Impact of a Patient Support Program on time to discontinuation of adalimumab in Australian adult patients with immune-mediated inflammatory diseases-an observational study.

This observational study evaluated the impact of a sponsor company-provided Patient Support Program (PSP) on discontinuation of adalimumab in adult Australian patients eligible for Pharmaceutical Benefit Scheme (PBS)-reimbursed adalimumab for Rheumatoid Arthritis (RA), Ankylosing Spondylitis (AS), Psoriatic Arthritis (PsA), Crohn's Disease (CD), Ulcerative Colitis (UC), or Hidradenitis Suppurativa (HS). Patients initiating adalimumab between May 2018 and September 2019 were enrolled into two prospective cohorts based on their decision to opt for or decline the PSP (PSP or non-PSP cohorts). In addition, a historical, retrospective Non-PSP cohort was established from the Services Australia 10% PBS dataset by extracting data of patients initiating adalimumab prior to the introduction of adalimumab PSPs and based on adalimumab PBS listing dates (AS: April 2007 to March 2009; PsA/RA: January 2007 to December 2008; CD: January 2009 to December 2010; HS and UC indications not included). Follow-up for all cohorts was 12 months. The primary endpoint was the time to discontinuation, compared between the prospective PSP cohort and the prospective or retrospective Non-PSP cohort. Inverse probability of treatment weighting was used to balance the cohorts. A Cox proportional hazards model indicated no difference in time to discontinuation between the prospective PSP (n = 162) and non-PSP (n = 65) cohorts (HR [95% CI] = 1.256 [0.616-2.563], p = 0.5304). The 12-month adalimumab persistence rates (95% CI) were 78% (69%, 84%) and 82% (67%, 90%), respectively. In contrast, discontinuation was less likely in the prospective PSP (n = 151) compared with the retrospective non-PSP (n = 297) cohort (HR [95% CI] = 0.44 [0.28-0.68], p<0.001). The 12-month persistence rates (95% CI) were 81% (76%, 90%) and 61% (56%, 67%), respectively. Overall, this study suggests that optimal adalimumab persistence can be achieved with either a structured PSP or healthcare support from other sources, but this was not the case more than a decade ago.

Chromatin disruption in the promoter of bovine leukemia virus during transcriptional activation.

Bovine leukemia virus expression relies on its chromatin organization after integration into the host cell genome. Proviral latency, which results from transcriptional repression in vivo, represents a viral strategy to escape the host immune system and likely allows for tumor progression. Here, we discriminated two types of latency: an easily reactivable latent state of the YR2 provirus and a 'locked' latent state of the L267 provirus. The defective YR2 provirus was characterized by the presence of nuclease hypersensitive sites at the U3/R junction and in the R/U5 region of the 5'-long terminal repeat (5'-LTR), whereas the L267 provirus displayed a closed chromatin configuration at the U3/R junction. Reactivation of viral expression in YR2 cells by the phorbol 12-myristate 13-acetate (PMA) plus ionomycin combination was accompanied by a rapid but transient chromatin remodeling in the 5'-LTR, leading to an increased PU.1 and USF-1/USF-2 recruitment in vivo sustained by PMA/ionomycin-mediated USF phosphorylation. In contrast, viral expression was not reactivated by PMA/ionomycin in L267 cells, because the 5'-LTR U3/R region remained inaccessible to nucleases and hypermethylated at CpG dinucleotides. Remarkably, we elucidated the BLV 5'-LTR chromatin organization in PBMCs isolated from BLV-infected cows, thereby depicting the virus hiding in vivo in its natural host.

A pervasive role of histone acetyltransferases and deacetylases in an NF-kappaB-signaling code.

Most nuclear factor-kappaB (NF-kappaB) inducers converge to activate the IkappaB kinase (IKK) complex, leading to NF-kappaB nuclear accumulation. However, depending on the inducer and the cell line, the subset of NF-kappaB-induced genes is different, underlining a complex regulation network. Recent findings have begun to delineate that histone and non-histone protein acetylation is involved, directly and indirectly, in controlling the duration, strength and specificity of the NF-kappaB-activating signaling pathway at multiple levels. Acetylation and deacetylation events, in combination with other post-translational protein modifications, generate an 'NF-kappaB-signaling code' and regulate NF-kappaB-dependent gene transcription in an inducer- and promoter-dependent manner. Indeed, the intricate involvement of histone acetyltransferases and histone deacetylases modulates both the NF-kappaB-signaling pathway and the transcriptional transactivation of NF-kappaB-dependent genes.

Hidradenitis Suppurativa (HS) prevalence, demographics and management pathways in Australia: A population-based cross-sectional study.

BACKGROUND: Hidradenitis Suppurativa (HS) is a painful, chronic inflammatory skin disease. Global estimates of prevalence vary between 0.03% and 4% of the population. Our main aim was to determine HS prevalence in the Australian adult population focussing on the demographics, management pathways and diagnosis rate of individuals living with HS. METHODS: In this population-based cross-sectional study, 17,050 individuals representative of the Australian adult population were asked through face-to-face household interviews to answer a previously validated HS screening questionnaire with high diagnostic power. Individuals who screened positive were asked additional questions, including previous diagnosis of HS and number/type of physicians consulted regarding their condition. RESULTS: 11,433 Australian residents answered the HS questionnaire, 88 screening positive for HS (0.77%; 95% CI 0.62-0.95). Considering the previously reported sensitivity (0.97) and positive predictive value (0.85) of the screening questionnaire, HS prevalence was estimated to be 0.67% (95% CI 0.53%-0.84%). 6 of 88 suspected HS individuals reported a pre-existing HS diagnosis (6.8%; 95% CI 3.2%-14.1%). 25.6% of the undiagnosed individuals suspected of having HS had not seen any clinicians regarding their boils; the remaining ones had consulted General Practitioners (96.7%), and clinicians from different specialties. Comparisons of individuals who screened positive for HS versus those who screened negative demonstrated statistically significant differences in gender (p = 0.0046), age (p<0.0001), BMI (p = 0.0307), smoking status (p<0.0001), employment status (p<0.0001) and income (p = 0.0321). CONCLUSIONS: The prevalence of HS in Australia was estimated to be 0.67% (95% CI 0.53%-0.84%). The diagnosis rate amongst the suspected HS cases was low, which appeared to be due to a combination of patients not seeking help and decentralization of care. Individuals suspected of having HS were more likely to be females, young, obese, smokers, unemployed or at home duties and having lower annual personal income in comparison with individuals not suspected of having HS.

Synergistic activation of HIV-1 expression by deacetylase inhibitors and prostratin: implications for treatment of latent infection.

The persistence of transcriptionally silent but replication-competent HIV-1 reservoirs in Highly Active Anti-Retroviral Therapy (HAART)-treated infected individuals, represents a major hurdle to virus eradication. Activation of HIV-1 gene expression in these cells together with an efficient HAART has been proposed as an adjuvant therapy aimed at decreasing the pool of latent viral reservoirs. Using the latently-infected U1 monocytic cell line and latently-infected J-Lat T-cell clones, we here demonstrated a strong synergistic activation of HIV-1 production by clinically used histone deacetylase inhibitors (HDACIs) combined with prostratin, a non-tumor-promoting nuclear factor (NF)- kappaB inducer. In J-Lat cells, we showed that this synergism was due, at least partially, to the synergistic recruitment of unresponsive cells into the expressing cell population. A combination of prostratin+HDACI synergistically activated the 5' Long Terminal Repeat (5'LTR) from HIV-1 Major group subtypes representing the most prevalent viral genetic forms, as shown by transient transfection reporter assays. Mechanistically, HDACIs increased prostratin-induced DNA-binding activity of nuclear NF-kappaB and degradation of cytoplasmic NF-kappaB inhibitor, IkappaBalpha . Moreover, the combined treatment prostratin+HDACI caused a more pronounced nucleosomal remodeling in the U1 viral promoter region than the treatments with the compounds alone. This more pronounced remodeling correlated with a synergistic reactivation of HIV-1 transcription following the combined treatment prostratin+HDACI, as demonstrated by measuring recruitment of RNA polymerase II to the 5'LTR and both initiated and elongated transcripts. The physiological relevance of the prostratin+HDACI synergism was shown in CD8(+)-depleted peripheral blood mononuclear cells from HAART-treated patients with undetectable viral load. Moreover, this combined treatment reactivated viral replication in resting CD4(+) T cells isolated from similar patients. Our results suggest that combinations of different kinds of proviral activators may have important implications for reducing the size of latent HIV-1 reservoirs in HAART-treated patients.