Rapid anti-myeloma activity by T cells expressing an anti-BCMA CAR with a human heavy-chain-only antigen-binding domain.

Multiple myeloma (MM) is a rarely curable malignancy of plasma cells. MM expresses B cell maturation antigen (BCMA). We developed a fully human anti-BCMA chimeric antigen receptor (CAR) with a heavy-chain-only antigen-recognition domain, a 4-1BB domain, and a CD3ζ domain. The CAR was designated FHVH33-CD8BBZ. We conducted the first-in-humans clinical trial of T cells expressing FHVH33-CD8BBZ (FHVH-T). Twenty-five patients with relapsed MM were treated. The stringent complete response rate (sCR) was 52%. Median progression-free survival (PFS) was 78 weeks. Of 24 evaluable patients, 6 (25%) had a maximum cytokine-release syndrome (CRS) grade of 3; no patients had CRS of greater than grade 3. Most anti-MM activity occurred within 2-4 weeks of FHVH-T infusion as shown by decreases in the rapidly changing MM markers serum free light chains, urine light chains, and bone marrow plasma cells. Blood CAR+ cell levels peaked during the time that MM elimination was occurring, between 7 and 15 days after FHVH-T infusion. C-C chemokine receptor type 7 (CCR7) expression on infusion CD4+ FHVH-T correlated with peak blood FHVH-T levels. Single-cell RNA sequencing revealed a shift toward more differentiated FHVH-T after infusion. Anti-CAR antibody responses were detected in 4 of 12 patients assessed. FHVH-T has powerful, rapid, and durable anti-MM activity.

AxSpA patients who also meet criteria for fibromyalgia: identifying distinct patient clusters using data from a UK national register (BSRBR-AS).

BACKGROUND: Around 1 in 8 patients with axial spondyloarthritis (axSpA) also meet criteria for fibromyalgia and such patients have considerable unmet need. Identifying effective therapy is important but to what extent fibromyalgia-like symptoms relate to axSpA disease severity has not been established. The aim of the current analysis was to determine whether distinct clusters of axSpA patients exist and if so to determine a) whether they differ in terms of prevalence of fibromyalgia and b) the features of patients in clusters with high prevalence. METHODS: The British Society for Rheumatology Biologics Register (BSRBR-AS) recruited axSpA patients from 83 centres 2012-2017. Clinical data, and information from patients was collected (including research criteria for fibromyalgia). Cluster analysis was undertaken using split samples for development and validation both in the whole population and the sub-group which met fibromyalgia criteria. RESULTS: One thousand three hundred thirty-eight participants were included of whom 23% met research criteria for fibromyalgia. Four clusters were identified. Two exhibited very high disease activity, one which was primarily axial (n = 347) and a smaller cluster (n = 32) with axial and peripheral disease, and in both groups more than half of members met criteria for fibromyalgia. The remaining two clusters (n = 437, n = 462) had overall less severe disease however the one which showed greater disease activity and poorer quality of life had a higher proportion meeting fibromyalgia criteria (16% v. 4%). Within those meeting fibromyalgia criteria there were three clusters. The two main groups were defined by level of symptom severity with a smaller third cluster noted to have high average swollen and tender joint counts and high levels of comorbidity. CONCLUSIONS: The major feature defining clusters with a high proportion of persons meeting criteria for fibromyalgia is high axSpA disease activity although clusters with features of fibromyalgia in the absence of high disease activity also show moderately high prevalence. Management may be most successful with pharmacologic therapy to target inflammation but enhanced by the concurrent use of non-pharmacologic therapy in such patients.

Influence of co-morbid fibromyalgia on disease activity measures and response to tumour necrosis factor inhibitors in axial spondyloarthritis: results from a UK national register.

Objective: To quantify the extent to which co-morbid FM is associated with higher disease activity, worse quality of life (QoL) and poorer response to TNF inhibitors (TNFis) in patients with axial SpA. Methods: A prospective study recruiting across 83 centres in the UK. Clinical information and patient-reported measures were available, including 2011 criteria for FM. Multivariable linear regression was used to model the effect of meeting the FM criteria on disease activity, QoL and response to TNFis. Results: A total of 1757 participants were eligible for analyses, of whom 22.1% met criteria for FM. Those with co-morbid FM criteria had higher disease activity [BASDAI average difference FM+ - FM- 1.04 (95% CI 0.75, 1.33)] and worse QoL [Ankylosing Spondylitis Quality of Life score difference 1.42 (95% CI 0.88, 1.96)] after adjusting for demographic, clinical and lifestyle factors. Among 291 participants who commenced biologic therapy, BASDAI scores in those with co-morbid FM were 2.0 higher at baseline but decreased to 1.1 higher at 12 months. There was no significant difference in the likelihood of meeting Assessment of SpondyloArthritis international Society 20 criteria at 12 months. Less improvement in disease activity and QoL over 3 months of TNFi therapy was most strongly related to high scores on the FM criteria symptom severity scale component. Conclusion: Fulfilling criteria for FM has a modest impact on the assessment of axial SpA disease activity and QoL and does not significantly influence response to biologic therapy. Those with a high symptom severity scale on FM assessment may benefit from additional specific management for FM.

Co-Occurrence and Characteristics of Patients With Axial Spondyloarthritis Who Meet Criteria for Fibromyalgia: Results From a UK National Register.

OBJECTIVE: To estimate the proportion of patients with axial spondyloarthritis (SpA) in a UK national biologics registry who met criteria for fibromyalgia (FM), and to delineate the characteristics of these patients. METHODS: Two cohorts of patients are prospectively recruited from across 83 centers in the UK for the British Society for Rheumatology Biologics Register in Ankylosing Spondylitis (BSRBR-AS). All patients are required to meet Assessment of SpondyloArthritis international Society (ASAS) criteria for axial SpA. Patients are either newly starting biologic therapy (biologics cohort) or are naive to treatment with biologic agents (non-biologics cohort) at the time of recruitment, and all patients are followed up prospectively. At recruitment and follow-up, clinical information and measurements are recorded while patients complete the 2011 research criteria for FM and assessments of the level of disease activity and work impact. RESULTS: Of the patients registered in the BSRBR-AS, 1,504 (68% male) were eligible for the current analysis, of whom 311 (20.7%) met the 2011 research criteria for FM. Prevalence of FM was similar between patients who fulfilled the modified New York criteria for AS (19.7%) and those who fulfilled ASAS imaging criteria but not the modified New York criteria (25.2%); however, among those who fulfilled only the ASAS clinical criteria, the prevalence of FM was lower (9.5%). Patients who met FM criteria reported significantly worse disease activity, function, global severity scores, and quality of life, and were more likely to have moderate or severe levels of mood disorder and clinically important fatigue. Patients who met FM criteria reported experiencing work impairment around half their working time. Meeting FM criteria was not related to elevated C-reactive protein levels or most extraspinal manifestations, but was associated with a higher likelihood of having received biologic therapy. CONCLUSION: Developing management approaches that would address the significant unmet clinical needs of the 1 in 5 patients with axial SpA who meet criteria for FM should be a research priority.

Physical Activity and Mental Well-being in a Cohort Aged 60-64 Years.

INTRODUCTION: Although evidence suggests physical activity (PA) may be associated with mental well-being at older ages, it is unclear whether some types of PA are more important than others. The purpose of this study is to investigate associations of monitored total PA under free-living conditions, self-reported leisure-time PA (LTPA), and walking for pleasure with mental well-being at age 60-64 years. METHODS: Data on 930 (47%) men and 1,046 (53%) women from the United Kingdom Medical Research Council (MRC) National Survey of Health and Development collected in 2006-2011 at age 60-64 were used in 2013-2014 to test the associations of PA (PA energy expenditure and time spent in different intensities of activity assessed using combined heart rate and acceleration monitors worn for 5 days, self-reported LTPA, and walking for pleasure) with the Warwick-Edinburgh Mental Well-being Scale (WEMWBS; range, 14-70). RESULTS: In linear regression models adjusted for gender, long-term limiting illness, smoking, employment, socioeconomic position, personality, and prior PA, those who walked for >1 hour/week had mean WEMWBS scores 1.47 (95% CI=0.60, 2.34) points higher than those who reported no walking. Those who participated in LTPA at least five times/month had WEMWBS scores 1.25 (95% CI=0.34, 2.16) points higher than those who did not engage in LTPA. There were no statistically significant associations between free-living PA and WEMWBS scores. CONCLUSIONS: In adults aged 60-64 years, participation in self-selected activities such as LTPA and walking are positively related to mental well-being, whereas total levels of free-living PA are not.

Changes in daily activity patterns with age in U.S. men and women: National Health and Nutrition Examination Survey 2003-04 and 2005-06.

OBJECTIVES: To compare daily and hourly activity patterns according to sex and age. DESIGN: Cross-sectional, observational. SETTING: Nationally representative community sample: National Health and Nutrition Examination Survey (NHANES) 2003-04 and 2005-06. PARTICIPANTS: Individuals (n = 5,788) aged 20 and older with 4 or more valid days of monitor wear-time, no missing data on valid wear-time minutes, and covariates. MEASUREMENTS: Activity was examined as average counts per minute (CPM) during wear-time; percentage of time spent in nonsedentary activity; and time (minutes) spent in sedentary (<100 counts), light (100-759), and moderate to vigorous physical activity (MVPA (≥ 760)). Analyses accounted for survey design, adjusted for covariates, and were sex specific. RESULTS: In adjusted models, men spent slightly more time (~1-2%) in nonsedentary activity than women aged 20 to 34, with levels converging at age 35 to 59, although the difference was not significant. Women aged 60 and older spent significantly more time (~3-4%) in nonsedentary activity than men, despite similarly achieved average CPM. With increasing age, all nonsedentary activity decreased in men; light activity remained constant in women (~30%). Older men had fewer CPM at night (~20), more daytime sedentary minutes (~3), fewer daytime light physical activity minutes (~4), and more MVPA minutes (~1) until early evening than older women. CONCLUSION: Although sex differences in average CPM declined with age, differences in nonsedentary activity time emerged as men increased sedentary behavior and reduced MVPA time. Maintained levels of light-intensity activity suggest that women continue engaging in common daily activities into older age more than men. Findings may help inform the development of behavioral interventions to increase intensity and overall activity levels, particularly in older adults.

Levels of physical activity among a nationally representative sample of people in early old age: results of objective and self-reported assessments.

BACKGROUND: Detailed assessment of physical activity (PA) in older adults is required to comprehensively describe habitual PA-levels in this growing population segment. Current evidence of population PA-levels is predominantly based on self-report. METHODS: We examined PA and sedentary behaviour in a nationally representative sample of British people aged 60-64, using individually-calibrated combined heart-rate and movement sensing and a validated questionnaire (EPAQ2), and the socio-demographic and behavioural factors that may explain between-individual variation in PA. RESULTS: Between 2006-2010, 2224 participants completed EPAQ2 capturing the past year's activity in four domains (leisure, work, transportation and domestic life) and 1787 participants provided 2-5 days of combined-sensing data. According to objective estimates, median(IQR) physical activity energy expenditure (PAEE) was 33.5 (25.3-42.2) and 35.5 (26.6- 47.3) kJ/kg/day for women and men, respectively. Median (IQR) time spent in moderate-to-vigorous PA (MVPA; >3MET), light-intensity PA (1.5-3 MET) and sedentary (<1.5 MET) was 26.0 (12.3-48.1) min/day, 5.4 (4.2-6.7) h/day and 18.0 (16.6-19.4) h/day, respectively, in women; and 41.0 (18.8-73.0) min/day, 5.2 (4.0-6.5) h/day and 17.9 (16.3-19.4) h/day in men. PAEE and time spent in MVPA were lower and sedentary time was greater in obese individuals, those with poor health, and those with lower educational attainment (women only). Questionnaire-derived PAEE and MVPA tended to have similar patterns of variation across socio-demographic strata. In the whole sample, domestic PA had the greatest relative contribution to total questionnaire-derived PAEE (58%), whereas occupational PA was the main driver among employed participants (54%). Only 2.2% of participants achieved an average of >30 min MVPA per day combined with >60 min strength-training per week. CONCLUSIONS: The use of both self-report and objective monitoring to assess PA in early old age provides important information on the domains of PA, PAEE and time spent at different intensity levels. Our findings suggest PA levels are generally low and observed patterns of variation indicate specific subgroups who might benefit from targeted interventions to increase PA.

Comparison of the EPIC Physical Activity Questionnaire with combined heart rate and movement sensing in a nationally representative sample of older British adults.

OBJECTIVES: To compare physical activity (PA) subcomponents from EPIC Physical Activity Questionnaire (EPAQ2) and combined heart rate and movement sensing in older adults. METHODS: Participants aged 60-64y from the MRC National Survey of Health and Development in Great Britain completed EPAQ2, which assesses self-report PA in 4 domains (leisure time, occupation, transportation and domestic life) during the past year and wore a combined sensor for 5 consecutive days. Estimates of PA energy expenditure (PAEE), sedentary behaviour, light (LPA) and moderate-to-vigorous PA (MVPA) were obtained from EPAQ2 and combined sensing and compared. Complete data were available in 1689 participants (52% women). RESULTS: EPAQ2 estimates of PAEE and MVPA were higher than objective estimates and sedentary time and LPA estimates were lower [bias (95% limits of agreement) in men and women were 32.3 (-61.5 to 122.6) and 29.0 (-39.2 to 94.6) kJ/kg/day for PAEE; -4.6 (-10.6 to 1.3) and -6.0 (-10.9 to -1.0) h/day for sedentary time; -171.8 (-454.5 to 110.8) and -60.4 (-367.5 to 246.6) min/day for LPA; 91.1 (-159.5 to 341.8) and 55.4 (-117.2 to 228.0) min/day for MVPA]. There were significant positive correlations between all self-reported and objectively assessed PA subcomponents (rho= 0.12 to 0.36); the strongest were observed for MVPA (rho = 0.30 men; rho = 0.36 women) and PAEE (rho = 0.26 men; rho = 0.25 women). CONCLUSION: EPAQ2 produces higher estimates of PAEE and MVPA and lower estimates of sedentary and LPA than objective assessment. However, both methodologies rank individuals similarly, suggesting that EPAQ2 may be used in etiological studies in this population.

Association of chronic widespread pain with objectively measured physical activity in adults: findings from the National Health and Nutrition Examination survey.

UNLABELLED: Chronic widespread pain (CWP) is a common and potentially debilitating disorder. Patterns of physical activity (PA) in adults with CWP have primarily been investigated using subjective, self-report measures. The current study sought to characterize PA among community-dwelling individuals with CWP, chronic regional pain, or no chronic pain using objective measurements obtained via accelerometry in the 2003 to 2004 National Health and Nutrition Examination Survey. Data from 3,952 participants ages 20 and older were analyzed to assess relationships between pain status and objective measurements of PA. Prevalence of CWP was 3.3% and 5.4% in men and women, respectively. In men and women, the average activity counts per minute and time spent in moderate-to-vigorous PA were significantly lower for the CWP group than for the no chronic pain group. Interestingly, time spent in sedentary, light, and lifestyle activities was not associated with pain status. Statistical interaction tests indicated that the effects of chronic pain on counts per minute were stronger in men than in women. Despite recommendations for increased moderate-to-vigorous PA as a pain management strategy for CWP, results from this nationally representative study indicate that adults with CWP participate in less moderate-to-vigorous PA than individuals without chronic pain. PERSPECTIVE: Using objective measurement of PA in a nationally representative sample, this study demonstrates that adults with CWP participate in reduced daily and moderate-to-vigorous PA in comparison to people with no chronic pain. Findings indicate that clinicians should emphasize the importance of increasing PA in patients with CWP.