Safety and clinical outcomes of rituximab therapy in patients with different autoimmune diseases: experience from a national registry (GRAID)

Introduction: Evidence from a number of open-label, uncontrolled studies has suggested that rituximab may benefit patients with autoimmune diseases who are refractory to standard-of-care. The objective of this study was to evaluate the safety and clinical outcomes of rituximab in several standard-of-care-refractory autoimmune diseases (within rheumatology, nephrology, dermatology and neurology) other than rheumatoid arthritis or non-Hodgkin's lymphoma in a real-life clinical setting. Methods: Patients who received rituximab having shown an inadequate response to standard-of-care had their safety and clinical outcomes data retrospectively analysed as part of the German Registry of Autoimmune Diseases. The main outcome measures were safety and clinical response, as judged at the discretion of the investigators. Results: A total of 370 patients (299 patient-years) with various autoimmune diseases (23.0% with systemic lupus erythematosus, 15.7% antineutrophil cytoplasmic antibody-associated granulomatous vasculitides, 15.1% multiple sclerosis and 10.0% pemphigus) from 42 centres received a mean dose of 2,440 mg of rituximab over a median (range) of 194 (180 to 1,407) days. The overall rate of serious infections was 5.3 per 100 patient-years during rituximab therapy. Opportunistic infections were infrequent across the whole study population, and mostly occurred in patients with systemic lupus erythematosus. There were 11 deaths (3.0% of patients) after rituximab treatment (mean 11.6 months after first infusion, range 0.8 to 31.3 months), with most of the deaths caused by infections. Overall (n = 293), 13.3% of patients showed no response, 45.1% showed a partial response and 41.6% showed a complete response. Responses were also reflected by reduced use of glucocorticoids and various immunosuppressives during rituximab therapy and follow-up compared with before rituximab. Rituximab generally had a positive effect on patient well-being (physician's visual analogue scale; mean improvement from baseline of 12.1 mm). Conclusions: Data from this registry indicate that rituximab is a commonly employed, well-tolerated therapy with potential beneficial effects in standard of care-refractory autoimmune diseases, and support the results from other open-label, uncontrolled studies

Ein neues Modell zur Untersuchung der mikrovaskulären Reaktivität des Menschen in vivo

GesamtdissertationIntroduction: Primary hypertension is one of today's most relevant and challenging medical conditions. It is the leading risk factor for cardiovascular disease (CVD) representing the most common cause of death in economically developed countries. As the major site of pressure reduction, the microcirculation plays a key role in the development and progression of arterial hypertension. One of the most prominent factors contributing to microcirculatory impairment as seen in hypertension is the key peptide of the Renin-Angiotensin-System (RAS), Angiotensin II (Ang II). However, at present only indirect or invasive measurement of microvascular reactivity to locally applied drugs (e.g. laser-Doppler technique following drug delivery by iontophoresis) is available. Therefore, the aim of the present study was to develop a new model to directly study human microcirculatory reactivity in vivo, in particular, to the effects of locally applied Ang II. Design and methods: Normotensive subjects were studied with a previously validated intravital microscopy system. Following an overnight fast, conjunctival arterioles and venules were recorded before and after application of placebo eye-drops in one eye, and Ang II (0.001%, 0.01%), or phenylephrine (0.25%) drops in the other eye (in random order). Microvascular diameter changes were measured using dedicated software. Results: Repeated analyses of the same microvessels in five subjects revealed a variability of measurement of 4 %. The repeated measurements of conjunctival microvascular diameters following placebo eye drops resulted in a variability of diameters of 3 % for arterioles and venules. A low concentration of Ang II (0.001%) had no effect on microvascular diameters. However, the higher concentration of Ang II (0.01%) and phenylephrine induced a statistically significant vascular constriction. This constriction lasted for at least 10 minutes. Conclusion: A new model for in vivo testing of microvascular reactivity in man with low variability to locally applied drugs is presented. Ang II acutely induced a constriction of conjunctival arterioles and venules, which lasted for at least 10 minutes. These data suggest that the proposed in vivo model is suitable for studying the RAS in the human microcirculation.Einleitung: Essentielle Hypertonie ist eine der weltweit häufigsten Erkrankungen und damit eine der größten medizinischen Herausforderungen der heutigen Zeit. Erhöhter Blutdruck ist einer der wichtigsten Risikofaktoren für die Entstehung von Herz- und Kreislauferkrankungen, welche in den Industrieländern zu den häufigsten Todesursachen zählen. Als Hauptort der Regulation des Blutdrucks, spielt die Mikrozirkulation eine Schlüsselrolle in der Ätiologie und während des Fortschreitens dieser Erkrankungen. Einer der wichtigsten Faktoren der zu den pathologischen Veränderungen bei Bluthochdruck führt ist das zentrale Hormon des Renin-Angiotensin-Systems (RAS), Angiotensin II (Ang II). Nichtsdestotrotz sind bisher nur indirekte oder invasive Methoden bekannt um die Reaktivität der kleinsten Blutgefässe auf lokal applizierte Substanzen im Menschen zu untersuchen (z.B. Laser-Doppler nach Iontophorese). Aus diesem Grund war das Ziel der vorliegenden Arbeit ein neues Modell für die in vivo Untersuchung der humanen Mikrozirkulation zu entwickeln und den Effekt von Ang II zu ermitteln. Methoden: Zu diesem Zweck wurden normotensive Probanden mit einem zuvor validierten biomikroskopischen Setup untersucht. Die nüchternen Teilnehmer wurden in randomisierter verblindeter Reihenfolge an je einem Auge mit Placebo und am Anderen mit Ang II in zwei verschiedenen Konzentrationen (0.001%, 0.01%) bzw. mit Phenylephrine (0.25 %) als pharmakologische Kontrolle behandelt. Es wurden je drei Arteriolen und drei Venolen pro Auge vor und nach der Gabe des jeweiligen Augentropfens auf eine DVD aufgezeichnet Anschließend wurden die Gefäßdurchmesser mittels spezieller Software gemessen und die relative Veränderung ermittelt. Ergebnisse: Die Validierung des Models ergab einen geringen Variationskoeffizienten von 4 % für die Gefäßmessungen. Die biologische Variabilität, ermittelt durch wiederholte Messungen vor und nach Placebo, lag bei 3 %. Ang II führte in der niedrigen Dosierung (0.001 %) nicht zu einer Vasokonstriktion. Die zehnfach höhere Dosis Ang II hatte genauso wie Phenylephrine einen statistisch signifikanten Effekt auf den Gefäßdurchmesser. Die Vasokonstriktion dauerte über 10 Minuten an und ließ im Verlauf langsam nach. Diskussion: Das vorgestellte Modell eignet sich zur non-invasiven Untersuchung der Mikrozirkulation des Menschen. Die Ergebnisse zeigen dass der Effekt von lokal appliziertem Phenylephrin und Ang II im Auge mit dem vorgeschlagenen Modell messbar ist. Somit eröffnet sich die Möglichkeit den Einfluss von Schlüsselhormonen aus dem RAS auf die Mikrozirkulation möglich macht