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Disease relapse is recognized as a risk in immune-mediated thrombotic thrombocytopenic purpura (iTTP) after treatment of the acute presenting episode. Identification of patients at risk of relapse and its patterns are yet to be clearly established. We reviewed patients with iTTP having had >3 years of follow-up over 10 years in the United Kingdom to identify patient characteristics for relapse, assess relapse rates and patterns, and response to anti-CD20 therapy in those with a disintegrin and metalloproteinase with a thrombospondin type 1 motif, member 13 (ADAMTS13) relapses (ADAMTS13 activity of 20%. Anti-CD20 therapy was demonstrated to be an effective long-term treatment regardless of relapse pattern and there was no loss of this treatment response after subsequent treatment episodes.

Rituximab, an anti-CD20 monoclonal antibody, can be used to treat immune thrombotic thrombocytopenic purpura (iTTP) during acute presentation or disease relapse. Undesirable side-effects include severe hypersensitivity reactions, particularly anaphylaxis and rituximab-induced serum sickness, with a minority not maintaining a response to treatment. Alternative humanised anti-CD20 treatments, obinutuzumab and ofatumumab, have been used. A review of the UK TTP Registry showed 15 patients received these drugs over 26 treatment episodes (eight obinutuzumab and 18 ofatumumab). Indications for alternative anti-CD20 treatment were severe infusion-related reactions, acute rituximab-induced serum sickness and a short duration of disease remission. All patients achieved disease remission (ADAMTS13 [A disintegrin and metalloproteinase with a thrombospondin type 1 motif, member 13] activity ≥30 iu/dl) after a median 15 days and 92% of episodes achieved complete remission (≥60 iu/dl). Seven patients required further treatment for disease relapse with a median relapse-free survival of 17.4 months. All patients continued to respond to re-treatment with the preceding drug when relapse occurred. There were four adverse events in 26 treatment episodes (15%) - two infections and two infusion reactions. These results suggest that obinutuzumab and ofatumumab may be considered as an alternative option to rituximab in the treatment of iTTP with a comparable safety profile, absence of significant hypersensitivity reactions and sustained normalisation of ADAMTS13.

Immune thrombotic thrombocytopenic purpura (iTTP) is an acute, multisystem thrombotic microangiopathy mediated by ADAMTS13 (a disintegrin and metalloproteinase with a thrombospondin type 1 motif, member 13) autoantibodies. Immunosuppression with anti-CD20 therapy is the mainstay of treatment. MabThera's patent has now expired and biosimilars have been approved. Eighty-four consecutive patient episodes over 2 years, prior to and following our switch to Truxima are presented. Day 1 (D1), Day 28 (D28) and 3-month platelet counts, ADAMTS13 activity, and CD19 levels, adverse reactions and infective complications were recorded. Platelet counts were not significantly different between acute MabThera and Truxima treatment (D1 P = 0.085, D28 P = 0.77, 3 months P = 0.71) and electively (D1 P = 0.79, D28 P = 0.68, 3 months P = 0.99). ADAMTS13 recovery also was not significantly different acutely (D1 P = 0.99, D28 P = 0.27, 3 months P = 0.26) and electively (D1 P = 0.59, D28 P = 0.61, 3 months P = 0.34). CD19% depletion at D1 and 3 months was not significantly different acutely (D1 P = 0.52, 3 months P = 0.56) and electively (D1 P = 0.22, 3 months P = 0.19). Infusion reactions and infective complications were comparable with both therapies. This is the first series of the Rituximab biosimilar Truxima to be reported in iTTP, demonstrating equivalence to MabThera in terms of ADAMTS13 recovery, CD19 depletion, and platelet count at D28 and 3 months post-administration, with comparable infusion and infective complications. The financial benefit of the biosimilar anti-CD20 is considerable.

The cornerstone of life-saving therapy in immune-mediated thrombotic thrombocytopenic purpura (iTTP) has been plasma exchange (PEX) combined with immunomodulatory strategies. Caplacizumab, a novel anti–von Willebrand factor nanobody trialed in 2 multicenter randomized controlled trials (RCTs) leading to European Union and US Food and Drug Administration approval, has been available in the United Kingdom (UK) through a patient access scheme. Data were collected retrospectively from 2018 to 2020 for 85 patients (4 children) receiving caplacizumab from 22 UK hospitals. Patient characteristics and outcomes in the real-world clinical setting were compared with caplacizumab trial end points and historical outcomes in the precaplacizumab era. Eighty-four of 85 patients received steroid and rituximab alongside PEX; 26% required intubation. Median time to platelet count normalization (3 days), duration of PEX (7 days), and hospital stay (12 days) were comparable with RCT data. Median duration of PEX and time from PEX initiation to platelet count normalization were favorable compared with historical outcomes (P < .05). Thrombotic thrombocytopenic purpura (TTP) recurred in 5 of 85 patients; all had persistent ADAMTS13 activity < 5 IU/dL. Of 31 adverse events in 26 patients, 17 of 31 (55%) were bleeding episodes, and 5 of 31 (16%) were thrombotic events (2 unrelated to caplacizumab); mortality was 6% (5/85), with no deaths attributed to caplacizumab. In 4 of 5 deaths, caplacizumab was introduced >48 hours after PEX initiation (3-21 days). This real-world evidence represents the first and largest series of TTP patients, including pediatric patients, receiving caplacizumab outside of clinical trials. Representative of true clinical practice, the findings provide valuable information for clinicians treating TTP globally.

A syndrome of vaccine-induced immune thrombotic thrombocytopenia (VITT) has recently been reported following the ChAdOx1 nCoV-19 (Oxford–AstraZeneca) recombinant adenoviral vector vaccine encoding the spike glycoprotein of SARS-CoV-2.1–4 Previously described patients developed thrombosis, mainly affecting cerebral venous sinuses, with thrombocytopenia and antibodies to platelet factor 4 (PF4), but the characteristics of VITT with arterial thrombosis have not previously been described. Here, we report three patients with VITT who presented with ischaemic stroke. Patient 1, a 35-year-old Asian woman, developed episodic right temporal and periorbital headache 6 days after receiving the ChAdOx1 nCoV-19 vaccine. Five days later, she awoke with left face, arm and leg weakness, right gaze preference and drowsiness. Non-contrast CT and CT angiography (CTA) revealed occlusion of the right middle cerebral artery (MCA) distal M1 segment with extensive ischaemia and haemorrhagic transformation (figure 1A-C)). Subsequent imaging revealed right portal vein thrombosis. The platelet count was 64 x 109/L (reference range 150 –400 x 109/L); D-dimer was raised at 11 220 µg/L (reference range 0–550); and the Asserachrom HPIA IgG assay for anti-PF4 antibodies was positive (76.1%). The patient underwent urgent decompressive hemicraniectomy …

BACKGROUND: Steroid-sensitive nephrotic syndrome (SSNS), the most common form of nephrotic syndrome in childhood, is considered an autoimmune disease with an established classic HLA association. However, the precise etiology of the disease is unclear. In other autoimmune diseases, the identification of loci outside the classic HLA region by genome-wide association studies (GWAS) has provided critical insights into disease pathogenesis. Previously conducted GWAS of SSNS have not identified non-HLA loci achieving genome-wide significance. METHODS: In an attempt to identify additional loci associated with SSNS, we conducted a GWAS of a large cohort of European ancestry comprising 422 ethnically homogeneous pediatric patients and 5642 ethnically matched controls. RESULTS: The GWAS found three loci that achieved genome-wide significance, which explain approximately 14% of the genetic risk for SSNS. It confirmed the previously reported association with the HLA-DR/DQ region (lead single-nucleotide polymorphism [SNP] rs9273542, P=1.59×10-43; odds ratio [OR], 3.39; 95% confidence interval [95% CI], 2.86 to 4.03) and identified two additional loci outside the HLA region on chromosomes 4q13.3 and 6q22.1. The latter contains the calcium homeostasis modulator family member 6 gene CALHM6 (previously called FAM26F). CALHM6 is implicated in immune response modulation; the lead SNP (rs2637678, P=1.27×10-17; OR, 0.51; 95% CI, 0.44 to 0.60) exhibits strong expression quantitative trait loci effects, the risk allele being associated with lower lymphocytic expression of CALHM6. CONCLUSIONS: Because CALHM6 is implicated in regulating the immune response to infection, this may provide an explanation for the typical triggering of SSNS onset by infections. Our results suggest that a genetically conferred risk of immune dysregulation may be a key component in the pathogenesis of SSNS. ispartof: JOURNAL OF THE AMERICAN SOCIETY OF NEPHROLOGY vol:30 issue:8 pages:1375-1384 ispartof: location:United States status: published

What you need to know Deep vein thrombosis (DVT) commonly affects the lower limb, with clot formation beginning in a deep calf vein and propagating proximally.1 It is a common venous thromboembolic (VTE) disorder with an incidence of nearly 1.6 per 1000 inhabitants a year.234 The rate of involvement of particular sites varies: distal veins 40%, popliteal 16%, femoral 20%, common femoral 20%, and iliac veins 4%.1 Certain medical conditions listed in box 1 increase the likelihood of clot formation in the deep veins. Upper limb DVT represents less than 10% of all DVT, and central venous catheters are the main risk factor.7 Venocaval thromboses are rare and are associated with malignancy, compression, and vascular abnormalities.8 This article provides an overview for non-specialists on initial approach to patients with suspected DVT. Box 1 ### DVT risk factors56 #### Transient risk factors #### Persistent risk factors #### Unprovoked VTERETURN TO TEXT ### Sources and selection criteria We searched Medline and Cochrane databases for clinical trials, systematic reviews, and meta-analyses relevant to the diagnosis and management of DVT. Search terms included “deep vein thrombosis,” …