A Phase II randomized controlled trial of oral prednisolone in early diffuse cutaneous systemic sclerosis (PRedSS).

OBJECTIVES: Although the painful and disabling features of early diffuse cutaneous SSc (dcSSc) have an inflammatory basis and could respond to corticosteroids, corticosteroids are a risk factor for scleroderma renal crisis. Whether or not they should be prescribed is therefore highly contentious. Our aim was to examine safety and efficacy of moderate-dose prednisolone in early dcSSc. METHODS: PRedSS set out as a Phase II, multicentre, double-blind randomized controlled trial, converted to open-label during the Covid-19 pandemic. Patients were randomized to receive either prednisolone (∼0.3 mg/kg) or matching placebo (or no treatment during open-label) for 6 months. Co-primary endpoints were the HAQ Disability Index (HAQ-DI) and modified Rodnan skin score (mRSS) at 3 months. Over 20 secondary endpoints included patient reported outcome measures reflecting pain, itch, fatigue, anxiety and depression, and helplessness. Target recruitment was 72 patients. RESULTS: Thirty-five patients were randomized (17 prednisolone, 18 placebo/control). The adjusted mean difference between treatment groups at 3 months in HAQ-DI score was -0.10 (97.5% CI: -0.29, 0.10), P = 0.254, and in mRSS -3.90 (97.5% CI: -8.83, 1.03), P = 0.070, both favouring prednisolone but not significantly. Patients in the prednisolone group experienced significantly less pain (P = 0.027), anxiety (P = 0.018) and helplessness (P = 0.040) than control patients at 3 months. There were no renal crises, but sample size was small. CONCLUSION: PRedSS was terminated early primarily due to the Covid-19 pandemic, and so was underpowered. Therefore, interpretation must be cautious and results considered inconclusive, indicating the need for a further randomized trial. TRIAL REGISTRATION: ClinicalTrials.gov, https://clinicaltrials.gov, NCT03708718.

Patterns and predictors of skin score change in early diffuse systemic sclerosis from the European Scleroderma Observational Study.

OBJECTIVES: Our aim was to use the opportunity provided by the European Scleroderma Observational Study to (1) identify and describe those patients with early diffuse cutaneous systemic sclerosis (dcSSc) with progressive skin thickness, and (2) derive prediction models for progression over 12 months, to inform future randomised controlled trials (RCTs). METHODS: The modified Rodnan skin score (mRSS) was recorded every 3 months in 326 patients. 'Progressors' were defined as those experiencing a 5-unit and 25% increase in mRSS score over 12 months (±3 months). Logistic models were fitted to predict progression and, using receiver operating characteristic (ROC) curves, were compared on the basis of the area under curve (AUC), accuracy and positive predictive value (PPV). RESULTS: 66 patients (22.5%) progressed, 227 (77.5%) did not (33 could not have their status assessed due to insufficient data). Progressors had shorter disease duration (median 8.1 vs 12.6 months, P=0.001) and lower mRSS (median 19 vs 21 units, P=0.030) than non-progressors. Skin score was highest, and peaked earliest, in the anti-RNA polymerase III (Pol3+) subgroup (n=50). A first predictive model (including mRSS, duration of skin thickening and their interaction) had an accuracy of 60.9%, AUC of 0.666 and PPV of 33.8%. By adding a variable for Pol3 positivity, the model reached an accuracy of 71%, AUC of 0.711 and PPV of 41%. CONCLUSIONS: Two prediction models for progressive skin thickening were derived, for use both in clinical practice and for cohort enrichment in RCTs. These models will inform recruitment into the many clinical trials of dcSSc projected for the coming years. TRIAL REGISTRATION NUMBER: NCT02339441.

Disability, fatigue, pain and their associates in early diffuse cutaneous systemic sclerosis: the European Scleroderma Observational Study.

Objectives: Our aim was to describe the burden of early dcSSc in terms of disability, fatigue and pain in the European Scleroderma Observational Study cohort, and to explore associated clinical features. Methods: Patients completed questionnaires at study entry, 12 and 24 months, including the HAQ disability index (HAQ-DI), the Cochin Hand Function Scale (CHFS), the Functional Assessment of Chronic Illness Therapy-fatigue and the Short Form 36 (SF36). Associates examined included the modified Rodnan skin score (mRSS), current digital ulcers and internal organ involvement. Correlations between 12-month changes were also examined. Results: The 326 patients recruited (median disease duration 11.9 months) displayed high levels of disability [mean (s.d.) HAQ-DI 1.1 (0.83)], with 'grip' and 'activity' being most affected. Of the 18 activities assessed in the CHFS, those involving fine finger movements were most affected. High HAQ-DI and CHFS scores were both associated with high mRSS (ρ = 0.34, P < 0.0001 and ρ = 0.35, P < 0.0001, respectively). HAQ-DI was higher in patients with digital ulcers (P = 0.004), pulmonary fibrosis (P = 0.005), cardiac (P = 0.005) and muscle involvement (P = 0.002). As anticipated, HAQ-DI, CHFS, the Functional Assessment of Chronic Illness Therapy and SF36 scores were all highly correlated, in particular the HAQ-DI with the CHFS (ρ = 0.84, P < 0.0001). Worsening HAQ-DI over 12 months was strongly associated with increasing mRSS (ρ = 0.40, P < 0.0001), decreasing hand function (ρ = 0.57, P < 0.0001) and increasing fatigue (ρ = -0.53, P < 0.0001). Conclusion: The European Scleroderma Observational Study highlights the burden of disability in early dcSSc, with high levels of disability and fatigue, associating with the degree of skin thickening (mRSS). Impaired hand function is a major contributor to overall disability.

Treatment outcome in early diffuse cutaneous systemic sclerosis: the European Scleroderma Observational Study (ESOS).

OBJECTIVES: The rarity of early diffuse cutaneous systemic sclerosis (dcSSc) makes randomised controlled trials very difficult. We aimed to use an observational approach to compare effectiveness of currently used treatment approaches. METHODS: This was a prospective, observational cohort study of early dcSSc (within three years of onset of skin thickening). Clinicians selected one of four protocols for each patient: methotrexate, mycophenolate mofetil (MMF), cyclophosphamide or 'no immunosuppressant'. Patients were assessed three-monthly for up to 24 months. The primary outcome was the change in modified Rodnan skin score (mRSS). Confounding by indication at baseline was accounted for using inverse probability of treatment (IPT) weights. As a secondary outcome, an IPT-weighted Cox model was used to test for differences in survival. RESULTS: Of 326 patients recruited from 50 centres, 65 were prescribed methotrexate, 118 MMF, 87 cyclophosphamide and 56 no immunosuppressant. 276 (84.7%) patients completed 12 and 234 (71.7%) 24 months follow-up (or reached last visit date). There were statistically significant reductions in mRSS at 12 months in all groups: -4.0 (-5.2 to -2.7) units for methotrexate, -4.1 (-5.3 to -2.9) for MMF, -3.3 (-4.9 to -1.7) for cyclophosphamide and -2.2 (-4.0 to -0.3) for no immunosuppressant (p value for between-group differences=0.346). There were no statistically significant differences in survival between protocols before (p=0.389) or after weighting (p=0.440), but survival was poorest in the no immunosuppressant group (84.0%) at 24 months. CONCLUSIONS: These findings may support using immunosuppressants for early dcSSc but suggest that overall benefit is modest over 12 months and that better treatments are needed. TRIAL REGISTRATION NUMBER: NCT02339441.

Identification of novel genetic markers associated with clinical phenotypes of systemic sclerosis through a genome-wide association strategy.

The aim of this study was to determine, through a genome-wide association study (GWAS), the genetic components contributing to different clinical sub-phenotypes of systemic sclerosis (SSc). We considered limited (lcSSc) and diffuse (dcSSc) cutaneous involvement, and the relationships with presence of the SSc-specific auto-antibodies, anti-centromere (ACA), and anti-topoisomerase I (ATA). Four GWAS cohorts, comprising 2,296 SSc patients and 5,171 healthy controls, were meta-analyzed looking for associations in the selected subgroups. Eighteen polymorphisms were further tested in nine independent cohorts comprising an additional 3,175 SSc patients and 4,971 controls. Conditional analysis for associated SNPs in the HLA region was performed to explore their independent association in antibody subgroups. Overall analysis showed that non-HLA polymorphism rs11642873 in IRF8 gene to be associated at GWAS level with lcSSc (P = 2.32×10(-12), OR = 0.75). Also, rs12540874 in GRB10 gene (P = 1.27 × 10(-6), OR = 1.15) and rs11047102 in SOX5 gene (P = 1.39×10(-7), OR = 1.36) showed a suggestive association with lcSSc and ACA subgroups respectively. In the HLA region, we observed highly associated allelic combinations in the HLA-DQB1 locus with ACA (P = 1.79×10(-61), OR = 2.48), in the HLA-DPA1/B1 loci with ATA (P = 4.57×10(-76), OR = 8.84), and in NOTCH4 with ACA P = 8.84×10(-21), OR = 0.55) and ATA (P = 1.14×10(-8), OR = 0.54). We have identified three new non-HLA genes (IRF8, GRB10, and SOX5) associated with SSc clinical and auto-antibody subgroups. Within the HLA region, HLA-DQB1, HLA-DPA1/B1, and NOTCH4 associations with SSc are likely confined to specific auto-antibodies. These data emphasize the differential genetic components of subphenotypes of SSc.

Promoting patient safety in India: situational analysis and the way forward.

Unsafe healthcare is a well-recognized issue internationally and is attracting attention in India as well. Drawing upon the various efforts that have been made to address this issue in India and abroad, we explore how we can accelerate developments and build a culture of patient safety in the Indian health sector. Using five international case studies, we describe experiences of promoting patient safety in various ways to inform future developments in India. We offer a roadmap for 2020, which contains suggestions on how India could build a culture of patient safety.

New insight on the Xq28 association with systemic sclerosis.

OBJECTIVE: To evaluate whether the systemic sclerosis (SSc)-associated IRAK1 non-synonymous single-nucleotide polymorphism rs1059702 is responsible for the Xq28 association with SSc or whether there are other independent signals in the nearby methyl-CpG-binding protein 2 gene (MECP2). METHODS: We analysed a total of 3065 women with SSc and 2630 unaffected controls from five independent Caucasian cohorts. Four tag single-nucleotide polymorphisms of MECP2 (rs3027935, rs17435, rs5987201 and rs5945175) and the IRAK1 variant rs1059702 were genotyped using TaqMan predesigned assays. A meta-analysis including all cohorts was performed to test the overall effect of these Xq28 polymorphisms on SSc. RESULTS: IRAK1 rs1059702 and MECP2 rs17435 were associated specifically with diffuse cutaneous SSc (PFDR=4.12×10(-3), OR=1.27, 95% CI 1.09 to 1.47, and PFDR=5.26×10(-4), OR=1.30, 95% CI 1.14 to 1.48, respectively), but conditional logistic regression analysis showed that the association of IRAK1 rs1059702 with this subtype was explained by that of MECP2 rs17435. On the other hand, IRAK1 rs1059702 was consistently associated with presence of pulmonary fibrosis (PF), because statistical significance was observed when comparing SSc patients PF+ versus controls (PFDR=0.039, OR=1.30, 95% CI 1.07 to 1.58) and SSc patients PF+ versus SSc patients PF- (p=0.025, OR=1.26, 95% CI 1.03 to 1.55). CONCLUSIONS: Our data clearly suggest the existence of two independent signals within the Xq28 region, one located in IRAK1 related to PF and another in MECP2 related to diffuse cutaneous SSc, indicating that both genes may have an impact on the clinical outcome of the disease.

Mortality as an indicator of patient safety in orthopaedics: lessons from qualitative analysis of a database of medical errors.

BACKGROUND: Orthopaedic surgery is a high-risk specialty in which errors will undoubtedly occur. Patient safety incidents can yield valuable information to generate solutions and prevent future cases of avoidable harm. The aim of this study was to understand the causative factors leading to all unnecessary deaths in orthopaedics and trauma surgery reported to the National Patient Safety Agency (NPSA) over a four-year period (2005-2009), using a qualitative approach. METHODS: Reports made to the NPSA are categorised and stored in the database as free-text data. A search was undertaken to identify the cases of all-cause mortality in orthopaedic and trauma surgery, and the free-text elements were used for thematic analysis. Descriptive statistics were calculated based on the incidents reported. This included presenting the number of times categories of incidents had the same or similar response. Superordinate and subordinate categories were created. RESULTS: A total of 257 incident reports were analysed. Four main thematic categories emerged. These were: (1) stages of the surgical journey - 118/191 (62%) of deaths occurred in the post-operative phase; (2) causes of patient deaths - 32% were related to severe infections; (3) reported quality of medical interventions - 65% of patients experienced minimal or delayed treatment; (4) skills of healthcare professionals - 44% of deaths had a failure in non-technical skills. CONCLUSIONS: Most complications in orthopaedic surgery can be dealt with adequately, provided they are anticipated and that risk-reduction strategies are instituted. Surgeons take pride in the precision of operative techniques; perhaps it is time to enshrine the multimodal tools available to ensure safer patient care.

A replication study confirms the association of TNFSF4 (OX40L) polymorphisms with systemic sclerosis in a large European cohort.

OBJECTIVES: The aim of this study was to confirm the influence of TNFSF4 polymorphisms on systemic sclerosis (SSc) susceptibility and phenotypic features. METHODS: A total of 8 European populations of Caucasian ancestry were included, comprising 3014 patients with SSc and 3125 healthy controls. Four genetic variants of TNFSF4 gene promoter (rs1234314, rs844644, rs844648 and rs12039904) were selected as genetic markers. RESULTS: A pooled analysis revealed the association of rs1234314 and rs12039904 polymorphisms with SSc (OR 1.15, 95% CI 1.02 to 1.31; OR 1.18, 95% CI 1.08 to 1.29, respectively). Significant association of the four tested variants with patients with limited cutaneous SSc (lcSSc) was revealed (rs1234314 OR 1.22, 95% CI 1.07 to 1.38; rs844644 OR 0.91, 95% CI 0.83 to 0.99; rs844648 OR 1.10, 95% CI 1.01 to 1.20 and rs12039904 OR 1.20, 95% CI 1.09 to 1.33). Association of rs1234314, rs844648 and rs12039904 minor alleles with patients positive for anti-centromere antibodies (ACA) remained significant (OR 1.23, 95% CI 1.10 to 1.37; OR 1.12, 95% CI 1.01 to 1.25; OR 1.22, 95% CI 1.07 to 1.38, respectively). Haplotype analysis confirmed a protective haplotype associated with SSc, lcSSc and ACA positive subgroups (OR 0.88, 95% CI 0.82 to 0.96; OR 0.88, 95% CI 0.80 to 0.96; OR 0.86, 95% CI 0.77 to 0.97, respectively) and revealed a new risk haplotype associated with the same groups of patients (OR 1.14, 95% CI 1.03 to 1.26; OR 1.20, 95% CI 1.08 to 1.35; OR 1.23, 95% CI 1.07 to 1.42, respectively). CONCLUSIONS: The data confirm the influence of TNFSF4 polymorphisms in SSc genetic susceptibility, especially in subsets of patients positive for lcSSc and ACA.

Improving global access to medical ethics education: a free self-paced online course on the Peoples-uni website.

In an attempt to increase global access to education about medical ethics, a free fully online course was developed on the Peoples-uni Open Online Courses site. Students came from 60 countries and were more likely to be medical practitioners, have come from the global North, and to have heard about the course through the web than other students enrolled in the Peoples-uni Open Online Courses site. Students scored high marks on the five quizzes. A third of the students gained a certificate of completion. Course feedback was overwhelmingly positive. Students stated that they learned the most from the lesson on professionalism, while other topics such as patient rights and autonomy, legal issues, and healthcare organisation and public health were also frequently mentioned. The course is an example of how open online courses can play a role in increasing awareness of medical ethics. Based on its analysis, the study identifies a need to attract interest in this area from low- and middle-income countries.

WITHDRAWN: Surgical interventions for treating distal radial fractures in adults.

BACKGROUND: Fracture of the distal radius is a common clinical problem, particularly in older white women with osteoporosis. OBJECTIVES: To determine when, and if so what type of, surgical intervention is the most appropriate treatment for fractures of the distal radius in adults. SEARCH STRATEGY: We searched the Cochrane Bone, Joint and Muscle Trauma Group specialised register (November 2002), the Cochrane Central Register of Controlled Trials (The Cochrane Library, Issue 1, 2003), MEDLINE (1966 to February 2003), EMBASE (1988 to 2003 Week 8), CINAHL (1982 to February 2003), the National Research Register (Issue 1, 2003), PEDro, conference proceedings and reference lists of articles. No language restrictions were applied. SELECTION CRITERIA: Randomised or quasi-randomised clinical trials involving skeletally mature patients with a fracture of the distal radius, which compared surgical treatment with conservative treatment, different types of surgical intervention or the duration of immobilisation after surgery. The main categories of surgical intervention were external fixation, percutaneous pinning, open reduction and internal fixation, and the insertion of bone scaffolding materials. DATA COLLECTION AND ANALYSIS: All trials, meeting the selection criteria, were independently assessed by both reviewers for methodological quality. Data were extracted for anatomical, functional and clinical outcomes (including complications). The trials were grouped into categories relating to the main comparisons and types of surgical intervention. Despite clear heterogeneity in the characteristics of comparable trials, pooling of data was undertaken where possible and appropriate. MAIN RESULTS: Forty eight trials, examining 25 treatment comparisons, met the inclusion criteria of this review. These involved a total of 3371 mainly female and older patients with generally displaced, often comminuted and potentially or evidently unstable fractures. Nearly half of the trials compared surgery with plaster cast immobilisation. Summarising the outcomes was hampered by the variation between the studies in participant characteristics, interventions, quality of trial methodology and reporting, and outcome measurement. Surgical methods were usually associated with better anatomical appearance after fracture healing, but there was inadequate evidence to confirm that these had resulted in better functional and clinical outcomes for the patients. AUTHORS' CONCLUSIONS: The 48 randomised trials do not provide robust evidence for most of the decisions necessary in the management of these fractures. Although, in particular, there is some evidence to support the use of external fixation or percutaneous pinning, their precise role and methods are not established. It is also unclear whether surgical intervention of most fracture types will produce consistently better long-term outcomes.There is a need for good quality evidence for the surgical management of these fractures.

WITHDRAWN: Co-ordinated multidisciplinary approaches for inpatient rehabilitation of older patients with proximal femoral fractures.

BACKGROUND: Hip fracture is a major cause of morbidity and mortality in older people and its impact, both on the individual and to society, is substantial. OBJECTIVES: To examine the effects of co-ordinated multidisciplinary inpatient rehabilitation, compared with usual (orthopaedic) care, for older patients with hip fracture. SEARCH STRATEGY: We searched the Cochrane Bone, Joint and Muscle Trauma Group specialised register (December 2002), MEDLINE (1966 to December 2002), conference proceedings and reference lists of articles and books. We also contacted colleagues and trialists. SELECTION CRITERIA: Randomised and quasi-randomised trials of post-surgical care using specialised rehabilitation of mainly older patients (aged 65 years or over) with hip fracture. DATA COLLECTION AND ANALYSIS: Trial assignment to included, excluded and awaiting assessment categories, was by consensus. Two reviewers independently assessed trial quality and extracted data. Limited additional information was sought from most trialists. As well as pooling data from primary outcomes, supplementary analyses were performed to combine clinically relevant outcomes and investigate possible explanatory factors. MAIN RESULTS: In this minor update, new data for two already included trials have been incorporated, resulting in only slight changes to the pooled results.The nine included trials involved 1887 patients. The combined outcomes of death or requiring institutional care showed no significant difference between intervention and control groups (relative risk 0.93; 95% confidence interval 0.83 to 1.05). There was considerable heterogeneity in length of stay and cost data. Using death and deterioration in function as a further combined outcome variable yielded a relative risk of 0.91 (95% confidence interval 0.83 to 1.01). This should be interpreted with caution due to heterogeneity. No quality of life measures were reported and the two trials investigating carer burden showed no evidence of detrimental effect from the intervention. The review update did not result in any new data for these outcomes. AUTHORS' CONCLUSIONS: The available trials reviewed had different aims, interventions and outcomes. Combined outcome measures (e.g. death or institutional care) tended to be better for patients receiving co-ordinated inpatient rehabilitation, but the results were heterogeneous and not statistically significant.Future trials of post-surgical care involving inpatient rehabilitation, or other models such as 'early supported discharge' and 'hospital at home' schemes, should aim to establish both effectiveness and cost effectiveness of multidisciplinary rehabilitation overall, rather than attempt to evaluate its components.

Protocol for the ProFHER (PROximal Fracture of the Humerus: Evaluation by Randomisation) trial: a pragmatic multi-centre randomised controlled trial of surgical versus non-surgical treatment for proximal fracture of the humerus in adults.

BACKGROUND: Proximal humeral fractures, which occur mainly in older adults, account for approximately 4 to 5% of all fractures. Approximately 40% of these fractures are displaced fractures involving the surgical neck. Management of this group of fractures is often challenging and the outcome is frequently unsatisfactory. In particular it is not clear whether surgery gives better outcomes than non-surgical management. Currently there is much variation in the use of surgery and a lack of good quality evidence to inform this decision. METHODS/DESIGN: We aim to undertake a pragmatic UK-based multi-centre randomised controlled trial evaluating the effectiveness and cost-effectiveness of surgical versus standard non-surgical treatment for adults with an acute closed displaced fracture of the proximal humerus with involvement of the surgical neck. The choice of surgical intervention is left to the surgeon, who must use techniques that they are fully experienced with. This will avoid 'learning curve' problems. We will promote good standards of non-surgical care, similarly insisting on care-provider competence, and emphasize the need for comparable provision of rehabilitation for both groups of patients.We aim to recruit 250 patients from a minimum of 18 NHS trauma centres throughout the UK. These patients will be followed-up for 2 years. The primary outcome is the Oxford Shoulder Score, which will be collected via questionnaires completed by the trial participants at 6, 12 and 24 months. This is a 12-item condition-specific questionnaire providing a total score based on the person's subjective assessment of pain and activities of daily living impairment. We will also collect data for other outcomes, including general health measures and complications, and for an economic evaluation. Additionally, we plan a systematic collection of reasons for non-inclusion of eligible patients who were not recruited into the trial, and their baseline characteristics, treatment preferences and intended treatment. DISCUSSION: This article presents the protocol for a multi-centre randomised controlled trial. It gives extensive details of, and the basis for, the chosen methods, and describes the key measures taken to avoid bias and to ensure validity. TRIAL REGISTRATION: Current Controlled Trials ISRCTN50850043.