ABSTRACT
Background: The relevance of studying immune response after SARS-CoV-2 vaccination in patients with infammatory immune-mediated diseases (IMIDs) represents a deep concern regarding the risk estimation and management of patients with these diseases on immunomodulatory drugs. It is well known that certain treatments as anti CD20 therapies results in a diminished immunogenicity against common vaccines but it is a scarce data regarding the cellular protection obtained upon vaccination between patients with different IMID and between different treatments. Objectives: To compare a potential detriment on cellular and antibody-mediated protection upon SARS-CoV-2 vaccination in patients with IMIDs treated with immunosuppressive drugs. Methods: We recruited 73 patients with rheumatoid arthritis-RA-(n=49), spondy-larthritis-SpA-(n=19), infammatory bowel disease-IBD-(n=5), idiopathic juvenile arthritis-IJA-(n=2) and heterogenous group composed of sclerodermia, lupus, uveitis(n=6). They were treated mainly with rituximab (n=27), TNFi (n=37) or JAKi (n=3). We collected data of age,sex, csDMARDs, previous SARS-CoV-2 infection, last RTX infusion and prednisone use. After one month of vaccination, we assessed the humoral response performing the Thermo Scientific EliA SARS-CoV-2-Sp1 IgG Test (positivity cut-off >0.70 IU/ml) which was also compared with the data with of 35 healthy controls. In addition, in 40 patients who had serum antibody levels under 100UI/ml, we analysed the cellular response by the use of the QuantiFERON SARS-CoV-2 Starter Pack (Quiagen). A cut-off value of 0.15 IU/ml discriminate between positive or negative cell-mediated immune responses. We compared differences among the different IMIDs and between the different immu-nosuppressive treatments through non-parametric test (p<0.05) Results: Regarding demographic characteristics of patients, older patients (>56 years) and female sex were factors which were associated with low titles of serum antibodies. Anti-spike IgG antibodies were present in an 86% of the IMIDs patients and in 100% healthy controls with signifcant different IgG titre (median [IQR]): 51[11-184] vs 700[440-940];p<0.0001. The differences between (median [IQR]) serum antibody levels were statistically different between IMID type: 33[1-138] in RA vs 94[34-191] in SpA vs 204[187-204] in IBD vs 133[61-204] in IJA vs 13[1.5-31.8] in the rest;p=0.04. Remarkably, patients with IBD who had the highest antibodies titles were the youngest compared with the other patients. Target of the therapy played also an important role in serum antibody levels being these: 3.6 [0.7-51] in RTX patients vs 156 [45-204] in TNFi vs 40 [18-58] in JAKi patients;p<0.0001. In those patients who the last infusion of rituximab was, at least, one year before vaccination presented CD19+ B cells detected by fow cytometry and anti-spike IgG antibodies as well. Cell-mediated responses to SARS-CoV-2 were positive in 33% of IMIDs patients, indeterminated in 3% and negative in 65% of the patients. Strikingly, out of the 33% positive patients, 85% were treated with RTX. A 61% of the RTX patients had inducible cell-mediated responses vs 14% of the patients treated with TNFi;p<0.01. On the other hand, there were not differences in cell-mediated responses between positive and negative antibody patients. Conclusion: Titres of serum antibodies against spike protein of SARS-CoV-2 were lower in IMIDs patients than in controls. Patients with RTX had lower rates of positivity humoral response as well as lower serum titles than patients treated with other therapies regardless the patients 'age. Neverthless, in those patients in whom RTX infusion was delayed because of vaccination they conserved a humoral response. On the other hand, more patients treated with RTX had inducible cell-mediated responses compared with patients with TNFi.
ABSTRACT
Background and importance Many patients with moderate- severe COVID-19 develop immune dysregulation characterised by marked activation of innate immunity, elevation of acute phase reactants and release of proinflammatory cytokines (eg, interleukin 1 (IL-1) and IL-6), thus creating a hyperinflammatory state. Aim and objectives To determine the feasibility and safety of fighting hyperinflammation in patients with refractory moderate- severe COVID-19 by using a 3 day course of low dose subcutaneous anakinra. Material and methods A prospective study was conducted in two hospitals in Spain, from 1 April to 8 May 2020, of nine hospitalised patients refractory to standard-of-care treatment with laboratory confirmed SARS-CoV-2 infection, a clinical course of at least 5 days, radiological pneumonia and moderate- severe COVID-19 according to clinical/analytical criteria. Patients received a daily subcutaneous dose of anakinra 100 mg for 3 consecutive days. The primary outcome was radiological improvement 72 hours after the first administration, together with appropriate clinical and analytical changes according to a combined set of response criteria. Secondary outcomes included incidence of serious adverse events, mortality, need for invasive ventilation at days 3 and 14, and days of hospitalisation. Results All patients (aged 48-88 years) had bilateral pneumonia and received hydroxychloroquine;7 received azithromycin, 5 ceftriaxone, 3 cyclosporine, 2 lopinavir/ritonavir, 1 interferon and 6 corticosteroids. Anakinra was introduced between 1 and 17 days (median 8 days) after admission. Six patients reached the primary outcome at day 3. An improvement in the chest X-ray at day 3 was observed in 7 of the 9 patients, and no radiological worsening was recorded in the 2 other patients. Median SpO2 at baseline was 92% (IQR 88-95), with a significant improvement of 97% (IQR 96-98) (p=0.007) at day 3. Significant differences were also observed in various laboratory parameters between days 0 and 3. No serious adverse events were observed. On days 3 and 14, no patient had died and none required invasive ventilation. One patient died after 21 days of hospitalisation;the remaining 8 were discharged (length of stay 6-45 days). Conclusion and relevance In this study of patients with refractory moderate-severe COVID-19, a 3 day course of low dose subcutaneous anakinra was effective and safe, resulting in radiological, clinical and analytical improvement in most cases. These observations require further evaluation in clinical trials.