Functional and Structural Connectivity Patterns Associated with Clinical Outcomes in Deep Brain Stimulation of the Globus Pallidus Internus for Generalized Dystonia.

BACKGROUND AND PURPOSE: Deep brain stimulation is a well-established treatment for generalized dystonia, but outcomes remain variable. Establishment of an imaging marker to guide device targeting and programming could possibly impact the efficacy of deep brain stimulation in dystonia, particularly in the absence of acute clinical markers to indicate benefit. We hypothesize that the stimulation-based functional and structural connectivity using resting-state fMRI and DTI can predict therapeutic outcomes in patients with generalized dystonia and deep brain stimulation. MATERIALS AND METHODS: We performed a retrospective analysis of 39 patients with inherited or idiopathic-isolated generalized dystonia who underwent bilateral globus pallidus internus deep brain stimulation. After electrode localization, the volumes of tissue activated were modeled and used as seed regions for functional and structural connectivity measures using a normative data base. Resulting connectivity maps were correlated with postoperative improvement in the Unified Dystonia Rating Scale score. RESULTS: Structural connectivity between the volumes of tissue activated and the primary sensorimotor cortex was correlated with Unified Dystonia Rating Scale improvement, while more anterior prefrontal connectivity was inversely correlated with Unified Dystonia Rating Scale improvement. Functional connectivity between the volumes of tissue activated and primary sensorimotor regions, motor thalamus, and cerebellum was most correlated with Unified Dystonia Rating Scale improvement; however, an inverse correlation with Unified Dystonia Rating Scale improvement was seen in the supplemental motor area and premotor cortex. CONCLUSIONS: Functional and structural connectivity with multiple nodes of the motor network is associated with motor improvement in patients with generalized dystonia undergoing deep brain stimulation. Results from this study may serve as a basis for future development of clinical markers to guide deep brain stimulation targeting and programming in dystonia.

Differential response to pallidal deep brain stimulation among monogenic dystonias: systematic review and meta-analysis.

OBJECTIVE: Genetic subtypes of dystonia may respond differentially to deep brain stimulation of the globus pallidus pars interna (GPi DBS). We sought to compare GPi DBS outcomes among the most common monogenic dystonias. METHODS: This systematic review and meta-analysis followed the Preferred Reporting Items for Systematic Reviews and Meta-analyses and Meta-analysis of Observational Studies in Epidemiology guidelines. We searched PubMed for studies on genetically confirmed monogenic dystonia treated with GPi DBS documenting pre-surgical and post-surgical assessments using the Burke-Fahn-Marsden Dystonia Rating Scale Motor Score (BFMMS) and Burke-Fahn-Marsden Disability Score (BFMDS). We performed (i) meta-analysis for each gene mutation; (ii) weighted ordinary linear regression analyses to compare BFMMS and BFMDS outcomes between DYT-TOR1A and other monogenic dystonias, adjusting for age and disease duration and (iii) weighted linear regression analysis to estimate the effect of age, sex and disease duration on GPi DBS outcomes. Results were summarised with mean change and 95% CI. RESULTS: DYT-TOR1A (68%, 38.4 points; p<0.001), DYT-THAP1 (37% 14.5 points; p<0.001) and NBIA/DYT-PANK2 (27%, 21.4 points; p<0.001) improved in BFMMS; only DYT-TOR1A improved in BFMDS (69%, 9.7 points; p<0.001). Improvement in DYT-TOR1A was significantly greater than in DYT-THAP1 (BFMMS -31%), NBIA/DYT-PANK2 (BFMMS -35%; BFMDS -53%) and CHOR/DYT-ADCY5 (BFMMS -36%; BFMDS -42%). Worse motor outcomes were associated with longer dystonia duration and older age at dystonia onset in DYT-TOR1A, longer dystonia duration in DYT/PARK-TAF1 and younger age at dystonia onset in DYT-SGCE. CONCLUSIONS: GPi DBS outcomes vary across monogenic dystonias. These data serve to inform patient selection and prognostic counselling.

Effects of ventral intermediate nucleus deep brain stimulation across multiple effectors in essential tremor.

OBJECTIVE: Essential tremor (ET) prominently affects the upper-limbs during voluntary movements, but can also affect the lower-limbs, head, and chin. Although deep brain stimulation (DBS) of the ventral intermediate nucleus (VIM) of thalamus improves both clinical ratings and quantitative measures of tremor, no study has quantified effects of DBS on tremor across multiple body parts. Our objective was to quantify therapeutic effects of DBS across multiple body parts in ET. METHODS: We performed quantitative assessment of tremor in ET patients who had DBS for at least one year. We assessed tremor on and off VIM-stimulation using triaxial accelerometers on the upper-limbs, lower-limbs, head and chin during seated and standing tasks. RESULTS: VIM-DBS significantly reduced tremor, but there was no statistical difference in degree of tremor reduction across the measured effectors. Compared to healthy controls, ET patients treated with DBS showed significantly greater tremor power (4-8 Hz) across all effectors during seated and standing tasks. CONCLUSIONS: VIM-DBS reduced tremor in ET patients. There was no significant difference in the degree of tremor reduction across the measured effectors. SIGNIFICANCE: This study provides new quantitative evidence that VIM-DBS is effective at reducing tremor across multiple parts of the body.

Adalimumab for nail psoriasis: efficacy and safety over 52 weeks from a phase-3, randomized, placebo-controlled trial.

BACKGROUND: Few clinical trials have evaluated long-term treatment of nail psoriasis with biologics. OBJECTIVE: Safety and efficacy of adalimumab [ADA; Humira AbbVie Inc, North Chicago, IL, USA)] long-term treatment (52 weeks) was evaluated in a phase-3, randomized trial in patients with moderate-to-severe plaque psoriasis and concomitant moderate-to-severe fingernail psoriasis. Results from the first 26 weeks (Period A) have been reported. METHODS: Patients receiving 40 mg ADA every other week or placebo in Period A, continued with or switched to 40 mg ADA every-other-week treatment in the subsequent 26-week open-label extension (OLE) period. Main efficacy evaluations were ≥75% improvement in total-fingernail modified Nail Psoriasis Severity Index (mNAPSI 75) and achievement of Physician's Global Assessment for Fingernail Psoriasis of clear or minimal disease (PGA-F 0/1) with a ≥2-grade improvement from baseline, across the trial for patients who continued ADA from Period A through the OLE (Continuous-ADA Population). Safety was evaluated during the OLE and for patients receiving ADA at any time during the study (All-ADA Population). RESULTS: Of the 217 patients initially randomized in Period A, 188 (86.6%; 94 in each treatment group) entered the OLE after completion of or early escape from Period A. For the Continuous-ADA Population (N = 109), endpoint achievement rates improved from OLE entry (Week 26) to Week 52, including total-fingernail mNAPSI 75 (47.4-54.5%); PGA-F 0/1 (51.1-55.6%) and total-fingernail mNAPSI = 0 (6.6-17.9%). Serious adverse event and serious infection rates for the All-ADA Population (N = 203) were 6.9% and 3.4%, respectively. CONCLUSIONS: In this population of psoriasis patients with concomitant, moderate-to-severe nail psoriasis, long-term efficacy and improvement in signs and symptoms of nail disease were demonstrated after every-other-week ADA treatment, including incremental improvements in rate of total clearance of nail disease. No new safety risks were identified for patients receiving at least one ADA dose across 52 weeks.

Adalimumab medium-term dosing strategy in moderate-to-severe hidradenitis suppurativa: integrated results from the phase III randomized placebo-controlled PIONEER trials.

BACKGROUND: Weekly adalimumab (Humira® ) is approved for the treatment of hidradenitis suppurativa (HS) based on the 12-week placebo-controlled periods of the two phase III PIONEER trials. OBJECTIVES: Using PIONEER integrated trial results, we aimed to evaluate the optimal medium-term adalimumab maintenance dosing strategy for moderate-to-severe HS. METHODS: Each trial had two double-blind periods; 12-week Period A and 24-week Period B. Patients randomized to adalimumab 40 mg every week (ADAew) (Period A), were rerandomized in Period B to ADAew (ADAew/ew), ADA every other week (ADAew/eow), or placebo (ADAew/pbo). Placebo-randomized patients were reassigned in Period B to ADAew (PIONEER I) or placebo (PIONEER II). The primary outcome was HS Clinical Response (HiSCR). Patients who lost response during Period B were discontinued from the study and offered an option to enter the open-label extension (OLE) to receive ADAew. Results are reported across the two study periods, and data were combined from the two study periods and the OLE. RESULTS: For week-12 HiSCR achievers, the HiSCR week-36 rate was 48·1% (ADAew/ew) vs. 46·2% (ADAew/eow) and 32·1% (ADAew/pbo). Combining (post hoc) these patients with week-12 partial responders further differentiated outcomes in Period B (ADAew/ew 55·7% vs. ADAew/eow 40·0% and ADAew/pbo 30·1%). Period-B adverse-event rates were ADAew/ew 59·6% vs. ADAew/eow 57·4% and ADAew/pbo 65·0%. One patient (ADAew/ew) reported a serious infection. CONCLUSIONS: Weekly adalimumab treatment, effective throughout 36 weeks, was the optimal maintenance medium-term dosing regimen for this population. At least partial response after 12 weeks with continued weekly dosing had better outcomes than dose reduction or interruption. Patients who do not show at least a partial response to weekly adalimumab by week 12 are unlikely to benefit from continued therapy. No new safety risks were identified. What's already known about this topic? Hidradenitis suppurativa (HS) is a chronic inflammatory disease, commonly misinterpreted as an infection and treated with long-term antibiotic regimens or surgical incisions. Based on the chronicity of HS and the lack of evidence for efficacious and safe long-term HS treatments, it is important to evaluate medium- to long-term therapies for HS. Weekly adalimumab (Humira® ) is approved for the treatment of moderate-to-severe HS based on the two phase III PIONEER trials. What does this study add? This study pooled data from the two PIONEER trials, providing a more robust assessment of outcomes. After at least partial treatment success with weekly adalimumab short-term therapy (12 weeks), continuing weekly dosing during the subsequent 24 weeks had better outcomes than dose reduction or treatment interruption. Patients who do not show at least a partial response to weekly adalimumab by week 12 are unlikely to benefit from continued therapy.

The role of inflammation in the association between gestational diabetes and obstructive sleep apnea: A pilot study.

BACKGROUND: Obstructive sleep apnea is associated with pregnancy complications including gestational diabetes. Mechanisms underlying the association between obstructive sleep apnea and gestational diabetes remain to be elucidated. METHODS: Twenty-three participants with gestational diabetes underwent home sleep apnea testing. Obstructive sleep apnea was defined as an apnea hypopnea index > 5. Fasting morning blood samples were measured using multianalyte profiling (xMAP) multiplexed bead array immunoassay for Interleukin 6, tumor necrosis factor-alpha, and Interleukin 8. RESULTS: Age, body mass index, and gestational age at enrollment were 31 + 4.4 years, 35.7 + 7.4 kg/m2, and 28 ± 4 weeks, respectively. Participants were 52% Caucasian and 16% had obstructive sleep apnea. We observed positive correlations between apnea hypopnea index and Interleukin 6 (r = 0.62, p = 0.005), Interleukin 8 (r = 0.56, p = .56), and tumor necrosis factor-alpha (r = .58, p = .009). Women with obstructive sleep apnea had higher levels of Interleukin 6 (F = 5.01, p = .037) and Interleukin 8 (F = 6.33, p = .021) vs. women without obstructive sleep apnea. CONCLUSION: These preliminary results indicate that in women with gestational diabetes, apnea hypopnea index is associated with an elevated inflammatory profile.

Segmentation of the Globus Pallidus Internus Using Probabilistic Diffusion Tractography for Deep Brain Stimulation Targeting in Parkinson Disease.

BACKGROUND AND PURPOSE: Although globus pallidus internus deep brain stimulation is a widely accepted treatment for Parkinson disease, there is persistent variability in outcomes that is not yet fully understood. In this pilot study, we aimed to investigate the potential role of globus pallidus internus segmentation using probabilistic tractography as a supplement to traditional targeting methods. MATERIALS AND METHODS: Eleven patients undergoing globus pallidus internus deep brain stimulation were included in this retrospective analysis. Using multidirection diffusion-weighted MR imaging, we performed probabilistic tractography at all individual globus pallidus internus voxels. Each globus pallidus internus voxel was then assigned to the 1 ROI with the greatest number of propagated paths. On the basis of deep brain stimulation programming settings, the volume of tissue activated was generated for each patient using a finite element method solution. For each patient, the volume of tissue activated within each of the 10 segmented globus pallidus internus regions was calculated and examined for association with a change in the Unified Parkinson Disease Rating Scale, Part III score before and after treatment. RESULTS: Increasing volume of tissue activated was most strongly correlated with a change in the Unified Parkinson Disease Rating Scale, Part III score for the primary motor region (Spearman r = 0.74, P = .010), followed by the supplementary motor area/premotor cortex (Spearman r = 0.47, P = .15). CONCLUSIONS: In this pilot study, we assessed a novel method of segmentation of the globus pallidus internus based on probabilistic tractography as a supplement to traditional targeting methods. Our results suggest that our method may be an independent predictor of deep brain stimulation outcome, and evaluation of a larger cohort or prospective study is warranted to validate these findings.

Potential indications for deep brain stimulation in neurological disorders: an evolving field.

Deep brain stimulation (DBS) is an established therapy for appropriately selected patients with movement disorders and neuropsychiatric conditions. Although the exact mechanisms and biology of DBS are not fully understood, it is a safe and well-tolerated therapy for many refractory cases of neuropsychiatric disease. Increasingly, DBS has been explored in other conditions with encouraging results. In this paper, available data is reviewed and new DBS targets, challenges and future directions in neurological disorders are explored. A detailed search of the medical literature discussing the potential use of DBS for neurological disorders excluding accepted indications was conducted. All reports were analyzed individually for content and redundant articles were excluded by examining individual abstracts. The level of evidence for each indication was summarized. Multiple studies report promising preliminary data regarding the safety and efficacy of DBS for a variety of neurological indications including chronic pain, tinnitus, epilepsy, Tourette syndrome, Huntington's disease, tardive dyskinesia and Alzheimer's disease. The initial results of DBS studies for diverse neurological disorders are encouraging but larger, controlled, prospective, homogeneous clinical trials are necessary to establish long-term safety and effectiveness. The field of neuromodulation continues to evolve and advances in DBS technology, stereotactic techniques, neuroimaging and DBS programming capabilities are shaping the present and future of DBS research and use in practice.

Towards global consensus on core outcomes for hidradenitis suppurativa research: an update from the HISTORIC consensus meetings I and II.

BACKGROUND: A core outcomes set (COS) is an agreed minimum set of outcomes that should be measured and reported in all clinical trials for a specific condition. Hidradenitis suppurativa (HS) has no agreed-upon COS. A central aspect in the COS development process is to identify a set of candidate outcome domains from a long list of items. Our long list had been developed from patient interviews, a systematic review of the literature and a healthcare professional survey, and initial votes had been cast in two e-Delphi surveys. In this manuscript, we describe two in-person consensus meetings of Delphi participants designed to ensure an inclusive approach to generation of domains from related items. OBJECTIVES: To consider which items from a long list of candidate items to exclude and which to cluster into outcome domains. METHODS: The study used an international and multistakeholder approach, involving patients, dermatologists, surgeons, the pharmaceutical industry and medical regulators. The study format was a combination of formal presentations, small group work based on nominal group theory and a subsequent online confirmation survey. RESULTS: Forty-one individuals from 13 countries and four continents participated. Nine items were excluded and there was consensus to propose seven domains: disease course, physical signs, HS-specific quality of life, satisfaction, symptoms, pain and global assessments. CONCLUSIONS: The HISTORIC consensus meetings I and II will be followed by further e-Delphi rounds to finalize the core domain set, building on the work of the in-person consensus meetings.

Focused stimulation of dorsal subthalamic nucleus improves reactive inhibitory control of action impulses.

Frontal-basal ganglia circuitry dysfunction caused by Parkinson's disease impairs important executive cognitive processes, such as the ability to inhibit impulsive action tendencies. Subthalamic Nucleus Deep Brain Stimulation in Parkinson's disease improves the reactive inhibition of impulsive actions that interfere with goal-directed behavior. An unresolved question is whether this effect depends on stimulation of a particular Subthalamic Nucleus subregion. The current study aimed to 1) replicate previous findings and additionally investigate the effect of chronic versus acute Subthalamic Nucleus stimulation on inhibitory control in Parkinson's disease patients off dopaminergic medication 2) test whether stimulating Subthalamic Nucleus subregions differentially modulate proactive response control and the proficiency of reactive inhibitory control. In the first experiment, twelve Parkinson's disease patients completed three sessions of the Simon task, Off Deep brain stimulation and medication, on acute Deep Brain Stimulation and on chronic Deep Brain Stimulation. Experiment 2 consisted of 11 Parkinson's disease patients with Subthalamic Nucleus Deep Brain Stimulation (off medication) who completed two testing sessions involving of a Simon task either with stimulation of the dorsal or the ventral contact in the Subthalamic Nucleus. Our findings show that Deep Brain Stimulation improves reactive inhibitory control, regardless of medication and regardless of whether it concerns chronic or acute Subthalamic Nucleus stimulation. More importantly, selective stimulation of dorsal and ventral subregions of the Subthalamic Nucleus indicates that especially the dorsal Subthalamic Nucleus circuitries are crucial for modulating the reactive inhibitory control of motor actions.

Impact of immunogenicity on pharmacokinetics, efficacy and safety of adalimumab in adult patients with moderate to severe chronic plaque psoriasis.

BACKGROUND: Adalimumab is a tumour necrosis factor-alpha antibody approved for treatment of moderate to severe chronic plaque psoriasis. OBJECTIVE: To characterise population pharmacokinetics of adalimumab 40 mg every other week dosing regimen and impact of immunogenicity on pharmacokinetics, efficacy and safety in psoriasis patients. METHODS: Patients were enrolled in a Phase 3 study comprising a 16-week double-blind, placebo-controlled period, a 17-week open-label period for Week 16 Psoriasis Area and Severity Index (PASI) 75 responders, and a 19-week double-blind, placebo-controlled period for Week 33 PASI 75 responders. Serum adalimumab and anti-adalimumab antibody (AAA) concentrations were measured and a population pharmacokinetic model devleoped to identify patient/disease factors affecting adalimumab pharmacokinetics. Impact of immunogenicity on treatment efficacy and safety was also assessed. RESULTS: Week 33 mean adalimumab concentration was 5.2 µg/mL. Week 16 responders had higher adalimumab concentrations than non-responders (6.3 vs. 2.2 µg/mL). Bodyweight and study were significant covariates in population pharmacokinetic model with weight accounting for 19% and 29% of variability in adalimumab clearance and volume of distribution, respectively. A total of 8.8% of adalimumab-treated patients tested AAA positive and had twofold higher adalimumab clearance. PASI 75 response rate was comparable between AAA+ and AAA- patients at Weeks 33 and 52 (Week 33: 36% vs. 22.5%, Week 52: 21.1% vs. 17.8%) and adverse events incidence was similar between the two groups. CONCLUSIONS: Patient weight and study significantly affect adalimumab clearance and volume of distribution in psoriasis patients. Development of AAAs result in lower adalimumab exposure and efficacy with no effect on adverse events incidence.

Efficacy and safety of adalimumab in Chinese patients with moderate-to-severe plaque psoriasis: results from a phase 3, randomized, placebo-controlled, double-blind study.

BACKGROUND: This phase 3 trial is the first to evaluate the efficacy and safety of treatment with the systemic TNF-α inhibitor, adalimumab, for Chinese patients with moderate-to-severe plaque psoriasis. METHODS: In the 12-week, double-blind, placebo-controlled Period A, patients were randomized 4 : 1 to receive adalimumab 40 mg every-other-week (following a single 80 mg dose), or placebo every-other-week. In the subsequent 12-week, open-label, Period B, all patients received adalimumab 40 mg every-other-week starting at week 13, following a single, blinded dose at week 12 of adalimumab 80 mg or matching placebo (for patients receiving placebo or adalimumab in Period A respectively). In Period A, efficacy was analysed for all randomized patients and safety for all patients receiving ≥1 dose of the study drug. RESULTS: For the 425 patients in this study (87 placebo; 338 adalimumab), a higher percentage randomized to adalimumab achieved the primary endpoint of ≥75% improvement from baseline in PASI score (PASI 75) at week 12: placebo 11.5% (10/87); adalimumab 77.8% (263/338; P < 0.001). Physician's Global Assessment of clear to minimal was achieved at week 12 by 14.9% placebo (13/87) and 80.5% adalimumab (272/338; P < 0.001). For patients who received adalimumab at any time during the study (All-adalimumab Population), treatment-emergent adverse events (AEs) were reported by 63.4%; the most common was upper respiratory infection (16.1%). Serious AEs were reported by 3.5% of the All-adalimumab Population, and serious infectious AEs by 1.2%, which include lung infection, pneumonia and tuberculosis [2 (0.5%) patients each]. There was one death (chronic heart failure). CONCLUSION: In these Chinese patients with moderate-to-severe psoriasis, a significantly greater percentage treated with adalimumab compared with placebo achieved efficacy endpoints at week 12 and efficacy was sustained to week 24. Safety results were consistent with the known adalimumab safety profile; no new safety signals were identified in the 24 weeks of treatment.

High rates of fatigue and sleep disturbances in dystonia.

BACKGROUND: Nonmotor symptoms in dystonia are increasingly recognized to impair the quality of life. The primary objective of this study was to determine the prevalence of fatigue and sleep disturbances in dystonia and to ascertain their impact on quality of life using standardized questionnaires. METHODS: Dystonia patients presenting to a Botulinum toxin clinic were prospectively administered Fatigue Severity Scale (FSS), Multidimensional Fatigue Inventory (MFI), Epworth Sleepiness Scale (ESS) and Parkinson's Disease Sleep Scale (PDSS) for assessment of fatigue and sleep disturbances. Health-related Quality of life (HRQOL) was determined using MOS SF-36 scale and depressive symptoms were assessed using the Beck Depression Inventory II. RESULTS: Ninety-one patients with dystonia participated (66 women, 25 men, mean age 60 ± 17 years). Nine subjects had generalized dystonia, 18 segmental dystonia and 64 had focal dystonia. Moderate to severe fatigue was present in 43% of the cohort (FSS), excessive daytime somnolence in 27% (ESS) and other sleep disturbances in 26% (PDSS). FSS and MFI scores correlated significantly with HRQOL even when controlled for depression and sleep disturbances. Excessive daytime somnolence and nocturnal sleep disturbances correlated significantly with the HRQOL; however, these effects were not seen for daytime somnolence when controlled for depression. Psychometric testing found adequate reliabilities and convergent validities for both fatigue and sleep scales. CONCLUSION: Fatigue and sleep disturbances revealed high prevalence rates in this large, first of its dystonia study. They negatively impacted the quality of life even when controlled for comorbid depression.

Motivational engagement in Parkinson's disease: Preparation for motivated action.

The current study investigated whether motivational dysfunction in Parkinson's patients is related to a deficit in preparing for motivated behavior. Based on previous studies, it was hypothesized that PD patients would show reduced preparation for action specifically when faced with threat (of loss) and that reduced action preparation would relate to self-report of apathy symptoms. The study measured an electrocortical correlate of preparation for action (CNV amplitude) in PD patients and healthy controls, as well as defensive and appetitive activation during emotional perception (LPP amplitude). The sample included 18 non-demented PD patients (tested on dopaminergic medications) and 15 healthy controls who responded as quickly as possible to cues signaling threat of loss or reward, in which the speed of the response determined the outcome. Results indicated that, whereas PD patients showed similar enhanced action preparation with the addition of incentives to controls, PD patients showed generally reduced action preparation, evidenced by reduced CNV amplitude overall. Results suggest that PD patients may have behavioral issues due to globally impaired action preparation but that this deficit is not emotion-specific, and movement preparation may be aided by incentive in PD patients.

Adalimumab retreatment successfully restores clinical response and health-related quality of life in patients with moderate to severe psoriasis who undergo therapy interruption.

BACKGROUND: Published evaluations of skin disease signs and health-related quality of life (HRQoL) upon therapy withdrawal and retreatment in psoriatic patients are limited to results of drug withdrawal after short-term treatment. Analyses are lacking that evaluate patients' response to retreatment for patients treated successfully long-term. OBJECTIVE: To study the efficacy and safety of adalimumab in patients with long-term clinical responses to adalimumab who then discontinue therapy and are retreated with the same dosing regimen as the initial course. Skin disease signs and patients' HRQoL are evaluated. METHODS: This post hoc analysis of an open-label study (NCT00195676) included patients who had responded favourably to adalimumab during initial treatment (≥75% improvement in Psoriasis Area and Severity Index [PASI 75 response]) and had maintained good clinical response for an extended period (up to 252 weeks); patients had Physician's Global Assessment (PGA) 0 or 1 before treatment interruption. Following drug withdrawal (up to 40 weeks), all patients were retreated with adalimumab 80 mg initial dose, followed by 40 mg every-other-week for 16 weeks. PASI response and HRQoL were evaluated. RESULTS: Of the 133 patients in this analysis, 24 (18%) relapsed during therapy withdrawal. After 16 weeks of retreatment, 75% who relapsed and 89.9% who did not relapse, had a PASI 75 response; 89.5% achieved European Consensus Programme treatment goals after 16 weeks of retreatment. During drug withdrawal, HRQoL disproportionally worsened compared to skin disease signs; HROoL also considerably worsened for patients who did not relapse. Patients regained HRQoL upon retreatment with adalimumab. No new safety signals were identified in this study. CONCLUSION: Retreatment with adalimumab was successful in improving psoriasis skin signs and HRQoL in this subgroup with initial and extended responses to therapy followed by relapse after treatment withdrawal. Patient's HRQoL should be considered, as it may substantially worsen during therapy interruption.

Assessing the validity, responsiveness and meaningfulness of the Hidradenitis Suppurativa Clinical Response (HiSCR) as the clinical endpoint for hidradenitis suppurativa treatment.

BACKGROUND: Quantification of disease severity supports the development of evidence-based treatments. Assessments to capture clinical improvement in hidradenitis suppurativa (HS) can be improved. OBJECTIVES: This study aimed to validate the Hidradenitis Suppurativa Clinical Response (HiSCR), which is defined as a ≥ 50% reduction in inflammatory lesion count (sum of abscesses and inflammatory nodules, AN), and no increase in abscesses or draining fistulas in HS when compared with baseline as a meaningful clinical endpoint for HS treatment. METHODS: Patients with ≥ 3 ANs at baseline in a Phase II adalimumab trial for HS were included for analysis. HiSCR achievers vs. nonachievers were assessed at week 16 and week 52. Criteria measures included physician-rated assessments [Hurley stage, modified Sartorius score (MSS), and HS Physician's Global Assessment] and patient-reported outcomes (PROs: visual analogue pain scale, Dermatology Life Quality Index, and Work Productivity and Activity Impairment questionnaire). Test-retest reliability, convergent validity, responsiveness and predictive validity of HiSCR, and its meaningfulness to patients were assessed. RESULTS: Among 138 eligible study participants, the majority were female (69·6%) with a mean age of 36·7 years. The mean (median) MSS was 125·2 (85·5) at baseline. Test-retest reliability of the AN count was 0·91. HiSCR was significantly correlated with improvements in all physician-rated and PRO measures (Spearman's rho between -0·61 and -0·27, all P < 0·001). Improvements of all PROs in HiSCR achievers exceeded the respective meaningful improvement thresholds. CONCLUSIONS: In patients with HS with ≥ 3 ANs, HiSCR achievers had significant improvements in physician-rated and patient-reported HS disease severity and impact. HiSCR is a valid and meaningful endpoint for assessing HS treatment effectiveness in controlling inflammatory manifestations in this population.

Mobility, mood and site of care impact health related quality of life in Parkinson's disease.

OBJECTIVE: Examine the correlates of Health Related Quality of Life (HRQL) in a large cohort of Parkinson's disease (PD) patients from National Parkinson Foundation (NPF) Centers of Excellence (COEs). BACKGROUND: Improving outcomes for PD will depend upon uncovering disease features impacting HRQL to identify targets for intervention and variables for risk-adjustment models. Differences in HRQL outcomes between COEs could uncover modifiable aspects of care delivery. METHODS: This cross-sectional study examined the relative contribution of demographic, social, clinical and treatment features potentially related to HRQL, as measured by the PDQ-39, in 4601 consecutive subjects from 18 COEs. Stepwise linear regression was utilized to identify correlates of HRQL. RESULTS: The variability in the PDQ-39 summary index score correlated with H&Y stage (R(2) = 22%), Timed up and Go (TUG) (17%), disease duration (11%), comorbidities (8%), cognitive status (8%), antidepressant use (6%) and center at which a patient received care (5%). Stepwise regression reordered the importance of the variables, with the H&Y first and TUG and the center becoming equal and the second most important variables determining the PDQ-39 total score. All independent variables together accounted for 44% of the variability in HRQL. CONCLUSIONS: We confirmed many but not all HRQL associations found in smaller studies. A novel observation was that the site of care was an important contributor to HRQL, suggesting that comparison of outcomes and processes among centers may identify best practices.

The late positive potential, emotion and apathy in Parkinson's disease.

Parkinson's disease is associated with emotional changes including depression, apathy, and anxiety. The current study investigated emotional processing in non-demented individuals with Parkinson disease (PD) using an electrophysiological measure, the centro-parietal late positive potential (LPP). Non-demented patients with Parkinson's disease (n=17) and healthy control participants (n=16) viewed pleasant, neutral, and unpleasant pictures while EEG was recorded from a 64-channel geodesic net. The Parkinson patients did not differ from controls in terms of early electrophysiological components that index perceptual processing (occipital P100, N150, P250). Parkinson patients, however, showed reduced LPP amplitude specifically when viewing unpleasant, compared to pleasant, pictures as well as when compared to controls, consistent with previous studies suggesting a specific difference in aversive processing between PD patients and healthy controls. Importantly, LPP amplitude during unpleasant picture viewing was most attenuated for patients reporting high apathy. The data suggest that apathy in PD may be related to a deficit in defensive activation, and may be indexed cortically using event-related potentials.