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BackgroundHereditary angioedema (HAE) is a rare disease caused by C1-esterase inhibitor (C1-INH) deficiency, characterized by periodic attacks of acute edema affecting subcutaneous (SC) tissues and mucous membranes. Human C1-INH concentrate given intravenously (IV) is effective and safe, but venous access may be difficult. We compared SC and IV administration of human pasteurized C1-INH concentrate with respect to pharmacokinetics, pharmacodynamics, and safety.Study Design and MethodsThis was a prospective, randomized, open-label, crossover study. Twenty-four subjects with mild or moderate HAE were randomly assigned during an attack-free interval to receive 1000 units of human pasteurized C1-INH concentrate IV or SC. Plasma levels of C1-INH activity and antigen, C4 antigen, cleaved high-molecular-weight kininogen (clHK), and C1-INH antibodies were measured.ResultsThe mean relative bioavailability of functional C1-INH after SC administration was 39.7%. Maximum C1-INH activity after SC administration occurred within 48 hours and persisted longer than after IV administration. C4 antigen levels increased and clHK levels decreased after IV and SC administration, indicating the pharmacodynamic action of C1-INH. The mean half-life of functional C1-INH was 62 hours after IV administration and 120 hours after SC administration (p = 0.0595). C1-INH concentrate was safe and well tolerated when administered via both routes. As expected, SC administration resulted in a higher incidence of injection site reactions, all of which were mild.ConclusionWith a relative bioavailability of 39.7%, SC administration of human pasteurized C1-INH yields potentially clinically relevant and sustained plasma levels of C1-INH and is safe and well tolerated.

Protein tyrosine phosphatase 1B (PTP1B) is a negative regulator of BCR-ABL-mediated transformation in vitro and in vivo. To investigate whether PTP1B modulates the biological effects of the abl kinase inhibitor STI571in BCR-ABL-positive cells, we transfected Philadelphia chromosomep ositive (Ph+) chronic myeloid leukemia cell-derived K562 cells with either wild-type PTP1B (K562/PTP1B), a substrate-trapping dominant-negative mutant PTP1B (K562/D181A), or empty vector (K562/mock). Cells were cultured with or without STI571and analyzed for its effects on proliferation, differentiation, and apoptosis. In both K562/mock and K562/PTP1B cells, 0.25 to 1 Amol/L STI571 induced dose-dependent growth arrest and apoptosis, as measured by a decrease of cell proliferation and an increase of Annexin V-positive cells and/or of cells in the sub-G 1 apoptotic phase. Western blot analysis showed increased protein levels of activated caspase-3 and caspase-8 and induction of poly(ADP-ribose) polymerase cleavage. Low concentrations of STI571promoted erythroid differentiation of these cells. Conversely, K562/D181A cells displayed significantly lower PTP1B-specific tyrosine phosphatase activity and were significantly less sensitive to STI571-induced growth arrest, apoptosis, and erythroid differentiation. Pharmacologic inhibition of PTP1B activity in wild-type K562 cells, using bis(N,N-dimethylhydroxamido)hydroxooxovanadate, attenuated STI571-induced apoptosis. Lastly, comparison of the STI571-sensitive Ph+ acute lymphoblastic leukemia cell line SupB15 with a STI571-resistant subline revealed significantly decreased PTP1B activity and enhanced BCR-ABL phosphorylation in the STI571-resistant SupB15 cells. In conclusion, functional PTP1B is involved in STI571-induced growth and cell cycle arrest, apoptosis, and differentiation, and attenuation of PTP1B function may contribute to resistance towards STI571.

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Objective To investigate the efficacy and safety of rituximab + leflunomide in patients with rheumatoid arthritis (RA). Methods In this investigator-initiated, randomised, double-blind, placebo-controlled phase 3 trial, patients with an inadequate response to leflunomide who had failed ≥1 disease-modifying antirheumatic drug were randomly assigned 2:1 to intravenous rituximab 1000 mg or placebo on day 1 and 15 plus ongoing oral leflunomide. The primary efficacy outcome was the difference between ≥50% improvement in American College of Rheumatology criteria (ACR50 response) rates at week 24 (p ≤ 0.025). Secondary endpoints included ACR20/70 responses, ACR50 responses at earlier timepoints, and adverse event (AE) rates. The planned sample size was not achieved due to events beyond the investigators’ control. Results Between August 13, 2010 and January 28, 2015 140 patients received rituximab (n = 93) or placebo (n = 47) plus ongoing leflunomide. Rituximab + leflunomide resulted in an increase in the ACR50 response rate which was significant at week 16 (32% vs 15%; p = 0.020), but not week 24 (27% vs 15%;] p = 0.081), the primary end point. Significant differences favoring the rituximab + leflunomide arm were observed in some secondary endpoints, including ACR20 rates from weeks 12–24. The rituximab and placebo arms had similar AE rates (71% vs 70%), but the rituximab arm had a higher rate of serious AEs (SAEs: 20% vs 2%), primarily infections and musculoskeletal disorders. Conclusion The primary end point was not reached, but rituximab + leflunomide demonstrated clinical benefits vs leflunomide in secondary endpoints. Although generally well tolerated, the combination was associated with additional SAEs and requires monitoring. Trial registration EudraCT: 2009–015950-39; ClinicalTrials.gov: NCT01244958.