Protocol for surgical and non-surgical treatment for metacarpal shaft fractures in adults: an observational feasibility study.

INTRODUCTION: Metacarpal shaft fractures (MSF) are common traumatic hand injuries that usually affect young people of working age. They place a significant burden on healthcare resources and society; however, there is a lack of evidence to guide their treatment. Identifying the most beneficial and cost-efficient treatment will ensure optimisation of care and provide economic value for the National Health Service. The aim of this study is to assess the feasibility of a randomised controlled trial comparing surgical and non-surgical treatment for MSF in adults. METHODS AND ANALYSIS: This is a multicentre prospective cohort study, with a nested qualitative study consisting of patient interviews and focus groups, and an embedded factorial randomised substudy evaluating the use of text messages to maximise data collection and participant retention. The outcomes of interest include eligibility, recruitment and retention rates, completion of follow-up, evaluation of primary outcome measures, calculation of the minimal clinically important difference (MCID) for selected outcome measures and establishing the feasibility of data collection methods and appropriate time-points for use in a future trial. Data will be captured using a secure online data management system. Data analyses will be descriptive and a thematic inductive analysis will be used for qualitative data. Minimum clinically important effects for each patient-reported outcome measure will be estimated using anchor-based responsiveness statistics and distribution-based methods. ETHICS AND DISSEMINATION: This study has received ethical approval from the Research Ethics Committee and the Health Research Authority (REC reference 20/EE/0124). Results will be made available to patients, clinicians, researchers and the funder via peer-reviewed publications and conference presentations. Social media platforms, local media and feedback from the Patient Advisory Group will be used to maximise circulation of findings to patients and the public. TRIAL REGISTRATION NUMBER: ISRCTN13922779.

The association between surgery for carpal and cubital tunnel syndrome: analysis of incidence and risk factors within a geographical area.

The relationship between surgery for cubital tunnel and carpal tunnel syndrome was examined in this retrospective study. Between 1997 and 2018, data from consecutive patients who underwent carpal tunnel release (8352 patients), cubital tunnel release (1681 patients) or both procedures (692 patients) were analysed. The relative risk of undergoing cubital tunnel release in the population who had carpal tunnel release compared with those with no carpal tunnel release was 15.3 (male 20.3; female 12.5). The relative risk of undergoing carpal tunnel release in the population who had cubital tunnel release compared with those who did not undergo carpal tunnel release was 11.5 (male 16.5; female 9.1). Our study showed that men and women who undergo carpal tunnel release are over 20 times and 10 times more likely to have cubital tunnel release than those who did not undergo carpal tunnel release, respectively. These findings suggest that the two conditions may share a similar aetiology.Level of evidence: IV.

Tool and machinery-related hand injuries: a review of national Hospital Episodes Statistics and data from a tertiary hand unit.

We sought to identify national trends in tool and machinery-related hand injuries. Hospital Episodes Statistics data in England from 1998 to 2017 were analysed. Data from our hand unit from 2011 to 2017 were also reviewed to establish the types of tool and machinery causing injury. During the 19-year study period 210,291 admissions occurred as a result of tool and machinery-related injuries. The overall incidence rate and mean age increased. The largest increase in incidence rate was in the oldest age group (75 years+). The incidence rate in children fell. During the period studied, 2150 patients underwent surgery in our unit for tool and machinery-related injuries. The hand was involved in 2069 (96%) of the injuries. Adult injuries were caused by a similar proportion of types of tool or machinery in all age groups. This study demonstrates a clear and sustained trend of increasing incidence of tool and machinery-related injuries in adults. The largest increase is in older patients.Level of evidence: IV.

The effect of social deprivation on the incidence rate of carpal and cubital tunnel syndrome surgery.

We sought to establish whether carpal and cubital tunnel syndrome requiring surgery is associated with deprivation in England. Data from 10,496 adult patients who were treated in our hand unit over a 20-year period were reviewed. The Index of Multiple Deprivation was used to measure deprivation from the patients' postcode. The mean age at surgery in the most deprived three quintiles was significantly lower than in the least deprived two quintiles for carpal tunnel release (55 vs 59 years, respectively) and cubital tunnel release (52 vs 57 years, respectively). The incidence rate was significantly lower for the three least deprived quintiles when compared with the most deprived quintile for both conditions. The incidence rate ratio of the least deprived quintile compared with the most deprived quintile for carpal tunnel release was 0.70 for men and 0.76 for women. The incidence rate ratio of the least deprived quintile compared with the most deprived quintile for cubital tunnel release was 0.79 for men and 0.49 for women. Carpal tunnel and cubital tunnel syndrome requiring surgery is more common in deprived patients and occurs at an earlier age.Level of evidence: IV.

The effect of the COVID-19 lockdown on hand trauma surgery utilization.

AIMS: The aim of this study was to evaluate the need for hand trauma services during the COVID-19 pandemic lockdown, specifically related to surgical requirements. This will provide useful information for planning and resource allocation in the event of any further lockdown. METHODS: A prospective analsysis of all patients attending our hand trauma unit throughout the UK COVID-19 lockdown period (24 March to 10 May 2020) was carried out. Prospectively collected departmental data from the same period in 2019 was obtained and reviewed for comparison. The number of patients attending clinic, undergoing surgery, the type of surgical procedure, and rate of surgery was compared. RESULTS: In all, 463 patients attended hand trauma services during the lockdown period compared to 793 in 2019 (32% reduction); 190 surgical procedures were carried out during lockdown compared to 236 in 2019 (20% reduction). Intervention rate was higher during the lockdown period (41% compared to 30%). There was no difference in the type of cases. In the first half of lockdown, 47% fewer procedures were performed than in 2019, but in the second half of lockdown 13% more procedures were carried out than the same period in 2019. CONCLUSION: Requirements for hand trauma surgery remain high during a pandemic lockdown. Attendances and surgical requirements can be expected to steadily return to normal levels during a prolonged lockdown period. Throughout any future lockdown period adequate surgical provision must be maintained for patients with hand injuries.Cite this article: Bone Joint Open 2020;1-10:639-643.

Identifying collagen VI as a target of fibrotic diseases regulated by CREBBP/EP300.

Fibrotic diseases remain a major cause of morbidity and mortality, yet there are few effective therapies. The underlying pathology of all fibrotic conditions is the activity of myofibroblasts. Using cells from freshly excised disease tissue from patients with Dupuytren's disease (DD), a localized fibrotic disorder of the palm, we sought to identify new therapeutic targets for fibrotic disease. We hypothesized that the persistent activity of myofibroblasts in fibrotic diseases might involve epigenetic modifications. Using a validated genetics-led target prioritization algorithm (Pi) of genome wide association studies (GWAS) data and a broad screen of epigenetic inhibitors, we found that the acetyltransferase CREBBP/EP300 is a major regulator of contractility and extracellular matrix production via control of H3K27 acetylation at the profibrotic genes, ACTA2 and COL1A1 Genomic analysis revealed that EP300 is highly enriched at enhancers associated with genes involved in multiple profibrotic pathways, and broad transcriptomic and proteomic profiling of CREBBP/EP300 inhibition by the chemical probe SGC-CBP30 identified collagen VI (Col VI) as a prominent downstream regulator of myofibroblast activity. Targeted Col VI knockdown results in significant decrease in profibrotic functions, including myofibroblast contractile force, extracellular matrix (ECM) production, chemotaxis, and wound healing. Further evidence for Col VI as a major determinant of fibrosis is its abundant expression within Dupuytren's nodules and also in the fibrotic foci of idiopathic pulmonary fibrosis (IPF). Thus, Col VI may represent a tractable therapeutic target across a range of fibrotic disorders.

Anti-granulocyte-macrophage colony-stimulating factor antibody otilimab in patients with hand osteoarthritis: a phase 2a randomised trial.

BACKGROUND: Granulocyte-macrophage colony-stimulating factor (GM-CSF) is a key mediator of signs and symptoms in preclinical models of osteoarthritis. We explored the efficacy, safety, and pharmacokinetics of an anti-GM-CSF antibody, otilimab, in patients with hand osteoarthritis. METHODS: This double-blind, randomised, placebo-controlled phase 2a study was done in 16 centres in the Netherlands, Germany, Poland, the UK, and the USA. Patients aged 18 years or older with inflammatory hand osteoarthritis, who had received at least one course of unsuccessful non-steroidal anti-inflammatory drugs, with two or more swollen and tender interphalangeal joints (on the same hand), signs of inflammation or synovitis identified with MRI in the affected hand, and a self-reported 24 h average hand pain intensity over the past 7 days of 5 or more on a 0-10 numerical rating scale were eligible for inclusion. Patients were randomly assigned (1:1) via interactive response technology (blocked randomisation; block size of four) to receive either subcutaneous otilimab 180 mg or placebo, administered weekly from week 0 to week 4, then every other week until week 10. Patients, investigators, and trial staff were masked to treatment; at least one administrator at each site was unmasked to prepare and administer treatment. The primary endpoint was change from baseline in 24 h average hand pain numeric rating scale averaged over 7 days before the visit at week 6. Secondary endpoints were: change from baseline in 24 h average and worst hand pain intensity at each visit; proportion of patients showing 30% and 50% reductions in 24 h average and worst hand pain intensity at each visit; change from baseline in Australian and Canadian Hand Osteoarthritis Index (AUSCAN) 3·1 numeric rating scale questionnaire components at each visit; change in number of swollen and tender hand joints at each visit; change from baseline in Patient and Physician Global Assessment of disease activity; serum concentration of otilimab; and safety parameters. Efficacy endpoints were assessed in the intention-to-treat population. The safety population included all patients who received at least one dose of study treatment. The study is registered with ClinicalTrials.gov, NCT02683785. FINDINGS: Between March 17, 2016, and Nov 29, 2017, 44 patients were randomly assigned (22 in the placebo group and 22 in the otilimab group). At week 6, difference in change from baseline in 24 h average hand pain numeric rating scale between the otilimab and placebo groups was -0·36 (95% CI -1·31 to 0·58; p=0·44); at week 12, the difference was -0·89 (-2·06 to 0·28; p=0·13). Patients receiving otilimab showed greater improvement in AUSCAN components versus placebo at each visit. The change from baseline in the 24 h worst hand pain numeric rating scale in the otilimab group at week 6 showed a difference over placebo of -0·33 (95% CI -1·28 to 0·63; p=0·49); at week 12, this difference was -1·01 (95% CI -2·22 to 0·20; p=0·098). The proportion of patients achieving 30% or higher or 50% or higher reduction from baseline in the 24 h average and worst hand pain numeric rating scale scores was consistently greater (although non-significant) with otilimab versus placebo. Similarly, patients receiving otilimab showed greater improvement in AUSCAN pain, functional impairment, and stiffness scores versus placebo at each visit. No differences were observed between otilimab and placebo in the change from baseline in the number of swollen and tender joints across the study. The Patient Global Assessment was consistently lower than placebo at all visits; the Physician Global Assessment showed reductions across the study period, but the changes were similar in both treatment groups. Median otilimab serum concentrations increased during weekly dosing from 1730 ng/mL at week 1 to a maximum of 3670 ng/mL at week 4, but declined after transitioning to dosing every other week (weeks 6-10). In total, 84 adverse events were reported by 24 patients: 54 adverse events in 13 (59%) patients in the otilimab group and 30 adverse events in 11 (50%) patients in the placebo group. The most common adverse events were cough (reported in 4 [9%] patients; 2 in each group), and nasopharyngitis (in 3 [7%] patients; 1 in the placebo group and 2 in the otilimab group). Three serious adverse events occurred in this study (all in the otilimab group) and were deemed not related to the study medication. There were no deaths during the study. INTERPRETATION: There was no significant difference between otilimab and placebo in the primary endpoint, although we noted a non-significant trend towards a reduction in pain and functional impairment with otilimab, which supports a potential role for GM-CSF in hand osteoarthritis-associated pain. There were no unexpected safety findings in this study, with no treatment-related serious adverse events reported. FUNDING: GlaxoSmithKline.

Efficacy of collagenase in patients who did and did not have previous hand surgery for Dupuytren's contracture.

Collagenase Clostridium histolyticum (CCH) is a non-surgical, efficacious therapy for Dupuytren's contracture (DC). This study evaluated the efficacy and safety of CCH in patients with previous DC surgery. Data from 12 CCH clinical trials were pooled. At screening, patients provided details about the type/date of previous DC surgery. Reviewers coded descriptions to the Operated Hand, finger, and joint. Of 1082 patients, 422 (39%) had previous DC surgery. For these patients with previous surgery, the CCH treatment was coded on the Operated (n = 206) or Non-operated Hand (n = 196). End-points included changes in fixed-flexion contracture (FFC) and range of motion (ROM). Adverse events (AEs) were monitored. After treatment with CCH, FFC at metacarpophalangeal joints was reduced by 75% in previously Operated Hands and by 80% for Non-operated Hands (p = 0.6). Improvements in ROM were 32° and 32°, respectively (p = 0.9). For proximal inter-phalangeal joints, the reductions in FFC for the Operated and Non-operated Hands were 52% and 50%, respectively (p = 0.6); improvements in ROM were 24° and 26°, respectively (p = 0.3). Some AE rates were significantly higher in the Operated vs Non-operated Hand groups, but were not clinically relevant. There were no between-group significant differences in AE duration (p > 0.08). Previous surgery for DC does not affect efficacy or safety of CCH, suggesting CCH is an option in patients with recurring DC. Some AE rates were significantly higher, but not clinically relevant.