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Comment on ‘Characteristics associated with hospitalisation for COVID-19 in people with rheumatic disease: data from the COVID-19 Global Rheumatology Alliance physician-reported registry’ by Gianfrancesco et al. Disease activity, rather than glucocorticoid therapy, may be associated with COVID-19 severity in patients with rheumatic musculoskeletal diseases
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  1. Alessandro Giollo1,
  2. Eugenia Bertoldo1,
  3. Giovanni Adami1,
  4. Adam J Cybulski2,
  5. Angelo Fassio1,
  6. Giovanni Orsolini1,
  7. Luca Idolazzi1,
  8. Davide Gatti1,
  9. Ombretta viapiana1,
  10. Maurizio Rossini1
  1. 1Department of Medicine, Rheumatology Unit, Universita degli Studi di Verona, Verona, Italy
  2. 2Department of Radiology, University of Verona, Verona, Veneto, Italy
  1. Correspondence to Dr Alessandro Giollo, Department of Medicine, Rheumatology Unit, Universita degli Studi di Verona, Verona 37134, Italy; alessandrogiollo{at}gmail.com

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The COVID-19 Global Rheumatology Alliance physician-reported registry has provided data on 600 individuals with rheumatic musculoskeletal disease (RMD) and COVID-19,1 277 (46%) of whom were hospitalised. The study was not powered to explore the association between disease activity and hospitalisation status; still, it was deemed to be non-significant (p=0.49). However, only 18% of patients had moderate and just 2% high disease activity. Therefore, the relationship between disease activity and COVID-19 severity deserves further investigation.

We collected clinical data of patients with RMD older than 18 years who reported a hospital admission for COVID-19 between 15 April and 15 June 2020. We retrieved 11 out of 1974 patients with RMD followed up in our rheumatology unit (0.55%) who tested positive for SARS-CoV-2 with real-time reverse transcription PCR analysis in the nasopharyngeal swab. We compared five patients with active versus six with remission disease status defined according to (1) persistency of signs or symptoms due to RMD for >50% of the time in the 3 months’ prior hospital admission plus (2) laboratory or imaging abnormalities typical of disease activity or (3) escalation of treatment for the RMD (increase in the dose of immunosuppressive treatment, adding a drug or glucocorticoid for at least 30 days) (table 1).

Table 1

Clinical characteristics of patients with rheumatic musculoskeletal disease according to their disease status

All patients had established RMD including rheumatoid arthritis (n=3), rheumatoid arthritis and Sjogren syndrome (n=1), psoriatic arthritis (n=4), systemic sclerosis (n=1), spondyloarthritis (n=1) and microscopic polyangiitis (n=1). No patient in both groups was on prednisone>10 mg/daily (mean dose 2.5±2.5 vs 1.7±2.5 mg/daily), and 6/11 (40% vs 67%) patients were off-steroid; 2/5 (40%) were on biological disease-modifying antirheumatic drug (bDMARD) therapy in the active group vs 4/6 (67%) in the remission group. Chest radiographs showed more frequently interstitial infiltrates in the active RMD group, who were more frequently smokers; however, when chest CT was performed in 3/5, ground-glass opacities were found in all. The former group of patients had lower values at the admission of blood oxygen (pO2 59±32 vs 74±28 mm Hg) than those in remission. ECG abnormalities were found more often in the active RMD group as well. The active RMD group had higher levels of C reactive protein (89±102 vs 44±32 mg/L), procalcitonin (1.9±2.0 vs 0.2±0.2 μg/L), ferritin (2019±1542 477±247 μg/L), D-dimer (1.7±1.7 vs 0.4±0.2 mg/L), lactate dehydrogenase (422±81 vs 265±66 IU/L), creatine kinase (188±185 vs 55±31 IU/L) and reduced estimated glomerular filtration rate (49±40 vs 78±26 mL/min/1.73 m2). Modified Early Warning Score of ≥5 was found in 40% vs 16%. Similar rates between the two groups were found in terms of requirement of oxygen supplementation (100% vs 83%), mechanical or high-flow oxygenation (no patient in both groups), antibiotics, lopinavir/ritonavir and hydroxychloroquine use. One patient died in the active disease group, while the remaining had a comparable time to discharge (17±7 vs 15±5 days).

In our series, patients with active RMDs on low-dose prednisone (< 10 mg/daily) and hospitalised for COVID-19 appeared to have a more severe systemic inflammatory response to SARS-CoV2 compared with those in remission. The key event in the infection of SARS-CoV-2 is the invasion of human tissues through the ACE 2 receptor expressed on the surface of alveolar epithelial cells and other target cells. Older individuals, especially those with hypertension and diabetes, have reduced ACE2 expression and upregulation of angiotensin II proinflammatory signalling.2 Patients with RMD have reduced expression of ACE2 due to ageing, multiple comorbidities and autoantibodies.3 Gianfrancesco and colleagues reported higher odds of hospitalisation with glucocorticoid therapy at prednisone-equivalent doses of ≥10 mg/day compared with no glucocorticoid therapy (OR=2.05, 95% CI 1.06 to 3.96; p=0.03). Noteworthy, systemic glucocorticoid therapy is not known to induce ACE2 receptor expression, but it can upregulate angiotensin II proinflammatory signalling and cause hypertension in a dose-dependent manner.4 However, glucocorticoid therapy is also associated with active or poorly controlled RMD.5 6 Although the authors confirmed the association between hospitalisation rates and glucocorticoid therapy after correction for disease activity (data not shown), the proportion of participants with moderate to high disease activity in the group taking prednisone-equivalent doses of ≥10 mg/day was not provided. Hence, one cannot exclude that patients with high levels of disease activity were treated with high doses of glucocorticoids for disease control, given the relatively small number of patients at prednisone-equivalent doses of ≥10 mg/day in each group (21/323 patients and 43/277 patients in the non-hospitalised and hospitalised groups, respectively).

In conclusion, we could not replicate the results by Gianfrancesco et al. Whether glucocorticoid therapy rather than disease activity is associated with COVID-19 severity in patients with RMD needs more robust data to be ascertained.

References

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Footnotes

  • Collaborators Not applicable.

  • Contributors AG provided the conception of the study, literature search and interpretation of data, drafted the article and revised it critically for important intellectual content; EB provided data search, interpretation of data, drafted the article and revised it critically for important intellectual content; AJ reviewed and commented on radiology images, provided interpretation of data, drafted the article and revised it critically for important intellectual content; GA, AF, GO, LI, OV, DG and MR revised the article critically for important intellectual content. All authors gave the final approval of the version to be submitted.

  • Funding The authors have not declared a specific grant for this research from any funding agency in the public, commercial or not-for-profit sectors.

  • Competing interests None declared.

  • Patient and public involvement Patients and/or the public were involved in the design, conduct, reporting or dissemination plans of this research.

  • Patient consent for publication Not required.

  • Ethics approval The institutional review board of the University of Verona approved this study (2598CESC).

  • Provenance and peer review Commissioned; externally peer reviewed.

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