Secukinumab sustains improvement in signs and symptoms of psoriatic arthritis: 2 year results from the phase 3 FUTURE 2 study

Objectives. To assess long-term efficacy, safety and tolerability of secukinumab up to 104 weeks in patients with active PsA. Methods. Patients with PsA (n = 397) were randomized to s.c. secukinumab 300, 150 or 75 mg or placebo at baseline, weeks 1, 2, 3 and 4 and every 4 weeks thereafter. Placebo-treated patients were re-randomized to receive secukinumab 300 or 150 mg s.c. from week 16 (placebo non-responders) or week 24 (placebo responders). Exploratory endpoints at week 104 included 20, 50 and 70% improvement in ACR criteria (ACR20, 50, 70); 75 and 90% improvement in the Psoriasis Area Severity Index, 28-joint DAS with CRP, presence of dactylitis and enthesitis and other patient-reported outcomes. For binary variables, missing values were imputed; continuous variables were analysed by a mixed-effects model for repeated measures. Results. A total of 86/100 (86%), 76/100 (76%) and 65/99 (66%) patients in the secukinumab 300, 150 and 75 mg groups, respectively, completed 104 weeks. At week 104, ACR20 response rates after multiple imputation in the 300, 150 and 75 mg groups were 69.4, 64.4 and 50.3%, respectively. Sustained clinical improvements were observed through week 104 with secukinumab across other clinically important domains of PsA. Responses were sustained through week 104 regardless of prior anti-TNF-a use. Over the entire treatment period the incidence, type and severity of adverse events were consistent with those reported previously. Conclusion. Secukinumab provided sustained improvements in signs and symptoms and multiple clinical domains in patients of active PsA through 2 years of therapy. Secukinumab was well tolerated, with a safety profile consistent with that reported previously. Trial registration: ClinicalTrials.gov (https://clinicaltrials.gov), NCT0175263

Interleukin-17+CD8+T Cells Are Enriched in the Joints of Patients With Psoriatic Arthritis and Correlate With Disease Activity and Joint Damage Progression

OBJECTIVE: Psoriatic arthritis (PsA) is associated with HLA class I genes, in contrast to the association with HLA class II in rheumatoid arthritis (RA). Since IL-17+ cells are considered important mediators of synovial inflammation, we sought to determine whether IL-17–producing CD8+ T cells may be found in the joints of patients with PsA and whether these cells might contribute to the disease process. METHODS: Mononuclear cells from paired samples of synovial fluid (SF) and peripheral blood (PB) from patients with PsA or patients with RA were stimulated ex vivo, and CD4− T cells were examined by flow cytometry for cytokine expression, cytotoxic markers, and frequencies of γ/δ or mucosal-associated invariant T cells. Clinical measures of arthritis activity (C-reactive protein [CRP] level, erythrocyte sedimentation rate [ESR], Disease Activity Score in 28 joints [DAS28]) and power Doppler ultrasound (PDUS) scores for the presence of active synovitis in the aspirated knee were recorded and assessed for correlations with immunologic markers. RESULTS: Within the CD3+ T cell compartment, both IL-17+CD4− (predominantly CD8+) and IL-17+CD4+ T cells were significantly enhanced in the SF compared to the PB of patients with PsA (P = 0.0003 and P = 0.002, respectively; n = 21), whereas in patients with RA, only IL-17+CD4+ T cells were increased in the SF compared to the PB (P = 0.008; n = 14). The frequency of IL-17+CD4− T cells in PsA SF was positively correlated with the CRP level (r = 0.52, P = 0.01), ESR (r = 0.59, P = 0.004), and DAS28 (r = 0.52, P = 0.01), and was increased in patients with erosive disease (P < 0.05). In addition, the frequency of IL-17+CD4− T cells positively correlated with the PDUS score, a marker for active synovitis (r = 0.49, P = 0.04). CONCLUSION: These results show, for the first time, that the PsA joint, but not the RA joint, is enriched for IL-17+CD8+ T cells. Moreover, the findings reveal that the levels of this T cell subset are correlated with disease activity measures and the radiographic erosion status after 2 years, suggesting a previously unrecognized contribution of these cells to the pathogenesis of PsA

Secukinumab, a human anti-interleukin-17A monoclonal antibody, in patients with psoriatic arthritis (FUTURE 2): a randomised, double-blind, placebo-controlled, phase 3 trial

Background: Interleukin 17A is a proinflammatory cytokine that is implicated in the pathogenesis of psoriatic arthritis. We assessed the efficacy and safety of subcutaneous secukinumab, a human anti-interleukin-17A monoclonal antibody, in patients with psoriatic arthritis. Methods: In this phase 3, double-blind, placebo-controlled study undertaken at 76 centres in Asia, Australia, Canada, Europe, and the USA, adults (aged &#8805;18 years old) with active psoriatic arthritis were randomly allocated in a 1:1:1:1 ratio with computer-generated blocks to receive subcutaneous placebo or secukinumab 300 mg, 150 mg, or 75 mg once a week from baseline and then every 4 weeks from week 4. Patients and investigators were masked to treatment assignment. The primary endpoint was the proportion of patients achieving at least 20% improvement in the American College of Rheumatology response criteria (ACR20) at week 24. Analysis was by intention to treat. This study is registered with ClinicalTrials.gov, number NCT01752634. Findings: Between April 14, and Nov 25, 2013, 397 patients were randomly assigned to receive secukinumab 300 mg (n=100), 150 mg (n=100), 75 mg (n=99), or placebo (n=98). A significantly higher proportion of patients achieved an ACR20 at week 24 with secukinumab 300 mg (54 [54%] patients; odds ratio versus placebo 6·81, 95% CI 3·42–13·56; p&#60;0·0001), 150 mg (51 [51%] patients; 6·52, 3·25–13·08; p&#60;0·0001), and 75 mg (29 [29%] patients; 2·32, 1·14–4·73; p=0·0399) versus placebo (15 [15%] patients). Up to week 16, the most common adverse events were upper respiratory tract infections (four [4%], eight [8%], ten [10%], and seven [7%] with secukinumab 300 mg, 150 mg, 75 mg, and placebo, respectively) and nasopharyngitis (six [6%], four [4%], six [6%], and eight [8%], respectively). Serious adverse events were reported by five (5%), one (1%), and four (4%) patients in the secukinumab 300 mg, 150 mg, and 75 mg groups, respectively, compared with two (2%) in the placebo group. No deaths were reported. Interpretation: Subcutaneous secukinumab 300 mg and 150 mg improved the signs and symptoms of psoriatic arthritis, suggesting that secukinumab is a potential future treatment option for patients with this disorder

Paradoxical Association of C-Reactive Protein with Endothelial Function in Rheumatoid Arthritis

Background: Within the general population, levels of C-reactive protein (CRP) are positively associated with atherosclerotic cardiovascular disease (CVD). Whether CRP is causally implicated in atherogenesis or is the results of atherosclerosis is disputed. A role of CRP to protect endothelium-derived nitric oxide (EDNO) has been suggested. We examined the association of CRP with EDNO-dependent vasomotor function and subclinical measures of atherosclerosis and arteriosclerosis in patients with raised CRP resulting from rheumatoid arthritis (RA).Methodology/Principal Findings: Patients with RA (n = 59) and healthy control subjects (n = 123), underwent measures of high sensitivity CRP, flow-mediated dilation (FMD, dependent on EDNO), intima-media thickness (IMT, a measure of subclinical atherosclerosis) and aortic pulse wave velocity (PWV, a measure of arteriosclerosis). IMT and PWV were elevated in patients with RA compared to controls but FMD was similar in the two groups. In patients with RA, IMT and PWV were not correlated with CRP but FMD was positively independently correlated with CRP (P<0.01).Conclusions/Significance: These findings argue against a causal role of CRP in atherogenesis and are consistent with a protective effect of CRP on EDNO bioavailability

The importance of integration of stakeholder views in core outcome set development: Otitis Media with Effusion in children with cleft palate

© 2015 Harman et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. Background: Approximately 75% of children with cleft palate (CP) have Otitis Media with Effusion (OME) histories. Evidence for the effective management of OME in these children is lacking. The inconsistency in outcome measurement in previous studies has led to a call for the development of a Core Outcome Set (COS). Despite the increase in the number of published COS, involvement of patients in the COS development process, and methods to integrate the views of patients and health professionals, to date have been limited. Methods and Findings: A list of outcomes measured in previous research was identified through reviewing the literature. Opinion on the importance of each of these outcomes was then sought from key stakeholders: Ear, Nose and Throat (ENT) surgeons, audiologists, cleft surgeons, speech and language therapists, specialist cleft nurses, psychologists, parents and children. The opinion of health professionals was sought in a three round Delphi survey where participants were asked to score each outcome using a bespoke online system. Parents and children were also asked to score outcomes in a survey and provided an in-depth insight into having OME through semi-structured interviews. The results of the Delphi survey, interviews and parent/patient survey were brought together in a final consensus meeting with representation from all stakeholders. A final set of eleven outcomes reached the definition of "consensus in" to form the recommended COS: hearing; chronic otitis media (COM); OME; receptive language skills; speech development; psycho social development; acute otitis media (AOM); cholesteatoma; side effects of treatment; listening skills; otalgia. Conclusions: We have produced a recommendation about the outcomes that should be measured, as a minimum, in studies of the management of OME in children with CP. The development process included input from key stakeholders and used novel methodology to integrate the opinion of healthcare professionals, parents and children

A Case of Pediatric Idiopathic Intracranial Hypertension Presenting with Divergence Insufficiency

An 11-year-old female presenting diplopia only at distance was found to have comitant esotropia of 20 prism diopters (PD) at distance and normal alignment at nearer proximity. Other ocular movement, including abduction, was normal and a thorough neurologic examination was also normal. The deviation angle of esotropia was increased to 35 PD in 6 months, and a brain magnetic resonance imaging with venogram at that time demonstrated no intracranial lesion. A lumbar puncture showed increased opening pressure but the cerebrospinal fluid composition was normal. The patient was diagnosed as having idiopathic intracranial hypertension and treated with oral acetazolamide. Three months after treatment, the deviation angle decreased to 10 PD. This is a case report of divergence insufficiency in pediatric idiopathic intracranial hypertension, with an increasing deviation angle of esotropia. Although sixth cranial nerve palsy is a common neurologic manifestation in intracranial hypertension, clinicians should be aware of the possibility of divergence insufficiency. Also, ophthalmoparesis may not be apparent and typical at first presentation, as seen in this case, and therefore ophthalmologists should be aware of this fact, while conducting careful and proper evaluation, follow-up, and intervention

Core outcome measurement instruments for clinical trials in nonspecific low back pain.

To standardize outcome reporting in clinical trials of patients with nonspecific low back pain, an international multidisciplinary panel recommended physical functioning, pain intensity, and health-related quality of life (HRQoL) as core outcome domains. Given the lack of a consensus on measurement instruments for these 3 domains in patients with low back pain, this study aimed to generate such consensus. The measurement properties of 17 patient-reported outcome measures for physical functioning, 3 for pain intensity, and 5 for HRQoL were appraised in 3 systematic reviews following the COSMIN methodology. Researchers, clinicians, and patients (n = 207) were invited in a 2-round Delphi survey to generate consensus (≥67% agreement among participants) on which instruments to endorse. Response rates were 44% and 41%, respectively. In round 1, consensus was achieved on the Oswestry Disability Index version 2.1a for physical functioning (78% agreement) and the Numeric Rating Scale (NRS) for pain intensity (75% agreement). No consensus was achieved on any HRQoL instrument, although the Short Form 12 (SF12) approached the consensus threshold (64% agreement). In round 2, a consensus was reached on an NRS version with a 1-week recall period (96% agreement). Various participants requested 1 free-to-use instrument per domain. Considering all issues together, recommendations on core instruments were formulated: Oswestry Disability Index version 2.1a or 24-item Roland-Morris Disability Questionnaire for physical functioning, NRS for pain intensity, and SF12 or 10-item PROMIS Global Health form for HRQoL. Further studies need to fill the evidence gaps on the measurement properties of these and other instruments.This is an open-access article distributed under the terms of the Creative Commons Attribution-Non Commercial-No Derivatives License 4.0 (CCBY-NC-ND), where it is permissible to download and share the work provided it is properly cited. The work cannot be changed in any way or used commercially without permission from the journal

Defining and evaluating novel procedures for involving patients in Core Outcome Set research: creating a meaningful long list of candidate outcome domains

Background Tinnitus is a complex audiological condition affecting many different domains of everyday life. Clinical trials of tinnitus interventions measure and report those outcome domains inconsistently and this hinders direct comparison between study findings. To address this problem, an ongoing project is developing a Core Outcome Set; an agreed list of outcome domains to be measured and reported in all future trials. Part of this project uses a consensus methodology (‘Delphi’ survey), whereby all relevant stakeholders identify important and critical outcome domains from a long list of candidates. This article addresses a gap in the patient involvement literature by describing and reflecting on our involvement of patients to create a meaningful long list of candidate outcome domains. Methods Two Public Research Partners with lived experience of tinnitus reviewed an initial list of 124 outcome domains over two face-to-face workshops. With the Study Management Team, they interpreted each candidate outcome domain and generated a plain language description. Following this, the domain names and descriptions underwent an additional lay review by 14 patients and 5 clinical experts, via an online survey platform. Results Insights gained from the workshops and survey feedback prompted substantial, unforeseen modifications to the long list. These included the reduction of the number of outcome domains (from 124 to 66) via the exclusion of broad concepts and consolidation of equivalent domains or domains outside the scope of the study. Reviewers also applied their lived experience of tinnitus to bring clarity and relevance to domain names and plain language descriptions. Four impacts on the Delphi survey were observed: recruitment exceeded the target by 171%, there were equivalent numbers of patient and professional participants (n=358 and n=312, respectively), feedback was mostly positive, and retention was high (87%). Conclusions Patient involvement was an integral and transformative step of the study design process. Patient involvement was impactful because the online Delphi survey was successful in recruiting and retaining participants, and there were many comments about a positive participatory experience. Seven general methodological features are highlighted which fit with general principles of good patient involvement. These can benefit other Core Outcome Set developers