Experimental models for posterior capsule opacification research

Millions of people worldwide are blinded due to cataract formation. At present the only means of treating a cataract is through surgical intervention. A modern cataract operation involves the creation of an opening in the anterior lens capsule to allow access to the fibre cells, which are then removed. This leaves in place a capsular bag that comprises the remaining anterior capsule and the entire posterior capsule. In most cases, an intraocular lens is implanted into the capsular bag during surgery. This procedure initially generates good visual restoration, but unfortunately, residual lens epithelial cells undergo a wound-healing response invoked by surgery, which in time commonly results in a secondary loss of vision. This condition is known as posterior capsule opacification (PCO) and exhibits classical features of fibrosis, including hyperproliferation, migration, matrix deposition, matrix contraction and transdifferentiation into myofibroblasts. These changes alone can cause visual deterioration, but in a significant number of cases, fibre differentiation is also observed, which gives rise to Soemmering's ring and Elschnig's pearl formation. Elucidating the regulatory factors that govern these events is fundamental in the drive to develop future strategies to prevent or delay visual deterioration resulting from PCO. A range of experimental platforms are available for the study of PCO that range from in vivo animal models to in vitro human cell and tissue culture models. In the current review, we will highlight some of the experimental models used in PCO research and provide examples of key findings that have resulted from these approaches

Acupuncture for chronic pain and depression in primary care : a programme of research

Abstract Background There has been an increase in the utilisation of acupuncture in recent years, yet the evidence base is insufficiently well established to be certain about its clinical effectiveness and cost-effectiveness. Addressing the questions related to the evidence base will reduce uncertainty and help policy- and decision-makers with regard to whether or not wider access is appropriate and provides value for money. Aim Our aim was to establish the most reliable evidence on the clinical effectiveness and cost-effectiveness of acupuncture for chronic pain by drawing on relevant evidence, including recent high-quality trials, and to develop fresh evidence on acupuncture for depression. To extend the evidence base we synthesised the results of published trials using robust systematic review methodology and conducted a randomised controlled trial (RCT) of acupuncture for depression. Methods and results We synthesised the evidence from high-quality trials of acupuncture for chronic pain, consisting of musculoskeletal pain related to the neck and low back, osteoarthritis of the knee, and headache and migraine, involving nearly 18,000 patients. In an individual patient data (IPD) pairwise meta-analysis, acupuncture was significantly better than both sham acupuncture (p < 0.001) and usual care (p < 0.001) for all conditions. Using network meta-analyses, we compared acupuncture with other physical therapies for osteoarthritis of the knee. In both an analysis of all available evidence and an analysis of a subset of better-quality trials, using aggregate-level data, we found acupuncture to be one of the more effective therapies. We developed new Bayesian methods for analysing multiple individual patient-level data sets to evaluate heterogeneous continuous outcomes. An accompanying cost-effectiveness analysis found transcutaneous electrical nerve stimulation (TENS) to be cost-effective for osteoarthritis at a threshold of £20,000 per quality-adjusted life-year when all trials were synthesised. When the analysis was restricted to trials of higher quality with adequate allocation concealment, acupuncture was cost-effective. In a RCT of acupuncture or counselling compared with usual care for depression, in which half the patients were also experiencing comorbid pain, we found acupuncture and counselling to be clinically effective and acupuncture to be cost-effective. For patients in whom acupuncture is inappropriate or unavailable, counselling is cost-effective. Conclusion We have provided the most robust evidence from high-quality trials on acupuncture for chronic pain. The synthesis of high-quality IPD found that acupuncture was more effective than both usual care and sham acupuncture. Acupuncture is one of the more clinically effective physical therapies for osteoarthritis and is also cost-effective if only high-quality trials are analysed. When all trials are analysed, TENS is cost-effective. Promising clinical and economic evidence on acupuncture for depression needs to be extended to other contexts and settings. For the conditions we have investigated, the drawing together of evidence on acupuncture from this programme of research has substantially reduced levels of uncertainty. We have identified directions for further research. Our research also provides a valuable basis for considering the potential role of acupuncture as a referral option in health care and enabling providers and policy-makers to make decisions based on robust sources of evidence

An economic evaluation of Alexander Technique lessons or acupuncture sessions for patients with chronic neck pain : A randomized trial (ATLAS)

OBJECTIVES: To assess the cost-effectiveness of acupuncture and usual care, and Alexander Technique lessons and usual care, compared with usual GP care alone for chronic neck pain patients. METHODS: An economic evaluation was undertaken alongside the ATLAS trial, taking both NHS and wider societal viewpoints. Participants were offered up to twelve acupuncture sessions or twenty Alexander lessons (equivalent overall contact time). Costs were in pounds sterling. Effectiveness was measured using the generic EQ-5D to calculate quality adjusted life years (QALYs), as well as using a specific neck pain measure-the Northwick Park Neck Pain Questionnaire (NPQ). RESULTS: In the base case analysis, incremental QALY gains were 0.032 and 0.025 in the acupuncture and Alexander groups, respectively, in comparison to usual GP care, indicating moderate health benefits for both interventions. Incremental costs were £451 for acupuncture and £667 for Alexander, mainly driven by intervention costs. Acupuncture was likely to be cost-effective (ICER = £18,767/QALY bootstrapped 95% CI £4,426 to £74,562) and was robust to most sensitivity analyses. Alexander lessons were not cost-effective at the lower NICE threshold of £20,000/QALY (£25,101/QALY bootstrapped 95% CI -£150,208 to £248,697) but may be at £30,000/QALY, however, there was considerable statistical uncertainty in all tested scenarios. CONCLUSIONS: In comparison with usual care, acupuncture is likely to be cost-effective for chronic neck pain, whereas, largely due to higher intervention costs, Alexander lessons are unlikely to be cost-effective. However, there were high levels of missing data and further research is needed to assess the long-term cost-effectiveness of these interventions

Efficacy and safety of paricalcitol in children with stages 3 to 5 chronic kidney disease

BACKGROUND: Elevated intact parathyroid hormone (iPTH) levels can contribute to morbidity and mortality in children with chronic kidney disease (CKD). We evaluated the pharmacokinetics, efficacy, and safety of oral paricalcitol in reducing iPTH levels in children with stages 3-5 CKD.METHODS: Children aged 10-16 years with stages 3-5 CKD were enrolled in two phase 3 studies. The stage 3/4 CKD study characterized paricalcitol pharmacokinetics and compared the efficacy and safety of paricalcitol with placebo followed by an open-label period. The stage 5 CKD study evaluated the efficacy and safety of paricalcitol (no comparator) in children with stage 5 CKD undergoing dialysis.RESULTS: In the stage 3/4 CKD study, mean peak plasma concentration and area under the time curve from zero to infinity were 0.13 ng/mL and 2.87 ng•h/((or ng×h/))mL, respectively, for 12 children who received 3 μg paricalcitol. Thirty-six children were randomized to paricalcitol or placebo; 27.8% of the paricalcitol group achieved two consecutive iPTH reductions of ≥30% from baseline versus none of the placebo group (P = 0.045). Adverse events were higher in children who received placebo than in those administered paricalcitol during the double-blind treatment (88.9 vs. 38.9%; P = 0.005). In the stage 5 CKD study, eight children (61.5%) had two consecutive iPTH reductions of ≥30% from baseline, and five (38.5%) had two consecutive iPTH values of between 150 and 300 pg/mL. Clinically meaningful hypercalcemia occurred in 21% of children.CONCLUSIONS: Oral paricalcitol in children aged 10-16 years with stages 3-5 CKD reduced iPTH levels and the treatment was well tolerated. Results support an initiating dose of 1 μg paricalcitol 3 times weekly in children aged 10-16 years.</p

Role of extracellular ATP and adenosine in the human lens and retinal pigment epithelium

EThOS - Electronic Theses Online ServiceGBUnited Kingdo

Improved patient-reported outcomes in patients with psoriatic arthritis treated with risankizumab: analysis of the Phase 3 trial KEEPsAKE 2

Objectives Determine the impact of 24-week risankizumab (RZB) versus placebo (PBO) on patient-reported outcomes (PROs) in patients with psoriatic arthritis (PsA) and inadequate response to one or two biologics (Bio-IR) and/or ≥1 conventional synthetic disease-modifying antirheumatic drug (csDMARD-IR).Methods Patients in the Phase 3 trial, KEEPsAKE 2, were randomised (1:1) to RZB 150 mg or PBO by subcutaneous injection. PROs assessed: 36-Item Short-Form Health Survey (SF-36), Functional Assessment of Chronic Illness Therapy—Fatigue (FACIT-Fatigue), Patient’s Assessment of Pain by visual analogue scale (VAS), Patient’s global assessment of disease activity (PtGA), EuroQoL-5 Dimension-5 Level (EQ-5D-5L) and Work Productivity and Activity Impairment—PsA (WPAI-PsA). Least squares mean change from baseline at week 24 was compared between RZB versus PBO by mixed-effects repeated regression modelling.Results At week 24, RZB versus PBO treatment resulted in significant differences (95% CIs) in mean change from baseline in ranked secondary endpoints SF-36 physical component summary score (3.9 (2.4 to 5.3); p&lt;0.001) and FACIT-Fatigue (2.2 (0.6 to 3.9); p=0.009) and improvements in pain (–8.1 (–12.8 to –3.5)), PtGA (–8.8 (–13.5 to –4.2)) and EQ-5D-5L index (0.08 (0.04 to 0.11)) and VAS (5.9 (1.9 to 9.8)) (all nominal p&lt;0.01). More RZB-treated versus PBO-treated patients reported improvements from baseline at week 24 in 7 of 8 SF-36 subdomains (nominal p&lt;0.05). At week 24, more RZB-treated versus PBO-treated patients reported improvements in 3 of 4 WPAI-PsA domains (nominal p≤0.01).Conclusion Overall, RBZ treatment resulted in improvements in pain, fatigue, health-related quality of life and ability to perform work in Bio-IR and/or csDMARD-IR patients with PsA.Trial registration number NCT03671148

Long-Term Efficacy and Safety of Risankizumab in Patients with Active Psoriatic Arthritis: Results from a 76-Week Phase 2 Randomized Trial.

INTRODUCTION: The objective of this work was to assess the efficacy and safety of risankizumab in psoriatic arthritis (PsA) over 76 weeks. METHODS: In this double-blind, dose-ranging phase 2 study, adults with active PsA were randomized 2:2:2:1:2 to risankizumab 150 mg at weeks 0, 4, 8, 12, and 16 (arm 1), 150 mg at weeks 0, 4, and 16 (arm 2), 150 mg at weeks 0 and 12 (arm 3), 75 mg at week 0 (arm 4), or placebo (arm 5). Patients completing week 24 could receive risankizumab 150 mg in a 52-week open-label extension study. Efficacy assessments included American College of Rheumatology (ACR) responses, Psoriasis Area Severity Index (PASI) responses, minimal disease activity (MDA), and 28-joint Disease Activity Score based on C-reactive protein (DAS28[CRP]). RESULTS: Of 185 randomized patients, 173 (93.5%) completed week 16 and 145 (78.4%) entered the open-label extension. Significantly more patients in each risankizumab arm achieved ACR20 at week 16 versus placebo (primary endpoint: pooled arms 1 + 2 [59.5%] versus placebo [35.7%]; treatment difference [90% CI] 24.0 [9.3, 38.7]; P = 0.007). Similarly, significantly more patients in most risankizumab arms achieved ACR20/50/70, PASI75/90/100, MDA, and greater improvements in DAS28(CRP) versus placebo at week 16. These benefits of risankizumab were maintained long term. Treatment-emergent adverse events were comparable across treatment arms. Risankizumab 150 mg was well tolerated over 76 weeks. CONCLUSIONS: Risankizumab improved joint and skin symptoms versus placebo in patients with active PsA over 16 weeks; improvements were sustained long term. Risankizumab was well tolerated over the long term with no new safety findings. TRIAL REGISTRATION NUMBERS: NCT02719171 and NCT02986373

Efficacy and safety of risankizumab for active psoriatic arthritis: 52-week results from the KEEPsAKE 2 study

Objective: Psoriatic arthritis (PsA) is a chronic inflammatory disease in which the skin and joints are affected. In this follow-up analysis, the 52-week efficacy and safety of risankizumab 150 mg in patients with active PsA who had previous inadequate response/intolerance to one or two biologic therapies (Bio-IR) or one or more conventional synthetic disease-modifying antirheumatic drug (csDMARD-IR) were evaluated. Methods: In the ongoing, phase 3, KEEPsAKE 2 trial, patients with active PsA were randomized 1:1 to receive subcutaneous risankizumab 150 mg or placebo at weeks 0, 4 and 16 (period 1). At week 24 (period 2), patients who received placebo were switched to risankizumab, and all patients received risankizumab 150 mg every 12 weeks from weeks 28-208. Results: At week 24, 51.3% of risankizumab-treated patients (N = 224) achieved ?20% improvement in American College of Rheumatology criteria (ACR20) vs 26.5% of placebo-treated patients (N = 220; P < 0.001). At week 52, 58.5% of patients randomized to receive continuous risankizumab achieved ACR20, and 55.7% of patients who switched from placebo to risankizumab at week 24 achieved ACR20. Similar trends were observed for other efficacy measures. Rates of serious treatment-emergent adverse events (TEAEs) and TEAEs leading to discontinuation remained stable through week 52, and no deaths were reported. Conclusion: Risankizumab was well tolerated and improved symptoms of PsA in Bio-IR/csDMARD-IR patients, with a consistent long-term safety profile from weeks 24-52.Funding: This work was supported by AbbVie, Inc. (North Chicago, IL, USA) Acknowledgements: AbbVie Inc. participated in the study design; study research; collection, analysis and interpretation of data; and writing, reviewing and approving this manuscript. All authors had access to the data and participated in the development, review, approval and decision to submit this manuscript for publication. AbbVie and the authors thank all study investigators for their contributions and the patients who participated in this study. Medical writing support, funded by AbbVie, was provided by Spencer Hughes, PhD, Jay Parekh, PharmD, and Melissa Julyanti, PharmD, of JB Ashtin, who developed the manuscript based on an author-approved outline and assisted in implementing author revisions throughout the editorial process. JB Ashtin adheres to Good Publication Practice (GPP3) guidelines and International Committee of Medical Journal Editors (ICMJE) recommendations. Disclosure statement: A.Ö. has received speaker or consulting fees and/or research grants from AbbVie, Bristol Myers Squibb, Celgene, Janssen, Lilly, Merck, Novartis, Pfizer, Roche, Sanofi and UCB. F.V.dB. has received speaker and/or consulting fees from AbbVie, Celgene, Galapagos, Gilead, Janssen, Lilly, Novartis, Pfizer and UCB. K.P. has received honoraria or fees for serving on advisory boards, as a speaker, and as a consultant, as well as grants as principal investigator from AbbVie, Amgen, Astellas, Bausch Health (Valeant), Baxalta, Baxter, Boehringer Ingelheim, Bristol Myers Squibb, Celgene, Coherus, Dermira, EMD Serono, Forward Pharma, Galderma, Genentech, GlaxoSmithKline, Janssen, Kyowa Kirin, Lilly, LEO Pharma, MedImmune, Merck, Novartis, Pfizer, Regeneron, Roche, Sanofi Genzyme, Stiefel, Sun Pharma, Takeda and UCB. C.A. has received honoraria or fees for serving on advisory boards or as a speaker, as well as research support from AbbVie, Amgen, Genentech, Janssen, Lilly, Pfizer, Roche and R-Pharm. R.B. has received grants or research support from AbbVie, Merck and Roche. He has received consultation fees or honoraria for serving as a speaker for AbbVie, Bristol Myers Squibb, Janssen, Lilly, Merck, Pfizer and Roche. J.A. has received grants or research support from AbbVie, Amgen, AstraZeneca, Bristol Myers Squibb, Galapagos/Gilead, Genentech, GlaxoSmithKline, Lilly, Mallinckrodt, Nektar Therapeutics, Nichi-Iko, Novartis, Pfizer, Regeneron, Roche, Sanofi, Selecta Biosciences and UCB. W.L., A.E., and B.P. are fulltime employees of AbbVie, and may hold AbbVie stock or stock options. A.M.S. is a full-time employee of AbbVie, may hold AbbVie stock or stock options and is a co-inventor on AbbVie patents. Z.W. is a former employee of AbbVie and may hold AbbVie stock. A.K. is a shareholder of or has received honoraria or fees as a consultant, speaker, or expert witness for AbbVie, Boehringer Ingelheim, Celgene, Flexion, Gilead, GlaxoSmithKline, Janssen, Lilly, Merck, Novartis, Pfizer, Regeneron, Sanofi Genzyme, Sun Pharma and UCB

Efficacy and safety of risankizumab for active psoriatic arthritis : 24-week results from the randomised, double-blind, phase 3 KEEPsAKE 2 trial

Objectives Risankizumab is an interleukin-23 inhibitor under study for the treatment of patients with psoriatic arthritis (PsA). The phase 3 KEEPsAKE 2 trial investigated the efficacy and safety of risankizumab versus placebo in patients with active PsA who had previous inadequate response or intolerance to = 1 conventional synthetic disease-modifying antirheumatic drug (csDMARD-IR). Results through week 24 are reported here. Methods Adults with PsA who were Bio-IR and/or csDMARD-IR were randomised to receive subcutaneously administered risankizumab 150 mg or placebo at weeks 0, 4 and 16 during a 24-week, double-blind treatment period. The primary endpoint was the proportion of patients who achieved >= 20% improvement in American College of Rheumatology score (ACR20) at week 24. Secondary endpoints assessed key domains of PsA and patient-reported outcomes. Results A total of 444 patients (median age 53 years, range 23-84 years) were randomised to risankizumab (n=224) or placebo (n=220); 206 patients (46.5%) were Bio-IR. At week 24, a significantly greater proportion of patients receiving risankizumab achieved the primary endpoint of ACR20 (51.3% vs 26.5%, p<0.001) and all secondary endpoints (p<0.05) compared with placebo. Serious adverse events were reported for 4.0% and 5.5% of risankizumab-treated and placebo-treated patients, respectively; serious infections were reported for 0.9% and 2.3%, respectively. Conclusion Treatment with risankizumab resulted in significant improvements versus placebo in key disease outcomes and was well tolerated in patients with PsA who were Bio-IR and/or csDMARD-IR.arthritis; arthritis; psoriatic; biological therap