Phase 2 Trial of Deucravacitinib in Psoriatic Arthritis: Biomarkers Associated With Disease Activity, Pharmacodynamics, and Clinical Responses.

OBJECTIVE: To evaluate the association of serum biomarkers with baseline psoriatic arthritis (PsA) disease activity, pharmacodynamic effects of deucravacitinib on biomarker levels, and relationship between biomarkers and clinical responses to deucravacitinib. METHODS: The phase 2 trial (NCT03881059) randomized 203 patients with PsA 1:1:1 to placebo, deucravacitinib 6 mg once daily (QD), or deucravacitinib 12 mg QD. Serum biomarkers associated with the IL-23 pathway (IL-17A, BD-2, and IL-19), Type I interferon pathway, inflammation, and collagen matrix turnover were measured by immunoassay. Clinical responses (≥75% improvement from baseline in Psoriasis Area and Severity Index [PASI 75] and ≥20% improvement from baseline in American College of Rheumatology [ACR 20] criteria responses) were measured at week 16. Hematologic variables were also assessed. RESULTS: IL-17A, BD-2, and IL-19 had a modest association with PASI scores (r=0.4, r=0.56, and r=0.5, respectively) at baseline. In deucravacitinib groups, IL-17A, BD-2, IL-19, CXCL-9, CXCL-10, CRP, MMP3, and C4M levels were significantly reduced at week 16 versus baseline (P<0.01); higher levels of IL-23 pathway-associated biomarkers predicted higher PASI 75 and ACR 20 response rates in deucravacitinib-treated patients. Significantly higher PASI 75 response rates were seen in patients with high baseline IL-17A (OR: 15.76) and BD-2 (OR: 15.41) versus low. Changes in hematologic variables that are characteristic of JAK inhibition were not observed with deucravacitinib. CONCLUSION: Deucravacitinib significantly impacted biomarkers associated with TYK2 signaling pathways of key inflammatory cytokines, including IL-23 and Type I IFN, and those related to collagen matrix turnover. These biomarkers may predict treatment responses to deucravacitinib.

Improvements in Patient-Reported Outcomes After Treatment With Deucravacitinib in Patients With Psoriatic Arthritis: Results From a Randomized Phase 2 Trial.

OBJECTIVE: Deucravacitinib, a tyrosine kinase 2 inhibitor, was assessed in a phase 2 trial in patients with active psoriatic arthritis (PsA). Here, we report effects of deucravacitinib from the patient perspective. METHODS: This phase 2, double-blind trial (NCT03881059) randomized patients with active PsA 1:1:1 to deucravacitinib 6 mg once daily (QD), 12 mg QD, or placebo, for 16 weeks. Key secondary end points were changes from baseline (CFBs) at week 16 in Health Assessment Questionnaire-Disability Index (HAQ-DI) and 36-item Short-Form Health Survey (SF-36) physical component summary (PCS) scores. Additional patient-reported outcomes (PROs) assessed disease impact, including fatigue, pain, and mental health. The mean CFBs in PROs and percentages of patients reporting improvements with minimum clinically important differences (MCIDs) or scores of greater than normal values were also assessed. RESULTS: This study comprised 203 patients (51.2% female; mean ± SD age, 49.8 ± 13.5 years). At week 16, the adjusted mean difference (95% confidence interval) versus placebo in HAQ-DI and SF-36 PCS CFB was significant for each deucravacitinib group (HAQ-DI 6 mg, -0.26 [-0.42 to -0.10], P = 0.0020; HAQ-DI 12 mg, -0.28 [-0.45 to -0.12], P = 0.0008; SF-36 PCS 6 mg, 3.3 [0.9 to 5.7], P = 0.0062; SF-36 PCS 12 mg, 3.5 [1.1 to 5.9], P = 0.0042). MCID at week 16 were reported for all PROs with either dose of deucravacitinib. Improvements of MCID or to normative values were reported by more patients receiving deucravacitinib than placebo. CONCLUSION: Deucravacitinib groups demonstrate significant and clinically meaningful improvements in PROs versus placebo in patients with active PsA, which warrants further study.

Leptin receptor gene polymorphisms in kidney transplant patients with post-transplant diabetes mellitus treated with tacrolimus.

Post-transplant diabetes mellitus (PTDM) is a metabolic complication that often occurs after kidney transplantation. Factors that increase the risk of this complication are currently being researched, including polymorphisms in genes affecting carbohydrate-lipid metabolism. Leptin is a hormone that affects appetite and adipose tissue and plays an important role in regulating insulin secretion as well as glucose and lipid metabolism. The aim of this study was to examine the association between leptin receptor gene polymorphisms and the development of post-transplant diabetes mellitus in patients treated with tacrolimus. The study was carried out in a group of 201 patients who underwent kidney transplantation. The follow-up period was 12 months. PTDM was diagnosed in 35 patients. Analysing the LEPR gene rs1137101 polymorphism, we observed in patients with PTDM an increased frequency of GG genotype carriers (GG vs AA, OR 3.36; 95 % CI 0.99-11.46; p = 0.04). There were no statistically significant differences in the distribution of the LEPR rs1137100 and LEPR rs1805094 polymorphisms between patients with and without PTDM. Multivariate regression analysis confirmed that female sex, advanced age, increased BMI and a higher number of LEPR rs1137101 G alleles were independent risk factors for PTDM development. The risk of PTDM development was almost 3.5 times greater in LEPR rs1137101 G allele carriers than in AA homozygotes (GG + AG vs AA; OR 3.48; 95 %CI (1.09-11.18), p = 0.035). The results suggest that patients after kidney transplantation with the LEPR gene rs1137101 G allele may have an increased risk of post-transplant diabetes development.

The Association between CDKAL1 Gene rs10946398 Polymorphism and Post-Transplant Diabetes in Kidney Allograft Recipients Treated with Tacrolimus.

Post-transplant diabetes mellitus (PTDM) is a common complication that occurs in kidney transplant patients, increasing the risk of infection, cardiovascular disease and loss of graft function. Currently, factors that increase the risk of this complication are being sought, among them polymorphisms in genes that regulate carbohydrate metabolism and influence pancreatic ß-cell function. The aim of this study was to evaluate the association of selected polymorphisms of genes affecting carbohydrate metabolism, such as CDKAL1 rs10946398, GCK rs1799884, GCKR rs780094 and DGKB/TMEM195 rs2191349, with the development of post-transplant diabetes in kidney transplant patients. This study included 201 Caucasian patients after kidney transplantation treated with tacrolimus. An association was observed between the CDKAL1 rs10946398 gene polymorphism and PTDM. Among patients with PTDM, there was an increased prevalence of the CC genotype in the PTDM group compared to the group without PTDM. The chance of PTDM in those with the CC genotype was 2.60 times higher compared to those with the AC + AA genotypes (CC vs. AC + AA OR (95% CI): 2.60 (1.02-6.61), p = 0.040). Multivariate logistic regression analysis showed that advanced age and the CC genotype (rare homozygote) of CDKAL1 rs10946398 were risk factors for the development of PTDM at 1 year after transplantation. There was no statistically significant association between GCK rs1799884, GCKR rs780094 or DGKB/TMEM195 rs2191349 polymorphisms and the development of post-transplant diabetes mellitus in kidney transplant patients. The results of this study suggest that the CDKAL1 rs10946398 CC genotype is associated with the increased risk of PTDM development in patients after kidney graft transplantation treated with tacrolimus.

Evaluation of BMS-986142, a reversible Bruton's tyrosine kinase inhibitor, for the treatment of rheumatoid arthritis: a phase 2, randomised, double-blind, dose-ranging, placebo-controlled, adaptive design study.

BACKGROUND: Bruton's tyrosine kinase (BTK) is a promising biological target for rheumatoid arthritis treatment. This study examined safety, efficacy, and pharmacokinetics of BMS-986142, an oral, reversible BTK inhibitor. The aim was to compare the efficacy of BMS-986142 with placebo on a background of methotrexate in patients with moderate-to-severe rheumatoid arthritis and inadequate response to methotrexate. METHODS: This phase 2, randomised, double-blind, dose-ranging, placebo-controlled, adaptive design study was conducted across 14 countries and 79 clinical sites. We recruited people aged 18 years or older with a documented diagnosis of rheumatoid arthritis at least 16 weeks before screening with an inadequate response to methotrexate with or without inadequate response to up to two tumour necrosis factor inhibitors. Participants were randomly assigned (1:1:1:1) to oral BMS-986142 (100 mg, 200 mg, or 350 mg) or placebo once daily for 12 weeks. Randomisation was done using an interactive voice response system and stratified by prior treatment status and geographical region. All participants, care providers, investigators, and outcome assessors were masked to treatment allocation. Co-primary endpoints were 20% and 70% improvement in American College of Rheumatology criteria (ACR20 and ACR70) at week 12. Primary endpoints were assessed in the efficacy analysis population (all randomised patients who received at least one dose of the study drug and did not discontinue the study). Safety endpoints were analysed in the as-treated analysis population, which included all patients who received at least one dose of the study drug (patients were grouped according to the treatment they actually received vs the treatment to which they were randomised). This trial was registered with ClinicalTrials.gov, number NCT02638948. FINDINGS: Between Feb 24, 2016 and May 3, 2018, 248 patients were randomised (73 in the BMS-986142 100 mg group, 73 in the 200 mg group, 26 in the 350 mg group, and 75 in the placebo group; one post-randomisation exclusion); mean age was 56·7 years (SD 12·7); 214 (87%) of 247 were women, 33 (13%) were men, and 188 (76%) were White. Pre-specified interim analysis resulted in discontinuation of the 350 mg BMS-986142 dose due to elevated liver enzymes and absence of benefit versus placebo. Co-primary endpoints were not met. Response rates for ACR20 (placebo: 23 [31%] of 75; 100 mg: 26 [36%] of 73; 200 mg: 31 [42%] of 73) and ACR70 (placebo: three [4%] of 75; 100 mg: three [4%] of 73; 200 mg: seven [10%] of 73) were not significantly different to placebo; estimate of difference versus placebo for ACR20 was 4·9 (95% CI -10·2 to 20·1; p=0·52) for 100 mg and 11·8 (-3·6 to 27·2; p=0·14) for 200 mg, and for ACR70 the estimate of difference was 0·1 (-16·0 to 16·5; nominal p=1·00) for 100 mg and 5·6 (-10·5 to 21·9; nominal p=0·21) for 200 mg. Six patients experienced serious adverse events (four in the placebo group [mouth ulceration, open globe injury, rheumatoid arthritis flare, and endometrial adenocarcinoma] and two in the BMS-986142 100 mg group [angina pectoris and intestinal obstruction]); there were no deaths. INTERPRETATION: Further investigation of BMS-986142 in people with rheumatoid arthritis is not warranted. An absence of clinical benefit in this study, together with other study results, highlights the need for additional research on the extent of BTK inhibition, treatment duration, and adequacy of drug distribution to inflammation sites, to understand the potential utility of BTK inhibition as a therapeutic strategy for rheumatoid arthritis. FUNDING: Bristol Myers Squibb.

Robots in Eldercare: How Does a Real-World Interaction with the Machine Influence the Perceptions of Older People?

(1) Background: Using autonomous social robots in selected areas of care for community-dwelling older adults is one of the promising approaches to address the problem of the widening care gap. We posed the question of whether a possibility to interact with the technology to be used had an impact on the scores given by the respondents in various domains of needs and requirements for social robots to be deployed in care for older individuals. (2) Methods: During the study, the opinions of older people (65+; n = 113; with no severe cognitive impairment) living in six social care institutions about a robot in care for older people were collected twice using the Users' Needs, Requirements and Abilities Questionnaire (UNRAQ): after seeing a photo of the robot only and after a 90−150 min interaction with the TIAGo robot. (3) Results: Mean total scores for both assistive and social functions were higher after the interaction (p < 0.05). A positive correlation was found between opinion changes in social and assistive functions (r = 0.4842; p = 0.0000). (4) Conclusions: Preimplementation studies and assessments should include the possibility to interact with the robot to provide its future users with a clear idea of the technology and facilitate necessary customisations of the machine.

Efficacy and safety of selective TYK2 inhibitor, deucravacitinib, in a phase II trial in psoriatic arthritis.

OBJECTIVE: To evaluate the efficacy and safety of an oral selective tyrosine kinase 2 (TYK2) inhibitor, deucravacitinib, in patients with active psoriatic arthritis (PsA). METHODS: In this double-blind, phase II trial, 203 patients with PsA were randomised 1:1:1 to placebo, deucravacitinib 6 mg once a day or 12 mg once a day. The primary endpoint was American College of Rheumatology-20 (ACR-20) response at week 16. RESULTS: ACR-20 response was significantly higher with deucravacitinib 6 mg once a day (52.9%, p=0.0134) and 12 mg once a day (62.7%, p=0.0004) versus placebo (31.8%) at week 16. Both deucravacitinib doses resulted in significant improvements versus placebo (p≤0.05) in the multiplicity-controlled secondary endpoints of change from baseline in Health Assessment Questionnaire-Disability Index and Short Form-36 Physical Component Summary score and in Psoriasis Area and Severity Index-75 response. Improvements were also seen in multiple exploratory endpoints with deucravacitinib treatment. The most common adverse events (AEs) (≥5%) in deucravacitinib-treated patients were nasopharyngitis, upper respiratory tract infection, sinusitis, bronchitis, rash, headache and diarrhoea. There were no serious AEs and no occurrence of herpes zoster, opportunistic infections and major adverse cardiovascular events, or differences versus placebo in mean changes in laboratory parameters with deucravacitinib treatment. CONCLUSIONS: Treatment with the selective TYK2 inhibitor deucravacitinib was well tolerated and resulted in greater improvements than placebo in ACR-20, multiplicity-controlled secondary endpoints and other exploratory efficacy measures in patients with PsA. Larger trials over longer periods of time with deucravacitinib are warranted to confirm its safety profile and benefits in PsA. TRIAL REGISTRATION NUMBER: NCT03881059.

Model-Based Meta-Analysis Compares DAS28 Rheumatoid Arthritis Treatment Effects and Suggests an Expedited Trial Design for Early Clinical Development.

A nonlinear mixed effects modeling approach was used to conduct a model-based meta-analysis (MBMA) of longitudinal, summary-level, baseline-corrected 28-joint Disease Activity Score (ΔDAS28) clinical trial data from seven approved rheumatoid arthritis (RA) drugs (abatacept, adalimumab, certolizumab, etanercept, rituximab, tocilizumab, and tofacitinib), representing 130 randomized clinical trials in 27,355 patients. All of the drugs except tocilizumab were found to have relatively similar ΔDAS28 time courses and efficacy (baseline-corrected and placebo-corrected) at 24 weeks and beyond of approximately 0.87-1.3 units in the typical RA patient population. Tocilizumab was estimated to have a differentially greater response of 1.99 at 24 weeks, likely due to its disproportionate effect on the acute-phase cytokine interleukin-6. Baseline DAS28, disease duration, percentage of male participants, and the year of conduct of the trial were found to have statistically significant effects on the timing and/or magnitude of ΔDAS28 in the control arms. Clinical trial simulations using the present MBMA indicated that abatacept, certolizumab, etanercept, tocilizumab, and tofacitinib would be expected to have a greater than 70% probability of showing a statistically significant difference vs. control at Week 6 with a sample size of ~ 30 patients per arm. In future RA clinical trials, an interim analysis conducted as early as 6 weeks after treatment initiation, with relatively small sample sizes, should be sufficient to detect the ΔDAS28 treatment effect vs. placebo.

Patient's experience of psoriatic arthritis: a conceptual model based on qualitative interviews.

INTRODUCTION: Psoriatic arthritis (PsA) is a heterogeneous chronic inflammatory musculoskeletal disorder that manifests as peripheral arthritis, dactylitis, enthesitis and spondylitis. PsA results in significant burden that impacts quality of life of patients. We examined the signs, symptoms and impacts reported by patients with PsA, to characterise the patient experience of PsA and develop a conceptual model representing this patient experience. METHODS: Semi-structured interviews were conducted with patients with PsA recruited through the FORWARD databank. Spontaneous and probed signs, symptoms and impacts of PsA were assessed. Patients rated the disturbance of these concepts on their lives using a scale from 0 ('does not disturb') to 10 ('greatly disturbs'). Signs, symptoms and impacts reported by >80% of patients with a disturbance rating of ≥5 were defined as salient concepts. Recruitment continued until concept saturation was achieved. RESULTS: 19 patients with PsA were interviewed. The interviews elicited 42 symptoms of which 8 had not been identified in a previous literature review encompassing 15 relevant articles. The most salient signs and symptoms elicited in the interviews were joint pain, skin symptoms, stiffness, swollen/inflamed joints and fatigue all with moderate to high disturbance ratings (range: 5.5-7.8). The most salient impacts were sleep disturbance, physical disability, effects on daily activities and feelings of frustration with also moderate to high disturbance ratings (range: 6.1-7.4). CONCLUSIONS: The interviews highlighted the adverse impact PsA has on the patient's life and may inform on outcome variables or areas suitable to be assessed in PsA studies.

Safety, pharmacokinetics and pharmacodynamics of branebrutinib (BMS-986195), a covalent, irreversible inhibitor of Bruton's tyrosine kinase: Randomised phase I, placebo-controlled trial in healthy participants.

AIMS: Branebrutinib (BMS-986195) is a potent, highly selective, oral, small-molecule, covalent inhibitor of Bruton's tyrosine kinase (BTK). This study evaluated safety, pharmacokinetics and pharmacodynamics of branebrutinib in healthy participants. METHODS: This double-blind, placebo-controlled, single- and multiple-ascending dose (SAD; MAD) Phase I study (NCT02705989) enrolled participants into 3 parts: SAD, MAD and JMAD (MAD in first-generation Japanese participants). In each part, participants were randomised 3:1 to receive branebrutinib (SAD: 0.3-30 mg; [J]MAD: 0.3-10 mg) or placebo. Participants in the MAD parts received branebrutinib daily for 14 days and were followed for 14 days postdosing. Safety was assessed by monitoring, laboratory and physical examinations, vital signs, and recording adverse events (AEs). Pharmacodynamics were assessed with a mass spectrometry assay that measured drug-occupied and free BTK. RESULTS: The SAD, MAD and JMAD parts of the study included 40, 32 and 24 participants. Branebrutinib was well tolerated and AEs were mild/moderate, except for 1 serious AE that led to discontinuation. Branebrutinib was rapidly absorbed, with maximum plasma concentration occurring within 1 hour and a half-life of 1.2-1.7 hours, dropping to undetectable levels within 24 hours. BTK occupancy was rapid, with 100% occupancy reached after a single 10-mg dose. BTK occupancy decayed predictably over time (mean half-life in MAD panels: 115-154 hours), such that pharmacodynamic effects were maintained after branebrutinib plasma levels fell below the lower limit of quantification. CONCLUSION: Rapid and high occupancy of BTK and the lack of notable safety findings support further clinical development of branebrutinib.

Occupational Therapy Students' Perceptions of the Role of Robots in the Care for Older People Living in the Community.

BACKGROUND: The question arises how recent developments in robotics can contribute to the care for older people. The study is part of the EU-funded ENRICHME project. OBJECTIVES OF STUDY: The aim of the study was to investigate opinions of occupational therapy students (OTS), as future professional caregivers, on the use of robots in care for older people. METHODS: It included 26 OTS from Poznan University of Medical Sciences. To collect data, the Users' Needs, Requirements, and Abilities Questionnaire (UNRAQ) was developed. FINDINGS: OTS perceived the robot as "a useful device" and "an assistant" rather than "a companion" (p < 0.01). In their opinion, the most important functions of the robot were related to health aspects (emergency alarms, health parameters monitoring, physical activity and memory training, and reminders about medication, drinks, etc.), scored positively by 23-26 OTS. Functions such as mood detection, encouraging to contact with friends, and monitoring of food consumption were accepted by 16-17 OTS. Two statements concerning social functions (accompanying in everyday activities and decreasing the sense of loneliness) were rated positively by less the than half of the participants. LIMITATIONS AND RECOMMENDATIONS FOR FURTHER RESEARCH: A module concerning technology use, including robotics, should constitute an important part of the curricula of both academic and continuous education of OTS.

Safety, pharmacokinetics, and pharmacodynamics of BMS-986142, a novel reversible BTK inhibitor, in healthy participants.

PURPOSE: BMS-986142 is an oral, small-molecule reversible inhibitor of Bruton's tyrosine kinase. The main objectives of our phase I studies were to characterize the safety and tolerability, pharmacokinetics, and pharmacodynamics of BMS-986142 in healthy participants, and to investigate the potential for the effect of BMS-986142 on the PK of methotrexate (MTX) in combination. METHODS: In a combined single ascending dose and multiple ascending dose study, the safety, pharmacokinetics, and pharmacodynamics of BMS-986142 were assessed in healthy non-Japanese participants following administration of a single dose (5-900 mg) or multiple doses (25-350 mg, once daily for 14 days). In a drug-drug interaction study, the effect of BMS-986142 (350 mg, once daily for 5 days) on the single-dose pharmacokinetics of MTX (7.5 mg) was assessed in healthy participants. RESULTS: BMS-986142 was generally well tolerated, alone and in combination with MTX. BMS-986142 was rapidly absorbed with peak concentrations occurring within 2 h, and was eliminated with a mean half-life ranging from 7 to 11 h. Exposure of BMS-986142 appeared dose proportional within the dose ranges tested. A dose- and concentration-dependent inhibition of CD69 expression was observed following administration of BMS-986142. BMS-986142 did not affect the pharmacokinetics of MTX. CONCLUSIONS: BMS-986142 was well tolerated at the doses tested, had pharmacokinetic and pharmacodynamic profiles which support once-daily dosing, and can be coadministered with MTX without the pharmacokinetic interaction of BMS-986142 on MTX.

Target volume for postoperative radiotherapy in non-small cell lung cancer: results from a prospective trial.

BACKGROUND AND PURPOSE: A previous prospective trial reported that three-dimensional conformal postoperative radiotherapy (PORT) for pN2 NSCLC patients using a limited clinical target volume (CTV) had a late morbidity rate and pulmonary function that did not differ from those observed in pN1 patients treated with surgery without PORT. The aim of this study was to assess locoregional control and localization of failure in patients treated with PORT. MATERIALS AND METHODS: The pattern of locoregional failure was evaluated retrospectively in 151 of 171 patients included in the PORT arm. The CTV included the involved lymph node stations and those with a risk of invasion >10%. Competing risk analysis was used to assess the incidence of locoregional failure and its location outside the CTV. RESULTS: Overall survival at 5years was 27.1% with a median follow-up of 67months for 40 living patients. The 5-year cumulative incidence of locoregional failure was 19.4% (95% CI: 18.2-20.5%) including a failure rate of 2% (95% CI: 0-17%) in locations outside or at the border of the CTV. CONCLUSIONS: The use of limited CTV was associated with acceptable risk of geographic miss. Overall locoregional control was similar to that reported by other studies using PORT for pN2 patients.

Cardiopulmonary morbidity and quality of life in non-small cell lung cancer patients treated with or without postoperative radiotherapy.

AIM: To prospectively assess the cardiopulmonary morbidity and quality of life in patients with non-small cell lung cancer (NSCLC) treated with postoperative radiotherapy (PORT) in comparison to those not receiving PORT. MATERIALS AND METHODS: From 2003 to 2007, 291 patients entered the study; 171 pN2 patients received 3D-planned PORT (PORT group), 120 pN1 patients (non-PORT group) did not. One month after surgery, all patients completed EORTC QLQ C-30 questionnaire and had pulmonary function tests (PFT); cardiopulmonary symptoms were assessed by modified LENT-SOM scale. Two years later, disease-free patients repeated the same examinations. The differences between baseline values and values recorded at two years in QLQ, LENT-SOM and the PFT of the two groups were compared. RESULTS: In the whole cohort, the rate of non-cancer related deaths was 5.3% and 5.0% in PORT and non-PORT group, respectively. Ninety-five patients (47 - PORT group, 48 - non-PORT group) were included into the final analysis. The differences in the QLQ and cardiopulmonary function (LENT/SOM, PFT) between both groups were insignificant. The forced expiratory volume in one second was on average 12.2% and 1.3% better in the PORT and the non-PORT group, respectively, p=0.2. CONCLUSIONS: Our findings support the hypothesis about insignificant morbidity of 3D-planned PORT.

Anti-N-methyl-D-aspartate receptor antibodies, cognitive dysfunction, and depression in systemic lupus erythematosus.

OBJECTIVE: To assess the association of cognitive dysfunction and depression with serum antibodies to N-methyl-D-aspartate (NMDA) receptor (anti-NR2) and analyze clinical and neuroimaging correlates in patients with systemic lupus erythematosus (SLE). METHODS: Sixty patients underwent neurocognitive assessment, evaluation for depression with the Beck Depression Inventory II (BDI-II) and psychiatric interview (Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition [DSM-IV] criteria), brain magnetic resonance imaging, and proton magnetic resonance spectroscopy imaging (1H-MRSI). Cognition was assessed in 5 domains: memory, attention/executive, visuospatial, motor, and psychomotor, and adjusted to each individual's best level of prior cognitive functioning estimated from the reading subtest of the Wide Range Achievement Test-3 (WRAT-3). Serum anti-NR2 antibodies were measured by enzyme-linked immunosorbent assay using a pentapeptide from the human NMDA receptor. RESULTS: Cognitive dysfunction was found in 28 of 60 patients (mild in 8, moderate in 20) before adjustment for WRAT-3 and in 35 of 60 patients (mild in 15, moderate in 11, and severe in 9) after adjustment for WRAT-3. The changes were most pronounced in the memory and visuospatial domains. There was no significant association between anti-NR2 antibody levels and cognition. On 1H-MRSI, patients with moderate or severe cognitive dysfunction had significantly higher choline:creatine ratios in the dorsolateral prefrontal cortex and the white matter, compared with patients with mild or absent cognitive dysfunction. Anti-NR2 antibodies were significantly correlated with BDI scores; patients with BDI-II scores of > or =14 had higher serum levels of anti-NR2 antibodies (P = 0.005, 95% confidence interval 0.83, 4.31), and there was a trend toward higher anti-NR2 antibody levels among patients who fulfilled the DSM-IV criteria for major depression. CONCLUSION: Serum anti-NR2 antibodies are associated with depressive mood but not with cognitive dysfunction in SLE at a given time point. Larger longitudinal studies are needed to address the possible association between anti-NR2 antibodies and depression in SLE.

Use of computerized assessment to predict neuropsychological functioning and emotional distress in patients with systemic lupus erythematosus.

OBJECTIVE: Cognitive dysfunction and neuropsychiatric disturbance are common in systemic lupus erythematosus (SLE). This study addressed the ability of the Automated Neuropsychological Assessment Metrics (ANAM), a computerized cognitive testing battery consisting of cognitive subtests, a sleepiness rating scale, and a mood scale, to predict neuropsychological status in patients with SLE. METHODS: Sixty individuals with SLE and no overt neuropsychiatric symptoms were administered ANAM to determine its validity as a screening measure of cognitive dysfunction and emotional distress in SLE. RESULTS: Performance on ANAM was compared with results of a consecutively administered, 2-hour battery of traditional neuropsychological tests and the Beck Depression Inventory II (BDI-II). Individual ANAM cognitive test scores were significantly correlated with most neuropsychological tests, particularly those measuring psychomotor processing speed and executive functioning. Using logistic regression, ANAM cognitive subtests successfully predicted individuals with SLE who had probable versus no impairment after controlling for premorbid levels of cognitive ability. Sensitivity of group classification was 76.2% and specificity was 82.8%, with 80% correct classification overall. ANAM's ability to predict neuropsychological functioning remained even after controlling for subjective reports of depressed mood and current sleepiness. Further, the ANAM mood scale was significantly correlated with the BDI-II (r = 0.67, P < 0.001), indicating its potential future use as a screening tool for emotional distress. CONCLUSION: ANAM shows promise as a time- and cost-efficient tool for screening and monitoring cognitive and emotional functioning in SLE, and can indicate when a more thorough neuropsychological investigation is warranted.

[Health resistance and its consequences for health education and promotion]. / "Opór zdrowotny" i jego konsekwencje dla edukacji i promocji zdrowia.

This paper presents analyses and discusses the phenomenon of 'health resistance' in health education and health promotion settings. The metaanalysis was used. British and American articles and books, published in the last ten years, were the materials. In particular, the concept of 'health resistance' is defined and its affinity with the psychological reactance theory is described. Finally, strategies and methods of reducing 'health resistance' in health education and health promotion are presented.

A pilot study of the use of 2-[18F]-fluoro-2-deoxy-D-glucose-positron emission tomography to assess the distribution of activated lymphocytes in patients with systemic lupus erythematosus.

OBJECTIVE: The 2-[(18)F]-fluoro-2-deoxy-D-glucose-positron emission tomography (FDG-PET) technique provides information on uptake and metabolism of glucose in various tissues. Compared with resting cells, activated lymphocytes take up radioactively labeled glucose analog at a higher rate, which makes it possible to identify lymphoid organs with higher concentrations of activated lymphocytes. This study was undertaken to compare the pattern of PET images and quantitative FDG uptake in lymphoid organs of patients with active systemic lupus erythematosus (SLE) versus patients with inactive SLE and to correlate these findings with peripheral blood lymphocyte phenotypes. METHODS: Ten patients with active SLE and 9 patients with inactive SLE were studied. FDG-PET images were obtained from the inguinal region to above the ear, starting at 60 minutes after injection of FDG. Standardized uptake values using lean body mass were determined over areas of interest. RESULTS: Both patients with active lupus and those with inactive lupus had increased FDG uptake in lymph nodes when compared with healthy volunteers, and there was no statistically significant difference between the 2 groups of lupus patients. Thymic uptake was demonstrated in 5 of 10 patients with active lupus compared with 0 of 9 patients with inactive disease. Three of the 5 patients with active SLE who were over 29 years of age had thymic uptake. Of the activation markers tested, only the CD3/CD71 population of cells was significantly different between the patient groups, with an increased percentage in the active disease group (P = 0.0247). CONCLUSION: Increased FDG uptake in lymph nodes of both patients with active SLE and patients with inactive SLE suggests that metabolic, and probably immunologic, activity is enhanced not only in active, but also in clinically quiescent, disease. The increased thymic uptake observed only in patients with active disease suggests that the thymus plays an important role during periods of disease activity.

De novo CIAS1 mutations, cytokine activation, and evidence for genetic heterogeneity in patients with neonatal-onset multisystem inflammatory disease (NOMID): a new member of the expanding family of pyrin-associated autoinflammatory diseases.

OBJECTIVE: Neonatal-onset multisystem inflammatory disease (NOMID; also known as chronic infantile neurologic, cutaneous, articular [CINCA] syndrome) is characterized by fever, chronic meningitis, uveitis, sensorineural hearing loss, urticarial skin rash, and a characteristic deforming arthropathy. We investigated whether patients with this disorder have mutations in CIAS1, the gene which causes Muckle-Wells syndrome and familial cold autoinflammatory syndrome, two dominantly inherited disorders with some similarities to NOMID/CINCA syndrome. METHODS: Genomic DNA from 13 patients with classic manifestations of NOMID/CINCA syndrome and their available parents was screened for CIAS1 mutations by automated DNA sequencing. Cytokine messenger RNA (mRNA) levels were assessed by real-time polymerase chain reaction on peripheral blood leukocyte mRNA, and serum cytokine levels were assayed by enzyme-linked immunosorbent assay. Protein expression was assessed by Western blotting of lysates from plastic-adherent peripheral blood mononuclear cells. RESULTS: In 6 of the 13 patients, we found 6 heterozygous missense substitutions in CIAS1. Five of the 6 mutations are novel. None of these sequence changes was observed in a panel of >900 chromosomes from healthy controls. Two distinct nucleotide changes in a single codon in unrelated patients resulted in the same amino acid change. In 4 mutation-positive children whose parental DNA was available, no mutation was found in the parental DNA, supporting the conclusion that the mutations arose de novo. Consistent with the recently discovered role of CIAS1 in the regulation of interleukin-1 (IL-1), we found evidence of increased IL-1beta, as well as tumor necrosis factor, IL-3, IL-5, and IL-6, but not transforming growth factor beta, in a mutation-positive patient compared with normal controls. CONCLUSION: Our data increase the total number of known germline mutations in CIAS1 to 20, causing a spectrum of diseases ranging from familial cold autoinflammatory syndrome to Muckle-Wells syndrome to NOMID/CINCA syndrome. Mutations in CIAS1 were only found in approximately 50% of the cases identified clinically as NOMID/CINCA syndrome, which raises the possibility of genetic heterogeneity. IL-1 regulation by CIAS1 suggests that IL-1 receptor blockade may constitute a rational approach to the treatment of NOMID/CINCA syndrome.