New insights into the pharmacokinetics and pharmacodynamics of natalizumab treatment for patients with multiple sclerosis, obtained from clinical and in vitro studies.

BACKGROUND: The monoclonal antibody natalizumab (NAT) inhibits the migration of lymphocytes throughout the blood-brain barrier by blocking very late antigen (VLA)-4 interactions, thereby reducing inflammatory central nervous system (CNS) activity in patients with multiple sclerosis (MS). We evaluated the effects of different NAT treatment regimens. METHODS: We developed and optimised a NAT assay to measure free NAT, cell-bound NAT and VLA-4 expression levels in blood and cerebrospinal fluid (CSF) of patients using standard and prolonged treatment intervals and after the cessation of therapy. RESULTS: In paired CSF and blood samples of NAT-treated MS patients, NAT concentrations in CSF were approximately 100-fold lower than those in serum. Cell-bound NAT and mean VLA-4 expression levels in CSF were comparable with those in blood. After the cessation of therapy, the kinetics of free NAT, cell-bound NAT and VLA-4 expression levels differed. Prolonged intervals greater than 4 weeks between infusions caused a gradual reduction of free and cell-bound NAT concentrations. Sera from patients with and without NAT-neutralising antibodies could be identified in a blinded assessment. The NAT-neutralising antibodies removed NAT from the cell surface in vivo and in vitro. Intercellular NAT exchange was detected in vitro. CONCLUSIONS: Incorporating assays to measure free and cell-bound NAT into clinical practice can help to determine the optimal individual NAT dosing regimen for patients with MS.

Successful treatment of systemic-sclerosis-related digital ulcers with a selective endothelin type A receptor antagonist (sitaxentan).

Digital ulcers represent a major vascular complication of systemic sclerosis (SSc) and can be difficult to treat with the common vasodilators. Herein, we report on a 39-year-old patient with recalcitrant SSc-related digital ulcers treated successfully with sitaxentan (100 mg q.d.), a selective endothelin type A receptor antagonist. During the 6 months of treatment, we noticed a remarkable decrease in pain, a nearly complete healing of the preexistent ulcers and no development of new ulcers. No side effects were noted.

[First manifestation of psoriasis vulgaris in tumor necrosis factor receptor-associated periodic syndrome during treatment with etanercept]. / Erstmanifestation einer Psoriasis vulgaris bei Tumornekrosefaktor-Rezeptor-1-assoziiertem periodischem Syndrom unter Therapie mit Etanercept.

Drugs antagonizing tumor necrosis factor (TNF) alpha have been increasingly and successfully used in the treatment of psoriasis vulgaris and psoriatic arthritis. We report a patient with TNF receptor 1-associated periodic syndrome (TRAPS) who received TNF-alpha antagonist etanercept. A month later, the patient developed for the first time generalized psoriasis vulgaris. This paradoxical phenomenon has been reported sporadically in patients receiving TNF-alpha antagonists for other inflammatory diseases. The cause of psoriasis induced by TNF-alpha antagonists is still obscure.