The outcome of COVID-19 in patients with autoimmune rheumatic diseases: Comparable to the general population or worse?

Since the beginning of the COVID-19 pandemic, patients with autoimmune rheumatic diseases (AIRDs) have been a focus of concern due to the underlying immune dysregulation and immunosuppressive drugs they are receiving. The data regarding the total effect of AIRDs and their treatment on COVID-19 course and outcome are currently inconclusive. Also, it is challenging, if not impossible, to dissect the impact of the underlying AIRDs from the effect of the immunosuppressive treatment and other comorbidities. Several factors associated with AIRDs could affect the COVID-19 course (Table 1). Severe COVID-19 course and complications of COVID-19 are generally caused by the hyperinflammatory immune response against SARS-CoV-2. Thus, the dysregulated immune system with a tendency to overreact could make AIRD patients more prone to negative COVID-19 outcomes. The type of AIRD, disease activity, and organ involvements are also important while analyzing the impact of AIRDs on the COVID-19 course.1, 2 In addition, classical comorbidities such as hypertension, obesity, and diabetes mellitus are generally more frequent among AIRD patients than the general population, and these comorbidities are associated with worse COVID-19 outcomes.3, 4 On the other hand, most AIRD patients are on chronic immunosuppressive therapies, which may limit the hyperinflammation before the cytokine storm commences. But also, the immunosuppressive treatment could lead to an increased risk for COVID-19 and the complications caused by SARS-CoV-2 itself rather than the host's immune system. Regarding immunosuppressive treatment, the duration of therapy, the type of drugs, and the dose of glucocorticoids are important factors that may differently affect the disease course.4-7 Lastly, the response to COVID-19 vaccines could be less efficient in AIRD patients due to immunosuppressive treatment or underlying immune dysregulation.7, 8 This may contribute to the more severe disease course in AIRD patients despite vaccination. Another important aspect about the pandemic's effects on care of AIRD patients is that the pandemic has caused interruptions in the routine follow-up of patients. Although telemedicine tools have been increasingly used in clinical practice, their efficacy is limited compared to in-person visits. George et al9 showed that stopping immunomodulatory treatment was more likely for patients followed up with telemedicine visits than those followed up with office visits. These may affect the adequate control of AIRDs during or after SARS-CoV-2 infections. Also, an effective collaboration between the internist who treats COVID-19 and the rheumatologist is of utmost importance for improving the outcome for both COVID-19 and AIRDs. Severely active disease and renal, cardiovascular, and pulmonary involvement may be associated with worse outcome Disease-specific factors may be associated with worse outcomes (such as erosive arthritis or seropositivity in rheumatoid arthritis). The efficiency of the vaccine response may decrease. Patients may be prone to hyperinflammatory COVID-19 complications. Generally associated with worse outcome Some drugs (such as anti-TNF agents) may be associated with a decreased hospitalization rate. Chronic immunosuppressive treatment may decrease the efficiency of the vaccine response. Some therapeutics may limit hyperinflammatory complications of COVID-19. Recently, Abdulnaby et al10 have compared COVID-19 outcomes between 66 patients with AIRDs and 64 without AIRDs. They failed to show significant differences between the two groups regarding COVID-19 outcome or severity. However, they observed a higher frequency of septic shock in AIRD patients, a longer duration of recovery in patients on glucocorticoids, and that hypertension was associated with more severe COVID-19.10 Although the outcome parameters seem similar, there were several significant differences between the AIRD and control groups regarding general features. For instance, male gender and smoking both of which have been associated with severe COVID-19 in most studies, were significantly more frequent among patients in the control group than AIRD patients. On the other hand, lung involvement was more common in the AIRD group. The negative effect coming from the AIRD and lung involvement in the AIRD group might have been balanced with a higher frequency of male gender and smoking in the control group. Another point is that the duration until recovery was longer in AIRD patients than in patients in the control group (10.5 days vs. 6 days; P < 0.001). However, treatment of COVID-19 significantly differed between the two groups. Around 40% of the control group patients (n = 27; 42.2%) received tocilizumab, while only 4 patients (6.3%) got tocilizumab treatment in the AIRD group. Tocilizumab, which is a strong anti-inflammatory biologic drug, might have decreased the duration till recovery in the control group. Furthermore, tocilizumab use had possibly affected the laboratory test results which were significantly different between AIRD patients and patients in the control group (i.e., higher ferritin, D-dimer, and C-reactive protein in AIRD patients). The reason for the significant difference between AIRD patients and controls regarding tocilizumab use rate could be the concomitant immunosuppressive therapy. Patients who were already on certain immunosuppressive drugs for AIRD might be less likely to be treated with tocilizumab due to concerns associated with the concomitant use of immunosuppressive agents. Septic shock was only observed in 7 AIRD patients in the whole cohort. However, this result should be evaluated carefully considering that the SARS-CoV-2 polymerase chain reaction was not performed in around 1/4 of patients in the AIRD group. Moreover, the pre-COVID-19 glucocorticoid dose and the AIRD disease activity are significant factors that might have caused tendency to this complication. The authors have failed to show significant differences between AIRD patients on glucocorticoids and those who were not receiving glucocorticoids, except the longer duration till recovery in the glucocorticoid group. It may be interesting to see the results between AIRD patients who were receiving ≥10 mg/d prednisone equivalent and patients who received lower doses of glucocorticoids. Having a rheumatic disease has been associated with worse COVID-19 outcomes in several studies.11-14 However, classical comorbidities such as obesity and cardiovascular diseases were also more frequent among patients with rheumatic diseases. And it is difficult to conclude that the negative effect on COVID-19 outcomes comes directly from the underlying rheumatic disease. In a systematic review and meta-analysis, Akiyama et al5 analyzed 62 observational studies, including 319 025 patients with autoimmune diseases, and demonstrated a slightly higher prevalence of COVID-19 in these patients than in the general population. They also investigated COVID-19 outcomes with the meta-analysis of 65 studies that included 2766 patients with autoimmune diseases. Among these patients, patients with AIRDs had the highest hospitalization and mortality rates. But it is essential to mention that studies on rheumatic diseases included more elderly patients and patients with comorbidities.5 Regarding treatment, they showed that using glucocorticoids, conventional synthetic disease-modifying anti-rheumatic drugs (csDMARDs), and combination therapies with biologic DMARDs were associated with an increased risk of negative COVID-19 outcomes.5 In the Global Rheumatology Alliance Physician Reported Registry, Strangfeld et al4 showed that COVID-19-related mortality was associated with rheumatic disease-specific factors such as moderate-high disease activity and specific drugs such as sulfasalazine and rituximab, along with known risk factors (male gender, older age, classical comorbidities). Rorat et al15 have recently compared the COVID-19 disease course between 185 patients with AIRDs and 8035 patients without AIRDs. The disease course was more severe in AIRD patients. However, pulmonary, cardiovascular, and chronic kidney diseases were more common among AIRD patients, and these patients were older than the patients without AIRDs. In most studies on COVID-19 outcomes in AIRD patients, mixed cohorts of patients with different AIRDs were included. This makes it challenging to analyze the individual effects of different AIRDs on the COVID-19 course. However, the number of studies focusing on specific AIRDs has been increasing. Bruera et al1 have recently reported that COVID-19 outcomes were worse in patients with systemic lupus erythematosus (SLE) compared to controls, even after adjustments for comorbidities. This finding suggests that negative outcomes are at least partially associated with SLE. They have also demonstrated that severe disease activity and glucocorticoids, mycophenolate mofetil, and tacrolimus in SLE treatment were other factors related to negative outcomes. It is worth mentioning that patients with severe disease activity usually receive more intensive immunosuppressive treatment, so negative COVID-19 outcomes may be due to both active disease and more intensive immunosuppressive AIRD therapy. Raiker et al16 compared COVID-19 outcome in 2135 SLE patients, and propensity score matched 2135 controls. They showed an increased risk of intensive care unit (ICU) admission, mechanic ventilation, and all-cause hospitalization in SLE patients than controls, although the mortality rates were comparable between the two groups.16 In a nationwide cross-sectional study including 125 119 patients, Bertoglio et al17 demonstrated that SLE patients had the highest risk for severe COVID-19 outcomes (adjusted for comorbidities) among all patients who were hospitalized with COVID-19 acute respiratory distress syndrome. Rheumatoid arthritis (RA) was also associated with severe COVID-19 in the large cohort study by England et al18 (33 886 RA patients and 33 886 matched non-RA controls). Figueroa-Parra et al19 analyzed COVID-19 outcome in 582 RA patients versus 2875 non-RA controls. They showed an increased risk for severe COVID-19 in RA patients and especially seropositivity (anticyclic citrullinated peptide or rheumatoid factor positivity), interstitial lung disease, and bone erosions were associated with this increased risk.19 Cordtz et al20 similarly depicted an increased risk of severe COVID-19 in RA patients both before and after vaccination in the Danish nationwide study, including 28 447 RA and 568 940 non-RA patients. There are several studies analyzing the differences in severe COVID-19 risk for different types of AIRDs. Bournia et al21 have recently investigated COVID-19 outcomes in patients with RA, ankylosing spondylitis (AS), psoriatic arthritis (PsA), SLE, and systemic sclerosis (SSc), compared to the general population. COVID-19 associated hospitalization rate was higher among RA, SLE, and SSc, while COVID-19 associated mortality was higher in RA patients than the general population. Also, Chevalier et al22 have analyzed COVID-19 outcomes in 1213 patients with AIRD. As specific AIRD types, sarcoidosis, vasculitis, and autoinflammatory diseases were associated with an increased risk of severe COVID-19 in the multivariate analysis. These results suggest that different AIRDs may introduce different levels of risk for severe COVID-19. It is also worth mentioning that some features of other specific AIRDs could make patients more prone to COVID-19-associated complications. For instance, patients with Behçet's disease or antiphospholipid syndrome (APLS) are more prone to thrombosis than patients with other AIRDs. This may cause a higher frequency of thrombotic COVID-19 complications in these patients. Interestingly, the frequency of thrombosis did not differ significantly in COVID-19 patients with APLS or Behçet's disease compared to the general population in previous studies.23-25 Regarding the treatment of AIRDs, glucocorticoids at a dose of ≥10 mg/d (prednisone equivalent), csDMARDs such as sulfasalazine, immunosuppressant drugs such as mycophenolate mofetil and tacrolimus, B cell depleting therapies such as rituximab and belimumab, and Janus kinase (JAK) inhibitors were the main drugs associated with worse COVID-19 outcomes.3, 4, 6, 26 On the other hand, several studies suggested that anti-tumor necrosis factor use was associated with a less severe COVID-19 outcome.5, 26-29 However, the results of different studies are conflicting regarding the effects of immunosuppressive drugs on COVID-19 severity. In the study by Bruera et al1 including 687 SLE patients and 6870 controls, negative effects of COVID-19 were associated with glucocorticoids, methotrexate, leflunomide, cyclosporine, and tacrolimus; but not with azathioprine, cyclophosphamide, or rituximab. Furthermore, belimumab had a protective effect against severe COVID-19.1 In contrast, Singh et al30 reported that rituximab conferred 3–5 fold higher odds of intensive care unit admission and mechanic ventilation in RA, in a national cohort study including 69 549 RA patients. The effect of the underlying AIRD, other comorbidities, and concomitant therapeutics make it challenging to dissect the effect of a single drug on COVID-19 outcome. Thus, the results regarding the risks conferred to different anti-rheumatic therapeutics should be evaluated with caution considering other factors that may contribute to the risk. Vaccination against COVID-19 has substantially changed the prevalence of severe infection both in the general population and AIRD patients. Most recently, Kharouf et al3 have analyzed the COVID-19 outcomes in AIRD patients considering the effect of different outbreaks and the vaccination campaigns. They showed that older age, AIRD-related lung involvement, diabetes mellitus, and treatment with glucocorticoids, mycophenolate mofetil, and JAK inhibitors were associated with a higher hospitalization rate in AIRD patients. And, older age, renal and vascular involvement by AIRD, congestive heart failure, and glucocorticoid or B cell depleting therapies were significantly associated with mortality. However, the mortality rate was lower in the outbreak caused by the delta variant compared to the previous outbreaks. The authors stated that vaccination campaigns were probably the main reason for this difference. Along the same lines as this study, Kawano et al31 have demonstrated a decreased proportion of AIRD patients with severe COVID-19 since early in the pandemic to the most recent periods. They also emphasized that this decrease was due to vaccination, along with advances in the diagnosis and management of COVID-19. An important consideration is that patients with AIRDs may not exert an efficient vaccine response both due to their underlying immune dysregulation stemming from AIRD and chronic immunosuppressive AIRD treatment. This keeps AIRD patients at the focus of concern regarding severe COVID-19 despite effective vaccination policies. In the study by Hoff et al,8 the use of immunosuppressive therapies was associated with higher odds of vaccine breakthrough in SARS-CoV-2 infections in patients with rheumatic diseases. Petri et al7 have recently shown that COVID-19 vaccine immunoglobulin G (IgG) levels were significantly lower in SLE patients than controls, regardless of their background immunosuppressive treatment. But also, mycophenolate mofetil, tacrolimus, and belimumab use significantly reduced vaccine IgG response. The treatment of COVID-19 in AIRD patients is also an area of debate. Qian et al have recently demonstrated that outpatient therapy with anti-viral drugs or monoclonal anti-SARS-CoV-2 antibodies were associated with lower odds of severe COVID-19 in AIRD patients.32 According to the recently published points to consider in the European Reference Network on Rare and Complex Connective Tissue and Musculoskeletal Diseases (ERN ReCONNET), treatment with anti-virals or a combination of anti-virals and monoclonal antibodies can be considered in AIRD patients during mild to moderate COVID-19.33 In conclusion, studies generally suggest that AIRDs could be associated with negative COVID-19 outcomes depending on the type and activity of the AIRD, the presence of classical comorbidities, and immunosuppressive treatment. Considering anti-viral drugs and/or monoclonal anti-SARS-CoV2 antibodies could improve the outcomes in patients with AIRDs. Batu ED wrote the first draft of the manuscript. Erden A critically revised the text. Both authors read and approved the final manuscript. None. This work did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors. The authors declare they have no conflicts of interest. The authors confirm that the data supporting the findings of this study are available within the article.