Factors Associated with Durable Response to Infliximab in Crohnʼs Disease 5 Years and Beyond: A Multicenter International Cohort

BACKGROUND: Infliximab (IFX) has been used for over a decade worldwide. Less is known about the natural history of IFX use beyond a few years and which patients are more likely to sustain benefits. METHODS: Patients with Crohn's disease (CD) exposed to IFX from Massachusetts General Hospital, Boston, Saint-Antoine Hospital, Paris, and the Swiss IBD Cohort Study were identified through retrospective and prospective data collection, complemented by chart abstraction of electronic medical records. We compared long-term users of IFX (>5 yr of treatment, long-term users of infliximab [LTUI]), with non-LTUI patients to identify prognostic factors. RESULTS: We pooled data on 1014 patients with CD from 3 different databases, of whom 250 were defined as LTUI. The comparison group comprised 290 patients with CD who discontinued IFX: 48 primary nonresponses, 95 loss of responses, and 147 adverse events. Factors associated with LTUI were colonic involvements and an earlier age at the start of IFX. The prevalence of active smokers and obese patients differed markedly, but inversely, between American and European centers but did not impact outcome. The discontinuation rate was stable around 3% to 6%, each year from years 3 to 10. CONCLUSIONS: Young age at start of IFX and colonic CD are factors associated with a beneficial long-term use of IFX. After 5 years of IFX, there is still a 3% to 5% discontinuation rate annually. Several factors associated with a good initial response such as nonsmoker and shorter disease duration at IFX initiation do not seem associated with a longer term response.

GABAergic modulation in central sensitization in humans: a randomized placebo-controlled pharmacokinetic-pharmacodynamic study comparing clobazam with clonazepam in healthy volunteers

Positive allosteric modulators of GABAA receptors (GAMs) acting at specific subtypes of GABAA receptors effectively restore compromised spinal pain control in rodents. Studies addressing a similar antihyperalgesic effect in humans are sparse and are hampered by sedative effects of nonselective GAMs available for use in humans. We present results from a randomized controlled double-blind crossover study in 25 healthy volunteers, which addressed potential antihyperalgesic actions of clobazam (CBZ) and clonazepam (CLN) at mildly sedating equianticonvulsive doses. Clobazam was chosen because of its relatively low sedative properties and CLN because of its use in neuropathic pain. Tolterodine (TLT) was used as an active placebo. The primary outcome parameter was a change in the area of cutaneous UVB irradiation-induced secondary hyperalgesia (ASH), which was monitored for 8 hours after drug application. Sedative effects were assessed in parallel to antihyperalgesia. Compared with TLT, recovery from hyperalgesia was significantly faster in the CBZ and CLN groups (P = 0.009). At the time point of maximum effect, the rate of recovery from hyperalgesia was accelerated by CBZ and CLN, relative to placebo by 15.7% (95% confidence interval [CI] 0.8-30.5), P = 0.040, and 28.6% (95% CI 4.5-52.6), P = 0.022, respectively. Active compounds induced stronger sedation than placebo, but these differences disappeared 8 hours after drug application. We demonstrate here that GAMs effectively reduce central sensitization in healthy volunteers. These results provide proof-of-principle evidence supporting efficacy of GAMs as antihyperalgesic agents in humans and should stimulate further research on compounds with improved subtype specificity.

Formungen neuzeitlicher Religionsverständnisse: Eine Landpredigt zum Thema "Was ist Religion?" (1799)

In den letzten drei Jahrzehnten ist das Interesse an einer historischen Verortung und Aufarbeitung der Entstehung neuzeitlicher Religionsverständnisse stetig gewachsen. Erst 2011 hat Michael Bergunder in der ZfR die Forderung nach einer konsequenten Historisierung von „Religion“ erneuert. Die Umsetzung eines solchen Programms orientiert sich bis heute stark an elitären, akademischen, intellektuellen Quellen, die in eine direkte Genealogie mit der im 19. Jahrhundert entstehenden Religionswissenschaft zu bringen sind. Mit der Forderung nach der Historisierung von Alltagsverständnissen von „Religion“ muss diese Perspektive jedoch erweitert werden, um auch nicht-elitäre Diskursstränge erfassen zu können. Zudem ist eine stärkere und konkretere historische Verortung der Diskursbeiträge anzustreben. Der Beitrag möchte zu einem solchen Programm einen Beitrag leisten, indem er die im April 1799 im Dorf Schwarzenbach bei Luzern gehaltene Predigt des katholischen Vikars Andreas Estermann zum Ausgangspunkt nimmt, die unter dem programmatischen Titel „Was ist Religion?“ stand. An ihr lässt sich zeigen, wie stark in diesem Fall die konkrete Ausformung des Religionsverständnisses von den Kontextfaktoren der Französischen Revolution, ihrer Umsetzung in der Helvetik, der lokalen Unruhen und Säkularisationen abhängig ist. Zudem kann gezeigt werden, wie Elemente eines oft im späten 19. Jahrhundert verorteten „protestantischen“ Religionsbegriffs bereits im späten 18. Jahrhundert in einem katholischen Kontext angelegt sind. Der Artikel stellt damit einige gängige Grundannahmen zur Geschichte moderner Religionsverständnisse in Frage.