20 years of experience with tumour necrosis factor inhibitors: what have we learned?

Caporali, Roberto; Crepaldi, G.; Codullo, Veronica; Benaglio, Francesca; Monti, Sara; Todoerti, Monica; Montecucco, Carlomaurizio

doi:10.1093/rheumatology/key059

Cited by 36 publications

(18 citation statements)

References 67 publications

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“…Currently, several Food and Drug Administration-approved biological inhibitors that broadly inhibit TNF activity across all cell types are in clinical use for the treatment of diverse autoimmune disorders (59). Although of great clinical value, these agents are also complicated by serious adverse events in some patients because of their broad mode of action (60,61).…”

Section: Discussionmentioning

confidence: 99%

Identification of a Distal Locus Enhancer Element That Controls Cell Type–Specific TNF and LTA Gene Expression in Human T Cells

Jasenosky

Nambu

Tsytsykova

et al. 2020

The Journal of Immunology

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The human TNF/LT locus genes TNF, LTA, and LTB are expressed in a cell type–specific manner. In this study, we show that a highly conserved NFAT binding site within the distal noncoding element hHS-8 coordinately controls TNF and LTA gene expression in human T cells. Upon activation of primary human CD4+ T cells, hHS-8 and the TNF and LTA promoters display increased H3K27 acetylation and nuclease sensitivity and coordinate induction of TNF, LTA, and hHS-8 enhancer RNA transcription occurs. Functional analyses using CRISPR/dead(d)Cas9 targeting of the hHS-8-NFAT site in the human T cell line CEM demonstrate significant reduction of TNF and LTA mRNA synthesis and of RNA polymerase II recruitment to their promoters. These studies elucidate how a distal element regulates the inducible cell type–specific gene expression program of the human TNF/LT locus and provide an approach for modulation of TNF and LTA transcription in human disease using CRISPR/dCas9.

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Section: Discussionmentioning

confidence: 99%

Identification of a Distal Locus Enhancer Element That Controls Cell Type–Specific TNF and LTA Gene Expression in Human T Cells

Jasenosky

Nambu

Tsytsykova

et al. 2020

The Journal of Immunology

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“…Mice are the most commonly used models because they are immunologically similar to humans, genetically tractable, and economical. Studies in inbred mice demonstrated the importance of CD4 ϩ T cells, gamma interferon (IFN-␥), and tumor necrosis factor alpha (TNF-␣) among other immunological mediators that are clearly relevant to tuberculosis in humans (5)(6)(7)(8)(9)(10). However, M. tuberculosis infection of the most commonly used inbred mouse strains, such as C57BL/6J (B6) or BALB/c, does not result in all aspects of human tuberculosis or outcomes after vaccination.…”

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confidence: 99%

The Diversity Outbred Mouse Population Is an Improved Animal Model of Vaccination against Tuberculosis That Reflects Heterogeneity of Protection

Kurtz

Rossi

Beamer

et al. 2020

mSphere

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Many studies of Mycobacterium tuberculosis infection and immunity have used mouse models. However, outcomes of vaccination and challenge with M. tuberculosis in inbred mouse strains do not reflect the full range of outcomes seen in people. Previous studies indicated that the novel Diversity Outbred (DO) mouse population exhibited a spectrum of outcomes after primary aerosol infection with M. tuberculosis. Here, we demonstrate the value of this novel mouse population for studies of vaccination against M. tuberculosis aerosol challenge. Using the only currently licensed tuberculosis vaccine, we found that the DO population readily controlled systemic Mycobacterium bovis BCG bacterial burdens and that BCG vaccination significantly improved survival across the DO population upon challenge with M. tuberculosis. Many individual DO mice that were vaccinated with BCG and then challenged with M. tuberculosis exhibited low bacterial burdens, low or even no systemic dissemination, little weight loss, and only minor lung pathology. In contrast, some BCG-vaccinated DO mice progressed quickly to fulminant disease upon M. tuberculosis challenge. Across the population, most of these disease parameters were at most modestly correlated with each other and were often discordant. This result suggests the need for a multiparameter metric to better characterize “disease” and “protection,” with closer similarity to the complex case definitions used in people. Taken together, these results demonstrate that DO mice provide a novel small-animal model of vaccination against tuberculosis that better reflects the wide spectrum of outcomes seen in people. IMPORTANCE We vaccinated the Diversity Outbred (DO) population of mice with BCG, the only vaccine currently used to protect against tuberculosis, and then challenged them with M. tuberculosis by aerosol. We found that the BCG-vaccinated DO mouse population exhibited a wide range of outcomes, in which outcomes in individual mice ranged from minimal respiratory or systemic disease to fulminant disease and death. The breadth of these outcomes appears similar to the range seen in people, indicating that DO mice may serve as an improved small-animal model to study tuberculosis infection and immunity. Moreover, sophisticated tools are available for the use of these mice to map genes contributing to control of vaccination. Thus, the present studies provided an important new tool in the fight against tuberculosis.

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“…The single observed improvement for cancer screening was the one related to skin cancer. This probably reflects the current interest in a potential higher risk of skin cancer on tumour necrosis factor inhibitors 36 37…”

Section: Discussionmentioning

confidence: 90%

Screening for and management of comorbidities after a nurse-led program: results of a 3-year longitudinal study in 769 established rheumatoid arthritis patients

et al. 2019

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Background/purposeCardiovascular (CV) risk, cancer, infections and osteoporosis should be screened for in rheumatoid arthritis (RA). The objective was to assess 3-year effects of a nurse visit for comorbidity counselling.MethodsThis was an open long-term (3 years) extension of the Comorbidities and Education in Rheumatoid Arthritis 6-month randomised controlled trial in which patients with definite, stable RA were visiting a nurse for comorbidity counselling. Comorbidity status was assessed and nurses provided advice on screening and management, at baseline and 3 years later. A score was developed to quantify comorbidity screening and management: 0–100, where lower scores indicate better screening and management. The score was compared between baseline and 3-year assessment using a Wilcoxon test for paired data.ResultsOf the 970 recruited patients, 776 (80%) were followed-up at 2–4 years and 769 (79%) had available data for comorbidities at both time points: mean (±SD) age 58 (±11) years and mean disease duration 14 (±10) years; 614 (80%) were women, the mean Disease Activity Score 28 was 3.0±1.3, and 538 (70%) were receiving a biologic. At baseline, the mean comorbidity screening score was 36.6 (±19.9) and it improved at 3 years to 24.3 (±17.8) (p<0.0001), thus with a relative improvement of 33% (improvement of 12 points). CV risk screening, vaccination status and bone densitometry performance improved the most.ConclusionsComorbidity screening was suboptimal but improved notably over 3 years, after a nurse-led programme aiming at checking systematically for comorbidity screening and giving patient advice. This long-term efficacy pleads in favour of nurse-led interventions to better address comorbidities in RA.Trial registration numberNCT01315652

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20 years of experience with tumour necrosis factor inhibitors: what have we learned?

Cited by 36 publications

References 67 publications

Identification of a Distal Locus Enhancer Element That Controls Cell Type–Specific TNF and LTA Gene Expression in Human T Cells

Identification of a Distal Locus Enhancer Element That Controls Cell Type–Specific TNF and LTA Gene Expression in Human T Cells

The Diversity Outbred Mouse Population Is an Improved Animal Model of Vaccination against Tuberculosis That Reflects Heterogeneity of Protection

Screening for and management of comorbidities after a nurse-led program: results of a 3-year longitudinal study in 769 established rheumatoid arthritis patients

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