mycophenolic-acid and Arterial-Occlusive-Diseases

Takayasu arteritis (TA) in the child remains a therapeutic challenge because corticosteroids and conventional immunosuppressive agents are not always safe or efficacious. The complex formed by interleukin-6 (IL-6) and soluble IL-6 receptor appears to play a pivotal role in the pathogenesis of TA. We describe a favorable response to the anti-IL-6 receptor antibody tocilizumab (TCZ) in a child with aggressive and refractory TA including an assessment of the proinflammatory cytokine profile. A 3-year-old girl with TA consisting of thickening of the aortic arch wall, severe obstruction of the supra-aortic branches, and complete occlusion of both common carotid arteries failed to respond to corticosteroids, methotrexate, tumor necrosis factor α blockade, cyclophosphamide, and mycophenolate mofetil, and 3 years later, the disease remained active with severe manifestations (brain ischemia). The patient underwent percutaneous angioplasty, although significant restenosis was soon documented. After a severe relapse, the patient started TCZ infusions (8 mg/kg for 2 weeks), and a rapid clinical remission was observed, associated with a drastic reduction of inflammatory markers and IL-6 levels. Corticosteroids were withdrawn, the patient's weight and height improved, and bone mineral density values returned to normal. Two years later, TCZ infusions were extended, with no significant side effects. Cerebral ischemia resolved, and recanalization of the previously occluded supra-aortic branches was performed.

Topics: Anti-Inflammatory Agents; Antibodies, Monoclonal, Humanized; Aorta, Thoracic; Arterial Occlusive Diseases; Brachiocephalic Trunk; Brain Ischemia; Carotid Stenosis; Child, Preschool; Drug Resistance; Drug Substitution; Drug Therapy, Combination; Female; Humans; Image Interpretation, Computer-Assisted; Imaging, Three-Dimensional; Immunosuppressive Agents; Inflammation Mediators; Infusions, Intravenous; Magnetic Resonance Angiography; Mycophenolic Acid; Platelet Aggregation Inhibitors; Prednisone; Recurrence; Subclavian Steal Syndrome; Takayasu Arteritis; Ultrasonography, Doppler

Replacement of calcineurin inhibitor (CI) with anti-metabolic agents in transplant patients with CI-induced nephrotoxicity is performed clinically and improves renal function, but increases the risk of rejection. We investigated whether the change from cyclosporine (CsA) to a limited dose of mycophenolic acid (MPA) together with a new sphingosine-1-phosphate (S1P) receptor agonist, KRP-203, is sufficient to prevent both transplant vasculopathy and CsA-induced nephrotoxicity.. Orthotopic aortic transplantation was conducted in a high-responder rat combination of Dark Agouti (DA; major histocompatibility complex [MHC] haplotype RT-1a) to Lewis (RT-1(l)). After CsA administration (15 mg/kg/day) for 2 weeks, the recipients were divided into the following treatment groups for 6 weeks: MPA (10 mg/kg); KRP-203 (KRP; 1 mg/kg); and MPA + KRP. Serum creatinine (Cr), arteriolar hyalinosis and expression of transforming growth factor (TGF)-beta1 in the recipient kidney were examined as parameters indicating nephrotoxicity. Intimal hyperplasia was assessed by vascular occlusion, and graft-infiltrated cells were semi-quantitatively evaluated histologically and then characterized immunohistochemically.. Continuous CsA treatment attenuated intimal hyperplasia and cell infiltration (2.9 +/- 0.3% and 0.4 +/- 0.1; p < 0.01 vs vehicle), but increased Cr and hyalinosis (0.43 +/- 0.03 mg/dl and 57.2 +/- 0.4%; p < 0.01) with upregulated TGF-beta1. Replacement of CsA by MPA or KRP treatment alone improved nephrotoxicity, but worsened intimal hyperplasia and cell infiltration. Conversion to MPA + KRP treatment prevented nephrotoxicity (Cr, 0.32 +/- 0.02 mg/dl; hyalinosis, 5.6 +/- 1.3%; p < 0.01 vs CsA) and markedly suppressed intimal hyperplasia and cell infiltration (3.6 +/- 1.2% and 1.0 +/- 0.3; p = not significant vs CsA), with reduced T-cell infiltrates in the graft.. Changing from CsA to a combined therapy of MMF with S1P agonist is a promising strategy in clinical transplantation to overcome CI-induced nephrotoxicity and chronic rejection.

Topics: Animals; Aorta; Aortic Diseases; Arterial Occlusive Diseases; Blood Cell Count; Cyclosporine; Drug Therapy, Combination; Hyperplasia; Immunohistochemistry; Immunosuppressive Agents; Kidney Diseases; Macrophages; Male; Mycophenolic Acid; Rats; Rats, Inbred Strains; Receptors, Lysosphingolipid; Retreatment; Sulfhydryl Compounds; T-Lymphocytes; Transplantation, Homologous; Tunica Intima

Topics: Arterial Occlusive Diseases; Graft Rejection; Heart Transplantation; Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Immunosuppressive Agents; Mycophenolic Acid; Sirolimus