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Ruan JS, Xu S, Shan NN. Inextricable association of connective tissue disease with B‑cell lymphoma (Review). Mol Clin Oncol 2025; 22:48. [PMID: 40236836 PMCID: PMC11995451 DOI: 10.3892/mco.2025.2843] [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: 02/24/2024] [Accepted: 08/13/2024] [Indexed: 04/17/2025] Open
Abstract
Connective tissue disease (CTD) is a kind of autoimmune disease with multisystem damage that mainly involves the bone, muscle and the vascular system. Patients with CTD have an increased incidence of malignant tumors, particularly hematological malignancies, compared to the general population. This association of autoimmune diseases with lymphoproliferative diseases is bidirectional. There is a heightened risk of B-cell lymphoma development among patients with CTD, and patients with autoimmune disease display a higher prevalence of non-Hodgkin lymphoma compared to the general population. More than 80% of malignant tumours occur after or at the same time as CTD develops. Among secondary lymphomas, the most common aggressive type of lymphoma is diffuse large B-cell lymphoma, while the most common indolent type is marginal zone lymphoma. Novel targets in patients with B-cell lymphoma are BCL2, the NF-κB pathway, components of the BCR activator of RhoGEF and GTPase signalling pathway and the PI3K-mTOR pathway. In this review, information is provided on the common types of B-cell lymphoma in CTD, the pathogenic factors implicated in lymphoma development and recent advancements in therapies effective for both autoimmune conditions and malignant lymphoproliferative diseases.
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Affiliation(s)
- Jing-Shu Ruan
- Department of Hematology, The Second Hospital of Shandong University, Jinan, Shandong 250033, P.R. China
| | - Shan Xu
- Department of Obstetrics, Central Hospital Affiliated to Shandong First Medical University, Jinan, Shandong 250013, P.R. China
| | - Ning-Ning Shan
- Department of Hematology, The Second Hospital of Shandong University, Jinan, Shandong 250033, P.R. China
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Cho IY, Han K, Jung JH, Cho MH, Lee D, Jeon KH, Shin DW. Rheumatoid arthritis and the risk of hematologic malignancies: a nationwide cohort study. Leukemia 2025; 39:755-759. [PMID: 39578532 DOI: 10.1038/s41375-024-02477-3] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/20/2024] [Revised: 11/13/2024] [Accepted: 11/14/2024] [Indexed: 11/24/2024]
Affiliation(s)
- In Young Cho
- Department of Family Medicine/Supportive Care Center, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Republic of Korea
- Department of Clinical Research Design and Evaluation, Samsung Advanced Institute for Health Science and Technology, Sungkyunkwan University, Seoul, Republic of Korea
| | - Kyungdo Han
- Department of Statistics and Actuarial Science, Soongsil University, Seoul, Republic of Korea.
| | - Jin Hyung Jung
- Samsung Biomedical Research Institute, Sungkyunkwan University School of Medicine, Suwon, Republic of Korea
| | - Mi Hee Cho
- Samsung C&T Medical Clinic, Kangbuk Samsung Hospital, Sungkyunkwan University School of Medicine, Seoul, Republic of Korea
| | - Dagyeong Lee
- Department of Family Medicine, Hallym University Dongtan Sacred Heart Hospital, Hwaseong, Republic of Korea
| | - Keun Hye Jeon
- Department of Family Medicine, CHA Gumi Medical Center, CHA University School of Medicine, Gumi, Republic of Korea
| | - Dong Wook Shin
- Department of Family Medicine/Supportive Care Center, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Republic of Korea.
- Department of Clinical Research Design and Evaluation, Samsung Advanced Institute for Health Science and Technology, Sungkyunkwan University, Seoul, Republic of Korea.
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Gong X, Yang SY, Wang ZY, Tang M. The role of hypoxic microenvironment in autoimmune diseases. Front Immunol 2024; 15:1435306. [PMID: 39575238 PMCID: PMC11578973 DOI: 10.3389/fimmu.2024.1435306] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/20/2024] [Accepted: 10/21/2024] [Indexed: 11/24/2024] Open
Abstract
The hypoxic microenvironment, characterized by significantly reduced oxygen levels within tissues, has emerged as a critical factor in the pathogenesis and progression of various autoimmune diseases (AIDs). Central to this process is the hypoxia-inducible factor-1 (HIF-1), which orchestrates a wide array of cellular responses under low oxygen conditions. This review delves into the multifaceted roles of the hypoxic microenvironment in modulating immune cell function, particularly highlighting its impact on immune activation, metabolic reprogramming, and angiogenesis. Specific focus is given to the mechanisms by which hypoxia contributes to the development and exacerbation of diseases such as rheumatoid arthritis (RA), systemic lupus erythematosus (SLE), multiple sclerosis (MS), and dermatomyositis (DM). In these conditions, the hypoxic microenvironment not only disrupts immune tolerance but also enhances inflammatory responses and promotes tissue damage. The review also discusses emerging therapeutic strategies aimed at targeting the hypoxic pathways, including the application of HIF-1α inhibitors, mTOR inhibitors, and other modulators of the hypoxic response. By providing a comprehensive overview of the interplay between hypoxia and immune dysfunction in AIDs, this review offers new perspectives on the underlying mechanisms of these diseases and highlights potential avenues for therapeutic intervention.
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Affiliation(s)
- Xun Gong
- Department of Rheumatology and Immunology, Affiliated Hospital of Jiangsu University, Zhenjiang, China
| | - Su-Yin Yang
- Department of Rheumatology and Immunology, Affiliated Hospital of Jiangsu University, Zhenjiang, China
| | - Zhen-Yu Wang
- Department of Rheumatology and Immunology, Affiliated Hospital of Jiangsu University, Zhenjiang, China
| | - Min Tang
- School of Life Sciences, Jiangsu University, Zhenjiang, China
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Imam AA. Anti-TNF Alpha and Risk of Lymphoma in Rheumatoid Arthritis: A Systematic Review and Meta-Analysis. MEDICINA (KAUNAS, LITHUANIA) 2024; 60:1156. [PMID: 39064585 PMCID: PMC11279006 DOI: 10.3390/medicina60071156] [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: 06/17/2024] [Revised: 07/10/2024] [Accepted: 07/15/2024] [Indexed: 07/28/2024]
Abstract
Background and Objectives: Anti-tumor necrosis factor-alpha (TNF-α) agents are effective in treating rheumatoid arthritis (RA) but may entail a risk of lymphoma due to TNF-α's role in immune surveillance. This systematic review and meta-analysis assesses the risk of lymphoma in patients with RA treated with anti-TNF agents versus patients treated with methotrexate and/or a placebo. Materials and Methods: The Cochrane Database of Systematic Reviews, Cochrane Central Register of Controlled Trials, Embase, PubMed, and Google Scholar were systematically searched for relevant literature. Data were extracted and analyzed to determine risk ratios (RRs) and 95% confidence intervals (CIs), with heterogeneity assessed using I2 statistics. Methodological quality and risk of bias were assessed using the Cochrane Risk of Bias tool for randomized controlled trials (RCTs) and the Newcastle-Ottawa Scale for observational studies. Results: The search yielded 932 articles, 13 of which were retained for qualitative review and 12 for quantitative synthesis. Overall, the studies reviewed included 181,735 participants: 3772 from six RCTs and 177,963 from seven observational studies. The meta-analysis of RCTs revealed no significant difference in the risk of lymphoma between patients receiving anti-TNF-α therapy and patients on conventional treatments, with an overall RR of 1.43 (95% CI: 0.32-5.16) and I2 of 0%. Conversely, observational studies showed some variability, with an overall RR of 1.43 (95% CI: 0.59-3.47) and significant heterogeneity (I2 = 95%), whereas others indicated a potentially elevated risk of lymphoma in specific subgroups but had inconsistent results. Conclusions: The systematic and meta-analysis revealed no significant difference in the risk of lymphoma for patients with RA treated with anti-TNF-α agents versus conventional therapies. However, given the limitations of the studies included, additional research is needed to validate the results and explore potential risk factors contributing to the development of lymphoma in patients with RA.
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Affiliation(s)
- Ahmad A Imam
- Internal Medicine Department, College of Medicine, Umm Al-Qura University, Makkah 24382, Saudi Arabia
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Battista T, Gallo L, Martora F, Fattore D, Potestio L, Cacciapuoti S, Scalvenzi M, Megna M. Biological Therapy for Psoriasis in Cancer Patients: An 8-Year Retrospective Real-Life Study. J Clin Med 2024; 13:1940. [PMID: 38610706 PMCID: PMC11012886 DOI: 10.3390/jcm13071940] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/22/2024] [Revised: 03/13/2024] [Accepted: 03/22/2024] [Indexed: 04/14/2024] Open
Abstract
Background: It is now recognized that psoriasis plays a key role in the development of several comorbidities, such as cardiovascular disease, and metabolic syndrome. Some authors have hypothesized that patients with psoriasis may have an increased risk of developing certain types of cancer. The efficacy and safety of biologic drugs are well-documented in clinical trials and in real-life studies. However, there is limited evidence on the safety of the use of biologic treatments in cancer patients with psoriasis, and the use of this therapeutic class in patients with a pre-existing or concomitant malignancy is still debated. Methods: We have conducted a retrospective observational study of a group of oncology patients with moderate-to-severe psoriasis treated with biologic therapy at the Dermatology Clinic of the University of Naples Federico II, during the period from 2016 to 2024. We included 20 adult patients; in 15 of them the diagnosis of neoplasm preceded the start of treatment biologic, while four of these patients had been diagnosed with cancer during the course of therapy biologics. Results: The most represented neoplasms in our population were breast carcinoma, prostate carcinoma, thyroid carcinoma, and chronic lymphatic leukemia. Anti-IL17 drugs were the most frequently prescribed (47.7%), followed by anti-IL23p19 (36.8%), anti-IL-12/23 (10.5%) and anti-TNF alpha (5.26%). All patients showed improvement of psoriasis after starting the therapy. Conclusions: Our experience supports the effectiveness and safety of biological therapy for psoriasis in patients with a history of cancer or recent onset neoplasia.
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Affiliation(s)
- Teresa Battista
- Section of Dermatology, Department of Clinical Medicine and Surgery, University of Naples Federico II, Via Pansini 5, 80131 Napoli, Italy; (L.G.); (D.F.); (S.C.); (M.M.)
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Soldin I, Pereira N. Autoimmunity and Cancer: Two Stations on the Same Continuum. Cureus 2024; 16:e54317. [PMID: 38496074 PMCID: PMC10944658 DOI: 10.7759/cureus.54317] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 02/16/2024] [Indexed: 03/19/2024] Open
Abstract
INTRODUCTION Autoimmunity has been associated with different types of cancer, including hematological malignancies like lymphomas, and solid tumors. Additionally, the potential role of medication-induced immunosuppression should be considered. AIM Our study aimed to investigate the relationship between autoimmunity and the development of cancer, as well as the impact of immunosuppressive drugs on increasing cancer risk. METHODS The study sample was composed of patients who developed cancer after the administration of biological agents for the treatment of autoimmune disorders. Selected patients were treated in our hospital between 1st January 2011 and 31st December 2021 and followed up in internal medicine, gastroenterology, or dermatology consult. From 434 patients with autoimmune diseases using biological agents, only 20 developed cancer, which was our final study sample. The data analysis was performed using the IQVIR package version 2.0.2 (IQVIA, Durham, NC). A p-value of <0.05 was considered statistically significant. RESULTS We found a significant correlation between long-term corticosteroid therapy and an increased risk of cancer. However, the effect of biological therapies on cancer risk was not statistically significant. It's worth noting that our sample size was small, so we cannot extrapolate these findings. CONCLUSIONS Physicians need to be aware that treating autoimmune diseases with immunosuppressive therapies may contribute to the development of cancer. Further research is needed to determine the impact of such treatments on cancer prognosis.
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Affiliation(s)
- Inês Soldin
- Medical Oncology, Instituto Português de Oncologia do Porto Francisco Gentil, Porto, PRT
| | - Nídia Pereira
- Internal Medicine, Hospital Pedro Hispano, Matosinhos, PRT
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Davis MS, Spencer RK, Johnson CE, Elhage KG, Jin JQ, Hakimi M, Bhutani T, Liao W. Risk of Cutaneous T Cell Lymphoma with Psoriasis Biologic Therapies. Dermatol Ther (Heidelb) 2024; 14:15-30. [PMID: 38043065 PMCID: PMC10828324 DOI: 10.1007/s13555-023-01074-z] [Citation(s) in RCA: 5] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/06/2023] [Accepted: 11/13/2023] [Indexed: 12/05/2023] Open
Abstract
BACKGROUND The risk of developing cutaneous T cell lymphoma (CTCL) in patients using psoriasis biologics has not been well characterized. The goals of this review were to investigate the incidence of CTCL in patients with psoriasis receiving biologic therapy in clinical trials and psoriasis registries, and to review cases of CTCL and biologic use reported in scientific publications. METHODS The US National Library of Medicine clinical trials database (clinicaltrials.gov) was queried to identify phase 3 and 4 clinical trials of the 12 biologic agents currently FDA approved for psoriatic disease. The incidence of CTCL in these trials was examined and summarized. To examine the incidence of CTCL in psoriasis registries, a Medline search was conducted. Finally, we performed a systematic review of CTCL cases reported in the literature. RESULTS Only two cases of CTCL were reported in 35,801 subjects with psoriasis receiving a biologic agent in the active arm of 108 psoriasis phase 3 clinical trials. One of these CTCL cases was determined by the investigator to be CTCL misdiagnosed as psoriasis prior to randomization. No cases of CTCL were reported in 5440 subjects with psoriasis in 34 phase 4 clinical trials. Only one case of CTCL was identified in 34,111 registry subjects. In the literature, tumor necrosis factor (TNF) inhibitors had the highest number of reported cases of CTCL (34 cases), followed by interleukin (IL)-17 inhibitors (7 cases), and IL-12/23 inhibitors (6 cases). No cases of CTCL were found to be reported with IL-23 inhibitors. CONCLUSION Our findings indicate that the development of CTCL is rare in the setting of psoriasis biologic use. Of the limited number of cases of CTCL found, most were in the setting of TNF inhibitor use and no cases of CTCL were reported in the setting of IL-23 inhibitor use.
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Affiliation(s)
- Mitchell S Davis
- Department of Dermatology, University of California San Francisco, Floor 04, Room N426, 2340 Sutter Street, Box 0808, San Francisco, CA, 94115, USA
| | - Riley K Spencer
- Department of Dermatology, University of California San Francisco, Floor 04, Room N426, 2340 Sutter Street, Box 0808, San Francisco, CA, 94115, USA
- Arizona College of Osteopathic Medicine, Midwestern University, Glendale, AZ, USA
| | - Chandler E Johnson
- Department of Dermatology, University of California San Francisco, Floor 04, Room N426, 2340 Sutter Street, Box 0808, San Francisco, CA, 94115, USA
- Medical College of Georgia, Augusta, GA, USA
| | - Kareem G Elhage
- Department of Dermatology, University of California San Francisco, Floor 04, Room N426, 2340 Sutter Street, Box 0808, San Francisco, CA, 94115, USA
| | - Joy Q Jin
- Department of Dermatology, University of California San Francisco, Floor 04, Room N426, 2340 Sutter Street, Box 0808, San Francisco, CA, 94115, USA
- School of Medicine, University of California San Francisco, San Francisco, CA, USA
| | - Marwa Hakimi
- Department of Dermatology, University of California San Francisco, Floor 04, Room N426, 2340 Sutter Street, Box 0808, San Francisco, CA, 94115, USA
| | - Tina Bhutani
- Department of Dermatology, University of California San Francisco, Floor 04, Room N426, 2340 Sutter Street, Box 0808, San Francisco, CA, 94115, USA
| | - Wilson Liao
- Department of Dermatology, University of California San Francisco, Floor 04, Room N426, 2340 Sutter Street, Box 0808, San Francisco, CA, 94115, USA.
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Wang F, Palmer N, Fox K, Liao KP, Yu KH, Kou SC. Large-scale real-world data analyses of cancer risks among patients with rheumatoid arthritis. Int J Cancer 2023; 153:1139-1150. [PMID: 37246892 PMCID: PMC10524922 DOI: 10.1002/ijc.34606] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/18/2023] [Revised: 04/16/2023] [Accepted: 04/27/2023] [Indexed: 05/30/2023]
Abstract
Rheumatoid arthritis (RA) affects 24.5 million people worldwide and has been associated with increased cancer risks. However, the extent to which the observed risks are related to the pathophysiology of rheumatoid arthritis or its treatments is unknown. Leveraging nationwide health insurance claims data with 85.97 million enrollees across 8 years, we identified 92 864 patients without cancers at the time of rheumatoid arthritis diagnoses. We matched 68 415 of these patients with participants without rheumatoid arthritis by sex, race, age and inferred health and economic status and compared their risks of developing all cancer types. By 12 months after the diagnosis of rheumatoid arthritis, rheumatoid arthritis patients were 1.21 (95% confidence interval [CI] [1.14, 1.29]) times more likely to develop any cancer compared with matched enrollees without rheumatoid arthritis. In particular, the risk of developing lymphoma is 2.08 (95% CI [1.67, 2.58]) times higher in the rheumatoid arthritis group, and the risk of developing lung cancer is 1.69 (95% CI [1.32, 2.13]) times higher. We further identified the five most commonly used drugs in treating rheumatoid arthritis, and the log-rank test showed none of them is implicated with a significantly increased cancer risk compared with rheumatoid arthritis patients without that specific drug. Our study suggested that the pathophysiology of rheumatoid arthritis, rather than its treatments, is implicated in the development of subsequent cancers. Our method is extensible to investigating the connections among drugs, diseases and comorbidities at scale.
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Affiliation(s)
- Feicheng Wang
- Department of Statistics, Harvard University, Cambridge, MA
| | - Nathan Palmer
- Department of Biomedical Informatics, Harvard Medical School, Boston, MA
| | - Kathe Fox
- Department of Biomedical Informatics, Harvard Medical School, Boston, MA
| | | | - Kun-Hsing Yu
- Department of Biomedical Informatics, Harvard Medical School, Boston, MA
- Department of Pathology, Brigham and Women’s Hospital, Boston, MA
| | - S. C. Kou
- Department of Statistics, Harvard University, Cambridge, MA
- Department of Biostatistics, Harvard T.H. Chan School of Public Health, Boston, MA
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Vale N, Pereira M, Mendes RA. Systemic Inflammatory Disorders, Immunosuppressive Treatment and Increase Risk of Head and Neck Cancers-A Narrative Review of Potential Physiopathological and Biological Mechanisms. Cells 2023; 12:2192. [PMID: 37681925 PMCID: PMC10487135 DOI: 10.3390/cells12172192] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/22/2023] [Revised: 08/28/2023] [Accepted: 08/30/2023] [Indexed: 09/09/2023] Open
Abstract
Head and neck cancers (HNCs) are known to present multiple factors likely to influence their development. This review aims to provide a comprehensive overview of the current scientific literature on the interplay between systemic inflammatory disorders, immunosuppressive treatments and their synergistic effect on HNC risk. Both cell-mediated and humoral-mediated systemic inflammatory disorders involve dysregulated immune responses and chronic inflammation and these inflammatory conditions have been associated with an increased risk of HNC development, primarily in the head and neck region. Likewise, the interaction between systemic inflammatory disorders and immunosuppressive treatments appears to amplify the risk of HNC development, as chronic inflammation fosters a tumor-promoting microenvironment, while immunosuppressive therapies further compromise immune surveillance and anti-tumor immune responses. Understanding the molecular and cellular mechanisms underlying this interaction is crucial for developing targeted prevention strategies and therapeutic interventions. Additionally, the emerging field of immunotherapy provides potential avenues for managing HNCs associated with systemic inflammatory disorders, but further research is needed to determine its efficacy and safety in this specific context. Future studies are warranted to elucidate the underlying mechanisms and optimize preventive strategies and therapeutic interventions.
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Affiliation(s)
- Nuno Vale
- OncoPharma Research Group, Center for Health Technology and Services Research (CINTESIS), Rua Doutor Plácido da Costa, 4200-450 Porto, Portugal;
- CINTESIS@RISE, Faculty of Medicine, University of Porto, Alameda Professor Hernâni Monteiro, 4200-319 Porto, Portugal
- Department of Community Medicine, Information and Health Decision Sciences (MEDCIDS), Faculty of Medicine, University of Porto, Rua Doutor Plácido da Costa, 4200-450 Porto, Portugal
| | - Mariana Pereira
- OncoPharma Research Group, Center for Health Technology and Services Research (CINTESIS), Rua Doutor Plácido da Costa, 4200-450 Porto, Portugal;
- CINTESIS@RISE, Faculty of Medicine, University of Porto, Alameda Professor Hernâni Monteiro, 4200-319 Porto, Portugal
| | - Rui Amaral Mendes
- CINTESIS@RISE, Faculty of Medicine, University of Porto, Alameda Professor Hernâni Monteiro, 4200-319 Porto, Portugal
- Department of Community Medicine, Information and Health Decision Sciences (MEDCIDS), Faculty of Medicine, University of Porto, Rua Doutor Plácido da Costa, 4200-450 Porto, Portugal
- Department of Oral and Maxillofacial Medicine and Diagnostic Sciences, Case Western Reserve University, 10900 Euclid Ave, Cleveland, OH 44106-7401, USA
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Duran E, Ozturk ZO, Bilgin E, Büyükaşık Y, Dizdar O, Yardimci GK, Farisogullari B, Özsoy Z, Ayan G, Uzun GS, Ekici M, Unaldi E, Kilic L, Akdoğan A, Karadag O, Bilgen ŞA, Kiraz S, Kalyoncu U, Ertenli AI. Hematologic Malignancy Risk in Inflammatory Arthritis Patients Treated with TNF Inhibitors: The Real-Life Data from the HUR-BIO Registry. Rheumatol Ther 2023; 10:969-981. [PMID: 37294405 PMCID: PMC10326223 DOI: 10.1007/s40744-023-00563-z] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/02/2023] [Accepted: 05/11/2023] [Indexed: 06/10/2023] Open
Abstract
INTRODUCTION This study aimed to assess the incidence of hematologic malignancy (HM) among inflammatory arthritis (IA) patients receiving tumor necrosis factor inhibitors (TNFi) compared with the general Turkish population. METHODS HUR-BIO (Hacettepe University Rheumatology Biologic Registry) is a single-center biological disease-modifying anti-rheumatic drug (bDMARD) registry since 2005. Patients with IA, including rheumatoid arthritis, spondyloarthritis, or psoriatic arthritis who had at least one visit after the TNFi were screened from 2005 to November 2021. Standardized incidence rates (SIR) were calculated after adjustment for age and gender and compared with the 2017 Turkish National Cancer Registry (TNCR). RESULTS Of the 6139 patients registered in the HUR-BIO, 5355 used any TNFi at least once. The median follow-up duration was 2.6 years for patients receiving TNFi. Thirteen patients developed a HM on follow-up. In these patients, the median age at the IA onset was 38 (range, 26-67), and the median age at the HM diagnosis was 55.5 (range, 38-76). Patients using TNFi had an increased HM incidence (SIR 4.23, 95% confidence interval (CI) 2.35-7.05). Ten patients with HM were under 65 years of age. In this group, there was a higher incidence of HM in both men (SIR 5.15, 95% CI 1.88-11.43) and women (SIR 4.76, 95% CI 1.74-10.55). CONCLUSIONS The risk of HMs in inflammatory arthritis patients receiving TNFi was four times higher than in the general Turkish population.
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Affiliation(s)
- Emine Duran
- Division of Rheumatology, Department of Internal Medicine, Hacettepe University Faculty of Medicine, Sihhiye, 06100, Ankara, Turkey
| | - Zeynep Ozge Ozturk
- Department of Internal Medicine, Hacettepe University Faculty of Medicine, Ankara, Turkey
| | - Emre Bilgin
- Division of Rheumatology, Department of Internal Medicine, Hacettepe University Faculty of Medicine, Sihhiye, 06100, Ankara, Turkey.
| | - Yahya Büyükaşık
- Division of Hematology, Department of Internal Medicine, Hacettepe University Faculty of Medicine, Ankara, Turkey
| | - Omer Dizdar
- Department of Medical Oncology, Hacettepe University Cancer Institute, Ankara, Turkey
| | - Gozde Kubra Yardimci
- Division of Rheumatology, Department of Internal Medicine, Hacettepe University Faculty of Medicine, Sihhiye, 06100, Ankara, Turkey
| | - Bayram Farisogullari
- Division of Rheumatology, Department of Internal Medicine, Hacettepe University Faculty of Medicine, Sihhiye, 06100, Ankara, Turkey
| | - Zehra Özsoy
- Division of Rheumatology, Department of Internal Medicine, Hacettepe University Faculty of Medicine, Sihhiye, 06100, Ankara, Turkey
| | - Gizem Ayan
- Division of Rheumatology, Department of Internal Medicine, Hacettepe University Faculty of Medicine, Sihhiye, 06100, Ankara, Turkey
| | - Gullu Sandal Uzun
- Division of Rheumatology, Department of Internal Medicine, Hacettepe University Faculty of Medicine, Sihhiye, 06100, Ankara, Turkey
| | - Mustafa Ekici
- Division of Rheumatology, Department of Internal Medicine, Hacettepe University Faculty of Medicine, Sihhiye, 06100, Ankara, Turkey
| | - Erdinc Unaldi
- Division of Rheumatology, Department of Internal Medicine, Hacettepe University Faculty of Medicine, Sihhiye, 06100, Ankara, Turkey
| | - Levent Kilic
- Division of Rheumatology, Department of Internal Medicine, Hacettepe University Faculty of Medicine, Sihhiye, 06100, Ankara, Turkey
| | - Ali Akdoğan
- Division of Rheumatology, Department of Internal Medicine, Hacettepe University Faculty of Medicine, Sihhiye, 06100, Ankara, Turkey
| | - Omer Karadag
- Division of Rheumatology, Department of Internal Medicine, Hacettepe University Faculty of Medicine, Sihhiye, 06100, Ankara, Turkey
| | - Şule Apraş Bilgen
- Division of Rheumatology, Department of Internal Medicine, Hacettepe University Faculty of Medicine, Sihhiye, 06100, Ankara, Turkey
| | - Sedat Kiraz
- Division of Rheumatology, Department of Internal Medicine, Hacettepe University Faculty of Medicine, Sihhiye, 06100, Ankara, Turkey
| | - Umut Kalyoncu
- Division of Rheumatology, Department of Internal Medicine, Hacettepe University Faculty of Medicine, Sihhiye, 06100, Ankara, Turkey
| | - Ali Ihsan Ertenli
- Division of Rheumatology, Department of Internal Medicine, Hacettepe University Faculty of Medicine, Sihhiye, 06100, Ankara, Turkey
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11
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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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Reyes A, Mohanty A, Pharaon R, Massarelli E. Association between Immunosuppressive Therapy Utilized in the Treatment of Autoimmune Disease or Transplant and Cancer Progression. Biomedicines 2022; 11:biomedicines11010099. [PMID: 36672607 PMCID: PMC9856025 DOI: 10.3390/biomedicines11010099] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/03/2022] [Revised: 12/28/2022] [Accepted: 12/28/2022] [Indexed: 01/01/2023] Open
Abstract
Autoimmunity and cancer rates have both been on the rise in Western civilization prompting many to investigate the link between the two entities. This review will investigate the complex interactions between the activation and deactivation of the immune system and the development of malignancy. Additional focus will be placed on the main classes of immune inhibitor therapy utilized in transplant patients and in autoimmune disease including TNF-alpha, Calcineurin, mTOR, purine synthesis antagonists and IMPDH inhibitors.
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13
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Zhang Y, Lin J, You Z, Tu H, He P, Li J, Gao R, Liu Z, Xi Z, Li Z, Lu Y, Hu Q, Li C, Ge F, Huo Z, Qiao G. Cancer risks in rheumatoid arthritis patients who received immunosuppressive therapies: Will immunosuppressants work? Front Immunol 2022; 13:1050876. [PMID: 36605209 PMCID: PMC9807750 DOI: 10.3389/fimmu.2022.1050876] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/22/2022] [Accepted: 11/29/2022] [Indexed: 12/24/2022] Open
Abstract
Background Exploring the cancer risks of rheumatoid arthritis (RA) patients with disease-modifying anti-rheumatic drugs (DMARDs) can help detect, evaluate, and treat malignancies at an early stage for these patients. Thus, a comprehensive analysis was conducted to determine the cancer risk of RA patients using different types of DMARDs and analyze their relationship with tumor mutational burdens (TMBs) reflecting immunogenicity. Methods A thorough search of PubMed, EMBASE, Web of Science, and Medline was conducted up to 20 August 2022. Standardized incidence ratios (SIRs) were constructed with a random-effect model to determine risks for different types of malignancies in comparison with the general population. We also analyzed the correlation between SIRs and TMBs using linear regression (LR). Results From a total of 22 studies, data on 371,311 RA patients receiving different types of DMARDs, 36 kinds of malignancies, and four regions were available. Overall cancer risks were 1.15 (SIR 1.15; 1.09-1.22; p < 0.001) and 0.91 (SIR 0.91; 0.72-1.14; p = 0.402) in RA populations using conventional synthetic DMARDs (csDMARDs) and biologic DMARDs (bDMARDs), respectively. RA patients taking csDMARDs displayed a 1.77-fold lung cancer risk (SIR 1.77; 1.50-2.09; p < 0.001), a 2.15-fold lymphoma risk (SIR 2.15; 1.78-2.59; p < 0.001), and a 1.72-fold melanoma risk (SIR 1.72; 1.26-2.36; p = 0.001). Correlation coefficients between TMBs and SIRs were 0.22 and 0.29 from those taking csDMARDs and bDMARDs, respectively. Conclusion We demonstrated a cancer risk spectrum of RA populations using DMARDs. Additionally, TMBs were not associated with elevated cancer risks in RA patients following immunosuppressive therapy, which confirmed that iatrogenic immunosuppression might not increase cancer risks in patients with RA. Interpretation Changes were similar in cancer risk after different immunosuppressive treatments, and there was a lack of correlation between SIRs and TMBs. These suggest that we should look for causes of increased risks from the RA disease itself, rather than using different types of DMARDs.
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Affiliation(s)
- Yuzhuo Zhang
- Guangzhou Medical University, Guangzhou, Guangdong, China
| | - Jiangpeng Lin
- Guangzhou Medical University, Guangzhou, Guangdong, China
| | - Zhixuan You
- Guangzhou Medical University, Guangzhou, Guangdong, China
| | - Hengjia Tu
- Guangzhou Medical University, Guangzhou, Guangdong, China
| | - Peng He
- Guangzhou Medical University, Guangzhou, Guangdong, China
| | - Jiarong Li
- Department of Medical Imaging, Changzhi Medical College, Changzhi, Shanxi, China
| | - Rui Gao
- Guangzhou Medical University, Guangzhou, Guangdong, China
| | - Ziyu Liu
- Guangzhou Medical University, Guangzhou, Guangdong, China
| | - Zhiyuan Xi
- College of Clinical Medicine, Jilin University, Changchun, Jilin, China
| | - Zekun Li
- Guangzhou Medical University, Guangzhou, Guangdong, China
| | - Yi Lu
- Guangzhou Medical University, Guangzhou, Guangdong, China
- Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, Hangzhou, China
| | - Qiyuan Hu
- Shanxi Medical University, Taiyuan, Shanxi, China
| | - Chenhui Li
- School of Basic Medical Sciences, Qiqihar Medical University, Qiqihar, Heilongjiang, China
| | - Fan Ge
- Guangzhou Medical University, Guangzhou, Guangdong, China
- National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Zhenyu Huo
- Guangzhou Medical University, Guangzhou, Guangdong, China
- National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Guibin Qiao
- Department of Thoracic Surgery, Guangdong Provincial People’s Hospital, Guangdong Academy of Medical Sciences, Guangzhou, Guangdong, China
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He C, Ge XP, Zhang XH, Chen P, Li BZ. Multiple myeloma presenting with amyloid arthropathy as the first manifestation: Two case reports. World J Clin Cases 2022; 10:13028-13037. [PMID: 36568992 PMCID: PMC9782929 DOI: 10.12998/wjcc.v10.i35.13028] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/20/2022] [Revised: 10/26/2022] [Accepted: 11/08/2022] [Indexed: 12/14/2022] Open
Abstract
BACKGROUND Multiple myeloma (MM) can be accompanied by amyloidosis, which occurs in a small number of patients and is characterized by deposition of light chains in the joints, leading to multiple myeloma-associated amyloid arthropathy (MAA). As a rare complication of MM, clinical manifestations of MAA are often similar to those of rheumatoid arthritis, and the two are easily confused.
CASE SUMMARY In recent years, our center treated two patients of MM with amyloid arthropathy as the first manifestation, both of whom presented with polyarthritis. After treatment for MM, both patients achieved complete remission. However, subsequently, the two patients underwent hip arthroplasty for femoral neck fractures. Congo red staining and immunofluorescence of the joint tissues confirmed MAA after surgery. Eventually, one of the patients died of MM recurrence, while the other survived.
CONCLUSION MAA should be regarded as an initial symptom of MM and should be taken seriously.
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Affiliation(s)
- Chuan He
- Department of Haematology, The Second Affiliated Hospital of Soochow University, Suzhou 215004, Jiangsu Province, China
| | - Xue-Ping Ge
- Department of Haematology, The Second Affiliated Hospital of Soochow University, Suzhou 215004, Jiangsu Province, China
| | - Xiao-Hui Zhang
- Department of Haematology, The Second Affiliated Hospital of Soochow University, Suzhou 215004, Jiangsu Province, China
| | - Ping Chen
- Department of Haematology, The Second Affiliated Hospital of Soochow University, Suzhou 215004, Jiangsu Province, China
| | - Bing-Zong Li
- Department of Haematology, The Second Affiliated Hospital of Soochow University, Suzhou 215004, Jiangsu Province, China
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15
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Yuan S, Chen J, Ruan X, Vithayathil M, Kar S, Li X, Mason AM, Burgess S, Larsson SC. Rheumatoid arthritis and risk of site-specific cancers: Mendelian randomization study in European and East Asian populations. Arthritis Res Ther 2022; 24:270. [PMID: 36514134 PMCID: PMC9746148 DOI: 10.1186/s13075-022-02970-z] [Citation(s) in RCA: 12] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/14/2022] [Accepted: 12/02/2022] [Indexed: 12/15/2022] Open
Abstract
BACKGROUND The associations of rheumatoid arthritis (RA) with risk of site-specific cancers beyond lymphohematopoietic cancer have been scarcely explored. We conducted a Mendelian randomization investigation of the associations of RA with site-specific cancers in European and East Asian populations. METHODS Independent genetic variants strongly associated with RA in European and East Asian populations were selected as instrumental variables from genome-wide association studies of 58,284 European individuals (14,361 cases and 43,923 controls) and 22,515 East Asian individuals (4873 cases and 17,642 controls), respectively. The associations of genetic variants with overall and 22 site-specific cancers were extracted from the UK Biobank study (n = 367,561), the FinnGen study (n = 260,405), Biobank Japan (n = 212,453), and international consortia. The associations for one outcome from different data sources were combined by meta-analysis. RESULTS In the European population, the combined odds ratios per 1-unit increase in log odds of genetic liability to RA were 1.06 (95% confidence interval [CI] 1.03-1.10) for head and neck cancer, 1.06 (95% CI 1.02-1.10) for cervical cancer, 0.92 (95% CI 0.87-0.96) for testicular cancer, and 0.94 (95% CI 0.90-0.98) for multiple myeloma. In the East Asian population, the corresponding odds ratios were 1.17 (95% CI 1.06-1.29) for pancreatic cancer, 0.91 (95% CI 0.88-0.94) for breast cancer, and 0.90 (95% CI 0.84-0.96) for ovarian cancer. There were suggestive associations for breast and ovarian cancer and overall cancer in the European population. No other associations were observed. CONCLUSION This study suggests that RA may play a role in the development of several site-specific cancers.
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Affiliation(s)
- Shuai Yuan
- Unit of Cardiovascular and Nutritional Epidemiology, Institute of Environmental Medicine, Karolinska Institutet, Nobelsväg 13, 17 177, Stockholm, Sweden
| | - Jie Chen
- Centre for Global Health, Zhejiang University School of Medicine, 866 Yuhangtang Road, Hangzhou, China
- Department of Gastroenterology, The Third Xiangya Hospital, Central South University, 138 Tongzipo Road, Changsha, China
| | - Xixian Ruan
- Department of Gastroenterology, The Third Xiangya Hospital, Central South University, 138 Tongzipo Road, Changsha, China
| | | | - Siddhartha Kar
- MRC Integrative Epidemiology Unit, Bristol Medical School, University of Bristol, Bristol, UK
| | - Xue Li
- Department of Big Data in Health Science School of Public Health, Center of Clinical Big Data and Analytics of The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China
| | - Amy M Mason
- British Heart Foundation Cardiovascular Epidemiology Unit, Department of Public Health and Primary Care, University of Cambridge, Cambridge, UK
| | - Stephen Burgess
- MRC Biostatistics Unit, University of Cambridge, Cambridge, UK
- Department of Public Health and Primary Care, University of Cambridge, Cambridge, UK
| | - Susanna C Larsson
- Unit of Cardiovascular and Nutritional Epidemiology, Institute of Environmental Medicine, Karolinska Institutet, Nobelsväg 13, 17 177, Stockholm, Sweden.
- Unit of Medical Epidemiology, Department of Surgical Sciences, Uppsala University, Uppsala, Sweden.
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16
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Rusiñol L, Camiña-Conforto G, Puig L. Biologic treatment of psoriasis in oncologic patients. Expert Opin Biol Ther 2022; 22:1567-1578. [PMID: 36422998 DOI: 10.1080/14712598.2022.2152322] [Citation(s) in RCA: 12] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/27/2022]
Abstract
INTRODUCTION There is a complex interplay between psoriasis and cancer, with therapeutic implications. Patients with psoriasis have an increased risk of developing several types of cancer, and safety concerns have arisen regarding biologic therapies and cancer. On the other hand, biologics can provide adequate control of psoriasis that appears or worsens as an immune-related adverse event following immune enhancing checkpoint inhibitor therapy for cancer, thus allowing prosecution of oncologic treatment without impairing its efficacy. PATIENTS AND METHODS We performed a retrospective observational study of patients with moderate-to-severe psoriasis under biological treatment and cancer who were treated at our Department between January 2009 and June 2022. RESULTS We included 31 adult patients with psoriasis and cancer; in 16 the diagnosis of cancer preceded the inception of biological treatment, and 9 of those patients were in remission. Most malignancies arose in the genitourinary system, followed by breast, hematologic, colorectal, thyroid, and others. Anti-IL23p19 biologics were most frequently used (36%), followed by anti-TNF (32%), anti-IL-17 (16%) and anti-IL-12/23 (16%) agents. All patients showed improvement of psoriasis after biologic initiation. CONCLUSIONS Biologic treatment for moderate-severe psoriasis should be considered in oncologic patients since it is not formally contraindicated and is safe. Moreover, the efficacy and safety profile of IL-23 and IL-17 inhibitors may be advantageous for those patients.
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Affiliation(s)
- Lluís Rusiñol
- Department of Dermatology, IIB Sant Pau, Hospital de la Santa Creu i Sant Pau, Universitat Autònoma de Barcelona, Barcelona, Spain
| | - Gemma Camiña-Conforto
- Department of Dermatology, IIB Sant Pau, Hospital de la Santa Creu i Sant Pau, Universitat Autònoma de Barcelona, Barcelona, Spain
| | - Luis Puig
- Department of Dermatology, IIB Sant Pau, Hospital de la Santa Creu i Sant Pau, Universitat Autònoma de Barcelona, Barcelona, Spain
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Wang X, Yang C, Körner H, Ge C. Tumor Necrosis Factor: What Is in a Name? Cancers (Basel) 2022; 14:5270. [PMID: 36358688 PMCID: PMC9656125 DOI: 10.3390/cancers14215270] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/13/2022] [Revised: 10/19/2022] [Accepted: 10/25/2022] [Indexed: 12/18/2024] Open
Abstract
Tumor Necrosis Factor was one of the first cytokines described in the literature as a soluble mediator of cytotoxicity to tumors. Over the years, more extensive research that tried to employ Tumor Necrosis Factor in cancer treatments showed nevertheless that it mainly functioned as a proinflammatory cytokine. However, this did not stop the search for the holy grail of cancer research: A cytokine that could act as a one-stop treatment for solid tumors and lymphomas. This review will summarize the long experimental history of Tumor Necrosis Factor that caused the initial observations of a tumor necrotizing cytokine that could serve as a potential cancer treatment and discuss the current state of research into this side of the activities of Tumor Necrosis Factor.
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Affiliation(s)
- Xinming Wang
- Department of Pharmacy, First Affiliated Hospital of Anhui Medical University, Hefei 230022, China
| | - Chunlan Yang
- Department of Pharmacy, First Affiliated Hospital of Anhui Medical University, Hefei 230022, China
| | - Heinrich Körner
- Menzies Institute for Medical Research, Liverpool Street, Hobart, TAS 7000, Australia
| | - Chaoliang Ge
- Department of Pharmacy, First Affiliated Hospital of Anhui Medical University, Hefei 230022, China
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18
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Vitali L, Merlini A, Galvagno F, Proment A, Sangiolo D. Biological and Exploitable Crossroads for the Immune Response in Cancer and COVID-19. Biomedicines 2022; 10:2628. [PMID: 36289890 PMCID: PMC9599827 DOI: 10.3390/biomedicines10102628] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/28/2022] [Revised: 10/05/2022] [Accepted: 10/14/2022] [Indexed: 12/15/2022] Open
Abstract
The outbreak of novel coronavirus disease 2019 (COVID-19) has exacted a disproportionate toll on cancer patients. The effects of anticancer treatments and cancer patients' characteristics shared significant responsibilities for this dismal outcome; however, the underlying immunopathological mechanisms are far from being completely understood. Indeed, despite their different etiologies, SARS-CoV-2 infection and cancer unexpectedly share relevant immunobiological connections. In the pathogenesis and natural history of both conditions, there emerges the centrality of the immune response, orchestrating the timed appearance, functional and dysfunctional roles of multiple effectors in acute and chronic phases. A significant number (more than 600) of observational and interventional studies have explored the interconnections between COVID-19 and cancer, focusing on aspects as diverse as psychological implications and prognostic factors, with more than 4000 manuscripts published so far. In this review, we reported and discussed the dynamic behavior of the main cytokines and immune system signaling pathways involved in acute vs. early, and chronic vs. advanced stages of SARS-CoV-2 infection and cancer. We highlighted the biological similarities and active connections within these dynamic disease scenarios, exploring and speculating on possible therapeutic crossroads from one setting to the other.
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Affiliation(s)
- Letizia Vitali
- Candiolo Cancer Institute, FPO-IRCCS, Strada Provinciale 142 Km 3.95, 10060 Candiolo, Italy
- Department of Oncology, University of Turin, Regione Gonzole 10, 10043 Orbassano, Italy
| | - Alessandra Merlini
- Candiolo Cancer Institute, FPO-IRCCS, Strada Provinciale 142 Km 3.95, 10060 Candiolo, Italy
- Department of Oncology, University of Turin, Regione Gonzole 10, 10043 Orbassano, Italy
| | - Federica Galvagno
- Candiolo Cancer Institute, FPO-IRCCS, Strada Provinciale 142 Km 3.95, 10060 Candiolo, Italy
- Department of Oncology, University of Turin, Regione Gonzole 10, 10043 Orbassano, Italy
| | - Alessia Proment
- Candiolo Cancer Institute, FPO-IRCCS, Strada Provinciale 142 Km 3.95, 10060 Candiolo, Italy
- Department of Oncology, University of Turin, Regione Gonzole 10, 10043 Orbassano, Italy
| | - Dario Sangiolo
- Candiolo Cancer Institute, FPO-IRCCS, Strada Provinciale 142 Km 3.95, 10060 Candiolo, Italy
- Department of Oncology, University of Turin, Regione Gonzole 10, 10043 Orbassano, Italy
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Immune-checkpoint inhibitor use in patients with cancer and pre-existing autoimmune diseases. Nat Rev Rheumatol 2022; 18:641-656. [PMID: 36198831 DOI: 10.1038/s41584-022-00841-0] [Citation(s) in RCA: 87] [Impact Index Per Article: 29.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 09/06/2022] [Indexed: 11/08/2022]
Abstract
Immune-checkpoint inhibitors (ICIs) have dramatically changed the management of advanced cancers. Designed to enhance the antitumour immune response, they can also cause off-target immune-related adverse events (irAEs), which are sometimes severe. Although the efficacy of ICIs suggests that they could have wide-ranging benefits, clinical trials of the drugs have so far excluded patients with pre-existing autoimmune disease. However, evidence is accumulating with regard to the use of ICIs in this 'at-risk' population, with retrospective data suggesting that they have an acceptable safety profile, but that there is a risk of disease flare or other irAE occurrence. The management of immunosuppressive drugs at ICI initiation in patients with autoimmune disease (or later in instances of disease flare or irAE) remains a question of particular interest in clinical practice, in which there is always a search for the balance between protecting against autoimmunity and ensuring a good tumour response. Although temporary use of immunosuppressants seems safe, prolonged use or use at ICI initiation might hamper the antitumour immune response, prompting clinicians to use the minimal efficient immunosuppressive regimen. However, a new paradigm is emerging, in which inhibitors of TNF or IL-6 could have synergistic effects with ICIs on tumour response, while also preventing severe irAEs. If confirmed, this 'decoupling' effect on toxicity and efficacy could change therapeutic practice in this field. Knowledge of the current use of ICIs in patients with pre-existing autoimmune disease, particularly with regard to the use of immunosuppressive drugs and/or biologic DMARDs, can help to guide clinical practice.
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Benucci M, Damiani A, Infantino M, Manfredi M, Lari B, Grossi V, Gobbi FL, Sarzi-Puttini P. Cardiovascular safety, cancer and Jak-inhibitors: Differences to be highlighted. Pharmacol Res 2022; 183:106359. [PMID: 35907434 DOI: 10.1016/j.phrs.2022.106359] [Citation(s) in RCA: 18] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/07/2022] [Revised: 07/07/2022] [Accepted: 07/15/2022] [Indexed: 11/29/2022]
Abstract
Rheumatoid arthritis (RA) is a chronic inflammatory disease whose natural history leads to articular and extra-articular damage. Both cardiovascular risk and malignancy risk results higher in RA patients, compared to general population. Janus kinase inhibitors (JAKis) are oral targeted synthetic disease modifying antirheumatic drugs (tsDMARDs) that disrupt cytokine cascade and exert anti-inflammatory effects by interfering with signaling through the JAK-STAT intracellular pathways. A recent RCT comparing tofacitinib 5 mg twice daily, tofacitinib 10 mg twice daily and anti-TNF in rheumatoid arthritis demonstrated an increased risk of MACE HR 1.33 and cancer HR 1.49 at a follow-up of 4 years. This has led the FDA to class warnings for tofacitinib, baricitinib and upadacitinib. Cumulative RCT data, RCT extension data demonstrated a safety profile for Jak inhibitors. Conflicting data results from real life registries; the different selectivity for JAKs (JAK1, JAK2, JAK3 and Tyk2) probably determines differences in efficacy and safety profiles among the members of this group which should actually be evaluated. In order to better understand the cardiovascular and neoplastic risk linked to these class of drugs, we aim to provide a literature review on existing evidence of the safety of Jak-Inhibitors in rheumatoid arthritis.
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Affiliation(s)
- Maurizio Benucci
- Rheumatology Unit, S.Giovanni di Dio Hospital, Azienda USL-Toscana Centro Florence, Italy.
| | - Arianna Damiani
- Rheumatology Unit, Department of Clinical and Experimental Medicine, University of Florence, Florence, Italy
| | - Maria Infantino
- Immunology and Allergology Laboratory, S.Giovanni di Dio Florence Italy, Italy
| | - Mariangela Manfredi
- Immunology and Allergology Laboratory, S.Giovanni di Dio Florence Italy, Italy
| | - Barbara Lari
- Immunology and Allergology Laboratory, S.Giovanni di Dio Florence Italy, Italy
| | - Valentina Grossi
- Immunology and Allergology Laboratory, S.Giovanni di Dio Florence Italy, Italy
| | - Francesca Li Gobbi
- Rheumatology Unit, S.Giovanni di Dio Hospital, Azienda USL-Toscana Centro Florence, Italy.
| | - Piercarlo Sarzi-Puttini
- Rheumatology Unit, ASST-Fatebenefratelli L. Sacco University Hospital, University of Milan, Italy
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Ben-Baruch A. Tumor Necrosis Factor α: Taking a Personalized Road in Cancer Therapy. Front Immunol 2022; 13:903679. [PMID: 35663982 PMCID: PMC9157545 DOI: 10.3389/fimmu.2022.903679] [Citation(s) in RCA: 20] [Impact Index Per Article: 6.7] [Reference Citation Analysis] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/24/2022] [Accepted: 04/25/2022] [Indexed: 11/29/2022] Open
Affiliation(s)
- Adit Ben-Baruch
- The Shmunis School of Biomedicine and Cancer Research, The George S. Wise Faculty of Life Sciences, Tel Aviv University, Tel Aviv, Israel
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22
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All-cause and cause-specific mortality of patients with rheumatoid arthritis in Korea: A nation-wide population-based study. Joint Bone Spine 2021; 89:105269. [PMID: 34534689 DOI: 10.1016/j.jbspin.2021.105269] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/31/2021] [Accepted: 08/16/2021] [Indexed: 12/17/2022]
Abstract
OBJECTIVE To compare all-cause and cause-specific mortality between rheumatoid arthritis (RA) patients versus the general population of Korea. METHODS A nationally representative RA population aged≥40 years was identified from Korea National Health Insurance Service (KNHIS) database. We estimated age- and sex-adjusted all-cause and cause-specific standardized mortality ratios (SMRs) with 95% confidence intervals (CIs), comparing RA patients to the general population. Subgroup analyses were done by sex, age group, calendar year, and biologics use. RESULTS We identified 79,352 RA patients with 6404 deaths during 2011-2016. The all-cause SMR [95% CI] of RA patients compared to the general population was 1.53 [1.49-1.56]. The top five causes of death were cancer (19.5%), respiratory disease (19.1%), cardiovascular disease (18.8%), systemic rheumatic diseases (9.5%, 9.1% due to RA), and infection (6.1%). Cause-specific SMRs [95% CI] were 0.95 [0.90-1.01] for cancer, 3.34 [3.15-3.52] for respiratory disease, 1.26 [1.18-1.33] for cardiovascular disease, 3.41 [3.08-3.75] for infection, and 4.88 [3.10-6.65] for non-RA systemic rheumatic disease. The SMR of RA population was slightly higher among men than women, and highest in their 60s and 70s. The yearly SMR increased from 1.10 [1.01-1.18] in 2011 to 1.85 [1.75-1.95] in 2016 due to population aging and comorbidity accumulation. Users of biologics showed a higher SMR than non-users (1.82 [1.69-1.96] vs. 1.50 [1.46-1.54]), due to higher RA activity, and more comorbidities despite a younger mean age. CONCLUSION RA patients in Korea experienced 1.5-fold increase in all-cause mortality compared to the general population. Except for cancer, the top five causes of death were associated with excess mortality among RA patients. RA-associated mortality was largely determined by age, RA activity, and comorbidity status.
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Ekmen N, Can G, Sasani H. Acute lymphoid leukemia developing in the course of Crohn's Disease: Are there any guilty agents? JOURNAL OF CLINICAL MEDICINE OF KAZAKHSTAN 2021; 18:65-67. [DOI: 10.23950/jcmk/10924] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 04/28/2025]
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Solipuram V, Mohan A, Patel R, Ni R. Effect of janus kinase inhibitors and methotrexate combination on malignancy in patients with rheumatoid arthritis: a systematic review and meta-analysis of randomized controlled trials. AUTOIMMUNITY HIGHLIGHTS 2021; 12:8. [PMID: 33910632 PMCID: PMC8080865 DOI: 10.1186/s13317-021-00153-5] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 01/23/2021] [Accepted: 03/25/2021] [Indexed: 12/14/2022]
Abstract
Background Rheumatoid arthritis (RA) is a systemic autoimmune disease. The combination therapy of methotrexate (MTX) and Janus kinase inhibitor (JAKi) is commonly used. Patients with RA are at increased risk of malignancy, however, it remains unclear whether the combination therapy is associated with a higher risk. Objective To assess the malignancy risk among patients with RA receiving combination therapy of JAKi and MTX compared to MTX alone. Methods PubMed, Cochrane and Embase were thoroughly searched for randomized controlled trials (RCTs) in patients with RA receiving JAKi and MTX, from inception to July 2020. Primary endpoints were malignancy events, Non melanomatous skin cancer (NMSC) and malignancy excluding NMSC and secondary endpoints were serious adverse events (SAE), deaths. Risk ratio (RR) and 95% CI were calculated using the Mantel–Haenszel random-effect method. Results 659 publications were screened and 13 RCTs with a total of 6911 patients were included in the analysis. There was no statistically significant difference in malignancy [RR = 1.42; 95% CI (0.59, 3.41)], neither NMSC [RR = 1.44 (0.36, 5.76)] nor malignancies excluding NMSC [RR = 1.12 (0.40, 3.13)]. No statistically significant difference between the two groups for SAE [RR = 1.15 (0.90, 1.47)] and deaths [RR = 1.99 (0.75, 5.27)] was found. Conclusion The adjunction of JAKi to MTX is not associated with an increased risk of malignancy when compared to MTX alone. There is no increased risk of SAE and deaths when compared to MTX alone in patients with RA. Supplementary Information The online version contains supplementary material available at 10.1186/s13317-021-00153-5.
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Affiliation(s)
- Vinod Solipuram
- Department of Internal Medicine, Ascension Saint Agnes Healthcare, 900S Caton Ave, Baltimore, 21229, USA
| | - Akhila Mohan
- Department of Internal Medicine, Ascension Saint Agnes Healthcare, 900S Caton Ave, Baltimore, 21229, USA
| | - Roshniben Patel
- Department of Internal Medicine, Ascension Saint Agnes Healthcare, 900S Caton Ave, Baltimore, 21229, USA
| | - Ruoning Ni
- Department of Internal Medicine, Ascension Saint Agnes Healthcare, 900S Caton Ave, Baltimore, 21229, USA.
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Hellgren K, Di Giuseppe D, Smedby KE, Sundström C, Askling J, Baecklund E. Lymphoma risks in patients with rheumatoid arthritis treated with biological drugs-a Swedish cohort study of risks by time, drug and lymphoma subtype. Rheumatology (Oxford) 2021; 60:809-819. [PMID: 32810256 DOI: 10.1093/rheumatology/keaa330] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/30/2020] [Revised: 05/11/2020] [Indexed: 12/17/2022] Open
Abstract
OBJECTIVES To estimate the association between biological DMARDs (bDMARDs; overall and by drug) as used in RA and the risk of malignant lymphomas including subtypes. METHODS By linking nationwide Swedish registers we identified cohorts of patients with RA initiating treatment with a bDMARD (n = 16 392), bDMARD-naïve (n = 55 253), an age- and sex-matched general population comparator cohort (n = 229 047), and all incident lymphomas 2001-16. We used Cox regression to calculate hazard ratios (HRs) of lymphoma taking calendar period and other factors into account. RESULTS There were 82 lymphomas among the bDMARD-treated patients with RA, crude incidence rate 76/100 000 person-years, and 310 lymphomas among the bDMARD-naïve patients with RA, crude incidence rate 90/100 000 person-years. This resulted in an adjusted HR (aHR) associated with bDMARD treatment (vs not) of 1.08 (95% CI: 0.83, 1.41). The corresponding aHR for bDMARD-treated and bDMARD-naïve vs the general population was 1.65 (95% CI: 1.31, 2.08) and 1.56 (95% CI: 1.37, 1.78) respectively. Restricting follow-up period to after 2006, the aHR of lymphoma for patients with RA starting a first bDMARD vs bDMARD-naïve was 0.69 (95% CI: 0.47, 1.00), and for bDMARD treated vs patients with RA switching from one conventional synthetic DMARDs to another, aHR was 0.46 (95% CI: 0.28, 0.73). There were no signals of different risks with any particular TNF inhibitor (TNFi) agent. We found no different lymphoma subtype pattern following bDMARD therapy. CONCLUSION Treatment with bDMARDs, including both TNFi and non-TNFi bDMARDs, does not further increase the lymphoma risk in RA; instead, bDMARD treatment may actually reduce the excess lymphoma risk in RA.
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Affiliation(s)
- Karin Hellgren
- Clinical Epidemiology Division, Department of Medicine Solna, Karolinska Institutet, Stockholm, Sweden
| | - Daniela Di Giuseppe
- Clinical Epidemiology Division, Department of Medicine Solna, Karolinska Institutet, Stockholm, Sweden
| | - Karin E Smedby
- Clinical Epidemiology Division, Department of Medicine Solna, Karolinska Institutet, Stockholm, Sweden
| | - Christer Sundström
- Department of Immunology, Genetics and Pathology, Uppsala University, Uppsala, Sweden
| | - Johan Askling
- Clinical Epidemiology Division, Department of Medicine Solna, Karolinska Institutet, Stockholm, Sweden
| | - Eva Baecklund
- Unit of Rheumatology, Department of Medical Sciences, Uppsala University, Uppsala, Sweden
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Honda S, Sakai R, Inoue E, Majima M, Konda N, Takada H, Kihara M, Yajima N, Nanki T, Yamamoto K, Takeuchi T, Harigai M. Association of methotrexate use and lymphoproliferative disorder in patients with rheumatoid arthritis: Results from a Japanese multi-institutional retrospective study. Mod Rheumatol 2021; 32:16-23. [PMID: 33428479 DOI: 10.1080/14397595.2020.1869370] [Citation(s) in RCA: 19] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/02/2020] [Accepted: 12/22/2020] [Indexed: 12/17/2022]
Abstract
OBJECTIVES To investigate the risk factors and clinical characteristics of lymphoproliferative disorder (LPD) in Japanese patients with rheumatoid arthritis (RA). METHODS We enrolled patients with RA aged ≥20 years who visited the participating hospitals between April 2011 and July 2011. We investigated the risk factors for LPD using a Cox proportional hazard model and described pathological features and vital prognosis of LPD in patients with RA. RESULTS We enrolled 9815 patients with the following characteristics at baseline: female 79.4%, median age 63 years; median disease duration 7 years; median DAS28-CRP (3) 3.1; prevalence of MTX use 60.0%. Sixty-eight patients (0.69%) developed LPD in 3-year observation period. Multivariable analysis showed that age by decade (hazard ratio [95% confidence interval], 1.47 [1.18-1.85]) and MTX use at baseline (2.35 [1.25-4.42] for ≤8 mg/week, 4.39 [2.07-9.32] for >8 mg/week versus non-use) were significant risk factors of LPD. Of 55 patients with pathological diagnosis, diffuse large B cell lymphoma was the most frequent (54%). The 5-year mortality of LPD was 24%. The major cause of death was lymphoma (81%). CONCLUSION This nationwide study revealed risk factors, clinical characteristics, and prognosis of LPD in the largest number of Japanese patients with RA.
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Affiliation(s)
- Suguru Honda
- Department of Rheumatology, Tokyo Women's Medical University School of Medicine, Tokyo, Japan
| | - Ryoko Sakai
- Department of Rheumatology, Tokyo Women's Medical University School of Medicine, Tokyo, Japan.,Division of Epidemiology and Pharmacoepidemiology of Rheumatic Diseases, Department of Rheumatology, Tokyo Women's Medical University School of Medicine, Tokyo, Japan
| | - Eisuke Inoue
- Showa University Research Administration Center, Showa University, Tokyo, Japan
| | - Masako Majima
- Department of Rheumatology, Tokyo Women's Medical University School of Medicine, Tokyo, Japan
| | - Naoko Konda
- Department of Rheumatology, Tokyo Women's Medical University School of Medicine, Tokyo, Japan
| | - Hideto Takada
- Department of Rheumatology, Tokyo Women's Medical University School of Medicine, Tokyo, Japan
| | - Mari Kihara
- Department of Rheumatology, Tokyo Medical and Dental University, Tokyo, Japan
| | - Nobuyuki Yajima
- Division of Rheumatology, Department of Internal Medicine, Showa University School of Medicine, Tokyo, Japan.,Center for Innovative Research for Communities and Clinical Excellence, Fukushima Medical University, Fukushima, Japan.,Department of Healthcare Epidemiology, School of Public Health in the Graduate School of Medicine, Kyoto University, Kyoto, Japan
| | - Toshihiro Nanki
- Division of Rheumatology, Department of Internal Medicine, Toho University School of Medicine, Tokyo, Japan
| | | | - Tsutomu Takeuchi
- Department of Internal Medicine, Division of Rheumatology, School of Medicine, Keio University, Tokyo, Japan
| | - Masayoshi Harigai
- Department of Rheumatology, Tokyo Women's Medical University School of Medicine, Tokyo, Japan.,Division of Epidemiology and Pharmacoepidemiology of Rheumatic Diseases, Department of Rheumatology, Tokyo Women's Medical University School of Medicine, Tokyo, Japan
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Mercogliano MF, Bruni S, Mauro F, Elizalde PV, Schillaci R. Harnessing Tumor Necrosis Factor Alpha to Achieve Effective Cancer Immunotherapy. Cancers (Basel) 2021; 13:cancers13030564. [PMID: 33540543 PMCID: PMC7985780 DOI: 10.3390/cancers13030564] [Citation(s) in RCA: 57] [Impact Index Per Article: 14.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/07/2020] [Revised: 01/17/2021] [Accepted: 01/22/2021] [Indexed: 12/12/2022] Open
Abstract
Tumor necrosis factor alpha (TNFα) is a pleiotropic cytokine known to have contradictory roles in oncoimmunology. Indeed, TNFα has a central role in the onset of the immune response, inducing both activation and the effector function of macrophages, dendritic cells, natural killer (NK) cells, and B and T lymphocytes. Within the tumor microenvironment, however, TNFα is one of the main mediators of cancer-related inflammation. It is involved in the recruitment and differentiation of immune suppressor cells, leading to evasion of tumor immune surveillance. These characteristics turn TNFα into an attractive target to overcome therapy resistance and tackle cancer. This review focuses on the diverse molecular mechanisms that place TNFα as a source of resistance to immunotherapy such as monoclonal antibodies against cancer cells or immune checkpoints and adoptive cell therapy. We also expose the benefits of TNFα blocking strategies in combination with immunotherapy to improve the antitumor effect and prevent or treat adverse immune-related effects.
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Affiliation(s)
- María Florencia Mercogliano
- Laboratorio de Biofisicoquímica de Proteínas, Instituto de Química Biológica de la Facultad de Ciencias Exactas y Naturales-Consejo Nacional de Investigaciones Científicas y Técnicas (IQUIBICEN-CONICET), Buenos Aires 1428, Argentina;
| | - Sofía Bruni
- Laboratory of Molecular Mechanisms of Carcinogenesis, Instituto de Biología y Medicina Experimental (IBYME-CONICET), Buenos Aires 1428, Argentina; (S.B.); (F.M.); (P.V.E.)
| | - Florencia Mauro
- Laboratory of Molecular Mechanisms of Carcinogenesis, Instituto de Biología y Medicina Experimental (IBYME-CONICET), Buenos Aires 1428, Argentina; (S.B.); (F.M.); (P.V.E.)
| | - Patricia Virginia Elizalde
- Laboratory of Molecular Mechanisms of Carcinogenesis, Instituto de Biología y Medicina Experimental (IBYME-CONICET), Buenos Aires 1428, Argentina; (S.B.); (F.M.); (P.V.E.)
| | - Roxana Schillaci
- Laboratory of Molecular Mechanisms of Carcinogenesis, Instituto de Biología y Medicina Experimental (IBYME-CONICET), Buenos Aires 1428, Argentina; (S.B.); (F.M.); (P.V.E.)
- Correspondence: ; Tel.: +54-11-4783-2869; Fax: +54-11-4786-2564
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Ahn C, Lee S, Park SK. Causal Inference between Rheumatoid Arthritis and Breast Cancer in East Asian and European Population: A Two-Sample Mendelian Randomization. Cancers (Basel) 2020; 12:cancers12113272. [PMID: 33167385 PMCID: PMC7694331 DOI: 10.3390/cancers12113272] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/05/2020] [Revised: 11/01/2020] [Accepted: 11/04/2020] [Indexed: 02/06/2023] Open
Abstract
Simple Summary Rheumatoid arthritis (RA) is one of the chronic autoimmune diseases that affects about 0.5 to 1.0% of the general population worldwide. The main symptom of RA is the destruction of the synovial joint, leading to a reduced quality of life and increased mortality. RA may be accompanied by several comorbidities, on which several studies have been conducted on the association between RA and breast cancer. However, the association between RA and breast cancer has shown different directions and has not been clearly established. In this study, we tried to determine whether RA had a causal effect on breast cancer using Mendelian randomization (MR) analysis, but causal evidence was not found. Therefore, additional studies are needed to determine whether RA patients are at high risk of breast cancer, based on large-scale cohorts to validate these results. Abstract Previous studies have been reported that the association between rheumatoid arthritis (RA) and breast cancer remains inconclusive. A two-sample Mendelian randomization (MR) analysis can reveal the potential causal association between exposure and outcome. A two-sample MR analysis using the penalized robust inverse variance weighted (PRIVW) method was performed to analyze the association between RA and breast cancer risk based on the summary statistics of six genome-wide association studies (GWAS) targeting RA in an East Asian population along with summary statistics of the BioBank Japan (BBJ), Breast Cancer Association Consortium (BCAC), and Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA) targeting breast cancer. We found that the direction of the effect of RA on breast cancer varied among GWAS-summary data from BBJ, BCAC, and CIMBA. Significant horizontal pleiotropy based on a penalized robust MR-Egger regression was observed only for BBJ and CIMBA BRCA2 carriers. As the results of the two-sample MR analyses were inconsistent, the causal association between RA and breast cancer was inconclusive. The biological mechanisms explaining the relationship between RA and breast cancer were unclear in Asian as well as in Caucasians. Further studies using large-scale patient cohorts are required for the validation of these results.
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Affiliation(s)
- Choonghyun Ahn
- Department of Preventive Medicine, Seoul National University College of Medicine, Seoul 03080, Korea; (C.A.); (S.L.)
- Department of Biomedical Science, Seoul National University Graduate School, Seoul 03080, Korea
- Tokyo University Hospital, Tokyo 1130033, Japan
| | - Sangjun Lee
- Department of Preventive Medicine, Seoul National University College of Medicine, Seoul 03080, Korea; (C.A.); (S.L.)
- Department of Biomedical Science, Seoul National University Graduate School, Seoul 03080, Korea
- Cancer Research Institute, Seoul National University, Seoul 03080, Korea
| | - Sue K. Park
- Department of Preventive Medicine, Seoul National University College of Medicine, Seoul 03080, Korea; (C.A.); (S.L.)
- Cancer Research Institute, Seoul National University, Seoul 03080, Korea
- Convergence Graduate Program in Innovative Medicine Science, Seoul National University College of Medicine, Seoul 03080, Korea
- Correspondence: ; Tel.: +82-2-740-8338
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The risk of leukemia in patients with rheumatoid arthritis: a systematic review and meta-analysis. Clin Rheumatol 2020; 40:1283-1289. [PMID: 32939570 DOI: 10.1007/s10067-020-05396-7] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/06/2020] [Revised: 08/18/2020] [Accepted: 09/12/2020] [Indexed: 10/23/2022]
Abstract
OBJECTIVES The relationship between rheumatoid arthritis (RA) and the risk of leukemia was still controversial. This study aimed to assess the risk of leukemia in patients with rheumatoid arthritis by systematic review and meta-analysis. METHODS Relevant studies were identified by searching PubMed, Embase, Cochrane Library, and SinoMed up to December 2019. Random effects model analysis was used to pool standardized incidence ratios (SIRs) and 95% confidence interval. RESULTS A total of 15 relevant studies that met the criteria were included. Compared with the general population, patients with RA showed an increased risk of leukemia (SIR = 1.51, 95% CI: 1.34-1.70). The statistical heterogeneity was moderate with an I2 of 55.5%. In subgroup analysis, the source of heterogeneity may be due to differences in sample size. Publication bias was not found in the Begg funnel plot and the Egger test. CONCLUSION Our findings suggested that the risk of leukemia in RA was increased compared with the general population. Key points • This is the first systematic review and meta-analysis to assess the risk of leukemia in RA. • Our study suggested that the risk of leukemia in RA was increased compared with the general population. • This study indicated that the risk of leukemia in RA was higher in non-Asian populations.
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Favalli EG. Understanding the Role of Interleukin-6 (IL-6) in the Joint and Beyond: A Comprehensive Review of IL-6 Inhibition for the Management of Rheumatoid Arthritis. Rheumatol Ther 2020; 7:473-516. [PMID: 32734482 PMCID: PMC7410942 DOI: 10.1007/s40744-020-00219-2] [Citation(s) in RCA: 81] [Impact Index Per Article: 16.2] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/05/2020] [Indexed: 12/17/2022] Open
Abstract
Rheumatoid arthritis (RA) is a chronic, debilitating autoimmune disorder involving inflammation and progressive destruction of the joints, affecting up to 1% of the population. The majority of patients with RA have one or more comorbid conditions, the most common being cardiovascular disease, osteoporosis, and depression, the presence of which are associated with poorer clinical outcomes and lower health-related quality of life. RA pathogenesis is driven by a complex network of proinflammatory cells and cytokines, and of these, interleukin-6 (IL-6) plays a key role in the chronic inflammation associated with RA. Through cell signaling that can be initiated by both membrane-bound and soluble forms of its receptor, IL-6 acts both locally to promote joint inflammation and destruction, and in the circulation to mediate extra-articular manifestations of RA, including pain, fatigue, morning stiffness, anemia, and weight loss. This narrative review describes the role of IL-6 in the pathogenesis of RA, its comorbidities, and extra-articular systemic manifestations, and examines the effects of the IL-6 receptor inhibitors sarilumab and tocilizumab on clinical endpoints of RA, patient-reported outcomes, and common comorbidities and extra-articular manifestations.
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Affiliation(s)
- Ennio G Favalli
- Department of Rheumatology, ASST Gaetano Pini-CTO Institute, University of Milan, Milan, Italy.
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31
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Bekele DI, Patnaik MM. Autoimmunity, Clonal Hematopoiesis, and Myeloid Neoplasms. Rheum Dis Clin North Am 2020; 46:429-444. [DOI: 10.1016/j.rdc.2020.03.001] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
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Abstract
People living with rheumatic diseases frequently encounter cancer, either as a potential harm of antirheumatic therapies or as a comorbidity that alters the conversation about management. This article provides a general overview of the issues related to cancer and rheumatic disease and serves as a springboard for the remaining chapters in this issue. Several topics are reviewed, including epidemiology, bidirectional causal pathways, and issues related to medications. Although uncertainties remain, the issue of cancer is of great importance to patients with rheumatic diseases, and an individualized, person-centered approach to assessment and management is necessary.
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Affiliation(s)
- John Manley Davis
- Division of Rheumatology, Mayo Clinic, 200 1st St SW, Rochester, MN 55905, USA.
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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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Mercogliano MF, Bruni S, Elizalde PV, Schillaci R. Tumor Necrosis Factor α Blockade: An Opportunity to Tackle Breast Cancer. Front Oncol 2020; 10:584. [PMID: 32391269 PMCID: PMC7189060 DOI: 10.3389/fonc.2020.00584] [Citation(s) in RCA: 86] [Impact Index Per Article: 17.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/18/2020] [Accepted: 03/30/2020] [Indexed: 12/14/2022] Open
Abstract
Breast cancer is the most frequently diagnosed cancer and the principal cause of mortality by malignancy in women and represents a main problem for public health worldwide. Tumor necrosis factor α (TNFα) is a pro-inflammatory cytokine whose expression is increased in a variety of cancers. In particular, in breast cancer it correlates with augmented tumor cell proliferation, higher malignancy grade, increased occurrence of metastasis and general poor prognosis for the patient. These characteristics highlight TNFα as an attractive therapeutic target, and consequently, the study of soluble and transmembrane TNFα effects and its receptors in breast cancer is an area of active research. In this review we summarize the recent findings on TNFα participation in luminal, HER2-positive and triple negative breast cancer progression and metastasis. Also, we describe TNFα role in immune response against tumors and in chemotherapy, hormone therapy, HER2-targeted therapy and anti-immune checkpoint therapy resistance in breast cancer. Furthermore, we discuss the use of TNFα blocking strategies as potential therapies and their clinical relevance for breast cancer. These TNFα blocking agents have long been used in the clinical setting to treat inflammatory and autoimmune diseases. TNFα blockade can be achieved by monoclonal antibodies (such as infliximab, adalimumab, etc.), fusion proteins (etanercept) and dominant negative proteins (INB03). Here we address the different effects of each compound and also analyze the use of potential biomarkers in the selection of patients who would benefit from a combination of TNFα blocking agents with HER2-targeted treatments to prevent or overcome therapy resistance in breast cancer.
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Affiliation(s)
- María Florencia Mercogliano
- Laboratorio de Biofisicoquímica de Proteínas, Instituto de Química Biológica de la Facultad de Ciencias Exactas y Naturales-Consejo Nacional de Investigaciones Científicas y Técnicas (IQUIBICEN-CONICET), Buenos Aires, Argentina
| | - Sofía Bruni
- Laboratory of Molecular Mechanisms of Carcinogenesis, Instituto de Biología y Medicina Experimental (IBYME-CONICET), Buenos Aires, Argentina
| | - Patricia V Elizalde
- Laboratory of Molecular Mechanisms of Carcinogenesis, Instituto de Biología y Medicina Experimental (IBYME-CONICET), Buenos Aires, Argentina
| | - Roxana Schillaci
- Laboratory of Molecular Mechanisms of Carcinogenesis, Instituto de Biología y Medicina Experimental (IBYME-CONICET), Buenos Aires, Argentina
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Yates M, Bechman K, Galloway J. The use of real-world data to address questions of patient safety. Rheumatology (Oxford) 2020; 59:26-30. [PMID: 31834407 DOI: 10.1093/rheumatology/kez158] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/21/2018] [Revised: 03/25/2019] [Indexed: 12/17/2022] Open
Abstract
Pharmacovigilance registries of biologics were established to evaluate the risk of adverse events that may be missed in trials due to shorter durations and homogeneous samples. This review will present the strengths and weaknesses of registry data in addressing patient safety issues. Since their inception, scope has broadened because registries represent a relatively inexpensive approach to answering many clinical questions, both research and non-research focused. They achieve high statistical power, allow direct comparability, and offer a level of detail about adverse events not possible with trial data. Registries have been central in clarifying the risk of infection and malignancy with anti-TNF therapy, despite the limitations of selection and channelling bias, incomplete case capture, unmeasured confounding, and the inability to infer causality. Routinely collected data from electronic health records and national audits offer alternative real-world resources, further assisting patients and clinicians in understanding the risks of biologic therapy choices.
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Affiliation(s)
- Mark Yates
- The Centre for Rheumatic Diseases, School of Immunology, Infection & Inflammatory Disease, King's College London, London, UK
| | - Katie Bechman
- The Centre for Rheumatic Diseases, School of Immunology, Infection & Inflammatory Disease, King's College London, London, UK
| | - James Galloway
- The Centre for Rheumatic Diseases, School of Immunology, Infection & Inflammatory Disease, King's College London, London, UK
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Melsheimer R, Geldhof A, Apaolaza I, Schaible T. Remicade ® (infliximab): 20 years of contributions to science and medicine. Biologics 2019; 13:139-178. [PMID: 31440029 PMCID: PMC6679695 DOI: 10.2147/btt.s207246] [Citation(s) in RCA: 70] [Impact Index Per Article: 11.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/01/2019] [Accepted: 05/16/2019] [Indexed: 12/17/2022]
Abstract
On August 24, 1998, Remicade® (infliximab), the first tumor necrosis factor-α (TNF) inhibitor, received its initial marketing approval from the US Food and Drug Administration for the treatment of Crohn’s disease. Subsequently, Remicade was approved in another five adult and two pediatric indications both in the USA and across the globe. In the 20 years since this first approval, Remicade has made several important contributions to the advancement of science and medicine: 1) clinical trials with Remicade established the proof of concept that targeted therapy can be effective in immune-mediated inflammatory diseases; 2) as the first monoclonal antibody approved for use in a chronic condition, Remicade helped in identifying methods of administering large, foreign proteins repeatedly while limiting the body’s immune response to them; 3) the need to establish Remicade’s safety profile required developing new methods and setting new standards for postmarketing safety studies, specifically in the real-world setting, in terms of approach, size, and duration of follow-up; 4) the study of Remicade has improved our understanding of TNF’s role in the immune system, as well as our understanding of the pathophysiology of a range of diseases characterized by chronic inflammation; and 5) Remicade and other TNF inhibitors have transformed treatment practices in these chronic inflammatory diseases: remission has become a realistic goal of therapy and long-term disability resulting from structural damage can be prevented. This paper reviews how, over the course of its development and 20 years of use in clinical practice, Remicade was able to make these contributions.
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Affiliation(s)
| | - Anja Geldhof
- Medical Affairs, Janssen Biologics BV, Leiden, the Netherlands
| | - Isabel Apaolaza
- Medical Affairs, Janssen Biologics BV, Leiden, the Netherlands
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Stamatis P, Turesson C, Willim M, Nilsson JÅ, Englund M, Mohammad AJ. Malignancies in Giant Cell Arteritis: A Population-based Cohort Study. J Rheumatol 2019; 47:400-406. [PMID: 31154410 DOI: 10.3899/jrheum.190236] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 05/08/2019] [Indexed: 12/19/2022]
Abstract
OBJECTIVE To investigate the risk of cancer in patients with biopsy-proven giant cell arteritis (GCA) from a defined population in southern Sweden. METHODS The study cohort consisted of 830 patients (mean age at GCA diagnosis was 75.3 yrs, 74% women) diagnosed with biopsy-proven GCA between 1997 and 2010. Temporal artery biopsy results were retrieved from a regional database and reviewed to ascertain GCA diagnosis. The cohort was linked to the Swedish Cancer Registry. The patients were followed from GCA diagnosis until death or December 31, 2013. Incident malignancies registered after GCA diagnosis were studied. Based on data on the first malignancy in each organ system, age- and sex-standardized incidence ratios (SIR) with 95% CI were calculated compared to the background population. RESULTS One hundred seven patients (13%) were diagnosed with a total of 118 new malignancies after the onset of GCA. The overall risk for cancer after the GCA diagnosis was not increased (SIR 0.98, 95% CI 0.81-1.17). However, there was an increased risk for myeloid leukemia (2.31, 95% CI 1.06-4.39) and a reduced risk for breast cancer (0.33, 95% CI 0.12-0.72) and upper gastrointestinal tract cancer (0.16, 95% 0.004-0.91). Rates of other site-specific cancers were not different from expected. CONCLUSION In this Swedish population-based cohort of GCA, the overall risk for cancer was not increased compared to the background population. However, there was an increased risk for leukemia and a decreased risk for breast and upper gastrointestinal tract cancer.
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Affiliation(s)
- Pavlos Stamatis
- From Lund University, Department of Clinical Sciences Lund, Section of Rheumatology, and Orthopaedics and Clinical Epidemiology Unit, Lund; Lund University, Department of Clinical Sciences Malmö, Section of Rheumatology, Malmö, Sweden; Department of Medicine, University of Cambridge, Cambridge, UK. .,P. Stamatis, MD, Consultant in Rheumatology, Department of Clinical Sciences Lund, Rheumatology, Lund University; C. Turesson, MD, PhD, Professor of Rheumatology, Senior Consultant Rheumatologist, Department of Clinical Sciences Malmö, Rheumatology, Lund University; M. Willim, IT Coordinator, Department of Clinical Sciences Lund, Rheumatology, Lund University; J.Å. Nilsson, PhD, Statistician, Department of Clinical Sciences Lund, Rheumatology, Lund University; M. Englund, MD, PhD, Professor of Epidemiology, Department of Clinical Sciences, Lund, Clinical Epidemiology Unit; A.J. Mohammad, MD, PhD, Associate Professor of Rheumatology, Senior Consultant Rheumatologist, Department of Clinical Sciences, Rheumatology, Clinical Epidemiology Unit, Lund University, and Department of Medicine, University of Cambridge.
| | - Carl Turesson
- From Lund University, Department of Clinical Sciences Lund, Section of Rheumatology, and Orthopaedics and Clinical Epidemiology Unit, Lund; Lund University, Department of Clinical Sciences Malmö, Section of Rheumatology, Malmö, Sweden; Department of Medicine, University of Cambridge, Cambridge, UK.,P. Stamatis, MD, Consultant in Rheumatology, Department of Clinical Sciences Lund, Rheumatology, Lund University; C. Turesson, MD, PhD, Professor of Rheumatology, Senior Consultant Rheumatologist, Department of Clinical Sciences Malmö, Rheumatology, Lund University; M. Willim, IT Coordinator, Department of Clinical Sciences Lund, Rheumatology, Lund University; J.Å. Nilsson, PhD, Statistician, Department of Clinical Sciences Lund, Rheumatology, Lund University; M. Englund, MD, PhD, Professor of Epidemiology, Department of Clinical Sciences, Lund, Clinical Epidemiology Unit; A.J. Mohammad, MD, PhD, Associate Professor of Rheumatology, Senior Consultant Rheumatologist, Department of Clinical Sciences, Rheumatology, Clinical Epidemiology Unit, Lund University, and Department of Medicine, University of Cambridge
| | - Minna Willim
- From Lund University, Department of Clinical Sciences Lund, Section of Rheumatology, and Orthopaedics and Clinical Epidemiology Unit, Lund; Lund University, Department of Clinical Sciences Malmö, Section of Rheumatology, Malmö, Sweden; Department of Medicine, University of Cambridge, Cambridge, UK.,P. Stamatis, MD, Consultant in Rheumatology, Department of Clinical Sciences Lund, Rheumatology, Lund University; C. Turesson, MD, PhD, Professor of Rheumatology, Senior Consultant Rheumatologist, Department of Clinical Sciences Malmö, Rheumatology, Lund University; M. Willim, IT Coordinator, Department of Clinical Sciences Lund, Rheumatology, Lund University; J.Å. Nilsson, PhD, Statistician, Department of Clinical Sciences Lund, Rheumatology, Lund University; M. Englund, MD, PhD, Professor of Epidemiology, Department of Clinical Sciences, Lund, Clinical Epidemiology Unit; A.J. Mohammad, MD, PhD, Associate Professor of Rheumatology, Senior Consultant Rheumatologist, Department of Clinical Sciences, Rheumatology, Clinical Epidemiology Unit, Lund University, and Department of Medicine, University of Cambridge
| | - Jan-Åke Nilsson
- From Lund University, Department of Clinical Sciences Lund, Section of Rheumatology, and Orthopaedics and Clinical Epidemiology Unit, Lund; Lund University, Department of Clinical Sciences Malmö, Section of Rheumatology, Malmö, Sweden; Department of Medicine, University of Cambridge, Cambridge, UK.,P. Stamatis, MD, Consultant in Rheumatology, Department of Clinical Sciences Lund, Rheumatology, Lund University; C. Turesson, MD, PhD, Professor of Rheumatology, Senior Consultant Rheumatologist, Department of Clinical Sciences Malmö, Rheumatology, Lund University; M. Willim, IT Coordinator, Department of Clinical Sciences Lund, Rheumatology, Lund University; J.Å. Nilsson, PhD, Statistician, Department of Clinical Sciences Lund, Rheumatology, Lund University; M. Englund, MD, PhD, Professor of Epidemiology, Department of Clinical Sciences, Lund, Clinical Epidemiology Unit; A.J. Mohammad, MD, PhD, Associate Professor of Rheumatology, Senior Consultant Rheumatologist, Department of Clinical Sciences, Rheumatology, Clinical Epidemiology Unit, Lund University, and Department of Medicine, University of Cambridge
| | - Martin Englund
- From Lund University, Department of Clinical Sciences Lund, Section of Rheumatology, and Orthopaedics and Clinical Epidemiology Unit, Lund; Lund University, Department of Clinical Sciences Malmö, Section of Rheumatology, Malmö, Sweden; Department of Medicine, University of Cambridge, Cambridge, UK.,P. Stamatis, MD, Consultant in Rheumatology, Department of Clinical Sciences Lund, Rheumatology, Lund University; C. Turesson, MD, PhD, Professor of Rheumatology, Senior Consultant Rheumatologist, Department of Clinical Sciences Malmö, Rheumatology, Lund University; M. Willim, IT Coordinator, Department of Clinical Sciences Lund, Rheumatology, Lund University; J.Å. Nilsson, PhD, Statistician, Department of Clinical Sciences Lund, Rheumatology, Lund University; M. Englund, MD, PhD, Professor of Epidemiology, Department of Clinical Sciences, Lund, Clinical Epidemiology Unit; A.J. Mohammad, MD, PhD, Associate Professor of Rheumatology, Senior Consultant Rheumatologist, Department of Clinical Sciences, Rheumatology, Clinical Epidemiology Unit, Lund University, and Department of Medicine, University of Cambridge
| | - Aladdin J Mohammad
- From Lund University, Department of Clinical Sciences Lund, Section of Rheumatology, and Orthopaedics and Clinical Epidemiology Unit, Lund; Lund University, Department of Clinical Sciences Malmö, Section of Rheumatology, Malmö, Sweden; Department of Medicine, University of Cambridge, Cambridge, UK.,P. Stamatis, MD, Consultant in Rheumatology, Department of Clinical Sciences Lund, Rheumatology, Lund University; C. Turesson, MD, PhD, Professor of Rheumatology, Senior Consultant Rheumatologist, Department of Clinical Sciences Malmö, Rheumatology, Lund University; M. Willim, IT Coordinator, Department of Clinical Sciences Lund, Rheumatology, Lund University; J.Å. Nilsson, PhD, Statistician, Department of Clinical Sciences Lund, Rheumatology, Lund University; M. Englund, MD, PhD, Professor of Epidemiology, Department of Clinical Sciences, Lund, Clinical Epidemiology Unit; A.J. Mohammad, MD, PhD, Associate Professor of Rheumatology, Senior Consultant Rheumatologist, Department of Clinical Sciences, Rheumatology, Clinical Epidemiology Unit, Lund University, and Department of Medicine, University of Cambridge
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38
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De Cock D, Hyrich K. Malignancy and rheumatoid arthritis: Epidemiology, risk factors and management. Best Pract Res Clin Rheumatol 2019; 32:869-886. [PMID: 31427060 DOI: 10.1016/j.berh.2019.03.011] [Citation(s) in RCA: 85] [Impact Index Per Article: 14.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/17/2022]
Abstract
Rheumatoid arthritis (RA) is a chronic inflammatory condition that can result in pain and functional disability. It is also associated with an increased occurrence of comorbidities, including an increased risk of certain cancers such as lung cancer and lymphoma. The aetiopathogenesis of this increased cancer risk is likely multifactorial and includes shared risk factors as well as chronic inflammation. There is also a concern that the treatment for RA itself may increase this risk further, particularly treatment with biologic disease-modifying anti-rheumatic drugs (DMARDs). This paper aims to review the evidence for the increased risk of cancer in RA as well as the latest evidence for the association between DMARDs and tumorigenesis. It also discusses the evidence for the management of patients with biologic DMARDs in the setting of existing cancer.
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Affiliation(s)
- Diederik De Cock
- Arthritis Research UK Centre for Epidemiology, Centre for Musculoskeletal Research, University of Manchester, Manchester, United Kingdom
| | - Kimme Hyrich
- Arthritis Research UK Centre for Epidemiology, Centre for Musculoskeletal Research, University of Manchester, Manchester, United Kingdom; National Institute of Health Research Manchester Biomedical Research Centre, Manchester NHS Foundation Trust, Manchester Academic Health Science Centre, Manchester, United Kingdom.
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39
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Myeloid disorders after autoimmune disease. Best Pract Res Clin Haematol 2019; 32:74-88. [PMID: 30927978 DOI: 10.1016/j.beha.2019.02.002] [Citation(s) in RCA: 23] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/26/2018] [Revised: 02/02/2019] [Accepted: 02/06/2019] [Indexed: 12/14/2022]
Abstract
Autoimmune diseases (ADs) are associated with an increased risk not only of lymphoproliferative disorders but also of myeloid malignancies. The excess risk of myelodysplastic syndromes and/or acute myeloid leukemia is observed across several AD types, including systemic lupus erythematosus, rheumatoid arthritis, inflammatory bowel disorders, multiple sclerosis, among others. The risk of developing myeloid neoplasms (MNs) is dependent on several variables, including the specific AD type, chronicity and severity of the AD, type and duration of exposure of disease modifying anti-rheumatic drugs or cytotoxics/immunosuppressives, and genetic predisposition risk. Putative triggering factors linking AD to elevated MN risk include AD-directed medications, shared genetic susceptibilities between the two disease entities, and chronic immune stimulation or bone marrow infiltration by the AD. Molecular mechanisms underpinning leukemogenesis remain largely speculative and warrant further investigation. Leukemias arising in patients with AD are not always 'therapy-related' in that MNs may develop in certain AD subtypes even among patients with no prior therapy exposure. Only a few studies have attempted to determine factors associated with MN development in AD but failed to demonstrate consistent characteristic clinical or paraclinical features. These reports have failed to demonstrate a clear correlation between individual agent exposure and subsequent leukemia development due to the low rates of therapy exposure compounded by the rarity of MN occurrence. Notwithstanding, the leukemogenic potential is best documented with agents such as azathioprine, cyclophosphamide, and mitoxantrone; this risk of MN development does not appear to be shared by biologic approaches such as anti-tumor necrosis factors-alpha inhibitors. In this article, we discuss plausible biologic mechanisms underlying MN pathogenesis in AD and review the data available on the development of MNs in patients with AD.
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40
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Di Marco M, Ramassone A, Pagotto S, Anastasiadou E, Veronese A, Visone R. MicroRNAs in Autoimmunity and Hematological Malignancies. Int J Mol Sci 2018; 19:ijms19103139. [PMID: 30322050 PMCID: PMC6213554 DOI: 10.3390/ijms19103139] [Citation(s) in RCA: 21] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/26/2018] [Accepted: 10/02/2018] [Indexed: 12/13/2022] Open
Abstract
Autoimmunity and hematological malignancies are often concomitant in patients. A causal bidirectional relationship exists between them. Loss of immunological tolerance with inappropriate activation of the immune system, likely due to environmental and genetic factors, can represent a breeding ground for the appearance of cancer cells and, on the other hand, blood cancers are characterized by imbalanced immune cell subsets that could support the development of the autoimmune clone. Considerable effort has been made for understanding the proteins that have a relevant role in both processes; however, literature advances demonstrate that microRNAs (miRNAs) surface as the epigenetic regulators of those proteins and control networks linked to both autoimmunity and hematological malignancies. Here we review the most up-to-date findings regarding the miRNA-based molecular mechanisms that underpin autoimmunity and hematological malignancies.
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Affiliation(s)
- Mirco Di Marco
- Ageing Research Center and Translational medicine-CeSI-MeT, 66100 Chieti, Italy.
- Department of Medical, Oral and Biotechnological Sciences (DSMOB), "G. d'Annunzio" University Chieti-Pescara, 66100 Chieti, Italy.
| | - Alice Ramassone
- Ageing Research Center and Translational medicine-CeSI-MeT, 66100 Chieti, Italy.
- Department of Medical, Oral and Biotechnological Sciences (DSMOB), "G. d'Annunzio" University Chieti-Pescara, 66100 Chieti, Italy.
| | - Sara Pagotto
- Ageing Research Center and Translational medicine-CeSI-MeT, 66100 Chieti, Italy.
- Department of Medical, Oral and Biotechnological Sciences (DSMOB), "G. d'Annunzio" University Chieti-Pescara, 66100 Chieti, Italy.
| | - Eleni Anastasiadou
- Harvard Medical School Initiative for RNA Medicine, Department of Pathology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215, USA.
| | - Angelo Veronese
- Ageing Research Center and Translational medicine-CeSI-MeT, 66100 Chieti, Italy.
- Department of Medicine and Aging Science (DMSI), "G. d'Annunzio" University Chieti-Pescara, 66100 Chieti, Italy.
| | - Rosa Visone
- Ageing Research Center and Translational medicine-CeSI-MeT, 66100 Chieti, Italy.
- Department of Medical, Oral and Biotechnological Sciences (DSMOB), "G. d'Annunzio" University Chieti-Pescara, 66100 Chieti, Italy.
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41
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Caporali R, Crepaldi G, Codullo V, Benaglio F, Monti S, Todoerti M, Montecucco C. 20 years of experience with tumour necrosis factor inhibitors: what have we learned? Rheumatology (Oxford) 2018; 57:vii5-vii10. [DOI: 10.1093/rheumatology/key059] [Citation(s) in RCA: 27] [Impact Index Per Article: 3.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/11/2017] [Indexed: 12/17/2022] Open
Affiliation(s)
- Roberto Caporali
- Division of Rheumatology, University of Pavia, IRCCS Policlinico San Matteo Foundation, Pavia
| | | | - Veronica Codullo
- Division of Rheumatology, University of Pavia, IRCCS Policlinico San Matteo Foundation, Pavia
| | - Francesca Benaglio
- Division of Rheumatology, University of Pavia, IRCCS Policlinico San Matteo Foundation, Pavia
| | - Sara Monti
- Division of Rheumatology, University of Pavia, IRCCS Policlinico San Matteo Foundation, Pavia
| | - Monica Todoerti
- Division of Rheumatology, University of Pavia, IRCCS Policlinico San Matteo Foundation, Pavia
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42
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Ozguler Y, Yazici Y, Hatemi G, Tascilar K, Yazici H. Assessing the possible association of anti-TNF use with new malignancies: A neglected methodological consideration. Pharmacoepidemiol Drug Saf 2018; 27:894-901. [PMID: 29920843 DOI: 10.1002/pds.4579] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/31/2017] [Revised: 04/29/2018] [Accepted: 05/25/2018] [Indexed: 12/17/2022]
Affiliation(s)
- Yesim Ozguler
- Division of Rheumatology, Department of Internal Medicine, Cerrahpasa Medical Faculty, Istanbul University, Istanbul, Turkey
| | - Yusuf Yazici
- New York University School of Medicine, New York, NY, USA
| | - Gulen Hatemi
- Division of Rheumatology, Department of Internal Medicine, Cerrahpasa Medical Faculty, Istanbul University, Istanbul, Turkey
| | - Koray Tascilar
- Okmeydani Research and Training Hospital, Istanbul, Turkey
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43
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Kridin K, Zelber-Sagi S, Comaneshter D, Batat E, Cohen AD. Pemphigus and hematologic malignancies: A population-based study of 11,859 patients. J Am Acad Dermatol 2018; 78:1084-1089.e1. [DOI: 10.1016/j.jaad.2017.11.039] [Citation(s) in RCA: 20] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/23/2017] [Revised: 11/10/2017] [Accepted: 11/15/2017] [Indexed: 12/17/2022]
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44
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Calip GS, Patel PR, Adimadhyam S, Xing S, Wu Z, Sweiss K, Schumock GT, Lee TA, Chiu BCH. Tumor necrosis factor-alpha inhibitors and risk of non-Hodgkin lymphoma in a cohort of adults with rheumatologic conditions. Int J Cancer 2018; 143:1062-1071. [PMID: 29603214 DOI: 10.1002/ijc.31407] [Citation(s) in RCA: 41] [Impact Index Per Article: 5.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/12/2017] [Revised: 03/01/2018] [Accepted: 03/13/2018] [Indexed: 12/17/2022]
Abstract
Based on limited evidence, the U.S. Food and Drug Administration (FDA) issued a black box warning for the use of tumor necrosis factor-alpha inhibitors (TNFIs) and risk of non-Hodgkin lymphoma (NHL). Our objective was to determine the risk of NHL associated with TNFI use by duration and type of anti-TNF agent. We performed a nested case-control study within a retrospective cohort of adults with rheumatologic conditions from a U.S. commercial health insurance database between 2009 and 2015. Use of TNFIs (infliximab, adalimumab, etanercept, golimumab and certolizumab pegol) and conventional-synthetic disease-modifying antirheumatic drugs (csDMARDs) was identified, and conditional logistic regression models were used to estimate adjusted odds ratios (OR) and 95% confidence intervals (CI) for risk of NHL. From a retrospective cohort of 55,446 adult patients, 101 NHL cases and 984 controls matched on age, gender and rheumatologic indication were included. Compared to controls, NHL cases had greater TNFI use (33% vs. 20%) but were similar in csDMARD use (70% vs. 71%). TNFI ever-use was associated with nearly two-fold increased risk of NHL (OR = 1.93; 95% CI: 1.16-3.20) with suggestion of increasing risk with duration (P-trend = 0.05). TNF fusion protein (etanercept) was associated with increased NHL risk (OR = 2.73; 95% CI: 1.40-5.33), whereas risk with anti-TNF monoclonal antibodies was not statistically significant (OR = 1.77; 95% CI: 0.87-3.58). In sensitivity analyses evaluating confounding by rheumatologic disease severity, channeling bias was not likely to account for our results. Our findings support the FDA black box warning for NHL. Continued surveillance and awareness of this rare but serious adverse outcome are warranted with new TNFIs and biosimilar products forthcoming.
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Affiliation(s)
- Gregory S Calip
- Department of Pharmacy Systems, Outcomes and Policy, University of Illinois at Chicago, Chicago, IL.,University of Illinois at Chicago, Center for Pharmacoepidemiology and Pharmacoeconomic Research, Chicago, IL.,Division of Public Health Sciences, Epidemiology Program, Fred Hutchinson Cancer Research Center, Seattle, WA
| | - Pritesh R Patel
- Department of Medicine, Division of Hematology Oncology, University of Illinois at Chicago, Chicago, IL
| | - Sruthi Adimadhyam
- Department of Pharmacy Systems, Outcomes and Policy, University of Illinois at Chicago, Chicago, IL
| | - Shan Xing
- Department of Pharmacy Systems, Outcomes and Policy, University of Illinois at Chicago, Chicago, IL
| | - Zhaoju Wu
- Department of Pharmacy Systems, Outcomes and Policy, University of Illinois at Chicago, Chicago, IL
| | - Karen Sweiss
- Department of Pharmacy Practice, University of Illinois at Chicago, Chicago, IL
| | - Glen T Schumock
- Department of Pharmacy Systems, Outcomes and Policy, University of Illinois at Chicago, Chicago, IL.,University of Illinois at Chicago, Center for Pharmacoepidemiology and Pharmacoeconomic Research, Chicago, IL
| | - Todd A Lee
- Department of Pharmacy Systems, Outcomes and Policy, University of Illinois at Chicago, Chicago, IL.,University of Illinois at Chicago, Center for Pharmacoepidemiology and Pharmacoeconomic Research, Chicago, IL
| | - Brian C-H Chiu
- Department of Public Health Sciences, The University of Chicago, Chicago, IL
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45
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Nijland ML, Koens L, Pals ST, Berge IJMT, Bemelman FJ, Kersten MJ. Clinicopathological characteristics of T-cell non-Hodgkin lymphoma arising in patients with immunodeficiencies: a single-center case series of 25 patients and a review of the literature. Haematologica 2017; 103:486-496. [PMID: 29269521 PMCID: PMC5830383 DOI: 10.3324/haematol.2017.169987] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/03/2017] [Accepted: 12/13/2017] [Indexed: 12/19/2022] Open
Abstract
Although it is known that B-cell lymphomas occur more frequently in immunocompromised patients, thus far such an association has not been clearly established for T-cell lymphomas. Of the 251 patients who were diagnosed with a T-cell non-Hodgkin lymphoma in our center between 1999 and 2014, at least 25 were identified in immunocompromised patients. Herein, we retrospectively analyzed the clinical and pathological characteristics of these 25 cases. In addition, we searched the literature and present an overview of 605 previously published cases. The actual number of patients with B-cell chronic lymphocytic leukemia and patients on immunosuppressive drugs for inflammatory bowel disease or rheumatoid arthritis in the total cohort of 251 patients diagnosed with T-cell non-Hodgkin lymphoma was much higher than the number of patients expected to have these diseases in this cohort, based on their prevalence in the general population. This, together with the large number of additional cases found in the literature, suggest that the risk of developing T-cell non-Hodgkin lymphoma is increased in immunocompromised patients. Compared to T-cell non-Hodgkin lymphoma in the general population, these lymphomas are more often located extranodally, present at a younger age and appear to have a poor outcome. The observations made in the study herein should raise awareness of the possible development of T-cell non-Hodgkin lymphoma in immunodeficient patients, and challenge the prolonged use of immunosuppressive drugs in patients who are in clinical remission of their autoimmune disease.
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Affiliation(s)
- Marieke L Nijland
- Renal Transplant Unit, Department of Nephrology, Academic Medical Center, Amsterdam, the Netherlands
| | - Lianne Koens
- Department of Pathology, Academic Medical Center, Amsterdam, the Netherlands
| | - Steven T Pals
- Department of Pathology and Lymphoma and Myeloma Center Amsterdam (LYMMCARE), Academic Medical Center, Amsterdam, the Netherlands
| | - Ineke J M Ten Berge
- Renal Transplant Unit, Department of Nephrology, Academic Medical Center, Amsterdam, the Netherlands
| | - Frederike J Bemelman
- Renal Transplant Unit, Department of Nephrology, Academic Medical Center, Amsterdam, the Netherlands
| | - Marie José Kersten
- Department of Hematology and Lymphoma and Myeloma Center Amsterdam (LYMMCARE), Academic Medical Center, Amsterdam, the Netherlands
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46
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Bouomrani S, Ghribi I, Regaïeg F, Belgacem N, Trabelsi S, Lassoued N, Baïli H, Béji M. Le mésothéliome péritonéal malin au cours de la fièvre méditerranéenne familiale. ONCOLOGIE 2017. [DOI: 10.1007/s10269-017-2739-4] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/18/2022]
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47
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Cañete JD, Hernández MV, Sanmartí R. Safety profile of biological therapies for treating rheumatoid arthritis. Expert Opin Biol Ther 2017; 17:1089-1103. [DOI: 10.1080/14712598.2017.1346078] [Citation(s) in RCA: 19] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/08/2023]
Affiliation(s)
- Juan D. Cañete
- Arthritis Unit, Rheumatology Department, Hospital Clinic and IDIBAPS, Barcelona, Spain
| | - Ma Victoria Hernández
- Arthritis Unit, Rheumatology Department, Hospital Clinic and IDIBAPS, Barcelona, Spain
| | - Raimon Sanmartí
- Arthritis Unit, Rheumatology Department, Hospital Clinic and IDIBAPS, Barcelona, Spain
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48
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Biologics registers in RA: methodological aspects, current role and future applications. Nat Rev Rheumatol 2017; 13:503-510. [PMID: 28569267 DOI: 10.1038/nrrheum.2017.81] [Citation(s) in RCA: 46] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
The beginning of the 21st century saw a biopharmaceutical revolution in the treatment of inflammatory rheumatic diseases, particularly rheumatoid arthritis. The fast-evolving use of biologic therapies highlighted the need to develop registers at national and international levels with the aim of collecting long-term data on patient outcomes. Over the past 15 years, many biologics registers have contributed a wealth of data and provided robust and reliable evidence on the use, effectiveness and safety of these therapies. The unavoidable challenges posed by the continuous introduction of new therapies, particularly with regard to understanding their long-term safety, highlights the importance of learning from experience with established biologic therapies. In this Perspectives article, the role of biologics registers in bridging the evidence gap between efficacy in clinical trials and real-world effectiveness is discussed, with a focus on methodological aspects of registers, their unique features and challenges and their role going forward.
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49
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Malignancy Incidence, Management, and Prevention in Patients with Rheumatoid Arthritis. Rheumatol Ther 2017; 4:333-347. [PMID: 28508282 PMCID: PMC5696277 DOI: 10.1007/s40744-017-0064-4] [Citation(s) in RCA: 48] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/03/2017] [Indexed: 12/17/2022] Open
Abstract
Traditional and biologic disease-modifying antirheumatic drugs (DMARDs) are effective medications for the management of rheumatoid arthritis (RA). However, the effects of these medications on immune function raises concern that they may increase long-term cancer risk. The baseline risk for some cancers appears to differ in patients with RA compared to the general population, with the former having an increased risk of lymphoma, lung cancer and renal cancer, but a decreased risk of colorectal and breast cancer. Some DMARDs appear to increase the rate of specific cancer types (such as bladder cancer with cyclophosphamide), but few appear to increase the overall cancer risk. Studying the link between lymphoma and disease severity in RA is complicated because patients with persistently active disease are at increased risk for lymphoma, and disease severity correlates with more intense use of immunosuppressive medications. Overall, cancer risk in patients with RA is slightly above that of the general population, with the increased risk likely secondary to an increased risk of lymphomas in those with high disease activity. Risk mitigation includes management of RA disease activity as well as age- and sex-appropriate cancer screening.
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50
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Shimizu Y, Nakajima A, Inoue E, Shidara K, Sugimoto N, Seto Y, Tanaka E, Momohara S, Taniguchi A, Yamanaka H. Characteristics and risk factors of lymphoproliferative disorders among patients with rheumatoid arthritis concurrently treated with methotrexate: a nested case-control study of the IORRA cohort. Clin Rheumatol 2017; 36:1237-1245. [DOI: 10.1007/s10067-017-3634-5] [Citation(s) in RCA: 21] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/28/2016] [Revised: 03/04/2017] [Accepted: 04/11/2017] [Indexed: 12/17/2022]
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