Daily Prednisolone Research Articles

Pamidronate Reduces Bone Loss after Allogeneic Stem Cell Transplantation

Rapid bone loss occurs from the proximal femur after allogeneic stem cell transplantation (alloSCT). The objective of the study was to evaluate effects of high-dose pamidronate therapy on bone loss (BMD) after alloSCT. This was a randomized, multicenter, open-label, 12-month prospective study of iv pamidronate (90 mg/month) beginning before conditioning vs. no pamidronate. All 116 patients also received calcitriol (0.25 microg/d) and calcium (1000 mg/d), which were continued for another year. Primary objectives were to compare changes in BMD 12 months after alloSCT at the femoral neck, lumbar spine, and total hip between the treatment arms and assess influences of glucocorticoid and cyclosporin therapy on these changes. Pamidronate reduced bone loss at the spine, femoral neck, and total hip by 5.6, 7.7, and 4.9% (all P < or = 0.003), respectively, at 12 months. However, BMD of the femoral neck and total hip was still 2.8 and 3.5% lower than baseline, respectively (P < 0.05) with pamidronate. Only differences at the total hip remained significant between the two groups at 24 months. Benefits were restricted to patients receiving an average daily prednisolone dose greater than 10 mg and cyclosporin therapy for more than 5 months within the first 6 months of alloSCT. Pamidronate markedly reduced but did not completely prevent postallogeneic bone marrow transplantation bone loss. BMD benefits were greatest in patients on higher doses of immunosuppressive therapy, but most were lost 12 months after stopping pamidronate. Studies of more potent bisphosphonates or anabolic therapy with PTH after alloSCT are warranted with the aim of durable maintenance of bone mass.

Treatment of acute graft-versus-host disease with prednisolone: significant survival advantage for day +5 responders and no advantage for nonresponders receiving anti–thymocyte globulin

Newly diagnosed patients with acute graft-versus-host disease (GvHD, grades I-IV; n = 211) were given 6-methylprednisolone (6MPred) 2 mg/kg per day for 5 consecutive days; 150 patients (71%) tapered 6MPred on day +5 and were considered responders; 61 patients (29%) could not taper their steroid dose and were considered nonresponders. The cumulative incidence of transplant-related mortality (TRM) for responders and nonresponders is, respectively, 27% and 49% (P = .009), and the 5-year survival is 53% and 35% (P = .007). Nonresponders on day +5 (n = 61) were randomized to receive 6MPred 5 mg/kg per day for 10 days alone (n = 34) or in combination with rabbit anti-thymocyte globulin (ATG, 6.25 mg/kg in 10 days; n = 27). The 2 groups were balanced for clinical and GvHD characteristics. One month after randomization, 26% had a complete response; 23%, a partial response; 33%, stable GvHD; 10%, worsened; and 8%, died. There was no significant difference in response, TRM, and survival between the non-ATG and ATG group. In conclusion, 5 days of prednisolone as first-line therapy of acute GvHD identifies patients with different risk of TRM, and second-line therapy with a combination of 6MPred + ATG does not improve patient outcome, compared with 6MPred alone.

A Newborn Who Has a Swollen Upper Extremity

A term male newborn presents with a swollen left upper extremity. ### Prenatal History: ### Birth History and Presentation: The infant was delivered from vertex presentation by spontaneous vaginal delivery. A pediatric team was not present at the delivery because there were no risk factors. Delivery was complicated by left shoulder dystocia. Because the labor and delivery nurse noted that the infant had poor tone and respiratory effort, he received positive pressure ventilation with bag and mask for approximately 1 minute, and the pediatric team was called. Apgar scores were 3 at 1 minute and 7 at 5 minutes. The birthweight was 3.7 kg. What other physical examination findings are pertinent? What laboratory tests would you order? What interventions are indicated? ### Vital Signs: ### Physical Examination: #### Photograph of infant's body The patient was started on oxygen by nasal …

Continuous prednisolone versus conventional prednisolone with VMCP–interferon‐α2b as first‐line chemotherapy in elderly patients with multiple myeloma

We report on a randomised trial that aimed to compare the efficacy of continued daily prednisolone treatment during the entire induction phase, with prednisolone given for 2 weeks of each cycle in combination with VMCP (vincristine, melphalan, cyclophosphamide, prednisolone)-interferon-alpha 2b (IFN-alpha 2b) treatment in 299 previously untreated elderly patients (median age: 67 years) with multiple myeloma. After completion of induction treatment patients were randomised to IFN-alpha 2b with or without prednisolone, thrice weekly. Response rate was 62% in the continuous and 60% in the control arm (intent to treat analysis, P=0.81). Progression-free survival [median: 20 months vs. 19 months; hazard ratio (HR): 0.99, 95% confidence interval (CI): 0.74-1.33, P=0.97] and overall survival (median: 34 months vs. 37 months; HR: 1.16, 95% CI: 0.85-1.59, P=0.35) were similar in both groups. Reduced performance status (Eastern Cooperative Oncology Group, grades 2-4) was the predominant risk factor for poor survival followed by age >65 years, high beta2-microglobulin, and impaired renal function. There was more grades 3-4 dyspnoea and cardiac impairment and grades 1-2 hyperglycaemia, but less nausea, emesis and anaemia in patients on continuous prednisolone therapy. In conclusion, continuing prednisolone treatment during the entire duration of the induction phase with VMCP-IFN-alpha 2b did not improve outcome.

Leukocytapheresis therapy for steroid‐naïve patients with active ulcerative colitis: Its clinical efficacy and adverse effects compared with those of conventional steroid therapy

Steroid administration currently plays a central role in the medical management of ulcerative colitis (UC); however, long-term steroid usage causes adverse effects, which necessitates stoppage of drug intake, leading to worsening of the disease. A steroid-sparing, well-tolerated treatment is therefore required. As several investigators have reported the efficacy of leukocytapheresis (LCAP) combined with steroid therapy, we investigated the clinical usefulness and safety of LCAP for steroid-naïve patients with active UC for comparison with those of conventional steroid therapy. Twenty-nine Japanese patients with active UC without a history of steroid usage were selected to be treated with LCAP (n = 9) or prednisolone (PSL) (n = 20). LCAP administration continued for 10 weekly cycles. In the PSL group, patients with moderately severe disease received 0.5 mg/kg per day of PSL and those with severe disease 1.0 mg/kg per day. The PSL dosage was gradually tapered in accordance with improvement. Eight (88.9%) of the LCAP group and 16 (80.0%) of the PSL group showed clinical improvement and three (33.3%) of the LCAP group and seven (35.0%) of the PSL group achieved remission. As for the treatment complications, three major adverse effects were observed in the PSL group, but none were observed in the LCAP group. The results of this study suggest that the efficacy and safety of LCAP are equivalent, and in terms of severe adverse effects, superior to those of steroid therapy. LCAP therapy may thus be a promising candidate therapy for steroid-naïve patients with active UC.

Cyclophosphamide pulses with oral prednisolone in the treatment of pemphigus: A pilot study

An open labeled clinical trial aimed at assessing the efficacy and safety of pulse intravenous cyclophosphamide with daily oral prednisolone in the treatment of pemphigus was carried out. Twenty-six patients (12 men, 14 women; mean age, 48.4 years), comprising 25 cases with pemphigus vulgaris and 1 with pemphigus vegetans (< 10% body surface area involvement) who did not achieve adequate control on corticosteroids with or without other adjuvants were included. After baseline evaluation, monthly intravenous boluses of cyclophosphamide (15 mg/kg) along with daily oral prednisolone (starting dose 1 mg/kg/day, tapered according to clinical response) were administered. Patients were assessed monthly for clinical activity and side-effects. All patients experienced significant clinical improvement within 1 month of starting treatment. Healing of skin and mucosal lesions occurred respectively at mean durations of 2.1 and 3.6 months. Three weeks to 8 months later, 9 patients had recurrences of activity on tapering/withdrawal of prednisolone, mainly in the oral mucosa. Side effects of treatment included amenorrhea (3 patients), microscopic hematuria (3) which cleared with co-administration of mesna, vomiting (1), weight gain (10), gastritis (1), and cataract (2). It is concluded that treatment with monthly intravenous cyclophosphamide boluses along with daily oral prednisolone clears lesions of pemphigus with < 10 percent body surface involvement, and this may be an alternative regimen for pemphigus. Monitoring for adverse effects is essential.

Insulin Resistance after Renal Transplantation

Cardiovascular disease is a prevalent and serious complication after solid organ transplantation. Treatment with glucocorticoids is associated with increased risk for diabetes mellitus, insulin resistance, weight gain, hypercholesterolemia, and hypertension, all shown to be independent risk factors for cardiovascular disease. We sought to test the hypothesis that tapering of prednisolone (TAP) the first year after renal transplantation improves insulin sensitivity (IS), and to assess the effect of complete steroid withdrawal (SW) on IS in patients on a cyclosporine-based immunosuppressive regimen. All patients (n = 57) completed two consecutive hyperinsulinemic euglycemic glucose clamp procedures, a TAP group (n = 34) and a control group (n = 12) at 3 and 12 mo after transplantation, and a SW group (n = 11) before and 5 mo after SW. The IS index (ISI) was calculated as the glucose disposal rate divided by mean serum insulin the last 60 min of the clamp. In the TAP group, the mean (range) daily prednisolone was reduced from 16 (10 to 30) to 9 (5 to 12.5) mg accompanied by an average increased ISI of 24% (P = 0.008). In contrast, no significant change in ISI was observed in the control group (0%, P = 0.988). In the SW group, withdrawal of 5 mg prednisolone did not influence mean ISI significantly (-8%, P = 0.206). Lowering daily prednisolone toward 5 mg/d has beneficial effects on insulin action after renal transplantation, but withdrawal of 5 mg prednisolone may not influence IS significantly.

Report of a Muscular Dystrophy Campaign funded workshop Birmingham, UK, January 16th 2004. Osteoporosis in Duchenne muscular dystrophy; its prevalence, treatment and prevention

A Muscular Dystrophy Campaign funded workshop to look into the potential problems of osteoporosis occurring in boys with DMD treated with steroids took place in Birmingham (UK) on the 16th January 2004. Fourteen participants met from varied backgrounds including, paediatric neuromuscular disease, neurology, paediatric and adult metabolic bone disease, paediatric rheumatology, genetics, physiotherapy and medical physics together with a representative from the Muscular Dystrophy Campaign. The aims of the workshop were to assess the evidence for the risk of osteoporosis in Duchenne muscular dystrophy (DMD), to assess the adverse effects of corticosteroid (steroid) treatment relating to bone mineral density and longitudinal growth and to assess the current evidence for the prevention and treatment of osteoporosis. Steroids are increasingly used in boys with DMD following the evidence from randomised controlled trials on their short-term benefit. However, the balance between long-term benefit and side effects has not been established. Long-term steroid use may be associated with significant side effects including weight gain, growth failure, cataracts and osteoporosis, so the development of strategies to prevent or treat these complications is important. We reviewed the literature to determine

Report on the 124th ENMC International Workshop. Treatment of Duchenne muscular dystrophy; defining the gold standards of management in the use of corticosteroids 2–4 April 2004, Naarden, The Netherlands

Thirty-two participants representing parents, funding agencies and clinicians involved in the care of children with Duchenne Muscular Dystrophy (DMD) from Belgium, Canada, Denmark, Finland, France, Germany, Italy, the Netherlands, Spain, Sweden, the UK and the USA met in Naarden on 2–4th April 2004. The meeting was held under the auspices of the ENMC Clinical Trials Network, and with the additional support of the United Parent Project. The aims of the workshop were to define the need for clinical trials in DMD and develop a protocol for such trials, relating primarily to the use of steroids (prednisolone, prednisone and deflazacort) in DMD. The first part of the meeting summarised the current state of practice on the use of steroids in DMD. Elizabeth Vroom (Netherlands) and Pat Furlong (USA) presented the views of parents surveyed by questionnaire by the United Parent Project. A major worry for parents was the lack of use of steroids at all in some countries, the multiplicity of steroid regimes used and the problems of getting firm information about which type of steroid or which regime for using steroids was best. This was reflected in the variation in practice amongst the participants at the Workshop, who between them used at least seven different regimes for giving steroids, and some did not use steroids at all. Adnan Manzur (UK), co-author of the Cochrane report on the use of glucocorticosteroids in DMD described the major findings of this systematic review [1]. Only five randomised controlled trials of the use of steroids in DMD were published in sufficient detail to be able to be included in the review. These trials did, however, present evidence that use of daily prednisolone (0.75 mg/kg per day) or deflazacort (0.9 mg/kg per day) increased strength in DMD. Robert Griggs, Richard Moxley (USA) and Doug Biggar (Canada) were able to confirm that long-term follow up of cohorts of patients treated under one or other of these regimes and who mostly continued using steroids beyond the loss of independent ambulation shows that this increase in strength is mirrored by improvement in function (with age at loss of ambulation in the mid teens, preservation of respiratory function, lack of need for scoliosis surgery and possibly preservation of cardiac function) [2–4]. With longterm use of steroids, the per kilogram dose of corticosteroid tended to reduce with time. In some cases, this was in response to side effects such as weight gain or behaviour changes, but in the majority represented a tendency not to keep up strictly with change in weight over time. Many different regimes for giving steroids in DMD have been suggested as a way to reduce the risk of the well-known side effects associated with the long-term use of daily steroids. The dose of 0.75 mg/kg per day was shown to be Neuromuscular Disorders 14 (2004) 526–534 www.elsevier.com/locate/nmd

Hand-Sewn versus Stapled Intestinal Anastomoses in a Chronically Steroid-Treated Porcine Model

Chronic steroid treatment is known to delay wound healing; however, there are no trials examining stapled intestinal anastomoses in subjects chronically treated with steroids. The current study compares mechanically stapled to manually sutured intestinal anastomoses in a steroid-treated porcine model. Twenty adult male pigs were treated with daily prednisolone (0.5 mg/kg IM) for 14 days. The pigs were divided between hand-sewn and stapled groups. All pigs underwent a laparotomy with construction of a jejunojejunostomy, an ileocecostomy, and a colocolostomy. Pigs were sacrificed on postoperative day 4. Bursting pressure, collagen content, and inflammatory scores were used to evaluate each anastomosis. Bursting pressure was greater for the hand-sewn group at the jejunojejunostomies only (1.52 vs 0.79 psi; P < 0.001). The collagen content and microscopic inflammatory scores were not significantly different at any location. The mean gross inflammatory score was greater for the hand-sewn colocolostomies only (5.20 vs 4.00; P < 0.01). Stapled ileocecostomies and colocolostomies appear to heal as well as hand-sewn anastomoses. This may not be true of the jejunojejunostomies as evidenced by the decreased bursting pressures. These data may provide evidence in support of the use of stapled anastomoses in steroid-treated patients.

Effective Therapy of a Child Case of Refractory Nephrotic Syndrome with Tacrolimus

We report here the case of a 9-year-old Japanese boy with nephrotic syndrome caused by focal segmental glomerulosclerosis, which was refractory to treatment. Although aggressive immunosuppressive therapy consisting of methylprednisolone pulse therapy combined with cyclosporine A (CsA) and intermittent low density lipoprotein apheresis was effective in overcoming his steroid-resistant state, the child became persistently steroid-dependent, that is, more than 0.75 mg/kg per day of prednisolone combined with CsA was required to maintain a negative test for proteinuria. Since adverse effects of prednisolone, such as short stature, obesity, osteoporosis and cataract, were noted, CsA in his treatment regimen was replaced with tacrolimus at the dose of 0.1 mg/kg per day, with the trough blood level of the drug maintained at around 10 ng/ml. Within 4 months of the inclusion of tacrolimus in the treatment regimen, complete remission was achieved, with no recurrence of the proteinuria, while the prednisolone dose could be tapered to 0.3 mg/kg per day. No adverse effects of tacrolimus were observed. These clinical results suggest that tacrolimus may be the drug of choice in selected patients with refractory nephrotic syndrome, even if pediatric-onset cases, at least those in whom the steroid-sparing effects of CsA is unsatisfactory.

Comparison of Oral and Depot Intra‐muscular Steroids in Assessing Steroid‐Responsiveness in COPD

Non‐compliance or euphoria may limit the usefulness of prednisolone tablets in assessing steroid‐responsiveness in chronic obstructive pulmonary disease (COPD). Depot intra‐muscular methyl‐prednisolone (imMP), producing a plateau steroid effect over two weeks, may be more reliable. Following two weeks of placebo, twenty‐seven COPD patients (mean FEV1 43% predicted) participated in a two‐week randomised, double‐blind, placebo‐controlled, parallel‐design trial taking either 120 mg imMP with placebo tablets or placebo injection with prednisolone 30 mg daily. After each period, post‐bronchodilator FEV1, forced vital capacity (FVC), inspiratory capacity (IC) and six‐minute walking distance (6MWD) were assessed and patients completed both quality‐of‐life scores (St. George's 30 and Short Form 36) and mood scores (Hospital Anxiety and Depression scores and Altman's Self‐rating Mania Scale). There were no significant changes in 6MWD, quality of life or mood scores after either type of steroids and no change in lung function after imMP. By contrast, there were small mean improvements in lung function on oral prednisolone (mean FEV1, FVC and IC increased by 100, 320 and 150 ml, respectively). Only the improvement in FVC was significantly greater after prednisolone compared with imMP. Single depot intra‐muscular injections of steroids have no advantage over oral daily prednisolone in testing steroid‐responsiveness in COPD patients.

Mycophenolate mofetil and prednisolone therapy in children with steroid-dependent nephrotic syndrome

Background: A proportion of patients with steroid-dependent nephrotic syndrome (SDNS) experience frequent relapses despite long-term treatment with steroids, levamisole, or/and cyclophosphamide. We prospectively examined the efficacy of long-term therapy with mycophenolate mofetil (MMF) as a steroid-sparing agent in this group. Methods: Nineteen patients with a mean age of 99.1 months (95% confidence interval [CI], 85.3 to 113) who had previously undergone long-term therapy with prednisolone (n = 19), levamisole (n = 16), and cyclophosphamide (n = 15), but had continued to show steroid dependence over many years, were studied. Renal biopsy showed minimal change disease and focal segmental glomerulosclerosis in 10 and 3 patients, respectively. Patients were administered MMF at a mean dose of 29 mg/kg/d (95% CI, 27.4 to 30.7) in 2 divided doses and decreasing doses of alternate-day prednisolone for a mean of 11.8 months (95% CI, 11.4 to 12.2). Relapses were treated with daily prednisolone until remission, with tapering later. They were additionally followed up for a mean of 17 months (95% CI, 15.9 to 18.1). Results: Mean relapse rates decreased from 6.6 (95% CI, 5.4 to 7.7) to 2 episodes/y (95% CI, 1.2 to 2.7) during MMF treatment (P < 0.0001). Four patients each had 0, 1, 2, and 3 relapses; failure of MMF therapy (>3 relapses during treatment) was seen in 3 patients. Treatment with MMF resulted in steroid sparing, with a reduction in mean prednisolone dose from 0.7 (95% CI, 0.6 to 0.8) to 0.3 mg/kg/d (95% CI, 0.2 to 0.4; P < 0.0001). Fourteen patients showed a 50% or greater reduction in relapse rates; prednisolone therapy could be discontinued for 6 or more months in 8 patients. No significant gastrointestinal or hematologic side effects of MMF treatment were noted. After discontinuation of MMF treatment, 68.4% of patients had an increased frequency of relapses and recurrence of steroid dependence, requiring treatment with other medications. Conclusion: Long-term therapy with MMF results in significant steroid sparing and reduction in relapse rates in patients with SDNS. Therapy with MMF and tapering doses of prednisolone appears to be a promising intervention in children with SDNS.

Role of intravenous immunoglobulin in severe steroid-dependent asthma.

Subgroups of asthma patients have extremely severe respiratory symptoms that require chronic use of steroids for disease control. These patients are at risk of significant side-effects from chronic exposure to high doses of oral steroids. Intravenous immunoglobulin (IVIG) has immunomodulatory properties as shown by its use in some immune disorders. A few trials have suggested a possible benefit in individuals with severe asthma. To evaluate the role of IVIG as an adjunctive therapy in steroid-dependent asthma, monitoring the outcomes of lung function and measured reduction in oral steroid requirement. Seven patients with severe steroid-dependent asthma were given IVIG at a dose of 1 g/kg each month for 6 months. Baseline pulmonary function tests and immunoglobulin levels were obtained. At the end of 6 months, the end-points observed were lung function and the degree of reduction in the dose of oral steroids. The number of hospital admissions during the 12 months following commencement of IVIG was compared with the preceding 12 months. There was a significant reduction in daily prednisolone dose from 56 +/- 31 mg to 39 +/- 35 mg (P=0.04, Wilcoxon rank sum test) and a decrease in the number of hospital admissions from 5.9 +/- 2.9 to 3.6 +/- 3.5 (P=0.04). No significant improvement occurred in lung function. IVIG provides a potentially important adjunctive therapy in severe steroid-dependent asthma, reducing steroid requirement and decreasing hospital admissions, but not improving lung function.

Anti-inflammatory activity of 1.8-cineol (eucalyptol) in bronchial asthma: a double-blind placebo-controlled trial

Airway hypersecretion is mediated by increased release of inflammatory mediators and can be improved by inhibition of mediator production. We have recently reported that 1.8-cineol (eucalyptol) which is known as the major monoterpene of eucalyptus oil suppressed arachidonic acid metabolism and cytokine production in human monocytes. Therefore, the aim of this study was to evaluate the anti-inflammatory efficacy of 1.8-cineol by determining its prednisolone equivalent potency in patients with severe asthma. Thirty-two patients with steroid-dependent bronchial asthma were enrolled in a double-blind, placebo-controlled trial. After determining the effective oral steroid dosage during a 2 month run-in phase, subjects were randomly allocated to receive either 200 mg 1.8-cineol t.i.d. or placebo in small gut soluble capsules for 12 weeks. Oral glucocorticosteroids were reduced by 2.5 mg increments every 3 weeks. The primary end point of this investigation was to establish the oral glucocorticosteroid-sparing capacity of 1.8-cineol in severe asthma. Reductions in daily prednisolone dosage of 36 % with active treatment (range 2.5–10 mg, mean: 3.75 mg) vs. a decrease of only 7% (2.5–5 mg, mean: 0.91 mg) in the placebo group ( P=0.006) were tolerated. Twelve of 16 cineol vs. four out of 16 placebo patients achieved a reduction of oral steroids ( P=0.012). Long-term systemic therapy with 1.8-cineol has a significant steroid-saving effect in steroid-depending asthma. This is the first evidence suggesting an anti-inflammatory activity of the monoterpene 1.8-cineol in asthma and a new rational for its use as mucolytic agent in upper and lower airway diseases.

Quadritherapy with cyclosporine for membranous lupus nephropathy

The therapeutic approach to patients with membranous lupus nephropathy (MLN) remains controversial. We have attempted combination therapy for MLN. Five patients with MLN (WHO class Va and Vb) and nephrotic syndrome were treated with 1 g methylprednisolone intravenously for 3 consecutive days followed by daily prednisolone at the dose of 30-40 mg plus cyclosporine at the dose of 100-200 mg and angiotensin receptor blocker(40 mg of valsartan). Initial dosage prednisolone was given for 1 month, and then tapered gradually in terms of dosage and interval. These patients were followed up for a minimum of 12 months. Complete remission was obtained in 4 patients after a mean of 7.3 +/- 2.1 months, and partial remission was obtained in the remaining patient. Daily prednisolone dosage significantly decreased from a baseline mean of 0.69 +/- 0.11 mg/kg to a mean of 0.10 +/- 0.02 mg/kg at the last follow-up. Lupus activity, as measured by SLE disease activity index, significantly decreased in all patients. Serum creatinine level and blood pressure remained stable. It was concluded that quadritherapy, including intravenous methylprednisolone, prednisolone, cyclosporine, and angiotensin receptor blocker, was beneficial in inducing remission of nephrotic syndrome, reducing lupus activity, and sparing prednisolone dosage with an acceptably low risk for side effects.

Insulin resistance after renal transplantation: impact of immunosuppressive and antihypertensive therapy.

The purpose of the present study was to validate various surrogate estimates of insulin sensitivity (IS) in a renal transplant population and to assess the influence of immunosuppressive and antihypertensive therapy on insulin resistance (IR) after renal transplantation. A total of 167 consecutive renal transplant recipients without previously known diabetes underwent a 75-g oral glucose tolerance test (OGTT) 3 months after renal transplantation. A total of 43 patients also underwent a euglycemic-hyperinsulinemic glucose clamp study. Six OGTT-derived IS indexes were validated against the euglycemic-hyperinsulinemic glucose clamp-derived IS index (ISI(CLAMP)). The OGTT-derived ISI(TX) correlated closely with the ISI(CLAMP) (r = 0.58, P < 0.001). The other surrogate estimates of IS were also significantly but less well correlated with the ISI(CLAMP) (Spearman's correlation; r = -0.45 to 0.41, P = 0.003-0.050). In the univariate model, BMI, daily prednisolone dose, creatinine clearance, hypertension, number of antihypertensive agents, and use of diuretics or beta-blockers were negatively associated with ISI(TX) (P < 0.05). After multiple regression analysis, BMI (P < 0.001), daily prednisolone dose (P < 0.001), cytomegalovirus infection (P = 0.030), and triglycerides (P = 0.034) were shown to be independent predictors of posttransplant IR. The OGTT-derived ISI(TX) may be a useful estimate of IS in Caucasian renal transplant recipients. Increasing daily prednisolone dose is an independent predictor of IR after renal transplantation. Hypertension and the use of beta-blockers and diuretics may also deteriorate IR in this group of patients.

Steering azathioprine safely: lessons from pharmacogenetics: Cuffari C, Hunt S, Bayless T, Utilisation of Erythrocyte 6-Thioguanine Metabolite Levels to Optimise Azathioprine Therapy in Patients With Inflammatory Bowel Disease, Gut 2001;48:642–6

The immunosuppressive properties of azathioprine and 6-mercaptopurine are mediated by their active metabolite 6-thioguanine. Cuffari and colleagues performed a prospective study to determine the relationship of erythrocyte 6-thioguanine levels and treatment efficacy in adult patients with inflammatory disease (IBD). The study design is summarized in Figure 1. Eighty-two patients (42 females) with IBD aged 17–77 yr (mean age = 42) were studied. Among 63 with Crohn’s disease (CD) 29 had ileocolonic disease (15 with previous bowel resection) and 26 had colonic disease (four with previous resection). Twelve of the 19 with ulcerative colitis (UC) had pancolitis and the rest had left-sided disease. The mean duration of IBD was 6.3 yr, and 72 patients were on 5-aminosalicylate. In patients with CD, activity was measured using the Harvey-Bradshaw index and for UC a clinical activity score was adapted to monitor response to therapy. Remission was defined as an HBI score of <5 in those who were weaned off on <20 mg/alternate day of prednisolone or 3 mg/alternate day of budesonide. Daily azathioprine of 1–1.5 mg/kg or an equivalent dose of 6-mercaptopurine was started on each patient. The levels of 6-thioguanine metabolites were measured while one was on treatment for at least 12 wk. The erythrocyte 6-thioguanine level was measured by reverse phase high performance liquid chromatography.Thirty-three patients with CD and 14 with UC achieved remission at an average daily dose of 1.44 mg of azathioprine or 1.16 mg of 6-mercaptopurine. The median 6-thioguanine level for CD patients in remission was 316 pmol/8 × 108 red blood cells (RBCs), compared with 176 pmol/8 × 108 RBCs in those with incomplete responses. A significantly higher number of patients who responded to therapy had 6-thioguanine levels of >250 pmol/8 × 108 RBCs relative to those who failed to achieve remission. Treatment efficacy correlated with a 6-thioguanine level of >250 pmol/8 × 108 RBCs in patients with colonic and fistulating CD, but not in those with ileocolonic CD. Twenty-two out of 30 patients with CD who were incompletely responsive and had 6-thioguanine levels below 250 pmol/8 × 108 RBCs were recruited to the dose optimization study. The dose of azathioprine was increased by 25 mg/day at 8-wk intervals up to a median dose of 1.5 mg/kg/day. This was associated with a rise in the median 6-thioguanine level to 303 pmol/8 × 108 RBCs. Eighteen out of 22 patients achieved remission on this regime.The authors conclude that serial measurements of 6-thioguanine levels would be useful in optimizing azathioprine treatment without inducing leucopenia. Patients who were unresponsive to therapy despite adequate 6-thioguanine levels (>250 pmol/8 × 108 RBCs) should be considered refractory to azathioprine/6-mercaptopurine and offered other forms of treatment.

ANCA-associated renal vasculitis

The hemoglobin level was 8.8 g/dL with normal indices. The CASE PRESENTATION erythrocyte sedimentation rate was 70 mm/hr. C-reactive proA 62-year-old white woman presented to another hospital tein was 30 mg/L (normal 10 mg/L), and she had a positive with a five-week history of profound malaise and small joint antineutrophil cytoplasmic antibody (ANCA) test to a titer of arthralgia. Initially she had noticed a mild sore throat that set1:400 serum dilution by indirect immunofluorescence with a tled spontaneously. She had transient redness of her left conperinuclear pattern. Subsequent antigen-specific ELISA conjunctiva. One week after the onset of symptoms, she had a firmed reactivity to myeloperoxidase (MPO), denoting MPOsingle episode of macroscopic hematuria for which she received ANCA (Fig. 1). The ANA, anti-DNA, and anti-GBM antibody antibiotics from her family doctor. She denied dysuria or uritests were negative. Complement C3 and C4 levels were nornary frequency. For one week prior to admission, she had mal, and cryoglobulins were not detectable. Hepatitis B and suffered nausea and vomiting without abdominal pain or bowel C serologies were negative. After control of blood pressure, a disturbance. She had lost one stone (14 pounds) in weight. She renal biopsy was performed; the tissue contained eight glomerhad been hypertensive five years previously, but she had had uli. Of these, one was globally sclerosed, three were normal, no other antecedent illnesses. There was no family history of and four contained acute segmental lesions of various sizes renal disease, hypertension, or rheumatic complaints. She had with thrombosis, tuft disruption, and a few cells in Bowman’s four adult children, all of whom were well. Medication on space (Fig. 2). Tubules were acutely damaged, with blood in admission comprised a beta blocker (atenolol, 100 mg daily) a few. A patchy infiltrate of chronic inflammatory cells was for hypertension. She did not smoke cigarettes and drank less present. Small arteries and arterioles appeared virtually northan three units (24 g) of alcohol per week. She was a poultry mal. Immunoperoxidase study revealed no significant immunofarmer and lived in a rural setting. protein deposition within glomeruli. Clinical examination revealed that she was pale and dehyThe clinical history, renal biopsy findings, and blood serology drated. She had no rash, no active synovitis, and no lymphadewere consistent with an acute vasculitic (pauci-immune) glonopathy. Her temperature was 37.2 C; pulse, 70 beats/min; merulonephritis of the microscopic polyangiitis type. An assessand blood pressure, 160/90 mm Hg lying and 145/80 mm Hg ment of vasculitic activity showed a Birmingham Vasculitis Acstanding. Her jugular venous pressure was not elevated and she tivity Score (BVAS) of 13 and a Vasculitis Damage Index (VDI) had no sacral or ankle edema. The heart sounds were normal score of 0. Therapy with prednisolone, 1 mg/kg/day, and oral

Tapering off prednisolone and cyclosporin the first year after renal transplantation: the effect on glucose tolerance.

Glucose intolerance is an untoward side effect of some immunosuppressive and anti-hypertensive drugs. The primary aim of the present prospective observational study was to test the hypothesis that tapering off prednisolone and cyclosporin (CsA) the first year after transplantation may have beneficial effects on glucose tolerance in renal transplant recipients. Ninety-one non-diabetic recipients were included, and 87 patients underwent a 75 g oral glucose tolerance test both 10 weeks and 1 year after renal transplantation. The change over time in 2-h blood glucose was compared with a number of variables potentially influencing glucose tolerance. The proportion of glucose intolerant recipients was reduced from 55 to 34% during the study. Univariate linear regression analysis showed a significant association between the reduction in daily prednisolone dose down to 5 mg and decline in blood glucose (P=0.001), whereas weight gain was associated with increasing blood glucose (P=0.031). Each 1-mg reduction of prednisolone dose leads to an estimated decline in 2-h blood glucose of 0.12 mmol/l based on the multiple linear regression model (P=0.003). Twelve out of 22 patients with post-transplant diabetes mellitus (PTDM) at baseline improved to normal or impaired glucose tolerance. Ten PTDM-subjects who remained diabetic 1 year after transplantation had lower serum insulin levels during the oral glucose challenge, and five patients treated with anti-diabetic drugs at baseline required hypoglycaemic drugs also at follow up. The decline in CsA level of 100 microg/l and the lower number of patients treated with beta-blockers at follow-up, did not alter glucose tolerance significantly. Tapering off prednisolone, but not CsA, significantly improves glucose tolerance during the first year after renal transplantation.