Long-term effectiveness of tumour necrosis factor-α inhibitor treatment for psoriatic arthritis in the UK: a multicentre retrospective study.

OBJECTIVE: Real-world evidence of the long-term effectiveness of TNF-α inhibitor (TNFi) therapy in patients with PsA is limited. This study was conducted to describe patterns of TNFi therapy and treatment responses in patients with PsA treated in UK clinical practice. METHODS: A multicentre, retrospective, observational cohort study of consenting patients treated with TNFi for PsA with ≥3 years follow-up from first TNFi initiation (observation period) was carried out in 11 UK National Health Service hospitals. Data were collected concerning baseline patient characteristics, PsA-related treatment pathways and TNFi treatment responses (PsA response criteria components: swollen/tender joint counts, physician and patient global assessments). RESULTS: The mean age of patients (n = 141) was 50.3 (s.d.: 12.1) years (50% male). During a median observation period of 4.5 (range: 3.4-5.5) years, patients received a median of one (range: one to five) TNFi. Twelve-week response rates for first TNFi (where available) were as follows: 80% (n = 64/80) for swollen joint counts, 79% (n = 63/79) for tender joint counts, 79% (n = 37/47) for physician global assessments, 69% (n = 41/59) for patient global assessments and 79% (n = 37/47) for PsA response criteria. At the end of the observation period, the proportions of patients remaining on first, second, third and fourth/fifth TNFi were 56, 15, 5 and 3%, respectively; 21% of patients permanently discontinued TNFi therapy. CONCLUSION: Long-term TNFi therapy is generally well tolerated and may be effective; however, after initial TNFi failure, there appears to be progressively less benefit and more adverse effects with successive TNFi switches. Strategies are needed for effective therapy for PsA beyond the first TNFi failure.

Introduction of a novel service model to improve uptake and adherence with cardiac rehabilitation within Buckinghamshire Healthcare NHS Trust.

BACKGROUND: Buckinghamshire Healthcare NHS Trust (BHT) carried out a cardiac rehabilitation (CR) service redesign aimed at optimising patient recruitment and retention and decreasing readmissions. METHODS: A single centre observational study and local service evaluation were carried out to describe the impact of the novel technology-enabled CR model. Data were collected for adult patients referred for CR at BHT, retrospectively for patients referred during the 12-month pre-implementation period (Cohort 1) and prospectively for patients referred during the 12-month post-implementation period (Cohort 2). The observational study included 350 patients in each cohort, seasonally matched; the service evaluation included all eligible patients. No data imputation was performed. RESULTS: In the observational study, a higher proportion of referred patients entered CR in Cohort 2 (84.3%) than Cohort 1 (76.0%, P = 0.006). Fewer patients in Cohort 2 had ≥1 cardiac-related emergency readmission within 6 months of discharge (4.3%) than Cohort 1 (8.9%, P = 0.015); readmissions within 30 days and 12 months were not significantly different. Median time to CR entry from discharge was significantly shorter in Cohort 2 (35.0 days) than Cohort 1 (46.0 days, P < 0.001). The CR completion rate was significantly higher in Cohort 2 (75.6%) than Cohort 1 (47.4%, P < 0.001); median CR duration for completing patients was significantly longer in Cohort 2 (80.0 days) than Cohort 1 (49.0 days, P < 0.001). Overall, similar results were observed in the service evaluation. CONCLUSIONS: Introduction of the novel technology-enabled CR model was associated with short-term improvements in emergency readmissions and sustained increases in CR entry, duration and completion.

Mre11 and Exo1 contribute to the initiation and processivity of resection at meiotic double-strand breaks made independently of Spo11.

During meiosis DNA double-strand breaks (DSBs) are induced and repaired by homologous recombination to create gene conversion and crossover products. Mostly these DSBs are made by Spo11, which covalently binds to the DSB ends. More rarely in Saccharomyces cerevisiae, other meiotic DSBs are formed by self-homing endonucleases such as VDE, which is site specific and does not covalently bind to the DSB ends. We have used experimentally located VDE-DSB sites to analyse an intermediate step in homologous recombination, resection of the single-strand ending 5' at the DSB site. Analysis of strains with different mutant alleles of MRE11 (mre11-58S and mre11-H125N) and deleted for EXO1 indicated that these two nucleases make significant contributions to repair of VDE-DSBs. Physical analysis of single-stranded repair intermediates indicates that efficient initiation and processivity of resection at VDE-DSBs require both Mre11 and Exo1, with loss of function for either protein causing severe delay in resection. We propose that these experiments model what happens at Spo11-DSBs after removal of the covalently bound protein, and that Mre11 and Exo1 are the major nucleases involved in creating resection tracts of widely varying lengths typical of meiotic recombination.

Evidence that MEK1 positively promotes interhomologue double-strand break repair.

During meiosis there is an imperative to create sufficient crossovers for homologue segregation. This can be achieved during repair of programmed DNA double-strand breaks (DSBs), which are biased towards using a homologue rather than sister chromatid as a repair template. Various proteins contribute to this bias, one of which is a meiosis specific kinase Mek1. It has been proposed that Mek1 establishes the bias by creating a barrier to sister chromatid repair, as distinct from enforcing strand invasion with the homologue. We looked for evidence that Mek1 positively stimulates strand invasion of the homologue. This was done by analysing repair of DSBs induced by the VMA1-derived endonuclease (VDE) and flanked by directly repeated sequences that can be used for intrachromatid single-strand annealing (SSA). SSA competes with interhomologue strand invasion significantly more successfully when Mek1 function is lost. We suggest the increase in intrachromosomal SSA reflects an opportunistic default repair pathway due to loss of a MEK1 stimulated bias for strand invasion of the homologous chromosome. Making use of an inhibitor sensitive mek1-as1 allele, we found that Mek1 function influences the repair pathway throughout the first4-5 h of meiosis. Perhaps reflecting a particular need to create bias for successful interhomologue events before chromosome pairing is complete.

Excess single-stranded DNA inhibits meiotic double-strand break repair.

During meiosis, self-inflicted DNA double-strand breaks (DSBs) are created by the protein Spo11 and repaired by homologous recombination leading to gene conversions and crossovers. Crossover formation is vital for the segregation of homologous chromosomes during the first meiotic division and requires the RecA orthologue, Dmc1. We analyzed repair during meiosis of site-specific DSBs created by another nuclease, VMA1-derived endonuclease (VDE), in cells lacking Dmc1 strand-exchange protein. Turnover and resection of the VDE-DSBs was assessed in two different reporter cassettes that can repair using flanking direct repeat sequences, thereby obviating the need for a Dmc1-dependent DNA strand invasion step. Access of the single-strand binding complex replication protein A, which is normally used in all modes of DSB repair, was checked in chromatin immunoprecipitation experiments, using antibody against Rfa1. Repair of the VDE-DSBs was severely inhibited in dmc1Delta cells, a defect that was associated with a reduction in the long tract resection required to initiate single-strand annealing between the flanking repeat sequences. Mutants that either reduce Spo11-DSB formation or abolish resection at Spo11-DSBs rescued the repair block. We also found that a replication protein A component, Rfa1, does not accumulate to expected levels at unrepaired single-stranded DNA (ssDNA) in dmc1Delta cells. The requirement of Dmc1 for VDE-DSB repair using flanking repeats appears to be caused by the accumulation of large quantities of ssDNA that accumulate at Spo11-DSBs when Dmc1 is absent. We propose that these resected DSBs sequester both resection machinery and ssDNA binding proteins, which in wild-type cells would normally be recycled as Spo11-DSBs repair. The implication is that repair proteins are in limited supply, and this could reflect an underlying mechanism for regulating DSB repair in wild-type cells, providing protection from potentially harmful effects of overabundant repair proteins.