Treatment sequence network meta-analysis in Crohn’s disease: a methodological case study

Objective: Several biologic therapies are available for the treatment of mild-to-moderate Crohn’s disease (CD). This network meta-analysis (NMA) aimed to assess the comparative efficacy of ustekinumab, adalimumab, vedolizumab and infliximab in the maintenance of clinical response and remission after 1?year of treatment.

Methods: A systematic literature search was performed to identify relevant randomized controlled trials (RCTs). Key outcomes of interest were clinical response (CD activity index [CDAI] reduction of 100 points; CDAI-100) and remission (CDAI score under 150 points; CDAI < 150). A treatment sequence Bayesian NMA was conducted to account for the re-randomization of patients based on different clinical definitions, the lack of similarity of the common comparator for each trial and the full treatment pathway from the induction phase onwards.

Results: Thirteen RCTs were identified. Ustekinumab 90?mg q8w was associated with statistically significant improvement in clinical response relative to placebo and vedolizumab 300?mg. For clinical remission, ustekinumab 90?mg q8w was associated with statistically significant improvement relative to placebo and vedolizumab 300?mg q8w. Findings from sub-population analyses had similar results but were not statistically significant.

Conclusions: The NMA suggest that ustekinumab is associated with the highest likelihood of reaching response or remission at 1?year compared with placebo, adalimumab and vedolizumab. Results should be interpreted with caution because this is a novel methodology; however, the treatment sequence analysis may be the most methodologically sound analysis to derive estimates of comparative efficacy in CD in the absence of head-to-head evidence.     

Glutamate receptor antagonists block cocaine-induced convulsions and death.

The involvement of excitatory amino acid (EAA) receptors in mediation of the toxic effects of cocaine was studied in male ICR mice. Cocaine HCl (90 mg/kg, IP) induced seizures in 95% and death within 24 h in 68% (n = 135) of the animals. There was a significant correlation (r = .54) between the time to onset of convulsions and the time to death in mice which died within 30 min of injection (n = 84). Pretreatment with selected EAA receptor antagonists 15 min prior to cocaine differentially blocked cocaine toxicity. Selective N-methyl-D-aspartic acid (NMDA) receptor antagonists (MK-801, dextrorphan, CPP) decreased both the incidence of seizures and mortality. A nonselective EAA antagonist, kynurenic acid, decreased lethality in doses which did not reduce convulsions. A similar action was observed following pretreatment with the selective kainic acid/AMPA receptor antagonist, GDEE. Antagonists at EAA receptors can provide significant protection against cocaine-induced toxicity. Moreover, the data provide evidence for the involvement of both NMDA and non-NMDA receptor subtypes in aspects of cocaine toxicity.     

Preliminary outcomes and efficacy of the first 360 consecutive kyphoplasties for the treatment of painful osteoporotic vertebral compression fractures.

BACKGROUND CONTEXT: Osteoporosis is a major cause of morbidity in worldwide elderly populations. Patients may become susceptible to vertebral compression fractures (VCFs) from low-impact situations. For patients who have failed conventional, palliative medical therapy, kyphoplasty not only reduces pain associated with vertebral fractures, but also offers a minimally invasive procedure with the potential to address fracture reduction and spinal sagittal alignment. Kyphoplasty involves expanding an inflatable balloon tamp to create a cavity within a vertebral body before cement deposition. PURPOSE: To evaluate the safety and efficacy of kyphoplasty to reduce and fix painful osteoporotic VCFs. STUDY DESIGN/SETTING: A retrospective, single-arm cohort study of consecutive kyphoplasty patients treated at a single center. PATIENT SAMPLE: Three hundred sixty VCFs were treated during 254 kyphoplasty procedures on 222 osteoporotic patients (mean age, 76 years [range, 28-98]; 28% male and 72% female). OUTCOME MEASURES: Patient-reported pain ratings were examined. Cement extravasation was monitored by intraoperative fluoroscopy and on postoperative radiographs. Anterior and midline vertebral height were assessed from standing, lateral radiographs obtained preoperatively and postoperatively. The number of patients who returned with symptomatic, new fractures was monitored. Perioperative complications were recorded. Mean follow-up occurred 21 months after kyphoplasty (range, 6 months through 36 months). RESULTS: Immediate pain relief was reported by 89% of patients by the first follow-up visit. One patient experienced postoperative pain as a result of radiculopathy related to bone filler leakage into the foramen. The remaining patients had persistent pain and were diagnosed with either a new fracture or underlying degenerative disc disease. Greater than or equal to 20% restoration of lost vertebral height (anterior) was observed in 63% of fractures with an overall mean restoration of 30%, and > or = 20% restoration of lost vertebral height (midline) was detected in 69% of fractures with an overall mean restoration of 50%. In this cohort, 12% (30/254) of the patients required additional kyphoplasty procedures to treat 36 symptomatic, new adjacent and remote fractures. No device-related complications occurred. CONCLUSIONS: Kyphoplasty is a safe and effective, minimally invasive procedure for relief of pain associated with VCF. In our series we also demonstrated some restoration of vertebral height and partial correction of sagittal alignment.