Secukinumab improves active psoriatic arthritis symptoms and inhibits radiographic progression: primary results from the randomised, double-blind, phase III FUTURE 5 study Ann. Rheum. Dis. (IF 12.811) Pub Date : 2018-03-22 Philip Mease, Désirée van der Heijde, Robert Landewé, Shephard Mpofu, Proton Rahman, Hasan Tahir, Atul Singhal, Elke Boettcher, Sandra Navarra, Karin Meiser, Aimee Readie, Luminita Pricop, Ken Abrams
Objectives To evaluate the effect of subcutaneous (s.c.) secukinumab, an interleukin-17A inhibitor, on clinical signs and symptoms and radiographic progression in patients with psoriatic arthritis (PsA). Methods Adults (n=996) with active PsA were randomised 2:2:2:3 to s.c. secukinumab 300 mg or 150 mg with loading dose (LD), 150 mg without LD or placebo. All groups received secukinumab or placebo at baseline, weeks 1, 2 and 3 and then every 4 weeks from week 4. The primary endpoint was the proportion of patients achieving an American College of Rheumatology 20 (ACR20) response at week 16. Results Significantly more patients achieved an ACR20 response at week 16 with secukinumab 300 mg with LD (62.6%), 150 mg with LD (55.5%) or 150 mg without LD (59.5%) than placebo (27.4%) (p<0.0001 for all; non-responder imputation). Radiographic progression, as measured by van der Heijde-modified total Sharp score, was significantly inhibited at week 24 in all secukinumab arms versus placebo (p < 0.01 for 300 mg with LD and 150 mg without LD and p<0.05 for 150 mg with LD; linear extrapolation). Adverse event rates at week 24 were similar across treatment arms: 63.1% (300 mg with LD), 62.7% (150 mg with LD), 61.1% (150 mg without LD) and 62.0% (placebo). No deaths or new safety signals were reported. Conclusion S.c. secukinumab 300 mg and 150 mg with and without LD significantly improved clinical signs and symptoms and inhibited radiographic structural progression versus placebo at week 24 in patients with PsA. Trial registration number [NCT02404350]; Results. : /lookup/external-ref?link_type=CLINTRIALGOV&access_num=NCT02404350&atom=%2Fannrheumdis%2Fearly%2F2018%2F03%2F22%2Fannrheumdis-2017-212687.atom
Phase III trial results with blisibimod, a selective inhibitor of B-cell activating factor, in subjects with systemic lupus erythematosus (SLE): results from a randomised, double-blind, placebo-controlled trial Ann. Rheum. Dis. (IF 12.811) Pub Date : 2018-03-21 Joan T Merrill, William R Shanahan, Morton Scheinberg, Kenneth C Kalunian, David Wofsy, Renee S Martin
Background Targeted inhibitors of B-cell activating factor (BAFF) have been evaluated in phase III trials in over 4000 patients with systemic lupus erythematosus (SLE). Post hoc analyses of these studies identify greater treatment effect in patients entering with higher disease activity, greater corticosteroid doses, anti double-stranded DNA (dsDNA) and low complement C3 or C4. Objectives To evaluate the efficacy and safety of blisibimod, a BAFF inhibitor, in a population of patients with SLE enriched for high disease activity. Methods 442 patients with SLE with antinuclear antibodies or anti-dsDNA and Safety of Estrogen in Lupus Erythematosus National Assessment – Systemic Lupus Erythematosus Disease Activity Index (SELENA-SLEDAI) score ≥10 on standard-of-care medications were randomised to receive weekly subcutaneous blisibimod (200 mg) or placebo. Corticosteroid taper was encouraged from week 8. The primary end point was the week 52 SLE Responder Index-6 (SRI-6). Results The SRI-6 primary end point was not met. There was a statistically significant steroid-sparing effect, and significantly more blisibimod-treated subjects achieved corticosteroid taper. Increased blisibimod treatment effect on SRI-6 was observed in subjects who achieved a concomitant decrease in corticosteroid dose from baseline. In subjects with baseline urinary protein:creatinine ratio (UPCR) ≥56.5 mg/mmol, significantly higher proportions of blisibimod subjects achieved >50% reduction in UPCR and/or UPCR <56.5 mg/mmol. Reductions in SLE autoantibodies and B cells, and increases in complement C3 and C4 were observed with blisibimod. Blisibimod was well-tolerated. The most common adverse events were upper respiratory tract infection, urinary tract infection, injection site erythema/reaction and diarrhoea. Conclusions Although the SRI-6 end point was not met, blisibimod was associated with successful steroid reduction, decreased proteinuria and biomarker responses. Trial registration number [NCT01395745]. : /lookup/external-ref?link_type=CLINTRIALGOV&access_num=http%3A%2F%2Fbmj.kriyadocs.com%2FNCT01395745&atom=%2Fannrheumdis%2Fearly%2F2018%2F03%2F21%2Fannrheumdis-2018-213032.atom
Response to: ‘The reference levels of serum urate for clinically evident incident gout’ by Chen and Ding Ann. Rheum. Dis. (IF 12.811) Pub Date : 2018-03-21 Nicola Dalbeth, Amanda Phipps-Green, Christopher Frampton, Tuhina Neogi, William J Taylor, Tony R Merriman
We thank Drs Chen and Ding1 for their interest in our recent paper describing the relationship between serum urate concentrations and risk of developing incident gout.2 They suggest that we calculate benchmark dose estimates for serum urate and gout …
Reference level of serum urate for clinically evident incident gout Ann. Rheum. Dis. (IF 12.811) Pub Date : 2018-03-21 Xiao Chen, Xiaoqiang Ding
I read the interesting study entitled ‘Relationship between serum urate concentration and clinically evident incident gout: an individual participant data analysis’ conducted by Dalbeth and colleagues.1 Their study showed the cumulative incidence of gout was increased with the serum urate levels and the cumulative years. The reference level of serum urate below which the risk of damage is low has not been completely clarified. The benchmark dose (BMD) method, first described by Crump in 1984,2 has been widely used in the field …
Tyrosine kinase Fyn promotes osteoarthritis by activating the β-catenin pathway Ann. Rheum. Dis. (IF 12.811) Pub Date : 2018-03-19 Kai Li, Yue Zhang, Yuwei Zhang, Wenqing Jiang, Junhui Shen, Song Xu, Daozhang Cai, Jie Shen, Bin Huang, Mangmang Li, Qiancheng Song, Yu Jiang, Anling Liu, Xiaochun Bai
Objectives To investigate the role of tyrosine kinase Fyn in the development of osteoarthritis (OA) and the underlying mechanisms, and to define whether targeting Fyn could prevent OA in mice. Methods Cartilage samples from normal and aged mice were analysed with proteome-wide screening. Fyn expression was examined with immunofluorescence in human and age-dependent or experimental mouse OA cartilage samples. Experimental OA in Fyn-knockout mice was induced by destabilisation of the medial meniscus. Primary cultured mouse chondrocytes were treated with proinflammatory cytokine interleukin-1β. The inhibitor of Src kinase family, AZD0530 (saracatinib), and inhibitor of Fyn, PP1, were used to treat experimental OA in mice. Results Fyn expression was markedly upregulated in human OA cartilage and in cartilage from aged mice and those with post-traumatic OA. Fyn accumulates in articular chondrocytes and interacts directly with and phosphorylates β-catenin at Tyr142, which stabilises β-catenin and promotes its nuclear translocation. The deletion of Fyn effectively delayed the development of post-traumatic and age-dependent OA in mice. Fyn inhibitors AZD0530 and PP1 significantly attenuated OA progression by blocking the β-catenin pathway and reducing the levels of extracellular matrix catabolic enzymes in the articular cartilage. Conclusions Fyn accumulates and activates β-catenin signalling in chondrocytes, accelerating the degradation of the articular cartilage and OA development. Targeting Fyn is a novel and potentially therapeutic approach to the treatment of OA.
Similar efficacy, safety and immunogenicity of adalimumab biosimilar BI 695501 and Humira reference product in patients with moderately to severely active rheumatoid arthritis: results from the phase III randomised VOLTAIRE-RA equivalence study Ann. Rheum. Dis. (IF 12.811) Pub Date : 2018-03-16 Stanley B Cohen, Alberto Alonso-Ruiz, Piotr A Klimiuk, Eric C Lee, Nuala Peter, Ivo Sonderegger, Deepak Assudani
Objective To demonstrate clinical equivalence of adalimumab biosimilar candidate BI 695501 with Humira. Methods Patients with active rheumatoid arthritis on stable methotrexate were randomised to BI 695501 or Humira in a double-blind, parallel-group, equivalence study. At week 24, patients were rerandomised to continue BI 695501 or Humira, or switch from Humira to BI 695501. The coprimary endpoints were the percentage of patients achieving the American College of Rheumatology 20% response criteria (ACR20) at weeks 12 and 24. Further efficacy and safety endpoints and immunogenicity were assessed up to week 58. Results 645 patients were randomised. At week 12, 67.0% and 61.1% (90% CI –0.9 to 12.7) of patients receiving BI 695501 (n=324) and Humira (n=321), respectively, achieved ACR20; at week 24 the corresponding values were 69.0% and 64.5% (95% CI –3.4 to 12.5). These differences were within prespecified margins (week 12: 90% CI (–12% to 15%); week 24: 95% CI (−15% to 15%)), demonstrating therapeutic bioequivalence. 593 patients were rerandomised at week 24. Up to week 48, mean change from baseline in Disease Activity Score 28-erythrocyte sedimentation rate and ACR20/ACR50/ACR70 response rates were similar across the switched (n=147), continuous BI 695501 (n=298) and continuous Humira (n=148) groups. Similar immunogenicity (antidrug antibodies (ADAs), ADA titres and neutralising antibodies) was seen between BI 695501 and Humira (to week 24) and across rerandomised groups (to week 48). Safety and tolerability profiles were similar between groups. Conclusions BI 695501 demonstrated similar efficacy, safety and immunogenicity to Humira; switch from Humira to BI 695501 had no impact on efficacy, safety and immunogenicity. Trial registration number [NCT02137226], Results. : /lookup/external-ref?link_type=CLINTRIALGOV&access_num=NCT02137226&atom=%2Fannrheumdis%2Fearly%2F2018%2F03%2F15%2Fannrheumdis-2017-212245.atom
Response to: ‘A20 haploinsufficiency (HA20): clinical phenotypes and disease course of patients with a newly recognised NF-kB-mediated autoinflammatory disease’ Ann. Rheum. Dis. (IF 12.811) Pub Date : 2018-03-16 Florian Berteau, Bénédicte Rouvière, Alice Nau, Rozenn Le Berre, Guillaume Sarrabay, Isabelle Touitou, Claire de Moreuil
We have read with interest the article by Aeschlimann1 and colleagues about clinical phenotypes and disease course of 16 American patients with A20 haploinsufficiency (HA20). We would like to share our experience of a French family of three new related patients with juvenile onset Behçet’s disease associated with HA20 (figure 1). Figure 1 Pedigree of a French family diagnosed with HA20. The arrow indicates the proband. Filled in blue symbols indicate subjects carrying a p.Glu332* mutation in TNFAIP3 . Men are indicated by squares, and women are indicated by circles. P1, a 48-year-old woman, was the first patient to be diagnosed with HA20 in July 2017 in our unit. She carries the heterozygous loss of function c.[994G>T] p.Glu332* truncating mutation, …
Response to ‘Detection of myositis-specific antibodies: additional notes’ Ann. Rheum. Dis. (IF 12.811) Pub Date : 2018-03-13 Maria Infantino, Mariangela Manfredi, Valentina Grossi, Maurizio Benucci
With great interest, we read the letters that have commented on the recent European League Against Rheumatism/American College of Rheumatology classification criteria for idiopathic inflammatory myopathies1 (IIMs) and ensuing discussions.2 3 This highlights how harmonising myositis-specific antibodies (MSA) testing methodologies is currently a hot topic of debate among laboratory specialists, clinicians and manufacturers. I would particularly like to share our own immunology laboratory experience by expanding on the letter entitled ‘Detection of myositis-specific antibodies: additional notes’ by M Mahler and M Fritzler4 with which we wholly agree. Newer technologies, such as line immunoassays (LIA) and dot blots (DB), which provide greater sensitivity and rapid serological diagnoses, have standardisation and specificity drawbacks, but the tight connection between autoantibodies and clinical phenotypes underline a great need …
Additional response to the correspondence: ‘Switching from the bio-originators to biosimilar: is it premature to recommend this procedure?’ by Cantini and Bennuci Ann. Rheum. Dis. (IF 12.811) Pub Date : 2018-03-13 Marc Scherlinger, Thierry Schaeverbeke
We read with great interest Cantini and Benucci’s response to our letter.1 However, we would like to add some points to the debate. To date and to our knowledge, every single clinical trial investigating efficacy and safety of biosimilars in rheumatology using a double-blinded design has failed to report any clinical difference with the original biologic. The double-blinded controlled trial NOR-SWITCH as well as open-label extension studies such as PLANETRA investigating efficacy and safety of the switch from original to biosimilar infliximab also failed to report any difference.2 3 These studies unequivocally condone the grade 1b recommendation 6 regarding the efficacy and safety of the switch published …
Efficacy and safety of biologics in relapsing polychondritis: a French national multicentre study Ann. Rheum. Dis. (IF 12.811) Pub Date : 2018-03-13 Guillaume Moulis, Grégory Pugnet, Nathalie Costedoat-Chalumeau, Alexis Mathian, Gaëlle Leroux, Jonathan Boutémy, Olivier Espitia, Laurence Bouillet, Sabine Berthier, Jean-Baptiste Gaultier, Pierre-Yves Jeandel, Amadou Konaté, Arsène Mékinan, Elisabeth Solau-Gervais, Benjamin Terrier, Daniel Wendling, Fanny Andry, Camille Garnier, Pascal Cathébras, Laurent Arnaud, Aurore Palmaro, Patrice Cacoub, Zahir Amoura, Jean-Charles Piette, Philippe Arlet, Maryse Lapeyre-Mestre, Laurent Sailler
Objectives To assess the efficacy and the safety of biologics in a cohort of patients with relapsing polychondritis (RP). Methods We conducted a French multicentre retrospective cohort study including patients treated with biologics for RP. Efficacy outcomes were clinical response (partial or complete) and complete response during the first 6 months of exposure, plus daily corticosteroid dose at 6 months. Other outcomes were adverse drug reactions (ADRs), persistence of biologics and factors associated with a response. Results This study included 41 patients exposed to 105 biologics (tumour-necrosis factor (TNF) inhibitors, n=60; tocilizumab, n=17; anakinra, n=15; rituximab, n=7; abatacept, n=6). Overall response rate during the first 6 months of exposure was 62.9%. Complete response rate was 19.0%. Reduced corticosteroid doses were highly variable among patients. ADRs were mostly infections (n=42). Reasons for biologic withdrawal (73.3%) were insufficient efficacy (34.3%; ranging from 23.5% for tocilizumab to 72.7% for etanercept), loss of efficacy (18.1%) and ADRs (20.9%; mostly for anakinra: 46.7%). Persistence was comparable among biologic classes. Among TNF inhibitors, the highest persistence was observed with adalimumab. Differences in clinical response rates were observed depending on biologics and organ involvement. There were trends towards a lower response rate in cases with associated myelodysplastic syndrome and for a higher response rate for nasal/auricular chondritis, sternal chondritis and concomitant exposure to non-biologic disease-modifying antirheumatic drugs. Conclusions This study describes the efficacy of biologics for refractory RP. However, the number of complete responses was low and there were concerns about the risk of ADRs, particularly infections.
Response to: ‘The role of temporal artery biopsy in patients with giant cell arteritis is debated’ by Moiseev et al Ann. Rheum. Dis. (IF 12.811) Pub Date : 2018-03-13 Christian Dejaco, Sofia Ramiro, Christina Duftner, Wolfgang A Schmidt
Moiseev et al 1 underlined the main message of the new European League Against Rheumatism (EULAR) recommendations for the use of imaging in large vessel vasculitis (LVV), namely the importance of imaging as a first-line test for the diagnosis of LVV.2 The EULAR task force also emphasised that the recommendations should not be understood as a recommendation against performing temporal artery biopsy (TAB) in giant cell arteritis (GCA), rather a biopsy still has its place when there is diagnostic doubt after having performed imaging or when imaging is not available or not performed with sufficient expertise. When a diagnosis can be …
Identification of calcium pyrophosphate deposition disease (CPPD) by ultrasound: reliability of the OMERACT definitions in an extended set of joints—an international multiobserver study by the OMERACT Calcium Pyrophosphate Deposition Disease Ultrasound Subtask Force Ann. Rheum. Dis. (IF 12.811) Pub Date : 2018-03-13 Georgios Filippou, Carlo Alberto Scirè, Antonella Adinolfi, Nemanja S Damjanov, Greta Carrara, George A W Bruyn, Tomas Cazenave, Maria Antonietta D’Agostino, Andrea Delle Sedie, Valentina Di Sabatino, Mario Enrique Diaz Cortes, Emilio Filippucci, Frederique Gandjbakhch, Marwin Gutierrez, Daryl K Maccarter, Mihaela Micu, Ingrid Möller Parera, Gaël Mouterde, Mohamed Atia Mortada, Esperanza Naredo, Carlos Pineda, Francesco Porta, Anthony M Reginato, Iulia Satulu, Wolfgang A Schmidt, Teodora Serban, Lene Terslev, Violeta Vlad, Florentin Ananu Vreju, Pascal Zufferey, Panagiotis Bozios, Carmela Toscano, Valentina Picerno, Annamaria Iagnocco
Objectives To assess the reliability of the OMERACT ultrasound (US) definitions for the identification of calcium pyrophosphate deposition disease (CPPD) at the metacarpal-phalangeal, triangular fibrocartilage of the wrist (TFC), acromioclavicular (AC) and hip joints. Methods A web-based exercise and subsequent patient-based exercise were carried out. A panel of 30 OMERACT members, participated at the web-based exercise by evaluating twice a set of US images for the presence/absence of CPPD. Afterwards, 19 members of the panel met in Siena, Italy, for the patient-based exercise. During the exercise, all sonographers examined twice eight patients for the presence/absence of CPPD at the same joints. Intraoberserver and interobserver kappa values were calculated for both exercises. Results The web-based exercise yielded high kappa values both in intraobserver and interobserver evaluation for all sites, while in the patient-based exercise, inter-reader agreement was acceptable for the TFC and the AC. TFC reached high interobserver and intraobserver k values in both exercises, ranging from 0.75 to 0.87 (good to excellent agreement). AC reached moderate kappa values, from 0.51 to 0.85 (moderate to excellent agreement) and can readily be used for US CPPD identification. Conclusions Based on the results of our exercise, the OMERACT US definitions for the identification of CPPD demonstrated to be reliable when applied to the TFC and AC. Other sites reached good kappa values in the web-based exercise but failed to achieve good reproducibility at the patient-based exercise, meaning the scanning method must be further refined.
Common language description of the term rheumatic and musculoskeletal diseases (RMDs) for use in communication with the lay public, healthcare providers and other stakeholders endorsed by the European League Against Rheumatism (EULAR) and the American College of Rheumatology (ACR) Ann. Rheum. Dis. (IF 12.811) Pub Date : 2018-03-13 Désirée van der Heijde, David I Daikh, Neil Betteridge, Gerd R Burmester, Afton L Hassett, Eric L Matteson, Ronald van Vollenhoven, Sharad Lakhanpal
A European League Against Rheumatism-American College of Rheumatology working group consisting of practising and academic rheumatologists, a rheumatology researcher and a patient representative created a succinct general statement describing rheumatic and musculoskeletal diseases (RMDs) in adults and children in language that can be used in conversations with the lay public, media, healthcare providers and other stakeholders. Based on the literature review, several elements were deemed important for inclusion in the description of RMDs. First, RMDs encompass many different diseases that can affect individuals at any age, including children. Second, there are various pathophysiological pathways underlying different RMDs. Third, the impact of RMDs on individuals and society should be emphasised. The working group agreed that the language should be comprehensible to the lay public. Thus, the following description of RMDs has been developed: ‘Rheumatic and musculoskeletal diseases (RMDs) are a diverse group of diseases that commonly affect the joints, but can affect any organ of the body. There are more than 200 different RMDs, affecting both children and adults. They are usually caused by problems of the immune system, inflammation, infections or gradual deterioration of joints, muscles and bones. Many of these diseases are long term and worsen over time. They are typically painful and limit function. In severe cases, RMDs can result in significant disability, having a major impact on both quality of life and life expectancy.’ This description can be used by rheumatology groups, researchers and those who work in advocacy and education related to RMDs.
Adalimumab concentration-based tapering strategy: as good as the recommended dosage Ann. Rheum. Dis. (IF 12.811) Pub Date : 2018-04-01 Denis Mulleman, Alejandro Balsa
Drug monitoring consists of observing, recording or detecting the effects of a substance administered to an individual. Therapeutic drug monitoring (TDM) aims at improving patient care based on drug concentration measurement in order to adjust the dose or time interval individually.1 TDM is based on the assumption of a definable relation between dose and plasma/blood drug concentration and between concentration and therapeutic effects. In ARD , l’Ami et al conducted an open-label randomised trial comparing an increasing dosing interval of adalimumab from 2 to 3 weeks with a standard-dose conservative strategy in patients with rheumatoid arthritis (RA) with an adalimumab trough concentration >8 mg/L.2 The authors concluded that the dose tapering strategy was not inferior to the conservative strategy over 26 weeks. This important contribution is a step towards implementation of TDM in clinical practice. Prior to this work, the same group found that a drug concentration between 5 and 8 mg/L was associated with a good clinical response and strongly suggested that no additional improvement could be expected by increasing the dose (ie, by reducing the time interval) in patients with trough concentration >8 mg/L.3 A similar range has been described for adalimumab in psoriatic arthritis, which validates these findings.4 In the economic context, this tapering strategy can be seen as an opportunity to alleviate the burden for society. However, in the l’Ami et al ’s study, the target sample size was not reached, which somehow minimises the strength of the conclusion and raises the question of acceptability by patients to participate in the study. Indeed, some patients could have feared a flare or, more probably, because they wanted to taper the dose, did not want to be allocated to the conservative arm. Whatever this limitation, tapering adalimumab seems to perform as good as the recommended dose in patients with RA with …
2017 EULAR recommendations for a core data set to support observational research and clinical care in rheumatoid arthritis Ann. Rheum. Dis. (IF 12.811) Pub Date : 2018-04-01 Helga Radner, Katerina Chatzidionysiou, Elena Nikiphorou, Laure Gossec, Kimme L Hyrich, Condruta Zabalan, Yvonne van Eijk-Hustings, Paula R Williamson, Andra Balanescu, Gerd R Burmester, Loreto Carmona, Maxime Dougados, Axel Finckh, Glenn Haugeberg, Merete Lund Hetland, Susan Oliver, Duncan Porter, Karim Raza, Patrick Ryan, Maria Jose Santos, Annette van der Helm-van Mil, Piet van Riel, Gabrielle von Krause, Jakub Zavada, William G Dixon, Johan Askling
Personalised medicine, new discoveries and studies on rare exposures or outcomes require large samples that are increasingly difficult for any single investigator to obtain. Collaborative work is limited by heterogeneities, both what is being collected and how it is defined. To develop a core set for data collection in rheumatoid arthritis (RA) research which (1) allows harmonisation of data collection in future observational studies, (2) acts as a common data model against which existing databases can be mapped and (3) serves as a template for standardised data collection in routine clinical practice to support generation of research-quality data. A multistep, international multistakeholder consensus process was carried out involving voting via online surveys and two face-to-face meetings. A core set of 21 items (‘what to collect’) and their instruments (‘how to collect’) was agreed: age, gender, disease duration, diagnosis of RA, body mass index, smoking, swollen/tender joints, patient/evaluator global, pain, quality of life, function, composite scores, acute phase reactants, serology, structural damage, treatment and comorbidities. The core set should facilitate collaborative research, allow for comparisons across studies and harmonise future data from clinical practice via electronic medical record systems.
Implementation of the EULAR cardiovascular risk management guideline in patients with rheumatoid arthritis: results of a successful collaboration between primary and secondary care Ann. Rheum. Dis. (IF 12.811) Pub Date : 2018-04-01 Julia M Weijers, Sanne A A Rongen-van Dartel, Dan M G M F Hoevenaars, Max Rubens, Marlies E J L Hulscher, Piet L C M van Riel
The updated European League Against Rheumatism (EULAR) guideline recommends cardiovascular disease (CVD) risk assessment at least once every 5 years in all patients with rheumatoid arthritis (RA). This viewpoint starts with a literature overview of studies that investigated the level of CVD risk factor (CVD-RF) screening in patients with RA in general practices or in outpatient clinics. These studies indicate that CVD-RF screening in patients with RA is marginally applied in clinical practice, in primary as well as secondary care. Therefore, the second part of this viewpoint describes an example of the successful implementation of the EULAR cardiovascular disease risk management (CVRM) guideline in patients with RA in a region in the south of the Netherlands where rheumatologists and general practitioners (GPs) closely collaborate to manage the cardiovascular risk of patients with RA. The different components of this collaboration and the responsibilities of respectively primary and secondary care professionals are described. Within this collaboration, lipid profile was used as an indicator to assess whether CVD-RF screening was performed in the previous 5 years. In 72% (n=454) of the 628 patients with RA, a lipid profile was determined in the previous 5 years. As part of routine quality control, a reminder was sent to the GP in case a patient with RA was not screened. After sending the reminder letter, in 88% of all patients with RA, CVD risk assessment was performed. This collaboration can be seen as good practice to provide care in line with the EULAR guideline.
Successful reduction of overexposure in patients with rheumatoid arthritis with high serum adalimumab concentrations: an open-label, non-inferiority, randomised clinical trial Ann. Rheum. Dis. (IF 12.811) Pub Date : 2018-04-01 Merel J l’Ami, Charlotte LM Krieckaert, Michael T Nurmohamed, Ronald F van Vollenhoven, Theo Rispens, Maarten Boers, Gerrit Jan Wolbink
Objective High adalimumab serum concentrations do not result in better response in patients with rheumatoid arthritis (RA), suggesting overexposure. We investigated whether patients with adalimumab concentrations >8 µg/mL can prolong their dosing interval by 50% without a clinically relevant change in disease activity. Methods Consecutive patients with RA, treated with adalimumab 40 mg every other week for at least 28 weeks, were approached for this randomised, open-label, non-inferiority trial. Patients with adalimumab trough concentrations >8 µg/mL were randomly (1:1) assigned to dose-interval prolongation of once every 3 weeks or continuation of every other week. Primary outcome was the change in disease activity score of 28 joints (ΔDAS28-ESR) after 28 weeks, with a non-inferiority margin of 0.6 points. Results In total, 147 patients were screened. Fifty-five patients had concentrations >8 µg/mL and were randomised. Mean ΔDAS28 after 28 weeks was –0.14±SD 0.61 in the prolongation group and 0.30±0.52 in the continuation group. Mean difference was significantly in favour of the prolongation group: 0.44 (95% CI 0.12 to 0.76, p=0.01). Conclusions Adalimumab-treated patients with RA with trough concentrations >8 µg/mL can prolong their standard dosing interval to once every 3 weeks without loss of disease control. Trial registration number NTR3509; Results.
Phase III, multicentre, double-blind, randomised, parallel-group study to evaluate the similarities between LBEC0101 and etanercept reference product in terms of efficacy and safety in patients with active rheumatoid arthritis inadequately responding to methotrexate Ann. Rheum. Dis. (IF 12.811) Pub Date : 2018-04-01 Hiroaki Matsuno, Masato Tomomitsu, Atsushi Hagino, Seonghye Shin, Jiyoon Lee, Yeong Wook Song
Objective To evaluate the similarities between LBEC0101 (etanercept biosimilar) and the etanercept reference product (ETN-RP) in terms of efficacy and safety, including immunogenicity, in patients with active rheumatoid arthritis despite methotrexate treatment. Methods This phase III, multicentre, randomised, double-blind, parallel-group, 54-week study was conducted in Japan and Korea. The primary efficacy endpoint was the change from baseline in the disease activity score in 28 joints based on erythrocyte sedimentation rate (DAS28-ESR) at week 24. American College of Rheumatology 20% (ACR20) response rate, adverse events (AEs), pharmacokinetics and development of antidrug antibodies (ADAs) were also evaluated. Results In total, 374 patients were randomised to LBEC0101 (n=187) or ETN-RP (n=187). The least squares mean changes from baseline in DAS28-ESR at week 24 in the per-protocol set were −3.01 (95% CI −3.198 to −2.820) in the LBEC0101 group and −2.86 (95% CI −3.051 to −2.667) in the ETN-RP group. The estimated between-group difference was −0.15 and its 95% CI was −0.377 to 0.078, which was within the prespecified equivalence margin of −0.6 to 0.6. ACR20 response rates at week 24 were similar between the groups (LBEC0101 93.3% vs ETN-RP 86.7%). The incidence of AEs up to week 54 was comparable between the groups (LBEC0101 92.0% vs ETN-RP 92.5%), although fewer patients in the LBEC0101 group (1.6%) than the ETN-RP group (9.6%) developed ADAs. Conclusion The clinical efficacy of LBEC0101 was equivalent to that of ETN-RP. LBEC0101 was well tolerated and had a comparable safety profile to ETN-RP. Trial registration number NCT02357069.
Efficacy and safety of tregalizumab in patients with rheumatoid arthritis and an inadequate response to methotrexate: results of a phase IIb, randomised, placebo-controlled trial Ann. Rheum. Dis. (IF 12.811) Pub Date : 2018-04-01 Ronald F van Vollenhoven, Edward Clark Keystone, Vibeke Strand, Cesar Pacheco-Tena, Jiří Vencovský, Frank Behrens, Arthur Racewicz, Daniela Zipp, Faiza Rharbaoui, Ralf Wolter, Luise Knierim, Rainer Schmeidl, Xuefei Zhou, Silke Aigner, Benjamin Dälken, Andrea Wartenberg-Demand
Objective To evaluate the efficacy, biological activity and safety of tregalizumab in patients with active rheumatoid arthritis (RA) and an inadequate response to methotrexate (MTX). Methods 321 patients were randomised (1:1:1:1) to placebo or tregalizumab 25, 100 or 200 mg once-weekly subcutaneously in addition to MTX treatment. Responders at week 12 continued the same treatment, and non-responders at week 12 were escalated to the next higher tregalizumab dose level or re-randomised from placebo to active treatment. After 24 weeks, patients could continue treatment with tregalizumab for 24 weeks (extension phase). The primary endpoint was the American College of Rheumatology 20% improvement criteria (ACR20) response rate at week 12. Safety and biological activity were monitored through week 48. Results At week 12, ACR20 response rates were not statistically significantly different between placebo and any of the tregalizumab doses. Tregalizumab injections were well tolerated; most adverse events were mild to moderate and comparable among treatment and placebo groups. Biological activity was shown by dose-dependent CD4 downmodulation. Conclusion Treatment with tregalizumab did not show significant clinical efficacy in patients with active RA compared with placebo but resulted in the expected biological effect on CD4 modulation. Tregalizumab was generally well tolerated, and no new safety findings were identified. Trial registration number [NCT01999192; Results]. : /lookup/external-ref?link_type=CLINTRIALGOV&access_num=NCT01999192&atom=%2Fannrheumdis%2F77%2F4%2F495.atom
Leflunomide use during pregnancy and the risk of adverse pregnancy outcomes Ann. Rheum. Dis. (IF 12.811) Pub Date : 2018-04-01 Anick Bérard, Jin-Ping Zhao, Irene Shui, Susan Colilla
Objectives Leflunomide is known to be embryotoxic and teratogenic in rodents. However, there is less evidence in humans. We quantified the risk of major congenital malformation (MCM), prematurity, low birth weight (LBW) and spontaneous abortion associated with leflunomide exposure during pregnancy in humans. Methods From a cohort of 289 688 pregnancies in Montreal, Quebec, Canada, from 1998 to 2015, first-trimester leflunomide exposure and other antirheumatic drug exposures were studied for their association with MCM and spontaneous abortions. Also second or third-trimester leflunomide exposures were examined for associations with prematurity and LBW. Logistic regression model-based generalised estimating equations were used. Results 51 pregnancies were exposed to leflunomide during the first trimester, and 21 during the second/third trimesters. Adjusting for potential confounders, use of leflunomide during the first trimester of pregnancy was not associated with the risk of MCM (adjusted OR (aOR) 0.97, 95% CI 0.81 to 1.16; 5 exposed cases). No association was found between second/third-trimester exposure to leflunomide and the risk of prematurity (aOR 4.03, 95% CI 0.91 to 17.85; 7 exposed cases) nor LBW (aOR 1.06, 95%CI 0.90 to 1.25; 8 exposed cases). Pregnancy exposure to leflunomide was also not associated with the risk of spontaneous abortion (aOR 1.09, 95% CI 0.90 to 1.32; 11 exposed cases). Conclusions Maternal exposure to leflunomide during pregnancy was not associated with statistically significant increased risk of MCMs, prematurity, LBW or spontaneous abortions. However, given that relatively few women were exposed to leflunomide during pregnancy in this cohort, caution remains warranted.
Risk of second malignant neoplasm and mortality in patients with rheumatoid arthritis treated with biological DMARDs: a Danish population-based cohort study Ann. Rheum. Dis. (IF 12.811) Pub Date : 2018-04-01 Lene Dreyer, René L Cordtz, Inger Marie J Hansen, Lars Erik Kristensen, Merete L Hetland, Lene Mellemkjaer
Objective To study the risk of a second malignant neoplasm (SMN) and mortality in patients with rheumatoid arthritis (RA) with a history of a primary cancer diagnosis and treated with biological disease-modifying antirheumatic drugs (bDMARD). Methods Among patients with RA (n=15 286) registered in the DANBIO Register during 2000–2011, 1678 had a primary cancer according to the Danish Cancer Registry. HRs for SMN and death were calculated. Results During follow-up there were 279 patients with RA contributing person-years to the bDMARDs use before their primary cancer diagnosis, 220 to the only after , 92 to the both before and after, while 1203 patients with RA contributed to the non-use strata. Ever use of bDMARDs was associated with a HR of 1.11 (95% CI 0.74 to 1.67) for developing a SMN compared with non-use (cancer site adjusted). The HR for death associated with bDMARD use before the primary cancer diagnosis was increased 1.53 (95% CI 1.13 to 2.09). After further adjustment for extent of the primary cancer, the HR for death was 1.20 (95% CI 0.88 to 1.63) for bDMARDs use before cancer, 1.36 (95% CI 0.78 to 2.39) for bDMARD use only after cancer and 1.22 (95% CI 0.70 to 2.13) for use both before and after the cancer. Conclusions Among patients with RA with a history of cancer, treatment with bDMARDs was not associated with increased risk of SMN. No clear conclusion can be drawn regarding mortality in bDMARD-treated patients with RA.
Risk of losing remission, low disease activity or radiographic progression in case of bDMARD discontinuation or tapering in rheumatoid arthritis: systematic analysis of the literature and meta-analysis Ann. Rheum. Dis. (IF 12.811) Pub Date : 2018-04-01 Sophie Henaux, Adeline Ruyssen-Witrand, Alain Cantagrel, Thomas Barnetche, Bruno Fautrel, Nathalie Filippi, Cédric Lukas, Bernd Raffeiner, Maurizio Rossini, Yannick Degboé, Arnaud Constantin
Objectives To assess the risk of losing remission, low disease activity (LDA) or radiographic progression in the case of (1) discontinuing or (2) tapering doses of biological disease-modifying antirheumatic drugs (bDMARDs) compared with continuation of the initial treatment regimen in rheumatoid arthritis (RA) patients with remission or LDA. Materials and methods A systematic literature analysis was carried out through May 2017 on the PubMed, Embase, Cochrane and international congress databases, selecting controlled trials comparing bDMARDs discontinuation/tapering versus continuation in RA patients with remission or LDA. The meta-analysis assessed the risk ratio (RR) and 95% CI of losing remission or LDA and the risk of radiographic progression after (1) discontinuing and (2) tapering doses of bDMARDs versus continuing the initial treatment. Results The meta-analysis comparing bDMARDs discontinuation versus continuation performed on nine trials showed an increased risk of losing remission (RR (95% CI)=1.97(1.43 to 2.73), P<0.0001) or LDA (RR (95% CI)=2.24(1.52 to 3.30), P<0.0001) and an increased risk of radiographic progression (RR (95% CI)=1.09(1.02 to 1.17), P=0.01) in case of bDMARD discontinuation. The meta-analysis comparing bDMARDs tapering versus continuation performed on 11 trials showed an increased risk of losing remission (RR (95% CI)=1.23(1.06 to 1.42), P=0.006) but no increased risk of losing LDA (RR (95% CI)=1.02 (0.85 to 1.23), P=0.81) nor any increased risk of radiographic progression (RR (95% CI)=1.09(0.94 to 1.26), P=0.26) in case of bDMARD tapering. Conclusion Discontinuation of bDMARDs leads to an increased risk of losing remission or LDA and radiographic progression, while tapering doses of bDMARDs does not increase the risk of relapse (LDA) or radiographic progression, even though there is an increased risk of losing remission.
Dual IL-17A and IL-17F neutralisation by bimekizumab in psoriatic arthritis: evidence from preclinical experiments and a randomised placebo-controlled clinical trial that IL-17F contributes to human chronic tissue inflammation Ann. Rheum. Dis. (IF 12.811) Pub Date : 2018-04-01 Sophie Glatt, Dominique Baeten, Terry Baker, Meryn Griffiths, Lucian Ionescu, Alastair D G Lawson, Ash Maroof, Ruth Oliver, Serghei Popa, Foteini Strimenopoulou, Pavan Vajjah, Mark I L Watling, Nataliya Yeremenko, Pierre Miossec, Stevan Shaw
Objective Interleukin (IL)-17A has emerged as pivotal in driving tissue pathology in immune-mediated inflammatory diseases. The role of IL-17F, sharing 50% sequence homology and overlapping biological function, remains less clear. We hypothesised that IL-17F, together with IL-17A, contributes to chronic tissue inflammation, and that dual neutralisation may lead to more profound suppression of inflammation than inhibition of IL-17A alone. Methods Preclinical experiments assessed the role of IL-17A and IL-17F in tissue inflammation using disease-relevant human cells. A placebo-controlled proof-of-concept (PoC) clinical trial randomised patients with psoriatic arthritis (PsA) to bimekizumab (n=39) or placebo (n=14). Safety, pharmacokinetics and clinical efficacy of multiple doses (weeks 0, 3, 6 (240 mg/160 mg/160 mg; 80 mg/40 mg/40 mg; 160 mg/80 mg/80 mg and 560 mg/320 mg/320 mg)) of bimekizumab, a humanised monoclonal IgG1 antibody neutralising both IL-17A and IL-17F, were investigated. Results IL-17F induced qualitatively similar inflammatory responses to IL-17A in skin and joint cells. Neutralisation of IL-17A and IL-17F with bimekizumab more effectively suppressed in vitro cytokine responses and neutrophil chemotaxis than inhibition of IL-17A or IL-17F alone. The PoC trial met both prespecified efficacy success criteria and showed rapid, profound responses in both joint and skin (pooled top three doses vs placebo at week 8: American College of Rheumatology 20% response criteria 80.0% vs 16.7% (posterior probability >99%); Psoriasis Area and Severity Index 100% response criteria 86.7% vs 0%), sustained to week 20, without unexpected safety signals. Conclusions These data support IL-17F as a key driver of human chronic tissue inflammation and the rationale for dual neutralisation of IL-17A and IL-17F in PsA and related conditions. Trial registration number NCT02141763; Results.
Evaluation of the impact of concomitant fibromyalgia on TNF alpha blockers’ effectiveness in axial spondyloarthritis: results of a prospective, multicentre study Ann. Rheum. Dis. (IF 12.811) Pub Date : 2018-04-01 Anna Moltó, Adrien Etcheto, Laure Gossec, Nadia Boudersa, Pascal Claudepierre, Nicolas Roux, Lucie Lemeunier, Antoine Martin, Lartitia Sparsa, Pascal Coquerelle, Martin Soubrier, Serge Perrot, Maxime Dougados
Objective To describe the prevalence of fibromyalgia (FM) in an axial spondyloarthritis (axSpA) population and to confirm that concomitant FM had a negative impact on tumour necrosis factor blockers’ (TNFb) response. Design Prospective observational study with two visits 3 months apart. Patients Adult patients with AxSpa initiating a TNFb. Study groups FM was defined by the Fibromyalgia Rapid Screening Tool (FiRST) at baseline and also by a sustained positive FiRST (both visits) and by a fulfilment of the 1990 American College of Rheumatology criteria for FM. Statistical analysis Prevalence of FM; evaluation of the impact of a concomitant FM on TNFb response (Bath Ankylosing Spondylitis Disease Activity Index (BASDAI 50) as primary endpoint), adjusted by factors known to have an impact on TNFb response. Results Among the 508 patients included in the main analysis, 192 (37.8%) were screened at baseline as FM. Percentage of success after 12 weeks of treatment was lower in the FM group for most of the effectiveness endpoints (eg, BASDAI 50: 45.3% vs 54.1% in the FM/not FM groups according to the FiRST), except for the C reactive protein change endpoints which were not different across groups. Conclusion This study confirms that FM coexists in patients with axSpA and that its presence seems to have a negative impact on TNFb response, which seems more related to the self-reported instruments used in its evaluation, rather than a different treatment effect of the molecule in this subgroup of patients.
Risk of cardiac rhythm disturbances and aortic regurgitation in different spondyloarthritis subtypes in comparison with general population: a register-based study from Sweden Ann. Rheum. Dis. (IF 12.811) Pub Date : 2018-04-01 Karin Bengtsson, Helena Forsblad-d’Elia, Elisabeth Lie, Eva Klingberg, Mats Dehlin, Sofia Exarchou, Ulf Lindström, Johan Askling, Lennart T H Jacobsson
Objectives To describe the incidence of atrioventricular (AV) block II–III, atrial fibrillation (AF), pacemaker implantation (PM) and aortic regurgitation in patients with ankylosing spondylitis (AS), undifferentiated spondyloarthritis (uSpA) and psoriatic arthritis (PsA) compared with the general population (GP) and with each other. Methods A prospective nationwide study with cohorts of patients with AS (n=6448), PsA (n=16 063) and uSpA (n=5190) and a GP (n=2 66 435) cohort, identified in 2001–2009 in the Swedish National Patient and Population registers. Follow-up began on 1 January 2006 and ended at event, death, emigration or 31 December 2012. Age-standardised and sex-standardised incidence rates and hazard ratios (HRs) were calculated. Results The highest incidence rates were noted for AF (5.5–7.4 events per 1000 person-years), followed by PM (1.0–2.0 events per 1000 person-years). HRs for AV block, AF, PM and aortic regurgitation were significantly increased in AS (HRs 2.3, 1.3, 2.1 and 1.9), uSpA (HRs 2.9, 1.3, 1.9 and 2.0) and PsA (HRs 1.5, 1.5, 1.6 and 1.8) compared with the GP cohort. The highest HRs were seen for AV block in male uSpA (HR 4.2) and AS (HR 2.5) compared with GP. Compared with PsA, significantly increased HRs were noted for PM (HR 1.5) in AS and for AV block (HR 1.8) in uSpA. Conclusions Patients with SpA are at increased risk of aortic regurgitation, cardiac rhythm disturbances and, as a probable consequence, also PM. Particularly for AF, the most common arrhythmia, increased caution is warranted, whereas AV block should be looked for especially in men with AS or uSpA.
Complement activation predicts adverse pregnancy outcome in patients with systemic lupus erythematosus and/or antiphospholipid antibodies Ann. Rheum. Dis. (IF 12.811) Pub Date : 2018-04-01 Mimi Y Kim, Marta M Guerra, Elianna Kaplowitz, Carl A Laskin, Michelle Petri, D Ware Branch, Michael D Lockshin, Lisa R Sammaritano, Joan T Merrill, T Flint Porter, Allen Sawitzke, Anne M Lynch, Jill P Buyon, Jane E Salmon
Objective Studies in mouse models implicate complement activation as a causative factor in adverse pregnancy outcomes (APOs). We investigated whether activation of complement early in pregnancy predicts APOs in women with systemic lupus erythematosus (SLE) and/or antiphospholipid (aPL) antibodies. Methods The PROMISSE Study enrolled pregnant women with SLE and/or aPL antibodies (n=487) and pregnant healthy controls (n=204) at <12 weeks gestation and evaluated them monthly. APOs were: fetal/neonatal death, preterm delivery <36 weeks because of placental insufficiency or preeclampsia and/or growth restriction <5th percentile. Complement activation products were measured on serial blood samples obtained at each monthly visit. Results APO occurred in 20.5% of SLE and/or aPL pregnancies. As early as 12–15 weeks, levels of Bb and sC5b-9 were significantly higher in patients with APOs and remained elevated through 31 weeks compared with those with normal outcomes. Moreover, Bb and sC5b-9 were significantly higher in patients with SLE and/or aPL without APOs compared with healthy controls. In logistic regression analyses, Bb and sC5b-9 at 12–15 weeks remained significantly associated with APO (ORadj=1.41 per SD increase; 95% CI 1.06 to 1.89; P=0.019 and ORadj=1.37 per SD increase; 95% CI 1.05 to 1.80; P=0.022, respectively) after controlling for demographic and clinical risk factors for APOs in PROMISSE. When analyses were restricted to patients with aPL (n=161), associations between Bb at 12–15 weeks and APOs became stronger (ORadj=2.01 per SD increase; 95% CI 1.16 to 3.49; P=0.013). Conclusion In pregnant patients with SLE and/or aPL, increased Bb and sC5b-9 detectable early in pregnancy are strongly predictive of APOs and support activation of complement, particularly the alternative pathway, as a contributor to APOs.
Scoring hypoechogenic areas in one parotid and one submandibular gland increases feasibility of ultrasound in primary Sjögren’s syndrome Ann. Rheum. Dis. (IF 12.811) Pub Date : 2018-04-01 Esther Mossel, Suzanne Arends, Jolien F van Nimwegen, Konstantina Delli, Alja J Stel, Frans G M Kroese, Fred K L Spijkervet, Arjan Vissink, Hendrika Bootsma
Objective To assess whether ultrasonographic scoring of (i) both parotid and submandibular salivary glands and (ii) all individual components of the Hocevar scoring system, is needed for classifying patients as primary Sjögren’s syndrome (pSS). Methods Ultrasound examination of the major salivary glands (sUS) was performed in 204 consecutive patients clinically suspected (n=171) or diagnosed (n=33) with pSS. Parenchymal echogenicity, homogeneity, hypoechogenic areas, hyperechogenic reflections and salivary gland posterior border were scored in left and right parotid and submandibular glands. Logistic regression analyses were performed to assess which glands and sUS components contributed significantly to classification as pSS or non-pSS according to the 2016 American College of Rheumatology-European League Against Rheumatism (ACR-EULAR) criteria. Results 116 (57%) patients were classified as pSS, the remaining as non-pSS. Instead of scoring both sides (area under the curve; AUC=0.856, Nagelkerke R2=0.526), multivariate analysis showed that sUS scoring of only right (AUC=0.850; R2=0.518) or left (AUC=0.852; R2=0.511) parotid and submandibular glands is sufficient to predict ACR-EULAR classification. Moreover, all individual components of the Hocevar scoring system significantly predicted classification. Multivariate analysis showed that parenchymal echogenicity and hypoechogenic areas contributed independently to ACR-EULAR classification (AUC=0.857; R2=0.539). Scoring these components in one parotid and one submandibular gland highly predicted ACR-EULAR classification (AUC=0.855; R2=0.539). Scoring only hypoechogenic areas on one side showed almost similar results (AUC=0.846; R2=0.498). Conclusion sUS examination of parotid and submandibular glands on one side is sufficient to predict classification of patients according to the ACR-EULAR criteria. To further increase feasibility of sUS in outpatient clinics worldwide, only hypoechogenic areas can be scored.
Patterns and predictors of skin score change in early diffuse systemic sclerosis from the European Scleroderma Observational Study Ann. Rheum. Dis. (IF 12.811) Pub Date : 2018-04-01 Ariane L Herrick, Sebastien Peytrignet, Mark Lunt, Xiaoyan Pan, Roger Hesselstrand, Luc Mouthon, Alan J Silman, Graham Dinsdale, Edith Brown, László Czirják, Jörg H W Distler, Oliver Distler, Kim Fligelstone, William J Gregory, Rachel Ochiel, Madelon C Vonk, Codrina Ancuţa, Voon H Ong, Dominique Farge, Marie Hudson, Marco Matucci-Cerinic, Alexandra Balbir-Gurman, Øyvind Midtvedt, Paresh Jobanputra, Alison C Jordan, Wendy Stevens, Pia Moinzadeh, Frances C Hall, Christian Agard, Marina E Anderson, Elisabeth Diot, Rajan Madhok, Mohammed Akil, Maya H Buch, Lorinda Chung, Nemanja S Damjanov, Harsha Gunawardena, Peter Lanyon, Yasmeen Ahmad, Kuntal Chakravarty, Søren Jacobsen, Alexander J MacGregor, Neil McHugh, Ulf Müller-Ladner, Gabriela Riemekasten, Michael Becker, Janet Roddy, Patricia E Carreira, Anne Laure Fauchais, Eric Hachulla, Jennifer Hamilton, Murat İnanç, John S McLaren, Jacob M van Laar, Sanjay Pathare, Susanna M Proudman, Anna Rudin, Joanne Sahhar, Brigitte Coppere, Christine Serratrice, Tom Sheeran, Douglas J Veale, Claire Grange, Georges-Selim Trad, Christopher P Denton
Objectives Our aim was to use the opportunity provided by the European Scleroderma Observational Study to (1) identify and describe those patients with early diffuse cutaneous systemic sclerosis (dcSSc) with progressive skin thickness, and (2) derive prediction models for progression over 12 months, to inform future randomised controlled trials (RCTs). Methods The modified Rodnan skin score (mRSS) was recorded every 3 months in 326 patients. ‘Progressors’ were defined as those experiencing a 5-unit and 25% increase in mRSS score over 12 months (±3 months). Logistic models were fitted to predict progression and, using receiver operating characteristic (ROC) curves, were compared on the basis of the area under curve (AUC), accuracy and positive predictive value (PPV). Results 66 patients (22.5%) progressed, 227 (77.5%) did not (33 could not have their status assessed due to insufficient data). Progressors had shorter disease duration (median 8.1 vs 12.6 months, P=0.001) and lower mRSS (median 19 vs 21 units, P=0.030) than non-progressors. Skin score was highest, and peaked earliest, in the anti-RNA polymerase III (Pol3+) subgroup (n=50). A first predictive model (including mRSS, duration of skin thickening and their interaction) had an accuracy of 60.9%, AUC of 0.666 and PPV of 33.8%. By adding a variable for Pol3 positivity, the model reached an accuracy of 71%, AUC of 0.711 and PPV of 41%. Conclusions Two prediction models for progressive skin thickening were derived, for use both in clinical practice and for cohort enrichment in RCTs. These models will inform recruitment into the many clinical trials of dcSSc projected for the coming years. Trial registration number NCT02339441.
Mitochondrial genetic variation and gout in Māori and Pacific people living in Aotearoa New Zealand Ann. Rheum. Dis. (IF 12.811) Pub Date : 2018-04-01 Anna L Gosling, James Boocock, Nicola Dalbeth, Jennie Harré Hindmarsh, Lisa K Stamp, Eli A Stahl, Hyon K Choi, Elizabeth A Matisoo-Smith, Tony R Merriman
Objective Mitochondria have an important role in the induction of the NLRP3 inflammasome response central in gout. The objective was to test whether mitochondrial genetic variation and copy number in New Zealand Māori and Pacific (Polynesian) people in Aotearoa New Zealand associate with susceptibility to gout. Methods 437 whole mitochondrial genomes from Māori and Pacific people (predominantly men) from Aotearoa New Zealand (327 people with gout, 110 without gout) were sequenced. Mitochondrial DNA copy number variation was determined by assessing relative read depth using data produced from whole genome sequencing (32 cases, 43 controls) and targeted resequencing of urate loci (151 cases, 222 controls). Quantitative PCR was undertaken for replication of copy number findings in an extended sample set of 1159 Māori and Pacific men and women (612 cases, 547 controls). Results There was relatively little mitochondrial genetic diversity, with around 96% of those sequenced in this study belonging to the B4a1a and derived sublineages. A B haplogroup heteroplasmy in hypervariable region I was found to associate with a higher risk of gout among the mitochondrial sequenced sample set (position 16181: OR=1.57, P = 0.001). Increased copies of mitochondrial DNA were found to protect against gout risk with the effect being consistent when using hyperuricaemic controls across each of the three independent sample sets (OR=0.89, P=0.007; OR=0.90, P=0.002; OR=0.76, P = 0.03). Paradoxically, an increase of mitochondrial DNA also associated with an increase in gout flare frequency in people with gout in the two larger sample sets used for the copy number analysis (β=0.003, P=7.1×10–7; β=0.08, P=1.2×10–4). Conclusion Association of reduced copy number with gout in hyperuricaemia was replicated over three Polynesian sample sets. Our data are consistent with emerging research showing that mitochondria are important for the colocalisation of the NLRP3 and ASC inflammasome subunits, a process essential for the generation of interleukin-1β in gout.
Visualising the interaction of CD4 T cells and DCs in the evolution of inflammatory arthritis Ann. Rheum. Dis. (IF 12.811) Pub Date : 2018-04-01 Catriona T Prendergast, Agapitos Patakas, Shaima Al-Khabouri, Claire L McIntyre, Iain B McInnes, James M Brewer, Paul Garside, Robert A Benson
Objectives Successful early intervention in rheumatoid arthritis (RA) with the aim of resetting immunological tolerance requires a clearer understanding of how specificity, cellular kinetics and spatial behaviour shape the evolution of articular T cell responses. We aimed to define initial seeding of articular CD4+ T cell responses in early experimental arthritis, evaluating their dynamic behaviour and interactions with dendritic cells (DCs) in the inflamed articular environment. Methods Antigen-induced arthritis was used to model articular inflammation. Flow cytometry and PCR of T cell receptor (TCR) diversity genes allowed phenotypic analysis of infiltrating T cells. The dynamic interactions of T cells with joint residing DCs were visualised using intravital multiphoton microscopy. Results Initial recruitment of antigen-specific T cells into the joint was paralleled by accumulation of CD4+ T cells with diverse antigen-receptor expression and ability to produce tumour necrosis factor alpha (TNFα) and interferon gamma (IFNγ) on mitogenic restimulation. A proportion of this infiltrate demonstrated slower motility speeds and engaged for longer periods with articular DCs in vivo. Abatacept treatment did not disrupt these interactions but did reduce T cell expression of inducible costimulatory (ICOS) molecule. We also demonstrated that non-specific CD4+ T cells could be recruited during these early articular events. Conclusions We demonstrate that CD4+ T cells engage with articular DCs supporting antigen specific T cell reactivation. This cellular dialogue can be targeted therapeutically to reduce local T cell activation.
Cross-phenotype analysis of Immunochip data identifies KDM4C as a relevant locus for the development of systemic vasculitis Ann. Rheum. Dis. (IF 12.811) Pub Date : 2018-04-01 Lourdes Ortiz-Fernández, Francisco David Carmona, Raquel López-Mejías, Maria Francisca González-Escribano, Paul A Lyons, Ann W Morgan, Amr H Sawalha, Kenneth G C Smith, Miguel A González-Gay, Javier Martín
Objetive Systemic vasculitides represent a heterogeneous group of rare complex diseases of the blood vessels with a poorly understood aetiology. To investigate the shared genetic component underlying their predisposition, we performed the first cross-phenotype meta-analysis of genetic data from different clinically distinct patterns of vasculitis. Methods Immunochip genotyping data from 2465 patients diagnosed with giant cell arteritis, Takayasu’s arteritis, antineutrophil cytoplasmic antibody-associated vasculitis or IgA vasculitis as well as 4632 unaffected controls were analysed to identify common susceptibility loci for vasculitis development. The possible functional consequences of the associated variants were interrogated using publicly available annotation data. Results The strongest association signal corresponded with an intergenic polymorphism located between HLA-DQB1 and HLA-DQA2 (rs6932517, P=4.16E-14, OR=0.74). This single nucleotide polymorphism is in moderate linkage disequilibrium with the disease-specific human leucocyte antigen (HLA) class II associations of each type of vasculitis and could mark them. Outside the HLA region, we identified the KDM4C gene as a common risk locus for vasculitides (highest peak rs16925200, P=6.23E-07, OR=1.75). This gene encodes a histone demethylase involved in the epigenetic control of gene expression. Conclusions Through a combined analysis of Immunochip data, we have identified KDM4C as a new risk gene shared between systemic vasculitides, consistent with the increasing evidences of the crucial role that the epigenetic mechanisms have in the development of complex immune-mediated conditions.
Changes in macrophage transcriptome associate with systemic sclerosis and mediate GSDMA contribution to disease risk Ann. Rheum. Dis. (IF 12.811) Pub Date : 2018-04-01 Aida Moreno-Moral, Marta Bagnati, Surya Koturan, Jeong-Hun Ko, Carmen Fonseca, Nathan Harmston, Laurence Game, Javier Martin, Voon Ong, David J Abraham, Christopher P Denton, Jacques Behmoaras, Enrico Petretto
Objectives Several common and rare risk variants have been reported for systemic sclerosis (SSc), but the effector cell(s) mediating the function of these genetic variants remains to be elucidated. While innate immune cells have been proposed as the critical targets to interfere with the disease process underlying SSc, no studies have comprehensively established their effector role. Here we investigated the contribution of monocyte-derived macrophages (MDMs) in mediating genetic susceptibility to SSc. Methods We carried out RNA sequencing and genome-wide genotyping in MDMs from 57 patients with SSc and 15 controls. Our differential expression and expression quantitative trait locus (eQTL) analysis in SSc was further integrated with epigenetic, expression and eQTL data from skin, monocytes, neutrophils and lymphocytes. Results We identified 602 genes upregulated and downregulated in SSc macrophages that were significantly enriched for genes previously implicated in SSc susceptibility (P=5×10−4), and 270 cis -regulated genes in MDMs. Among these, GSDMA was reported to carry an SSc risk variant (rs3894194) regulating expression of neighbouring genes in blood. We show that GSDMA is upregulated in SSc MDMs (P=8.4×10−4) but not in the skin, and is a significant eQTL in SSc macrophages and lipopolysaccharide/interferon gamma (IFNγ)-stimulated monocytes. Furthermore, we identify an SSc macrophage transcriptome signature characterised by upregulation of glycolysis, hypoxia and mTOR signalling and a downregulation of IFNγ response pathways. Conclusions Our data further establish the link between macrophages and SSc, and suggest that the contribution of the rs3894194 risk variant to SSc susceptibility can be mediated by GSDMA expression in macrophages.
Splicing variant of WDFY4 augments MDA5 signalling and the risk of clinically amyopathic dermatomyositis Ann. Rheum. Dis. (IF 12.811) Pub Date : 2018-04-01 Yuta Kochi, Yoichiro Kamatani, Yuya Kondo, Akari Suzuki, Eiryo Kawakami, Ryosuke Hiwa, Yukihide Momozawa, Manabu Fujimoto, Masatoshi Jinnin, Yoshiya Tanaka, Takashi Kanda, Robert G Cooper, Hector Chinoy, Simon Rothwell, Janine A Lamb, Jiří Vencovský, Heřman Mann, Koichiro Ohmura, Keiko Myouzen, Kazuyoshi Ishigaki, Ran Nakashima, Yuji Hosono, Hiroto Tsuboi, Hidenaga Kawasumi, Yukiko Iwasaki, Hiroshi Kajiyama, Tetsuya Horita, Mariko Ogawa-Momohara, Akito Takamura, Shinichiro Tsunoda, Jun Shimizu, Keishi Fujio, Hirofumi Amano, Akio Mimori, Atsushi Kawakami, Hisanori Umehara, Tsutomu Takeuchi, Hajime Sano, Yoshinao Muro, Tatsuya Atsumi, Toshihide Mimura, Yasushi Kawaguchi, Tsuneyo Mimori, Atsushi Takahashi, Michiaki Kubo, Hitoshi Kohsaka, Takayuki Sumida, Kazuhiko Yamamoto
Objectives Idiopathic inflammatory myopathies (IIMs) are a heterogeneous group of rare autoimmune diseases in which both genetic and environmental factors play important roles. To identify genetic factors of IIM including polymyositis, dermatomyositis (DM) and clinically amyopathic DM (CADM), we performed the first genome-wide association study for IIM in an Asian population. Methods We genotyped and tested 496 819 single nucleotide polymorphism for association using 576 patients with IIM and 6270 control subjects. We also examined the causal mechanism of disease-associated variants by in silico analyses using publicly available data sets as well as by in in vitro analyses using reporter assays and apoptosis assays. Results We identified a variant in WDFY4 that was significantly associated with CADM (rs7919656; OR=3.87; P=1.5×10−8). This variant had a cis-splicing quantitative trait locus (QTL) effect for a truncated WDFY4 isoform (tr- WDFY4 ), with higher expression in the risk allele. Transexpression QTL analysis of this variant showed a positive correlation with the expression of NF-κB associated genes. Furthermore, we demonstrated that both WDFY4 and tr-WDFY4 interacted with pattern recognition receptors such as TLR3, TLR4, TLR9 and MDA5 and augmented the NF-κB activation by these receptors. WDFY4 isoforms also enhanced MDA5-induced apoptosis to a greater extent in the tr-WDFY4-transfected cells. Conclusions As CADM is characterised by the appearance of anti-MDA5 autoantibodies and severe lung inflammation, the WDFY4 variant may play a critical role in the pathogenesis of CADM.
Aberrant tRNA processing causes an autoinflammatory syndrome responsive to TNF inhibitors Ann. Rheum. Dis. (IF 12.811) Pub Date : 2018-04-01 Angeliki Giannelou, Hongying Wang, Qing Zhou, Yong Hwan Park, Mones S Abu-Asab, Kris Ylaya, Deborah L Stone, Anna Sediva, Rola Sleiman, Lucie Sramkova, Deepika Bhatla, Elisavet Serti, Wanxia Li Tsai, Dan Yang, Kevin Bishop, Blake Carrington, Wuhong Pei, Natalie Deuitch, Stephen Brooks, Jehad H Edwan, Sarita Joshi, Seraina Prader, Daniela Kaiser, William C Owen, Abdullah Al Sonbul, Yu Zhang, Julie E Niemela, Shawn M Burgess, Manfred Boehm, Barbara Rehermann, JaeJin Chae, Martha M Quezado, Amanda K Ombrello, Rebecca H Buckley, Alexi A Grom, Elaine F Remmers, Jana M Pachlopnik, Helen C Su, Gustavo Gutierrez-Cruz, Stephen M Hewitt, Raman Sood, Kimberly Risma, Katherine R Calvo, Sergio D Rosenzweig, Massimo Gadina, Markus Hafner, Hong-Wei Sun, Daniel L Kastner, Ivona Aksentijevich
Objectives To characterise the clinical features, immune manifestations and molecular mechanisms in a recently described autoinflammatory disease caused by mutations in TRNT1 , a tRNA processing enzyme, and to explore the use of cytokine inhibitors in suppressing the inflammatory phenotype. Methods We studied nine patients with biallelic mutations in TRNT1 and the syndrome of congenital sideroblastic anaemia with immunodeficiency, fevers and developmental delay (SIFD). Genetic studies included whole exome sequencing (WES) and candidate gene screening. Patients’ primary cells were used for deep RNA and tRNA sequencing, cytokine profiling, immunophenotyping, immunoblotting and electron microscopy (EM). Results We identified eight mutations in these nine patients, three of which have not been previously associated with SIFD. Three patients died in early childhood. Inflammatory cytokines, mainly interleukin (IL)-6, interferon gamma (IFN-γ) and IFN-induced cytokines were elevated in the serum, whereas tumour necrosis factor (TNF) and IL-1β were present in tissue biopsies of patients with active inflammatory disease. Deep tRNA sequencing of patients’ fibroblasts showed significant deficiency of mature cytosolic tRNAs. EM of bone marrow and skin biopsy samples revealed striking abnormalities across all cell types and a mix of necrotic and normal-appearing cells. By immunoprecipitation, we found evidence for dysregulation in protein clearance pathways. In 4/4 patients, treatment with a TNF inhibitor suppressed inflammation, reduced the need for blood transfusions and improved growth. Conclusions Mutations of TRNT1 lead to a severe and often fatal syndrome, linking protein homeostasis and autoinflammation. Molecular diagnosis in early life will be crucial for initiating anti-TNF therapy, which might prevent some of the severe disease consequences.
A novel variant in GLIS3 is associated with osteoarthritis Ann. Rheum. Dis. (IF 12.811) Pub Date : 2018-04-01 Elisabetta Casalone, Ioanna Tachmazidou, Eleni Zengini, Konstantinos Hatzikotoulas, Sophie Hackinger, Daniel Suveges, Julia Steinberg, Nigel William Rayner, arcOGEN Consortium, Jeremy Mark Wilkinson, Kalliope Panoutsopoulou, Eleftheria Zeggini
Objectives Osteoarthritis (OA) is a complex disease, but its genetic aetiology remains poorly characterised. To identify novel susceptibility loci for OA, we carried out a genome-wide association study (GWAS) in individuals from the largest UK-based OA collections to date. Methods We carried out a discovery GWAS in 5414 OA individuals with knee and/or hip total joint replacement (TJR) and 9939 population-based controls. We followed-up prioritised variants in OA subjects from the interim release of the UK Biobank resource (up to 12 658 cases and 50 898 controls) and our lead finding in operated OA subjects from the full release of UK Biobank (17 894 cases and 89 470 controls). We investigated its functional implications in methylation, gene expression and proteomics data in primary chondrocytes from 12 pairs of intact and degraded cartilage samples from patients undergoing TJR. Results We detect a genome-wide significant association at rs10116772 with TJR (P=3.7×10−8; for allele A: OR (95% CI) 0.97 (0.96 to 0.98)), an intronic variant in GLIS3 , which is expressed in cartilage. Variants in strong correlation with rs10116772 have been associated with elevated plasma glucose levels and diabetes. Conclusions We identify a novel susceptibility locus for OA that has been previously implicated in diabetes and glycaemic traits.
Application of the 2015/2016 EULAR recommendations for cardiovascular risk in daily practice: data from an observational study Ann. Rheum. Dis. (IF 12.811) Pub Date : 2018-04-01 Claire Immediato Daïen, Amandine Tubery, Guilhem du Cailar, Thibault Mura, François Roubille, Jacques Morel, Jean Bousquet, Pierre Fesler, Bernard Combe
The European League Against Rheumatism (EULAR) recently updated the recommendations for cardiovascular disease (CVD) risk management in patients with rheumatoid arthritis (RA).1 In contrast to the 2009 recommendations which advised to multiply by 1.5 the global CVD risk in the presence of certain RA-specific criteria,2 the 2015/2016 update recommends to multiply by 1.5 the global CVD risk for all patients with RA. It also considers the use of carotid ultrasound to screen asymptomatic atherosclerotic plaques. Indeed, the majority of the CVD events occur in the ‘low’ and ‘intermediate’ risk groups and carotid plaque detection to classify patients improves cardiovascular risk prediction.3 The European Society of Cardiology guidelines classify patients with carotid plaque at very high CVD risk.4 Immediate statin use is indicated in those patients if low-density lipoprotein cholesterol is ≥0.7 g/L.4 In a post hoc analysis, we evaluated the impact of the updated 2015/2016 EULAR CVD recommendations …
Elevated serum levels of sonic hedgehog are associated with fibrotic and vascular manifestations in systemic sclerosis Ann. Rheum. Dis. (IF 12.811) Pub Date : 2018-04-01 Christian Beyer, Dörte Huscher, Andreas Ramming, Christina Bergmann, Jerome Avouac, Serena Guiducci, Florian Meier, Serena Vettori, Elise Siegert, Veronika K Jaeger, Britta Maurer, Gabriela Riemekasten, Ulrich Walker, Ulf Müller-Ladner, Gabriele Valentini, Marco Matucci-Cerinic, Yannick Allanore, Oliver Distler, Georg Schett, Jörg H W Distler
Fibrotic tissue remodelling and vascular alterations cause high morbidity and mortality in patients with systemic sclerosis (SSc).1 2 While the pathogenesis of SSc is only partially understood, recent evidence demonstrates a fundamental role of hedgehog signalling in fibrotic disease manifestations. Hedgehog signalling is activated in fibrotic SSc skin, and it induces an SSc-like phenotype in resting fibroblasts.3 Overexpression of sonic hedgehog (SHH) induces skin fibrosis, whereas inhibition of hedgehog signalling ameliorates experimental fibrosis.4 Based on these experimental findings, this European Scleroderma Trials and Research group (EUSTAR) multicentre cooperative study investigates whether circulating SHH may serve as a surrogate marker for a more severe disease phenotype in patients with SSc. We decided to evaluate SHH serum levels rather than total circulating SHH. Measurements of SHH serum levels are easy and robust but may not assess particulated SHH in various different extracellular vesicles. …
Advanced imaging assessment of gout: comparison of dual-energy CT and MRI with anatomical pathology Ann. Rheum. Dis. (IF 12.811) Pub Date : 2018-04-01 Ashika Chhana, Anthony Doyle, Amy Sevao, Satya Amirapu, Peter Riordan, Michael Dray, Sue McGlashan, Jillian Cornish, Nicola Dalbeth
Dual-energy CT (DECT) and MRI are advanced imaging methods used to visualise gout pathology. DECT can identify monosodium urate (MSU) crystals in people with gout,1 ,2 and also has conventional CT properties, allowing assessment of tophus and bone pathology.3 ,4 MRI is used to assess inflammation, bone erosion and cartilage damage in gout.5–7 This study aimed to compare DECT and MRI with corresponding anatomical pathology in the assessment of gout. Cadaveric joint specimens were obtained from two donors; a donor aged 82 years with crystal-proven tophaceous gout and a control donor aged 89 years without gout (12 joints from each). All joints were scanned by DECT (SOMATOM Definition Flash, Siemens Medical, Erlangen, Germany) and MRI (3T MAGNETOM Skyra, Siemens Medical), and then processed for histology, including digital photography of sectioned digits (sagittal plane) for macroscopic analysis, and preparation of histology slides from each individual joint for microscopic analysis. Slides were stained with H&E or 1% toluidine blue. Collection and use of cadaveric tissue was in accordance with the New Zealand Human Tissue Act 2008. All images and histology data were systematically assessed for gout pathology by experienced readers who were blinded to diagnosis and each other's scores. …
Correction: 2016 American college of rheumatology/European league against rheumatism criteria for minimal moderate, and major clinical response in juvenile dermatomyositis Ann. Rheum. Dis. (IF 12.811) Pub Date : 2018-04-01 BMJ Publishing Group Ltd and European League Against Rheumatism
Rider LG, Aggarwal R, Pistorio A, et al . 2016 American college of rheumatology/European league against rheumatism criteria for …
Important but incomplete data analysis? Ann. Rheum. Dis. (IF 12.811) Pub Date : 2018-04-01 Philipp Sewerin, Annika Hoyer, Matthias Schneider, Ben Ostendorf, Ralph Brinks
We are grateful to the article about incidence and prevalence of psoriatic arthritis (PsA) in Denmark by Egeberg et al .1 The comprehensive health registers from Denmark and other Nordic countries have proven to yield many insights into the epidemiology of chronic diseases. The authors of the article provide very detailed information about the age-specific incidence of PsA, including its time trend. However, we have a question about reporting the overall age-specific incidence rate, combined for both sexes. Could the authors comment …
Impact of age and sex on the incidence and prevalence of psoriatic arthritis Ann. Rheum. Dis. (IF 12.811) Pub Date : 2018-04-01 Alexander Egeberg, Lars Erik Kristensen
We thank Sewerin and colleagues1 for the interest in our paper regarding the incidence and prevalence of psoriatic arthritis (PsA).2 The questions that were raised are relevant and important. Our paper included only a limited amount of age-stratified and sex-stratified estimates. The sex distribution among patients with (rheumatologist-diagnosed) incident PsA based on the population described in our initial publication2 is presented in figure 1. However, we emphasise that interpretation …
EULAR gout treatment guidelines by Richette et al.: uric acid and neurocognition Ann. Rheum. Dis. (IF 12.811) Pub Date : 2018-04-01 Jasvinder A Singh, N Lawrence Edwards
We appreciate the efforts of the authors of the recent ‘2016 updated EULAR evidence-based recommendations for the management of gout’ and congratulate them on the publication.1 We would like to draw attention to recommendation #6: ‘For patients on urate-lowering therapy (ULT), serum urate (SUA) level should be monitored and maintained to <6 mg/dL (360 µmol/L). A lower SUA target (<5 mg/dL; 300 µmol/L) to facilitate faster dissolution of crystals is recommended for patients with severe gout (tophi, chronic arthropathy, frequent attacks) until total crystal dissolution and resolution of gout. SUA level <3 mg/dL is not recommended in the long term’. We agree with the first half of the recommendation that proposes the treat-to-target recommendations similar to that in the American College of Rheumatology 2012 gout treatment guidelines of reducing serum urate to <6.0 mg/dL in all patients with gout …
SUA levels should not be maintained <3 mg/dL for several years. Response to ‘EULAR gout treatment guidelines by Richette et al: uric acid and neurocognition by Singh et al’ Ann. Rheum. Dis. (IF 12.811) Pub Date : 2018-04-01 Pascal Richette, Michael Doherty, Eliseo Pascual, Thomas Bardin
We thank Drs Singh and Edwards for their interest in our 2016 revised EULAR recommendations for the management of gout.1 Drs Singh and Edwards were concerned about the latter part of our sixth recommendation, in which we indicate that a serum uric acid (SUA) level <3 mg/dL (<180 µmol/L) is not recommended in the long term. They consider that this part of the recommendation was not evidence based and that it might present a barrier to care. Specifically, they fear that it could make general practitioners (GPs) less engaged and less likely to use urate-lowering therapy (ULT) in the long term.2 First, in the care of people with gout, do we suggest that it is necessary to maintain such low levels of SUA indefinitely? No; we do not. In the discussion following recommendation 6 in our paper, we qualified that ‘long term’ stands for ‘several years’. Recommendation 6 clearly specifies that there is a therapeutic window during which physicians can clear crystals faster by lowering the SUA levels well below, rather than …
Thank you to our reviewers 2017 Ann. Rheum. Dis. (IF 12.811) Pub Date : 2018-04-01 BMJ Publishing Group Ltd and European League Against Rheumatism
The Editor would like to publicly acknowledge the people listed below who served as reviewers on the journal during 2017. Without their efforts, the quality of the journal could not be sustained. Abhishek, Abhishek Abramson, Steven Aggarwal, Amita Aggarwal, Rohit Ahuja, Sunil Aksentijevich, Ivona Aksoy, Ezra Alarcón, Graciela Alarcon-Riquelme, Marta Alberici, Federico Albrecht, Katinka Alcocer-Varela, Jorge Aletaha, Daniel Alevizos, Ilias Alfredsson, Lars Allaart, Cornelia Allanore, Yannick Alten, Rieke Altman, Roy Amato, Anthony Anders, Hans-Joachim Andrade, Felipe Andrés, Mariano Antony, Benny Appel, Silke Aringer, Martin Arkema, Elizabeth Arnaud, Laurent Asano, Yoshihide Askling, Johan Atsumi, Tatsuya Aulie, Hanne Avina-Zubieta, Juan Avouac, Jerome Baer, Alan Baerwald, Christoph Bailey, Mark Baker, Olga J Bakland, Gunnstein Baldini, Chiara Balint, Peter Balsa, Alejandro Baraliakos, Xenofon Barbhaiya, Medha Barnado, April Baron, Murray Barone, Francesca Barter, Matthew Bartold, P Mark Barton, Anne Bay-Jensen, Anne Beauvais, Catherine Becker, Michael Becker, Mike Beier, Frank Bennett, Alexander Benseler, Susanne Benveniste, Olivier Berard, Roberta Berenbaum, Francis Berg, Stefan Bergfeldt, Lennart Bergman, Martin Bernatsky, Sasha Bertsias, George Betteridge, Zoe Bhattacharyya, Swati Bijl, Marc Bingham Iii, Clifton Bird, Paul Blueml, Stephan Boers, Maarten Bogunia-Kubik, Katarzyna Boilard, Eric Boire, Gilles Boissier, Marie-Christophe Bolstad, Nils Bombardieri, Michele Bonelli, Michael Bong, David Boot-Handford, Ray Borenstein, David Bos, Steffan Bossuyt, Xavier Bottini, Nunzio Boumpas, Dimitrios T Bowes, John Bowman, Simon Bøyesen, Pernille Braun, Juergen Breban, Maxime Breedveld, Ferry Brembilla, Nicolò Briggs, Andrew Broder, Anna Brokstad, Karl Albert Brouwer, Elisabeth Brucato, Antonio Bruce, Ian Brunner, Hermine Bruyere, Olivier Buch, Maya Bukhari, Marwan Burgos-Vargas, Ruben Burkhardt, Harald Burmester, Gerd Buttgereit, Frank Bykerk, Vivian Cabral, David Cacoub, Patrice Calabrese, Leonard Callahan, Leigh Canete, Juan D Canhão, Helena Caporali, Roberto Cappelli, Laura Carmona, F David Carmona, Loreto Cassina, Matteo Castaneda, Gilberto Catrina, Anca Irinel Cervera, R Cervera, Ricard Chaigne, Benjamin Chalès, Gérard Chambers, Christina Chan, Edward Chatzidionysiou, Katerina Chen, Yan Chevalier, Xavier …
Determinants of psychological well-being in axial spondyloarthritis: an analysis based on linked claims and patient-reported survey data Ann. Rheum. Dis. (IF 12.811) Pub Date : 2018-03-10 Imke Redeker, Falk Hoffmann, Johanna Callhoff, Hildrun Haibel, Joachim Sieper, Angela Zink, Denis Poddubnyy
Objectives The aim of this study was to assess the psychological well-being and to analyse factors associated with depressive symptoms in axial spondyloarthritis (axSpA). Methods A stratified random sample of subjects with a diagnosis of axSpA (International Classification of Diseases, Tenth Revision, German Modification M45) was drawn from health insurance data in Germany. These persons received a postal questionnaire on disease-related, psychological and lifestyle factors as well as socioeconomic status. Additional information to verify the axSpA diagnosis was also collected. The psychological well-being was assessed by means of the 5-item WHO Well-Being Index (WHO-5), which is considered a screening tool for depression. The following established cut-offs on the WHO-5 were applied: >50: good well-being, no depressive symptoms; 29–50: mild depressive symptoms; ≤28: moderate-to-severe depressive symptoms. Information on comorbidities, drug prescriptions and non-pharmacological treatment was retrieved from claims data and linked to the questionnaire data. Results A total of 1736 persons with a confirmed axSpA diagnosis were included. Using the cut-offs on the WHO-5, 533 persons (31%) were found to have moderate-to-severe depressive symptoms, 479 (28%) had mild depressive symptoms and 724 (42%) had a good well-being. Multivariable logistic regression revealed that higher disease activity, higher level of functional impairment, lower income, self-reported stress and lack of exercise, and younger age represent factors associated with moderate-to-severe depressive symptoms. Conclusions The prevalence of depressive symptoms in axSpA subjects is high and associated with disease-related parameters, socioeconomic status and lifestyle factors. These findings highlight the need for the careful evaluation of depressive symptoms as a part of the management strategy for axSpA.
Can ultrasound of the major salivary glands assess histopathological changes induced by treatment with rituximab in primary Sjögren’s syndrome? Ann. Rheum. Dis. (IF 12.811) Pub Date : 2018-03-09 Esther Mossel, Konstantina Delli, Suzanne Arends, Erlin A Haacke, Bert van der Vegt, Jolien F van Nimwegen, Alja J Stel, Fred K L Spijkervet, Arjan Vissink, Frans G M Kroese, Hendrika Bootsma
With great interest we have read the recent publication by Fisher et al ,1 entitled ‘Effect of rituximab on a salivary gland ultrasound score in primary Sjögren’s syndrome: results of the TRACTISS randomised double-blind multicenter substudy’ in which the authors demonstrated a significant improvement in total ultrasound score (TUS) after rituximab treatment compared with placebo at weeks 16 and 48 in 52 patients with primary Sjögren’s syndrome (pSS). We and others have shown that treatment with rituximab, a chimeric anti-CD20 monoclonal antibody, affects the histopathology of the salivary glands and results in a decrease in area of lymphocytic infiltrate in the labial and parotid glands.2–5 This reduction in infiltrated area, that is, up to 50%, is mainly caused by B cell depletion.2 Rituximab treatment also causes a significant loss of germinal centres.2 Interestingly, rituximab treatment also leads to a significant restoration of the ductal epithelium glandular tissue itself. This is illustrated by a significant decrease in number and severity of lymphoepithelial lesions (LELs) in parotid gland tissue 12 weeks after rituximab treatment.2 6 The normalisation of the epithelium appears to be a direct consequence of depletion of intraepithelial B cells.7 Significant improvement of the parotid gland ultrasound score of patients with pSS has been observed before in another randomised controlled trial (RCT) with rituximab, the Tolerance and Efficacy of Rituximab in Primary Sjogren’s Syndrome (TEARS) study.8 This is an RCT with rituximab versus placebo, performed by a French group. Together with the improvement of the histopathology of the gland, it might not be a surprise that Fisher et al 1 also observed a significant improvement in TUS. This newly …
Ultrasonography in psoriatic arthritis: which sites should we scan? Ann. Rheum. Dis. (IF 12.811) Pub Date : 2018-03-09 Alen Zabotti, Matteo Piga, Marco Canzoni, Garifallia Sakellariou, Annamaria Iagnocco, Carlo Alberto Scirè
In psoriatic arthritis (PsA), ultrasonography (US) plays a growing role in the differential diagnosis and in monitoring treatment response.1 PsA is a heterogeneous disease with different domains and peculiar sites involved.2 Therefore, a dedicated US composite score is needed to monitor disease activity and to identify structural damage progression. A recently published Systematic Literature Review (SLR) identified only two US scores specifically developed for PsA (ie, 5TPD and PsA-Son) and, although these had a good sensitivity to detect inflammation and a good feasibility, they have not been validated in other series.1 3 4 Recently, the Study Group for US of the Italian Society of Rheumatology promoted the Ultrasound in PSoriatic Arthritis TREAtMent (UPSTREAM) study (registered at ClinicalTrial.gov, NCT03330769). UPSTREAM is a multicentre observational prospective cohort study and it represents the first …
Cardiovascular events in ankylosing spondylitis: a 2018 meta-analysis Ann. Rheum. Dis. (IF 12.811) Pub Date : 2018-03-09 Sylvain Mathieu, Martin Soubrier
In an article published in the Annals of the Rheumatic Diseases , Schieir et al 1 reported a trend of increased cardiovascular risk in patients with ankylosing spondylitis (AS). In this letter, we wish to add data to support the conclusions of that article. We performed an updated meta-analysis to investigate the risks of myocardial infarction (MI) and stroke in patients with AS and controls. We searched PubMed to find reports of interest, published up to February 2018. We included all observational or case/control studies that reported rates of MI or stroke. We calculated the incidences of MI and stroke in a meta-analysis of proportions (inverse variance method) and expressed them in terms of …
Cell function in disease: there are more than two parties at play Ann. Rheum. Dis. (IF 12.811) Pub Date : 2018-03-09 Jacques Behmoaras, Enrico Petretto
In the quest for identification of genes for complex disorders, the functional annotation of disease-risk variants in the relevant cell type remains a challenge. Lescoat and colleagues1 pose the question ‘ what is a scleroderma macrophage? ’ and in view of current literature (including the study by Moreno-Moral et al 2), argued how the heterogeneous range of activated macrophages can vary between target organs of interest and possibly across different fibrotic diseases. While we share Lescoat’s point of view on the underlying complexity of functional cells in disease, it remains open to debate whether GM-CSF or M-CSF-mediated differentiation conditions of peripheral blood monocytes are sufficient to fully capture the characteristics of these cells in their disease context. As stated by Lescoat et …
Dual-energy CT: a new imaging modality for bone marrow oedema in rheumatoid arthritis Ann. Rheum. Dis. (IF 12.811) Pub Date : 2018-03-09 Lennart Jans, Isabelle De Kock, Nele Herregods, Koenraad Verstraete, Filip Van den Bosch, Philippe Carron, Edwin H Oei, Dirk Elewaut, Peggy Jacques
Active joint inflammation is a key feature in rheumatoid arthritis (RA). Treatment guidelines for RA,1 including ‘Treat-to-Target’ strategies,2 stress the importance of abrogation of inflammation. MRI clearly demonstrates bone marrow oedema lesions (BMEL) as a sign of inflammation.3 Dual-energy CT (DECT) scanners could provide a new approach to visualise BME.4–7 We investigated if DECT could visualise BME of the hand and wrist in patients with active RA, with MRI-proven BME as a gold standard. Institutional review board approval was obtained. Twenty consecutive patients with active clinical synovitis of a metacarpophalangeal, proximal interphalangeal or wrist joint provided written informed consent and were included; 9 men and 11 women with a mean age of 60.7 (±10.3) years. Thirteen patients were ACPA positive and 8 were ACPA and RF positive; mean tender joint count and swollen joint count were both 5.9. Mean DAS28 was 4.37 (±1.4). The mean disease duration was 6.6 (±6.1) years. Seventeen patients were treated with conventional disease-modifying antirheumatic drugs, 7 were also treated with biologicals. DECT was performed on a dual-source CT, data were post-processed with SyngioVia ‘Bone Marrow Oedema’ application (see the online supplementary text). Images were …
Novel gene variants associated with cardiovascular disease in systemic lupus erythematosus and rheumatoid arthritis Ann. Rheum. Dis. (IF 12.811) Pub Date : 2018-03-07 Dag Leonard, Elisabet Svenungsson, Johanna Dahlqvist, Andrei Alexsson, Lisbeth Ärlestig, Kimberly E Taylor, Johanna K Sandling, Christine Bengtsson, Martina Frodlund, Andreas Jönsen, Susanna Eketjäll, Kerstin Jensen-Urstad, Iva Gunnarsson, Christopher Sjöwall, Anders A Bengtsson, Maija-Leena Eloranta, Ann-Christine Syvänen, Solbritt Rantapää-Dahlqvist, Lindsey A Criswell, Lars Rönnblom
Objectives Patients with systemic lupus erythematosus (SLE) and rheumatoid arthritis (RA) have increased risk of cardiovascular disease (CVD). We investigated whether single nucleotide polymorphisms (SNPs) at autoimmunity risk loci were associated with CVD in SLE and RA. Methods Patients with SLE (n=1045) were genotyped using the 200K Immunochip SNP array (Illumina). The allele frequency was compared between patients with and without different manifestations of CVD. Results were replicated in a second SLE cohort (n=1043) and in an RA cohort (n=824). We analysed publicly available genetic data from general population, performed electrophoretic mobility shift assays and measured cytokine levels and occurrence of antiphospholipid antibodies (aPLs). Results We identified two new putative risk loci associated with increased risk for CVD in two SLE populations, which remained after adjustment for traditional CVD risk factors. An IL19 risk allele, rs17581834(T) was associated with stroke/myocardial infarction (MI) in SLE (OR 2.3 (1.5 to 3.4), P=8.5×10−5) and RA (OR 2.8 (1.4 to 5.6), P=3.8×10−3), meta-analysis (OR 2.5 (2.0 to 2.9), P=3.5×10−7), but not in population controls. The IL19 risk allele affected protein binding, and SLE patients with the risk allele had increased levels of plasma-IL10 (P=0.004) and aPL (P=0.01). An SRP54-AS1 risk allele, rs799454(G) was associated with stroke/transient ischaemic attack in SLE (OR 1.7 (1.3 to 2.2), P=2.5×10−5) but not in RA. The SRP54-AS1 risk allele is an expression quantitative trait locus for four genes. Conclusions The IL19 risk allele was associated with stroke/MI in SLE and RA, but not in the general population, indicating that shared immune pathways may be involved in the CVD pathogenesis in inflammatory rheumatic diseases.
Intramuscular glucocorticoid injection versus placebo injection in hip osteoarthritis: a 12-week blinded randomised controlled trial Ann. Rheum. Dis. (IF 12.811) Pub Date : 2018-03-07 Desirée M J Dorleijn, Pim A J Luijsterburg, Max Reijman, Margreet Kloppenburg, Jan A N Verhaar, Patrick J E Bindels, Pieter Koen Bos, Sita M A Bierma-Zeinstra
Objectives Guidelines recommend intra-articular glucocorticoid injection in patients with painful hip osteoarthritis. However, intra-articular hip injection is an invasive procedure. The efficacy of systemic glucocorticoid treatment for pain reduction in hip osteoarthritis is unknown. This randomised, double-blind, trial assessed effectiveness in hip pain reduction of an intramuscular glucocorticoid injection compared with a placebo injection in patients with hip osteoarthritis. Methods Patients with painful hip osteoarthritis were randomised to either 40 mg triamcinolone acetate or placebo with an intramuscular injection into the gluteus muscle. The primary outcomes were severity of hip pain at rest, during walking (0–10) and WOMAC pain at 2-week postinjection. We used linear mixed models for repeated measurements at 2, 4, 6 and 12 weeks for the intention-to-treat data analysis. Results Of the 107 patients randomised, 106 could be analysed (52 in the glucocorticoid group, 54 in the placebo group). At 2-week follow-up, compared with placebo injection, the intramuscular glucocorticoid injection showed a significant and clinically relevant difference in hip pain reduction at rest (difference −1.3, 95% CI −2.3 to −0.3). This effect persisted for the entire 12-week follow-up. For hip pain during walking, the effect was present at 4-week, 6-week and 12-week follow-ups, and for WOMAC pain the effect was present at 6-week and 12-week follow-up. Conclusions An intramuscular glucocorticoid injection showed effectiveness in patients with hip osteoarthritis on one of the three primary outcomes at 2-week postinjection. All primary outcomes showed effectiveness from 4 to 6 weeks, up to a 12-week follow-up. Trial registration number NTR2966[.] : http://www.trialregister.nl
Risk of preterm delivery and small-for-gestational-age births in women with autoimmune disease using biologics before or during pregnancy: a population-based cohort study Ann. Rheum. Dis. (IF 12.811) Pub Date : 2018-03-07 Nicole W Tsao, Eric C Sayre, Gillian Hanley, Mohsen Sadatsafavi, Larry D Lynd, Carlo A Marra, Mary A De Vera
Objectives To assess the risk of preterm delivery and small-for-gestational-age (SGA) births in women with autoimmune diseases using biologics before or during pregnancy. Methods Using population-based administrative data in British Columbia, Canada, women with one or more autoimmune diseases who had pregnancies between 1 January 2002 and 31 December 2012 were included. Exposure to biologics was defined as having at least one biologic prescription 3 months before or during pregnancy. Each exposed pregnancy was matched with five unexposed pregnancies using high-dimensional propensity scores (HDPS). Logistic regression modelling was used to evaluate the association between biologics use and preterm delivery and SGA. Results There were 6218 women with 8607 pregnancies who had an autoimmune disease diagnosis; of which 109 women with 120 pregnancies were exposed to biologics 3 months before or during pregnancy. In unadjusted analyses, the ORs for the association of biologics exposure with preterm deliveries were 1.64 (95% CI 1.02 to 2.63) and 1.34 (95% CI 0.72 to 2.51) for SGA. After HDPS matching with 600 unexposed pregnancies, the ORs for the association of biologics exposure and preterm deliveries were 1.13 (95% CI 0.67 to 1.90) and 0.91 (95% CI 0.46 to 1.78) for SGA. Sensitivity analyses using HDPS deciles, continuous HDPS covariate or longer exposure window did not result in marked changes in point estimates and CIs. Conclusions These population-based data suggest that the use of biologics before and during pregnancy is not associated with an increased risk of preterm delivery or SGA births.
‘Deep Koebner’ phenomenon of the flexor tendon-associated accessory pulleys as a novel factor in tenosynovitis and dactylitis in psoriatic arthritis Ann. Rheum. Dis. (IF 12.811) Pub Date : 2018-03-06 Ilaria Tinazzi, Dennis McGonagle, Sibel Zehra Aydin, Donatella Chessa, Antonio Marchetta, Pierluigi Macchioni
Objectives Skin and joint involvement in psoriasis (PsO) and psoriatic arthritis (PsA) are thought to relate to the so-called Koebner response. Given that dactylitis is non-randomly distributed in the digits, this study tested the hypothesis that the accessory pulleys linked to the flexor tendons were thickened in PsA and thus exhibited koebnerisation. Methods Ninety-six subjects (27 PsA, 27 rheumatoid arthritis (RA), 23 PsO and 19 healthy controls (HCs)) were enrolled. The A1, A2 and A4 pulley thickness was measured using a high-resolution probe (22 MHz). All patients were in remission or low disease activity with current dactylitis being excluded. Results Within 864 pulleys investigated, patients with PsA had thicker pulleys in every digit compared with both RA (P<0.001 and P=0.003) and HCs (P<0.001). RA and PsO groups had some pulleys in some digits thicker than HCs whereas some others were comparable. The second digit A1 pulley thickness was higher in patients with PsA with previous dactylitis (P=0.020). More pulleys were thickened in the PsA group (165/243, 68%) than RA (41/243, 17%; P<0.001) and HCs (13/171, 7.6%; P<0.001). Conclusions In established PsA, the accessory pulleys are thickened compared with RA, PsO or HCs and especially in subjects with a history of dactylitis. These findings implicate the involvement of pulleys in PsA-related tenosynovitis and dactylitis supporting the idea of deep koebnerisation in dactylitis and sites of high physical stress.
Transmission of rheumatoid arthritis through blood transfusion: a retrospective cohort study Ann. Rheum. Dis. (IF 12.811) Pub Date : 2018-03-06 Søren Andreas Just, Klaus Rostgaard, Kjell Titlestad , Gustaf Edgren, Christian Erikstrup, Henrik Ullum, Ole Birger Pedersen, Kaspar Rene Nielsen, Johan Askling, Hanne Lindegaard, Henrik Hjalgrim
The long preclinical phase of rheumatoid arthritis (RA), where some factors involved in RA pathogenesis circulate peripherally, raises concern of RA transmissibility through blood transfusion.1 Specifically, this possibility is suggested by murine RA models in which anticitrullinated peptide/protein antibodies may induce and enhance arthritis, and precursors of the RA-fibroblast-like synoviocyte cells may aggravate and spread the disease between joints.2 3 We used a large Danish–Swedish population-based research donations and transfusions database (SCANDAT2) with health register information on 1.5 million blood donors and 2.1 million recipients of their blood to investigate (1) RA occurrence in recipients of blood from donors who later developed RA and (2) clustering of RA among recipients of blood from individual donors, regardless of the donor’s RA status.4–6 We used two different approaches to analyse RA transmission. First, we identified all donors who developed RA after blood donation. For each of these index donors, we identified up to 10 donors matched on age, sex, county, date of first donation, number of donations and ABO blood group, who were free of RA at the date …
Adalimumab for childhood onset uveitis Ann. Rheum. Dis. (IF 12.811) Pub Date : 2018-03-06 A V Ramanan, Catherine Guly
Juvenile idiopathic arthritis (JIA)-associated uveitis is the most common cause of paediatric uveitis and is associated with significant visual morbidity.1 Despite considerable improvements in the treatment of JIA, most trials of biological agents in JIA excluded children with uveitis for methodological reasons. This has meant a limited evidence base and availability of biological therapies for paediatric uveitis. The ADJUVITE study2 published in this journal and the recently published SYCAMORE study3 both provide much needed evidence for use of biologics in children with uveitis. The ADJUVITE study2 randomised 32 patients with childhood onset anterior uveitis and an inadequate response to topical steroid and methotrexate (MTX), based on a laser flare photometry (LFP) reading of ≥30 photon units/ms, to fortnightly adalimumab or placebo. The primary outcome was response to treatment at the end of month 2, defined as a reduction of at least 30% of ocular inflammation on LFP with no worsening of anterior chamber cells or flare according to Standardised Uveitis Nomenclature (SUN) criteria.4 In the adalimumab group, 9/16 patients had a 30% reduction in flare on LFP compared with 3/15 in the placebo group, which was statistically significant, but as the authors acknowledge should be interpreted with some caution as the CI included 1. There was no significant reduction in anterior chamber cell scores. This small study, following on from the SYCAMORE trial,3 which was stopped early due to evidence of efficacy of adalimumab for JIA-associated uveitis, provides further support for the use of adalimumab in childhood uveitis. However, there are striking differences between the ADJUVITE …
Forward to the past: ultrasound might be necessary in some patients with rheumatoid arthritis Ann. Rheum. Dis. (IF 12.811) Pub Date : 2018-03-06 Ottar Gadeholt
In the January issue of ARD , Caporali and Smolen1 argue against the use of ultrasound in the management of rheumatoid arthritis (RA), citing the negative findings of the TaSER2 and ARCTIC3 studies and a lack of standardisation. Even disregarding that the results were not unequivocal, showing a slight, but not statistically significant difference between the ultrasound and control groups after a longer time span, I strongly disagree with the overall conclusion. There is no doubt that modern disease management has led to excellent outcomes for most patients with RA, with the mutilating disease courses of the prebiological era largely a thing of the past.4 However, there are still patients, …
The role of temporal artery biopsy in patients with giant-cell arteritis is debated Ann. Rheum. Dis. (IF 12.811) Pub Date : 2018-03-02 Sergey V Moiseev, Ilya Smitienko, Nikolay Bulanov, Pavel I Novikov
Over a few decades, temporal artery biopsy (TAB) was regarded as the gold standard for diagnosis of giant-cell arteritis (GCA). However, is it really necessary to use this invasive test in all patients with GCA, particularly in those with typical clinical features of the disease? Can we replace TAB with imaging modalities, including ultrasound and [18F]-fluorodeoxyglucose positron emission tomography (PET), that are more sensitive and/or more readily available in many institutions? Dejaco et al said yes in the recently published European League Against Rheumatism recommendations for the use of imaging in large-vessel vasculitis in clinical practice.1 The authors suggested that in patients in whom there is a high clinical suspicion of GCA and a positive ultrasound, the diagnosis of GCA may be made without biopsy or further imaging. Other imaging modalities, that is, PET and/or MRI, are more valuable in patients with Takayasu-like GCA without cranial signs and symptoms. Noteworthy, the task force clearly emphasised that TAB should be performed in all cases, where GCA cannot be confirmed or excluded based on clinical, laboratory and imaging results. Moreover, TAB should still be a …
How the gut inflames the joints Ann. Rheum. Dis. (IF 12.811) Pub Date : 2018-03-02 David S Pisetsky
A study by Pianta et al published in the Journal of Clinical Investigation provides new evidence that the pathogenesis of rheumatoid arthritis (RA) may involve molecular mimicry, one of the most venerable models for the aetiology of rheumatic disease.1 Molecular mimicry represents the development of cross-reactive B or T cell responses to a component of an infecting agent. As shown in this study, the agent in question may be a commensal in the gut microbiome rather than a bacterium or virus inducing clinical disease. While a violation of tolerance, molecular mimicry can occur due to the sharing of amino sequences by proteins from pathogen and host. If an immune response during infection goes awry, autoreactivity to the shared sequence can ensue. The most dramatic example of molecular mimicry is acute rheumatic fever (ARF), still a major problem worldwide. The scenario is now classic: within weeks of an infection with group A Streptococcus , usually pharyngitis, an inflammatory syndrome encompassing arthritis strikes a susceptible person. In ARF, the infection is obvious; the culprit bacterial antigen is the M protein.2 In a novel approach to finding molecular mimics, Pianta et al …
Relationship between serum urate concentration and clinically evident incident gout: an individual participant data analysis Ann. Rheum. Dis. (IF 12.811) Pub Date : 2018-02-28 Nicola Dalbeth, Amanda Phipps-Green, Christopher Frampton, Tuhina Neogi, William J Taylor, Tony R Merriman
Objectives To provide estimates of the cumulative incidence of gout according to baseline serum urate. Methods Using individual participant data from four publicly available cohorts (Atherosclerosis Risk in Communities Study, Coronary Artery Risk Development in Young Adults Study, and both the Original and Offspring cohorts of the Framingham Heart Study), the cumulative incidence of clinically evident gout was calculated according to baseline serum urate category. Cox proportional hazards modelling was used to evaluate the relation of baseline urate categories to risk of incident gout. Results This analysis included 18 889 participants who were gout-free at baseline, with mean (SD) 11.2 (4.2) years and 212 363 total patient-years of follow-up. The cumulative incidence at each time point varied according to baseline serum urate concentrations, with 15-year cumulative incidence (95% CI) ranging from 1.1% (0.9 to 1.4) for <6 mg/dL to 49% (31 to 67) for ≥10 mg/dL. Compared with baseline serum urate <6 mg/dL, the adjusted HR for baseline serum urate 6.0–6.9 mg/dL was 2.7, for 7.0–7.9 mg/dL was 6.6, for 8.0–8.9 mg/dL was 15, for 9.0–9.9 mg/dL was 30, and for ≥10 mg/dL was 64. Conclusions Serum urate level is a strong non-linear concentration-dependent predictor of incident gout. Nonetheless, only about half of those with serum urate concentrations ≥10mg/dL develop clinically evident gout over 15 years, implying a role for prolonged hyperuricaemia and additional factors in the pathogenesis of gout.
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