Progressive exercise compared with best practice advice, with or without corticosteroid injection, for the treatment of patients with rotator cuff disorders (GRASP): a multicentre, pragmatic, 2 × 2 factorial, randomised controlled trial

Background Corticosteroid injections and physiotherapy exercise programmes are commonly used to treat rotator cuff disorders but the treatments' effectiveness is uncertain. We aimed to compare the clinical effectiveness and cost-effectiveness of a progressive exercise programme with a single session of best practice physiotherapy advice, with or without corticosteroid injection, in adults with a rotator cuff disorder. Methods In this pragmatic, multicentre, superiority, randomised controlled trial (2 × 2 factorial), we recruited patients from 20 UK National Health Service trusts. We included patients aged 18 years or older with a rotator cuff disorder (new episode within the past 6 months). Patients were excluded if they had a history of significant shoulder trauma (eg, dislocation, fracture, or full-thickness tear requiring surgery), neurological disease affecting the shoulder, other shoulder conditions (eg, inflammatory arthritis, frozen shoulder, or glenohumeral joint instability), received corticosteroid injection or physiotherapy for shoulder pain in the past 6 months, or were being considered for surgery. Patients were randomly assigned (centralised computer-generated system, 1:1:1:1) to progressive exercise (≤6 sessions), best practice advice (one session), corticosteroid injection then progressive exercise, or corticosteroid injection then best practice advice. The primary outcome was the Shoulder Pain and Disability Index (SPADI) score over 12 months, analysed on an intention-to-treat basis (statistical significance set at 1%). The trial was registered with the International Standard Randomised Controlled Trial Register, ISRCTN16539266, and EuDRACT, 2016-002991-28. Findings Between March 10, 2017, and May 2, 2019, we screened 2287 patients. 708 patients were randomly assigned to progressive exercise (n=174), best practice advice (n=174), corticosteroid injection then progressive exercise (n=182), or corticosteroid injection then best practice advice (n=178). Over 12 months, SPADI data were available for 166 (95%) patients in the progressive exercise group, 164 (94%) in the best practice advice group, 177 (97%) in the corticosteroid injection then progressive exercise group, and 175 (98%) in the corticosteroid injection then best practice advice group. We found no evidence of a difference in SPADI score between progressive exercise and best practice advice when analysed over 12 months (adjusted mean difference −0·66 [99% CI −4·52 to 3·20]). We also found no evidence of a difference between corticosteroid injection compared with no injection when analysed over 12 months (−1·11 [–4·47 to 2·26]). No serious adverse events were reported. Interpretation Progressive exercise was not superior to a best practice advice session with a physiotherapist in improving shoulder pain and function. Subacromial corticosteroid injection provided no long-term benefit in patients with rotator cuff disorders

Ability of the Bristol Impact of Hypermobility questionnaire to discriminate between people with and without Joint Hypermobility Syndrome: a known-group validity study

© 2020 John Wiley & Sons, Ltd. Introduction: A number of psychometric properties of the Bristol Impact of Hypermobility (BIoH) questionnaire have previously been demonstrated, including strong concurrent validity and test–retest reliability. This study aimed to identify whether it can discriminate between those with and without Joint Hypermobility Syndrome (JHS). Methods: The wording of a small number of BIoH questionnaire items was adapted to create a generic version that asked about ‘general health’ rather than ‘hypermobility’. The generic questionnaire was distributed online to university students and staff. A sampling frame was used to create age and sex-matched samples from the non-JHS respondents in the current study and a pre-existing JHS cohort. Questionnaire scores were then compared between samples. Results: 790 responses were received. 414 were excluded, mainly due to self-reported generalized joint hypermobility or a JHS diagnosis. The sampling frame was applied to the remaining non-JHS responders (n = 376) and the pre-existing JHS cohort (n = 448), resulting in 206 age and sex-matched participants in each sample. The median (IQR) BIoH scores (out of a maximum 360) were 81 (57.25) and 231.5 (74.25) in the non-JHS and JHS samples respectively (p < 0.001). There was a very strong correlation between BIoH score and the number of painful areas (r = 0.867, p < 0.001). Conclusions: The BIoH questionnaire discriminates between those with and without JHS. The median difference (151.5 points) far exceeds the smallest detectable change of 42 points previously identified. The results provide further evidence of the psychometric properties of the BIoH questionnaire and its potential to support research and clinical practice

Multicentre Genome Wide Association Study Identifies Risk Alleles for Progressive Chronic Lymphocytic Leukaemia [Conference Abstract]

The increased incidence of chronic lymphocytic leukemia (CLL) in first-degree relatives of affected patients indicates an element of genetic susceptibility to this malignancy, borne out in large scale genome-wide association studies (GWAS), which have identified over 40 constitutional risk alleles. Given the important genetic contribution to CLL susceptibility we hypothesized that constitutional genetic variants also affect disease progression. We employed GWAS methods in a large United Kingdom multi-center cohort study of well-characterized predominantly early-stage CLL cases to identify risk alleles for progressive CLL. We conducted six GWAS for single nucleotide polymorphisms (SNPs) associating with progressive CLL incorporating a total of 774 cases of European ancestry recruited to 6 clinical centers across the United Kingdom. CLL cases were genotyped on the Illumina OmniExpress platform and genotypes were determined using Illumina GenomeStudio software. After imputation, we combined the association test statistic for 5,199,911 autosomal SNPs common to all 6 GWAS after exclusion of those with an imputation quality score of <0.9 and a minor allele frequency (MAF) of < 2.5%, and conducted a meta-analysis under a fixed-effect model. The primary outcome assessed was time to first treatment (TTFT), defined as the interval between CLL diagnosis and first treatment or last follow-up. Pooling data from the 6 GWAS identified 5 SNPs at two genomic locations that surpassed genome-wide significance (P ≤ 5 x 10-8) for association with TTFT. The strongest statistical evidence for an association with progressive disease was for rs736456 (hazard ratio (HR) = 1.76, 95% confidence interval (CI) = 1.45-2.14; P = 1.26 x 10-8), which maps to chromosome 10q26.13. The second strongest association with progressive disease was for rs3778076 (HR = 2.03, 95% CI = 1.58-2.62; P = 3.89 x 10-8) which maps to chromosome 6p. Both markers showed consistent direction and magnitude of effect sizes across all six GWAS with no evidence of heterogeneity, and retained prognostic significance in multivariate models for disease progression, particularly in models restricted to Binet A patients. Whilst not as powerful as IGVH status, rs736456 and rs3778076 had prognostic utility equivalent to CD38 status, and are particularly powerful when considered together, identifying 5% of CLL patients carrying 2 or more risk alleles at high risk of progressive disease (Figure). To identify cis-regulated genes at each locus associated with progressive disease we interrogated gene expression data derived from a meta-analysis of 31,624 blood samples collated by the eQTLGen consortium. Of the thirteen genes annotated to within 1Mb of the chromosome 10 association signal rs736456 is eQTL for the PLEKHA1 gene (TAPP-1)(Benjamini-Hochberg corrected P-value [P BH] = 1.29 x 10-15). Of the 27 genes annotated to within 1Mb of the chromosome 6 signal, rs3778076 is eQTL for 5 genes including UHRF1BP1 (PBH = 6.73 x 10-139) and C6ORF106 (PBH = 3.54 x 10-64). Annotated genes at both loci have been implicated in modulating B-cell receptor or innate immune responses, key pathways in CLL pathogenesis. Data on post-treatment survival were available on 390 CLL cases, with 231 deaths and 159 censored at last follow-up, and neither the lead SNP at chromosome 10 or chromosome 6 were significantly associated with post-treatment survival in patients primarily treated with regimens that included chlorambucil, fludarabine or cyclophosphamide. It will be important to determine whether these markers predict overall survival in patients treated with novel targeted therapies. Taken together, these data identify rs736456 and rs3778076 as prognostic in early stage CLL patients demonstrating that progression of CLL from asymptomatic to symptomatic disease is determined by constitutional genetic variation as well as the more established somatic drivers. Constitutional genetic markers have the advantage of being easy to perform, highly reproducible and inexpensive making them ideal for incorporation into multivariate prognostication models for early stage CLL. Figure Disclosures Fegan: Roche: Honoraria; Janssen: Honoraria; Gilead: Honoraria; Abbvie: Consultancy, Other: Conference attendance sponsorship. Forconi: Gilead Sciences: Research Funding; Janssen-Cilag: Consultancy, Honoraria, Other: Travel, Accommodations, Expenses, Speakers Bureau; Novartis: Honoraria; Menarini: Consultancy; Abbvie: Consultancy, Honoraria, Other: Travel, Accommodations, Expenses, Speakers Bureau; Roche: Honoraria. Schuh: AbbVie: Consultancy, Speakers Bureau; Genentech: Consultancy, Speakers Bureau; Pharmacyclics: Consultancy, Speakers Bureau; Verastem: Speakers Bureau; Gilead: Speakers Bureau; Seattle Genetics: Speakers Bureau; Jazz Pharmaceuticals: Speakers Bureau; Bristol-Myers Squibb: Research Funding; Janssen: Speakers Bureau; Kite: Speakers Bureau. Hillmen: Pharmacyclics LLC, an AbbVie Company: Consultancy, Honoraria, Research Funding; AbbVie: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel Expenses, Research Funding; Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel Expenses, Research Funding; Roche: Research Funding; Gilead: Research Funding; Apellis: Research Funding; Acerta: Membership on an entity's Board of Directors or advisory committees. Pratt: Binding Site, Amgen, Takeda, Janssen, Gilead: Consultancy, Honoraria, Other: Travel support