Article Text

Outcomes following SARS-CoV-2 infection in individuals with and without inflammatory rheumatic diseases: a Danish nationwide cohort study
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  1. Annemarie Lyng Lyng Svensson1,
  2. Hanne-Dorthe Emborg2,
  3. Lars Erik Bartels3,
  4. Torkell Ellingsen4,
  5. Thomas Adelsten5,
  6. René Cordtz6,7,
  7. Lene Dreyer8,9,
  8. Niels Obel2,10
  1. 1 Department of Rheumatology, Center for Rheumatology and Spine Diseases, Rigshospitalet HovedOrtoCentret, Kobenhavn, Denmark
  2. 2 Department of Infectious Disease Epidemiology and Prevention, Statens Serum Institut, Kobenhavn, Denmark
  3. 3 Rheumatology, Aarhus University Hospital, Aarhus N, Denmark
  4. 4 Rheumatology, Odense University Hospital, Odense, Denmark
  5. 5 Department of Rheumatology, Sjællands Universitetshospital Køge, Koge, Denmark
  6. 6 Department of Rheumatology, Aalborg University Hospital, Aalborg, Denmark
  7. 7 Department of Rheumatology, Gentofte Hospital, Hellerup, Denmark
  8. 8 Department of Rheumatology and Clinical Medicine, Aalborg University Hospital, Aalborg, Denmark
  9. 9 Department of Clinical Medicine, Aalborg University, Aalborg, Denmark
  10. 10 Department of Infectious Diseases, Copenhagen University Hospital, Kobenhavn, Denmark
  1. Correspondence to Dr Annemarie Lyng Lyng Svensson, Center for Rheumatology and Spine Diseases, Rigshospitalet HovedOrtoCentret, Kobenhavn, 0045-2855512, Denmark; annemarie.lyng.svensson.01{at}regionh.dk

Abstract

Objective In a setting with an extensive SARS-CoV-2 test strategy and availability of effective vaccines, we aimed to investigate if patients with inflammatory rheumatic diseases (IRD) face greater risk of contracting SARS-CoV-2 and have a worse prognosis of increased risk of hospitalisation, assisted ventilation and death compared with the general population.

Methods This was a nationwide, population-based register study that compared outcomes of SARS-CoV-2 infection in Danish patients with IRD (n=66 840) with matched population controls (n=668 400). The study period was from March 2020 to January 2023. Cox regression analyses were used to calculate incidence rate ratios (IRRs) for SARS-CoV-2-related outcomes.

Results We observed a difference in time to first and second positive SARS-CoV-2 test in patients with IRD compared with the general population (IRR 1.06, 95% CI 1.05 to 1.07) and (IRR 1.21, 95% CI 1.15 to 1.27). The risks of hospital contact with COVID-19 and severe COVID-19 were increased in patients with IRD compared with population controls (IRR 2.11, 95% CI 1.99 to 2.23) and (IRR 2.18, 95% CI 1.94 to 2.45). The risks of assisted ventilation (IRR 2.33, 95% CI 1.89 to 2.87) and COVID-19 leading to death were increased (IRR 1.98, 95% CI 1.69 to 2.33). Patients with IRD had more comorbidities compared with the general population. A third SARS-CoV-2 vaccination was associated with a reduced need for hospitalisation with COVID-19 and reduced the risk of death.

Conclusion Patients with IRD have a risk of SARS-CoV-2, which nearly corresponds to the general population but had a substantial increased risk of hospitalisation with COVID-19, severe COVID-19, requiring assisted ventilation and COVID-19 leading to death, especially in patients with comorbidities.

  • COVID-19
  • arthritis
  • autoimmune diseases
  • epidemiology
  • vaccination

Data availability statement

No data are available.

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WHAT IS ALREADY KNOWN ON THIS TOPIC

  • The impact of COVID-19 on morbidity and mortality among patients with inflammatory rheumatic diseases (IRD) compared with the general population in the different periods of the SARS-CoV-2 pandemic is not known.

  • Since many of the available studies are from the first year of the pandemic, the later periods where Omicron became the predominant strain the consequences for patients with IRD compared with the general population remain unknown.

  • The impact of the third and fourth SARS-CoV-2 vaccination is not completely understood.

WHAT THIS STUDY ADDS

  • During March 2020–January 2023, patients with IRD have a risk of SARS-CoV-2 which nearly corresponds to the general population but have a substantial risk of hospitalisation with COVID-19, severe COVID-19, requiring assisted ventilation and COVID-19 leading to death compared with the general population.

  • A third SARS-CoV-2 vaccination was associated with a reduced need for hospitalisation with COVID-19 and reduced the risk of death.

  • The risk of hospitalisation after first SARS-CoV-2 infection in the Omicron period was increased in the IRD population compared with the control cohort.

  • The risk of death decreased substantially after the Omicron variant became the dominating strain; however, death after first positive SARS-CoV-2 test in the Omicron period was increased in patients with ANCA-associated necrotising vasculitis (AAV) and rheumatoid arthritis (RA) compared with population controls.

HOW THIS STUDY MIGHT AFFECT RESEARCH, PRACTICE OR POLICY

  • These data suggest that despite effective SARS-CoV-2 vaccines in most patients with IRD, some patients with AAV, RA, systemic lupus erythematosus and systemic sclerosis are associated with higher number of comorbidities and have a substantial risk of COVID-19 leading to death compared with the general population.

  • Patients with IRD are well advised to strictly follow hygiene and distance measures to avoid infections with SARS-CoV-2.

Introduction

In December 2019, SARS-CoV-2 was reported as the infectious agent leading to COVID-19.1 Globally, >762 million cases and 6.8 million deaths of COVID-19 have been confirmed by WHO as of April 2023.2 Vaccines against SARS-CoV-2 reduced the risk of transmission of the virus and the severity of the disease.3 From January 2022, the Omicron variant has been the main SARS-CoV-2 variant in most countries including Denmark. The effectiveness and protection from vaccines and past infections will attenuate as virus mutates and more breakthrough infections are expected.

Patients with inflammatory rheumatic diseases (IRD) comprise a heterogenous group of patients with ANCA-associated necrotising vasculitis (AAV), rheumatoid arthritis (RA), systemic lupus erythematosus (SLE), systemic sclerosis (SSC), Sjögren syndrome (SS), giant cell arteritis (GCA), psoriasis arthritis (PsA) and spondylarthritis (SpA). Patients with IRD may have increased risk of infection due to their underlying rheumatic disease, comorbidities, older age and immunosuppressive treatments.4 The SARS-CoV-2 pandemic initially raised concerns about the risk of severe infection in patients with IRD. Preliminary data were reassuring about the risk of severe COVID-19 pneumonia in patients with IRD treated with targeted biological or synthetic disease-modifying anti-inflammatory agents.5 6 Studies on patients with IRD regarding severity and mortality from COVID-19 has shown diverging results. In a recent meta-analysis comprising 100 studies, it was shown that patients with IRD had a 52% increased risk of testing positive for SARS-CoV-2 and their relative risk of death increased by 74% compared with the general population.4 A review from September 2021 conclude that COVID-19 in patients with IRD is not associated with increased risk of death, but the analyses was based on six studies, five of which were retrospective and all were conducted during the first wave of the pandemic.7 The wave of infections caused by the omicron variant has been reported to cause less severe COVID-19 outcomes in the general population and in patients with IRD.8 9

In a meta-analysis based on 25 studies, the authors demonstrated that the serological response to SARS-CoV-2 vaccines in patients with IRD was attenuated compared with patients without IRD.10 A population-based study reported that vaccination in patients with RA induced a reduction in COVID-19 hospitalisation comparable with that in the general population.11 Four population-based studies reported a higher serological response rate to a third SARS-CoV-2 vaccination in patients with IRD.6 12–14 Most studies were from specialised centres comparing breakthrough SARS-CoV-2 infections in full vaccinated patients with IRD with patients with IRD with incomplete vaccinations and only a few compared with a control cohort from the general population. Since breakthrough infections can be asymptomatic or mild, surveillance data are likely to reflect under-reported cases.6

In a nationwide setting with an extensive SARS-CoV-2 test strategy and availability of effective vaccines, we aimed to investigate if patients with IRD face increased risk of contracting SARS-CoV-2 infection and have a worse prognosis with increased risk of hospitalisation, assisted ventilation and death compared with individuals from the general population.

Methods

Study design

The study was performed as a nationwide, population-based, matched cohort study comparing the incidence and outcomes of SARS-CoV-2 infection in patients with IRD with the risk in the general Danish population.

Settings

In Denmark, the first case of SARS-CoV-2 was detected on 27 February 2020, and the first vaccine was administered on 27 December 2020.15 15 16

The Danish tax-funded healthcare system provides vaccination, testing and treatment for SARS-CoV-2 free-of-charge for all Danish residents. The Danish vaccination programme was rolled out by personal invitation letter starting with risk groups defined by high age or comorbidity. Pfizer/BioNTech Corminatory and Moderna mRNA-1273 were the first vaccines to be approved.

The public vaccine programme succeeded in vaccinating 82% of the 5.8 million people living in Denmark by 15 May 2022 and 61.5% were vaccinated three times with Pfizer or Moderna.3 Vaxzeria (previously AstraZeneca) or Janssen vaccines were used infrequently in Denmark. Patients with severe IRD was prioritised for earlier vaccination and administrated September 2021 to mitigate their COVID-19 risk and third vaccination was rolled out in December 2021 to January 2022 in the general population.17 The Omicron variant was predominant in Denmark after December 2021.

As of 23 November 2022, 3.35 million individuals (58% of the population) had tested positive for SARS-CoV-2 at least once and >128 million PCR and antigen tests had been performed in the country.16

Data sources

The unique personal identification number assigned to all residents at birth or on immigration into Denmark was used to link data from Danish national registers. We obtained information on sex, date of birth, death, immigration and emigration from the Danish Civil Registration System that has recorded information on all Danish residents since 1968.18 19 Results of SARS-CoV-2 PCR tests were obtained from the national COVID-19 surveillance system maintained by Statens Serum Institut, which captures the results of all SARS-CoV-2-PCR and antigen tests performed in public (including hospitals) and private testing facilities.20 SARS-CoV-2 vaccination status was retrieved from the Danish Vaccination Register which contains individual-level information on the date and type of vaccines given in Denmark.21 We obtained data on admission, discharge, diagnoses and procedures as recorded by the International Classification Diseases Classification system (ICD-10) (WHO 2010) in the Danish National Patient Register (DNPR).22–24

Diagnostic groups

We categorised IRD diagnoses in the following subgroups by ICD-10 codes: AAV: M31.3, M31.7, M31.8, M30.0, M30.1, M30.8, M31.0; RA: M05.0, M05.1, M05.2, M05.8, M05.9, M06.0, M06.8, M06.9; SLE: M32.0, M32.1, M32.8, M32.9; SSC: M34.0, M34.8, M34; SS: M35.0; GCA: M31.6, M31.5; SpA and PsA: M45.0, M46.1, M46.8, M46.9, M47.9, M07.0, M7.1, M07.2. We used three ICD codes separate in time. A patient was included in one of the above-described subgroups and with IRD at the date, the individual was registered three times with a subgroup diagnosis. In case an individual was categorised with more than one subgroup diagnosis, the individual was categorised with the first subgroup diagnosis.

Study populations

IRD patient cohort: we included all Danish residents who were diagnosed with an IRD and were between 18 and 90 years of age on 1 March 2020 (n=66 840). Date of study inclusion was the latest of 1 March 2020, immigration and IRD diagnosis.

Comparison cohort: for each patient with IRD, we extracted 10 population controls at random from the Danish general population, matched on sex and date of birth, alive, residing in Denmark on the date of study inclusion and who were not included in IRD patient cohort (n=6 68 400). For the population controls, study inclusion was the date of inclusion for the IRD index patient.

Outcomes

Outcomes were time to the following events:

Date of first positive SARS-CoV-2 test: date of first positive PCR or antigen test for SARS-CoV-2 as registered in the national COVID-19 surveillance system.3

Date of second SARS-CoV-2 test: first date the individual was registered with a positive test for SARS-CoV-2 (either by PCR or antigen) >90 days after the first positive SARS-CoV-2 test.9 25

Date of first hospitalisation with a diagnosis of COVID-19: first date an individual was hospitalised for ≥24 hours with a diagnosis in the DNPR of ICD-10 code B342 (COVID-19 infection, unspecified sites) or hospitalised with severe COVID-19 as described below combined with a positive test for SARS-CoV-2 within 14 days of diagnosis.

Date of first hospitalisation with severe COVID-19: first date of hospitalisation with a diagnosis in the DNPR of either B972 and/or procedures involving mechanical ventilation (SKS code: BGDA, the procedure code for mechanical ventilation in the Danish health care classification system) combined with a positive SARS-CoV-2 test within 14 days of diagnosis.

Date of first hospitalisation with COVID-19 with procedures involving mechanical ventilation: first date of hospitalisation procedure involving mechanical ventilation (SKS code: BGDA) combined with a positive SARS-CoV-2 test within 14 days of diagnosis.

Date of first hospitalisation with COVID-19 leading to death: date of death in case an individual died within 30 days of hospitalisation with an associated diagnosis of COVID-19.

Date of all-cause death: date of death as registered in the Danish Civil Registration System.

Statistical analyses

Time was calculated from the date of the study inclusion until the first of date of emigration, death, 1 January 2023 or the outcome of interest. In analyses of time to vaccination, time was calculated from 1 January 2021. In analyses of time to hospitalisation and death after first positive SARS-CoV-2 test, time was calculated from date of the first positive SARS-CoV-2 test. We computed Kaplan-Meier life tables using calendar time as a time scale. In analyses of time to hospitalisation and death after first positive SARS-CoV-2 test, we used days after first positive test as a time scale. We calculated the incidence rate ratios (IRRs) in patients with IRD versus individuals in the matched control cohort for the outcomes described above using Cox regression. In analyses of hospitalisation and death after a SARS-CoV-2 test, estimates were adjusted for age as continuous variable and sex. To elucidate the impact of the Omicron variant, we stratified analyses of time to hospitalisation and death on whether the individual tested SARS-CoV-2 positive before or after 1 January 2022. In subanalyses, we stratified the results into seven groups: (1) AAV, (2) RA, (3) SLE, (4) SSC, (5) SS, (6) GCA and (7) SpA and PsA. We further calculated risk estimates adjusted for Charlson Comorbidity Index (grouped as scores of 0, 1, 2, 3, 4, 5, >6).26

Data were analysed using STATA V.14 statistical software.27 27

Results

We included 66 840 patients with IRD including 1948 AAV; 30 391 RA; 2480 SLE; 1569 SSC; 2611 SS; 5984 GCA and 21 329 SpA and 668 400 matched population controls. In the IRD population, 66% were females and the median age was 63.1 years (IQR 50.4–73.9 years). The study included 165 068 years of follow-up in the IRD cohort and 1 659 413 years in control cohort (table 1). Mean follow-up time was 2.8 years (IQR 2.8–2.8). In the study period, 30 131 individuals with IRD were tested positive for SARS-CoV-2, of whom 29 420 were PCR SARS-Cov-2 positive. The patients with IRD had more comorbidity compared with population controls. Patients with AAV, RA, SLE and SSC had the highest burden of comorbidity (table 1).

Table 1

Characteristics of individuals with rheumatic and musculoskeletal diseases and population controls in Denmark (1 March 2020 to 1 January 2023)

Risk of positive SARS-CoV-2 test

There was a discrete increased risk of a first and second positive SARS-CoV-2 test in patients with IRD compared with the general population (IRR 1.06, 95% CI 1.05 to 1.07) and (IRR 1.21, 95% CI 1.15 to 1.27). The increased risk of positive SARS-CoV-2 test was exclusively observed in patients with AAV, RA, GCA and SpA (table 2). We observed no substantial difference in the test frequency for SARS-CoV-2 in patients with IRD compared with population controls from the general population (figure 1).

Figure 1

(A) Time to first and second positive test for SARS-CoV-2: black line: patients with inflammatory rheumatic disease, grey line: population controls, solid line: first positive test, time starts on 1 March 2020 and ends 1 January 2023. (B) Time to second, third and fourth vaccination for SARS-CoV-2, black line: patients with inflammatory rheumatic disease, grey line: population controls, full line: second vaccination, dashed line: third vaccination: dotted line: fourth vaccination, time starts on 1 January 2021 and ends 1 January 2023. (C) SARS-CoV-2 test frequency (tests/1000 observation days): black columns: patients with inflammatory rheumatic disease, white columns: population controls, time starts on 1 March 2020 and ends 1 January 2023.

Table 2

Relative risk (95% CI) of first positive SARS-CoV-2 test, hospitalisation and death in patients with inflammatory rheumatic diseases versus general population controls in Denmark (1 March 2020 to 1 January 2023)

Vaccination for SARS-CoV-2

The patients with IRD received their second, third and fourth vaccine doses earlier than the population controls (figure 1). On 1 January 2023, cumulative incidence of two, three and four vaccination was 94.8% (95% CI 94.6 to 95.0), 93.7% (95% CI 93.5 to 93.9) and 75.5% (95% CI 75.1 to 75.8) of the IRD compared with 93.5% (95% CI 93.5 to 93.6), 93.0% (95% CI 92.9 to 93.0) and 72.5% (95% CI 72.4 to 72.6) in the matched controls from the general population.

Risk of hospitalisation and death from COVID-19

The risk of hospitalisation with COVID-19 and severe COVID-19 was more than doubled in patients with IRD compared with the population controls (IRR 2.11, 95% CI 1.99 to 2.23) and (IRR 2.18, 95% CI 1. 94 to 2.45) (table 2). Also, the risks of hospitalisation requiring assisted ventilation and hospitalisation with COVID-19 leading to death were increased in the IRD population (IRR 2.33, 95% CI 1.89 to 2.87) and (IRR 1.98, 95% CI 1.69 to 2.33) (table 2, figure 2A–D). The risks of hospitalisation requiring assisted ventilation were particularly increased in patients with AAV, RA, SLE and SSC and hospitalisation with COVID-19 leading to death were increased in patients with AAV and RA (table 2). The risk of hospitalisation after first SARS-CoV-2 infection in the Omicron period was increased in the IRD population compared with the control cohort (figure 2E,F). The risk of death decreased substantially after the Omicron variant became the dominating strain (figure 2E,F). However, death after first positive SARS-CoV-2 test in the Omicron period was increased in patients with AAV and RA compared with population controls (IRR 2.59, 95% CI 1.40 to 4.79) and (IRR 1.54, 95% CI 1.28 to 1.87). Adjustment for Charlsons Comorbidity Index slightly attenuated the estimates (adjusted estimates in online supplemental table 1).

Supplemental material

Figure 2

Cumulative incidence of (A) first hospitalisation with a COVID-19 diagnosis, (B) hospitalisation with severe COVID-19, (C) hospitalisation with assisted ventilation, (D) hospitalisation with COVID-19 leading to death within 90 days (outcome described in detail in ‘Methods’ section). (E) Time to hospitalisation in ≥24 hours after first positive SARS-CoV-2 test, (F) time to death after first positive SARS-CoV-2 test. Solid line: inflammatory rheumatic diseases, dotted line: population controls. Time starts on 1 March 2020 or the date of a positive SARS-CoV-2 test, respectively.

Discussion

In this study, we found a discrete increased risk of testing positive for SARS-CoV-2 and being vaccinated in patients with IRD compared with the general population in Denmark. Patients with AAV, RA, SLE and SSC had a substantially higher risk of hospitalisation, severe COVID-19, need of assisted ventilation and death compared with the matched controls from the general population and patients with IRD in general. Thus, the observed risk of serious progressing of SARS CoV-2 infection in the IRD population is not due to an increased risk of infection or a lower vaccination rate but may originate from increased risk of organ manifestations from SARS-CoV-2 when infected. This may be a result of immunosuppressive treatment, disease activity and comorbidities. In our data, comorbidities among patients with IRD may play a role in hospitalisation and death among patients with IRD since this has been previously shown in patients with IRD with influenza infection.28

Patients with AAV and RA had an increased risk of death after hospitalisation with COVID-19. In the Omicron period, hospitalisation with COVID-19 were increased in all patients with IRD, compared with controls despite a high coverage of SARS-CoV-2 vaccines. However, the mortality rate decreased in patients with IRD in the Omicron period compared with controls, with the only exception in patients with AAV and RA where we observed an increased mortality rate. In the Danish general population, the mortality rate after three vaccination for SARS- CoV-2 was significantly reduced in the Omicron period compared with the pre-Omicron period.

A Swedish nationwide cohort register study demonstrated an increased all-cause mortality in patients with RA and other inflammatory joint diseases (IJD) during March to September 2020, which was proportional to that in the general population and the pre-SARS-CoV-2 period (2015–2019) and was largely explained by comorbidities and socioeconomic factors.29 However, a discrete increased risk of COVID-19-related intensive care unit admittance and COVID-19 leading to death was found in patients with IJD and the RA cohort had the most pronounced excess mortality compared with the general population.28 A recent study suggests that interstitial lung disease or its treatment among patients with RA might be a major contributor to severe COVID-19 outcomes.30 In accordance with our study, four Danish nationwide cohort studies, two in patients with RA and one in patients with SLE and one in patients with AAV, found an increased risk of COVID-19 hospitalisations compared with the general population also after adjustments for comorbidities.11 31–33 These studies only include the early period of the SARS-CoV-2 epidemic and does not include the period after the introduction of Omicron subtype.

In a Danish nationwide study including >12 000 patients with RA, SpA and PsA, patients reported to self-isolate more compared with others of the same age, 48% vs 38%.34 In our study, we found the risk of testing positive for SARS-CoV-2 in patients with IRD was almost equivalent to the general Danish population, despite the increased frequency of self-isolation among the patients with RA, SpA and PsA, which may indicate a higher susceptibility to the infection.

In a systematic review and meta-analysis including 100 studies of patients with IRD, the authors found an increased risk of contracting SARS-CoV-2 infection in patients with IRD, but it remains unclear if patients with IRD were tested more often compared with the general population.4

The extensive Danish SARS-CoV-2 test strategy gave us access to >128 million SARS-CoV-2 PCR and antigen test results registered in Denmark. Our data showed no difference in the test frequency in patients with IRD compared with the control cohort. Regarding data on patients with IRD estimating the risk of testing positive for SARS-CoV-2 from the systematic review and a meta-analysis, it was not clear, whether there were any differences in SARS-CoV-2 testing activity in patients with IRD compared with the general population.4 7 We found a discrete increased risk of a positive SARS-CoV-2 test in IRD overall, but patients with AAV, RA, GCA and SpA had a considerably increased risk of reinfection. Previous studies have shown diverging results.4 7 The studies showing no increased risk in patients with IRD for testing positive for SARS-CoV-2 might be a result of differences in test strategies or lack of testing facilities not testing patients with mild COVID-19 symptoms.7 For the general population, risk for more severe COVID-19 infection is male sex, age and comorbidities. For patients with IRD, risk factors of concern include treatment with rituximab (RTX), prednisolone >10 mg (Pred) and mycophenolate (MMF).7 Patient groups with more severe disease in our study are patients with AAV, RA, SLE and SSC all with more comorbidities compared with the general population and treatments often includes RTX and Pred and for SLE and SSC treatments can also include MMF. Overall, patients with IRD and several subgroups of patients with IRD had a higher risk of a second infection with SARS-CoV-2 (being test positive >90 days after first positive test). This observation may have several explanations: (1) the natural protection following the first SARS-CoV-2 infection may be less pronounced in the patients with IRD, (2) despite early SARS-CoV-2 vaccination coverage in patients with IRD some may not be able to mount an adequate antibody response.

We found an increased risk of hospitalisation with SARS-CoV-2 followed by death in Danish patients with IRD in the pre-Omicron period. Although the mortality rate decreased in the Omicron period, it was substantially higher in the patients with IRD compared with controls. In the review of 208 studies in patients with IRD with SARS-CoV-2 infection, the authors found no increased risk of death in the six included studies.7 The review comprised studies with many different categories of diseases and organ manifestations, differences in severity, treatments and short periods of follow-up, which makes it difficult to evaluate the risk for specific IRD subgroups.

Our study is the first large population-based study including patients with AAV compared with other rheumatic diseases and a control group from the general population, which minimise the risk of selection bias. We found that patients with AAV had a doubled risk of death after a SARS-CoV-2 infection. Kronbichler et al reported the mortality in patients with AAV with a COVID-19 infection was higher than in the general population and the risk of death was comparable to the increased risk observed in kidney transplanted patients or patients undergoing haemodialysis (mortality rate 20%–25%).35–37 But data on specific risk factors for patients with AAV are lacking. A French study of patients with SLE demonstrated increased risk of death after hospitalisation with COVID-19.38 Yet a study including data from the EULAR COVID-19 registry and C19-GRA registry in the USA suggested that patients with SLE with COVID-19 infection in the later periods of the pandemic had better outcomes relative to the first period of the pandemic, which is in accordance with the overall trends in the general population.39 It is important to consider that chronic kidney disease was the strongest predictor for a poor COVID-19 outcome in patients with SLE.38 39 In a review of patients with SSC, data from registers and single cohort studies have shown that the risk of contracting SARS-CoV-2 does not seem to increase substantially among patients with SSC. However, severe outcomes are more frequently observed in patients with SSC compared with the general population, specifically in patients with organ involvement and those treated with RTX.40

Initially when vaccines were limited, the Danish health authorities prioritised vaccination of immunosuppressed individuals. Patients with IRD with AAV, SLE, SSC and some patients with RA were among the first to be invited for vaccination for SARS-CoV-2. Our data support that this strategy was successful and led to a high vaccine coverage of Danish patients with IRD, with almost all patients with IRD vaccinated with third vaccine in May 2022 and a substantial fraction of the high-risk groups vaccinated with the fourth SARS-CoV-2 vaccine by January 2023. From 15 September, all Danes aged 50 years and above were offered fourth vaccine dose.

The Danish public healthcare system is in several ways comparable to that in other Western World countries, why we presume our data can be generalised to populations in the Western World.

Our study is the largest nationwide cohort register study on patients with IRD compared with a control group from the general population investigating the impact of the SARS-CoV-2 pandemic evaluating the Danish excessive SARS-CoV-2 test strategy and the SARS-CoV-2 vaccination programme with a long follow-up. Another strength of our study was the population-based, nationwide design, with access to complete registers of hospital diagnosis and vital status and complete follow-up from 1 March 2020 to 1 January 2023. In Denmark, the free-of-charge SARS-CoV-2 test strategy that also allowed for testing of asymptomatic individuals gives us a unique possibility to minimise under-reporting.

Our study has some limitations. First the test strategy for SARS-CoV-2 changed during the study period, which could potentially introduce bias. In the beginning of the pandemic, test capacity were limited where symptomatic individuals and high-risk individuals were tested. In later periods, testing asymptomatic individuals increased, as a negative SARS-CoV-2 test was mandatory to participate in cultural activities in specific periods (COVID-19 certificate) in the summer 2021. This might have resulted in more frequent testing in patients with IRD in the beginning of the epidemic and later we observed a higher frequency of testing in the general population in the summer 2021.3 Most patients included in our study had either a positive PCR test or a positive antigen test which were later confirmed with a PCR test.

Second, we cannot exclude misclassification of the IRD diagnosis. To increase the specificity of the diagnosis, we only included individuals who were registered at least three times with the specific IRD diagnosis. This strategy may have led to exclusion of individuals with minimal IRD disease. A recent study in patients with IBD based on Danish hospital register data showed that the validity of the IBD diagnosis in the registry of individuals increased with the number of registrations and patients with at least three registrations had the highest validity >90%.41 Third, there may be some inaccuracy in registration of COVID-19 diagnosis in DNPR. However, a Danish study of COVID-19 discharge diagnosis found a high predictive value of the COVID-19 diagnosis in Danish National Patient Register (DNHP).42 Also procedure codes for assisted ventilation have been shown to have high predictive value.3 Other limitations include lack of access to medication data, potential lack of accuracy of rheumatic diseases and differences in behavioural changes by groups.

Conclusion

In conclusion, Danish patients with IRD had nearly the same risk of testing positive for SARS-CoV-2 as the general population but had a substantial increased risk of hospitalisation with COVID-19, severe COVID-19, requiring assisted ventilation and COVID-19 leading to death, especially in patients with comorbidities. The IRD population is heterogeneous with some substantial differences between the groups, however subgroups of patients with IRD are at a greater risk of more severe COVID-19 infections. Patients with AAV, RA, GCA and SpA had an increased risk for SARS-CoV-2 reinfection. Patients with AAV, RA, SLE and SSC have increased risk of hospitalisation with COVID-19, severe COVID-19, requiring assisted ventilation and COVID-19 leading to death compared with the general population. Patients with AAV and RA had a higher risk of death after hospitalisation with a COVID-19 infection compared with other patients with IRD.

Data availability statement

No data are available.

Ethics statements

Patient consent for publication

Ethics approval

This analysis was performed as national surveillance under the authority task of the Danish national infectious disease control institute at the Statens Serum Institut. The analysis was approved by The Danish Data Protection Agency (permission no 21/04383). According to Danish regulations, national surveillance activities solely relying on register information do not require individual consent or approval from an ethics committee.

Acknowledgments

The authors would like to thank Christian Ammitzbøl for contributing with scientific advice.

References

Supplementary materials

  • Supplementary Data

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Footnotes

  • Handling editor Josef S Smolen

  • Twitter @Doktor77

  • Contributors ALLS designed the study, analysed and interpreted data and wrote the report. NO designed the study, analysed and interpreted data and reviewed the manuscript. LEB, H-DE, TE, LD, RC, TA interpreted data and reviewed the manuscript. All authors have approved the final draft and vouch for the accuracy and completeness of the data and analysis. ALLS is the guarantor.

  • 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 not involved in the design, or conduct, or reporting, or dissemination plans of this research.

  • 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.