Efficacy and safety of secukinumab in patients with spondyloarthritis and enthesitis at the Achilles tendon: results from a phase 3b trial.

OBJECTIVE: ACHILLES aimed to demonstrate efficacy of secukinumab on Achilles' tendon enthesitis in spondyloarthritis (SpA) patients. METHODS: Patients ≥18 years (n = 204) with active PsA or axial SpA and heel enthesitis were randomized 1:1 to secukinumab 150/300 mg or placebo up to week 24, and thereafter placebo patients were switched to secukinumab. RESULTS: At week 24, a higher, yet statistically non-significant (P = 0.136), proportion of patients in secukinumab vs placebo reported resolution of Achilles tendon enthesitis in affected foot (42.2% vs 31.4%; odds ratio [OR] = 1.63; 95% CI: 0.87, 3.08). Proportion of patients reporting resolution of enthesitis based on Leeds Enthesitis Index was higher with secukinumab vs placebo (33.3% vs 23.5%; OR = 1.65; 95% CI: 0.85, 3.25) at week 24. Mean change from baseline in heel pain at week 24 was higher in secukinumab patients vs placebo (-2.8 [3.0] vs -1.9 [2.7]). Greater improvements with secukinumab were observed in heel enthesopathy activity and global assessment of disease activity. Imaging evaluation by local reading confirmed heel enthesitis on MRI at screening for all patients. Based on central reading, 56% presented with bone marrow oedema and/or tendinitis; according to Heel Enthesitis MRI Scoring System (HEMRIS) post hoc analysis, 76% had signs of entheseal inflammation while 86% had entheseal inflammation and/or structural changes. CONCLUSION: A substantial proportion of patients showed no signs of inflammation on the centrally read MRIs despite a clinical diagnosis of heel enthesitis, thus highlighting that the discrepancy between the clinical and imaging assessments of enthesitis requires further investigation. Although ACHILLES did not meet the primary end point, the study reported clinically meaningful improvements in patient-related outcomes. TRIAL REGISTRATION: clinicaltrials.gov, NCT02771210.

Achilles tendon enthesitis evaluated by MRI assessments in patients with axial spondyloarthritis and psoriatic arthritis: a report of the methodology of the ACHILLES trial.

BACKGROUND: The currently available scoring methods for enthesitis are often measures of pain but not of inflammation at entheseal sites. The Outcome Measures in Rheumatology Clinical Trials (OMERACT) psoriatic arthritis (PsA) magnetic resonance imaging (MRI) scoring system (PsAMRIS) assesses inflammation and damage in PsA and was particularly developed for the hands. The ACHILLES trial used clinical measures for heel enthesitis in combination with MRI scoring based on PsAMRIS. METHODS: Patients (age ≥ 18 years) with spondyloarthritis (SpA) and PsA were included in the trial if they presented with clinical and MRI-positive heel enthesitis. MRI of the affected heel was performed at three time points: screening, Week 24 and Week 52. Inflammatory MRI findings (tendinitis, bursitis and bone marrow oedema [BME]) in the area of the Achilles tendon and/or plantar aponeurosis, periarticular inflammation of the ankle joint and heel erosion were assessed qualitatively (absent/present). In addition, BME and bone erosion were quantitatively assessed based on PsAMRIS, where their proportion was compared to the volume of the affected bone. Mean scores of BME and bone erosion quantification were calculated, and the mean composite score (based on PsAMRIS) was calculated based on the individual score of each subject for periarticular inflammation, BME and bone erosion and further extended for bursitis and tendinitis. Modifications to PsAMRIS were introduced by categorising oedema length as ≤/> 0.5 cm and locating bone erosion. CONCLUSIONS: In ACHILLES, MRI was used to assess and evaluate heel enthesitis. Due to the lack of a validated scoring system for heel enthesitis at the time of ACHILLES initiation, this trial applied quantitative scoring based on PsAMRIS, with specific adaptations for the heel. TRIAL REGISTRATION: National Clinical Trial Registry, NCT02771210 . Registered 13 May 2016.

Vision-related quality of life in patients receiving intravitreal ranibizumab injections in routine clinical practice: baseline data from the German OCEAN study.

BACKGROUND: Vision-related quality of life (vrQoL) is advancing more and more into the focus of interest in ophthalmological clinical research. However, to date only little information is available about vrQoL from large non-interventional studies in terms of "real-world evidence". The purpose of this investigation was to describe baseline VFQ-25 visual function scores, to evaluate whether they differ from previous phase III clinical trials, to determine which contributing factors (e.g. indication, age, gender) affect VFQ-25 scores and to identify its impact on driving. METHODS: The non-interventional OCEAN study (Observation of treatment patterns with LuCEntis and real life ophthalmic monitoring, including optional OCT in Approved iNdications) is the largest ophthalmic study conducted in Germany, to evaluate the real world situation of patients treated with ranibizumab (NCT02194803). The NEI-VFQ-25 questionnaire was conducted at baseline, months 4, 12 and 24. Descriptive statistics was used to analyse the baseline data. ANOVA was performed to evaluate the impact of various contributing factors on composite and selected subscale scores. RESULTS: Overall, 4844 (84.1 %) of all 5760 OCEAN patients completed the VFQ-25 questionnaire at baseline. Thereof, 3414 treatment-naïve patients were further analysed. Overall, the VFQ subscore general health was most affected by the ocular disease, followed by general vision. No major differences were detected in comparison to corresponding VFQ-25 scores of previous phase III clinical trials, except in DME patients, or with respect to possible contributing factors. A tendency towards a more decreased VFQ-25 composite score was observed for nAMD, for elderly patients ≥75 years of age, for female patients, for patients with low baseline visual acuity (VA; <50 letters) and for those with statutory health insurance. Indication, age, gender, baseline VA (all p <0.01) and the interaction of age and indication, as well as baseline VA and indication (p <0.01 each) had a significant impact on composite, general vision and distance vision scores (ANOVA). About 10 % of patients gave up driving due to eyesight issues. CONCLUSIONS: The knowledge of a patient's subjective disease burden is crucial to understanding anxieties and mental anguish. Additionally, the understanding of the impact of various contributing factors on the VFQ-25 scores and the extent to which they can be influenced help to optimize patient care. It demonstrates the need for medical and mental support by all medical staff, to encourage patients' compliance with a comprehensive anti-VEGF therapy, to increase BCVA and, consecutively, VFQ-25 scores. TRIAL REGISTRATION: NCT02194803.

Cooperation of German ophthalmologists in routine care of patients with neovascular age-related macular degeneration: results of the non-interventional BRIDGE study.

PURPOSE: In the non-interventional ophthalmological study 'BRIDGE' the routine care of patients with neovascular age-related macular degeneration (nAMD) treated with ranibizumab was observed in Germany. A patient regularly sees the general ophthalmologist (GO) for monitoring and, if needed, the injecting ophthalmologist (IO) for intravitreal injections (IVI). Thus, patients are routinely treated by two ophthalmologists in parallel and patient care depends on their collaboration. This cooperation was evaluated based on network questionnaires. METHODS: 'BRIDGE' was a multicenter, national, open-label, prospective, observational study, conducted between July 2010 and December 2012. The network questionnaire for GOs consisted of 51 questions, while the similar questionnaire for IOs consisted of 43 questions, addressing the type and details of the individual collaboration. The statistical analysis was purely descriptive. RESULTS: The network questionnaire for GOs was completed by 152 GOs, regularly cooperating with 2.5 ± 1.1 IOs, while the questionnaire for IOs was completed by 43 IOs, regularly cooperating with 23.2 ± 23.6 GOs. Generally, both GOs and IOs stated that they regularly exchange information regarding the patients' situation. Diagnostic standards were only established for 15 % of the GOs' collaborations and for 35 % of the IOs' collaborations. After initial treatment, both GOs and IOs agreed on the medical significance of regular monitoring visits performed by the GOs. Agreements on re-treatment criteria were only established in the case of 16 % of the GOs and 28 % of the IOs. Overall, both GOs and IOs were satisfied with the current situation, with regard to the medical treatment situation for patients and to the cooperation within the networks. CONCLUSIONS: The network questionnaires revealed well-established cooperation between IOs and GOs in Germany with an accepted division of responsibilities for the routine care of patients with nAMD. However, the cooperation between two ophthalmologists treating one patient harbors risks. Agreements on diagnostic and re-treatment criteria would help to improve network performance and outcomes.

Uridine adenosine tetraphosphate (Up4A) is a strong inductor of smooth muscle cell migration via activation of the P2Y2 receptor and cross-communication to the PDGF receptor.

The recently discovered dinucleotide uridine adenosine tetraphosphate (Up(4)A) was found in human plasma and characterized as endothelium-derived vasoconstrictive factor (EDCF). A further study revealed a positive correlation between Up(4)A and vascular smooth muscle cell (VSMC) proliferation. Due to the dominant role of migration in the formation of atherosclerotic lesions our aim was to investigate the migration stimulating potential of Up(4)A. Indeed, we found a strong chemoattractant effect of Up(4)A on VSMC by using a modified Boyden chamber. This migration dramatically depends on osteopontin secretion (OPN) revealed by the reduction of the migration signal down to 23% during simultaneous incubation with an OPN-blocking antibody. Due to inhibitory patterns using specific and unspecific purinoreceptor inhibitors, Up(4)A mediates it's migratory signal mainly via the P2Y(2). The signaling behind the receptor was investigated with luminex technique and revealed an activation of the extracellular signal-regulated kinases 1 and 2 (ERK1/2) pathway. By use of the specific PDGF receptor (PDGFR) inhibitor AG1296 and siRNA technique against PDGFR-ß we found a strongly reduced migration signal after Up(4)A stimulation in the PDGFR-ß knockdown cells compared to control cells. In this study, we present substantiate data that Up(4)A exhibits migration stimulating potential probably involving the signaling cascade of MEK1 and ERK1/2 as well as the matrix protein OPN. We further suggest that the initiation of the migration process occurs predominant through direct activation of the P2Y(2) by Up(4)A and via transactivation of the PDGFR.

Adenosine 5'-tetraphosphate is a highly potent purinergic endothelium-derived vasoconstrictor.

Besides serving as a mechanical barrier, the endothelium has important regulatory functions. The discovery of nitric oxide revolutionized our understanding of vasoregulation. In contrast, the identity of endothelium-derived vasoconstrictive factors still remains uncertain. The supernatant from mechanically stimulated human microvascular endothelial cells elicited a potent vasoconstrictive response in the isolated perfused rat kidney. Whereas a nonselective purinoceptor blocker blocked this vasoactivity most potently, the inhibition of the endothelin receptor by BQ123 weakly affected that vasoconstrictive response. As a compound responsible for that vasoconstrictive effect, we have isolated from HMECs and identified the mononucleotide adenosine 5'-tetraphosphate (AP4). This nucleotide proved to be the most potent vasoactive purinergic mediator identified to date, exerting the vasoconstriction predominantly through activation of the P2X1 receptor. The intraarterial application of AP4 in a Wistar-Kyoto rat induced a strong increase of the mean arterial pressure. The plasma concentration of AP4 is in the nanomolar range, which, in vivo, induces a significant change in the mean arterial pressure. To our knowledge, AP4, which exerts vasoactive effects, is the most potent endogenous mononucleotide identified to date in mammals. The effects of AP4, the plasma concentration of AP4, and its release suggest that this compound functions as an important vasoregulator.

Mass-spectrometric identification of a novel angiotensin peptide in human plasma.

OBJECTIVE: Angiotensin peptides play a central role in cardiovascular physiology and pathology. Among these peptides, angiotensin II (Ang II) has been investigated most intensively. However, further angiotensin peptides such as Ang 1-7, Ang III, and Ang IV also contribute to vascular regulation, and may elicit additional, different, or even opposite effects to Ang II. Here, we describe a novel Ang II-related, strong vasoconstrictive substance in plasma from healthy humans and end-stage renal failure patients. METHODS AND RESULTS: Chromatographic purification and structural analysis by matrix-assisted laser desorption/ionisation time-of-flight/time-of-flight (MALDI-TOF/TOF) revealed an angiotensin octapeptide with the sequence Ala-Arg-Val-Tyr-Ile-His-Pro-Phe, which differs from Ang II in Ala1 instead of Asp1. Des[Asp1]-[Ala1]-Ang II, in the following named Angiotensin A (Ang A), is most likely generated enzymatically. In the presence of mononuclear leukocytes, Ang II is converted to Ang A by decarboxylation of Asp1. Ang A has the same affinity to the AT1 receptor as Ang II, but a higher affinity to the AT2 receptor. In the isolated perfused rat kidney, Ang A revealed a smaller vasoconstrictive effect than Ang II, which was not modified in the presence of the AT2 receptor antagonist PD 123319, suggesting a lower intrinsic activity at the AT1 receptor. Ang II and Ang A concentrations in plasma of healthy subjects and end-stage renal failure patients were determined by matrix-assisted laser desorption/ionisation mass-analysis, because conventional enzyme immunoassay for Ang II quantification did not distinguish between Ang II and Ang A. In healthy subjects, Ang A concentrations were less than 20% of the Ang II concentrations, but the ratio Ang A/Ang II was higher in end-stage renal failure patients. CONCLUSIONS: Ang A is a novel human strong vasoconstrictive angiotensin-derived peptide, most likely generated by enzymatic transformation through mononuclear leukocyte-derived aspartate decarboxylase. Plasma Ang A concentration is increased in end-stage renal failure. Because of its stronger agonism at the AT2 receptor, Ang A may modulate the harmful effects of Ang II.

The endothelium-derived contracting factor uridine adenosine tetraphosphate induces P2Y(2)-mediated pro-inflammatory signaling by monocyte chemoattractant protein-1 formation.

It is very well established that purinergic signaling plays a relevant role in vascular physiology and pathophysiology. Recently, a new purinoceptor agonist uridine adenosine tetraphosphate (Up(4)A) has been identified as a highly potent endothelial-derived contracting factor (EDCF). The purpose of the study was to investigate Up(4)A's influence on pro-inflammatory mechanisms. An early component of the inflammatory response in atherogenesis is the oxidative stress-induced formation of monocyte chemoattractant protein-1 (MCP-1). Here, we investigated the influence of Up(4)A on MCP-1 formation and characterized the underlying signaling transduction mechanisms in rat vascular smooth muscle cells (VSMCs). Up(4)A induced MCP-1 expression and secretion in VSMCs via the activation of P2Y(2) in a concentration-dependent manner. MCP-1 formation depends on generation of reactive oxygen species (ROS). To determine whether the predominant source of ROS in the vasculature, the NAD(P)H oxidase (Nox), is involved, we used different approaches. The ROS scavenger, tiron, the Nox inhibitor, apocynin and diphenyl-iodonium, as well as Nox1 knockdown, diminished the Up(4)A-induced MCP-1 formation. Rac1 activation and p47(phox) translocation from cytosol to the plasma membrane-both required for assembling and activation of Nox, were stimulated by Up(4)A. ERK1/2 and p38 activation is essential for the intracellular signal transduction. In summary, Up(4)A induced Nox1-dependent ROS generation, which further stimulated MCP-1 formation via MAPK phosphorylation in VSMCs. This process requires the activation of the G-protein coupled receptor P2Y(2). Therefore, Up(4)A is not only a potent EDCF but also a potent inductor of pro-inflammatory response in the vascular wall.

Differential effects of uridine adenosine tetraphosphate on purinoceptors in the rat isolated perfused kidney.

BACKGROUND AND PURPOSE: Purinergic signalling plays an important role in vascular tone regulation in humans. We have identified uridine adenosine tetraphosphate (Up(4)A) as a novel and highly potent endothelial-derived contracting factor. Up(4)A induces strong vasoconstrictive effects in the renal vascular system mainly by P2X(1) receptor activation. However, other purinoceptors are also involved and were analysed here. EXPERIMENTAL APPROACH: The rat isolated perfused kidney was used to characterize vasoactive actions of Up(4)A. KEY RESULTS: After desensitization of the P2X(1) receptor by α,ß-methylene ATP (α,ß-meATP), Up(4)A showed dose-dependent P2Y(2)-mediated vasoconstriction. Continuous perfusion with Up(4)A evoked a biphasic vasoconstrictor effect: there was a strong and rapidly desensitizing vasoconstriction, inhibited by P2X(1) receptor desensitization. In addition, there is a long-lasting P2Y(2)-mediated vasoconstriction. This vasoconstriction could be blocked by suramin, but not by PPADS or reactive blue 2. In preparations of the rat isolated perfused kidney model with an elevated vascular tone, bolus application of Up(4)A showed a dose-dependent vasoconstriction that was followed by a dose-dependent vasodilation. The vasoconstriction was in part sensitive to P2X(1) receptor desensitization by α,ß-meATP, and the remaining P2Y(2)-mediated vasoconstriction was only inhibited by suramin. The Up(4)A-induced vasodilation depended on activation of nitric oxide synthases, and was mediated by P2Y(1) and P2Y(2) receptor activation. CONCLUSIONS AND IMPLICATIONS: Up(4)A activated P2X(1) and P2Y(2) receptors to act as a vasoconstrictor, whereas endothelium-dependent vasodilation was induced by P2Y(1/2) receptor activation. Up(4)A might be of relevance in the physiology and pathophysiology of vascular tone regulation.