Andrew L. Taylor

Therapeutic efficacy and safety of chaperonin 10 in patients with rheumatoid arthritis: a double-blind randomised trial

BACKGROUND Chaperonin 10 (heat shock protein 10, XToll) has anti-inflammatory properties related to the inhibition of Toll-like receptor signalling pathways. Our aim was to establish whether chaperonin 10 is safe and effective in the treatment of rheumatoid arthritis. METHODS In this randomised, double-blind, multicentre study, 23 patients with moderate to severe active rheumatoid arthritis receiving disease-modifying antirheumatic drugs were randomly allocated to three treatment groups receiving intravenous chaperonin 10 twice weekly for 12 weeks at doses of 5 mg (n=8), 7.5 mg (8), or 10 mg (7). The primary outcomes were change in disease activity score (DAS28) and improvement of core disease measures (American College of Rheumatology response score) from baseline to week 12. All analyses were done by intention to treat. This study is registered with the Australian Clinical Trials Registry, number ACTRNO12606000041550. FINDINGS Primary endpoint measures improved from day 14 in all groups and continued to improve to day 84. By end of study, a 20% improvement of core disease measures was seen in six (86%, 95% CI 43-100), a 50% improvement in four (57%, 14-86), and a 70% improvement in two (29%, 0-57) patients given the highest dose of chaperonin 10. Clinical remission (as defined by a DAS28 <2.6) was achieved in three (13%) of 23 patients. Three individuals dropped out during the study: one in the 5 mg group (rheumatoid arthritis not controlled), one in the 7.5 mg group (adverse event), and one in the 10 mg group (lost to follow-up). The most common adverse events were exacerbation of rheumatoid arthritis (both during and after the study) and upper respiratory tract infection. Only one adverse event was judged to be of severe intensity. INTERPRETATION Chaperonin 10 seems to be well tolerated and efficacious in treatment of the symptoms of rheumatoid arthritis, at least in the short term.

Failure to restore vision after optic nerve regeneration in reptiles: interspecies variation in response to axotomy.

Optic nerve regeneration within the reptiles is variable. In a snake, Viper aspis, and the lizard Gallotia galloti, regeneration is slow, although some retinal ganglion cell (RGC) axons eventually reach the visual centers (Rio et al. [ 1989 ] Brain Res 479:151–156; Lang et al. [ 1998 ] Glia 23:61–74). By contrast, in a lizard, Ctenophorus ornatus, numerous RGC axons regenerate rapidly to the visual centers, but unless animals are stimulated visually, the regenerated projection lacks topography and animals remain blind via the experimental eye (Beazley et al. [ 2003 ] J. Neurotrauma 20:1263–1269). V. aspis, G. galloti, and C. ornatus belong respectively to the Serpentes, Lacertidae, and Agamidae within the Eureptilia, the major modern group of living reptiles comprising the Squamata (snakes, lizards, and geckos) and the Crocodyllia. Here we have extended the findings on Eureptilia to include two geckos (Gekkonidae), Cehyra variegata and Nephrurus stellatus. We also examined a turtle, Chelodina oblonga, the Testudines being the sole surviving representatives of the Parareptilia, the more ancient reptilian group. In all three species, visually elicited behavioral responses were absent throughout regeneration, a result supported electrophysiologically; axonal tracing revealed that only a small proportion of RGC axons crossed the lesion and none entered the contralateral optic tract. RGC axons failed to reach the chiasm in C. oblonga, and in G. variegata, and N. stellatus RGC axons entered the opposite optic nerve; a limited ipsilateral projection was seen in G. variegata. Our results support a heterogeneous response to axotomy within the reptiles, each of which is nevertheless dysfunctional. J. Comp. Neurol. 478:292–305, 2004.

Training on a Visual Task Improves the Outcome of Optic Nerve Regeneration

Optic nerve regeneration in a lizard, Ctenophorus ornatus, is dysfunctional despite survival of most retinal ganglion cells and axon regeneration to the optic tectum. The regenerated retino-tectal projection at 6 months has crude topography but by 1 year is disordered; visually-elicited behavior is absent via the experimental eye. Here, we assess the influence of training on the outcome of optic nerve regeneration. Lizards were trained to catch prey presented within the monocular field of either eye. One optic nerve was then severed and visual stimulation resumed throughout regeneration. In the trained group, presentation was restricted to the eye undergoing optic nerve regeneration; for the untrained group, the unoperated eye was stimulated. Pupil responses returned in trained but not in untrained animals. At 1 year, trained animals oriented to and captured prey; untrained animals demonstrated minimal orienting and failed to capture prey. Regenerated retino-tectal projections were topographic in the trained but not in the untrained group as assessed by in vitro electrophysiological recording and by carbocyanine dye tracing. In vitro electrophysiological recording during application of neurotransmitter antagonists to the tectum revealed that the level of GABAergic inhibition was modest in trained animals but elevated in the untrained group; responses were mainly AMPA-mediated in both groups. We conclude that training improves the behavioral outcome of regeneration, presumably by stabilizing and refining the transient retino-tectal map and preventing a build-up of tectal inhibition. The results suggest that for successful central nerve regeneration to occur in mammals, it may be necessary to introduce training to complement procedures stimulating axon regeneration.

Australian and New Zealand recommendations for the diagnosis and management of gout: integrating systematic literature review and expert opinion in the 3e Initiative

To develop evidence‐based recommendations for the diagnosis and management of gout in Australia and New Zealand as part of the multi‐national 3e Initiative.

The balance of NMDA- and AMPA/kainate receptor-mediated activity in normal adult goldfish and during optic nerve regeneration

Retinotectal topography is established during development and relies on the sequential recruitment of glutamate receptors within postsynaptic tectal cells. NMDA receptors underpin plastic changes at early stages when retinal ganglion cell (RGC) terminal arbors are widespread and topography is coarse; AMPA/kainate receptors mediate fast secure neurotransmission characteristic of mature circuits once topography is refined. Here, we have examined the relative contributions of these receptors to visually evoked activity in normal adult goldfish, in which retinotectal topography is constantly adjusted to compensate for the continual neurogenesis and the addition of new RGC arbors. Furthermore, we examined animals at two stages of optic nerve regeneration. In the first, RGC arbors are widespread and receptive fields large resulting in coarse topography; in the second, RGC arbors are pruned to reduce receptive fields leading to refined topography. Antagonists were applied to the tectum during multiunit recording of postsynaptic responses. Normal goldfish have low levels of NMDA receptor-mediated activity and high levels of AMPA/kainate. When coarse topography has been restored, NMDA receptor-mediated activity is increased and that of AMPA/kainate decreased. Once topography has been refined, the balance of NMDA and AMPA/kainate receptor-mediated activity returns to normal. The data suggest that glutamatergic neurotransmission in normal adult goldfish is dual with NMDA receptors fine-tuning topography and AMPA receptors allowing stable synaptic function. Furthermore, the normal operation of both receptors allows a response to injury in which the balance can be transiently reversed to restore topography and vision.

Consensus statements on the imaging of axial spondyloarthritis in Australia and New Zealand

Free to read Spondyloarthritis (SpA) describes a group of related inflammatory conditions, including ankylosing spondylitis (AS), psoriatic arthritis, reactive arthritis, SpA associated with inflammatory bowel disease and undifferentiated SpA.[1] Classification criteria have been developed and validated by the Assessment of SpondyloArthritis international Society (ASAS) to distinguish axial-predominant SpA from peripherally predominant SpA (Fig. 1).[1, 2] These criteria contribute to diagnosis, but are not ideal diagnostic criteria as they possess only moderate sensitivity.[3] Diagnosis of axial SpA should be established by a rheumatologist, after careful consideration of these criteria and individual patient factors.

AB0442 Regional Patterns of Tocilizumab Use, Efficacy, and Safety in Patients with Rheumatoid Arthritis: Interim Results from a Multinational Observational Study

Background Tocilizumab (TCZ) is an anti–interleukin-6 receptor antibody indicated for the treatment of patients with rheumatoid arthritis (RA). It can be prescribed either as monotherapy or in combination with disease-modifying antirheumatic drugs (DMARDs). ACT-UP is an umbrella project incorporating data from several prospective, international, observational, postmarketing studies investigating TCZ use in patients with RA in routine care. Objectives To investigate regional patterns of intravenous (IV) TCZ use, efficacy, and safety over 6 months of treatment in ACT-UP. Methods Adults with moderate to severe RA who started IV TCZ within 8 weeks of enrollment were observed in clinical practice for 6 months. There were no specified dosing regimens (concomitant RA treatments were permitted) and no interventional procedures, clinic visits, or laboratory analyses outside routine practice. Regional differences were investigated across studies performed in different countries. Results Of 1257 patients who received their first TCZ dose by January 31, 2014, 679 were from Europe, 198 from Canada, 184 from Israel, 115 from South America, 44 from Indonesia, and 37 from Australia. The mean age of patients was 55.0 years and ranged from 44.1 years in Indonesia to 59.3 years in Australia. While 81% of all patients were female, the percentage of female patients was lowest in Australia (57%) and highest in Central America (92%). Patterns of TCZ use by region are shown in the table. Overall, 22 of 431 patients (5.1%) receiving monotherapy switched to combination therapy during the study. The proportion of patients remaining on TCZ after 6 months was 82.7% (95% confidence interval: 80.5%, 84.8%). Mean concomitant MTX dose including baseline and during the study ranged from 10.0 to 18.8 mg/week across regions. Corticosteroids (CSs) were taken by 43.8% of patients at baseline, and mean (range) CS dose was 8.3 (5.0-10.3) mg/day, with some fluctuations among regions. Of 466 patients who had an assessment of disease activity at 6 months, 92.7% reported EULAR good or moderate responses, with similar response rates across all regions (Table). Overall, 650/1257 (52%) patients reported adverse events (AEs), and 102/1257 (8%) reported serious AEs (SAEs). Events occurring under the system organ class of infections and infestations were the most common AEs (19.5%) and SAEs (2.0%) reported. Conclusions At 6 months, there was high persistence of TCZ use that was greater than 90% in some regions of the world. Although there were some regional differences in baseline characteristics and patterns of TCZ use, the effectiveness of TCZ at 6 months was high across regions. Over 6 months of use in clinical settings, the reported safety of TCZ was consistent with the known safety profile. Disclosure of Interest B. Haraoui Grant/research support from: AbbVie, Amgen, BMS, Celgene, Janssen, Pfizer, Roche, UCB, Consultant for: AbbVie, Amgen, BMS, Celgene, Janssen, Pfizer, Roche, UCB, Speakers bureau: AbbVie, Amgen, BMS, Celgene, Janssen, Pfizer, Roche, UCB, G. Casado: None declared, E. Theander Speakers bureau: Roche, L. Czirják: None declared, A. Taylor Consultant for: Roche, Celgene, AbbVie, Pfizer, UCB, E. Mikes Employee of: Roche, W. Reiss Employee of: Roche, R. Caporali: None declared

FRI0141 Vaccination decisions and incidence of neonatal infections in mothers exposed to biologicals during pregnancy

Background Rheumatologic diseases commonly affect women of childbearing age(.1, 2 There is currently limited data available regarding the safety of vaccinations in infants after in utero exposure to biologics. Objectives To determine the vaccination decisions of mothers with rheumatologic diseases exposed to biologics during pregnancy and the incidence of serious neonatal infections after third trimester exposure. Methods All Australian women with inflammatory arthritis, exposed to biologics during the preconception, antenatal and/or postpartum periods, were invited to participate in the Pregnancy Exposed to Biological (PEB) study from May 2009 – . Jan 2018 Recruitment was via direct invitation from patients treating rheumatologists, community groups, and via social media. Following self-referral to the study, retrospective data was collected, including biological exposure, vaccination history and the incidence of serious neonatal infections, defined as infection requiring hospitalisation. Results Preliminary data is available regarding 35 offspring from 28 mothers. 34 of 35 offspring were vaccinated. 29 received vaccinations in accordance with the Australian National Immunisation Program Schedule. 1 mother declined to immunise her infant due to personal preference. 13 infants were exposed to a tumour necrosis factor inhibitor (TNFi) during the third trimester. Of these, 4 had Rotavirus vaccine delayed from 2 to 4 months and 1 infant until 6 months. 1 infant did not receive the Rotavirus vaccine at 2 months due to exposure to a TNFi while breastfeeding. There were no incidences of serious neonatal infections. Conclusions Current guidelines recommend deferring live vaccines, such as rotavirus, until after 6 months if exposed to a biologic in the third trimesterr.(2–5 Compliance with these recommendations was only observed in one infant in our study. One infant received delayed Rotavirus vaccination due to concern about TNFi exposure during breastfeeding; this is not in keeping with current guidelines. Of the 12 infants exposed to a biologic during the third trimester who did not delay live vaccination until after 6 months, there were no incidents of serious neonatal infections, in keeping with the findings of current published case series. References [1] Brouwer J, Hazes JM, Laven JS, Dolhain RJ. Fertility in women with rheumatoid arthritis: influence of disease activity and medication. Ann Rheum Dis. 2015;74(10):1836–41. [2] Gotestam Skorpen C, Hoeltzenbein M, Tincani A, Fischer-Betz R, Elefant E, Chambers C, et al. The EULAR points to consider for use of antirheumatic drugs before pregnancy, and during pregnancy and lactation. Ann Rheum Dis. 2016;75(5):795–810. [3] Flint J, Panchal S, Hurrell A, van de Venne M, Gayed M, Schreiber K, et al. BSR and BHPR guideline on prescribing drugs in pregnancy and breastfeeding-Part I: standard and biologic disease modifying anti-rheumatic drugs and corticosteroids. Rheumatology (Oxford). 2016;55(9):1693–7. [4] Health AGDo. 3.3 Groups with special vaccination requirements2017. [5] Ostensen M. The use of biologics in pregnant patients with rheumatic disease. Expert Rev Clin Pharmacol2017;10(6):661–9. Disclosure of Interest None declared

Evidence‐based recommendations for the monitoring and treatment of ankylosing spondylitis: results from the Australian 3E initiative in rheumatology

Aim:  To develop a set of Australian recommendations for the monitoring and treatment of ankylosing spondylitis (AS) through systematic literature review combined with the opinion of practicing rheumatologists.

Opic Nerve Regeneration: Molecular Pre-Requisites and the Role of Training

The vertebrate visual system is a valuable model for examining recovery after injury to the central nervous system (CNS). It is a relatively “simple” part of the CNS having one major class of projection neuron, the retinal ganglion cells (RGCs), which make topographic connections within well defined visual nuclei, thus recreating visual space within the brain. Topographic maps can be readily assessed electrophysiologically and anatomically and are a critical template for useful visually guided behaviour which can be examined behaviourally. Furthermore, the optic nerve is accessible, an extra-foramenal crush injury severing all RGC axons but leaving the meningeal sheath intact as a conduit for regeneration and preventing gross axonal mis-routing. The procedure also leaves the blood supply to the eye patent, avoiding ischaemic-induced RGC death.