Biologic prescribing decisions following serious infection: results from the British Society for Rheumatology Biologics Register-Rheumatoid Arthritis.

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.

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.

Does tuberculosis threaten our ageing populations?

BACKGROUND: The 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). DISCUSSION: Ongoing 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. More 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.

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.

Primary care attitudes to methotrexate monitoring.

BACKGROUND: Rheumatoid arthritis affects 1% of the UK population. First-line treatment is with the immunosuppressant, methotrexate (MTX). This is generally regarded as a safe and effective medication when taken at the right dose, with appropriate monitoring. Very occasionally it causes serious harm or death. In 2006, the National Patient Safety Agency issued a safety alert following increasing reports of prescribing errors and toxicity. Over the last decade, Northwick Park Hospital has seen two MTX-related deaths and other morbidity. Repeat prescriptions and monitoring are generally undertaken in primary care, although concerns have been raised about variation in local practice. Poor communication and inadequate monitoring are safety concerns. Duplication of monitoring has cost implications. Local (hospital Shared Care Guidelines (SCG) ) and national guidelines, from the British Society of Rheumatology (BSR), on MTX monitoring are freely available and accessible. METHOD: We surveyed our local GP community to better understand their practice and establish where patient care could be improved. RESULTS: We contacted 86 practices, of which 31 replied (a response rate of 36%). On average, there was one patient on MTX per 743 in the practice (0.13%), ranging from 0-0.5%. All GPs admitted they repeated MTX prescriptions, but only 77.4% monitored these. Of those who did monitor, 58.6% were aware of local guidelines and only 48.4% were aware of national guidelines. A total of 26.7% of GPs were monitoring and prescribing MTX but not aware of any guidelines. Among this number, 37.5% did not feel they needed further education. CONCLUSION: Serious safety concerns have been raised, including the poor response rate. Any doctor prescribing MTX should also be monitoring according to guidelines. Low numbers of patients on MTX per practice are surprising, possibly reflecting inadequate records or under-diagnosis. With these data, we have encouraged commissioners to fund a computer monitoring system accessible to primary and secondary care for improved patient safety, and to ultimately save costs by reducing duplication of work.

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.

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.

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.

Options for taking time out of specialty training.

Trainees in higher specialty training programmes may have the option to take time out of their training programme to enhance or broaden their skills and perhaps develop a subspecialty interest. Traditionally, out of programme experience has been mostly taken by clinical academic trainees in order to undertake a higher research degree. However, there are a growing number of other ways to usefully spend time out of programme. This article is intended to highlight the range of opportunities and explain the modern processes for obtaining permissions to enable trainees to make good choices for themselves.

Infections in biological agents used in rheumatic disease.

Immunosuppression and biological therapies are being used exponentially to treat inflammatory arthritis and connective tissue diseases. This article discusses the potential infectious complications of these therapies.

Management of persistent inflammatory large joint monoarthritis.

Persistent inflammatory monoarthritis is inflammation of one joint, with symptoms lasting beyond 3 months. Approximately 50 % of cases are self-limiting; others will transform into oligo- or polyarticular disease, but a significant minority remain as a persistent inflammatory monoarthritis, which are often resistant to standard therapies used for oligo- or polyarticular disease and constitute a difficult therapeutic problem. However, there are no clear guidelines for treatment of this category of patients or an evidence-based consensus view on best treatment. A literature search was done through PubMed using 'monoarthritis', 'chronic synovitis' and 'persistent inflammatory monoarthritis' as search terms. Reports were located using references to related articles; reports in humans and animals, published in English, were included. Persistent inflammatory monoarthritis has a variable disease course, generally with a better prognosis than polyarthritis. There is no clear evidence for the use of traditional DMARDS in monoarthritis, and treatment algorithms are extrapolated from oligo- or polyarticular disease. Intra-articular anti-tumour necrosis factor (TNF) has been used with similar efficacy to intra-articular corticosteroids, and as yet, there are no reported cases of systemic anti-TNF use in monoarthritis. Synovectomy may be of use, with lower risk of recurrent disease, in open synovectomy. There is paucity of evidence for best practice in the management of chronic monoarthritis. Questions remain concerning the indications for invasive procedures and the balance between toxicity of systemic therapies versus the intended benefits to prevent disability. There is a pressing need for further studies and randomised controlled trials to be performed in this subset of patients.