Rachel Byng-Maddick

The impact of biological therapy on regulatory T cells in rheumatoid arthritis

Regulatory T cells (Treg) are functionally defective in patients with RA. Restoring their function may not only control inflammation but also restore tolerance in these patients. Biologic therapies have been tremendously successful in treating RA. Here we review numerous reports suggesting that these immunomodulatory therapies have an impact on Treg and that this may contribute to their beneficial effects. Better understanding of their mode of action may not only lead to improvements in therapies and sustained remission but also enable the development of biomarkers of response, which would be the first steps towards personalized medicine.

Does tuberculosis threaten our ageing populations

BackgroundThe global population is ageing quickly and our understanding of age-related changes in the immune system suggest that the elderly will have less immunological protection from active tuberculosis (TB).DiscussionOngoing global surveillance of TB notifications shows increasing age of patients with active TB. This effect of age is compounded by changes to clinical manifestations of disease, confounding of diagnostic tests and increased rates of adverse reactions to antimicrobial treatment of TB. Future epidemiological surveillance, development of diagnostic tests and trials of treatment shortening should all include a focus on ageing people.SummaryMore detailed surveillance of TB notifications in elderly people should be undertaken and carefully evaluated. Risk stratification will help target care for those in greatest need, particularly those with comorbidities or on immunosuppressive therapies. Novel diagnostics and treatment regimes should be designed specifically to be used in this cohort.

Quantitative Characterization of the T Cell Receptor Repertoire of Naïve and Memory Subsets Using an Integrated Experimental and Computational Pipeline Which Is Robust, Economical, and Versatile

The T cell receptor (TCR) repertoire can provide a personalized biomarker for infectious and non-infectious diseases. We describe a protocol for amplifying, sequencing, and analyzing TCRs which is robust, sensitive, and versatile. The key experimental step is ligation of a single-stranded oligonucleotide to the 3′ end of the TCR cDNA. This allows amplification of all possible rearrangements using a single set of primers per locus. It also introduces a unique molecular identifier to label each starting cDNA molecule. This molecular identifier is used to correct for sequence errors and for effects of differential PCR amplification efficiency, thus producing more accurate measures of the true TCR frequency within the sample. This integrated experimental and computational pipeline is applied to the analysis of human memory and naive subpopulations, and results in consistent measures of diversity and inequality. After error correction, the distribution of TCR sequence abundance in all subpopulations followed a power law over a wide range of values. The power law exponent differed between naïve and memory populations, but was consistent between individuals. The integrated experimental and analysis pipeline we describe is appropriate to studies of T cell responses in a broad range of physiological and pathological contexts.

Recurrent serious infections in patients with rheumatoid arthritis—results from the British Society for Rheumatology Biologics Register

Objectives To establish the rate of recurrent infection in RA patients recruited to the British Society for Rheumatology Biologics Register - Rheumatoid Arthritis. Secondary objectives were to establish whether the organ class of index infection predicted future serious infection (SI). Methods Using data from the British Society for Rheumatology Biologics Register - Rheumatoid Arthritis, a prospective observational cohort, we identified patients with at least one episode of SI. Incidence rates of SI, recurrent SI within the same organ class as the index infection and recurrent SI (of any class) were calculated. A Cox proportional hazards model was used to identify predictors of SI. Results In total, 5289 subjects with at least one SI contributing 19 431 patient-years follow-up were studied. The baseline annual rate of first SI was 4.6% (95% CI: 4.5, 4.7), increasing to 14.1% (95% CI: 13.5, 14.8) following an index infection. Respiratory infections were the most frequent (44% of all events). Recurrent infections mirrored the organ class of the index infection. Sepsis, increasing age and polypharmacy were significant predictors of infection recurrence in a fully adjusted model. The system class of index infection was associated with the risk of a recurrent event; subjects who experienced sepsis had the highest risk of subsequent SI within 12 months, 19.7% (95% CI: 15.1, 25.7). Conclusion Recurrent infections in RA are common. Understanding patterns and predictors of recurrent infection together with the differential infection risk associated with immunosuppressive agents will help personalize RA care, tailor treatment choices better and mitigate against episodes of SI.

Validation of Immune Cell Modules in Multicellular Transcriptomic Data

Numerous gene signatures, or modules have been described to evaluate the immune cell composition in transcriptomes of multicellular tissue samples. However, significant diversity in module gene content for specific cell types is associated with heterogeneity in their performance. In order to rank modules that best reflect their purported association, we have generated the modular discrimination index (MDI) score that assesses expression of each module in the target cell type relative to other cells. We demonstrate that MDI scores predict modules that best reflect independently validated differences in cellular composition, and correlate with the covariance between cell numbers and module expression in human blood and tissue samples. Our analyses demonstrate that MDI scores provide an ordinal summary statistic that reliably ranks the accuracy of gene expression modules for deconvolution of cell type abundance in transcriptional data.

Tumor Necrosis Factor (TNF) Bioactivity at the Site of an Acute Cell-Mediated Immune Response Is Preserved in Rheumatoid Arthritis Patients Responding to Anti-TNF Therapy

The impact of anti-tumor necrosis factor (TNF) therapies on inducible TNF-dependent activity in humans has never been evaluated in vivo. We aimed to test the hypothesis that patients responding to anti-TNF treatments exhibit attenuated TNF-dependent immune responses at the site of an immune challenge. We developed and validated four context-specific TNF-inducible transcriptional signatures to quantify TNF bioactivity in transcriptomic data. In anti-TNF treated rheumatoid arthritis (RA) patients, we measured the expression of these biosignatures in blood, and in skin biopsies from the site of tuberculin skin tests (TSTs) as a human experimental model of multivariate cell-mediated immune responses. In blood, anti-TNF therapies attenuated TNF bioactivity following ex vivo stimulation. However, at the site of the TST, TNF-inducible gene expression and genome-wide transcriptional changes associated with cell-mediated immune responses were comparable to that of RA patients receiving methotrexate only. These data demonstrate that anti-TNF agents in RA patients do not inhibit inducible TNF activity at the site of an acute inflammatory challenge in vivo, as modeled by the TST. We hypothesize instead that their therapeutic effects are limited to regulating TNF activity in chronic inflammation or by alternative non-canonical pathways.

Biologic Prescribing Decisions Following Serious Infection; Results from the British Society for Rheumatology Biologics Register – Rheumatoid Arthritis (BSRBR-RA)

Objectives To establish whether the decision to stop, continue or switch TNF inhibitor (TNFi) therapy to a biologic drug with an alternative mode of action following a serious infection (SI) impacts upon the risk of recurrent SI in patients with RA. Methods Patients recruited to the British Society for Rheumatology Biologics Register-RA with at least one episode of SI while on TNFi were included. The biologic treatment decision following SI was considered. A multivariable adjusted Cox proportional hazards model was used to identify predictors of recurrent SI and whether biologic treatment choices influenced future SI risk. Results In total, 1583 patients suffered at least one SI while on TNFi. Most patients (73%) were recorded as continuing TNFi 60 days after an index SI. The rate of recurrent SI was 25.6% per annum (95% CI: 22.5, 29.2%). The rate of recurrent SI was highest in patients who stopped their TNFi (42.6% per annum, 95% CI: 32.5, 55.7%) and lowest in those who switched biologic drug class (12.1% per annum, 95% CI: 3.9, 37.4%). Compared with patients stopping biologic therapy, patients who continued or switched drug class had significantly lower risk of recurrent SI (drug continuation hazard ratio = 0.54, 95% CI: 0.40, 0.74; drug switch hazard ratio = 0.29, 95% CI: 0.09, 0.95). Conclusions Patients who continued or switched their TNFi post-index SI had a lower risk of recurrent SI infection compared with those who stopped the drug. This may be explained by better control of disease activity with reintroduction of biologic therapy, a driving factor for SI or alternatively channelling fitter patients to restart biologic therapy.