Efficacy of secukinumab and adalimumab in patients with psoriatic arthritis and concomitant moderate-to-severe plaque psoriasis: results from EXCEED, a randomized, double-blind head-to-head monotherapy study.

BACKGROUND: Secukinumab [an interleukin (IL)-17A inhibitor] has demonstrated significantly higher efficacy vs. etanercept (a tumour necrosis factor inhibitor) and ustekinumab (an IL-12/23 inhibitor) in patients with moderate-to-severe plaque psoriasis. OBJECTIVES: To report 52-week results from a prespecified analysis of patients with active psoriatic arthritis (PsA) having concomitant moderate-to-severe plaque psoriasis from the head-to-head EXCEED monotherapy study comparing secukinumab with adalimumab. METHODS: Patients were randomized to receive secukinumab 300 mg via subcutaneous injection at baseline, week 1-4, and then every 4 weeks until week 48 or adalimumab 40 mg via subcutaneous injection every 2 weeks from baseline until week 50. Assessments in patients with concomitant moderate-to-severe psoriasis, defined as having affected body surface area > 10% or Psoriasis Area and Severity Index (PASI) ≥ 10 at baseline, included musculoskeletal, skin and quality-of-life outcomes. Missing data were handled using multiple imputation. RESULTS: Of the 853 patients [secukinumab (N = 426), adalimumab (N = 427)], 211 (24·7%) had concomitant moderate-to-severe psoriasis [secukinumab (N = 110, 25·8%), adalimumab (N = 101, 23·7%)]. Up to week 50, 5·5% of patients discontinued secukinumab vs.17·8% in the adalimumab group. The proportion of patients who achieved American College of Rheumatology (ACR) 20 response was 76·4% with secukinumab vs. 68·3% with adalimumab (P = 0·175), PASI 100 response was 39·1% vs. 23·8% (P = 0·013), and simultaneous improvement in ACR 50 and PASI 100 response at week 52 was 28·2% vs. 17·7%, respectively (P = 0·06). Secukinumab demonstrated consistently higher responses vs. adalimumab across skin endpoints. CONCLUSIONS: This prespecified analysis in PsA patients with concomitant moderate-to-severe plaque psoriasis in the EXCEED study provides further evidence that IL-17 inhibitors offer a comprehensive biological treatment to manage the concomitant features of psoriasis and PsA.

Tofacitinib in psoriatic arthritis patients: skin signs and symptoms and health-related quality of life from two randomized phase 3 studies.

BACKGROUND: Psoriatic arthritis (PsA) is a chronic, systemic immune-mediated inflammatory musculoskeletal disease. The onset of dermatologic symptoms often precedes rheumatic manifestations. Tofacitinib is an oral Janus kinase inhibitor for the treatment of PsA that has been shown to improve dermatologic symptoms in patients with PsA. OBJECTIVES: To investigate the efficacy of tofacitinib in improving dermatologic endpoints in adult patients with active PsA. METHODS: This analysis included data from two placebo-controlled, double-blind, phase 3 studies in patients with active PsA and an inadequate response (IR) to ≥1 conventional synthetic disease-modifying antirheumatic drug (csDMARD) who were tumor necrosis factor inhibitor (TNFi)-naïve (OPAL Broaden; NCT01877668) or an IR to ≥1 TNFi (OPAL Beyond; NCT01882439). Patients had active plaque psoriasis at screening and received a stable dose of one csDMARD during the study. Patients were randomized to tofacitinib 5 mg twice daily (BID), 10 mg BID, adalimumab 40 mg subcutaneous injection once every 2 weeks (OPAL Broaden only) or placebo (to Month 3). Dermatologic endpoints: Psoriasis Area and Severity Index (PASI) total score; PASI90 overall; PASI75 and PASI90 by baseline PASI severity; Physician's Global Assessment of Psoriasis; Nail Psoriasis Severity Index; Dermatology Life Quality Index total and sub-dimension scores; Itch Severity Item; and Patient's Global Joint and Skin Assessment-Visual Analog Scale-Psoriasis question. RESULTS: In patients with active PsA, including those stratified by mild or moderate/severe dermatologic symptoms, greater improvements from baseline and percentage of responders were observed in tofacitinib-treated patients vs. placebo for the majority of analyzed dermatologic endpoints at Months 1 and 3, and improvements were maintained to Month 12 in OPAL Broaden and Month 6 in OPAL Beyond. Similar effects were observed in adalimumab-treated patients vs. placebo in OPAL Broaden across dermatologic endpoints. CONCLUSIONS: Tofacitinib provides a treatment option for patients with active PsA, including the burdensome dermatologic symptoms of PsA.

CQESTR-Simulated Response of Soil Organic Carbon to Management, Yield, and Climate Change in the Northern Great Plains Region.

Traditional dryland crop management includes fallow and intensive tillage, which have reduced soil organic carbon (SOC) over the past century, raising concerns regarding soil health and sustainability. The objectives of this study were: (i) to use CQESTR, a process-based C model, to simulate SOC dynamics from 2006 to 2011 and to predict relative SOC trends in cropping sequences that included barley ( L.), pea ( L.), and fallow under conventional tillage or no-till, and N fertilization rates through 2045; and (ii) to identify best dryland cropping systems to increase SOC and reduce CO emissions under projected climate change in eastern Montana. Cropping sequences were conventional-till barley-fallow (CTB-F), no-till barley-fallow (NTB-F), no-till continuous barley (NTCB), and no-till barley-pea (NTB-P), with 0 and 80 kg N ha applied to barley. Under current crop production, climatic conditions, and averaged N rates, SOC at the 0- to 10-cm depth was predicted to increase by 1.74, 1.79, 2.96, and 4.57 Mg C ha by 2045 for CTB-F, NTB-F, NTB-P, and NTCB, respectively. When projected climate change and the current positive US barley yield trend were accounted for in the simulations, SOC accretion was projected to increase by 0.69 to 0.92 Mg C ha and 0.41 to 0.47 Mg C ha, respectively. According to the model simulations, adoption of NT, elimination of fallow years, and N fertilizer management will likely have the greatest impact on SOC stocks in the top soil as of 2045 in the Northern Great Plains.

Simulated Soil Organic Carbon Changes in Maryland Are Affected by Tillage, Climate Change, and Crop Yield.

The impact of climate change on soil organic C (SOC) stocks in no-till (NT) and conventionally tilled (CT) agricultural systems is poorly understood. The objective of this study was to simulate the impact of projected climate change on SOC to 50-cm soil depth for grain cropping systems in the southern Mid-Atlantic region of the United States. We used SOC and other data from the long-term Farming Systems Project in Beltsville, MD, and CQESTR, a process-based soil C model, to predict the impact of cropping systems and climate (air temperature and precipitation) on SOC for a 40-yr period (2012-2052). Since future crop yields are uncertain, we simulated five scenarios with differing yield levels (crop yields from 1996-2014, and at 10 or 30% greater or lesser than these yields). Without change in climate or crop yields (baseline conditions) CQESTR predicted an increase in SOC of 0.014 and 0.021 Mg ha yr in CT and NT, respectively. Predicted climate change alone resulted in an SOC increase of only 0.002 Mg ha yr in NT and a decrease of 0.017 Mg ha yr in CT. Crop yield declines of 10 and 30% led to SOC decreases between 2 and 8% compared with 2012 levels. Increasing crop yield by 10 and 30% was sufficient to raise SOC 2 and 7%, respectively, above the climate-only scenario under both CT and NT between 2012 and 2052. Results indicate that under these simulated conditions, the negative impact of climate change on SOC levels could be mitigated by crop yield increases.

Simulated Soil Organic Carbon Response to Tillage, Yield, and Climate Change in the Southeastern Coastal Plains.

Intensive tillage, low-residue crops, and a warm, humid climate have contributed to soil organic carbon (SOC) loss in the southeastern Coastal Plains region. Conservation (CnT) tillage and winter cover cropping are current management practices to rebuild SOC; however, there is sparse long-term field data showing how these management practices perform under variable climate conditions. The objectives of this study were to use CQESTR, a process-based C model, to simulate SOC in the top 15 cm of a loamy sand soil (fine-loamy, kaolinitic, thermic Typic Kandiudult) under conventional (CvT) or CnT tillage to elucidate the impact of projected climate change and crop yields on SOC relative to management and recommend the best agriculture management to increase SOC. Conservation tillage was predicted to increase SOC by 0.10 to 0.64 Mg C ha for six of eight crop rotations compared with CvT by 2033. The addition of a winter crop [rye ( L.) or winter wheat ( L.)] to a corn ( L.)-cotton ( L.) or corn-soybean [ (L.) Merr.] rotation increased SOC by 1.47 to 2.55 Mg C ha. A continued increase in crop yields following historical trends could increase SOC by 0.28 Mg C ha, whereas climate change is unlikely to have a significant impact on SOC except in the corn-cotton or corn-soybean rotations where SOC decreased up to 0.15 Mg C ha by 2033. The adoption of CnT and cover crop management with high-residue-producing corn will likely increase SOC accretion in loamy sand soils. Simulation results indicate that soil C saturation may be reached in high-residue rotations, and increasing SOC deeper in the soil profile will be required for long-term SOC accretion beyond 2030.

Simulated Soil Organic Carbon Responses to Crop Rotation, Tillage, and Climate Change in North Dakota.

Understanding how agricultural management and climate change affect soil organic carbon (SOC) stocks is particularly important for dryland agriculture regions that have been losing SOC over time due to fallow and tillage practices, and it can lead to development of agricultural practice(s) that reduce the impact of climate change on crop production. The objectives of this study were: (i) to simulate SOC dynamics in the top 30 cm of soil during a 20-yr (1993-2012) field study using CQESTR, a process-based C model; (ii) to predict the impact of changes in management, crop production, and climate change from 2013 to 2032; and (iii) to identify the best dryland cropping systems to maintain or increase SOC stocks under projected climate change in central North Dakota. Intensifying crop rotations was predicted to have a greater impact on SOC stocks than tillage (minimum tillage [MT], no-till [NT]) during 2013 to 2032, as SOC was highly correlated to biomass input ( = 0.91, = 0.00053). Converting from a MT spring wheat (SW, L.)-fallow rotation to a NT continuous SW rotation increased annualized biomass additions by 2.77 Mg ha (82%) and SOC by 0.22 Mg C ha yr. Under the assumption that crop production will stay at the 1993 to 2012 average, climate change is predicted to have a minor impact on SOC (approximately -6.5%) relative to crop rotation management. The CQESTR model predicted that the addition of another SW or rye ( L.) crop would have a greater effect on SOC stocks (0- to 30-cm depth) than conversion from MT to NT or climate change from 2013 to 2032.

Cost savings with a new screening algorithm for pulmonary arterial hypertension in systemic sclerosis.

BACKGROUND: Screening for pulmonary arterial hypertension (PAH) in systemic sclerosis (SSc) is now standard care in this disease. The existing Australian Scleroderma Interest Group algorithm (ASIGSTANDARD ) is based on transthoracic echocardiography (TTE) and pulmonary function tests (PFT). Recently, ASIG has derived and validated a new screening algorithm (ASIGPROPOSED ) that incorporates N-terminal pro-B-type natriuretic peptide level together with PFT in order to decrease reliance on TTE, which has some limitations. Right heart catheterisation (RHC) remains the gold standard for the diagnosis of PAH in patients who screen 'positive'. AIM: To compare the cost of PAH screening in SSc with ASIGSTANDARD and ASIGPROPOSED algorithms. METHODS: We applied both ASIGSTANDARD and ASIGPROPOSED algorithms to 643 screen-naïve SSc patients from the Australian Scleroderma Cohort Study (ASCS), assuming a PAH prevalence of 10%. We compared the costs of screening, the number of TTE required and both the total number of RHC required and the number of RHC needed to diagnose one case of PAH, and costs, according to each algorithm. We then extrapolated the costs to the estimated total Australian SSc population. RESULTS: In screen-naïve patients from the ASCS, ASIGPROPOSED resulted in 64% fewer TTE and 10% fewer RHC compared with ASIGSTANDARD , with $1936 (15%) saved for each case of PAH diagnosed. When the costs were extrapolated to the entire Australian SSc population, there was an estimated screening cost saving of $946 000 per annum with ASIGPROPOSED , with a cost saving of $851 400 in each subsequent year of screening. CONCLUSIONS: ASIGPROPOSED substantially reduces the number of TTE and RHC required and results in substantial cost savings in SSc-PAH screening compared with ASIGSTANDARD .

The association of antiphospholipid antibodies with cardiopulmonary manifestations of systemic sclerosis.

OBJECTIVES: To determine the prevalence and correlates of antiphospholipid antibodies (APLA) in systemic sclerosis (SSc). METHODS: Nine hundred and forty SSc patients were tested for APLA using an ELISA assay at recruitment. Clinical manifestations were defined as present, if ever present from SSc diagnosis. Logistic regression analysis was used to determine the associations of APLA. RESULTS: One or more types of APLA were present in 226 (24.0%) patients. Anticardiolipin (ACA) IgG (ACA-IgG) antibodies were associated with right heart catheter-diagnosed pulmonary arterial hypertension (PAH), with higher titres corresponding with a higher likelihood of PAH (moderate titre (20-39 U/ml) ACA-IgG odds ratio [OR] 1.70, 95% CI: 1.01-2.93, p=0.047; high titre (>40 U/ml) ACA-IgG OR 4.60, 95% CI:1.02-20.8, p=0.047). Both ACA-IgM (OR 2.04, 95% CI: 1.4-3.0, p<0.0001) and ACA-IgG (OR 1.84, 95% CI: 1.2-2.8, p=0.005) were associated with interstitial lung disease (ILD). Increasing ACA-IgM and IgG titres were associated with increased likelihood of ILD. ACA-IgG was a marker of coexistent pulmonary hypertension and ILD (ILD-PH) (OR 2.10, 95% CI: 1.1-4.2, p=0.036). We also found an association between ACA-IgG and digital ulcers (OR 1.76, 95% CI: 1.16-2.67, p=0.008) and ACA-IgM and Raynaud's phenomenon (OR 2.39, 95% CI: 1.08-5.27, p=0.031). There was no association between APLA and SSc disease subtype, peak skin score, presence of other autoantibodies, mortality or other disease manifestations. CONCLUSIONS: The association of APLA with PAH, ILD, ILD-PH, Raynaud's phenomenon and digital ulcers suggests that endothelial abnormalities and small vessel thrombosis may be important in the pathogenesis of these disease features.

The ictal bradycardia syndrome: persistence of seizures despite cardiac pacemaker implantation.

Ictal bradycardic syndrome (IBS), a rare manifestation of temporal lobe epilepsy is both difficult to diagnose and treat. Our case study of a 24 year old with persistent and unexplained syncope highlights the typical presentation, investigation and treatment of IBS.

An Online Resident-as-Teacher Curriculum Improves First-Year Residents' Self-Confidence Teaching in the Clinical Learning Environment.

We implemented an online Resident-as-Teacher curriculum for all incoming residents (PGY1s) to provide them with a basic foundation for effective teaching in the clinical learning environment. The curriculum consisted of 5 asynchronous modules delivered via the web from 2017-2021. Prior to starting the course, the PGY1s completed a self-assessment of their teaching ability (pre-test) and then again 7-8 months after completing the course (post-test). Analysis of the paired data from 421 PGY1s showed a statistically significant improvement in the self-ratings of their teaching from pre-test to post-test (p < 0.001). Our findings suggest that an online Resident-as-Teacher curriculum can produce lasting benefits in new residents' self-confidence as educators.

Early growth response-1 contributes to steatosis development after acute ethanol administration.

BACKGROUND: Previous work demonstrated that the transcription factor, early growth response-1 (Egr-1), participates in the development of steatosis (fatty liver) after chronic ethanol (EtOH) administration. Here, we determined the extent to which Egr-1 is involved in fatty liver development in mice subjected to acute EtOH administration. METHODS: In acute studies, we treated both wild-type and Egr-1 null mice with either EtOH or phosphate-buffered saline (PBS) by gastric intubation. At various times after treatment, we harvested sera and livers and quantified endotoxin, indices of liver injury, steatosis, and hepatic Egr-1 content. In chronic studies, groups of mice were fed liquid diets containing either EtOH or isocaloric maltose-dextrin for 7 to 8 weeks. RESULTS: Compared with controls, acute EtOH-treated mice showed a rapid, transient elevation in serum endotoxin beginning 30 minutes after treatment. One hour postgavage, livers from EtOH-treated mice exhibited a robust elevation of both Egr-1 mRNA and protein. By 3 hours postgavage, liver triglyceride increased in EtOH-treated mice as did lipid peroxidation. Acute EtOH treatment of Egr-1-null mice showed no Egr-1 expression, but these animals still developed elevated triglycerides, although significantly lower than EtOH-fed wild-type littermates. Despite showing decreased fatty liver, EtOH-treated Egr-1 null mice exhibited greater liver injury. After chronic EtOH feeding, steatosis and liver enlargement were clearly evident, but there was no indication of elevated endotoxin. Egr-1 levels in EtOH-fed mice were equal to those of pair-fed controls. CONCLUSIONS: Acute EtOH administration induced the synthesis of Egr-1 in mouse liver. However, despite its robust increase, the transcription factor had a smaller, albeit significant, function in steatosis development after acute EtOH treatment. We propose that the rise in Egr-1 after acute EtOH is an hepatoprotective adaptation to acute liver injury from binge drinking that is triggered by EtOH metabolism and elevated levels of endotoxin.

Subcutaneous abatacept versus intravenous abatacept: a phase IIIb noninferiority study in patients with an inadequate response to methotrexate.

OBJECTIVE: To compare the efficacy and safety of subcutaneous (SC) and intravenous (IV) abatacept. METHODS: In this phase IIIb double-blind, double-dummy, 6-month study, patients with rheumatoid arthritis (RA) and inadequate responses to methotrexate were randomized to receive 125 mg SC abatacept on days 1 and 8 and weekly thereafter (plus an IV loading dose [∼10 mg/kg] on day 1) or IV abatacept (∼10 mg/kg) on days 1, 15, and 29 and every 4 weeks thereafter. The primary end point for determining the noninferiority of SC abatacept to IV abatacept was the proportion of patients in each group meeting the American College of Rheumatology 20% improvement criteria (achieving an ACR20 response) at month 6. Other efficacy end points, immunogenicity, and safety were also assessed. RESULTS: Of 1,457 patients, 693 of 736 (94.2%) treated with SC abatacept and 676 of 721 (93.8%) treated with IV abatacept completed 6 months. At month 6, 76.0% (95% confidence interval 72.9, 79.2) of SC abatacept-treated patients versus 75.8% (95% confidence interval 72.6, 79.0) of IV abatacept-treated patients achieved an ACR20 response (estimated difference between groups 0.3% [95% confidence interval -4.2, 4.8]), confirming noninferiority of SC abatacept to IV abatacept. Onset and magnitude of ACR responses and disease activity and physical function improvements were comparable between the SC and IV abatacept-treated groups. The proportions of adverse events (AEs) and serious AEs over 6 months were 67.0% and 4.2%, respectively, in the SC abatacept-treated group and 65.2% and 4.9%, respectively, in the IV abatacept-treated group, with comparable frequencies of serious infections, malignancies, and autoimmune events between groups. SC injection site reactions (mostly mild) occurred in 19 SC abatacept (IV placebo)-treated patients (2.6%) and 18 IV abatacept (SC placebo)-treated patients (2.5%). Abatacept-induced antibodies occurred in 1.1% of SC abatacept-treated patients and 2.3% of IV abatacept-treated patients. CONCLUSION: SC abatacept provides efficacy and safety comparable with that of IV abatacept, with low immunogenicity and high retention rates, consistent with the established IV abatacept profile. Rates of injection site reactions were low. SC abatacept will provide additional treatment options, such as an alternative route of administration, for patients with RA.

The psychological impact of COVID-19 on ear, nose and throat (ENT) specialists.

INTRODUCTION: Ear, nose and throat (ENT) specialists are a high-risk group for COVID-19. Although the implications of SARS-CoV-2 infection on physical health are well-documented, the psychological impact is frequently overlooked. AIMS: The aim of this study was to gauge the psychological impact of COVID-19 on ENT specialists in Ireland. METHODS: A national, cross-sectional, web-based survey was distributed to ENT specialists during the peak of the COVID-19 pandemic (21st May 2020-21st June 2020). The questionnaire collected sociodemographic and COVID-19 related data. The GAD-7 was utilized to measure symptoms of clinically significant anxiety disorder. RESULTS: Thirty-eight ENT specialists (M/F:24/12, median age, 38.7 years (23-60 years)) completed the survey. About 34% (n = 13) of participants screened positive for an anxiety disorder, of which 2 (5%) had moderate symptoms. The majority of participants (n = 32, 84%) felt ENT specialists had increased exposure to SARS-CoV-2 compared with other medical specialties. Additionally, 32% (n = 12) felt incapable of protecting themselves from infection. An encouraging proportion of ENT specialists (n = 22, 58%) were aware of psychological support available from national and institutional organizations. CONCLUSIONS: The long-term psychological sequelae of COVID-19 will be felt as the physical burden eases. As we adjust to new normalities, ENT surgeons must be conscientious of the mental health issues that arise from the working environment. Sources of anxiety emanated from a lack of control over infection risk, increased vulnerability to COVID-19 relative to other specialties and the implications this has for ENT specialists and their families. Future interventions must focus on increasing awareness of the available psychological support services for our healthcare workers.

The efficacy and safety of abatacept in patients with non-life-threatening manifestations of systemic lupus erythematosus: results of a twelve-month, multicenter, exploratory, phase IIb, randomized, double-blind, placebo-controlled trial.

OBJECTIVE: To evaluate abatacept therapy in patients with non-life-threatening systemic lupus erythematosus (SLE) and polyarthritis, discoid lesions, or pleuritis and/or pericarditis. METHODS: In a 12-month, multicenter, exploratory, phase IIb randomized, double-blind, placebo-controlled trial, SLE patients with polyarthritis, discoid lesions, or pleuritis and/or pericarditis were randomized at a ratio of 2:1 to receive abatacept (∼10 mg/kg of body weight) or placebo. Prednisone (30 mg/day or equivalent) was given for 1 month, and then the dosage was tapered. The primary end point was the proportion of patients with new flare (adjudicated) according to a score of A/B on the British Isles Lupus Assessment Group (BILAG) index after the start of the steroid taper. RESULTS: A total of 118 patients were randomized to receive abatacept and 57 to receive placebo. The baseline characteristics were similar in the 2 groups. The proportion of new BILAG A/B flares over 12 months was 79.7% (95% confidence interval [95% CI] 72.4, 86.9) in the abatacept group and 82.5% (95% CI 72.6, 92.3) in the placebo group (treatment difference -3.5 [95% CI -15.3, 8.3]). Other prespecified flare end points were not met. In post hoc analyses, the proportions of abatacept-treated and placebo-treated patients with a BILAG A flare were 40.7% (95% CI 31.8, 49.5) versus 54.4% (95% CI 41.5, 67.3), and the proportions with physician-assessed flare were 63.6% (95% CI 54.9, 72.2) and 82.5% (95% CI 72.6, 92.3), respectively; treatment differences were greatest in the polyarthritis group. Prespecified exploratory patient-reported outcomes (Short Form 36 health survey, sleep problems, fatigue) demonstrated a treatment effect with abatacept. The frequency of adverse events (AEs) was comparable in the abatacept and placebo groups (90.9% versus 91.5%), but serious AEs (SAEs) were higher in the abatacept group (19.8 versus 6.8%). Most SAEs were single, disease-related events occurring during the first 6 months of the study (including the steroid taper period). CONCLUSION: Although the primary/secondary end points were not met in this study, improvements in certain exploratory measures suggest some abatacept efficacy in patients with non-life-threatening manifestations of SLE. The increased rate of SAEs requires further assessment.

Possible new role for NF-kappaB in the resolution of inflammation.

Inflammation involves the sequential activation of signaling pathways leading to the production of both pro- and anti-inflammatory mediators. Although much attention has focused on pro-inflammatory pathways that initiate inflammation, relatively little is known about the mechanisms that switch off inflammation and resolve the inflammatory response. The transcription factor NF-kappaB is thought to have a central role in the induction of pro-inflammatory gene expression and has attracted interest as a new target for the treatment of inflammatory disease. We show here that NF-kappaB activation in leukocytes recruited during the onset of inflammation is associated with pro-inflammatory gene expression, whereas such activation during the resolution of inflammation is associated with the expression of anti-inflammatory genes and the induction of apoptosis. Inhibition of NF-kappaB during the resolution of inflammation protracts the inflammatory response and prevents apoptosis. This suggests that NF-kappaB has an anti-inflammatory role in vivo involving the regulation of inflammatory resolution.

Inducible cyclooxygenase may have anti-inflammatory properties.

Cyclooxygenase (COX) has two isoforms. Generally, COX 1 is constitutively expressed in most tissues, where it maintains physiological processes; inducible COX 2 is considered a pro-inflammatory enzyme and a chief target for the treatment of inflammatory diseases. Here we present evidence that COX 2 may have anti-inflammatory properties. In carrageenin-induced pleurisy in rats, the predominant cells at 2 hours are polymorphonuclear leucocytes, whereas mononuclear cells dominate from 24 hours until resolution at 48 hours. In this model, COX 2 protein expression peaked initially at 2 hours, associated with maximal prostaglandin E2 synthesis. However, at 48 hours there was a second increase in COX 2 expression, 350% greater than that at 2 hours. Paradoxically, this coincided with inflammatory resolution and was associated with minimal prostaglandin E2 synthesis. In contrast, levels of prostaglandin D2, and 15deoxy delta(12-14)prostaglandin J2 were high at 2 hours, decreased as inflammation increased, but were increased again at 48 hours. The selective COX 2 inhibitor NS-398 and the dual COX 1/COX 2 inhibitor indomethacin inhibited inflammation at 2 hours but significantly exacerbated inflammation at 48 hours. This exacerbation was associated with reduced exudate prostaglandin D2 and 15deoxy delta(12-14)prostaglandin J2 concentrations, and was reversed by replacement of these prostaglandins. Thus, COX 2 may be pro-inflammatory during the early phase of a carrageenin-induced pleurisy, dominated by polymorphonuclear leucocytes, but may aid resolution at the later, mononuclear cell-dominated phase by generating an alternative set of anti-inflammatory prostaglandins.

Anatomical changes in human motor cortex and motor pathways following complete thoracic spinal cord injury.

A debilitating consequence of complete spinal cord injury (SCI) is the loss of motor control. Although the goal of most SCI treatments is to re-establish neural connections, a potential complication in restoring motor function is that SCI may result in anatomical and functional changes in brain areas controlling motor output. Some animal investigations show cell death in the primary motor cortex following SCI, but similar anatomical changes in humans are not yet established. The aim of this investigation was to use voxel-based morphometry (VBM) and diffusion tensor imaging (DTI) to determine if SCI in humans results in anatomical changes within motor cortices and descending motor pathways. Using VBM, we found significantly lower gray matter volume in complete SCI subjects compared with controls in the primary motor cortex, the medial prefrontal, and adjacent anterior cingulate cortices. DTI analysis revealed structural abnormalities in the same areas with reduced gray matter volume and in the superior cerebellar cortex. In addition, tractography revealed structural abnormalities in the corticospinal and corticopontine tracts of the SCI subjects. In conclusion, human subjects with complete SCI show structural changes in cortical motor regions and descending motor tracts, and these brain anatomical changes may limit motor recovery following SCI.

Treatment recommendations for psoriatic arthritis.

OBJECTIVE: To develop comprehensive recommendations for the treatment of the various clinical manifestations of psoriatic arthritis (PsA) based on evidence obtained from a systematic review of the literature and from consensus opinion. METHODS: Formal literature reviews of treatment for the most significant discrete clinical manifestations of PsA (skin and nails, peripheral arthritis, axial disease, dactylitis and enthesitis) were performed and published by members of the Group for Research and Assessment of Psoriasis and Psoriatic Arthritis (GRAPPA). Treatment recommendations were drafted for each of the clinical manifestations by rheumatologists, dermatologists and PsA patients based on the literature reviews and consensus opinion. The level of agreement for the individual treatment recommendations among GRAPPA members was assessed with an online questionnaire. RESULTS: Treatment recommendations were developed for peripheral arthritis, axial disease, psoriasis, nail disease, dactylitis and enthesitis in the setting of PsA. In rotal, 19 recommendations were drafted, and over 80% agreement was obtained on 16 of them. In addition, a grid that factors disease severity into each of the different disease manifestations was developed to help the clinician with treatment decisions for the individual patient from an evidenced-based perspective. CONCLUSIONS: Treatment recommendations for the cardinal physical manifestations of PsA were developed based on a literature review and consensus between rheumatologists and dermatologists. In addition, a grid was established to assist in therapeutic reasoning and decision making for individual patients. It is anticipated that periodic updates will take place using this framework as new data become available.

The challenge of early systemic sclerosis for the EULAR Scleroderma Trial and Research group (EUSTAR) community. It is time to cut the Gordian knot and develop a prevention or rescue strategy.

Early diagnosis of systemic sclerosis (SSc) may allow the start of treatment that could slow disease progression. For this reason early diagnosis of the disease is of pivotal importance. However, the lack of diagnostic criteria and valid predictors significantly limit patient evaluation and the use of potentially effective drugs in the earliest phase of SSc. Early SSc may be suspected on the basis of Raynaud's phenomenon, puffy fingers, autoantibodies and SSc capillaroscopic pattern. In practice, the aim is to have criteria for the diagnosis of very early SSc. The criteria that are proposed are obviously provisional and need to be validated: (a) initially through a Delphi technique; (b) thereafter perhaps using already available datasets; but (c) of critical importance, through prospective studies. Only after prospective studies can these potential criteria be considered validated. The consensus on criteria for the classification of very early SSc might be part of the evolving EULAR/ACR project of reclassification of SSc.

Pulmonary arterial hypertension: the most devastating vascular complication of systemic sclerosis.

Pulmonary arterial hypertension (PAH) is a devastating vascular complication of a number of CTDs. In patients with SSc, PAH has a dramatic impact on prognosis and survival and is the single most common cause of disease-related death.Yearly echocardiographic screening for PAH is recommended in patients with SSc. If suspected, confirmation of PAH diagnosis by right heart catheterization is necessary. Treatment goals for patients with PAH associated with SSc (PAH-SSc) aim to slow disease progression and improve quality of life. Some measures used to gauge the effect of treatment in patients with PAH-SSc remain to be fully validated; the 6-min walk distance, for example, is a simple and reproducible means of assessing exercise capacity, but there exists a need to understand what constitutes a clinically relevant change in this specific patient population. Currently, pharmacological intervention in PAH-SSc may target one or more of three pathophysiological pathways in PAH. The prostacyclin analogue epoprostenol has been shown to improve exercise capacity and haemodynamics in PAH-SSc patients and similar data are available from smaller studies on trepostinil and iloprost. The dual endothelin receptor antagonist bosentan has been shown to improve exercise capacity and haemodynamics in PAH-SSc, and similar data have been obtained in small numbers of patients treated with the endothelin receptor A antagonists sitaxsentan and ambrisentan. Impaired production of nitric oxide may be addressed by inhibiting phosphodiesterase type-5 with sildenafil or possibly tadalafil. Combinations of multiple targeted therapies may be beneficial to this patient population.