ABSTRACT
Background: The treatment of COVID-19 caused by SARS-CoV-2 posed serious challenges to health care systems. In 8-10% of patients with severe COVID-19 have a cytokine storm syndrome, highlighting the importance of host immune response in pathogenesis. Objectives: Our aim was to evaluate the effect of tocilizumab treatment in COVID-19 patients with severe cytokine storm who were refractory to standard of care therapy. To determine the prognostic factors that indicate the success of treatment in these patients. Methods: Fifty-three patients were treated with tocilizumab during waves 2 and 3 of the pandemic due to a cytokine storm associated with SARS-CoV-2 infection. All patients underwent physical examination, saturation monitoring, laboratory examination, blood gas analysis and chest CT examination. Deteriorating clinical status, elevated IL-6 and other acute phase protein levels observed in patients treated with standard therapy suggest cytokine storm syndrome. The treatment of these patients was supplemented with 8 mg/kg (max. 800 mg) tocilizumab (1 or 2 times within 24 hours). We assessed the clinical and laboratory response of these patients to IL-6-R inhibitor therapy, the need for ventilation, the need for intensive care and mortality. Results: Immunological consultations were performed in 31 patients, of whom 21 (68%) were successfully treated. Eleven patients of them (22%) died. In the 22 non-consulted patients, this rate was reversed: 7 (22%) were successful and 15 (68%) were treatment failures. The success of the treatment was mainly influenced by the well-established indication, the recognition of contraindications, and the condition that did not require invasive ventilation method. The 29 tocilizumab therapies initiated in the non-intensive care unit avoided intensive care unit treatment in 18 patients. Eleven patients were admitted to the intensive care unit, but 7 patients required temporary respiratory support and recovered, 4 patients required invasive mechanical ventilation and later died (14%). In contrast, 24 treatments initiated in the intensive care unit saved the lives of only 3 patients, and 21 patients were lost (87.5%). The effectiveness of treatment was not affected by age, with survival rates of 40%, 44%, 57% and 55% for the 40-49, 50-59, 60-69, 70-79 age groups, respectively. Interestingly, the extent of lung involvement also did not show a signifcant difference. Although it was a prerequisite for initiating tocilizumab treatment to have fresh alveolitis on the CT image of the chest. Conclusion: Use of tocilizumab is most effective in patients with COVID-19 who have high levels of infammatory activity and IL-6, who are at an early stage of lung involvement and who do not respond to high-dose corticosteroid therapy, who have no bacterial superinfection and require not invasive mechanical ventilation. It is also important that specialist who has immunological approach and routine with biological treatment be also involved in the care of patients with severe COVID-19 disease.
ABSTRACT
Background: Low-dose glucocorticoid (GC) therapy is widely used in RA but the true balance of beneft and harm is still unknown. Objectives: We studied the effects of prednisolone (5 mg/day, 2 years) in RA patients aged 65+, requiring adjustment of antirheumatic therapy (DAS28≥2.60). Methods: Pragmatic double-blind placebo-controlled randomized trial;all co-treatments and changes therein were allowed during the trial except longterm open label GC;Ca/D supplementation was advised in all patients. Minimal exclusion criteria were tailored to seniors. Harm outcome: the number of patients with ≥1 serious adverse event (SAE), or ≥1 'other adverse event of special interest' (other AESI). Other AESI comprised any AE (except worsening of RA) causing study discontinuation, and GC-specifc events (Table 1). Beneft outcomes: improvement in disease activity (DAS28) and joint damage progression (Sharp/van der Heijde). Longitudinal mixed models analyzed the data. Given prior knowledge we report one-sided 95% confdence limit (95%CL) and statistical tests, performed only for the main outcomes. Results: We randomized 451 RA patients in 7 EU countries, 449 received the intervention;of these 63% prednisolone vs 61% placebo patients completed 2 years of follow up. Discontinuations were similar in both groups: for AE (14%) and active disease (4%);the remainder mostly for 'trial fatigue' and covid-related access issues (20%). Mean time on study drug was 19 (SD 8) months. 70% of patients were female, mean age was 72 (max 88) years, RA duration 11 years;67% were RF+, 56% ACPA+, 96% had joint damage on radiographs: mean score 20, median 8. Mean DAS28 was 4.5. Most patients (79%) were on current DMARD treatment, including 14% on biologics;47% had previously used GC, 14% changed DMARD therapy at baseline. Patients had mean 2.1 active comorbidities, and used median 7 drugs. Beneft: Disease activity rapidly declined to stabilize after 1 year (Figure 1), and was lower on prednisolone (adjusted mean difference in DAS28 over 2 years: 0.37, 95%CL 0.23, p<0.0001). The contrast in early (3-month) response was larger in 331 patients adherent to protocol on stable treatment: mean difference in DAS28 0.62 (95%CL 0.44), more responders on prednisolone (Figure 1). Sig-nifcant time-treatment interaction in secondary analyses suggested a decrease in contrast after the frst year, most likely caused by signifcantly more changes in DMARD treatment on placebo. Joint damage progression over 2 years was signifcantly lower on prednisolone: mean 0.6 (SD 1.9) v 1.8 (6.4) score points on placebo, difference 1.2 (95%CL 0.2, p=0.02). Harm: 60% prednisolone vs 49% placebo patients experienced the harm outcome: adjusted RR 1.24, 95%CL 1.04, p=0.02;number needed to harm 9.5 (Table 1). During the study 1 vs 2 patients died, and 3 vs 0 died within 5 months of discontinuation. Per 100 patient-years, AE totaled 278 in prednisolone vs 206 in placebo patients, and the difference was most marked for infections (Table 1);these were mostly mild or moderately severe. Other GC-specifc AESI were rare without relevant differences. Conclusion: Add-on low dose prednisolone has benefcial long-term effects on disease activity and damage progression in senior RA patients on standard treatment. The tradeoff is a 24% increase in patients with mostly mild to moderate AE, suggesting a favorable balance of beneft and harm.