GM-CSF blockade with mavrilimumab in severe COVID-19 pneumonia and systemic hyperinflammation: a single-centre, prospective cohort study.

BACKGROUND: Mortality in patients with COVID-19 pneumonia and systemic hyperinflammation is high. We aimed to examine whether mavrilimumab, an anti-granulocyte-macrophage colony-stimulating factor receptor-α monoclonal antibody, added to standard management, improves clinical outcomes in patients with COVID-19 pneumonia and systemic hyperinflammation. METHODS: This single-centre prospective cohort study included patients aged 18 years or older who were admitted to San Raffaele Hospital (Milan, Italy) with severe COVID-19 pneumonia, hypoxia, and systemic hyperinflammation. Patients received a single intravenous dose (6 mg/kg) of mavrilimumab added to standard care given by the hospital at the time. The control group consisted of contemporaneous patients with similar baseline characteristics who received standard care at the same hospital. The main outcome was time to clinical improvement (defined as improvement of two or more points on the seven-point ordinal scale of clinical status). Other outcomes included proportion of patients achieving clinical improvement, survival, mechanical ventilation-free survival, and time to fever resolution. Adverse events were monitored daily. FINDINGS: Between March 17 and April 15, 2020, 13 non-mechanically ventilated patients (median age 57 years [IQR 52-58], 12 [92%] men) received mavrilimumab and 26 patients (median age 60 [IQR 53-67], 17 [65%] men) in the control group received standard care. During the 28-day follow-up, no patients in the mavrilimumab group died, and seven (27%) patients in the control group died (p=0·086). At day 28, all patients in the mavrilimumab group and 17 (65%) patients in the control group showed clinical improvement (p=0·030), with earlier improvement in the mavrilimumab than in the control group (mean time to improvement 8 days [IQR 5 to 11] vs 19 days [11 to >28], p=0·0001). By day 28, one (8%) patient in the mavrilimumab group progressed to mechanical ventilation compared with nine (35%) patients in the control group who progressed to mechanical ventilation or died (p=0·14). By day 14, fever resolved in ten (91%) of 11 febrile patients in the mavrilimumab group, compared with 11 (61%) of 18 febrile patients in the control group (p=0·18); fever resolution was faster in mavrilimumab recipients versus controls (median time to resolution 1 day [IQR 1 to 2] vs 7 days [3 to >14], p=0·0093). Mavrilimumab was well tolerated, with no infusion reactions. Three (12%) patients in the control group developed infectious complications. INTERPRETATION: Mavrilimumab treatment was associated with improved clinical outcomes compared with standard care in non-mechanically ventilated patients with severe COVID-19 pneumonia and systemic hyperinflammation. Treatment was well tolerated. Confirmation of efficacy requires controlled testing. FUNDING: IRCCS San Raffaele Scientific Institute.

Treating Heart Inflammation With Interleukin-1 Blockade in a Case of Erdheim-Chester Disease.

Pericarditis is an inflammatory heart disease, which may be idiopathic or secondary to autoimmune or auto-inflammatory diseases and often leads to severe or life-threatening complications. Colchicine and non-steroidal anti-inflammatory drugs represent the mainstay of treatment, whereas use of corticosteroids is associated with recurrence of disease flares. While effective and safe anti-inflammatory therapies remain an unmet clinical need, emerging clinical and experimental evidence points at a promising role of inhibition of the pro-inflammatory cytokine interleukin-1 (IL-1). We thus evaluated treatment with the IL-1 receptor antagonist anakinra in a case of extremely severe pericarditis with cardiac tamponade and heart failure secondary to Erdheim-Chester disease (ECD), a rare clonal disorder of macrophages characterized by rampant inflammation and multiorgan involvement. A 62-year-old man was admitted to the Emergency Department with severe pericardial effusion requiring the creation of a pleuro-pericardial window. A whole-body contrast-enhanced computed tomography pointed at a diagnosis of ECD with involvement of the heart and pericardium and of the retroperitoneal space. Over the following days, an echocardiography revealed a closure of the pleuro-pericardial window and a relapse of the pericardial effusion. Treatment with anakinra, the recombinant form of the naturally occurring IL-1 receptor antagonist, was started at a standard subcutaneous dose of 100 mg/day. After 2 days, we observed a dramatic clinical improvement, an abrupt reduction of the inflammatory markers, and a reabsorption of the pericardial effusion. Anakinra was maintained as monotherapy, and the patient remained asymptomatic in the absence of disease flares for the following year. Recent studies point at inhibition of IL-1 activity as an attractive treatment option for patients with refractory idiopathic recurrent pericarditis. Anakinra treatment may also have a role in patients with pericarditis in the setting of systemic inflammatory disorders, such as ECD.

Bortezomib in type I cryoglobulinemic vasculitis: are we acting too late?

Type II and type III cryoglobulinemic vasculitis (CV) are characterized by a deranged immune function due to concomitant chronic infections or rheumatic disorders. Conversely, type I CV is caused by plasma cell dyscrasia. Bortezomib is a proteasome inhibitor that is largely employed as a first-line treatment for multiple myeloma. The use of bortezomib in cases of monoclonal gammopathy of undetermined significance (MGUS)-related refractory type I CV has been reported in only four patients. In the current report, we discuss the efficacy of bortezomib treatment in a patient with type I CV, with a focus on the suitability and early application of this drug.