Chronic Corticosteroid Research Articles

A Prospective, Randomized, Double-Blind, Placebo-Controlled Multicenter Trial Comparing Early (7 Day) Corticosteroid Cessation Versus Long-Term, Low-Dose Corticosteroid Therapy

To compare outcomes with early corticosteroid withdrawal (CSWD) and chronic low dose corticosteroid therapy (CCS). Final, 5-year results from the first randomized, double-blind, placebo-controlled trial of early CSWD (at 7 days posttransplant) are presented. Adult recipients of deceased and living donor kidney transplants without delayed graft function were randomized to receive prednisone (5 mg/d after 6 months posttransplant) or CSWD. Blinding was maintained for 5 years. This clinical trial is registered at www.clinicaltrials.gov (NCT00650468). Results in 386 patients CSWD (n = 191), CCS (n = 195) are presented (CSWD; CCS). No differences were observed at 5 years in the proportion of patients experiencing: primary end point (composite of death, graft loss, or moderate/severe acute rejection) (30/191 (15.7%); 28/195 (14.4%)), patient death (11/191(5.8%);13/195 (6.7%)), death-censored graft loss (11/191 (5.8%); 7/195(3.6%)), biopsy confirmed acute rejection (BCAR) (34/191 (17.8%); 21/195 (10.8%), P = 0.058), moderate/severe acute rejection (15/191 (7.9%); 12/195 (6.2%)). Kaplan Meier analyses of the primary end point and its components also showed no differences; but BCAR was higher with CSWD (P = 0.04). Increased BCAR episodes were primarily corticosteroid-sensitive Banff 1A rejections: the incidence of antibody-treated BCAR was similar between groups (11/191 (5.8%); 13/195 (6.7%)). No differences in renal function were observed at 5 years: mean serum creatinine (1.5 +/- 0.6; 1.5 +/- 0.7 mg/dL), or Cockroft Gault calculated creatinine clearance (58.6 +/- 19.7; 59.8 +/- 20.5 mL/min). CSWD was associated with improved serum triglycerides (evaluated by mean and median change from baseline) at all time points (except at 5 years measured by mean change). Weight change also demonstrated changes favoring CSWD (median change from baseline at 5 years: 5.1 vs. 7.7 kg, P = 0.05). New onset diabetes after transplant (NODAT) was similar with respect to proportions who required treatment (23/107 (21.5%)); 18/86 (20.9%); however, fewer CSWD patients required insulin for NODAT at 5 years (4/107 (3.7%)); 10/86 (11.6%), P = 0.049). Changes in HgA1c values (from baseline) were lower in CSWD patients at all time points except 4 years. Early CSWD, compared with CCS, is associated with an increase in BCAR primarily because of mild, Banff 1A, steroid-sensitive rejection, yet provides similar long-term renal allograft survival and function. CSWD provides improvements in cardiovascular risk factors (triglycerides, NODAT requiring insulin, weight gain). Tacrolimus/MMF/antibody induction therapy allows early CSWD with results comparable to long-term low dose (5 mg/d) prednisone therapy.

Epidemiology of community-acquired pneumonia in older adults: A population-based study

This study assessed incidence, aetiology, clinical outcomes and risk factors for community-acquired pneumonia (CAP) in older adults. This was a population-based cohort study that included 11,241 community-dwelling individuals aged 65 years or more, who were followed between 2002 and 2005 in the region of Tarragona, Spain. Primary endpoints were all-cause CAP (hospitalised and outpatient) and 30-day mortality after the diagnosis. All cases were radiographically proved and validated by checking clinical records. Incidence rate of overall CAP was 14 cases per 1000 person-years (10.5 and 3.5 for hospitalised and outpatient cases, respectively). Incidence was almost three-fold higher among immunocompromised patients (30.9 per 1000) than among immunocompetent subjects (11.6 per 1000). Maximum incidences were observed among patients with chronic lung disease and long-term corticosteroid therapy (46.5 and 40.1 cases per 1000 person-years, respectively). Overall 30-day case-fatality rate was 12.7% (2% in cases managed as outpatient and 15% in hospitalised patients). Among 358 patients with an aetiological work-up, a total of 142 pathogens were found (single pathogen in 121 cases and mixed pathogens in 10 cases). Streptococcus pneumoniae was the most common pathogen (49%), followed by Pseudomonas aeruginosa (15%), Chlamydia pneumoniae (9%) and Haemophilus influenzae (6%). In multivariable analysis, the variables most strongly associated with increasing risk of CAP were history of hospitalisation for CAP in the previous 2 years and presence of any chronic lung disease. CAP remains a major cause of morbidity and mortality in older adults. Incidence rates in this study largely doubled prior rates reported in Southern European regions.

Chronic urticaria: Diagnosis and management

Chronic urticaria (CU) is a common condition faced by the practicing allergist. There is a considerable degree of variation in the evaluation of patients with CU. The intent of this article is to provide the practicing allergist with an appropriate, evidence-based strategy for diagnosis and initial management of patients with CU. A review was performed of pertinent literature of CU pertaining to its natural history, impact on quality of life, subtypes, utility of diagnostic tests, and initial treatment recommendations. The reported duration of CU varies based on the nature of the referring center; however, physical urticarias persist longer than idiopathic CU. CU has adverse effects on quality of life and is comparable with other chronic diseases. Idiopathic urticaria, autoimmune CU, and physical urticarias are the most common types of CU. A detailed history is the best diagnostic tool in determining an etiology of CU and routine laboratory tests are of little value in the evaluation of CU patients. Antihistamines, particularly first-generation antihistamines, are the preferred initial treatment for CU and higher doses may be required for adequate control. Several alternative agents exist for patients who have antihistamine-resistant CU. A detailed history is the best tool for diagnosing the etiology of CU although most patients will not have a specific etiology found. The ultimate goal should be to control urticaria to reduce its impact on the quality of life of the patient, minimize adverse effects of medications, and eliminate chronic or frequent oral corticosteroids.

Gastrointestinale Erkrankungen und Osteomalazie

Osteomalacia is a metabolic bone disease associated with impaired mineralization of the bone due to Vitamin D and Calcium deficiency that can develop in gastrointestinal disorders. Gastrointestinal malabsorption after surgery, in disorders of the small bowl, in diseases of the hepatobiliary tree and in pancreatic insufficiency can lead to decreased enteral resorption of the fat-soluble Vitamin D and/or depletion of endogenous Vitamin D stores due to abnormal enterohepatic circulation. As a consequence of the Vitamin D deficiency in combination with the underlying condition patients develop an impaired calcium absorption resulting in hypocalcaemia, which leads to defective bone mineralization. Additionally chronic gastrointestinal inflammation and corticosteroid therapy - which is often needed in these patients - have a negative effect on bone metabolism as well. The therapy consists of oral substitution of Vitamin D and Calcium as well as sufficient sun light exposure or in severe cases the use of artificial UVB-radiation.

Risks factors for low bone mineral density in pre-menopausal Mexican women with systemic lupus erythematosus

The aim of this study was to determine the prevalence and risk factors for low bone mineral density (BMD) in women with systemic lupus erythematosus (SLE). A cross-sectional study was conducted among 100 pre-menopausal patients with SLE. Patients were evaluated using a questionnaire about the following variables: age, disease duration, disease activity, chronic disease damage, cumulative corticosteroid dose, and history of fracture. Lumbar spine and hip measurements of BMD were performed by dual absorptiometry. Univariate and multivariate statistical analyses were used to assess the relationship between risk factors and BMD. The mean age was 32.8 +/- 8.7 years, and the median duration of SLE was 73.2 +/- 65 months. The mean cumulative corticosteroid dose was 20.0 +/- 21.3 g. The mean BMD was 1.09 +/- .18 g/cm(2) in the lumbar spine and 1.0 +/- .14 g/cm(2) in the hip. Osteopenia was present in 40% of patients and osteoporosis in 5%. In the multiple regression analysis, low BMD in the lumbar spine was associated with chronic disease damage and low body mass index (BMI). Low BMD in the hip was associated with cumulative corticosteroid dose and low BMI. Chronic disease damage, low BMI, and cumulative corticosteroid dose are risks factors for low BMD in pre-menopausal SLE patients. Osteopenia was found in 40% of patients, while osteoporosis was found in only 5%.

Endotracheal Stent Granulation Stenosis Resolution after Colchicine Therapy in a Dog

Endotracheal Stent Granulation Stenosis Resolution after Colchicine Therapy in a Dog

Chronic oral administration of dexamethasone to rats increases cytotoxicity, but not interleukin-1 elaboration, by alveolar macrophages

Chronic administration of corticosteroids has been used to induce pulmonary infection in animals. but the specific mechanisms by which corticosteroids modulate pulmonary host defence have not been clarified. Specifically, little is known about how corticosteroids influence the function of lung cells, such as alveolar macrophages. Cytotoxicity and interleukin-1 elaboration are two important mechanisms of macrophage defence against pathogens. To determine whether chronic administration of dexamethasone alters cytotoxicity and interleukin-1 elaboration by alveolar macrophages, we studied alveolar macrophages from rats treated with oral doses of dexamethasone for 2 weeks. We found that unstimulated alveolar macrophages from dexamethasone-treated rats exhibited increased cytotoxicity compared with alveolar macrophages from control rats. Moreover, alveolar macrophages from both groups of rats showed enhanced cytotoxicity after in vitro interferon-gamma and lipopolysaccharide treatment, in a dose-dependent manner. Although no spontaneous interleukin-1 elaboration was detected from alveolar macrophages from either group of rats, lipopolysaccharide increased interleukin-1 elaboration by alveolar macrophages from both groups of rats equivalently. These results indicate that chronic oral administration of dexamethasone to rats increases cytotoxicity, and does not alter the capacity of alveolar macrophages to elaborate interleukin-1. Therefore, chronic corticosteroid administration appears to produce selective alterations in these defence mechanisms of alveolar macrophages.

Randomized phase III trial of gemcitabine/cisplatin with or without PF-3512676 as first line treatment of advanced non-small cell lung cancer (NSCLC)

8017 Background: Gemcitabine/cisplatin (GC) is standard first line therapy for patients (pts) with Stage IIIB/IV NSCLC. PF- 3512676 (PF-676) is an oligodeoxynucleotide toll-like receptor 9 (TLR9) agonist. In a randomized phase 2 trial, addition of PF-676 to first line taxane/platinum chemotherapy produced a higher objective response rate and a trend toward improved overall survival (OS) in pts with advanced NSCLC. Confirmatory phase 3 trials were subsequently conducted. Methods: Chemotherapy naïve pts with Stage IIIB (pleural effusion) or Stage IV NSCLC, ECOG PS 0 or 1, measurable disease, adequate bone marrow, renal and hepatic function, no pre- existing autoimmune disease, no brain metastases and no chronic systemic corticosteroid therapy were included. All pts received G (1250 mg/m2) on D1 and 8 and C (75mg/m2) on D1 of each 21 day cycle (max 6 cycles). In the investigational arm pts also received PF-676 (0.2 mg/kg) SC on D 8 and 15 of each chemotherapy cycle and weekly thereafter until progression. The primary endpoint was OS. Results: 839 pts were randomized (416 GC + PF-676, 423 GC) from Nov ‘05 to Dec ‘06. Interim data reviewed by an external DSMC is reported. No increment in OS (120 deaths on GC + PF-676, 118 on GC [HR 0.978, 95 % CI 0.74, 1.29]) or PFS (Median 4.9 mos on GC+PF-676, 5.1 mos on GC) was noted for addition of PF-676. Many pts in the PF-676 arm experienced mild/moderate injection site reactions (62% [8 % G3/4]) or flu-like symptoms (37% [4% G3/4]). G3/4/5 thrombocytopenia and neutropenia and transfusions were reported more commonly in pts receiving PF-676 (61% vs 33%, 69% vs 47%, 19% vs 10%). The DSMC recommended termination of the trial due to lack of incremental efficacy and added toxicity. PF-676 administration was discontinued in all pts but collection of follow-up data continues. Updated results will be reported. Conclusions: Addition of PF-676 to GC did not improve the outcome of pts with advanced NSCLC. Alternative development opportunities are being explored for TLR9 agonists in the treatment of cancer. Author Disclosure Employment or Leadership Consultant or Advisory Role Stock Ownership Honoraria Research Expert Testimony Other Remuneration Pfizer Pfizer Pfizer Pfizer

Antineutrophil Cytoplasmic Antibody–Associated Active Scleritis

To determine whether antineutrophil cytoplasmic antibody (ANCA) testing provides prognostic information in evaluating scleritis. Retrospective medical record review of patients evaluated at a tertiary care center from January 1, 1995, to June 30, 2006, was performed to compare clinical features, treatments, and associated systemic disease in patients who test positive for ANCA vs patients whose ANCA tests are negative. Among 78 patients identified, 14 tested positive for ANCA. Patients with positive ANCA test results were more likely to have an associated systemic disorder (10 of 14 or 71%) than were patients who tested negative for ANCA (26 of 64 or 41%; P = .04), and the disorder was more likely to have been diagnosed as a result of scleritis work-up (2 of 10 or 20% vs 19 of 26 or 73%; P = .007). Patients with positive ANCA test results had significantly more ocular complications (21 of 14 or 86% vs 20 of 64 or 31%; P < .001), including keratopathy (5 of 14 or 36% vs 6 of 64 or 9%; P = .02), visual acuity of 20/50 or worse (8 of 14 or 57% vs 11 of 64 or 17%; P = .001), and vascular pannus (3 of 14 or 21% vs 1 of 64 or 2%; P = .02). Aggressive therapy, such as chronic systemic corticosteroids (9 of 14 or 64% vs 9 of 64 or 14%; P < .001) and alkylator therapy (8 of 14 or 57% vs 7 of 64 or 11%; P < .001), was more likely to be recommended for patients who tested positive for ANCA. A substantial subset of patients with scleritis are also positive for ANCA. These patients are more likely to have severe ocular disease and undiagnosed primary vasculitic disease, thereby requiring more aggressive therapy. An ANCA test may be useful in the evaluation and treatment of patients with scleritis.

Bone involvement in exogenous hypercortisolism

Corticosteroids remain a key component in the management of many disorders. Bone loss resulting from long-term administration of these drugs is common and osteoporosis induced by corticosteroids is the most frequent cause of secondary osteoporosis in nearly 50% of individuals on chronic corticosteroid therapy suffering from an osteoporotic fracture at some point. This article reviews the epidemiology and pathogenesis of glucocorticoid-induced osteoporosis.

Obesity following kidney transplantation and steroid avoidance immunosuppression

Obesity is an important co-morbidity within end-stage renal disease (ESRD) and renal transplant populations. Previous studies have suggested that chronic corticosteroids result in increased body weight post-transplant. With the recent adoption of steroid-sparing immunosuppressive strategies, we evaluated the effect of these strategies on body mass index (BMI) after renal transplantation. We examined 95 renal transplant recipients enrolled in National Institutes of Health clinical transplant trials over the past three yr who received either lymphocyte depletion-based steroid sparing or traditional immunosuppressive therapy that included steroids for maintenance immunosuppression. Recipients were overweight prior to transplant and no significant differences existed in pre-transplant BMI among treatment groups. Regardless of therapy, BMI increased post-transplant in all recipients. The BMI increase consisted of an average weight gain of 5.01 +/- 7.12 kg (mean, SD) post-transplant. Additionally, in a number of recipients placed on maintenance steroids, subsequent withdrawal at a mean of 100 d post-transplant had no impact on weight gain. Thus, body weight and BMI increase following kidney transplantation, even in the absence of steroids. Thus, patients gain weight after renal transplantation regardless of the treatment strategy. Steroid avoidance alone does not reduce risk factors associated with obesity in our patient population.

Sarcoidosis as risk factor for cryptococcal meningitis in an apparently immunocompetent patient

Cryptoccus neoformans meningitis (CNM) is an opportunistic infection that typically occurs in immunosuppressed patients. Subjects affected by sarcoidosis, a systemic granulomatous disease of unknown cause, are predisposed to CNM because of the impairment of cell-mediated immunity and because of the chronic corticosteroid therapy they frequently receive. Here we report the case of a 38-year-old man who developed CNM as the first clinical manifestation of sarcoidosis. The patient developed CNM even though he was apparently immunocompetent and was not on therapy with either corticosteroid or cytotoxic drugs.

Spontaneous bilateral patellar tendon rupture: a case report and review of the literature

Bilateral rupture of the patellar tendon is a very rare injury. It occurs in association with chronic systemic diseases or corticosteroid medications. We report a case of a 13-year-old child with Ehlers-Danlos syndrome presenting a bilateral patellar tendon disruption of proximal insertion that occurred with a trivial trauma. Surgical management consisting in tendon repair with a suture anchor technique protected temporarily with a cerclage wiring gives a good outcome.

Idiopathic hypertrophic cranial pachymeningitis treated by oral methotrexate: a case report and review of literature

Idiopathic hypertrophic cranial pachymeningitis (IHCP) is a rare clinical entity, characterized by a chronic inflammation causing thickening of the dura. Adequate therapeutic management is still a matter of debate. We present a patient with an IHCP, non-responsive to corticotherapy. Oral methotrexate was introduced (12.5 mg weekly) and total remission was observed after 6 weeks, both clinically and after neuro-imaging. We conclude that methotrexate can be effective and a therapeutical option in patients with IHCP who are resistant to corticotherapy or present major side-effects of chronic corticosteroids use.

Intraperitoneal modification of the Rives-Stoppa repair for large incisional hernias

Recurrence rates for open repair of ventral/incisonal hernias historically range from 6% for the classic Rives-Stoppa repair to 35-45% for some of the techniques more commonly used in the United States. We report a modification to the classic Rives-Stoppa repair that allows intraperitoneal placement of the prosthetic, secured with a running suture. The abdominal muscles are closed over the mesh to protect it from any superficial wound problems that might develop and to restore normal architecture of the abdominal wall. A chart review was undertaken on all patients undergoing open ventral incisional hernia repair by a single surgeon from 2000 to 2006. All hernias were repaired with the intraperitoneal modification mimicking the principles of the Rives-Stoppa repair. Patient characteristics and operative and postoperative data were collected. Primary outcome was recurrence of hernia. Secondary outcomes were complications and rate of mesh infection. One hundred and fifteen patients were evaluated. Thirty-four patients had repair of recurrent ventral hernias. The average patient was obese, female, and 59 years old. Twenty-five patients used tobacco, eleven were diabetic, and seven used chronic corticosteroids. Meshes utilized included ePTFE, coated polyester, coated polypropylene, and biologic mesh. Average size of mesh was 465.4 cm2. There were four recurrences (3.4%), three of which were due to mesh infection requiring mesh removal. Recurrence rate not secondary to mesh removal was 0.9%. Complications occurred in 26% with seroma formation being the most frequent (16%). The intraperitoneal modification to the original Rives-Stoppa repair leads to a very low recurrence rate for large ventral hernia repairs with minimal complications and low rate of mesh infection.

Steroid-Free Maintenance Immunosuppression With Rapamune and Low-Dose Neoral in Pancreas Transplant Recipients

Steroid-free immunosuppression is an attractive option because it avoids the many side effects of chronic corticosteroid use. It is especially attractive in pancreas recipients because it avoids the diabetogenic effects of steroids. We evaluated the outcome of a steroid-free maintenance immunosuppressive protocol in pancreas transplant recipients. Between August 2003 and May 2006, a total of 97 pancreas transplant recipients received steroid-free maintenance immunosuppression, consisting of induction with thymoglobulin and prednisone for the first 5 days. Patients were maintained on sirolimus adjusted to a target rapamycin trough level and reduced-dose cyclosporine adjusted to target C2 levels. All pancreas transplants (n=124) performed in the previous 3 years and maintained on a steroid-based immunosuppressive protocol with cyclosporine and mycophenolate mofetil were used for comparison. One-year patient and death censored pancreas graft survival were 93.8% and 94.8% for the steroid free group versus 95.2% and 87.9% for the comparator group, respectively. The incidence of acute rejection was 9.3% in the steroid-free group versus 28.3% in the comparator group (P<0.01). No pancreas loss in the steroid-free group was caused by acute rejection, whereas seven (5.6%) patients in the comparator group lost their pancreases because of acute rejection (P<0.05). At 1 year after transplant, the mean serum glucose and creatinine levels were not different between the two groups. We conclude that excellent graft survival with a significantly lower incidence of acute rejection can be achieved using a steroid-free maintenance immunosuppressive protocol consisting of sirolimus and cyclosporine.

Cardiovascular risk, cardiovascular events, and metabolic syndrome in renal transplantation: comparison of early steroid withdrawal and chronic steroids

Cardiovascular disease (CVD) is the leading cause of death with a functioning graft in renal transplant recipients. The purpose of this study was to compare Framingham Risk Score (FRS), metabolic syndrome (MS), and cardiovascular events (CVE) in patients receiving early corticosteroid withdrawal (ECSWD), or chronic corticosteroid therapy (CCS). In all, 251 ECSWD and 146 CCS patients were evaluated. FRS and MS were identified at baseline, six, 12, and 24 months post-transplant. A total of 124 patients with diabetes mellitus prior to transplantation were excluded from MS analysis. CVE were defined as sudden-death, MI, angina, or CVA/TIA. Repeat-measure logistic regression was used for statistical analysis. Fifty-four patients experienced 72 CVE. Mean follow-up was 755 +/- 312 d and time to CVE was 14.8 +/- 8.3 months. Demographics were similar between groups. FRS was not different between groups. CVE were significantly greater in CCS patients then ECSWD (20% vs. 10%, p = 0.024). New-onset MS occurred more frequently in patients receiving CCS then ECSWD (45% vs. 22%, p < 0.001) and was associated with more CVE (p < 0.015). Patients receiving ECSWD regimens have significantly decreased CVE and new onset MS compared with CCS. MS is associated with increased CV risk and CVE.

Amygdala Volume in Patients Receiving Chronic Corticosteroid Therapy

Hippocampal volume reduction and declarative memory deficits are reported in humans and animals exposed to exogenous corticosteroids. The amygdala is another brain structure involved in the stress response that has important interactions with the hypothalamic-pituitary-adrenal axis. To our knowledge, no studies in animals or humans have examined the impact of exogenous corticosteroid administration on the amygdala. We assessed amygdala volume in patients receiving chronic prescription corticosteroid therapy and control subjects with similar medical histories not receiving corticosteroids. Fifteen patients on long-term prednisone therapy and 13 control subjects of similar age, gender, ethnicity, education, height, and medical history were assessed with magnetic resonance imaging. Amygdala volume was manually traced and compared between groups using a two-way analysis of variance (ANOVA). Correlations between amygdala volume, age, and corticosteroid dose/duration were assessed using Pearson's correlation coefficient. Compared with control subjects, corticosteroid-treated patients had significantly smaller amygdala volumes. Right amygdala volume correlated significantly with age in control subjects and with duration of corticosteroid therapy in patients. Patients receiving chronic corticosteroid therapy had smaller amygdala volumes than control subjects that correlated with duration of corticosteroid therapy. These findings suggest that corticosteroid exposure may be associated with changes in the amygdala as well as hippocampus.

Growth Hormone Treatment for Children on Chronic Corticosteroids

Growth Hormone Treatment for Children on Chronic Corticosteroids

Bisphosphonates in Corticosteroid-Induced Osteoporosis

Corticosteroid osteoporosis is a common clinical problem with the risk of fracture, highest in postmenopausal women. The first choice for prevention is a potent oral bisphosphonate such as alendronate or risedronate. In patients intolerant of oral bisphosphonates, intravenous bisphosphonates should be used. Prophylactic therapy should be continued whilst patients continue significant doses of corticosteroid therapy. In patients receiving chronic low-dose corticosteroids where the BMD is substantially reduced, other therapies such as PTH should be considered, followed by a bisphosphonate.