Influence of aminosteroid and glucocorticoid treatment on inflammation and immune function during cardiopulmonary bypass. Analysis of the quality of reporting of randomized controlled trials in acute and chronic myeloid leukemia, and myelodysplastic syndromes as governed by the CONSORT statement. Secular changes in the quality of published randomized clinical trials in rheumatology. Corticosteroid-free immunosuppression with tacrolimus, mycophenolate mofetil, and daclizumab induction in renal transplantation. Immunologic and hemodynamic effects of "low-dose" hydrocortisone in septic shock: a double-blind, randomized, placebo-controlled, crossover study. Cyclosporine A versus methotrexate in the treatment of polymyositis and dermatomyositis. The quality of reporting of randomized controlled trials in solid organ transplantation. Reduced exposure to calcineurin inhibitors in renal transplantation. Treatment of refractory myositis: a randomized crossover study of two new cytotoxic regimens.
During cardiopulmonary bypass, inflammation and immunosuppression is present. We measured circulating mediators and monocyte-based functions and tested the hypothesis that these variables are influenced by methylprednisolone (MP) or tirilazad mesylate (TM) treatment.
                Randomized, controlled, double-blind prospective trial.
                A university hospital.
                Thirty-nine patients scheduled for conventional coronary surgery with three-vessel disease.
                Preoperative application of MP (15 mg/kg) or TM (10 mg/kg) compared with placebo (PL).
                Circulating proinflammatory markers including interleukin (IL)-6, IL-8, monocyte chemoattractant protein 1, and C-reactive protein were all decreased by MP treatment but not by TM treatment. Whereas rapid increases in circulating anti-inflammatory IL-10 were superinduced by MP but not TM, plasma levels of IL-1RA and transforming growth factor beta were not altered by either treatment. Decreased ex vivo lipopolysaccharide-stimulated secretion of tumor necrosis factor alpha was prolonged after MP treatment but not after TM treatment. Perioperative stimulated secretion of IL-12 and interferon gamma was diminished in all groups, whereas ex vivo IL-1RA secretion tended to increase in all groups. Depression of monocyte surface expression of HLA-DR was significantly greater in patients treated with MP, whereas CD14 expression did not change.
                These data confirm that, during cardiopulmonary bypass, pro- and anti-inflammatory systems are activated at the same time, whereas monocyte-based immune functions are depressed. Treatment with MP abrogates proinflammatory mediators and induces a shift toward anti-inflammation at the cost of further functional monocyte deficits, whereas treatment with TM apparently has neither anti-inflammatory nor immunosuppressive actions in this setting. Randomized controlled trials (RCTs) are the best tool to evaluate the effectiveness of clinical interventions. The CONSORT (Consolidated Standards of Reporting Trials) statement is an evidence-based approach to improve the quality of RCTs. The aim of this study was to evaluate the reporting quality of published RCTs concerning myeloid hematologic malignancies according to the CONSORT statement.
                PubMed was searched for English-language RCTs involving patients with acute myeloid leukemia (AML), chronic myeloid leukemia (CML) and myelodysplastic syndromes (MDS). Trials were considered eligible when participants were randomly assigned to at least two treatment arms and included patients with AML, CML or MDS. Quality of reporting was assessed using a 24-item questionnaire based on the CONSORT checklist. Reporting was assessed in one pre-CONSORT (1988-1995) and one post-CONSORT (1996-2008) period. The effect of CONSORT statement in high- and low-ranked journals, according to their impact factor, has also been evaluated.
                The search identified 261 eligible articles for analysis. Only 13 of the 24 items of CONSORT statement were addressed in 75% or more of the studies. Most items concerning the methodological issues were reported by fewer than 50% of the studies. Significant improvements over time were seen for items that assessed the methodological quality, while RCTs published in high-ranked journals showed better quality of reporting.
                Quality of reporting in RCTs focusing on myeloid malignancies remains unsatisfactory. Further improvement of reporting is necessary to assess the validity of clinical research. To assess the quality of published randomized clinical trials (RCTs) in rheumatology and to determine whether there has been improvement in quality between 2 time periods, 1987-1988 and 1997-1998.
                Using MEDLINE and a hand search of selected rheumatology journals, we identified RCTs of adult rheumatic diseases published in English in 1987-1988 or 1997-1998. We examined trial quality with an expanded version of the Jadad scale, which assesses the adequacy of reported random sequence generation, allocation concealment, blinding, and analysis. All trials were read by 1 reviewer, with prior standardization using a random sample read by 2 reviewers. We also evaluated "high"- versus "low"-impact journals based on citation index.
                Two hundred forty RCTs (1987-1988 119 RCTs, 1997-1998 121 RCTs) were assessed. Results showed improvement in the quality of the trials, but the rates of reported random sequence generation, allocation concealment, power, and intent-to-treat analyses were persistently low. Low rates of reports of random sequence generation, allocation concealment, and intent-to-treat analyses were present even in the high-impact journals.
                There has been improvement in the quality of reporting of RCTs in rheumatology between 1987-1988 and 1997-1998. However, methodologic problems such as lack of allocation concealment, inadequate random sequence generation, lack of reporting of power, and lack of intent-to-treat analyses remain common. Many of these problems are established sources of bias in RCTs and are easily rectifiable. Corticosteroid-free maintenance immunosuppression after organ transplantation eliminates the well-known corticosteroid-related side effects and may help to improve long-term outcome. We investigated whether a corticosteroid-free tacrolimus (Tac)/mycophenolate mofetil (MMF) regimen, in combination with daclizumab (Dac) induction therapy, provides adequate immunosuppression after renal transplantation.
                This 6-month, open-label, multicenter, parallel-group study involved 538 renal patients randomized (1:1) to a Dac/Tac/MMF regimen (n = 260) or a Tac/MMF/corticosteroids regimen (n = 278) as a control group.
                Of the patients who completed the study, 88.8% in the Dac/Tac/MMF group were free from corticosteroid therapy at month 6. The incidence of biopsy-proven acute rejection was 16.5% in both treatment groups; the incidence of biopsy-proven corticosteroid-resistant acute rejection was 4.3% and 5.0% with Tac/MMF/corticosteroids and Dac/Tac/MMF, respectively (P = NS for both comparisons). Renal function was also similar in both groups: median serum creatinine at month 6 was 125.0 micromol/L (Tac/MMF/corticosteroids) and 131.0 microml/L (Dac/Tac/MMF), P = 0.277. The overall safety profile was similar with both regimens. However, compared with the Tac/MMF/steroid regimen, a significantly reduced incidence of new-onset insulin-dependent diabetes mellitus (5.4% vs. 0.4%, P = 0.003) was found with steroid-free immunosuppression. Moreover, mean total cholesterol concentrations increased from baseline in the Tac/MMF/corticosteroids group by 0.19 mmol/L, whereas in the Dac/Tac/MMF group, levels decreased by 0.19 mmol/L, P = 0.005.
                Corticosteroid-free immunosuppression with a Dac/Tac/MMF regimen is as effective at preventing acute rejection after renal transplantation as a standard triple regimen of Tac/MMF/corticosteroids. Furthermore, the safety benefits reported with Dac/Tac/MMF treatment may help improve the long-term outcome for renal-transplant patients. Within the last few years, increasing evidence of relative adrenal insufficiency in septic shock evoked a reassessment of hydrocortisone therapy. To evaluate the effects of hydrocortisone on the balance between proinflammatory and antiinflammation, 40 patients with septic shock were randomized in a double-blind crossover study to receive either the first 100 mg of hydrocortisone as a loading dose and 10 mg per hour until Day 3 (n = 20) or placebo (n = 20), followed by the opposite medication until Day 6. Hydrocortisone infusion induced an increase of mean arterial pressure, systemic vascular resistance, and a decline of heart rate, cardiac index, and norepinephrine requirement. A reduction of plasma nitrite/nitrate indicated inhibition of nitric oxide formation and correlated with a reduction of vasopressor support. The inflammatory response (interleukin-6 and interleukin-8), endothelial (soluble E-selectin) and neutrophil activation (expression of CD11b, CD64), and antiinflammatory response (soluble tumor necrosis factor receptors I and II and interleukin-10) were attenuated. In peripheral blood monocytes, human leukocyte antigen-DR expression was only slightly depressed, whereas in vitro phagocytosis and the monocyte-activating cytokine interleukin-12 increased. Hydrocortisone withdrawal induced hemodynamic and immunologic rebound effects. In conclusion, hydrocortisone therapy restored hemodynamic stability and differentially modulated the immunologic response to stress in a way of antiinflammation rather than immunosuppression. To determine the effectiveness and tolerance of treatment with cyclosporine A (CyA) or methotrexate (MTX) added to corticosteroids in patients with severe, active polymyositis (PM) and dermatomyositis (DM).
                Thirty-six patients (20 with DM, 16 with PM) were enrolled into the study and randomized in MTX (n = 17) and CyA (n = 19) groups. Muscle endurance and functional test (MEFT), clinical assessment (CA), global patient's assessment (GPA), muscle MRI, serum CK, myoglobin, IL-1Ra, and autoantibody status were used to assess the response to therapy after 1, 3, and 6 months.
                Significant improvement in MEFT, CA, GPA, and muscle MRI was found in both groups. Patients treated with MTX showed insignificantly better response than patients with CyA. CK levels in the MTX group decreased significantly after 1, 3, and 6 months, whereas a significant reduction in the CyA group was first observed after 6 months. IL-1Ra serum levels significantly dropped in the CyA group after two weeks, whereas in the MTX group the significant decrease was first seen after 3 months of treatment. Good correlation was found between each of the clinical parameters (MEFT, CA, and GPA), none of them showed any correlation with CK or IL-1Ra levels.
                Administration of MTX or CyA added to corticosteroids was associated with clinical and laboratory improvement. Changes in CK and IL-1Ra levels were not associated with parameters of clinical disease severity measured in this study. Randomized controlled trials (RCTs) of interventions provide the highest level of evidence about efficacy but their value either alone or within a meta-analysis is dependent on its methodological quality. For this reason recent RCTs in organ transplantation were assessed for quality. RCTs published between 2004 and 2006 (n = 332) were assessed, after excluding duplicate and nonEnglish reports. Quality was evaluated using the Jadad score plus allocation concealment and intention to treat analysis. We noted journal type, journal author instructions, funding source, sample size and number and location of study centres. Around one-third of RCTs had a Jadad score of 3 or greater (indication of a methodologically good quality trial) and the other two parameters were satisfied in just over one third. Although the majority of trials were published in speciality journals the quality of those published in general journals was superior. Commercially sponsored trials were of better quality as were multicentre trials in contrast to single centre trials. Overall quality of reporting of RCTs in organ transplantation is poor and as RCTs provide the highest level of evidence in evaluations of interventions there needs to be a concerted effort within the transplant community to improve the standards of RCTs. Immunosuppressive regimens with the fewest possible toxic effects are desirable for transplant recipients. This study evaluated the efficacy and relative toxic effects of four immunosuppressive regimens.
                We randomly assigned 1645 renal-transplant recipients to receive standard-dose cyclosporine, mycophenolate mofetil, and corticosteroids, or daclizumab induction, mycophenolate mofetil, and corticosteroids in combination with low-dose cyclosporine, low-dose tacrolimus, or low-dose sirolimus. The primary end point was the estimated glomerular filtration rate (GFR), as calculated by the Cockcroft-Gault formula, 12 months after transplantation. Secondary end points included acute rejection and allograft survival.
                The mean calculated GFR was higher in patients receiving low-dose tacrolimus (65.4 ml per minute) than in the other three groups (range, 56.7 to 59.4 ml per minute). The rate of biopsy-proven acute rejection was lower in patients receiving low-dose tacrolimus (12.3%) than in those receiving standard-dose cyclosporine (25.8%), low-dose cyclosporine (24.0%), or low-dose sirolimus (37.2%). Allograft survival differed significantly among the four groups (P=0.02) and was highest in the low-dose tacrolimus group (94.2%), followed by the low-dose cyclosporine group (93.1%), the standard-dose cyclosporine group (89.3%), and the low-dose sirolimus group (89.3%). Serious adverse events were more common in the low-dose sirolimus group than in the other groups (53.2% vs. a range of 43.4 to 44.3%), although a similar proportion of patients in each group had at least one adverse event during treatment (86.3 to 90.5%).
                A regimen of daclizumab, mycophenolate mofetil, and corticosteroids in combination with low-dose tacrolimus may be advantageous for renal function, allograft survival, and acute rejection rates, as compared with regimens containing daclizumab induction plus either low-dose cyclosporine or low-dose sirolimus or with standard-dose cyclosporine without induction. (ClinicalTrials.gov number, NCT00231764 [ClinicalTrials.gov].).
                Copyright 2007 Massachusetts Medical Society. To assess the clinical usefulness of 2 novel therapies for treatment-resistant myositis.
                Thirty patients with refractory myositis, of whom 25 had an inadequate or no response to previous cytotoxic therapy, were randomized to begin either a combination of weekly oral methotrexate and daily azathioprine (MTX/AZA) or intravenous methotrexate with leucovorin rescue (I.V. MTX) every 2 weeks for 6 months. Crossover to the alternate therapy occurred according to defined rules; evaluations of muscle strength and functional abilities were performed at the beginning, and after 3 and 6 months, of each treatment.
                Of the 15 patients initially randomized to oral MTX/AZA, 8 improved with oral therapy and 1 improved with I.V. MTX during the crossover period. Of the 15 patients initially randomized to I.V. MTX therapy, 3 improved with the I.V. therapy and 4 with the oral combination during the crossover period. Although the study lacked the power to directly compare both treatments, intention-to-treat analysis showed a trend in favor of those patients who first received oral combination therapy (P = 0.025). There were 0.09 adverse events per patient-month with oral combination therapy and 0.16 per patient-month with I.V. therapy (P = 0.09).
                Combination oral MTX/AZA may benefit patients with treatment-resistant myositis, including those who previously had inadequate responses to either MTX or AZA alone. I.V. MTX with leucovorin rescue may also benefit some patients with refractory myositis.
This systematic review highlights the lack of high quality RCTs that assess the efficacy and toxicity of immunosuppressants in inflammatory myositis.