher in patients with psoriasis, RA and IBD. In conclusion, cancer incidences vary across different studies, indications, cancer types and studies with different individual TNFi. Treatment with TNFi is not associated with increased malignant risks of overall cancer, lymphoma or melanoma. Results of NMSC risk were inconsistent among studies. A latest prospective registry study demonstrated a small increased risk of squamous cell cancer in RA patients treated with TNFi (one additional case for every 1600years of treatment experience). Further prospective studies are needed to verify whether TNFi users have higher NMSC risk than non-TNFi users.
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31
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Silva-Fernández L, Lunt M, Kearsley-Fleet L, Watson KD, Dixon WG, Symmons DPM, Hyrich KL. The incidence of cancer in patients with rheumatoid arthritis and a prior malignancy who receive TNF inhibitors or rituximab: results from the British Society for Rheumatology Biologics Register-Rheumatoid Arthritis. Rheumatology (Oxford) 2016; 55:2033-2039. [PMID: 27550304 PMCID: PMC5088627 DOI: 10.1093/rheumatology/kew314] [Citation(s) in RCA: 54] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/28/2015] [Revised: 07/22/2016] [Indexed: 11/18/2022] Open
Abstract
Objective. To explore the influence of TNF inhibitor (TNFi) therapy and rituximab (RTX) upon the incidence of cancer in patients with RA and prior malignancy. Methods. The study population comprised RA subjects with a prior malignancy reported to the UK national cancer registers, recruited to the British Society for Rheumatology Biologics Register from 2001 to 2013. We compared rates of first incident malignancy in a TNFi cohort, RTX cohort and synthetic DMARDs (sDMARD) cohort. Results. We identified 425 patients with a prior malignancy from 18 000 RA patients in the study. Of these, 101 patients developed a new malignancy. The rates of incident malignancy were 33.3 events/1000 person-years (py) in the TNFi cohort, 24.7 events/1000 py in the RTX cohort and 53.8 events/1000 py in the sDMARD cohort. The age- and gender-adjusted hazard ratio was 0.55 (95% CI: 0.35, 0.86) for the TNFi cohort and 0.43 (95% CI: 0.10, 1.80) for the RTX cohort in comparison with the sDMARDs cohort. The 17.0% of patients in the sDMARDs cohort had a recurrence of the same cancer in comparison with the 12.8% and the 4.3% in the TNFi and RTX cohorts, respectively. Conclusions. Although numbers are still low, it seems that patients with RA and prior malignancy selected to receive either a TNFi or RTX in the UK do not have an increased risk of future incident malignancy.
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Affiliation(s)
- Lucía Silva-Fernández
- Arthritis Research UK Centre for Epidemiology, The University of Manchester, Manchester, UK.,Rheumatology Department, Complexo Hospitalario Universitario de Ferrol, Ferrol, Spain
| | - Mark Lunt
- Arthritis Research UK Centre for Epidemiology, The University of Manchester, Manchester, UK
| | - Lianne Kearsley-Fleet
- Arthritis Research UK Centre for Epidemiology, The University of Manchester, Manchester, UK
| | - Kath D Watson
- Arthritis Research UK Centre for Epidemiology, The University of Manchester, Manchester, UK
| | - William G Dixon
- Arthritis Research UK Centre for Epidemiology, The University of Manchester, Manchester, UK.,NIHR Manchester Musculoskeletal Biomedical Research Unit, Central Manchester University Hospitals NHS Foundation Trust and University of Manchester Partnership, Manchester, UK
| | - Deborah P M Symmons
- Arthritis Research UK Centre for Epidemiology, The University of Manchester, Manchester, UK
| | - Kimme L Hyrich
- Arthritis Research UK Centre for Epidemiology, The University of Manchester, Manchester, UK .,NIHR Manchester Musculoskeletal Biomedical Research Unit, Central Manchester University Hospitals NHS Foundation Trust and University of Manchester Partnership, Manchester, UK
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32
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Singh JA, Hossain A, Tanjong Ghogomu E, Kotb A, Christensen R, Mudano AS, Maxwell LJ, Shah NP, Tugwell P, Wells GA, Cochrane Musculoskeletal Group. Biologics or tofacitinib for rheumatoid arthritis in incomplete responders to methotrexate or other traditional disease-modifying anti-rheumatic drugs: a systematic review and network meta-analysis. Cochrane Database Syst Rev 2016; 2016:CD012183. [PMID: 27175934 PMCID: PMC7068903 DOI: 10.1002/14651858.cd012183] [Citation(s) in RCA: 41] [Impact Index Per Article: 4.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Abstract
BACKGROUND This is an update of the 2009 Cochrane overview and network meta-analysis (NMA) of biologics for rheumatoid arthritis (RA). OBJECTIVES To assess the benefits and harms of nine biologics (abatacept, adalimumab, anakinra, certolizumab pegol, etanercept, golimumab, infliximab, rituximab, tocilizumab) and small molecule tofacitinib, versus comparator (MTX, DMARD, placebo (PL), or a combination) in adults with rheumatoid arthritis who have failed to respond to methotrexate (MTX) or other disease-modifying anti-rheumatic drugs (DMARDs), i.e., MTX/DMARD incomplete responders (MTX/DMARD-IR). METHODS We searched for randomized controlled trials (RCTs) in the Cochrane Central Register of Controlled Trials (CENTRAL) (via The Cochrane Library Issue 6, June 2015), MEDLINE (via OVID 1946 to June 2015), and EMBASE (via OVID 1947 to June 2015). Data extraction, risk of bias and GRADE assessments were done in duplicate. We calculated both direct estimates using standard meta-analysis and used Bayesian mixed treatment comparisons approach for NMA estimates to calculate odds ratios (OR) and 95% credible intervals (CrI). We converted OR to risk ratios (RR) which are reported in the abstract for the ease of interpretation. MAIN RESULTS This update included 73 new RCTs for a total of 90 RCTs; 79 RCTs with 32,874 participants provided usable data. Few trials were at high risk of bias for blinding of assessors/participants (13% to 21%), selective reporting (4%) or major baseline imbalance (8%); a large number had unclear risk of bias for random sequence generation (68%) or allocation concealment (74%).Based on direct evidence of moderate quality (downgraded for inconsistency), biologic+MTX/DMARD was associated with a statistically significant and clinically meaningful improvement in ACR50 versus comparator (RR 2.71 (95% confidence interval (CI) 2.36 to 3.10); absolute benefit 24% more patients (95% CI 19% to 29%), number needed to treat for an additional beneficial outcome (NNTB) = 5 (4 to 6). NMA estimates for ACR50 in tumor necrosis factor (TNF) biologic+MTX/DMARD (RR 3.23 (95% credible interval (Crl) 2.75 to 3.79), non-TNF biologic+MTX/DMARD (RR 2.99; 95% Crl 2.36 to 3.74), and anakinra + MTX/DMARD (RR 2.37 (95% Crl 1.00 to 4.70) were similar to the direct estimates.Based on direct evidence of moderate quality (downgraded for inconsistency), biologic+MTX/DMARD was associated with a clinically and statistically important improvement in function measured by the Health Assessment Questionnaire (0 to 3 scale, higher = worse function) with a mean difference (MD) based on direct evidence of -0.25 (95% CI -0.28 to -0.22); absolute benefit of -8.3% (95% CI -9.3% to -7.3%), NNTB = 3 (95% CI 2 to 4). NMA estimates for TNF biologic+MTX/DMARD (absolute benefit, -10.3% (95% Crl -14% to -6.7%) and non-TNF biologic+MTX/DMARD (absolute benefit, -7.3% (95% Crl -13.6% to -0.67%) were similar to respective direct estimates.Based on direct evidence of moderate quality (downgraded for inconsistency), biologic+MTX/DMARD was associated with clinically and statistically significantly greater proportion of participants achieving remission in RA (defined by disease activity score DAS < 1.6 or DAS28 < 2.6) versus comparator (RR 2.81 (95% CI, 2.23 to 3.53); absolute benefit 18% more patients (95% CI 12% to 25%), NNTB = 6 (4 to 9)). NMA estimates for TNF biologic+MTX/DMARD (absolute improvement 17% (95% Crl 11% to 23%)) and non-TNF biologic+MTX/DMARD (absolute improvement 19% (95% Crl 12% to 28%) were similar to respective direct estimates.Based on direct evidence of moderate quality (downgraded for inconsistency), radiographic progression (scale 0 to 448) was statistically significantly reduced in those on biologics + MTX/DMARDs versus comparator, MD -2.61 (95% CI -4.08 to -1.14). The absolute reduction was small, -0.58% (95% CI -0.91% to -0.25%) and we are unsure of the clinical relevance of this reduction. NMA estimates of TNF biologic+MTX/DMARD (absolute reduction -0.67% (95% Crl -1.4% to -0.12%) and non-TNF biologic+MTX/DMARD (absolute reduction, -0.68% (95% Crl -2.36% to 0.92%)) were similar to respective direct estimates.Based on direct evidence of moderate quality (downgraded for imprecision), results for withdrawals due to adverse events were inconclusive, with wide confidence intervals encompassing the null effect and evidence of an important increase in withdrawals, RR 1.11 (95% CI 0.96 to 1.30). The NMA estimates of TNF biologic+MTX/DMARD (RR 1.24 (95% Crl 0.99 to 1.57)) and non-TNF biologic+MTX/DMARD (RR 1.20 (95% Crl 0.87 to 1.67)) were similarly inconclusive and downgraded to low for both imprecision and indirectness.Based on direct evidence of high quality, biologic+MTX/DMARD was associated with clinically significantly increased risk (statistically borderline significant) of serious adverse events on biologic+MTX/DMARD (Peto OR [can be interpreted as RR due to low event rate] 1.12 (95% CI 0.99 to 1.27); absolute risk 1% (0% to 2%), As well, the NMA estimate for TNF biologic+MTX/DMARD (Peto OR 1.20 (95% Crl 1.01 to 1.43)) showed moderate quality evidence of an increase in the risk of serious adverse events. The other two NMA estimates were downgraded to low quality due to imprecision and indirectness and had wide confidence intervals resulting in uncertainty around the estimates: non-TNF biologics + MTX/DMARD: 1.07 (95% Crl 0.89 to 1.29) and anakinra: RR 1.06 (95% Crl 0.65 to 1.75).Based on direct evidence of low quality (downgraded for serious imprecision), results were inconclusive for cancer (Peto OR 1.07 (95% CI 0.68 to 1.68) for all biologic+MTX/DMARD combinations. The NMA estimates of TNF biologic+MTX/DMARD (Peto OR 1.21 (95% Crl 0.63 to 2.38) and non-TNF biologic+MTX/DMARD (Peto OR 0.99 (95% Crl 0.58 to 1.78)) were similarly inconclusive and downgraded to low quality for both imprecision and indirectness.Main results text shows the results for tofacitinib and differences between medications. AUTHORS' CONCLUSIONS Based primarily on RCTs of 6 months' to 12 months' duration, there is moderate quality evidence that the use of biologic+MTX/DMARD in people with rheumatoid arthritis who have failed to respond to MTX or other DMARDs results in clinically important improvement in function and higher ACR50 and remission rates, and increased risk of serious adverse events than the comparator (MTX/DMARD/PL; high quality evidence). Radiographic progression is slowed but its clinical relevance is uncertain. Results were inconclusive for whether biologics + MTX/DMARDs are associated with an increased risk of cancer or withdrawals due to adverse events.
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Affiliation(s)
- Jasvinder A Singh
- Birmingham VA Medical CenterDepartment of MedicineFaculty Office Tower 805B510 20th Street SouthBirminghamALUSA35294
| | - Alomgir Hossain
- University of Ottawa Heart InstituteCardiovascular Research Methods Centre40 Ruskin StreetRoom H‐2265OttawaONCanadaK1Y 4W7
| | | | - Ahmed Kotb
- University of Ottawa Heart InstituteCardiovascular Research Methods Centre40 Ruskin StreetRoom H‐2265OttawaONCanadaK1Y 4W7
| | - Robin Christensen
- Copenhagen University Hospital, Bispebjerg og FrederiksbergMusculoskeletal Statistics Unit, The Parker InstituteNordre Fasanvej 57CopenhagenDenmarkDK‐2000
| | - Amy S Mudano
- University of Alabama at BirminghamDepartment of Medicine ‐ RheumatologyBirminghamUSA
| | - Lara J Maxwell
- Ottawa Hospital Research Institute (OHRI), The Ottawa Hospital ‐ General CampusCentre for Practice‐Changing Research (CPCR)501 Smyth Road, Box 711OttawaONCanadaK1H 8L6
| | - Nipam P Shah
- University of Alabama at BirminghamDepartment of Clinical Immunology and RheumatologyFaculty Office Tower, Suite 805, 510 20th Street SouthBirminghamALUSA35294
| | - Peter Tugwell
- Faculty of Medicine, University of OttawaDepartment of MedicineOttawaONCanadaK1H 8M5
| | - George A Wells
- University of OttawaDepartment of Epidemiology and Community MedicineRoom H128140 Ruskin StreetOttawaONCanadaK1Y 4W7
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Navarro-Compán V, Plasencia-Rodríguez C, de Miguel E, Balsa A, Martín-Mola E, Seoane-Mato D, Cañete JD. Anti-TNF discontinuation and tapering strategies in patients with axial spondyloarthritis: a systematic literature review. Rheumatology (Oxford) 2016; 55:1188-94. [PMID: 26998860 DOI: 10.1093/rheumatology/kew033] [Citation(s) in RCA: 52] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/17/2015] [Indexed: 12/17/2022] Open
Abstract
OBJECTIVE The aim was to evaluate whether anti-TNF discontinuation and tapering strategies are efficacious for maintaining remission or low disease activity (LDA) in patients with axial spondyloarthritis. METHODS A systematic literature review up to September 2014 was performed using Medline, EMBASE and Cochrane databases. Longitudinal studies evaluating the efficacy of discontinuation/tapering of anti-TNF therapy to maintain clinical response achieved after receiving a standard dose of the same drug were included. The results were grouped according to the type of strategy (discontinuation or tapering) evaluated. RESULTS Thirteen studies out of 763 retrieved citations were included. Overall, published data are scarce and the level of evidence of the studies is weak. Five studies provided evidence for assessing discontinuation strategy. The frequency of patients developing flare during the follow-up period ranged between 76 and 100%. The median (range) follow-up period was 52 (36-52) weeks and time to flare 16 (6-24) weeks. Additionally, eight studies evaluating tapering strategy were selected. The percentage of patients maintaining LDA or remission was reported in five studies and ranged between 53 and 100%. The remaining three studies reported the mean change in BASDAI and CRP after reducing the anti-TNF dose and did not observe any relevant increase in these parameters. CONCLUSION Published data indicate that a tapering strategy for anti-TNF therapy is successful in maintaining remission or LDA in most patients with axial spondyloarthritis. However, a discontinuation strategy is not recommended because it leads to flare in most cases. Further studies with an appropriate design covering the whole spectrum of the disease are required to confirm these results.
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Affiliation(s)
| | | | | | | | | | | | - Juan D Cañete
- Department of Rheumatology, Hospital Clinic and IDIBAPS, Barcelona, Spain
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Harigai M, Nanki T, Koike R, Tanaka M, Watanabe-Imai K, Komano Y, Sakai R, Yamazaki H, Koike T, Miyasaka N. Risk for malignancy in rheumatoid arthritis patients treated with biological disease-modifying antirheumatic drugs compared to the general population: A nationwide cohort study in Japan. Mod Rheumatol 2016; 26:642-50. [DOI: 10.3109/14397595.2016.1141740] [Citation(s) in RCA: 38] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/23/2023]
Affiliation(s)
- Masayoshi Harigai
- Department of Pharmacovigilance and
- Department of Rheumatology Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University, Tokyo, Japan,
| | - Toshihiro Nanki
- Department of Pharmacovigilance and
- Department of Rheumatology Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University, Tokyo, Japan,
| | - Ryuji Koike
- Department of Pharmacovigilance and
- Department of Rheumatology Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University, Tokyo, Japan,
- Clinical Research Center, Tokyo Medical and Dental University Hospital, Tokyo, Japan, and
| | - Michi Tanaka
- Department of Pharmacovigilance and
- Department of Rheumatology Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University, Tokyo, Japan,
| | - Kaori Watanabe-Imai
- Department of Pharmacovigilance and
- Department of Rheumatology Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University, Tokyo, Japan,
| | - Yukiko Komano
- Department of Pharmacovigilance and
- Department of Rheumatology Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University, Tokyo, Japan,
| | - Ryoko Sakai
- Department of Pharmacovigilance and
- Department of Rheumatology Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University, Tokyo, Japan,
| | - Hayato Yamazaki
- Department of Pharmacovigilance and
- Department of Rheumatology Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University, Tokyo, Japan,
| | - Takao Koike
- NTT Sapporo Medical Center, Sapporo, Hokkaido, Japan
| | - Nobuyuki Miyasaka
- Department of Rheumatology Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University, Tokyo, Japan,
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Gossen N, Jacob L, Kostev K. Second-line therapy with biological drugs in rheumatoid arthritis patients in German rheumatologist practices: a retrospective database analysis. Rheumatol Int 2016; 36:1113-8. [DOI: 10.1007/s00296-016-3448-9] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/27/2015] [Accepted: 02/18/2016] [Indexed: 12/19/2022]
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36
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Fantò M, Peragallo MS, Pietrosanti M, Di Rosa R, Picchianti Diamanti A, Salemi S, D'Amelio R. Risk of malignancy in patients with rheumatoid arthritis, psoriatic arthritis and ankylosing spondylitis under immunosuppressive therapy: a single-center experience. Intern Emerg Med 2016; 11:31-40. [PMID: 26099279 DOI: 10.1007/s11739-015-1270-0] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/13/2015] [Accepted: 06/01/2015] [Indexed: 12/19/2022]
Abstract
Systemic inflammatory rheumatic diseases are associated with an increased risk of malignancy, in particular of lymphoproliferative disorders. Chronic inflammation, due to the disease itself, generates a microenvironment able to promote cancer development, but it is still controversial whether immunosuppressive therapy may contribute to carcinogenesis. The aim of the study was to evaluate the risk of malignancy in 399 patients affected by rheumatoid arthritis (RA), psoriatic arthritis and ankylosing spondylitis, all treated with either tumor necrosis factor α-inhibitors plus disease-modifying anti-rheumatic drugs (DMARDs) or DMARDs alone. The risk of malignancy in this cohort of patients, observed in the period between 2005 and 2011 at S. Andrea Hospital-Sapienza University of Rome, was compared with that of the general Italian population, matched for age, sex, and area of residence. Fourteen (3.5%) malignancies, five of which were hematologic, have been observed. The overall cancer risk was not significantly increased in comparison to the general population, whereas the risk of hematologic malignancies appeared significantly higher in RA patients (SIR 4.94, 95% CI 1.35-12.64), particularly in female gender (SIR 6.9, 0.95% CI 1.88-17.66). No significant association between therapy and malignancy was demonstrated in RA patients.
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MESH Headings
- Adult
- Aged
- Aged, 80 and over
- Antirheumatic Agents/therapeutic use
- Arthritis, Psoriatic/complications
- Arthritis, Psoriatic/drug therapy
- Arthritis, Psoriatic/pathology
- Arthritis, Rheumatoid/complications
- Arthritis, Rheumatoid/drug therapy
- Arthritis, Rheumatoid/pathology
- Female
- Humans
- Immunosuppressive Agents/therapeutic use
- Incidence
- Male
- Middle Aged
- Neoplasms/epidemiology
- Neoplasms/pathology
- Retrospective Studies
- Spondylitis, Ankylosing/complications
- Spondylitis, Ankylosing/drug therapy
- Spondylitis, Ankylosing/pathology
- Tumor Necrosis Factor-alpha/antagonists & inhibitors
- Young Adult
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Affiliation(s)
- Marta Fantò
- Unit of Allergy and Immuno-Rheumatology, S. Andrea Hospital, Sapienza University of Rome, Rome, Italy.
| | | | - Mario Pietrosanti
- Unit of Allergy and Immuno-Rheumatology, S. Andrea Hospital, Sapienza University of Rome, Rome, Italy
| | - Roberta Di Rosa
- Unit of Allergy and Immuno-Rheumatology, S. Andrea Hospital, Sapienza University of Rome, Rome, Italy
| | | | - Simonetta Salemi
- Unit of Allergy and Immuno-Rheumatology, S. Andrea Hospital, Sapienza University of Rome, Rome, Italy
| | - Raffaele D'Amelio
- Unit of Allergy and Immuno-Rheumatology, S. Andrea Hospital, Sapienza University of Rome, Rome, Italy.
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Patel S, Patel T, Kerdel FA. The risk of malignancy or progression of existing malignancy in patients with psoriasis treated with biologics: case report and review of the literature. Int J Dermatol 2015; 55:487-93. [DOI: 10.1111/ijd.13129] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/16/2015] [Revised: 03/16/2015] [Accepted: 05/07/2015] [Indexed: 12/17/2022]
Affiliation(s)
- Shailee Patel
- Department of Dermatology & Cutaneous Surgery; University of Miami; Miami FL USA
| | - Tejas Patel
- Department of Dermatology & Cutaneous Surgery; University of Miami; Miami FL USA
| | - Francisco A. Kerdel
- Department of Dermatology & Cutaneous Surgery; University of Miami; Miami FL USA
- Florida Academic Dermatology Centers; Miami FL USA
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Lebrec H, Brennan FR, Haggerty H, Herzyk D, Kamperschroer C, Maier CC, Ponce R, Preston BD, Weinstock D, Mellon RD. HESI/FDA workshop on immunomodulators and cancer risk assessment: Building blocks for a weight-of-evidence approach. Regul Toxicol Pharmacol 2015; 75:72-80. [PMID: 26743742 DOI: 10.1016/j.yrtph.2015.12.018] [Citation(s) in RCA: 18] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/24/2015] [Accepted: 12/27/2015] [Indexed: 12/22/2022]
Abstract
Profound immunosuppression (e.g., AIDS, transplant therapy) is epidemiologically associated with an increased cancer risk, and often with oncogenic viruses. It is currently unclear how broadly this association translates to therapeutics that modulate immunity. A workshop co-sponsored by the FDA and HESI examined how perturbing the immune system may contribute to carcinogenesis, and highlighted priorities for improving non-clinical risk assessment of targeted immunomodulatory therapies. Conclusions from the workshop were as follows. 1) While profound altered immunity can promote tumorigenesis, not all components of the immune system are equally important in defense against or promotion of cancer and a similar cancer risk for all immunomodulatory molecules should not be assumed. 2) Rodent carcinogenicity studies have limitations and are generally not reliable predictors of cancer risk associated with immunosuppression. 3) Cancer risk needs to be evaluated based on mechanism-based weight-of-evidence, including data from immune function tests most relevant to tumor immunosurveillance or promotion. 4) Information from nonclinical experiments, clinical epidemiology and immunomodulatory therapeutics show that immunosurveillance involves a complex network of cells and mediators. To support a weight-of-evidence approach, an increased focus on understanding the quantitative relationship between changes in relevant immune function tests and cancer risk is needed.
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Affiliation(s)
- H Lebrec
- Amgen Inc, 1120 Veterans Blvd, South San Francisco, CA 94080, USA.
| | - F R Brennan
- UCB-Celltech, 208 Bath Road, Slough SL1 3WE, UK
| | - H Haggerty
- Bristol-Myers Squibb Company, 1 Squibb Dr., New Brunswick, NJ 08903, USA
| | - D Herzyk
- Merck & Co Inc, 770 Sumneytown Pike, PO Box 4, MS WP45-233, West Point, PA, USA
| | | | - C C Maier
- GlaxoSmithKline, 709 Swedeland Rd, King of Prussia, PA 19406, USA
| | - R Ponce
- Amgen Inc, 1120 Veterans Blvd, South San Francisco, CA 94080, USA
| | - B D Preston
- Amgen Inc, 1120 Veterans Blvd, South San Francisco, CA 94080, USA
| | - D Weinstock
- Janssen Research & Development, LLC, Welsh & McKean Roads, Spring House, PA 19477, USA
| | - R D Mellon
- Food and Drug Administration, 10903 New Hampshire Ave, Silver Spring, MD 20993, USA
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Chen Y, Sun J, Yang Y, Huang Y, Liu G. Malignancy risk of anti-tumor necrosis factor alpha blockers: an overview of systematic reviews and meta-analyses. Clin Rheumatol 2015; 35:1-18. [PMID: 26573205 DOI: 10.1007/s10067-015-3115-7] [Citation(s) in RCA: 36] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/30/2015] [Accepted: 11/08/2015] [Indexed: 02/05/2023]
Abstract
The objective of the study is to systematically review the malignancy risk of anti-tumor necrosis factor alpha (anti-TNFα) agents. Databases of PubMed Medline, OVID EMBASE, and Cochrane Library were searched to identify published systematic reviews and meta-analyses of randomized control trials, observational studies, and case series that evaluated malignancy risk of anti-TNFα blockers. Search time duration was restricted from January 1st, 2000 to July 16th, 2015. Overview Quality Assessment Questionnaires were used to assess the quality of included reviews. Two methodology trained reviewers separately and repeatedly screened searched studies according to study selection criteria, collected data, and assessed quality. Totally, 42 reviews proved eligible with only one Cochrane review. Anti-TNFα antagonists were extensively used to treat various diseases; nevertheless, malignancy risks were most commonly described in patients with rheumatoid arthritis (RA) and inflammatory bowel disease (IBD). In RA patients, no increased risks of breast cancer, lymphoma, and non-melanoma skin cancer were found, but if the use of anti-TNFα agents was associated with elevated risk of overall malignancy was still uncertainty. In IBD patients, the use of anti-TNFα inhibitors was not connected with enhanced risk of overall cancer. No increased cancer risk was found in other disease conditions. Twenty-nine reviews were rated as good quality, 12 as moderate, and one as poor. There are no sufficient evidences to draw the conclusion that anti-TNFα blockers have relationship with increased malignancy risk.
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Affiliation(s)
- Yuehong Chen
- Department of Rheumatology and Immunology, West China Hospital, Sichuan University, 37 Guoxue Xiang, Chengdu, Sichuan, 610041, China
| | - Jianhong Sun
- Department of Rheumatology and Immunology, West China Hospital, Sichuan University, 37 Guoxue Xiang, Chengdu, Sichuan, 610041, China
| | - Yuan Yang
- Department of Rheumatology and Immunology, West China Hospital, Sichuan University, 37 Guoxue Xiang, Chengdu, Sichuan, 610041, China
| | - Yupeng Huang
- Department of Rheumatology and Immunology, West China Hospital, Sichuan University, 37 Guoxue Xiang, Chengdu, Sichuan, 610041, China
| | - Gang Liu
- Department of Rheumatology and Immunology, West China Hospital, Sichuan University, 37 Guoxue Xiang, Chengdu, Sichuan, 610041, China.
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Simmonds M, Stewart G, Stewart L. A decade of individual participant data meta-analyses: A review of current practice. Contemp Clin Trials 2015; 45:76-83. [PMID: 26091948 DOI: 10.1016/j.cct.2015.06.012] [Citation(s) in RCA: 74] [Impact Index Per Article: 7.4] [Reference Citation Analysis] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/02/2015] [Revised: 06/05/2015] [Accepted: 06/15/2015] [Indexed: 02/07/2023]
Affiliation(s)
- Mark Simmonds
- Centre for Reviews and Dissemination, University of York, UK.
| | - Gavin Stewart
- School of Agriculture, Food and Rural Development, Newcastle University, UK
| | - Lesley Stewart
- Centre for Reviews and Dissemination, University of York, UK
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Lau CS, Chia F, Harrison A, Hsieh TY, Jain R, Jung SM, Kishimoto M, Kumar A, Leong KP, Li Z, Lichauco JJ, Louthrenoo W, Luo SF, Nash P, Ng CT, Park SH, Suryana BPP, Suwannalai P, Wijaya LK, Yamamoto K, Yang Y, Yeap SS. APLAR rheumatoid arthritis treatment recommendations. Int J Rheum Dis 2015; 18:685-713. [DOI: 10.1111/1756-185x.12754] [Citation(s) in RCA: 99] [Impact Index Per Article: 9.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/01/2023]
Affiliation(s)
- Chak Sing Lau
- Division of Rheumatology and Clinical Immunology; Queen Mary Hospital; University of Hong Kong; Hong Kong
| | - Faith Chia
- Department of Rheumatology, Allergy and Immunology; Tan Tock Seng Hospital; Singapore City Singapore
| | - Andrew Harrison
- Department of Medicine; University of Otago Wellington; Wellington South New Zealand
| | - Tsu-Yi Hsieh
- Section of Allergy, Immunology and Rheumatology, and Section of Clinical Skills Training; Taichung Veterans General Hospital; Taichung Taiwan
| | | | - Seung Min Jung
- Division of Rheumatology; Department of Internal Medicine; The Catholic University of Korea; St. Mary's Hospital; Seoul South Korea
| | | | - Ashok Kumar
- Department of Rheumatology; Fortis Flt. Lt Rajan Dhall Hospital; New Delhi India
| | - Khai Pang Leong
- Department of Rheumatology, Allergy and Immunology; Tan Tock Seng Hospital; Singapore City Singapore
| | - Zhanguo Li
- Department of Rheumatology; Peking University People's Hospital; Beijing China
| | | | - Worawit Louthrenoo
- Division of Rheumatology; Department of Internal Medicine; Faculty of Medicine; Chiang Mai University; Chiang Mai Thailand
| | - Shue-Fen Luo
- Department of Rheumatology, Allergy and Immunology; Chang Gung Memorial Hospital and Chang Gung University; Tao-Yuan Taiwan
| | - Peter Nash
- Department of Medicine; University of Queensland; Brisbane Queensland Australia
| | - Chin Teck Ng
- Department of Rheumatology and Immunology; Singapore General Hospital; Singapore City Singapore
| | - Sung-Hwan Park
- Division of Rheumatology; Department of Internal Medicine; The Catholic University of Korea; St. Mary's Hospital; Seoul South Korea
| | - Bagus Putu Putra Suryana
- Rheumatology Division; Department of Internal Medicine; Brawijaya University; Saiful Anwar General Hospital; Malang Indonesia
| | - Parawee Suwannalai
- Allergy, Immunology and Rheumatology Division; Internal Medicine Department; Faculty of Medicine; Ramathibodi Hospital; Mahidol University; Bangkok Thailand
| | - Linda Kurniaty Wijaya
- Division of Rheumatology; Department of Internal Medicine; University of Indonesia; Jakarta Indonesia
| | - Kazuhiko Yamamoto
- Department of Allergy and Rheumatology; Graduate School of Medicine; The University of Tokyo; Tokyo Japan
| | - Yue Yang
- Department of Rheumatology; Peking University People's Hospital; Beijing China
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Cordero-Coma M, Sobrin L. Anti-tumor necrosis factor-α therapy in uveitis. Surv Ophthalmol 2015; 60:575-89. [PMID: 26164735 DOI: 10.1016/j.survophthal.2015.06.004] [Citation(s) in RCA: 89] [Impact Index Per Article: 8.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/22/2014] [Revised: 06/14/2015] [Accepted: 06/15/2015] [Indexed: 12/14/2022]
Abstract
Since the first reported use in 2001 of an anti-tumor necrosis factor-alpha (TNF-α) agent, infliximab, for the treatment of uveitis, several new anti-TNF-α agents have emerged for the treatment of refractory noninfectious uveitides, although their use remains off-label in the US. These agents have demonstrated remarkable clinical antiinflammatory efficacy and a potential immunoregulatory role in selected uveitis patients, but it is currently unclear whether they can modify the natural history of disease. We review the rationale and clinical indications for this therapy, the differences between agents, how to manage dosing and intervals, and how to screen for and identify potential side effects. We also present a summary of the science behind the use of anti-TNF-α agents in ocular inflammation and the evidence for their efficacy.
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Affiliation(s)
- Miguel Cordero-Coma
- Head of the Uveitis Unit, Department of Ophthalmology, University Hospital of León, León, Spain; Instituto Biomedicina (IBIOMED), University of León, León, Spain.
| | - Lucia Sobrin
- Uveitis and Retina Services, Department of Ophthalmology, Massachusetts Eye and Ear Infirmary, Boston, Massachusetts, USA; Associate Professor of Ophthalmology, Harvard Medical School, Boston, Massachusetts, USA
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Abstract
With its approval more than 15 years ago, subcutaneous etanercept (Enbrel(®)) was the first biological disease-modifying antirheumatic drug (bDMARD) and the first tumour necrosis factor inhibitor to be approved for use in rheumatic diseases. Etanercept remains an important cost-effective treatment option in adult patients with rheumatoid arthritis, ankylosing spondylitis, psoriatic arthritis or plaque psoriasis, and in paediatric patients with juvenile idiopathic arthritis or plaque psoriasis. In all of these populations, etanercept (with or without methotrexate) effectively reduced signs and symptoms, disease activity and disability, and improved health-related quality of life, with these benefits sustained during long-term treatment. The safety profile of etanercept during short- and long-term treatment was consistent with the approved product labelling, with adverse events being of a predictable and manageable nature. The introduction of etanercept and other bDMARDs as therapeutic options for patients with autoimmune rheumatic diseases and spondyloarthropathies revolutionized disease management and these agents continue to have a central role in treatment strategies. This article reviews the extensive clinical experience with etanercept in these patient populations.
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Affiliation(s)
- Lesley J Scott
- Springer, Private Bag 65901, Mairangi Bay, 0754, Auckland, New Zealand,
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van Herwaarden N, van der Maas A, Minten MJM, van den Hoogen FHJ, Kievit W, van Vollenhoven RF, Bijlsma JWJ, van den Bemt BJF, den Broeder AA. Disease activity guided dose reduction and withdrawal of adalimumab or etanercept compared with usual care in rheumatoid arthritis: open label, randomised controlled, non-inferiority trial. BMJ 2015; 350:h1389. [PMID: 25858265 PMCID: PMC4391970 DOI: 10.1136/bmj.h1389] [Citation(s) in RCA: 134] [Impact Index Per Article: 13.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/04/2022]
Abstract
OBJECTIVE To evaluate whether a disease activity guided strategy of dose reduction of two tumour necrosis factor (TNF) inhibitors, adalimumab or etanercept, is non-inferior in maintaining disease control in patients with rheumatoid arthritis compared with usual care. DESIGN Randomised controlled, open label, non-inferiority strategy trial. SETTING Two rheumatology outpatient clinics in the Netherlands, from December 2011 to May 2014. PARTICIPANTS 180 patients with rheumatoid arthritis and low disease activity using adalimumab or etanercept; 121 allocated to the dose reduction strategy, 59 to usual care. INTERVENTIONS Disease activity guided dose reduction (advice to stepwise increase the injection interval every three months, until flare of disease activity or discontinuation) or usual care (no dose reduction advice). Flare was defined as increase in DAS28-CRP (a composite score measuring disease activity) greater than 1.2, or increase greater than 0.6 and current score of at least 3.2. In the case of flare, TNF inhibitor use was restarted or escalated. MAIN OUTCOME MEASURES Difference in proportions of patients with major flare (DAS28-CRP based flare longer than three months) between the two groups at 18 months, compared against a non-inferiority margin of 20%. Secondary outcomes included TNF inhibitor use at study end, functioning, quality of life, radiographic progression, and adverse events. RESULTS Dose reduction of adalimumab or etanercept was non-inferior to usual care (proportion of patients with major flare at 18 months, 12% v 10%; difference 2%, 95% confidence interval -12% to 12%). In the dose reduction group, TNF inhibitor use could successfully be stopped in 20% (95% confidence interval 13% to 28%), the injection interval successfully increased in 43% (34% to 53%), but no dose reduction was possible in 37% (28% to 46%). Functional status, quality of life, relevant radiographic progression, and adverse events did not differ between the groups, although short lived flares (73% v 27%) and minimal radiographic progression (32% v 15%) were more frequent in dose reduction than usual care. CONCLUSIONS A disease activity guided, dose reduction strategy of adalimumab or etanercept to treat rheumatoid arthritis is non-inferior to usual care with regard to major flaring, while resulting in the successful dose reduction or stopping in two thirds of patients.Trial registration Dutch trial register (www.trialregister.nl), NTR 3216.
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Affiliation(s)
- Noortje van Herwaarden
- Department of Rheumatology, Sint Maartenskliniek, Nijmegen, PO Box 9011, 6500 GM, Netherlands
| | - Aatke van der Maas
- Department of Rheumatology, Sint Maartenskliniek, Nijmegen, PO Box 9011, 6500 GM, Netherlands
| | - Michiel J M Minten
- Department of Rheumatology, Sint Maartenskliniek, Nijmegen, PO Box 9011, 6500 GM, Netherlands
| | - Frank H J van den Hoogen
- Department of Rheumatology, Sint Maartenskliniek, Nijmegen, PO Box 9011, 6500 GM, Netherlands Department of Rheumatology, Radboud University Medical Centre (UMC), Nijmegen
| | | | | | | | - Bart J F van den Bemt
- Department of Pharmacy, Sint Maartenskliniek Department of Pharmacy, Radboud UMC, Nijmegen
| | - Alfons A den Broeder
- Department of Rheumatology, Sint Maartenskliniek, Nijmegen, PO Box 9011, 6500 GM, Netherlands
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Nardo LG, El-Toukhy T, Stewart J, Balen AH, Potdar N. British Fertility Society Policy and Practice Committee: Adjuvants in IVF: Evidence for good clinical practice. HUM FERTIL 2014; 18:2-15. [DOI: 10.3109/14647273.2015.985454] [Citation(s) in RCA: 36] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/13/2022]
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Michaud TL, Rho YH, Shamliyan T, Kuntz KM, Choi HK. The comparative safety of tumor necrosis factor inhibitors in rheumatoid arthritis: a meta-analysis update of 44 trials. Am J Med 2014; 127:1208-32. [PMID: 24950486 DOI: 10.1016/j.amjmed.2014.06.012] [Citation(s) in RCA: 68] [Impact Index Per Article: 6.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/18/2013] [Revised: 05/22/2014] [Accepted: 06/09/2014] [Indexed: 02/07/2023]
Abstract
OBJECTIVE The study objective was to evaluate and update the safety data from randomized controlled trials of tumor necrosis factor inhibitors in patients treated for rheumatoid arthritis. METHODS A systematic literature search was conducted from 1990 to May 2013. All studies included were randomized, double-blind, controlled trials of patients with rheumatoid arthritis that evaluated adalimumab, certolizumab pegol, etanercept, golimumab, or infliximab treatment. The serious adverse events and discontinuation rates were abstracted, and risk estimates were calculated by Peto odds ratios (ORs). RESULTS Forty-four randomized controlled trials involving 11,700 subjects receiving tumor necrosis factor inhibitors and 5901 subjects receiving placebo or traditional disease-modifying antirheumatic drugs were included. Tumor necrosis factor inhibitor treatment as a group was associated with a higher risk of serious infection (OR, 1.42; 95% confidence interval [CI], 1.13-1.78) and treatment discontinuation due to adverse events (OR, 1.23; 95% CI, 1.06-1.43) compared with placebo and traditional disease-modifying antirheumatic drug treatments. Specifically, patients taking adalimumab, certolizumab pegol, and infliximab had an increased risk of serious infection (OR, 1.69, 1.98, and 1.63, respectively) and showed an increased risk of discontinuation due to adverse events (OR, 1.38, 1.67, and 2.04, respectively). In contrast, patients taking etanercept had a decreased risk of discontinuation due to adverse events (OR, 0.72; 95% CI, 0.55-0.93). Although ORs for malignancy varied across the different tumor necrosis factor inhibitors, none reached statistical significance. CONCLUSIONS These meta-analysis updates of the comparative safety of tumor necrosis factor inhibitors suggest a higher risk of serious infection associated with adalimumab, certolizumab pegol, and infliximab, which seems to contribute to higher rates of discontinuation. In contrast, etanercept use showed a lower rate of discontinuation. These data may help guide clinical comparative decision making in the management of rheumatoid arthritis.
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Affiliation(s)
- Tzeyu L Michaud
- Division of Health Policy and Management, School of Public Health, University of Minnesota, Minneapolis
| | - Young Hee Rho
- Section of Rheumatology and the Clinical Epidemiology Unit, Boston University School of Medicine, Boston, Mass
| | - Tatyana Shamliyan
- Evidence-Based Medicine Quality Assurance Elsevier, Clinical Solutions, Philadelphia, PA
| | - Karen M Kuntz
- Division of Health Policy and Management, School of Public Health, University of Minnesota, Minneapolis
| | - Hyon K Choi
- Section of Rheumatology and the Clinical Epidemiology Unit, Boston University School of Medicine, Boston, Mass.
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Yan SY, He LY, Liu BY. Individual patient data meta-analysis is needed in Chinese medical research. Chin J Integr Med 2014; 20:805-11. [PMID: 25411018 DOI: 10.1007/s11655-014-1852-0] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/18/2013] [Indexed: 11/29/2022]
Abstract
Publication biases and collection limitations are the main disadvantages of a traditional meta-analysis based on aggregate patient data (APD) from published articles. Individual patient data (IPD) meta-analysis, as the gold standard of systematic review, is a possible alternative in this context. However, the publications relative to IPD meta-analyses are still rare compared with the traditional ones, especially in the research oriented to Chinese medicine (CM). In this article, the strengths and detailed functioning of IPD meta-analysis are described. Furthermore, the need for IPD meta-analysis to assess the treatments based on CM was also discussed. Compared with the traditional APD meta-analysis, the IPD meta-analysis might give a more accurate and unbiased assessment and is worth to be recommended to CM researchers.
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Affiliation(s)
- Shi-Yan Yan
- Institute of Basic Research in Clinical Medicine, China Academy of Chinese Medical Sciences, Beijing, 100700, China
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48
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Wu CY, Chen DY, Shen JL, Ho HJ, Chen CC, Kuo KN, Liu HN, Chang YT, Chen YJ. The risk of cancer in patients with rheumatoid arthritis taking tumor necrosis factor antagonists: a nationwide cohort study. Arthritis Res Ther 2014; 16:449. [PMID: 25267341 PMCID: PMC4201718 DOI: 10.1186/s13075-014-0449-5] [Citation(s) in RCA: 42] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/14/2014] [Accepted: 09/02/2014] [Indexed: 02/08/2023] Open
Abstract
Introduction The association between cancer and use of biologic therapy among rheumatoid arthritis (RA) patients remains controversial. We aimed to compare the relative risk of cancer development between RA patients taking tumor necrosis factor α (TNFα) antagonists and those taking nonbiologic disease-modifying anti-rheumatic drugs (nbDMARDs). Methods We conducted a nationwide cohort study between 1997 and 2011 using the Taiwan National Health Insurance Research Database. The risk of newly diagnosed cancer was compared between patients starting TNF-α antagonists (biologics cohort) and matched subjects taking nbDMARDs only (nbDMARDs cohort). Cumulative incidences and hazard ratios (HR) were calculated after adjusting for competing mortality. Standardized incidence ratio (SIR) was calculated for cancer risk. Multivariate analyses were performed using Cox proportional hazards model. Results We compared 4426 new users of TNF-α antagonists and 17704 users of nbDMARDs with similar baseline covariate characteristics. The incidence rates of cancer among biologics and nbDMARDs cohorts were 5.35 (95% confidence interval (CI) 4.23 to 6.46) and 7.41 (95% CI 6.75 to 8.07) per 1000 person-years, respectively. On modified Cox proportional hazards analysis, the risk of cancer was significantly reduced in subjects in biologics cohort (adjusted HR 0.63, 95% CI 0.49 to 0.80, P < .001), after adjusting for age, gender, disease duration, major co-morbidities, and prior use of DMARDs and corticosteroids. However, there was an increased risk for hematologic cancers in biologics cohort, yet without statistical significance. The effect of biologics was consistent across all multivariate stratified analyses and the association between biologics use and cancer risk was independent of dosage of concomitant nbDMARDs. Conclusion These findings suggested that RA patients taking TNF-α antagonist are associated with a lower risk of cancer, but not for hematologic cancers, than RA patients taking nbDMARDs alone. Electronic supplementary material The online version of this article (doi:10.1186/s13075-014-0449-5) contains supplementary material, which is available to authorized users.
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Ben Musa R, Usha L, Hibbeln J, Mutlu EA. TNF inhibitors to treat ulcerative colitis in a metastatic breast cancer patient: a case report and literature review. World J Gastroenterol 2014; 20:5912-5917. [PMID: 24914353 PMCID: PMC4024802 DOI: 10.3748/wjg.v20.i19.5912] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/01/2013] [Revised: 12/02/2013] [Accepted: 01/03/2014] [Indexed: 02/07/2023] Open
Abstract
Adalimumab (ADA) is a tumor necrosis factor (TNF) inhibitor, used for the treatment of inflammatory bowel disease. Previous studies have reported an increased risk of cancer following exposure to TNF inhibitors, but little has been reported for patients with cancer receiving TNF-inhibitor treatment. We present a female patient with metastatic breast cancer and ulcerative colitis (UC) who was treated with ADA. A 54-year-old African American female with a past history of left-sided breast cancer (BC) diagnosed at age 30 was initially treated with left-breast lumpectomy, axillary dissection, followed by chemotherapy and radiation therapy. Years after initial diagnosis, she developed recurrent, bilateral BC and had bilateral mastectomy. Subsequent restaging computed tomography (CT) scan demonstrated distant metastases to the bone and lymph nodes. Three years into her treatment of metastatic breast cancer, she was diagnosed with UC by colonoscopy. Her UC was not controlled for 5 mo with 5-aminosalicylates. Subcutaneous ADA was started and resulted in dramatic improvement of UC. Four months after starting ADA, along with ongoing chemotherapy, restaging CT scan showed resolution of the previously seen metastatic lymph nodes. Bone scan and follow-up positron emission tomography/CT scans performed every 6 mo indicated the stability of healed metastatic bone lesions for the past 3 years on ADA. While TNF-α inhibitors could theoretically promote further metastases in patients with prior cancer, this is the first report of a patient with metastatic breast cancer in whom the cancer has remained stable for 3 years after ADA initiation for UC.
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Liu Y, Fan W, Chen H, Yu MX. Risk of Breast Cancer and Total Malignancies in Rheumatoid Arthritis Patients Undergoing TNF-α Antagonist Therapy: a Meta-analysis of Randomized Control Trials. Asian Pac J Cancer Prev 2014; 15:3403-10. [DOI: 10.7314/apjcp.2014.15.8.3403] [Citation(s) in RCA: 22] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/10/2022] Open
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