sirolimus and Vasculitis

Several novel immunosuppressive agents have been developed in recent years. They exhibited not only remarkable immunosuppressive potency but also side effects. They are still short of the final goal in terms of immunosuppression for organ transplantation. Combination treatment is more effective and safer to use, and it will prevail in the future.

Topics: Amylases; Animals; Antibodies, Monoclonal; Cell Adhesion Molecules; Cyclosporine; Drug Therapy, Combination; Graft Rejection; Humans; Immunosuppressive Agents; Polyenes; Sirolimus; Tacrolimus; Transplantation, Heterologous; Vasculitis

Out-stent plaque characteristics and eosinophilic inflammatory response, which correlates with positive remodeling after first-generation drug-eluting stent implantation, may be associated with late restenosis and very late stent thrombosis. The differences of out-stent plaque characteristics were compared between paclitaxel-eluting stents (PES) and zotarolimus-eluting stents (ZES), using integrated backscatter-intravascular ultrasound (IB-IVUS).. Of 78 patients enrolled, 25 receiving PES and 25 receiving ZES had adequate IVUS assessment. Volumetric IVUS analysis was performed after stenting and at 8-month follow-up. Out-stent plaque change in the stented segment was compared on IB-IVUS. The relationship between systemic inflammatory response and out-stent plaque change was evaluated. In PES, vessel volume significantly increased (365-389 mm(3), P<0.0001), whereas it did not change in ZES (315-314 mm(3), P=0.81). In culprit lesions at baseline in PES, fibrous plaque tended to increase (3.1-3.6mm(2), P=0.051) and lipid plaque significantly increased (4.3-5.1mm(2), P=0.02), whereas in ZES the fibrous plaque significantly increased (2.9-4.0mm(2), P<0.0001) but lipid plaque significantly decreased (5.1-3.6mm(2), P<0.0001). Systemic eosinophil increase was significantly correlated with positive remodeling and out-stent lipid plaque increase.. Chronic out-stent plaque change in ZES consisted of less positive remodeling and more favorable effects on out-stent plaque characteristics than PES. Systemic eosinophil change might be a marker of out-stent lipid plaque change.

Topics: Aged; Aged, 80 and over; Angioplasty, Balloon, Coronary; Coronary Artery Disease; Coronary Restenosis; Drug-Eluting Stents; Eosinophils; Female; Follow-Up Studies; Humans; Male; Middle Aged; Paclitaxel; Risk Factors; Sirolimus; Treatment Outcome; Tubulin Modulators; Ultrasonography, Interventional; Vasculitis; Ventricular Remodeling

Topics: Biomimetics; Humans; Nanoparticles; Sirolimus; Vasculitis

Mammalian target of rapamycin complex 1 (mTORC 1) drives the proinflammatory expansion of T helper (TH) type 1, TH17 cells and controls fibroblast proliferation, typical features of large vessel vasculitis (LVV) pathogenesis. Molecular pathways involved in arterial lesions of LVV are unknown.. We evaluate mTORC pathway activation in vascular aorta lesions and in T cell homeostasis of patients with LVV.. Proliferation of both endothelial cells and vascular smooth-muscle cells was shown in vascular lesions in LVV. The vascular endothelium of proliferating aorta vessels from patients with LVV showed indications of activation of the mTORC1 pathway (S6RP phosphorylation). In cultured vascular endothelial cells, sera from patients with LVV stimulated mTORC1 through the phosphorylation of S6RP. mTORC1 activation was found also in Th1 and Th17 cells both systemically and in inflamed vessels. Patients with LVV exhibited a diminished S6RP phosphorylation in Tregs. Inhibition of mTORC1 pathway with rapamycin, increase Tregs and decrease effector CD4. We provided evidence that mTORC1 pathway has a central role in driving T cell inflammation and vascular lesions in LVV. Targeting mTORC pathway may represent a new therapeutic option in patients with LVV.

Topics: Adult; Aged; Aorta; Case-Control Studies; Cell Proliferation; Endothelial Cells; Female; Gene Expression Regulation; Humans; Interferon-gamma; Interleukin-17; Interleukins; Male; Mechanistic Target of Rapamycin Complex 1; Middle Aged; Myocytes, Smooth Muscle; Phosphorylation; Primary Cell Culture; Signal Transduction; Sirolimus; T-Lymphocytes, Regulatory; Th1 Cells; Th17 Cells; TOR Serine-Threonine Kinases; Vasculitis

Coronary adventitia harbors a wide variety of components, such as inflammatory cells and vasa vasorum (VV). Adventitial VV initiates the development of coronary artery diseases as an outside-in supply route of inflammation. We have recently demonstrated that drug-eluting stent implantation causes the enhancement of VV formation, with extending to the stent edges in the porcine coronary arteries, and also that optical frequency domain imaging (OFDI) is capable of visualizing VV in humans in vivo. However, it remains to be fully validated whether OFDI enables the precise measurement of VV formation in pigs and humans.. In the pig protocol, a total of 6 bare-metal stents and 12 drug-eluting stents were implanted into the coronary arteries, and at 1 month, the stented coronary arteries were imaged by OFDI ex vivo. OFDI data including the measurement of VV area at the stent edge portions were compared with histological data. There was a significant positive correlation between VV area on OFDI and that on histology (R=0.91, P<0.01). In the human protocol, OFDI enabled the measurement of the VV area at the stent edges after coronary stent implantation in vivo.. These results provide the first direct evidence that OFDI enables the precise measurement of the VV area in coronary arteries after stent implantation in pigs and humans.

Topics: Adventitia; Aged; Aged, 80 and over; Animals; Aspirin; Clopidogrel; Coronary Stenosis; Coronary Vessels; Disease Progression; Drug-Eluting Stents; Everolimus; Female; Humans; Interferometry; Male; Middle Aged; Neointima; Neovascularization, Physiologic; Platelet Aggregation Inhibitors; Postoperative Period; Prosthesis Implantation; Sirolimus; Stents; Swine; Swine, Miniature; Ticlopidine; Tomography, Optical Coherence; Vasa Vasorum; Vasculitis

Rapamycin has been reported to inhibit mesenchymal cell proliferation in a murine model of pulmonary fibrosis. In the present study, we examined the effects of rapamycin on vascular remodeling including intraluminal myofibroblast proliferation in a murine model of allergic vasculitis with eosinophil infiltration.. C57BL/6 mice were sensitized with ovalbumin (OVA) and alum. The positive controls were exposed to aerosolized OVA daily for 7 days. The other group of mice was administered with rapamycin (1mg/kg) intraperitoneally, in parallel with daily exposure to aerosolized OVA for 7 days. On the 3rd and 7th day, bronchoalveolar lavage (BAL) was performed and the lungs were excised for pathological analysis. Cell differentials were determined and concentrations of IL-4, IL-5, IL-13 and TGF-β in the BAL fluid (BALF) were measured. Semi-quantitative analysis of pathological changes in the pulmonary arteries was evaluated according to the severity of vasculitis.. The number of eosinophils in BALF was reduced significantly in the mice treated with rapamycin compared to the positive control. There was a significant decrease in the TGF-β concentration of the BALF in the rapamycin-treated group compared to that of the positive control. The pathological scores were reduced significantly in the rapamycin-treated group compared to the positive control group. Intraluminal myofibroblasts in pulmonary arteries were reduced dramatically in the rapamycin-treated group compared to the positive control group.. Rapamycin suppressed pulmonary vascular remodeling in a murine model of allergic vasculitis with eosinophil infiltration through reducing eosinophil infiltration and TGF-β production in the lung and inhibition against biological action of TGF-β.

Topics: Animals; Cell Proliferation; Disease Models, Animal; Disease Progression; Eosinophils; Female; Humans; Hypersensitivity; Immunosuppressive Agents; Lung Diseases; Mice; Mice, Inbred C57BL; Myofibroblasts; Pulmonary Artery; Sirolimus; Transforming Growth Factor beta; Vascular Remodeling; Vasculitis

The Absorb everolimus-eluting bioresorbable vascular scaffold (Absorb) has shown promising clinical results; however, only limited preclinical data have been published. We sought to investigate detailed pathological responses to the Absorb versus XIENCE V (XV) in a porcine coronary model with duration of implant extending from 1 to 42 months.. A total of 335 devices (263 Absorb and 72 XV) were implanted in 2 or 3 main coronary arteries of 136 nonatherosclerotic swine and examined by light microscopy, scanning electron microscopy, pharmacokinetics, and gel permeation chromatography analyses at various time points. Vascular responses to Absorb and XV were largely comparable at all time points, with struts being sequestered within the neointima. Inflammation was mild to moderate (with absence of inflammation at 1 month) for both devices, although the scores were greater in Absorb at 6 to 36 months. Percent area stenosis was significantly greater in Absorb than XV at all time points except at 3 months. The extent of fibrin deposition was similar between Absorb and XV, which peaked at 1 month and decreased rapidly thereafter. Histomorphometry showed expansile remodeling of Absorb-implanted arteries starting after 12 months, and lumen area was significantly greater in Absorb than XV at 36 and 42 months. These changes correlated with dismantling of Absorb seen after 12 months. Gel permeation chromatography analysis confirmed that degradation of Absorb was complete by 36 months.. Absorb demonstrates comparable long-term safety to XV in porcine coronary arteries with mild to moderate inflammation. Although Absorb was associated with greater percent stenosis relative to XV, expansile remodeling was observed after 12 months in Absorb with significantly greater lumen area at ≥ 36 months. Resorption is considered complete at 36 months.

Topics: Absorbable Implants; Animals; Chromium Alloys; Coronary Angiography; Coronary Vessels; Drug-Eluting Stents; Everolimus; Incidence; Microscopy, Electron, Scanning; Models, Animal; Neointima; Sirolimus; Stents; Swine; Swine, Miniature; Time Factors; Tissue Scaffolds; Vasculitis

Topics: Biopsy; Cardiovascular Agents; Coronary Thrombosis; Coronary Vessels; Drug-Eluting Stents; Humans; Middle Aged; Myocardial Infarction; Percutaneous Coronary Intervention; Prosthesis Design; Sirolimus; Thrombectomy; Time Factors; Tomography, Optical Coherence; Treatment Outcome; Vasculitis; Wound Healing

Although durable polymer coated drug-eluting stents (DES) are standard care in percutaneous coronary interventions, new stent platforms employing biodegradable polymer based drug delivery are increasingly being used in clinical practice.. To evaluate the short- (28 days) and medium-term (90 days) vascular effects of the new biodegradable polymer coated sirolimus-eluting stent - the PROLIM stent.. The objectives of the study were evaluated using standard angiographic and histological methods. In addition, the mechanical integrity of tested stents was assessed using Faxitron imaging. A total of 12 PROLIM stents, 11 biodegradable polymer only coated stents (BPCS), and 12 bare metal stents (BMS) were implanted in the coronary arteries of 16 female non-atheroslerotic domestic swine using an overstretch of 1.1:1.0.. At 28 days, neointimal proliferation was significantly lower in the PROLIM and BMS stents compared to the BPCS stents (p ≤ 0.05). Interestingly, despite thin neointima found at this time in the PROLIM group, there was a further significant decrease in neointimal formation between 28 and 90 days (p = 0.04). Although a statistically bigger neointima was found in BPCS stents at 28 days compared to the PROLIM and BMS stents, there was a 50% decrease in the neointimal area at 90 days follow-up (p = 0.02) which reached the level seen in other groups. The endothelialisation was completed in all tested stents after 28 days. There was a significant increase of fibrin depositions in the PROLIM treated arteries at 28 days which were resorbed nearly completely at 90 days follow-up. At 28 days, the inflammatory response was found to be numerically higher in the BPCS stents (p = NS) compared to other tested groups. On the contrary, at 90 days follow-up when the degradation process of the polymer had been completed, the inflammatory reaction decreased substantially to the level seen in the PROLIM and BMS stents. Faxitron analysis of the stented arteries revealed no major abnormalities except for isolated strut fractures observed in the mid portions of two BMS stents and one BPCS stent.. The PROLIM - a biodegradable polymer coated sirolimus-eluting stent - demonstrates very good short-term and medium-term angiographic and histological results. The lack of 'catch-up phenomenon', fast endothelialisation process, and minimal inflammatory reaction may contribute to favourable clinical outcomes using PROLIM stents.

Topics: Absorbable Implants; Animals; Coated Materials, Biocompatible; Coronary Angiography; Coronary Vessels; Drug-Eluting Stents; Female; In Vitro Techniques; Materials Testing; Polyesters; Prosthesis Design; Sirolimus; Swine; Vasculitis

Topics: Adrenal Cortex Hormones; Adult; Chronic Disease; Dose-Response Relationship, Drug; Drug Administration Schedule; Drug Resistance; Female; Follow-Up Studies; Humans; Male; Middle Aged; Recurrence; Risk Assessment; Sampling Studies; Severity of Illness Index; Sirolimus; Treatment Outcome; Urticaria; Vasculitis

Sirolimus and everolimus belong to the novel class of immunosuppressant agents known as proliferation signal inhibitors (PSIs). They act by preventing antigen-driven T cell proliferation. While PSIs are widely used in transplantation, there are few reports of PSI usage in the treatment of autoimmune rheumatic diseases. The author has presented a series in the APLAR 2006 conference. This report summarizes the clinical experience with PSIs in the treatment of resistant or relapsed rheumatic diseases where conventional immunosuppressive agents have failed. This is a retrospective review of patients with various autoimmune rheumatic diseases who had sirolimus and everolimus treatment from the rheumatological clinics of Changi Hospital or the Arthritis and Rheumatism Specialist Medical Centre. The period of review was from April 2006 to April 2008. A total of 46 patients were reviewed, 39 females and 7 males. The racial distribution was 33 Chinese, 7 Malays, and 6 Indians. Their disease conditions were as follows: 26 (57%) rheumatoid arthritis, 7 psoriatic arthritis, 4 systemic lupus erythematosus, 3 scleroderma, 2 anti-Jo-1 syndrome, 2 spondyloarthropathy, 1 MCTD, and 1 vasculitis. All patients had failed at least three DMARDs or immunosuppressants. Twenty-eight patients received sirolimus and 28 patients received everolimus. Overall positive response rate was 48.2%. Twenty-seven percent had adverse events. 20% had no response. 7% relapsed after initial response. PSIs, namely sirolimus and everolimus, are a novel class of immunosuppressants that can be added to the armamentarium of rheumatologists for the treatment of patients with refractory autoimmune rheumatic diseases.

Topics: Adult; Aged; Arthritis, Psoriatic; Arthritis, Rheumatoid; Autoimmune Diseases; Drug Resistance; Everolimus; Female; Humans; Immunosuppressive Agents; Lupus Erythematosus, Systemic; Male; Middle Aged; Molecular Structure; Retrospective Studies; Rheumatic Diseases; Scleroderma, Systemic; Sirolimus; Spondylarthropathies; Treatment Outcome; Vasculitis

We report the case of a child with microscopic polyangiitis (myeloperoxidase-antineutrophil cytoplasmic antibody [p-ANCA]-positive vasculitis) whose disease progressed to end-stage renal failure, in whom sirolimus contributed to normalization of myeloperoxidase and ANCA titers. The disease course, various therapies, and outcome are discussed, as is the rationale for using sirolimus.

Topics: Adolescent; Antibodies, Antineutrophil Cytoplasmic; Female; Humans; Immunosuppressive Agents; Kidney Failure, Chronic; Kidney Transplantation; Peroxidase; Sirolimus; Transplantation Conditioning; Vasculitis