Abstract
Introduction
Patients with SLE (systemic lupus erythematosus) have a higher risk of infection due to dysregulated immune system as well as long-term use of immunosuppressants (IS). This could influence the risk of COVID-19 and its outcome.
Methods
We conducted a longitudinal prospective study across 15 rheumatology centres during the first wave of the pandemic to understand the risk factors contributing to COVID-19 in SLE patients. During the 6 months follow-up, those who tested positive for COVID-19, their clinical course and outcome information were recorded.
Results
Through the study period (April–December 2020), 36/1379 lupus patients (2.9%) developed COVID-19. On analysing the COVID-19 positive versus negative cohort during the study period, male gender (adjusted RR 3.72, 95% C.I. 1.85,7.51) and diabetes (adjusted RR 2.94, 95% C.I. 1.28, 6.79) emerged as the strongest risk factors for COVID-19, in the adjusted analysis. There was no significant influence of organ involvement, hydroxychloroquine, glucocorticoid dosage (prednisolone< 7.5 mg or ≥ 7.5 mg/day) or IS on the risk of COVID-19. There was only one death (1/36) among the lupus patients due to COVID-19.
Conclusion
Traditional risk factors rather than lupus disease process or IS influenced the risk of COVID-19 in our cohort.
Keywords: autoimmune rheumatic diseases, SARS-CoV-2 infection, risk factors, outcome, systemic lupus erythematosus
What does this paper add?
During the COVID-19 pandemic, physicians and patients with systemic autoimmune diseases such as systemic lupus erythematosus (SLE) were concerned about their risk of SARS-CoV-2 infection. They were worried on mainly two fronts, firstly that their immune system is already flawed or poorly balanced. Secondly, their mainstay of treatment is immunosuppressive drugs which further expose them to the risk of infections. SLE being a rather uncommon disease, the information about the risk of SARS-CoV-2 infection as well as outcome has not been well represented in medical literature. We have conducted a prospective longitudinal study in real-life setting in a well-defined cohort, consisting of over 1300 SLE patients from specialized rheumatology centres. Our findings describe the risk, and reaffirm that the traditional risk factors such as diabetes and male gender influence occurrence of COVID-19 in SLE patients. And that the extent of their disease, the treatments employed including glucocorticoid and hydroxychloroquine do not have any significant impact. In view of significant geographic variation in the genome of SARS-CoV-2 and resultant variable clinical phenotype and severity, it is imperative that data emanates from all parts of the world in order to fully understand its impact on specific subgroups of affected population.
Introduction
Systemic Lupus Erythematosus (SLE) is uniquely poised at crossroads between the dysregulated immune system and the risk of viral infections, especially in the context of the current COVID-19 pandemic. This risk can be attributed to a multitude of factors such as lupus-related critical organ system dysfunction, accompanying comorbidities and the use of immunosuppressive drugs. 1 Several series have shown high dose glucocorticoids, to impact the occurrence as well as the outcome of COVID-19 in SLE. 2 Ugarte-Gil et.al, on examining 1606 patients with SLE in a global registry – described rituximab, mycophenolate and cyclophosphamide apart from rituximab to be associated with worst outcomes in age and sex-adjusted models. 3 There are several cross-sectional questionnaire-based studies and tele surveys attempting to gather information on the impact of COVID-19 on patients with SLE.3,4 However, the information on the influence of lupus disease subsets, presence of antiphospholipid antibodies and comorbidities is largely deficient.
We report incidence and outcome analysis on SLE patients in the AIRD (AutoImmune Rheumatic Disease) cohort whom we followed-up longitudinally for 6 months during the first wave of COVID-19 in India.
Methods
A prospective, multicentre, non-interventional longitudinal study involving 14 specialized rheumatological centres across Karnataka and one centre in Kerala, India, was conducted during the 1st wave of COVID-19 pandemic between April and December 2020.5,6 Consecutive patients diagnosed with any of the AIRD and in follow-up with collaborating centres were recruited. Patient’s medical records were accessed for baseline information and disease characteristics. All the patients were followed-up by the trained tele-callers seeking information regarding COVID-19 tests and symptoms such as fever, cough, coryza, loss of taste and smell, breathlessness, hospitalisation and recovery at baseline, 1, 3 and 6 months. Their exposure risk was assessed by seeking information regarding contact with anyone who had tested positive for COVID-19 and the results of any COVID-19 test [RT-PCR or Rapid Antigen Test(RAT)], if conducted. Further, for those who tested positive for COVID-19, their outcome information was recorded. COVID-19 testing protocols for symptomatic infection or exposed contacts were as per prevalent ICMR (Indian Council of Medical Research) guidelines at the time of the study (all patients with influenza-like illness/severe acute respiratory illness/asymptomatic contacts of lab-confirmed cases between 5 and 14 days of exposure). 7
Data for 1379 patients who were diagnosed as SLE by the treating rheumatologist as per ACR 1997 and/or SLICC 2012 criteria was extracted and analysed from this entire cohort of 9212 AIRD patients. From the existing database, their baseline demographics, disease characteristics, current immunosuppressants (IS) and current dose of steroids prescribed at the time of recruitment, use of antihypertensive such as angiotensin-converting enzyme inhibitor (ACEi) or angiotensin receptor blockers (ARBs), antiplatelet agents and anticoagulants were noted. We also recorded the comorbidities such as diabetes and hypertension. Pre-existing lung diseases such as interstitial lung disease, asthma and chronic obstructive pulmonary disease were noted. The data collection was halted at the time of the decline of the 1st wave of COVID-19 in India.
Ethics approval
The current analysis is part of a study titled ‘Role of HCQ in COVID-19 pandemic in Rheumatologic disorders study’. All patients provided written consent for participation in the study and the proposal was approved by respective ethics committees (Manipal Hospitals −07/2020, St John’s Medical College, Bangalore - IERB No-127/2020, Chanre Rheumatology and Immunology Center & Research - CRICR/SN-130/099/2020).
Statistical methods
Descriptive statistics were reported as mean and SD for continuous variables, number and percentages for categorical variables. The association of COVID-19 and mortality with various characteristics of the study population was assessed using Chi-square/Fisher’s exact test and Student test-test. Bivariate and multivariable log binomial regression analysis was performed to assess the predictors for SARS CoV2 positivity and mortality, considering the study design of a prospective study (cohort study). Variables that had a p value less than 0.10 in the Bivariate analysis were subjected for multivariable analysis. Unadjusted (uRR) and adjusted (aRR) (for covariates) relative risk along with 95% C.I. were reported. p value less than 5% was considered statistically significant. Statistical analyses were carried out using SPSS version 25.0.
Results
A total of 1379 SLE patients from the total cohort of 9212 patients were analysed. Thirty-six (2.6%) patients developed lab confirmed COVID-19 during the study period, their mean duration of follow-up in the study was 5.52 ± 1.17 months. Only 1/36 (2.8%) patients who contracted the disease succumbed to COVID-19 while 10/1343 (0.7%) died due to non-COVID related factors. A comparison of epidemiologic factors and disease characteristics between lupus COVID and lupus Non-COVID is presented in Table 1. In the unadjusted model, male gender and the presence of diabetes conferred significant risk for acquiring COVID-19 (Table 1). Results remained significant in the multivariable analysis, even after adjusting for age. Adjusted for age, male gender (aRR 3.72, 95% C.I. 1.85–7.51) and the presence of diabetes (aRR 2.94, 95% C.I. 1.28–6.79) had the higher risk of acquiring COVID-19. There was no influence of disease subsets such as lupus nephritis (p = 0.79), neuropsychiatric (p = 0.72) and antiphospholipid positivity (p = 0.45) on the occurrence of COVID-19 (Table 1). Current immunosuppressants including steroids, mycophenolate, cyclophosphamide and rituximab did not influence the risk in developing COVID-19 (Table 2). Almost 88% of our cohort was using HCQ, however, it did not impact the occurrence of COVID-19. There were no hospitalisations related to uncontrolled disease activity during the period of this study.
Table 1.
Comparison of epidemiologic factors and disease characteristics between lupus COVID and lupus Non-COVID.
| Lupus COVID N = 36 |
Lupus non-COVID N = 1343 |
p value | Unadjusted relative risk (95% CI) | |
|---|---|---|---|---|
| Age (in years) (mean ± SD) | 37.89 ± 14.29 | 34.48 ± 12.08 | 0.095 | 1.02 (0.99–1.05) |
| Male | 10 (27.8%) | 115 (8.6%) | <0.001 | 3.85 (1.90–7.81) |
| Duration of illness in months (SD) | 209.36 ± 46.87 | 205.90 ± 54.74 | 0.708 | 0.99 (0.99–1.01) |
| Renal lupus* | 27 (81.8%) | 1037 (83.5%) | 0.790 | 1.12 (0.46–2.77) |
| NPSLE | 5 (13.81%) | 206 (16.1%) | 0.722 | 0.82 (0.32–2.13) |
| Lung disease (any) | 1 (2.8%) | 32 (2.4%) | 0.892 | 1.15 (0.16–8.11) |
| Diabetes mellitus | 6 (16.7%) | 77 (5.9%) | 0.020 | 3.06 (1.31–7.14) |
| Hypertension | 10 (27.8) | 247 (18.7%) | 0.172 | 1.64 (0.80–3.36) |
| Antiphospholipid antibody** | 7 (19.4%) | 201 (14.96%) | 0.45 | 1.3 (0.73–1.37) |
NPSLEs: Neuropsychiatric systemic lupus erythematosus.
*Renal lupus- biopsy proven lupus nephritis.
**Antiphospholipid antibody positivity was defined as positive test for one or more of: Lupus anticoagulant, anticardiolipin IgG/IgM (>40 GPL/MPL units, respectively)/ß 2 GPI IgG/IgM antibodies (>99th percentile in a standardised ELISA).
Table 2.
Comparison of current medications in lupus patients with and without COVID-19.
| Lupus COVID N = 36 |
Lupus no COVID N = 1343 |
p value | Unadjusted relative risk (95% CI) | ||
|---|---|---|---|---|---|
| Current GC | GC <7.5 mg/day | 16 (65.0%) | 590 (85.4%) | 0.089 | 2.00 (0.89–4.46) |
| GC≧7.5 mg/day | 19 (35.0%) | 753 (14.6%) | |||
| HCQ | 31 (86.1%) | 1181 (87.3%) | 0.692 | 1.20 (0.47–3.06) | |
| CYC | 1 (2.9%) | 30 (2.3%) | 0.562 | 0.80 (0.11–5.67) | |
| Tacrolimus | 5 (13.9%) | 177 (14.8%) | 0.932 | 0.96 (0.37–2.54) | |
| MMF | 12 (36.2%) | 400 (30.8%) | 0.592 | 0.83 (0.41–1.65) | |
| AZA | 4 (11.2%) | 226 (17.2%) | 0.339 | 0.60 (0.22–1.71) | |
| Rituximab | 2 (5.6%) | 73 (5.4%) | 0.975 | 0.97 (0.23–3.99) | |
MMF: Mycophenolate mofetil, AZA: Azathioprine, CYC: Cyclophosphamide, HCQ: Hydroxychloroquine, GC: Glucocorticoid.
Discussion
We envisaged this longitudinal prospective study early on during the COVID-19 pandemic to understand the risk factors associated with SARS-CoV-2 infection and its outcome. In our longitudinal follow-up of 1379 SLE patients during the first wave of COVID-19, 2.6% (36/1379) of our lupus cohort developed RT-PCR confirmed COVID-19. In the same time period, Karnataka and Kerala (together with a combined population of approximately 98.7 M) experienced 1.68 M COVID-19 cases which bring the incidence in the general population to 1.70%. Hence, in our cohort, SLE patients had a higher risk of COVID-19 compared to the general population. However, a retrospective analysis in Spain of over twenty thousand patients with AIRD, which included more than two thousand lupus patients, found no significant increase in the risk of COVID-19 compared to the reference population. 8
A higher morbidity and mortality due to COVID-19 has been reported as compared to the general population in SLE. 9 However, a propensity score matched analysis of 2140 lupus COVID-19 patients demonstrated a higher risk of hospitalisation, ICU admissions and mechanical ventilation, without a significant increase in mortality compared to the general population. 10 In our cohort, there was only one death [1/36(2.8%)] reported rendering the interpretation difficult. She was a 23 years old lady with class 5 lupus nephritis and prior pulmonary embolism and was currently on treatment with mycophenolate mofetil and anticoagulants.
At the beginning of the pandemic, several high-risk groups were identified for COVID-19. These included patients with diabetes, hypertension, cardiovascular disease and malignancy. 11 Similarly, we found male gender and diabetes to be significantly associated with the risk of SARS-CoV-2 infection.
In our cohort study, we did not find a significant influence of disease subsets, duration of illness, organ manifestations such as renal and neurological involvement or antiphospholipid antibody status on the risk of SARS-CoV-2 infection and mortality. Similarly, Zucchi et al. 12 from Italy evaluated 332 SLE patients during 1st COVID-19 wave and found no influence of organ system involvement.
We found no significant influence of the current use of low dose (<7.5 mg/day of prednisolone or equivalent) or the moderate-high dose of steroids (≥7.5 mg/day) on the risk of COVID-19. Gianfrancesco et al. evaluated 600 patients with AIRD which included 82 patients with SLE and found steroid use of >10 mg/day of prednisolone was associated with higher odds of hospitalisation (OR 2.05). 13 The same group followed 1606 SLE patients through March 2020 to June 2021, demonstrating consistently worse outcomes with steroid use across different dosages. 3 However, a French multicentre study that analysed the risk of various antirheumatic drugs on the risk of COVID-19 in 459 patients which included 193 lupus patients, found no significant influence of steroids on the risk of developing COVID-19 (OR 1.41, p = 0.51). 14
Further, we did not find any impact of immunosuppressive therapy on risk of COVID-19 in SLE patients. In a Belgian study of 225 lupus patients, immunosuppressives were not associated with the risk of SARS-CoV-2 infection or hospitalisation. 15
Our data reconfirmed that concomitant HCQ therapy does not alter the risk COVID-19 in lupus patients. Multiple studies across the globe have failed to demonstrate a significant reduction in the SARS-CoV-2 infection in SLE patients who are on long-term HCQ therapy.15–17 Furthermore, in a large population-based survey involving more than 26,000 patients of lupus in the UK, HCQ did not influence the mortality due to COVID-19. 18
The strengths of our study include a prospective collection of data from a well-defined cohort, a large sample size of more than 1300 SLE patients from specialized rheumatology centres, and the inclusion of only RT-PCR/RAT confirmed cases for the definition. Limitations include reporting bias as patients with lupus are intuitively more likely to test for COVID-19 compared to the general population which could have been the reason for increased incidence. Also, we could not accurately assess the lupus disease activity due to the use of teleconsultations/telephonic calls for follow-up data capture. Lupus disease activity/damage could have contributed risk of SARS-COV-2 infection and outcome. Further, the socio-demographic factors and personal protective measures may have had a major influence which has not been evaluated in our study.
Conclusion
Traditional risk factors such as diabetes and male gender rather than lupus disease subsets or IS including glucocorticoids and hydroxychloroquine influenced the risk of COVID-19 in our cohort. Our findings reinforce that traditional risk factors such as diabetes should be optimally controlled in lupus patients with COVID-19.
Footnotes
Author’s contribution: (1) Conception and design of the study- Vineeta Shobha, Chandrasekhara CS. (2) Analysis and interpretation of data- Abhishek Patil, Vineeta Shobha. (3) Data acquisition - All authors. (4) Drafted the work and revised it critically for important intellectual content – All authors. (5) Approved the version to be published- All authors. (6) Agree to be accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved- All authors
The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.
Funding: The author(s) disclosed receipt of the following financial support for the research, authorship, and/or publication of this article: This work was supported by the Karnataka Rheumatology Association
Ethical approval: Ethics approval was obtained from respective ethics committee (IERB No-127/2020,CRICR/SN-130/099/2020, JSSMC/IEC/180820/12NCT/2020–21).We hereby confirm that approval was provided for the study titled ‘Role of HCQ in COVID-19 pandemic in Rheumatological disorder’
ORCID iDs
Vineeta Shobha https://orcid.org/0000-0001-5271-0766
Chandrashekara S https://orcid.org/0000-0003-2661-9840
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