Role of IFN-α in Rheumatoid Arthritis

\ua9 2023, The Author(s).Purpose of Review: Type 1 interferons (IFN-I) are of increasing interest across a wide range of autoimmune rheumatic diseases. Historically, research into their role in rheumatoid arthritis (RA) has been relatively neglected, but recent work continues to highlight a potential contribution to RA pathophysiology. Recent Findings: We emphasise the importance of disease stage when examining IFN-I in RA and provide an overview on how IFN-I may have a direct role on a variety of relevant cellular functions. We explore how clinical trajectory may be influenced by increased IFN-I signalling, and also, the limitations of scores composed of interferon response genes. Relevant environmental triggers and inheritable RA genetic risk relating to IFN-I signalling are explored with emphasis on intriguing data potentially linking IFN-I exposure, epigenetic changes, and disease relevant processes. Summary: Whilst these data cumulatively illustrate a likely role for IFN-I in RA, they also highlight the knowledge gaps, particularly in populations at risk for RA, and suggest directions for future research to both better understand IFN-I biology and inform targeted therapeutic strategies

A unifying theory for cognitive abnormalities in functional neurological disorders, fibromyalgia and chronic fatigue syndrome: systematic review.

BACKGROUND: Functional cognitive disorder (FCD) describes cognitive dysfunction in the absence of an organic cause. It is increasingly prevalent in healthcare settings yet its key neuropsychological features have not been reported in large patient cohorts. We hypothesised that cognitive profiles in fibromyalgia (FM), chronic fatigue syndrome (CFS) and functional neurological disorders (FNDs) would provide a template for characterising FCD. METHODS: We conducted a systematic review of studies with cognition-related outcomes in FM, CFS and FND. RESULTS: We selected 52 studies on FM, 95 on CFS and 39 on FND. We found a general discordance between high rates of subjective cognitive symptoms, including forgetfulness, distractibility and word-finding difficulties, and inconsistent objective neuropsychological deficits. Objective deficits were reported, including poor selective and divided attention, slow information processing and vulnerability to distraction. In some studies, cognitive performance was inversely correlated with pain, exertion and fatigue. Performance validity testing demonstrated poor effort in only a minority of subjects, and patients with CFS showed a heightened perception of effort. DISCUSSION: The cognitive profiles of FM, CFS and non-cognitive FND are similar to the proposed features of FCD, suggesting common mechanistic underpinnings. Similar findings have been reported in patients with mild traumatic brain injury and whiplash. We hypothesise that pain, fatigue and excessive interoceptive monitoring produce a decrease in externally directed attention. This increases susceptibility to distraction and slows information processing, interfering with cognitive function, in particular multitasking. Routine cognitive processes are experienced as unduly effortful. This may reflect a switch from an automatic to a less efficient controlled or explicit cognitive mode, a mechanism that has also been proposed for impaired motor control in FND. These experiences might then be overinterpreted due to memory perfectionism and heightened self-monitoring of cognitive performance

Non-Hyperammonaemic Valproate encephalopathy after 20 years of treatment.

Sodium valproate is a commonly used antiseizure drug with broad indications for different seizuretypes and epilepsy syndromes. Well-recognised side effects include weight gain, tremor, dizziness, and unsteadiness. Non-hyperammonaemic parkinsonism, with or without cognitive impairment, is a rare adverse effect of sodium valproate. We present the case of a sixty year-old lady with a generalized seizure disorder, treated with phenytoin, valproate, lamotrigine and clonazepam. Following withdrawal of phenytoin she developed an akinetic-rigid syndrome, with ataxia and marked cognitive impairment. Extensive investigation failed to identify a cause. Serum ammonia and valproate levels were normal. Hypothesizing this might be valproate encephalopathy, valproate was rapidly substituted with levetiracetam. Her severe motor symptoms resolved within two weeks and cognitive impairment markedly improved. Valproate-induced encephalopathy, with or without hyperammonaemia and liver toxicity are typically recognizable for their temporal relation between the start of therapy with valproate and emergence of the clinical syndrome. Reversible disorders of motor function and cognition attributable to valproate are well described, but few cases have been reported presenting years after starting treatment. Given the insidious progression, delayed onset, lack of association with drug levels or presence of hyperammonaemia, a high index of suspicion is needed to make the diagnosis

Quasi-diffusion magnetic resonance imaging (QDI): A fast, high b-value diffusion imaging technique.

To enable application of non-Gaussian diffusion magnetic resonance imaging (dMRI) techniques in large-scale clinical trials and facilitate translation to clinical practice there is a requirement for fast, high contrast, techniques that are sensitive to changes in tissue structure which provide diagnostic signatures at the early stages of disease. Here we describe a new way to compress the acquisition of multi-shell b-value diffusion data, Quasi-Diffusion MRI (QDI), which provides a probe of subvoxel tissue complexity using short acquisition times (1-4 min). We also describe a coherent framework for multi-directional diffusion gradient acquisition and data processing that allows computation of rotationally invariant quasi-diffusion tensor imaging (QDTI) maps. QDI is a quantitative technique that is based on a special case of the Continuous Time Random Walk model of diffusion dynamics and assumes the presence of non-Gaussian diffusion properties within tissue microstructure. QDI parameterises the diffusion signal attenuation according to the rate of decay (i.e. diffusion coefficient, D in mm2 s-1) and the shape of the power law tail (i.e. the fractional exponent, α). QDI provides analogous tissue contrast to Diffusional Kurtosis Imaging (DKI) by calculation of normalised entropy of the parameterised diffusion signal decay curve, Hn, but does so without the limitations of a maximum b-value. We show that QDI generates images with superior tissue contrast to conventional diffusion imaging within clinically acceptable acquisition times of between 84 and 228 s. We show that QDI provides clinically meaningful images in cerebral small vessel disease and brain tumour case studies. Our initial findings suggest that QDI may be added to routine conventional dMRI acquisitions allowing simple application in clinical trials and translation to the clinical arena

Differences in care between younger and older patients in the 2019 English national memory service audit.

AIMS AND METHOD: This paper analyses how practice varied between patients aged <65 and ≥65 years in the 2019 UK national memory service audit. RESULTS: Data on 3959 patients were analysed. Those aged <65 (7% of the sample) were less likely than those aged ≥65 to be diagnosed with dementia (23 v. 67%) and more likely to receive a functional, psychiatric or no diagnosis. Younger patients were more likely to have magnetic resonance imaging; use of dementia biomarkers was low in both groups. Frontotemporal dementia and functional cognitive disorder were diagnosed infrequently. Use of dementia navigators/advisors and carer psychoeducation was similar between groups; younger patients were less likely to be offered but more likely to accept cognitive stimulation therapy. CLINICAL IMPLICATIONS: Memory services seeing younger people need expertise in functional cognitive disorder, alongside clinical skills and technologies to diagnose rarer forms of dementia. Further work is needed to understand why cognitive stimulation therapy is less frequently offered to younger people

The London memory service audit and quality improvement programme.

Aims and methodMemory services have expanded significantly in the UK, but limited performance data have been published. The aim of this programme was to determine variation in London memory services and address this through service improvement projects. In 2016 London memory services were invited to participate in an audit consisting of case note reviews of at least 50 consecutively seen patients. RESULTS: Ten services participated in the audit, totalling 590 patients. Variation was noted in neuroimaging practice, neuropsychology referrals, diagnosis subtype, non-dementia diagnoses, waiting times and post-diagnostic support. Findings from the audit were used to initiate four service improvement projects.Clinical ImplicationsMemory services should consider streamlining pathways to reduce waiting times, implementing pathways for patients who do not have dementia, monitoring appropriateness of neuroimaging, and working with commissioners and primary care to ensure that access to post-diagnostic interventions is consistent with the updated National Institute for Health and Care Excellence (NICE) dementia guideline.Declaration of interestJ.D.I. received an honorarium from Biogen for an advisory board. He has been Principal Investigator in clinical trials sponsored by Roche, Merck and Lupin pharmaceuticals. He was a member of the 2018 NICE dementia clinical guideline committee

The effect of phosphodiesterase-5 inhibitors on cerebral blood flow in humans: A systematic review.

Agents that augment cerebral blood flow (CBF) could be potential treatments for vascular cognitive impairment. Phosphodiesterase-5 inhibitors are vasodilating drugs established in the treatment of erectile dysfunction (ED) and pulmonary hypertension. We reviewed published data on the effects of phosphodiesterase-5 inhibitors on CBF in adult humans. A systematic review according to PRISMA guidelines was performed. Embase, Medline and Cochrane Library Trials databases were searched. Sixteen studies with 353 participants in total were retrieved. Studies included healthy volunteers and patients with migraine, ED, type 2 diabetes, stroke, pulmonary hypertension, Becker muscular dystrophy and subarachnoid haemorrhage. Most studies used middle cerebral artery flow velocity to estimate CBF. Few studies employed direct measurements of tissue perfusion. Resting CBF velocity was unaffected by phosphodiesterase-5 inhibitors, but cerebrovascular regulation was improved in ED, pulmonary hypertension, diabetes, Becker's and a group of healthy volunteers. This evidence suggests that phosphodiesterase-5 inhibitors improve responsiveness of the cerebral vasculature, particularly in disease states associated with an impaired endothelial dilatory response. This supports the potential therapeutic use of phosphodiesterase-5 inhibitors in vascular cognitive impairment where CBF is reduced. Further studies with better resolution of deep CBF are warranted. The review is registered on the PROSPERO database (registration number CRD42016029668)