Jump to comment:

• Correspondence on "Factors associated with COVID-19–related death in people with rheumatic diseases: results from the COVID-19 Global Rheumatology Alliance physician-reported registry"
  Manuel Baturone, Caridad Perez Sumariva and Francisco Gallo
  Published on: 9 August 2021

• Published on: 9 August 2021

  Correspondence on "Factors associated with COVID-19–related death in people with rheumatic diseases: results from the COVID-19 Global Rheumatology Alliance physician-reported registry"

  • Manuel Baturone, Rheumatologist CEAL private rheumatology unit. Sevilla, Andalucía, ES
  • Other Contributors:
    • Caridad Perez Sumariva, Rheumatologist
    • Francisco Gallo, Rheumatologish

  Strangfeld et al (1) recently reported on the association between death of patients affected by inflammatory rheumatic diseases and COVID-19 and a series of factors, the most notable of which were advanced age, specific comorbid conditions, and, surprisingly, sulfasalazine. This finding differed from those for other drugs in the overall model and in all the subgroups, with an odds ratio that was only exceeded by
  that of rituximab. However, the finding only applied to those with a current or previous history of smoking.
  While we should not attribute causality to the association between sulfasalazine and COVID-19–related death, and despite the limitations arising from selection bias due to the voluntary nature of the registry in the study under discussion, we need to find an explanation for this association, especially given the coincidence with another series discussed by Strangefeld et al (1), where COVID-19 was more severe in patients treated with sulfasalazine or its metabolite 5-ASA for inflammatory bowel disease.
  In their attempt to provide an explanation for their findings, the authors state that the choice of sulfasalazine over other DMARDs in groups of patients who are affected by more comorbid conditions and are therefore more likely to die is a confounding factor. However, this does not explain the findings in the series of patients with inflammatory bowel disease the authors themselves comment on.
  We believe there may be a reason for this...

  Show More

  Strangfeld et al (1) recently reported on the association between death of patients affected by inflammatory rheumatic diseases and COVID-19 and a series of factors, the most notable of which were advanced age, specific comorbid conditions, and, surprisingly, sulfasalazine. This finding differed from those for other drugs in the overall model and in all the subgroups, with an odds ratio that was only exceeded by
  that of rituximab. However, the finding only applied to those with a current or previous history of smoking.
  While we should not attribute causality to the association between sulfasalazine and COVID-19–related death, and despite the limitations arising from selection bias due to the voluntary nature of the registry in the study under discussion, we need to find an explanation for this association, especially given the coincidence with another series discussed by Strangefeld et al (1), where COVID-19 was more severe in patients treated with sulfasalazine or its metabolite 5-ASA for inflammatory bowel disease.
  In their attempt to provide an explanation for their findings, the authors state that the choice of sulfasalazine over other DMARDs in groups of patients who are affected by more comorbid conditions and are therefore more likely to die is a confounding factor. However, this does not explain the findings in the series of patients with inflammatory bowel disease the authors themselves comment on.
  We believe there may be a reason for this unexpected finding. It is pointed out that smoking (2) and sulfasalazine (3) coincide in one of the mechanisms involved, ferroptosis, which leads to cell damage and death by SARS Cov2 (4).
  Of particular interest in the present case, innervation of the tracheobronchial tree and heart by the vagus nerve constitutes a neuroimmune unit (5) that is negatively affected by age and has a decisive effect on the response to infection or inflammation. Via specific receptors (M2/M3) in “nerve- and airway-associated macrophages”, the vagus modulates the inflammatory process to prevent its excessive activation, thus diminishing the production of cytokines and infiltration of tissue by defense cells.
  Consequently, we can see that advanced age and cardiorespiratory disease share the vagal dysfunction that leads to an exaggerated innate immune response (5).
  This aberrant neuroimmune response culminates in the activation of the NF-κB pathway and increased production of reactive oxygen species, which in turn activate mitogen-activated protein kinase Jun N-terminal kinase (MAPK JNK) at the site of inflammation (6).
  Importantly, sulfasalazine inhibits the system Xc – transporter, thus triggering ferroptosis, a type of programmed cell death associated with MAPK JNK (see above) (3). Smoking also fits in with this hypothesis, since it has been shown to activate the development of ferroptosis in human tissue and its secretions (2).
  Hepcidin, which is stimulated mainly by interleukin 6, is the key to serum iron and the underlying reason for sequestration in enterocytes and macrophages. Excess tissue iron also triggers ferroptosis by activating peroxidation mechanisms, which leads to multiorgan damage and, interestingly, is associated with ageusia and anosmia (4).
  The hypothesis put forward associates age, cardiovascular disease, smoking, and sulfasalazine and suggests that hyperferritinemia is not a systemic marker, but rather a key element of the pathogenesis of COVID 19.
  Until robust evidence is available, sulfasalazine should be used with caution.

  References
  [1] Strangfeld, A., Schäfer, M., Gianfrancesco, M. A., Lawson-Tovey, S., et al. 2021. Factors associated with COVID-19-related death in people with rheumatic diseases: results from the COVID-19 Global Rheumatology Alliance physicianreported registry. Ann Rheum Dis doi: 10.1136/annrheumdis-2020-219498.
  [2] Ou Z, Wen Q, Deng Y, Yu Y, et al. Cigarette smoking is associated with high level of ferroptosis in seminal plasma and affects semen quality. Reprod Biol Endocrinol. 2020 May 27;18(1):55.
  [3] Xie Y, Hou W, Song X, Yu Y, et al. Ferroptosis: process and function. Cell Death Differ. 2016 Mar;23(3):369-79.
  [4] Edeas M, Saleh J, Peyssonnaux C. Iron: Innocent bystander or vicious culprit in COVID-19 pathogenesis? Int J Infect Dis. 2020 Aug;97:303-305.
  [5] De Virgiliis F, Di Giovanni S. Lung innervation in the eye of a cytokine storm: neuroimmune interactions and COVID-19. Nat Rev Neurol. 2020;16(11):645-652.
  [6] Ask TF, Lugo RG, Sütterlin S. The Neuro-Immuno-Senescence Integrative Model (NISIM) on the Negative Association Between Parasympathetic Activity and Cellular Senescence. Front Neurosci. 2018 Oct 9;12:726.

  Show Less

  Conflict of Interest:
  None declared.

  • Back to top