Recent Submissions

  • IBRUTINIB AND RITUXIMAB AS FIRST LINE THERAPY FOR MANTLE CELL LYMPHOMA: A MULTICENTRE, REAL-WORLD UK STUDY.

    Smith, Susan; Jones, Steve (HemaSphere, 2022-06)
    Background: Ibrutinib (IBR) is an oral covalent Bruton tyrosine kinase inhibitor (BTKi), licensed for treatment of relapsed or refractory mantle cell lymphoma (MCL). Under NHS interim Covid-19 agreements in England, IBR with or without rituximab (R) was approved for the frontline treatment for MCL patients (pts) as a safer alternative to conventional immunochemotherapy. Although recent phase 2 studies have reported high response rates in low-risk patients for this combination in the frontline setting, randomised phase 3 and real-world data are currently lacking. Aims: To describe the real-world response rates (overall response rate (ORR), complete response (CR) rate) and toxicity profile of IBR +/- R in adult patients with previously untreated MCL. Methods: Following institutional approval, adults commencing IBR +/- R for untreated MCL under interim Covid-19 arrangements were prospectively identified by contributing centres. Hospital records were interrogated for demographic, pathology, response, toxicity and survival data. ORR/CR were assessed per local investigator according to the Lugano criteria using CT and/or PET-CT. Results: Data were available for 66 pts (72.7% male, median age 71 years, range 41-89). Baseline demographic and clinical features are summarised in Table 1. 23/66 pts (34.8%) had high-risk disease (defined as presence of TP53 mutation/deletion, blastoid or pleomorphic variant MCL, or Ki67%/MiB-1 ≥30%). IBR starting dose was 560mg in 56/62 pts (90%) and was given with R in 22/64 pts (34%). At a median follow up of 8.7 months (m) (range 0-18.6), pts had received a median of 7 cycles of IBR. 19/60 pts (32%) required a dose reduction or delay in IBR treatment. New atrial fibrillation and grade ≥3 any-cause toxicity occurred in 3/59 pts (5.8%) and 8/57 (14.0%) respectively.
  • THE ASSOCIATION of PAINFUL and NON-PAINFUL COMORBIDITIES with CENTRAL MECHANISMS of KNEE PAIN.

    Walsh, David A (Annals of the Rheumatic Diseases, 2022-05)
    Background Central mechanisms of knee pain occur in the central nervous system and may intensify and prolong pain. Central pain mechanisms might be facilitated by ongoing nociceptive input. A link between multimorbidity and central mechanisms of knee pain is proposed; ongoing sensory inputs due to comorbidities may trigger changes in pain processing by the CNS. This might be particularly expected with painful comorbidities. Objectives To investigate potential relationships of painful and non-painful multimorbidity with central mechanisms of knee pain. Methods Cross-sectional analysis of self-report data from participants of the Investigating Musculoskeletal Health and Wellbeing cohort, who reported knee as their most bothersome site of joint pain over the previous month, with pain rated ≥1/10, and who had completed FRAIL and CAP-Knee (1) questionnaires. Two indirect measures suggesting central mechanisms involvement in knee pain were used as dependent variables; pain intensity (0-10 numerical rating scale) and CAP-Knee score (0-16 scale). Comorbidities were assigned either “painful comorbidity” or “non-painful comorbidity” status based on IASP classification of chronic pain criteria (2). Multivariable linear regression models, adjusted for age and sex, were employed to explore associations of comorbidity counts with pain intensity and CAP-Knee score. Results 736 participants satisfied inclusion criteria. 55% were female, mean age 71 (range 40 to 95). Painful comorbidity count and non-painful comorbidity count each had positive associations with pain intensity (β=0.42, 95% CI=0.29 to 0.54, p<0.001; and β=0.31, 95%CI=0.16 to 0.45, p<0.001, respectively). Painful and non-painful comorbidity counts each also were associated with CAP-Knee score (β=0.80, 95% CI=0.59 to 1.01, p<0.001; and β=0.52, 95% CI=0.27 to 0.77, p<0.001, respectively). Painful and non-painful comorbidity counts each remained significantly associated both with pain intensity and with CAP-Knee scores when both types of comorbidity count were included in the same multivariable model. Conclusion Both painful and non-painful comorbidities were positively associated with central mechanisms of knee pain, providing further insight into the interconnectedness of pain processing systems and the rest of the body. The explanation behind these relationships may depend on more than just ongoing nociceptive input. Future work should address possible contributions from genetic, pathophysiological, psychological, and pharmacological factors associated with comorbid diagnosis.
  • Critical care usage after major gastrointestinal and liver surgery: a prospective, multicentre observational study.

    Sagar, R; Jathana, N; Rothwell, L (BJA: British Journal of Anaesthesia, 2019-01)
    Background: Patient selection for critical care admission must balance patient safety with optimal resource allocation. This study aimed to determine the relationship between critical care admission, and postoperative mortality after abdominal surgery. Methods: This prespecified secondary analysis of a multicentre, prospective, observational study included consecutive patients enrolled in the DISCOVER study from UK and Republic of Ireland undergoing major gastrointestinal and liver surgery between October and December 2014. The primary outcome was 30-day mortality. Multivariate logistic regression was used to explore associations between critical care admission (planned and unplanned) and mortality, and inter-centre variation in critical care admission after emergency laparotomy. Results: Of 4529 patients included, 37.8% (n=1713) underwent planned critical care admissions from theatre. Some 3.1% (n=86/2816) admitted to ward-level care subsequently underwent unplanned critical care admission. Overall 30-day mortality was 2.9% (n=133/4519), and the risk-adjusted association between 30-day mortality and critical care admission was higher in unplanned [odds ratio (OR): 8.65, 95% confidence interval (CI): 3.51-19.97) than planned admissions (OR: 2.32, 95% CI: 1.43-3.85). Some 26.7% of patients (n=1210/4529) underwent emergency laparotomies. After adjustment, 49.3% (95% CI: 46.8-51.9%, P<0.001) were predicted to have planned critical care admissions, with 7% (n=10/145) of centres outside the 95% CI. Conclusions: After risk adjustment, no 30-day survival benefit was identified for either planned or unplanned postoperative admissions to critical care within this cohort. This likely represents appropriate admission of the highest-risk patients. Planned admissions in selected, intermediate-risk patients may present a strategy to mitigate the risk of unplanned admission. Substantial inter-centre variation exists in planned critical care admissions after emergency laparotomies.
  • A colitis bundle initiative to improve the outcome of acute IBD colitis patients

    Bahrin, MHK; El Atrash, Malik Satea; Danish, Farheen; Ali, Ahmed
    Introduction Early detection and assessment of the severity are crucial in the management of an IBD flare-ups. This is so steroid therapy, the initial remission-inducing treatment can be administered at that right time. However, in those with severe colitis where steroid therapy is inadequate, often rescue therapy, either in the form of biologics or surgery is required. Simple measures during flare-ups would help to achieve this and potentially be life-saving. Methods This project aims to review the current performance against the IBD management NICE guideline and to introduce a trust-wide Colitis bundle to ensure junior doctors and consultants can make important decisions regarding colitis patient care. A retrospective audit was carried out on 40 In-patients with a diagnosis of an acute flare of ulcerative and Crohn’s colitis over the year 2021. A proforma was created based on the latest colitis management guidelines. This reviewed step-by-step management plans over the first 3 days period – which, if perfectly followed, will ensure deliverance of rescue therapy safely by day 3 or day 4. Results The results showed a delay in managing acute IBD flare-ups, in which the initial steroid therapy was given to only 82.8% and the VTE prophylaxis was commenced only on 65.7% of the cases. Recognition of colitis severity as defined by Truelove and Witt’s score was also poor as it happened in only 20% of the cases. This downplayed the urgency of acknowledging the need for an escalated treatment strategy, which subsequently resulted in a delay in pre-biologics screening test – this happened in 25.7% of cases only within the first 2 days of diagnosis. As this test was essential in those requiring rescue biologic therapies, this resulted in an overall delay in its initiation as demonstrated in Figure 1. Abstract P21 Figure 1 Time between the biologic therapy decision and its first dose administration Conclusions The quality improvement project has demonstrated poor recognition and assessment of acute IBD flare-ups as recommended by the NICE guideline. This subsequently led to a delay in initiation of the steroid therapy, pre-biologic screening test, and initiation of rescue biologic therapies in those with severe colitis. This is due to the lack of exposure among junior and senior doctors towards the guideline. As a response, a mass education at a Trust level for the doctors was recommended and a colitis bundle was constructed, which comprised of evidence-based action plans checklist divided into Day 1 to Day 3 to make sure that all the aspects are not missed.
  • Routine Pressure Wire Assessment Versus Conventional Angiography in the Management of Patients With Coronary Artery Disease: The RIPCORD 2 Trial

    Fazal, Iftikhar (Circulation, 2022-08)
    Background: Measurement of fractional flow reserve (FFR) has an established role in guiding percutaneous coronary intervention. We tested the hypothesis that, at the stage of diagnostic invasive coronary angiography, systematic FFR-guided assessment of coronary artery disease would be superior, in terms of resource use and quality of life, to assessment by angiography alone. Methods: We performed an open-label, randomized, controlled trial in 17 UK centers, recruiting 1100 patients undergoing invasive coronary angiography for the investigation of stable angina or non-ST-segment-elevation myocardial infarction. Patients were randomized to either angiography alone (angiography) or angiography with systematic pressure wire assessment of all epicardial vessels >2.25 mm in diameter (angiography+FFR). The coprimary outcomes assessed at 1 year were National Health Service hospital costs and quality of life. Prespecified secondary outcomes included clinical events. Results: In the angiography+FFR arm, the median number of vessels examined was 4 (interquartile range, 3-5). The median hospital costs were similar: angiography, £4136 (interquartile range, £2613-£7015); and angiography+FFR, £4510 (£2721-£7415; P=0.137). There was no difference in median quality of life using the visual analog scale of the EuroQol EQ-5D-5L: angiography, 75 (interquartile range, 60-87); and angiography+FFR, 75 (interquartile range, 60-90; P=0.88). The number of clinical events was as follows: deaths, 5 versus 8; strokes, 3 versus 4; myocardial infarctions, 23 versus 22; and unplanned revascularizations, 26 versus 33, with a composite hierarchical event rate of 8.7% (48 of 552) for angiography versus 9.5% (52 of 548) for angiography+FFR (P=0.64). Conclusions: A strategy of systematic FFR assessment compared with angiography alone did not result in a significant reduction in cost or improvement in quality of life.
  • Considering the impact of patient ethnicity on cystic fibrosis related bone disease.

    Akbari, Amir R (Journal of Clinical & Translational Endocrinology, 2022-07)
    We found the article “Bone accrual and structural changes over one year in youth with cystic fibrosis” by Rosara M.Bass et al [1] to be of great interest. The study investigated bone changes over one year in individuals aged 5–18 with both cystic fibrosis (CF). The aim of this was to see how much bone development in youth and emerging adults contributes to cystic fibrosis related bone disease (CFBD). The study accounted for the following patient demographics: weight, height, age, pubertal status, and gender [1]. Although these are important factors, we believe it is important to consider the impact of patient ethnicity on the development of structural changes in the bone. Several studies across western countries have found that vitamin D deficiencies are more prevalent in ethnic minority groups, including South Asian and Black African-Caribbean populations [2], [3]. This is thought to be due to skin pigmentation being a factor which impacts the levels of vitamin D produced in the skin after sun exposure [2]. Furthermore, vitamin D deficiency is also the most recognised cause of CFBD [4]. Therefore, it is important to recognise the potential impact of ethnicity on changes in bone development in patients with CF. Additionally, it is important to note that studies have demonstrated that CF patients from ethnic minority backgrounds are more likely to experience worse outcomes compared to white patients [5]. For example, a study in the United States found that Hispanic and Black patients with CF had worse respiratory function compared to white patients [5]. We therefore propose that future studies should include ethnicity as a patient demographic. Further research into the impact of ethnicity on CFBD will enable a more inclusive and holistic approach towards diagnosis and treatment of CF.
  • Improving the delivery of acute NIV at Kings Mill Hospital: A closed loop quality improvement project.

    Slaich, Bhavandeep; Garrett, Frederick
    Background: The British Thoracic Society (BTS) Acute Non-Invasive Ventilation (NIV) standards state all patients who require acute NIV should be initiated on NIV within two hours of hospital admission. The delivery of acute NIV is a time critical intervention as prompt application of acute NIV substantially reduces mortality for patients with acute hypercapnic respiratory failure. Objective: This audit aimed to assess the number of patients for whom there is a delay in the initiation of acute NIV. We also assessed the outcome of admission for patients started on acute NIV. Methods: Data was collected on patients admitted to Kings Mill Hospital for acute NIV between 1/2/2019 and 31/3/2019. Awareness and knowledge of acute NIV was highlighted as an area for improvement. E-learning packages on 'Acute NIV' were designed and sent to medical-staff. The audit was repeated for patients admitted for acute NIV between 1/2/2020 and 31/3/2020 and analysed using chi-square tests. Results: 25 patients were included in the initial audit and 30 patients in the re-audit. Prior to intervention 31% of patients had a delay in the initiation of acute NIV, which increased to 77% post-intervention (p < 0.0001). Prior to intervention there was a mortality rate of 17% and a mortality rate of 13% post-intervention (p > 0.05). Conclusion: Further work is required to ensure the sustained delivery of acute NIV to BTS standards, however variable achievements in the targets does not seem to have a significant adverse effect on patient outcomes.
  • Antibiotic prophylaxis in breast surgery: a meta-analysis to identify the optimal strategy to reduce infection rates in breast surgery.

    Akbari, Amir R
    Intro: Breast surgeries are an increasingly frequent operation, with an exponential rise in breast cancer diagnoses, and women opting for cosmetic surgeries. SSIs are the most common post-operative complication with many negative consequences including sepsis and even death. These are treated with prophylactic antibiotics prior to surgery. Breast surgery is currently defined as 'clean', although literature indicates that the infection rate is higher than should be expected for this classification. The aim of this meta-analysis is to evaluate whether pre-operative antibiotics reduce SSI frequency and which class of antibiotics achieve the best reduction. Methods: A literature search through online libraries was used to find clinical trials investigating pre-breast-surgery antibiotics and SSI frequency. These were grouped all together and separately by class of antibiotics. Additionally studies investigating breast cancer surgeries and non-cancer surgeries were grouped separately. A forest-plot was created for each group to calculate an estimated effect, these were then compared against each other. Results: Use of antibiotics resulted in a reduction in SSI frequency by 3.55% overall, and reduced frequency in all types of surgeries performed. Cephalosporins reduced SSI frequency by 2.23%, Beta-lactamase inhibitors 4.17% and macrolides achieved the greatest effect with a 14.58% reduction. Conclusion: This meta-analysis proves that antibiotics reduce SSI frequency in breast surgery and supports the notion to remove the 'clean' classification. This definition may result in failure to provide prophylaxis, resulting in patients suffering from preventable SSIs and their negative consequences. Macrolides were the most effective followed by beta-lactamase inhibitors and cephalosporins, this may be implemented in structuring new guidelines favouring use of macrolides before conducting breast surgery.
  • Invasive coronary physiology assessment - safety of pressure wire study as a diagnostic tool at a district general hospital

    Dardas, Sotirios; Jesudason, Daniel (Heart, 2022-06)
    Introduction Pressure wire study (PWS) is a well-established tool for the assessment of the haemodynamic significance of intermediate coronary artery stenoses (40–90%). This, according to the 2018 ESC myocardial revascularization guidelines, has Class IA indication when evidence of ischaemia is not present. It can be used to calculate the fractional flow reserve (FFR), instantaneous wave-free ratio (iFR) or resting full cycle ratio (RFR) to guide revascularization decisions, with similar diagnostic accuracy between the tests. Despite the above, the utilization of PWS varies across the U.K., as reflected in the recent BCIS annual data. One possible explanation might be the fact that there are still numerous centres in the U.K, where diagnostic only coronary angiography lists take place, precluding the use of PWS at the same sitting. In our study, we aimed to review the safety of PWS as an invasive diagnostic tool and determine whether it could be incorporated in diagnostic only lists for the assessment of coronary stenoses.
  • eQTL set-based association analysis identifies novel susceptibility loci for Barrett's esophagus and esophageal adenocarcinoma

    Jankowski, Janusz
    Background: Over 20 susceptibility single-nucleotide polymorphisms (SNPs) have been identified for esophageal adenocarcinoma (EAC) and its precursor, Barrett's esophagus (BE), explaining a small portion of heritability. Methods: Using genetic data from 4,323 BE and 4,116 EAC patients aggregated by international consortia including the Barrett's and Esophageal Adenocarcinoma Consortium (BEACON), we conducted a comprehensive transcriptome-wide association study (TWAS) for BE/EAC, leveraging Genotype Tissue Expression (GTEx) gene expression data from six tissue types of plausible relevance to EAC etiology: mucosa and muscularis from the esophagus, gastroesophageal (GE) junction, stomach, whole blood, and visceral adipose. Two analytical approaches were taken: standard TWAS using the predicted gene expression from local expression quantitative trait loci (eQTLs), and set-based SKAT association using selected eQTLs that predict the gene expression. Results: While the standard approach did not identify significant signals, the eQTL set-based approach identified eight novel associations, three of which were validated in independent external data (eQTL SNP sets for EXOC3, ZNF641 and HSP90AA1). Conclusions: This study identified novel genetic susceptibility loci for EAC and BE using an eQTL set based genetic association approach. Impact: This study expanded the pool of genetic susceptibility loci for EAC and BE, suggesting the potential of the eQTL set based genetic association approach as an alternative method for TWAS analysis.
  • Validation of methods for converting the original Disease Activity Score (DAS) to the DAS28

    Walsh, David A (Rheumatology Internatiaonal, 2018-12)
    The Disease Activity Score (DAS) is integral in tailoring the clinical management of rheumatoid arthritis (RA) patients and is an important measure in clinical research. Different versions have been developed over the years to improve reliability and ease of use. Combining the original DAS and the newer DAS28 data in both contemporary and historical studies is important for both primary and secondary data analyses. As such, a methodologically robust means of converting the old DAS to the new DAS28 measure would be invaluable. Using data from The Early RA Study (ERAS), a sub-sample of patients with both DAS and DAS28 data were used to develop new regression imputation formulas using the total DAS score (univariate), and using the separate components of the DAS score (multivariate). DAS were transformed to DAS28 using an existing formula quoted in the literature, and the newly developed formulas. Bland and Altman plots were used to compare the transformed DAS with the recorded DAS28 to ascertain levels of agreement. The current transformation formula tended to overestimate the true DAS28 score, particularly at the higher end of the scale. A formula which uses all separate components of the DAS was found to estimate the scores with a higher level of precision. A new formula is proposed that can be used by other early RA cohorts to convert the original DAS to DAS28.
  • Is incident rheumatoid arthritis interstitial lung disease associated with methotrexate treatment? Results from a multivariate analysis in the ERAS and ERAN inception cohorts

    Walsh, David A (BMJ Open, 2019-05)
    Objectives: To assess predictive factors for rheumatoid arthritis interstitial lung disease (RA-ILD) in two early rheumatoid arthritis (RA) inception cohorts with a focus on methotrexate (MTX) exposure. Design: Multicentre prospective early RA inception cohort studies; the early RA study (ERAS) and the early RA network (ERAN). Setting: Secondary care, ERAS nine centres, ERAN 23 centres in England, Wales and Ireland. Participants: Patients with new diagnosis of RA, n=2701. Standardised data including demographics, drug therapies and clinical outcomes including the presence of RA-ILD were collected at baseline, within 3-6 months, at 12 months and annually thereafter. Primary and secondary outcome measures: Primary outcome was the association of MTX exposure on RA-ILD diagnosis. Secondary outcomes were the association of demographic, comorbid and RA-specific factors on RA-ILD diagnosis and the association of MTX exposure on time to RA-ILD diagnosis. Results: Of 92 eligible ILD cases, 39 occurred in 1578 (2.5%) MTX exposed and 53 in 1114 (4.8%) non-MTX exposed cases. The primary analysis of RA-ILD cases only developing after any conventional synthetic disease-modifying antirheumatic drug treatment (n=67) showed MTX exposure not to be associated with incident RA-ILD (OR 0.85, 95% CI 0.49 to 1.49, p=0.578) and a non-significant trend for delayed ILD diagnosis (OR 0.54, 95% CI 0.28 to 1.06, p=0.072). In an extended analysis including RA-ILD cases present at RA diagnosis (n=92), MTX exposure was associated with a significantly reduced risk of incident RA-ILD (OR 0.48, 95% CI 0.3 to 0.79, p=0.004) and longer time to ILD diagnosis (OR 0.41, 95% CI 0.23 to 0.75, p=0.004). Other independent baseline associations with incident RA-ILD were higher age of RA onset, ever smoking, male gender, rheumatoid nodules and longer time from first RA symptom to first outpatient visit. Conclusions: MTX treatment was not associated with an increased risk of RA-ILD diagnosis. On the contrary, evidence suggested that MTX may delay the onset of ILD.
  • Thresholds of ultrasound synovial abnormalities for knee osteoarthritis - a cross sectional study in the general population

    Walsh, David A (Osteoarthritis and Cartilage, 2019-03)
    Objective: To establish "normal" ranges for synovial thickness and effusion detected by ultrasound (US) and to determine cut-offs associated with knee pain (KP) and radiographic knee osteoarthritis (RKOA) in the community. Methods: 147 women and 152 men ≥40 years old were randomly selected from the Nottingham KP and Related Health in the Community (KPIC) cohort (n = 9506). The "normal" range was established using the percentile method in 163 participants who had no KP and no RKOA. Optimal (maximum sensitivity and specificity) and high specificity (90%) cut-offs were established using receiver operating characteristic (ROC) curve analysis in a comparison between people with both KP and RKOA and normal controls. Results: Effusion and synovial hypertrophy differed by gender but not by age or laterality, therefore gender-specific reference limits were estimated. However, the "normal" ranges between men and women were similar for effusion (0-10.3 mm vs 0-9.8 mm), but different for synovial hypertrophy (0-6.8 mm vs 0-5.4 mm). Power Doppler Signal (PDS) in the healthy controls was uncommon (1.2% in men and 0.0% in women). The optimal cut-off was 7.4 mm for men and 5.3 mm for women for effusion, and 3.7 and 1.6 for hypertrophy respectively. The high specificity cut-off was 8.9 for men and 7.8 for women for effusion, and 5.8 and 4.2 for hypertrophy respectively. Conclusions: US effusion and synovial hypertrophy but not PDS are common, but differ by gender, in community-derived people without painful knee OA. Currently used cut-offs for abnormality need reappraisal.
  • Peripheral brain-derived neurotrophic factor contributes to chronic osteoarthritis joint pain

    Walsh, David A (Pain, 2020-01)
    Brain-derived neurotrophic factor (BDNF) and the high-affinity receptor tropomyosin receptor kinase B (TrkB) have important roles in neuronal survival and in spinal sensitization mechanisms associated with chronic pain. Recent clinical evidence also supports a peripheral role of BDNF in osteoarthritis (OA), with synovial expression of TrkB associated with higher OA pain. The aim of this study was to use clinical samples and animal models to explore the potential contribution of knee joint BDNF/TrkB signalling to chronic OA pain. Brain-derived neurotrophic factor and TrkB mRNA and protein were present in knee synovia from OA patients (16 women, 14 men, median age 67 years [interquartile range: 61-73]). There was a significant positive correlation between mRNA expression of NTRK2 (TrkB) and the proinflammatory chemokine fractalkine in the OA synovia. Using the surgical medial meniscal transection (MNX) model and the chemical monosodium iodoacetate (MIA) model of OA pain in male rats, the effects of peripheral BDNF injection, vs sequestering endogenous BDNF with TrkB-Fc chimera, on established pain behaviour were determined. Intra-articular injection of BDNF augmented established OA pain behaviour in MIA rats, but had no effect in controls. Intra-articular injection of the TrkB-Fc chimera acutely reversed pain behaviour to a similar extent in both models of OA pain (weight-bearing asymmetry MIA: -11 ± 4%, MNX: -12 ± 4%), compared to vehicle treatment. Our data suggesting a contribution of peripheral knee joint BDNF/TrkB signalling in the maintenance of chronic OA joint pain support further investigation of the therapeutic potential of this target.
  • Remission vs low disease activity: function, quality of life and structural outcomes in the Early Rheumatoid Arthritis Study and Network

    Walsh, David A (Reumatology, 2020-06)
    Objectives: To examine associations between function, quality of life and structural outcomes in patients achieving remission vs low disease activity in early RA. Methods: Demographic, clinical and radiographic variables were collected at baseline and then annually from the Early Rheumatoid Arthritis Study (ERAS) and Early Rheumatoid Arthritis Network (ERAN) inception cohorts in routine care from 1986 to 2012. Disease activity was categorized: mean DAS28 score between years 1 and 5: remission [mean remission DAS (mRDAS) <2.6] or low [mean low DAS (mLDAS) 2.6-3.2]; sustained low/remission DAS28 (sLDAS/sRDAS) at years 1 and 2; and sustained Boolean remission (sBR) at years 1 and 2. Changes in HAQ and Short Form 36 Health Survey Questionnaire [SF-36; physical (PCS) and mental (MCS) component score]) and total Sharp van der Heijde (SvdH) scores for each disease activity category were modelled using multi-level models. Covariates included year of onset, age, gender and DMARD use at first visit. Results: Of 2701 patients, 562 (21%) were categorized mRDAS, 330 (12%) mLDAS, 279 (10%) sRDAS, 203 (7.5%) sLDAS and 93 (3%) sBR. Patients categorized as mRDAS had increasingly divergent improved HAQ, SF-36 PCS, MCS and total SvdH scores compared with mLDAS (P-values 0.001 to <0.0001, all time points). Patients categorized as sRDAS had better HAQ, SF-36 PCS and MCS scores (P-values 0.05 to <0.0001, all time points) and SvdH scores (P = 0.05, years 3-5) over sLDAS. sBR was associated with better HAQ, and SF-36 PCS and MCS scores over sLDAS (P-values 0.002 to <0.0001, all time points). Conclusion: These findings from routine care support ACR/EULAR guidelines that remission is a preferable goal over low disease activity in early RA.
  • Predictors of response to topical non-steroidal anti-inflammatory drugs in osteoarthritis: an individual patient data meta-analysis of randomised controlled trials

    Walsh, David A (Rheumatology, 2020-09)
    Objectives: To identify predictors of the specific (difference between treatment and placebo) and overall (change from baseline in treatment arm) treatment effects of topical NSAIDs in OA. Methods: Randomized controlled trials (RCTs) of topical NSAIDs in OA were identified through systematic literature searching and inquiry to pharmaceutical companies. The raw, de-identified data were analysed in one-stage individual patient data meta-analysis (IPD-MA). Negative values for treatment effects (0-100 scale) indicate pain reduction. Results: Of 63 eligible RCTs, 15 provided IPD (n = 1951 on topical NSAID), including 11 placebo-controlled RCTs (n = 1587 on topical NSAIDs, 1553 on placebo). Seven potential predictors of response were examined. Topical NSAIDs were superior to placebo [-6 (95% CI -9, -4)], with a small, but statistically significant greater effect in women than men [difference -4 (95% CI -8, -1)]. The overall treatment effect was 4-fold larger than the specific effect [-25 (95% CI -31, -19)] and increased with greater baseline pain severity (P < 0.001). No differences in efficacy were observed for age, BMI, features of inflammation, duration of complaints or radiographic OA severity. Conclusion: Topical NSAIDs are effective for OA pain relief. Greater overall pain relief in individuals with more baseline pain might be due to contextual and non-specific effects, including regression to the mean. Additional factors that have been linked either mechanistically or through empirical evidence to outcomes should be selected for inclusion across future RCTs in order to facilitate the identification of response predictors through IPD-MA.
  • Secular changes in the progression of clinical markers and patient reported outcomes in early rheumatoid arthritis

    Walsh, David A (Rheumatology, 2020-09)
    Objectives To examine secular trends in the progression of clinical and patient-reported outcomes in early RA. Methods A total of 2701 patients recruited to the Early Rheumatoid Arthritis Study or Early Rheumatoid Arthritis Network with year of diagnosis from 1986 to 2011. The 5-year progression rates for patients diagnosed at different points in time were modelled using mixed-effects regression; 1990, 2002 and 2010, were compared. Clinical markers of disease included the 28-joint count DAS and the ESR. Patient-reported markers included the HAQ, visual analogue scale of pain and global health, and the Short-Form 36. Results Statistically significant improvements in both 28-joint count DAS and ESR were seen over the 5 years in patients diagnosed with RA compared with those diagnosed earlier. By 5 years, 59% of patients with diagnosis in 2010 were estimated to reach low disease activity compared with 48% with diagnosis in 2002 and 32% with diagnosis in 1990. Whilst HAQ demonstrated statistically significant improvements, these improvements were small, with similar proportions of patients achieving HAQ scores of ≤1.0 by 5 years with a diagnosis in 1990 compared with 2010. Levels of the visual analogue scale and the Mental Component Scores of the Short-Form 36 indicated similar, statistically non-significant levels over the 5 years, irrespective of year diagnosed. Conclusion This study demonstrates improvements in inflammatory markers over time in early RA, in line with improved treatment strategies. These have not translated into similar improvements in patient-reported outcomes relating to either physical or mental health.
  • Brain perfusion patterns are altered in chronic knee pain: A spatial covariance analysis of arterial spin labelling MRI

    Walsh, David A (Pain, 202-06)
    Chronic musculoskeletal pain is a common problem globally. Current evidence suggests that maladapted central pain pathways are associated with pain chronicity, for example, in postoperative pain after knee replacement. Other factors such as low mood, anxiety, and tendency to catastrophize are also important contributors. We aimed to investigate brain imaging features that underpin pain chronicity based on multivariate pattern analysis of cerebral blood flow (CBF), as a marker of maladaptive brain changes. This was achieved by identifying CBF patterns that discriminate chronic pain from pain-free conditions and by exploring their explanatory power for factors thought to drive pain chronification. In 44 chronic knee pain and 29 pain-free participants, we acquired both CBF and T1-weighted data. Participants completed questionnaires related to affective processes and pressure and cuff algometry to assess pain sensitization. Two factor scores were extracted from these scores representing negative affect and pain sensitization. A spatial covariance principal component analysis of CBF identified 5 components that significantly discriminated chronic pain participants from controls, with the unified network achieving 0.83 discriminatory accuracy (area under the curve). In chronic knee pain, significant patterns of relative hypoperfusion were evident in anterior default-mode and salience network hubs, while hyperperfusion was seen in posterior default mode, thalamus, and sensory regions. One component correlated positively with the pain sensitization score (r = 0.43, P = 0.006), suggesting that this CBF pattern reflects neural activity changes encoding pain sensitization. Here, we report a distinct chronic knee pain-related representation of CBF, pointing toward a brain signature underpinning central aspects of pain sensitization.

View more