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• Malignancy risk with tofacitinib versus TNF inhibitors in rheumatoid arthritis: results from the open-label, randomized controlled ORAL surveillance trial: Comment on the Article by Curtis et al.
  Yukitomo URATA
  Published on: 13 January 2023

• Published on: 13 January 2023

  Malignancy risk with tofacitinib versus TNF inhibitors in rheumatoid arthritis: results from the open-label, randomized controlled ORAL surveillance trial: Comment on the Article by Curtis et al.

  • Yukitomo URATA, Rheumatologist Department of Rheumatology, Tsugaru General Hospital, United Municipalities of Tsugaru

  I read the paper by Curtis et al. with great interest [1]. A new analysis using this paper’s data has yielded important results that should be presented here.
  The authors state that (1) in patients with rheumatoid arthritis (RA) aged ≥50 years with ≥1 additional cardiovascular risk factor, the risk of adjudicated malignancies excluding non-melanoma skin cancer (NMSC), lung cancer and NMSC was higher with tofacitinib versus tumor necrosis factor inhibitor (TNFi); (2) lung cancer was the most frequently reported malignancy in tofacitinib-treated patients; and (3) history of atherosclerotic cardiovascular disease (ASCVD) or increasing risk scores were associated with higher malignancy incidence rates (IRs) across treatment.
  Atherosclerosis can be caused by various factors, such as smoking, high cholesterol, hypertension, hyperglycemia, diabetes, and genetic factors [2]. However, atherosclerosis can also develop due to infection [3]. These infections include Helicobacter pylori (H. pylori), pneumonia, periodontal disease, and viruses such as cytomegalovirus, human immunodeficiency virus (HIV), herpes simplex virus, Epstein-Barr virus (EBV), human papilloma viruses (HPV), hepatitis B virus (HBV), hepatitis C virus (HCV), and recently, severe acute respiratory syndrome coronavirus-2 [3, 4].
  Some infections that cause atherosclerosis are thought to contribute to cancer in humans. The fractions of different types of cancer, and of all cancers worldwide and in dif...

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  I read the paper by Curtis et al. with great interest [1]. A new analysis using this paper’s data has yielded important results that should be presented here.
  The authors state that (1) in patients with rheumatoid arthritis (RA) aged ≥50 years with ≥1 additional cardiovascular risk factor, the risk of adjudicated malignancies excluding non-melanoma skin cancer (NMSC), lung cancer and NMSC was higher with tofacitinib versus tumor necrosis factor inhibitor (TNFi); (2) lung cancer was the most frequently reported malignancy in tofacitinib-treated patients; and (3) history of atherosclerotic cardiovascular disease (ASCVD) or increasing risk scores were associated with higher malignancy incidence rates (IRs) across treatment.
  Atherosclerosis can be caused by various factors, such as smoking, high cholesterol, hypertension, hyperglycemia, diabetes, and genetic factors [2]. However, atherosclerosis can also develop due to infection [3]. These infections include Helicobacter pylori (H. pylori), pneumonia, periodontal disease, and viruses such as cytomegalovirus, human immunodeficiency virus (HIV), herpes simplex virus, Epstein-Barr virus (EBV), human papilloma viruses (HPV), hepatitis B virus (HBV), hepatitis C virus (HCV), and recently, severe acute respiratory syndrome coronavirus-2 [3, 4].
  Some infections that cause atherosclerosis are thought to contribute to cancer in humans. The fractions of different types of cancer, and of all cancers worldwide and in different regions, have been estimated using several methods, but primarily by reviewing evidence for the strength of associations and the prevalence of infection in different areas. The estimated total of infection-attributable cancer (IAC) in 2002 was 1.9 million cases, or 17.8% of the global cancer burden. The principal agents were H. pylori (5.5% of all cancers), HPV (5.2%), HBV and HCV (4.9%), EBV (1%), and HIV and human herpes virus 8 (0.9%) [5]. Helicobacter pylori–attributable gastric cancer, HBV/HCV-attributable hepatocellular cancer, HPV-attributable cervical, penile, anal, vulva, vaginal, oral cavity, and pharyngeal cancer, and EBV-attributable pharyngeal cancer and malignant lymphoma account for the majority of IACs [6]. Thus, many infections associated with ASCVD contribute to cancer.
  I extracted IACs from Table 2 and Supplemental Table 3 of their paper (Table 1) and compared the ratio of IACs among all cancers (n = 186) between tofacitinib and TNFi. Vaginal and anal cancers were rare, and cervical cancer was observed only with tofacitinib. Fisher's exact test analysis using JMP software (version 14, SAS Institute Inc., Cary, NC, USA) indicated that tofacitinib (n = 27) was higher than TNFi (n = 3) (14.5% vs. 5.2%, p=0.045). Comparing tofacitinib 5 and 10 mg twice per day with TNFi, the IR of IAC tended to be higher with tofacitinib at each dose (15.1% vs 5.2%, p=0.0502) and (14.0% vs 5.2%, p=0.0715) by Fisher's exact test.
  Of course, the extracted cancers were not confirmed to be related to infectious diseases. In addition, due to insufficient data, the hazard ratios of tofacitinib and TNFi could not be determined for the incidence of IACs. Thanks to these results, the relationship between tofacitinib and IAC will become clearer.
  In the treatment of all RA patients, it is necessary to consider the potential for IACs, treatments for any infections, the effectiveness of treatment, and continued surveillance and monitoring of smoking history with or without tofacitinib. Until a causal relationship between tofacitinib and IACs is clarified, screening and surveillance for IACs are essential in the treatment of all RA patients aged ≥50 years with ≥1 additional cardiovascular risk factor.
  Finally, I would like to give credit to the authors for their efforts in compiling data from many patients from multiple centers and sharing it in their paper.

  REFERENCES
  1 Curtis JR, Yamamoka K, Chen YH, et al. Malignancy risk with tofacitinib versus TNF inhibitors in rheumatoid arthritis: results from the open-label, randomised controlled ORAL Surveillance trial. Ann Rheum Dis. 2022 Dec 5:annrheumdis-2022-222543. doi: 10.1136/ard-2022-222543.
  2 Goff DC Jr, Lloyd-Jones DM, Bennett G, et al. 2013 ACC/AHA guideline on the assessment of cardiovascular risk: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines. J Am Coll Cardiol 2014;63:2935–59.
  3 Szwed P, Gąsecka A, Zawadka M, et al. Infections as novel risk factors of atherosclerotic cardiovascular diseases: pathophysiological links and therapeutic implications. J Clin Med 2021;10:2539.
  4 Dhakal BP, Sweitzer NK, Indik JH, et al. SARS-CoV-2 infection and cardiovascular disease: COVID-19 heart. Heart Lung Circ 2020;29:973–87.
  5 Parkin DM. The global health burden of infection-associated cancers in the year 2002. Int J Cancer 2006;118:3030–44.
  6 Inoue M, Sawada N, Matsuda T, et al. Attributable causes of cancer in Japan in 2005--systematic assessment to estimate current burden of cancer attributable to known preventable risk factors in Japan. Ann Oncol 2012;23:1362–69.

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  Conflict of Interest:
  None declared.

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