Blockade of tumor necrosis factor in collagen-induced arthritis reveals a novel immunoregulatory pathway for Th1 and Th17 cells

IL-17 is implicated in the pathogenesis of rheumatoid arthritis (RA) and has previously been shown to be induced by tumor necrosis factor (TNF) in vitro. The aim of this study was to assess the impact of TNF inhibition on IL-17 production in collagen-induced arthritis, a model of RA. TNF blockade using TNFR-Fc fusion protein or anti-TNF monoclonal antibody reduced arthritis severity but, unexpectedly, expanded populations of Th1 and Th17 cells, which were shown by adoptive transfer to be pathogenic. Th1 and Th17 cell populations were also expanded in collagen-immunized TNFR p55−/− but not p75−/− mice. The expression of IL-12/IL-23 p40 was up-regulated in lymph nodes (LN) from p55−/− mice, and the expansion of Th1/Th17 cells was abrogated by blockade of p40. Treatment of macrophages with rTNF also inhibited p40 production in vitro. These findings indicate that at least one of the ways in which TNF regulates Th1/Th17 responses in arthritis is by down-regulating the expression of p40. Finally, although TNF blockade increased numbers of Th1 and Th17 cells in LN, it inhibited their accumulation in the joint, thereby providing an explanation for the paradox that anti-TNF therapy ameliorates arthritis despite increasing numbers of pathogenic T cells

The British Society for Rheumatology Biologics Registers in Ankylosing Spondylitis (BSRBR-AS) study: Protocol for a prospective cohort study of the long-term safety and quality of life outcomes of biologic treatment

This is the final version of the article. Available from BioMed Central via the DOI in this record.BACKGROUND: Axial spondyloarthropathy typically has its onset in early adulthood and can impact significantly on quality of life. In the UK, biologic anti-tumour necrosis factor therapy is recommended for patients who are unresponsive to non-steroidal anti-inflammatory drugs. There remain several unresolved issues about the long-term safety and quality of life outcomes of biologic treatment in axial spondyloarthropathy. Long-term "real-world" surveillance data are required to complement data from randomised controlled trials. METHODS/DESIGN: We are conducting a UK-wide prospective cohort study of patients with axial spondyloarthropathy who are naïve to biologic therapy at the time of recruitment. Those about to commence anti-tumour necrosis factor biologic therapy will enter a "biologic" sub-cohort with other patients assigned to a "non-biologic" sub-cohort. The primary objective is to determine whether the use of biologic therapy is associated with an increased risk of serious infection, while secondary objectives are to assess differences in malignancy, serious comorbidity, all-cause mortality but also assess impact on specific clinical domains (physical health, mental health and quality of life) including work outcomes between biologic and non-biologic patient cohorts. Patients will be followed-up for up to 5 years. Data are obtained at baseline and at standard clinical follow-up visits - at 3, 6 and 12 months and then annually for the biologic cohort and annually for the non-biologic cohort. This study will also collect biological samples for genetic analysis. DISCUSSION: Although biologic therapy is widely used for ankylosing spondylitis patients who are unresponsive to non-steroidal anti-inflammatory drugs, the majority of the available safety information comes from rheumatoid arthritis, where increased infection risk has consistently been shown. However, given the typical demographic differences between rheumatoid arthritis and axial spondyloarthropathy patients, it is important to develop an epidemiologically rigorous cohort of patients receiving biologic therapy to effectively evaluate outcomes with regard not only to safety but also to quantify benefits across clinical, psychosocial and work outcomes. CLINICAL TRIAL REGISTRATION: This is an observational cohort study and clinical trial registration was not required or obtained.BSRBR-AS is funded by the BSR, which in turn receives funding from the manufacturers of the biologic therapies included in this study (currently AbbVie, Pfizer and UCB). Pharmaceutical companies providing funds to BSR do not have a role in the oversight of the study, but they do receive advance notice of publications on which they are able to comment. They do not have access to the data collected but can request analyses of the data, for which additional funds are provided. GJM chairs a Pfizer competitive grant committee for which he receives an honorarium. GJM and GTJ have received separate funding from AbbVie and Pfizer to study spondyloarthritis in the Scotland Registry for Ankylosing Spondylitis (SIRAS) study. LK has received an unrestricted educational grant from UCB. AK has received research funding from Abbvie and Pfizer as well as speaker/chairman fees and payments for attending advisory boards from Abbvie, Pfizer and UCB. The remaining authors have no competing interests

Chlorhexidine versus povidone–iodine skin antisepsis before upper limb surgery (CIPHUR) : an international multicentre prospective cohort study

Introduction Surgical site infection (SSI) is the most common and costly complication of surgery. International guidelines recommend topical alcoholic chlorhexidine (CHX) before surgery. However, upper limb surgeons continue to use other antiseptics, citing a lack of applicable evidence, and concerns related to open wounds and tourniquets. This study aimed to evaluate the safety and effectiveness of different topical antiseptics before upper limb surgery. Methods This international multicentre prospective cohort study recruited consecutive adults and children who underwent surgery distal to the shoulder joint. The intervention was use of CHX or povidone–iodine (PVI) antiseptics in either aqueous or alcoholic form. The primary outcome was SSI within 90 days. Mixed-effects time-to-event models were used to estimate the risk (hazard ratio (HR)) of SSI for patients undergoing elective and emergency upper limb surgery. Results A total of 2454 patients were included. The overall risk of SSI was 3.5 per cent. For elective upper limb surgery (1018 patients), alcoholic CHX appeared to be the most effective antiseptic, reducing the risk of SSI by 70 per cent (adjusted HR 0.30, 95 per cent c.i. 0.11 to 0.84), when compared with aqueous PVI. Concerning emergency upper limb surgery (1436 patients), aqueous PVI appeared to be the least effective antiseptic for preventing SSI; however, there was uncertainty in the estimates. No adverse events were reported. Conclusion The findings align with the global evidence base and international guidance, suggesting that alcoholic CHX should be used for skin antisepsis before clean (elective upper limb) surgery. For emergency (contaminated or dirty) upper limb surgery, the findings of this study were unclear and contradict the available evidence, concluding that further research is necessary

HspB1 deficiency results in increased neutrophil but slightly decreased macrophage infiltration of wounds.

<p>A, Neutrophil infiltration in d1 wound granulation tissue assessed by IHC for neutrophil elastase (NE) and macrophage infiltration at d3 detected by F4/80 staining. B, Plot shows elastase positive neutrophils (NE+) per high power field (hpf); 7 fields/wound; 2 wounds per mouse; n = 4 mice; **P<0.01. B, Plot as for (B) showing F4/80-positive cells/hpf; *P<0.05.</p

Histological analysis showing reduced re-epithelialisation, impaired collagen deposition and increased cellular infiltration in <i>hspB1</i>^del/del relative to wild-type wounds.

<p>A, Masson’s trichrome staining of wild-type and <i>hspB1</i>^del/del d3 and B, d7 wounds as in Fig. 5; bar = 500 µm. C, High power images of cellular infiltrate from boxed regions indicated in (A) are shown (bar = 100 µm). D, as for (C) but at higher magnification showing cells with multi-lobed nuclei characteristic of neutrophils; (bar = 20 µm).E, Plot showing mean areas of incomplete collagen deposition in d7 wild-type and <i>hspB1</i>^del/del wounds (n = 5); **P<0.01. F, Plot of mean distance±SEM (n = 3 mice per group) between re-epithelialisation margins (re-ep) in wild-type and <i>hspB1</i>^del/del mice in d3 wounds; (*P<0.05 calculated by Student’s <i>t</i>-test of 12 individual wounds per group from 3 experiments). 11–14 week age-matched female wild-type and <i>hspB1</i>^del/del mice were used.</p

HspB1 deficiency inhibits entry into S phase and increases the expression of p21^waf1 and p27 ^kip1.

<p>A, BrdU incorporation following a 2-positive cells (mean % ± SEM) from three independent experiments performed; **P<0.01. C, Western blot of asynchronous MEF lysates for p21^waf1, p27^kip1, hspB1 and GAPDH as a loading control with molecular weights (kDa) of markers indicated. Western blots are representative of three independent experiments.</p

HspB1 protein expression in unwounded and wounded murine skin.

<p>A, Unwounded female wild-type skin was stained with Masson’s trichrome; (bar = 100 µm). B, HspB1 was detected by IHC in unwounded female wild-type. Inset: High power image showing hspB1 staining in cells with fibroblast-like morphology in connective tissue beneath panniculus carnosus. C, Unwounded female <i>hspB1</i>^del/del skin showing lack of staining with anti-hspB1 antibody. Inset as for (B); (bar = 10 µm). D, HspB1 staining at d3 post-wounding showing expression in epithelial tongues and cells in granulation tissue (representative wounds from 11 mice in three experiments) E, High power image of boxed region indicated in (D) showing hspB1 expressing cells with fibroblast-like morphology in granulation tissue. F, hspB1 staining at d7 showing expression in newly formed muscle, and epithelium (representative wounds from 7–8 mice in two experiments); (bar = 500 µm). G, High power image of boxed region indicated in (F) showing expression of hspB1 in newly formed skeletal muscle and microvasculature; (bar = 10 µm). 11–14 week age-matched female wild-type mice were used.</p

Expression of hspB1 protein and mRNA is controlled by the cell cycle.

<p>A, MEF were synchronized by serum starvation for 48% FCS-containing medium and analysed by western blot for hspB1, PCNA, p27^kip1 and actin. B, Comparison of the expression of mRNAs for hspB1 and the cell cycle-regulated genes, Myc, and Cyclin E1 determined by qRT-PCR and normalized to GAPDH in a representative synchronized MEF serum release time course. C, Western blot for hspB1, PCNA and loading control, actin, in lysates of MEF following release from nocodazole G2/M block (40 ng/ml). All western blots shown are representative of at least two independent experiments.</p