Improve Disease Burden Research Articles

P0232 Increasing awareness of joint symptoms in Inflammatory Bowel Disease clinic using recognised clinical joint pain scoring symptoms may aid early diagnosis of spondyloarthropathy

Abstract Background Axial spondyloarthropathy(axSpA) is under-recognised and underdiagnosed in lnflammatory Bowel Disease (IBD) patients. The aim of our study is to assess the prevalence of subclinical axSpA in our IBD patient cohort, assess risk factors and improve patient health through early recognition and referral. Methods A prospective observational study assessing presence of clinical symptoms suggestive of spondyloarthropathy was performed. Patients with established IBD and no previous history of joint pain or documented rheumatological disease attending a specialist IBD clinic were screened over a 6 month period from January to July 2024. All patients reporting lower back pain were assessed with a screening questionnaire using the Bath Ankylosing Spondylitis Disease Activity Index (BASDAI) score. BASDAI score ≥ 4 suggests moderate activity of axial spondyloarthropathy. Radiographic imaging of the sacroiliac joints were performed. BASDAI scores were correlated with CRP and calprotectin levels. Other demographic factors were also recorded from patient records. Results 590 patient visits for IBD were recorded from January to July 2024. 320 patients were screened for the study. 34 (10.6%) patients reported symptoms suggestive of axial spondyloarthropathy when questioned. The mean age was 45 years of age (19-82). 55.9% of patients were female. 14.7% of patients had symptoms of other extra-intestinal manifestations (EIMs). 50% of patients had Ulcerative colitis, 44% of patients had Crohn’s disease and 6% had IBD-U. Mean CRP level was 2.36 (0.5–7). Mean calprotectin was 151 (13-1100). 21/34 (62%) of patients had a BASDAI score suggestive of moderately active clinical symptoms of arthropathy. Mean BASDAI score was 4.97. 2/21 (9.5%) of those with BASDAI ≥ 4 had radiographic evidence of sacroiliitis. Of those patients with radiographic axSpA, the mean BASDAI was 5.1. Patients with radiographic axSpA were referred to the rheumatology outpatient service. 84% females screened had BASDAI ≥ 4 compared to 40 % males (Fisher exact test, p=0.015). There was no correlation noted between reporting of joint symptoms and age, CRP or calprotectin nor did it correlate with disease type or behaviour. Conclusion The use of rheumatological screening tests in the IBD clinic could contribute to the early diagnosis of axial spondyloarthropathy in IBD patients. Raising awareness of musculoskeletal manifestations of IBD could improve diagnosis, early involvement of the multidisciplinary team and improve disease burden.

Estimating disease burden using national linked electronic health records: a study using an English population-based cohort.

Electronic health records (EHRs) have the potential to be used to produce detailed disease burden estimates. In this study we created disease estimates using national EHR for three high burden conditions, compared estimates between linked and unlinked datasets and produced stratified estimates by age, sex, ethnicity, socio-economic deprivation and geographical region. EHRs containing primary care (Clinical Practice Research Datalink), secondary care (Hospital Episode Statistics) and mortality records (Office for National Statistics) were used. We used existing disease phenotyping algorithms to identify cases of cancer (breast, lung, colorectal and prostate), type 1 and 2 diabetes, and lower back pain. We calculated age-standardised incidence of first cancer, point prevalence for diabetes, and primary care consultation prevalence for low back pain. 7.2 million people contributing 45.3 million person-years of active follow-up between 2000-2014 were included. CPRD-HES combined and CPRD-HES-ONS combined lung and bowel cancer incidence estimates by sex were similar to cancer registry estimates. Linked CPRD-HES estimates for combined Type 1 and Type 2 diabetes were consistently higher than those of CPRD alone, with the difference steadily increasing over time from 0.26% (2.99% for CPRD-HES vs. 2.73 for CPRD) in 2002 to 0.58% (6.17% vs. 5.59) in 2013. Low back pain prevalence was highest in the most deprived quintile and when compared to the least deprived quintile the difference in prevalence increased over time between 2000 and 2013, with the largest difference of 27% (558.70 per 10,000 people vs 438.20) in 2013. We use national EHRs to produce estimates of burden of disease to produce detailed estimates by deprivation, ethnicity and geographical region. National EHRs have the potential to improve disease burden estimates at a local and global level and may serve as more automated, timely and precise inputs for policy making and global burden of disease estimation.

Effects of microbiome-based interventions on neurodegenerative diseases: a systematic review and meta-analysis

Neurodegenerative diseases (NDDs) are characterized by neuronal damage and progressive loss of neuron function. Microbiome-based interventions, such as dietary interventions, biotics, and fecal microbiome transplant, have been proposed as a novel approach to managing symptoms and modulating disease progression. Emerging clinical trials have investigated the efficacy of interventions modulating the GM in alleviating or reversing disease progression, yet no comprehensive synthesis have been done. A systematic review of the literature was therefore conducted to investigate the efficacy of microbiome-modulating methods. The search yielded 4051 articles, with 15 clinical trials included. The overall risk of bias was moderate in most studies. Most microbiome-modulating interventions changed the GM composition. Despite inconsistent changes in GM composition, the meta-analysis showed that microbiome-modulating interventions improved disease burden (SMD, − 0.57; 95% CI − 0.93 to − 0.21; I2 = 42%; P = 0.002) with a qualitative trend of improvement in constipation. However, current studies have high methodological heterogeneity and small sample sizes, requiring more well-designed and controlled studies to elucidate the complex linkage between microbiome, microbiome-modulating interventions, and NDDs.

Immunological perturbations, psychiatric disorders and associated therapeutics: a new era for psychiatry?

The three main theories explaining major mental illness, namely mood disorders, psychoses and dementias, have been partially discredited. Alongside this, there are emerging links between perturbations of the immune system and the onset and phenotypic features of these disorders. This article outlines the alternative pathophysiology and suggests potential treatments which could improve disease burden and avoid the need for psychotropic medication, with their associated side effects and relapse following withdrawal.

Estimating disease burden using national linked electronic health records: a study using an English population-based cohort.

Background: Electronic health records (EHRs) have the potential to be used to produce detailed disease burden estimates. In this study we created disease estimates using national EHR for three high burden conditions, compared estimates between linked and unlinked datasets and produced stratified estimates by age, sex, ethnicity, socio-economic deprivation and geographical region. Methods: EHRs containing primary care (Clinical Practice Research Datalink), secondary care (Hospital Episode Statistics) and mortality records (Office for National Statistics) were used. We used existing disease phenotyping algorithms to identify cases of cancer (breast, lung, colorectal and prostate), type 1 and 2 diabetes, and lower back pain. We calculated age-standardised incidence of first cancer, point prevalence for diabetes, and primary care consultation prevalence for low back pain. Results: 7.2 million people contributing 45.3 million person-years of active follow-up between 2000-2014 were included. CPRD-HES combined and CPRD-HES-ONS combined lung and bowel cancer incidence estimates by sex were similar to cancer registry estimates. Linked CPRD-HES estimates for combined Type 1 and Type 2 diabetes were consistently higher than those of CPRD alone, with the difference steadily increasing over time from 0.26% (2.99% for CPRD-HES vs. 2.73 for CPRD) in 2002 to 0.58% (6.17% vs. 5.59) in 2013. Low back pain prevalence was highest in the most deprived quintile and when compared to the least deprived quintile the difference in prevalence increased over time between 2000 and 2013, with the largest difference of 27% (558.70 per 10,000 people vs 438.20) in 2013. Conclusions: We use national EHRs to produce estimates of burden of disease to produce detailed estimates by deprivation, ethnicity and geographical region. National EHRs have the potential to improve disease burden estimates at a local and global level and may serve as more automated, timely and precise inputs for policy making and global burden of disease estimation.

French cohort of children and adolescents with neurofibromatosis type 1 and symptomatic inoperable plexiform neurofibromas: CASSIOPEA study.

Surgery is a treatment option for neurofibromatosis type 1 (NF1)-related plexiform neurofibromas (PN), but complete resection is often not feasible. Real-world studies are warranted to understand disease burden, progression, and need for medical treatment in patients with inoperable PN. CASSIOPEA was a retrospective study of French pediatric patients (aged ≥3 to <18 years) presenting at a national multidisciplinary team (MDT) review with NF1 and ≥1 symptomatic, inoperable PN. Medical records were reviewed from the time of MDT review and over a follow-up period of up to 2 years. Primary objectives were to describe patient characteristics and target PN-associated therapy patterns. A secondary objective was evolution of target PN-related morbidities. Patients with prior, ongoing, or MDT recommendation of mitogen-activated protein kinase kinase (MEK) inhibitor treatment were excluded. Overall, 78 target PN were identified in 76 patients. At MDT review, median age was 8.4 years, with approximately 30% of patients aged 3-6 years. Target PN were primarily internal (77.3%), and 43.2% were progressive. Target PN location was evenly distributed. 34 target PN had documented MDT recommendations; of these, a majority (76.5%) were for non-medication management, including surveillance. At least one follow-up visit was recorded for 74 target PN. Despite initially being considered inoperable, 12.3% of patients underwent surgery for target PN. At MDT review, most (98.7%) target PN were associated with ≥1 morbidity, primarily pain (61.5%) and deformity (24.4%); severe morbidities were identified in 10.3%. Of 74 target PN with follow-up data, 89.2% were associated with ≥1 morbidity, primarily pain (60.8%) and deformity (25.7%). Of 45 target PN associated with pain, pain improved in 26.7%, was stable in 44.4%, and deteriorated in 28.9%. Deformity improved in 15.8% and remained stable in 84.2% of 19 target PN associated with deformity. None deteriorated. In this real-world study in France, NF1-PN disease burden was considerable, and a considerable proportion of patients were very young. Most patients received only supportive care without medication for target PN management. Target PN-related morbidities were frequent, heterogeneous, and generally did not improve during follow-up. These data highlight the importance of effective treatments that target PN progression and improve disease burden.

Ligelizumab improves sleep interference and disease burden in patients with chronic spontaneous urticaria.

BackgroundChronic spontaneous urticaria (CSU) negatively impacts patients' sleep, thereby reducing health‐related quality of life (HRQoL). Half of patients with inadequately controlled CSU report sleep interference often or every night, which can lead to depression, anxiety, social, and work‐related problems.MethodsThis randomized, double‐blind, placebo‐controlled Phase 2b core study (NCT02477332) included adult patients ≥18 years with moderate to severe CSU inadequately controlled with H1‐antihistamines. The current analysis includes patients randomized to receive ligelizumab 72 or 240 mg, omalizumab 300 mg or placebo every 4 weeks (q4w) for five injections over 20 weeks with treatment‐free follow‐up for 24 weeks. Patients could enter the open‐label extension study (NCT02649218) from Week 32 onwards if their weekly urticaria activity score was ≥12, which included an open‐label treatment (52 weeks of ligelizumab 240 mg q4w) and a 48‐week post‐treatment follow‐up. Weekly Sleep Interference Scores (SIS7, range 0 [no interference]–21 [substantial interference]), Weekly Activity Interference Score (AIS7), Dermatology Life Quality Index (DLQI) scores, and Overall Work Impairment were assessed.ResultsMean baseline SIS7 scores were balanced between the treatment arms for ligelizumab 72 mg (n = 84) and 240 mg (n = 85), omalizumab 300 mg (n = 85), and placebo (n = 43). By Week 12, patients experienced large improvements in sleep interference, with least square mean (standard error) changes from baseline (CFB) in SIS7 of −7.84 (0.58), −7.55 (0.61), −6.98 (0.60), and −5.85 (0.81), respectively. By Week 12, CFB in AIS7 were −8.25 (0.57), −8.25 (0.59), −7.30 (0.60), and −5.62 (0.79), DLQI scores were −9.79 (0.77), −9.93 (0.81), −8.35 (0.79), and −6.99 (1.11), and Overall Work Impairment scores were −28.96 (3.73), −30.76 (3.71), −25.74 (3.91), and −20.13 (5.10) for ligelizumab 72 and 240 mg, omalizumab 300 mg and placebo, respectively. Improvements in each patient‐reported outcome were sustained with ligelizumab 240 mg treatment during the extension study.ConclusionsLigelizumab showed effective and sustained responses in managing sleep interference in patients with CSU, and numerically higher responses than with omalizumab and placebo. Treating the symptoms of CSU with ligelizumab improved disease burden, HRQoL, and markedly improved sleep quality.

P514 Optimising response to infliximab in the management of perianal Crohn’s disease

Abstract Background Perianal Crohn’s Disease (PCD) remains a refractory phenotype of Crohn’s Disease (CD)1. Despite initial demonstration of the benefit of infliximab (IFX) in PCD over 20 years ago2, it remains clear how IFX treatment can be optimised for PCD patients3. In this retrospective observational study, a cohort of PCD patients based at St Mark’s Hospital was reviewed to understand their disease-journeys whilst on treatment with IFX. Methods A cohort of 59 patients with PCD on treatment with IFX as of January 2020 were identified from a prospective database of IFX treated patients. Twenty-seven patients were classed as fluctuating IFX levels and underwent disease-journey analysis. Detailed qualitative analysis of individual patients journeys were carried out to correlate IFX levels, where available, to C-Reactive Protein (CRP), Magnetic Resonance Imaging (MRI) and Examinations Under Anaesthetic (EUA). These journeys were then graphed as a timeline for each of these patients. Results Four disease-journeys have been selected to exemplify key learning points in the management of PCD. Graph 1: Improving drainage and reducing inflammatory burden with EUA can help to recover IFX levels and regain disease control. This suggests a well-timed EUA can have a synergistic effect on treatment with IFX. Graph 2: In a subgroup of patients, optimised medical therapy with IFX alone remains adequate to perianal fistula healing. Graph 3: Patients may benefit from temporary dose escalations with IFX to recapture response and to improve disease burden. Graph 4: Some patients require longer periods of dose-escalated therapy as seen in this graph &amp; higher IFX levels may be required for radiological healing. Conclusion These cases highlight interesting learning points and can help to manage complicated PCD patients. Further work is needed to determine how significant the link is between improvement in IFX levels post-EUA and how this correlates with the overall clinical picture of the patient.

The Design of a Phase 2 Study to Evaluate the Safety and Efficacy of Ropeginterferon Alfa-2b (P1101) in Chinese Patients with Polycythemia Vera Resistant or Intolerant to Hydroxyurea (HU)

▪Background: Polycythemia vera (PV) is the most common type of Philadelphia-negative myeloproliferative neoplasms (MPNs). PV is a long-term debilitating and life-threatening cancer that is associated with the risk of thrombosis, hemorrhage, and a long-term risk of developing myelofibrosis and acute myeloid leukemia. Early intervention with a disease-modifying treatment that can eradicate the mutated clones is needed to prevent disease progression and transformation. To date, therapeutic options for PV are limited and they only address the signs and symptoms. Most low-risk patients with PV are treated with phlebotomy and low-dose aspirin to manage increased blood viscosity and reduce the risk of vascular events, whereas high-risk and certain low-risk patients are treated with cytoreductive agents. Several cytoreductive agents are available such as hydroxyurea (HU) which is commonly used as a first-line therapy. Ruxolitinib, a JAK2 inhibitor, is also used. While interferon alfa agents have been used off label in clinical practice for more than three decades, their use has been limited due to the tolerability concerns.Ropeginterferon alfa-2b (P1101), a long-acting, mono-pegylated proline interferon, was developed for the treatment of MPNs, including PV. The novel formulation of P1101 improves its pharmacokinetic properties allowing treatment every 2 weeks with improved tolerability and convenience. P1101 was evaluated for the treatment of PV in the phase 3 PROUD-PV trial and its extension study CONTINUATION-PV. In the PROUD-PV study, due to the slow P1101 titration schedule, the maximum P1101 dose was not reached until week 28 and the primary analysis was done at 52 weeks. In CONTINUATION-PV, when patients were on their effective doses, a significantly higher proportion of patients treated with P1101 achieved a complete hematologic response (CHR) with improved disease burden compared to HU-treated patients. At 48 months there was a significant reduction in allelic burden from a baseline of 37.3% to 9.8% with 13.8% of patients achieving a complete molecular response (CMR). The molecular response rates (complete + partial) at 60 months was 69.1%. P1101 was approved by the European Medicines Agency in 2019 and the Taiwan Food and Drug Administration in 2020 as monotherapy in adults for the treatment of PV without symptomatic splenomegaly. Here, we describe a phase 2 study of P1101 in Chinese patients with PV utilizing an accelerated P1101 dose titration schedule.Study Design and Methods: This phase 2, multicenter, single-arm study is designed to evaluate safety and efficacy of P1101 in Chinese patients with PV utilizing a 250-350-500 ug P1101 dose titration schedule. The primary analysis will be conducted at 24 weeks. The study will recruit approximately 49 subjects in 15-20 sites in China. Key eligibility criteria include diagnosis of PV according to the 2016 WHO criteria, and resistance or intolerance to prior HU according to 2020 guidelines of CSCO. Patients who previously received interferon therapy have to be anti-P1101 binding antibody negative during the screening visit to be eligible. The study excludes patients with symptomatic splenomegaly.Eligible patients receive subcutaneous administration of P1101. Patients will receive an initial dose of 250 µg at Week 0, 350 µg at Week 2, and then 500 µg at Week 4. The dose is maintained at the highest dose that can be tolerated and delivers the best disease response. The maximum recommended dose is 500 μg every 2 weeks. Low-dose aspirin is administered during the 52 weeks of study treatment, unless contraindicated. The primary efficacy endpoint is the phlebotomy-free CHR rate at Week 24. Secondary endpoints include changes in hematocrit, white blood cell count, platelet count; time requiring no phlebotomy; time to first response; and duration of response. All patients will continue receiving treatment until week 52 to provide long-term follow-up information (blood parameters, molecular and cytogenetic data, safety parameters, and optional bone marrow data).This study has been granted IND approval by China CDE on Apr2021. Recruitment is expected to begin in early September 2021 with trial results expected in Q3 2022.Figure： Study Design [Display omitted] DisclosuresZagrijtschuk: PharmaEssentia U.S.A. Corp.: Current Employment. Urbanski: PharmaEssentia Corporation: Current Employment. Qin: PharmaEssentia Corp.: Current Employment.

The Rationale, Design, and Baseline Characteristics of a Phase 2 Study to Evaluate the Safety and Efficacy of Ropeginterferon Alfa-2b (P1101) in Japanese Patients with Polycythemia Vera for Whom the Current Standard of Care Is Difficult to Apply

The Rationale, Design, and Baseline Characteristics of a Phase 2 Study to Evaluate the Safety and Efficacy of Ropeginterferon Alfa-2b (P1101) in Japanese Patients with Polycythemia Vera for Whom the Current Standard of Care Is Difficult to Apply

Improving Evaluation of Disease Burden at Diagnosis in Hodgkin Lymphoma

Introduction: Hodgkin lymphoma (HL) is a hematological malignancy, with an inflammatory majority component of reactive cells and a few (1-2%) Reed-Sternberg cells (RSC). A high percentage of patients are cured with conventional strategies but approximately 15-30% relapse or progress. The standard tool to assess disease burden is the Ann Arbor Stage that classically categorizes HL in early (I-II) and advanced stages (III-IV). However, AA staging lacks accuracy in predicting outcome. New ways to asses tumor burden, such as baseline fluorodeoxyglucose positron emission tomography/computed tomography (FDG PET/CT), detect active disease with higher sensitivity in comparison with computed tomography (CT). Additionally, different volumetric parameters, such as metabolic tumor volume (MTV) and total lesion glycolysis (TLG), may be obtained from FDG PET/TC. We aim to improve disease burden testing using FDG PET/TC-related parameters, to better stratify HL patients at the time of diagnosis. Methods: We retrospectively selected patients with HL, homogeneously treated with ABVD +/- RT, at Son Espases and Son Llatzer University Hospitals in Palma de Mallorca from the databases of Pharmacy, Pathology and Nuclear Medicine Departments, to avoid selection bias. FDG PET/TC was done at baseline. MTV was measured with a semiautomatic method using a 41% maximum standardized uptake value (SUVmax) threshold and represents the sum of metabolic volumes of tumor tissues with increased FDG uptake. TLG was calculated by multiplying MTV and the mean SUV (SUVmean) of the MTV and was representative of the metabolic activity throughout the entire tumor. We used receiver operating curves (ROC) analysis to obtain the optimal cutoff for progression or death of all experimental FDG PET/TC-related variables. Standard clinical prognostic variables were obtained from medical records (age, gender, stage, bulky and ECOG PS) and main prognostic scores (IPS, EORTC and GHSG) were calculated. Progression-free survival (PFS) was considered the time from diagnosis to disease progression or death of any cause. Univariate survival analysis was done using Kaplan-meier plots and comparison between variables with log-rank test. Results: From August-2011 to November-2018, we included 101 patients. Table 1 shows main characteristics of patients. Median age was 37 years (14-83 years), 53% of patients had an advanced stage and 10% had bulky disease. With a median follow-up of 45 months (11-90), median PFS was 78%. The optimal cuttoffs obtained for MTV, TLG and SUVmax were 32.5, 167.8 and 10.4, respectively. In the univariate survival analysis, PFS was significantly influenced by MTV (p=0,007) and TLG (p=0.003), but not AA stage (Table 2). OS was significantly influenced by TLG (p=0.007) and SUVmax (p=0.001). With the three FDG PET/TC-related variables influencing HL survival we designed a FDG PET/TC score as follows: 1 point for high level of MTV, TLG or SUVmax (from 0 to 3). As shown in Table 2, this new FDG PET/TC score had a much better risk assessment that standard AA stage, being able to differentiate three risk groups with 100%, 84% and 65% 4-y PFS and 100%, 84% and 75% OS. Conclusions: The combination of functional 3D measurement of tumor burden (MTV, TLG and SUVmax) obtained from the FDG PET/TC at diagnosis, in HL, could be a valuable tool to better stratify the risk patients from tumor burden at the moment of diagnosis, when compared with standard AA staging. Disclosures No relevant conflicts of interest to declare.

Spontaneous Regression of Recurrent Respiratory Papillomatosis with HPV Vaccination: A Case Study

Recurrent respiratory papillomatosis (RRP) is characterized by recurrent laryngeal papillomas and treated with repeated surgical excision. The human papillomavirus (HPV) vaccine prevents infection with strains of HPV unrelated to RRP, and has recently been shown to increase the interval between surgeries when used as an adjuvant. The objective of this study was to report one case from our institution in which HPV vaccination was found to induce spontaneous regression of disease, absent of surgical intervention or use of other adjuvants. Retrospective case study. Records of one patient with RRP receiving partial HPV vaccination was reviewed with attention to videolaryngostroboscopic findings, Derkay score, need for surgical intervention, and voice quality. Spontaneous regression of disease after vaccination was seen in this patient, as evidenced by reduced tumor burden and decreased voice handicap index. The patient was a 30-year old female, who had improved disease burden and voice quality after one dose and total resolution of disease following the second dose. Vaccine administration was the sole therapeutic mechanism. These findings suggest that HPV vaccination can treat RRP without surgical intervention. Further studies are needed to investigate the underlying mechanism of disease regression and which patients may benefit most. We believe that HPV vaccination for all patients with RRP, even over the age of 45 years, may decrease treatment costs for individuals and the healthcare system overall.

International severe asthma registry (ISAR): protocol for a global registry

BackgroundSevere asthma exerts a disproportionately heavy burden on patients and health care. Due to the heterogeneity of the severe asthma population, many patients need to be evaluated to understand the clinical features and outcomes of severe asthma in order to facilitate personalised and targeted care. The International Severe Asthma Registry (ISAR) is a multi-country registry project initiated to aid in this endeavour.MethodsISAR is a multi-disciplinary initiative benefitting from the combined experience of the ISAR Steering Committee (ISC; comprising 47 clinicians and researchers across 29 countries, who have a special interest and/or experience in severe asthma management or establishment and maintenance of severe asthma registries) in collaboration with scientists and experts in database management and communication. Patients (≥18 years old) receiving treatment according to the 2018 definitions of the Global Initiative for Asthma (GINA) Step 5 or uncontrolled on GINA Step 4 treatment will be included. Data will be collected on a core set of 95 variables identified using the Delphi method. Participating registries will agree to provide access to and share standardised anonymous patient-level data with ISAR. ISAR is a registered data source on the European Network of Centres for Pharmacoepidemiology and Pharmacovigilance. ISAR’s collaborators include Optimum Patient Care, the Respiratory Effectiveness Group (REG) and AstraZeneca. ISAR is overseen by the ISC, REG, the Anonymised Data Ethics & Protocol Transparency Committee and the ISAR operational committee, ensuring the conduct of ethical, clinically relevant research that brings value to all key stakeholders.ConclusionsISAR aims to offer a rich source of real-life data for scientific research to understand and improve disease burden, treatment patterns and patient outcomes in severe asthma. Furthermore, the registry will provide an international platform for research collaboration in respiratory medicine, with the overarching aim of improving primary and secondary care of adults with severe asthma globally.

Ropeginterferon alfa-2b versus standard therapy for polycythaemia vera (PROUD-PV and CONTINUATION-PV): a randomised, non-inferiority, phase 3 trial and its extension study

The PROUD-PV and CONTINUATION-PV trials aimed to compare the novel monopegylated interferon ropeginterferon alfa-2b with hydroxyurea, the standard therapy for patients with polycythaemia vera, over 3 years of treatment. PROUD-PV and its extension study, CONTINUATION-PV, were phase 3, randomised, controlled, open-label, trials done in 48 clinics in Europe. Patients were eligible if 18 years or older with early stage polycythaemia vera (no history of cytoreductive treatment or less than 3 years of previous hydroxyurea treatment) diagnosed by WHO's 2008 criteria. Patients were randomly assigned 1:1 to ropeginterferon alfa-2b (subcutaneously every 2 weeks, starting at 100 μg) or hydroxyurea (orally starting at 500 mg/day). After 1 year, patients could opt to enter the extension part of the trial, CONTINUATION-PV. The primary endpoint in PROUD-PV was non-inferiority of ropeginterferon alfa-2b versus hydroxyurea regarding complete haematological response with normal spleen size (longitudinal diameter of ≤12 cm for women and ≤13 cm for men) at 12 months; in CONTINUATION-PV, the coprimary endpoints were complete haematological response with normalisation of spleen size and with improved disease burden (ie, splenomegaly, microvascular disturbances, pruritus, and headache). We present the final results of PROUD-PV and an interim analysis at 36 months of the CONTINUATION-PV study (per statistical analysis plan). Analyses for safety and efficacy were per-protocol. The trials were registered on EudraCT, 2012-005259-18 (PROUD-PV) and 2014-001357-17 (CONTINUATION-PV, which is ongoing). Patients were recruited from Sept 17, 2013 to March 13, 2015 with 306 enrolled. 257 patients were randomly assigned, 127 were treated in each group (three patients withdrew consent in the hydroxyurea group), and 171 rolled over to the CONTINUATION-PV trial. Median follow-up was 182·1 weeks (IQR 166·3-201·7) in the ropeginterferon alfa-2b and 164·5 weeks (144·4-169·3) in the standard therapy group. In PROUD-PV, 26 (21%) of 122 patients in the ropeginterferon alfa-2b group and 34 (28%) of 123 patients in the standard therapy group met the composite primary endpoint of complete haematological response with normal spleen size. In CONTINUATION-PV, complete haematological response with improved disease burden was met in 50 (53%) of 95 patients in the ropeginterferon alfa-2b group versus 28 (38%) of 74 patients in the hydroxyurea group, p=0·044 at 36 months. Complete haematological response without the spleen criterion in the ropeginterferon alfa-2b group versus standard therapy group were: 53 (43%) of 123 patients versus 57 (46%) of 125 patients, p=0·63 at 12 months (PROUD-PV), and 67 (71%) of 95 patients versus 38 (51%) of 74 patients, p=0·012 at 36 months (CONTINUATION-PV). The most frequently reported grade 3 and grade 4 treatment-related adverse events were increased γ-glutamyltransferase (seven [6%] of 127 patients) and increased alanine aminotransferase (four [3%] of 127 patients) in the ropeginterferon alfa-2b group, and leucopenia (six [5%] of 127 patients) and thrombocytopenia (five [4%] of 127 patients) in the standard therapy group. Treatment-related serious adverse events occurred in three (2%) of 127 patients in the ropeginterferon alfa-2b group and five (4%) of 127 patients in the hydroxyurea group. One treatment-related death was reported in the standard therapy group (acute leukaemia). In patients with early polycythaemia vera, who predominantly presented without splenomegaly, ropeginterferon alfa-2b was effective in inducing haematological responses; non-inferiority to hydroxyurea regarding haematological response and normal spleen size was not shown at 12 months. However, response to ropeginterferon alfa-2b continued to increase over time with improved responses compared with hydroxyurea at 36 months. Considering the high and durable haematological and molecular responses and its good tolerability, ropeginterferon alfa-2b offers a valuable and safe long-term treatment option with features distinct from hydroxyurea. AOP Orphan Pharmaceuticals AG.

Blocking extracellular Galectin-3 in patients with osteoarthritis

ObjectiveThis pilot clinical trial examined the efficacy of blocking extracellular Galectin-3 (Gal-3) with modified citrus pectin (MCP), in patients suffering from knee osteoarthritis (OA). Methods50 patients were randomized in a 1:1 ratio to receive MCP or placebo at a dose of 4 g (5 capsules) twice daily for 12 weeks. Serum Gal-3 levels and OA severity were evaluated at baseline and 12 weeks. Gal-3 levels were detected by sandwich ELISA and OA severity was determined using WOMAC-knee, SF-36, and RAPID3 surveys during these visits. MCP tolerability was assessed by a basic metabolic panel during a week 6 follow up visit. ResultsPatients enrolled in both the MCP treatment and placebo groups shared similar baseline characteristics in OA severity, serum Gal-3 levels, and pain management. Improvement across all surveys was noted independent of supplement or placebo treatment. No significant change in Gal-3 levels were observed in either cohort over the 12-week study. ConclusionTreatment of knee OA with a 12-week course of MCP did not significantly improve disease burden compared to placebo.

Estimating cause-specific mortality in Madagascar: an evaluation of death notification data from the capital city

BackgroundTrends in cause-specific mortality in most African countries are currently estimated from epidemiological models because the coverage of the civil registration system is low and national statistics on causes of death are unreliable at the national level. We aim to evaluate the performance of the death notification system in Antananarivo, the capital city of Madagascar, to inform cause-of-death statistics.MethodsInformation on the sex of the deceased, dates of birth and death, and underlying cause of death were transcribed from death registers maintained in Antananarivo. Causes of death were coded in ICD-9 and mapped to cause categories from the Global Burden of Disease 2016 Study (GBD). The performance of the notification system was assessed based on the Vital Statistics Performance Index, including six dimensions: completeness of death registration, quality of cause of death reporting, quality of age and sex reporting, internal consistency, level of cause-specific detail, and data availability and timeliness. We redistributed garbage codes and compared cause-specific mortality fractions in death records and estimates from the GBD with concordance correlation coefficients.ResultsThe death notification system in Antananarivo performed well on most dimensions, although 31% of all deaths registered over the period 1976–2015 were assigned to ICD codes considered as “major garbage codes” in the GBD 2016. The completeness of death notification, estimated with indirect demographic techniques, was higher than 90% in the period 1975–1993, and recent under-five mortality rates were consistent with estimates from Demographic and Health Surveys referring to the capital city. After redistributing garbage codes, cause-specific mortality fractions derived from death notification data were consistent with GBD 2016 for the whole country in the 1990s, with concordance correlation coefficients higher than 90%. There were larger deviations in recent years, with concordance correlation coefficients in 2015 at 0.74 (95% CI 0.66–0.81) for men and 0.81 (95% CI 0.74–0.86) for women.ConclusionsDeath notification in Antananarivo is a low-cost data source allowing real-time mortality monitoring, with a potential to improve disease burden estimates. Further efforts should be directed towards evaluating data quality in urban centers in Madagascar and other African countries to fill important data gaps on causes of death.

Ropeginterferon Alfa-2b versus Standard Therapy for Polycythaemia Vera; a Randomised, Controlled, Phase III Trial

Background: Ropeginterferon alfa-2b (ropeg) is a novel, mono-pegylated interferon (IFN) for treatment of polycythemia vera (PV). The PROUD-PV/CONTINUATION-PV trial compared ropeg with hydroxyurea (HU), the standard therapy for PV, over three years of treatment. Methods: This phase III, randomised, controlled, open-label trial was conducted in 48 clinics in Europe in patients aged =18 years, with early-stage PV (cytoreduction-naive or less than three years of prior HU treatment), diagnosed by WHO 2008 criteria. In the PROUD-PV part, patients were randomised 1:1 with block-stratification by prior HU treatment, age (=60 or >60 years) and history of thromboembolic events to receive ropeg (subcutaneously every two weeks, starting at 100 µg) or HU (orally starting at 500 mg/day). After one year, patients rolled over to the CONTINUATION-PV part. The primary endpoint was disease response rate at 3 monthly assessment visits from 12 months onwards. Composite evaluation criteria were applied: complete haematological response (CHR) with normalisation of spleen size (PROUD-PV/CONTINUATION-PV), and CHR with improved disease burden (signs and symptoms) (CONTINUATION-PV only). The trial was registered on EudraCT (2012-005259-18; 2014-001357-17). Findings: Recruitment took place from October 2013 to March 2015; 257 patients were randomised, three withdrew consent and 127 per arm were treated. Overall, 171 patients rolled over to the ongoing CONTINUATION-PV part. All patients treated were analysed for safety; the intent-to-treat population was analysed for efficacy. After three years of treatment, response rates were significantly higher in the ropeg arm compared to control for CHR (67/95 [70·5%] versus 38/74 [51·4%]; p=0·01) and CHR with improved disease burden (50/95 [52·6%] versus 28/74 [37·8%]; p=0·04). Only 27/254 patients had splenomegaly at baseline precluding meaningful assessment of spleen size normalisation. JAK2V617F allele burden at three years showed a sustained decline in the ropeg arm only (molecular response in ropeg arm: 62/94 [66·0%]; control: 20/74 [27·0%]; p<0·0001). Comparable numbers of patients experienced treatment-related adverse events (ropeg: 95/127 [74·8%]; control: 100/127 [78·7%]). One treatment-related death occurred in the control arm (acute leukaemia attributed to HU). Interpretation: These data demonstrate high and durable haematological and molecular responses with good tolerability under ropeginterferon alfa-2b, offering a valuable and safe long-term treatment option with features distinct from hydroxyurea. Trial Registration Number: The trial was registered on EudraCT (2012-005259-18; 2014-001357-17). Funding: AOP Orphan Pharmaceuticals AG. Declaration of Interest: HG reports grants and personal fees from AOP Orphan during the conduct of the study; grants and personal fees from Novartis and personal fees from PharmaEssentia, MyeloPro Diagnostics and Research, Janssen-Cilag, Roche, and Celgene, outside the submitted work. CK, KK, and BGI report that they were employees of AOP Orphan during the conduct of the study. JM reports grants from AOP Orphan during the conduct of the study. RK reports personal fees from AOP Orphan Pharmaceuticals and PharmaEssentia, during the conduct of the study; personal fees from Qiagen and Novartis and stock ownership in MyeloPro Diagnostics and Research, outside the submitted work. HH reports Data Monitoring Board honoraria from AOP Orphan during the conduct of the study; grants from Novartis outside the submitted work. JJK reports grants and personal fees from AOP Orphan during the conduct of the study; grants and personal fees from Novartis and personal fees from Celgene, outside the submitted work. The remaining authors have nothing to disclose. Ethical Approval: The trial was conducted in accordance with the Declaration of Helsinki and International Conference on Harmonization Good Clinical Practice Guidelines. The protocol was approved by the institutional review board or independent ethics committees at each participating site.

Protocol for a systematic literature review and network meta-analysis of the clinical benefit of inhaled maintenance therapies in chronic obstructive pulmonary disease

IntroductionChronic obstructive pulmonary disease (COPD) exacerbations progress the course of disease and impair lung function. Inhaled maintenance therapy reduces exacerbations. It is not yet established which inhaled therapy combination is...

Malignancy Risk and Recurrence with Psoriasis and its Treatments: A Concise Update.

Psoriasis is a common inflammatory cutaneous disease that affects approximately 120 million people worldwide. Systemic treatments have significantly improved disease burden, but concerns persist regarding their association with increased risk of malignancy. Patients with psoriasis have a slightly elevated baseline risk of lymphoproliferative diseases. Studies on methotrexate and cyclosporine, as well as older biological agents such as tumor necrosis factor inhibitors, have found no increased risk of non-cutaneous solid tumors; however, positive associations between cutaneous squamous cell carcinomas and certain therapies have been found. There is conflicting evidence regarding the risk of lymphoma and melanoma. Further studies are needed to determine the long-term safety of newer psoriasis treatments (interleukin [IL]-12/23, IL-17, Janus kinase 1/3, and phosphodiesterase-4 inhibitors), specifically their safety in patients with a history of cancer. This review summarizes the most recent studies on malignancy risk from psoriasis, and its treatments in patients and cancer survivors, with the highest available level of evidence.

Alcohol, Cannabis, and Opioid Use Disorders, and Disease Burden in an Integrated Health Care System.

We examined prevalence of major medical conditions and extent of disease burden among patients with and without substance use disorders (SUDs) in an integrated health care system serving 3.8 million members. Medical conditions and SUDs were extracted from electronic health records in 2010. Patients with SUDs (n = 45,461; alcohol, amphetamine, barbiturate, cocaine, hallucinogen, and opioid) and demographically matched patients without SUDs (n = 45,461) were compared on the prevalence of 19 major medical conditions. Disease burden was measured as a function of 10-year mortality risk using the Charlson Comorbidity Index. P-values were adjusted using Hochberg's correction for multiple-inference testing within each medical condition category. The most frequently diagnosed SUDs in 2010 were alcohol (57.6%), cannabis (14.9%), and opioid (12.9%). Patients with these SUDs had higher prevalence of major medical conditions than non-SUD patients (alcohol use disorders, 85.3% vs 55.3%; cannabis use disorders, 41.9% vs 23.0%; and opioid use disorders, 44.9% vs 26.1%; all P < 0.001). Patients with these SUDs also had higher disease burden than non-SUD patients; patients with opioid use disorders (M = 0.48; SE = 1.46) had particularly high disease burden (M = 0.23; SE = 0.09; P < 0.001). Common SUDs, particularly opioid use disorders, are associated with substantial disease burden for privately insured individuals without significant impediments to care. This signals the need to explore the full impact SUDs have on the course and outcome of prevalent conditions and initiate enhanced service engagement strategies to improve disease burden.