Ischaemic manifestations in giant cell arteritis are associated with area level socio-economic deprivation, but not cardiovascular risk factors.

OBJECTIVES: To determine whether ischaemic manifestations of GCA are associated with pre-existing hypertension, atherosclerosis or area-level socio-economic deprivation. METHODS: We conducted an observational study of rheumatologist/ophthalmologist-diagnosed GCA in eight UK centres. The main outcome measure was ischaemic manifestations observed during active GCA: visual loss/blurring, aura, diplopia, jaw/tongue/limb claudication, cerebral/myocardial ischaemia or scalp necrosis. RESULTS: Out of 271 patients, 222 had ischaemic manifestations. Adjusted odds ratios (ORs) for the influence of hypertension and atherosclerosis were 1.6 (95% CI 0.8, 3.1) and 1.5 (0.6, 3.5). The most striking finding was an association of ischaemic manifestations with increasing Index of Deprivation 2007 score: OR 4.2 (95% CI 1.3, 13.6) for the most-deprived quartile compared with the least-deprived quartile. Similar effect sizes were seen within each recruitment centre. Deprivation was associated with smoking and negatively associated with previous polymyalgia. However, neither of these variables, nor hypertension or atherosclerosis, appeared responsible for mediating the effect of deprivation on ischaemic complications. Smoking was not associated with ischaemic manifestations. Median symptom duration before treatment was 30 days; after adjusting for symptom duration, the OR for ischaemic complications was 3.2 (95% CI 1.0, 10.8) for the most-deprived quartile compared with the least-deprived quartile. CONCLUSIONS: In GCA, area-level socio-economic deprivation was associated with ischaemic manifestations: this was not mediated by traditional cardiovascular risk factors. These findings are novel and require replication. Delay between first symptoms and treatment may play a role. Public awareness campaigns about GCA should aim especially to engage individuals living in more deprived areas to encourage early presentation and prompt treatment.

Vaccines for a healthy future: 21st DCVMN Annual General Meeting 2020 report.

The Developing Countries Vaccine Manufacturers' Network held its 21st Annual General Meeting virtually in November 2020 given the COVID-19 pandemic. Vaccine manufacturing experts, leaders from local and global public health organizations and multilateral organizations, through diverse presentations, questions and answers, focused on the pandemic and the response of vaccine manufacturers where many are engaged in research and development and production agreements. The pandemic is expanding rapidly which makes the global availability and equitable access to safe and effective COVID-19 vaccines critical. Strategies put in place include the establishment of the Access to COVID-19 Tools Accelerator (ACT-A) within which the COVAX facility aims to distribute 2 billion COVID-19 vaccine doses by the end of 2021, with procurement mechanisms already being established. At the same time, regulatory authorities have emergency use authorizations aimed at the rapid approval of safe and effective vaccines, with a push for harmonization in regulatory approaches being advocated. The Meeting was also apprised of other innovations being developed for vaccines including multi-array patches for easier vaccine application, increased heat stability for mitigating cold chain and storage challenges, the barcoding of primary packaging for enhancing vaccine traceability, and gathering data for decision-making. Over time, these innovations will facilitate the widespread availability and equitable access of vaccines including those addressing epidemics and pandemics. In addition, a number of manufacturers described technologies they have for accelerating vaccine manufacturing and supply globally. Overall, there was agreement that manufacturers from developing countries play a critical role in the global research, development and supply of vaccines for a healthy future, with increasing collaboration and partnering between them a growing strength.

The importance of vaccine stockpiling to respond to epidemics and remediate global supply shortages affecting immunization: strategic challenges and risks identified by manufacturers.

While stockpiling vaccines adds another layer of complexity to vaccine manufacturing, it constitutes a crucial component of comprehensive disease preparedness and control strategies in public health management. Stockpiling provides the ability to immediately respond to epidemics, disease outbreaks, vaccine shortages or stock-outs at local, regional or global levels. Some stockpiles are static, not shipped until an emergency occurs; other stockpiles are rotating with vaccines used in on-going routine immunization programmes. Programmatic use indicates which vaccines to stockpile, the nature of the stockpile and the amount of vaccine to be held at any time. For immediate shipment, fully released product must be stockpiled with the challenge of monitoring remaining shelf-life requirements and the potential risk of expiry. Existing stockpiles are managed and financed globally under the purview of international organizations in the global immunization community, except for buffer stocks held by manufacturers for short periods. The added challenges to manufacturers of stockpiling vaccines, including storage, human resources and other related costs including vaccine destruction when no longer useable, needs to be recognized. This is all the more so with the likelihood of vaccine stockpiling becoming more prominent with changing disease patterns due to climate change and population movements, as well as the significant investment in the research and development of new epidemic prevention vaccines. While vaccine stockpiles managed and financed globally provide rapid response to country requests, more attention is needed in the future to ways that vaccine stockpiling can be brought under the direct purview of individual countries or regional groupings.

Roadmap for strengthening the vaccine supply chain in emerging countries: Manufacturers' perspectives.

Manufacturers have a significant stake in the vaccine supply chain as their reputations rest on the effectiveness of their vaccines at the point of vaccination. The risks of low performing supply chains are detrimental for the safety and effectiveness of vaccines, with potential consequences to future supply in the case of adverse events. For this reason, a study was set up to explore the involvement of developing country manufacturers in the vaccine supply chain over the next decade to determine the areas where innovations could have a positive impact on the supply chain, focusing on the secondary stages of production where formulation, filling and packaging take place. An expert desk review identified eight areas of interest for the vaccine supply chain and informed the development of a survey to assess the relevance of the areas identified. The review also conjectured whether the overall effect of the identified areas is cost-neutral or resulting in net savings to countries. Overall, respondents identified five areas as of highest interest and subsequently an expert working group of representative manufacturers prioritized three of them. Specifically, traceability in the context of global digital health initiatives, stockpiling in the context of addressing vaccine shortages, stock-outs, outbreaks and epidemic prevention, and new packaging technologies are discussed in this report. It is important that vaccine manufacturers be actively engaged in global stakeholders' forums, as equal partners in determining the best ways for improving the vaccine supply chain.

The role of manufacturers in the implementation of global traceability standards in the supply chain to combat vaccine counterfeiting and enhance safety monitoring.

The counterfeiting of vaccines is an increasing problem globally with the safety of persons vaccinated, the trust in vaccines generally and the associated reputation of vaccine manufacturers and regulatory agencies at risk. This risk is especially critical with the on-going development of COVID-19 vaccines. The ability to track and trace vaccines through the vaccine supply chain down to persons vaccinated has to be enhanced. In this context of traceability, the global immunization community has recently set the barcoding of the primary packaging of vaccines, specifically vaccine vials and pre-filled syringes, as a top priority. Emerging vaccine manufacturers are already engaged in investigating ways to incorporate barcoding in their labelling and packaging using GS1 international standards. A specific pilot taking place in Indonesia by the national vaccine manufacturer, Bio Farma, shows the innovation of barcoding on primary packaging already underway with a relatively modest level of investment and success at this stage. This article highlights the efforts of industry and governments on the value of traceability and introduction to 2D barcodes. Access to financial resources and support from the international immunization community would accelerate such innovations leading to enhanced security of the vaccine supply chain.

Emerging manufacturers engagements in the COVID -19 vaccine research, development and supply.

The World Health Organization declared the COVID-19 disease as a pandemic requiring a rapid response. Through online search, direct communication with network members and an internal survey, engagements of developing countries' vaccine manufacturers' network members in the research and development of COVID-19 vaccines and their capacities in the manufacturing, fill-finish and distribution of vaccines were assessed. Currently, 19 network members engaged in research and development of COVID-19 vaccines, using six principal technology platforms. In addition, an internal survey showed that the number of vaccines supplied collectively by 37 members, in 2018-19, was about 3.5 billion doses annually. Almost a third of network members having vaccines prequalified by the World Health Organization comply with international regulations and mechanisms to distribute vaccines across borders. The use of existing manufacturing, fill-finish and distribution capabilities can support an efficient roll-out of vaccines against COVID-19, while maintaining supply security of existing vaccines for on-going immunization programmes.

Anakinra as a diagnostic challenge and treatment option for systemic autoinflammatory disorders of undefined etiology.

BACKGROUND: Some adult patients presenting with unexplained pyrexia, serositis, skin rashes, arthralgia, myalgia, and other symptoms commonly found in autoinflammatory disorders may not fit a specific diagnosis, either because their clinical phenotype is nondiagnostic or genetic tests are negative. We used the term undifferentiated systemic autoinflammatory disorder (uSAID) to describe such cases. Given that well-defined autoinflammatory diseases show responses to IL-1 blockade, we evaluated whether anakinra was useful for both diagnosing and treating uSAID patients. METHODS: We performed a retrospective analysis of consecutive patients presenting with uSAID between 2012-2015 who were treated with the recombinant IL-1 receptor antagonist anakinra. uSAID was diagnosed after excluding malignancy, infection, and pathogenic mutations in known hereditary fever syndromes (HFS) genes and where clinical criteria for adult onset Still's disease (AOSD) were not met. RESULTS: A total of 11 patients presented with uSAID (5 males and 6 females), with a mean time to diagnosis of 3.5 years (1-8 years). Patients were unresponsive or only partially controlled on disease-modifying antirheumatic drug (DMARD)/steroid treatment. Anakinra controlled symptoms within 4-6 weeks of starting treatment in 9 of 11 cases. Two patients discontinued therapy - one due to incomplete response and another due to severe injection-site reactions. CONCLUSION: This retrospective case series demonstrates that the spectrum of poorly defined autoinflammatory disorders that show responsiveness to anakinra is considerable. Anakinra seems a viable treatment option for these patients, who are unresponsive to standard steroid/DMARD treatments. Moreover, given the mechanisms of action, response to anakinra implicates underlying IL-1 dysregulation in the disease pathogenesis of responding uSAIDs patients.

Association of HLA-DRB1 amino acid residues with giant cell arteritis: genetic association study, meta-analysis and geo-epidemiological investigation.

INTRODUCTION: Giant cell arteritis (GCA) is an autoimmune disease commonest in Northern Europe and Scandinavia. Previous studies report various associations with HLA-DRB1*04 and HLA-DRB1*01; HLA-DRB1 alleles show a gradient in population prevalence within Europe. Our aims were (1) to determine which amino acid residues within HLA-DRB1 best explained HLA-DRB1 allele susceptibility and protective effects in GCA, seen in UK data combined in meta-analysis with previously published data, and (2) to determine whether the incidence of GCA in different countries is associated with the population prevalence of the HLA-DRB1 alleles that we identified in our meta-analysis. METHODS: GCA patients from the UK GCA Consortium were genotyped by using single-strand oligonucleotide polymerization, allele-specific polymerase chain reaction, and direct sequencing. Meta-analysis was used to compare and combine our results with published data, and public databases were used to identify amino acid residues that may explain observed susceptibility/protective effects. Finally, we determined the relationship of HLA-DRB1*04 population carrier frequency and latitude to GCA incidence reported in different countries. RESULTS: In our UK data (225 cases and 1378 controls), HLA-DRB1*04 carriage was associated with GCA susceptibility (odds ratio (OR) = 2.69, P = 1.5×10(-11)), but HLA-DRB1*01 was protective (adjusted OR = 0.55, P = 0.0046). In meta-analysis combined with 14 published studies (an additional 691 cases and 4038 controls), protective effects were seen from HLA-DR2, which comprises HLA-DRB1*15 and HLA-DRB1*16 (OR = 0.65, P = 8.2×10(-6)) and possibly from HLA-DRB1*01 (OR = 0.73, P = 0.037). GCA incidence (n = 17 countries) was associated with population HLA-DRB1*04 allele frequency (P = 0.008; adjusted R(2) = 0.51 on univariable analysis, adjusted R(2) = 0.62 after also including latitude); latitude also made an independent contribution. CONCLUSIONS: We confirm that HLA-DRB1*04 is a GCA susceptibility allele. The susceptibility data are best explained by amino acid risk residues V, H, and H at positions 11, 13, and 33, contrary to previous suggestions of amino acids in the second hypervariable region. Worldwide, GCA incidence was independently associated both with population frequency of HLA-DRB1*04 and with latitude itself. We conclude that variation in population HLA-DRB1*04 frequency may partly explain variations in GCA incidence and that HLA-DRB1*04 may warrant investigation as a potential prognostic or predictive biomarker.

Improving basic health service delivery in low-income countries: 'voice' to the poor.

Public social services, such as basic health care, represent the effective option for the poor, especially in the rural areas of low-income countries. The quality of such services are at present extremely deficient, largely due to resource constraints and lack of political will to make them function effectively. The state can no longer provide the comprehensive services it has in the past and which were highly successful in a number of 'high-achieving' developing countries. Yet, the state must turn priority attention to providing public services for the poor, in order to close the widening gap between rich and poor. It needs to do this in partnership with the population it aims to reach, through effective linkage with grass-roots organizations and with the support of non-governmental organizations. Giving 'voice' and participation to the population can not only increase the resource base for public services, but can also significantly improve the accountability of providers and lead to a cost-effective option for the poor.

Renal cell carcinoma-associated adult dermatomyositis treated laparoscopic nephrectomy.

A 77-year-old female, who suffered from rheumatoid arthritis and hypothyroidism, developed severe muscle weakness. Clinical features, blood results and muscle biopsy suggested a possible diagnosis of dermatomyositis. A computed tomography of the chest, abdomen and pelvis showed a solid mass in the left kidney. She underwent a left laparoscopic nephrectomy and histology confirmed conventional (clear cell) renal cell carcinoma. She recovered slowly and almost back to normal life after 6 months. Early appreciation of the typical skin rash may provide a clue to the diagnosis and screening for neoplasm may improve prognosis.