Clinical course, severity and mortality in a cohort of patients with COVID-19 with rheumatic diseases

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Abstract

The recent outbreak caused by a novel severe acute respiratory syndrome coronavirus 2 disease 2019 (COVID-19) has spread rapidly worldwide, and it has been declared a pandemic by the WHO.1 Elder people, male sex and some underlying comorbidities seem to be risk factors for morbidity and mortality, although an immunosuppressive status could favour the infection and the development of complications.2 However, as progress is made in the knowledge of the physiopathology of COVID-19, it has been observed that severe respiratory forms occur as a result of an hyperinflammatory status and an excessive production of cytokines.3 In this descriptive retrospective study, we aimed to characterise features related to severity and mortality in these patients and the influence of immune modulating drugs on the course of the infection. Patients were included from 25 February 2020 to 8 June 2020 with COVID-19 infection and rheumatic inflammatory diseases from Rheumatology Department of La Paz University Hospital. One hundred and twenty-two patients were included. One hundred (82.0%) were confirmed through nasopharyngeal swabs. Twenty-two patients (18.0%) exhibited compatible symptoms with compatible lung imaging and/or positive serology. Patients characteristics are shown in table 1. Table 1 Patients with COVID-19 characteristics Demographics Female sex, n (%) 80 (65.6) Caucasian ethnicity, n (%) 98 (80.3) Age (mean±SD), 58.3±16.3 Comorbidity, n (%) Hypertension 48 (39.3) Obesity 27 (23.6) Chronic pulmonary disease 20 (16.4) Cardiovascular disease 21 (17.2) Diabetes mellitus 14 (11.5) Active smokers 7 (5.6) Treatment with ACE/ARB, n (%) 34 (27.9) Rheumatic diseases, n (%) RA 41 (33.6) SpA 24 (19.7) SLE 13 (10.7) PsA 13 (10.7) Miscellaneous* 31 (25.4) Duration of rheumatic disease (mean±SD), years 12.2±9.3 Concomitant treatment, n (%) Hydroxychloroquine 26 (21.3) Glucocorticoids 48 (39.3) cDMARDs 80 (65.6) Methotrexate 54 (44.3) Sulfasalazine 19 (15.6) Leflunomide 13 (10.7) Azathioprine 2 (1.6) Cyclophosphamide 1 (0.8) bDMARDs/tsDMARDs 42 (34.4) Anti-TNF 28 (23.0) Rituximab 7 (5.7) Abatacept 3 (2.5) Tocilizumab 1 (0.8) Sarilumab† – Secukinumab 0 (0.0) Tofacitinib 1 (0.8) Baricitinib 1 (0.8) Symptoms, n (%) Dry, non-productive cough 84 (74.3) Fever 74 (64.3) Dyspnoea 59 (50.0) Arthromyalgia 42 (36.5) Anosmia/ageusia 41 (37.5) Nausea/vomiting 39 (33.9) Respiratory insufficiency, n (%) 54 (52.5) Non-invasive oxygen supplementation, n (%) 50 (41.0) Pneumonia, n (%) 67 (54.9) Time from disease onset to hospital admission, days (median, IQR) 7.2 (4.1–10.5) Hospital admission, n (%) 69 (56.6) ICU admission, n (%) 6 (4.9) Time of hospital admission, days (median, IQR) 8.0 (5.0–15.2) COVID-19 specific treatment, n (%) Hydroxychloroquine 76 (62.3) Azithromycin 50 (41.0) Glucocorticoids 8 (6.6) Lopinavir/ritonavir 6 (4.9) Anti-IL6 6 (4.9) Anti-IL1 2 (1.6) IVIg 3 (2.5) Recovered patients, n (%) 106 (87.6) Exitus, n (%) 14 (11.5) *See online supplementary table S1. †One patient on double blind clinical trial with sarilumab versus placebo. ARB, angiotensin-receptor blocker; bDMARDs, biological disease-modifying antirheumatic drugs; cDMARDs, conventional synthetic disease-modifying antirheumatic drugs; ICU, intensive care units; IL, interleukin; IVIg, intravenous immunoglobulins; PsA, psoriatic arthritis; RA, rheumatoid arthritis; SLE, systemic lupus erythematosus; SpA, spondyloarthritis; TNF, tumour necrosis factor; tsDMARDs, targeted synthetic disease-modifying antirheumatic drugs. 10.1136/annrheumdis-2020-218054.supp1 Supplementary data Variables associated with hospital admission in univariate analysis (table 2) were age (5-year intervals; OR 1.34, 95% CI 1.17-1.55), prednisone dose >5 mg/day (OR 2.55, 95% CI 1.07–5.59), chronic pulmonary disease (OR 5.34, 95% CI 1.47-19.35) and hypertension (OR 4.06, 95% CI 1.79-9.19). Independent risk factors for hospital admission were methotrexate (OR 2.06, 95% CI 1.01-5.29) and age (5-year intervals; OR 1.31, 95% CI 1.11-1.48). No association was found with hydroxychloroquine, other conventional disease-modifying antirheumatic drugs (cDMARDs), targeted synthetic disease-modifying antirheumatic drugs or biological disease-modifying antirheumatic drugs (bDMARDs) or laboratory parameters. Methotrexate treatment was not associated with age, sex, glucocorticoids or subtype of rheumatic disease. Table 2 Factors associated with hospital admission in patients with COVID-19 Variable Inpatients(n=69) Outpatients(n=53) P value Demographics Female sex, n (%) 42 (60.8) 37 (71.1) 0.25 Age (mean±SD) 63.9±15.6 50.5±14.1 <0.01 Comorbidity Hypertension 36 (52.1) 11 (21.1) 0.01 Obesity 25 (36.2) 17 (32.6) 0.58 Chronic pulmonary disease 17 (24.6) 3 (5.7) 0.01 Cardiovascular disease 15 (21.7) 5 (9.6) 0.08 Diabetes mellitus 11 (15.9) 3 (5.7) 0.09 Active smokers 4 (5.7) 3 (5.7) 1.00 Concomitant treatment, n (%) Hydroxychloroquine 13 (18.8) 12 (23.0) 0.62 Glucocorticoids 33 (47.8) 14 (26.9) 0.02 Low-dose prednisone (≤5 mg/day) 27 (39.1) 11 (20.7) 0.04 cDMARDs 47 (68.1) 32 (61.5) 0.43 Methotrexate 36 (52.1) 18 (34.6) 0.06 Leflunomide 6 (8.6) 7 (13.4) 0.11 Sulfasalazine 10 (14.4) 9 (17.3) 0.33 Azathioprine 1 (1.4) – – Cyclophosphamide 1 (1.4) – – bDMARDs/tsDMARDs 20 (28.9) 22 (42.3) 0.12 Anti-TNF 9 (13.0) 19 (36.5) 0.04 Rituximab 7 (10.1) – 0.01 Abatacept 2 (2.8) 1 (1.9) – Tocilizumab – 1 (1.9) – Sarilumab* – – – Secukinumab – – – Tofacitinib – 1 (1.9) 0.36 Baricitinib – 1 (1.9) 0.36 *One patient on double blind clinical trial with sarilumab versus placebo. bDMARDs, biological disease-modifying antirheumatic drugs; cDMARDs, conventional disease-modifying antirheumatic drugs; TNF, tumour necrosis factor; tsDMARDs, targeted synthetic disease-modifying antirheumatic drugs. Fourteen patients died (11.5%) due to respiratory failure. Nine patients were on cDMARDs (either in monotherapy or in combination), one was on bDMARD (rituximab) and four were taking only oral glucocorticoids. Hydroxychloroquine did not show differences in mortality. On univariate analysis, factors associated with mortality were age (OR 1.60, 95% CI 1.20-2.01), arterial hypertension (OR 12.17, 95% CI 2.58-57.38), pulmonary disease (OR 5.36, 95% CI 1.60-17.94) and prednisone dose >5 mg/day (OR 5.70, 95% CI 1.63-19.92). The recent outbreak of COVID-19 represents a source of concern for the management of patients with inflammatory rheumatic diseases. However, there are some reports that suggest that treatments typically used for rheumatic diseases might be effective against COVID-19.4 In our series, there was a high proportion of patients that needed hospital admission due to severity of infection (56.6%) compared with other cohorts, which may be explained by the higher prevalence of comorbidity, particularly hypertension, the higher use of glucocorticoids or a potential selection bias towards more severe cases.5 6 Interestingly, methotrexate was a risk factor for hospital admission, but not for mortality, while other cDMARDs did not show differences. Notably, only one of our patients on tocilizumab was infected while all of our infected patients on rituximab needed hospital admission and one died. Additionally, patients on glucocorticoids had worse survival (78.5% vs 34.2%, p<0.01; see online supplementary material). However, mortality rate in hospitalised patients (17.4%) was lower compared with general population in our hospital (20.7%).7 Our preliminary results suggest that COVID-19 does not have a major impact on mortality in patients with rheumatic disease. However, glucocorticoids seem to increase the risk of mortality, while methotrexate and rituximab may have an increased risk of hospital admission. These findings suggest differences in drug mechanism, which may influence COVID-19 course and emphasise the importance of further investigating the impact of immunosuppressive treatment.

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Clinical Characteristics of Coronavirus Disease 2019 in China

Wei-jie Guan, Zheng-yi Ni, Yu Hu … (2020)

Abstract Background Since December 2019, when coronavirus disease 2019 (Covid-19) emerged in Wuhan city and rapidly spread throughout China, data have been needed on the clinical characteristics of the affected patients. Methods We extracted data regarding 1099 patients with laboratory-confirmed Covid-19 from 552 hospitals in 30 provinces, autonomous regions, and municipalities in mainland China through January 29, 2020. The primary composite end point was admission to an intensive care unit (ICU), the use of mechanical ventilation, or death. Results The median age of the patients was 47 years; 41.9% of the patients were female. The primary composite end point occurred in 67 patients (6.1%), including 5.0% who were admitted to the ICU, 2.3% who underwent invasive mechanical ventilation, and 1.4% who died. Only 1.9% of the patients had a history of direct contact with wildlife. Among nonresidents of Wuhan, 72.3% had contact with residents of Wuhan, including 31.3% who had visited the city. The most common symptoms were fever (43.8% on admission and 88.7% during hospitalization) and cough (67.8%). Diarrhea was uncommon (3.8%). The median incubation period was 4 days (interquartile range, 2 to 7). On admission, ground-glass opacity was the most common radiologic finding on chest computed tomography (CT) (56.4%). No radiographic or CT abnormality was found in 157 of 877 patients (17.9%) with nonsevere disease and in 5 of 173 patients (2.9%) with severe disease. Lymphocytopenia was present in 83.2% of the patients on admission. Conclusions During the first 2 months of the current outbreak, Covid-19 spread rapidly throughout China and caused varying degrees of illness. Patients often presented without fever, and many did not have abnormal radiologic findings. (Funded by the National Health Commission of China and others.)

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Prevalence of comorbidities and its effects in patients infected with SARS-CoV-2: a systematic review and meta-analysis

Jing Yang, Ya Zheng, Xi Gou … (2020)

Highlights • COVID -19 cases are now confirmed in multiple countries. • Assessed the prevalence of comorbidities in infected patients. • Comorbidities are risk factors for severe compared with non-severe patients. • Help the health sector guide vulnerable populations and assess the risk of deterioration.

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Clinical course of COVID-19 in a series of patients with chronic arthritis treated with immunosuppressive targeted therapies

Sara Monti, Silvia Balduzzi, Paolo Delvino … (2020)

Different viral agents are associated with an increased risk of more severe disease course and respiratory complications in immunocompromised patients.1–3 The recent outbreak of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) disease 2019 (COVID-19) responsible for a severe acute respiratory syndrome (SARS) represents a source of concern for the management of patients with inflammatory rheumatic diseases. Lombardy is the region in Northern Italy with the highest incidence of COVID-19 cases, with more than 33 000 confirmed patients and 1250 requiring admission to the intensive care unit within 1 month. Since the first reports of COVID-19 cases in Italy, we have circulated a survey with a 2-week follow-up contact to patients with chronic arthritis treated with biological disease-modifying antirheumatic drugs (bDMARDs) or targeted synthetic disease-modifying antirheumatic drugs (tsDMARDs) followed up at our biological outpatient clinic in Pavia, Lombardy. The survey investigated the patients’ health conditions, the presence of contacts with subjects known to be affected by COVID-19 and management of the DMARDs during the first few weeks of pandemic. All patients had provided their informed consent for the use of personal and clinical data for scientific purposes, and no patient refused to participate. During the first month, we have collected information on 320 patients (female 68%, mean age 55±14 years) treated with bDMARDs or tsDMARDs (57% with rheumatoid arthritis, 43% with spondyloarthritis, 52% treated with tumour necrosis factor inhibitors, 40% with other bDMARDs and 8% with tsDMARDs). As shown in table 1, four were confirmed cases of COVID-19 identified through rhinopharyngeal swabs. Another four patients reported symptoms which were highly suggestive of COVID-19. Five additional patients with reported certain contacts remained asymptomatic at the end of the 2-week observation period. Table 1 Clinical characteristics of the patients with confirmed or suspected COVID-19 Confirmed COVID-19 Clinical picture highly suggestive of COVID-19 Contact with a known COVID-19 patient Number of patients 4 4 5 Age (years) (mean±SD) 58±5 56±8 54±12 Female, n (%) 4 (100) 3 (75) 4 (80) Comorbidities, n (%) Hypertension 1 (25) 2 (50) 1 (20) Diabetes 0 0 0 Cardiovascular disease 0 0 1 (20) Other 4 (100) 4 (100) 3 (60) Smoking, n (%) Active 1 (25) 0 0 Previous 2 (50) 3 (75) 1 (20) Rheumatological diagnosis RA, n (%) 3 (75) 3 (75) 5 (100) SpA/PA,* n (%) 1 (25) 1* (25) 0 Rheumatological treatment, n (%) bDMARD Adalimumab 0 0 1 (20) Etanercept 2 (50) 2 (50) 0 Abatacept 1 (25) 1 (25) 0 Tocilizumab 0 0 1 (20) tsDMARD Tofacitinib 1 (25) 0 1 (20) Baricitinib 0 1 (25) 2 (40) Concomitant csDMARD Methotrexate 2 (50) 1 (25) 3 (60) Leflunomide 1 (25) 0 1 (20) Sulfasalazine 0 1 (25) 0 Concomitant hydroxychloroquine 1 (25) 2 (50) 2 (40) Low-dose glucocorticoids* 2 (50) 2 (50) 2 (40) Known contact with COVID-19 0 1 (25) 5 (100) Symptoms, n (%) Fever 4 (100) 1 (25) 0 Non-productive cough 3 (75) 2 (50) 0 Sputum production 1 (25) 0 0 Rhinorrhea 2 (50) 1 (25) 0 Sore throat 0 0 0 Fatigue 4 (100) 2 (50) 0 Myalgia 2 (50) 1 (25) 0 Arthralgia 1 (25) 1 (25) 0 Anosmia/dysgeusia 3 (75) 3 (75) 0 Dyspnoea at rest 1 (25) 0 0 Dyspnoea on exertion 2 (50) 1 (25) 0 Headache 2 (50) 0 0 Diarrhoea 1 (25) 0 0 Nausea/vomiting 0 0 0 Chest X-ray performed 4 (100) 0† 0 Chest X-ray pathological findings 0 0 0 Hospital admission 1 (25) 0 0 *Glucocorticoids≤5 mg/day prednisone equivalent. †Subject to home quarantine. bDMARD, biological disease-modifying antirheumatic drug; COVID-19, coronavirus disease 2019; csDMARD, conventional synthetic disease-modifying antirheumatic drug; PA, psoriatic arthritis; RA, rheumatoid arthritis; SpA, spondyloarthritis; tsDMARD, targeted synthetic disease-modifying antirheumatic drug. All patients with confirmed COVID-19 received at least one antibiotic course, and the hospitalised patient also received antiviral therapy and hydroxychloroquine. Overall, five patients were on previous stable treatment with hydroxychloroquine. All patients with symptoms of infection temporarily withdrew the bDMARD or tsDMARD at the time of symptom onset. To date, there have been no significant relapses of the rheumatic disease. None of the patients with a confirmed diagnosis of COVID-19 or with a highly suggestive clinical picture developed severe respiratory complications or died. Only one patient, aged 65, required admission to hospital and low-flow oxygen supplementation for a few days. Our findings do not allow any conclusions on the incidence rate of SARS-CoV-2 infection in patients with rheumatic diseases, nor on the overall outcome of immunocompromised patients affected by COVID-19. A high level of vigilance and strict follow-up should be maintained on these patients, including the exclusion of superimposed infections. However, our preliminary experience shows that patients with chronic arthritis treated with bDMARDs or tsDMARDs do not seem to be at increased risk of respiratory or life-threatening complications from SARS-CoV-2 compared with the general population. These findings are not surprising as the severe respiratory complications caused by coronaviruses are thought to be driven by the aberrant inflammatory and cytokine response perpetuated by the host immune system.4 During different coronavirus outbreaks, such as SARS and Middle East respiratory syndrome, there has been no increased mortality reported in patients undergoing immunosuppression for organ transplantation, cancer or autoimmune diseases.3 5 Accordingly, among 700 patients admitted for severe COVID-19 at our hospital (a referral centre for SARS-CoV-2 infection) during last month, none was receiving bDMARDs or tsDMARDs. Although continuous surveillance of patients with rheumatic diseases receiving immunosuppressive drugs is warranted, these data can support rheumatologists for the management and counselling of their patients, avoiding the unjustifiable preventive withdrawal of DMARDs, which could lead to an increased risk of relapses and morbidity from the chronic rheumatological condition.