Real-world single centre use of JAK inhibitors across the rheumatoid arthritis pathway.

OBJECTIVES: To evaluate real-world efficacy of approved JAK inhibitors (JAKi) tofacitinib and baricitinib in a large, single-centre cohort of RA patients across the treatment pathway, including those refractory to multiple biologic drugs. METHODS: All RA patients, treated with tofacitinib (from time of compassionate access scheme) or baricitinib since approval in 2017 had DAS28-CRP scores and components recorded at baseline, 3 and 6 months (with retrospective data for compassionate access scheme). Efficacy was evaluated in the total cohort, each treatment group, and subgroups of number of prior biologic classes failed. RESULTS: One hundred and fifteen patients were treated with a JAKi (tofacitinib 54, baricitinib 69, 8 both); 76.4% female; mean (s.d.) age 57.3 (14.3) years. On average patients had received three previous bDMARDs; 11 (9.6%) were bDMARD naïve. Combined group baseline DAS28-CRP (s.d.) 5.62(1.14) improved by 1.49(1.44) and 1.67(1.61) at 3 and 6 months, respectively, comparable in individual JAKi groups; with 24% in at least low disease activity at 3 months. The biggest improvement was observed in the biologic-naïve group (mean DAS28-CRP improved from 5.16-2.14 after 6 months); while those with prior exposure to minimum three bDMARD classes had DAS28-CRP improvement of >1.2. Five out of 8 patients treated with both JAKi sequentially responded. Twelve patients previously unresponsive to IL-6 blockade responded to JAKi. No unexpected safety events were recorded. Two cases of venous thromboembolism were observed. CONCLUSION: JAK inhibition is effective in a real-world population of RA patients, including in a subset of patients refractory to multiple previous bDMARDs.

Real-world experience of effectiveness of non-medical switch from originator to biosimilar rituximab in rheumatoid arthritis.

OBJECTIVE: To evaluate the impact of non-medical switch from rituximab originator (RTX-O) to biosimilar (RTX-B) in patients with RA. METHODS: Between October 2017 and October 2019, all patients on RTX-O in our centre requiring re-treatment were switched to RTX-B unless declined by the patient or specified by the treating clinician. Switch strategy effectiveness was assessed retrospectively using DAS28-CRP(3) and RTX retention, with patients remaining on RTX-O as a comparator group. RESULTS: The number of patients switching to RTX-B was 255/337 (75.7%) while 82 (24.3%) remained on RTX-O. There was no difference in DAS28-CRP(3) 4 months post-RTX-B switch vs the same time point post-RTX-O previous cycle (paired data available in 60%). Eighteen-month retention estimates were 75.6% (95% CI: 69.4, 80.7%) for RTX-B group and 82.3% (95% CI: 70.4, 89.8%) for RTX-O [adjusted hazard ratio 1.52 (95% CI: 0.85, 2.73)]. The number of patients who discontinued RTX-B for loss of effectiveness (LOE) was 42/255 (16.5%), five (2.0%) for adverse effects (AEs). Risk of RTX-B discontinuation was associated with comorbidities and ≥2 previous biologic DMARDs. Risk of adverse outcome RTX cessation was associated with comorbidities, and reduced risk with number of previous RTX-O cycles and pre-switch cycle B cell depletion. The number of patients who switched back to RTX-O was 34/255 (13.3%) (LOE: 30, AEs: 4), while 13/255 (5.1%) started other biologic/targeted synthetic DMARDs. Of patients who switched back for LOE, 28/30 remained on RTX-O at a mean 7.7 months follow-up. CONCLUSION: Non-medical switch to RTX-B was largely effective. Factors associated with RTX-B discontinuation, including comorbidities, previous biologic DMARDs, and RTX-O treatment history, may inform switch decisions. Most patients who switched back to RTX-O for LOE remained on treatment at short-term follow-up.

Real-world use of pomalidomide and dexamethasone in double refractory multiple myeloma suggests benefit in renal impairment and adverse genetics: a multi-centre UK experience.

Myeloma patients who become refractory to immunomodulatory agents (IMiDs) and bortezomib have poor survival, with limited therapeutic options. Pomalidomide has shown improved survival and good tolerability in this patient cohort in clinical trials, but real world data are scarce. We retrospectively analysed all patients treated with pomalidomide at five UK centres between 2013 and 2016. Of 85 patients identified, 70 had sufficient information for response assessments. Median age was 66 years [40-89], 96·5% were refractory to IMiDs, 72·9% were refractory to both an IMiD and bortezomib and 92·9% were refractory to their last treatment. Of 45 patients with fluorescence in situ hybridization results 64% had adverse risk, 19 patients (22·4%) had an estimated glomerular filtration rate <45 ml/min. Grade ≥3 non-haematological toxicities occurred in 42·4%, and grade ≥3 neutropenia and thrombocytopenia in 38% and 24% respectively, but only 18·8% had dose reductions. The overall response rate was 52·9%. At a median follow-up of 13·2 months, median progression-free survival was 5·2 months [95% confidence interval (CI) 4·150-6·238], and median overall survival was 13·7 months (95% CI 11·775-15·707). No significant difference was seen in response, survival or tolerability by renal function, age or cytogenetic risk. This real-world data support the results seen in published clinical trials.

Admission to Intensive Care for Palliative Care or Potential Organ Donation: Demographics, Circumstances, Outcomes, and Resource Use.

OBJECTIVES: To describe the characteristics, circumstances, change over time, resource use, and outcomes of patients admitted to ICUs in Australia and New Zealand for the purposes of "palliative care of a dying patient" or "potential organ donation," and compare with actively managed ICU patients. DESIGN: A retrospective study of data from the Australian and New Zealand Intensive Care Society Adult Patient Database and a nested cohort analysis of a single center. SETTING: One hundred seventy-seven ICUs in Australia and New Zealand and a nested analysis of one university-affiliated hospital ICU in Melbourne, VIC, Australia. PATIENTS: Three thousand seven hundred "palliative care of a dying patient" and 1,115 "potential organ donation" patients from 2007 to 2016. The nested cohort included 192 patients. INTERVENTIONS: No interventions. Data extracted included patient demographics, diagnoses, length of stay, circumstances, and outcome of admission. MEASUREMENTS AND MAIN RESULTS: ICU admissions for "palliative care of a dying patient" and "potential organ donation" increased from 179 in 2007 to 551 in 2016 and from 44 in 2007 to 174 in 2016 in each respective group, though only the "potential organ donation" cohort showed an increase in proportion of total ICU admissions. Lengths of stay in ICU were a mean of 33.8 hours (median, 17.5; interquartile range, 6.4-38.8) and 44.7 hours (26.6; 16.0-44.6), respectively, compared with 74.2 hours (41.5; 21.7-77.0) in actively managed patients. Hospital mortality was 86.6% and 95.9%, respectively. In the nested cohort of 192 patients, facilitating family discussions about goals of treatment and organ donation represented the most common reason for ICU admission. CONCLUSIONS: Patients admitted to ICU to manage end-of-life care represent a small proportion of overall ICU admissions, with an increasing proportion of "potential organ donation" admissions. They have shorter ICU lengths of stay than actively managed patients, suggesting resource use for these patients is not disproportionate.

The effect of restrictive compared to liberal intravenous fluid volume on hypotension in adults undergoing major abdominal surgery.

In a cardiac output (CO) sub-study of the Restrictive versus Liberal Fluid Therapy in Major Abdominal Surgery (RELIEF) trial, it was shown that restrictive fluid management was associated with lower cardiac index at the end of surgery. However, the association of the fluid protocol with intraoperative blood pressure was less clear. This paper primarily compares rates of hypotension between the two fluid regimens. The haemodynamic effects of these protocols may increase our understanding of perioperative fluid prescription. Using a data set of arterial pressure and cardiac output measurements, this observational cohort study primarily compares intraoperative hypotension rates defined by a mean arterial pressure < 65 mmHg between liberal and restrictive fluid protocols. Secondary analyses explore predictors of invasive mean arterial pressure and doppler-derived cardiac output, including fluid volume regimens and surgical duration. 105 patients had a combined total of 835 haemodynamic data capture events from the beginning to the end of the surgery. Here we report that a restrictive regimen is not associated with a greater proportion of participants who experience at least one episode of hypotension than the liberal regimen 64.1% vs. 61.5% (mean difference 2.6%, 95% CI - 15.9% to 21%, p = 0.78). Duration of surgery was associated with an increased risk of hypotension (OR 1.05, 1 to 1.1, p = 0.038). A fluid restriction protocol compared to liberal fluid administration is not associated with lower blood pressure.

Validation of the Southend giant cell arteritis probability score in a Scottish single-centre fast-track pathway.

OBJECTIVE: The aim was to provide external validation of the Southend GCA probability score (GCAPS) in patients attending a GCA fast-track pathway (GCA FTP) in NHS Lanarkshire. METHODS: Consecutive GCA FTP patients between November 2018 and December 2020 underwent GCAPS assessment as part of routine care. GCA diagnoses were supported by US of the cranial and axillary arteries (USS), with or without temporal artery biopsy (TAB), and confirmed at 6 months. Percentages of patients with GCA according to GCAPS risk group, performance of total GCAPS in distinguishing GCA/non-GCA final diagnoses, and test characteristics using different GCAPS binary cut-offs were assessed. Associations between individual GCAPS components and GCA and the value of USS and TAB in the diagnostic process were also explored. RESULTS: Forty-four of 129 patients were diagnosed with GCA, including 0 of 41 GCAPS low-risk patients (GCAPS <9), 3 of 40 medium-risk patients (GCAPS 9-12) and 41 of 48 high-risk patients (GCAPS >12). Overall performance of GCAPS in distinguishing GCA/non-GCA was excellent [area under the receiver operating characteristic curve, 0.976 (95% CI 0.954, 0.999)]. GCAPS cut-off ≥10 had 100.0% sensitivity and 67.1% specificity for GCA. GCAPS cut-off ≥13 had the highest accuracy (91.5%), with 93.2% sensitivity and 90.6% specificity. Several individual GCAPS components were associated with GCA. Sensitivity of USS increased by ascending GCAPS risk group (nil, 33.3% and 90.2%, respectively). TAB was diagnostically useful in cases where USS was inconclusive. CONCLUSION: This is the first published study to describe application of GCAPS outside the specialist centre where it was developed. Performance of GCAPS as a risk stratification tool was excellent. GCAPS might have additional value for screening GCA FTP referrals and guiding empirical glucocorticoid treatment.

Single-centre experience of refractory rheumatoid arthritis.

Objectives: The aim was to evaluate the proportion of RA patients who are refractory to multiple targeted therapies (TTs) in a real-world cohort of patients in a tertiary rheumatology referral centre, to describe patterns of drug sequencing associated with the development of refractory RA (RefRA) and to identify whether there is a subgroup of RefRA patients in whom successive drugs have shown primary lack of efficacy. Methods: Patients at a single centre were defined as refractory if they had failed two or more classes of TT and were identified from a dedicated TT clinic database. Reasons for drug failure were recorded, and patients were categorized pragmatically as having mild [failure of two biologic DMARD (bDMARD) classes], moderate [failure of at least three bDMARD classes] or severe [failure of at least two bDMARD classes and JAK inhibitor] refractory disease. Results: One hundred and seventy-two patients were identified as RefRA (>10% of our TT-exposed cohort); median [interquartile range (IQR)] TT exposures of four (two), 81.5% female, 82% seropositive, mean (s.d.) age of 63 (12.3) years. Detailed analysis of 60 patients showed a median (IQR) disease duration of 22 (10.75) years, median (IQR) time from diagnosis to initiation of first TT of 5 (10) years, and mean (s.d.) baseline DAS28CRP before starting first-line TT of 5.91 (0.84). Among RefRA patients, 15% were severely refractory, and 6% had demonstrated no clinical response to any TT. Conclusion: A small proportion of patients have true RefRA. Most patients fail multiple therapies owing to a combination of inefficacy and adverse events.

Cross-Sectional Transcriptional Analysis of the Aging Murine Heart.

Cardiovascular disease accounts for millions of deaths each year and is currently the leading cause of mortality worldwide. The aging process is clearly linked to cardiovascular disease, however, the exact relationship between aging and heart function is not fully understood. Furthermore, a holistic view of cardiac aging, linking features of early life development to changes observed in old age, has not been synthesized. Here, we re-purpose RNA-sequencing data previously-collected by our group, investigating gene expression differences between wild-type mice of different age groups that represent key developmental milestones in the murine lifespan. DESeq2's generalized linear model was applied with two hypothesis testing approaches to identify differentially-expressed (DE) genes, both between pairs of age groups and across mice of all ages. Pairwise comparisons identified genes associated with specific age transitions, while comparisons across all age groups identified a large set of genes associated with the aging process more broadly. An unsupervised machine learning approach was then applied to extract common expression patterns from this set of age-associated genes. Sets of genes with both linear and non-linear expression trajectories were identified, suggesting that aging not only involves the activation of gene expression programs unique to different age groups, but also the re-activation of gene expression programs from earlier ages. Overall, we present a comprehensive transcriptomic analysis of cardiac gene expression patterns across the entirety of the murine lifespan.

Understanding Refractory Rheumatoid Arthritis: Implications for a Therapeutic Approach.

Refractory rheumatoid arthritis (RA) has emerged as an area of unmet need in a landscape of generally well-controlled disease. Whilst most patients are adequately treated on methotrexate and other first-line disease-modifying anti-rheumatic drugs (DMARDs), a proportion requires biologic (b) and targeted synthetic (ts) DMARDs, with a further subsection failing multiple agents. Recent observational studies have adopted working definitions of refractory RA based on number of failed DMARDs, with prevalence estimates of 6-21% depending on threshold and study population. Risk factors include treatment delay, baseline disease activity and function, female gender, smoking, obesity and lower socioeconomic status. Practical and conceptual challenges in defining refractory RA arise from limitations of disease activity scores used to assess response, with attendant misclassification risk of co-existent non-inflammatory pathology, and failure to capture additional outcomes, such as fatigue, that have variable treatment response. Time is an important factor in defining refractory disease; registry studies show that growing treatment options have resulted in rapid b/tsDMARD cycling and earlier refractory status, and refractory RA is itself a dynamic concept, evolving with each new therapeutic class. Whilst the biology underpinning refractory RA remains largely unknown, a general overview of biomarker studies and clinical trials old and new offers insights into prediction of response and treatment failure. Whilst the future holds promise, current data are insufficient to personalise or meaningfully sequence b/tsDMARDs. Therefore, avoidance of a refractory course is best achieved by following proven management paradigms (e.g. early diagnosis and treat-to-target), addressing modifiable risk factors, and considering enrolment in novel trials.

Synovial Tissue Heterogeneity in Rheumatoid Arthritis and Changes With Biologic and Targeted Synthetic Therapies to Inform Stratified Therapy.

The treatment of rheumatoid arthritis (RA) has been transformed with the introduction of biologic disease modifying anti-rheumatic drugs (bDMARD) and more recently, targeted synthetic DMARD (tsDMARD) therapies in the form of janus-kinase inhibitors. Nevertheless, response to these agents varies such that a trial and error approach is adopted; leading to poor patient quality of life, and long-term outcomes. There is thus an urgent need to identify effective biomarkers to guide treatment selection. A wealth of research has been invested in this field but with minimal progress. Increasingly recognized is the importance of evaluating synovial tissue, the primary site of RA, as opposed to peripheral blood-based investigation. In this mini-review, we summarize the literature supporting synovial tissue heterogeneity, the conceptual basis for stratified therapy. This includes recognition of distinct synovial pathobiological subtypes and associated molecular pathways. We also review synovial tissue studies that have been conducted to evaluate the effect of individual bDMARD and tsDMARD on the cellular and molecular characteristics, with a view to identifying tissue predictors of response. Initial observations are being brought into the clinical trial landscape with stratified biopsy trials to validate toward implementation. Furthermore, development of tissue based omics technology holds still more promise in advancing our understanding of disease processes and guiding future drug selection.

Systematic identification and referral of smokers attending HIV ambulatory care highlights the failure of current service provision in an at-risk population.

Introduction: People living with HIV (PLWH) are more likely to smoke than the general population and are at greater risk of smoking-related illness. Healthcare services need to address this burden of preventable disease. Methods: We evaluated the impact of a brief intervention that asked service users about smoking when they attended for ambulatory HIV care in London, UK, and offered referral to smoking cessation. Results: Overall, 1548 HIV-positive individuals were asked about their smoking status over a 12-month period. Of this group, 385 (25%) reported that they were current smokers, 372 (97%) were offered referral to smoking cessation services and 154 (40%) accepted this. We established an outcome of referral for 114 (74%) individuals. A total of 36 (10% of smokers) attended stop smoking clinics and 16 (4%) individuals were recorded as having quit smoking. Discussion: The simple intervention of asking PLWH about tobacco smoking and offering referral to smoking cessation services rapidly identified current smokers, 40% of whom accepted referral to smoking cessation services. This highlights the importance of promoting behaviour and lifestyle changes with every contact with health services. However, a large proportion of those referred were either not seen in local services or the outcome of referral could not be ascertained. If the risk of smoking-related morbidity among PLWH is to be reduced, more sustainable referral pathways and ways of improving uptake of smoking cessation services must be developed.

Spatial analysis of stable isotope data to determine primary sources of nutrition for fish.

Carbon and nitrogen stable isotopes were used to determine the ultimate autotrophic sources supporting production of three commercially important fish species over unvegetated mudflats in a subtropical estuary. Mean isotope values over the whole estuary for fish and autotroph sources were modeled to indicate feasible combinations of sources. Variability in isotope values among nine locations (separated by 3-10 km) was then used as a further test of the likelihood that sources were involved in fish nutrition. A positive spatial correlation between isotope values of a fish species and an autotroph indicates a substantial contribution from the autotroph. Spatial correlations were tested with a newly developed randomization procedure using differences between fish and autotroph values at each location, based on carbon and nitrogen isotopes combined in two-dimensional space. Both whole estuary modeling and spatial analysis showed that seagrass, epiphytic algae and particulate organic matter in the water column, including phytoplankton, are likely contributors to bream (Acanthopagrus australis) nutrition. However, spatial analysis also showed that mangroves were involved (up to 33% contribution), despite a very low contribution from whole estuary modeling. Spatial analysis on sand whiting (Sillago ciliata) demonstrated the importance of two sources, mangroves (up to 25%) and microalgae on the mudflats, considered unimportant based on whole estuary modeling. No spatial correlations were found between winter whiting (Sillago maculata) and autotrophs, either because fish moved among locations or relied on different autotrophs at different locations. Spatial correlations between consumer and source isotope values provide a useful analytical tool for identifying the role of autotrophs in foodwebs, and demonstrated here that both in situ production of microalgae and organic matter from adjacent habitats were important to fish over mudflats.

Sulfur stable isotopes separate producers in marine food-web analysis.

Ecological applications of stable isotope analysis rely on different producers having distinct isotopic ratios to trace energy and nutrient transfer to consumers. Carbon (C) and nitrogen (N) are the usual elements analysed. We tested the hypothesis that producers unable to be separated using C and N would be separated by sulphur (S), by reviewing estuarine and marine food web studies using all three elements (total of 836 pairwise comparisons between producers). S had a wider range of values across all producers than C and N (S: 34.4, C: 23.3, N: 18.7 per thousand ), and a higher mean difference among producers (S: 9.3, C: 6.5, N: 3.3 per thousand ). We varied from 1 to 10 per thousand the distance producers must be apart to be considered separate. For each of these gap distances, S-separated producers tied on C and N in 40% or more of cases. Comparing the three elements individually, S had fewer tied pairs of producers for any gap distance than C or N. However, S also has higher within-producer variability. Statistical tests on simulated data showed that this higher variability caused S to be less effective than C for analysing differences among mean producer values, yet mixing models showed that S had the smallest confidence intervals around mean estimates of source contributions to consumers. We also examined the spatial and temporal scales over which S isotope signatures of the saltmarsh plant Spartina alterniflora varied. Differences between samples taken within tens of metres were smallest, but between samples hundreds of metres apart were as different as samples thousands of kilometres apart. The time between samples being taken did not influence S signatures. Overall, the use of S is recommended because it has a high probability of distinguishing the contribution of different producers to aquatic food webs. When two elements are employed, the combination of S and C separates more producers than any other combination.