Anterior uveitis in patients with spondyloarthritis treated with secukinumab or tumour necrosis factor inhibitors in routine care: does the choice of biological therapy matter?

BACKGROUND: The effect of interleukin 17-inhibitors on anterior uveitis (AU) in spondyloarthritis (SpA) is poorly understood. This study aimed to compare the risk of AU during treatment with secukinumab versus tumour necrosis factor inhibitors (TNFi). METHODS: Patients with SpA starting secukinumab or a TNFi 2015 through 2018 were identified in the Swedish Rheumatology Quality Register. Occurrence of AU was identified based on diagnosis codes in outpatient ophthalmology care in the National Patient Register. The main outcomes were crude rates of AU-diagnoses per 100 patient-years, and adjusted HRs for AU, during treatment, in patients without AU during the year before treatment start (in order to reduce confounding by indication). HRs were adjusted for age, sex, history of AU and patient global assessment of disease activity. RESULTS: Based on 4851 treatment starts (456 secukinumab; 4395 any TNFi), the rate of AU-diagnoses per 100 patient-years was 6.8 (95% CI 5.2 to 8.7) for secukinumab. Among the TNFi, the rate varied from 2.9 (95% CI 2.1 to 3.7) for infliximab and 4.0 (95% CI 3.3 to 4.9) for adalimumab to 7.5 (95% CI 6.7 to 8.4) for etanercept. The adjusted HRs for first AU (adalimumab as reference) were: secukinumab 2.32 (95% CI 1.16 to 4.63), infliximab 0.99 (95% CI 0.49 to 1.96), etanercept 1.82 (95% CI 1.13 to 2.93), golimumab 1.59 (95% CI 0.90 to 2.80) and certolizumab 1.12 (95% CI 0.44 to 2.83). Sensitivity analyses confirmed the pattern of higher AU rates with secukinumab and etanercept versus monoclonal TNFi. CONCLUSION: As used in clinical practice in SpA, secukinumab appears to be associated with a higher risk of AU, compared with the monoclonal TNFi and a similar risk compared with etanercept.

Incidence of extra-articular manifestations in ankylosing spondylitis, psoriatic arthritis and undifferentiated spondyloarthritis: results from a national register-based cohort study.

OBJECTIVES: To estimate the incidence and strength of association of extra-articular manifestations [EAMs, here: anterior uveitis (AU), IBD and psoriasis] in patients with AS, undifferentiated SpA (uSpA) and PsA, compared with controls. METHODS: Three mutually exclusive cohorts of patients aged 18-69 years with AS (n = 8517), uSpA (n = 10 245) and PsA (n = 22 667) were identified in the Swedish National Patient Register 2001-2015. Age-, sex- and geography-matched controls were identified from the Swedish Population Register. Follow-up began 1 January 2006, or six months after the first SpA diagnosis, whichever occurred later, and ended at the first date of the EAM under study, death, emigration, 70 years of age, and 31 December 2016. Incidence rates (IRs) and incidence rate ratios were calculated for each EAM, and stratified by sex and age. RESULTS: Incidence rate ratios for incident AU, IBD and psoriasis were significantly increased in AS (20.2, 6.2, 2.5), uSpA (13.6, 5.7, 3.8) and PsA (2.5, 2.3, n.a) vs controls. Men with AS and uSpA had significantly higher IRs per 1000 person-years at risk for incident AU than women with AS (IR 15.8 vs 11.2) and uSpA (IR 10.1 vs 6.0), whereas no such sex difference was demonstrated in PsA or for the other EAMs. CONCLUSIONS: AU, followed by IBD and psoriasis, is the EAM most strongly associated with AS and uSpA. Among the SpA subtypes, AS and uSpA display a largely similar pattern of EAMs, whereas PsA has a considerably weaker association with AU and IBD.

Patient characteristics influence the choice of biological drug in RA, and will make non-TNFi biologics appear more harmful than TNFi biologics.

OBJECTIVES: With the wide range of biological disease-modifying anti-rheumatic drugs (bDMARDs) available for treating rheumatoid arthritis (RA), and limited evidence to guide the choice for individual patients, we wished to evaluate whether patient characteristics influence the choice of bDMARD in clinical practice, and to quantify the extent to which this would bias direct comparisons of treatment outcome. METHODS: Register-based study of all Swedish patients with RA initiating necrosis factor inhibitor (TNFi), rituximab, abatacept or tocilizumab in 2011-2015 as their first bDMARD (n=6481), or after switch from TNFi as first bDMARD (n=2829). Group differences in demographics, clinical characteristics and medical history were assessed in multivariable regression models. Predicted differences in safety and treatment outcomes were calculated as a function of patient characteristics, through regression modelling based on observed outcomes among patients with RA starting bDMARDs 2006-2010. RESULTS: Patients starting non-TNFi were older than those starting TNFi, had lower socioeconomic status, higher disease activity and higher burden of diseases including malignancy, serious infections and diabetes. Differences were most pronounced at first bDMARD initiation. These factors were linked to treatment outcome independent of therapy, yielding worse apparent safety and effectiveness for non-TNFi biologics, most extreme for rituximab. Standardising to the age/sex distribution of the TNFi group reduced differences considerably. CONCLUSIONS: There was significant channelling of older and less healthy patients with RA to non-TNFi bDMARDs, in particular as first bDMARD. Whether this channelling represents a maximised benefit/risk ratio is unclear. Unless differences in age, medical history and disease activity are accounted for, they will substantially confound non-randomised comparative studies of available bDMARDs' safety and effectiveness.

Risk of cardiac rhythm disturbances and aortic regurgitation in different spondyloarthritis subtypes in comparison with general population: a register-based study from Sweden.

OBJECTIVES: To describe the incidence of atrioventricular (AV) block II-III, atrial fibrillation (AF), pacemaker implantation (PM) and aortic regurgitation in patients with ankylosing spondylitis (AS), undifferentiated spondyloarthritis (uSpA) and psoriatic arthritis (PsA) compared with the general population (GP) and with each other. METHODS: A prospective nationwide study with cohorts of patients with AS (n=6448), PsA (n=16 063) and uSpA (n=5190) and a GP (n=2 66 435) cohort, identified in 2001-2009 in the Swedish National Patient and Population registers. Follow-up began on 1 January 2006 and ended at event, death, emigration or 31 December 2012. Age-standardised and sex-standardised incidence rates and hazard ratios (HRs) were calculated. RESULTS: The highest incidence rates were noted for AF (5.5-7.4 events per 1000 person-years), followed by PM (1.0-2.0 events per 1000 person-years). HRs for AV block, AF, PM and aortic regurgitation were significantly increased in AS (HRs 2.3, 1.3, 2.1 and 1.9), uSpA (HRs 2.9, 1.3, 1.9 and 2.0) and PsA (HRs 1.5, 1.5, 1.6 and 1.8) compared with the GP cohort. The highest HRs were seen for AV block in male uSpA (HR 4.2) and AS (HR 2.5) compared with GP. Compared with PsA, significantly increased HRs were noted for PM (HR 1.5) in AS and for AV block (HR 1.8) in uSpA. CONCLUSIONS: Patients with SpA are at increased risk of aortic regurgitation, cardiac rhythm disturbances and, as a probable consequence, also PM. Particularly for AF, the most common arrhythmia, increased caution is warranted, whereas AV block should be looked for especially in men with AS or uSpA.

Is ankylosing spondylitis a risk factor for cardiovascular disease, and how do these risks compare with those in rheumatoid arthritis?

AIMS: To assess and compare the incidence of cardiovascular (CV) events, by CV phenotype, between patients with ankylosing spondylitis (AS), rheumatoid arthritis (RA) and the general population. METHODS: Using linkages of national and population-based registers, we identified one cohort of prevalent patients with AS (n=5358), one with RA (n=37 245) and one with matched general population subjects (n=25 006). These cohorts were identified in 2006 through 2011 and were followed in 31 December 2012, for first ever occurrence of acute coronary syndromes (ACS), deep venous thromboembolism, pulmonary embolism and stroke, respectively. For each outcome, we calculated incidence rates standardised to the age and sex distribution of the AS cohort, as well as relative risks using Cox proportional hazards models. RESULTS: Based on 69 ACS events during 20 251 person-years of follow-up of the patients with AS, and 966 events during 127 014 person-years in the RA cohort, the age/sex-adjusted relative risks for ACS compared with the general population was 1.3 (95% CI 1.0 to 1.7) for AS and 1.7 (1.4 to 2.0) for RA. For thromboembolic events, the corresponding risks were 1.4 (1.1 to 1.9) in AS and 1.8 (1.5 to 2.1) in RA. Finally, for stroke, the relative risks were 1.5 (1.1 to 2.0) in AS and 1.5 (1.2 to 1.8) in RA, compared with the general population. CONCLUSIONS: Prevalent patients with AS are at a 30%-50% increased risk of incident CV events. When compared with patients with RA, this level of increase was similar for stroke, but only half as high for ACS and thrombotic events.

Innate immune responses induced by the saponin adjuvant Matrix-M in specific pathogen free pigs.

Saponin-based adjuvants have been widely used to enhance humoral and cellular immune responses in many species, but their mode of action is not fully understood. A characterization of the porcine transcriptional response to Matrix-M was performed in vitro using lymphocytes, monocytes or monocyte-derived dendritic cells (MoDCs) and in vivo. The effect of Matrix-M was also evaluated in specific pathogen free (SPF) pigs exposed to conventionally reared pigs. The pro-inflammatory cytokine genes IL1B and CXCL8 were up-regulated in monocytes and lymphocytes after Matrix-M exposure. Matrix-M also induced IL12B, IL17A and IFNG in lymphocytes and IFN-α gene expression in MoDCs. Several genes were indicated as up-regulated by Matrix-M in blood 18 h after injection, of which the genes for IFN-α and TLR2 could be statistically confirmed. Respiratory disease developed in all SPF pigs mixed with conventional pigs within 1-3 days. Two out of four SPF pigs injected with saline prior to contact exposure displayed systemic symptoms that was not recorded for the four pigs administered Matrix-M. Granulocyte counts, serum amyloid A levels and transcription of IL18 and TLR2 coincided with disease progression in the pigs. These results support further evaluation of Matrix-M as a possible enhancer of innate immune responses during critical moments in pig management.

The demography of climate-driven and density-regulated population dynamics in a perennial plant.

Identifying the internal and external drivers of population dynamics is a key objective in ecology, currently accentuated by the need to forecast the effects of climate change on species distributions and abundances. The interplay between environmental and density effects is one particularly important aspect of such forecasts. We examined the simultaneous impact of climate and intraspecific density on vital rates of the dwarf shrub Fumana procumbens over 20 yr, using generalized additive mixed models. We then analyzed effects on population dynamics using integral projection models. The population projection models accurately captured observed fluctuations in population size. Our analyses suggested the population was intrinsically regulated but with annual fluctuations in response to variation in weather. Simulations showed that implicitly assuming variation in demographic rates to be driven solely by the environment can overestimate extinction risks if there is density dependence. We conclude that density regulation can dampen effects of climate change on Fumana population size, and discuss the need to quantify density dependence in predictions of population responses to environmental changes.

Comparisons between comorbid conditions and health care consumption in rheumatoid arthritis patients with or without biological disease-modifying anti-rheumatic drugs: a register-based study.

BACKGROUND: Symptoms and prognosis of patients with rheumatoid arthritis (RA) have improved with more intensive therapy, including the biological disease-modifying anti-rheumatic drugs (bDMARDs). Real life data concerning how comorbidities are distributed among patients treated or not treated with bDMARDs are scarce. Our objective was to investigate differences in comorbidity and health care consumption in RA patients, with and without bDMARDs. METHODS: This cross-sectional study was performed in the Southwestern part of Sweden. Patients, aged ≥ 18 years and diagnosed with RA in secondary health care during 2009-2010, were identified in the regional health care database. Aggregated data of comorbidity and health care consumption were retrieved between 2006 and 2010. RA patients treated with bDMARDs on 31st December 2010 were identified in the Swedish Rheumatology Quality Register (SRQ), which includes the biologics register Anti-Rheumatic Therapy in Sweden (ARTIS). Descriptive, comparative, univariate and multiple logistic regression analyses were used to identify factors associated with bDMARDs. RESULTS: Seven thousand seven hundred and twelve (7712) RA patients were identified (age 64.8 ± 14.9 years, women 74.3%), of whom 1137 (14.7%) were treated with bDMARDs. Overall, the most common comorbidities were infections (69.2%), hypertension (41.1%), chronic respiratory disease (15.3%), ischemic heart disease (14.0%) and malignancy (13.7%). Patients without bDMARDs were older and had more comorbidity. In the multiple logistic regression analysis, older age, cerebrovascular and chronic respiratory disease, heart failure, depression and malignancy were all associated with no present bDMARDs. Infections were associated with bDMARDs. Patients treated with bDMARDs consumed more secondary outpatient care but less visits in primary health care compared to patients without bDMARDs. CONCLUSIONS: Patients treated with bDMARDs versus no bDMARDs were younger and had significantly lower period prevalence for most common comorbidities, with the exception of infections. Differences in comorbidities between RA patients with or without bDMARDs should be taken into consideration when evaluating effectiveness and safety of bDMARDs in ordinary care.

Drug adherence, response and predictors thereof for tocilizumab in patients with rheumatoid arthritis: results from the Swedish biologics register.

OBJECTIVE: To evaluate drug adherence, clinical response and predictors thereof for tocilizumab in patients with RA in routine care based on prospectively collected data from the Swedish biologics register, Anti-Rheumatic Therapies in Sweden. METHODS: RA patients who had started with tocilizumab from September 2008 until March 2012 were identified. Cox regression and logistic regression models were used. RESULTS: A total of 530 RA patients were included, of whom 80.6% were female, 64.7% were on concomitant DMARDs, of which 300 were on MTX and 12% were biologic naive. The overall 6 month, 1 and 2 year estimated drug continuations were 79%, 64% and 50%, respectively. In the multivariate analyses, a low initial level of CRP [hazard ratio (HR) 0.76/1 S.D. (95% CI 0.63, 0.91)], high HAQ score [HR 1.23/1 S.D. (95% CI 1.06, 1.44)] and prior exposure to different biologics [HR 1.43 (95% CI 1.12, 1.83)] were predictors for drug termination, whereas concomitant DMARD therapy was not. European League Against Rheumatism (EULAR) good, moderate, and no response were achieved by 184 (46.7%), 133 (33.8%) and 77 (19.5%) patients, respectively. Predictors for EULAR good response vs no response (at 2.5-8 months) were low HAQ [odds ratio (OR) 0.56/1 S.D. (95% CI 0.40, 0.78)], high 28-joint DAS [OR 2.0/1 S.D. (95% CI 1.44, 2.78)] and not being on prednisolone [OR 0.47 (95% CI 0.25, 0.88)] at baseline. CONCLUSION: In this RA cohort treated with tocilizumab, the estimated 1 year drug continuation was 64% and 80% of the patients achieved a EULAR response. Drug discontinuation was not predicted by no concomitant DMARD, but by low CRP, high HAQ and prior exposure to biologics.

Matrix-M™ adjuvation broadens protection induced by seasonal trivalent virosomal influenza vaccine.

BACKGROUND: Influenza virus infections are responsible for significant morbidity worldwide and therefore it remains a high priority to develop more broadly protective vaccines. Adjuvation of current seasonal influenza vaccines has the potential to achieve this goal. METHODS: To assess the immune potentiating properties of Matrix-M™, mice were immunized with virosomal trivalent seasonal vaccine adjuvated with Matrix-M™. Serum samples were isolated to determine the hemagglutination inhibiting (HAI) antibody titers against vaccine homologous and heterologous strains. Furthermore, we assess whether adjuvation with Matrix-M™ broadens the protective efficacy of the virosomal trivalent seasonal vaccine against vaccine homologous and heterologous influenza viruses. RESULTS: Matrix-M™ adjuvation enhanced HAI antibody titers and protection against vaccine homologous strains. Interestingly, Matrix-M™ adjuvation also resulted in HAI antibody titers against heterologous influenza B strains, but not against the tested influenza A strains. Even though the protection against heterologous influenza A was induced by the adjuvated vaccine, in the absence of HAI titers the protection was accompanied by severe clinical scores and body weight loss. In contrast, in the presence of heterologous HAI titers full protection against the heterologous influenza B strain without any disease symptoms was obtained. CONCLUSION: The results of this study emphasize the promising potential of a Matrix-M™-adjuvated seasonal trivalent virosomal influenza vaccine. Adjuvation of trivalent virosomal vaccine does not only enhance homologous protection, but in addition induces protection against heterologous strains and thus provides overall more potent and broad protective immunity.

Immunization of macaques with soluble HIV type 1 and influenza virus envelope glycoproteins results in a similarly rapid contraction of peripheral B-cell responses after boosting.

The envelope glycoproteins (Env) represent a critical component of a successful antibody-mediated human immunodeficiency virus type 1 (HIV-1) vaccine. However, immunization with soluble Env was reported to induce short-lived antibody responses, suggesting that Env has unusual immunogenic properties. Here, we directly compared the magnitude and durability of B-cell responses induced by HIV-1 Env and an unrelated soluble viral protein, influenza virus hemagglutinin (HA), in simultaneously inoculated macaques. We demonstrate robust peak responses followed by rapid contraction of circulating antibody and memory B cells for both antigens, suggesting that short-lived responses are not unique to HIV-1 Env but may be a common feature of soluble protein vaccines.

A randomized first-in-human phase I trial of differentially adjuvanted Pfs48/45 malaria vaccines in Burkinabé adults.

BACKGROUNDMalaria transmission-blocking vaccines aim to interrupt the transmission of malaria from one person to another.METHODSThe candidates R0.6C and ProC6C share the 6C domain of the Plasmodium falciparum sexual-stage antigen Pfs48/45. R0.6C utilizes the glutamate-rich protein (GLURP) as a carrier, and ProC6C includes a second domain (Pfs230-Pro) and a short 36-amino acid circumsporozoite protein (CSP) sequence. Healthy adults (n = 125) from a malaria-endemic area of Burkina Faso were immunized with 3 intramuscular injections, 4 weeks apart, of 30 µg or 100 µg R0.6C or ProC6C each adsorbed to Alhydrogel (AlOH) adjuvant alone or in combination with Matrix-M (15 µg or 50 µg, respectively). The allocation was random and double-blind for this phase I trial.RESULTSThe vaccines were safe and well tolerated with no vaccine-related serious adverse events. A total of 7 adverse events, mild to moderate in intensity and considered possibly related to the study vaccines, were recorded. Vaccine-specific antibodies were highest in volunteers immunized with 100 µg ProC6C-AlOH with Matrix-M, and 13 of 20 (65%) individuals in the group showed greater than 80% transmission-reducing activity (TRA) when evaluated in the standard membrane feeding assay at 15 mg/mL IgG. In contrast, R0.6C induced sporadic TRA.CONCLUSIONAll formulations were safe and well tolerated in a malaria-endemic area of Africa in healthy adults. The ProC6C-AlOH/Matrix-M vaccine elicited the highest levels of functional antibodies, meriting further investigation.TRIAL REGISTRATIONPan-African Clinical Trials Registry (https://pactr.samrc.ac.za) PACTR202201848463189.FUNDINGThe study was funded by the European and Developing Countries Clinical Trials Partnership (grant RIA2018SV-2311).

Incident Gout and Risk of First-Time Acute Coronary Syndrome: A Prospective, Population-Based Cohort Study in Sweden.

OBJECTIVE: To investigate the risk of first-time acute coronary syndrome (ACS) in a large cohort of primary and secondary care patients with incident gout compared to the general population. METHODS: Using register data for the period 2007-2017, we conducted a prospective, population-based cohort with 20,146 patients with incident gout (mean age 65.6 years; 67.4% male) and 83,517 matched population controls without prior history of coronary heart disease. We calculated incidence rates (IRs) and hazard ratios (HRs) adjusted for baseline comorbidities and dispensed prescriptions. In a sensitivity analysis, we included gout cases and controls with no previously diagnosed comorbidity (6,075 cases and 44,091 controls). RESULTS: The IR of first-time ACS was significantly increased in the gout cohort compared to controls (9.1 versus 6.3 of 1,000 person-years). Unadjusted Cox regression showed that gout patients had higher risk of first-time ACS compared to controls (HR 1.44 [95% confidence interval (95% CI) 1.33-1.56]), with a higher HR in women (HR 1.64 [95% CI 1.41-1.90]) than in men (HR 1.36 [95% CI, 1.24-1.50]). In multivariable analysis, the risk diminished but remained significant (HR 1.15 [95% CI 1.06-1.25]). The risk was similar in the sensitivity analysis (HR 1.20 [95% CI 1.01-1.44]) and still higher in women (HR 1.34 [95% CI 0.86-2.08]) than in men (HR 1.18 [95% CI 0.97-1.44]). CONCLUSION: Patients with incident gout have a 44% increased risk of first-time ACS, higher in women than in men. This risk is largely explained by the underlying comorbidities, but there is still a modestly increased risk that may be due to gout-related factors.

Occurrence and relative risks for non-vertebral fractures in patients with ankylosing spondylitis compared with the general population: a register-based study from Sweden.

OBJECTIVES: To estimate the incidence of non-vertebral fractures in ankylosing spondylitis (AS) compared with the general population. METHODS: Nationwide register-based cohort study including patients with AS (n=11 611, 65% men, mean age 48 years), and matched general population controls (n=58 050). Five prespecified fracture outcomes: (1) non-vertebral; (2) fracture of the proximal humerus, distal forearm or hip; (3) proximal humerus; (4) distal forearm and (5) hip) were identified through register linkages with follow-up 2007-2016. We used Poisson regression to calculate incidence rates (IRs), number of fractures per 1000 person-years at risk and IR ratios (IRRs), overall and by sex and age. IRRs were adjusted for history of any prior fracture. RESULTS: IRs (men/women) for non-vertebral fracture in AS were 11.9 (95% CI 11.0 to 12.9)/14.5 (95% CI 13.1 to 16.1) and in controls 10.0 (95% CI 9.7 to 10.4)/11.8 (95% CI 11.1 to 12.4), IRR (men/women) 1.2 (95% CI 1.1 to 1.3)/1.2 (95% CI 1.1 to 1.4). IRs (men/women) for fractures of the humerus, forearm or hip in AS were 4.0 (95% CI 3.5 to 4.6)/6.3 (95% CI 5.4 to 7.3) and in controls 2.7 (95% CI 2.5 to 2.9)/5.5 (95% CI 5.1 to 6.0), IRR (men/women) 1.5 (95% CI 1.3 to 1.7)/1.1 (95% CI 0.9 to 1.3). IRRs were statistically significantly elevated in men with AS versus controls for forearm fracture (1.4 (95% CI 1.1 to 1.7)) and hip fracture (1.8 (95% CI 1.4 to 2.3)), whereas not in women with AS where the IRRs were 1.1 (95% CI 0.9 to 1.4) and 1.0 (95% CI 0.6 to 1.4). For humerus fracture, IRRs were 1.4 (95% CI 0.99 to 1.9) in men with AS versus controls and 1.1 (95% CI 0.8 to 1.6) in women. CONCLUSIONS: Both men and women with AS have a slightly higher risk of non-vertebral fractures than the general population. A statistically significantly higher risk of fractures of the proximal humerus, distal forearm or hip was found in men with AS in comparison to general population, where the relative risk was especially pronounced for hip fracture.

The Matrix-M™ adjuvant: A critical component of vaccines for the 21st century.

Matrix-M™ adjuvant is a key component of several novel vaccine candidates. The Matrix-M adjuvant consists of two distinct fractions of saponins purified from the Quillaja saponaria Molina tree, combined with cholesterol and phospholipids to form 40-nm open cage-like nanoparticles, achieving potent adjuvanticity with a favorable safety profile. Matrix-M induces early activation of innate immune cells at the injection site and in the draining lymph nodes. This translates into improved magnitude and quality of the antibody response to the antigen, broadened epitope recognition, and the induction of a Th1-dominant immune response. Matrix-M-adjuvanted vaccines have a favorable safety profile and are well tolerated in clinical trials. In this review, we discuss the latest findings on the mechanisms of action, efficacy, and safety of Matrix-M adjuvant and other saponin-based adjuvants, with a focus on the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) subunit vaccine candidate NVX-CoV2373 developed to prevent coronavirus disease 2019 (COVID-19).

Immunogenicity of a recombinant hemagglutinin neuraminidase-Porcine rubulavirus produced by Escherichia coli of Porcine rubulavirus gives protective immunity of litter after challenge.

Porcine rubulavirus (PRV) is a contagious virus that affects the Mexican swine industry. This work aimed to evaluate the immunogenicity of an recombinant hemagglutinin neuraminidase-Porcine rubulavirus (rHN-PorPV) candidate vaccine on pregnant sows, and the protective efficacy afforded to their 7-day-old suckling piglets against PRV lethal challenge. Three sows were immunized with rHN-PorPV formulated with immune-stimulating complex (ISCOMs) and two sows with rHN-PorPV protein alone as well as a mock-immunized pregnant sow (negative control). Quantitative ELISA detected a high concentration of anti-rHN-PorPV Immunoglobulin G (IgG) antibodies in sow sera after the second dose of vaccine administered on day 14 until farrowing, showing viral-neutralizing and cross-neutralization activity against different variants of PRV. Sera samples from piglets of immunized sows (with or without adjuvant), showed high concentrations of IgG antibodies. As expected, piglets from the negative control sow (n=5), exhibited severe signs of disease and 100% of mortality after PRV challenge study. Conversely, 75% and 87.5% of the piglets born from the rHN-PorPV and the rHN-PorPV-ISCOMs-immunized sows (n=8), survived, respectively, showing milder PRV clinical signs. Our data indicate that rHN-PorPV candidate vaccine produced in Escherichia coli induces efficient humoral response in pregnant sows and that the maternally derived immunity provides high protection to suckling piglets against PRV lethal challenge.

Characteristics and outcome of a first acute myocardial infarction in patients with ankylosing spondylitis.

OBJECTIVES: To study clinical characteristics, mortality, and secondary prevention, after a first incident acute myocardial infarction (AMI) in patients with ankylosing spondylitis (AS) compared with the general population. METHODS: In total, 292 subjects with AS and a first AMI between Jan 2006 and Dec 2014 were identified using the Swedish national patient register. Each subject was matched with up to 5 general population comparators per AS-patient (n = 1276). Follow-up started at the date of admission for AMI and extended until death or 365 days of follow-up. Cox regression was used to assess mortality in two time intervals: days 0-30 and days 31-365. For a subgroup with available data, clinical presentation at admission, course, treatment for AMI, and secondary prevention were compared. RESULTS: During the 365-day follow-up, 56/292 (19%) AS patients and 184/1276 (14%) comparators died. There were no difference in mortality due to cardiovascular-related causes, although the overall mortality day 31-365 was increased among patients with AS compared with comparators (HR [95% CI] = 2.0 [1.3;3.0]). At admission, AS patients had a higher prevalence of cardiovascular comorbidities compared with comparators. At discharge, patients with AS were less often prescribed lipid-lowering drugs and non-aspirin antiplatelet therapy. CONCLUSIONS: Patients with AS tend to have a higher comorbidity burden at admission for first AMI. The mortality after a first AMI due to cardiovascular-related causes does not seem to be elevated, despite an increased overall mortality during days 31-365 among patients with AS compared with the general population. Key Points • The all-cause mortality after a first AMI was higher in patients with AS. • Mortality after a first AMI due to CVD-related causes does not seem to be elevated for patients with AS. • In patients with AS suffering a first AMI, more attention should be given to other comorbidities causing an excess in mortality.

Biomechanical Properties of Common Carotid Arteries Assessed by Circumferential 2D Strain and ß Stiffness Index in Patients With Ankylosing Spondylitis.

OBJECTIVE: Ankylosing spondylitis (AS) is associated with an elevated risk of cardiovascular disease (CVD) related to atherosclerosis, preceded by arterial stiffness. We aimed to examine common carotid artery (CCA) biomechanical properties using ultrasound to calculate ß stiffness index (indicating arterial stiffness) and, a more recently developed technique, 2-dimensional (2D) speckle tracking strain (indicating arterial motion and deformation, strain) to (1) compare with age- and sex-matched controls, and (2) analyze relationships between strain and stiffness with disease characteristics and traditional risk factors for CVD in patients with AS. METHODS: In this cross-sectional study, a cohort of 149 patients with AS, mean age 55.3 ± 11.2 years, 102 (68.5%) men, and 146 (98%) HLA-B27-positive, were examined. Bilateral CCA were examined for circumferential 2D strain and ß stiffness index. A subgroup of 46 patients was compared with 46 age- and sex-matched controls, both groups without hypertensive disease, diabetes, myocardial infarction, or stroke. RESULTS: Mean bilateral circumferential 2D strain was lower in AS patients compared with controls (7.9 ± 2.6% vs 10.3 ± 1.9%, P < 0.001), whereas mean bilateral ß stiffness index was higher (13.1 ± 1.7 mmHg/mm vs 12.3 ± 1.3 mmHg/mm, P = 0.02). In multivariable linear regression analyses, strain was associated with age, erythrocyte sedimentation rate, history of anterior uveitis, and treatment with conventional synthetic disease-modifying antirheumatic drugs (DMARD) and/or biological DMARD (R2 0.33), while stiffness was associated with age (R2 0.19). CONCLUSION: Both CCA circumferential 2D strain and ß stiffness index differed between patients with AS and controls. Strain was associated with AS-related factors and age, whereas only age was associated with stiffness, suggesting that the obtained results reflect different pathogenic vascular processes.

Preclinical development of a Pfs230-Pfs48/45 chimeric malaria transmission-blocking vaccine.

The Plasmodium falciparum Pfs230 and Pfs48/45 proteins are leading candidates for a malaria transmission-blocking vaccine (TBV). Previously, we showed that a Pfs230-Pfs48/45 fusion protein elicits higher levels of functional antibodies than the individual antigens, but low yields hampered progression to clinical evaluation. Here we identified a modified construct (ProC6C) with a circumsporozoite protein (CSP) repeat-linker sequence that enhances expression. A scalable and reproducible process in the Lactococcus lactis expression system was developed and ProC6C was successfully transferred for manufacturing under current Good Manufacturing Practices (cGMP). In addition, a panel of analytical assays for release and stability were developed. Intact mass spectrometry analysis and multiangle light scattering showed that the protein contained correct disulfide bonds and was monomeric. Immunogenicity studies in mice showed that the ProC6C adsorbed to Alhydrogel®, with or without Matrix-MTM, elicited functional antibodies that reduced transmission to mosquitoes and sporozoite invasion of human hepatocytes. Altogether, our data support manufacture and clinical evaluation of ProC6C as a multistage malaria-vaccine candidate.