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Westermann R, Cordtz R, Duch K, Mellemkjaer L, Hetland ML, Rasmussen LA, Dreyer L. Cancer recurrence risk with bDMARD treatment in patients with rheumatoid arthritis and a history of cancer: a nationwide Danish register-based cohort study. RMD Open 2025; 11:e005247. [PMID: 40254339 DOI: 10.1136/rmdopen-2024-005247] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/13/2024] [Accepted: 04/03/2025] [Indexed: 04/22/2025] Open
Abstract
OBJECTIVE To investigate the risk of cancer recurrence in patients with rheumatoid arthritis (RA) and a prior solid cancer in remission treated with biological disease-modifying antirheumatic drugs (bDMARDs) compared with those who received only conventional synthetic DMARDs (csDMARDs). METHODS Nationwide registry-based cohort study of Danish patients with RA and one of the six algorithm-specific solid cancers in remission (breast, colorectal, melanoma, bladder, endometrial and lung) who initiated treatment with a bDMARD or a csDMARD. Three bDMARD exposure groups were defined according to the type(s) of bDMARD initiated: (1) any bDMARD, (2) tumour necrosis factor inhibitors (TNFi) and (3) rituximab. Patients were identified in Danish Rheumatology Quality Register and followed for cancer recurrence from 2002 to 2021 using validated cancer-specific recurrence algorithms. Inverse probability of treatment weighting and weighted cause-specific Cox models were used to calculate HRs for cancer recurrence in each bDMARD exposure group compared with a csDMARD-treated group. RESULTS Among 720 unique patients with RA and an algorithm-specific solid cancer in remission, 170 any bDMARD, 81 TNFi, 99 rituximab and 651 csDMARD initiators were identified. No statistically significant increased HRs for cancer recurrence were found with any type of bDMARD 0.92 (95% CI 0.38 to 1.73), TNFi 1.10 (95% CI 0.21 to 3.16) or rituximab 0.94 (95% CI 0.32 to 2.11). Also, no increased HRs were shown for breast cancer recurrence specifically. CONCLUSION No indications of increased cancer recurrence risk were found for bDMARDs as used in clinical practice in patients with RA and a solid cancer in remission when compared with csDMARD treatment.
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Affiliation(s)
- Rasmus Westermann
- Center of Rheumatic Research Aalborg (CERRA), Department of Rheumatology, Aalborg University Hospital, Aalborg, Denmark
- Clinical Cancer Research Center, Aalborg University Hospital, Aalborg, Denmark
| | - René Cordtz
- Center of Rheumatic Research Aalborg (CERRA), Department of Rheumatology, Aalborg University Hospital, Aalborg, Denmark
| | - Kirsten Duch
- Center of Rheumatic Research Aalborg (CERRA), Department of Rheumatology, Aalborg University Hospital, Aalborg, Denmark
- Research Data and Biostatistics, Aalborg University Hospital, Aalborg, Denmark
| | - Lene Mellemkjaer
- Danish Cancer Institute, Danish Cancer Society, Copenhagen, Denmark
| | - Merete Lund Hetland
- The DANBIO registry and Copenhagen Center for Arthritis Research (COPECARE), Center for Rheumatology and Spine Diseases, Centre of Head and Orthopedics, Rigshospitalet Glostrup, Glostrup, Denmark
- Department of Clinical Medicine, University of Copenhagen Faculty of Health and Medical Sciences, Copenhagen, Denmark
| | | | - Lene Dreyer
- Center of Rheumatic Research Aalborg (CERRA), Department of Rheumatology, Aalborg University Hospital, Aalborg, Denmark
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Alhusayen R, Dienes S, Lam M, Alavi A, Alikhan A, Aleshin M, Bahashwan E, Daveluy S, Goldfarb N, Garg A, Gulliver W, Jaleel T, Kimball AB, Kirchhof MG, Kirby J, Lenczowski J, Lev-Tov H, Lowes MA, Lara-Corrales I, Micheletti R, Okun M, Orenstein L, Poelman S, Piguet V, Porter M, Resnik B, Sibbald C, Shi V, Sayed C, Wong SM, Zaenglein A, Veillette H, Hsiao JL, Naik HB. North American clinical practice guidelines for the medical management of hidradenitis suppurativa in special patient populations. J Am Acad Dermatol 2025; 92:825-852. [PMID: 39725212 DOI: 10.1016/j.jaad.2024.11.071] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/20/2024] [Revised: 11/16/2024] [Accepted: 11/23/2024] [Indexed: 12/28/2024]
Abstract
BACKGROUND Hidradenitis suppurativa (HS) affects different patient populations that require unique considerations in their management. However, no HS guidelines for these populations exist. OBJECTIVE To provide evidence-based consensus recommendations for patients with HS in 7 special patient populations: (i) pregnancy, (ii) breastfeeding, (iii) pediatrics, (iv) malignancy, (v) tuberculosis infection, (vi) hepatitis B or C infection, and (vii) HIV disease. METHODS Recommendations were developed using the Grading of Recommendations Assessment, Development, and Evaluation system to ascertain level of evidence and selected through a modified Delphi consensus process. RESULTS One hundred eighteen expert consensus statements are provided for the management of patients with HS across these 7 special patient populations.
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Affiliation(s)
- Raed Alhusayen
- Sunnybrook Research Institute, Toronto, Ontario, Canada; Division of Dermatology, Department of Medicine, University of Toronto, Toronto, Ontario, Canada.
| | - Serena Dienes
- Temerty Faculty of Medicine, University of Toronto, Toronto, Ontario, Canada
| | - Megan Lam
- Division of Dermatology, Department of Medicine, University of Toronto, Toronto, Ontario, Canada
| | - Afsaneh Alavi
- Department of Dermatology, Mayo Clinic, Rochester, Minnesota
| | - Ali Alikhan
- Sutter Medical Foundation, Sacramento, California
| | - Maria Aleshin
- Department of Dermatology, Stanford University School of Medicine, Stanford, California
| | - Emad Bahashwan
- Division of Dermatology, Faculty of Medicine, University of Bisha, Bisha, Saudi Arabia
| | - Steve Daveluy
- Department of Dermatology, Wayne State University School of Medicine, Detroit, Michigan
| | - Noah Goldfarb
- Department of Dermatology, University of Minnesota, Minneapolis, Minnesota
| | - Amit Garg
- Department of Dermatology, Donald and Barbara Zucker School of Medicine at Hofstra/Northwell, New Hyde Park, New York
| | - Wayne Gulliver
- Department of Dermatology, Memorial University of Newfoundland, St. John's, Canada
| | - Tarannum Jaleel
- Department of Dermatology, Duke University School of Medicine, Durham, North Carolina
| | - Alexa B Kimball
- Clinical Laboratory for Epidemiology and Applied Research in Skin (CLEARS), Department of Dermatology, Beth Israel Deaconess Medical Center, Boston, Massachusetts; Department of Dermatology, Harvard Medical School, Boston, Massachusetts
| | - Mark G Kirchhof
- Division of Dermatology, Department of Medicine, University of Ottawa, Ottawa, Ontario, Canada; Division of Dermatology, Department of Medicine, Ottawa Hospital, Ottawa, Ontario, Canada
| | - Joslyn Kirby
- Incyte Corporation, Wilmington, Delaware; Department of Dermatology, Penn State Health, Hershey, Pennsylvania
| | | | - Hadar Lev-Tov
- Dr. Phillip Frost Department of Dermatology and Cutaneous Surgery, University of Miami, Miller School of Medicine, Miami, Florida
| | - Michelle A Lowes
- Laboratory for Investigative Dermatology, The Rockefeller University, New York, New York
| | - Irene Lara-Corrales
- Division of Dermatology, Department of Pediatrics, Hospital for Sick Children, Toronto, Ontario, Canada
| | - Robert Micheletti
- Departments of Dermatology and Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania
| | | | - Lauren Orenstein
- Department of Dermatology, Emory University School of Medicine, Atlanta, Georgia
| | - Susan Poelman
- Division of Dermatology, University of Calgary and Beacon Dermatology, Calgary, Alberta, Canada
| | - Vincent Piguet
- Division of Dermatology, Department of Medicine, University of Toronto and Women's College Hospital, Toronto, Ontario, Canada
| | - Martina Porter
- Department of Dermatology, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, Massachusetts
| | - Barry Resnik
- Dr. Phillip Frost Department of Dermatology and Cutaneous Surgery, University of Miami, Miller School of Medicine, Miami, Florida; Resnik Skin Institute, Miami, Florida
| | - Cathryn Sibbald
- Division of Dermatology, Department of Medicine, University of Toronto, Toronto, Ontario, Canada; Division of Dermatology, Department of Pediatrics, Hospital for Sick Children, Toronto, Ontario, Canada
| | - Vivian Shi
- Department of Dermatology, University of Washington, Seattle, Washington
| | - Christopher Sayed
- Department of Dermatology, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina
| | - Se Mang Wong
- Department of Dermatology, University of British Columbia, Vancouver, British Columbia, Canada
| | - Andrea Zaenglein
- Department of Dermatology, Penn State Health, Hershey, Pennsylvania; Penn State Children's Hospital, Hershey, Pennsylvania
| | - Helene Veillette
- Division of Dermatology, Department of Medicine, CHU de Québec-Université Laval, Québec, Canada
| | - Jennifer L Hsiao
- Department of Dermatology, University of Southern California, Los Angeles, California
| | - Haley B Naik
- Department of Dermatology, University of California, San Francisco, California
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Kwon OC, Lee HS, Yang J, Park MC. Risk of Cancers According to the Use of Biological Agents in Patients With Radiographic Axial Spondyloarthritis: A Nationwide Population-Based Cohort Study. J Clin Rheumatol 2025; 31:e13-e21. [PMID: 39869756 DOI: 10.1097/rhu.0000000000002188] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/29/2025]
Abstract
OBJECTIVE As the duration of use of biological disease-modifying antirheumatic drugs (bDMARDs) in patients with radiographic axial spondyloarthritis (r-axSpA) accumulates over time, long-term real-world safety data on cancer risk are needed. This study assessed the association between tumor necrosis factor inhibitors (TNFis) and interleukin 17 inhibitors (IL-17is) exposures and cancer risk in patients with r-axSpA. METHODS From the Korean nationwide database, we assembled 41,889 patients without prior history of cancer who were diagnosed with r-axSpA from 2010 onwards. Patients were followed up through 2021. Multivariable time-varying Cox models were performed to estimate the adjusted hazards ratios (aHRs) and 95% confidence intervals (CIs) of (1) overall cancers and (2) cancer subtypes according to TNFis exposure versus bDMARDs nonexposure, IL-17is exposure versus bDMARDs nonexposure, and IL-17is exposure versus TNFis exposure. RESULTS The incident rates of overall cancers during bDMARDs nonexposure, TNFis exposure, and IL-17is exposure were 53.8, 37.6, and 67.3 per 10,000 person-years, respectively. TNFis exposure versus bDMARDs nonexposure was not associated with an increased risk of overall cancers (aHR = 0.9, 95% CI = 0.8-1.1). IL-17is exposure was not associated with an increased risk of overall cancers compared with bDMARDs nonexposure (aHR = 1.2, 95% CI = 0.5-3.0) or TNFis exposure (aHR = 1.3, 95% CI = 0.6-3.3). Similarly, no significant associations were observed between bDMARDs exposures and the risk of cancer subtypes. CONCLUSIONS In patients with r-axSpA, there was no evidence of increased cancer risk with TNFis and IL-17is exposures compared with bDMARDs nonexposure, suggesting that the use of bDMARDs is safe with respect to cancer risk in patients with r-axSpA.
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Affiliation(s)
- Oh Chan Kwon
- From the Division of Rheumatology, Department of Internal Medicine, Yonsei University College of Medicine, Seoul, South Korea
| | - Hye Sun Lee
- Biostatistics Collaboration Unit, Yonsei University College of Medicine, Seoul, South Korea
| | - Juyeon Yang
- Biostatistics Collaboration Unit, Yonsei University College of Medicine, Seoul, South Korea
| | - Min-Chan Park
- From the Division of Rheumatology, Department of Internal Medicine, Yonsei University College of Medicine, Seoul, South Korea
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Studenic P, Meissner Y, Kearsley-Fleet L, De Cock D. Role of rheumatoid arthritis registries worldwide: What have they taught us? Best Pract Res Clin Rheumatol 2025; 39:102017. [PMID: 39406599 DOI: 10.1016/j.berh.2024.102017] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/30/2024] [Accepted: 10/05/2024] [Indexed: 03/17/2025]
Abstract
Rheumatoid arthritis (RA) is one of the most common rheumatic conditions, impacting quality of life on several domains. Major breakthroughs have been achieved over the past three decades in the management benefitting the patients' lives. With increasing as well as novel treatment options, clinical registries have been established and continuously evolve to portray patient characteristics, monitor disease activity of RA, effectiveness and safety of the novel compounds. The greatest insights derived from registries is our current knowledge on the risks for malignancies and infections but also extending our knowledge collected in clinical trials on comparative effectiveness, long-term drug utilisation and under-represented populations. Moreover, the possible evolution of registries involving Big Data and AI, and the increased focus on patient centredness is discussed.
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Affiliation(s)
- Paul Studenic
- Medical University of Vienna, Department of Internal Medicine 3, Division of Rheumatology, Währinger Gürtel 18-20, 1090, Vienna, Austria; Karolinska Institute, Department of Medicine (Solna), Division of Rheumatology, Stockholm, Sweden.
| | - Yvette Meissner
- German Rheumatology Research Center, Epidemiology and Health Services Research, Charitéplatz 1, 10117, Berlin, Germany; Charité University Medicine Berlin, Institute for Social Medicine, Epidemiology and Health Economics, Schumannstraße 20 - 21, 10117, Berlin, Germany.
| | - Lianne Kearsley-Fleet
- Centre for Epidemiology Versus Arthritis, Centre for Musculoskeletal Research, Division of Musculoskeletal and Dermatological Sciences, University of Manchester, Manchester Academic Health Science Centre, Manchester, UK.
| | - Diederik De Cock
- Biostatistics and Medical Informatics Research Group, Department of Public Health, Vrije Universiteit Brussel, Laarbeeklaan 103, Brussels, Belgium.
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Tan J, Huang H, Tan L, Li B. Telitacicept for systemic lupus erythematosus with post‑surgical papillary thyroid carcinoma: A case report. Biomed Rep 2025; 22:48. [PMID: 39882332 PMCID: PMC11775643 DOI: 10.3892/br.2025.1926] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/24/2024] [Accepted: 11/05/2024] [Indexed: 01/31/2025] Open
Abstract
Systemic lupus erythematosus (SLE) is a chronic autoimmune disease with a complex etiology primarily linked to abnormalities in B lymphocytes within the human body, resulting in the production of numerous pathogenic autoantibodies. Telitacicept is a relatively novel humanized, recombinant transmembrane activator, calcium modulator and cyclophilin ligand interactor fused with the Fc portion (TACI-Fc). It works by competitively inhibiting the TACI site, neutralizing the activity of B-cell lymphocyte stimulator and A proliferation-inducing ligand. This, in turn, inhibits the development and survival of plasma cells and mature B cells. A 28-year-old female was admitted to the Department of Rheumatology and Immunology (People's Hospital of Longhua; Shenzhen, China) in June 2021 due to systemic edema for more than a month and hair loss lasting for a week. After comprehensive examination, the patient was diagnosed with SLE with hematological system involvement, serositis, lupus nephritis and secondary antiphospholipid syndrome. After receiving medications including glucocorticoids, mycophenolate mofetil and cyclosporine, the patient's white blood cells, platelets, hemoglobin, urinary protein and multiple serositis returned to normal. However, the levels of complement 3 (C3) and C4 did not significantly improve. Subsequently, the patient underwent thyroid ultrasound examination, which suggested thyroid nodules. After thyroid puncture biopsy, the patient was diagnosed with papillary thyroid carcinoma (PTC). After surgical resection, the patient was confirmed to have PTC by pathological biopsy, with no lymph node metastasis. At two months after surgery, the patient was treated with telitacicept, and the complement levels not only returned to normal but also remained stable for a long time. The present case was the first to report the use of telitacicept for the successful treatment of a patient with SLE with post-surgical PTC, providing a potential therapeutic option for SLE with a prior history of carcinoma. The role of telitacept in this field requires further research and attention.
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Affiliation(s)
- Jinhui Tan
- Department of Rheumatology and Immunology, People's Hospital of Longhua, Shenzhen, Guangdong 518109, P.R. China
| | - Hai Huang
- Department of Health Management, People's Hospital of Longhua, Shenzhen, Guangdong 518109, P.R. China
| | - Linghua Tan
- Department of Health Management, Jiangmen Wuyi Hospital of Chinese Medicine, Jiangmen, Guangdong 529099, P.R. China
| | - Bo Li
- Department of Rheumatology and Immunology, People's Hospital of Longhua, Shenzhen, Guangdong 518109, P.R. China
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Ruiz JI, Lei X, Chi-Fang W, Giordano SH, Zhao H, Rajan SS, Lin H, Suarez-Almazor ME. Survival in patients with rheumatoid arthritis and early breast cancer treated with tumor necrosis factor inhibitors. Breast Cancer 2024; 31:1059-1070. [PMID: 39117793 PMCID: PMC11808625 DOI: 10.1007/s12282-024-01618-x] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/13/2024] [Accepted: 07/13/2024] [Indexed: 08/10/2024]
Abstract
BACKGROUND There have been concerns about the use of tumor necrosis factor inhibitors (TNFi) for autoimmune disease in patients with recently diagnosed cancer. We assessed the survival of patients with rheumatoid arthritis (RA) and newly diagnosed early breast cancer (BC) treated with TNFi in the first two years after BC diagnosis. METHODS We identified patients in two datasets: (1) Optum's de-identified Clinformatics® Data Mart Database (CDM), (2) Surveillance, Epidemiology, and End Results program (SEER) and Texas Cancer Registry (TCR) Medicare-linked cohort. We grouped patients according to whether they received TNFi, conventional synthetic disease-modifying antirheumatic drugs (csDMARDs) only, or no DMARDs within 2 years after BC. Outcomes were overall survival (OS) and BC-specific survival (BCSS). We conducted landmark analyses at years 1 and 2, with multivariable Cox regressions using propensity scores for adjustment. RESULTS In the first year after BC, 165/970 (17.0%) and 201/1246 (16.1%) patients received TNFi in CDM and SEER/TCR-Medicare respectively. In the 1 year landmark, no significant differences in OS were observed between patients treated with TNFi and patients treated with csDMARDs only in CDM (hazard ratio [HR] = 0.77, 95% confidence interval [CI] 0.42-1.40) or SEER/TCR-Medicare (HR = 0.84, 95% CI 0.54-1.31). BCSS (SEER/TCR-Medicare) was better in patients receiving TNFi than in those receiving csDMARDs only (HR = 0.28, 95% CI 0.08-0.98). In CDM, glucocorticoid therapy had worse OS than those without glucocorticoids (HR = 2.18, 95% CI 1.13-4.18). This was also observed in SEER/TCR-Medicare (not statistically significant). Similar results were observed for the 2 year landmark. CONCLUSIONS TNFi treatment during the first two years after early BC was not associated with worse survival.
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Affiliation(s)
- Juan I Ruiz
- Department of Health Services Research, The University of Texas MD Anderson Cancer Center, 1400 Pressler St, Unit 1444, Houston, TX, 77030, USA
| | - Xiudong Lei
- Department of Health Services Research, The University of Texas MD Anderson Cancer Center, 1400 Pressler St, Unit 1444, Houston, TX, 77030, USA
| | - Wu Chi-Fang
- Department of Health Services Research, The University of Texas MD Anderson Cancer Center, 1400 Pressler St, Unit 1444, Houston, TX, 77030, USA
| | - Sharon H Giordano
- Department of Health Services Research, The University of Texas MD Anderson Cancer Center, 1400 Pressler St, Unit 1444, Houston, TX, 77030, USA
| | - Hui Zhao
- Department of Health Services Research, The University of Texas MD Anderson Cancer Center, 1400 Pressler St, Unit 1444, Houston, TX, 77030, USA
| | - Suja S Rajan
- Department of Management, Policy and Community Health, School of Public Health, The University of Texas Health Science Center at Houston, Houston, TX, USA
| | - Heather Lin
- 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, 1400 Pressler St, Unit 1444, Houston, TX, 77030, USA.
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Álvaro-Gracia Álvaro JM, Díaz Del Campo Fontecha P, Andréu Sánchez JL, Balsa Criado A, Cáliz Cáliz R, Castrejón Fernández I, Corominas H, Gómez Puerta JA, Manrique Arija S, Mena Vázquez N, Ortiz García A, Plasencia Rodríguez C, Silva Fernández L, Tornero Molina J. Update of the Consensus Statement of the Spanish Society of Rheumatology on the use of biological and synthetic targeted therapies in rheumatoid arthritis. REUMATOLOGIA CLINICA 2024; 20:423-439. [PMID: 39341701 DOI: 10.1016/j.reumae.2024.09.002] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 05/13/2024] [Accepted: 05/24/2024] [Indexed: 10/01/2024]
Abstract
OBJECTIVE To update the consensus document of the Spanish Society of Rheumatology (SER) regarding the use of targeted biological and synthetic therapies in rheumatoid arthritis (RA) with the aim of assisting clinicians in their therapeutic decisions. METHODS A panel of 13 experts was assembled through an open call by SER. We employed a mixed adaptation-elaboration-update methodology starting from the 2015 Consensus Document of the Spanish Society of Rheumatology on the use of biological therapies in RA. Starting with systematic reviews (SR) of recommendations from EULAR 2019, American College of Rheumatology 2021, and GUIPCAR 2017, we updated the search strategies for the PICO questions of GUIPCAR. An additional SR was conducted on demyelinating disease in relation to targeted biological and synthetic therapies. Following the analysis of evidence by different panelists, consensus on the wording and level of agreement for each recommendation was reached in a face-to-face meeting. RESULTS The panel established 5 general principles and 15 recommendations on the management of RA. These encompassed crucial aspects such as the importance of early treatment, therapeutic goals in RA, monitoring frequency, the use of glucocorticoids, the application of conventional synthetic disease-modifying antirheumatic drugs (csDMARDs), biological DMARDs (bDMARDs), and targeted synthetic DMARDs. Additionally, recommendations on dose reduction of these drugs in stable patients were included. This update also features recommendations on the use of bDMARDs and Janus Kinase inhibitors in some specific clinical situations, such as patients with lung disease, a history of cancer, heart failure, or demyelinating disease. CONCLUSIONS This update provides recommendations on key aspects in the management of RA using targeted biological and synthetic therapies.
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Affiliation(s)
- José María Álvaro-Gracia Álvaro
- Servicio de Reumatología, Hospital General Universitario Gregorio Marañón, IiSGM, Universidad Complutense Madrid, Madrid, Spain.
| | | | - José Luis Andréu Sánchez
- Servicio de Reumatología, H.U. Puerta de Hierro Majadahonda, Facultad de Medicina, Universidad Autónoma de Madrid, Madrid, Spain
| | | | | | - Isabel Castrejón Fernández
- Servicio de Reumatología, Instituto de Investigación Sanitaria Gregorio Marañón, Hospital Gregorio Marañón, Departamento de Medicina, Universidad Complutense de Madrid, Madrid, Spain
| | - Hèctor Corominas
- Servicio de Reumatología, Hospital Universitari de la Santa Creu i Sant Pau & Hospital Dos de Maig, Barcelona, Spain
| | | | - Sara Manrique Arija
- Instituto de Investigación Biomédica de Málaga (IBIMA)-Plataforma Bionand, UGC de Reumatología, Hospital Regional Universitario de Málaga, Departamento de Medicina, Universidad de Málaga, Málaga, Spain
| | - Natalia Mena Vázquez
- UGC de Reumatología, Instituto de Investigación Biomédica de Málaga (IBIMA)-Plataforma Bionand, Hospital Regional Universitario de Málaga, Universidad de Málaga, Málaga, Spain
| | - Ana Ortiz García
- Servicio de Reumatología, Hospital Universitario de La Princesa, Instituto de Investigación Sanitaria Hospital Universitario de La Princesa, Madrid, Spain
| | | | - Lucía Silva Fernández
- Servicio de Reumatología, Complexo Hospitalario Universitario de A Coruña, A Coruña, Spain
| | - Jesús Tornero Molina
- Servicio de Reumatología, Hospital Universitario de Guadalajara, Departamento de Medicina, Universidad de Alcalá de Henares, Alcalá de Henares, Madrid, Spain
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Harigai M, Tanaka E, Inoue E, Sakai R, Sugitani N, Toyoizumi S, Sugiyama N, Yamanaka H. Incidence of Malignancies and the Association with Biological Disease-Modifying Antirheumatic Drugs in Japanese Patients with Rheumatoid Arthritis: A Time-Dependent Analysis from the IORRA Patient Registry. Rheumatol Ther 2024; 11:1181-1195. [PMID: 39017907 PMCID: PMC11422331 DOI: 10.1007/s40744-024-00689-8] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/22/2024] [Accepted: 05/29/2024] [Indexed: 07/18/2024] Open
Abstract
INTRODUCTION Patients with rheumatoid arthritis (RA) may have an increased malignancy risk versus the general population, potentially elevated by biological disease-modifying antirheumatic drug (bDMARD) use. Using patient registry data, we determined malignancy risk, stratified by bDMARD use, among Japanese patients with RA versus the Japanese general population and investigated whether bDMARD use is a time-dependent risk factor for the development of malignancy. METHODS Patients aged ≥ 18 years with ≥ 2 data entries of RA in the IORRA (Institute of Rheumatology, Rheumatoid Arthritis) patient registry, enrolled from January 2013-December 2018, were identified ('All RA' cohort). Patients were stratified into bDMARD (≥ 1 bDMARD received) or non-bDMARD (no history of bDMARDs) sub-cohorts. Malignancy incidence rates and standardized incidence ratios (SIRs) with 95% confidence intervals (CIs) versus the Japanese general population were calculated. Risk of RA medication use was analyzed using a time-dependent Cox proportional hazards model, after adjusting for covariates. RESULTS A total of 8020 patients were identified for the All RA cohort; 2187 and 5833 for the bDMARD and non-bDMARD sub-cohorts, respectively. For all three cohorts, incidence of overall malignancies was similar versus the Japanese general population. Incidence of specific malignancies was also similar, but incidence of lymphoma was higher for all three cohorts (SIRs [95% CIs] 3.72 [2.71-4.93], 5.97 [3.34-9.59], and 2.79 [1.82-4.02], respectively). In the bDMARD sub-cohort, no increase in SIRs was observed for other site-specific malignancies. In the All RA cohort, use of methotrexate, tacrolimus, glucocorticoids, non-steroidal anti-inflammatory drugs, and bDMARDs were not associated with the risk of overall malignancy; the hazard ratio (95% CI) was 1.36 (0.96-1.93) for bDMARD use. Increased disease activity was a time-dependent risk factor of overall malignancy with a hazard ratio (95% CI) of 1.35 (1.15-1.59). CONCLUSIONS The use of bDMARDs was not a time-dependent risk factor for malignancy.
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Affiliation(s)
- Masayoshi Harigai
- Department of Rheumatology, Sanno Hospital, 8-10-16 Akasaka, Minato-ku, Tokyo, 107-0052, Japan.
| | - Eiichi Tanaka
- Division of Rheumatology, Department of Internal Medicine, Tokyo Women's Medical University School of Medicine, 8-1 Kawada-Cho, Shinjuku-Ku, Tokyo, 162-8666, Japan
| | - Eisuke Inoue
- Division of Rheumatology, Department of Internal Medicine, Tokyo Women's Medical University School of Medicine, 8-1 Kawada-Cho, Shinjuku-Ku, Tokyo, 162-8666, Japan
- Showa University Research Administration Center, Showa University, Tokyo, Japan
| | - Ryoko Sakai
- Division of Rheumatology, Department of Internal Medicine, Tokyo Women's Medical University School of Medicine, 8-1 Kawada-Cho, Shinjuku-Ku, Tokyo, 162-8666, Japan
| | - Naohiro Sugitani
- Division of Rheumatology, Department of Internal Medicine, Tokyo Women's Medical University School of Medicine, 8-1 Kawada-Cho, Shinjuku-Ku, Tokyo, 162-8666, Japan
| | | | | | - Hisashi Yamanaka
- Division of Rheumatology, Department of Internal Medicine, Tokyo Women's Medical University School of Medicine, 8-1 Kawada-Cho, Shinjuku-Ku, Tokyo, 162-8666, Japan
- Sanno Medical Center, Tokyo, Japan
- Department of Rheumatology, International University of Health and Welfare, Tokyo, Japan
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Sen R, Riofrio M, Singh JA. A narrative review of the comparative safety of disease-modifying anti-rheumatic drugs used for the treatment of rheumatoid arthritis. Expert Opin Drug Saf 2024; 23:687-714. [PMID: 38695151 DOI: 10.1080/14740338.2024.2348575] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/29/2023] [Accepted: 04/24/2024] [Indexed: 05/24/2024]
Abstract
INTRODUCTION Disease-modifying anti-rheumatic drugs (DMARDs) have improved the outcomes of patients with rheumatoid arthritis (RA). DMARDs are classified into three categories: conventional synthetic DMARDs, biological DMARDs (including biosimilars), and targeted synthetic DMARDs. DMARDs, by way of their effect on the immune system, are associated with increased risk of adverse events, including infections, malignancies, cardiovascular disease, gastrointestinal perforations, and other less common events. AREAS COVERED In this narrative literature review performed with searches of the PubMed database from 1 January 2010 through 1 January 2023, we compare the risk of safety events between DMARDs using data from both randomized clinical trials and observational studies. EXPERT OPINION DMARD use in RA is associated with higher rates of serious infections, tuberculosis reactivation, opportunistic infections, and possibly malignancies. Specific biologic DMARDs and higher doses are associated with elevated risks of various adverse events (gastrointestinal perforations, thromboembolism, serious infection). Shared decision-making is paramount when choosing a treatment regimen for patients based on their own comorbidities. JAKi are the newest class of medications used for RA with robust safety data provided in clinical trials. However, more real-world evidence and phase-IV pharmacovigilance data are needed to better understand comparative safety profile of DMARDs in RA.
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Affiliation(s)
- Rouhin Sen
- Division of Clinical Immunology and Rheumatology, The University of Alabama Birmingham, Birmingham, AL, USA
- Medicine/Rheumatology Birmingham Veterans Affairs Medical Center (VAMC), Birmingham, AL, USA
| | - Maria Riofrio
- Division of Clinical Immunology and Rheumatology, The University of Alabama Birmingham, Birmingham, AL, USA
| | - Jasvinder A Singh
- Division of Clinical Immunology and Rheumatology, The University of Alabama Birmingham, Birmingham, AL, USA
- Medicine/Rheumatology Birmingham Veterans Affairs Medical Center (VAMC), Birmingham, AL, USA
- Department of Epidemiology, UAB School of Public Health, Birmingham, AL, USA
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10
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Wang X, Zhang X, Liu Z, Zhao N, Li X, Su P, Zheng G, Zhang X, Wang H, Zhang Y. Naringenin nanoparticles targeting cyclin B1 suppress the progression of rheumatoid arthritis-associated lung cancer by inhibiting fibroblast-to-myofibroblast transition. Int J Biochem Cell Biol 2024; 169:106557. [PMID: 38460905 DOI: 10.1016/j.biocel.2024.106557] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/13/2023] [Revised: 02/28/2024] [Accepted: 03/06/2024] [Indexed: 03/11/2024]
Abstract
There is growing evidence of an elevated risk of lung cancer in patients with rheumatoid arthritis. The poor prognosis of rheumatoid arthritis-associated lung cancer and the lack of therapeutic options pose an even greater challenge to the clinical management of patients. This study aimed to identify potential molecular targets associated with the progression of rheumatoid arthritis-associated lung cancer and examine the efficacy of naringenin nanoparticles targeting cyclin B1. Mendelian randomizatio analysis revealed that rheumatoid arthritis has a positive correlation with the risk of lung cancer. Cyclin B1 was significantly upregulated in patients with rheumatoid arthritis-associated lung cancer and was significantly overexpressed in synovial tissue fibroblasts. Furthermore, the overexpression of cyclin B1 in rheumatoid arthritis fibroblast-like synoviocytes, which promotes their proliferation and fibroblast-to-myofibroblast transition, can significantly contribute to the growth and infiltration of lung cancer cells. Importantly, our prepared naringenin nanoparticles targeting cyclin B1 effectively attenuated proliferation and fibroblast-to-myofibroblast transition by blocking cells at the G2/M phase. In vivo experiments, naringenin nanoparticles targeting cyclin B1 significantly alleviated the development of collagen-induced arthritis and lung orthotopic tumors. Collectively, our results reveal that naringenin nanoparticles targeting cyclin B1 can suppress the progression of rheumatoid arthritis-associated lung cancer by inhibiting fibroblast-to-myofibroblast transition. These findings provide new insights into the treatment of rheumatoid arthritis-associated lung cancer therapy.
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Affiliation(s)
- Xilong Wang
- Department of Clinical Laboratory, Qilu Hospital of Shandong University, Jinan 250012, China; Shandong Engineering Research Center of Biomarker and Artificial Intelligence Application, Jinan 250012, China
| | - Xiaoyu Zhang
- Department of Hematology, Qilu Hospital of Shandong University, Jinan 250012, China
| | - Zhipu Liu
- Department of Clinical Laboratory, Qilu Hospital of Shandong University, Jinan 250012, China; Shandong Engineering Research Center of Biomarker and Artificial Intelligence Application, Jinan 250012, China
| | - Na Zhao
- Department of Clinical Laboratory, Qilu Hospital of Shandong University, Jinan 250012, China; Shandong Engineering Research Center of Biomarker and Artificial Intelligence Application, Jinan 250012, China
| | - Xiaohan Li
- Department of Clinical Laboratory, Qilu Hospital of Shandong University, Jinan 250012, China; Shandong Engineering Research Center of Biomarker and Artificial Intelligence Application, Jinan 250012, China
| | - Peng Su
- Department of Pathology, Qilu Hospital of Shandong University, Jinan 250012, China
| | - Guixi Zheng
- Department of Clinical Laboratory, Qilu Hospital of Shandong University, Jinan 250012, China; Shandong Engineering Research Center of Biomarker and Artificial Intelligence Application, Jinan 250012, China
| | - Xin Zhang
- Department of Clinical Laboratory, Qilu Hospital of Shandong University, Jinan 250012, China; Shandong Engineering Research Center of Biomarker and Artificial Intelligence Application, Jinan 250012, China
| | - Hongxing Wang
- Department of Clinical Laboratory, Qilu Hospital of Shandong University, Jinan 250012, China; Shandong Engineering Research Center of Biomarker and Artificial Intelligence Application, Jinan 250012, China.
| | - Yi Zhang
- Department of Clinical Laboratory, Qilu Hospital of Shandong University, Jinan 250012, China; Shandong Engineering Research Center of Biomarker and Artificial Intelligence Application, Jinan 250012, China.
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Gupta A, Peyrin-Biroulet L, Ananthakrishnan AN. Risk of Cancer Recurrence in Patients With Immune-Mediated Diseases With Use of Immunosuppressive Therapies: An Updated Systematic Review and Meta-Analysis. Clin Gastroenterol Hepatol 2024; 22:499-512.e6. [PMID: 37579866 PMCID: PMC10859547 DOI: 10.1016/j.cgh.2023.07.027] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/09/2023] [Revised: 07/25/2023] [Accepted: 07/29/2023] [Indexed: 08/16/2023]
Abstract
BACKGROUND & AIMS There are limited data on the safety of immunosuppressive therapy use in individuals with immune-mediated diseases with a history of malignancy, particularly with newer biologic and small-molecule treatments. METHODS We performed a systematic search of PubMed and Embase databases to identify studies examining the impact of immunosuppressive therapies on cancer recurrence across several immune-mediated diseases. Studies were pooled together using random-effects meta-analysis and stratified by type of treatment. Primary outcome was occurrence of incident cancers, defined as new or recurrent. RESULTS Our meta-analysis included 31 studies (17 inflammatory bowel disease, 14 rheumatoid arthritis, 2 psoriasis, and 1 ankylosing spondylitis) contributing 24,328 persons and 85,784 person-years (p-y) of follow-up evaluation. Rates of cancer recurrence were similar among individuals not on immunosuppression (IS) (1627 incident cancers, 43,765 p-y; 35 per 1000 p-y; 95% CI, 27-43), receiving an anti-tumor necrosis factor (571 incident cancers, 17,772 p-y; 32 per 1000 p-y; 95% CI, 25-38), immunomodulators (1104 incident cancers, 17,018 p-y; 46 per 1000 p-y; 95% CI, 31-61), combination immunosuppression (179 incident cancers, 2659 p-y; 56 per 1000 p-y; 95% CI, 31-81). Patients receiving ustekinumab (5 incident cancers, 213 p-y; 21 per 1000 p-y; 95% CI, 0-44) and vedolizumab (37 incident cancers, 1951 p-y; 16 per 1000 p-y; 95% CI, 5-26) had numerically lower rates of cancer. There were no studies on Janus kinase inhibitors. Stratification of studies by timing of immunosuppression initiation did not reveal a medication effect based on early (<5 years) or delayed treatment initiation. CONCLUSIONS In patients with immune-mediated diseases and a history of malignancy, we observed similar rates of cancer recurrence in those on no immunosuppression compared with different immunosuppressive treatments.
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Affiliation(s)
- Akshita Gupta
- Department of Medicine, Massachusetts General Hospital, Boston, Massachusetts
| | - Laurent Peyrin-Biroulet
- Department of Gastroenterology, Centre Hospitalier Régional Universitaire-Nancy, Nancy, France; University of Lorraine, Inserm, Nutrition-Genetics and Exposure to Environmental Risks, Nancy, France
| | - Ashwin N Ananthakrishnan
- Department of Medicine, Massachusetts General Hospital, Boston, Massachusetts; Department of Gastroenterology, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts.
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12
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Molina-Collada J, Alonso F, Otero L, Bohórquez C, Díaz Torné C, Pérez García C, Blanco Madrigal JM, Vela P, Álvaro-Gracia JM, Castrejón I. Cancer risk with biologic and targeted synthetic DMARDs in patients with rheumatic diseases and previous malignancies: Results from the BIOBADASER register. Semin Arthritis Rheum 2024; 64:152341. [PMID: 38128174 DOI: 10.1016/j.semarthrit.2023.152341] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/08/2023] [Revised: 11/29/2023] [Accepted: 12/04/2023] [Indexed: 12/23/2023]
Abstract
OBJECTIVE to investigate the occurrence and relative risk of incident malignancy in patients with rheumatic diseases and previous malignancies treated with biologic and targeted synthetic DMARDs (b/tsDMARDs). METHODS Cohort study of patients included in BIOBADASER 3.0 up to 2021, treated with b/tsDMARDs and history of a previous malignancy. Incident cancer was defined as any cancer (new primary, local recurrence or metastases) during the drug exposure. Incidence rate ratios of cancer per 1,000 patients-year (PY) and 95 % confidence interval (CI) were estimated. Rates of incident cancer in tsDMARDs and other bDMARDs versus TNFi were compared. RESULTS A total of 352 patients from over 9,129 patients recorded in BIOBADASER 3.0 had a history of a previous malignancy. Overall, there were 47 incident malignancies (28 solid cancers, 18 non-melanoma skin cancers and 1 melanoma). The overall rate of incident malignancy was 47.4 (95 % CI 35.6-63.1) events/1,000 PY, ranging between 24.5 events/1000 PY in the anti-CD20 group to 93 events/1000 PY in the anti-CTLA-4 group. We did not find differences in the adjusted rate of incident cancer in patients exposed to JAKi [0.5 (95 % CI 0.2-1.7)], anti-CD20 [0.4(95 % CI 0.1-1)], or anti-IL6 [1.1(95 % CI 0.5-2.4)], anti-CTLA-4 [1.5 (95 % CI 0.7-3.1) or anti-IL17 [0.7 (95 % CI 0.2-2.4) versus TNFi therapy. CONCLUSIONS We did not find differences in the risk of incident cancer in patients with rheumatic diseases and a previous malignancy between TNFi and other b/tsDMARDs. While incident cancers in our cohort were limited, our data is reassuring, awaiting validation in future studies.
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Affiliation(s)
- Juan Molina-Collada
- Department of Rheumatology, Hospital General Universitario Gregorio Marañón, Madrid, Spain; Instituto de Investigación Sanitaria Gregorio Marañón (IiSGM), Madrid, Spain.
| | - Fernando Alonso
- Department of Rheumatology, Unidad de investigación, Sociedad Española de Reumatología, Madrid, Spain
| | - Lucía Otero
- Department of Rheumatology, Unidad de investigación, Sociedad Española de Reumatología, Madrid, Spain
| | - Cristina Bohórquez
- Department of Rheumatology, Hospital Príncipe de Asturias, Madrid, Spain
| | - César Díaz Torné
- Department of Rheumatology, Hospital de la Santa Creu i Sant Pau, Barcelona, Spain
| | | | | | - Paloma Vela
- Department of Rheumatology, Hospital General Universitario Doctor Balmis, Alicante, Spain; SABIAL, Alicante, Spain
| | - José María Álvaro-Gracia
- Department of Rheumatology, Hospital General Universitario Gregorio Marañón, Madrid, Spain; Instituto de Investigación Sanitaria Gregorio Marañón (IiSGM), Madrid, Spain
| | - Isabel Castrejón
- Department of Rheumatology, Hospital General Universitario Gregorio Marañón, Madrid, Spain; Instituto de Investigación Sanitaria Gregorio Marañón (IiSGM), Madrid, Spain
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13
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Simon TA, Suissa S, Boers M, Hochberg MC, Skovron ML, Askling J, Michaud K, Strangfeld A, Pedro S, Frisell T, Meissner Y, Dominique A, Gomez A. Malignancy outcomes in patients with rheumatoid arthritis treated with abatacept and other disease-modifying antirheumatic drugs: Results from a 10-year international post-marketing study. Semin Arthritis Rheum 2024; 64:152240. [PMID: 37500379 DOI: 10.1016/j.semarthrit.2023.152240] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/07/2022] [Revised: 05/12/2023] [Accepted: 06/25/2023] [Indexed: 07/29/2023]
Abstract
OBJECTIVE To evaluate the risk of malignancy (overall, breast, lung, and lymphoma) in patients with rheumatoid arthritis treated with abatacept, conventional synthetic (cs) disease-modifying antirheumatic drugs (DMARDs), and other biologic/targeted synthetic (b/ts)DMARDs in clinical practice. METHODS Four international observational data sources were included: ARTIS (Sweden), RABBIT (Germany), FORWARD (USA), and BC (Canada). Crude incidence rates (IRs) per 1000 patient-years of exposure with 95% confidence intervals (CIs) for a malignancy event were calculated; rate ratios (RRs) were estimated and adjusted for demographics, comorbidities, and other potential confounders. RRs were then pooled in a random-effects model. RESULTS Across data sources, mean follow-up for patients treated with abatacept (n = 5182), csDMARDs (n = 73,755), and other b/tsDMARDs (n = 37,195) was 3.0-3.7, 2.9-6.2, and 3.1-4.7 years, respectively. IRs per 1000 patient-years for overall malignancy ranged from 7.6-11.4 (abatacept), 8.6-13.2 (csDMARDs), and 5.0-11.8 (other b/tsDMARDs). IRs ranged from: 0-4.4, 0-3.3, and 0-2.5 (breast cancer); 0.1-2.8, 0-3.7, and 0.2-2.9 (lung cancer); and 0-1.1, 0-0.9, and 0-0.6 (lymphoma), respectively, for the three treatment groups. The numbers of individual cancers (breast, lung, and lymphoma) in some registries were low; RRs were not available. There were a few cases of lymphoma in some of the registries; ARTIS observed an RR of 2.8 (95% CI 1.1-6.8) with abatacept versus csDMARDs. The pooled RRs (95% CIs) for overall malignancy with abatacept were 1.1 (0.8-1.5) versus csDMARDs and 1.0 (0.8-1.3) versus b/tsDMARDs. CONCLUSIONS This international, post-marketing observational safety study did not find any statistically significant increase in the risk of overall malignancies in pooled data in patients treated with abatacept compared with csDMARDs or with other b/tsDMARDs. Assessment of larger populations is needed to further evaluate the risks for individual cancers, especially lymphoma.
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Affiliation(s)
| | | | - Maarten Boers
- Department of Epidemiology & Data Science, Amsterdam University Medical Centers, Vrije Universiteit, Amsterdam, the Netherlands
| | - Marc C Hochberg
- Departments of Medicine and Epidemiology and Public Health, University of Maryland School of Medicine, Baltimore, MD, USA
| | | | - Johan Askling
- Department of Medicine Solna, Karolinska Institutet, Stockholm, Sweden
| | - Kaleb Michaud
- University of Nebraska Medical Center, Omaha, NE, USA; FORWARD, The National Databank for Rheumatic Diseases, Wichita, KS, USA
| | - Anja Strangfeld
- Pharmacoepidemiology and Health Services Research, German Rheumatism Research Center, Berlin, Germany; Charité University Medicine, Berlin, Germany
| | - Sofia Pedro
- FORWARD, The National Databank for Rheumatic Diseases, Wichita, KS, USA
| | - Thomas Frisell
- Department of Medicine Solna, Karolinska Institutet, Stockholm, Sweden
| | - Yvette Meissner
- Pharmacoepidemiology and Health Services Research, German Rheumatism Research Center, Berlin, Germany
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14
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Li W, Lv R, Wang W. Rheumatoid arthritis was causally related to an increased risk of prostate cancer. Int J Rheum Dis 2024; 27:e15054. [PMID: 38389394 DOI: 10.1111/1756-185x.15054] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/02/2023] [Revised: 01/02/2024] [Accepted: 01/19/2024] [Indexed: 02/24/2024]
Affiliation(s)
- Wenjie Li
- Department of Radiation Oncology, Nanfang Hospital, Southern Medical University, Guangzhou, China
| | - Ruxue Lv
- Department of Radiation Oncology, Nanfang Hospital, Southern Medical University, Guangzhou, China
| | - Wei Wang
- Department of Radiation Oncology, Nanfang Hospital, Southern Medical University, Guangzhou, China
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15
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Yang V, Kragstrup TW, McMaster C, Reid P, Singh N, Haysen SR, Robinson PC, Liew DFL. Managing Cardiovascular and Cancer Risk Associated with JAK Inhibitors. Drug Saf 2023; 46:1049-1071. [PMID: 37490213 PMCID: PMC10632271 DOI: 10.1007/s40264-023-01333-0] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 06/20/2023] [Indexed: 07/26/2023]
Abstract
Janus kinase inhibitors (JAKi) have enormous appeal as immune-modulating therapies across many chronic inflammatory diseases, but recently this promise has been overshadowed by questions regarding associated cardiovascular and cancer risk emerging from the ORAL Surveillance phase 3b/4 post-marketing requirement randomized controlled trial. In that study of patients with rheumatoid arthritis with existing cardiovascular risk, tofacitinib, the first JAKi registered for chronic inflammatory disease, failed to meet non-inferiority thresholds when compared with tumor necrosis factor inhibitors for both incident major adverse cardiovascular events and incident cancer. While this result was unexpected by many, subsequently published observational data have also supported this finding. Notably, however, such a risk has largely not yet been demonstrated in patients outside the specific clinical situation examined in the trial, even in the face of many studies examining this. Nevertheless, this signal has practically re-aligned approaches to both tofacitinib and other JAKi to varying extents, in other patient populations and contexts: within rheumatoid arthritis, but also in psoriatic arthritis, axial spondyloarthritis, inflammatory bowel disease, atopic dermatitis, and beyond. Application to individual patients can be more challenging but remains important to harness the substantive potential of JAKi to the maximum extent safely possible. This review not only explores the evolution of the regulatory response to the signal, its informing data, biological plausibility, and its impact on guidelines, but also the many factors that clinicians must consider in navigating cardiovascular and cancer risk for their patients considering JAKi as immune-modulating therapy.
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Affiliation(s)
- Victor Yang
- Department of Rheumatology, Level 1, North Wing, Heidelberg Repatriation Hospital, Austin Health, 300 Waterdale Road, PO Box 5444, Heidelberg West, VIC, 3081, Australia
| | - Tue W Kragstrup
- Department of Rheumatology, Aarhus University Hospital, Aarhus, Denmark
- Department of Biomedicine, Aarhus University, Aarhus, Denmark
- Sector for Rheumatology, Diagnostic Center, Silkeborg Regional Hospital, Silkeborg, Denmark
| | - Christopher McMaster
- Department of Rheumatology, Level 1, North Wing, Heidelberg Repatriation Hospital, Austin Health, 300 Waterdale Road, PO Box 5444, Heidelberg West, VIC, 3081, Australia
- Department of Clinical Pharmacology and Therapeutics, Austin Health, Melbourne, VIC, Australia
- Centre for Digital Transformation of Health, University of Melbourne, Melbourne, VIC, Australia
| | - Pankti Reid
- Division of Rheumatology and Committee on Clinical Pharmacology and Pharmacogenomics, Department of Medicine, University of Chicago Biological Sciences Division, Chicago, IL, USA
| | - Namrata Singh
- Division of Rheumatology, Department of Medicine, University of Washington, Seattle, WA, USA
| | - Stine R Haysen
- Department of Biomedicine, Aarhus University, Aarhus, Denmark
| | - Philip C Robinson
- Faculty of Medicine, University of Queensland, Brisbane, QLD, Australia
- Royal Brisbane and Women's Hospital, Metro North Hospital and Health Service, Herston, QLD, Australia
| | - David F L Liew
- Department of Rheumatology, Level 1, North Wing, Heidelberg Repatriation Hospital, Austin Health, 300 Waterdale Road, PO Box 5444, Heidelberg West, VIC, 3081, Australia.
- Department of Clinical Pharmacology and Therapeutics, Austin Health, Melbourne, VIC, Australia.
- Department of Medicine, University of Melbourne, Melbourne, VIC, Australia.
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Surandran S, Ahmed S, Walton T, Nikiphorou E, Dey M. Multimorbidity in rheumatoid arthritis: common mechanistic links and impact and challenges in routine clinical practice. Rheumatology (Oxford) 2023; 62:SI260-SI270. [PMID: 37871920 DOI: 10.1093/rheumatology/kead489] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/01/2023] [Accepted: 09/13/2023] [Indexed: 10/25/2023] Open
Abstract
Early identification and management of multimorbidity in patients with rheumatic and musculoskeletal diseases (RMDs), such as RA, is an integral, but often neglected, aspect of care. The prevalence and incidence of conditions such as osteoporosis, cardiovascular disease, pulmonary disease and malignancies, often co-existing with RA, continues to have significant implications for the management of this patient group. Multimorbidity in RMDs can be associated with inflammatory disease activity and target organ damage. Lifestyle factors, such as smoking and inactivity, further contribute to the burden of disease. Inflammation is the underlying factor, not just in RA but also many comorbidities. The current framework of a treat-to-target approach focuses on achieving early remission and inflammatory activity suppression. We describe how the comorbidity burden in people with RMDs impacts on disease outcome and treatment response. The importance of addressing comorbidity at an early stage and adopting a patient centred approach is critical in modern practice.
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Affiliation(s)
| | - Saad Ahmed
- Department of Rheumatology, Colchester General Hospital, Colchester, UK
| | - Tom Walton
- Department of Rheumatology, Colchester General Hospital, Colchester, UK
| | - Elena Nikiphorou
- Centre for Rheumatic Diseases, King's College London, London, UK
- Rheumatology Department, King's College Hospital, London, UK
| | - Mrinalini Dey
- Institute of Life Course and Medical Sciences, University of Liverpool, Liverpool, UK
- Department of Rheumatology, Countless of Chester Hospital NHS Foundation Trust, Chester, UK
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17
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Miyata H, Sonomoto K, Fukuyo S, Nakayamada S, Nakano K, Iwata S, Miyazaki Y, Kawabe A, Aoki T, Tanaka Y. Computed tomography for malignancy screening in patients with rheumatoid arthritis before initiation of disease modifying antirheumatic drug. Rheumatology (Oxford) 2023; 62:3339-3349. [PMID: 36782362 DOI: 10.1093/rheumatology/kead075] [Citation(s) in RCA: 8] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/11/2022] [Revised: 01/14/2023] [Accepted: 02/01/2023] [Indexed: 02/15/2023] Open
Abstract
OBJECTIVES This study aimed to clarify the usefulness of screening for malignancies using CT before the initiation of biologic and targeted synthetic DMARDs (b/tsDMARDs) in patients with active RA. METHODS We examined 2192 patients with RA who underwent plain CT scans prior to the initiation of b/tsDMARDs. The sensitivity for detecting malignancy was measured and compared with that of regular screening (physical examination and X-ray). We then evaluated the clinical characteristics, prognosis and treatment of patients with RA with concomitant malignancies. Additionally, we determined the incidence rate of malignancy in patients with RA who were initiated on b/tsDMARDs after CT screening. RESULTS Of the 2192 patients, 33 (1.5%) were diagnosed with malignancy after CT screening. Whereas regular screening detected only seven malignancies, CT screening further detected 26 (including 19 at the early stage). On the other hand, 86% of the malignancies detectable by regular screening were at an advanced stage. Patients diagnosed with early-stage malignancies received RA treatments that included b/tsDMARDs after curative resection; 80% of these patients achieved low disease activity after 1 year. This rate was comparable to the patients without malignancy detection after screening (70%). The 5 year incidence of malignancy after the initiation of b/tsDMARDs after CT screening was lower than that of the RA cohort without CT screening (standardized incidence ratio: 0.35). CONCLUSION Screening in patients with RA using CT before the initiation of b/tsDMARDs allows for the early detection and treatment of malignancy, resulting in safer and more stable b/tsDMARD treatments.
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Affiliation(s)
- Hiroko Miyata
- The First Department of Internal Medicine, University of Occupational and Environmental Health, Japan, Kitakyushu, Japan
| | - Koshiro Sonomoto
- The First Department of Internal Medicine, University of Occupational and Environmental Health, Japan, Kitakyushu, Japan
- Department of Clinical Nursing, School of Health Sciences, University of Occupational and Environmental Health, Japan, Kitakyushu, Japan
| | - Shunsuke Fukuyo
- The First Department of Internal Medicine, University of Occupational and Environmental Health, Japan, Kitakyushu, Japan
- Department of Rheumatology, Wakamatsu Hospital of the University of the Occupational and Environmental Health, Japan, Kitakyushu, Japan
| | - Shingo Nakayamada
- The First Department of Internal Medicine, University of Occupational and Environmental Health, Japan, Kitakyushu, Japan
| | - Kazuhisa Nakano
- The First Department of Internal Medicine, University of Occupational and Environmental Health, Japan, Kitakyushu, Japan
- Department of Rheumatology, Kawasaki Medical School, Okayama, Japan
| | - Shigeru Iwata
- The First Department of Internal Medicine, University of Occupational and Environmental Health, Japan, Kitakyushu, Japan
- Department of Rheumatology, Wakayama Medical University, Wakayama, Japan
| | - Yusuke Miyazaki
- The First Department of Internal Medicine, University of Occupational and Environmental Health, Japan, Kitakyushu, Japan
| | - Akio Kawabe
- The First Department of Internal Medicine, University of Occupational and Environmental Health, Japan, Kitakyushu, Japan
| | - Takatoshi Aoki
- Department of Radiology, University of Occupational and Environmental Health, Japan, Kitakyushu, Japan
| | - Yoshiya Tanaka
- The First Department of Internal Medicine, University of Occupational and Environmental Health, Japan, Kitakyushu, Japan
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18
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Yamaoka K, Oku K. JAK inhibitors in rheumatology. Immunol Med 2023; 46:143-152. [PMID: 36744577 DOI: 10.1080/25785826.2023.2172808] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/04/2022] [Accepted: 01/22/2023] [Indexed: 02/07/2023] Open
Abstract
Janus kinase inhibitors (JAKis) are a group of drugs with a different mechanism of action from biologics and are most rapidly uptaken in the rheumatology field. JAK is a protein kinase activated in the cytoplasm by multiple cytokines and hormones involved in inflammatory pathology. The expression of JAK has been observed in various diseases, indicating the utility of JAK inhibitors in a wide variety of immune-mediated inflammatory diseases. Clinical trials are underway for a number of different rheumatic diseases based on the therapeutic efficacy of JAKis, which is comparable to that of biologics. This article will review the current status of JAKis for rheumatic diseases in terms of efficacy and safety and extend to future clinical applications for rare diseases.
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Affiliation(s)
- Kunihiro Yamaoka
- Department of Rheumatology and Infectious Diseases, Kitasato University School of Medicine, Kanagawa, Japan
| | - Kenji Oku
- Department of Rheumatology and Infectious Diseases, Kitasato University School of Medicine, Kanagawa, Japan
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Russell MD, Stovin C, Alveyn E, Adeyemi O, Chan CKD, Patel V, Adas MA, Atzeni F, Ng KKH, Rutherford AI, Norton S, Cope AP, Galloway JB. JAK inhibitors and the risk of malignancy: a meta-analysis across disease indications. Ann Rheum Dis 2023; 82:1059-1067. [PMID: 37247942 PMCID: PMC10359573 DOI: 10.1136/ard-2023-224049] [Citation(s) in RCA: 54] [Impact Index Per Article: 27.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/17/2023] [Accepted: 04/25/2023] [Indexed: 05/31/2023]
Abstract
OBJECTIVES To estimate the association of Janus kinase inhibitors (JAKi) with the incidence of malignancy, compared with placebo, tumour necrosis factor (TNF)-α inhibitors (TNFi) and methotrexate. METHODS Systematic searches of databases were performed, to December 2022, to identify phase II/III/IV randomised clinical trials (RCTs) and long-term extension (LTE) studies of JAKi (tofacitinib, baricitinib, upadacitinib, filgotinib, peficitinib) compared with placebo, TNFi or methotrexate, in adults with rheumatoid arthritis, psoriatic arthritis, psoriasis, axial spondyloarthritis, inflammatory bowel disease or atopic dermatitis. Network and pairwise meta-analyses were performed to estimate incidence rate ratios (IRRs) for malignancy between JAKi and comparators. Bias was assessed using the Cochrane Risk of Bias-2 tool. RESULTS In 62 eligible RCTs and 16 LTE studies, there were 82 366 person-years of exposure to JAKi, 2924 to placebo, 7909 to TNFi and 1074 to methotrexate. The overall malignancy incidence rate was 1.15 per 100 person-years in RCTs, and 1.26 per 100 person-years across combined RCT and LTE data. In network meta-analyses, the incidence of all malignancies including non-melanomatous skin cancers (NMSCs) was not significantly different between JAKi and placebo (IRR 0.71; 95% CI 0.44 to 1.15) or between JAKi and methotrexate (IRR 0.77; 95% CI 0.35 to 1.68). Compared with TNFi, however, JAKi were associated with an increased incidence of malignancy (IRR 1.50; 95% CI 1.16 to 1.94). Findings were consistent when analysing NMSC only and when analysing combined RCT/LTE data. CONCLUSIONS JAKi were associated with a higher incidence of malignancy compared with TNFi but not placebo or methotrexate. Cancers were rare events in all comparisons. PROSPERO REGISTRATION NUMBER CRD42022362630.
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Affiliation(s)
- Mark D Russell
- Centre for Rheumatic Diseases, King's College London, London, UK
| | | | - Edward Alveyn
- Centre for Rheumatic Diseases, King's College London, London, UK
| | - Olukemi Adeyemi
- Centre for Rheumatic Diseases, King's College London, London, UK
| | | | - Vishit Patel
- Centre for Rheumatic Diseases, King's College London, London, UK
| | - Maryam A Adas
- Centre for Rheumatic Diseases, King's College London, London, UK
| | - Fabiola Atzeni
- Rheumatology Unit, University of Messina, Messina, Italy
| | - Kenrick K H Ng
- Department of Medical Oncology, University College London, London, UK
| | | | - Sam Norton
- Centre for Rheumatic Diseases, King's College London, London, UK
| | - Andrew P Cope
- Centre for Rheumatic Diseases, King's College London, London, UK
| | - James B Galloway
- Centre for Rheumatic Diseases, King's College London, London, UK
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20
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Sonomoto K, Tanaka Y. Malignancies and rheumatoid arthritis, csDMARDs, biological DMARDs, and JAK inhibitors: challenge and outlook. Expert Rev Clin Immunol 2023; 19:1325-1342. [PMID: 37578325 DOI: 10.1080/1744666x.2023.2247158] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/24/2023] [Accepted: 08/08/2023] [Indexed: 08/15/2023]
Abstract
INTRODUCTION Rheumatoid arthritis (RA) is an autoimmune disorder necessitating immunosuppressive therapy. Remarkable progress has been made in the treatment of RA over recent decades, particularly with the development of biological disease-modifying antirheumatic drugs (bDMARDs) and Janus kinase inhibitors (JAKi). Nonetheless, the development of new drugs has been accompanied by concerns regarding the association between these novel therapies and the risk of malignancy. AREAS COVERED This narrative review aims to discuss the understanding of RA, conventional synthetic (cs) DMARDs, bDMARDs, JAKi, and their association with malignancy. Furthermore, the review discusses the management of malignancy in patients receiving b/tsDMARDs. EXPERT OPINION Although recent studies suggest that the potential risk of malignancy of methotrexate and a JAKi tofacitinib, it is essential to avoid indiscriminate withholding of treatment by those agents, as this may lead functional impairment and increased mortality. Therefore, the adoption of a Treat-to-Target (T2T) approach considering individual patient characteristics, becomes of utmost importance. Rheumatologists should maintain a vigilant stance regarding malignancy in this context, recognizing the importance of early detection and management. Implementing a screening program for malignancies is indispensable, and the use of computed tomography screening may enhance the effectiveness of management strategies.
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Affiliation(s)
- Koshiro Sonomoto
- Department of Clinical Nursing, School of Health Sciences, University of Occupational and Environmental Health Japan, Fukuoka, Japan
- The First Department of Internal Medicine, School of Medicine, University of Occupational and Environmental Health Japan, Fukuoka, Japan
| | - Yoshiya Tanaka
- The First Department of Internal Medicine, School of Medicine, University of Occupational and Environmental Health Japan, Fukuoka, Japan
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21
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Conceição D, Saraiva MR, Rosa I, Claro I. Inflammatory Bowel Disease Treatment in Cancer Patients-A Comprehensive Review. Cancers (Basel) 2023; 15:3130. [PMID: 37370740 DOI: 10.3390/cancers15123130] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/30/2023] [Revised: 05/30/2023] [Accepted: 06/07/2023] [Indexed: 06/29/2023] Open
Abstract
Inflammatory bowel disease (IBD) is a chronic disease for which medical treatment with immunomodulating drugs is increasingly used earlier to prevent disability. Additionally, cancer occurrence in IBD patients is increased for several reasons, either IBD-related or therapy-associated. Doctors are therefore facing the challenge of managing patients with IBD and a past or current malignancy and the need to balance the risk of cancer recurrence associated with immunosuppressive drugs with the potential worsening of IBD activity if they are withdrawn. This review aims to explore the features of different subtypes of cancer occurring in IBD patients to present current evidence on malignancy recurrence risk associated with IBD medical therapy along with the effects of cancer treatment in IBD and finally to discuss current recommendations on the management of these patients. Due to sparse data, a case-by-case multidisciplinary discussion is advised, including inputs from the gastroenterologist, oncologist, and patient.
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Affiliation(s)
- Daniel Conceição
- Department of Gastroenterology, Instituto Português de Oncologia de Lisboa Francisco Gentil, 1099-023 Lisboa, Portugal
| | - Margarida R Saraiva
- Department of Gastroenterology, Instituto Português de Oncologia de Lisboa Francisco Gentil, 1099-023 Lisboa, Portugal
| | - Isadora Rosa
- Department of Gastroenterology, Instituto Português de Oncologia de Lisboa Francisco Gentil, 1099-023 Lisboa, Portugal
| | - Isabel Claro
- Department of Gastroenterology, Instituto Português de Oncologia de Lisboa Francisco Gentil, 1099-023 Lisboa, Portugal
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22
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Krüger K. [DMARD (disease-modifying antirheumatic drug) treatment in patients with former or current cancer]. Z Rheumatol 2023; 82:206-211. [PMID: 36757415 DOI: 10.1007/s00393-023-01316-7] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 12/19/2022] [Indexed: 02/10/2023]
Abstract
In contrast to the original fear that treatment with disease-modifying antirheumatic drugs (DMARDs) and especially with biologic DMARDs (bDMARDs), was associated with an increased risk of the induction of malignancies, this has meanwhile fortunately not been confirmed over the long-term administration. Evaluations from register-based investigations as well as from other long-term cohort studies confirm that neither conventional DMARDs, such as methotrexate, nor tumor necrosis factor (TNF) inhibitors or biologics with a different mode of action show such a risk for induction of cancer or hematological malignancies (for skin tumors see the other article). Regarding the question whether recurrences of former malignancies can be induced by DMARDs, the database is considerably smaller; however, published investigations dealing with this topic so far signal that also in this respect no increased risk can be found. When comparing the individual substances with each other no substantial differences can be found. Although used in the treatment of hematological cancers, rituximab does not offer any advantages in comparison to other biologics. For the group of Janus kinase (JAK) inhibitors, which have been in use only for a few years, data outside the randomized controlled studies (which are limited in time and are conducted with a selected patient population) are limited so that a clear statement regarding the malignancy risk is not yet possible for these substances. In a solitary study comparing tofacitinib with TNF inhibitors in high-risk patients, the malignancy risk of the JAK inhibitor was increased compared to that under TNF inhibitor treatment; however, these results have not yet been confirmed by a second investigation.
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Affiliation(s)
- Klaus Krüger
- Rheumatologisches Praxiszentrum, St. Bonifatius Str. 5, 81541, München, Deutschland.
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23
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Therapeutic Management of Adults with Inflammatory Bowel Disease and Malignancies: A Clinical Challenge. Cancers (Basel) 2023; 15:cancers15020542. [PMID: 36672491 PMCID: PMC9856548 DOI: 10.3390/cancers15020542] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/13/2022] [Revised: 01/11/2023] [Accepted: 01/14/2023] [Indexed: 01/19/2023] Open
Abstract
Patients with chronic inflammatory bowel diseases (IBD) have increased risk of developing intestinal and extraintestinal cancers. However, once a diagnosis of malignancy is made, the therapeutic management of Crohn's disease (CD) and ulcerative colitis (UC) can be challenging as major guidelines suggest discontinuing the ongoing immunosuppressant and biological therapies for at least 2-5 years after the end of cancer treatment. Recently, new molecules such as vedolizumab and ustekinumab have been approved for IBD and limited data exist on the real risk of new or recurrent cancer in IBD patients with prior cancer, exposed to immunosuppressants and biologic agents. Thus, a multidisciplinary approach and case-by-case management is the preferred choice. The primary aim of our review was to summarize the current evidence about the safety of reintroducing an immunosuppressant or biologic agent in patients with a history of malignancy and to compare the different available therapies, including gut-selective agents. The secondary aim was to evaluate the clinical course of the IBD patients under cancer treatment who do not receive any specific immunosuppressant treatment after the diagnosis of cancer.
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24
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Li H, Yu L, Zhang X, Shang J, Duan X. Exploring the molecular mechanisms and shared gene signatures between rheumatoid arthritis and diffuse large B cell lymphoma. Front Immunol 2022; 13:1036239. [PMID: 36389761 PMCID: PMC9659608 DOI: 10.3389/fimmu.2022.1036239] [Citation(s) in RCA: 15] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/04/2022] [Accepted: 10/17/2022] [Indexed: 07/25/2023] Open
Abstract
The relationship between rheumatoid arthritis (RA) and diffuse large B-cell lymphoma (DLBCL) is well characterized, but the molecular mechanisms underlying this association have not been clearly investigated. Our study aimed to identify shared gene signatures and molecular mechanisms between RA and DLBCL. We selected multiple Gene Expression Omnibus (GEO) datasets (GSE93272, GSE83632, GSE12453, GSE1919) to obtain gene expression levels and clinical information about patients with RA and DLBCL. Weighted gene co-expression network analysis (WGCNA) was used to research co-expression networks associated with RA and DLBCL. Subsequently, we performed enrichment analysis of shared genes and screened the most significant core genes. We observed expression of the screened target gene, galectin 2 (LGALS2), in DLBCL patients and its impact on patient prognosis. Finally, we analyzed the molecular functional mechanism of LGALS2 and observed its relationship with the immune response in DLBCL using single-sample Gene Set Enrichment Analysis (ssGSEA). WGCNA recognized two major modules for RA and DLBCL, respectively. Shared genes (551) were identified for RA and DLBCL by observing the intersection. In addition, a critical shared gene, LGALS2, was acquired in the validation tests. Next, we found that the expression level of LGALS2 gradually decreased with tumor progression in DLBCL and that increased expression of LGALS2 predicted a better prognosis for DLBCL patients. ssGSEA revealed that LGALS2 is involved in immune-related pathways and has a significant regulatory effect on human immune responses. Additionally, we observed that LGALS2 is closely related to the sensitivity of multiple chemotherapeutic drugs. There is extremely little research on the molecular mechanism of correlation between RA and DLBCL. Our study identified that LGALS2 is a potential therapeutic target and an immune-related biomarker for patients with RA and DLBCL.
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25
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Choi B, Park HJ, Song YK, Oh YJ, Kim IW, Oh JM. The risk of newly diagnosed cancer in patients with rheumatoid arthritis by TNF inhibitor use: a nationwide cohort study. Arthritis Res Ther 2022; 24:191. [PMID: 35945635 PMCID: PMC9364556 DOI: 10.1186/s13075-022-02868-w] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/21/2021] [Accepted: 07/15/2022] [Indexed: 11/10/2022] Open
Abstract
Background Tumor necrosis factor (TNF) inhibitors use in patients with rheumatoid arthritis (RA) has raised safety concerns about cancer risk, but study results remain controversial. This largest nationwide study to date compared cancer risk in TNF inhibitor users to non-biologic disease-modifying anti-rheumatic drug (nbDMARD) users in Korean patients with RA. Methods Data on all the eligible patients diagnosed with RA between 2005 and 2016 were retrieved from the Korean National Health Information Database. The one-to-one matched patients consisted of the matched cohort. The risks for developing all-type and site-specific cancers were estimated using incidence and incidence rate (IR) per 1000 person-years. Adjusted hazard ratio (HR) and 95% confidence interval (CI) were estimated using a Cox regression model. Results Of the 22,851 patients in the before matching cohort, 4592 patients were included in the matched cohort. Treatment with TNF inhibitors was consistently associated with a lower risk of cancer than in the nbDMARD cohort (IR per 1000 person-years, 6.5 vs. 15.6; adjusted HR, 0.379; 95% CI, 0.255–0.563). The adjusted HR (95% CI) was significantly lower in the TNF inhibitor cohort than the nbDMARD cohort for gastrointestinal cancer (0.432; 0.235–0.797), breast cancer (0.146; 0.045–0.474), and genitourinary cancer (0.220; 0.059–0.820). Conclusions The use of TNF inhibitors was not associated with an increased risk of cancer development, and rather associated with a lower cancer incidence in Korean patients with RA. Cautious interpretation is needed not to oversimplify the study results as cancer-protective effects of TNF inhibitors. A further study linking claims and clinical data is needed to confirm our results. Supplementary Information The online version contains supplementary material available at 10.1186/s13075-022-02868-w.
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Affiliation(s)
- Boyoon Choi
- Department of Pharmacy, College of Pharmacy and Institute of Pharmaceutical Sciences, CHA University, Pocheon-si, Gyeonggi, Republic of Korea
| | - Hyun Jin Park
- College of Pharmacy and Research Institute of Pharmaceutical Sciences, Seoul National University, 1 Gwanak-ro, Gwanak-gu, Seoul, 08826, Republic of Korea
| | - Yun-Kyoung Song
- College of Pharmacy and Research Institute of Pharmaceutical Sciences, Seoul National University, 1 Gwanak-ro, Gwanak-gu, Seoul, 08826, Republic of Korea.,College of Pharmacy, Daegu Catholic University, Gyeongsan-si, Gyeongbuk, Republic of Korea
| | - Yoon-Jeong Oh
- Division of Rheumatology, Department of Internal Medicine, Kangwon National University School of Medicine, Chuncheon-si, Kangwon, Republic of Korea
| | - In-Wha Kim
- College of Pharmacy and Research Institute of Pharmaceutical Sciences, Seoul National University, 1 Gwanak-ro, Gwanak-gu, Seoul, 08826, Republic of Korea
| | - Jung Mi Oh
- College of Pharmacy and Research Institute of Pharmaceutical Sciences, Seoul National University, 1 Gwanak-ro, Gwanak-gu, Seoul, 08826, Republic of Korea.
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26
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Schmalzing M. [Management of inflammatory rheumatic diseases during and after malignancies]. Z Rheumatol 2022; 81:766-777. [PMID: 35796758 DOI: 10.1007/s00393-022-01237-x] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 06/09/2022] [Indexed: 11/24/2022]
Abstract
The management of inflammatory rheumatic diseases in patients with a simultaneous or previous malignant disease is associated with complex questions. Difficulties and possible solutions in the interpretation of meaningful studies are presented. Recommendations in guidelines on this topic are discussed. National registries and health insurance databases were examined with respect to the risk of tumor recurrence under disease-modifying antirheumatic drugs; however, these analyses mainly refer to tumor necrosis factor (TNF) inhibitors and rituximab. Data on tumor incidence and, if available, risk of tumor recurrence are summarized for commonly used disease-modifying antirheumatic drugs. Finally, an attempt is made to formulate proposals for rheumatological treatment in patients with a history of malignancy.
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Affiliation(s)
- Marc Schmalzing
- Rheumatologie/Klinische Immunologie, Medizinische Klinik und Poliklinik II, Universitätsklinikum Würzburg, Oberdürrbacher Str. 6, 97080, Würzburg, Deutschland.
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27
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Joo YB, Jeong SM, Park YJ, Kim KJ, Park KS. Use of Disease-modifying Antirheumatic Drugs After Cancer Diagnosis in Rheumatoid Arthritis Patients. JOURNAL OF RHEUMATIC DISEASES 2022; 29:162-170. [PMID: 37475975 PMCID: PMC10324922 DOI: 10.4078/jrd.2022.29.3.162] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/20/2022] [Revised: 03/09/2022] [Accepted: 04/05/2022] [Indexed: 07/22/2023]
Abstract
Objective There is no recommendation for the use of disease-modifying antirheumatic drugs (DMARDs) in patients with rheumatoid arthritis (RA) who developed cancer. We examined changes in the DMARDs prescription patterns associated with cancer diagnosis in RA patients. Methods We reviewed the medical records of 2,161 RA patients who visited rheumatology clinic between January 2008 and February 2017 and found 40 patients who developed cancer during RA treatment. In these patients, we examined DMARDs prescription patterns before and right after cancer diagnosis and at recent outpatient clinic visits. Results Before cancer diagnosis, methotrexate (MTX)-combined conventional synthetic DMARDs (csDMARDs) were most commonly prescribed (22, 55.0%) and biological DMARDs (biologics) in nine patients (22.5%). For cancer treatment, 19 patients received chemotherapy (including adjuvant chemotherapy) and 21 patients had surgery only. Right after cancer diagnosis, changes in the DMARDs prescription patterns were similar in discontinuation (13, 32.5%), switching (14, 35.0%), and maintenance (13, 32.5%). DMARDs were discontinued more frequently in the chemotherapy group (9/19, 47.4%) than the surgery only group (4/2, 19.0%) (p<0.05). Among the 13 patients who discontinued DMARDs, nine (69.2%) resumed DMARDs after a median of 5.5 months (interquartile range [IQR] 2.9, 18.3) due to arthritis flare. At a median of 4.6 years (IQR 3.3, 6.7) after cancer diagnosis, 25 patients were evaluated at recent outpatient clinic visits. Four patients received no DMARD, three MTX monotherapies, 11 csDMARDs combination therapies, and seven biologics. Conclusion A significant number of RA patients who developed cancer during RA treatment were still receiving DMARDs including biologics after cancer diagnosis.
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Affiliation(s)
- Young Bin Joo
- Division of Rheumatology, Department of Internal Medicine, Hanyang University Guri Hospital, Guri, Korea
| | - Seung Min Jeong
- Division of Rheumatology, Department of Internal Medicine, College of Medicine, The Catholic University of Korea, Seoul, Korea
| | - Yune-Jung Park
- Division of Rheumatology, Department of Internal Medicine, College of Medicine, The Catholic University of Korea, Seoul, Korea
| | - Ki-Jo Kim
- Division of Rheumatology, Department of Internal Medicine, College of Medicine, The Catholic University of Korea, Seoul, Korea
| | - Kyung-Su Park
- Division of Rheumatology, Department of Internal Medicine, College of Medicine, The Catholic University of Korea, Seoul, Korea
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28
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Abadie BQ, Cremer PC. Interleukin-1 Antagonists for the Treatment of Recurrent Pericarditis. BioDrugs 2022; 36:459-472. [PMID: 35639340 PMCID: PMC9152656 DOI: 10.1007/s40259-022-00537-7] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 04/26/2022] [Indexed: 11/21/2022]
Abstract
Although most patients with acute pericarditis will recover, a minority will have recurrent, debilitating episodes. In these patients, refractory symptoms result in high morbidity, and typically require a prolonged duration of anti-inflammatory treatment. Initially, the efficacy of colchicine in both recurrent pericarditis and periodic fever syndromes suggested the central role of the inflammasome in pericarditis. Subsequently, the success of interleukin-1 antagonists in autoinflammatory diseases prompted further investigation in recurrent pericarditis. In current clinical practice, interleukin-1 antagonists include canakinumab, anakinra, and rilonacept. Both anakinra and rilonacept have demonstrated efficacy in randomized trials of patients with recurrent pericarditis. The aim of the current review is to explain the biological rationale for interleukin-1 antagonists in recurrent pericarditis, highlight supporting clinical evidence, and emphasizing future areas of investigation.
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Affiliation(s)
- Bryan Q Abadie
- Center for the Diagnosis and Treatment of Pericardial Diseases, Section of Cardiovascular Imaging, Department of Cardiovascular Medicine, Heart, Vascular, and Thoracic Institute, Cleveland Clinic, Cleveland, OH, USA
| | - Paul C Cremer
- Center for the Diagnosis and Treatment of Pericardial Diseases, Section of Cardiovascular Imaging, Department of Cardiovascular Medicine, Heart, Vascular, and Thoracic Institute, Cleveland Clinic, Cleveland, OH, USA.
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29
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Huss V, Bower H, Wadström H, Frisell T, Askling J. Short- and longer-term cancer risks with biologic and targeted synthetic disease-modifying antirheumatic drugs as used against rheumatoid arthritis in clinical practice. Rheumatology (Oxford) 2022; 61:1810-1818. [PMID: 34324640 PMCID: PMC9071561 DOI: 10.1093/rheumatology/keab570] [Citation(s) in RCA: 37] [Impact Index Per Article: 12.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/15/2021] [Revised: 07/05/2021] [Indexed: 11/14/2022] Open
Abstract
OBJECTIVE To estimate the occurrence and relative risks of first-ever-incident non-cutaneous cancer overall and for 16 sites in patients with RA treated with biologic and targeted synthetic DMARDs (b/tsDMARDs), by time since treatment start, attained age, and duration of active treatment. METHODS This is an observational nationwide and population-based cohort study of patients with RA (n = 69 308), treated with TNF inhibitors (TNFi; adalimumab, certolizumab, etanercept, golimumab, infliximab) or other b/tsDMARDs (abatacept, rituximab, baricitinib, tofacitinib and tocilizumab) compared with RA patients not treated with b/tsDMARDs, and matched general population referents (n = 109 532), 2001-2018. The study was based on prospectively collected data from the Swedish Rheumatology Quality Register and from other registers, linked to the national Swedish Cancer Register. Incidence rates and hazard ratios were estimated via Cox regression adjusted for co-morbidities and other health characteristics. RESULTS Based on 8633 incident cancers among RA patients, the overall relative risk of cancer with TNFi [hazard ratio (HR) = 1.0] was neither increased nor did it change with time since treatment start, duration of active treatment, or attained age, when compared with b/tsDMARD-naïve RA. For other b/tsDMARDs, we noted no consistent signal of increased overall risks (HRs ranged from 1.0 to 1.2), but there were statistically significant estimates above 1 for abatacept with 2-5 years of active treatment, for older age groups, and between several of the bDMARDs and urinary tract cancer. CONCLUSION TNFis, as used long term in clinical practice against RA, are not linked to increased risks for cancer overall. For other b/tsDMARDs, and for site-specific risks, our results are generally reassuring but contain signals that call for replication.
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Affiliation(s)
- Viking Huss
- Clinical Epidemiology Division, Karolinska Institutet, Stockholm, Sweden
- Rheumatology, Karolinska University Hospital Solna, Stockholm, Sweden
| | - Hannah Bower
- Clinical Epidemiology Division, Karolinska Institutet, Stockholm, Sweden
| | - Hjalmar Wadström
- Clinical Epidemiology Division, Karolinska Institutet, Stockholm, Sweden
| | - Thomas Frisell
- Clinical Epidemiology Division, Karolinska Institutet, Stockholm, Sweden
| | - Johan Askling
- Clinical Epidemiology Division, Karolinska Institutet, Stockholm, Sweden
- Rheumatology, Karolinska University Hospital Solna, Stockholm, Sweden
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30
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Strangfeld A, Albrecht K, Regierer A, Callhoff J, Zink A, Minden K. [Celebrating 33 years of the DRFZ: Epidemiology and Health Services Research]. Z Rheumatol 2022; 81:642-651. [PMID: 35380251 PMCID: PMC8980768 DOI: 10.1007/s00393-022-01187-4] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 11/25/2021] [Indexed: 11/18/2022]
Abstract
Der wissenschaftliche Fokus des Programmbereichs Epidemiologie und Versorgungsforschung des DRFZ liegt einerseits auf der Erforschung der Versorgungssituation rheumakranker Menschen in Deutschland einschließlich ihrer Defizite, Fortschritte und zeitlichen Trends. Andererseits ist ein wesentliches Ziel, durch die langfristige Beobachtung von Krankheitsverläufen in großen Kohorten Risikofaktoren für ungünstige Krankheitsverläufe, aber auch protektive Faktoren aufzudecken. Mit der Zulassung innovativer, zielgerichteter Therapien zu Beginn dieses Jahrtausends wurde die Thematik der Sicherheit und Wirksamkeit der verschiedenen antirheumatischen Therapien unter Alltagsbedingungen zu einer für Ärzte und Patienten vorrangigen Frage. Die Biologika-Register entwickelten sich zu zentralen Instrumenten des Programmbereichs, mit denen Fragen zur vergleichenden Therapiesicherheit, aber auch zur Therapiewirksamkeit und Reduktion von Risiken durch wirksame Therapie, belastbar beantwortet werden können. Im vorliegenden Artikel werden ausgewählte Ergebnisse epidemiologischer Forschung am DRFZ dargestellt. Das übergreifende Ziel der Forschung war und ist es, zur Verbesserung der Lebensqualität rheumakranker Kinder und Erwachsener beizutragen. Dem dient die klinisch-evaluative Versorgungsforschung ebenso wie die Gewinnung von Erkenntnissen, die eine wirksame, individualisierte Therapie unterstützen. Als unverzichtbare Instrumente haben sich große, langfristige Patientenkohorten und ein stabiles Netzwerk mit den klinisch tätigen Rheumatologen und Betroffenen erwiesen.
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Affiliation(s)
- Anja Strangfeld
- Programmbereich Epidemiologie und Versorgungsforschung, Deutsches Rheuma-Forschungszentrum Berlin, Charitéplatz 1, 10117, Berlin, Deutschland. .,Medizinische Klinik mit Schwerpunkt Rheumatologie und Klinische Immunologie, Charité - Universitätsmedizin Berlin, Berlin, Deutschland.
| | - Katinka Albrecht
- Programmbereich Epidemiologie und Versorgungsforschung, Deutsches Rheuma-Forschungszentrum Berlin, Charitéplatz 1, 10117, Berlin, Deutschland
| | - Anne Regierer
- Programmbereich Epidemiologie und Versorgungsforschung, Deutsches Rheuma-Forschungszentrum Berlin, Charitéplatz 1, 10117, Berlin, Deutschland
| | - Johanna Callhoff
- Programmbereich Epidemiologie und Versorgungsforschung, Deutsches Rheuma-Forschungszentrum Berlin, Charitéplatz 1, 10117, Berlin, Deutschland
| | - Angela Zink
- Programmbereich Epidemiologie und Versorgungsforschung, Deutsches Rheuma-Forschungszentrum Berlin, Charitéplatz 1, 10117, Berlin, Deutschland
| | - Kirsten Minden
- Programmbereich Epidemiologie und Versorgungsforschung, Deutsches Rheuma-Forschungszentrum Berlin, Charitéplatz 1, 10117, Berlin, Deutschland.,Medizinische Klinik mit Schwerpunkt Rheumatologie und Klinische Immunologie, Charité - Universitätsmedizin Berlin, Berlin, Deutschland
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Kragstrup TW, Glintborg B, Svensson AL, McMaster C, Robinson PC, Deleuran B, Liew DF. Waiting for JAK inhibitor safety data. RMD Open 2022; 8:e002236. [PMID: 35197363 PMCID: PMC8867353 DOI: 10.1136/rmdopen-2022-002236] [Citation(s) in RCA: 50] [Impact Index Per Article: 16.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/24/2022] [Accepted: 02/04/2022] [Indexed: 12/23/2022] Open
Abstract
The US Food and Drug Administration (FDA) has recently added a new 'black box warning' on all currently approved Janus kinase (JAK) inhibitors indicated for the treatment of arthritis and other inflammatory conditions based on results from the ORAL Surveillance study of tofacitinib versus tumour necrosis factor alpha inhibitors in rheumatoid arthritis. This is a warning difficult to ignore because the data, being from a randomised controlled trial, are of high fidelity and hard to reproach. It is especially problematic because safety data for all the other JAK inhibitors will be pending for several years. So how might we proceed, without being bound by our stasis? The lack of absolute certainty seems to require a pragmatic approach to the routine care use of JAK inhibitors. The patients who were at greatest risk were older and had other risk factors for the corresponding adverse events, in keeping with effect modification. This highlights the need to focus on risk stratification when tailoring therapy. In this viewpoint, we propose a simple illustration to guide clinical decision-making. First, identify general risk factors for venous thromboembolic event (VTE), major adverse cardiac event (MACE) and cancer (age>65 years and smoking) and whether there is a previous history of VTE, MACE or cancer. Then, evaluate risk based on the number of other risk factors for VTE and the number of other risk factors for MACE. Ultimately, 'treat-to-target' will in the end always be 'treat-to-agreement'. As we have done in the past, and will do in the future, the optimal treatment strategy will have to be tailored based on individual patient risk factors and preferences in a shared-decision process.
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Affiliation(s)
- Tue Wenzel Kragstrup
- Department of Biomedicine, Aarhus University, Aarhus, Denmark
- Diagnostic Center, Silkeborg Regional Hospital, Silkeborg, Denmark
| | - Bente Glintborg
- Department of Clinical Medicine, University of Copenhagen, Kobenhavn, Denmark
- DANBIO and Copenhagen Center for Arthritis Research (COPECARE), Center for Rheumatology and Spine Diseases, Centre of Head and Orthopedics, University Hospital of Copenhagen Rigshospitalet, Glostrup, Denmark
| | - Annemarie L Svensson
- Department of Rheumatology, Center for Rheumatology and Spine Diseases, Centre of Head and Orthopedics, University Hospital of Copenhagen Rigshospitalet, Glostrup, Denmark
| | - Christopher McMaster
- Department of Rheumatology, Austin Health, Heidelberg, Victoria, Australia
- Department of Clinical Pharmacology and Therapeutics, Austin Health, Heidelberg, Victoria, Australia
- The Centre for Digital Transformation of Health, University of Melbourne, Parkville, Victoria, Australia
| | - Philip C Robinson
- Faculty of Medicine, University of Queensland School of Clinical Medicine, Brisbane, Queensland, Australia
- Department of Rheumatology, Royal Brisbane and Women's Hospital, Herston, Queensland, Australia
| | - Bent Deleuran
- Department of Biomedicine, Aarhus University, Aarhus, Denmark
- Department of Rheumatology, Aarhus University Hospital, Aarhus, Denmark
| | - David Fl Liew
- Department of Rheumatology, Austin Health, Heidelberg, Victoria, Australia
- Department of Clinical Pharmacology and Therapeutics, Austin Health, Heidelberg, Victoria, Australia
- Department of Medicine, University of Melbourne, Parkville, Victoria, Australia
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Vedamurthy A, Gangasani N, Ananthakrishnan AN. Vedolizumab or Tumor Necrosis Factor Antagonist Use and Risk of New or Recurrent Cancer in Patients With Inflammatory Bowel Disease With Prior Malignancy: A Retrospective Cohort Study. Clin Gastroenterol Hepatol 2022; 20:88-95. [PMID: 33065312 DOI: 10.1016/j.cgh.2020.10.007] [Citation(s) in RCA: 20] [Impact Index Per Article: 6.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/22/2020] [Revised: 10/05/2020] [Accepted: 10/08/2020] [Indexed: 02/07/2023]
Abstract
BACKGROUND & AIMS Treatment of patients with inflammatory bowel diseases (IBD; Crohn's disease (CD), ulcerative colitis (UC) who have a prior history of cancer pose a unique challenge. The impact of Vedolizumab (VDZ) on the risk of new or recurrent cancers in patients with a previous malignancy is unknown. METHODS This was a retrospective study of patients with IBD with a history of current or prior cancer who were subsequently initiated on VDZ, tumor necrosis factor α antagonists (anti-TNF), or had no immunosuppressive therapy after the index cancer diagnosis. The occurrence of a new primary cancer or recurrent cancer was ascertained on follow-up. Multivariable Cox-proportional hazard models were used to determine the independent effect of post-cancer treatment on new/recurrent cancer. RESULTS The study included 96 patients exposed to VDZ after a prior diagnosis of cancer who were compared to 184 and 183 patients exposed to anti-TNF or no immunosuppressive therapy, respectively. The most common primary cancer were solid tumors (50%). Over a median of 6.2 person-years of follow-up, 18 patients on VDZ developed new (7) or recurrent (11) cancer corresponding to a rate of 22 per 1000 person-years after cancer diagnosis. In a multivariable Cox-model, after adjusting for confounders, there was no increase in the risk of new or recurrent cancer with VDZ (HR 1.38 95% CI 0.38 - 1.36) or anti-TNF therapy (HR 1.03, 95% CI 0.65 - 1.64), when compared to no IS. CONCLUSIONS Neither Vedolizumab nor TNF-antagonists were associated with increased risk of new or recurrent cancers in patients with prior malignancy.
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Affiliation(s)
- Amar Vedamurthy
- Department of Medicine, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts
| | - Nikitha Gangasani
- Department of Medicine, Boston Medical Center, Boston, Massachusetts
| | - Ashwin N Ananthakrishnan
- Department of Medicine, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts.
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Fatani AZ, Bugshan NA, AlSayyad HM, Shafei MA, Hariri NM, Alrashid LT, Lasker AY, Aldauig BA, Attar SM. Causes of the Failure of Biological Therapy at a Tertiary Center: A Cross-Sectional Retrospective Study. Cureus 2021; 13:e18253. [PMID: 34712530 PMCID: PMC8542393 DOI: 10.7759/cureus.18253] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 09/24/2021] [Indexed: 11/12/2022] Open
Abstract
Introduction Rheumatoid arthritis (RA) is one of the most commonly encountered autoimmune diseases. Treatment generally includes disease-modifying anti-rheumatic drugs (DMARDs) and/or biological therapy. However, a significant proportion of the patients do not respond to treatment either as a (primary failure) or lose efficacy over time (secondary failure). Several factors are assumed to influence these conditions. Objectives To estimate the prevalence of failure of biological therapy in patients with RA and its causes. Methods A total of 335 RA patients who were diagnosed at a tertiary center in Jeddah, Saudi Arabia, and had a failure after receiving biological therapy were included in this study. Several variables were considered; patient’s socio-demographic data, comorbid conditions, types of biological therapy, the duration of using biological therapy in months, number of biological therapies, allergic reactions, disease activity, and treatment duration. Results Overall the prevalence of failure to biological therapy was 58%; 77% primary failure and 23% secondary failure. Patients with negative rheumatoid factor (RF) (p=0.006), using low-dose steroids, and with a longer disease duration had a significant failure of biological therapy (p=0.023). Conclusion A high percentage of RA patients had a failure of biological therapy. A multicentric trial is recommended to look for additional factors.
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Affiliation(s)
- Arwa Z Fatani
- Faculty of Medicine, King Abdulaziz University, Jeddah, SAU
| | - Nada A Bugshan
- Faculty of Medicine, King Abdulaziz University, Jeddah, SAU
| | | | - Mayar A Shafei
- Faculty of Medicine, King Abdulaziz University, Jeddah, SAU
| | - Nada M Hariri
- Faculty of Medicine, King Abdulaziz University, Jeddah, SAU
| | | | - Ahlam Y Lasker
- Faculty of Medicine, King Abdulaziz University, Jeddah, SAU
| | | | - Suzan M Attar
- Department of Internal Medicine, King Abdulaziz University, Jeddah, SAU
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Imazio M, Lazaros G, Gattorno M, LeWinter M, Abbate A, Brucato A, Klein A. Anti-interleukin-1 agents for pericarditis: a primer for cardiologists. Eur Heart J 2021; 43:2946-2957. [PMID: 34528670 PMCID: PMC9375710 DOI: 10.1093/eurheartj/ehab452] [Citation(s) in RCA: 39] [Impact Index Per Article: 9.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/13/2021] [Revised: 02/21/2021] [Accepted: 07/02/2021] [Indexed: 01/24/2023] Open
Abstract
Anti-interleukin (IL)-1 agents have been developed for the treatment of autoinflammatory and rheumatic conditions, where overproduction of IL-1 is an important pathophysiologic process. IL-1α and IL-1β are the most studied members of the IL-1 family of cytokines and have the strongest proinflammatory effects. A naturally occurring antagonist (IL-1Ra) mitigates their proinflammatory effects. Overproduction of both IL-1α (released by inflamed/damaged pericardial cells) and IL-1β (released by inflammatory cells) is now a well-recognized therapeutic target in patients with recurrent idiopathic pericarditis. Currently, there are three available anti-IL-1 agents: anakinra (recombinant human IL-1Ra), rilonacept (a soluble decoy receptor ‘trap’, binding both IL-1α and IL-1β), and canakinumab (human monoclonal anti-IL-1β antibody). For patients with corticosteroid-dependent and colchicine-resistant recurrent pericarditis with evidence of systemic inflammation, as evidenced by elevated C-reactive protein, the efficacy and safety of anakinra (2 mg/kg/day up to 100 mg/day subcutaneously usually for at least 6 months, then tapered) and rilonacept (320 mg subcutaneously for the first day followed by 160 mg subcutaneously weekly) have been clearly demonstrated in observational studies and randomized controlled clinical trials. Severe side effects are rare and discontinuation rates are very low (<4%). The most common reported side effect is injection site reactions (>50% of patients). In this article, we describe the historical and pathophysiological background and provide a comprehensive review of these agents, which appear to be the most significant advance in medical therapy of recurrent pericarditis in the last 5 years.
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Affiliation(s)
- Massimo Imazio
- Head of Cardiology, Cardiothoracic Department, University Hospital "Santa Maria della Misericordia", ASUFC, Piazzale Santa Maria della Misericordia 15, Udine 33100, Italy
| | - George Lazaros
- 1st Cardiology Clinic, National and Kapodistrian University of Athens, School of Medicine, Hippokration General Hospital, Athens, Greece
| | - Marco Gattorno
- Center for Autoinflammatory Diseases and Immunodeficiencies, IRCCS G. Gaslini, Genova, Italy
| | - Martin LeWinter
- Cardiology Unit, University of Vermont Medical Center, Burlington, VT, USA
| | - Antonio Abbate
- VCU Pauley Heart Center, Virginia Commonwealth University, Richmond, USA
| | - Antonio Brucato
- Department of Biomedical and Clinical Sciences "Sacco", Fatebenefratelli Hospital, Università di Milano, Milan, Italy
| | - Allan Klein
- Center for the Diagnosis and Treatment of Pericardial Diseases, Section of Cardiovascular Imaging, Department of Cardiovascular Medicine, Heart, Vascular, and Thoracic Institute, Cleveland Clinic, USA
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D'Arcy ME, Beachler DC, Pfeiffer RM, Curtis JR, Mariette X, Seror R, Mahale P, Rivera DR, Yanik EL, Engels EA. Tumor Necrosis Factor Inhibitors and the Risk of Cancer among Older Americans with Rheumatoid Arthritis. Cancer Epidemiol Biomarkers Prev 2021; 30:2059-2067. [PMID: 34426413 DOI: 10.1158/1055-9965.epi-21-0125] [Citation(s) in RCA: 17] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/29/2021] [Revised: 04/28/2021] [Accepted: 08/09/2021] [Indexed: 11/16/2022] Open
Abstract
BACKGROUND TNF inhibitors (TNFi) effectively treat rheumatoid arthritis but may increase patient risk of some malignancies, particularly lymphomas or skin cancers. METHODS We used Surveillance, Epidemiology, and End Results (SEER)-Medicare data to conduct a case-control study in patients with rheumatoid arthritis (2007-2015). Cases were individuals with a first cancer diagnosed in SEER registries (ages 66-99, 22 cancer sites, N = 10,263). Skin cancer cases [nonmelanoma skin cancer (NMSC, N = 501), basal cell carcinoma (BCC, N = 161), squamous cell carcinoma (SCC, N = 150)] and cancer-free controls (N = 30,475) were selected from Medicare beneficiaries residing in SEER areas. Cases and controls had prior Medicare claims-based evidence for rheumatoid arthritis, and TNFi exposure was ascertained from part B and part D claims. Logistic regression was used to estimate adjusted odds ratios (aOR). RESULTS TNFi exposure was present in 16.2% of controls and 12.8% to 33.7% of cancer cases, varying by site. TNFi use was associated with increased risk of NMSC overall (aOR 1.32, 95% confidence interval 1.06-1.63), non-Hodgkin lymphoma (NHL) overall (1.28, 1.06-1.56) and, specifically, follicular lymphoma (2.63, 1.63-4.24). TNFi exposure was not associated with other SEER cancer sites, BCC or SCC specifically, or other common NHL subtypes. CONCLUSIONS Among older adults with rheumatoid arthritis, TNFi exposure was associated with elevated risk of NMSC and NHL, driven specifically by follicular lymphoma. Exposure was not associated with increased risk for other cancer sites. IMPACT Our results support a role for TNF in lymphomagenesis. Given the association with NMSC, patients initiating TNFi therapy may benefit from skin cancer screening and sun protection measures.
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Affiliation(s)
- Monica E D'Arcy
- Division of Cancer Epidemiology and Genetics, National Cancer Institute, Rockville, Maryland. monica.d'
| | | | - Ruth M Pfeiffer
- Division of Cancer Epidemiology and Genetics, National Cancer Institute, Rockville, Maryland
| | | | - Xavier Mariette
- Hôpital Bicêtre, Assistance Publique -Hôpitaux de Paris, Université Paris-Saclay, Le Kremlin Bicêtre, Paris, France
| | - Raphaele Seror
- Hôpital Bicêtre, Assistance Publique -Hôpitaux de Paris, Université Paris-Saclay, Le Kremlin Bicêtre, Paris, France
| | - Parag Mahale
- Division of Cancer Epidemiology and Genetics, National Cancer Institute, Rockville, Maryland
| | - Donna R Rivera
- Division of Cancer Control and Population Sciences, National Cancer Institute, Rockville, Maryland
| | | | - Eric A Engels
- Division of Cancer Epidemiology and Genetics, National Cancer Institute, Rockville, Maryland
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Sellam J, Morel J, Tournadre A, Bouhnik Y, Cornec D, Devauchelle-Pensec V, Dieudé P, Goupille P, Jullien D, Kluger N, Lazaro E, Le Goff B, de Lédinghen V, Lequerré T, Nocturne G, Seror R, Truchetet ME, Verhoeven F, Pham T, Richez C. PRACTICAL MANAGEMENT of patients on anti-TNF therapy: Practical guidelines drawn up by the Club Rhumatismes et Inflammation (CRI). Joint Bone Spine 2021; 88:105174. [PMID: 33992225 DOI: 10.1016/j.jbspin.2021.105174] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/26/2022]
Affiliation(s)
- Jérémie Sellam
- Service de Rhumatologie, CHU Saint-Antoine, Paris, France
| | - Jacques Morel
- Service de Rhumatologie, CHU Montpellier, Montpellier, France
| | - Anne Tournadre
- Service de Rhumatologie, CHU Clermont-Ferrand, Clermont-Ferrand, France
| | - Yoram Bouhnik
- Service de Gastro-entérologie, CHU Hôpital Beaujon, Clichy, France
| | - Divi Cornec
- Service de Rhumatologie, CHRU La Cavale Blanche, Brest, France
| | | | - Philippe Dieudé
- Service de Rhumatologie, CHU Bichat-Claude Bernard, Paris, France
| | | | | | - Nicolas Kluger
- Dpt Dermatology, Helsinki, Finland; Service de Dermatologie, CHU Bichat-Claude Bernard, Paris, France
| | - Estibaliz Lazaro
- Service de Médecine interne, Hôpital Haut-Lévêque, CHU Bordeaux, Pessac, France
| | | | - Victor de Lédinghen
- Unité d'Hépatologie et transplantation hépatique, Hôpital Haut-Lévêque, CHU Bordeaux, Pessac, France
| | | | | | - Raphaèle Seror
- Service de Rhumatologie, Bicêtre, Le Kremlin-Bicêtre, France
| | | | | | - Thao Pham
- Service de Rhumatologie, CHU Sainte-Marguerite, Marseille, France
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Imazio M. Current treatment of recurrent pericarditis: safety considerations and future directions. Expert Opin Drug Saf 2021; 21:183-190. [PMID: 34334059 DOI: 10.1080/14740338.2021.1960980] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/20/2022]
Abstract
INTRODUCTION Recurrent pericarditis is one of the most troublesome complications of pericarditis affecting a substantial amount of patients and often severely impairing the quality of life. Current medical treatments range from non-steroidal anti-inflammatory drugs (NSAIDs), colchicine and corticosteroids to biological agents (anti IL-1 agents, especially anakinra and rilonacept), intravenous immunoglobulins and immunosuppressive treatments. Safety is a major issue to deal with since the disease often affects relatively young or middle-aged patients. AREAS COVERED The review is aimed at providing an update on the efficacy and safety of current medical therapies for recurrent pericarditis including most recent advances represented by anti IL-1 agents. EXPERT OPINION Therapy of recurrent pericarditis has evolved over years leading to a more evidence-based and personalized treatment based on clinical presentation and pathophysiology. The main distinction is between patients with an inflammatory phenotype (e.g. fever, elevation of markers of inflammation, pericardial and/or pleural effusion) vs. those without an inflammatory phenotype. Colchicine and anti IL-1 agents are especially efficacious and indicated for those with an inflammatory phenotype, while corticosteroids, azathioprine and immunoglobulins seem more indicated for those without evidence of systemic inflammation.
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Affiliation(s)
- Massimo Imazio
- Cardiology, Cardiothoracic Department, Santa Maria della Misericordia University Hospital, Azienda Sanitaria Universitaria del Friuli Centrale (ASUFC), Udine, Italy
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Lebwohl M, Deodhar A, Griffiths CEM, Menter MA, Poddubnyy D, Bao W, Jehl V, Marfo K, Primatesta P, Shete A, Trivedi V, Mease PJ. The risk of malignancy in patients with secukinumab-treated psoriasis, psoriatic arthritis and ankylosing spondylitis: analysis of clinical trial and postmarketing surveillance data with up to five years of follow-up. Br J Dermatol 2021; 185:935-944. [PMID: 33829482 DOI: 10.1111/bjd.20136] [Citation(s) in RCA: 31] [Impact Index Per Article: 7.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 04/06/2021] [Indexed: 11/29/2022]
Abstract
BACKGROUND Data on the use of biologic therapy and malignancy risk are inconsistent due to limited long-term robust studies. OBJECTIVES To assess the malignancy risk in patients with secukinumab-treated psoriasis, psoriatic arthritis (PsA) and ankylosing spondylitis (AS). METHODS This integrated safety analysis from both the secukinumab clinical trial programme and postmarketing safety surveillance data included any patient receiving at least one approved dose of secukinumab with a maximum of 5 years of follow-up. Safety analyses evaluated the rate of malignancy using exposure-adjusted incidence rates [EAIR; incidence rates per 100 patient treatment-years (PTY)]. Standardized incidence ratios (SIRs) were reported using the Surveillance, Epidemiology, and End Results Program (SEER) database as a reference population. Crude incidence of malignancy was also reported using postmarketing surveillance data. RESULTS Safety data from 49 clinical trials with secukinumab-treated patients were included: 10 685 patients with psoriasis, 2523 with PsA and 1311 with AS. Across indications over a 5-year period, the EAIR of malignancy was 0·85 per 100 PTY [95% confidence interval (CI) 0·74-0·98] in secukinumab-treated patients, corresponding to 204 patients per 23 908 PTY. Overall, the observed vs. expected number of malignancies from secukinumab clinical trial data were comparable, as indicated by an SIR of 0·99 (95% CI 0·82-1·19) across indications. The estimated crude cumulative incidence reporting rate per 100 PTY for malignancy was 0·27 in the postmarketing surveillance data across indications with a cumulative exposure of 285 811 PTY. CONCLUSIONS In this large safety analysis, the risk of malignancy was low for up to 5 years of secukinumab treatment. These data support the long-term use of secukinumab in these indications.
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Affiliation(s)
- M Lebwohl
- Kimberly and Eric J. Waldman Department of Dermatology, Icahn School of Medicine at Mount Sinai, New York City, NY, USA
| | - A Deodhar
- Oregon Health & Science University, Portland, OR, USA
| | - C E M Griffiths
- The Dermatology Centre, The University of Manchester, Manchester Academic Health Science Centre, Salford Royal NHS Foundation Trust, Manchester, UK
| | - M A Menter
- Division of Dermatology, Baylor Scott & White Health, Dallas, TX, USA
| | - D Poddubnyy
- Division of Gastroenterology, Infectious Diseases and Rheumatology, Charité, Universitätsmedizin Berlin, Germany, and Epidemiology Unit, German Rheumatism Research Centre, Berlin, Germany
| | - W Bao
- Novartis Pharmaceuticals Corporation, East Hanover, NJ, USA
| | - V Jehl
- Novartis Pharma AG, Basel, Switzerland
| | - K Marfo
- Novartis Pharma AG, Basel, Switzerland
| | | | - A Shete
- Novartis Pharma AG, Basel, Switzerland
| | - V Trivedi
- Novartis Pharmaceuticals Corporation, East Hanover, NJ, USA
| | - P J Mease
- Department of Rheumatology, Swedish Health Services/Providence St Joseph Health and University of Washington, Seattle, WA, USA
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Kremer JM, Bingham CO, Cappelli LC, Greenberg JD, Madsen AM, Geier J, Rivas JL, Onofrei AM, Barr CJ, Pappas DA, Litman HJ, Dandreo KJ, Shapiro AB, Connell CA, Kavanaugh A. Postapproval Comparative Safety Study of Tofacitinib and Biological Disease-Modifying Antirheumatic Drugs: 5-Year Results from a United States-Based Rheumatoid Arthritis Registry. ACR Open Rheumatol 2021; 3:173-184. [PMID: 33570260 PMCID: PMC7966883 DOI: 10.1002/acr2.11232] [Citation(s) in RCA: 80] [Impact Index Per Article: 20.0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/02/2020] [Accepted: 12/17/2020] [Indexed: 12/30/2022] Open
Abstract
OBJECTIVE Tofacitinib is an oral Janus kinase inhibitor for the treatment of rheumatoid arthritis (RA). We compared 5-year adverse event (AE) incidence rates (IRs) between patients initiating tofacitinib and those initiating new biological disease-modifying antirheumatic drugs (bDMARDs) within the United States (US) Corrona RA registry. METHODS IRs (number of first events/100 patient-years) of major adverse cardiovascular events (MACE), serious infection events (SIEs), herpes zoster (HZ), malignancies, and death were estimated among tofacitinib and bDMARD initiators, regardless of dose/schedule, between November 6, 2012 (US Food and Drug Administration tofacitinib approval), and July 31, 2018 (follow-up through January 31, 2019). Propensity score (PS) methods were used to control for nonrandom prescribing practices. Hazard ratios (HRs) were calculated to compare rates using multivariable-adjusted Cox regression. Different risk windows were used for acute (MACE, SIEs, HZ, and venous thromboembolic events [VTEs]) and long-term (malignancy and death) events. VTEs were assessed descriptively. RESULTS For MACE, SIEs, and HZ, 1999 (3152.1 patient-years) and 8358 (12 869.4 years) tofacitinib and bDMARD initiators were included, respectively; for malignancy/death, 1999 (4505.6 patient-years) and 6354 (16 670.8 patient-years) initiators were included, respectively. AE rates were similar across cohorts, except for HZ, which was significantly higher with tofacitinib versus bDMARDs (PS-trimmed adjusted HR 2.32; 95% confidence interval [CI] 1.43-3.75). There were 45 (zero serious) and 88 (five serious) HZ events with tofacitinib and bDMARDs, respectively. Sensitivity analyses demonstrated similar results. VTE IRs (95% CI) were 0.29 (0.13-0.54) and 0.33 (0.24-0.45) for tofacitinib and bDMARDs, respectively. CONCLUSION In this registry analysis, both cohorts had similar MACE, SIE, malignancy, death, and VTE rates; HZ rates were higher for tofacitinib initaitors than for bDMARD initiators.
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Affiliation(s)
- Joel M. Kremer
- Albany Medical CollegeCenter for RheumatologyAlbanyNew York
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Schmalzing M. Rheumatologische medikamentöse Therapie bei Malignomanamnese. AKTUEL RHEUMATOL 2020. [DOI: 10.1055/a-1247-4252] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/23/2022]
Abstract
ZusammenfassungRheumatologische Therapie bei Patienten mit Malignomanamnese ist mit komplexen Fragestellungen verbunden. Schwierigkeiten und Lösungsmöglichkeiten bei der Interpretation aussagekräftiger Studien werden dargestellt. Empfehlungen in Leitlinien zu diesem Thema werden diskutiert. Nationale Register und Versicherungsdatenbanken wurden mit der Frage nach Tumorrezidivrisiko unter Basistherapeutika untersucht ; diese Analysen beziehen sich aber v. a. auf TNF-Inhibitoren und Rituximab. Zu den gängigen Substanzen der Basistherapie werden Daten zur Tumorinzidenz und wenn vorhanden zum Tumorrezidivrisiko zusammengefasst. Abschließend wird der Versuch unternommen Vorschläge zur rheumatolgischen Therapie bei Malignomanamnese zu formulieren.
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Affiliation(s)
- Marc Schmalzing
- Rheumatologie / Klinische Immunologie, Medizinische Klinik und Poliklinik II, Universitätsklinikum Würzburg, Würzburg
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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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Rituximab as a treatment option in a patient with rheumatoid arthritis and a history of malignancy-intracranial chondrosarcoma/osteochondroma-case based review. Rheumatol Int 2020; 41:463-468. [PMID: 33001390 DOI: 10.1007/s00296-020-04706-1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/17/2020] [Accepted: 09/15/2020] [Indexed: 10/23/2022]
Abstract
When compared to general population, patients with rheumatoid arthritis are at higher risk of some malignancies (especially lymphomas and lung cancer). Genetic predisposition, chronic inflammatory stimuli and viral infections are some of the reasons untreated patients are at higher risk. Clinical studies and national/international registries collect the data about the malignancies with higher incidence (such as lung, skin and breast cancer) but on the other hand, malignancies with lower incidence (such as sarcomas) are rarely reported. We report a case of a 47-year-old male with a history of a malignant intracranial chondrosarcoma/osteochondroma who developed seropositive rheumatoid arthritis. Due to progression of erosions, the patient was initialy treated with conventional synthetic Disease-Modifying Antirheumatic Drugs (csDMARDs) and later on with rituximab. The patient's rheumatoid arthritis went and remained in remission on maintenance therapy with rituximab (every 6-8 months) and low-dose methotrexate with no relapse of malignant intracranial chondrosarcoma/osteochondroma. Rituximab should be considered as a treatment option in patients with rare and agressive malignancies, such as sarcomas.
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Szekanecz Z, Gomez I, Soós B, Bodoki L, Szamosi S, András C, Juhász B, Váróczy L, Antal-Szalmás P, Szodoray P, Bittner N, Árkosy P, Illés Á, Szűcs G, Dankó K, Bender T, Tamási L, Szekanecz É. Eight pillars of oncorheumatology: Crossroads between malignancies and musculoskeletal diseases. Autoimmun Rev 2020; 19:102658. [PMID: 32942035 DOI: 10.1016/j.autrev.2020.102658] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/24/2020] [Accepted: 03/31/2020] [Indexed: 02/07/2023]
Abstract
ONCORHEUMATOLOGY RELATIONSHIP BETWEEN MALIGNANCIES AND MUSCULOSKELETAL DISEASES: Oncorheumatology is the meeting point of tumor formation and rheumatic musculoskeletal diseases (RMD). Multiple interactions exist between these two medical specialties. One major field is the topic of malignancies associated with rheumatic diseases, while the other topic covers the development of musculoskeletal disease in cancer patients. Within the first group, secondary malignancies may be associated with rheumatic diseases. Mostly sustained inflammation is responsible for transition into cancer. Tumor-associated antigens (TAA) with adhesive properties are present on tumor cells. These molecules may also be expressed by inflammatory leukocytes and soluble TAA levels may be elevated in RMDs. There has been continuous debate with respect to the possible carcinogenicity of conventional and targeted antirheumatic drugs. Very recent data from registries suggest that neither biologics, nor JAK inhibitors increase cancer risk in arthritis patients. The issue of physiotherapy in rheumatic patients with recent or current cancer has also been controversial. Some modalities, primarily exercise, may be safely applied to patients with RMD and cancer. The second large topic includes paraneoplastic syndromes. Musculoskeletal paraneoplasias are triggered by tumor-derived mediators. These syndromes are sometimes slightly different from the classical RMDs. Various chemotherapies may also be associated with autoimmune side effects. Recently, these immune-related complications have also been observed in cancer patients treated with immune-checkpoint inhibitors. Sex hormone-deprivation therapies, such as aromatase inhibitors and anti-androgens are widely used for the treatment of breast and prostate cancer, respectively. These compounds may induce bone loss and lead to osteoporosis. Finally, primary and secondary malignancies of the musculoskeletal system may also interest rheumatologists. In this review, the clinical, practical aspects of these eight pillars of oncorheumatology will be discussed.
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Affiliation(s)
- Zoltán Szekanecz
- Division of Rheumatology, Department of Medicine, Faculty of Medicine, University of Debrecen, Debrecen, Hungary.
| | - Izabella Gomez
- Division of Rheumatology, Department of Medicine, Faculty of Medicine, University of Debrecen, Debrecen, Hungary; National Institute of Rheumatology and Physiotherapy, Budapest, Hungary
| | - Boglárka Soós
- Division of Rheumatology, Department of Medicine, Faculty of Medicine, University of Debrecen, Debrecen, Hungary
| | - Levente Bodoki
- Division of Rheumatology, Department of Medicine, Faculty of Medicine, University of Debrecen, Debrecen, Hungary
| | - Szilvia Szamosi
- Division of Rheumatology, Department of Medicine, Faculty of Medicine, University of Debrecen, Debrecen, Hungary
| | - Csilla András
- Department of Oncology, Faculty of Medicine, University of Debrecen, Debrecen, Hungary
| | - Balázs Juhász
- Department of Oncology, Faculty of Medicine, University of Debrecen, Debrecen, Hungary
| | - László Váróczy
- Division of Hematology, Department of Medicine, Faculty of Medicine, University of Debrecen, Debrecen, Hungary
| | - Péter Antal-Szalmás
- Department of Laboratory Medicine, Faculty of Medicine, University of Debrecen, Debrecen, Hungary
| | - Péter Szodoray
- Division of Clinical Immunology, Department of Medicine, Faculty of Medicine, University of Debrecen, Debrecen, Hungary; Institute of Immunology, Rikshospitalet, Oslo University Hospital, Oslo, Norway
| | - Nóra Bittner
- Department of Pulmonology, Faculty of Medicine, University of Debrecen, Debrecen, Hungary
| | - Péter Árkosy
- Department of Oncology, Faculty of Medicine, University of Debrecen, Debrecen, Hungary
| | - Árpád Illés
- Division of Hematology, Department of Medicine, Faculty of Medicine, University of Debrecen, Debrecen, Hungary
| | - Gabriella Szűcs
- Division of Rheumatology, Department of Medicine, Faculty of Medicine, University of Debrecen, Debrecen, Hungary
| | - Katalin Dankó
- Division of Clinical Immunology, Department of Medicine, Faculty of Medicine, University of Debrecen, Debrecen, Hungary
| | - Tamás Bender
- Buda Hospital of the Hospitaller Order of Saint John of God, Budapest, Hungary
| | - László Tamási
- Department of Rheumatology, Borsod-Abaúj-Zemplén County Hospital and University Teaching Hospital, Miskolc;, Hungary
| | - Éva Szekanecz
- Department of Oncology, Faculty of Medicine, University of Debrecen, Debrecen, Hungary
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Abstract
BACKGROUND The treatment of axial spondyloarthritis (axSpA) and psoriatic arthritis (PsA) has changed enormously in recent years due to market authorization of a number of new biologicals with different modes of action and the increasing use of biosimilars. Real-world data on long-term safety and efficacy under routine daily conditions is not yet sufficient. Therefore, the German Rheumatism Research Center has initiated a new cohort study covering axSpA and PsA. OBJECTIVE Presentation of initial results from the new register RABBIT-SpA, which was started in May 2017. MATERIAL AND METHODS This is a prospective longitudinal cohort study with a similar study design to the German biologics register RABBIT. Patients can be included at the start of a new treatment either in the so-called index drug group or in the comparison group (conventional systemic treatment, including non-steroidal anti-inflammatory drugs, NSAID). Follow-up per patient should be at least 5 years and preferably 10 years. The RABBIT-SpA uses a web-based documentation system. RESULTS Up to mid-December 2018 a total of 514 axSpA patients had been documented in RABBIT-SpA, 410 with an index drug and 104 with conventional treatment. There are differences between these treatment groups, e. g. in the duration of the disease and in parameters of disease activity. It is also noticeable that in axSpA patients, approximately 5 years lie between the onset of the symptoms and confirmation of the diagnosis. Of the 355 PsA patients, 265 were included with an index drug and 90 with conventional treatment. Of the PsA patients 86% have a dominant peripheral manifestation. The average number of pressure tender joints is 8 and the average number of swollen joints is 4. CONCLUSION The online register RABBIT-SpA is well-received by the participating rheumatological institutions. The electronic recording of patient data can be carried out in a reasonable time. Participation in the RABBIT-SpA is open to new rheumatological institutions at any time.
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Smolen JS, Landewé RBM, Bijlsma JWJ, Burmester GR, Dougados M, Kerschbaumer A, McInnes IB, Sepriano A, van Vollenhoven RF, de Wit M, Aletaha D, Aringer M, Askling J, Balsa A, Boers M, den Broeder AA, Buch MH, Buttgereit F, Caporali R, Cardiel MH, De Cock D, Codreanu C, Cutolo M, Edwards CJ, van Eijk-Hustings Y, Emery P, Finckh A, Gossec L, Gottenberg JE, Hetland ML, Huizinga TWJ, Koloumas M, Li Z, Mariette X, Müller-Ladner U, Mysler EF, da Silva JAP, Poór G, Pope JE, Rubbert-Roth A, Ruyssen-Witrand A, Saag KG, Strangfeld A, Takeuchi T, Voshaar M, Westhovens R, van der Heijde D. EULAR recommendations for the management of rheumatoid arthritis with synthetic and biological disease-modifying antirheumatic drugs: 2019 update. Ann Rheum Dis 2020; 79:685-699. [PMID: 31969328 DOI: 10.1136/annrheumdis-2019-216655] [Citation(s) in RCA: 1705] [Impact Index Per Article: 341.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/17/2019] [Revised: 12/16/2019] [Accepted: 12/18/2019] [Indexed: 02/06/2023]
Abstract
OBJECTIVES To provide an update of the European League Against Rheumatism (EULAR) rheumatoid arthritis (RA) management recommendations to account for the most recent developments in the field. METHODS An international task force considered new evidence supporting or contradicting previous recommendations and novel therapies and strategic insights based on two systematic literature searches on efficacy and safety of disease-modifying antirheumatic drugs (DMARDs) since the last update (2016) until 2019. A predefined voting process was applied, current levels of evidence and strengths of recommendation were assigned and participants ultimately voted independently on their level of agreement with each of the items. RESULTS The task force agreed on 5 overarching principles and 12 recommendations concerning use of conventional synthetic (cs) DMARDs (methotrexate (MTX), leflunomide, sulfasalazine); glucocorticoids (GCs); biological (b) DMARDs (tumour necrosis factor inhibitors (adalimumab, certolizumab pegol, etanercept, golimumab, infliximab), abatacept, rituximab, tocilizumab, sarilumab and biosimilar (bs) DMARDs) and targeted synthetic (ts) DMARDs (the Janus kinase (JAK) inhibitors tofacitinib, baricitinib, filgotinib, upadacitinib). Guidance on monotherapy, combination therapy, treatment strategies (treat-to-target) and tapering on sustained clinical remission is provided. Cost and sequencing of b/tsDMARDs are addressed. Initially, MTX plus GCs and upon insufficient response to this therapy within 3 to 6 months, stratification according to risk factors is recommended. With poor prognostic factors (presence of autoantibodies, high disease activity, early erosions or failure of two csDMARDs), any bDMARD or JAK inhibitor should be added to the csDMARD. If this fails, any other bDMARD (from another or the same class) or tsDMARD is recommended. On sustained remission, DMARDs may be tapered, but not be stopped. Levels of evidence and levels of agreement were mostly high. CONCLUSIONS These updated EULAR recommendations provide consensus on the management of RA with respect to benefit, safety, preferences and cost.
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Affiliation(s)
- Josef S Smolen
- Division of Rheumatology, Department of Medicine 3, Medical University of Vienna, Vienna, Austria
| | - Robert B M Landewé
- Amsterdam University Medical Center, Amsterdam, The Netherlands
- Zuyderland Medical Center, Heerlen, The Netherlands
| | - Johannes W J Bijlsma
- Department of Rheumatology and Clinical Immunology, University Medical Center Utrecht, Utrecht, The Netherlands
| | - Gerd R Burmester
- Department of Rheumatology and Clinical Immunology, Charité - University Medicine Berlin, Free University and Humboldt University Berlin, Berlin, Germany
| | - Maxime Dougados
- Rhumatologie B, Hopital Cochin, 27 rue du Fbg Saint-Jacques, Paris, France
| | - Andreas Kerschbaumer
- Division of Rheumatology, Department of Medicine 3, Medical University of Vienna, Vienna, Austria
| | - Iain B McInnes
- Institute of Infection, Immunity and Inflammation, College of Medical, Veterinary and Life Sciences, University of Glasgow, Glasgow, UK
| | - Alexandre Sepriano
- NOVA Medical School, Universidade Nova de Lisboa, Lisbon, Portugal, and Department of Rheumatology, Leiden University Medical Center, Leiden, The Netherlands
| | | | - Maarten de Wit
- EULAR Patient Research Partner; Department Medical Humanities, Amsterdam University Medical Center, Amsterdam, The Netherlands
| | - Daniel Aletaha
- Division of Rheumatology, Department of Medicine 3, Medical University of Vienna, Vienna, Austria
| | - Martin Aringer
- Division of Rheumatology, Department of Medicine III, University Medical Center and Faculty of Medicine Carl Gustav Carus, Dresden, Germany
| | - John Askling
- Department of Rheumatology, Karolinska University Hospital, Stockholm, Sweden
| | - Alejandro Balsa
- Servicio de Reumatologia Hospital Universitario La Paz, Instituto de Investigacion IdiPAZ, Madrid, Spain
| | - Maarten Boers
- Department of Epidemiology and Biostatistics and Amsterdam Rheumatology and Immunology Center, Amsterdam UMC, Vrije Universiteit Amsterdam, Amsterdam, The Netherlands
| | | | - Maya H Buch
- Division of Musculoskeletal and Dermatological Sciences, University of Manchester; NIHR Manchester Biomedical Research Centre, Manchester University NHS Foundation Trust, Manchester, UK
| | - Frank Buttgereit
- Department of Rheumatology and Clinical Immunology, Charité - University Medicine Berlin, Free University and Humboldt University Berlin, Berlin, Germany
| | - Roberto Caporali
- Department of Clinical Sciences and Community Health, University of Milan, and IRCCS S Matteo Foundation, Pavia, Italy
| | | | - Diederik De Cock
- Department of Development and Regeneration, Skeletal Biology and Engineering Research Center, KU Leuven; Rheumatology, University Hospitals Leuven, Leuven, Belgium
| | - Catalin Codreanu
- Center of Rheumatic Diseases, University of Medicine and Pharmacy, Bucharest, Romania
| | - Maurizio Cutolo
- Research Laboratory and Division of Clinical Rheumatology, Department of Internal Medicine - University of Genoa, Genoa, Italy
| | - Christopher John Edwards
- Musculoskeletal Research Unit, NIHR Clinical Research Facility, University Hospital Southampton, Southampton, UK
| | - Yvonne van Eijk-Hustings
- Department of Patient & Care and Department of Rheumatology, University of Maastricht, Maastricht, The Netherlands
| | - Paul Emery
- NIHR Leeds Musculoskeletal Biomedical Research Unit, Leeds Teaching Hospitals NHS Trust and Leeds Institute of Rheumatic and Musculoskeletal Medicine, University of Leeds, Leeds, UK
| | - Axel Finckh
- Division of Rheumatology, University Hospitals of Geneva, Geneva, Switzerland
| | - Laure Gossec
- Sorbonne Université, INSERM, Institut Pierre Louis d'Epidémiologie et de Santé Publique, Paris and Pitié Salpêtrière hospital, AP-HP, Rheumatology Department, Paris, France
| | - Jacques-Eric Gottenberg
- Strasbourg University Hospital and University of Strasbourg, CNRS, Institut de Biologie Moléculaire et Cellulaire, Immunopathologie, et Chimie Thérapeutique, Strasbourg, France
| | - Merete Lund Hetland
- Copenhagen Center for Arthritis Research, Center for Rheumatology and Spine Diseases, Rigshospitalet and Department of Clinical Medicine, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
| | - Tom W J Huizinga
- Department of Rheumatology, Leiden University Medical Center, Leiden, The Netherlands
| | - Marios Koloumas
- European League Against Rheumatism, Zurich, Switzerland
- Cyprus League against Rheumatism, Nikosia, Cyprus
| | - Zhanguo Li
- Department of Rheumatology and Immunology, Beijing University People's Hospital, Beijing, China
| | - Xavier Mariette
- Université Paris-Sud, AP-HP, Université Paris-Saclay, Le Kremlin Bicêtre, France
| | - Ulf Müller-Ladner
- Department of Rheumatology and Clinical Immunology, Campus Kerckhoff, Justus-Liebig University Giessen, Bad Nauheim, Germany
| | | | - Jose A P da Silva
- Serviço de Reumatologia, Centro Hospitalar e Universitário de Coimbra Praceta Mota Pinto, and Coimbra Institute for Clinical and Biomedical Research (i-CRB), Faculty of Medicine of Coimbra, Coimbra, Portugal
| | - Gyula Poór
- National Institute of Rheumatology & Physiology, Semmelweis University, Budapest, Hungary
| | - Janet E Pope
- University of Western Ontario, Schulich School of Medicine & Dentistry, Department of Medicine, London, Ontario, Canada
| | | | | | - Kenneth G Saag
- Department of Medicine, Division of Rheumatology, University of Alabama at Birmingham, Brmingham, Alabama, USA
| | - Anja Strangfeld
- Programme Area Epidemiology, Deutsches Rheumaforschungszentrum Berlin, Berlin, Germany
| | - Tsutomu Takeuchi
- Keio University School of Medicine, Keio University Hospital, Tokyo, Japan
| | - Marieke Voshaar
- Department of Psychology, Health and Technology, University of Twente, Enschede, The Netherlands
| | - René Westhovens
- Department of Development and Regeneration, Skeletal Biology and Engineering Research Center, KU Leuven; Rheumatology, University Hospitals Leuven, Leuven, Belgium
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Atzeni F, Nucera V, Gerratana E, Cirillo M, Marino F, Miceli G, Sangari D, Boccassini L, Masala IF. Concerns about the safety of anti-TNF agents when treating rheumatic diseases. Expert Opin Drug Saf 2020; 19:695-705. [DOI: 10.1080/14740338.2020.1763299] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/17/2022]
Affiliation(s)
- Fabiola Atzeni
- Rheumatology Unit, University of Messina, Messina, Italy
| | - Valeria Nucera
- Rheumatology Unit, University of Messina, Messina, Italy
| | | | | | | | | | | | - Laura Boccassini
- Department of Rheumatology, ASST Fatebenefratelli-Sacco, Milan, Italy
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Predicting, Preventing, and Managing Treatment-Related Complications in Patients With Inflammatory Bowel Diseases. Clin Gastroenterol Hepatol 2020; 18:1324-1335.e2. [PMID: 32059920 DOI: 10.1016/j.cgh.2020.02.009] [Citation(s) in RCA: 75] [Impact Index Per Article: 15.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/09/2019] [Revised: 01/17/2020] [Accepted: 02/03/2020] [Indexed: 02/07/2023]
Abstract
Risk of complications from specific classes of drugs for inflammatory bowel diseases (IBDs) can be kept low by respecting contraindications. Patients with IBD frequently develop serious infections resulting from the disease itself or its treatment. At the time of diagnosis, patients' vaccination calendars should be updated according to IBD guidelines-live vaccines should be postponed for patients receiving immunosuppressive drugs. Opportunistic infections should be detected and the vaccine against pneumococcus should be given before patients begin immunosuppressive therapy. Thiopurines promote serious viral infections in particular, whereas tumor necrosis factor (TNF) antagonists promote all types of serious and opportunistic infections. Severe forms of varicella can be prevented by vaccinating seronegative patients against varicella zoster virus. Detection and treatment of latent tuberculosis is mandatory before starting anti-TNF therapy and other new IBD drugs. Tofacitinib promotes herpes zoster infection in a dose- and age-dependent manner. Physicians should consider giving patients live vaccines against herpes zoster before they begin immunosuppressive therapy or a recombinant vaccine, when available, at any time point during treatment. The risk of thiopurine-induced lymphomas can be lowered by limiting the use of thiopurines in patients who are seronegative for Epstein-Barr virus (especially young men) and in older men. The risk of lymphoma related to monotherapy with anti-TNF agents is still unclear. There are no robust data on the carcinogenic effects of recently developed IBD drugs. For patients with previous cancer at substantial risk of recurrence, physicians should try to implement a pause in the use of immunosuppressive therapy (except in patients with severe disease and no therapeutic alternative) and prioritize use of IBD drugs with the lowest carcinogenic effects. Finally, sun protection and skin surveillance from the time of diagnosis are recommended.
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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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Stürmer T, Wang T, Golightly YM, Keil A, Lund JL, Jonsson Funk M. Methodological considerations when analysing and interpreting real-world data. Rheumatology (Oxford) 2020; 59:14-25. [PMID: 31834408 DOI: 10.1093/rheumatology/kez320] [Citation(s) in RCA: 51] [Impact Index Per Article: 10.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/17/2018] [Revised: 06/14/2019] [Indexed: 12/11/2022] Open
Abstract
In the absence of relevant data from randomized trials, nonexperimental studies are needed to estimate treatment effects on clinically meaningful outcomes. State-of-the-art study design is imperative for minimizing the potential for bias when using large healthcare databases (e.g. claims data, electronic health records, and product/disease registries). Critical design elements include new-users (begin follow-up at treatment initiation) reflecting hypothetical interventions and clear timelines, active-comparators (comparing treatment alternatives for the same indication), and consideration of induction and latent periods. Propensity scores can be used to balance measured covariates between treatment regimens and thus control for measured confounding. Immortal-time bias can be avoided by defining initiation of therapy and follow-up consistently between treatment groups. The aim of this manuscript is to provide a non-technical overview of study design issues and solutions and to highlight the importance of study design to minimize bias in nonexperimental studies using real-world data.
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Affiliation(s)
- Til Stürmer
- Department of Epidemiology, Gillings School of Global Public Health, University of North Carolina, Chapel Hill, NC, USA
| | - Tiansheng Wang
- Department of Epidemiology, Gillings School of Global Public Health, University of North Carolina, Chapel Hill, NC, USA
| | - Yvonne M Golightly
- Department of Epidemiology, Gillings School of Global Public Health, University of North Carolina, Chapel Hill, NC, USA.,Thurston Arthritis Research Center, University of North Carolina, Chapel Hill, NC, USA.,Injury Prevention Research Center, University of North Carolina, Chapel Hill, NC, USA.,Division of Physical Therapy, University of North Carolina, Chapel Hill, NC, USA
| | - Alex Keil
- Department of Epidemiology, Gillings School of Global Public Health, University of North Carolina, Chapel Hill, NC, USA
| | - Jennifer L Lund
- Department of Epidemiology, Gillings School of Global Public Health, University of North Carolina, Chapel Hill, NC, USA
| | - Michele Jonsson Funk
- Department of Epidemiology, Gillings School of Global Public Health, University of North Carolina, Chapel Hill, NC, USA
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