Regional differences in baseline disease activity and remission rates following golimumab treatment for RA: results from the GO-MORE trial

Clinical Rheumatology - GO-MORE (NCT00975130) was a large open-label, multinational, multicenter, prospective phase 3 trial evaluating add-on therapy with golimumab in biologic-naïve patients...     

Plasma sLOX-1 is a potent biomarker of clinical remission and disease activity in patients with seropositive RA

Objectives: Soluble lectin-like oxidized low-density lipoprotein receptor 1 (sLOX-1) is present in the circulation and synovial fluid in patients with rheumatoid arthritis (RA). The aim of this study was to assess whether sLOX-1 level is associated with clinical remission and disease activity in patients with RA.

Methods: Clinical and laboratory data were analyzed for 282 patients with RA. Plasma sLOX-1 level was measured by enzyme-linked immunosorbent assay (ELISA). The remission status and sLOX-1 levels were compared between four groups of patients based on the positivity of rheumatoid factor (RF) and anti-citrullinated protein antibodies (ACPAs). Relationships between sLOX-1 level and the 28-joint Disease Activity Score with erythrocyte sedimentation rate (DAS28-ESR) were analyzed by multivariate logistic regression.

Results: The patients in the RF?+?ACPA?+?group tended to exhibit higher sLOX-1 levels when compared to the other three groups. In the RF?+?ACPA?+?group, the sLOX-1 level was significantly higher in the non-remission group than in the remission group, irrespective of treatment. Multivariate logistic regression showed significant correlations between sLOX-1 level and DAS28-ESR.

Conclusions: sLOX-1 level might be a useful biomarker for assessing clinical remission and disease activity in double-positive RA patients.     

Adalimumab for maintenance treatment of Crohn's disease: results of the CLASSIC II trial

BACKGROUND: Adalimumab induced clinical remission after four weeks in patients with active Crohn's disease in the CLASSIC I trial. OBJECTIVE: To evaluate long term efficacy and safety of adalimumab maintenance therapy in Crohn's disease in a follow-on randomised controlled trial (CLASSIC II). METHODS: In the preceding CLASSIC I trial, 299 patients with moderate to severe Crohn's disease naive to tumour necrosis factor antagonists received induction therapy with adalimumab 40 mg/20 mg, 80 mg/40 mg, or 160 mg/80 mg, or placebo, at weeks 0 and 2. In all, 276 patients from CLASSIC I enrolled in CLASSIC II and received open-label adalimumab 40 mg at weeks 0 (week 4 of CLASSIC I) and 2; 55 patients in remission at both weeks 0 and 4 were re-randomised to adalimumab 40 mg every other week, 40 mg weekly, or placebo for 56 weeks. Patients not in remission at both weeks 0 and 4 were enrolled in an open-label arm and received adalimumab 40 mg every other week. With non-response or flare, these patients could have their dosages increased to 40 mg weekly. Patients in the randomised arm with continued non-response or disease flare could switch to open-label adalimumab 40 mg every other week and again to 40 mg weekly. The primary end point was maintenance of remission (CDAI <150) in randomised patients through week 56. RESULTS: Of 55 patients randomised at week 4, 79% who received adalimumab 40 mg every other week and 83% who received 40 mg weekly were in remission at week 56, v 44% for placebo (p<0.05). In all, 204 patients entered the open-label arm. Of these, 93 (46%) were in clinical remission at week 56. Adalimumab was generally well-tolerated in all patients. CONCLUSIONS: Adalimumab induced and maintained clinical remission for up to 56 weeks in patients with moderate to severe Crohn's disease naive to anti-TNF treatment.     

Impact of lesion complexity on the capacity of a trial to detect differences in stent performance: results from the ISAR-STEREO trial

Background

A number of stent-versus-stent trials have not been able to disclose differences in stent performance. It has been hypothesized that the selection of patient subsets with simple lesion morphologies may have masked differences among the stent designs under testing. The randomized Intracoronary Stenting and Angiographic Results Strut Thickness Effect on Restenosis Outcome (ISAR-STEREO) trial has shown that a reduced stent strut thickness is associated with a reduced risk for restenosis. The rationale of this study was to investigate the role of lesion complexity on the capacity of a stent-versus-stent trial to distinguish between superior and inferior stents.

Methods

In the ISAR-STEREO trial, 651 patients were randomly assigned to receive either a thin-strut (n = 326) or a thick-strut stent (n = 325) with a comparable stent design. Restenosis, defined as a ≥50% diameter stenosis at follow-up angiography, was analyzed according to the lesion complexity, which was assessed with the use of the American College of Cardiology/American Heart Association classification system.

Results

The restenosis rate did not differ between stent designs in patients with noncomplex lesions (type A or B₁; restenosis rate: 16.7% vs 16.7%, P = 1.0 for thin-strut vs thick-strut stents). In patients with complex lesions (type B₂ or C), there was a significant reduction in restenosis in the thin-strut stent group (restenosis rate: 14.5% vs 29.0%; P < .01 for thin-strut vs thick-strut stents).

Conclusions

The results of this study suggest that the potential to detect differences in the risk for restenosis in stent-versus-stent trials is strongly dependent on the inclusion of patients with complex lesions. These findings may be relevant when planning new stent-versus-stent trials.     

Comparative efficacy of golimumab,infliximab, and adalimumab for moderately to severely active ulcerative colitis: a network meta-analysis accounting for differences in trial designs

Aim: To conduct a network meta-analysis (NMA) to establish the comparative efficacy of infliximab, adalimumab and golimumab for the treatment of moderately to severely active ulcerative colitis (UC). Design: A systematic literature search identified five randomized controlled trials for inclusion in the NMA. One trial assessed golimumab, two assessed infliximab and two assessed adalimumab. Outcomes included clinical response, clinical remission, mucosal healing, sustained clinical response and sustained clinical remission. Innovative methods were used to allow inclusion of the golimumab trial data given the alternative design of this trial (i.e., two-stage re-randomization). Results: After induction, no statistically significant differences were found between golimumab and adalimumab or between golimumab and infliximab. Infliximab was statistically superior to adalimumab after induction for all outcomes and treatment ranking suggested infliximab as the superior treatment for induction. Golimumab and infliximab were associated with similar efficacy for achieving maintained clinical remission and sustained clinical remission, whereas adalimumab was not significantly better than placebo for sustained clinical remission. Golimumab and infliximab were also associated with similar efficacy for achieving maintained clinical response, sustained clinical response and mucosal healing. Finally, golimumab 50 and 100 mg was statistically superior to adalimumab for clinical response and sustained clinical response, and golimumab 100 mg was also statistically superior to adalimumab for mucosal healing. Conclusion: The results of our NMA suggest that infliximab was statistically superior to adalimumab after induction, and that golimumab was statistically superior to adalimumab for sustained outcomes. Golimumab and infliximab appeared comparable in efficacy.     

Long-term remission rates after pituitary surgery for Cushing's disease: the need for long-term surveillance

OBJECTIVE: There have been a few reports on long-term remission rates after apparent early remission following pituitary surgery in the management of Cushing's disease. An undetectable postoperative serum cortisol has been regarded as the result most likely to predict long-term remission. Our objective was to assess the relapse rates in patients who underwent transsphenoidal surgery in order to determine whether undetectable cortisol following surgery was predictive of long-term remission and whether it was possible to have long-term remission when early morning cortisol was measurable but not grossly elevated. Endocrinological factors associated with late relapse were also studied. PATIENTS: We reviewed the long-term outcome in 63 patients who had pituitary surgery for the treatment of Cushing's disease between 1979 and 2000. MEASUREMENTS: Case notes were reviewed and the current clinical and biochemical status assessed. Our usual practice was that early after the operation, an 08:00 h serum cortisol was measured 24 h after the last dose of hydrocortisone. This was followed by a formal low-dose dexamethasone suppression test. Current clinical status and recent 24-h urinary free cortisol values were used as an index of activity of the Cushing's disease. If there was evidence suggesting relapse, a low-dose dexamethasone suppression test was performed. In many patients, sequential collections of early morning urine specimens for urinary cortisol to creatinine ratio were also performed in an attempt to diagnose cyclical and intermittent forms of recurrent hypercortisolism. We did this if there was conflicting endocrine data, or if patients were slow to lose abnormal clinical features. RESULTS: Mean age at diagnosis was 40.3 years (range 14-70 years). Mean follow-up up time was 9.6 years (range 1-21 years). Forty-five patients (9 males/36 females) achieved apparent remission immediately after surgery and were subsequently studied long term. Of these 45 patients, four have subsequently died while in remission from hypercortisolism. Ten of the remaining 41 patients have relapsed. Of those 10, six demonstrated definite cyclical cortisol secretion. Two of the 10 had undetectable basal serum cortisol levels in the immediate postoperative period. Thirty-one patients are still alive and in remission. Fourteen (45%) of the 31 who remained in remission had detectable serum cortisol levels (> 50 nmol/l) immediately postoperatively, and remain in remission after a mean of 8.8 years. Our relapse rate was therefore 10/45 (22%), after a mean follow-up time of 9.6 years, with mean time to relapse 5.3 years. CONCLUSIONS: The overall remission rate of 56% (35/63) at 9.6 years follow-up is disappointing and merits some re-appraisal of the widely accepted principle that pituitary surgery must be the initial treatment of choice in pituitary-dependent Cushing's syndrome. Following pituitary surgery, careful ongoing expert endocrine assessment is mandatory as the incidence of relapse increases with time and also with increasing rigour of the endocrine evaluation. A significant number of our patients were shown to have relapsed with a cyclical form of hypercortisolism.     

Organ iron accumulation in chronically transfused children with sickle cell anaemia: baseline results from the TWiTCH trial

Transcranial Doppler (TCD) With Transfusions Changing to Hydroxyurea (TWiTCH) trial is a randomized, open‐label comparison of hydroxycarbamide (also termed hydroxyurea) versus continued chronic transfusion therapy for primary stroke prevention in patients with sickle cell anaemia (SCA) and abnormal TCD. Severity and location of iron overload is an important secondary outcome measure. We report the baseline findings of abdominal organ iron burden in 121 participants. At enrollment, patients were young (9·8 ± 2·9 years), predominantly female (60:40), and previously treated with transfusions (4·1 ± 2·4 years) and iron chelation (3·1 ± 2·1 years). Liver iron concentration (LIC; 9·0 ± 6·6 mg/g dry weight) and serum ferritin were moderately elevated (2696 ± 1678 μg/l), but transferrin was incompletely saturated (47·2 ± 23·6%). Spleen R2* was 509 ± 399 Hz (splenic iron ~13·9 mg/g) and correlated with LIC (r² = 0·14, P = 0·0008). Pancreas R2* was increased in 38·3% of patients but not to levels associated with endocrine toxicity. Kidney R2* was increased in 80·7% of patients; renal iron correlated with markers of intravascular haemolysis and was elevated in patients with increased urine albumin‐creatinine ratios. Extra‐hepatic iron deposition is common among children with SCA who receive chronic transfusions, and could potentiate oxidative stress caused by reperfusion injury and decellularized haemoglobin.     

Vascular basis for the treatment of myocardial ischemia study: trial design and baseline characteristics

Background

Increased low-density lipoprotein (LDL) and oxidized LDL cholesterol levels adversely affect endothelial function in patients with stable coronary artery disease (CAD). Statin drugs are efficacious in primary and secondary prevention of clinical CAD events, but they have not been extensively studied as a treatment for ischemia during routine daily activities or during exercise, indicators of high-risk in patients with stable CAD. The purpose of the Vascular Basis for the Treatment of Myocardial Ischemia study is to determine whether aggressive lowering of LDL cholesterol level with atorvastatin, with or without supplemental antioxidant vitamins C and E, can improve endothelial function and ischemia during ambulatory electrocardiogram (AECG) monitoring and exercise treadmill testing (ETT).

Methods

Patients are eligible when they have ischemia during an ETT and AECG monitoring and when their fasting total cholesterol level is ≤250 mg/dL. Eligible patients are randomized to receive 1 of 3 treatments: intensive atorvastatin to reduce LDL cholesterol level to ≤80 mg/dL, intensive atorvastatin to reduce LDL cholesterol level to ≤80 mg/dL plus antioxidant vitamins C and E, and control of diet and low-dose lovastatin, when needed, to reduce LDL cholesterol level ≤ to 130 mg/dL. Patients undergo endothelial function testing, 48-hour AECG monitoring, and ETT at randomization and at 6 and 12 months.

Results

A total of 300 patients have been randomized: 101 to receive atorvastatin alone, 103 to receive atorvastatin plus antioxidant vitamins, and 96 to receive placebo. Baseline characteristics are similar across treatment groups.

Conclusions

The Vascular Basis study will provide important insight on the effects of aggressive management of dyslipidemia with statin drugs and antioxidant vitamins in patients with stable but high-risk CAD.     

The prevalence of clinical remission in RA patients treated with anti-TNF: results from the Dutch Rheumatoid Arthritis Monitoring (DREAM) registry

Objectives. To evaluate the prevalence of clinical remission and minimal disease activity according to the ACR/European League Against Rheumatism (EULAR) remission, DAS-28 <2.6 and minimal disease activity (MDA) criteria, and to compare the extent of residual disease activity with disability in RA patients after 6 months of treatment with anti-TNF. Methods. In the Dutch Rheumatoid Arthritis Monitoring (DREAM) biologic registry the prevalence of DAS-28 <2.6, MDA and ACR/EULAR remission criteria was assessed. Residual disease activity during MDA or remission was assessed as the percentage of patients with swollen and tender joints, elevated acute-phase reactants and general health on a visual analogue scale (VAS). Disability was evaluated with the HAQ score. Results. Prevalence of DAS-28 <2.6 was 27%, prevalence of MDA was 34% and ACR/EULAR remission was reached by 6% of patients. Residual disease activity was present mostly in the most lenient criteria and occurred most frequently on the level of swollen joint count and VAS score: at least one swollen joint in DAS-28 <2.6, MDA and ACR/EULAR remission was present in, respectively, 51, 54 and 34% of the patients. VAS >1 occurred in, respectively, 67, 69 and 0% of the patients. Modification of the cut-point of the patient-reported outcome increased the prevalence of ACR/EULAR remission, but also the level of disability. Conclusion. MDA and DAS-28 <2.6 are reachable treatment targets in RA with anti-TNF, although residual disease activity might still be present. In turn, ACR/EULAR remission criteria leave little residual disease activity, but might be too stringent for use in daily clinical practice due to the strict cut-point in the patient-reported outcome.     

Racial differences in the characteristics of patients admitted for acute decompensated heart failure and their relation to outcomes: results from the OPTIME-CHF trial

BackgroundRecent data suggest that differences in response to therapy and survival exist between African Americans and Caucasians with heart failure. Whether these differences exist in acute decompensated heart failure (ADHF) is uncertain.Methods and ResultsWe analyzed data from the OPTIME-CHF (Outcomes of a Prospective Trial of Intravenous Milrinone for Exacerbations of Chronic Heart Failure) study, a randomized trial of intravenous milrinone versus placebo in 949 patients hospitalized with ADHF. We evaluated differences in clinical characteristics, outcomes, and response to milrinone therapy in African American patients compared with Caucasians. The primary end point of OPTIME-CHF was days hospitalized for cardiovascular causes or death within 60 days of randomization. Thirty-three percent (n = 310) of patients were African American. African American patients were younger (57 vs. 70 years, P < .0001) and more likely to have non-ischemic cardiomyopathy (74% vs. 36%, P < .0001). In unadjusted analysis, African American patients had a lower 60-day mortality (5% vs. 12%, P = .0004) and tended to have better overall clinical outcomes. After adjustment for baseline differences, however, these differences were no longer significant. We found no differential effect of milrinone therapy by race.ConclusionAfrican American patients with acute decompensated heart failure present with a different clinical profile than Caucasian patients. Although unadjusted clinical outcomes are better for African Americans presenting with ADHF, these differences diminished after adjustment for baseline characteristics.     

Improvement in disease activity among patients with rheumatoid arthritis who switched from intravenous infliximab to intravenous golimumab in the ACR RISE registry

Clinical Rheumatology - Infliximab and golimumab are intravenously (IV) administered tumor necrosis factor inhibitors approved to treat moderate-to-severe rheumatoid arthritis (RA) with concomitant...     

Subgroup analysis of the placebo-controlled CHARM trial: Increased remission rates through 3 years for adalimumab-treated patients with early Crohn's disease

Background and aimsWe examined the impact of disease duration on clinical outcomes and safety in a post hoc analysis of a remission maintenance trial with adalimumab in patients with moderate to severe CD.MethodsPatients in the CHARM trial were divided into 3 disease duration categories: < 2 (n = 93), 2 to < 5 (n = 148), and ≥ 5 years (n = 536). Clinical remission and response rates at weeks 26 and 56 were compared between adalimumab and placebo subgroups, and assessed through 3 years of adalimumab treatment in the ADHERE follow-on trial. Logistic regression assessed the effect of disease duration and other factors on remission and safety.ResultsAt week 56, clinical remission rates were significantly greater for adalimumab-treated versus placebo-treated patients in all 3 duration subgroups (19% versus 43% for < 2 years; P = 0.024; 13% versus 30% for 2 to < 5 years; P = 0.028; 8% versus 28% for ≥ 5 years, P < 0.001). Logistic regression identified shorter duration as a significant predictor for higher remission rate in adalimumab-treated patients. Patients with disease duration < 2 years maintained higher remission rates than patients with longer disease duration through 3 years of treatment. The incidence of serious adverse events in adalimumab-treated patients was lowest with disease duration < 2 years.ConclusionsAdalimumab was superior to placebo for maintaining clinical remission in patients with moderately to severely active CD after 1 year of treatment regardless of disease duration. Clinical remission rates through 3 years of treatment were highest in the shortest disease duration subgroup in adalimumab-treated patients, with a trend to fewer side effects.     

Adalimumab for maintenance of clinical response and remission in patients with Crohn's disease: the CHARM trial

BACKGROUND & AIMS: This study evaluated the efficacy and safety of adalimumab, a fully human, anti-tumor necrosis factor monoclonal antibody administered subcutaneously, in the maintenance of response and remission in patients with moderate to severe Crohn's disease (CD). METHODS: Patients received open-label induction therapy with adalimumab 80 mg (week 0) followed by 40 mg (week 2). At week 4, patients were stratified by response (decrease in Crohn's Disease Activity Index > or =70 points from baseline) and randomized to double-blind treatment with placebo, adalimumab 40 mg every other week (eow), or adalimumab 40 mg weekly through week 56. Co-primary end points were the percentages of randomized responders who achieved clinical remission (Crohn's Disease Activity Index score <150) at weeks 26 and 56. RESULTS: The percentage of randomized responders in remission was significantly greater in the adalimumab 40-mg eow and 40-mg weekly groups versus placebo at week 26 (40%, 47%, and 17%, respectively; P < .001) and week 56 (36%, 41%, and 12%, respectively; P < .001). No significant differences in efficacy between adalimumab eow and weekly were observed. More patients receiving placebo discontinued treatment because of an adverse event (13.4%) than those receiving adalimumab (6.9% and 4.7% in the 40-mg eow and 40-mg weekly groups, respectively). CONCLUSIONS: Among patients who responded to adalimumab, both adalimumab eow and weekly were significantly more effective than placebo in maintaining remission in moderate to severe CD through 56 weeks. Adalimumab was well-tolerated, with a safety profile consistent with previous experience with the drug.