The analysis of factors influencing pulmonary inflammation in RD-COVID-19 patients conducted in this study holds critical implications for the early identification of severe cases and bolstering the cure rate. In their research, Goyal P et al. [5] implied that patients with concomitant cardiovascular disease and diabetes have a higher incidence of hospitalization. Pablos et al. [6] elucidated that advanced age, male gender, and associated morbidities (cardio-cerebrovascular disease, diabetes, or pulmonary disease) augment the risk of disease severity. Strangfeld A et al. [7] posited that patients over 60 years old with a history of chronic lung disease have a significantly higher risk of severe illness. Our findings mirror previous studies, revealing an elevated incidence of pulmonary inflammation in male RD-COVID-19 patients with cardiovascular and cerebrovascular diseases, interstitial lung disease, and chronic obstructive pulmonary disease. Some collinearity between diabetes and the factors mentioned above may account for the negative results in the multivariate analysis. Compared to CIA, SAC often induces multi-system involvement leading to damage across multiple organs. Our results indicate that patients with SAC have a heightened risk of viral pneumonia compared to those with CIA, mirroring the conclusions drawn by Javier Bachiller-Corral[8].
In their compilation of 27 studies on booster doses of SARS-CoV-2 vaccines, Chenchula S et al. [9] demonstrated that booster vaccination substantially amplifies neutralizing immunity and antibody titer levels against Omicron in the general population. However, no extensive studies have been carried out on the efficacy of booster vaccination in RD patients. Our research demonstrates that RD-COVID-19 patients who received a booster dose (i.e., the third vaccine dose) manifested a significantly lower risk of lung inflammation compared to unvaccinated patients. Despite multivariate analysis failing to show risk reduction of pulmonary inflammation in nine of our patients who received a two-dose booster vaccine, none of these nine patients developed pulmonary inflammation, a phenomenon potentially attributable to the small sample size. Booster vaccination can effectively curtail the risk of severe illness in RD patients, although 39.5% of RD patients in our study had not received the booster vaccination. As the SARS-CoV-2 virus continues to evolve, the gradual strengthening of broad coverage vaccination, particularly for individuals with underlying conditions and immunosuppressed individuals, is imperative.
The deleterious effects of NSAIDs on clinical outcomes have yet to be conclusively determined in our current study. Day M[10]'s study suggested that NSAID usage in COVID-19 patients may lead to detrimental outcomes. In contrast, Gianfrancesco M[11]'s study did not find a correlation between NSAID usage and hospitalization status, but found that GC≥10 mg/day was associated with an elevated likelihood of hospitalization. The study by Boteanu A et al. [3] indicated that GC >10 mg/day was independently associated with worse outcomes. Strangfeld A asserted that GC substantially escalates the risk of severe disease [7]. However, given the wide range of NSAID indications and easy over-the-counter access, it is challenging to accurately ascertain long-term NSAID usage prior to medical consultation, resulting in reporting bias. Our logistic analysis found that NSAIDs and GC do not augment the risk of pulmonary inflammation, providing some reassurance. In our study, these were rheumatid disease patients in low disease activity or remission. So patients with GC > 10mg/d were not included here. The above is one of the limitations of our research.
Due to its anti-inflammatory and immunomodulatory effects, HCQ has been widely employed in RD and COVID-19 treatment protocols. Gautret P[12] suggested that HCQ was significantly associated with a reduction of viral load in COVID-19 patients. Conversely, Magagnoli J[13] et al. were unable to substantiate that HCQ reduced the risk of mechanical ventilation in hospitalized COVID-19 patients. Boteanu A[3] et al. implied that the usage of hydroxychloroquine is safe. Our study found that regular HCQ usage does not influence the risk of viral pneumonia.
In patients diagnosed with rheumatic diseases (RD), the utilization of disease-modifying anti-rheumatic drugs (DMARDs) can potentially present a dichotomy of effects: the first being the debilitation of the immune response to COVID-19, while paradoxically, most of these agents are believed to precipitate severe COVID-19. Existing research has identified DMARDs as one of the risk factors associated with severe COVID-19 [14]. However, the impact of conventional synthetic DMARDs (csDMARDs) currently remains elusive, with varying effects observed on disease progression [15]. Ungaro, R.C. et al. [16] proposed that Sulfasalazine (SSZ), Azathioprine (AZA) monotherapy, and AZA coupled with tumor necrosis factor inhibitors (TNFi) were related to severe COVID-19. Brenner E J et al. [17] collated 525 cases across 33 countries, establishing a correlation between SSZ treatment and a dire prognosis in COVID-19. The study by Boteanu A et al. [3] ascertained that the usage of SSZ, Mycophenolate mofetil (MMF) were independently linked to worse outcomes, whereas Methotrexate (MTX), AZA, Cyclophosphamide (CTX), and Leflunomide (LEF) were deemed safe. Multiple studies have connected SSZ with severe COVID-19, necessitating specific research to elucidate a causal association and the role of confounding factors. Our study found that the regular use of AZA, CTX, SSZ, and MMF appeared safe in RD-COVID-19 patients. Still, the results may have been influenced by the small sample size, with AZA being administered to only two patients. Interestingly, MTX and LEF were identified as protective factors, reducing the risk of viral pneumonia. The Calcineurin inhibitor (CNI), inclusive of Cyclosporine A (CsA) and FK506, counteracts rheumatism by blocking the T cell receptor signaling pathway. Hage R's study [18] posited that patients treated with oral CNI post-organ transplantation were less susceptible to COVID-19. Our study did not consider CNI treatment as a risk factor. Collectively, the application of csDMARDs can be deemed safe.
Biologic/targeted synthetic DMARDs (b/tsDMARDs) are prevalently utilized in the treatment of rheumatic diseases, owing to their high efficiency and minimal toxicity. Both Boteanu A and Avouac J [19] documented that Rituximab (RTX) treatment could precipitate severe COVID-19. The study conducted by Sparks JA et al. [20], encompassing 2869 RA patients, associated RTX and JAK inhibitors (JAKi) with severe COVID-19 compared to TNFi. This finding was consistent with the study conducted by Bachiller-Corral J [21]. Brenner EJ [22] demonstrated that TNFi did not correlate with severe COVID-19 in patients with chronic intestinal inflammatory diseases. Despite Strangfeld A's study [7] suggesting that TNFi amplified the risk of severe disease, the majority of the studies [11, 17] deemed TNFi safe. Our study, however, did not establish any effect of TNFi and RTX on the progression of RD-COVID-19, potentially due to the small sample size, with only three patients receiving RTX treatment. The administration of Interleukin-6 inhibitors (IL-6i) can rapidly ameliorate the clinical outcome of severe COVID-19 patients [23]. IL-6i presents an effective treatment option for the inflammatory storm incited by COVID-19 [24], though its ability to forestall pulmonary inflammation remains unclear. While our study found IL-6i effective in treating severe COVID-19 patients, it did not prevent viral pneumonia. The use of Belimumab, employed in the treatment of systemic lupus erythematosus, did not correlate with the severity of RD-COVID-19 [3], which is in agreement with our study's findings. The study by Kridin K[25] indicated that Interleukin-17 inhibitors (IL-17i) did not affect the severity of COVID-19 infection in psoriasis patients. Our findings demonstrated IL-17i and TNFi as protective factors in univariate analysis, but multivariate analysis did not yield significance, potentially due to the younger age and fewer comorbidities of patients administered these drugs. None of the various b/tsDMARDs were statistically significant in the multivariable adjusted model. Despite potential immunodeficiency and immunosuppressive therapy in RD patients, our study concluded that b/tsDMARDs are safe in patients with RD-COVID-19 and do not amplify the risk of viral pneumonia, offering reassurance amidst widespread clinical concern that immunosuppressive therapy may compromise an adequate immune response.
We obtain new conclusions: in RD-COVID-19 patients, male gender, Systemic Autoimmune Condition (SAC) type of RD, and concomitant pulmonary and cardiovascular diseases escalate the risk of pulmonary inflammation. Conversely, the risk of viral pneumonia is mitigated in patients receiving SARS-CoV-2 booster vaccination, and MTX and LEF treatment. These straightforward, intuitive clinical measures can swiftly quantify the risk for severe disease in patients with RD-COVID-19. Such simple quantitative criteria can assist physicians in swiftly prioritizing patients in settings with constrained medical resources. However, there are some limitations to our single center study. We overlooked a few details: the interruption of immunomodulating medications after COVID-19 onset. Additionally, our patients are all in low disease activity or remission.