Consequences of cathepsin C inactivation for membrane exposure of proteinase 3, the target antigen in autoimmune vasculitis

Membrane-bound proteinase 3 (PR3(m)) is the main target antigen of anti-neutrophil cytoplasmic autoantibodies (ANCA) in granulomatosis with polyangiitis, a systemic small-vessel vasculitis. Binding of ANCA to PR3(m) triggers neutrophil activation with the secretion of enzymatically active PR3 and related neutrophil serine proteases, thereby contributing to vascular damage. PR3 and related proteases are activated from pro-forms by the lysosomal cysteine protease cathepsin C (CatC) during neutrophil maturation. We hypothesized that pharmacological inhibition of CatC provides an effective measure to reduce PR3(m) and therefore has implications as a novel therapeutic approach in granulomatosis with polyangiitis. We first studied neutrophilic PR3 from 24 patients with Papillon-Lefevre syndrome (PLS), a genetic form of CatC deficiency. PLS neutrophil lysates showed a largely reduced but still detectable (0.5-4%) PR3 activity when compared with healthy control cells. Despite extremely low levels of cellular PR3, the amount of constitutive PR3(m) expressed on the surface of quiescent neutrophils and the typical bimodal membrane distribution pattern were similar to what was observed in healthy neutrophils. However, following cell activation, there was no significant increase in the total amount of PR3(m) on PLS neutrophils, whereas the total amount of PR3(m) on healthy neutrophils was significantly increased. We then explored the effect of pharmacological CatC inhibition on PR3 stability in normal neutrophils using a potent cell-permeable CatC inhibitor and a CD34(+) hematopoietic stem cell model. Human CD34(+) hematopoietic stem cells were treated with the inhibitor during neutrophil differentiation over 10 days. We observed strong reductions in PR3(m), cellular PR3 protein, and proteolytic PR3 activity, whereas neutrophil differentiation was not compromised

Rapidly Growing Tumour on the Forearm of an 83-year-old Woman: A Quiz

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Effect of Diet in Chronic Spontaneous Urticaria: A Systematic Review

International audienceStrategies for diets in chronic spontaneous urticaria (CSU) are controversial. This systematic review assessed the interest in diet for managing CSU. We searched for original reports in MEDLINE, EMBASE, CENTRAL and LILACS. Among the 278 reports screened, 20 were included, involving 1,734 patients. Reports described 3 types of systematic diet: pseudoallergen-free diet (n = 1,555 patients), low-histamine diet (n = 223) and diet without fish products (n = 47), which induced complete remission in 4.8%, 11.7% and 10.6% of patients, respectively, and partial remission in 37.0%, 43.9% and 4.3%. Eight reports described personalized exclusion diets (66 patients) adapted to symptoms/allergological test results and led to complete remission in 74.6% of patients, although the diagnosis of CSU was doubtful. No comparative randomized studies of diets were available. The only randomized studies were based on oral provocation tests with the suspected responsible diet. Population and outcomes were heterogeneous. In conclusion, there is evidence for the benefit of diets in CSU only in individual patients with clinical symptoms. However, the level of evidence is low for the benefit of systematic diets in CSU because systematic double-blind controlled trials of diet are lacking

Efficacy and safety of methotrexate versus placebo as add-on therapy to H1 antihistamines for patients with difficult-to-treat chronic spontaneous urticaria: A randomized, controlled trial

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Evaluation of a low-dose methotrexate added to h1-antihistamines regimen for severe chronic spontaneous urticaria: a phase III, randomized, placebo-controlled trial

International audienceIntroduction: H1-antihistamines (anti-H1) are the first-line treatment for chronic spontaneous urticaria (CSU). Immunosuppressive drugs may be proposed in case of incomplete improvement of CSU. Objective: To evaluate the efficacy of a low-dose methotrexate added to H1-antihistamines regimen for CSU resistant to anti-H1 treatment, compared with anti-H1 monotherapy in a randomized, placebo-controlled trial. Materials and Methods: Patients with CSU resistant to at least a 3 month-period of anti-H1 were randomly assigned to receive either low-dose methotrexate (0.2 mg/kg/week) or placebo in addition to anti-H1. Primary outcome was the proportion of patient with complete remission of CSU after 18 weeks (W18), defined as no urticarial lesion within the previous 30 days. Intention to treat analyses were performed (failure was considered when data on primary outcome were missing). Results: From November 2011 to May 2016, 75 patients were randomized: 39 were allocated to methotrexate and 36 to placebo. In the intention to treat population, 3 patients in the methotrexate group (7.9%) and 0 patient in the placebo group (0.0%) had a complete remission at W18 (difference, 7.9 percentage points, [95% confidence interval (CI) -4.0 to 20.8], p=0.24). Eleven patients in the methotrexate group (29.0%) and 6 patients in the placebo group (18.8%) had less than 7 days with urticarial lesions within the 30 days before W18 (difference, 10.2 percentage points, [95% CI -10.2 to 28.8], p=0.40). Clinical adverse events occurred in 56.4% of patients in the methotrexate group and 50.0% in the placebo group (p=0.58), mostly gastrointestinal symptoms. Biological adverse events occurred in 59.0% of patients in the methotrexate group and 30.6% in the placebo group (p=0.01), mainly increased blood level of transaminases. Conclusions: We did not evidence any superiority of a low dose methotrexate added to anti-H1, compared with anti-H1 monotherapy, for patients with chronic spontaneous urticarial