Recombinant ADAMTS13 for Immune Thrombotic Thrombocytopenic Purpura.

In patients with immune thrombotic thrombocytopenic purpura (iTTP), autoantibodies against the metalloprotease ADAMTS13 lead to catastrophic microvascular thrombosis. However, the potential benefits of recombinant human ADAMTS13 (rADAMTS13) in patients with iTTP remain unknown. Here, we report the clinical use of rADAMTS13, which resulted in the rapid suppression of disease activity and complete recovery in a critically ill patient whose condition had proved to be refractory to all available treatments. We also show that rADAMTS13 causes immune complex formation, which saturates the autoantibody and may promote its clearance. Our data support the role of rADAMTS13 as a novel adjunctive therapy in patients with iTTP.

T-cell prolymphocytic leukaemia associated with immune checkpoint inhibitor (pembrolizumab).

We describe the case of a man in his 60s with squamous cell carcinoma of the lung with brain metastasis treated with pembrolizumab who subsequently developed T-cell prolymphocytic leukaemia. He was transferred to our hospital with worsening dyspnoea, suspected hyperviscosity syndrome and tumour lysis syndrome. He was intubated and admitted to our critical care unit. Emergent leucapheresis was started due to worsening renal function in the setting of tumour lysis and hyperviscosity syndromes. He continued to deteriorate and required continuous renal replacement therapy. Unfortunately, he eventually died from haemodynamic decompensation. There are only a few anecdotal cases pointing at a possible association between the use of immune checkpoint inhibitors and the progression or exacerbation of secondary haematological malignancies. The poor prognosis of these haematological malignancies warrants further investigation to determine if checkpoint inhibitors increase the risk of developing or propagating these potentially fatal diseases.

Serum sickness reaction to obinutuzumab in a patient with chronic lymphocytic leukaemia.

Serum sickness (SS) is a known phenomenon; however, it is commonly missed due to vague symptoms, and is usually confounded by other aetiologies that present similarly. Obinutuzumab is a novel anti-CD20 antibody agent that has been approved for chronic lymphocytic leukaemia (CLL) treatment. At the time of approval, it was not linked to SS; however, this phenomenon has been recognised with other anti-CD20 agents like rituximab. SS remains a rare entity, but it is important to be recognised accurately and quickly in the appropriate circumstances, so that effective treatment with corticosteroids can be initiated to alleviate inflammatory symptoms. Here we present a patient with CLL who developed maculopapular rash, fever and polyarthritis and elevated inflammatory markers consistent with serum sickness triggered by obinutuzumab and was effectively treated with corticosteroids.

Disruption of the open conductance in the ß-tongue mutants of Cytolysin A.

Cytolysin A (ClyA) is a water-soluble alpha pore-forming toxin that assembles to form an oligomeric pore on host cell membranes. The ClyA monomer possesses an α-helical bundle with a ß-sheet subdomain (the ß-tongue) previously believed to be critical for pore assembly and/or insertion. Oligomerization of ClyA pores transforms the ß-tongue into a helix-turn-helix that embeds into the lipid bilayer. Here, we show that mutations of the ß-tongue did not prevent oligomerization or transmembrane insertion. Instead, ß-tongue substitution mutants yielded pores with decreased conductance while a deletion mutation resulted in pores that rapidly closed following membrane association. Our results suggest that the ß-tongue may play an essential structural role in stabilizing the open conformation of the transmembrane domain.