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Challenges in the diagnosis of early rheumatoid arthritis in times of COVID-19
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  1. Bernardo D'Onofrio1,2,
  2. Ludovico De Stefano1,2,
  3. Bianca Lucia Palermo1,2,
  4. Blerina Xoxi1,
  5. Antonio Manzo1,2,
  6. Carlomaurizio Montecucco1,2,
  7. Serena Bugatti1,2
  1. 1 Division of Rheumatology, IRCCS Policlinico San Matteo Foundation, Pavia, Italy
  2. 2 Department of Internal Medicine and Therapeutics, University of Pavia, Pavia, Italy
  1. Correspondence to Professor Serena Bugatti, Division of Rheumatology, IRCCS Policlinico San Matteo Foundation, Pavia 27100, Italy; serena.bugatti{at}unipv.it

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Challenges in the provision of care and patients’ reluctance to access healthcare services and adhere to drug prescriptions in course of COVID-19 pandemic undermine the fundamental principles of early diagnosis and treat to target, which have revolutionised the natural history of many chronic inflammatory diseases starting from rheumatoid arthritis (RA).1 Although most rheumatologists have the impression that the intervals between symptom onset and first consultation have increased,2 no data currently indicate whether and to what extent the picture of early RA has changed during COVID-19.

Here, we analysed data from the Pavia Early Arthritis Clinic (EAC) inception cohort. Referral criteria have been described previously, and include the presence of signs and symptoms of suspected inflammatory arthritis for <12 months of duration.3 By 31 December 2020, the EAC collects information on 2.508 patients. The service has undergone complete closure during the first wave of COVID-19 pandemic from 9 March to 18 May 2020. In this period, emergency visits were guaranteed through the general rheumatology outpatient clinic. For this study, baseline characteristics of patients referred in the semester following the lockdown (July to December 2020) were compared with: (1) patients referred in the semester immediately preceding the lockdown (July to December 2019); (2) patients referred in a semester of routine use of the 2010 RA criteria (July to December 2015); (3) patients referred in the semester following the dissemination of the 2010 RA criteria (July to December 2011); and (4) patients referred in the semester preceding the publication of the 2010 criteria (July to December 2009). Data were extracted from 452 patients. Overall, the access of patients with new-onset suspected inflammatory arthritis was relatively stable over the years until 2019, while COVID-19 pandemic coincided with a marked reduction in new referrals (−25.9%) and in the proportion of patients fulfilling RA criteria at presentation (36.1% vs 45.4%, p=0.19) (figure 1A). Furthermore, while the ratio between autoantibody-positive and autoantibody-negative RA was well balanced before the lockdown, and in line with the prevalence of autoantibody negativity recognised over the past decade,4 nearly 70% of patients with RA referred in the second semester of 2020 were autoantibody positive (online supplemental table S1). As shown in figure 1B–F and in online supplemental table S2, restriction measures imposed by COVID-19 profoundly impacted on the clinical presentation of autoantibody-positive RA. The introduction and progressive consolidation of the 2010 classification criteria had indeed favoured a reduction of the diagnostic delay until 2019, with 55.7% of the patients seen within the ‘window of opportunity’ of 12 weeks compared with 37.5% of those classified according to the 1987 criteria in 2009 (p=0.20). Furthermore, autoantibody-positive RA had become progressively milder, with lower levels of objective parameters of inflammation. In contrast, in patients seen during the pandemic, the diagnostic delay was significantly longer, with only 5.6% of the patients captured within 12 weeks (p<0.001 vs 2019, 2015 and 2011 semesters grouped together; p=0.04 vs the 2009 semester). Overall disease activity was increased as a result of an inversion of the trend towards lower levels of inflammatory features as well as further increase in the historical trend towards worsening of patient-derived measures.5 The proportion of erosive RA was not significantly different, likely due to the latency between disease activity and its effects on radiographic progression.6 The introduction of the 2010 criteria had instead produced smaller changes in the pattern of presentation of autoantibody-negative RA (online supplemental table S3). Yet, COVID-19 pandemic also impacted on this autoantibody serotype by selecting fewer patients with more frequent polymyalgic involvement (50% vs 21.1% in 2019, 2015 and 2011 semesters grouped together, p=0.17) and higher inflammatory features, and more urgent need of medical advice, as expressed by the lower diagnostic delay. No significant changes neither in the rates of new referrals nor in disease characteristics were observed in relation to different restriction measures imposed by the Italian government in course of 2020.

Figure 1

Frequency and characteristics at presentation of new-onset rheumatoid arthritis (RA) referred in course of COVID-19 pandemic. (A) Temporal trends of the rate of new referrals to our Early Arthritis Clinic (EAC) of patients with suspected inflammatory arthritis (IA) and patients fulfilling classification criteria for RA already at presentation. (B) Diagnostic delay (from symptom onset to diagnosis, in weeks) of patients with new-onset RA referred to the Pavia EAC during COVID-19 pandemic in comparison with reference semesters before the pandemic. (C–F) Temporal trends of objective measures of inflammation (28-joint swollen joint count, SJC28, C; levels of C-reactive protein, CRP, D) and patient-reported measures (28-tender joint count, TJC28, E; patient global assessment (PGA) of disease activity, F). Data are expressed as mean (SD) values. *, **, *** and # indicate significant differences (p<0.05) between each group by means of one-way analysis of variance (ANOVA) with Bonferroni correction for multiple comparisons. ACR, American College of Rheumatology; EULAR, European League Against Rheumatism; VAS, visual analogue scale.

We acknowledge that the small sample sizes derived from monocentric EAC cohorts need replication. However, our data provide first evidence of how COVID-19 pandemic is changing the pattern of presentation of RA. The remarkable improvements in the outcomes of autoantibody-positive RA achieved over the past 20 years7 risk to be rapidly vanished by a retrogression back to the diagnostic delay and the severity typical of EAC cohorts prior to the introduction of the 2010 criteria.8 Equally important, despite the incidence of autoantibody-negative RA is increasing,4 restrictions imposed by the pandemic, together with the erroneous but common beliefs attributing to this disease subtype a harmless course, may leave patients with less abrupt onsets underdiagnosed, with further impact on prognosis which remains per se unfavourable even in the modern treatment era.7 The challenge is thus to keep on fighting COVID-19 without forgetting non-COVID-19 diseases.

Ethics statements

Ethics approval

The study was approved by the local ethical committee of the IRCCS Policlinico San Matteo Foundation (08004598/b).

References

Supplementary materials

  • Supplementary Data

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Footnotes

  • Handling editor Josef S Smolen

  • Contributors BDO contributed to the acquisition, analysis and interpretation of data and drafted the manuscript. LDS contributed to the analysis and interpretation of data. BLP and BX contributed to the acquisition of data. AM and CM contributed to the interpretation of data. SB conceived the work, contributed to the analysis and interpretation of data and drafted the manuscript. LDS, BLP, BX, AM and CM revised the manuscript critically for important intellectual content. All the authors provided final approval of the version to be published.

  • Funding This study was supported in part by fundings from the IRCCS Policlinico San Matteo Foundation, Pavia, Italy.

  • Competing interests None declared.

  • Provenance and peer review Not commissioned; externally peer reviewed.

  • Supplemental material This content has been supplied by the author(s). It has not been vetted by BMJ Publishing Group Limited (BMJ) and may not have been peer-reviewed. Any opinions or recommendations discussed are solely those of the author(s) and are not endorsed by BMJ. BMJ disclaims all liability and responsibility arising from any reliance placed on the content. Where the content includes any translated material, BMJ does not warrant the accuracy and reliability of the translations (including but not limited to local regulations, clinical guidelines, terminology, drug names and drug dosages), and is not responsible for any error and/or omissions arising from translation and adaptation or otherwise.

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