An Age-Progression Intervention for Smoking Cessation: A Pilot Study Investigating the Influence of Two Sets of Instructions on Intervention Efficacy.

BACKGROUND: Research on age-progression facial morphing interventions for smoking cessation has not investigated the effect of different instructions for intervention delivery. The objective of this pilot study was to investigate the influence of two instruction types used to deliver the intervention on efficacy of the intervention. METHOD: Women were recruited and randomly allocated to an age-progression intervention session with (i) neutral instructions; (ii) instructions designed to reassure; or (iii) a condition that controlled for participant engagement ("control"). The conditions were delivered in a one-time procedure, after which primary (quitting intentions) and secondary (cigarettes/week, quit attempts) outcomes were measured immediately post-intervention, and at 1 and 3 months. RESULTS: Seventy-two women (M = 25.7; SD = 0.9) were recruited and randomly allocated to condition (Neutral n = 27, Reassuring n = 22, Control n = 23). Quitting intentions were higher in the Reassuring versus Control arm (3 months post-intervention, F = 4.37, p = 0.016, 95% CI [0.231, 2.539], eta2 = 0.11); quit attempts were greater in the two intervention arms (58%) versus Control (1-month post-intervention, 15%) (χ2 = 9.83, p < 0.05, OR 1.00 [0.28, 3.63]). CONCLUSIONS: Findings highlight the importance of optimising instructions to enhance intervention efficacy. TRIAL REGISTRATION: clinicaltrials.gov Record: NCT03749382.

Can artificial intelligence make elective hand clinic letters easier for patients to understand?

We investigated whether ChatGPT was able to increase the Flesch reading ease and the Flesch-Kincaid reading level of elective clinic letters written by hand surgeons. ChatGPT could not reliably simplify the hand clinic letters any further.

Inhibition of Receptor-Interacting Protein Kinase 1 in Chronic Plaque Psoriasis: A Multicenter, Randomized, Double-Blind, Placebo-Controlled Study.

INTRODUCTION: Receptor-interacting protein kinase 1 (RIPK1), a key mediator of inflammation through necroptosis and proinflammatory cytokine production, may play a role in the pathogenesis of immune-mediated inflammatory diseases such as chronic plaque psoriasis. An experimental medicine study of RIPK1 inhibition with GSK2982772 immediate-release formulation at doses up to 60 mg three times daily in mild to moderate plaque psoriasis indicated that efficacy may be improved with higher trough concentrations of GSK2982772. METHODS: This multicenter, randomized, double-blind, placebo-controlled, repeat-dose study (NCT04316585) assessed the efficacy, safety, pharmacokinetics, and pharmacodynamics of 960 mg GSK2982772 (once-daily modified-release formulation) in patients with moderate to severe plaque psoriasis. Twenty-nine patients were randomized 2:1 to GSK2982772 (N = 19) or placebo (N = 10) for 12 weeks. RESULTS: GSK2982772 was well tolerated with trough concentrations greater than tenfold higher than the previous phase 1 study with immediate release. Despite near complete RIPK1 target engagement in blood and modest reduction in circulating inflammatory cytokines, the proportion of patients achieving 75% improvement from baseline in Psoriasis Area Severity Index score at week 12 was similar between GSK2982772 and placebo (posterior median 1.8% vs 4.9%, respectively), with an estimated median treatment difference of - 2.3%. This analysis incorporated historical placebo data through the use of an informative prior distribution on the placebo arm. Week 4 changes in skin biopsy gene expression suggested sufficient local drug exposure to elicit a pharmacodynamic response. CONCLUSION: Administration of the RIPK1 inhibitor GSK2982772 to patients with moderate to severe plaque psoriasis did not translate into meaningful clinical improvements.

Psoriasis is thought to be caused by problems with the immune system, including possibly receptor-interacting protein kinase 1 (RIPK1), which plays an important role in the development of inflammation. A previous study suggested that the drug, GSK2982772, which interferes with RIPK1, might improve symptoms in patients with psoriasis. This study examined whether higher doses of GSK2982772 than previously studied would be beneficial for patients with psoriasis. The study found that the severity of psoriasis was similar in patients treated with GSK2982772 for 12 weeks as in those who did not receive the drug, indicating that GSK298772 did not improve psoriasis.

T-cell help in the germinal center: homing in on the role of IL-21.

Interleukin 21 (IL-21) is a pleiotropic cytokine that is overproduced in multiple autoimmune settings. Provision of IL-21 from follicular helper T cells is an important component of T-cell help within germinal centers (GC), and the last few years have seen a resurgence of interest in IL-21 biology in the context of the GC environment. While it has been more than a decade since T cell-derived IL-21 was found to upregulate B-cell expression of the GC master transcription factor B-cell lymphoma 6 (Bcl-6) and to promote GC expansion, several recent studies have collectively delivered significant new insights into how this cytokine shapes GC B-cell selection, proliferation, and fate choice. It is now clear that IL-21 plays an important role in GC zonal polarization by contributing to light zone GC B-cell positive selection for dark zone entry as well as by promoting cyclin D3-dependent dark zone inertial cycling. While it has been established that IL-21 can contribute to the modulation of GC output by aiding the generation of antibody-secreting cells (ASC), recent studies have now revealed how IL-21 signal strength shapes the fate choice between GC cycle re-entry and ASC differentiation in vivo. Both provision of IL-21 and sensitivity to this cytokine are finely tuned within the GC environment, and dysregulation of this pathway in autoimmune settings could alter the threshold for germinal center B-cell selection and differentiation, potentially promoting autoreactive B-cell responses.

Change in organism between first- and second-stage revision for periprosthetic joint infection of knee arthroplasty independently associated with increased risk of failure.

Aims: Achievement of accurate microbiological diagnosis prior to revision is key to reducing the high rates of persistent infection after revision knee surgery. The effect of change in the microorganism between the first- and second-stage revision of total knee arthroplasty for periprosthetic joint infection (PJI) on the success of management is not clear. Methods: A two-centre retrospective cohort study was conducted to review the outcome of patients who have undergone two-stage revision for treatment of knee arthroplasty PJI, focusing specifically on isolated micro-organisms at both the first- and second-stage procedure. Patient demographics, medical, and orthopaedic history data, including postoperative outcomes and subsequent treatment, were obtained from the electronic records and medical notes. Results: The study cohort consisted of 84 patients, of whom 59.5% (n = 50) had successful eradication of their infection at a mean follow-up of 4.7 years. For the 34 patients who had recurrence of infection, 58.8% (n = 20) had a change in isolated organism, compared to 18% (n = 9) in the infection eradication group (p < 0.001). When adjusting for confound, there was no association when the growth on the second stage was the same as the first (odd ratio (OR) 2.50, 95% confidence interval (CI) 0.49 to 12.50; p = 0.269); however, when a different organism was identified at the second stage, this was independently associated with failure of treatment (OR 8.40, 95% CI 2.91 to 24.39; p < 0.001). There were no other significant differences between the two cohorts with regard to patient demographics or type of organisms isolated. Conclusion: Change in the identified microorganism between first- and second-stage revision for PJI was associated with failure of management. Identification of this change in the microorganism prior to commencement of the second stage may help target antibiotic management and could improve the success of surgery in these patients.

The "COVID-19 Approach" to Distal Radius Fracture Management.

Background In response to the coronavirus pandemic the British Orthopaedic Association Standards for Trauma and Orthopaedics (BOAST) guidelines advised treating distal radius fractures (DRFs) non-operatively where possible. Questions/Purpose The aim of this study was to assess whether the coronavirus disease 2019 (COVID-19) pandemic lockdown within the United Kingdom did alter the management of DRFs and whether there was any subsequent change in patient outcome or complication rate. Patients and Methods A retrospective cohort study was performed at a single orthopaedic center within the United Kingdom. The cohort of patients presenting with DRFs during the first lockdown was identified through the virtual fracture clinic database. The cohort of patients from the previous year was also identified for comparison. Data was collected on patient demographics, radiological features of the fractures, management, patient outcome and subsequent complications. Comparisons were then made between the cohorts for each year. Results The pre-COVID cohort had a significantly higher number of patients reviewed in face-to-face clinic appointments ( p = 0.0044) and the mean number of clinic appointments for those patients was significantly higher ( p = 0.0149). There was no significant difference between the cohorts regarding patient complications or any need for return to theater with a minimum 10 month follow-up period. Conclusion Despite comparative numbers and patterns of DRFs as well as no significant difference in the number of injuries requiring orthopaedic intervention, the burden on fracture clinic services was significantly reduced during the COVID pandemic. Encouragingly, this reduction in follow-up has not translated into an increased prevalence of complications or requirement for further surgery. Level of Evidence The level of evidence of the study is level III.

Stratification of PD-1 blockade response in melanoma using pre- and post-treatment immunophenotyping of peripheral blood.

Efficacy of checkpoint inhibitor therapies in cancer varies greatly, with some patients showing complete responses while others do not respond and experience progressive disease. We aimed to identify correlates of response and progression following PD-1-directed therapy by immunophenotyping peripheral blood samples from 20 patients with advanced malignant melanoma before and after treatment with the PD-1 blocking antibody pembrolizumab. Our data reveal that individuals responding to PD-1 blockade were characterised by increased CD8 T cell proliferation following treatment, while progression was associated with an increase in CTLA-4-expressing Treg. Remarkably, unsupervised clustering analysis of pre-treatment T cell subsets revealed differences in individuals that went on to respond to PD-1 blockade compared to individuals that did not. These differences mapped to expression of the proliferation marker Ki67 and the costimulatory receptor CD28 as well as the inhibitory molecules 2B4 and KLRG1. While these results require validation in larger patient cohorts, they suggest that flow cytometric analysis of a relatively small number of T cell markers in peripheral blood could potentially allow stratification of PD-1 blockade treatment response prior to therapy initiation.

Optimising the use of cell salvage in revision hip arthroplasty.

BACKGROUND: Intraoperative cell salvage is an established method to reduce the requirement for and the volume of allogenic blood transfusion but adds to the financial cost of performing surgery. AIMS: The primary aim of this study was to determine which patients and what type of revision hip surgery benefit most from intraoperative cell salvage. METHODS: This observational study included patients who underwent revision hip surgery performed by the senior author at a single orthopaedic unit. The cohort was divided into single and two-component revision groups; then, the transfusion requirement combined with analysis of patient factors was used to create a decision-making protocol. FINDINGS: The two-component group had a significantly higher number of cases using cell salvage and a higher total transfusion volume. Patients who required postoperative allogenic blood transfusions had a higher mean age, were less likely to have received tranexamic acid and had a lower preoperative haemoglobin level. CONCLUSION: Based on these results, a decision-making protocol was developed for when to use cell salvage in revision hip surgery.

Treatment of congenital thrombocytopenia and decreased collagen reactivity in G6b-B-deficient mice.

Mice lacking the immunoreceptor tyrosine-based inhibition motif-containing co-inhibitory receptor G6b-B (Mpig6b, G6b knockout, KO) are born with a complex megakaryocyte (MK) per platelet phenotype, characterized by severe macrothrombocytopenia, expansion of the MK population, and focal myelofibrosis in the bone marrow and spleen. Platelets are almost completely devoid of the glycoprotein VI (GPVI)-FcRγ-chain collagen receptor complex, have reduced collagen integrin α2ß1, elevated Syk tyrosine kinase activity, and a subset has increased surface immunoglobulins. A similar phenotype was recently reported in patients with null and loss-of-function mutations in MPIG6B. To better understand the cause and treatment of this pathology, we used pharmacological- and genetic-based approaches to rescue platelet counts and function in G6b KO mice. Intravenous immunoglobulin resulted in a transient partial recovery of platelet counts, whereas immune deficiency did not affect platelet counts or receptor expression in G6b KO mice. Syk loss-of-function (R41A) rescued macrothrombocytopenia, GPVI and α2ß1 expression in G6b KO mice, whereas treatment with the Syk kinase inhibitor BI1002494 partially rescued platelet count but had no effect on GPVI and α2ß1 expression or bleeding. The Src family kinase inhibitor dasatinib was not beneficial in G6b KO mice. In contrast, treatment with the thrombopoietin mimetic romiplostim rescued thrombocytopenia, GPVI expression, and platelet reactivity to collagen, suggesting that it may be a promising therapeutic option for patients lacking functional G6b-B. Intriguingly, GPVI and α2ß1 expression were significantly downregulated in romiplostim-treated wild-type mice, whereas GPVI was upregulated in romiplostim-treated G6b KO mice, suggesting a cell intrinsic feedback mechanism that autoregulates platelet reactivity depending on physiological needs.

Therapeutic gene editing of T cells to correct CTLA-4 insufficiency.

Heterozygous mutations in CTLA-4 result in an inborn error of immunity with an autoimmune and frequently severe clinical phenotype. Autologous T cell gene therapy may offer a cure without the immunological complications of allogeneic hematopoietic stem cell transplantation. Here, we designed a homology-directed repair (HDR) gene editing strategy that inserts the CTLA-4 cDNA into the first intron of the CTLA-4 genomic locus in primary human T cells. This resulted in regulated expression of CTLA-4 in CD4+ T cells, and functional studies demonstrated CD80 and CD86 transendocytosis. Gene editing of T cells isolated from three patients with CTLA-4 insufficiency also restored CTLA-4 protein expression and rescued transendocytosis of CD80 and CD86 in vitro. Last, gene-corrected T cells from CTLA-4-/- mice engrafted and prevented lymphoproliferation in an in vivo murine model of CTLA-4 insufficiency. These results demonstrate the feasibility of a therapeutic approach using T cell gene therapy for CTLA-4 insufficiency.

Associations Between Covid-19-Related Threat, Stress, and Smoking in UK Adults Aged Under- and Over-30.

It has been suggested that smoking and age are associated with higher vulnerability to Covid-19. While threat of Covid-19 may reduce or stop smoking, increased stress due to lockdown could increase smoking behaviour. This study aimed to investigate changes in smoking behaviour in relation to age, Covid-19-related threat and subjective perceived stress during the UK lockdown. A cross-sectional study was performed. Online adverts were used to recruit UK residents who smoked combustible tobacco any time from January 2020. A questionnaire measured demographic information, smoking behaviour pre- and during-lockdown, perceived subjective stress (PSS), and Covid-19 related threat. Data were collected from a total of 145 participants (58% women, 39% men, 3% non-binary; mean age: 26 years, SD = 7.7), during UK lockdown between 22nd May and 22nd June 2020. Independent of stress and Covid-19-related threat, smoking was reduced in those aged less than 30 years. In participants aged 30 and above, increases in smoking behaviour were associated with higher PSS. The results highlight the relevance of the different stages of life on the relationship between stress, threat, and smoking behaviour. Greater emphasis should be placed on stress reduction for adult smokers aged 30 and above to enable smoking cessation.

Differences in CD80 and CD86 transendocytosis reveal CD86 as a key target for CTLA-4 immune regulation.

CD28 and CTLA-4 (CD152) play essential roles in regulating T cell immunity, balancing the activation and inhibition of T cell responses, respectively. Although both receptors share the same ligands, CD80 and CD86, the specific requirement for two distinct ligands remains obscure. In the present study, we demonstrate that, although CTLA-4 targets both CD80 and CD86 for destruction via transendocytosis, this process results in separate fates for CTLA-4 itself. In the presence of CD80, CTLA-4 remained ligand bound, and was ubiquitylated and trafficked via late endosomes and lysosomes. In contrast, in the presence of CD86, CTLA-4 detached in a pH-dependent manner and recycled back to the cell surface to permit further transendocytosis. Furthermore, we identified clinically relevant mutations that cause autoimmune disease, which selectively disrupted CD86 transendocytosis, by affecting either CTLA-4 recycling or CD86 binding. These observations provide a rationale for two distinct ligands and show that defects in CTLA-4-mediated transendocytosis of CD86 are associated with autoimmunity.

Targeting TFH cells in human diseases and vaccination: rationale and practice.

The identification of CD4+ T cells localizing to B cell follicles has revolutionized the knowledge of how humoral immunity is generated. Follicular helper T (TFH) cells support germinal center (GC) formation and regulate clonal selection and differentiation of memory and antibody-secreting B cells, thus controlling antibody affinity maturation and memory. TFH cells are essential in sustaining protective antibody responses necessary for pathogen clearance in infection and vaccine-mediated protection. Conversely, aberrant and excessive TFH cell responses mediate and sustain pathogenic antibodies to autoantigens, alloantigens, and allergens, facilitate lymphomagenesis, and even harbor viral reservoirs. TFH cell generation and function are determined by T cell antigen receptor (TCR), costimulation, and cytokine signals, together with specific metabolic and survival mechanisms. Such regulation is crucial to understanding disease pathogenesis and informing the development of emerging therapies for disease or novel approaches to boost vaccine efficacy.

COVID-19 and liver cancer: lost patients and larger tumours.

BACKGROUND: Northern England has been experiencing a persistent rise in the number of primary liver cancers, largely driven by an increasing incidence of hepatocellular carcinoma (HCC) secondary to alcohol-related liver disease and non-alcoholic fatty liver disease. Here we review the effect of the COVID-19 pandemic on primary liver cancer services and patients in our region. OBJECTIVE: To assess the impact of the COVID-19 pandemic on patients with newly diagnosed liver cancer in our region. DESIGN: We prospectively audited our service for the first year of the pandemic (March 2020-February 2021), comparing mode of presentation, disease stage, treatments and outcomes to a retrospective observational consecutive cohort immediately prepandemic (March 2019-February 2020). RESULTS: We observed a marked decrease in HCC referrals compared with previous years, falling from 190 confirmed new cases to 120 (37%). Symptomatic became the the most common mode of presentation, with fewer tumours detected by surveillance or incidentally (% surveillance/incidental/symptomatic; 34/42/24 prepandemic vs 27/33/40 in the pandemic, p=0.013). HCC tumour size was larger in the pandemic year (60±4.6 mm vs 48±2.6 mm, p=0.017), with a higher incidence of spontaneous tumour haemorrhage. The number of new cases of intrahepatic cholangiocarcinoma (ICC) fell only slightly, with symptomatic presentation typical. Patients received treatment appropriate for their cancer stage, with waiting times shorter for patients with HCC and unchanged for patients with ICC. Survival was associated with stage both before and during the pandemic. 9% acquired COVID-19 infection. CONCLUSION: The pandemic-associated reduction in referred patients in our region was attributed to the disruption of routine healthcare. For those referred, treatments and survival were appropriate for their stage at presentation. Non-referred or missing patients are expected to present with more advanced disease, with poorer outcomes. While protective measures are necessary during the pandemic, we recommend routine healthcare services continue, with patients encouraged to engage.

Types, management and complications in paediatric distal radial fractures sustained during COVID-19 lockdown.

In response to the coronavirus pandemic the British Orthopaedic Association Standards for Trauma and Orthopaedics (BOAST) guidelines advised treating distal radial fractures non-operatively where possible. A cohort was studied retrospectively to assess whether the COVID pandemic lockdown within the UK altered types, the management and complications of paediatric distal radial fractures. The cohort studied comprised of 194 paediatric distal radial fractures in the pre-COVID cohort and 101 fractures in the COVID cohort. There was no significant differences in the type of fractures in the two cohorts. Significantly more high energy injuries were sustained among the COVID cohort than the pre-COVID (p < 0.001). The COVID cohort had significantly more patients managed in cast (p < 0.001) and significantly more managed with K-wire fixation (p = 0.049). The COVID cohort had significantly more complications (p = 0.016) at minimum 10-month follow-up. The results suggest that treatment of paediatric distal radial fractures during lockdown was too conservative and subsequent complications may put additional strain on orthopaedic services.Level of evidence: IV.

UK women smokers' experiences of an age-progression smoking cessation intervention: Thematic analysis of accounts.

Objectives: Appearance-related interventions to promote healthy behaviour have been found effective to communicate health risks. The current study aimed to explore women smokers' experiences of age-progression software showing the effects of smoking on the face. Methods: A qualitative design was implemented, utilizing both individual interviews and focus groups within a critical realist framework. Fifteen, 19-52 year-old women smokers were administered an age-progression intervention. All participants responded to the intervention, engaged in semi-structured interviews, and were invited back to attend one of three focus groups. Data were analysed using inductive thematic analysis. Results: Four main themes were identified: Health versus Appearance, Shock Reaction, Perceived Susceptibility, and Intention to Quit. Participants found the intervention useful, voicing need for a comprehensive approach that includes both appearance and health. Despite increases in appearance-based apps which could diminish impact, women's accounts of shock induced by the aged smoking-morphed images were similar to previous work conducted more than ten years previously. Conclusions: The study provides novel insights in how women smokers currently perceive, and react to, an age-progression intervention for smoking cessation. Innovation: Findings emphasise the implementation of this intervention type accompanied by health information in a range of patient settings.

How has COVID-19 lockdown impacted smoking? A thematic analysis of written accounts from UK smokers.

Objective. This study was designed to investigate UK smokers' accounts of impacts of COVID-19 on their smoking, to develop implications for supporting smoking cessation.Design. One hundred and thirty-two smokers aged 19-52 years (mean age 25 years), recruited through an advert distributed through social media and a dedicated Twitter page, completed an anonymous online questionnaire.Main Outcome Measures. Smokers produced written accounts of how COVID-19 had impacted their smoking. Responses were of unlimited length and completed online 22nd May-22nd June 2020 during UK COVID-19 lockdown.Results. Inductive thematic analysis generated three themes: i) increased smoking as a coping mechanism to deal with anxiety, boredom, stress, and anger in COVID-19 lockdown; ii) lockdown as enabling quitting through lifting social barriers and enabling a focus on health benefits; and iii) no change, avoiding Government/media COVID-19 information due to disbelief, lack of trust, and perceptions of bias.Conclusions. Results demonstrate a need for credible public health messaging on COVID-19 risk aimed at smokers. Implications for supporting smoking cessation are discussed, including maintaining quitting in those "social smokers" who quit during lockdown, and support on stress-management and emotion regulation in those who use smoking as a way to cope with stress, anger, and boredom.

The alpha defensin lateral flow test is effective in predicting eradication of periprosthetic joint infection after surgical debridement.

The primary aim of this study was to assess the utility of the alpha defensin lateral flow (ADLF) test for predicting the eradication of PJI after surgical debridement. The secondary aim was to describe the reliability of ADLF test in diagnosis of PJI intra- operatively. A prospective observational study was conducted in three independent orthopaedic centres. Twenty-two patients undergoing revision surgery (debridement, antibiotics and implant retention (DAIR), single or two-stage revision) for PJI were recruited, 13 female and 9 male with an average age of 64 years. Samples were collected intra-operatively at the start of the first surgical procedure and then at the completion of debridement or prior to reimplantation depending on the operation performed. These samples were tested using ADLF and then sent for microbiological analysis. The ADLF result was then compared to the corresponding culture result in order to determine the diagnostic predictive accuracy. The reliability of ADLF test to predict eradication of infection after debridement of PJI was excellent for specificity and positive predictive value (PPV) of which both where 100%, but had a poor sensitivity (14.3%) and negative predictive value (NPV) (62.5%). The reliability of ADLF test to predict PJI was poor with only a 50% sensitivity and specificity. The ADLF test has a high specificity and PPV for diagnosing eradication of infection after debridement. In contrast the ADLF testing appears to have poor diagnostic accuracy for PJI when used on intra-operative samples, prior to surgical intervention.

Diagnostic value of routine pre-operative investigations used in combination in the diagnosis of periprosthetic joint infection.

The primary aim of this study was to assess the diagnostic accuracy of joint aspiration culture, serum C-reactive protein (CRP) and serum erythrocyte sedimentation rate (ESR), individually, and in combination for the diagnosis of periprosthetic joint infection (PJI). A consecutive patient series with pre-operative inflammatory marker levels, an aspiration culture of either hip or knee arthroplasty and intra-operative culture samples from subsequent revision surgery was compiled. This retrospective patient cohort analysis included 128 aspiration. The data were analysed to compare pre-operative aspiration cultures, serum ESR and CRP levels to the chosen gold standard for PJI diagnosis of intra-operative culture samples. A diagnostic algorithm was created using the above tests combined with clinical suspicion index. The values that had the highest sensitivity and specificity of predicting PJI were >5 for CRP and >16 for ESR. CRP used individually had the highest sensitivity and negative predictive value (NPV) of any test (75.0% and 75.9%, respectively). ESR + aspirate had the highest specificity and positive predictive value (PPV), of 100% for both. Using all three tests together the specificity and PPV were higher than the test individual values (95.3% and 85.0% respectively). Based on subgroup analyses the combination of ESR or CRP plus joint aspiration has superior PPV compared to individual tests. ESR and CRP had the highest NPV when used in isolation. An algorithm has been developed to guide clinical diagnosis.

Targeting co-stimulatory molecules in autoimmune disease.

Therapeutic targeting of immune checkpoints has garnered significant attention in the area of cancer immunotherapy, in which efforts have focused in particular on cytotoxic T lymphocyte antigen 4 (CTLA4) and PD1, both of which are members of the CD28 family. In autoimmunity, these same pathways can be targeted to opposite effect: to curb the over-exuberant immune response. The CTLA4 checkpoint serves as an exemplar, whereby CTLA4 activity is blocked by antibodies in cancer immunotherapy and augmented by the provision of soluble CTLA4 in autoimmunity. Here, we review the targeting of co-stimulatory molecules in autoimmune diseases, focusing in particular on agents directed at members of the CD28 or tumour necrosis factor receptor families. We present the state of the art in co-stimulatory blockade approaches, including rational combinations of immune inhibitory agents, and discuss the future opportunities and challenges in this field.