Magnetic resonance imaging characteristics in patients with spondyloarthritis and clinical diagnosis of heel enthesitis: post hoc analysis from the phase 3 ACHILLES trial.

OBJECTIVE: To investigate the imaging characteristics and clinically assess heel enthesitis in spondyloarthritis (SpA) by applying in a post hoc analysis the Heel Enthesitis Magnetic Resonance Imaging Scoring system (HEMRIS) in blinded and centrally-read MRI data from the ACHILLES trial (NCT02771210). METHODS: ACHILLES included patients (≥18 years) with active psoriatic arthritis or axial SpA with clinical and MRI-positive heel enthesitis refractory to standard treatment. Patients were randomized to receive subcutaneous secukinumab 150/300 mg or placebo. At week 24, patients on placebo were switched to secukinumab treatment. MRI-positive heel enthesitis was confirmed in all patients by local investigators. MRIs were performed at 3 timepoints: screening and weeks 24 and 52. In the present analysis, all MRIs were re-evaluated by 2 blinded central readers in a consensus read fashion for a priori defined MRI parameters based on HEMRIS. RESULTS: At screening, 171/204 (83.8%) of patients presented with entheseal inflammation and/or structural damage, considering both the Achilles tendon and plantar fascia. Pathologies were more evident in the Achilles tendon area compared to the plantar aponeurosis. The most frequent pathologies were intra-tendon hypersignal and retrocalcaneal bursitis. The mean total entheseal inflammation score at screening in the Achilles tendon area was 2.99 (N=204) and the mean change (standard deviation [SD]) from screening to weeks 24 and 52 was - 0.91 (1.99) and - 0.83 (2.12) in the secukinumab group vs - 0.48 (1.86) and - 0.80 (1.98) in the placebo-secukinumab group, respectively. The mean total structural damage score at screening was 1.36 (N=204) and the mean change (SD) from screening to weeks 24 and 52 was 0.00 (0.65) and - 0.06 (0.56) in the secukinumab group vs 0.08 (0.48) and 0.04 (0.75) in the placebo-secukinumab group, respectively. CONCLUSIONS: Based on the newly developed HEMRIS, entheseal inflammation and/or structural damage was confirmed in 83.3% of ACHILLES patients. Pathologies were more evident in the Achilles tendon area compared to plantar fascia, with the inflammatory parameters being more responsive with secukinumab treatment compared to placebo. The present analysis, with detailed information on individual MRI parameters, contributes to the scientific debate on heel enthesitis. TRIAL REGISTRATION: ClinicalTrials.gov NCT02771210 .

Demographics of patients receiving Intravitreal anti-VEGF treatment in real-world practice: healthcare research data versus randomized controlled trials.

BACKGROUND: While randomized controlled trials (RCTs) are based on strict inclusion/exclusion criteria, non-interventional studies (NISs) might provide additional information to guide management in patients more representative to the real-world setting. The aim of this study was to compare baseline characteristics of patients receiving intravitreal treatment in the NIS OCEAN with those from published RCTs. METHODS: The ongoing OCEAN study enrolled patients treated with ranibizumab for neovascular age-related macular degeneration (nAMD), diabetic macular oedema (DME) or branch/central retinal vein occlusion (B/CRVO). Baseline patient characteristics were compared by indication within the OCEAN cohort. Furthermore, the characteristics were set in reference to those of published RCTs in the same indications. Confidence intervals (CIs) were calculated and assessed for statistically significant differences as indicated by non-overlapping CIs. RESULTS: Patient characteristics in the NIS OCEAN were evaluated for 3,614 patients with nAMD, 1,211 with DME, 204 with BRVO and 121 with CRVO. Between these groups, significant differences in mean age, gender distributions, and mean baseline VA were seen, reflecting known differences between the indications. Compared to the patient characteristics of published RCTs (trials selected by literature search: nAMD: 13 RCTs, DME: 9, RVO: 5), the OCEAN patients' mean age was significantly higher in every indication. The gender distributions across the trials were comparable, with only few differences between OCEAN and the RCTs. Regarding the mean baseline VA, notable differences were found in nAMD and in DME, with VA significantly higher in some RCTs and lower in others. CONCLUSIONS: The described differences underline the complementarity of NISs and RCTs. OCEAN covers a broader spectrum and more variability of patients than do RCTs. As baseline values may have impact on the treatment response (ceiling effect), there is an ongoing need for research in all patient subgroups. Country-specific assessments of patient populations can better reflect the real-world situation. NISs can deliver insights that RCTs may not, as NISs can include non-typical patients, patients with comorbidities, a broader age spectrum and patients of various disease stages. TRIAL REGISTRATION: The NIS OCEAN was registered on www.clinicaltrials.gov (identifier: NCT02194803 ).

[Regional Differences in the Care of Patients with Neovascular Age-Related Macular Degeneration, Based on the Non-Interventional OCEAN Study]. / Regionale Unterschiede in der Versorgung von Patienten mit neovaskulärer  altersabhängiger Makuladegeneration in einer nicht interventionellen Beobachtungsstudie (OCEAN).

Background: The main cause of blindness in the elderly in Germany is neovascular age-related macular degeneration (nAMD). In the non-interventional OCEAN study, data were prospectively collected on the routine clinical care of patients treated with the drug ranibizumab. Patients: As part of an interim analysis within the ongoing study (NCT02194803), stratification was performed by the 17 regions of the German associations of panel physicians and by areas of different population density. Only data were analysed for patients for whom the first treatment with ranibizumab was documented. Results: A total of 5,606 patients were documented. The present manuscript reviews 2,658 treatment-naive patients with nAMD, documented by 324 ophthalmologists. Most patients receiving an intravitreal injection were female (60 %). The average patient was aged 77.7 ± 8.2 years at study start. The great majority of patients had statutory health insurance (91 %). At baseline, fluorescein angiography (FLA) was performed for 72 % of patients, while optical coherence tomography (OCT) was carried out for 76 %. A combination of both was performed for 54 % of patients, varying regionally from 26 % (Saxony-Anhalt) to 100 % (Berlin). The average waiting time between the first examination and the first injection was 20.0 ± 18.5 days. With different statistical models (ANOVA adjusted, with/without interactions), significant effects on treatment delay were found for district type (population density), federal state and type of specialist. Conclusion: No major regional differences were observed in the demographic characteristics of the patient population. The main regional disparities in the care of nAMD patients were in the application of diagnostic methods and the waiting times between the first examination and the first drug administration. The regional variations in treatment delays could clearly influence the risk of worse functional outcome.

Regulation of endothelial nitric oxide synthase activation in endothelial cells by S1P1 and S1P3.

Endothelial nitric oxide synthase (eNOS) plays a crucial role in vascular homeostasis. Lysophospholipid interaction with sphingosine 1-phosphat (S1P) receptors results in eNOS activation in different cells. In endothelial cells, eNOS activation via S1P1 or S1P3 was shown controversially. The aim of this study is to investigate the meaning of both S1P receptors for eNOS activation in human endothelial cells. Therefore, several S1P1 and S1P3 agonists in combination with antagonists and specific RNAi approach were used. eNOS activation was measured in human umbilical vein endothelial cells (HUVEC) via DAF2-DA-based fluorescence microscopy. For investigation of the signaling pathway, agonists/antagonist studies, RNAi approach, Luminex™ multiplex, and Western Blot were used. In HUVEC, both the S1P1 agonist AUY954 as well as the S1P1,3 agonist FTY720P induced eNOS activation in a time- and dose-dependent manner. Other S1P1 agonists activated eNOS to a lesser extent. The AUY954-induced eNOS activation was blocked by the S1P1 antagonist W146, the combination of W146 and the S1P3 antagonist CAY10444 and the S1P1,3 antagonist VPC23019, but not by CAY10444 indicating the meaning of S1P1 for the AUY954-induced eNOS activation. The FTY720P-induced eNOS activation was blocked only by the combination of W146 and CAY10444 and the combined S1P1,3 antagonist VPC23019, but not by W146 or CAY10444 indicating the importance of both S1P1 and S1P3 for FTY720-induced eNOS activation. These results were confirmed using specific siRNA against S1P1 and S1P3. The S1P1,3 activation results in Akt phosphorylation and subsequent activation of eNOS via phosphorylation at serine(1177) and dephosphorylation at threonine(495). Beside former investigations with rather unspecific S1P receptor activation these data show potent selective S1P1 activation by using AUY954 and with selective S1P receptor inhibition evidence was provided that both S1P1 and S1P3 lead to downstream activation of eNOS in HUVEC in the same experimental setting. Inhibition or knockdown of one of these receptor subtypes did not abolish the eNOS activation and subsequent NO production.

[Design of the ORCA module in the OCEAN study : Evaluation of SD-OCT results in daily routine practice]. / Design des ORCA-Moduls der OCEAN-Studie : Evaluierung der SD-OCT-Befunderhebung in der täglichen Praxisroutine.

BACKGROUND: The prevalence of blindness as defined by law could be reduced by the introduction of anti-vascular endothelial growth factor (VEGF) therapy. Because the treatment is governed by patient needs, mostly using morphological criteria, imaging diagnostics are of particular importance. The non-interventional OCEAN study investigates the treatment with ranibizumab in the clinical routine practice. In a subgroup of patients the interpretation of spectral domain optical coherence tomography (SD-OCT) scans by the treating physicians will be analyzed (ORCA module). METHODS: Over a period of 24 months data from patients with exudative age-related macular degeneration (AMD), macular edema due to retinal vein occlusion or diabetes mellitus, who are receiving intravitreal injections of ranibizumab, will be assessed. Information on examinations, visual acuity, treatment and recordings from imaging techniques will be documented using a questionnaire. The SD-OCT scans, fluorescence angiography and fundus photography will be independently analyzed by the ophthalmologist of the study center and by three reading centers (CIRCL Cologne, GRADE Bonn and M3 Münster). Automated measurements of retinal thickness by the manufacturers' software will be checked and if necessary manually corrected. A qualitative interpretation in terms of morphological criteria for (further) treatment will be performed. CONCLUSION: A thorough assessment of SD-OCT images during anti-VEGF therapy provides the basis for the best possible needs-oriented treatment regimen. The control of the quality of data from daily routine practice may indicate possible weaknesses allowing explicit training and therefore optimization of patient treatment.