[Safety and efficacy of off-label use of biologic therapies in patients with inflammatory rheumatic diseases refractory to standard of care therapy : Data from a nationwide German registry (GRAID2)]. / Sicherheit und Wirksamkeitshinweise zum Off-label-Einsatz von Biologikatherapien nach Versagen konventioneller Therapien bei Patienten mit entzündlich rheumatischen Erkrankungen : Ergebnisse eines nationalen Registers (GRAID2).

BACKGROUND: The German Registry of Autoimmune Diseases 2 (GRAID2) is a retrospective, non-interventional, multicenter registry study collecting data from patients with inflammatory, mainly rheumatic diseases refractory to standard of care therapy and treated with an off-label biologic therapy. The retrospective documentation comprised case history, diagnosis, course of disease (including safety and global efficacy). The objective was to evaluate the global clinical outcome and safety of off-label biologic therapy in clinical practice. RESULTS: Data from 311 patients with an overall observation period of 338.5 patient-years were collected. The mean patients age was 47.8 years with 56.9% females. The most frequently documented diagnoses comprised rejection prophylaxis/therapy after renal transplantation (NTX, 18.3%), ANCA-vasculitides (17.4%), systemic lupus erythematosus (SLE, 10.3%), autoinflammatory fever syndromes (8.4%), autoimmune myositis (7.4%) and pemphigus (5.8%). Documented biologic therapies included rituximab (RTX, 70.1%), tocilizumab (TCZ, 9.3%), infliximab (IFX, 7.1%), anakinra (ANK, 5.5%), adalimumab (ADA, 3.5%), etanercept (ETA, 2.3%) and certolizumab (CTZ, 0.6%). After initiation of off-label biologic treatment, tolerability was assessed by the physicians as "very good"/"good" in 95.5%. Altogether, 275 adverse events were documented and of these, 104 were classified as serious adverse events and occurred in 62 patients. In 19 of these patients severe infections (30.6%) were documented, resulting in a rate of 5.6 severe infections per 100 patient years. A total of six deaths were documented, while five of these cases were rated as not related to the biologics treatment. Notably, the use of RTX in patients with small vessel vasculitides and of TCZ in patients with large vessel vasculitides prior to their approval support their relevance in clinical management of patients with severe diseases. CONCLUSION: The results of this registry together with data of GRAID1 provide evidence that use of off-label biologic therapies in patients with inflammatory rheumatic diseases refractory to conventional treatment did not result in any new safety signal already known for these compounds or subsequently shown by clinical trials in certain entities.

[Do we still need clinical studies in rheumatology?]. / Brauchen wir noch klinische Studien in der Rheumatologie?

Despite a large number of approved therapies demonstrating efficacy in the treatment of rheumatic diseases, only 60-85 % of patients with the indications for rheumatoid arthritis are adequately treated in Germany. Additionally, approved therapies for other immune-mediated diseases are often entirely lacking, indicating the great medical need for the development of new innovative therapies in this specialized field. The development of new drugs is expensive due to the high costs of conducting clinical trials in all phases of development up to obtaining approval; therefore, pharmaceutical companies are looking for ways to save costs in the particular developmental stages. Although the classical regions for drug development (i.e. western Europe, the USA and Japan) offer both a high level of data quality and a good infrastructure to conduct clinical trials due to high standards of education and quality, clinical trials are expensive in these regions. Beside high costs, the comparatively low recruitment rates in these regions are one of the main reasons for the shifting of drug developmental stages from classical regions to eastern European, Latin American and Asian countries, which provide services for drug development and high recruitment rates for comparatively less money. However, there are many strong arguments for the participation of regions in western Europe, especially German sites in clinical trials. In this article these arguments are discussed and possible solutions and strategies for conducting and compensation of study centers in Germany for clinical trials in the field of rheumatology are provided.

Life cycle and parasitic interaction of the lizard-parasitizing mite Ophionyssus galloticolus (Acari: Gamasida: Macronyssidae), with remarks about the evolutionary consequences of parasitism in mites.

Wild-caught specimens of the lacertid lizard Gallotia galloti eisentrauti from the Canary Island of Tenerife were checked for ectoparasites. The parasitic gamasid mite Ophionyssus galloticolus Fain and Bannert (2000) was very abundant on these lizards. Additionally, parasitism by larvae of two species of Trombiculidae (Prostigmata: Parasitengona) was observed. O. galloticolus was reared in the laboratory on its natural host in order to investigate its life cycle, reproductive biology, and development. The life history of O. galloticolus is documented in detail and compared to literature data of other Ophionyssus species. O. galloticolus was found to be similar to other species of the same genus with respect to the duration of development, the precopulatory association of protonymphs, and the arrhenotokous development of eggs. However, it seems to be more tolerant towards low relative humidity and longer starvation periods than other Ophionyssus species. Evolutionary transformations of the life-history pattern of this genus and other parasitic mites in comparison to its predatory precursors involve a reduction or partial suppression of ontogenetic instars in order to decrease mortality during host-seeking phases, and a compensating increase in growth capacity of the remaining feeding instars facilitated by replacement of sclerites through elastic cuticle or by growth of new cuticle unrelated to a moult (neosomy).

Recognition of cyclic transmission of Sarcocystis stehlinii n. sp. in the Gran Canarian giant lizard.

The transmission of Sarcocystis species via cannibalism seems to be common among lizards of the genus Gallotia that are endemic to the Canary Islands. Gran Canarian giant lizards, Gallotia stehlini, were screened for the presence of sarcosporidian parasites. Sarcocysts, measuring 90-400 micrometers in length and 60-160 micrometers in width, were found in the musculature of the lizards' tails. In their feces the lizards passed sporocysts of 8.5(8.2-9.4) x 6.5(5.9-7.0) micrometers. A series of laboratory infections was carried out to shed light on the life cycle of Sarocystis stehlinii n.sp., proving it to be another dihomoxenous Sarcocystis species.

Cannibalism and autotomy as predator-prey relationship for monoxenous Sarcosporidia.

In search for the final host of Sarcocystis gallotiae, sarcocysts of naturally infected Canarian lizards, Gallotia galloti, were fed to vertebrate predators of the lizard. Repeated transmission experiments remained negative. Routine check of the feces of the wild G. galloti revealed shedding of sporocysts. The sporocysts were administered to small vertebrates, which may function as prey for G. galloti. The transmission experiments remained negative. The observation of a high intraspecific aggression of G. galloti, including cannibalism and autotomy, seemed to support the hypothesis that this behavior might be the base of a an unexpected predator-prey relationship. Sarcocysts of S. gallotiae, fed to two laboratory-bred G. galloti resulted in excretion of sporulated sporocysts measuring 9.7 (9.2-12.2) X 7.7 (6.6-9.2) microns. Oral inoculation of two laboratory-bred G. galloti with experimentally gained sporocysts, led to the development of sarcocysts of 150-200 microns in length and 80-110 microns in width in the musculature of the lizards 153 days p.i. The sarcocysts were identified as S. gallotiae by light and electron microscopy. In epithelial cells of the intestine of G. galloti, which had experimentally been infected with sarcocysts of S. gallotiae, stages of gamogony and sporogony were found. We suggest that the life cycle of S. gallotiae is monoxenous and not obligatorily heteroxenous. The genus Sarcocystis seems to be more flexible in its biologic adaptability to utilize autotomy and cannibalism for completing its cycle than had heretofore been assumed.