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

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

Real-world effectiveness and rheumatologist satisfaction with secukinumab in the treatment of patients with axial spondyloarthritis.

OBJECTIVES: To assess the effectiveness of secukinumab in patients with axSpA treated in routine clinical settings in 5 European countries. METHODS: Retrospective analysis of a cross-sectional survey to assess real-world effectiveness of secukinumab in the management of axSpA and rheumatologist satisfaction with treatment in France, Germany, Italy, Spain and the UK from March to December 2018. Outcomes collected included patient demographics, clinical characteristics and rheumatologist- and patient-reported satisfaction with secukinumab treatment. RESULTS: Five hundred thirty-five patients receiving secukinumab for more than 4 months were assessed, 359 of whom were diagnosed with AS and 178 with nr-axSpA. Rheumatologist assessment of disease status at treatment initiation indicated that 39 (7.3%) had stable/improving disease. Secukinumab treatment for 4 months or longer resulted in 515 (95.9%) patients judged as stable/improving. Treatment was associated with benefits from initiation to assessment in terms of BASDAI (6.2 vs 2.8), 44-joint count score (9.7 vs 6.6), rheumatologist global VAS score (56.9 vs 23.0) and patient global VAS scores (64.4 vs 25.5). These benefits for key clinical outcomes were sustained for periods of 12 months or longer. Patient-reported outcomes on health status using EQ-5D, global functioning using the ASAS health index and overall work impairment via WPAI were sustained over the treatment period, while patient and rheumatologist satisfaction with secukinumab treatment remained very high at 80.2 and 91.2%, respectively. CONCLUSION: Consistent benefits across multiple clinical and patient-reported outcomes were seen with secukinumab treatment in patients with AS and nr-axSpA treated in routine clinical settings across five European countries. Key Points • In routine clinical settings across five European countries, secukinumab treatment resulted in improvements in a wide range of clinical outcomes including physician-reported disease severity, disease status, pain, BASDAI, 44-joint count score and global VAS scores. • Key clinical and patient reported outcomes were sustained for a 12-month period or longer with secukinumab treatment. • Rheumatologist- and patient-reported treatment satisfaction was high with secukinumab.

Molecular pathology of Multiple Sclerosis lesions reveals a heterogeneous expression pattern of genes involved in oligodendrogliogenesis.

Little is known about the decisive molecular factors that regulate lesion remyelination in Multiple Sclerosis. To identify such factors, we performed a differential gene expression analysis of normal appearing white matter (NAWM), active, remyelinating, and inactive demyelinated lesions. As expected, many genes involved in inflammatory processes were detected to be differentially regulated between these tissue types. Among them, we found an increased expression of members of the STAT6 pathway such as STAT6, IL4 and IL4R in active, remyelinated and inactive demyelinated lesions. This suggests that a protective, anti-inflammatory reaction, as already reported to be present in MS NAWM, is further enhanced in lesion tissues. Focusing on genes influencing oligodendrogliogenesis, we found a decreased expression of NKX2-2 in active, remyelinated and inactive demyelinated lesions, whereas SOX10 was downregulated in inactive demyelinated lesions, when compared to NAWM. Simultaneously, CXCL12 (SDF1) expression was strongly increased in active, remyelinated and inactive demyelinated lesions, but increased expression of the IGF1 and IGF2 genes was found in inactive demyelinated lesions. This demonstrates that, in principle, expression of genes promoting oligodendrogliogenesis occurs in MS lesion tissue - even in inactive demyelinated lesions. In contrast, oligodendrogenesis inhibiting genes such as JAG1 were also expressed at higher levels in inactive demyelinated lesions. Both, oligodendrogliogenesis promoting as well as inhibiting genes are expressed in all lesion tissues. However, no clear promoting or inhibiting expression pattern could be detected in any of the different types of lesioned tissues. This might reflect the heterogeneity of lesion development in MS patients, both in terms of mechanisms and temporal differences.

Disruption of neurofascin localization reveals early changes preceding demyelination and remyelination in multiple sclerosis.

Saltatory conduction in the nervous system is enabled through the intimate association between the leading edge of the myelin sheath and the axonal membrane to demarcate the node of Ranvier. The 186 kDa neuron specific isoform of the adhesion molecule neurofascin (Nfasc186) is required for the clustering of voltage gated Na+ channels at the node, whilst the 155 kDa glial specific isoform (Nfasc155) is required for the assembly of correct paranodal junctions. In order to understand the relationship between these vital structures and how they are affected in multiple sclerosis we have examined the expression of Nfasc155 and Nfasc186 in areas of inflammation, demyelination and remyelination from post-mortem brains. Fourteen cases of neuropathologically confirmed multiple sclerosis (8 female and 6 male; post-mortem delay 7-24 h; age 37-77 years; and disease duration 15-40 years), comprising 20 tissue blocks with 32 demyelinating or remyelinating lesions, were used in this study. A significant early alteration in Nfasc155+ paranodal structures occurs within and adjacent to actively demyelinating white matter lesions that are associated with damaged axons. Shaker-type Kv1.2 channels, normally located distally to the paranode, overlapped with the disrupted Nfasc155+ structures. In the absence of Nfasc155, Kv1.2 channels abutted normally clustered Nfasc186+ nodes, indicating that complete disruption of the paranodal structure and movement of Kv1.2 channels precede alterations at the node itself. Within areas of partial remyelination, a number of atypical triple-Nfasc155+ structures were noted that may represent transient oligodendrocyte-axonal contacts during the process of myelin repair or aberrant interactions. Within shadow plaques discretely clustered Na+v, Nfasc186+ and Nfasc155+ domains indicated the restoration of normal nodal architecture. The alterations in oligodendrocyte Nfasc155 expression that accompany inflammation and demyelination suggest an ongoing disruption to the axonal-oligodendrocyte complex within newly forming as well as established lesions in multiple sclerosis, resulting in destruction of the Nfasc186+/Na+v nodal complex vital to successful fast neurotransmission in the CNS.

Loss of the major GABA(A) receptor subtype in the brain is not lethal in mice.

The alpha1beta2gamma2 is the most abundant subtype of the GABA(A) receptor and is localized in many regions of the brain. To gain more insight into the role of this receptor subtype in the modulation of inhibitory neurotransmission, we generated mice lacking either the alpha1 or beta2 subunit. In agreement with the reported abundance of this subtype, >50% of total GABA(A) receptors are lost in both alpha1-/- and beta2-/- mice. Surprisingly, homozygotes of both mouse lines are viable, fertile, and show no spontaneous seizures. Initially half of the alpha1-/- mice died prenatally or perinatally, but they exhibited a lower mortality rate in subsequent generations, suggesting some phenotypic drift and adaptive changes. Both adult alpha1-/- and beta2-/- mice demonstrate normal performances on the rotarod, but beta2-/- mice displayed increased locomotor activity. Purkinje cells of the cerebellum primarily express alpha1beta2gamma2 receptors, and in electrophysiological recordings from alpha1-/- mice GABA currents in these neurons are dramatically reduced, and residual currents have a benzodiazepine pharmacology characteristic of alpha2- or alpha3-containing receptors. In contrast, the cerebellar Purkinje neurons from beta2-/- mice have only a relatively small reduction of GABA currents. In beta2-/- mice expression levels of all six alpha subunits are reduced by approximately 50%, suggesting that the beta2 subunit can coassemble with alpha subunits other than just alpha1. Our data confirm that alpha1beta2gamma2 is the major GABA(A) receptor subtype in the murine brain and demonstrate that, surprisingly, the loss of this receptor subtype is not lethal.

Density and pharmacology of alpha5 subunit-containing GABA(A) receptors are preserved in hippocampus of Alzheimer's disease patients.

The anatomical localization and pharmacology of alpha5 subunit-containing GABA type-A receptors in the human hippocampal formation of Alzheimer's disease patients were studied with an alpha5 receptor selective ligand, [3H]L-655,708 and compared to age-matched human controls. Autoradiographic analyses revealed a heterogeneous distribution of [3H]L-655,708 binding sites in CA1-CA3 areas with high levels in stratum oriens, stratum pyramidale and stratum radiatum contrasting with low levels in stratum lacunosum. The highest quantity of alpha5 receptors was found in the molecular layer of the dentate gyrus. This pattern of expression was identical in both hippocampus from control and Alzheimer's disease subjects. Quantitative studies demonstrated that the number of [3H]L-655,708 binding sites is well preserved in Alzheimer's disease with only a moderate reduction (25-30%) in the CA1 subfield and entorhinal cortex. Furthermore, saturation and competition experiments with [3H]L-655,708 and representative benzodiazepine site ligands revealed that alpha5 receptors in Alzheimer's hippocampus have an alpha5beta2/3gamma2 pharmacology and structure as in control human brain.Overall, the data reported here provide evidence for a specific expression and relative sparing of alpha5 subunit-containing gamma-aminobutyric acid type-A receptors in the hippocampus of Alzheimer's patients.

Changes in [3H]zolpidem and [3H]Ro 15-1788 binding in rat globus pallidus and substantia nigra pars reticulata following a nigrostriatal tract lesion.

Changes in GABA(A) receptor alpha(1) subunit gene expression occur in the globus pallidus and substantia nigra pars reticulata following lesions of the nigrostriatal tract. To determine whether these changes are translated at the protein level, we performed quantitative autoradiography with the alpha(1) selective ligand, [3H]zolpidem, and the non-selective benzodiazepine site ligand, [3H]Ro 15-1788. Binding of both [3H]zolpidem and [3H]Ro 15-1788 was significantly increased in the substantia nigra pars reticulata (13. 5+/-4.1 and 26.3+/-2.9%, respectively) and significantly reduced in the globus pallidus (20.9+/-0.8 and 18.3+/-1.3%, respectively). These changes in alpha(1) subunit protein expression may help to compensate for the pathological changes in GABAergic activity that occur after striatal dopamine depletion.

Sedative but not anxiolytic properties of benzodiazepines are mediated by the GABA(A) receptor alpha1 subtype.

Inhibitory neurotransmission in the brain is largely mediated by GABA(A) receptors. Potentiation of GABA receptor activation through an allosteric benzodiazepine (BZ) site produces the sedative, anxiolytic, muscle relaxant, anticonvulsant and cognition-impairing effects of clinically used BZs such as diazepam. We created genetically modified mice (alpha1 H101R) with a diazepam-insensitive alpha1 subtype and a selective BZ site ligand, L-838,417, to explore GABA(A) receptor subtypes mediating specific physiological effects. These two complimentary approaches revealed that the alpha1 subtype mediated the sedative, but not the anxiolytic effects of benzodiazepines. This finding suggests ways to improve anxiolytics and to develop drugs for other neurological disorders based on their specificity for GABA(A) receptor subtypes in distinct neuronal circuits.

Autoradiographic localization of alpha5 subunit-containing GABAA receptors in rat brain.

Multiple subtypes of GABAA receptors are expressed in the rat central nervous system (CNS). To determine the distribution and proportion of alpha5 subunit containing receptors, quantitative autoradiographic analyses were performed with both [3H]L-655,708 and [3H]Ro15-1788, an alpha5 selective and a non selective benzodiazepine binding site ligand, respectively. High densities of [3H]L-655,708 binding sites were observed in hippocampus and olfactory bulb, where alpha5 receptors accounted for 20-35% of total [3H]Ro15-1788 binding sites. Low levels of [3H]L-655,708 sites were associated with the cortex as well as amygdala, thalamic, hypothalamic and midbrain nuclei. These observations indicate that although [3H]L-655,708 binding sites have an overall low expression in rat CNS, they may contribute significantly to GABAergic inhibition in specific brain regions.