Cyclosporine in the treatment of azathioprine-induced red cell aplasia following renal transplantation

Azathioprine, a well-known immunosuppressive agent, is used extensively in renal transplantation. There have been several case reports of pure red cell aplasia induced by this drug following a successful kidney transplant. Previous management of azathioprine-induced red cell aplasia included reduction of azathioprine dose, or treatment with cyclophosphamide. We propose the substitution of cyclosporine for azathioprine, in this clinical setting. Not only does cyclosporine allow recovery of bone marrow function, but it maintains a level of immunosuppression which stabilizes renal function in the post-transplant patient.     

Mycophenolate Mofetil Is Associated with Altered Expression of Chronic Renal Transplant Histology

Mycophenolate mofetil (MMF) reduces acute rejection in controlled trials of kidney transplantation and is associated with better registry graft survival. Recent experimental studies have demonstrated additional antifibrotic properties of MMF, however, human histological data are lacking. We evaluated sequential prospective protocol kidney biopsies from two historical cohorts treated with cyclosporine (CSA)-based triple therapy including prednisolone and either MMF (n = 25) or azathioprine (AZA, n = 25). Biopsies (n = 360) were taken from euglycemic kidney-pancreas transplant recipients. Histology was independently assessed by the Banff schema and electron microscopic morphometry. MMF reduced acute rejection and OKT3 use (p < 0.05) compared with AZA. MMF therapy was associated with limited chronic interstitial fibrosis, striped fibrosis and periglomerular fibrosis (p < 0.05-0.001), mesangial matrix accumulation (p < 0.01), chronic glomerulopathy scores (p < 0.05) and glomerulosclerosis (p < 0.05). MMF was associated with delayed expression of CSA nephrotoxicity, reduced arteriolar hyalinosis, striped fibrosis and tubular microcalcification (p < 0.05-0.001). The beneficial effects of MMF remained in recipients without acute rejection. Retrospective analysis shows that MMF therapy was associated with substantially reduced fibrosis in the glomerular, microvascular and interstitial compartments, and a delayed expression of CSA nephrotoxicity. These outcomes may be due to a limitation of immune-mediated injury and suggest a direct effect of reduced fibrogenesis.     

Endocrine and metabolic abnormalities following kidney transplantation

Summary Various endocrine and metabolic disturbances associated with long standing uremia persist after kidney transplantation or arise from the use of immunosuppressive drugs. Hyperlipidemia for long time being implicated as the cause of corticosteroids is also observed in renal transplant recipients treated with cyclosporin A monotherapy. After conversion from cyclosporin to azathioprine serum cholesterol and triglyceride concentration fall, and elevation of LDL-cholesterol may also be reversed. There is a tendency for higher HDL-cholesterol in azathioprine and prednisolone treated transplant patients. Those patients who are at risk for clinically significant cholesterol elevations can be predicted by their pretransplant lipid levels, specifically the LDL-fraction. Risk-benefit ratio of conversion and of treatment with lipid-lowering drugs, especially with lovastatin, should be carefully examined, also in view of glucose intolerance.Higher incidence of diabetes mellitus requiring insulin therapy in cyclosporin treated transplant recipients has been reported. Cyclosporin may cause toxic effects on pancreatic beta-cells resulting in inhibition of insulin secretion. High doses of cyclosporin induce inhibition of glycogen synthesis in rat liver. Glucose intolerance is reversible after reduction of cyclosporin dose or conversion to azathioprine. Therefore glucose metabolism in kidney transplant recipients treated with cyclosporin should be carefully followed.Immunosuppressive therapy may affect reproductive function, arachidonate metabolism and renin-angiotensin-aldosterone system as well as posttransplant calcium and phophate metabolism.Endocrine and metabolic abnormalities are associated with long standing uremia. After successful kidney transplantation several observations are normalized but further complications arise from the use of immunosuppressive drugs. The present paper reviews various endocrine and metabolic disturbances described following renal transplantation.     

Efficacy of infliximab in acute severe ulcerative colitis:A single-centre experience

AIM:To suggest infliximab(IFX) is effective for acute severe ulcerative colitis,from real-life clinical practice.METHODS:All patients receiving IFX for the treatment of acute severe ulcerative colitis in a single centre were included.Data were extracted from clinical records in order to assess response to IFX therapy.The primary endpoint was colectomy-free survival,and secondary outcomes included glucocorticosteroid-free remission and safety,which was evaluated by recording deaths and adverse events.Demographic and clinical characteristics of those who underwent colectomy and those who were colectomy-free,both at discharge from their index admission,and during follow-up after an initial response to IFX were compared.RESULTS:Forty-four patients(16 females,mean age 36 years) received IFX between May 2006 and January 2012 for acute severe ulcerative colitis.The median duration of follow-up post-first infusion was 396 d(interquartile range = 173-828 d).There were 21(47.7%) patients with < 1 year of follow-up,10(22.7%) with 1 years to 2 years of follow-up,and 13(29.5%) with > 2 years of follow-up post-first infusion of IFX.Overall,35(79.5%) responded to IFX,avoiding colectomy during their index admission,29(65.9%) were colectomyfree at last point of follow-up(median follow-up 396 d),and 25(56.8%) were in glucocorticosteroid-free remission at end of follow-up.There was one death from post-operative sepsis,20 d after a single IFX infusion.Colectomy rates were generally lower among those "bridging" to thiopurine.Of 18 patients "bridged" to thiopurine therapy,17(94.4%) were colectomyfree,and 15(83.3%) were in glucocorticosteroid-free remission at study end.No predictors of response were identified.CONCLUSION:IFX is effective for acute severe ulcerative colitis in real-life clinical practice.Two-thirds of patients avoided colectomy,and more than 50% were in glucocorticosteroid-free remission.     

Non-biologic remission maintenance therapy in adult patients with ANCA-associated vasculitis: A systematic review and network meta-analysis

ObjectiveTo determine the comparative efficacy of non-biologic treatments for remission maintenance in ANCA-associated vasculitis.MethodsWe identified all randomized trials comparing leflunomide, azathioprine, methotrexate or mycophenolate mofetil in adult patients with granulomatosis with polyangiitis or microscopic polyangiitis. Relapse-free survival was compared through hazard ratios (HR) using a Bayesian fixed-effects network meta-analysis. Multiple sensitivity analyses were performed to explore biases identified in one trial using original trial data.ResultsThree trials were available (leflunomide-methotrexate, methotrexate- azathioprine, azathioprine-mycophenolate). Mycophenolate was inferior to all treatments, although the 95% credible interval (CrI) of the HR relative to methotrexate crossed 1. Leflunomide was superior to azathioprine (HR 0.43 [95% CrI: 0.14–1.3]) and methotrexate (HR 0.47 [95% CrI: 0.18–1.2]), although the 95% CrI also crossed 1. There was a 90% probability that leflunomide was the best treatment. After down weighting the effect of leflunomide vs. methotrexate for early trial termination and slow MTX dose escalation, there remained a 55% probability leflunomide was best.ConclusionBased on indirect evidence, leflunomide is effective in maintaining remission in granulomatosis with polyangiitis or microscopic polyangiitis relative to other non-biologic treatments. Further randomized trials of leflunomide are needed for confirmation.     

Optimization of azathioprine dose in combined treatment with anti-TNF-alpha in inflammatory bowel disease

IntroductionThe dose of thiopurine drugs in combined treatments with anti-TNF in inflammatory bowel disease (IBD) has not been clearly established. The purpose of this study is to assess whether the dose of azathioprine influences clinical and biochemical response/remission rates, and anti-TNF drug levels/antibody formation.Material and methodsPatients with IBD on combined maintenance treatment with azathioprine and infliximab or adalimumab were selected. Based on the dose of azathioprine, two groups were defined (standard: 2–2.5 mg/kg/day; and decreased: less than 2 mg/kg/day).ResultsIn the IFX group, there were no statistically significant differences (p = 0.204) in the rates of remission (39% vs 41.3%), response (10% vs 21.7%) or failure (51.5% vs 37%) depending on the dose of thiopurine drugs. No differences were found between AZA-dose dependent IFX levels (2.46 vs 3.21 μg/mL; p = 0.211). In the adalimumab group, there were no statistically significant differences (p = 0.83) in the rates of remission (66% vs 56%), response without remission (15.38% vs 25%) or failure (18% vs 18%) depending on the dose of thiopurines. With respect to ADA-levels, no differences were found in both groups (7.69 vs 8.23 μg/mL; p = 0.37).ConclusionIn our experience, no statistically significant differences were found in either anti-TNF levels or clinical-biological response/remission rates based on doses of azathioprine.     

Risk Prediction and Comparative Efficacy of Anti-TNF vs Thiopurines,for Preventing Postoperative Recurrence in Crohn's Disease: A Pooled Analysis of 6 Trials

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Azathioprine in the treatment of systemic lupus erythematosus. A three-year prospective study

Summary In a prospective study, the effect of azathioprine on the clinical course and the anti-dsDNA profile was evaluated in 17 patients with systemic lupus erythematosus (SLE). During this prospective longitudinal study, exacerbations were never observed. Three periods of continuous anti-dsDNA increases with a doubling time (T2) shorter than 10 weeks were noted. Both the clinical symptoms and the anti-dsDNA levels improved after the administration of azathioprine. These results necessitate a careful double-blind trial for the use of this drug to prevent SLE exacerbations.     

High-dose azathioprine pulse therapy as a new treatment option in patients with active Wegener’s granulomatosis and lupus nephritis refractory or intolerant to cyclophosphamide

The objective of this study was to evaluate the feasibility and safety of high-dose azathioprine pulse (HAP) therapy in the induction of remission in patients with active Wegeners granulomatosis (WG) or progressive lupus nephritis (LN) refractory to or intolerant of cyclophosphamide. Four patients with antineutrophil cytoplasmic antibody (ANCA)-associated WG and two patients with progressive LN were treated with HAP (1200–1800 mg) applied monthly as continuous intravenous infusions at 50 mg/h. Patients received a total of 50 courses of intravenous azathioprine (AZA) therapy. Disease activity was assessed using the Birmingham Vasculitis Activity Score (BVAS) and the Systemic Lupus Erythematosus Activity Index (SLEDAI). As only partial remission was induced in patients with progressive LN on this regimen, an additional 18 cycles were applied in these patients in which oral AZA at 100 mg/day in weeks 2 and 3 was added between two intravenous courses. A hereditary defect in thiopurine methyltransferase activity was excluded before initiation of treatment. High-dose azathioprine pulse and the intensified HAP treatment were well tolerated. Complete remission was achieved in two patients with WG suffering from three relapses of disease on application of 2–6 courses of HAP. Remission was maintained for 16–24 months. The remaining two patients with WG were withdrawn after 2–3 courses due to unchanged disease activity. In two patients with LN, partial remission was noted on 6–9 courses of HAP; however, the patients relapsed despite therapy with methotrexate and mycophenolate mofetil. The intensified HAP regimen led to partial or complete remission in both LN patients which was confirmed by sequential renal biopsies. Our results suggest that HAP therapy represents a well-tolerated regimen in patients with active WG and LN intolerant of or refractory to cyclophosphamide. As partial or complete remission was observed in four of six patients, further studies seem warranted to assess clinical efficacy in these patients.