Prospective trial of natalizumab personalised extended interval dosing by therapeutic drug monitoring in relapsing-remitting multiple sclerosis (NEXT-MS).

BACKGROUND: Extended interval dosing (EID) of natalizumab is a promising strategy to optimise treatment in multiple sclerosis (MS). Personalised EID by therapeutic drug monitoring can enable further extension of treatment intervals. METHODS: The NEXT-MS trial is an investigator-initiated prospective phase IV non-randomised study. Adults with a diagnosis of relapsing-remitting MS who received ≥6 natalizumab infusions were included in three groups: personalised EID with a target drug trough concentration of 10 µg/mL (EID10), an exploratory group of personalised EID with a target of 5 µg/mL (EID5) and standard interval dosing (SID) of 4 weeks. The primary outcome is radiological disease activity (new/newly enlarged T2 lesions) comparing the EID10 group to a historical cohort of SID (HSID). RESULTS: Results of the first phase of the NEXT-MS trial are reported here (n=376) as the study will continue with an amended protocol. In the EID10 group (n=251), incidence rate of radiological activity was 10.0 per 1000 person-years, which was non-inferior to the HSID cohort (24.7 per 1000 person-years (n=87), incidence rate difference 14.7, 90% CI -4.5 to 34.0). Incidence rate of radiological activity was 10.0 per 1000 person-years in the EID5 group (n=65), and 47.0 per 1000 person-years in the SID group (n=60). Serum neurofilament light levels did not increase over time within the EID groups. There were no cases of progressive multifocal leukoencephalopathy. CONCLUSIONS: MS disease activity is adequately controlled with personalised natalizumab EID. Interval extension to a drug trough concentration of 5 µg/mL is likely a safe target to extend natalizumab treatment intervals >6 weeks. TRIAL REGISTRATION NUMBER: NCT04225312.

Serum glial fibrillary acidic protein in natalizumab-treated relapsing-remitting multiple sclerosis: An alternative to neurofilament light.

BACKGROUND: There is a need in Relapsing-Remitting Multiple Sclerosis (RRMS) treatment for biomarkers that monitor neuroinflammation, neurodegeneration, treatment response, and disease progression despite treatment. OBJECTIVE: To assess the value of serum glial fibrillary acidic protein (sGFAP) as a biomarker for clinical disease progression and brain volume measurements in natalizumab-treated RRMS patients. METHODS: sGFAP and neurofilament light (sNfL) were measured in an observational cohort of natalizumab-treated RRMS patients at baseline, +3, +12, and +24 months and at the last sample follow-up (median 5.17 years). sGFAP was compared between significant clinical progressors and non-progressors and related to magnetic resonance imaging (MRI)-derived volumes of the whole brain, ventricle, thalamus, and lesion. The relationship between sGFAP and sNfL was assessed. RESULTS: A total of 88 patients were included, and 47.7% progressed. sGFAP levels at baseline were higher in patients with gadolinium enhancement (1.3-fold difference, p = 0.04) and decreased in 3 months of treatment (adj. p < 0.001). No association was found between longitudinal sGFAP levels and progressor status. sGFAP at baseline and 12 months was significantly associated with normalized ventricular (positively), thalamic (negatively), and lesion volumes (positively). Baseline and 12-month sGFAP predicted annualized ventricle volume change rate after 1 year of treatment. sGFAP correlated with sNfL at baseline (p < 0.001) and last sample follow-up (p < 0.001) but stabilized earlier. DISCUSSION: sGFAP levels related to MRI markers of neuroinflammation and neurodegeneration.

Glial fibrillary acidic protein and multiple sclerosis progression independent of acute inflammation.

BACKGROUND: The clinical relevance of serum glial fibrillary acidic protein (sGFAP) concentration as a biomarker of MS disability progression independent of acute inflammation has yet to be quantified. OBJECTIVE: To test whether baseline values and longitudinal changes in sGFAP concentration are associated with disability progression without detectable relapse of magnetic resonance imaging (MRI) inflammatory activity in participants with secondary-progressive multiple sclerosis (SPMS). METHODS: We retrospectively analyzed longitudinal sGFAP concentration and clinical outcome data from the Phase 3 ASCEND trial of participants with SPMS, with no detectable relapse or MRI signs of inflammatory activity at baseline nor during the study (n = 264). Serum neurofilament (sNfL), sGFAP, T2 lesion volume, Expanded Disability Status Scale (EDSS), Timed 25-Foot Walk (T25FW), 9-Hole Peg Test (9HPT), and composite confirmed disability progression (CDP) were measured. Linear and logistic regressions and generalized estimating equations were used in the prognostic and dynamic analyses. RESULTS: We found a significant cross-sectional association between baseline sGFAP and sNfL concentrations and T2 lesion volume. No or weak correlations between sGFAP concentration and changes in EDSS, T25FW, and 9HPT, or CDP were observed. CONCLUSION: Without inflammatory activity, changes in sGFAP concentration in participants with SPMS were neither associated with current nor predictive of future disability progression.

Association between age and inflammatory disease activity on magnetic resonance imaging in relapse onset multiple sclerosis during long-term follow-up.

BACKGROUND AND PURPOSE: Inflammatory disease activity in multiple sclerosis (MS) decreases with advancing age. Previous work found a decrease in contrast-enhancing lesions (CELs) with age. Here, we describe the relation of age and magnetic resonance imaging (MRI) measures of inflammatory disease activity during long-term follow-up in a large real-world cohort of people with relapse onset MS. METHODS: We investigated MRI data from the long-term observational Amsterdam MS cohort. We used logistic regression models and negative binomial generalized estimating equations to investigate the associations between age and radiological disease activity after a first clinical event. RESULTS: We included 1063 participants and 10,651 cranial MRIs. Median follow-up time was 6.1 years (interquartile range = 2.4-10.9 years). Older participants had a significantly lower risk of CELs on baseline MRI (40-50 years vs. <40 years: odds ratio [OR] = 0.640, 95% confidence interval [CI] = 0.45-0.90; >50 years vs. <40 years: OR = 0.601, 95% CI = 0.33-1.08) and a lower risk of new T2 lesions or CELs during follow-up (40-50 years vs. <40 years: OR = 0.563, 95% CI = 0.47-0.67; >50 years vs. <40 years: OR = 0.486, 95% CI = 0.35-0.68). CONCLUSIONS: Greater age is associated with a lower risk of inflammatory MRI activity at baseline and during long-term follow-up. In patients aged >50 years, a less aggressive treatment strategy might be appropriate compared to younger patients.

The first report of meningitis in a Greenland shark (Somniosus microcephalus).

The Greenland shark (Somniosus microcephalus) is a large species of shark found in the North Atlantic and Arctic Oceans and is believed to be the longest living vertebrate. Relatively little is known about its biology, abundance, health or diseases. In March 2022, only the third reported UK stranding of this species occurred and it was the first to undergo post-mortem examination. The animal was a sexually immature female, measuring 3.96 m in length and 285 kg in weight, and was in poor nutritional state. Gross findings included haemorrhages in the skin and soft tissues, particularly of the head, and silt in the stomach suggestive of live stranding, bilateral corneal opacity, slightly turbid cerebrospinal fluid (CSF) and patchy congestion of the brain. Histopathological findings included keratitis and anterior uveitis, fibrinonecrotic and lymphohistiocytic meningitis of the brain and proximal spinal cord and fibrinonecrotizing choroid plexitis. A near pure growth of a Vibrio organism was isolated from CSF. This is believed to be the first report of meningitis in this species.

Hepatic Amyloidosis in a Chronically Entangled Grey Seal (Halichoerus grypus).

Grey seal (Halichoerus grypus) entrapment in fishing gear is well documented, consisting of two forms: peracute underwater entrapment and chronic entanglement. We now highlight a previously undescribed sequela to chronic entanglement in a female grey seal estimated to be at least 2 years of age. The animal was first observed in September 2018 on the coast of north Cornwall, southwest England, with a large encircling neck wound consistent with monofilament net entanglement. In April 2021, it was admitted for attempted rehabilitation but had to be euthanized after 9 days due to clinical deterioration despite treatment. At post-mortem examination, the seal was in poor nutritional state, the nose to flipper length was low for its estimated age and the liver was markedly enlarged, pale and friable in texture with evidence of recent and previous hepatic haemorrhage. Histopathology revealed hepatic amyloidosis and evidence of amyloid in one kidney and one adrenal gland. Proteomic analysis of microdissected amyloid from the liver indicated type AA amyloid. Chronic entanglement is the most plausible cause of AA amyloidosis in this animal, indicating that amyloidosis should be considered as a pathological sequela and welfare concern associated with chronic entanglement of grey seals.

Investigation into an outbreak of Border disease virus in pigs in England.

Border disease (BD) was first reported in 1959 in lambs from the border region of England and Wales. The causative virus (BD virus; BDV) has since been identified in several other ruminant species and pigs. The virus is prevalent in sheep flocks of UK, Europe and USA and has potential to inflict substantial economic losses. Natural BDV infection of pigs was first reported in the UK in 1992 from pigs with haemorrhagic lesions and more recently from healthy pigs in Spain and Japan. Here, a persistent problem of poor growth and anaemia in a small proportion of growing pigs on a mixed pig and sheep holding was investigated and tissues were tested in a pan viral microarray. The microarray detected BDV RNA in several tissues which was further confirmed by sequencing, specific BDV PCR and immunohistochemistry. Phylogenetically, the virus clustered with other BDVs in the sub-genotype 1b. This investigation highlights likely interspecies transmission of pestiviruses and their impact on pestivirus detection and eradication programs.

To scan or not to scan? Efficacy of transthoracic ultrasonography for ovine pulmonary adenocarcinoma screening in a large commercial UK sheep flock.

BACKGROUND: Transthoracic ultrasonography (TTUS) is currently the only widely used method to diagnose preclinical or subclinical ovine pulmonary adenocarcinoma (OPA) in the live sheep. However, little is known about the test characteristics of TTUS. METHODS: One thousand and seventy-four breeding ewes in a flock with evidence of low OPA prevalence underwent TTUS by an experienced operator. Fifty-one sheep were diagnosed with OPA and underwent gross postmortem examination (PME). RESULTS: Lesions consistent with OPA were found in only 24% (12/51) of the culled ewes. Thirty-five percent (18/51) of culled ewes had gross lesions consistent with other pulmonary disease and 41% (21/51) had no detectable gross lesions on PME. Histopathology and immunohistochemistry confirmed OPA in only the 12 animals identified with OPA lesions from PME. CONCLUSION: Great caution should be exercised when deciding if TTUS is an appropriate screening test in groups of sheep where OPA prevalence may be anticipated to be low. TTUS is a subjective test and thus individual operator ability will influence the sensitivity and specificity of TTUS for OPA diagnosis while the underlying prevalence influences the eventual positive predictive value.

Systemic Erysipelothrix rhusiopathiae in seven free-ranging delphinids stranded in England and Wales.

Microbiology records for 1127 cetaceans stranded on English and Welsh beaches and examined at the Institute of Zoology between 1990 and 2019 were reviewed to identify cases of Erysipelothrix rhusiopathiae, an uncommon but potentially fatal zoonotic pathogen. Once cases were identified, prevalence was calculated, corresponding postmortem reports were reviewed, common gross and histopathological findings were identified, and antibiotic susceptibilities were determined. Overall prevalence for E. rhusiopathiae was 0.62% (7/1127; 95% CI: 0.30-1.28%). It was isolated from 3 bottlenose dolphins Tursiops truncatus, 3 harbor porpoises Phocoena phocoena, and 1 short-beaked common dolphin Delphinus delphis, with a prevalence of 21.4% (3/14; 95% CI: 7.6-47.9%), 0.39% (3/779; 95% CI: 0.13-1.13%), and 0.47% (1/212; 95% CI: 0.08-2.62%) for each species, respectively. E. rhusiopathiae resulted in septicemia in all cases from which it was isolated. Gross necropsy findings included pulmonary edema (5/7), hemorrhage (5/7) and/or congestion of various organs (4/7), and serosanguineous effusion (3/7; pericardial: 3/7, pleural: 2/6, abdominal: 2/6). Congestion (5/5), bacterial emboli (4/5), and hemorrhage (4/5) were commonly observed on histopathology, and acute renal tubular injury (2/5) and pulmonary edema (2/5) were occasionally observed. Routine bacterial cultures were vital in identifying E. rhusiopathiae, since gross lesions were often subtle and nonspecific. The liver, kidney, and brain were key organs from which E. rhusiopathiae was consistently isolated. Antibiotic resistance was uncommon and was only observed for amikacin and trimethoprim sulfonamide. Penicillins were consistently effective, along with fluoroquinolones, macrolides, clindamycin, cephalexin, and oxytetracycline.

Novel Presentation of DMV-Associated Encephalitis in a Long-Finned Pilot Whale (Globicephala melas).

Cetacean morbillivirus (CeMV) is an important global cause of morbidity and mortality in cetacean populations, with four pathological presentations including non-suppurative encephalitis. We describe an unusual case of dolphin morbillivirus (DMV)-associated non-suppurative encephalitis in a long-finned pilot whale (Globicephala melas), in which the lesions were orientated on the periventricular white matter and comprised prominent multifocal syncytia formation in the absence of systemic lesions. DMV RNA was detected in brain tissue by qRT-PCR and immunohistochemistry for morbillivirus antigen yielded intense labelling of syncytia in periventricular sites, with sparse involvement of the deeper neuroparenchyma. The pattern of lesions raises the possibility of viral dissemination through the cerebrospinal fluid, as described for canine distemper virus, suggesting that similar pathogenic mechanisms may be implicated in lesion development. Further investigation is required to establish the pathogenesis of CeMV encephalitis and the behaviour of the virus within the central nervous system of cetaceans.

Systemic Necrotizing Vasculitis in Sheep Is Associated With Ovine Herpesvirus 2.

Ovine herpesvirus 2 (OvHV-2) is one of the gammaherpesviruses in the genus Macavirus that can cause malignant catarrhal fever (MCF) in ungulates. Sheep are the adapted host for OvHV-2 and it is generally assumed that infection is not associated with disease in this species. However, cases of "polyarteritis nodosa" or idiopathic systemic necrotizing vasculitis reported in sheep are similar to vascular lesions in clinically susceptible species with MCF. Using a recently developed in situ hybridization (ISH) method, we were able to identify OvHV-2 nucleic acids within lesions and correlate the viral distribution with systemic necrotizing vasculitis in 9 sheep, including both naturally and experimentally OvHV-2-infected animals. ISH, combined with polymerase chain reaction and histology, identify OvHV-2 as the likely agent responsible for sporadic, MCF-like vascular disease in sheep.

Systemic necrotizing polyarteritis in three weaned lambs from one flock.

Systemic necrotizing polyarteritis was diagnosed in three 7-11-mo-old lambs from the same flock. Aneurysmal dilation and rupture of the gastroduodenal artery in 1 lamb resulted in fatal hemorrhage. All lambs had severe necrotizing vasculitis involving the small intestine, abomasum, mesentery, kidney, and heart with concurrent lymphocytic enteritis. Immunohistochemistry for T- and B-lymphocytes and macrophages found a T-cell- and macrophage-dominant transmural vascular infiltrate and T-cell-associated enteritis. PCR analysis for pestivirus failed to identify infection in 1 lamb, and more extensive viral microarray techniques applied to the second and third lamb failed to detect viral nucleic acid. The identification of 3 cases within 1 flock raises the possibility of a common etiology; however, no cause was established. A genetic etiology was not considered likely as not all of the lambs were related. The presence of concurrent T-lymphocyte-associated enteritis raises the possibility of an immune-mediated disease process linking the vasculitis and enteric lesions.