MRI-Targeted or Standard Biopsy in Prostate Cancer Screening.

BACKGROUND: High rates of overdiagnosis are a critical barrier to organized prostate cancer screening. Magnetic resonance imaging (MRI) with targeted biopsy has shown the potential to address this challenge, but the implications of its use in the context of organized prostate cancer screening are unknown. METHODS: We conducted a population-based noninferiority trial of prostate cancer screening in which men 50 to 74 years of age from the general population were invited by mail to participate; participants with prostate-specific antigen (PSA) levels of 3 ng per milliliter or higher were randomly assigned, in a 2:3 ratio, to undergo a standard biopsy (standard biopsy group) or to undergo MRI, with targeted and standard biopsy if the MRI results suggested prostate cancer (experimental biopsy group). The primary outcome was the proportion of men in the intention-to-treat population in whom clinically significant cancer (Gleason score ≥7) was diagnosed. A key secondary outcome was the detection of clinically insignificant cancers (Gleason score 6). RESULTS: Of 12,750 men enrolled, 1532 had PSA levels of 3 ng per milliliter or higher and were randomly assigned to undergo biopsy: 603 were assigned to the standard biopsy group and 929 to the experimental biopsy group. In the intention-to-treat analysis, clinically significant cancer was diagnosed in 192 men (21%) in the experimental biopsy group, as compared with 106 men (18%) in the standard biopsy group (difference, 3 percentage points; 95% confidence interval [CI], -1 to 7; P<0.001 for noninferiority). The percentage of clinically insignificant cancers was lower in the experimental biopsy group than in the standard biopsy group (4% [41 participants] vs. 12% [73 participants]; difference, -8 percentage points; 95% CI, -11 to -5). CONCLUSIONS: MRI with targeted and standard biopsy in men with MRI results suggestive of prostate cancer was noninferior to standard biopsy for detecting clinically significant prostate cancer in a population-based screening-by-invitation trial and resulted in less detection of clinically insignificant cancer. (Funded by the Swedish Research Council and others; STHLM3-MRI ClinicalTrials.gov number, NCT03377881.).

Tailoring biopsy strategy in the MRI-fusion prostate biopsy era: systematic, targeted or neither?

BACKGROUND: Magnetic  resonance imaging (MRI) followed by targeted biopsy (TBx) is utilized for prostate cancer (PCa) detection. However, the value of adding systematic biopsies (SBx) to targeted biopsy procedures (combined biopsy; CBx) in men with suspicious MRI findings has not been determined. METHODS: We analysed biopsy outcomes in 429 men with MRI lesions in the prospective multicenter STHLM3MRI pilot study, planned for prostate biopsy. Participants underwent 1.5T biparametric MRI without contrast enhancement, reported according to the PI-RADS v2, and with TBx plus SBx if the MRI lesion score was ≥ 3. The endpoints were clinically nonsignificant (nsPCa) and clinically significant PCa (csPCa), defined as ISUP grade groups 1 and ≥ 2, respectively. RESULTS: The median age was 65 years (59-70), and the median PSA 6.0 ng/ml (4.1-9.0). The detection rates of csPCa when using TBx or SBx combined were 18%, 46%, and 85% in men with PIRADS scores of 3 (n = 195), 4 (n = 121), and 5 (n = 113), respectively. This combined strategy detected csPCa in more men than TBx alone (43.6% vs 39.2%, p < 0.02), with similar detection of nsPCa (19.3% vs 17.7%, p = 0.2). In men with equivocal lesions (PI-RADS 3), the detection rates for csPCa were similar for the combined strategy and for TBx alone (17.9% and 15.4%, p = 0.06). However, there was an increase in the detection of nsPCa when using the combined strategy (21.0% vs 15.4%, p < 0.02). Men with equivocal lesions and a PSA density < 0.1 ng/ml2 or a Stockholm 3 test < 0.11 had a low risk of harboring csPCa. CONCLUSIONS: Supplementing targeted with systematic biopsies enhances clinically significant cancer detection. However, in men with equivocal lesions, this combination has potential for detecting nonsignificant disease. A subgroup of men with equivocal MRI findings may be identified as having a low risk for significant cancer and spared unnecessary biopsies.

Media use and trust during the COVID-19 pandemic: evidence from eight cross-sectional surveys in Sweden.

BACKGROUND: While a lot has been written about Sweden's COVID-19 control strategy, less is known about Swedish residents' media use during the pandemic and trust in and perceived agreement among key stakeholders commenting in the media. METHODS: Eight online, nationwide surveys were fielded between March and August 2020, during the first wave of the coronavirus pandemic in Sweden, with 8146 responses. Questions were asked on media usage, perceived tone of media, trust in key pandemic stakeholder groups commenting in the media (politicians, journalists, government officials, doctors/healthcare professionals and researchers) and perceived agreement among these key stakeholders about how the pandemic was handled in Sweden. RESULTS: Using five or more information sources was associated with increased perceived alarmism in the media. Women and those with tertiary education were more likely to trust key pandemic actors. Trust in doctors/healthcare professionals and researchers remained high over the course of the study, trust in politicians and journalists was relatively low throughout the study period, with a slight increase in April 2020. Trust in key stakeholders was strongly associated with perceived agreement among the key stakeholders. CONCLUSIONS: Our results show that trust in stakeholders was strongly associated with perceived consistency of messages from those stakeholders. The inverse also holds: perceived conflicting messages among stakeholders was associated with low trust in them. Taken together, this could point to the importance of building trust before a crisis. Trust-building efforts could be targeted to men and those with lower educational attainment, as they had lower trust in key stakeholders.

Prostate cancer screening using a combination of risk-prediction, MRI, and targeted prostate biopsies (STHLM3-MRI): a prospective, population-based, randomised, open-label, non-inferiority trial.

BACKGROUND: Screening for prostate cancer using prostate-specific antigen (PSA) reduces prostate cancer mortality but can lead to adverse outcomes. We aimed to compare a traditional screening approach with a diagnostic strategy of blood-based risk prediction combined with MRI-targeted biopsies. METHODS: We did a prospective, population-based, randomised, open-label, non-inferiority trial (STHLM3-MRI) in Stockholm county, Sweden. Men aged 50-74 years were randomly selected by Statistics Sweden and invited by mail to participate in screening; those with an elevated risk of prostate cancer, defined as either a PSA of 3 ng/mL or higher or a Stockholm3 score of 0·11 or higher were eligible for randomisation. Men with a previous prostate cancer diagnosis, who had undergone a prostate biopsy within 60 days before the invitation to participate, with a contraindication for MRI, or with severe illness were excluded. Eligible participants were randomly assigned (2:3) using computer-generated blocks of five, stratified by clinically significant prostate cancer risk, to receive either systematic prostate biopsies (standard group) or biparametric MRI followed by MRI-targeted and systematic biopsy in MRI-positive participants (experimental group). The primary outcome was the detection of clinically significant prostate cancer at prostate biopsy, defined as a Gleason score of 3 + 4 or higher. We used a margin of 0·78 to assess non-inferiority for the primary outcome. Key secondary outcome measures included the proportion of men with clinically insignificant prostate cancer (defined as a Gleason score of 3 + 3), and the number of any prostate MRI and biopsy procedures done. We did two comparisons: Stockholm3 (using scores of 0·11 and 0·15 as cutoffs) versus PSA in the experimental group (paired analyses) and PSA plus standard biopsy versus Stockholm3 plus MRI-targeted and systematic biopsy (unpaired, randomised analyses). All analyses were intention to treat. This study is registered with ClinicalTrials.gov, NCT03377881. FINDINGS: Between Feb 5, 2018, and March 4, 2020, 49 118 men were invited to participate, of whom 12 750 were enrolled and provided blood specimens, and 2293 with elevated risk were randomly assigned to the experimental group (n=1372) or the standard group (n=921). The area under the receiver-operating characteristic curve for detection of clinically significant prostate cancer was 0·76 (95% CI 0·72-0·80) for Stockholm3 and 0·60 (0·54-0·65) for PSA. In the experimental group, a Stockholm3 of 0·11 or higher was non-inferior to a PSA of 3 ng/mL or higher for detection of clinically significant prostate cancer (227 vs 192; relative proportion [RP] 1·18 [95% CI 1·09-1·28], p<0·0001 for non-inferiority), and also detected a similar number of low-grade prostate cancers (50 vs 41; 1·22 [0·96-1·55], p=0·053 for superiority) and was associated with more MRIs and biopsies. Compared with PSA of 3 ng/mL or higher, a Stockholm3 of 0·15 or higher provided identical sensitivity to detect clinically significant cancer, and led to fewer MRI procedures (545 vs 846; 0·64 [0·55-0·82]) and fewer biopsy procedures (311 vs 338; 0·92 (0·86-1·03). Compared with screening using PSA and systematic biopsies, a Stockholm3 of 0·11 or higher combined with MRI-targeted and systematic biopsies was associated with higher detection of clinically significant cancers (227 [3·0%] men tested vs 106 [2·1%] men tested; RP 1·44 [95% CI 1·15-1·81]), lower detection of low-grade cancers (50 [0·7%] vs 73 [1·4%]; 0·46 [0·32-0·66]), and led to fewer biopsy procedures. Patients randomly assigned to the experimental group had a lower incidence of prescription of antibiotics for infection (25 [1·8%] of 1372 vs 41 [4·4%] of 921; p=0·0002) and a lower incidence of admission to hospital (16 [1·2%] vs 31 [3·4%]; p=0·0003) than those in the standard group. INTERPRETATION: The Stockholm3 test can inform risk stratification before MRI and targeted biopsies in prostate cancer screening. Combining the Stockholm3 test with an MRI-targeted biopsy approach for prostate cancer screening decreases overdetection while maintaining the ability to detect clinically significant cancer. FUNDING: The Swedish Cancer Society, the Swedish Research Council, and Stockholm City Council.

Upadacitinib improves patient-reported outcomes vs placebo or adalimumab in patients with rheumatoid arthritis: results from SELECT-COMPARE.

OBJECTIVE: To evaluate the impact of upadacitinib vs placebo and adalimumab treatment, on patient-reported outcomes (PROs) in SELECT-COMPARE in an active RA population with inadequate responses to MTX (MTX-IR). METHODS: PROs in patients receiving upadacitinib (15 mg QD), placebo, or adalimumab (40 mg EOW) while on background MTX were evaluated over 48 weeks. PROs included Patient Global Assessment of Disease Activity (PtGA) and pain by visual analogue scale (VAS), the HAQ Disability Index (HAQ-DI), the 36-Item Short Form Survey (SF-36), morning (AM) stiffness duration and severity, the Functional Assessment of Chronic Illness Therapy-Fatigue (FACIT-F), and work instability. Least squares mean (LSM) changes and proportions of patients reporting improvements ≥ minimal clinically important differences (MCIDs) and scores ≥ normative values were evaluated. RESULTS: Upadacitinib and adalimumab resulted in greater LSM changes from baseline vs placebo across all PROs (P < 0.05) at week 12, and pain and AM stiffness severity (P < 0.05) at week 2. More upadacitinib- vs placebo-treated (P < 0.05) and similar percentages of upadacitinib- vs adalimumab-treated patients reported improvements ≥ MCID across all PROs at week 12. Upadacitinib vs adalimumab resulted in greater LSM changes from baseline in PtGA, pain, HAQ-DI, stiffness severity, FACIT-F, and the SF-36 Physical Component Summary (PCS) (all P < 0.05) at week 12. More upadacitinib- vs adalimumab-treated patients reported scores ≥ normative values in HAQ-DI and SF-36 PCS (P < 0.05) at week 12. More upadacitinib- vs adalimumab-treated patients maintained clinically meaningful improvements in PtGA, pain, HAQ-DI, FACIT-F, and AM stiffness through 48 weeks. CONCLUSION: In MTX-IR patients with RA, treatment with upadacitinib resulted in statistically significant and clinically meaningful improvements in PROs equivalent to or greater than with adalimumab. TRIAL REGISTRATION: ClinicalTrials.gov, http://clinicaltrials.gov, NCT02629159.

Upadacitinib monotherapy improves patient-reported outcomes in rheumatoid arthritis: results from SELECT-EARLY and SELECT-MONOTHERAPY.

OBJECTIVE: To evaluate the effect of upadacitinib (UPA) monotherapy vs MTX on patient-reported outcomes (PROs) in patients with RA who were MTX-naïve or who had an inadequate response to MTX (MTX-IR). METHODS: PROs from the SELECT-EARLY and SELECT-MONOTHERAPY randomized controlled trials were evaluated at Weeks 2 and 12/14. Patients were ≥18 years of age with RA symptoms for ≥6 weeks (SELECT-EARLY, MTX-naïve) or diagnosed RA for ≥3 months (SELECT-MONOTHERAPY, MTX-IR) and received UPA monotherapy (15 or 30 mg) or MTX. PROs included Patient Global Assessment of Disease Activity (PtGA), pain visual analogue scale, HAQ Disability Index (HAQ-DI), morning stiffness duration/severity, Functional Assessment of Chronic Illness Therapy (FACIT)-Fatigue (SELECT-EARLY), health-related quality of life (HRQOL) by the 36-iem Short Form Health Survey and Work Productivity and Activity Impairment (WPAI; SELECT-EARLY). Least square mean (LSM) changes and proportions of patients reporting improvements greater than or equal to the minimum clinically important differences and normative values were determined. RESULTS: In 945 MTX-naïve and 648 MTX-IR patients, UPA monotherapy (15 mg, 30 mg) vs MTX resulted in greater reported LSM changes from baseline at Weeks 12/14 in PtGA, pain, HAQ-DI, morning stiffness duration/severity, FACIT-F (SELECT-EARLY), HRQOL and WPAI (SELECT-EARLY). These changes were statistically significant with both doses of UPA vs MTX at Weeks 12/14 in both RCTs. Improvements were reported as early as week 2. Compared with MTX, more UPA-treated MTX-naïve and MTX-IR patients reported improvements greater than or equal to the minimum clinically important differences and scores greater than or equal to normative values. CONCLUSION: Among MTX-naïve and MTX-IR patients with active RA, UPA monotherapy at 15 or 30 mg for 12/14 weeks resulted in statistically significant and clinically meaningful improvements in pain, physical function, morning stiffness, HRQOL and WPAI compared with MTX alone. CLINICAL TRIAL REGISTRATION NUMBER: SELECT-EARLY (NCT02706873) and SELECT-MONOTHERAPY (NCT02706951) are registered with ClinicalTrials.gov.

Seeing the world through the eyes of a butterfly: visual ecology of the territorial males of Pararge aegeria (Lepidoptera: Nymphalidae).

Combining studies of animal visual systems with exact imaging of their visual environment can get us a step closer to understand how animals see their "Umwelt". Here, we have combined both methods to better understand how males of the speckled wood butterfly, Pararge aegeria, see the surroundings of their perches. These males are well known to sit and wait for a chance to mate with a passing females, in sunspot territories in European forests. We provide a detailed description of the males' body and head posture, viewing direction, visual field and spatial resolution, as well as the visual environment. Pararge aegeria has sexually dimorphic eyes, the smallest interommatidial angles of males are around 1°, those of females 1.5°. Perching males face the antisolar direction with their retinal region of the highest resolution pointing at an angle of about 45° above the horizon; thus, looking at a rather even and dark background in front of which they likely have the best chance to detect a sunlit female passing through the sunspot.

Disease activity measures at baseline predict structural damage progression: data from the randomized, controlled AMPLE and AVERT trials.

OBJECTIVE: Data from two double-blind, randomized, Phase III studies were analysed to investigate the ability of Routine Assessment of Patient Index Data 3, DAS28 (CRP), modified (M)-DAS28 (CRP) and Simplified or Clinical Disease Activity Indices to predict structural damage progression in RA. METHODS: This post hoc analysis included data from the 2-year Abatacept vs adaliMumab comParison in bioLogic-naïvE RA subjects with background MTX (AMPLE) trial in biologic-naïve patients with active RA (<5 years) and an inadequate response to MTX, and the 12-month treatment period of the Assessing Very Early Rheumatoid arthritis Treatment (AVERT) trial in MTX-naïve patients with early RA (⩽2 years) and poor prognostic indicators. Adjusted logistic regression analysis assessed the relationship between baseline disease activity and structural damage progression (defined as change from baseline greater than the smallest detectable change) at 12 and 24 months in AMPLE and 6 and 12 months in AVERT. Areas under the receiver operating characteristic curves for the impact of baseline disease activity on structural damage progression were calculated. RESULTS: Adjusted logistic regression analyses included all randomized and treated patients in AMPLE (N = 646) and those who received abatacept plus MTX or MTX monotherapy in AVERT (N = 235). Baseline Routine Assessment of Patient Index Data 3, DAS28 (CRP) and M-DAS28 (CRP) scores significantly predicted structural progression at months 12 and 24 in AMPLE (P < 0.05) and months 6 and 12 in AVERT (P < 0.01), and were stronger predictors than Simplified or Clinical Disease Activity Indices. CONCLUSION: In this post hoc analysis of two patient populations with RA, Routine Assessment of Patient Index Data 3, DAS28 (CRP) and M-DAS28 (CRP) were good at predicting structural damage. TRIAL REGISTRATION: ClinicalTrials.gov, http://clinicaltrials.gov: NCT00929864 (AMPLE); NCT01142726 (AVERT).

Invasiveness and Metastatic Aggressiveness in Small Differentiated Thyroid Cancers: Demography of Small Papillary Thyroid Carcinomas in the Swedish Population.

BACKGROUND: The western world is seeing a rising incidence of thyroid cancer. Improved diagnostic methods do not entirely explain this increase. Papillary thyroid carcinoma (PTC) is the most common subtype of thyroid cancer. Small PTC (≤20 mm) and especially papillary thyroid microcarcinomas (PTMC ≤10 mm) are considered to be low-risk tumors but some cases are considerably more aggressive. Sufficient understanding of these mechanisms is a long-term goal for more efficient and safer treatment of these tumors. METHODS: We identified 959 cases of small PTCs in the validated Scandinavian Quality Register for Thyroid, Parathyroid and Adrenal Surgery, grouped according to lymph node metastasis. These were analyzed according to age, gender, tumor size and geographic region. RESULTS: Patients with N1b disease (lateral lymph nodes metastases) had a smaller tumor size compared to patients with N1a disease (8.6 mm vs 10.1 mm respectively, p < 0.05). Patients and specifically females with N1b disease were younger than those with N0 or N1a disease. Patients with N1b disease had a lower proportion of females (60%) compared to N0 and N1a groups (81% and 78%, respectively). The incidence of operated small PTCs and of lymph node engagement differs between geographic regions in Sweden. CONCLUSIONS: Small PTC and especially PTMC seem to show different patterns of aggressiveness and demography regarding lateral lymph node metastases and 7% had N1b disease and tumor <1 cm, underscoring the importance of lymph node evaluation in PTMC patients. More understanding of predictive factors, mechanisms for metastatic disease and causes of regional differences, is needed.

Osteoarthritis is as severe as rheumatoid arthritis: evidence over 40 years according to the same measure in each disease.

Osteoarthritis (OA) may be associated with substantial work disability, morbidity, costs, and increased mortality rates, often similar to rheumatoid arthritis (RA), documented in many published reports over the last 4 decades. However, OA generally has been viewed as less severe than RA. This discrepancy may be explained in part by:a) RA may have been considerably more severe in the past, prior to effective therapies.b) most older individuals have radiographic joint damage, which often is not associated with clinical symptoms.c) RA is associated with abnormal laboratory tests, which are regarded as conveying greater significance than symptoms of pain and disability according to a "biomedical model," the dominant paradigm of modern medicine.d) Most reports of OA and RA have emphasised differences between the 2 diseases even beyond laboratory abnormalities in pathogenesis, physical findings, and imaging.e) Even pain and functional disability seen in both diseases are assessed using different patient self-report questionnaires, a WOMAC (Western Ontario McMaster Universities osteoarthritis index) in OA, and HAQ (health assessment questionnaire) in RA.An identical measure is required for optimal direct comparisons, which has been used in 8 studies performed between 1979 and 2019 at 8 sites in North America, Europe, and Australia. These studies were primarily based on retrospective analyses at sites which collected a patient questionnaire in routine clinical care by all patients at all visits to inform clinical decisions. A pain visual analogue scale (VAS) was higher in OA compared to RA in 11/12 patient groups, while physical function on a HAQ (health assessment questionnaire) or derivative MDHAQ (multidimensional HAQ) and RAPID3 (routine assessment of patient index data) were slightly higher in RA before 2013 and higher in OA in later reports. Furthermore, a study of population-based data from the 1978 US Health Interview Survey indicated similar levels of disability and earnings losses according to surrogate variables for OA and RA. Therefore, at least over the last 40 years, pain and functional disability in OA have appeared to be severe and similar to RA. These observations also-illustrate the potential value of using an identical patient questionnaire in all patients at all visits in routine care settings, analogous to using the same laboratory tests such as erythrocyte sedimentation rate (ESR) or C-reactive protein (CRP) in all rheumatic diseases, and maintaining a database of the results for later analyses.

Cost per response for abatacept versus adalimumab in patients with seropositive, erosive early rheumatoid arthritis in the US, Germany, Spain, and Canada.

BACKGROUND: Effective treatment of rheumatoid arthritis (RA) with biologic DMARDs poses a significant economic burden. The AMPLE (Abatacept versus adaliMumab comParison in bioLogic-naïvE RA subjects with background methotrexate) trial was a head-to-head, randomized study comparing abatacept with adalimumab. A post hoc analysis showed improved efficacy for abatacept in patients with versus without seropositive, erosive early RA. OBJECTIVE: The aim of the current study was to evaluate the cost per response (ACR20/50/70/90 and HAQ-DI) and patient in remission (DAS28-CRP, CDAI, and SDAI) for abatacept relative to adalimumab, in patients with seropositive, erosive early RA in the US, Germany, Spain, and Canada. METHODS: A previously published model was used to compare abatacept and adalimumab in a cohort of 1000 patients over 2 years. Clinical inputs were updated based on two subpopulations from the AMPLE trial. Cohort 1 included patients with early RA (disease duration ≤ 6 months), RF and/or ACPA seropositivity, and > 1 radiographic erosion. Cohort 2 included patients with RA in whom at least one of these criteria was absent. RESULTS: For cohort 1, all incremental costs per additional health gain (patient response or patient in remission) favoured abatacept in all countries, except for DAS28-CRP remission in Canada. Cost savings versus adalimumab were greater when more stringent response criteria were applied and also in cohort 1 patient (versus cohort 2 patients). CONCLUSION: The cost per responder and patient in remission favoured abatacept in patients with seropositive, erosive early RA across all the countries. In this patient population, the use of abatacept instead of adalimumab can lead to lower costs in the US, Germany, Spain, and Canada.

Managing morbidity and treatment-related toxicity in patients with ankylosing spondylitis.

AS is the prototypical member of the family of spondyloarthropathies, and is characterized by seronegativity, axial predominance and new bone formation, which underlie symptoms of inflammatory back pain, enthesopathy and extra-articular manifestations, including anterior uveitis, psoriasis and colitis. Patients with AS typically experience a wide variety of morbidities. These include both morbidities related to the disease itself-most prominently progressive, irreversible, structural damage to the axial or peripheral skeleton-and morbidities stemming from treatments for the disease, including toxicities from NSAID use, and increased risk of infections and immunogenicity concerns with biologics. AS is also associated with a number of comorbidities. We review the risks associated with AS, its comorbidities and its treatments, as well as strategies that can be used to mitigate these risks in patients with AS.

Cost per response for abatacept versus adalimumab in rheumatoid arthritis by ACPA subgroups in Germany, Italy, Spain, US and Canada.

Rheumatoid arthritis (RA) is a chronic inflammatory disorder leading to disability and reduced quality of life. Effective treatment with biologic DMARDs poses a significant economic burden. The Abatacept versus Adalimumab Comparison in Biologic-Naïve RA Subjects with Background Methotrexate (AMPLE) trial was a head-to-head, randomized study comparing abatacept in serum anti-citrullinated protein antibody (ACPA)-positive patients, with increasing efficacy across ACPA quartile levels. The aim of this study was to evaluate the cost per response accrued using abatacept versus adalimumab in ACPA-positive and ACPA-negative patients with RA from the health care perspective in Germany, Italy, Spain, the US and Canada. A cost-consequence analysis (CCA) was designed to compare the monthly costs per responding patient/patient in remission. Efficacy, safety and resource use inputs were based on the AMPLE trial. A one-way deterministic sensitivity analysis (OWSA) was also performed to assess the impact of model inputs on the results for total incremental costs. Cost per response in ACPA-positive patients favoured abatacept compared with adalimumab (ACR20, ACR90 and HAQ-DI). Subgroup analysis favoured abatacept with increasing stringency of response criteria and serum ACPA levels. Cost per remission (DAS28-CRP) favoured abatacept in ACPA-negative patients, while cost per CDAI and SDAI favoured abatacept in ACPA-positive patients. Abatacept was consistently favoured in ACPA-Q4 patients across all outcomes and countries. Cost savings were greater with abatacept when more stringent response criteria were applied and also with increasing ACPA levels, which could lead to a lower overall health care budget impact with abatacept compared with adalimumab.

Treating rheumatoid arthritis to target: 2014 update of the recommendations of an international task force.

BACKGROUND: Reaching the therapeutic target of remission or low-disease activity has improved outcomes in patients with rheumatoid arthritis (RA) significantly. The treat-to-target recommendations, formulated in 2010, have provided a basis for implementation of a strategic approach towards this therapeutic goal in routine clinical practice, but these recommendations need to be re-evaluated for appropriateness and practicability in the light of new insights. OBJECTIVE: To update the 2010 treat-to-target recommendations based on systematic literature reviews (SLR) and expert opinion. METHODS: A task force of rheumatologists, patients and a nurse specialist assessed the SLR results and evaluated the individual items of the 2010 recommendations accordingly, reformulating many of the items. These were subsequently discussed, amended and voted upon by >40 experts, including 5 patients, from various regions of the world. Levels of evidence, strengths of recommendations and levels of agreement were derived. RESULTS: The update resulted in 4 overarching principles and 10 recommendations. The previous recommendations were partly adapted and their order changed as deemed appropriate in terms of importance in the view of the experts. The SLR had now provided also data for the effectiveness of targeting low-disease activity or remission in established rather than only early disease. The role of comorbidities, including their potential to preclude treatment intensification, was highlighted more strongly than before. The treatment aim was again defined as remission with low-disease activity being an alternative goal especially in patients with long-standing disease. Regular follow-up (every 1-3 months during active disease) with according therapeutic adaptations to reach the desired state was recommended. Follow-up examinations ought to employ composite measures of disease activity that include joint counts. Additional items provide further details for particular aspects of the disease, especially comorbidity and shared decision-making with the patient. Levels of evidence had increased for many items compared with the 2010 recommendations, and levels of agreement were very high for most of the individual recommendations (≥9/10). CONCLUSIONS: The 4 overarching principles and 10 recommendations are based on stronger evidence than before and are supposed to inform patients, rheumatologists and other stakeholders about strategies to reach optimal outcomes of RA.

Ion transport in polycarbonate based solid polymer electrolytes: experimental and computational investigations.

Among the alternative host materials for solid polymer electrolytes (SPEs), polycarbonates have recently shown promising functionality in all-solid-state lithium batteries from ambient to elevated temperatures. While the computational and experimental investigations of ion conduction in conventional polyethers have been extensive, the ion transport in polycarbonates has been much less studied. The present work investigates the ionic transport behavior in SPEs based on poly(trimethylene carbonate) (PTMC) and its co-polymer with ε-caprolactone (CL) via both experimental and computational approaches. FTIR spectra indicated a preferential local coordination between Li(+) and ester carbonyl oxygen atoms in the P(TMC20CL80) co-polymer SPE. Diffusion NMR revealed that the co-polymer SPE also displays higher ion mobilities than PTMC. For both systems, locally oriented polymer domains, a few hundred nanometers in size and with limited connections between them, were inferred from the NMR spin relaxation and diffusion data. Potentiostatic polarization experiments revealed notably higher cationic transference numbers in the polycarbonate based SPEs as compared to conventional polyether based SPEs. In addition, MD simulations provided atomic-scale insight into the structure-dynamics properties, including confirmation of a preferential Li(+)-carbonyl oxygen atom coordination, with a preference in coordination to the ester based monomers. A coupling of the Li-ion dynamics to the polymer chain dynamics was indicated by both simulations and experiments.

Limitations of clinical trials in chronic diseases: is the efficacy of methotrexate (MTX) underestimated in polyarticular psoriatic arthritis on the basis of limitations of clinical trials more than on limitations of MTX, as was seen in rheumatoid arthritis?

Clinical trials are the optimal method to establish efficacy of a drug versus placebo or another drug. Nonetheless, important limitations are seen, particularly in chronic diseases over long periods, although most are ignored. Pragmatic limitations of clinical trials include a relatively short observation period, suboptimal dosage schedules, suboptimal surrogate markers for long-term outcomes, statistically significant results which may not be clinically unimportant and vice versa. Even ideal clinical trials have intrinsic limitations, including the influence of design on results, data reported in groups which ignore individual variation, non-standard observer-dependent interpretation of a balance of efficacy and toxicity, and distortion of a "placebo effect." Limitations are seen in many clinical trials of methotrexate (MTX) in rheumatoid arthritis (RA) and psoriatic arthritis (PsA). The first MTX clinical trial in rheumatology documented excellent efficacy in PsA, but frequent adverse events in 1964, explained by intravenous doses up to 150 kg. MTX was abandoned until the 1980s for RA, while gold salts and penicillamine were termed "remission-inducing," on the basis limitations of clinical trials. In the most recent MTX in PsA (MIPA) trial, all outcomes favoured MTX, but only patient and physician global estimates met the p<0.05 criterion. A conclusion of "no evidence for MTX improving synovitis" appears explained by insufficient statistical power, wide individual variation, no subsets, low doses, and other limitations. MTX appears less efficacious in PsA than RA, but may be underestimated in PsA, similar to historical problems in RA, resulting more from limitations of clinical trials than from limitations of MTX.

The association of fatigue, comorbidity burden, disease activity, disability and gross domestic product in patients with rheumatoid arthritis. Results from 34 countries participating in the Quest-RA program.

OBJECTIVES: The aim is to assess the prevalence of comorbidities and to further analyse to which degree fatigue can be explained by comorbidity burden, disease activity, disability and gross domestic product (GDP) in patients with rheumatoid arthritis (RA). METHODS: Nine thousands eight hundred seventy-four patients from 34 countries, 16 with high GDP (>24.000 US dollars [USD] per capita) and 18 low-GDP countries (<24.000 USD) participated in the Quantitative Standard monitoring of Patients with RA (QUEST-RA) study. The prevalence of 31 comorbid conditions, fatigue (0-10 cm visual analogue scale [VAS] [10=worst]), disease activity in 28 joints (DAS28), and physical disability (Health Assessment Questionnaire score [HAQ]) were assessed. Univariate and multivariate linear regression analyses were performed to assess the association between fatigue and comorbidities, disease activity, disability and GDP. RESULTS: Overall, patients reported a median of 2 comorbid conditions of which hypertension (31.5%), osteoporosis (17.6%), osteoarthritis (15.5%) and hyperlipidaemia (14.2%) were the most prevalent. The majority of comorbidities were more common in high-GDP countries. The median fatigue score was 4.4 (4.8 in low-GDP countries and 3.8 in high-GDP countries, p<0.001). In low-GDP countries 25.4% of the patients had a high level of fatigue (>6.6) compared with 23.0% in high-GDP countries (p<0.001). In univariate analysis, fatigue increased with increasing number of comorbidities, disease activity and disability in both high- and low-GDP countries. In multivariate analysis of all countries, these 3 variables explained 29.4% of the variability, whereas GDP was not significant. CONCLUSIONS: Fatigue is a widespread problem associated with high comorbidity burden, disease activity and disability regardless of GDP.