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Background:Although seronegative RA patients often present with substantial disease burden [1], patients are underrepresented in research cohorts or clinical trials. Consequently, less knowledge about this subgroup has been accumulated.Objectives:To describe outcome of seronegative vs. seropositive RA patients treated with sarilumab in regular care in Germany.Methods:The prospective, observational, 24-month single-arm PROSARA study (SARILL08661) is currently running in Germany at 96 sites, aiming to enroll up to 750 RA patients treated with sarilumab. RA patients are prospectively selected at physician’s discretion according to label, and medical history is documented before treatment. This interim analysis included patients with data available up to 24 months. Here we focus on sustained treatment response after 6 and 12 months, respectively. Patients were stratified according to serostatus (RF- AND ACPA- as seronegative or RF+ AND/OR ACPA+ as seropositive). All analyses are descriptive only.Results:To date 473 patients were included in the study, of which 22.2% (n=105) were seronegative and 59.0% (n=279) were seropositive (Table 1). For 89 patients (18.8%) serostatus was not specified.Table 1.Baseline data regarding patient characteristics, prior treatment and disease activityseronegativeseropositivepatients [n] (%)105(22.2)279(59.0)patient characteristicsSex female [n] (%)81(77.1)207(74.2)Age mean [years] (SD)56.6(12.5)59.6(10.9)BMI mean (SD) [kg/m2]29.2(6.7)28(6.0)Smoking history current/former [%]22.1/11.525.5/20.4Time since diagnosis of RA mean [years] (SD)7.9(7.6)11.5(9.9)prior RA treatmentcsDMARD [n] (%)102(97.1)273(97.8)bDMARD (TNFi) [n] (%)54(51.4)167(59.9)bDMARD (non-TNFi) [n] (%)32(30.5)83(29.7)tsDMARD (JAKi) [n] (%)25(23.8)57(20.4)disease activityCRP [mg/l] (SD)12.9(30.9)14.2(31.0)ESR [mm/h] (SD)23.7(20.5)25.3(22.4)SJC mean (SD)5.3(5.5)4.6(4.8)TJC mean (SD)10.2(8.2)7.2(6.6)HAQ-DI mean (SD)1.4(0.7)1.2(0.7)DAS28-ESR mean (SD)5.0(1.5)4.6(1.5)CDAI mean (SD)27.7(14.7)23.0(12.9)Fatigue [VAS] (SD)64.0(25.5)51.1(28.1)The mean time since diagnosis of RA was shorter in seronegative than in seropositive patients (7.9±7.6 years vs. 11.5±9.9 years) (Table 1).At baseline, CDAI score was 27.7±14.7 (n=104) and 23.0±12.9 (n=272) in seronegative and seropositive patients, respectively. After 12 months of sarilumab treatment, CDAI improved to 15.6±12.3 (n=38) and 9.1±8.7 (n=101) in seronegative and seropositive, respectively, for patients with post-baseline data available. At that time, remission/low disease activity according to CDAI was reached by 5.3% (n=2/38) / 39.5% (n=15/38) of seronegative patients, respectively and by 26.7% (n=27/101) / 68.3% (n=69/101) of seropositive patients, respectively (Fig. 1A, B).Figure 1.CDAI (A, B) and HAQ-DI (C) outcomes in seronegative and seropositive patientsPhysical function, assessed by HAQ-DI, was slightly more impaired in seronegative patients (1.4±0.7) than in seropositive patients (1.2±0.7) at baseline. HAQ-DI improved over 12 months to 0.9±0.7 in seropositive patients (n=90) but showed no change in seronegative patients (1.4±0.7; n=37) (Fig. 1C).Safety was consistent with the anticipated profile of IL-6-R-inhibition and no new safety signals occurred. Adverse events and serious adverse events were described in 61.7% and 12.8% of seronegative patients, respectively and in 55.2% and 13.7% of seropositive patients, respectively.Conclusion:Sarilumab treatment ameliorated CDAI in both seronegative (ΔCDAI -17.0±16.5) and seropositive (ΔCDAI -15.4±14.3) patients to the same extent over the course of 12 months, with a higher remission rate in seropositive patients. Functional capacity improved meaningfully in the seropositive cohort but had no significant impact in seronegative patients. The safety profile was consistent with data reported from controlled clinical trials.References:[1]Choi S-T et al. (2018) PLoS ONE 13(4): e0195550.Acknowledgements:We thank Cornelia Kühne (Haldensleben) for substantial contribution to patient recruitment in PROSARA.Disclosure of Interests:Harald Burkhardt Speakers bureau: Sanofi, Pfizer, Roche, Abb- vie, Boehringer Ingelheim, UCB, Eli Lilly, Chugai, Bristol Myer Scribb, Janssen, and Novartis, Consultant of: Sanofi, Pfizer, Roche, Abbvie, Boehringer Ingelheim, UCB, Eli Lilly, Chugai, Bristol Myer Scripps, Janssen, and Novartis, Grant/research support from: Pfizer, Roche, Abbvie, Hans-Peter Tony Consultant of: AbbVie, Astra-Zeneca, BMS, Chugai, Janssen, Lilly, MSD, Novartis, Pfizer, Roche, Sanofi, Peer-Malte Aries Speakers bureau: Abbvie, Biogen, Berlin Chemie, Celgene, GSK, Hexal, Mylan, Novartis, Pfizer, UCB, Consultant of: Abbvie, Celgene, Hexal, Janssen, Medac, Novartis, Pfizer, Sanofi, UCB, Silke Zinke: None declared, Klaus Krueger Speakers bureau: Sanofi, Jonas Ahlers Employee of: Sanofi, Rolf Hecker Employee of: Sanofi, Inka Albrecht Employee of: Sanofi, Stefanie Kalus Consultant of: Sanofi, Oliver Bley Employee of: Sanofi, Patrizia Sternad: None declared, Ann-Dörthe Holst: None declared, Niklas Thomas Baerlecken: None declared, Thilo Klopsch: None declared, Martin Welcker Speakers bureau: Abbvie, Aescu, Amgen, Biogen, Berlin Chemie, Celgene, GSK, Hexal, Mylan, Novartis, Pfizer, UCB, Consultant of: Abbvie, Actelion, Aescu, Amgen, Cel- gene, Hexal, Janssen, Medac, Novartis, Pfizer, Sanofi, UCB, Grant/research support from: Abbvie, Novartis, UCB, Hexal, BMS, Lilly, Roche, Celgene, Sanofi, Eugen Feist Speakers bureau: Novartis, Roche, Sobi, Lilly, Pfizer, Abbvie, BMS, MSD, Sanofi, Consultant of: Novartis, Roche, Sobi, Lilly, Pfizer, Abbvie, BMS, MSD, Sanofi

Background:Blockade of IL-6 signaling by sarilumab has been demonstrated to be an effective treatment approach for rheumatoid arthritis. Due to strict inclusion and exclusion criteria, randomized controlled trials may not represent the heterogeneous RA patient population encountered in regular care.Objectives:The current study investigated the safety and effectiveness of sarilumab in the treatment of RA in regular care in Germany.Methods:The prospective, observational, single-arm 24-months PROSARA study (SARILL08661) is currently running in Germany at 79 sites, aiming to include up to 750 RA patients treated with sarilumab. RA patients are selected at physician discretion and treated according to the label. Study objectives include the documentation of safety and various effectiveness outcomes. This interim analysis included patients with data available up to 12 weeks. All analyses are descriptive only.Results:To date 348 patients were included in the study; of which 265 patients had post-baseline data. The mean age of the patients analyzed was 58.6 years (24-83); 76.3% are female. The mean disease duration was 10.3 years; comorbidities were present in 80.7% of patients. At baseline, 32.5% were biologic naïve. Most common pretreatment with b/ts DMARDs included TNF-inhibitors (TNFi, 56.2%), non-TNFi biologics (29.1%) or JAK-inhibitors (JAKi, 17.4%). At baseline, 49% received sarilumab as monotherapy and 29% in combination with conventional DMARDs (not specified for 22%). After 12 weeks of treatment with sarilumab, the mean DAS28-ESR decreased from 5.0±1.46 to 3.0±1.44 and CDAI from 26.7±13.79 to 13.6±11.4, respectively. DAS28-ESR remission/ low disease activity was achieved in 42.8% [n=77/180 patients with valid data on this parameter]/ 59.4% [n=107/180] of patients; 13.6% [n=28/206] and 49% [n=101/206] of patients reached CDAI remission and low disease activity. Boolean remission was observed in 9.5% [n=19/201] of patients at week 12. HAQ-DI improved from 1.3 at baseline to 1.1 at week 12 (n=195). The mean CDAI improvement was similar for autoantibody-positive (RF and/or ACPA; CDAI -12.5 at week 12) compared to -negative patients (CDAI -15.4 at week 12). Patients switching from JAKi to sarilumab (n=32), were more severely affected, had longer disease duration and received more prior treatments than patients switched from another compound. Of note, similar efficacy was observed among patients that switched from JAKi to sarilumab vs patients switched from other DMARDs; disease activity outcome measures including DAS28, CDAI, TJC, SJC and global assessments improved consistently (Figure 1).Safety was consistent with the anticipated profile of IL-6-R-inhibition and no new safety signals occurred. Adverse events and serious adverse events were described in 33.9% and 6.3% of patients, respectively.Conclusion:Sarilumab administered in regular care demonstrated rapid and clinically meaningful improvement in a general RA patient population including patients switching from JAKi. The safety profile was consistent with data reported from controlled clinical trials.Disclosure of Interests:Eugen Feist Consultant of: Novartis, Roche, Sobi, Lilly, Pfizer, Abbvie, BMS, MSD, Sanofi, Speakers bureau: Novartis, Roche, Sobi, Lilly, Pfizer, Abbvie, BMS, MSD, Sanofi, Peer-Malte Aries Consultant of: Sanofi, Speakers bureau: Sanofi, Silke Zinke: None declared, Harald Burkhardt Grant/research support from: Pfizer, Roche, Abbvie, Consultant of: Sanofi, Pfizer, Roche, Abbvie, Boehringer Ingelheim, UCB, Eli Lilly, Chugai, Bristol Myer Scripps, Janssen, and Novartis, Speakers bureau: Sanofi, Pfizer, Roche, Abbvie, Boehringer Ingelheim, UCB, Eli Lilly, Chugai, Bristol Myer Scripps, Janssen, and Novartis, Inka Albrecht Employee of: Sanofi, Oliver Bley Employee of: Sanofi, Michael Obermeier: None declared, Patrizia Sternad: None declared, Martin Welcker Grant/research support from: Abbvie, Novartis, UCB, Hexal, BMS, Lilly, Roche, Celgene, Sanofi, Consultant of: Abbvie, Actelion, Aescu, Amgen, Celgene, Hexal, Janssen, Medac, Novartis, Pfizer, Sanofi, UCB, Speakers bureau: Abbvie, Aescu, Amgen, Biogen, Berlin Chemie, Celgene, GSK, Hexal, Mylan, Novartis, Pfizer, UCB, Cornelia Kühne Grant/research support from: Novartis, Amgen, Roche/Chugai, Pfizer, Celgene, AbbVie, Sanofi, Ann-Dörthe Holst: None declared, Niklas Thomas Baerlecken: None declared, Hans-Peter Tony Consultant of: AbbVie, Astra-Zeneca, BMS, Chugai, Janssen, Lilly, MSD, Novartis, Pfizer, Roche, Sanofi

The Observations and Modeling of the Green Ocean Amazon 2014–2015 (GoAmazon2014/5) experiment took place around the urban region of Manaus in central Amazonia across 2 years. The urban pollution plume was used to study the susceptibility of gases, aerosols, clouds, and rainfall to human activities in a tropical environment. Many aspects of air quality, weather, terrestrial ecosystems, and climate work differently in the tropics than in the more thoroughly studied temperate regions of Earth. GoAmazon2014/5, a cooperative project of Brazil, Germany, and the United States, employed an unparalleled suite of measurements at nine ground sites and on board two aircraft to investigate the flow of background air into Manaus, the emissions into the air over the city, and the advection of the pollution downwind of the city. Herein, to visualize this train of processes and its effects, observations aboard a low-flying aircraft are presented. Comparative measurements within and adjacent to the plume followed the emissions of biogenic volatile organic carbon compounds (BVOCs) from the tropical forest, their transformations by the atmospheric oxidant cycle, alterations of this cycle by the influence of the pollutants, transformations of the chemical products into aerosol particles, the relationship of these particles to cloud condensation nuclei (CCN) activity, and the differences in cloud properties and rainfall for background compared to polluted conditions. The observations of the GoAmazon2014/5 experiment illustrate how the hydrologic cycle, radiation balance, and carbon recycling may be affected by present-day as well as future economic development and pollution over the Amazonian tropical forest.

The synthesis and degradation of cyclic AMP was studied in the hearts and aortas of spontaneous hypertensive rats (SHR) and of controls of corresponding age. While no changes in phosphodiesterase activity were observed, in the aortas of SHR the basal values of adenylate cyclase as well as fluoride stimulation were doubled and the stimulatory effect of isoproterenol was reduced. As these changes in adenylate cyclase activity were observed as early as in 20-day-old rats, where no elevation of blood pressure could be found, these findings might represent one of the basic deviation rather than a secondary compensatory mechanism.

Male and female rats developing spontaneous hypertension (SHR) were treated with dihydralazine and guanethidine during the prehypertensive period. A therapeutic effect lasted for 100 days after termination of therapy. Treated animals showed no cardiovascular lesions associated with hypertension in this strain. Untreated males showed a high incidence of cardiovascular lesions, as opposed to untreated females. Pulmonary lesions were the main cause of death in treated males. There were no cardiovascular lesions observable macroscopically in treated SHR animals of both sexes. We conclude that antihypertensive therapy administered in the critical period of prehypertension has a long term action.

Cardiac output and regional blood flows to myocardium, gut, uterus and kidney were determined in anaesthetised female rats by a single injection of 86RbCl. The haemodynamic responses were measured at various time intervals up to 2 h after single I. V. injections of lysine-vasopressin and the following of its analogues: a) with extended peptide chains at the N-terminal (including “hormonogens”) Na-glycyl-glycyl-glycyl-lysine-vasopressin, Na-glycyl-glycyl-glycyl-arginine-vasopressin and Na-D-valyl-lysine-vasopressin, b) “carba” modifications desamino-carba6-arginine-vasopressin, desamino-carba6-D-arginine8-vasopressin, desamino-carba6-ornithine8-vasopressin, desamino-dicarba-arginine-vasopressin and c) other steric alterations - desamino-D-arginine8-vasopressin and desamino-N-methylarginine8-vasopressin. Sub-pressor doses of lysine-vasopressin were followed by marked reductions in gut and uterus blood flows which reached a peak at 10 min. and had completely receded by 60 min. The presence of steric alterations in the C-terminal tripeptide of the molecule- D-arginine or N-methylarginine in sequence position 8- practically completely eliminated vascular activity. The same was true for Na-D-valyl-lysine-vasopressin. None of the latter three analogues showed any inhibitor properties to the action of lysine-vasopressin. The two hormonogens (triglycyl N-terminal extensions) had to be given in doses 10 times greater to obtain a vasoconstrictor effect in gut and uterus equivalent in amplitude to that of lysine-vasopressin, but this effect was still present to the same degree 2 h later with the hormonogen of lysine-vasopressin, and was only starting to return to baseline values at the same time with the arginine-vasopressin hormonogen. The vascular potency of both mono-carba L-analogues was higher than that of lysine-vasopressin, and the effect was as prolonged as with the hormonogens. The dicarba analogue also showed a prolonged action, but with much reduced potency. No significant changes in renal or myocardial blood flows were observed at all. Molecular features of vasopressin smooth muscle activity were discussed, and a receptor model was proposed. It was suggested that the -S-S-, -SCH2 and -CH2CH2-bridges in the above analogues are not directly bound in the peptide-receptor complex and constitute the limiting factor determining complex duration, or persistence of the active peptide in the “receptor compartment”. These results provide an experimental basis for possible clinical application of triglycyl-vasopressin and carba-vasopressin in bleeding from both gut and uterus and for induction of menstruation.

Ovarian blood flow measurements were carried out in pseudopregnant anesthetized rabbits in order to compare three different techniques. Direct measurement by venous cannulation and flow determination by 15-mum radioactive microspheres resulted in values 5 and 10 times higher, respectively, than indicator fraction technique using -86Rb. The direct method inevitably involves surgical handling of the ovary and its vessels, which may account for the lower values found with this method than with microspheres. A comparison between the dynamics of -86Rb uptake in the luteal ovary and the hindleg tissues, mainly consisting of striated muscle, indicated that this technique will underestimate ovarian blood flow due to a low ovarian extraction of the radionuclide. In the preparation for direct measurement the relation between blood pressure and flow was linear. This lack of autorgeulation is an important factor to consider in studies of ovarian steroid secretion rates. Theradioactive microsphere technique appears to reflect physiological blood flow in the ovary and corpus leteum of the rabbit and can be useful in studies of vascular mechanisms in this gland.

Rats anaesthetised with Inactin, body temp. maintained at 37°C, were infused with mannitol-saline until both urine flow rate and conductivity reached a balanced state. In separate experiments under analogous conditions cardiac output was measured by dye dilution and organ flow rates by86Rb distribution. Doses of oxytocin of 3 ng or less, injected at or just below the carotid bifurcation, caused a highly significant natriuresis with increased tubular rejection, but no measureable haemodynamic changes. The same oxytocin dose given into the internal or external carotid artery above the bifurcation caused neither haemodynamic changes nor natriuresis. Injection of vasopressin, angiotensin and α-MSH at the sensitive site did not result in natriuresis in the same dosage range. Section of the sinus nerve significantly decreased the natriuretic response to oxytocin. It is suggested that the carotid body contains a specific oxytocin receptor capable of eliciting natriuresis in the rat.

Publisher Summary This chapter discusses a study to investigate aortic wall enzymes in spontaneously hypertensive (SH) and spontaneously atherosclerotic (CP) rats. The study examined the activity of some enzymes of basic metabolic cycles in the aorta whose changes usually accompany or precede the onset of pathological processes in the arterial wall. The study compared their activity in the aortic wall of adult hypertensive, corpulent, and normal Wistar rats of the same age, reared under uniform conditions. The aorta of spontaneously hypertensive rats showed altered activities of all the investigated enzymes compared with normotensive rats. The activities of alkaline phosphatase, acid phosphatase, and 5-Nu were significantly elevated; those of malate dehydrogenase, lactate dehydrogenase, and carboxylic esterase were reduced. The enzyme spectrum of the aorta in hypertensive rats is similar to that of arteries more susceptible to atherosclerosis or various models of vascular lesion in experimental animals and agrees with earlier the findings of reduced activity of enzymes of the Kreb's cycle and elevated activity of phosphomonoesterases, resulting in lipid accumulation and atherosclerotic lesions in the arterial wall.

Publisher Summary Repeated stress produces a rise in the blood pressure of rats. This stress-induced hypertension is dependent on changes in the peripheral sympathetic system. This chapter discusses the reactions of the sympatho-adrenal system under the influence of immobilization stress. Repeated immobilization (IMO) of rats was found to bring about enhanced levels of catecholamines (CA). This conclusion was supported by the increased levels of adrenal, plasma, and urinary CA, by increased biosynthesis of adrenal CA, measured in vivo after administration of labeled precursors, and by increases in the activity of adrenal catecholamine-synthesizing enzymes tyrosine hydroxylase (TH), dopamine-β-hydroxylase (DBH), and phenylethanolamine-N-methyltransferase (PNMT). Increased CA levels in the organism of repeatedly IMO rats might not only be because of enhanced CA synthesis but to diminished CA degradation as well. It has been found that stress affects a significant decrease of catechol-O-methyltransferase (COMT) activity in the liver of rats, which is related to the inhibitory effect of corticosterone (B), which under stress is increased in the plasma of these rats. The inhibitory effect of corticosteroids on liver COMT activity has been established in vitro on liver explants in tissue culture.

ALBRECHT, I., M. HALLBACK, S. JULIUS, Y. LUNDGREN, L. STAGE, L. WEISS and B. FOLKOW. Arterial pressure, cardiac output and systemic resistance before and after pithing in normotensive and sponfaneously hypertensive rats. Acta physiol. scand. 1975. 94. 378-385. After complete cardiovascular denervation mean arterial pressure (MAP) falls to almost equally low levels in spontaneously hypertensive rats (SHR) and normotensive control rats (NCR). This has earlier been suggested to indicate a dominance of neurogenic mechanisms in established SHR hypertension. - In the present study, total peripheral resistance (TPR) remains, however, some 35 per cent higher in adult SHR than in NCR after pithing while cardiac output (CO), and stroke volume, is 35 per cent lower in SHR. These opposite differences in TPR and CO after denervation, resulting in equal MAP levels in SHR and NCR, seem rather to be a consequence of the rapidly established structural adaptation that affects all SHR high-pressure cardiovascular sections. Thus, the SHR precapillary resistance vessels display thickened walls and luminal narrowing, which keeps TPR higher than in NCR even during maximal vasodilatation. Due to hypertrophy, the SHR left ventricle exhibits a reduced myocardial stretch for a given filling pressure and stroke volume is consequently reduced more than in NCR after complete denervation. Paradoxically, therefore, rather than reflecting any dominance of neurogenic mechanisms in established SHR hypertension the MAP equalization in SHR and NCR after cardiovascular denervation emphasizes the hemodynamic importance of cardiovascular structural changes present in hypertension.

A new vaginal contraceptive method that offers the ease of use with none of the potentially harmful physiologic effects of hormonal contraception was subjected to direct in vivo tests of its efficacy in immobilizing spermatozoa and preventing their entry into the cervical canal. The new contraceptive, a small ovoid only 2.8cm long and 1.4cm wide, is easily inserted into the vagina without the need for special applicators. It offers protection through the delivery of a highly effective spermicide by the effervescent formation of foam that disperses over the uterine opening. In the trials, no motile spermatozoa could be found in any samples obtained from the vagina, the os externum, or the cervical canal immediately after intercourse protected with the new agent. In no case were any sperm, even immotile sperm, observed in the cervical canal. By contrast, examination of 30 samples obtained immediately after coitus protected with another contraceptive agent (used as a control) revealed motile spermatozoa in the cervical canal in nine cases, and propulsive motility was seen on five occasions. The new contraceptive proved highly effective in preventing conception.

SummaryOur findings that PlGF is a cancer target and anti-PlGF is useful for anticancer treatment have been challenged by Bais et al. Here we take advantage of carcinogen-induced and transgenic tumor models as well as ocular neovascularization to report further evidence in support of our original findings of PlGF as a promising target for anticancer therapies. We present evidence for the efficacy of additional anti-PlGF antibodies and their ability to phenocopy genetic deficiency or silencing of PlGF in cancer and ocular disease but also show that not all anti-PlGF antibodies are effective. We also provide additional evidence for the specificity of our anti-PlGF antibody and experiments to suggest that anti-PlGF treatment will not be effective for all tumors and why. Further, we show that PlGF blockage inhibits vessel abnormalization rather than density in certain tumors while enhancing VEGF-targeted inhibition in ocular disease. Our findings warrant further testing of anti-PlGF therapies.