Tocilizumab Dose Tapering Based on a Model-Based Algorithm is Feasible in Clinical Practice: A Short Communication.

BACKGROUND: Tocilizumab in the treatment of rheumatoid arthritis (RA) is a potential candidate for concentration-guided tapering because the standard dose of tocilizumab results in a wide range of serum concentrations, usually above the presumed therapeutic window, and an exposure-response relationship has been described. However, no clinical trials have been published to date on this subject. Therefore, the objective of this study was to assess the feasibility of the tapering of intravenous (iv) tocilizumab with the use of a pharmacokinetic model-based algorithm in RA patients. METHODS: A randomized controlled trial with a double-blind design and follow-up of 24 weeks was conducted. RA patients who received the standard of tocilizumab for at least the past 24 weeks, which is 8 mg/kg every 4 weeks, were included. Patients with a tocilizumab serum concentration above 5 mg/L at trough were randomized between concentration-guided dose tapering, referred to as therapeutic drug monitoring (TDM), or the standard 8 mg/kg dose. In the TDM group, the tocilizumab dose was tapered with a recently published model-based algorithm to achieve a target concentration of 4-6 mg/L after 20 weeks of dose tapering. RESULTS: Twelve RA patients were included and 10 were randomized between the TDM and standard dose group. The study was feasible regarding the predefined feasibility criteria and patients had a positive attitude toward therapeutic drug monitoring. In the TDM group, the tocilizumab trough concentration within patients decreased on average by 24.5 ± 18.3 mg/L compared with a decrease of 2.8 ± 12 mg/L in the standard dose group. None of the patients in the TDM group reached the drug range of 4-6 mg/L. Instead, tocilizumab concentrations of 1.6 and 1.5 mg/L were found for the 2 patients who completed follow-up on the tapered dose. No differences in RA disease activity were observed between the 2 study groups. CONCLUSIONS: This study was the first to show that it is feasible to apply a dose-reduction algorithm based on a pharmacokinetic model in clinical practice. However, the current algorithm needs to be optimized before it can be applied on a larger scale.

Antibiotic prescriptions to children with periodic fever, aphthous stomatitis, pharyngitis and cervical adenitis.

AIM: To investigate the rate of dispensed antibiotic prescriptions to children and adolescents with PFAPA and compare this with the rate for children in the general population. Furthermore, to compare dispensed antibiotic prescription rates before and after a diagnosis of PFAPA was established. METHODS: Patients aged 0-17 years and diagnosed with PFAPA between 1 January 2006 to 31 October 2017 were included retrospectively. Data on dispensed drug prescriptions were obtained from the Swedish National Prescribed Drug Register. RESULTS: The PFAPA cohort received more antibiotic prescriptions than the general population in all but one of the age groups and time periods that were analysed. The largest difference was seen in 2014-2017 in the youngest age group (0-4 years) when children with PFAPA received 1218 antibiotic prescriptions per 1000 person years compared to 345 in the general population (IRR 3.5; 95% CI 2.8-4.4). The yearly number of antibiotic prescriptions to PFAPA patients was reduced from 2.1 before diagnosis to 0.8 after diagnosis, a reduction of 62%. CONCLUSION: This study shows higher rates of dispensed antibiotic prescriptions for children with PFAPA than in the general population. The reduction of prescriptions after an established PFAPA diagnosis indicates that antibiotics were previously incorrectly prescribed for PFAPA episodes.

From farm to table: exploring food handling and hygiene practices of meat and milk value chain actors in Ethiopia.

Livestock value chains constitute a source of livelihood for meat and milk value chain actors in Ethiopia, from dairy farmers to other associated value chain actors such as milk traders, abattoir workers, public health officials, veterinarians, butcheries selling meats, milk cooperatives, artisanal milk processors, and transporters. The development of these livestock value chains, however, is constrained by poor food safety and quality, while consumers are also exposed to public health risks due to milk and meat value chain actors' food handling and hygiene practices.This study used Photovoice and participant observation to explore meat and milk value chain actors' food handling and hygiene practices in suburban areas of Addis Ababa and neighbouring Oromia in Ethiopia. The results of this study reveal that milk and meat value chain actors' food handling practices are not aligned with the recommended Ethiopian food safety and quality standards. Low compliance with food safety and quality standards reflected a combination of factors such as lack of incentives, poor road infrastructure and low enforcement of food safety standards.Participatory and visual research methods enable a researcher to collect context-aware data that can lead to the development of policies and intervention strategies that reflect local needs and priorities. The results of this study affirm the need to identify socially acceptable and economically viable policies and intervention strategies that are acceptable to all chain actors; and suggest there is an imperative to train milk and meat value chain actors on good hygiene handling practices, improve road infrastructure, and facilitate access equipment such as fridges and freezers that can contribute to maintaining food safety and quality.

Milk and meat consumption patterns and the potential risk of zoonotic disease transmission among urban and peri-urban dairy farmers in Ethiopia.

BACKGROUND: In the Ethiopian dairy farming system, prevalence of zoonotic diseases such as bovine tuberculosis (bTB) is high in the cattle population. This, combined with some risky milk and meat consumption habits, such as raw milk and uninspected raw meat consumption, poses a considerable risk of zoonotic disease transmission. A survey was conducted to investigate milk and meat consumption patterns, and the level of exposure to urban and peri-urban dairy-keeping households for risks of zoonotic disease transmission. METHODS: Data on milk and meat consumption behaviours and other socioeconomic and demographic variables were collected from 480 urban and peri-urban dairy farms randomly surveyed in major towns in Ethiopia (Mekele, Hawassa, and Gondar towns, Addis Ababa city, as well as five Oromia towns around Addis Ababa). Determinants of raw milk consumption associated with a number of demographic and socio-economic factors were analysed using a generalised ordered logistic model. RESULTS: The results indicated that about 20% the population consumed raw milk and their awareness about pasteurisation and its benefits were low. Location, gender of the household head, previous bTB testing of cattle on the farm, knowledge of zoonotic risks associated with raw milk consumption, household size, and per-capita milk consumption were found to be important determinants of the frequency of raw milk consumption. About 60% of the respondents were exposed to the risk of zoonotic diseases through their habit of frequently consuming raw meat. This was despite that over 90% of the respondents were aware of possible zoonotic risks of raw meat consumption. The determinants of raw meat consumption behaviours were associated with location, gender and age of the household head, household size, meat type preference, per-capita meat consumption, knowledge about disease transmission risks, and training on zoonoses. CONCLUSION: Creating awareness about the risk factors for zoonotic transmission of diseases through training and media campaigns, improving meat hygiene through better abattoir services, and inducing behavioural change around meat sourcing, raw meat and raw milk consumption, are all crucial to the successful prevention and control of the spread of zoonotic diseases, including bTB.

Population-based study of multisystem inflammatory syndrome associated with COVID-19 found that 36% of children had persistent symptoms.

AIM: Our aim was to describe the outcomes of multisystem inflammatory syndrome in children (MIS-C) associated with COVID-19. METHODS: This national, population-based, longitudinal, multicentre study used Swedish data that were prospectively collected between 1 December 2020 and 31 May 2021. All patients met the World Health Organization criteria for MIS-C. The outcomes 2 and 8 weeks after diagnosis are presented, and follow-up protocols are suggested. RESULTS: We identified 152 cases, and 133 (87%) participated. When followed up 2 weeks after MIS-C was diagnosed, 43% of the 119 patients had abnormal results, including complete blood cell counts, platelet counts, albumin levels, electrocardiograms and echocardiograms. After 8 weeks, 36% of 89 had an abnormal patient history, but clinical findings were uncommon. Echocardiogram results were abnormal in 5% of 67, and the most common complaint was fatigue. Older children and those who received intensive care were more likely to report symptoms and have abnormal cardiac results. CONCLUSION: More than a third (36%) of the patients had persistent symptoms 8 weeks after MIS-C, and 5% had abnormal echocardiograms. Older age and higher levels of initial care appeared to be risk factors. Structured follow-up visits are important after MIS-C.

Anti-tumour necrosis factor treatment for the prevention of ischaemic events in patients with deficiency of adenosine deaminase 2 (DADA2).

OBJECTIVE: To evaluate the impact of anti-Tumour Necrosis Factor-α (anti-TNF) treatment on the occurrence of vasculitic ischaemic events in patients with deficiency of adenosine deaminase 2 (DADA2). METHODS: A retrospective analysis of DADA2 patients referred from six centres to Great Ormond Street Hospital for Children was conducted. Ischaemic events, vasculitic disease activity, biochemical, immunological, and radiological features were compared, before and after anti-TNF treatment. RESULTS: A total of 31 patients with genetically confirmed DADA2 were included in the study. The median duration of active disease activity prior to anti-TNF treatment was 73 months (inter-quartile range [IQR] 27.5-133.5 months). Twenty seven/31 patients received anti-TNF treatment for a median of 32 months (IQR 12.0-71.5 months). The median event rate of central nervous system (CNS) and non-CNS ischemic events before anti-TNF treatment was 2.37 per 100 patient-months (IQR 1.25-3.63); compared with 0.00 per 100 patient-months (IQR 0.0-0.0) post-treatment (p< 0.0001). Paediatric vasculitis activity score (PVAS) was also significantly reduced: median score of 20/63 (IQR 13.0-25.8/63) pre-treatment vs. 2/63 (IQR 0.0-3.8/63) following anti-TNF treatment (p< 0.0001), with mild livedoid rash being the main persisting feature. Anti-TNF treatment was not effective for severe immunodeficiency or bone marrow failure, which required haematopoietic stem cell transplantation (HSCT). CONCLUSION: Anti-TNF treatment significantly reduced the incidence of ischaemic events and other vasculitic manifestations of DADA2, but was not effective for immunodeficiency or bone marrow failure.

Genetic and phenotypic spectrum associated with IFIH1 gain-of-function.

IFIH1 gain-of-function has been reported as a cause of a type I interferonopathy encompassing a spectrum of autoinflammatory phenotypes including Aicardi-Goutières syndrome and Singleton Merten syndrome. Ascertaining patients through a European and North American collaboration, we set out to describe the molecular, clinical and interferon status of a cohort of individuals with pathogenic heterozygous mutations in IFIH1. We identified 74 individuals from 51 families segregating a total of 27 likely pathogenic mutations in IFIH1. Ten adult individuals, 13.5% of all mutation carriers, were clinically asymptomatic (with seven of these aged over 50 years). All mutations were associated with enhanced type I interferon signaling, including six variants (22%) which were predicted as benign according to multiple in silico pathogenicity programs. The identified mutations cluster close to the ATP binding region of the protein. These data confirm variable expression and nonpenetrance as important characteristics of the IFIH1 genotype, a consistent association with enhanced type I interferon signaling, and a common mutational mechanism involving increased RNA binding affinity or decreased efficiency of ATP hydrolysis and filament disassembly rate.

Network analysis of dairy cattle movement and associations with bovine tuberculosis spread and control in emerging dairy belts of Ethiopia.

BACKGROUND: Dairy cattle movement could be a major risk factor for the spread of bovine tuberculosis (BTB) in emerging dairy belts of Ethiopia. Dairy cattle may be moved between farms over long distances, and hence understanding the route and frequency of the movements is essential to establish the pattern of spread of BTB between farms, which could ultimately help to inform policy makers to design cost effective control strategies. The objective of this study was, therefore, to investigate the network structure of dairy cattle movement and its influence on the transmission and prevalence of BTB in three emerging areas among the Ethiopian dairy belts, namely the cities of Hawassa, Gondar and Mekelle. METHODS: A questionnaire survey was conducted in 278 farms to collect data on the pattern of dairy cattle movement for the last 5 years (September 2013 to August 2018). Visualization of the network structure and analysis of the relationship between the network patterns and the prevalence of BTB in these regions were made using social network analysis. RESULTS: The cattle movement network structure display both scale free and small world properties implying local clustering with fewer farms being highly connected, at higher risk of infection, with the potential to act as super spreaders of BTB if infected. Farms having a history of cattle movements onto the herds were more likely to be affected by BTB (OR: 2.2) compared to farms not having a link history. Euclidean distance between farms and the batch size of animals moved on were positively correlated with prevalence of BTB. On the other hand, farms having one or more outgoing cattle showed a decrease on the likelihood of BTB infection (OR = 0.57) compared to farms which maintained their cattle. CONCLUSION: This study showed that the patterns of cattle movement and size of animal moved between farms contributed to the potential for BTB transmission. The few farms with the bulk of transmission potential could be efficiently targeted by control measures aimed at reducing the spread of BTB. The network structure described can also provide the starting point to build and estimate dynamic transmission models for BTB, and other infectious diseases.

Brucellosis in the Addis Ababa dairy cattle: the myths and the realities.

BACKGROUND: Bovine brucellosis is considered as an important disease among livestock and people in sub-Saharan African countries including Ethiopia. A cross-sectional study was conducted from November 2016 to May 2017 to estimate the prevalence and associated risk factors, and to assess knowledge-attitude and practices (KAP) of farm workers about bovine brucellosis in Addis Ababa dairy farms. RESULTS: A total of 1550 cattle from 127 dairy farms were serially tested using the Rose Bengal Plate Test (RBPT), Competitive Enzyme-Linked Immunosorbant Assay (c-ELISA) and Complement Fixation Test (CFT). Forty-three (2.77%) of the collected sera were positive by the RBPT and only one of these was positive by c-ELISA (0.06%) and none was positive by CFT. The knowledge of farm workers towards the disease was very low and risk factors associated with Brucella infection were apparent in the study area. CONCLUSION: Seropositivity for Brucella spp. was found in only a very small percentage by c-ELISA test, although risk factors for transmitting Brucella infection were present. The results suggest that bovine brucellosis is currently not a generalized problem in dairy cattle of Addis Ababa. Since this favorable disease situation is not the result of informed policy, there is no guarantee that it will continue unchanged. Setting clear policy in control of the disease and implementing "One Health" are the most constructive approaches recommended.

Neutrophils from patients with SAPHO syndrome show no signs of aberrant NADPH oxidase-dependent production of intracellular reactive oxygen species.

OBJECTIVE: We aimed to investigate if aberrant intracellular production of NADPH oxidase-derived reactive oxygen species (ROS) in neutrophils is a disease mechanism in the autoinflammatory disease SAPHO syndrome, characterized by synovitis, acne, pustulosis, hyperostosis and osteitis, as has previously been suggested based on a family with SAPHO syndrome-like disease. METHODS: Neutrophil function was explored in a cohort of four patients with SAPHO syndrome, two of whom were sampled during both inflammatory and non-inflammatory phase. Intracellular neutrophil ROS production was determined by luminol-amplified chemiluminescence in response to phorbol myristate acetate. RESULTS: Cells from all patients produced normal amounts of ROS, both intra- and extracellularly, when compared with internal controls as well as with a large collection of healthy controls assayed in the laboratory over time (showing an extensive inter-personal variability in a normal population). Further, intracellular production of ROS increased during the inflammatory phase. Neutrophil activation markers were comparable between patients and controls. CONCLUSION: Dysfunctional generation of intracellular ROS in neutrophils is not a generalizable feature in SAPHO syndrome. Secondly, serum amyloid A appears to be a more sensitive inflammatory marker than CRP during improvement and relapses in SAPHO syndrome.

Epidemiology of invasive pneumococcal infections: manifestations, incidence and case fatality rate correlated to age, gender and risk factors.

BACKGROUND: Incidence, manifestations and case-fatality rate (CFR) of invasive pneumococcal disease (IPD) vary with age and comorbidities. New vaccines, changing age distribution, prolonged survival among immunocompromised patients and improved sepsis management have created a need for an update of basic facts to inform vaccine recommendations. METHODS: Age, gender and comorbidities were related to manifestations and death for 2977 consecutive patients with IPD in a Swedish region with 1.5 million inhabitants during 13 years before introduction of pneumococcal conjugate vaccines (PCV) in the infant vaccination program. These data were related to population statistics and prevalence of several comorbidities, and compared with two previous studies giving a total follow-up of 45 years in the same area. RESULTS: The annual incidence was 15/100,000 for any IPD and 1.1/100,000 for meningitis; highest among elderly followed by children < 2 years. It was 2238/100,000 among myeloma patients, followed by chronic lymphatic leukemia, hemodialysis and lung cancer, but not elevated among asthma patients. CFR was 10 % among all patients, varying from 3 % below 18 years to 22 % ≥ 80 years. During 45 years, the IPD incidence increased threefold and CFR dropped from 20 to 10 %. Meningitis incidence remained stable (1.1/100,000/year) but CFR dropped from 33 to 13 %. IPD-specific mortality decreased among children <2 years from 3.1 to 0.46/100,000/year but tripled among those ≥65 years. CONCLUSIONS: IPD incidence and CFR vary widely between age and risk groups and over time even without general infant vaccination. Knowledge about specific epidemiological characteristics is important for informing and evaluating vaccination policies.

Review of autoinflammatory diseases, with a special focus on periodic fever, aphthous stomatitis, pharyngitis and cervical adenitis syndrome.

UNLABELLED: There have been remarkable developments in the field of autoinflammatory diseases over the last 20 years. Research has led to definitions of new conditions, increased understanding of disease mechanisms and specific treatment. The polygenic autoinflammatory condition of periodic fever, aphthous stomatitis, pharyngitis and cervical adenitis (PFAPA) is the most common autoinflammatory disorder among children in many parts of the world. The clinical features often include clockwork regularity of episodes, prompt responses to corticosteroids and therapeutic effects of tonsillectomy, but the disease mechanisms are largely unknown. CONCLUSION: This review discusses the emerging understanding of autoinflammatory diseases, with special emphasis on PFAPA.

Revisiting the peripheral sink hypothesis: inhibiting BACE1 activity in the periphery does not alter ß-amyloid levels in the CNS.

Aggregation of amyloid beta (Aß) peptides and the subsequent neural plaque formation is a central aspect of Alzheimer's disease. Various strategies to reduce Aß load in the brain are therefore intensely pursued. It has been hypothesized that reducing Aß peptides in the periphery, that is in organs outside the brain, would be a way to diminish Aß levels and plaque load in the brain. In this report, we put this peripheral sink hypothesis to test by investigating how selective inhibition of Aß production in the periphery using a ß-secretase (BACE)1 inhibitor or reduced BACE1 gene dosage affects Aß load in the brain. Selective inhibition of peripheral BACE1 activity in wild-type mice or mice over-expressing amyloid precursor protein (APPswe transgenic mice; Tg2576) reduced Aß levels in the periphery but not in the brain, not even after chronic treatment over several months. In contrast, a BACE1 inhibitor with improved brain disposition reduced Aß levels in both brain and periphery already after acute dosing. Mice heterozygous for BACE1, displayed a 62% reduction in plasma Aß40, whereas brain Aß40 was only lowered by 11%. These data suggest that reduction of Aß in the periphery is not sufficient to reduce brain Aß levels and that BACE1 is not the rate-limiting enzyme for Aß processing in the brain. This provides evidence against the peripheral sink hypothesis and suggests that a decrease in Aß via BACE1 inhibition would need to be carried out in the brain. Aggregation of amyloid beta (Aß) peptides in the brain is a central aspect of Alzheimer's disease. In this study, we demonstrate that inhibition of Aß formation by BACE1 inhibitors needs to be carried out in the brain and that reduction of Aß in the periphery is not sufficient to reduce brain Aß levels. This information is useful for developing future Aß-targeting therapies for Alzheimer's disease.

Marked variability in clinical presentation and outcome of patients with C1q immunodeficiency.

OBJECTIVE: Globally approximately 60 cases of C1q deficiency have been described with a high prevalence of Systemic Lupus Erythematosus (SLE). So far treatment has been guided by the clinical presentation rather than the underlying C1q deficiency. Recently, it was shown that C1q production can be restored by allogeneic hematopoietic stem cell transplantation. Current literature lacks information on disease progression and quality of life of C1q deficient persons which is of major importance to guide clinicians taking care of patients with this rare disease. METHODS: We performed an international survey, of clinicians treating C1q deficient patients. A high response rate of >70% of the contacted clinicians yielded information on 45 patients with C1q deficiency of which 25 are published. RESULTS: Follow-up data of 45 patients from 31 families was obtained for a median of 11 years after diagnosis. Of these patients 36 (80%) suffer from SLE, of which 16 suffer from SLE and infections, 5 (11%) suffer from infections only and 4 (9%) have no symptoms. In total 9 (20%) of the C1q deficient individuals had died. All except for one died before the age of 20 years. Estimated survival times suggest 20% case-fatality before the age of 20, and at least 50% of patients are expected to reach their middle ages. CONCLUSION: Here we report the largest phenotypic data set on C1q deficiency to date, revealing high variance; with high mortality but also a subset of patients with an excellent prognosis. Management of C1q deficiency requires a personalized approach.

Serotypes of group B streptococci in western Sweden and comparison with serotypes in two previous studies starting from 1988.

BACKGROUND: Group B Streptococci (GBS) are the most common neonatal pathogens and infect immunocompromised and elderly individuals. The species has 10 different serotypes. Serotypes have been studied in the south-west area of Sweden in 1988-1997 and 1998-2001. The aim of this study was to study serotypes in the same area from 2004 to 2009. METHODS: Invasive GBS isolates were collected prospectively from 2004 to 2009 in two counties in western Sweden with a population of 1.8 million, and were serotyped by latex agglutination. Clinical data were obtained from hospital records. During the study period 410 invasive GBS isolates from 398 patients were collected (multiple episodes ≥ 1 month apart). Clinical data were not available for two patients who are excluded. Four isolates were from stillborn neonates, 88 were from live born neonates and infants, and 318 from adults. RESULTS: Serotype III was the most common serotype (48%) in neonates and infants followed by serotypes Ia (18%) and V (16%). In adults serotype V (39%) dominated followed by serotypes III (20%) and Ib (14%). There was a significant increase of serotype V in comparison with the first study (1988-1997) but there were no significant changes in the serotype distribution between the present study and the second study (1998-2001). There were a few cases of serotype VI-IX, both in children and adults, not seen in the previous studies. Serotype V was more common among patients with arthritis than with any other manifestation. CONCLUSIONS: Changes in GBS serotypes occur over time in the same region, which must be considered when GBS vaccines are formulated.

Investigation of the high rates of extrapulmonary tuberculosis in Ethiopia reveals no single driving factor and minimal evidence for zoonotic transmission of Mycobacterium bovis infection.

BACKGROUND: Ethiopia, a high tuberculosis (TB) burden country, reports one of the highest incidence rates of extra-pulmonary TB dominated by cervical lymphadenitis (TBLN). Infection with Mycobacterium bovis has previously been excluded as the main reason for the high rate of extrapulmonary TB in Ethiopia. METHODS: Here we examined demographic and clinical characteristics of 953 pulmonary (PTB) and 1198 TBLN patients visiting 11 health facilities in distinct geographic areas of Ethiopia. Clinical characteristics were also correlated with genotypes of the causative agent, Mycobacterium tuberculosis. RESULTS: No major patient or bacterial strain factor could be identified as being responsible for the high rate of TBLN, and there was no association with HIV infection. However, analysis of the demographic data of involved patients showed that having regular and direct contact with live animals was more associated with TBLN than with PTB, although no M. bovis was isolated from patients with TBLN. Among PTB patients, those infected with Lineage 4 reported "contact with other TB patient" more often than patients infected with Lineage 3 did (OR = 1.6, CI 95% 1.0-2.7; p = 0.064). High fever, in contrast to low and moderate fever, was significantly associated with Lineage 4 (OR = 2.3; p = 0.024). On the other hand, TBLN cases infected with Lineage 4 tended to get milder symptoms overall for the constitutional symptoms than those infected with Lineage 3. CONCLUSIONS: The study suggests a complex role for multiple interacting factors in the epidemiology of extrapulmonary TB in Ethiopia, including factors that can only be derived from population-based studies, which may prove to be significant for TB control in Ethiopia.

Clinical manifestations of invasive pneumococcal disease by vaccine and non-vaccine types.

Pneumococcal conjugated vaccines (PCVs) have shown protection against invasive pneumococcal disease by vaccine serotypes, but an increase in non-vaccine serotype disease has been observed. Type-specific effects on clinical manifestation need to be explored. Clinical data from 2096 adults and 192 children with invasive pneumococcal disease were correlated to pneumococcal molecular serotypes. Invasive disease potential for pneumococcal serotypes were calculated using 165 invasive and 550 carriage isolates from children. The invasive disease potential was lower for non-PCV13 compared to vaccine-type strains. Patients infected with non-PCV13 strains had more underlying diseases, were less likely to have pneumonia and, in adults, tended to have a higher mortality. Furthermore, patients infected with pneumococci belonging to clonal serotypes only expressing non-PCV13 capsules had a higher risk for septicaemia and mortality. PCV vaccination will probably lead to a decrease in invasive pneumococcal disease but an alteration in the clinical manifestation of invasive pneumococcal disease. Genetic lineages causing invasive pneumococcal disease in adults often express non-vaccine serotypes, which can expand after vaccination with an increased risk of infection in patients with underlying diseases.

International periodic fever, aphthous stomatitis, pharyngitis, cervical adenitis syndrome cohort: description of distinct phenotypes in 301 patients.

OBJECTIVES: The aims of this study were to describe the clinical features of periodic fever, aphthous stomatitis, pharyngitis and cervical adenitis (PFAPA) and identify distinct phenotypes in a large cohort of patients from different countries. METHODS: We established a web-based multicentre cohort through an international collaboration within the periodic fevers working party of the Pediatric Rheumatology European Society (PReS). The inclusion criterion was a diagnosis of PFAPA given by an experienced paediatric rheumatologist participating in an international working group on periodic fever syndromes. RESULTS: Of the 301 patients included from the 15 centres, 271 had pharyngitis, 236 cervical adenitis, 171 oral aphthosis and 132 with all three clinical features. A total of 228 patients presented with additional symptoms (131 gastrointestinal symptoms, 86 arthralgias and/or myalgias, 36 skin rashes, 8 neurological symptoms). Thirty-one patients had disease onset after 5 years and they reported more additional symptoms. A positive family history for recurrent fever or recurrent tonsillitis was found in 81 patients (26.9%). Genetic testing for monogenic periodic fever syndromes was performed on 111 patients, who reported fewer occurrences of oral aphthosis or additional symptoms. Twenty-four patients reported symptoms (oral aphthosis and malaise) outside the flares. The CRP was >50 mg/l in the majority (131/190) of the patients tested during the fever. CONCLUSION: We describe the largest cohort of PFAPA patients presented so far. We confirm that PFAPA may present with varied clinical manifestations and we show the limitations of the commonly used diagnostic criteria. Based on detailed analysis of this cohort, a consensus definition of PFAPA with better-defined criteria should be proposed.

Population PKPD modeling of BACE1 inhibitor-induced reduction in Aß levels in vivo and correlation to in vitro potency in primary cortical neurons from mouse and guinea pig.

PURPOSE: The aims were to quantify the in vivo time-course between the oral dose, the plasma and brain exposure and the inhibitory effect on Amyloid ß (Aß) in brain and cerebrospinal fluid, and to establish the correlation between in vitro and in vivo potency of novel ß-secretase (BACE1) inhibitors. METHODS: BACE1-mediated inhibition of Aß was quantified in in vivo dose- and/or time-response studies and in vitro in SH-SY5Y cells, N2A cells, and primary cortical neurons (PCN). An indirect response model with inhibition on Aß production rate was used to estimate unbound in vivo IC 50 in a population pharmacokinetic-pharmacodynamic modeling approach. RESULTS: Estimated in vivo inhibitory potencies varied between 1 and 1,000 nM. The turnover half-life of Aß40 in brain was predicted to be 0.5 h in mouse and 1 h in guinea pig. An excellent correlation between PCN and in vivo potency was observed. Moreover, a strong correlation in potency was found between human SH-SY5Y cells and mouse PCN, being 4.5-fold larger in SH-SY5Y cells. CONCLUSION: The strong in vivo-in vitro correlation increased the confidence in using human cell lines for screening and optimization of BACE1 inhibitors. This can optimize the design and reduce the number of preclinical in vivo effect studies.