ABSTRACT
Background: Patients with autoimmune systemic diseases have an increased risk to contract infections and develop severe complications;infections in turn can reactivated and worsen the disease itself in a vicious circle. Thus, vaccination is the main weapon to prevent infectious diseases and represents an important and safe instrument of care for rheumatic patients that needs to be further promoted. However, the immunosuppressive drugs used to treat rheumatic diseases may impair response to vaccines, in particular those targeting B or T cells directly (1). Objectives: The aim of this study is to evaluate the B and T-cell mediated immune response to mRNA vaccination in patients with systemic autoimmune diseases, such as vasculitis or systemic connective tissue diseases, early or continuously treated with B-cell targeting therapies, rituximab (RTX) or beli-mumab (BEL), by comparing with controls and each other. Secondary we evaluated the in vitro effective neutralizing capacity in belimumab-exposed patients. Methods: Twenty-eight consecutive patients under treatment with rituximab (RTX, n=11) or belimumab (BEL, n=17) and 13 age/sex matched controls (non-rheumatic healthcare personnel) were enrolled in the study. Nobody presented anti-SARS-CoV2 antibodies related to previous viral contact and all were always negative at the molecular swab monthly control. All patients and controls received mRNA vaccines and were tested three to four weeks after complete vaccination. All RTX patients started vaccination within 5 months from the last infusion, and all but one of them were B-cell depleted. Anti-SARS-CoV-2 RBD total antibodies were analysed by a diagnostic assay (Elecsys, Roche) while T-cell response was evaluated using the IGRA test (Euroimmun). A subgroup of BEL-patients was tested with pseudovirus neutralization assay. Results: Detectable anti-SARS-CoV2 RBD antibodies were documented in 1/11 RTX patients versus 16/17 BEL patients (p<0.0001). The median concentration was signifcantly lower than that observed in controls (39.6 AU/ml vs 1133 AU/ml, p<0.0001). A very low titer of anti-RBD antibodies were documented only in 1 out of 11 patients in the RTX subgroup (0.93 U/ml, positive if >0,79 U/ml) and the patient was the only one who showed an initial B-cell recovery (CD19+ B-cell 5 cells/microL). Anti-RBD antibodies were documented in 16 out 17 of patients in the BEL subgroup. The median anti-RBD antibody titer in patients receiving BEL was 243 [77.55-744.0] U/ml, and it was signifcantly lower compared to the controls (p=0.002). The IGRA test was positive in 8/11 (72.7%) RTX patients vs 16/17 (94.1%) BEL patients (p=0.7), with interferon release comparable to control subjects (p=0.2). Six patients with BEL were also stratifed according to total antibodies (IgG+I-gA+IgM) against-RBD into high responders (>800 AU/mL, n=3) and low responders (≤45 AU/mL, n=3) and tested with pseudovirus neutralization assay. Two thirds of low titer group of patients neutralized the Wuhan-Hu1 strain at medium-low titer (IC50 ≈102) but were almost ineffective in inhibiting the B.1.1.7 entry into target cells (IC50 =10). Regarding high responders, while two patients were able to inhibit both the strains at medium-high titer (approximately IC50 ≈103 for Wuhan-Hu1 and B.1.1.7), one patient neutralized only the WT strain. Conclusion: B-cell targeting therapies do not preclude SARS-CoV-2 vaccination since a cellular immunity can raise even in the absence of circulating B cells. Most importantly, the immunogenicity of COVID-19 vaccination in SLE patients treated with belimumab is supported. However, patients showing the lowest humoral response to vaccine could remain at higher risk of infections, due to low neutralizing capacity.
ABSTRACT
Renin-angiotensin system (RAS) blockers are extensively used worldwide to treat many cardiovascular disorders, where they are effective in reducing both mortality and morbidity. These drugs are known to induce an increased expression of angiotensin-converting enzyme 2 (ACE2). ACE2 acts as receptor for the novel SARS coronavirus-2 (SARS-CoV-2) which raising the important issue of possible detrimental effects that RAS blockers could exert on the natural history and pathogenesis of the coronavirus disease-19 (COVID-19) and associated excessive inflammation, myocarditis and cardiac arrhythmias. We review the current knowledge on the interaction between SARS-CoV-2 infection and RAS blockers and suggest a scientific rationale for continuing RAS blockers therapy in patients with COVID-19 infection.