The protective effect of tumor necrosis factor-alpha inhibitors in COVID-19 in patients with inflammatory rheumatic diseases compared to the general population—A comparison of two German registries

Objectives To investigate, whether inflammatory rheumatic diseases (IRD) inpatients are at higher risk to develop a severe course of SARS-CoV-2 infections compared to the general population, data from the German COVID-19 registry for IRD patients and data from the Lean European Survey on SARS-CoV-2 (LEOSS) infected patients covering inpatients from the general population with SARS-CoV-2 infections were compared. Methods 4310 (LEOSS registry) and 1139 cases (IRD registry) were collected in general. Data were matched for age and gender. From both registries, 732 matched inpatients (LEOSS registry: n = 366 and IRD registry: n = 366) were included for analyses in total. Results Regarding the COVID-19 associated lethality, no significant difference between both registries was observed. Age > 65°years, chronic obstructive pulmonary disease, diabetes mellitus, rheumatoid arthritis, spondyloarthritis and the use of rituximab were associated with more severe courses of COVID-19. Female gender and the use of tumor necrosis factor-alpha inhibitors (TNF-I) were associated with a better outcome of COVID-19. Conclusion Inflammatory rheumatic diseases (IRD) patients have the same risk factors for severe COVID-19 regarding comorbidities compared to the general population without any immune-mediated disease or immunomodulation. The use of rituximab was associated with an increased risk for severe COVID-19. On the other hand, the use of TNF-I was associated with less severe COVID-19 compared to the general population, which might indicate a protective effect of TNF-I against severe COVID-19 disease.


Introduction
In December 2019, the first cases of patients with unexplained pneumonia were reported in Wuhan, China (1), which was identified in January 2020 as an infection with SARS-CoV-2.
At the same time, first cases of COVID-19 were reported in Germany (2).Since March 2020, a global pandemic SARS-CoV-2 has been declared (2).The highest fatality rate was observed in elderly and multi-morbid persons (3).Patients with autoimmune disease were expected to harbour an increased risk for severe COVID-19, especially under the treatment with glucocorticoids (4,5).In addition, disease activity of inflammatory rheumatic diseases (IRD) was associated with more severe COVID-19 compared to patients with sustained remission (6).Further, IRD patients under treatment with rituximab revealed a poor outcome of COVID-19 (6)(7)(8)(9).For some patient groups (e.g., patients with oncological morbidities), a worse outcome of COVID-19 has been described compared to non-pre-diseased patients (10).Some data suggested an increased risk for IRD-patients to develop severe COVID-19, such as COVID-19 related pneumonia, compared to the general population (11,12).Especially in patients with rheumatoid arthritis and systemic vasculitis, a higher risk for severe COVID-19 could be observed (12).As disease activity of IRD plays a crucial role regarding COVID-19, severity and different healthcare systems might have an influence on this aspect.The aim of this study was to investigate whether inpatients with IRD are at higher risk to poor outcomes of COVID-19 compared to the general population in Germany.In addition, the question was whether IRD could be considered as a comorbidity increasing the risk for severe COVID-19 and if so, whether specific types of disease-modifying antirheumatic drugs (DMARD) were contributing factors.

Materials and methods
Data from the German COVID-19 registry for patients with IRD 1 and data from the Lean European Open Survey on SARS-CoV-2 infected patients (LEOSS registry) 2 obtained between March 2020 until January 2021 were analysed.Patients with IRD and SARS-CoV-2 infection were included in the ongoing IRD registry by their rheumatologists (13).The LEOSS cohort includes cases of SARS-CoV-2 infections in the general German population (14).Here data were entered by treating physicians, study nurses and other medical staff.In both registries, participating centres included both academic and non-academic clinics throughout Germany.
Data and missing values of patients with immune-mediated inflammatory diseases, cancer, a history of cancer, organ transplantation or immunomodulatory/immunosuppressive treatment (including glucocorticoids) were excluded for further analyses from both cohorts due to the known poorer outcomes of patients with SARS-CoV-2 infection (details see Figure 1).As in LEOSS, mainly COVID-19 inpatients were reported, our analysis focussed on COVID-19 inpatients only from both registries.
For comparison, age-matching and gender-matching were used, as these two variables have been shown to strongly impact on the course of COVID-19.For age and gender a 1:1 matching was performed.
The respective statistical significance level of group differences between both registries (see Tables 1(5) were calculated using the Mann-Whitney U test (scipy.stats.mannwhitneyu)for continuous variables as well as the Chi-Square test (scipy.stats.chi2_contingency)for categorical variables.P-values <0.05 were considered significant.
Univariate ordinal logistic regression was used to assess the individual association between the COVID-19 severity outcome (dependent variable) and the respective independent variable (Figure 1A).Multivariate ordinal logistic regression was used to assess the independent associations between the COVID-19 severity outcome and all independent variables (n = 23) considered in the analysis (Figure 1B).Results were reported as odd ratios (OR) including their respective 95% confidence intervals (CI).P-values were reported to describe the significance of the respective independent variable's influence on the COVID-19 severity outcome.P-values <0.05 were considered significant (marked bold and colored blue, see Figure 2).
In order to reduce model complexity, the obtained multivariate ordinal logistic regression model was iteratively reduced by pruning the independent variable exhibiting lowest significance and re-evaluating the reduced model.This backward elimination procedure was repeated until all remaining independent variables exhibited p-values <0.1.This threshold was set to retain potentially confounding variables with a strong influence on the model.Only p-values <0.05 were considered significant (marked bold and colored blue, see Figure 2).

Baseline characteristics
From March 2020 to January 2021, 4310 cases (LEOSS registry) and 1139 cases (IRD registry) of SARS-COV-2 infection were reported.After performing the exclusion criteria and focusing on COVID-19 inpatients, matched pairs by age and gender were developed, consequently 732 patients (LEOSS registry: n = 366 and IRD registry: n = 366) were subsequently available for analysis.
Frontiers in Medicine 05 frontiersin.orgMultivariate ordinal logistic regression (excluding body mass index) revealed a significant increased risk for severe COVID-19 in older patients (age > 65 years: OR of 1.5, 95% CI 1.1 to 2.2), patients with chronic obstructive pulmonary disease (OR of 2.3; 95% CI 1.4 to 3.7) or patients treated with rituximab (OR of 2.6; 95% CI 1.3 to 5.1) (see Figure 2B).On the other hand, female gender was associated with lower risk for severe COVID-19 (OR of 0.5; 95% CI 0.4 to 0.7).Although univariate logistic regression model showed an increased association with severe COVID-19 in the case of moderate/high disease activity, this was not statistically confirmed in the multivariate ordinal logistic regression (OR of 1.1, 95% CI 0.8 to 1.7).
An equivalent result was observed for the multivariate model (details see Figure 3B).

Discussion
The aim of this study was to evaluate whether IRD inpatients harbour a higher risk for a poor outcome of SARS-CoV-2 infections compared to the general population and to add evidence whether immunomodulatory treatment has an impact on the outcome of COVID-19.
For both registries, arterial hypertension was shown to be the most common comorbidity in patients with COVID-19 infection (IRD registry: 53.8% and LEOSS registry: 54.4%).A previous published study showed a lower rate of arterial hypertension (33%) in IRD-patients (4).In our study the comorbidity arterial hypertension had an association with hospitalization.Furthermore, 27.7% of non-hospitalized IRD patients had arterial hypertension compared to 43.6% of the hospitalized ones without invasive and 61.5% of the hospitalized ones with invasive ventilation.Additionally, it should be noted that chronic kidney disease or interstitial lung disease were more frequently detected as comorbidities in IRD patients.Both, chronic kidney disease (odds ratio 1.8) and interstitial lung disease (odds ratio 2.0) were associated with a worse outcome of COVID-19 as individual parameter, although no increased mortality was demonstrated for the IRD patients.Furthermore, 7.1% of patients in the IRD registry smoked compared to 5.5% of patients in the LEOSS registry.The prevalence of smoking in both registries is lower than the smoking prevalence in Germany (2019: 23.8%) (17).A similar result can be shown for the harmful use of alcohol (Germany 2019: 3.1%; IRD registry: 2.7% and LEOSS registry: 0%) (17).
For COVID-19 related death, no significant differences were observed in our cohorts, although IRD patients were significantly more frequently treated with oxygen administration (IRD registry: 72.1% and LEOSS: 51.6%) and non-invasive ventilation (IRD registry: 11.5% and LEOSS: 1.1%) compared to the LEOSS cohort.
This study confirmed known risk factors such as age, male gender in both cohorts.Regarding immunomodulatory therapies rituximab was a significant risk factor for a severe course and poor outcome of COVID-19 in IRD patients, whereas the use of TNF-I was associated with a significantly better outcome in IRD patients, even when compared to the general population without any immune-mediated disease or immunomodulatory treatment.This is an important finding of our analysis, as most of the studies investigating the impact of TNF-I were performed only in IRD patients without employing any comparison to the general population/control group (6,18,19).Although the mechanism of SARS-CoV-2 associated hyperinflammation is not fully understood, it is already known that increased TNF concentration in the serum is associated with COVID-19 related organ damage and worse outcome (20).Therefore, blocking of TNF might inhibit COVID-19 related organ damage.A case series already reported beneficial effects of TNF-I in the context of COVID-19 (21) and further studies are ongoing investigating the association of TNF-I and COVID-19 related outcome (22).Reports from the early phase of the pandemic from Wuhan (China) and Boston (USA) reported significant higher risk for severe COVID-19 in IRD patients compared to non-IRD patients, although there was no significant higher rate of death (23,24).Our data are in Results of the univariate (A) and multivariate regression (B,C) sub-analysis for the IRD cohort on the outcome of COVID-19 infection using the data of the IRD registry (significant variable were marked bold and colored blue.LEOSS Registry, Lean European Open Survey on SARS-CoV-2; BMI, body mass index; COPD, Chronic obstructive pulmonary disease; ILD, interstitial lung disease; IRD, inflammatory rheumatic diseases; DSA, disease activity; bDMARD, biological disease-modifying antirheumatic drugs; csDMARD, conventional synthetic disease-modifying antirheumatic drug; TNF inhibitors, tumor necrosis factor-alpha inhibitors).
accordance with these data, as the COVID-19 related lethality was similar in both registries.

Strengths and limitations
The strength of our study is the collaboration of two large nationwide registries.Compared to previous studies, data of our study derives from one country with patients treated within the same healthcare system.In addition, until December 2021 (the time period taken for this analysis) no COVID-19 vaccines were available, ruling out the influence of vaccination.To our knowledge, this is the largest study comparing IRD patients to the general population without any immune-mediated diseases, and without any immunomodulatory treatment with detailed clinical information.This allows proper estimation of the role or type of IRD and of immunomodulatory treatments in the context of COVID-19.As the data derived from a phase of the pandemic without any available antiviral treatment, there were no differences in specific COVID-19 treatments.
Limitations of this study include the risk of reporting bias because the registries used convenience sampling.However, our data are in accordance with previous published data, even analysis of health record network, suggesting that reporting bias was not a substantial bias of this study.Although the case report forms were similar, the data were not completely uniform.For example, comorbidities, pre-existing medication were recorded slightly differently across both registries.For this reason, no analysis of former medication was performed.Another limitation concerns the small number of patients who received specific types of immunomodulatory treatment, such as JAK-I.Only few patients with nicotine use were reported which might also be due to reporting bias.For this reason, no conclusion could be drawn regarding the effect of these immunomodulatory treatments and nicotine use in the context of COVID-19.As a further limitation, it should be pointed out, that the study covers the first two waves of the pandemic.SARS-CoV-2 variants and SARS-CoV-2 infection has been changed over time as well as in the clinical presentation of patients.Nevertheless, the study provides an insight into the disease process in patients with IRD and immunosuppressive/immunomodulatory therapy.

Conclusions
In conclusion, risk factors for increased severity of SARS-CoV-2 infection known for the general population, such as age, male gender, and certain chronic conditions, play a similar role in patients with IRD.Although, chronic kidney disease and interstitial lung disease showed an increased risk for severe 10.3389/fmed.2024.1332716

FIGURE 2
FIGURE 2 Results of the univariate (A) and multivariate regression analysis (B,C) for the verification of comorbidities, IRD and rheumatic treatment on the outcome of COVID-19 infection based on the LEOSS Registry and IRD registry.Significant independent variable's influence (p-values <0.05) on the COVID-19 severity outcome marked bold and colored blue.(LEOSS Registry, Lean European Open Survey on SARS-CoV-2; BMI, body mass index; COPD, chronic obstructive pulmonary disease; ILD, interstitial lung disease; IRD, inflammatory rheumatic diseases; DSA, disease activity; bDMARD biological disease-modifying antirheumatic drugs, csDMARD, conventional synthetic disease-modifying antirheumatic drug; TNF Inhibitors, tumor necrosis factor-alpha inhibitors).
n. s., not significant; n. a., not applicable.n. s., not significant; n. a., not applicable
n. s., not significant; n. a., not applicable.

TABLE 5
In the univariate ordinal logistic regression, age > 65 • years [odds ratio (OR) of 1.6, 95% confidence interval (CI) 1.1 to 2.2], cardiovascular disease (OR of 1.3; 95% CI 1.0 to 1.7), arrhythmia (OR of 1.6; 95% CI 1.0 to 2.6), chronic obstructive pulmonary (OR of 1.8; 95% CI 1.2 to 2.6), diabetes mellitus (OR of 1.6; 95% CI 1.2 to 2.3) and rituximab (OR of 2.5; 95% CI 1.4 to 4.7) were significantly associated with severe COVID-19.Female patients (OR of 0.5; 95% CI 0.4 to 0.7) showed a significant lower risk for severe COVID-19 compared to males.Regarding arterial hypertension, bronchial asthma, interstitial lung diseases, active COVID-19 compared to the general population, no higher risk for COVID-19 related death could be observed in IRD patients.Regarding treatment, rituximab was associated with worse outcome of COVID-19 and most importantly, our data show that treatment with TNF-I was associated with better outcome of COVID-19 compared to the herewith untreated control group, indicating a protective effect of TNF-inhibition against severe COVID-19 disease during the first two waves of pandemic.