Usage of C-Reactive Protein Testing in the Diagnosis and Monitoring of Psoriatic Arthritis (PsA): Results from a Real-World Survey in the USA and Europe.

INTRODUCTION: C-reactive protein (CRP) is an important non-specific marker of both acute and chronic inflammation and can be elevated in patients with psoriatic arthritis (PsA). However, the use of CRP testing in the management of PsA can vary. This study investigated how CRP testing is implemented in real-world clinical practice for disease management of PsA. METHODS: A point-in-time survey of rheumatologists and dermatologists and their next six consulting patients with PsA was conducted in France, Germany, Italy, Spain, UK (EU5), and the USA between June and August 2018. Use of CRP testing was obtained by asking the physician to state (yes/no) whether CRP was used to aid PsA diagnosis and/or to monitor the patient's disease activity. The number of CRP tests conducted in the last 12 months for each patient enrolled was provided. RESULTS: Data were collected for 2270 patients (USA, n = 595; EU5, n = 1675). In the EU5, CRP testing was conducted to aid diagnosis in 78.7% of patients (vs. 43.4% in USA) and CRP was used to monitor disease activity in 72.0% (vs. 34.6% in USA). The majority (80.9%) of patients in the EU5 had at least one CRP test in the last 12 months compared to 42.9% in the USA. Patients treated by rheumatologists (vs. dermatologists) were at least 50% more likely to have CRP tested for monitoring purposes, this difference being most pronounced in the USA. In the EU5, CRP testing was conducted a mean ± standard deviation of 2.7 ± 1.7 times during the last 12 months, versus 2.0 ± 1.4 in the USA. CONCLUSIONS: CRP was more commonly used for the diagnosis and monitoring of PsA in Europe compared to the USA and was more commonly ordered by rheumatologists than dermatologists. In the absence of a better serum biomarker of inflammation, more data are needed to understand how CRP testing should be used in the diagnosis and management PsA.

Sex-specific differences and how to handle them in early psoriatic arthritis.

OBJECTIVES: The prevalence of psoriatic arthritis (PsA) is the same in men and women; however, the latter experience a higher burden of disease and are affected more frequently by polyarthritis. Here, we performed an early PsA cohort analysis to assess sex-related differences in demographics, disease characteristics, and evolution over 1 year including applied treatment strategies. METHODS: Our study is embedded in the Dutch south-west Early Psoriatic Arthritis cohoRt. We described patient characteristics and treatment decisions. For the comparison across sexes and baseline and 1 year follow-up, appropriate tests depending on the distribution were used. RESULTS: Two hundred seventy-three men and 294 women with no significant differences in age and ethnicity were included. Women reported significantly longer duration of symptoms before diagnosis and significantly higher tender joint count, a higher disease activity, higher levels of pain, and lower functional capacity. Although minimal disease activity (MDA) rates increased over time for both sexes, MDA remained significantly more prevalent among men at 1 year (58.1% vs 35.7%, p < 0.00). Initially, treatment strategies were similar in both sexes with methotrexate being the most frequently used drug during the first year. Women received methotrexate for a shorter period [196 (93-364) vs 306 (157-365), p < 0.00] and therefore received a lower cumulative dose compared to men. Retention time was shorter for all DMARDs, and women had a delayed start on b-DMARDs. CONCLUSION: After 1 year of standard-of-care treatment, women did not surpass their baseline disadvantages. Despite the overall improvement, they still presented higher disease activity, higher levels of pain, and lower functional capacity score than men. The nature of these findings may advocate a need for sex specific adjustment of treatment strategies and evaluation in early PsA patients.

Supercomputer-Based Ensemble Docking Drug Discovery Pipeline with Application to Covid-19.

We present a supercomputer-driven pipeline for in silico drug discovery using enhanced sampling molecular dynamics (MD) and ensemble docking. Ensemble docking makes use of MD results by docking compound databases into representative protein binding-site conformations, thus taking into account the dynamic properties of the binding sites. We also describe preliminary results obtained for 24 systems involving eight proteins of the proteome of SARS-CoV-2. The MD involves temperature replica exchange enhanced sampling, making use of massively parallel supercomputing to quickly sample the configurational space of protein drug targets. Using the Summit supercomputer at the Oak Ridge National Laboratory, more than 1 ms of enhanced sampling MD can be generated per day. We have ensemble docked repurposing databases to 10 configurations of each of the 24 SARS-CoV-2 systems using AutoDock Vina. Comparison to experiment demonstrates remarkably high hit rates for the top scoring tranches of compounds identified by our ensemble approach. We also demonstrate that, using Autodock-GPU on Summit, it is possible to perform exhaustive docking of one billion compounds in under 24 h. Finally, we discuss preliminary results and planned improvements to the pipeline, including the use of quantum mechanical (QM), machine learning, and artificial intelligence (AI) methods to cluster MD trajectories and rescore docking poses.

Supercomputer-Based Ensemble Docking Drug Discovery Pipeline with Application to Covid-19.

We present a supercomputer-driven pipeline for in-silico drug discovery using enhanced sampling molecular dynamics (MD) and ensemble docking. We also describe preliminary results obtained for 23 systems involving eight protein targets of the proteome of SARS CoV-2. THe MD performed is temperature replica-exchange enhanced sampling, making use of the massively parallel supercomputing on the SUMMIT supercomputer at Oak Ridge National Laboratory, with which more than 1ms of enhanced sampling MD can be generated per day. We have ensemble docked repurposing databases to ten configurations of each of the 23 SARS CoV-2 systems using AutoDock Vina. We also demonstrate that using Autodock-GPU on SUMMIT, it is possible to perform exhaustive docking of one billion compounds in under 24 hours. Finally, we discuss preliminary results and planned improvements to the pipeline, including the use of quantum mechanical (QM), machine learning, and AI methods to cluster MD trajectories and rescore docking poses.

Results of a global, patient-based survey assessing the impact of psoriatic arthritis discussed in the context of the Psoriatic Arthritis Impact of Disease (PsAID) questionnaire.

BACKGROUND: Psoriatic arthritis (PsA) is a chronic immune-mediated inflammatory musculoskeletal disease, manifesting as peripheral arthritis, enthesitis, dactylitis, spondylitis, and skin and nail psoriasis. A core set of domains for measuring the impact of PsA has been developed, including pain, patient global assessment, physical function, health-related quality of life (HRQoL), and fatigue. To understand the impact of PsA on health domains from a patient's perspective, a global survey was developed and results reported in the context of the 12-item Psoriatic Arthritis Impact of Disease (PsAID-12) questionnaire. METHODS: An online patient-based global survey was conducted by The Harris Poll in Australia, Brazil, Canada, France, Spain, Taiwan, the UK, and the US between November 2, 2017 and March 12, 2018. Eligible patients were ≥ 18 years old with a diagnosis of PsA for > 1 year, had visited a rheumatologist/dermatologist in the past 12 months and reported using ≥ 1 synthetic/biologic disease-modifying antirheumatic drug for PsA. Patients reported on PsA severity and symptoms, and the impact of PsA on HRQoL. After survey completion, responses were aligned with PsAID health domains. Descriptive statistics and chi-square tests were conducted. RESULTS: This analysis included 1286 patients from eight countries. Most patients (97%) reported musculoskeletal symptoms relating to PsA in the past year. Common moderate/major impacts of PsA were on physical activity (78%), ability to perform certain activities (76%), work productivity (62%), and career path (57%). Skin/nail symptoms occurred in 80% of patients. Overall, 69% of patients reported that PsA had a moderate/major impact on emotional/mental wellbeing, 56% on romantic relationships/intimacy, and 44% on relationships with family and friends. Social impacts included emotional distress (58%), social shame or disapproval (32%), and ceased participation in social activities (45%). Over half of all patients experienced unusual fatigue over the past 12 months (52%). The health domains that patients reported as being impacted by PsA aligned with life impact domains of the patient-derived PsAID health domains. CONCLUSION: These results highlight the impact of PsA on multiple health domains from a patient perspective that should be considered during shared decision-making processes between healthcare providers and patients.

Comparing the efficacy and tolerability of biologic therapies in psoriasis: an updated network meta-analysis.

BACKGROUND: The rapid expansion of psoriasis biologics has led to an urgent need to understand their relative efficacy and tolerability to inform treatment decisions better and, specifically, to inform guideline development. OBJECTIVES: To update a 2017 meta-analysis on the comparative efficacy and tolerability of biologic treatments for psoriasis. METHODS: We searched the MEDLINE, PubMed, Embase and Cochrane databases for randomized controlled trials (RCTs), published up to 7 September 2018, of 11 licensed, NICE-approved biologics targeting tumour necrosis factor (adalimumab, etanercept, infliximab, certolizumab pegol), interleukin (IL)-12/IL-23p40 (ustekinumab), IL-17A (secukinumab, ixekizumab), IL-17RA (brodalumab) and IL-23p19 (guselkumab, tildrakizumab, risankizumab). A frequentist network meta-analysis ascertained direct or indirect evidence comparing biologics with one another, methotrexate or placebo. This was combined with hierarchical cluster analyses to consider efficacy (≥ 90% improvement in Psoriasis Area and Severity Index (PASI 90) or Physician's Global Assessment 0 or 1; PASI 75; Dermatology Life Quality Index improvement) and tolerability (drug withdrawal due to adverse events) outcomes at 10-16 weeks, followed by assessments of study quality, heterogeneity and inconsistency. RESULTS: We identified 62 RCTs presenting data on direct comparisons (31 899 participants). All biologics were efficacious compared with placebo or methotrexate at 10-16 weeks. Hierarchical cluster analyses revealed that adalimumab, brodalumab, certolizumab pegol, guselkumab, risankizumab, secukinumab, tildrakizumab and ustekinumab were comparable with respect to high short-term efficacy and tolerability. Infliximab and ixekizumab clustered together, with high short-term efficacy but relatively lower tolerability than the other agents, although the number of drug withdrawal events across the network was low, so these findings should be treated with caution. CONCLUSIONS: Using our methodology we found that most biologics cluster together with respect to short-term efficacy and tolerability, and we did not identify any single agent as 'best'. These data need to be interpreted in the context of longer-term efficacy, effectiveness data, safety, posology and drug acquisition costs when making treatment decisions.

International league of associations for rheumatology recommendations for the management of psoriatic arthritis in resource-poor settings.

BACKGROUND: Psoriatic arthritis (PsA) is a challenging heterogeneous disease. The European League Against Rheumatism (EULAR) and the Group for Research and Assessment of Psoriasis and PsA (GRAPPA) last published their respective recommendations for the management of PsA in 2015. However, these guidelines are primarily based on studies conducted in resource replete countries and may not be applicable in countries in the Americas (except Canada and USA) and Africa. We sought to adapt the existing recommendations for these regions under the auspices of the International League of Associations for Rheumatology (ILAR). PROCESS: The ADAPTE Collaboration (2009) process for guideline adaptation was followed to adapt the EULAR and GRAPPA PsA treatment recommendations for the Americas and Africa. The process was conducted in three recommended phases: set-up phase; adaptation phase (defining health questions, assessing source recommendations, drafting report), and finalization phase (external review, aftercare planning, and final production). RESULT: ILAR recommendations have been derived principally by adapting the GRAPPA recommendations, additionally, EULAR recommendations where appropriate and supplemented by expert opinion and literature from these regions. A paucity of data relevant to resource-poor settings was found in PsA management literature. CONCLUSION: The ILAR Treatment Recommendations for PsA intends to serve as reference for the management of PsA in the Americas and Africa. This paper illustrates the experience of an international working group in adapting existing recommendations to a resource-poor setting. It highlights the need to conduct research on the management of PsA in these regions as data are currently lacking.Key Points• The paper presents adapted recommendations for the management of psoriatic arthritis in resource-poor settings.• The ADAPTE process was used to adapt existing GRAPPA and EULAR recommendations by collaboration with practicing clinicians from the Americas and Africa.• The evidence from resource-poor settings to answer clinically relevant questions was scant or non-existent; hence, a research agenda is proposed.

Long-term efficacy and safety of secukinumab in the treatment of the multiple manifestations of psoriatic disease.

Psoriatic disease is a multifaceted disorder, which develops in the skin, its appendages and joints. Though characterized by different pathogenic background and clinical manifestations, skin plaque psoriasis (PsO), psoriatic arthritis (PsA) and ankylosing spondylitis (AS) are related, sharing key inflammatory mechanisms and hence mode of management. Secukinumab is a fully human monoclonal antibody that selectively binds and neutralizes interleukin-17A. It has been approved for use as a subcutaneous injection for the treatment of moderate-to-severe PsO, PsA and AS. The current review highlights the long-term efficacy and safety profile of secukinumab in the treatment of plaque psoriasis and its multiple manifestations from its phase 3 clinical trial programme. The long-term extension of pivotal trials has shown sustainable efficacy and safety of secukinumab up to 5 years in PsO, PsA and AS and up to 2.5 years in moderate-to-severe nail and palmoplantar PsO through dedicated randomized controlled trials. The effect of secukinumab therapy in all these indications has corresponding effects on improvement in quality-of-life and daily activities. Overall, secukinumab is an effective and safe treatment choice for patients suffering from psoriatic disease in its multiple clinical variants.

Secukinumab provides sustained PASDAS-defined remission in psoriatic arthritis and improves health-related quality of life in patients achieving remission: 2-year results from the phase III FUTURE 2 study.

BACKGROUND: Secukinumab has demonstrated sustained improvement in the signs and symptoms of psoriatic arthritis (PsA) over 2 years in the FUTURE 2 study (NCT01752634). This post hoc analysis assessed the ability of secukinumab to achieve Psoriatic Arthritis Disease Activity Score (PASDAS)-based remission or low disease activity (LDA) through 2 years among patients with PsA in the FUTURE 2 study. METHODS: PASDAS (cut-off scores: remission ≤ 1.9; LDA > 1.9 and < 3.2; Moderate Disease Activity ≥ 3.2 and < 5.4; and high disease activity [HDA] ≥ 5.4) was assessed in the overall population (tumour necrosis factor inhibitor [TNFi]-naïve and TNFi-experienced), in patients stratified by prior TNFi use and by disease duration at weeks 16, 52 and 104. The impact of secukinumab on individual PASDAS core components and on the relationship between PASDAS states and patient-reported outcomes (PROs), including physical function, health-related quality of life (HRQoL) and work productivity, were also assessed. Data for the approved doses of secukinumab (300 and 150 mg) are reported. PASDAS scores and core components were reported as observed, and PROs were analysed using mixed models for repeated measures. RESULTS: In the overall population, PASDAS remission and LDA were achieved in 15.6% and 22.9%, respectively, of patients treated with secukinumab 300 mg and in 15.2% and 19.2%, respectively, in the secukinumab 150 mg group versus 2.3% and 13.8%, respectively, with placebo at week 16. In the TNFi-naïve group, a higher proportion of patients achieved remission + LDA at week 16 with secukinumab 300 and 150 mg (46.2% and 42.9%, respectively) versus placebo (17.5%), with corresponding responses in TNFi-experienced patients being 22.6% and 19.4% versus 13.3%. Remission/LDA responses with secukinumab were sustained through 2 years. Patients achieving remission/LDA reported greater improvements in PROs than patients in HDA through 2 years. CONCLUSIONS: Secukinumab-treated patients achieved higher PASDAS-defined remissions or LDA compared with placebo at week 16, which were sustained through 2 years. Remission/LDA was achieved by both TNFi-naïve and TNFi-experienced patients treated with secukinumab, with higher rates in TNFi-naïve patients. Secukinumab-treated patients achieving remission/LDA reported significantly greater improvements in PROs, including physical function and different dimensions of health-related quality of life and work, than patients in HDA. TRIAL REGISTRATION: ClinicalTrials.gov, NCT01752634 . Registered on December 19, 2012. EUDRACT, 2012-004439-22 . Registered on December 12, 2012.

A suite-level review of the neutron single-crystal diffraction instruments at Oak Ridge National Laboratory.

The nascent suite of single-crystal neutron diffractometers at the Oak Ridge National Laboratory has no equal at any other neutron scattering facility worldwide and offers the potential to re-assert single-crystal diffraction using neutrons as a significant tool to study nuclear and magnetic structures of small unit cell crystals, nuclear structures of macromolecules, and diffuse scattering. Signature applications and features of single-crystal neutron diffraction are high resolution nuclear structure analysis, magnetic structure and spin density determinations, contrast variation (particularly D2O/H2O) for nuclear structural studies, lack of radiation damage when using crystals of biological molecules such as proteins, and the fidelity to measure nuclear and magnetic diffuse scattering with elastic discrimination.

Assessment of two screening tools to identify psoriatic arthritis in patients with psoriasis.

BACKGROUND: Many patients with psoriasis have undiagnosed psoriatic arthritis. Low specificity is found with many PsA screening tools. A new instrument, the CONTEST questionnaire, was developed utilizing the most discriminative items from existing instruments. OBJECTIVE: The aim of this study was to compare the CONTEST and PEST screening tools. METHODS: People attending secondary care clinics with psoriasis, but not PsA, completed the questionnaires, were assessed for function and quality of life, and had a physical examination. Patients thought to have PsA were compared to those without. The performance of CONTEST and PEST was compared using area under the receiver operating curve (AUC), and sensitivity and specificity at the previously published cut-offs. RESULTS: A total of 451 dermatology patients were approached, 35% were reviewed and 27 (17%, 95% CI 12.3-21.7) had unidentified psoriatic arthritis. The sensitivity and specificity (95% CI) of PEST were 0.60 (0.42-0.78)/0.76 (0.69-0.83) and for CONTEST 0.53 (0.34-0.72)/0.71 (0.63-0.79). The confidence limits for the AUC overlapped (AUC for PEST 0.72 (0.61-0.84), for CONTEST 0.66 (0.54-0.77). CONCLUSIONS: PEST and CONTEST questionnaires performed equally well, with no superiority of the new CONTEST tool.

Structural studies of substrate and product complexes of 5-aminolaevulinic acid dehydratase from humans, Escherichia coli and the hyperthermophile Pyrobaculum calidifontis.

A number of X-ray analyses of an enzyme involved in a key early stage of tetrapyrrole biosynthesis are reported. Two structures of human 5-aminolaevulinate dehydratase (ALAD), native and recombinant, have been determined at 2.8 Šresolution, showing that the enzyme adopts an octameric quaternary structure in accord with previously published analyses of the enzyme from a range of other species. However, this is in contrast to the finding that a disease-related F12L mutant of the human enzyme uniquely forms hexamers [Breinig et al. (2003), Nature Struct. Biol. 10, 757-763]. Monomers of all ALADs adopt the TIM-barrel fold; the subunit conformation that assembles into the octamer includes the N-terminal tail of one monomer curled around the (α/ß)8 barrel of a neighbouring monomer. Both crystal forms of the human enzyme possess two monomers per asymmetric unit, termed A and B. In the native enzyme there are a number of distinct structural differences between the A and B monomers, with the latter exhibiting greater disorder in a number of loop regions and in the active site. In contrast, the second monomer of the recombinant enzyme appears to be better defined and the active site of both monomers clearly possesses a zinc ion which is bound by three conserved cysteine residues. In native human ALAD, the A monomer also has a ligand resembling the substrate ALA which is covalently bound by a Schiff base to one of the active-site lysines (Lys252) and is held in place by an ordered active-site loop. In contrast, these features of the active-site structure are disordered or absent in the B subunit of the native human enzyme. The octameric structure of the zinc-dependent ALAD from the hyperthermophile Pyrobaculum calidifontis is also reported at a somewhat lower resolution of 3.5 Å. Finally, the details are presented of a high-resolution structure of the Escherichia coli ALAD enzyme co-crystallized with a noncovalently bound moiety of the product, porphobilinogen (PBG). This structure reveals that the pyrrole side-chain amino group is datively bound to the active-site zinc ion and that the PBG carboxylates interact with the enzyme via hydrogen bonds and salt bridges with invariant residues. A number of hydrogen-bond interactions that were previously observed in the structure of yeast ALAD with a cyclic intermediate resembling the product PBG appear to be weaker in the new structure, suggesting that these interactions are only optimal in the transition state.

Comparison of screening questionnaires to identify psoriatic arthritis in a primary-care population: a cross-sectional study.

BACKGROUND: Many questionnaires are available for assessment of psoriatic arthritis (PsA), but there is little evidence comparing them. OBJECTIVES: To test the proposed CONTEST questionnaire, which was developed to identify patients with psoriasis who have undiagnosed PsA, and compare it with the validated Psoriasis Epidemiology Screening Tool (PEST) questionnaire in a primary-care setting. METHODS: A random sample of adult patients with psoriasis and no diagnosis of arthritis was identified from five general practice surgeries in Yorkshire, U.K. Consenting patients completed both questionnaires and were assessed by a dermatologist and rheumatologist. Diagnosis of PsA was made by the assessing rheumatologist. Receiver operator characteristic (ROC) curve analysis examined the sensitivity and specificity of potential cut points. RESULTS: In total 932 packs were sent to recruit 191 (20·5%) participants. Of these, 169 (88·5%) were confirmed to have current or previous psoriasis. Using physician diagnosis 17 (10·1%) were found to have previously undiagnosed PsA, while 90 (53·3%) had another musculoskeletal complaint and 62 (36·7%) had no musculoskeletal problems. Using ROC curve analysis, all of the questionnaires showed a significant ability to identify PsA. The area under the curve (AUC) for the CONTEST questionnaires was slightly higher than that of PEST (0·69 and 0·70 vs. 0·65), but there was no significant difference identified. Examining the sensitivities and specificities for the different cut points suggested that a PEST score ≥ 2 would perform better in this dataset, and the optimal scores for CONTEST and CONTEST plus joint manikin were 3 and 4, respectively. CONCLUSIONS: The accuracy of the questionnaires to identify PsA appeared similar, with a slightly higher AUC for the CONTEST questionnaires. The optimal cut points in this study appeared lower than in previous studies.

Integrative review on the non-invasive management of lower urinary tract symptoms in men following treatments for pelvic malignancies.

AIM: To develop a non-invasive management strategy for men with lower urinary tract symptoms (LUTS) after treatment for pelvic cancer, that is suitable for use in a primary healthcare context. METHODS: PubMed literature searches of LUTS management in this patient group were carried out, together with obtaining a consensus of management strategies from a panel of authors for the management of LUTS from across the UK. RESULTS: Data from 41 articles were investigated and collated. Clinical experience was sought from authors where there was no clinical evidence. The findings discussed in this paper confirm that LUTS after the cancer treatment can significantly impair men's quality of life. While many men recover from LUTS spontaneously over time, a significant proportion require long-term management. Despite the prevalence of LUTS, there is a lack of consensus on best management. This article offers a comprehensive treatment algorithm to manage patients with LUTS following pelvic cancer treatment. CONCLUSION: Based on published research literature and clinical experience, recommendations are proposed for the standardisation of management strategies employed for men with LUTS after the pelvic cancer treatment. In addition to implementing the algorithm, understanding the rationale for the type and timing of LUTS management strategies is crucial for clinicians and patients.