Biochemical marker research in hemophilic arthropathy: A systematic review

Hemophilic arthropathy (HA) causes major morbidity. Breakthrough therapies reduce the bleeding frequency tremendously, but well-defined joint outcome assessments with a focus on early changes and subclinical damage are lacking. Biomarkers reflecting joint tissue turnover/inflammation might be useful to predict invalidating arthropathy. This systematic review summarized and categorized publications on blood/urinary biomarkers in HA to provide leads for implementation. A PubMed/EMBASE search was performed on September 9, 2019. All publications were assessed and allocated to one or several BIPED-categories, based on the utility of biomarkers. Of the initial 1307 publications found, 27 were eligible for inclusion. The majority (81%, n = 32/42) was cross-sectional in design, including relatively small numbers of patients (median 44, interquartile range 35-78). Fourteen percent (n = 6/42) investigated dynamic changes around a bleeding or treatment. Only two studies investigated the prognostic value of biomarkers. Most promising biomarkers were serum Coll2-1, COL-18N, COMP, C1,2C, C2M, CS846, MIF, plasma sVCAM-1 and urinary CTX-II. Comparing performances and pooling data was not possible due to heterogeneity. Currently, biomarker research in HA is still in an explorative stage and not yet sufficient for translation into daily practice. Clearly, larger homogeneous longitudinal studies in well-defined populations should be performed for further development

Towards Personalized Treatment in Haemophilia: The Role of Genetic Factors in Iron and Heme Control to Identify Patients at Risk for Haemophilic Arthropathy

The treatment landscape for haemophilia is changing rapidly, creating opportunities for personalized treatment. As major morbidity is still caused by haemophilic arthropathy, understanding the factors affecting joint damage and joint damage progression might lead to more individualized treatment regimens. We investigated the association of HFE mutations or HMOX1 polymorphisms affecting iron/heme handling with radiographic joint damage in 252 haemophilia patients (severe and moderate). Although iron levels and transferrin saturation were significantly increased in the 95 patients with an HFE mutation, neither carrying this mutation nor the HMOX1 polymorphism was associated with radiographic joint damage, and the same was true after adjustment for well-known factors associated with arthropathy. In conclusion, this study does not support the hypothesis that HFE mutations or HMOX1 polymorphisms can be used to predict the development of haemophilic arthropathy

Subchondral bone changes after joint distraction treatment for end stage knee osteoarthritis

Objective: Increased subchondral cortical bone plate thickness and trabecular bone density are characteristic of knee osteoarthritis (OA). Knee joint distraction (KJD) is a joint-preserving knee OA treatment where the joint is temporarily unloaded. It has previously shown clinical improvement and cartilage regeneration, indicating reversal of OA-related changes. The purpose of this research was to explore 3D subchondral bone changes after KJD treatment using CT imaging. Design: Twenty patients were treated with KJD and included to undergo knee CT imaging before, one, and two years after treatment. Tibia and femur segmentation and registration to canonical surfaces were performed semi-automatically. Cortical bone thickness and trabecular bone density were determined using an automated algorithm. Statistical parametric mapping (SPM) with two-tailed F-tests was used to analyze whole-joint changes. Results: Data was available of 16 patients. Subchondral cortical bone plate thickness and trabecular bone density were higher in the weight-bearing region of the most affected compartment (MAC; mostly medial). Especially the MAC showed a decrease in thickness and density in the first year after treatment, which was sustained towards the second year. Conclusions: KJD treatment results in bone changes that include thinning of the subchondral cortical bone plate and decrease of subchondral trabecular bone density in the first two years after treatment, potentially indicating a partial normalization of subchondral bone

Structural changes after ankle joint distraction in haemophilic arthropathy: an explorative study investigating biochemical markers and 3D joint space width

INTRODUCTION: Ankle joint distraction (AJD) is a promising treatment for patients with severe haemophilic ankle arthropathy (HAA). However, some patients showed no clinical improvement after AJD and these differences may be related to structural differences. AIM: Primarily to quantify the structural changes after AJD in patients with HAA by the use of 3D joint space width (JSW) measurements and biochemical markers and secondarily to correlate these findings with clinical pain/function. METHODS: Patients with haemophilia A/B who underwent AJD were included for this study. Bone contours on MRI (performed before and 12 and 36 months after AJD) were drawn manually and percentage change in JSW was calculated. Blood/urine (before and 6, 12, 24 and 36 months after AJD) was collected for biomarker measurement (COMP, CS846, C10C, CALC2, PRO-C2, CTX-II) and combined indexes of markers were calculated. Mixed effects models were used for analyses on group level. Structural changes were compared with clinical parameters. RESULTS: Eight patients were evaluated. On group level, percentage changes in JSW showed a slight decrease after 12 months followed by a non-statistically significant increase in JSW after 36 months compared to baseline. Biochemical marker collagen/cartilage formation also showed an initial decrease, followed by a trend towards net formation 12, 24 and 36 months after AJD. On individual patient level, no clear correlations between structural changes and clinical parameters were observed. CONCLUSION: Cartilage restoration activity on group level in patients with HAA after AJD was in concordance with clinical improvements. Correlating structural modifications with clinical parameters in the individual patient remains difficult

Original COVID-19 priming regimen impacts the immunogenicity of bivalent BA.1 and BA.5 boosters

Waning antibody responses after COVID-19 vaccination combined with the emergence of the SARS-CoV-2 Omicron lineage led to reduced vaccine effectiveness. As a countermeasure, bivalent mRNA-based booster vaccines encoding the ancestral spike protein in combination with that of Omicron BA.1 or BA.5 were introduced. Since then, different BA.2-descendent lineages have become dominant, such as XBB.1.5, JN.1, or EG.5.1. Here, we report post-hoc analyses of data from the SWITCH-ON study, assessing how different COVID-19 priming regimens affect the immunogenicity of bivalent booster vaccinations and breakthrough infections (NCT05471440). BA.1 and BA.5 bivalent vaccines boosted neutralizing antibodies and T-cells up to 3 months after boost; however, cross-neutralization of XBB.1.5 was poor. Interestingly, different combinations of prime-boost regimens induced divergent responses: participants primed with Ad26.COV2.S developed lower binding antibody levels after bivalent boost while neutralization and T-cell responses were similar to mRNA-based primed participants. In contrast, the breadth of neutralization was higher in mRNA-primed and bivalent BA.5 boosted participants. Combined, our data further support the current use of monovalent vaccines based on circulating strains when vaccinating risk groups, as recently recommended by the WHO. We emphasize the importance of the continuous assessment of immune responses targeting circulating variants to guide future COVID-19 vaccination policies.</p

Original COVID-19 priming regimen impacts the immunogenicity of bivalent BA.1 and BA.5 boosters

Waning antibody responses after COVID-19 vaccination combined with the emergence of the SARS-CoV-2 Omicron lineage led to reduced vaccine effectiveness. As a countermeasure, bivalent mRNA-based booster vaccines encoding the ancestral spike protein in combination with that of Omicron BA.1 or BA.5 were introduced. Since then, different BA.2-descendent lineages have become dominant, such as XBB.1.5, JN.1, or EG.5.1. Here, we report post-hoc analyses of data from the SWITCH-ON study, assessing how different COVID-19 priming regimens affect the immunogenicity of bivalent booster vaccinations and breakthrough infections (NCT05471440). BA.1 and BA.5 bivalent vaccines boosted neutralizing antibodies and T-cells up to 3 months after boost; however, cross-neutralization of XBB.1.5 was poor. Interestingly, different combinations of prime-boost regimens induced divergent responses: participants primed with Ad26.COV2.S developed lower binding antibody levels after bivalent boost while neutralization and T-cell responses were similar to mRNA-based primed participants. In contrast, the breadth of neutralization was higher in mRNA-primed and bivalent BA.5 boosted participants. Combined, our data further support the current use of monovalent vaccines based on circulating strains when vaccinating risk groups, as recently recommended by the WHO. We emphasize the importance of the continuous assessment of immune responses targeting circulating variants to guide future COVID-19 vaccination policies.</p

Comparison of the Heel Enthesitis MRI Scoring System (HEMRIS) with clinical enthesitis and local metabolic activity on PET-CT

OBJECTIVE: To compare the Heel Enthesitis MRI Scoring model (HEMRIS) with clinical and PET/CT outcomes in patients with cutaneous psoriasis (Pso), psoriatic arthritis (PsA) or ankylosing spondylitis (AS). METHODS: This prospective, observational study included 38 patients with Pso, PsA and AS. Patients were included regardless of presence or absence of clinical heel enthesitis. MRI-scans of both ankles and a whole-body 18F-FDG PET/CT were acquired. MRIs were assessed for enthesitis by two independent and blinded observers according to the HEMRIS. A physician, blinded for imaging results, performed clinical evaluations of enthesitis at the Achilles tendon and plantar fascia. RESULTS: In total, 146 entheses were scored according to the HEMRIS and clinically assessed for enthesitis (6 entheses were clinically affected). In Achilles tendons with clinical enthesitis, the HEMRIS structural damage score was significantly higher, compared to Achilles tendons without clinical enthesitis (respective median scores 1.0 and 0.5; p=0.04). In clinically unaffected entheses, HEMRIS abnormalities occurred in 44/70 (63%) of Achilles tendons and in 23/70 (33%) of plantar fascia. At the Achilles tendon, local metabolic activity measured on PET/CT was weakly associated with the structural (rs=0.25, p=0.03) and total HEMRIS (rs=0.26, p=0.03). CONCLUSION: This study revealed a high prevalence of subclinical HEMRIS abnormalities and discrepancy between HEMRIS and clinical and PET/CT findings. This may suggest that the HEMRIS is a sensitive method for detection of inflammatory and structural disease of enthesitis at the Achilles tendon and plantar fascia, although the clinical significance of these MRI findings remains to be determined in longitudinal studies

No association between use of angiotensin-converting enzyme inhibitors or angiotensin II receptor blockers prior to hospital admission and clinical course of COVID-19 in the COvid MEdicaTion (COMET) study

Since the outbreak of SARS-CoV-2, also known as COVID-19, conflicting theories have circulated on the influence of angiotensin-converting enzyme inhibitors (ACEi) and angiotensin II receptor blockers (ARB) on incidence and clinical course of COVID-19, but data are scarce. The COvid MEdicaTion (COMET) study is an observational, multinational study that focused on the clinical course of COVID-19 (i.e. hospital mortality and intensive care unit [ICU] admission), and included COVID-19 patients who were registered at the emergency department or admitted to clinical wards of 63 participating hospitals. Pharmacists, clinical pharmacologists or treating physicians collected data on medication prescribed prior to admission. The association between the medication and composite clinical endpoint, including mortality and ICU admission, was analysed by multivariable logistic regression models to adjust for potential confounders. A total of 4870 patients were enrolled. ACEi were used by 847 (17.4%) patients and ARB by 761 (15.6%) patients. No significant association was seen with ACEi and the composite endpoint (adjusted odds ratio [OR] 0.94; 95% confidence interval [CI] 0.79 to 1.12), mortality (OR 1.03; 95%CI 0.84 to 1.27) or ICU admission (OR 0.96; 95%CI 0.78 to 1.19) after adjustment for covariates. Similarly, no association was observed between ARB and the composite endpoint (OR 1.09; 95%CI 0.90 to 1.30), mortality (OR 1.12; OR 0.90 to 1.39) or ICU admission (OR 1.21; 95%CI 0.98 to 1.49). In conclusion, we found no evidence of a harmful or beneficial effect of ACEi or ARB use prior to hospital admission on ICU admission or hospital mortality

Risk factors for acute respiratory tract infections in general practitioner patients in The Netherlands: a case-control study

<p>Abstract</p> <p>Background</p> <p>Acute respiratory tract infections (ARTI) are an important public health problem. Improved identification of risk factors might enable targeted intervention. Therefore we carried out a case-control study with the aim of identifying environmental risk factors for ARTI consultations in the Dutch general population.</p> <p>Methods</p> <p>A subset of patients visiting their GP in the period of 2000–2003 with an ARTI (cases) and age-matched controls (visiting for other complaints) were included in a case-control study. They were asked to complete a questionnaire about potential risk factors. Conditional logistic regression was used to calculate odds ratio's (OR) and 95% confidence intervals (CI) to estimate the independent effect of potential risk factors.</p> <p>Results</p> <p>A total of 493 matched pairs of case and control subjects were enrolled. Exposure to persons with respiratory complaints, both inside and outside the household, was found to be an independent risk factor for visiting a GP with an ARTI (respectively OR_adj= 1.9 and OR_adj= 3.7). Participants exposed to dampness or mould at home (OR_adj=0.5) were significantly less likely to visit their GP. In accordance with the general risk of consultations for ARTI, participants with a laboratory-confirmed ARTI who were exposed to persons with respiratory complaints outside the household were also significantly more likely to visit their GP (OR_adj=2.5).</p> <p>Conclusion</p> <p>This study confirmed that heterogeneity in the general population as well as in pathogens causing ARTI makes it complicated to detect associations between potential risk factors and respiratory infections. Whereas it may be difficult to intervene on the risk posed by exposure to persons with respiratory complaints, transmission of ARTI in the general population might be reduced by improved hygienic conditions.</p