Efficacy and safety of Infliximab in systemic sarcoidosis according to GenPhenReSa organ-involvement phenotype: a retrospective study of 55 patients.

BACKGROUND: Infliximab is currently recommended as a third-line treatment for refractory sarcoidosis. Data in function of clinical phenotype are currently lacking. We evaluated patients' characteristics and responses to infliximab according to their GenPhenReSa cluster. METHODS: We evaluated clinical and biological characteristics of patients diagnosed with sarcoidosis who received infliximab between September 2008 and April 2019 at our centre. RESULTS: Fifty-five patients (median disease duration, 87 months) received infliximab: 48 (87%) as a second- or third-line treatment, and 7 (13%) as a first-line treatment. After a median duration of 12 months, 24 (45%) and 14 (25%) patients achieved complete and partial responses, respectively, together with a significant decrease in the number of affected organs and tapering of steroid doses. All patients with neurosarcoidosis (OR 17), 90% in group 2 (ocular-cardiac-cutaneous-CNS, OR 7.4), and approximately two-thirds of those in groups 1 (abdominal organs), 4 (pulmonary-lympho-nodal), and 5 (extrapulmonary), achieved a response, whereas patients in group 3 (musculoskeletal-cutaneous) had a treatment-failure OR of 9. Infliximab could be stopped after complete remission was achieved in 7 patients: 4 relapsed after a median of 6 months. Overall, 36% of patients experienced serious adverse events, mainly infections, which led to treatment cessation in 29% of patients and caused two deaths. CONCLUSIONS: Other than patients with musculoskeletal-cutaneous involvement (group 3), infliximab led to a good response for patients with CNS (group 2) and liver (group 1) organ-predominant sarcoidosis. However, it led to serious infections and merely suspended sarcoidosis, so further research on factors predictive of relapse is needed.

Pilot study on accelerated aging in lupus using epigenetic biomarkers of age.

OBJECTIVE: Despite an important increase in lifespan over the last decades, patients with systemic lupus erythematosus (SLE) still have to face a high morbi-mortality, particularly related to cardiovascular diseases, infections and cancers. Such events are more commonly found during old age in the general population, raising the hypothesis of an acceleration of the aging process in SLE patients. In this pilot study, we wanted to test the hypothesis that SLE would be associated with an accelerated biological aging measured by the epigenetic clocks models. METHODS: We applied DNA methylation-based biomarkers of age in publicly available datasets of SLE patients. For every SLE patient and control included in the dataset, we calculated their epigenetic age and a measure of epigenetic age acceleration, according to Horvath's epigenetic clock model. RESULTS: We included in our analysis two distinct DNA methylation datasets of 30 subjects (among which 15 with SLE) and 55 subjects (among which 30 with SLE), respectively. In both datasets, there was a statistically significant correlation between chronological age and epigenetic age. We did not observe any statistically significant difference in the measure of epigenetic age acceleration between SLE patients and controls. CONCLUSION: We did not observe any evidence of an accelerated biological aging in SLE patients, according to Horvath's epigenetic clock model.

The epigenetics of inflammaging: The contribution of age-related heterochromatin loss and locus-specific remodelling and the modulation by environmental stimuli.

A growing amount of evidences indicates that inflammaging - the chronic, low grade inflammation state characteristic of the elderly - is the result of genetic as well as environmental or stochastic factors. Some of these, such as the accumulation of senescent cells that are persistent during aging or accompany its progression, seem to be sufficient to initiate the aging process and to fuel it. Others, like exposure to environmental compounds or infections, are temporary and resolve within a (relatively) short time. In both cases, however, a cellular memory of the event can be established by means of epigenetic modulation of the genome. In this review we will specifically discuss the relationship between epigenetics and inflammaging. In particular, we will show how age-associated epigenetic modifications concerned with heterochromatin loss and gene-specific remodelling, can promote inflammaging. Furthermore, we will recall how the exposure to specific nutritional, environmental and microbial stimuli can affect the rate of inflammaging through epigenetic mechanisms, touching also on the recent insight given by the concept of trained immunity.

Update on the cellular pathogenesis of lupus.

PURPOSE OF REVIEW: Aberrations in the innate and in the adaptive arms of the immune system play both important roles in the initiation and progression of systemic lupus erythematosus (SLE). The aim of this study was to provide an update on the most recent findings on the cellular pathogenesis of SLE. Our overview focused particularly on results obtained over the last 18 months. RECENT FINDINGS: Recent observations have provided an improved understanding of the importance of low-density granulocytes, a highly proinflammatory subset of neutrophils. We also highlighted in this work recent descriptions of the various cellular sources associated with the interferon signature. In addition, novel contributions have also developed our understanding of the potential importance of extrafollicular T-B-cell interactions in SLE pathogenesis. Finally, the role of recently described B and T-cell subsets, that is, atypical memory B cells, T-peripheral helper cells, and Th10 T cells, were also reviewed. SUMMARY: Recent findings in the cellular pathogenesis of SLE give a deeper comprehension of previously described mechanisms which drive SLE pathogenesis and shed light on novel players in immune dysregulation that could help to identify potential therapeutic targets.

Down Syndrome, Ageing and Epigenetics.

During the past decades, life expectancy of subjects with Down syndrome (DS) has greatly improved, but age-specific mortality rates are still important and DS subjects are characterized by an acceleration of the ageing process, which affects particularly the immune and central nervous systems. In this chapter, we will first review the characteristics of the ageing phenomenon in brain and in immune system in DS and we will then discuss the biological hallmarks of ageing in this specific population. Finally, we will also consider in detail the knowledge on epigenetics in DS, particularly DNA methylation.

The Impact of Caloric Restriction on the Epigenetic Signatures of Aging.

Aging is characterized by an extensive remodeling of epigenetic patterns, which has been implicated in the physiopathology of age-related diseases. Nutrition plays a significant role in modulating the epigenome, and a growing amount of data indicate that dietary changes can modify the epigenetic marks associated with aging. In this review, we will assess the current advances in the relationship between caloric restriction, a proven anti-aging intervention, and epigenetic signatures of aging. We will specifically discuss the impact of caloric restriction on epigenetic regulation and how some of the favorable effects of caloric restriction on lifespan and healthspan could be mediated by epigenetic modifications.

T follicular helper cells, interleukin-21 and systemic lupus erythematosus.

SLE is a chronic systemic autoimmune disease characterized by a breakdown of tolerance to nuclear antigens and generation of high-affinity pathogenic autoantibodies. These autoantibodies form, with autoantigens, immune complexes that are involved in organ and tissue damages. Understanding how the production of these pathogenic autoantibodies arises is of prime importance. T follicular helper cells (Tfh) and IL-21 have emerged as central players in this process. This article reviews the pathogenic role of Tfh cells and IL-21 in SLE.

The epigenetic landscape of age-related diseases: the geroscience perspective.

In this review, we summarize current knowledge regarding the epigenetics of age-related diseases, focusing on those studies that have described DNA methylation landscape in cardio-vascular diseases, musculoskeletal function and frailty. We stress the importance of adopting the conceptual framework of "geroscience", which starts from the observation that advanced age is the major risk factor for several of these pathologies and aims at identifying the mechanistic links between aging and age-related diseases. DNA methylation undergoes a profound remodeling during aging, which includes global hypomethylation of the genome, hypermethylation at specific loci and an increase in inter-individual variation and in stochastic changes of DNA methylation values. These epigenetic modifications can be an important contributor to the development of age-related diseases, but our understanding on the complex relationship between the epigenetic signatures of aging and age-related disease is still poor. The most relevant results in this field come from the use of the so called "epigenetics clocks" in cohorts of subjects affected by age-related diseases. We report these studies in final section of this review.

Immunogenicity and impact on disease activity of influenza and pneumococcal vaccines in systemic lupus erythematosus: a systematic literature review and meta-analysis.

OBJECTIVES: The aim was to assess the immunogenicity and the impact on disease activity of pneumococcal and influenza vaccines in SLE patients. METHODS: We conducted a systematic literature review and meta-analysis of studies comparing the humoral response of either pneumococcal (serotype 23F) or influenza (AH1N1, AH3N2 and B strains) vaccines between SLE patients and healthy controls, assessed by a seroconversion or a seroprotection rate 3-6 weeks after vaccination. The impact on disease activity was assessed by the comparison of the SLEDAI score before and 3-8 weeks after vaccination. Odds ratios (ORs), risk ratios and their 95% CIs were pooled using the generic inverse variance method. RESULTS: Twenty studies were included, three for pneumococcal vaccine and 17 for influenza vaccine, gathering 1665 SLE patients and 826 healthy controls. For pneumococcal vaccination, no significant difference was observed, either for seroconversion rate between SLE patients and controls or for the SLEDAI score. For influenza vaccination, the response against AH1N1 was significantly reduced in SLE patients, with a lower rate of seroconversion (OR = 0.38; 95% CI: 0.27, 0.54; P < 0.00001, I(2) = 39%) and seroprotection (OR = 0.36; 95% CI: 0.28, 0.47; P < 0.00001, I(2) = 25%). For AH3N2, only seroprotection rate was significantly lower in SLE patients (OR = 0.26; 95% CI: 0.14, 0.50; P < 0.0001, I(2) = 21%). For B strain, neither seroconversion nor seroprotection rates were significantly different. Influenza vaccine did not modify the SLEDAI score. CONCLUSION: The immunogenicity of influenza vaccine in SLE patients depends on the viral strains. A reduced immunogenicity against influenza A is noted, while the immunogenicity against the B strain is preserved. The pneumococcal vaccine against 23F serotype has a preserved immunogenicity. These vaccines have no impact on the SLEDAI score.

Anifrolumab: first biologic approved in the EU not restricted to patients with a high degree of disease activity for the treatment of moderate to severe systemic lupus erythematosus.

INTRODUCTION: Type 1 interferons (IFNs) play a crucial role in the pathogenesis of systemic lupus erythematosus (SLE) and various type I IFNs targeting therapeutic approaches have been developed. Anifrolumab, a monoclonal antibody that binds to the subunit 1 of the type I IFN receptor, has acquired considerable interest and has entered different clinical human trials willing to evaluate its efficacy and safety. AREAS COVERED: This review summarizes the data obtained in phases 1, 2, and 3 clinical trials of anifrolumab for SLE patients. A focus is made on data of clinical efficacy and safety obtained in MUSE, TULIP-1 and TULIP-2 trials. EXPERT OPINION/COMMENTARY: Anifrolumab is a promising therapeutic option for patients with SLE, currently authorized for moderate-to-severe SLE. Extensive real-world use is now going to generate data required to gain experience on the type of patients who benefit the most from the drug, and the exact positioning of anifrolumab in the therapeutic plan.

Preventing hyperhomocysteinemia using vitamin B6 supplementation in Givosiran-treated acute intermittent porphyria: Highlights from a case report and brief literature review.

Acute hepatic porphyrias are inherited metabolic disorders of heme biosynthesis characterized by the accumulation of toxic intermediate metabolites responsible for disabling acute neurovisceral attacks. Givosiran is a newly approved siRNA-based treatment of acute hepatic porphyria targeting the first and rate-limiting δ-aminolevulinic acid synthase 1 (ALAS1) enzyme of heme biosynthetic pathway. We described a 72-year old patient who presented with severe inaugural neurological form of acute intermittent porphyria evolving for several years which made her eligible for givosiran administration. On initiation of treatment, the patient developed a major hyperhomocysteinemia (>400 µmol/L) which necessitated to discontinue the siRNA-based therapy. A thorough metabolic analysis in the patient suggests that hyperhomocysteinemia could be attributed to a functional deficiency of cystathionine ß-synthase (CBS) enzyme induced by givosiran. Long-term treatment with vitamin B6, a cofactor of CBS, allowed to normalize homocysteinemia while givosiran treatment was maintained. We review the recently published cases of hyperhomocysteinemia in acute hepatic porphyria and its exacerbation under givosiran therapy. We also discuss the benefits of vitamin B6 supplementation in the light of hypothetic pathophysiological mechanisms responsible for hyperhomocysteinemia in these patients. Our results confirmed the importance of monitoring homocysteine metabolism and vitamin status in patients with acute intermittent porphyria in order to improve management by appropriate vitamin supplementation during givosiran treatment.

Adrenal insufficiency revealing bilateral adrenal hemorrhage related to JAK2 V617F-positive essential thrombocythemia: about two cases.

Bilateral adrenal hemorrhage is a rare cause of adrenal insufficiency which has been rarely associated with myeloproliferative neoplasms. Here, we report two cases of bilateral adrenal hemorrhage revealed by abdominal pain, malaise, and fatigue in two octogenarian males previously diagnosed with JAK2 V617F-positive essential thrombocythemia. Both patients were on long-term direct oral anticoagulant treatment for atrial fibrillation. Evolution was favorable under steroid replacement therapy, associated with cytoreduction, aspirin, and switch of direct oral anticoagulants for vitamin K antagonists.

DNA Methylation Analysis of Ribosomal DNA in Adults With Down Syndrome.

Control of ribosome biogenesis is a critical aspect of the regulation of cell metabolism. As ribosomal genes (rDNA) are organized in repeated clusters on chromosomes 13, 14, 15, 21, and 22, trisomy of chromosome 21 confers an excess of rDNA copies to persons with Down syndrome (DS). Previous studies showed an alteration of ribosome biogenesis in children with DS, but the epigenetic regulation of rDNA genes has not been investigated in adults with DS so far. In this study, we used a targeted deep-sequencing approach to measure DNA methylation (DNAm) of rDNA units in whole blood from 69 adults with DS and 95 euploid controls. We further evaluated the expression of the precursor of ribosomal RNAs (RNA45S) in peripheral blood mononuclear cells (PBMCs) from the same subjects. We found that the rDNA promoter tends to be hypermethylated in DS concerning the control group. The analysis of epihaplotypes (the combination of methylated and unmethylated CpG sites along the same DNA molecule) showed a significantly lower intra-individual diversity in the DS group, which at the same time was characterized by a higher interindividual variability. Finally, we showed that RNA45S expression is lower in adults with DS. Collectively, our results suggest a rearrangement of the epigenetic profile of rDNA in DS, possibly to compensate for the extranumerary rDNA copies. Future studies should assess whether the regulation of ribosome biogenesis can contribute to the pathogenesis of DS and explain the clinical heterogeneity characteristic of the syndrome.

A Targeted Epigenetic Clock for the Prediction of Biological Age.

Epigenetic clocks were initially developed to track chronological age, but accumulating evidence indicates that they can also predict biological age. They are usually based on the analysis of DNA methylation by genome-wide methods, but targeted approaches, based on the assessment of a small number of CpG sites, are advisable in several settings. In this study, we developed a targeted epigenetic clock purposely optimized for the measurement of biological age. The clock includes six genomic regions mapping in ELOVL2, NHLRC1, AIM2, EDARADD, SIRT7 and TFAP2E genes, selected from a re-analysis of existing microarray data, whose DNA methylation is measured by EpiTYPER assay. In healthy subjects (n = 278), epigenetic age calculated using the targeted clock was highly correlated with chronological age (Spearman correlation = 0.89). Most importantly, and in agreement with previous results from genome-wide clocks, epigenetic age was significantly higher and lower than expected in models of increased (persons with Down syndrome, n = 62) and decreased (centenarians, n = 106; centenarians' offspring, n = 143; nutritional intervention in elderly, n = 233) biological age, respectively. These results support the potential of our targeted epigenetic clock as a new marker of biological age and open its evaluation in large cohorts to further promote the assessment of biological age in healthcare practice.

Knowledge of Nutrition and Physical Activity Guidelines is Not Associated with Physical Function in Dutch Older Adults Attending a Healthy Ageing Public Engagement Event.

Purpose: Evidence-based guidelines on nutrition and physical activity are used to increase knowledge in order to promote a healthy lifestyle. However, actual knowledge of guidelines is limited and whether it is associated with health outcomes is unclear. Participants and Methods: This inception cohort study aimed to investigate the association of knowledge of nutrition and physical activity guidelines with objective measures of physical function and physical activity in community-dwelling older adults attending a public engagement event in Amsterdam, The Netherlands. Knowledge of nutrition and physical activity according to Dutch guidelines was assessed using customized questionnaires. Gait speed and handgrip strength were proxies of physical function and the Minnesota Leisure Time Physical Activity Questionnaire was used to assess physical activity in minutes/week. Linear regression analysis, stratified by gender and adjusted for age, was used to study the association between continuous and categorical knowledge scores with outcomes. Results: In 106 older adults (mean age=70.1 SD=6.6, years) who were highly educated, well-functioning, and generally healthy, there were distinct knowledge gaps in nutrition and physical activity which did not correlate with one another (R2=0.013, p=0.245). Knowledge of nutrition or physical activity guidelines was not associated with physical function or physical activity. However, before age-adjustment nutrition knowledge was positively associated with HGS in males (B= 0.64 (95% CI: 0.05, 1.22)) and having knowledge above the median was associated with faster gait speed in females (B=0.10 (95% CI: 0.01, 0.19)). Conclusion: Our findings may represent a ceiling effect of the impact knowledge has on physical function and activity in the this high performing and educated population and that there may be other determinants of behavior leading to health status such as attitude and perception to consider in future studies.

Down syndrome, accelerated aging and immunosenescence.

Down syndrome is the most common chromosomal disorder, associated with moderate to severe intellectual disability. While life expectancy of Down syndrome population has greatly increased over the last decades, mortality rates are still high and subjects are facing prematurely a phenomenon of atypical and accelerated aging. The presence of an immune impairment in Down syndrome subjects is suggested for a long time by the existence of an increased incidence of infections, the incomplete efficacy of vaccinations, and a high prevalence of autoimmunity. Immunologic abnormalities have been described since many years in this population, both from a numerical and a functional points of view, and these abnormalities can mirror the ones observed during normal aging. In this review, we summarize our knowledge on immunologic disturbances commonly observed in subjects with Down syndrome, and in innate and adaptive immunity, as well as regarding chronic inflammation. We then discuss the role of accelerated aging in these observed abnormalities and finally review the potential age-associated molecular and cellular mechanisms involved.

Age-related DNA methylation changes are sex-specific: a comprehensive assessment.

The existence of a sex gap in human health and longevity has been widely documented. Autosomal DNA methylation differences between males and females have been reported, but so far few studies have investigated if DNA methylation is differently affected by aging in males and females. We performed a meta-analysis of 4 large whole blood datasets, comparing 4 aspects of epigenetic age-dependent remodeling between the two sexes: differential methylation, variability, epimutations and entropy. We reported that a large fraction (43%) of sex-associated probes undergoes age-associated DNA methylation changes, and that a limited number of probes show age-by-sex interaction. We experimentally validated 2 regions mapping in FIGN and PRR4 genes and showed sex-specific deviations of their methylation patterns in models of decelerated (centenarians) and accelerated (Down syndrome) aging. While we did not find sex differences in the age-associated increase in epimutations and entropy, we showed that the number of probes having an age-related increase in methylation variability is 15 times higher in males compared to females. Our results can offer new epigenetic tools to study the interaction between aging and sex and can pave the way to the identification of molecular triggers of sex differences in longevity and age-related diseases prevalence.