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Phalangeal microgeodic syndrome (PMS) is a rare condition typically affecting children and is characterised by painful digits precipitated by cold temperatures. In medical literature, cases appear to be clustered in Japan. Adult-onset PMS is particularly rare and although imaging features are characteristic, it may go undiagnosed, as it is not commonly encountered. We present, to our knowledge, the fifth reported case in the literature of adult PMS, the second to affect the feet rather than hands, and the first in a Caucasian adult patient. This case report aims to raise awareness of this likely underdiagnosed condition to allow optimal management and avoidance of unnecessary diagnostic procedures.

OBJECTIVES To examine concurrent validity and discrimination of modified minimal disease activity (mMDA) criteria in peripheral spondyloarthritis (pSpA) following OMERACT filter principles and determine predictors of mMDA response. METHODS Four mMDA versions were derived in the ABILITY-2 study using the SPondyloArthritis Research Consortium of Canada (SPARCC) or Leeds Enthesitis Index (LEI) but excluding psoriasis. To assess concurrent validity, mMDA versions were correlated with Peripheral SpondyloArthritis Response Criteria (PSpARC) remission, Ankylosing Spondylitis Disease Activity Score for inactive disease (ASDAS ID), and physician global. Treatment discrimination was assessed between adalimumab and placebo at week 12. Multiple logistic regression was used to determine baseline predictors of long-term mMDA responses and sustained mMDA. RESULTS The four mMDA versions showed a stronger positive correlation with PSpARC remission (rtet >0.95) versus ASDAS ID (rtet >0.75) at week 12 and years 1-3 and were able to show discrimination (p

Objective Expression of the translocator protein (TSPO) on inflammatory cells has facilitated imaging of synovitis with TSPO-targeted positron emission tomography (PET). We aimed to quantitatively assess the specificity of the second-generation TSPO PET radioligand, [11C]PBR28, and to generate simplified PET protocols in patients with inflammatory joint disease (IJD) in this pilot study. Methods Three IJD patients (two rheumatoid arthritis and one osteoarthritis) with knee involvement underwent dynamic [11C]PBR28-PET scans before and after administration of 90 mg of oral emapunil (XBD-173), a TSPO ligand the same day. Radial arterial blood sampling was performed throughout the scan, and total radioactivity and radioactive metabolites were obtained. A semi-automated method was used to generate regions of interest. Standardized uptake value (SUV) and SUV ratio corrected for activity in bone and blood between 50 and 70 min (SUVr50–70 bone, SUVr50–70 blood, respectively) and PET volume of distribution (VT) of the radioligand were calculated. Results A mean [11C]PBR28 radioactivity of 378 (range 362–389) MBq was administered. A significant decrease (p VT, SUVr50–70 bone and SUVr50–70 blood observed after oral emapunil confirmed the TSPO specificity of [11C]PBR28. A decrease in SUV was not observed in the post-block scan. Conclusion [11C]PBR28 is TSPO-specific radioligand in IJD patients. Simplified PET protocols with static PET acquisition can be used in the management and evaluation of novel therapeutics that target TSPO overexpressing cells.

The implications of COVID-19 are wide-ranging for specialties such as rheumatology in which immunomodulatory therapies are prescribed. There has been much trepidation among many healthcare professionals regarding the best course of management during this time.

Community organisations have a crucial role in involving under-represented population groups

The outbreak of SARS-CoV-2 has resulted in wide-ranging turmoil at an international level. During the peak of the pandemic, healthcare services in countries worst hit by COVID-19 were required to drastically reconfigure models of care delivery in order to optimise access to both resources and a

Over recent years the increasing pressures on hospital based services has raised the question as to whether more clinical facilities can be provided in the community. Accordingly, commissioning groups have focused much of their energy towards research into whether this shift in healthcare models is feasible, cost-effective and satisfactory to both patients and healthcare providers. Specialties which lend themselves towards the possibility of community based models of care include those that manage patients with chronic but stable diseases and Rheumatology, in particular, has been a focus of such research.

Background Despite the availability of several treatment options some patients with Rheumatoid Arthritis (RA) fail to benefit and for those who do response rates are similar across therapeutic classes. Thus there remains a need for new therapies with novel mechanisms of action. MBS2320 is a selective modulator of immune metabolism that shows anatomically appropriate osteoid layering and a broader spectrum of osteoprotective efficacy compared to TNFα inhibition in preclinical models. Objectives To investigate the safety, tolerability and pharmacokinetics of MBS2320 in healthy volunteers and patients with Rheumatoid Arthritis (RA) receiving a stable dose of methotrexate (MTX). Methods Cohorts of healthy volunteers (randomised 6:2 drug:placebo) received single or multiple oral doses of MBS2320 for 14 days. Single Ascending Dose (SAD) cohorts comprised 2, 10, 25, 50, 75, 125, 250, 375 mg (PO) and Multiple Ascending Dose (MAD) cohorts 75, 100, 160 mg/d. Patients with RA received 75 mg/d for 14 days in addition to their existing weekly MTX treatment. Safety and tolerability were assessed throughout. Plasma MBS2320 (SAD, MAD and patients with RA) and MTX (patients with RA only) were measured using LC-MS/MS. In patients with RA, C-reactive protein (CRP) and biomarkers of bone turnover were assessed on Day 14. Results A total of 96 healthy subjects and 9 patients with RA entered the Study and were randomised to the drug or matching placebo. MBS2320 was well tolerated by healthy subjects at single oral doses of 2 to 375 mg. There were no serious adverse events (SAEs). Nausea was the most commonly reported adverse event (AE) and occurred most frequently at the high doses but was mild and resolved without treatment. Daily doses of 75 to 160 mg QD MBS2320 for 14 days were generally well tolerated by healthy subjects. The most common drug-related treatment emergent adverse events (TEAEs) were gastrointestinal disorders, particularly nausea. There were no significant effects on clinical laboratory tests, vital signs, ECG or physical examination. Multiple doses of MBS2320 (75 mg) were also generally well tolerated by subjects with RA when co-administered with MTX. There were no clinically significant findings or trends in the laboratory tests, vital signs or ECG data, and no clinically significant findings on physical examination. No SAEs were reported. The majority of TEAEs were mild in severity with diarrhoea and nausea reported most frequently. In healthy subjects, MBS2320 was steadily absorbed following doses of 50 to 375 mg MBS2320. Systemic exposure (AUC) increased in a dose-proportional manner across all doses and was unaffected by food. In RA patients there was no indication of a PK interaction between MTX and MBS2320 in either direction. In patients with RA, serum CTX-1, P1NP and osteocalcin increased following 14 days of treatment, while TRAP5b was decreased or unchanged. Median CRP was decreased relative to baseline in after 7 days’ treatment with MBS2320, and remained low on Day 14. Conclusion MBS2320 was well tolerated for up to 14 days when administered to healthy volunteers and to patients with RA receiving MTX. Systemic exposure was dose-proportional with no evidence of a pharmacokinetic interaction with MTX. Evaluation of biomarkers of bone turnover and inflammation in RA patients showed changes consistent with those expected of an agent with the potential to directly protect the bone and simultaneously ameliorate inflammation. Louise Jopling, Ian Anderson, Ian Gourley, Helen Marley and Ezi Otti Disclosure of Interests Lisa Patel Shareholder of: Shareholder of Istesso Ltd, Employee of: Employee of Istesso, Paul Marcus Consultant for: Istesso Ltd, Jim Bush Shareholder of: Labcorp, Employee of: Covance, Andy Gray Shareholder of: Shareholder of Istesso Ltd, Consultant for: Istesso Ltd, Employee of: Astra Zeneca, Richard Fitzgerald: None declared, Sonya Abraham Shareholder of: UCB Pharma, Grant/research support from: Pfizer, Riche, Abbvie, Consultant for: Abbvie Roche Pfizer BMS UCB pharma, Eli Lilly, Employee of: UCB Pharma, Martyn Foster Shareholder of: AstraZeneca, Consultant for: Istesso, Levicept, Employee of: AstraZeneca, Hiep Huatan Consultant for: Istesso Ltd, Employee of: Pfizer, Laurence Skillern Consultant for: Istesso, Employee of: Astellas, Anna Daroszewska Consultant for: Istesso Ltd, Rob van’t Hof Shareholder of: OsteoRx Ltd, Sam Williams Shareholder of: Shareholders of Istesso Ltd, Employee of: Employees of Istesso

Summary Background Chlamydia is the most common sexually transmitted bacterial infection worldwide. National screening programmes and antibiotic treatment have failed to decrease incidence, and to date no vaccines against genital chlamydia have been tested in clinical trials. We aimed to assess the safety and immunogenicity, in humans, of a novel chlamydia vaccine based on a recombinant protein subunit (CTH522) in a prime–boost immunisation schedule. Methods This phase 1, first-in-human, double-blind, parallel, randomised, placebo-controlled trial was done at Hammersmith Hospital in London, UK, in healthy women aged 19–45 years. Participants were randomly assigned (3:3:1) to three groups: CTH522 adjuvanted with CAF01 liposomes (CTH522:CAF01), CTH522 adjuvanted with aluminium hydroxide (CTH522:AH), or placebo (saline). Participants received three intramuscular injections of 85 μg vaccine (with adjuvant) or placebo to the deltoid region of the arm at 0, 1, and 4 months, followed by two intranasal administrations of 30 μg unadjuvanted vaccine or placebo (one in each nostril) at months 4·5 and 5·0. The primary outcome was safety and the secondary outcome was humoral immunogenicity (anti-CTH522 IgG seroconversion). This study is registered with Clinicaltrials.gov, number NCT02787109. Findings Between Aug 15, 2016, and Feb 13, 2017, 35 women were randomly assigned (15 to CTH522:CAF01, 15 to CTH522:AH, and five to placebo). 32 (91%) received all five vaccinations and all participants were included in the intention-to-treat analyses. No related serious adverse reactions were reported, and the most frequent adverse events were mild local injection-site reactions, which were reported in all (15 [100%] of 15) participants in the two vaccine groups and in three (60%) of five participants in the placebo group (p=0·0526 for both comparisons). Intranasal vaccination was not associated with a higher frequency of related local reactions (reported in seven [47%] of 15 participants in the active treatment groups vs three [60%] of five in the placebo group; p=1·000). Both CTH522:CAF01 and CTH522:AH induced anti-CTH522 IgG seroconversion in 15 (100%) of 15 participants after five immunisations, whereas no participants in the placebo group seroconverted. CTH522:CAF01 showed accelerated seroconversion, increased IgG titres, an enhanced mucosal antibody profile, and a more consistent cell-mediated immune response profile compared with CTH522:AH. Interpretation CTH522 adjuvanted with either CAF01 or aluminium hydroxide appears to be safe and well tolerated. Both vaccines were immunogenic, although CTH522:CAF01 had a better immunogenicity profile, holding promise for further clinical development. Funding European Commission and The Innovation Fund Denmark.

Trial design We present a study protocol for a multi-centre, randomised, double-blind, parallel-group, placebo-controlled trial that seeks to test the feasibility, acceptability and effectiveness of a 52-week period of treatment with the first-in-class co-stimulatory blocker abatacept for preventing or delaying the onset of inflammatory arthritis. Methods The study aimed to recruit 206 male or female subjects from the secondary care hospital setting across the UK and the Netherlands. Participants who were at least 18 years old, who reported inflammatory sounding joint pain (clinically suspicious arthralgia) and who were found to be positive for serum autoantibodies associated with rheumatoid arthritis (RA) were eligible for enrolment. All study subjects were randomly assigned to receive weekly injections of investigational medicinal product, either abatacept or placebo treatment over the course of a 52-week period. Participants were followed up for a further 52 weeks. The primary endpoint was defined as the time to development of at least three swollen joints or to the fulfilment of the 2010 American College of Rheumatology/European League Against Rheumatism (ACR/EULAR) classification criteria for RA using swollen but not tender joints, whichever endpoint was met first. In either case, swollen joints were confirmed by ultrasonography. Participants, care givers, and those assessing the outcomes were all blinded to group assignment. Clinical assessors and ultrasonographers were also blinded to each other’s assessments for the duration of the study. Conclusions There is limited experience of the design and implementation of trials for the prevention of inflammatory joint diseases. We discuss the rationale behind choice and duration of treatment and the challenges associated with defining the “at risk” state and offer pragmatic solutions in the protocol to enrolling subjects at risk of RA. Trial registration Current Controlled Trials, ID: ISRCTN46017566. Registered on 4 July 2014. Electronic supplementary material The online version of this article (10.1186/s13063-019-3403-7) contains supplementary material, which is available to authorized users.

Background: Individuals with joint pain and carrying serum autoantibodies associated with rheumatoid arthritis (RA) are at high risk of developing RA. While there are currently no evidence-based guidelines to inform therapy decisions for such subjects, there are therapies licensed for the treatment of established RA that target pathways implicated in the earliest phase of the disease. Accordingly, we set out to test the feasibility, acceptability and effectiveness of a 52-week period of treatment with the first in class costimulatory blocker abatacept for preventing or delaying the onset of inflammatory arthritis. Methods and Design The APIPPRA study was designed as a randomised, double blind, parallel group placebo-controlled clinical trial, aiming to recruit 206 male or female subjects from the secondary care hospital setting across the UK and the Netherlands. Participants aged 18 or over who report inflammatory sounding joint pain (clinically suspicious arthralgia) and who are found to be positive for serum autoantibodies associated with RA, will be randomised to receive weekly injections of investigational medicinal product (IMP), either abatacept or placebo treatment over a 52-week period. All study subjects consent to a further 52 weeks of follow up to monitor for the primary endpoint, the time to development of ≥ 3 swollen joints, or to the fulfillment of the 2010 ACR/EULAR classification criteria for RA using swollen but not tender joints, whichever endpoint is met first. In either case, swollen joints are confirmed by ultrasonography. Discussion There is limited experience of the design and implementation of trials for the prevention of inflammatory joint diseases. Here, we propose to explore the effects of immunomodulatory therapy at the very earliest detectable phase of disease using an intervention that is already licensed for use in established RA. We discuss the rationale behind choice and duration of treatment, the challenges associated with defining the “at risk” state, and offer pragmatic solutions in the protocol to enrolling subjects at risk of RA. Trial registration Current Controlled Trials, ID: ISRCTN46017566. Registered on 04 July 2014

The term ‘inflammatory arthritis’ (IA) encompasses a spectrum of diseases, of which the most common forms are rheumatoid arthritis (RA), psoriatic arthritis (PsA), and ankylosing spondylitis (AS). Over the past decade, the advent of immunomodulatory biological therapies has dramatically changed the management of such diseases, and offers alternatives for patients with a poor response to the more conventional disease-modifying anti-rheumatic drugs (DMARDs). Over recent years, more emphasis has been placed on the concept of shared care between specialist and primary care physicians for many chronic conditions once on a stable treatment regime, in order to improve hospital workload and enable more flexibility for patients. This brief review highlights the key points relevant to primary care physicians involved in the care of patients with IA on biologic agents. Immunomodulatory biologic agents (Table 1) are proteins derived from human genes that are genetically engineered to inhibit precise components of the immune system.1 By doing so, they suppress specific pathways that play a pivotal role in IA pathogenesis and, hence, differ from the more commonly used DMARDs, which have broader targets.1 If tolerated, biologic agents are used in combination with methotrexate, or an alternative DMARD, in view of enhanced efficacy. View this table: Table 1. Summary of biologic agents licensed for …

Summary The mechanisms underlying the exaggerated inflammatory response in Behçet's syndrome (BS) remain poorly understood. We investigated the response of CD14+ blood monocytes to interferon (IFN)-γ, focusing on the chemokine CXCL10. Chemokine synthesis and release were analysed at a protein and mRNA level following stimulation with IFN-γ. Findings in BS patients were compared with 25 healthy controls (HC), 15 rheumatoid arthritis (RA) and 15 systemic lupus erythematosus (SLE) disease control patients. BS monocytes produced significantly more CXCL10 protein than HC monocytes from 2 h following IFN-γ stimulation, despite equivalent quantities of mRNA, suggesting more efficient translation. This was significantly more pronounced in BS with high disease activity and in those with ocular and neurological clinical manifestations. The imbalance between CXCL10 protein and mRNA expression was not observed in either RA or SLE patients, and was not seen with other chemokines studied (CXCL9, CXCL11 and CCL2). Furthermore, BS monocytes treated with an alternative stimulant (LPS) did not show abnormal tumour necrosis factor (TNF)-α release. Sucrose density gradients to segregate monocyte CXCL10 mRNA into free RNA or polysome-associated RNA showed equal proportions in BS and HC samples, suggesting that the difference between BS and HC may be due to reduced negative control of CXCL10 translation in BS at a post-initiation level. We conclude that BS monocytes have dysfunctional post-transcriptional regulation of CXCL10 mRNA, resulting in over-expression of CXCL10 protein upon IFN-γ stimulation. As CXCL10 is a chemokine that recruits mononuclear cells, this abnormality may contribute to the exaggerated inflammatory responses that characterizes BS.

International audience; Intradermal (i.d.) and intramuscular (i.m.) injections when administered with or without electroporation (EP) have the potential to tailor the immune response to DNA vaccination. This Phase I randomized controlled clinical trial in human immunodeficiency virus type 1-negative volunteers investigated whether the site and mode of DNA vaccination influences the quality of induced cellular and humoral immune responses following the DNA priming phase and subsequent protein boost with recombinant clade C CN54 gp140. A strategy of concurrent i.d. and i.m. DNA immunizations administered with or without EP was adopted. Subtle differences were observed in the shaping of vaccine-induced virus-specific CD4+ and CD8+ T cell-mediated immune responses between groups receiving: i.d.EP + i.m., i.d. + i.m.EP, and i.d.EP + i.m.EP regimens. The DNA priming phase induced 100% seroconversion in all of the groups. A single, non-adjuvanted protein boost induced a rapid and profound increase in binding antibodies in all groups, with a trend for higher responses in i.d.EP + i.m.EP. The magnitude of antigen-specific binding immunoglobulin G correlated with neutralization of closely matched clade C 93MW965 virus and Fc-dimer receptor binding (FcγRIIa and FcγRIIIa). These results offer new perspectives on the use of combined skin and muscle DNA immunization in priming humoral and cellular responses to recombinant protein.

The seronegative spondyloarthropathies, including psoriatic arthritis (PsA) and ankylosing spondylitis (AS), are characterized by varied clinical symptoms, severity, and disease course [1], [2]. Diagnosis and monitoring can be challenging because there is no definitive laboratory biomarker for reliably measuring inflammation or other disease processes associated with spondyloarthropathies. Over time, many patients with PsA and AS eventually experience significant disability and impaired quality of life [1], [2]. This may be partially accounted for by delays in diagnosis and subsequent treatment [3], as well as the presence of comorbidities. In recent years, research efforts aimed at identifying risk factors for PsA, including clinical, imaging, genetic, and laboratory assessments, have yielded major advances. The Platform for the Exchange of Expertise and Research (PEER) was formed to facilitate the exchange of research insights, sharing of expertise, and discussion of unmet needs in rheumatology research. The objective of the current report is to provide an overview of the 2017 PEER meeting, which was held on May 19–20, 2017, in London, UK, and highlighted the most up-to-date research findings regarding PsA and AS pathophysiology, early detection, comorbidities, and treatment.

Psoriatic arthritis (PsA) causes inflammation in and around the joints and usually affects people who already have psoriasis. However, some patients develop the joint problems before the psoriasis. Currently, there are five anti-TNF-α agents licensed for use in patients with PsA: adalimumab, certolizumab pegol, etanercept, golimumab and infliximab. Golimumab, a human monoclonal antibody, has been approved by the US FDA for the treatment of PsA and is targeted against the pro-inflammatory molecule TNF-α. The Phase III GO-REVEAL study confirmed this drug was well tolerated and showed significant improvement in disease activity compared with placebo.

Background There is a lack of validated outcome measures in non-psoriatic peripheral spondyloarthritis (pSpA). Therefore, a modified version of the minimal disease activity (mMDA) 1 was developed and validated. Identification of factors that predict long-term mMDA response in pSpA patients (pts) can facilitate decisions regarding treatment initiation and maintenance. Objectives The purpose of this analysis was to determine predictors of long-term mMDA response following adalimumab (ADA) treatment in pSpA pts from the ABILITY-2 study. Methods ABILITY-2 2 was a phase 3 randomized, double-blind trial evaluating the efficacy and safety of 40 mg ADA every other week versus placebo (PBO) over 12 weeks (wks) followed by open-label (OL) ADA for 144 wks in pts with pSpA. This post-hoc analysis included pts who received at least one dose of ADA during the PBO-controlled period or OL extension. The mMDA for pSpA was defined as achieving at least 5 out of the following 6 criteria: 1) TJC78 ≤1; 2) SJC76 ≤1; 3) pt pain visual analog scale (VAS) ≤15 of 100 mm; 4) pt global activity (PtGA) VAS ≤20 of 100 mm; 5) HAQ-DI ≤0.5; and 6) tender entheseal points ≤1 (Leeds Enthesitis Index [LEI] or Spondyloarthritis Research Consortium of Canada [SPARCC] Enthesitis Index). In this post hoc analysis, multiple logistic regression with stepwise variable selection was used to determine predictors of long-term (yrs 1–3) and sustained (defined as mMDA for at least 24 consecutive wks) mMDA responses. Variable selection of baseline (BL) pt demographics and disease characteristics were performed with and without mMDA response at wk 16 (mMDA16) as a candidate. In pts achieving mMDA at wk 16, ADA exposure ranged between 4 and 16 wks. Results In pSpA pts treated with ADA, mMDA (5/6 LEI or SPARCC) was achieved by almost 41%, 49%, and 50% of pts at yrs 1, 2, and 3, respectively and sustained mMDA response was achieved by 42% of pts. Regardless of mMDA definition, achieving mMDA response at wk 16 (up to 16 wks of ADA) was a robust positive predictor of attaining both long-term mMDA at yrs 1–3 and sustained mMDA (Figure). In the model examining the BL predictors (model without mMDA16), age, BL enthesitis and BL BASDAI scores were most commonly selected as negative predictors for achieving long-term and sustained mMDA. Other selected predictors included BL dactylitis, physician9s global assessment, hsCRP, and male sex; however, these predictors were not consistently selected for all time points or sustained mMDA. Conclusions Early mMDA response is a stronger and more consistent predictor of long-term mMDA, whether at 1, 2, or 3 yrs or sustained over time, than BL characteristics. The 5/6 versions of mMDA could be an appropriate treatment target in pSpA pts. References Coates LC, et al., Ann Rheum Dis, 2016; 75:334. Mease PJ, et al., Arthritis Rheumatol, 2015; 67(4): p.914–23. Acknowledgements AbbVie funded the study (NCT01064856), contributed to its design, and participated in data collection, analysis and interpretation of the data, and in writing, review, and approval of the publication. Medical writing support was provided by Deepa Venkitaramani, PhD, of AbbVie. Disclosure of Interest L. Coates Grant/research support from: AbbVie, Boehringer-Ingelheim, BMS, Celgene, Eli Lilly, Janssen, MSD, Novartis, Pfizer, Sun Pharma, and UCB, Consultant for: AbbVie, Boehringer-Ingelheim, BMS, Celgene, Eli Lilly, Janssen, MSD, Novartis, Pfizer, Sun Pharma, and UCB, Speakers bureau: AbbVie, Boehringer-Ingelheim, BMS, Celgene, Eli Lilly, Janssen, MSD, Novartis, Pfizer, Sun Pharma, and UCB, S. Abraham Grant/research support from: AbbVie, Celgene, Novartis, Pfizer, and UCB, Consultant for: AbbVie, Celgene, Novartis, Pfizer, and UCB, Speakers bureau: AbbVie, Celgene, Novartis, Pfizer, and UCB, W. Tillett Grant/research support from: AbbVie, Celgene, Novartis, Pfizer, and UCB, Consultant for: AbbVie, Celgene, Novartis, Pfizer, and UCB, Speakers bureau: AbbVie, Celgene, Novartis, Pfizer, and UCB, P. Mease Grant/research support from: AbbVie, Amgen, Bristol Myers, Celgene, Genentech, Janssen, Lilly, Merck, Novartis, Pfizer, Sun Pharma, and UCB, Consultant for: AbbVie, Amgen, Bristol Myers, Celgene, Genentech, Janssen, Lilly, Merck, Novartis, Pfizer, Sun Pharma, and UCB, Speakers bureau: AbbVie, Amgen, Bristol Myers, Celgene, Genentech, Janssen, Lilly, Merck, Novartis, Pfizer, Sun Pharma, and UCB, S. Ramiro: None declared, T. Wu Shareholder of: AbbVie, Employee of: AbbVie, X. Wang Shareholder of: AbbVie, Employee of: AbbVie, A. Pangan Shareholder of: AbbVie, Employee of: AbbVie, I.-H. Song Shareholder of: AbbVie, Employee of: AbbVie

Objective.To assess the evolution of preexisting extraarticular manifestations of rheumatoid arthritis (EA-RA) in patients treated with anti-tumor necrosis factor-α (TNF-α), as well as the development of new EA-RA.Methods.We assessed EA-RA in 152 patients receiving anti-TNF-α treatment.Results.In 22 cases, a new EA-RA developed. In 5 cases, there was evidence of progression of preexisting EA-RA. Regression was found in 4 cases. Some patients were in disease remission when they developed EA-RA, whereas some patients had moderate/high disease activity.Conclusion.EA-RA are still present in patients treated with anti-TNF-α. Development of new severe EA-RA is rare in patients receiving anti-TNF therapy.

To the Editor: Psoriatic arthritis (PsA) is a chronic inflammatory disease involving the skin and joints. It requires detection in primary care, subsequent referral, and initiation of management in secondary care and ongoing joint management. PsA has been associated with greater cardiovascular (CV) disease mortality, morbidity, and atherosclerosis1. The increased CV mortality risk has been shown to be comparable with that of rheumatoid arthritis (RA) and diabetes (risk ratio 1.74, 95% CI 1.32–2.30)2. In addition, risk factors for CV disease, such as hypercholesterolemia, impaired glucose tolerance, and obesity, have all been associated with PsA1,2,3. We sought to establish the current knowledgebase and lifestyle choices of patients with PsA managed in secondary care. This data could then guide changes to services to assist patients in reducing their risk of CV morbidity and mortality. A hundred patients diagnosed with PsA sequentially attending a rheumatology outpatient clinic completed an anonymous electronic questionnaire. Patients were asked to … Address correspondence to Dr. Anna Timmis, Imperial GP Specialty Training, Department of Primary Care and Public Health, Imperial College London, Charing Cross Campus, Reynolds Building, London W6 8RP, UK. E-mail: anna.timmis{at}doctors.org.uk

“It is more important to know what sort of a patient has a disease than what sort of a disease a patient has” (Hippocrates 460 BC-370 BC). The holy grail of drug discovery is to ensure that an individual responds positively to an investigational drug with minimal or no adverse events. This could then translate to newly discovered drugs being licenced for prescribing as safe and effective therapeutics. Pharmacogenomics may herald the technology for this aspiration to become reality. Uniting the disciplines of pharmacology and genomics, pharmacogenomics provides a mechanism to understand and predict the response of an individual to a drug or group of drugs. This is based on the premise that an individual’s genotype affects the pharmacokinetics, pharmacodynamics and, ultimately, the individual’s their response to a drug. This review will begin by reviewing the history of drug development and then proceed to discuss the use of pharmacogenomics in drug development through case studies in oncology, respiratory and vaccinology. It will then go on to discuss how pharmacogenomics presently influences prescribing practices and how this technology may have the potential to enhance patient safety when medicines are administered.

Aim To assess the efficacy of microvascular imaging in detecting low-grade inflammation in arthritis compared with Power Doppler ultrasound (PDUS). Method and materials Patients presenting for ultrasound with arthralgia were assessed with grey-scale, PDUS and Superb Microvascular Imaging (SMI). Videoclips were stored for analysis at a later date. Three musculoskeletal radiologists scored grey-scale changes, signal on PDUS and/or SMI within these joints. If a signal was detected on both PDUS and SMI, the readers graded the conspicuity of vascular signal from the two Doppler techniques using a visual analogue scale. Results Eighty-three patients were recruited with 134 small joints assessed. Eighty-nine of these demonstrated vascular flow with both PD and SMI, whilst in five no flow was detected. In 40 joints, vascularity was detected with SMI but not with PDUS (p = 0.007). Out of the 89 joints with vascularity on both SMI and PDUS, 23 were rated as being equal; while SMI scored moderately or markedly better in 45 cases (p

Objectives To establish if changes in Th1/Th17 cell populations previously reported in experimental arthritis occur in patients with rheumatoid arthritis (RA) treated with anti-tumour necrosis factor α (TNFα) agents, and whether the therapeutic response to anti-TNFα is compromised in patients and mice because of elevated Th17/IL-17 levels. Finally, to assess the efficacy of combined blockade of anti-TNFα and anti-IL-17 in experimental arthritis. Methods A longitudinal study of two independent cohorts (cohort 1, n=24; cohort 2, n=19) of patients with RA treated with anti-TNFα biological agents was carried out to assess their Th17/IL-17 levels before and after the start of anti-TNFα therapy. IL-12/23p40 production was assessed in plasma Peripheral blood lymphocytes (PBLs) and monocytes. Mice with collagen-induced arthritis (CIA) were treated with anti-TNFα alone, anti-IL17 alone or a combination of the two. Efficacy of treatment and response was assessed from changes in Disease Activity Score 28–erythrocyte sedimentation rate scores in patients, and in clinical scores and histological analysis in CIA. Results Significant increases in circulating Th17 cells were observed in patients after anti-TNFα therapy and this was accompanied by increased production of IL-12/23p40. There was an inverse relationship between baseline Th17 levels and the subsequent response of patients with RA to anti-TNFα therapy. In addition, PBLs from non-responder patients showed evidence of increased IL-17 production. Similarly, in anti-TNFα-treated mice, there was a strong correlation between IL-17 production and clinical score. Finally combined blockade of TNFα and IL-17 in CIA was more effective than monotherapy, particularly with respect to the duration of the therapeutic effect. Conclusions These findings, which need to be confirmed in a larger cohort, suggest that a Th17-targeted therapeutic approach may be useful for anti-TNFα non-responder patients or as an adjunct to anti-TNFα therapy, provided that safety concerns can be addressed.

Objective Bone formation and destruction are usually tightly linked; however, in disorders such as rheumatoid arthritis, periodontal disease, and osteoporosis, elevated osteoclast activity leads to bone destruction. Osteoclast formation and activation are controlled by many signaling pathways, including p38 MAPK. Dual-specificity phosphatase 1 (DUSP-1) is a factor involved in the negative regulation of p38 MAPK. The purpose of this study was to examine the effect of Dusp1 deficiency on bone destruction. Methods Penetrance, onset, and severity of collagen-induced arthritis were recorded in DUSP-1+/+ and DUSP-1−/− mice. Bone destruction was assessed by histologic and micro–computed tomographic examination of the joints. The in vitro formation and activation of osteoclasts from DUSP-1+/+ and DUSP-1−/− precursors were assessed in the absence or presence of tumor necrosis factor (TNF). Results The formation and activation of osteoclasts in vitro in the presence of TNF were enhanced by Dusp1 gene disruption. DUSP-1−/− mice exhibited higher penetrance, earlier onset, and increased severity of experimental arthritis, accompanied by greater numbers of osteoclasts in inflamed joints and more extensive loss of bone. A DUSP-1−/− mouse colony of mixed genetic background also demonstrated striking spontaneous osteolytic destruction of distal phalanges. Conclusion DUSP-1 is a critical regulator of osteoclast activity and limits bone destruction in an experimental model of rheumatoid arthritis. Defects in the expression or activity of DUSP1 in humans may correlate with a propensity to develop osteolytic lesions in arthritis.

Secretory phospholipase A2 group IIA (sPLA2-IIA) was examined as a point of care marker for determining disease activity in rheumatoid (RA) and psoriatic (PsA) arthritis. Serum concentration and activity of sPLA2-IIA were measured using in-house antibodies and a novel point of care lateral flow device assay in patients diagnosed with varying severities of RA (n = 30) and PsA (n = 25) and found to correlate strongly with C-reactive protein (CRP). Levels of all markers were elevated in patients with active RA over those with inactive RA as well as both active and inactive PsA, indicating that sPLA2-IIA can be used as an analogue to CRP for RA diagnosis at point of care.

The human body consists of millions of commensal bacteria (the microbiome), with the intestinal tract being the most prevalent site of colonization. This colonization process begins at birth, and despite numerous factors such as ageing, diet and drug use affecting the microbiome make-up, by adulthood the composition of the gut bacteria is relatively consistent across local populations. The recent advent of new scientific techniques has enabled us to explore how the microbiome affects health and, in particular, has shed light on the involvement of the microbiome in the pathogenesis of inflammatory disease. In this review we highlight the current evidence for microbiome manipulation in inflammatory arthritis in animal and human models and discuss potential therapeutics targeting the microbiome as treatment for these diseases.

Clinical Question How should we manage disease-modifying antirheumatic drugs (DMARDs) in primary care when used as part of a shared-care arrangement in inflammatory arthritis? Inflammatory arthritis such as rheumatoid and psoriatic arthritis are chronic diseases requiring long-term management. The overall goal of treatment is to achieve remission or sustained low disease activity.1 The majority of patients are managed effectively using disease-modifying antirheumatic drugs (DMARDs). Traditionally, patients have been managed in secondary care by planned consultation with a rheumatologist every 3–6 months. This system of follow-up accounts for >75% of a rheumatologist’s workload2 and evidence has shown that up to 45% of routine consultations are undertaken without demonstrated patient need.3 Projected future shortages of specialist physicians including rheumatologists mean this arrangement may be untenable in the near future.3 Greater emphasis has therefore been placed on managing patients with stable inflammatory arthritis within the community using shared-care arrangements. Innovations within primary care have developed the role of specialist nurse practitioners and interface teams responsible for the continued monitoring of DMARDs. Shared care is defined as: ‘… the joint participation of GPs and specialists in the planned delivery of care for patients with a chronic condition, informed by an enhanced information exchange, over and above the routine discharge/referral letters.’ 4 This model has been used successfully for >10 years in chronic conditions including asthma and diabetes. Studies have consistently demonstrated that versions of shared care are not inferior to traditional follow-up in controlling disease activity in patients with inflammatory arthritis.3,5,6 Furthermore, symptom control facilitated by shared care is likely to be more cost-effective than treatment delivered in secondary care in 60–90% of cases.7 In the UK it is becoming common to manage patients with stable inflammatory arthritis within primary care using a shared-care arrangement, once …

Summary We investigated changes in circulating T helper type 17 (Th17) cells following anti-tumour necrosis factor (TNF) in rheumatoid arthritis (RA), ankylosing spondylitis (AS) and psoriatic arthritis (PsA) patients. Peripheral blood mononuclear cells (PBMC) were isolated from 25 RA, 15 AS and eight PsA patients at baseline 4 and 12 weeks after treatment, and Th17 cell frequencies were analysed using interleukin (IL)-17 enzyme-linked immunospot (ELISPOT) and flow cytometry. A significant increase in IL-17-producing cells was observed by ELISPOT in RA and AS patients at 12 weeks. Flow cytometry confirmed significant increases in CD4+IL-17+ cells at 12 weeks in RA and AS and 4 weeks in PsA patients. Anti-TNF treatment increases circulating Th17 cells in three different diseases.

Innate immune responses are critically dependent on MAPK (mitogen-activated protein kinase) signalling pathways, in particular JNK (c-Jun N-terminal kinase) and p38 MAPK. Both of these kinases are negatively regulated via their dephosphorylation by DUSP1 (dual­-specificity phosphatase 1). Several pro- and anti-inflammatory stimuli converge to regulate the DUSP1 gene and to modulate the time course of its expression. In turn, the pattern of expression of DUSP1 dictates the kinetics of activation of JNK and p38 MAPK, and this influences the expression of several mediators of innate immunity. DUSP1 is therefore a central regulator of innate immunity, and its expression can profoundly affect the outcome of inflammatory challenges. We discuss possible implications for immune-mediated inflammatory diseases and their treatment.

Glucocorticoids (GCs), which are used in the treatment of immune-mediated inflammatory diseases, inhibit the expression of many inflammatory mediators. They can also induce the expression of dual specificity phosphatase 1 (DUSP1; otherwise known as mitogen-activated protein kinase [MAPK] phosphatase 1), which dephosphorylates and inactivates MAPKs. We investigated the role of DUSP1 in the antiinflammatory action of the GC dexamethasone (Dex). Dex-mediated inhibition of c-Jun N-terminal kinase and p38 MAPK was abrogated in DUSP1−/− mouse macrophages. Dex-mediated suppression of several proinflammatory genes (including tumor necrosis factor, cyclooxygenase 2, and interleukin 1α and 1β) was impaired in DUSP1−/− mouse macrophages, whereas other proinflammatory genes were inhibited by Dex in a DUSP1-independent manner. In vivo antiinflammatory effects of Dex on zymosan-induced inflammation were impaired in DUSP1−/− mice. Therefore, the expression of DUSP1 is required for the inhibition of proinflammatory signaling pathways by Dex in mouse macrophages. Furthermore, DUSP1 contributes to the antiinflammatory effects of Dex in vitro and in vivo.

The stress-activated protein kinase p38 stabilizes a number of mRNAs encoding inflammatory mediators, such as cyclooxygenase 2 (Cox-2). In HeLa cells the anti-inflammatory glucocorticoid dexamethasone destabilizes Cox-2 mRNA by inhibiting p38 function. Here we demonstrate that this effect is phosphatase dependent. Furthermore, in HeLa cells dexamethasone induced the sustained expression of mitogen-activated protein kinase phosphatase 1 (MKP-1), a potent inhibitor of p38 function. The inhibition of p38 and the induction of MKP-1 by dexamethasone occurred with similar dose dependence and kinetics. No other known p38 phosphatases were induced by dexamethasone, and other cell types which failed to express MKP-1 also failed to inhibit p38 in response to dexamethasone. The proinflammatory cytokine interleukin 1 (IL-1) induced MKP-1 expression in a p38-dependent manner and acted synergistically with dexamethasone to induce MKP-1 expression. In HeLa cells treated with IL-1 or IL-1 and dexamethasone, the dynamics of p38 activation mirrored the expression of MKP-1. These observations suggest that MKP-1 participates in a negative-feedback loop which regulates p38 function and that dexamethasone may inhibit proinflammatory gene expression in part by inducing MKP-1 expression.

Background Due to lack of validated outcome measures in non-psoriatic peripheral spondyloarthritis (pSpA), recent studies in this patient (pt) population have used varying endpoints [1]. Thus, developing new pSpA-specific indices may be worthwhile. Minimal Disease Activity (MDA) has been validated in psoriatic arthritis but not in pSpA. Objectives To evaluate the performance of a modification of the MDA criteria (excluding psoriasis) in pSpA patients (pts) from the ABILITY-2 study [2]. Methods This post-hoc analysis evaluated the validity of a modified MDA (mMDA) in pSpA. ABILITY-2 was a 12-week trial comparing adalimumab (ADA) with placebo (PBO) in pSpA followed by a 144 week extension. The mMDA for pSpA was defined as achieving at least 4 or 5 out of the following 6 criteria: (1) tender joint count (TJC, 78 joints) ≤1; (2) swollen joint count (SJC, 76 joints) ≤1; (3) pt pain visual analog scale (VAS) ≤15 of 100 mm; (4) pt global activity (PtGA) VAS ≤20 of 100 mm; (5) health assessment questionnaire–disability index (HAQ-DI)≤0.5; and (6) tender entheseal points ≤1. Enthesitis was assessed by the Leeds Enthesitis Index (LEI) or the Spondyloarthritis Research Consortium of Canada (SPARCC) Enthesitis Index for this analysis. The proportion of pts achieving the 4 different versions of mMDA were evaluated (either 4 or 5 of 6 using LEI and either 4 or 5 of 6 using SPARCC). The correlations between mMDA and the novel pSpA response criteria [PSpARC] remission from ABILITY-2 and Ankylosing Spondylitis Disease Activity Score Inactive Disease [ASDAS ID] were evaluated by tetrachoric correlation ( r tet ). Results Of the 163 pts (82 ADA, 81 PBO) who completed wk 12, significantly greater proportion of pts receiving ADA achieved mMDA (regardless of the definition) compared with PBO (P r tet >0.9) than ASDAS ID ( r tet >0.75) at wk 12, and yrs 1–3. Among pts who fulfilled the 4/6 criteria (LEI or SPARCC), approximately 20–30% of pts did not meet TJC and SJC criterion (Table 1b). However, the 5/6 criteria (LEI or SPARCC) were more stringent with approximately 5% and 13% not meeting the TJC and SJC criterion, respectively. Conclusions All 4 versions of mMDA discriminated between ADA and PBO treatment groups; both entheseal indices performed similarly. The mMDA (particularly the 5/6 versions which closely represents the concept of MDA) could be an appropriate treatment target in pSpA pts. References Turina, M.C., et al., Ann Rheum Dis, 2015. (doi: 10.1136/annrheumdis-2014-207235). Mease, P., et al., Arthritis Rheumatol, 2015. 67(4): p. 914–23. Acknowledgement AbbVie funded the study (NCT01064856), contributed to its design and participated in data collection, analysis and interpretation of the data, and in writing, review, and approval of the publication. Statistical support was provided by Nupun Varothai, former employee of AbbVie. Medical writing was provided by Deepa Venkitaramani, PhD, of AbbVie. Disclosure of Interest L. Coates Grant/research support from: AbbVie, Celgene, Janssen, Novartis, Pfizer, and UCB, Consultant for: AbbVie, Celgene, Janssen, Novartis, Pfizer, and UCB, Speakers bureau: AbbVie, Celgene, Janssen, Novartis, Pfizer, and UCB, S. Abraham Grant/research support from: AbbVie, Celgene, Novartis, Pfizer, and UCB, Consultant for: AbbVie, Celgene, Novartis, Pfizer, and UCB, Speakers bureau: AbbVie, Celgene, Novartis, Pfizer, and UCB, W. Tillett Grant/research support from: AbbVie, Celgene, Pfizer, and UCB, Consultant for: AbbVie, Celgene, Pfizer, and UCB, Speakers bureau: AbbVie, Celgene, Pfizer, and UCB, P. Mease Grant/research support from: AbbVie, Amgen, Bristol Myers, Celgene, Genentech, Janssen, Lilly, Merck, Novartis, Pfizer, and UCB., Consultant for: AbbVie, Amgen, Bristol Myers, Celgene, Genentech, Janssen, Lilly, Merck, Novartis, Pfizer, and UCB., Speakers bureau: AbbVie, Amgen, Bristol Myers, Celgene, Genentech, Janssen, Lilly, Merck, Novartis, Pfizer, and UCB., S. Ramiro: None declared, Y. Xia Employee of: Former AbbVie contract employee, X. Wang Shareholder of: AbbVie, Employee of: AbbVie, A. Pangan Shareholder of: AbbVie, Employee of: AbbVie, I.-H. Song Shareholder of: AbbVie, Employee of: AbbVie

Mycobaterium tuberculosis (MTB) accounts for significant morbidity and mortality worldwide. Non-tuberculous mycobacteria (NTM) species, usually considered benign contaminants, are increasingly recognized to be associated with pulmonary disease in immuno-compromised hosts. The tuberculin skin test (TST) is of limited benefit in immuno-supressed individuals who often fail to mount a delayed type hypersensitivity reaction. In such patients, the ELISpot assay is considered a more robust method of diagnosing tuberculosis. We present a case which illustrates that ELISpot can be negative in mycobacterial disease. A 51 year old Jamaican housekeeper, living in the UK for the past 45 years, presented with a 5-month history of a productive cough, shortness of breath and fatigue. She had a 10 year history of sero-positive rheumatoid arthritis which was well controlled with methotrexate and etanercept, an anti-tumour necrosis factor (TNF) biologic. She had …

Psoriasis arthritis (PsA) is a chronic, inflammatory disease, affecting predominantly skin and joints (Figure 1). Skin psoriasis develops before arthritis in the majority of cases, with a typical time lag of 5 to 10 years. However, around 20% of PsA patients never develop psoriasis.1 The prevalence of psoriasis in the UK is approximately 2% of the adult population.2 Figure 1. Typical clinical presentation of psoriasis arthritis. The white arrow denotes dactylitis and the black arrows denote psoriasis. Epidemiological studies indicate that between 10% and 30% of people with psoriasis will go on to develop PsA, giving a population prevalence for PsA of 0.4%. Out of 40 million adults in England, around 160 000 would be expected to have PsA. According to the National Institute for Health and Care Excellence (NICE), only 6200 people in England are currently registered to receive biological therapies for PsA, representing 4% of this population. Of the 350 000 people in the UK who have rheumatoid arthritis (RA), 35 000 (10%) are on biological therapies. PsA appears to be underdiagnosed not only in the UK but also abroad. According to the American Psoriasis Foundation, there are over 7 million adults in the US who have psoriasis but only 520 000 (7.4%) of these patients have …