Somatic mutations at methionine 41 (Met41) in UBA1, encoding the major E1 enzyme responsible for initiating ubiquitylation, were recently identified as the cause of a novel autoinflammatory disease, named VEXAS (Vacuoles, E1 enzyme, X-linked, autoinflammatory, somatic). We sought to determine the prevalence of UBA1 mutations in a UK cohort of patients matching the VEXAS clinical phenotype. We identified 10 new patients with somatic mutations in UBA1, but only 8 had altered p.Met41. A novel variant, c.167C>T; p.Ser56Phe was identified, which was present in myeloid, and not lymphoid lineages and led to preferential loss of the catalytic activity of cytoplasmic UBA1. An additional novel variant, c.118-1G>C was identified at the splice acceptor site of exon 3 leading to altered splicing in vitro. Bone marrow biopsies from two patients with a Met41 substitution and the novel splice site variant were consistent with previously reported features of VEXAS. The bone marrow of the patient with the p.Ser56Phe variant was less similar, likely driven by a distinct but overlapping disease mechanism. Our study therefore confirms somatic p.Met41 substitutions in UBA1 as a major cause of VEXAS syndrome and identifies two new disease causing mutations.

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Nineteen patients out of 250 subjects with antiphospholipid antibodies, who had initially presented to the lupus clinic at St Thomas's Hospital, London five or more years ago with a history of venous/arterial occlusions, were entered into the study. The patients were divided into two main groups: I those who remained well without any further thromboembolic complications (n= 10); H those who developed recurrent thrombotic events in the five year period (n=9).The patients were followed up to determine the relation between the level or the isotype of the anticardiolipin antibodies, or both, to the recurrent thromboembolic events, and the effect of a variety of treatments (corticosteroids, immunosuppression, anticoagulation) in the prevention of further vascular occlusions. Lupus activity over the five year period varied considerably between the two groups-those

Certain subgroups of lupus patients and those with circulating antiphospholipid antibodies (aPL) in particular, suffer a high rate of fetal loss. Over the past 4 years, we have prospectively studied 100 pregnancies in patients with systemic lupus erythematosus (SLE) and primary antiphospholipid syndrome. In addition to conventional methods of monitoring SLE and fetal development, we have also used Doppler flow assessment of placental perfusion from the 14th wk of pregnancy onward. Patients with the antiphospholipid syndrome and previous history of thrombotic events were treated with daily heparin (10,000 IU) and low-dose aspirin (75 mg). Those without a history of thrombosis were treated with low-dose prednisolone, azathioprine, or hydroxychloroquine. Pregnancy loss was reduced from 81.3% in 101 previous pregnancies to 36.8% in 100 pregnancies managed by us. None of the patients who received hydroxychloroquine throughout the pregnancy presented fetal malformations. Careful management and close monitoring of the lupus pregnancy has substantially improved fetal outcome.

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