WORKWELL process evaluation: qualitative data analyses of the participant interviews at 12 and 36-month follow-ups

ObjectivesThis study aimed to qualitatively examine the delivery of the WORKWELL trial, a job retention vocational rehabilitation (JRVR) programme designed to help individuals with inflammatory arthritis (IA) maintain employment. A qualitative process evaluation used the Normalization Process Theory (NPT) to understand participant experiences and identify factors influencing implementation and outcomes.MethodsData were collected via one-to-one telephone interviews with trial participants at 12 and 36 months. An inductive reflexive thematic analysis was followed by a deductive analysis based on NPT’s four constructs (coherence, cognitive participation, collective action and reflexive monitoring).ResultsSixty-two participants (mean age 51.0; 82.3% female) were interviewed, most diagnosed with RA (75.8%). Four secondary themes were generated under NPT constructs. For ‘Coherence’, themes included ‘Exploring the Purpose and Impact of Taking Part in WORKWELL’ and ‘Questionnaires as Instrument for Reflection’. In ‘Cognitive Participation’, the theme was ‘Commitment and Investment to WORKWELL’. For ‘Collective Action’, we identified ‘Key Actions for Successful WORKWELL’, and under ‘Reflexive Monitoring’, the theme was ‘Suggestions for Improving WORKWELL’. These themes reflected participants’ mixed feelings about the intervention, finding value in the intervention but highlighting the need for more tailored, timely and relevant content. Workplace support was crucial but often insufficient. Follow-up calls from researchers to ensure questionnaire completion were seen as a way to reflect and monitor their conditions. The pandemic’s impact on work environments also influenced outcomes.ConclusionFindings suggest that WORKWELL provided work support for participants, though its impact could be enhanced through greater customization, early intervention and stronger workplace engagement

Case Reports1. A Late Presentation of Loeys-Dietz Syndrome: Beware of TGFβ Receptor Mutations in Benign Joint Hypermobility

Background: Thoracic aortic aneurysms (TAA) and dissections are not uncommon causes of sudden death in young adults. Loeys-Dietz syndrome (LDS) is a rare, recently described, autosomal dominant, connective tissue disease characterized by aggressive arterial aneurysms, resulting from mutations in the transforming growth factor beta (TGFβ) receptor genes TGFBR1 and TGFBR2. Mean age at death is 26.1 years, most often due to aortic dissection. We report an unusually late presentation of LDS, diagnosed following elective surgery in a female with a long history of joint hypermobility. Methods: A 51-year-old Caucasian lady complained of chest pain and headache following a dural leak from spinal anaesthesia for an elective ankle arthroscopy. CT scan and echocardiography demonstrated a dilated aortic root and significant aortic regurgitation. MRA demonstrated aortic tortuosity, an infrarenal aortic aneurysm and aneurysms in the left renal and right internal mammary arteries. She underwent aortic root repair and aortic valve replacement. She had a background of long-standing joint pains secondary to hypermobility, easy bruising, unusual fracture susceptibility and mild bronchiectasis. She had one healthy child age 32, after which she suffered a uterine prolapse. Examination revealed mild Marfanoid features. Uvula, skin and ophthalmological examination was normal. Results: Fibrillin-1 testing for Marfan syndrome (MFS) was negative. Detection of a c.1270G > C (p.Gly424Arg) TGFBR2 mutation confirmed the diagnosis of LDS. Losartan was started for vascular protection. Conclusions: LDS is a severe inherited vasculopathy that usually presents in childhood. It is characterized by aortic root dilatation and ascending aneurysms. There is a higher risk of aortic dissection compared with MFS. Clinical features overlap with MFS and Ehlers Danlos syndrome Type IV, but differentiating dysmorphogenic features include ocular hypertelorism, bifid uvula and cleft palate. Echocardiography and MRA or CT scanning from head to pelvis is recommended to establish the extent of vascular involvement. Management involves early surgical intervention, including early valve-sparing aortic root replacement, genetic counselling and close monitoring in pregnancy. Despite being caused by loss of function mutations in either TGFβ receptor, paradoxical activation of TGFβ signalling is seen, suggesting that TGFβ antagonism may confer disease modifying effects similar to those observed in MFS. TGFβ antagonism can be achieved with angiotensin antagonists, such as Losartan, which is able to delay aortic aneurysm development in preclinical models and in patients with MFS. Our case emphasizes the importance of timely recognition of vasculopathy syndromes in patients with hypermobility and the need for early surgical intervention. It also highlights their heterogeneity and the potential for late presentation. Disclosures: The authors have declared no conflicts of interes

Basic science232. Certolizumab pegol prevents pro-inflammatory alterations in endothelial cell function

Background: Cardiovascular disease is a major comorbidity of rheumatoid arthritis (RA) and a leading cause of death. Chronic systemic inflammation involving tumour necrosis factor alpha (TNF) could contribute to endothelial activation and atherogenesis. A number of anti-TNF therapies are in current use for the treatment of RA, including certolizumab pegol (CZP), (Cimzia ®; UCB, Belgium). Anti-TNF therapy has been associated with reduced clinical cardiovascular disease risk and ameliorated vascular function in RA patients. However, the specific effects of TNF inhibitors on endothelial cell function are largely unknown. Our aim was to investigate the mechanisms underpinning CZP effects on TNF-activated human endothelial cells. Methods: Human aortic endothelial cells (HAoECs) were cultured in vitro and exposed to a) TNF alone, b) TNF plus CZP, or c) neither agent. Microarray analysis was used to examine the transcriptional profile of cells treated for 6 hrs and quantitative polymerase chain reaction (qPCR) analysed gene expression at 1, 3, 6 and 24 hrs. NF-κB localization and IκB degradation were investigated using immunocytochemistry, high content analysis and western blotting. Flow cytometry was conducted to detect microparticle release from HAoECs. Results: Transcriptional profiling revealed that while TNF alone had strong effects on endothelial gene expression, TNF and CZP in combination produced a global gene expression pattern similar to untreated control. The two most highly up-regulated genes in response to TNF treatment were adhesion molecules E-selectin and VCAM-1 (q 0.2 compared to control; p > 0.05 compared to TNF alone). The NF-κB pathway was confirmed as a downstream target of TNF-induced HAoEC activation, via nuclear translocation of NF-κB and degradation of IκB, effects which were abolished by treatment with CZP. In addition, flow cytometry detected an increased production of endothelial microparticles in TNF-activated HAoECs, which was prevented by treatment with CZP. Conclusions: We have found at a cellular level that a clinically available TNF inhibitor, CZP reduces the expression of adhesion molecule expression, and prevents TNF-induced activation of the NF-κB pathway. Furthermore, CZP prevents the production of microparticles by activated endothelial cells. This could be central to the prevention of inflammatory environments underlying these conditions and measurement of microparticles has potential as a novel prognostic marker for future cardiovascular events in this patient group. Disclosure statement: Y.A. received a research grant from UCB. I.B. received a research grant from UCB. S.H. received a research grant from UCB. All other authors have declared no conflicts of interes

WORKWELL process evaluation: insights from therapists and line managers

ObjectivesMany individuals diagnosed with inflammatory arthritis are of working age and experience challenges in maintaining employment. The WORKWELL vocational rehabilitation programme, delivered by occupational therapists in National Health Service rheumatology clinics, is designed to support job retention by aligning individuals’ abilities with their work demands. As part of a multicentre randomized controlled trial, this qualitative process evaluation explored therapists’ and line managers’ perspectives on the training, implementation and delivery of WORKWELL to inform its future integration and scalability.MethodsA qualitative study was conducted using semi-structured interviews with 18 occupational therapists (26 interviews in total, pre- and post-trial) and 5 line managers across 17 National Health Service Trusts in England, Wales, and Scotland. Reflexive thematic analysis was applied inductively, followed by a deductive Normalization Process Theory analysis to explore intervention coherence, engagement, implementation and sustainability.ResultsBefore the trial, work support was inconsistent, with occupational therapists providing informal advice and signposting but lacking structured vocational rehabilitation assessments. Post-trial, therapists viewed WORKWELL as a valuable, structured intervention, enhancing job retention support. Remote delivery during COVID-19 was well-received, improving accessibility. However, implementation challenges included time constraints, increased workloads and staffing shortages. Line managers had limited involvement but recognized the programme’s benefits, though concerns about long-term sustainability remained.ConclusionsWORKWELL was successfully integrated into National Health Service practice, with remote delivery enhancing accessibility. Addressing workforce constraints, managerial engagement and digital integration could improve long-term feasibility and impact, ensuring sustained access to job retention support for people with inflammatory arthritis.Trial registrationClinicalTrials.gov NCT03942783; ISRCTN Registry ISRCTN61762297

WORKWELL process evaluation: insights from therapists and line managers

Objectives Many individuals diagnosed with inflammatory arthritis (IA) are of working age and experience challenges in maintaining employment. The WORKWELL vocational rehabilitation programme, delivered by occupational therapists (OT) in National Health Service (NHS) rheumatology clinics, is designed to support job retention by aligning individuals’ abilities with their work demands. As part of a multi-centre randomised controlled trial, this qualitative process evaluation explored therapists’ and line managers’ perspectives on the training, implementation, and delivery of WORKWELL to inform its future integration and scalability. Methods A qualitative study was conducted using semi-structured interviews with 26 therapists and five line managers across 17 NHS Trusts in England, Wales, and Scotland, both before and after the trial. Reflexive Thematic Analysis (RTA) was applied inductively, followed by a deductive Normalisation Process Theory (NPT) analysis to explore intervention coherence, engagement, implementation, and sustainability. Results Before the trial, work support was inconsistent, with OTs providing informal advice and signposting but lacking structured vocational rehabilitation (VR) assessments. Post-trial, therapists viewed WORKWELL as a valuable, structured intervention, enhancing job retention support. Remote delivery during COVID-19 was well-received, improving accessibility. However, implementation challenges included time constraints, increased workloads, and staffing shortages. Line managers had limited involvement but recognised the programme’s benefits, though concerns about long-term sustainability remained. Conclusions WORKWELL was successfully integrated into NHS practice, with remote delivery enhancing accessibility. Addressing workforce constraints, managerial engagement, and digital integration could improve long-term feasibility and impact, ensuring sustained access to job retention support for people with IA. Trial registration ClinicalTrials.gov NCT03942783; ISRCTN Registry ISRCTN61762297

Sickness behaviour pushed too far – the basis of the syndrome seen in severe protozoal, bacterial and viral diseases and post-trauma

Certain distinctive components of the severe systemic inflammatory syndrome are now well-recognized to be common to malaria, sepsis, viral infections, and post-trauma illness. While their connection with cytokines has been appreciated for some time, the constellation of changes that comprise the syndrome has simply been accepted as an empirical observation, with no theory to explain why they should coexist. New data on the effects of the main pro-inflammatory cytokines on the genetic control of sickness behaviour can be extended to provide a rationale for why this syndrome contains many of its accustomed components, such as reversible encephalopathy, gene silencing, dyserythropoiesis, seizures, coagulopathy, hypoalbuminaemia and hypertriglyceridaemia. It is thus proposed that the pattern of pathology that comprises much of the systemic inflammatory syndrome occurs when one of the usually advantageous roles of pro-inflammatory cytokines – generating sickness behaviour by moderately repressing genes (Dbp, Tef, Hlf, Per1, Per2 and Per3, and the nuclear receptor Rev-erbα) that control circadian rhythm – becomes excessive. Although reversible encephalopathy and gene silencing are severe events with potentially fatal consequences, they can be viewed as having survival advantages through lowering energy demand. In contrast, dyserythropoiesis, seizures, coagulopathy, hypoalbuminaemia and hypertriglyceridaemia may best be viewed as unfortunate consequences of extreme repression of these same genetic controls when the pro-inflammatory cytokines that cause sickness behaviour are produced excessively. As well as casting a new light on the previously unrationalized coexistence of these aspects of systemic inflammatory diseases, this concept is consistent with the case for a primary role for inflammatory cytokines in their pathogenesis across this range of diseases

Mutations in the histone methyltransferase gene KMT2B cause complex early-onset dystonia.

Histone lysine methylation, mediated by mixed-lineage leukemia (MLL) proteins, is now known to be critical in the regulation of gene expression, genomic stability, cell cycle and nuclear architecture. Despite MLL proteins being postulated as essential for normal development, little is known about the specific functions of the different MLL lysine methyltransferases. Here we report heterozygous variants in the gene KMT2B (also known as MLL4) in 27 unrelated individuals with a complex progressive childhood-onset dystonia, often associated with a typical facial appearance and characteristic brain magnetic resonance imaging findings. Over time, the majority of affected individuals developed prominent cervical, cranial and laryngeal dystonia. Marked clinical benefit, including the restoration of independent ambulation in some cases, was observed following deep brain stimulation (DBS). These findings highlight a clinically recognizable and potentially treatable form of genetic dystonia, demonstrating the crucial role of KMT2B in the physiological control of voluntary movement.Funding for the project was provided by the Wellcome Trust for UK10K (WT091310) and DDD Study. The DDD study presents independent research commissioned by the Health Innovation Challenge Fund [grant number HICF-1009-003] - see www.ddduk.org/access.html for full acknowledgement. This work was supported in part by the Intramural Research Program of the National Human Genome Research Institute and the Common Fund, NIH Office of the Director. This work was supported in part by the German Ministry of Research and Education (grant nos. 01GS08160 and 01GS08167; German Mental Retardation Network) as part of the National Genome Research Network to A.R. and D.W. and by the Deutsche Forschungsgemeinschaft (AB393/2-2) to A.R. Brain expression data was provided by the UK Human Brain Expression Consortium (UKBEC), which comprises John A. Hardy, Mina Ryten, Michael Weale, Daniah Trabzuni, Adaikalavan Ramasamy, Colin Smith and Robert Walker, affiliated with UCL Institute of Neurology (J.H., M.R., D.T.), King’s College London (M.R., M.W., A.R.) and the University of Edinburgh (C.S., R.W.)