Characteristics of pain and their relationship to disease activity in UK patients with Behçet's syndrome: a prospective cohort study.

Background: Behçet's syndrome (BS) is a rare multi-systemic vasculitis of unknown aetiology. Fibromyalgia syndrome (FMS) is more prevalent in rheumatological conditions such-as BS, than the general population. However, there is limited research into the aetiology and characteristics of pain in BS. Objectives: To describe the pain characteristics and incidence of FMS in people with BS and investigate their relationship with BS disease activity. Methods: A cohort study of BS patients attending the Liverpool Behçet's Centre between February 2017 and March 2019. BS was defined using the International Study Group Criteria. BS severity was assessed using the Behçet's Disease Current Activity Form. FMS was determined from consultant diagnosis. Assessments of pain included: Pain Visual Analogue Scale (PVAS), Pain Mannequin, Brief Pain Inventory, EQ-5D-3L and Short Form McGill. Pain and FMS prevalence were compared between high and low disease activity. Results: 90% reported moderate-severe pain with a median PVAS score of 68/100 [38, 81]. 35.6% of participants had FMS and 46.5% experienced generalized pain. 76% of participants with high disease activity reported severe pain, compared to 39.1% with low disease activity (p = .003). Pain was more generalised in high disease activity (72%) compared to low disease activity (37.7%) (p = .003). FMS was more prevalent in the high disease activity group (52%) than the low disease activity group (29%) (p = .04). Conclusions: This is the first study to explore pain in participants with BS in the United Kingdom. The majority of BS patients experience moderate-severe widespread pain. Severe widespread pain is more prevalent in those with high disease activity. We have demonstrated a relationship between high disease activity, worse pain intensity, and FMS. This paper contributes to the understanding of two conditions which remain to be fully understood, FMS and BS, and generates new hypotheses to describe the interplay between.

Commentary: an industry perspective on the importance of incorporating participant voice before, during, and after clinical trials.

It is increasingly recognized that involving patients and the public in the design of clinical trials can lead to better recruitment, retention, and satisfaction. A recent scoping review determined that between 1985 and 2018, just 23 articles meeting quality criteria obtained feedback from clinical trial participants after a trial had been completed. In a timespan that presumably included thousands of trials across hundreds of indications, the paucity of the literature seems surprising, if not outright disappointing. By contrast, practitioners in the life sciences industry are increasingly incorporating patient research into their trial design process before, during, and after trial completion. Examples of approaches used include recruitment of "look alike" participant samples through online communities, surveys, and the use of smartphone apps to directly record participants' spoken reactions to trial materials like recruitment materials, site visit schedules, or informed consent materials. However, commercial organizations tend not to publish their findings, leading to a potential two-tier experience for trial participants depending on whether the trial they participate in will be industry-funded or government-funded. This seems problematic on a number of levels. Increasing regulatory, funder, and publisher interest in improving the inclusivity of clinical trial participants may act as a timely lever to spur patient-centered coproduction of trials. Until continuous feedback processes are the mandated, funded, and published norm, participating in a clinical trial will be more arduous than it needs to be.

What role can decentralized trial designs play to improve rare disease studies?

People affected by rare diseases want to be involved in research and the search for new treatments. Randomized controlled trials remain the best way of finding new interventions, but many elements of traditional study design are not best suited for rare diseases. Barriers to patients and families include the use of specialist hospital sites for recruitment, requiring frequent site-based study visits for data collection, and a high burden of tests and outcome measures in research. While decentralized clinical trial (DCT) designs have been developed in some rare disease trials, changes necessitated by the COVID-19 pandemic present an opportunity for them to become a standard approach. DCT approaches have been shown to be more resilient to changes in enrolment and attrition during COVID-19 than traditional designs and offer benefits in terms of patient burden, convenience, inclusion, and data quality. Digital tools such as wearable devices and electronic clinical outcome assessments may also provide more convenient and environmentally valid measures of how a condition affects the life of an individual in their regular environment (e.g. mobility around the home versus a hospital corridor). Digital solutions have greater ability to support language localization, accessibility, and may lead to increase access to global rare disease trials. In parallel, challenges exist, such as the technical support, the digital divide, ensuring high quality data, and delivering safe trials.

Time-dependent bidirectional effects of chronic caffeine on functional recovery of the dorsal light reflex after hemilabyrinthectomy in the goldfish Carassius auratus.

Caffeine works through a variety of complex mechanisms to exert an often bidirectional set of functional and structural neurological changes in vertebrates. We investigated the effects of chronic caffeine exposure on functional recovery of the dorsal light reflex (DLR) in hemilabyrinthectomized common goldfish, Carassius auratus. In this lesion model, the unilateral removal of the vestibular organs results in a temporary loss of gravitationally modulated postural control which is quantifiable via the DLR. We compared the functional recovery over 24 days of post-surgery goldfish continuously held in a caffeine solution of 2.5mg/L (n=10), 5.0mg/L (n=10), 10.0mg/L (n=11), or 0.0mg/L control (n=9). Comparison to a sham surgery group (n=11) indicated statistically significant changes in the DLR of all hemilabyrinthectomized fish on day 1. The control group recovered over the study period and approached, but did not reach sham surgery DLR. Although the caffeine-treated fishes appeared to initiate some postural recovery within the first 2 weeks, beginning on day 10, all caffeine groups diverged from the control group with a deterioration of postural control. All three caffeine groups were significantly deficient in comparison with the control on days 10-24. These results suggest that caffeine exposure can at first be benign, but that high dosage or prolonged exposure hinders functional recovery.

Non-steroidal anti-inflammatory drug use does not appear to be associated with increased cardiovascular mortality in patients with inflammatory polyarthritis: results from a primary care based inception cohort of patients.

OBJECTIVES: There is controversy about the effects of non-steroidal anti-inflammatory drugs (NSAIDs) on cardiovascular disease (CVD) mortality. The aim of this study was to explore associations between NSAID use and mortality in patients with inflammatory polyarthritis (IP). SUBJECTS AND METHODS: A total of 923 patients with new onset (IP), recruited to the UK Norfolk Arthritis Register (NOAR) between 1990-1994, were followed up to the end of 2004. Current medication was recorded annually for the first 6 years and then every 2-3 years. Rheumatoid factor (RF) and C-reactive protein (CRP) were measured. Logistic regression was used to calculate all cause and CVD mortality odds ratios (OR) for NSAID use at baseline and during follow-up, adjusting for gender and time-varying covariates: RF, CRP, joint counts, smoking, steroid use, DMARD use and other medication use. RESULTS: By 2004 there were 203 deaths, 85 due to CVD. At baseline, NSAIDs were used by 66% of patients. In final multivariate models, baseline NSAID use was inversely associated with all cause mortality (adjusted OR 0.62, 95% CI 0.45 to 0.84) and CVD mortality (adjusted OR 0.54, 95% CI 0.34 to 0.86). Interval NSAID use had weaker mortality associations: all cause mortality (adjusted OR 0.72, 95% CI 0.52 to 1.00), CVD mortality (adjusted hazard ratio (HR) 0.66, 95% CI 0.40 to 1.08). CONCLUSION: No excess CVD or all cause mortality was observed in NSAID users in this cohort of patients with IP. This is at variance with the literature relating to NSAID use in the general population. It is unclear whether this represents unmeasured confounders influencing a doctor's decision to avoid NSAIDs in the treatment of IP.

Patterns of cardiovascular risk in rheumatoid arthritis.

BACKGROUND: Although it is known that rheumatoid arthritis is associated with an increased risk of cardiovascular disease (CVD), the pattern of this risk is not clear. This study investigated the relative risk of myocardial infarction, stroke and CVD mortality in adults with rheumatoid arthritis compared with adults without rheumatoid arthritis across age groups, sex and prior CVD event status. METHODS: We conducted a cohort study among all residents aged >or=18 years residing in British Columbia between 1999 and 2003. Residents who had visited the doctor at least thrice for rheumatoid arthritis (International Classification of Disease = 714) were considered to have rheumatoid arthritis. A non-rheumatoid arthritis cohort was matched to the rheumatoid arthritis cohort by age, sex and start of follow-up. The primary composite end point was a hospital admission for myocardial infarction, stroke or CVD mortality. RESULTS: 25 385 adults who had at least three diagnoses for rheumatoid arthritis during the study period were identified. During the 5-year study period, 375 patients with rheumatoid arthritis had a hospital admission for myocardial infarction, 363 had a hospitalisation for stroke, 437 died from cardiovascular causes and 1042 had one of these outcomes. The rate ratio for a CVD event in patients with rheumatoid arthritis was 1.6 (95% confidence interval (CI) 1.5 to 1.7), and the rate difference was 5.7 (95% CI 4.9 to 6.4) per 1000 person-years. The rate ratio decreased with age, from 3.3 in patients aged 18-39 years to 1.6 in those aged >or=75 years. However, the rate difference was 1.2 per 1000 person-years in the youngest age group and increased to 19.7 per 1000 person-years in those aged >or=75 years. Among patients with a prior CVD event, the rate ratios and rate differences were not increased in rheumatoid arthritis. CONCLUSIONS: This study confirms that rheumatoid arthritis is a risk factor for CVD events and shows that the rate ratio for CVD events among subjects with rheumatoid arthritis is highest in young adults and those without known prior CVD events. However, in absolute terms, the difference in event rates is highest in older adults.

Cardiovascular involvement in rheumatoid arthritis.

Cardiovascular (CV) disease morbidity and mortality are increased in patients with rheumatoid arthritis (RA) and much of the excess CV disease morbidity appears to be due to atherosclerosis. The pathogenesis of atherosclerosis (ATS) in RA is complex and there is increasing evidence that many factors including novel and traditional cardiovascular risk factors, RA treatments and the RA inflammatory disease process are involved in the development of CV disease in these patients. Of particular interest are the effects of chronic inflammation and immune dysregulation associated with RA. These have been shown to be associated with endothelial dysfunction, which is an early, potentially reversible, functional abnormality of the arterial wall. However, as several CV disease risk factors and drug prescribing are also influenced by RA disease severity it is very difficult to separate out the effects of the inflammatory disease burden on the cardiovascular system in RA.

Cardiovascular admissions and mortality in an inception cohort of patients with rheumatoid arthritis with onset in the 1980s and 1990s.

BACKGROUND: There is increased cardiovascular disease mortality in rheumatoid arthritis. This may reflect an increased prevalence of cardiovascular disease or an increased case fatality in patients with rheumatoid arthritis. OBJECTIVES: To examine whether rheumatoid patients with disease onset in the 1980s-1990s have increased mortality, and to compare cardiovascular admission rates in rheumatoid patients with those of the general population. METHODS: An inception cohort of 1010 rheumatoid patients attending Stockport rheumatology clinics between 1981 and 1996 was followed up to December 2002 through the Office for National Statistics. Standardised mortality ratios (SMR) were calculated for all-cause and cause specific mortality, using the population of Stockport as reference. Cardiovascular disease admission rates were ascertained for a subgroup of patients using national hospital episode statistics; standardised cardiovascular disease admission rates (SAR) and SMRs were calculated for this subgroup. RESULTS: 470 patients (48%) died during a median follow up of 11.4 years. All-cause mortality was increased in men (SMR = 1.45 (95% confidence interval, 1.22 to 1.71)) and women (SMR = 1.84 (1.64 to 2.05)), as was cardiovascular disease mortality in men (SMR = 1.36 (1.04 to 1.75) and women (SMR = 1.93 (1.65 to 2.26)). No difference in cardiovascular disease admission rates was observed in men (SAR 1.20 (0.89 to 1.58) or women (SAR = 1.10 (0.88 to 1.36)), despite excess cardiovascular disease mortality in this subgroup. CONCLUSIONS: Patients with rheumatoid arthritis have reduced life expectancy and excess cardiovascular disease mortality. Nevertheless, standardised admission rates for cardiovascular disease were not raised. This suggests either that cardiovascular disease in rheumatoid arthritis has a higher case fatality than in the general population or that it often goes unrecognised before the fatal event.

Vitamin C and the risk of developing inflammatory polyarthritis: prospective nested case-control study.

OBJECTIVE: To investigate whether, there is an association between consumption of fruit and vegetables and dietary antioxidants and the risk of developing inflammatory polyarthritis (IP). METHODS: In a prospective, population based, nested case-control study of residents of Norfolk, UK, men and women aged 45-74 years were recruited, between 1993 and 1997 through general practice age-sex registers to the Norfolk arm of the European Prospective Investigation of Cancer (EPIC-Norfolk). Dietary intake was assessed at baseline using 7 day diet diaries. Seventy three participants who went on to develop IP between 1993 and 2001 and were registered by the Norfolk Arthritis Register (NOAR) were identified. Incident cases of IP, assessed by general practitioners, fulfilled the criteria of two or more swollen joints, persisting for a minimum of 4 weeks. Each case of IP was matched for age and sex with two controls free of IP. RESULTS: Lower intakes of fruit and vegetables, and vitamin C were associated with an increased risk of developing IP. Those in the lowest category of vitamin C intake, compared with the highest, increased their risk of developing IP more than threefold, adjusted odds ratio (OR) with 95% confidence intervals (CI) 3.3 (95% CI 1.4 to 7.9). Weak inverse associations between vitamin E and beta-carotene intake and IP risk were found. CONCLUSION: Patients with IP (cases) consumed less fruit and vitamin C than matched controls, which appeared to increase their risk of developing IP. The mechanism for this effect is uncertain. Thus similar studies are necessary to confirm these results.

Traditional cardiovascular risk factors measured prior to the onset of inflammatory polyarthritis.

BACKGROUND: Cardiovascular mortality is increased in patients with seropositive inflammatory polyarthritis (IP). We tested the hypothesis that the increased risk of cardiovascular disease (CVD) can be explained by elevated traditional CVD risk factor levels in persons prior to development of IP. METHODS: In a population-based, prospective nested case-control study, 25 600 people aged 45-75 yr participated in a health survey, including standard CVD risk factor assessment, between the years 1993 and 1997. There were 91 incident IP cases (one-third were seropositive at presentation) identified during follow-up to the end of July 2001. Baseline CVD risk factors in the IP cases were compared with those in two age/gender-matched controls. RESULTS: Current smokers had an odds ratio of 2.0 (95% CI 1.0-4.0) for IP. Other risk factors, including total and LDL cholesterol, systolic and diastolic blood pressure and obesity, did not differ significantly between cases and controls. Importantly, in combination, using a standard coronary disease risk score, these factors only had a modest association with future IP, and no association when analysis was restricted to the smaller number of cases who were seropositive. CONCLUSION: Of the traditional cardiovascular risk factors, only smoking increases CVD risk prior to the onset of IP. Therefore the increased CVD observed in these patients is likely to be a consequence of factors operating after the onset of the arthritis.

Raised pulmonary artery pressures measured with Doppler echocardiography in rheumatoid arthritis patients.

OBJECTIVE: To study the prevalence of echocardiographic abnormality and pulmonary hypertension in an unselected population of patients with rheumatoid arthritis (RA). METHOD: One hundred and forty-six RA patients, irrespective of cardiopulmonary symptoms, were assessed clinically and by echocardiography, including pulmonary artery pressure measurement, ECG, pulmonary function tests and high-resolution computed tomography scanning of the thorax. RESULTS: Two-dimensional echocardiography demonstrated significant cardiac disease in the form of reduced left ventricular ejection fraction (<64%) in 9% of patients, moderate mitral regurgitation in 4%, aortic stenosis in 4%, aortic regurgitation in 3% and Valsalva sinus rupture in 0.7%. In addition, 1% had detectable pericardial effusions. Thirty-one per cent of the RA patients had an estimated pulmonary artery systolic pressure of 30 mmHg or more, and 21% of all the RA patients had pulmonary hypertension without significant cardiac disease or lung disease evident on pulmonary function testing. CONCLUSIONS: A wide and frequent variety of echocardiographic cardiac abnormalities may be found in an unselected population of patients with RA. Using Doppler echocardiography, we have found pulmonary hypertension secondary to lung disease in 6% of the population and a larger than expected prevalence of mild primary pulmonary hypertension in patients with RA. The latter observation may be relevant to the high incidence of cardiovascular-related deaths observed in patients with RA