INTRODUCTION

Since 12 March 2020, the WHO has declared the outbreak of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) disease 2019 (COVID-19) a pandemic. The main symptoms of respiratory infection include fever and cough.^{1 2} Eighty-one per cent of the patients show a mild course, 14% are seriously affected and 5% of the patients are critically ill.² On 25 April 2020, the Johns Hopkins University reported 2 954 106 confirmed cases worldwide.³ The mortality rate at that time point was 6.95% (n=205 398).³ The presence and the number of comorbidities (eg, arterial hypertension (AHT), coronary heart disease), age (immunosenescence) and lifestyle factors (eg, smoking) appear to have deteriorating effects on the course of the infection.² In this situation, patients with inflammatory rheumatic diseases (IRD) may face a particular risk as their disease, especially when clinically active, and their immunomodulatory treatment may impact the course of COVID-19 infection. However, firm knowledge of the course of SARS-CoV-2 infection in patients with IRD is missing, and therefore, evidence-based recommendations for the management of COVID-19 in patients with rheumatic disorders and antirheumatic treatments are lacking.

The German Society for Rheumatology (DGRh) developed at an early-stage first concise recommendations for the management of patients with IRD during the COVID-19 pandemic.⁴ Interruption or reduction of immunomodulators is not recommended as this might result in relapses, which would increase the risk of infections, and in addition may lead to the necessity of an even riskier treatment (ie, additional glucocorticoids (GC)).⁵ In a cross-sectional multicentric study, patients with IRD were asked anonymously in the first weeks of the pandemic on their opinion of their immunomodulating therapy. Over 90% of the patients followed the recommendation of the rheumatologists to continue the antirheumatic therapy, and only a small percentage of patients terminated the therapy on their own.⁶ Whether first recommendations based on responsible care and expert’s opinion is indeed the best option for the management of patients with IRD urgently needs to be validated.

Incidence and course of COVID-19, including lethal outcomes, vary considerably in different cohorts according to pre-existing conditions and healthcare systems. Investigation of special disease groups may contribute to a better understanding of the role of the immune system regarding the risk to get infected or to develop a more severe course of COVID-19. Therefore, patients with IRD, who are treated with different types, combinations and dosages of immunomodulatory therapies represent an interesting population to collect data regarding SARS-CoV-2 infection.

Registries with a large number of case reports are required to answer the questions, whether antirheumatic drugs increase or decrease the risk for a severe course of SARS-CoV-2 infection. As necessary data cannot be extracted from clinical charts or health insurance records, the DGRh and the Justus-Liebig University Giessen decided to establish a web-based registry, which allows a rapid and timely collection of IRD cases with confirmed SARS-CoV-2 infections in Germany to analyse the clinical course of SARS-CoV-2 infections in patients with IRD and to develop guidance for the management of patients with IRD during the COVID-19 pandemic.

RESULTS

Between 30 March (first patient in) and 25 April, 104 patients with IRD and a SARS-CoV-2 infection were documented in the database by rheumatologists. The development of recruitment during the first 4 weeks is depicted in figure 1. To date, 138 rheumatologists have registered to take part in the project and 71 have already documented at least one patient. Entering a patient case took on average 5 min. Each data entry is logged by a time stamp allowing calculations of the time used for the documentation procedure up to the time required for single items in the survey.

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Figure 1

Cumulative number of cases which have been reported until 25 April 2020.

The 104 patients reported so far included 40 males, 63 females and 1 diverse, the age range was between 23 and 87 years (median age 56 years; figure 2A). Most patients with COVID-19 (24%) were between 50 and 59 years old. About two-thirds of the patients were reported from private practices, 32% from hospitals and 6% of the patients had a telephone interview by a rheumatologist at the coordination site. In relation to population numbers, most cases have been notified from Hamburg, Baden-Württemberg, Berlin, North Rhine-Westphalia and Rhineland Palatinate (table 1). The presence of antibodies was not included in our registry, which is comparable to the EULAR and GRA COVID-19 database.

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Figure 2

Overview of the reported data. (A) Age of the reported patients (in %): 4% of the patients were aged between 20 and 29 years, 12% between 30 and 39 years, 18% between 40 and 49 years, 24% between 50 and 59 years, 20% between 60 and 69 years, 11% between 70 and 79 and 12% between 80 and 89 years. (B) Distribution of inflammatory rheumatic diseases in the database (in %): 45% of the reported patients suffered from RA; 18% from PsA; 10% from AS; 7% from other inflammatory diseases (eg, gout, fever syndromes); 4% each from SSc, SLE, GPA and PMR; 2% from EA; 1% each from PM/DM/IBM, Sjö, MCTD, GCA and BD. (C) Distribution of antirheumatic drugs reported in the database (in %): 36% were with GC 6 DMARDs, 34% with csDMARDs, 24% with bDMARDs, 18% with csDMARDs and bDMARDs, 8% had no therapy, 7% received other medication, 7% were treated with glucocorticosteroids, 2% with MMF and 1% each with NSAIDs and tsDMARDs. (D) Distribution of comorbidities (in %): 41% had no comorbidities, 37% suffered from AHT, 15% from other relevant comorbidities, 13% from CVD, 9% each from bronchial asthma and DM, 8% each from COPD and CRF, 6% from OSP, 5% from cancer/history of cancer, 2% from ILD, 1% from PAH and 15% from other relevant comorbidities, 30% had more than two comorbidities. AHT, arterial hypertension; AS, ankylosing spondylitis; bDMARD, biological disease-modifying antirheumatic drugs; Comorb, comorbidities; COPD, chronic obstructive pulmonary disease; CRF, chronic renal failure; CVD, cardiovascular diseases; csDMARD, conventional synthetic disease-modifying antirheumatic drugs; DM, diabetes mellitus; DMARDs, disease-modifying antirheumatic drugs; EA, enteropathic arthritis; EGPA, eosinophilic granulomatosis with polyangiitis; GCA, giant cell arteritis; GPA, granulomatosis with polyangiitis; ILD, interstitial lung disease; MCTD, mixed connective tissue disease; MMF, mycophenolate-mofetil; NSAIDs, nonsteroidal anti-inflammatory drugs; OSP, osteoporosis; PAH, pulmonary arterial hypertension; PM/DM/IBM, polymyositis, dermatomyositis, inclusion body myositis; PMR, polymyalgia rheumatica; PsA, psoriatic arthritis; RA, rheumatoid arthritis; Sjö, Sjögren-syndrome; SSc, systemic sclerosis; SLE, systemic lupus erythematosus; tsDMARDs, targeted synthetic disease-modifying antirheumatic drugs.

Regarding diagnosis, 45% of the patients with IRD had rheumatoid arthritis, 18% were diagnosed with psoriatic arthritis, 10% with ankylosing spondylitis and 5% systemic sclerosis. The proportion of other IRD was below 5% (figure 2B).

Prior to the SARS-CoV-infection, 34% of the patients were receiving conventional synthetic disease-modifying antirheumatic drugs (csDMARDs), 42% were on bDMARDs, 24% in monotherapy and 18% in combination with csDMARDs. Forty-three per cent were treated with GC, 7% without any other immunomodulation and 8% of the patients did not receive DMARDs or GC (figure 2C).

In 59% of the cases, relevant comorbidities were reported. This included AHT in 37% of the patients, other relevant comorbidities in 15%, cardiovascular diseases (CVD) in 13%, 9% each suffered from bronchial asthma and diabetes, 8% each from chronic obstructive pulmonary disease and chronic renal failure, 6% from osteoporosis, 5% from cancer/history of cancer, 2% from interstitial lung disease, 1% from pulmonary arterial hypertension and 30% had more than two comorbidities (figure 2D). In 41% of the cases, no relevant comorbidities were reported.

Thirty-nine per cent of the patients had been vaccinated against seasonal influenza, 26% against pneumococci and 22% against both. Ten per cent of the documented patients were smokers, 1% were using e-cigarettes and 8% of the patients were drinking alcohol on a regular basis.

The most common reported symptoms of COVID-19 included cough (69%), fever (59%), fatigue (42%), headache (36%), myalgia (33%), dyspnea (32%), loss of odour (26%) or taste (25%), rhinitis (23%), loss of appetite (16%), vertigo (15%), diarrhoea (15%), expectoration (13%), other relevant symptoms (13%), abdominal pain (3%) and vomiting (2%) (figure 3A). Most of the patients (86%) had more than two symptoms, and 7% of the patients were reported as asymptomatic.

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Figure 3

Symptoms and courses of COVID-19 infection (in %). (A) Distribution of the symptoms of COVID-19 infection (in%): 86% of the affected patients had more than two symptoms, 69% reported cough, 59% fever, 42% fatigue, 36% headache, 33% myalgia, 32% dyspnea, 26% loss of odour, 25% loss of taste, 23% rhinitis, 16% loss of appetite, 15% vertigo, 15% diarrhoea, 13% expectoration, 13% other symptoms, 7% had no symptoms, 3% abdominal pain and 2% vomit. (B) Distribution of the course of COVID-19 infection (in%): 60% of the patients already recovered, 32% of the patients needed to be hospitalised, 22% of the patients were treated with oxygen (5% non-invasive ventilation (NIV), 8% invasive ventilation (IV)). Six deadly courses were already reported.

One-third (32%) of the patients was hospitalised, in 70% (23/33) of these cases, oxygen supply was necessary, 15% (5/33) received non-invasive and 24% (8/33) invasive ventilation. Unfortunately, six patients (6%) died in the context of COVID-19 (figure 3B), three male and three female patients (table 2). The median age in this group was 71 years (range 59–80 years), the median BMI 27.8 kg/m² (range 23.9–40.6 kg/m² ). All patients had at least AHT and/or other CVD (table 2). All deceased patients needed to be ventilated invasively. Five of the six patients were treated with low-dose GC (≤7.5 mg/day), which was not interrupted due to the infection in four cases. Only two of eight patients recovered after invasive ventilation.

Hospitalised patients were older than non-hospitalised patients (median age 69 vs 52 years). Even though women represented 62% of all registered patients, the hospitalisation rate was equal in both genders (48% male vs 52% female). More hospitalised patients were on GC (64% vs 34%), but less were treated with bDMARD (33% vs 48%). In addition, more comorbidities (>2) were documented in hospitalised patients (48% vs 21%, figure 4).

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Figure 4

Distribution between hospitalised and non-hospitalised patients.

Median age in group of hospitalised patients (HOSP) was 69 years and in non-hospitalised (NON-HOSP) was 52 years. More male patients were hospitalised (48%) compared to NON-HOSP (34%). HOSP were treated in 64% of the cases with GC, NON-HOSP in 34%. Thirty-three per cent of HOSP received bDMARDs compared to 48% of NON-HOSP. In HOSP, more comorbidities were observed (48%) compared to NON-HOSP (21%). bDMARD, biological disease-modifying antirheumatic drugs; Comorb., comorbidities; GC, glucocorticosteroids.

At the last rheumatological visit, 37% (38/104) of the patients were in remission, 17% (18/104) patients were reported to have low disease activity, 13% (13/104) moderate and 2% (2/104) high disease activity. In 29% (30/104), disease activity was not reported. Interestingly, the two cases with reported high disease activity developed a severe course of COVID-19 leading to hospitalisation. Comparing remission (33% vs 38%) and moderate (9% vs 14%) disease activity, the proportion was similar in the hospitalised versus non-hospitalised groups, and different in patients with low disease activity (27% vs 13%).

DISCUSSION

Patients affected by IRD are at an increased overall risk of infection compared to the general population.^8–10 However, the infection risk varies and is highly dependent on the type and activity of the autoimmune disease, on co-morbidities and on the intensity of the immunosuppressive/immunomodulatory treatment.^{8 11} Most patients with IRD are treated with GC, csDMARDs, bDMARDs and tsDMARDs on a regular basis. Especially, GC increase the risk of serious infection in a dose-dependent manner. Moreover, treatment with DMARDs can be associated with infectious complications. Most frequently, these are of bacterial origin,¹² but also certain viral infections like Herpes zoster may complicate the course of many antirheumatic therapies.¹³ Treatment with tumour necrosis factor (TNF) inhibitors is associated with an increased risk of serious infections at the beginning of treatment, but when effective, the risk decreases due to better functional capacity and decreased use of GC.¹⁴

Currently, there is no evidence, whether and to what extent patients with IRD are at an increased risk for COVID-19 and if antirheumatic treatment, especially GC and DMARDs, are harmful to patients in the context of COVID-19. Interestingly, some of the antirheumatic drugs such as hydroxychloroquine,^{15 16} anakinra and interleukin 6 inhibitors^{17 18} have been discussed to have a beneficial role in the course of SARS-CoV-2 infection, whereas others may exert deleterious effects similar to that recently observed in rituximab-treated patients.^{19 20} Data from the global rheumatology alliance physician-reported registry indicate that GC exposure of ≥10 mg/day is associated with higher ORs of hospitalisation.²¹

This is the first report of a cross-sectional study of patients with IRD and COVID-19 in Germany. The distribution of cases within the 16 federal states of Germany is consistent with the validated infection rates in the general German population that have been electronically reported to the Robert Koch Institute (table 1). Of all patients in our database, more women were affected by COVID-19 (62% female/38% male, what had to be expected, since most IRD show a considerable preponderance of females (~78%).²² In our cohort, there was a slight relative preponderance of male patients with IRD suffering from severe COVID-19, which is consistent with data from the Chinese general population.² The proportion of male patients with IRD was even considerably higher in our register among those who needed to be hospitalised, in which both genders were represented nearly equally (52% female/48% male, figure 4). This was not as clear in the global register, in which the distribution for hospitalised patients was 67% females vs 33% males and 74% vs 36% for non-hospitalised patients, respectively.²¹ These findings argue that—as in the general population—also in IRD, male patients tend to develop COVID-19 more than female patients²³ and might be at risk for a more severe course of COVID-19.²²

With respect to infections of the airways, TNF-α is discussed to mediate pulmonary inflammation in viral pneumonia.²⁴ Of note, TNF-α inhibition might inherit positive effects on symptoms and severity of virus-specific lung immunopathology, especially the inflammatory burst that finally damages the lungs.²⁵ In the RABBIT registry (German register for the long-term observation of therapy with biologics in adult patients with rheumatoid arthritis), TNF-inhibitors seemed to be beneficial for the course of severe infections by lowering the risk of sepsis and fatal outcome.¹⁴ In the global registry, anti-TNF treatment was associated with a decreased hospitalisation rate.²¹

In our case series, 24 patients (23%) were treated with TNF-α-inhibitors, and none of these needed oxygen treatments. Conversely, hospitalised patients tended to be treated predominantly with GC and/or csDMARDs, and 33% of them have been treated with bDMARDs compared to 48% in the non-hospitalised group. However, at present, the use of bDMARDs other than TNF-inhibition is too scarce to draw conclusions regarding risks or benefits of individual biologics, but with growing numbers of patients entered, we are confident in being able to do so in the near future.

Taken together, as a first result of our project, it could be shown that establishing an online-registry of patients with IRD and COVID-19 is feasible in short time and allows for rapid collection of possibly relevant data in the context of the SARS-CoV-2 pandemic. As in the general population, also in our study, male gender might be a potential risk factor for COVID-19 in patients with IRD, and as in the global register, treatment with GC seemed to be a disease-related risk factor in patients with IRD. With recruitment of more patients in the near future the trend of lower hospitalisation rates in patients with IRD treated with bDMARDs compared to those treated with csDMARDs will be further investigated. It is also worthwhile to compare data from Germany with those from other countries in and outside the European Union.