ABSTRACT
Background: Prinflammatory extracellular chromatin from neutrophil extracellular traps (NETs) and other cellular sources is found in COVID-19 patients and may promote pathology. We determined whether pulmonary administration of the endonuclease dornase alfa reduced systemic inflammation by clearing extracellular chromatin. Methods: Eligible patients were randomized (3:1) to the best available care including dexamethasone (R-BAC) or to BAC with twice-daily nebulized dornase alfa (R-BAC + DA) for seven days or until discharge. A 2:1 ratio of matched contemporary controls (CC-BAC) provided additional comparators. The primary endpoint was the improvement in C-reactive protein (CRP) over time, analyzed using a repeated-measures mixed model, adjusted for baseline factors. Results: We recruited 39 evaluable participants: 30 randomized to dornase alfa (R-BAC +DA), 9 randomized to BAC (R-BAC), and included 60 CC-BAC participants. Dornase alfa was well tolerated and reduced CRP by 33% compared to the combined BAC groups (T-BAC). Least squares (LS) mean post-dexamethasone CRP fell from 101.9 mg/L to 23.23 mg/L in R-BAC +DA participants versus a 99.5 mg/L to 34.82 mg/L reduction in the T-BAC group at 7 days; p=0.01. The anti-inflammatory effect of dornase alfa was further confirmed with subgroup and sensitivity analyses on randomised participants only, mitigating potential biases associated with the use of CC-BAC participants. Dornase alfa increased live discharge rates by 63% (HR 1.63, 95% CI 1.01-2.61, p=0.03), increased lymphocyte counts (LS mean: 1.08 vs 0.87, p=0.02) and reduced circulating cf-DNA and the coagulopathy marker D-dimer (LS mean: 570.78 vs 1656.96 µg/mL, p=0.004). Conclusions: Dornase alfa reduces pathogenic inflammation in COVID-19 pneumonia, demonstrating the benefit of cost-effective therapies that target extracellular chromatin. Funding: LifeArc, Breathing Matters, The Francis Crick Institute (CRUK, Medical Research Council, Wellcome Trust). Clinical trial number: NCT04359654.
Subject(s)
Anti-Inflammatory Agents , COVID-19 Drug Treatment , COVID-19 , Deoxyribonuclease I , Humans , Male , Female , Deoxyribonuclease I/administration & dosage , Deoxyribonuclease I/therapeutic use , Middle Aged , Anti-Inflammatory Agents/administration & dosage , Anti-Inflammatory Agents/therapeutic use , Aged , Recombinant Proteins/administration & dosage , Recombinant Proteins/therapeutic use , Extracellular Traps/drug effects , SARS-CoV-2 , C-Reactive Protein/analysis , C-Reactive Protein/metabolism , Dexamethasone/administration & dosage , Dexamethasone/therapeutic use , Adult , Nebulizers and Vaporizers , Treatment Outcome , Administration, InhalationABSTRACT
Systemic lupus erythematosus, scleroderma, myositis and Sjögren's syndrome are rare, complex, multi-systemic rheumatic diseases associated with significant morbidity and mortality. Thorough assessments of disease activity are required to guide clinical management and assess response to new therapies in clinical trials. This article reviews the commonly used outcome measures to assess this group of diseases and discusses the limitations of their use.
Subject(s)
Lupus Erythematosus, Systemic/complications , Myositis/complications , Patient Reported Outcome Measures , Scleroderma, Systemic/complications , Severity of Illness Index , Sjogren's Syndrome/complications , HumansABSTRACT
The most common types of chronic inflammatory arthritis are rheumatoid arthritis, psoriatic arthritis and ankylosing spondylitis. In order to assess the activity of these diseases and tailor therapy, several outcome measures have been developed. They include composite scores based on clinical findings, biochemical markers and patient questionnaires. This article discusses the most commonly used outcome measures and looks at their limitations in quantifying the complex clinical features of different types of inflammatory arthritis, focusing in particular on rheumatoid arthritis, psoriatic arthritis and ankylosing spondylitis.
