Recombinant von Willebrand factor and tranexamic acid for heavy menstrual bleeding in patients with mild and moderate von Willebrand disease in the USA (VWDMin): a phase 3, open-label, randomised, crossover trial.

BACKGROUND: Heavy menstrual bleeding occurs in 80% of women with von Willebrand disease and is associated with iron deficiency and poor response to current therapies. International guidelines indicate low certainty regarding effectiveness of hormonal therapy and tranexamic acid. Although von Willebrand factor (VWF) concentrate is approved for bleeds, no prospective trials guide its use in heavy menstrual bleeding. We aimed to compare recombinant VWF with tranexamic acid for reducing heavy menstrual bleeding in patients with von Willebrand disease. METHODS: VWDMin, a phase 3, open-label, randomised crossover trial, was done in 13 haemophilia treatment centres in the USA. Female patients aged 13-45 years with mild or moderate von Willebrand disease, defined as VWF ristocetin cofactor less than 0·50 IU/mL, and heavy menstrual bleeding, defined as a pictorial blood assessment chart (PBAC) score more than 100 in one of the past two cycles were eligible for enrolment. Participants were randomly assigned (1:1) to two consecutive cycles each of intravenous recombinant VWF, 40 IU/kg over 5-10 min on day 1, and oral tranexamic acid 1300 mg three times daily on days 1-5, the order determined by randomisation. The primary outcome was a 40-point reduction in PBAC score by day 5 after two cycles of treatment. Efficacy and safety were analysed in all patients with any post-baseline PBAC scores. The trial was stopped early due to slow recruitment on Feb 15, 2022, by a data safety monitoring board request, and was registered at ClinicalTrials.gov, NCT02606045. FINDINGS: Between Feb 12, 2019, and Nov 16, 2021, 39 patients were enrolled, 36 of whom completed the trial (17 received recombinant VWF then tranexamic acid and 19 received tranexamic acid then recombinant VWF). At the time of this unplanned interim analysis (data cutoff Jan 27, 2022), median follow-up was 23·97 weeks (IQR 21·81-28·14). The primary endpoint was not met, neither treatment corrected PBAC score to the normal range. Median PBAC score was significantly lower after two cycles with tranexamic acid than with recombinant VWF (146 [95% CI 117-199] vs 213 [152-298]; adjusted mean treatment difference 46 [95% CI 2-90]; p=0·039). There were no serious adverse events or treatment-related deaths and no grade 3-4 adverse events. The most common grade 1-2 adverse events were mucosal bleeding (four [6%] patients during tranexamic acid treatment vs zero during recombinant VWF treatment) and other bleeding (four [6%] vs two [3%]). INTERPRETATION: These interim data suggest that recombinant VWF is not superior to tranexamic acid in reducing heavy menstrual bleeding in patients with mild or moderate von Willebrand disease. These findings support discussion of treatment options for heavy menstrual bleeding with patients based on their preferences and lived experience. FUNDING: National Heart Lung Blood Institute (National Institutes of Health).

Significance of palpable tendon friction rubs in early diffuse cutaneous systemic sclerosis.

OBJECTIVE: Palpable tendon friction rubs (TFRs) in systemic sclerosis (SSc; scleroderma) have been associated with diffuse skin thickening, increased disability, and poor survival. Our objective was to quantify the prognostic implications of palpable TFRs on the development of disease complications and longer-term mortality in an incident cohort of early diffuse cutaneous SSc (dcSSc) patients. METHODS: We identified early dcSSc patients (disease duration <2 years from the first SSc symptom) first evaluated at the University of Pittsburgh Scleroderma Center between 1980 and 2006 and found to have palpable TFRs. These patients were matched 1:1 with the next consecutive early dcSSc patient without TFRs as a control. All had ≥2 clinic visits and 5 years of followup from the first visit. RESULTS: A total of 287 early dcSSc patients with TFR were identified and matched to 287 controls. The median disease duration was 0.83 years in TFR patients and 1.04 years in controls. The median followup was 10.1 years in TFR patients and 7.9 years in controls. Over the course of their illness, patients with TFRs had a >2-fold risk of developing renal crisis and cardiac and gastrointestinal disease complications, even after adjustment for other known risk factors. Patients with TFRs had poorer 5- and 10-year survival rates. CONCLUSION: Patients with early dcSSc having ≥1 TFRs are at an increased risk of developing renal, cardiac, and gastrointestinal involvement before and after their first Scleroderma Center visit and have reduced survival. Patients presenting with TFRs should be carefully monitored for serious internal organ involvement.

GATA-3 up-regulation in CD8+ T cells as a biomarker of immune dysfunction in systemic sclerosis, resulting in excessive interleukin-13 production.

OBJECTIVE: Despite the importance of interleukin-13 (IL-13) in systemic sclerosis (SSc) and other fibrotic diseases, its mechanisms of action are not understood. We have reported that excessive amounts of IL-13 are produced by peripheral blood effector CD8+ T cells from patients with diffuse cutaneous SSc (dcSSc). The aim of the present study was to establish the molecular basis of IL-13 dysregulation in the pathogenesis of SSc. METHODS: Quantitative polymerase chain reaction analysis and intracellular staining were used to study the transcription factors that control naive peripheral blood CD8+ T cell differentiation into type 1 and type 2 cytokine-secreting cells. Intracellular staining revealed that GATA-3 levels in freshly isolated naive CD8+ T cells correlated with specific clinical manifestations. We therefore assessed the effects of GATA-3 inhibition on IL-13 production in CD8+ T cells from the SSc patients. RESULTS: Freshly isolated naive peripheral blood CD8+ T cells expressed high levels of GATA-3 and failed to down-regulate IL-13 production when cultured under type 1-skewing conditions, but maintained adequate levels of interferon-γ production. Cellular GATA-3 levels were significantly higher in patients with dcSSc and early inflammatory disease. Silencing of GATA-3 with small interfering RNA significantly reduced IL-13 production by CD8+ T cells, demonstrating a causal relationship between GATA-3 and IL-13. CONCLUSION: These results provide important new insights into SSc pathogenesis and suggest that increased GATA-3 expression in CD8+ T cells could be a highly relevant biomarker of immune dysfunction in patients with dcSSc. GATA-3 could be a novel therapeutic target for this currently incurable disease.